o-Silylaryl Triflates: Kobayashi Aryne Precursors Review

pubs.acs.org/CR Review o‑Silylaryl Triflates: A Journey of Kobayashi Aryne Precursors Jiarong Shi,† Lianggui Li,† and Yang Li* Cite This: Chem. Rev. 2021, 121, 3892−4044 Downloaded via UNIV VIGO on June 24, 2025 at 13:50:00 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. ACCESS Read Online Metrics & More Article Recommendations ABSTRACT: Arynes are among the most active organic intermediates and have found numerous applications in expeditious preparation of substituted arenes. In the past 20 years, chemists have witnessed a resurgence in aryne chemistry, which is mainly attributed by the extensive utilization of Kobayashi’s method, a fluoride-induced removal of the TMS group with concomitant departure of its ortho OTf group on o-silylaryl triflates. Nowadays, o-silylaryl triflates are the most frequently employed aryne precursors. This review provides an overview of the history of Kobayashi’s method, its methodological achievements, and its applications in the synthesis of natural products, bioactive molecules, and polycyclic aromatic hydrocarbons. CONTENTS 1. Introduction 2. Preparation Methods and Activation Conditions 2.1. Preparation Methods 2.2. Activation Conditions 2.2.1. Solvents 2.2.2. Fluoride Sources 2.2.3. Additives 2.2.4. Temperature 2.2.5. Microwave 2.2.6. Safety 3. Regioselectivity 3.1. Steric Effect 3.2. Electronic Effect 3.3. Distortion/Interaction Model 3.4. Effect of a Fused Small Ring 4. Pericyclic Reactions 4.1. Diels−Alder Reactions 4.1.1. With Furans 4.1.2. With 2-Pyranones 4.1.3. With Anthracenes 4.1.4. With Cyclic 1,3-Dienes 4.1.5. With Acyclic 1,3-Dienes 4.1.6. Intramolecular Diels−Alder Reactions 4.2. 1,3-Dipolar Cycloaddition Reactions 4.2.1. With 4-Hydroxyisoquinolinium and 3Oxidopyridinium 4.2.2. With Diazo Compounds 4.2.3. With Azides 4.2.4. With Nitrile Oxides 4.2.5. With Nitrones 4.2.6. With Azomethine Imines and Nitrile Imines 4.2.7. With N-Heteroaromatic Ring Imides 4.2.8. With Cyclic 1,3-Dipoles 4.2.9. With Other 1,3-Dipoles 4.3. [2 + 2] Cycloaddition Reactions 4.4. [n + 2] Cycloaddition Reactions 4.5. Ene Reactions 5. Nucleophilic Addition Reactions 5.1. N-Arylation Reactions 5.2. O-Arylation Reactions 5.3. C-Arylation Reactions 5.4. S-Arylation Reactions 5.5. P-Arylation Reactions 5.6. With B-Nucleophile 5.7. With F-Nucleophile 6. Nucleophilic Annulation Reactions 6.1. With O-Nucleophiles 6.2. With N-Nucleophiles 6.3. With C-Nucleophiles 6.4. With S- and Se-Nucleophiles 6.5. With P-Nucleophiles 7. Insertion Reactions 7.1. Insertion into C−N σ-Bonds 7.2. Insertion into C−C σ-Bonds 7.3. Insertion into C−O σ-Bonds 7.4. Insertion into Other σ-Bonds 7.5. Insertion into π-Bonds 8. Multicomponent Reactions (MCRs) 8.1. Isocyanide-Triggered MCRs 8.2. N-Nucleophile-Triggered MCRs 8.3. Other Nucleophile-Triggered MCRs 8.4. DMF-Involved MCRs 3893 3896 3896 3898 3898 3899 3899 3899 3899 3899 3899 3899 3900 3901 3902 3903 3903 3903 3903 3903 3903 3904 3906 3906 3907 3907 3909 3909 3910 3912 3913 3913 3914 3915 3917 3917 3919 3920 3921 3921 3921 3921 3922 3924 3925 3926 3926 3927 3928 3930 3930 3933 3935 3935 3937 3941 3945 Received: September 17, 2020 Published: February 18, 2021 3910 3910 3911 3911 © 2021 American Chemical Society 3892 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews 8.5. MCRs via Aryne [3 + 2] Cycloaddition Reaction 9. Cascade or Tandem Reactions 9.1. Cycloaddition Reaction-Initiated Cascade Reactions 9.1.1. Initiated by Diels−Alder Reaction 9.1.2. Initiated by [3 + 2] Cycloaddition Reaction 9.1.3. Initiated by [2 + 2] Cycloaddition Reaction 9.1.4. Initiated by Other Cycloaddition Reaction 9.2. Nucleophilic Addition-Initiated Rearrangements 9.2.1. Claisen Rearrangements 9.2.2. [2,3]/[1,2] Sigmatropic Rearrangements 9.2.3. Other Rearrangements 9.3. Nucleophilic Addition-Triggered Other Cascade Reactions 9.4. Nucleophilic Annulation-Induced Cascade Reactions 9.5. Insertion Reaction-Triggered Cascade Reactions 9.5.1. Through C−C Bond Insertion 9.5.2. Through Other Insertion Reactions 9.6. Other Cascade Reactions 10. Transition-Metal-Catalyzed Reactions 10.1. Palladium-Catalyzed Reactions 10.1.1. (Co)cyclotrimerization 10.1.2. With π-Allylpalladium Species 10.1.3. With Arylpalladium Species 10.1.4. With Alkylpalladium and Vinylpalladium 10.1.5. With Azapalladium Species 10.1.6. Other Palladium-Catalyzed Reactions 10.1.7. Insertion into Element−Element σBonds 10.2. Nickel-Catalyzed Reactions 10.3. Copper-Catalyzed/Mediated Reactions 10.4. Silver-Catalyzed/Mediated Reactions 10.5. Gold-Catalyzed Reactions 10.6. Platinum-Catalyzed Reactions 10.7. Cobalt-Catalyzed Reaction 11. Benzdiyne Chemistry 11.1. 1,4-Benzdiyne Chemistry 11.2. 1,3-Benzdiyne Chemistry 11.3. 1,2-Benzdiyne Chemistry 12. Hetaryne Chemistry 12.1. Pyridynes and 2,3-Quinolyne 12.1.1. 2,3-Pyridyne 12.1.2. 3,4-Pyridyne 12.1.3. 2,3-Quinolyne 12.2. Indolynes 12.3. Other Hetarynes 12.3.1. 4,5-Benzofuranyne 12.3.2. 6,7-Thienobenzyne 13. Cyclohexyne, 1,2-Cyclohexadiene, and 1,2,3Cyclohexatriene 13.1. Preparation Methods 13.2. Cyclohexyne Reactions 13.3. 1,2-Cyclohexadiene Reactions 13.4. 1,2,3-Cyclohexatriene Reactions pubs.acs.org/CR Review 14. Syntheses of Natural Products and Bioactive Molecules 14.1. Cycloaddition Strategies 14.2. Nucleophilic Annulation Strategies 14.3. Insertion Reaction Strategies 14.4. Cascade Reaction and MCR Strategies 14.5. Transition-Metal-Catalyzed Strategies 14.6. Benzdiyne Strategies 15. PAHs, Polymer Chemistry, and Materials Science 15.1. Preparation of PAHs 15.1.1. Through Pd-Catalyzed Cyclotrimerization 15.1.2. Through Pd-Catalyzed Cocyclotrimerization 15.1.3. Through Pd-Catalyzed Annulation Reactions 15.1.4. Benzdiyne and Naphthodiyne Strategies 15.1.5. Other Cycloaddition Strategies 15.2. Polymer Chemistry 15.3. Materials Science 15.3.1. Triptycene-Based Materials 15.3.2. Nanotube and Graphene 16. Conclusions Author Information Corresponding Author Authors Author Contributions Notes Biographies Acknowledgments Abbreviations References 3947 3948 3948 3948 3950 3951 3953 3953 3953 3954 3955 3956 3958 3960 3960 3961 3963 3964 3964 3964 3966 3968 3973 3974 3975 3996 3996 3998 4000 4003 4004 4005 4006 4006 4006 4009 4010 4010 4013 4014 4015 4015 4015 4015 4017 4017 4017 4017 4017 4017 4017 4017 4018 1. INTRODUCTION Arynes are a family of transient species that are among the most active organic intermediates. The history of aryne chemistry can be traced back to 1902 when Stoermer and Kahlert first postulated the formation of 2,3-didehydrobenzofuran from 3-bromobenzofuran with bases in ethanol (Figure 1).1 Based on their experimental observations, Bachmann and Clarke in 19272 and Wittig et al. in 19423 proposed the generation of a benzyne intermediate. In 1953, Roberts performed a 14C-labeling experiment on chlorobenzene using potassium amide in liquid ammonia as the activating reagent and suggested the formation of a symmetrical benzyne species.4 As short-lived intermediates,5,6 arynes possess some unique properties. The triple bond on an aryne is somewhere between a double and a triple bond. One π-bond belongs to the aromatic system and the other one is formed by the lateral overlap of the two sp2 orbitals in the plane of the benzene ring. Accordingly, these angle-strained cyclic alkynes are significantly weakened. For instance, the IR stretching frequency for the triple bond on benzyne is 1846 cm−1 in a neon matrix,7 whereas it is 2150 cm−1 for normal alkynes. The bond length of a benzyne was determined to be 1.24 Å through the simulation of the 13C dipolar NMR spectrum,8 which is in good agreement with theoretical calculations.9 Consequently, arynes are typically described as strained alkynes other than biradicals. Other properties of benzyne, such as microwave,10 3975 3976 3977 3981 3982 3982 3982 3983 3983 3984 3985 3986 3987 3987 3988 3989 3990 3991 3991 3991 3991 3991 3993 3995 3995 3893 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review Figure 1. Timeline for aryne generation methods. mass spectrometry,11 photoelectron spectroscopy,12 and NMR spectroscopy,8,13 have also been measured. Particularly, Warmuth isolated benzyne in a hemicarcerand as a molecular container.13−15 In addition, the ring strain induced by the formal triple bond on the six-membered ring results in their low-lying LUMO orbitals with small energy gap between the HOMO and LUMO orbitals,16 making arynes superior electrophiles that are amenable to a broad spectrum of arynophiles as well as transformations. In the past ∼70 years, numerous achievements have been realized in the realm of aryne chemistry. Since the early era of aryne chemistry, people have endeavored to search for “ideal” aryne generation methods. Why do we need to care much about the constitution of an aryne precursor and its generation conditions? Because arynes are transient intermediates, they have to be generated in situ. Consequently, even a simple aryne reaction, i.e., nucleophilic reaction or Diels−Alder reaction, is no longer a single-step operation after counting aryne generation as a step. To this end, both the constitution and the accompanied generation conditions of an aryne precursor are indispensable in any aryne transformation. In many cases, they are the key factors for the success of an aryne reaction. Therefore, people should be aware of the ways on how to generate an aryne species associated with the compatibility considerations with respect to functional groups, reactive intermediates, and reaction media. The first strategy to generate benzyne was through dehydrohalogenation of halobenzenes, i.e., chlorobenzene and fluorobenzene, along with the early investigations in this field (Figure 1). Strong bases, such as PhLi, NaNH2, and LDA, were normally utilized. In the 1950s, o-dihalobenzenes started to serve as benzyne precursors, which could be activated through two means: (1) lithium-halogen exchange-demetalha- logenation with lithium amalgam or n-BuLi and (2) by forming Grignard reagent with magnesium.17−19 Both strategies, however, fall short of compatibility with functional groups and arynophiles that are vulnerable under these harsh conditions. Several generation methods were then developed in the 1960s. In 1960, o-benzenediazonium carboxylate (caution: o-benzenediazonium carboxylates are potentially explosive), conveniently prepared by diazotization of anthranilic acid, was reported by Stiles and Miller to be able to release benzyne through thermal decomposition at 40−60 °C.20,21 Later in 1962, diphenyliodonium-2-carboxylate was also disclosed to produce benzyne at 160 °C in diglyme.22 In the same year, Wittig and Hoffmann developed 1,2,3benzothiadiazole S,S-dioxide as a benzyne precursor, which could be activated via thermal decomposition.23 In 1964, benzyne was found to be formed via the oxidation of 1aminobenzotriazole with lead tetraacetate (LTA) or nickel peroxide.24,25 In 1973, a bulky base, lithium 2,2,6,6-tetramethylpiperidide (LiTMP), was first applied to the dehydrohalogenation strategy in order to avoid undesired nucleophilic addition by the base,26 the efficiency of which was further enhanced by the employment of lithium diadamantylamide (LDAM) in 2018.27 o-Bromoaryl tosylates were first introduced by Tochtermann as aryne precursors in 1974 for the preparation of polycyclic aromatic hydrocarbons, which could be activated through a sequential metal−halogen exchange with organolithium reagent and an elimination of the sulfonate.28 In 1987, Furukawa et al. disclosed that o-haloaryl sulfoxides were able to serve as aryne precursors by using Grignard reagents as the activating reagents.29 In 1991, Suzuki et al. first demonstrated that o-iodophenyl triflate could be facilely converted to benzyne in the presence of n-BuLi, the method of which was then found to have many useful applications.30 Subsequently, 3894 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review Figure 2. Structures of Kobayashi aryne precursors. was then enhanced by employing LiZnEt2(TMP)40 or Li[Zn(n-Bu)TMP2]41 as the activating reagents. Since 2000, many new generation protocols have been discovered. In 2002, Uchiyama et al. demonstrated that lithium dialkyl(2,2,6,6-tetramethylpiperidino)zincate (R2Zn(TMP)Li) could efficiently activate halobenzenes.42,43 In 2004, Knochel and co-workers revealed that o-iodoaryl sulfonates were able to serve as versatile aryne precursors by using isopropylmagnesium chloride (i-PrMgCl) as the activating reagent.44−46 Notably, aryne precursors bearing silyl groups as accepting modifications on this protocol by using trimethylsilylmethyl Grignard reagent, TMSCH2MgCl,31 and catalytic amounts of alkynyllithium32 as activating reagents were realized. In 1997, Johnson33 and Ueda34 independently reported an unprecedented aryne generation protocol via the [4 + 2] cycloaddition reaction of alkyne and 1,3-diyne, which is now known as hexadehydro-Diels−Alder (HDDA) reaction and has obtained many achievements mainly by Hoye et al. in the past decade.35−38 A benzyne generation method between PhOTf and LDA was first disclosed in 1999,39 the efficiency of which 3895 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review method has also been expanded to benzdiynes, heterocyclic arynes (hetarynes), cyclohexynes, and 1,2-cyclohexadienes. Along with the advances of Kobayashi’s method, many exciting applications have been accomplished in the fields of natural product synthesis, preparation of polycyclic aromatic hydrocarbons (PAHs), and materials science. In the past 2 decades, there are many review articles that have elaborated on various aspects of aryne chemistry.38,69,71−102 None of them, however, provided a comprehensive survey on o-silylaryl triflates. This review aims to summarize different aspects of Kobayashi’s method from the preparation and activation of aryne precursors to diverse types of transformations and to its applications. groups (AGs) were developed by the groups of Kitamura (2006),47 Akai (2011),48 Novák (2012),49 Xu/Jiang/Wang (2015),50 Daugulis (2016),51 and Raminelli (2020),52 all of which were found to facilely generate benzyne under fluorideinduced conditions. Meanwhile, precursors containing OTf group as the LG were realized by Hosoya, where the AGs could be boronic ester (2013),53 arylsulfoxide (2014),54 and diarylphosphinyl groups (2018).55 In 2016, Stuart et al. reexamined the early method using diaryliodonium salts as aryne precursors56 and demonstrated that a combination of aryl(mesityl)iodonium tosylates and LiHMDS could efficiently generate arynes.57,58 Since 2006, a series of Pd-catalyzed generation protocols have been realized by Hu (2006),59 Kim (2008),60 and Greaney (201061 and 201462). In 2017, Li et al. reported an aryne generation method via Grob fragmentation on the [2 + 2] cycloadducts of 3-triflyloxyarynes.63 Similarly, obromoacetophenone derivatives were found to serve as aryne precursors, where t-BuOK was used as the activating reagent.64 Very recently, generation methods based on one-pot protocols were realized.65−67 In 1983, Kobayashi and co-workers published a seminal work for the preparation of o-(trimethylsilyl)phenyl triflate as a benzyne precursor, the activation of which employed a fluoride-induced removal of the TMS group with concomitant departure of its ortho OTf group.68 This aryne generation protocol, however, received almost no attention in a period of 15 years. Until the end of 1990s, o-silylaryl triflates started to be increasingly explored as aryne precursors. Astonishingly, in the past 2 decades, people have witnessed a blooming advance in aryne chemistry, which was mainly attributed by the exponential applications of Kobayashi’s method. The most distinct advantage of this generation method is not because it CAN generate aryne but the way how it maintains a low-level concentration of aryne species under arynophile-friendly conditions. The combination of CsF and acetonitrile solvent, sometimes with toluene as cosolvent, is a magic recipe in Kobayashi’s protocol. An explanation for this is that CsF has low solubility in acetonitrile, which in turn would only activate a small portion of o-silylaryl triflate at any reaction stage.69 In addition, DFT calculations on the fluoride-induced benzyne generation process of o-silylphenyl triflate revealed that the removal of the TMS group by fluoride is through a pseudo-SN2 mechanism with the formation of a pentacoordinated silicon ate complex as the rate-determining step.70 Therefore, this system could provide a constant supply of a suitably low concentration of aryne intermediate. As a consequence of Kobayashi’s method, the reaction efficiency can be generally enhanced with high functional group tolerance, which could also accommodate different aryne reaction modes. Figure 2 lists some of the Kobayashi aryne precursors that have been utilized in the field of aryne chemistry. These structures include Kobayashi precursors of various substituted benzynes, naphthalynes, phenanthrynes, arynes with polycyclic frameworks, pyridynes, and indolynes. Moreover, Kobayashi precursors of polyarynes are also shown in Figure 2. A significant contribution of Kobayashi’s method to modern aryne chemistry is its potential to promote continuous discovery of new reaction modes. Some new types of aryne transformations include transition-metal-catalyzed reactions since the end of 1990s, aryne insertion reactions since early 2000, multicomponent aryne reactions, and aryne-triggered or aryne-involved cascade reactions. Moreover, Kobayashi’s 2. PREPARATION METHODS AND ACTIVATION CONDITIONS 2.1. Preparation Methods In Kobayashi’s seminal report, they depicted the preparation of o-(trimethylsilyl)phenyl triflate (2-1) from 2-chlorophenol. 2Chlorophenol was first converted to o-(trimethylsilyl)phenoxytrimethylsilane (2-2) in two steps, which was then treated with dropwise addition of excess n-BuLi and a subsequent triflation with triflic anhydride (Tf2O) to afford 2-1 (Scheme 1a).68 Suzuki et al. employed this method to Scheme 1. Metal−Halogen Exchange Strategies prepare 3-bromo substituted o-silylaryl triflates by using 2,6dibromophenol.103 This preparation procedure was then modified by several groups in order to increase the efficiency. In 2002, Pérez, Guitián and co-workers developed a facile onepot procedure to prepare 2-1 and its analogues (Scheme 1b).104 Starting from substituted 2-bromophenols, a sequential O-silylation with hexamethyldisilazane (HMDS), metal− halogen exchange with n-BuLi at low temperature, O- to Csilyl group migration, and triflation could afford functionalized Kobayashi aryne precursors 2-1 in good to excellent yields. Moreover, this method has also been employed in the preparation of polycyclic aryne precursors. Subsequently, Greaney et al. developed a scalable continuous flow process that could readily synthesize functionalized 2-1 in excellent yields from substituted 2-bromophenols.105 A further modification on Kobayashi’s original procedure was reported by Brimble and co-workers, the pathway of which avoided the employment of n-BuLi (Scheme 1c).106 After the generation of 3896 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR 2-2, selective desilylation with TBAF and triflation could afford compound 2-1 in 81% overall yield in a four-step procedure. Another strategy to access o-silylaryl triflates is through direct metalation on the ortho C−H bond of phenol with strong base, which is followed by a subsequent incorporation of a TMS group. In 1984, Snieckus et al. employed an amide directing group to realize an ortho deprotonation-silyl group migration (retro-Brook rearrangement) event to obtain compound 2-3. After triflation, compound 2-4 with an amide functional group on the C3 position was produced (Scheme 2a).107 In 2005, Danheiser and co-workers reported a one-pot Review Scheme 3. Preparation Method by Pérez and Vollhardt Scheme 2. ortho-Lithiation Strategies thoxyborane/acidic workup. Subsequent oxidation and triflation produced o-silylaryl triflates 2-13 in good to excellent yields. In 2010, Harrity et al. demonstrated a new approach to access substituted Kobayashi aryne precursor 2-1. In this protocol, the benzene ring was constructed through a [4 + 2] cycloaddition reaction of 2-pyrones and trimethylsilyl alkynylboronate 2-14. After C−B bond oxidation with H2O2 and triflation, functionalized 2-1 were obtained (Scheme 4a).111 The Diels−Alder reaction step, however, was not Scheme 4. Arene Ring Formation Strategies preparation of o-silyl salicylaldehyde 2-6 from the methoxymethyl (MOM) either of phenol 2-5 (Scheme 2b).108 An ortho-lithiation with n-BuLi on 2-5 was followed by silylation to introduce a TMS group. After another directed metalation and subsequent quenching with DMF in the same flask, o-silyl salicylaldehyde 2-6 was obtained upon acid workup, which could be then converted to o-silylaryl triflates 2-7. In 2009, Garg et al. developed a facile ortho-lithiation protocol on the N-monoalkyl carbamate derivative of phenol 2-8 to prepare compound 2-9 after capturing the phenyllithium intermediate with TMSCl. After removal of the carbamate group on 2-9 and triflation with PhNTf2, compound 2-1 could be produced in good overall yield from phenol (Scheme 2c).109 The 4,5indolyne precursor was also efficiently prepared using this protocol. The methods through direct construction of a benzene ring bearing a TMS and/or an OTf group were reported as well. In a study carried out by Pérez, Vollhardt and co-workers, they developed a procedure for the preparation of 3-trimethylsilyl-2biphenylenyl triflates (2-13) from 2-10.110 As shown in Scheme 3, a cobalt-catalyzed cycloaddition of 2-10 with bis(trimethylsilyl)acetylene (BTMSA) assembled 2-11, the structure of which contains a biphenylene core. Boronic acid 212 was then obtained via a sequence of selective monobromination/metal−halogen exchange/quenching with trime- regioselective. In 2015, in a study carried out by Yoshikai and co-workers on one-pot preparation of the benzo[b]phosphole derivative, they started with Grignard reagent 2-15 and produced compound 2-16 through a sequential transitionmetal-catalyzed arylmagnesiation of diphenylacetylene, reaction with dichlorophenylphosphine, and an intramolecular phospha-Friedel−Crafts reaction process. After removal of the benzyl group and triflation, o-silylaryl triflate 2-17 was obtained (Scheme 4b).112 In recent years, transition-metal-catalyzed ortho-C−H functionalization strategies were applied in the preparation of o-silylaryl triflates. In 2015, Gevorgyan et al. developed a 2-fold C−H functionalization protocol on arene 2-18 by using pyrimidyldiisopropylsilyl (PyrDipSi) as the directing group, 3897 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR which could produce compound 2-19 (Scheme 5a).113 In this study, they demonstrated the preparation of a substituted Review also prepared Kobayashi aryne precursors of 2,3-carbazolyne and 2,3-fluorenyne. Postfunctionalization directly on the o-silylaryl triflate framework represents a straightforward and economical approach toward substituted Kobayashi aryne precursors. Both the TMS and OTf groups, however, are vulnerable to many arene functionalization conditions. In 2015, Pilarski and co-workers achieved a distinct Ir-catalyzed C−H borylation reaction on o-silyl(hetero)aryl triflates 2-28 in chemoselective manner, furnishing 2-29 by introducing a (pinacolato)boryl group (B(pin)) directly on the sterically less hindered positions (Scheme 6a).117,118 Furthermore, the B(pin) group Scheme 5. Transition-Metal-Catalyzed ortho-C−H Bond Functionalization Strategies Scheme 6. Postfunctionalization Strategies could be converted to a variety of functional groups. Meanwhile, Hosoya et al. reported an identical transformation with a different substrate scope from Pilarski’s work.119 In addition, Yoshida, Hosoya, and co-workers could further convert B(pin) to sulfide by using their developed Cucatalyzed deborylthiolation method.120 In 2017, Raminelli et al. reported a modular synthesis of functionalized silylbiaryl triflates 2-31 through a chemoselective Suzuki reaction on iodinated silylaryl triflates 2-30, which was readily prepared from phenols through diiodination and a modified PérezGuitián procedure104 (Scheme 6b).121 Kobayashi aryne precursor by converting the acetate group on 2-19 to OTf, giving rise to o-silylaryl triflate 2-20 in 83% yield. As an application on the methodology developed by Jeon and co-workers on catalytic reductive C−H silylation of phenols with traceless acetal directing groups,114 they realized a onepot procedure to directly transform the benzodioxasiline products 2-21 to o-silylaryl triflates 2-22 through a nucleophilic addition by MeLi and triflation procedure (Scheme 5b).115 This protocol could also be utilized in the preparation of sterically encumbered 1,2,3-trisubstituted osilylaryl triflates. Recently, Pilarski et al. reported a procedure to reach substituted o-silylaryl triflates 2-27 from arylboronic acids 2-23.116 As shown in Scheme 5c, the key step in this procedure involved a Ru-catalyzed ortho-C−H silylation on anthranilamido boronates ArB(aam) 2-24, generated from 223, to furnish compound 2-25. Upon oxidation on 2-25, orthosilylphenols 2-26 were produced. Finally, protection of 2-26 using 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (NfF) afforded aryne precursors 2-27. In this study, they 2.2. Activation Conditions The key factors for the success of a typical aryne reaction are not only the conditions that can generate the corresponding aryne species but also the compatibility of these conditions with respect to substrate structures, functional groups, and reaction modes. Consequently, more needs to be considered beyond the aryne generation method itself. In addition, the highly reactive nature of an aryne species requires a slowreleasing process so that arynophiles could effectively capture this transient intermediate in the course of an aryne transformation. However, arynophiles behave quite differently, and many factors, such as reactivity, stability, and competing side reactions, might also affect the overall efficiency. Therefore, the “conditions” that are chosen to generate arynes from the corresponding o-silylaryl triflates are crucial for the success of a designated aryne reaction. 2.2.1. Solvents. Acetonitrile is the most prevailingly employed solvent, which usually accommodates well with 3898 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR various fluoride sources as well as reaction modes. The CsF/ MeCN system can constantly supply a low concentration of fluoride ion. In order to further slow down the aryne generation rate, toluene can be added as a cosolvent. THF is another commonly employed solvent. Due to the low solubility of inorganic salts in THF, KF/18-c-6 is normally used. Other solvents that have been employed or examined include 1,4dioxane, 1,2-dimethoxyethane (DME), 1,2-diethoxyethane (DEE), triglyme, dichloromethane (DCM), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), acetone, EtOAc, chlorobenzene, methyl tert-butyl ether (MTBE), butyronitriles (n-PrCN, i-PrCN), and DMSO. 2.2.2. Fluoride Sources. Fluoride salts are indispensable activating reagents for o-silylaryl triflates. The key factor for the success of an aryne transformation, however, is not how fast a fluoride species could kick out the TMS group. In contrast, it matters on how to manage various factors together in order to maintain a constant supply of aryne species in manageable rate. Among those fluoride salts, CsF, KF, n-Bu4NF (TBAF), and tetra-n-butylammonium difluorotriphenylsilicate (TBAT) are normally utilized. Other fluoride salts, such as Me4NF, BnMe3NF, and tris(dimethylamino)sulfonium difluorotrimethylsilicate (TAS-F), have also been reported. CsF is the most commonly used fluoride source in Kobayashi aryne generation conditions. Because CsF is hygroscopic and wet CsF would diminish the reaction efficiency due to aggregation during the reaction, dry CsF is recommended in order to ensure reproducible aryne reactions. In this context, CsF could be dried at 140 °C under vacuum for hours and should be stored in a vacuum desiccator with drying agent or within a glovebox. When an aryne reaction is performed in acetonitrile under a dilute solution, the initial suspension of CsF in acetonitrile would become a homogeneous solution by the end of the reaction (the generated CsOTf is soluble in acetonitrile). In recent years, fluoride-free generation of arynes from osilylaryl triflates was reported and utilized.88,122 Moreover, with two vicinal electron-withdrawing groups on domino aryne precursors, carbonates could replace fluoride as efficient activating reagents to trigger the generation of the corresponding arynes.102 2.2.3. Additives. In order to fulfill the demands on different types of aryne reactions, additives are usually added. 18-Crown-6 (18-c-6) has been commonly employed to enhance the solubility of fluoride salts. In order to remove the adventitious water from the solvent or reagents, drying agent, i.e., 4 Å MS, can be added. In an opposite way, certain amount of water could be intentionally added to the reaction media to serve as a proton source. Bases are frequently utilized additives in aryne reactions, those of which include K2CO3, Cs2CO3, Na2CO3, Li2CO3, KHCO3, NaHCO3, (NH4)HCO3, t-BuOK, K3PO4, LiOAc, NaOAc, KOAc, CsOAc, NaOH, CsOPiv, Et 3 N, N,N,N′,N′-tetramethylethylenediamine (TMEDA), pyridine, 2,6-lutidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), and diisopropylethylamine (DIPEA). In some cases, phase transfer catalysts, such as tetra-n-butylammonium iodide (TBAI) and bromide (TBAB), can be employed as well. 2.2.4. Temperature. The normal reaction temperature for a standard benzyne reaction ranges from room temperature to 100 °C. In some uncommon cases, higher than 100 °C or lower than 0 °C was reported. Particularly, the employment of Review low temperature might alter the chemoselectivity of an aryne reaction. 2.2.5. Microwave. Microwave was also employed in aryne reactions, which could promote both the generation and the reaction rate of an aryne transformation.123−126 2.2.6. Safety. Besides, safety issue upon activation of osilylaryl triflates have been assessed by Garg et al. through calorimetric analysis. They concluded that o-silylaryl triflates may be used under mild conditions with no general concern for a runaway reaction.127 3. REGIOSELECTIVITY Regioselectivity is a fundamental issue in aryne chemistry. When an unsymmetrically substituted benzyne participates in a reaction with an unsymmetrical or polar arynophile, two regioisomeric products will be envisioned. In this context, the diminished reaction efficiency attributed by the formation of an unwanted regioisomer in an aryne transformation will severely damage its synthetic application. Therefore, it is essential to find ways in order to reach a high level of regioselectivity in an aryne reaction. A further outlook in this aspect of aryne chemistry would not only enhance the regioselective ratio but also be able to “overturn” the preferred site of attack under certain circumstances so as to achieve more diversified synthesis. So far, certain rules and protocols have been disclosed to manipulate the regioselectivity in intermolecular aryne transformations along with the advances of recent aryne chemistry, those of which are steric effect, electronic effect, and ring-strain (Figure 3). Particularly Figure 3. Effects that tune the regioselectivity. noteworthy is a recent application of a distortion/interaction model128 by the groups of Houk and Garg, which could explain the electronic factors in the regioselective control of an aryne reaction. In contrast, intramolecular aryne reactions always prefer ortho-selectivity in annulation reactions, which have found many applications in natural product synthesis.78,79,92 Because intramolecular aryne transformations normally employ the generation methods other than Kobayashi’s, they will not be covered in this section. 3.1. Steric Effect Presumably, the earliest tuning factor used to differentiate the two aryne triple-bond carbons in intermolecular transformations is through steric repulsion, which requires the incorporation of a bulky group on the 3-position of a benzyne intermediate (Scheme 7a). For instance, 3-tert-butylbenzyne is known to favor the less sterically congested meta-position of the t-Bu group when it reacts with arynophiles. This steric effect was demonstrated by Kazmaier et al. in an aryne insertion reaction into the Sn−H bond of Bu3SnH, in which a single product 3-2a was obtained from aryne precursor 3-1a 3899 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review tert-butylbenzyne 3-9a resulted in a mixture of regioisomers in only a 1.7:1 ratio (Scheme 8b).132 Subsequently, this silylbased aryne strategy was successfully utilized by the groups of Akai-Ikawa,48,133 Du Bois,134 and Hosoya.135 Furthermore, Houk, Garg, and co-workers revealed that the regioselective preference can be affected by the structure of arynophiles.130 As shown in Scheme 8c, they systematically investigated the reaction of 3-triethylsilylbenzyne (3-12) with various nucleophiles. It was found that only when a nucleophile is bulky enough will the meta-3-13 product be formed exclusively. When a nucleophile is less sterically congested, a certain amount of ortho-3-13 product could be obtained as well. Other than 3-silyl groups as effective sterically congested groups, 3-boronic esters could serve as a suitable steric tuning factor in aryne reactions as well. In 2010, Akai and co-workers discovered that a 3-borylbenzyne species 3-14, generated from o-iodoaryl triflates, underwent regioselective Diels−Alder reactions with 2-substituted furans, furnishing various cycloadducts anti-3-15 and syn-3-15 in generally excellent antiselectivity (Scheme 9).136,137 Their theoretical study revealed Scheme 7. Steric Repulsion by 3-Alkyl Groups on Arynes with no observation of its regioisomer 3-3a (Scheme 7a).129 In contrast, 3,5-dimethylbenzyne, generated from aryne precursor 3-1b, has a smaller steric effect than that of 3-1a and, hence, afforded a mixture of 3-2b and 3-3b in a 68:32 ratio in the reaction with Bu3SnH. Moreover, in a study carried out by Houk, Garg, and co-workers, they demonstrated that the reactions of 3-tert-butylbenzyne 3-4 with various nucleophiles always prefer the meta-position to yield 3-5 (Scheme 7b).130 3-Silyl groups were found to be efficient sterically congested tuning factors in regioselective aryne transformations. In 2005, Schlosser et al. disclosed that the Diels−Alder reaction of 3fluoro-6-(trimethylsilyl)benzyne (3-6) with 2-(trimethylsilyl)furan (3-7) furnished a single cycloadduct 3-8 (Scheme 8a).131 In a study carried out by Akai and co-workers, they found that the benzyne intermediate containing either a 3-TMS group 39b or a 3-tert-butyldimethylsilyl (3-TBS) group 3-9c could react with 2-tert-butylfuran (3-10) to preferentially afford anticycloadducts 3-11b and 3-11c; whereas, the reaction with 3- Scheme 9. 3-Boronic Ester as Sterically Congested Groups that for those furans containing an electron-withdrawing substituent on the 2-position, such as ester, ketone, nitrile, and phenyl group, the regioselectivity was controlled by steric repulsion. Scheme 8. 3-Silyl Groups as Sterically Congested Groups 3.2. Electronic Effect Electronic effect is the most broadly employed tuning factor in aryne transformations, which could provide versatile means to realize high regioselective control. Both inductively electronwithdrawing (EW) and electron-donating (ED) substituents have been employed. Because of the nature of inductive effect, only when these groups are on the 3- or 6-position of a benzyne ring will they exhibit obvious differentiation ability. When these substituents are on the 4- or 5-position of a benzyne, however, the inductive effect will be largely attenuated.138−140 3-Alkoxy groups and 3-halogens have been traditionally utilized as effective EW tuning groups in aryne transformations, giving rise to products with preferential metaselectivity in the reactions with both nucleophiles and other polar arynophiles (Figure 3b). Because the EW effect induced by these groups has been broadly employed in many aryne transformations and is widely recognized in aryne chemistry,74,141 it will not be discussed in this section. On the other hand, the ED effect was disclosed behind the EW effect, which could result in opposite regioselective outcomes in the aryne reactions. In 1993, Suzuki and coworkers found that a silyl group on the 3-position of benzyne possesses a remarkable electron-donating inductive ability in 1,3-dipolar reactions with nitrones (Scheme 10a).103 For instance, the reaction of both 3-16a and 3-16b with nitrones 3900 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review study, they proposed that the regioselectivity between the reaction of 3-14 and 2-substituted furans containing a methyl, n-butyl, methoxy, or TMS group was controlled by an electrostatic effect and aryne distortion,136,137 and a more definite electronic effect was later observed by the same group on nucleophilic addition reactions with aryne precursor 3-21, which could generate 3-borylbenzyne 3-22 in a chemoselective manner in the presence of fluoride (Scheme 10c).143 This 3borylbenzyne 3-22 exhibited good to high ortho-selectivity with respect to amines, affording ortho-3-23 preferentially over meta-3-23. Among different boryl groups, 1,8-diaminonaphthalene (dan) protected 3-borylbenzyne gave the highest ortho to meta ratio. Scheme 10. ED-Inductive Effect by 3-Silyl and 3-Boryl Groups 3.3. Distortion/Interaction Model In recent years, Garg, Houk, and co-workers employed a distortion/interaction model128 in aryne transformations to explain and predict aryne regioselectivity.144−148 This model divides the activation energy of a bimolecular process into two components: a distortion energy that allows the reactants to reach the transition state geometry and a second energy that accounts for the interaction between two distorted species. With the assistance of this aryne distortion/interaction model, they could also predict the regioselectivity in the reactions with hetarynes (indolynes, pyridynes, and benzofuranyne),144,145,147−153 cyclohexynes,153−155 and 1,2-cyclohexadienes.156,157 Intriguingly, their experimental results are highly consistent with this model. Besides, the groups of Suzuki,158 Buszek,159 and Akawa/Akai137,143 have also tried to explain the regioselective issue in their studies. Recently, Mirzaei and Khosravi employed frontier molecular orbital contribution analysis160 and orbital electronegativity161 to predict the aryne regioselectivity. More theoretical studies on the structure of substituted benzynes were reported by Schaefer et al.162 Figure 4 lists the geometry optimized structures of some commonly substituted benzynes, 1 3 0 , 1 4 3 , 1 4 6 hetarynes,145,149,152,153 cyclohexynes,153−155 and 1,2-cyclohexadienes156,157 using DFT methods. Based on the aryne afforded the [3 + 2] cycloadducts 3-18a and 3-18b as the major regioisomers. In comparison, the reaction of aryne 3-16c with a 3-methoxymethoxy (3-MOMO) group as the EW group produced cycloadduct 3-17c exclusively. In 2011, Akai et al. found that the nucleophilic addition reaction of primary amines with 3-trimethylsilylbenzyne precursor 3-19 preferred the ortho-position of the TMS group, furnishing ortho-3-20 as the major products (Scheme 10b).142 Although in Akai’s 2010 Figure 4. Geometry optimized substituted benzynes, hetarynes, and angle-strained cyclic alkynes/allenes. 3901 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR distortion/interaction model, when a triple-bond carbon on aryne has a larger internal angle over the other one, this site is more electrophilic. This model also reveals that the internal angle difference is closely related to regioselectivity. As long as the internal angle difference is larger than 4°, a distinct regioselectivity will be realized.145,146,148 With the assistance of the aryne distortion/interaction model, Garg and co-workers could readily predict the regioselective preference with respect to different substituents on the benzyne ring. Distinctively, they could also overturn the regioisomeric ratios by positioning a designated EW group on the proximal position of an aryne triple bond. As shown in Scheme 11, they demonstrated that by employing 3-24b with a Review Scheme 12. Manipulating Regioselectivity on 3,4-Pyridyne Scheme 11. Reversing the Regioselectivity on 4,5-Indolynes 3.4. Effect of a Fused Small Ring Another factor that could tune aryne regioselectivity is through ring-strain on small ring-fused arynes, which is uncommon in aryne chemistry. This tuning factor was accidentally discovered by Suzuki and co-workers, when they studied the [2 + 2] cycloaddition reaction of a four-membered ring-fused aryne precursor 3-31 (Scheme 13a).158 Two regioisomers 3-32a and bromo group on the C6-position of 4,5-indolyne, the original geometry of 4,5-indolyne (3-24a) changed and the C4position of 3-24b became more electrophilic, which could produce 3-25 preferentially.151 In the absence of the 6-bromo group, a typical 4,5-indolyne (3-24a) favors the C5-position in nucleophilic addition reactions and afforded 3-26 as the major products. In 2013, Garg and Goetz demonstrated another excellent example by using the inductively EW tuning factor to manipulate the regioselectivity on 3,4-pyridyne.152 As shown in Scheme 12a, their DFT calculations indicated similar internal angles (125.3° and 124.7°) on the triple bond of a typical 3,4-pyridyne, suggesting a lack of regioselective control with respect to 3,4-pyridyne. Notably, both C2- and C5substituted 3,4-pyridynes with various EWGs could change the internal angles on the triple-bond carbons. In addition, these changes are in opposite trends, depending on the location of the EWG, on either the 2- or 5-position. Under the guidance of these theoretical insights, they examined the regioselective outcomes of these substituted 3,4-pyridynes with various arynophiles. As shown in Scheme 12b, the reaction of 3-27a− 3-27c with N-methylaniline afforded the corresponding products 3-28, 3-29, and 3-30, respectively. Although the reaction with simple 3,4-pyridyne (3-27a) showed almost no selectivity, both 5-bromo-3,4-pyridyne (3-27b) and 2-substituted 3,4-pyridyne 3-27c exhibited noticeably enhanced meta-selectivity with respect to the EWGs, affording 3-29b and 3-30a, respectively, as the major products. Scheme 13. Study on Small Ring-Fused Arynes 3-32b were obtained in a 31:1 ratio. Although they first speculated that steric repulsion might be responsible for the regioselective control, this possibility was then ruled out by employing different ring-fused aryne precursors. In a study carried out by Houk, Garg, and co-workers on indolyne precursors, they calculated a four-membered ring-fused benzyne 3-33 (Scheme 13b).150 Because the internal angle difference for two triple-bond carbons is 8°, it could easily recognize that the position with a larger internal angle is the preferred site of attack. By taking advantage of this tuning factor, Suzuki et al. accomplished the syntheses of a series of hexasubstituted benzenes, those of which were otherwise difficult to access via other methods.163−165 It should be 3902 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review scaffolds from anthracenes and o-silylaryl triflates.190−197 Because of the rigidity of a triptycene framework, it has found useful applications in materials science, which will be covered in section 15. 4.1.4. With Cyclic 1,3-Dienes. Cyclic 1,3-diene arynophiles other than furan and 2-pyranone were studied. In 2012, Biju and co-workers reported a highly efficient [4 + 2] cycloaddition reaction of both 6-substituted and 6,6-disubstituted pentafulvenes 4-1 with arynes, affording benzonorbornadiene derivatives 4-2 in good to excellent yields (Scheme 16a).198 This type of transformation was also utilized by Ho mentioned that in an early study on cyclopropabenzyne 3-34 carried out by Apeloig, Halton and co-workers in 1986, they proposed that the regioselectivity in the reaction of 3-34 should be significant (Scheme 13c).166 However, there was no follow-up study on this intermediate. Although this tuning factor has been reported with only limited examples, it does not mean that this effect is rare. In contrast, it might have already existed in aryne chemistry. For instance, both the 4,5-indolyne and 4,5-benzofuranyne have an internal angle difference equal or larger than 4° (Figure 4). Accompanied with the recent rapid advance in hexadehydroDiels−Alder (HDDA) aryne chemistry, the ring strain induced by the fused small rings on those aryne intermediates might, at least in part, attribute to their excellent regioselectivity.35,38,167 Scheme 16. Aryne Diels−Alder Reactions with Pentafulvenes, 1,2-Benzoquinones, and Tropones 4. PERICYCLIC REACTIONS 4.1. Diels−Alder Reactions Pericyclic reactions are the earliest as well as the most wellinvestigated reaction modes in aryne chemistry. Among them, aryne Diels−Alder reactions with various dienes as arynophiles have been extensively studied (Scheme 14). With the recent Scheme 14. General Scheme for Aryne Diels−Alder Reactions intensive exploration on o-silylaryl triflates, not only conventional dienes but also new types of diene arynophiles were developed in aryne Diels−Alder reactions. 4.1.1. With Furans. Furans are fundamental arynophiles in aryne Diels−Alder reactions, which have been utilized since the early era of aryne chemistry (Scheme 15a). With the employment of Kobayashi’s method, many applications on this reaction mode were realized,134,168−182 which will not be discussed in this section. and Huang.199 Meanwhile, Biju and co-workers studied the reaction between 1,2-benzoquinones (4-3) and arynes, which could construct dioxobenzobicyclooctadienes 4-4 (Scheme 16b).200 Further derivatization on the products gave rise to both benzoquinoxalinobarrelene and naphthalene derivatives. This protocol was also employed by Liu and co-workers in their syntheses of diterpenoid derivatives.201,202 Subsequently, Biju et al. applied tropones (4-5) in the Diels−Alder reaction with arynes, affording functionalized benzobicyclo[3.2.2]nonatrienone derivatives 4-6 in modest to high yields (Scheme 16c).203 Moreover, this type of [4 + 2] cycloaddition was also utilized by Hoye et al.167 In a study carried out by Cheng, Zhai, and co-workers on Narylation of 2-aminopyridine with o-silylaryl triflates, they disclosed that the N-arylated products, 1-arylpyridin-2(1H)imine derivatives 4-7, could further participate in an aryne Diels−Alder reaction to produce benzoisoquinuclidines 4-8 (Scheme 17a).204 In 2018, Tejedor, Garcı ́a-Tellado, and coworkers demonstrated that 2,2-dimethyl-2H-pyrans 4-9 could serve as efficient electron-rich diene arynophiles to react with arynes.205 As shown in Scheme 17b, a sequential Diels−Alder/ retro-Diels−Alder reaction process with the extrusion of acetone occurred, furnishing polysubstituted methyl 2naphthoates 4-10 in good to excellent yields. This protocol was recently employed by Garcı ́a-Tellado et al.206 Besides, both isoindoles207 and cyclohexadienes208,209 have been shown to serve as efficient dienes in aryne Diels−Alder reactions as well. Intriguingly, Wang and co-workers demonstrated that η5indenyl complexes 4-11 of both iron210 and ruthenium211 as well as the η5-fluorenyl ruthenium complex211 could participate Scheme 15. Aryne Diels−Alder Reactions with Furan, 2Pyranone, and Anthracene 4.1.2. With 2-Pyranones. Another type of common diene arynophile is 2-pyranone, the [4 + 2] cycloadduct of which could then undergo an extrusion of CO2 to form a naphthalene framework (Scheme 15b).183−189 4.1.3. With Anthracenes. The central ring of an anthracene could serve as a 1,3-diene moiety, which has been traditionally utilized in an efficient preparation of triptycene framework with arynes generated through the methods other than Kobayashi’s (Scheme 15c). Hence, there are limited recent examples in the preparation of triptycene 3903 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 17. Aryne Diels−Alder Reactions with Other Cyclic 1,3-Dienes Review Scheme 18. Aryne Diels−Alder Reactions with Linear 1,3Dienes Scheme 19. Aryne Diels−Alder Reaction/Eliminative Aromatization Processes in the aryne Diels−Alder reaction to afford the corresponding cycloadducts 4-12 (Scheme 17c). 4.1.5. With Acyclic 1,3-Dienes. Although cyclic 1,3dienes have been broadly employed as efficient arynophiles in aryne Diels−Alder reactions, acyclic 1,3-dienes received much less attention with respect to the aryne generation methods other than Kobayashi’s. In 2005, Lautens and co-workers demonstrated that ethyl sorbate and its analogues 4-13 could participate in the Diels−Alder reactions with benzyne, generated from benzenediazonium-2-carboxylate. In this study, they also revealed that substrate 4-13 bearing Oppolzer’s sultam as the chiral auxiliary could react with osilylaryl triflates to yield cycloadducts 4-14 in excellent diastereoselectivities (Scheme 18a).212 Subsequently, the same group applied Oppolzer’s sultam as the chiral auxiliary in diastereoselective Diels−Alder reactions between either the pyrrole or furan moiety and o-silylaryl triflates, affording enantiomerically pure benzofused [2.2.1] heterobicycles.213 Moreover, aryne Diels−Alder reactions with linear dienes were then utilized by various groups.214−223 It is worth mentioning that Vankar and co-workers applied this strategy in the preparation of 1,2-annulated-C-aryl glycosides 4-16 from 1,3diene 4-15, the products of which could be further converted to sugar-fused and sugar-branched naphthalenes as well (Scheme 18b).224 In some cases, the cycloadducts could undergo eliminative aromatization to assemble naphthalene rings. In 2003, Comins et al. demonstrated that a tandem [4 + 2] cycloaddition reaction between arynes and 5-vinyl-2,3-dihydro-4-pyridones (4-17) with a following eliminative aromatization could afford β-amino-ketones 4-18 (Scheme 19a).225,226 Similarly, Wu, Sha, and co-workers disclosed that in the presence of TFA orthohydroxybenzophenones 4-20 were obtained in moderate to excellent yields from 3-vinylchromones 4-19 and o-silylaryl triflates (Scheme 19b).227 In 2018, Mukherjee and co-workers developed a unique protocol to prepare a series of metadisubstituted fused aromatic systems 4-22 with chiral side chains through a successive aryne Diels−Alder reaction with glycal-based dienes 4-21 and eliminative aromatization (Scheme 19c).228 1,3-Dienes containing heteroatoms are useful arynophiles in aryne hetero-Diels−Alder reactions. In 2006, Piers and coworkers examined benzyne Diels−Alder reaction with borabenzenes 4-23, which produced highly Lewis acidic 1borabenzobarrelene derivatives 4-24 (Scheme 20).229 The products in this transformation exhibited high stability. In 2014, Romero-Ortega and co-workers employed 2(trichloromethyl)-1,3-diazabutadienes (4-25) as 1,3-dienes to react with benzyne and harvested 4-susbstituted 2(trichloromethyl)quinazolines 4-26 in good to excellent yields 3904 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 20. Aryne Diels−Alder Reactions with Borabenzenes Review Scheme 22. Other Aryne Aza-Diels−Alder Reactions after the elimination of a secondary amine moiety (Scheme 21a).230 In 2016, He et al. reported an inverse electronScheme 21. Aryne Diels−Alder Reactions with Aza-1,3dienes sequential aza-Diels−Alder reaction/N-arylation pathway (Scheme 22b).237 Stable o-quinone methides 4-34 could also participate in hetero-Diels−Alder reaction with arynes, giving rise to both 9-aryl and 9-cinnamyl substituted xanthenes 4-35 in moderate to high yields (Scheme 23).238 The same transformation was also realized by Panda et al.239 Scheme 23. Aryne Diels−Alder Reaction with o-Quinone Methides Styrenes are good Diels−Alder partners with arynes. In 2012, Wu et al. first reported a sequential aryne Diels−Alder/ dehydrogenation reaction with α,β-unsaturated compounds containing styrene moiety. Various acyl-/ethoxycarbonyl-/ cyano-substituted styrenes 4-36 could be used in the reaction to furnish the corresponding 9-functionalized phenanthrenes 4-37 (Scheme 24a).240 In 2014, Biju and co-workers disclosed that unactivated styrenes 4-38 participated in the aryne Diels− Alder reaction to produce cycloadducts 4-39 (Scheme 24b).241 Particularly, when styrenes bearing an electron-withdrawing group (EWG) on the 4-position of the benzene ring, a proton transfer/aromatization process readily took place to afford 439. Recently, Tiwari et al. employed β-bromovinylarenes 4-40 as 1,3-dienes in the aryne Diels−Alder reaction, furnishing phenanthrenes, chrysenes, and tetraphenes 4-41 (Scheme 24c).242 The presence of the β-bromo group on 4-40 allowed a facile eliminative aromatization after the [4 + 2] cycloaddition reaction. In 2015, Wu, Shi and co-workers found that the aryne Diels−Alder reaction with γ-arylallenylcarboxyamides 4-42 occurred in a highly chemoselective manner to afford 4-43, whereas the amide moiety did not involve in this transformation (Scheme 24d).243 Notably, this transformation required the presence of an allene moiety. In 2012, Li, Jia, and co-workers realized an aryne Diels− Alder reaction with methyleneindolinones 4-44, which allowed a quick construction of structurally unprecedented naphthofused oxindoles 4-46 in modest to high yields (Scheme demand aza-Diels−Alder reaction of arynes with 2-aza-dienes, generated in situ from anilines and ethylglyoxylate, the cycloadduct of which underwent a further N-arylation to afford N-aryl dihydrophenanthridine derivatives 4-27 (Scheme 21b).231 In 2018, Zhang and co-workers developed a tandem transformation that involved a Rh(I)-catalyzed coupling reaction of vinyl azides with isonitriles to form vinyl carbodiimide intermediates 4-28, which then proceeded through an aryne Diels−Alder reaction to furnish isoquinoline derivatives 4-29 (Scheme 21c).232 In addition, other examples on this type of transformations have also been reported.233−235 In 2015, Rodriguez, Coquerel and co-workers reported two aryne aza-Diels−Alder reactions using electron-rich 2-azadienes 4-30 as 1,3-dienes (Scheme 22a).236 The first transformation involved an in situ oxidation of the cycloadducts with MnO2 to produce isoquinolines 4-31, while the second approach directly afforded isoquinolines 4-32 by employing formimidamides as 1,3-dienes, the structure of which equips with a sacrificial dimethylamino group that could promote a following eliminative aromatization reaction. Moreover, this study also led to a total synthesis of benzo[c]phenanthridine alkaloid nornitidine, which will be covered in section 14. Subsequently, the same group employed an excess amount of aryne to obtain compounds 4-33 via a 3905 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 24. Aryne Diels−Alder Reactions with Styrenes Review Scheme 25. Aryne Diels−Alder Reactions with Methylene(iso)indolinones and Fluorene-Derived Alkenes 25a).244 In this study, they proposed a fluoride-assisted deprotonation on the cycloadduct 4-45 with departure of hydride to account for the formation of 4-46. However, there might be other possibilities to reach this dehydrative aromatization step. In 2017, Jeganmohan et al. developed a unique transformation between o-silylaryl triflates and 3methyleneisoindolin-1-ones 4-47, furnishing the skeleton of aristolactam alkaloids 4-49 (Scheme 25b).245 This reaction involves a [4 + 2] cycloaddition reaction and a fluoridemediated desulfonylation of the cycloadduct 4-48. Recently, He and co-workers demonstrated that the Diels−Alder reactions between arynes and fluorene-derived alkenes 4-50 could produce benzo[b]fluoranthenes (4-51) after in situ dehydrogenative oxidation with MnO2 (Scheme 25c).246 Both alkenylindoles and alkenylpyrroles were utilized in aryne Diels−Alder reactions, allowing the rapid construction of polycyclic heterocycles. In 2014, Wu, Sha, and co-workers employed 3-alkenylindoles 4-52 as 1,3-dienes in the aryne Diels−Alder reaction, affording benzo[a]carbazole-5-carboxylates 4-53 after an in situ oxidation with molecular oxygen (Scheme 26a).247 Subsequently, the same protocol was utilized by Liang, Pi, and co-workers.248 In addition, 2-alkenylindoles 4-54 were also employed in the aryne Diels−Alder reaction (Scheme 26b).249,250 Depending on the stoichiometry of osilylaryl triflates, both 6,7-dihydrobenzo[c]carbazoles 4-55 and aryl substituted 7,11b-dihydrobenzo[c]carbazoles 4-56 were obtained in good to excellent yields. In the presence of molecular oxygen, benzo[c]carbazole derivatives 4-57 were produced. In 2016, Wu, Sha, and co-workers demonstrated an interesting chemoselective aryne Diels−Alder reaction with 2vinylpyrroles 4-58, furnishing benzo[e]indoles 4-59 in moderate to high yields (Scheme 26c).251 Notably, they found that a N-benzhydryl (CHPh2) protecting group was crucial to prevent a possible competing [4 + 2] cycloaddition reaction on the pyrrole ring. 4.1.6. Intramolecular Diels−Alder Reactions. In 2005, Danheiser and co-workers reported an intramolecular aryne Diels−Alder reaction with conjugated enynes and arenynes 460, giving rise to highly condensed polycyclic aromatic compounds 4-61 (Scheme 27a).108 Recently, Ohmori, Suzuki, and co-workers demonstrated an intramolecular [4 + 2] cycloaddition of aryne and phenolate by employing obromoaryl tosylates as the aryne precursors.252 In this study, they showed one example with o-silylaryl triflate 4-62 as the precursor and obtained cycloadduct 4-63 in 89% yield (Scheme 27b). 4.2. 1,3-Dipolar Cycloaddition Reactions Along with the study on Kobayashi’s method, a family of 1,3dipolar cycloaddition reactions were explored and utilized. The mild generation conditions with respect to o-silylaryl triflates allow the compatibility of this method with not only diverse functional groups but also a variety of 1,3-dipoles, some of which might be otherwise unstable under harsh reaction/ 3906 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 26. Aryne Reactions with Alkenylindoles and Alkenylpyrroles Review Scheme 28. General Scheme for Aryne 1,3-Dipolar Cycloaddition Reactions 4.2.1. With 4-Hydroxyisoquinolinium and 3-Oxidopyridinium. The earliest study on the 1,3-dipolar cycloaddition reaction with o-silylaryl triflates was carried out by Carroll and co-workers. In 1996, they reported a convenient strategy toward the synthesis of MK801, which is known to inhibit opioid tolerance and dependence (Scheme 29a).253 In Scheme 29. Aryne 1,3-Dipolar Cycloaddition Reactions with 4-Hydroxyisoquinolinium and 3-Oxidopyridinium Species Scheme 27. Intramolecular Aryne Diels−Alder Reactions this work, N-alkyl-4-hydroxy-1-methylisoquinolinium betaines 4-64 participated in the aryne 1,3-dipolar cycloaddition reaction and afforded N-alkyl-5-methyl-1l-oxo-5H-dibenzo[a,d]cyclohepten-5,l0-imines 4-65 in high efficiency, which was then converted to MK801. They also examined the reactivity of 4-64 with two other benzyne precursors, namely, 1-aminobenzotriazole (4-66) (generated via oxidation with lead tetraacetate) and anthranilic acid (4-67) (generated via diazotization), both of which gave either low yield or no desired product at all (Scheme 29a). In 2012, Shi and coworkers further expanded the scope of this protocol to 3oxidopyridinium species 4-68, giving rise to bicyclo[3.2.1] skeleton 4-69 under mild conditions (Scheme 29b).254 4.2.2. With Diazo Compounds. Diazo compounds are prevalently utilized in 1,3-dipolar cycloaddition reactions with o-silylaryl triflates. In 2007, Yamamoto and Jin first demonstrated that 1H-indazoles 4-70 and 1-arylated indazoles 4-71 could be readily synthesized in good to high yields from diazo compounds by simply varying the reaction conditions generation conditions. Scheme 28a summarizes a general equation for the aryne 1,3-dipolar reaction, which can also be seen as a formal [3 + 2] cycloaddition reaction. Benzofused heterocyclic rings can be facilely prepared, those of which have found useful synthetic applications. Among 1,3-dipoles, azides, diazo compounds, nitrones, and nitrile oxides are commonly utilized in aryne cycloaddition reactions (Scheme 28b). 3907 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR and the stoichiometry of o-silylaryl triflates (Scheme 30a).255 Later in 2008, in a study carried out by Larock and co-workers, Review to fused-2H-indazoles via an acid- or heat-mediated rearrangement (Scheme 31c).261 Diazo compounds with electron-withdrawing activating groups other than carbonyl were also examined. In 2015, Ma and co-workers achieved a 1,3-dipolar cycloaddition reaction of o-silylaryl triflates with 2,2,2-trifluorodiazoethane (CF3CHN2), affording potentially bioactive 3-trifluoromethyl-1H-indazoles 4-80 in good to high yields with moderate regioselectivities (Scheme 32a).262 In 2018, Peng and co-workers disclosed that Scheme 30. Aryne 1,3-Dipolar Cycloadditions with Diazo Compounds Scheme 32. Aryne 1,3-Dipolar Cycloaddition Reactions with CF3CHN2 and α-Diazomethylphosphonates they disclosed that dicarbonyl-containing diazo compounds 472 could enforce carbonyl migration to produce 1-acyl- or 1alkoxycarbonyl indazoles 4-73 in high to excellent yields (Scheme 30b).256 In 2009, Hari, Aoyama, and co-workers developed a one-pot, two step procedure for the preparation of 3-substituted indazoles 4-75 from arynes and 2-diazo-(2-trimethylsilyl)ethanols 4-74, which could be readily synthesized from diazo(trimethylsilyl)methylmagnesium bromide with various ketones and aldehydes (Scheme 31a).257 Recently, the groups two types of [3 + 2] cycloadducts, namely, 3-alkyl/aryl-1Hindazoles 4-82 and 3-alkyl/aryl-3H-indazole-3-phosphonates 4-83, could be prepared from α-substituted α-diazomethylphosphonates 4-81 (Scheme 32b).263 By simply varying the phosphoryl group, 3-alkyl/aryl-1H-indazoles 4-82 could be obtained from dimethyl α-diazoalkylphosphonates (R2 = Me), whereas 3-alkyl/aryl-3H-indazole-3-phosphonates 4-83 were achieved from diisopropyl α-diazoalkylphosphonates (R2 = iPr). N-Substituted hydrazones were employed as stable and readily accessible precursors of diazo compounds. In 2011, Shi and co-workers demonstrated that under fluoride-induced activation conditions, N-tosylhydrazones 4-84 could generate the corresponding diazo compounds, which then underwent 1,3-dipolar cycloaddition reaction with arynes (Scheme 33a).264 Notably, TEBAC (Et3NBn+Cl−) served as a phase transfer catalyst to effectively enhance the reaction yields. Later in 2012, the same group reported an aryne 1,3-dipolar reaction with N-aryl/alkylhydrazones 4-85, affording 1,3-disubstituted Scheme 31. Aryne 1,3-Dipolar Cycloaddition Reactions with Other Diazo Compounds Scheme 33. Aryne 1,3-Dipolar Cycloaddition Reactions with N-Substituted Hydrazones of Zhai258,259 and Reddy260 independently developed an aryne 1,3-dipolar cycloaddition reaction with 3-diazoindolin-2-ones 4-76, furnishing spiro[indazole-3,3′-indolin]-2′-ones 4-77 in good to excellent yields (Scheme 31b). Subsequently, Cheng, Zhai, and co-workers utilized 6-diazocyclohex-2-en-1-one derivatives 4-78 as 1,3-dipoles to react with arynes, giving rise to spiro-3H-indazoles 4-79 that could be further converted 3908 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR indazoles 4-86 through an annulation/oxidation process (Scheme 33b).265 4.2.3. With Azides. Azides are very efficient 1,3-dipoles and have been extensively utilized in alkyne click chemistry. Not surprisingly, they could be employed in aryne [3 + 2] cycloaddition reactions as well to build a benzotriazole framework. Distinctively, these aryne-azide [3 + 2] cycloaddition reactions are under copper-free conditions. The preparation of benzotriazoles 4-87 via the aryne 1,3-dipolar reaction with azides was realized in 2008 independently by the groups of Larock,266 Chandrasekhar,267 and Feringa268 (Scheme 34a). In 2009, Biehl and Ankati reported a Review Scheme 35. Aryne 1,3-Dipolar Cycloaddition Reactions with Other Azides Scheme 34. Aryne 1,3-Dipolar Cycloaddition Reactions with Azides zoles could find more useful applications. In this context, Zajc and co-workers developed a sequential aryne-azide 1,3-dipolar annulation/Julia−Kocienski reaction process to synthesize N1vinyl benzotriazoles 4-92 from azidomethyl phenyl-1Htetrazol-5-yl sulfide (4-91) (Scheme 35c).271 This strategy smartly avoided the N1/N2 regioselective problem in conventional alkylation reaction of benzotriazoles. Beside the aforementioned examples, this transition-metal-free aryneazide [3 + 2] cycloaddition protocol turned out to be quite general and has found a broad spectrum of synthetic applications.272−292 4.2.4. With Nitrile Oxides. In 2010, the groups of Larock293 and Browne294 independently reported aryne 1,3dipolar cycloaddition reactions with nitrile oxides, in situ generated from N-hydroxybenzimidoyl chloride analogues 493 via fluoride-induced deprotonation reaction, furnishing substituted benzisoxazoles 4-94 in moderate to excellent yields with high functional group tolerance (Scheme 36). Distinctively, this protocol allowed a simultaneous generation of two highly active species, namely, an aryne and a nitrile oxide, in the same reaction media. Subsequently, Larock and coworkers further expanded the synthetic application of this microwave-assisted aryne click protocol using either aryl/ alkyl azides or those in situ generated from alkyl halides and sodium azide (Scheme 34b).123 Notably, they found that the departure rate of the OTf group from o-silylaryl triflates could be significantly promoted under microwave irradiation conditions. Recently, Biju and co-workers studied the reaction between NaN3 and o-silylaryl triflates. They found that N-H benzotriazoles could be obtained by using CsF/18-c-6 in acetonitrile; whereas N-aryl benzotriazoles were formed when the reaction employed KF/18-c-6 in THF in an open-flask (Scheme 34c).269 In 2009, Moses and Zhang demonstrated that aromatic azides 4-88, generated in situ from anilines, t-BuONO, and TMSN3, could react with arynes to give benzotriazoles in good to high yields (Scheme 35a).124 Both anthranilic acids and osilylaryl triflates could serve as efficient aryne precursors in this transformation. They also noticed that microwave irradiation dramatically shortened the reaction time of this one-pot protocol. An advantage for this protocol is to avoid the handling of potentially explosive aliphatic/aromatic azides. In 2011, Reddy et al. employed glycosyl azides 4-89 with the azide group on different positions of the glycosyl ring to prepare benzotriazole-linked glycoconjugates 4-90, those of which might be applied in nucleoside synthesis (Scheme 35b).270 The selective formation of 1-substituted benzotria- Scheme 36. Aryne 1,3-Dipolar Cycloaddition Reactions with Nitrile Oxides 3909 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR protocol and prepared a library of building blocks containing 3substituted benzisoxazoles, those of which possess potential biological activity.295 4.2.5. With Nitrones. In 2012, Larock et al. demonstrated that nitrones could participate in aryne 1,3-dipolar cycloaddition reactions to furnish substituted benzisoxazolines 4-95 with high functional group tolerance (Scheme 37a).296 Review Scheme 38. Aryne 1,3-Dipolar Cycloaddition Reactions with Azomethine Imines and Nitrile Imines Scheme 37. Aryne 1,3-Dipolar Cycloaddition Reactions with Nitrones Scheme 39. Aryne 1,3-Dipolar Cycloaddition Reactions with N-Heteroaromatic Ring Imides Meanwhile, Kaliappan and Khangarot developed a highly diastereoselective aryne 1,3-dipolar cycloaddition protocol with sugar-derived chiral cyclic nitrone 4-96 (Scheme 37b).297 The resulting sugar-based benzo[d]isoxazoline products 4-97 could be further converted to aza-C-aryl glycosides via a selective N−O bond cleavage. In 2017, Yao and co-workers realized an in situ generation of nitrone species from ketoximes 4-98 and a subsequent aryne 1,3-dipolar cycloaddition reaction (Scheme 37c).298 A ketonitrone intermediate was first generated between ketoxime and aryne, which then participated in a [3 + 2] cycloaddition reaction with another aryne to furnish benzisoxazolines 4-99. In this study, they also disclosed that under high reaction temperature benzisoxazolines 4-99 could isomerize to dihydrobenzo[d]oxazoles 4-100. Moreover, this aryne-nitrone cycloaddition protocol was utilized in many synthetic applications as well.299−304 4.2.6. With Azomethine Imines and Nitrile Imines. In 2009, Larock and co-workers demonstrated that stable azomethine imines 4-101 could participate in aryne 1,3-dipolar cycloaddition reaction, giving rise to tricyclic pyrazoloindazolones 4-102 (Scheme 38a).305 Recently, Sha, Wu, and coworkers reported a [3 + 2] cycloaddition reaction of C,N-cyclic azomethine imines 4-103 with o-silylaryl triflates, furnishing Nsubstituted indazolo[3,2-a]isoquinolines 4-104 (Scheme 38b).306 Similarly, nitrile imines 4-106, generated in situ from aryl/heterocyclic substituted hydrozonyl chlorides 4-105, could react with arynes to afford 1-substitued-1H-indazoles 4107 in modest to excellent yields (Scheme 38c).307 4.2.7. With N-Heteroaromatic Ring Imides. N-Tosylpyridinium imides 4-108 were utilized by Wu, Shi and coworkers as 1,3-dipoles in aryne reactions (Scheme 39a).308,309 The [3 + 2] cycloaddition reaction breaks the aromaticity of pyridine ring and generates intermediate 4-109, which could then transform to pyrido[1,2-b]indazoles 4-110 after eliminative aromatization.308 Furthermore, a one-pot process was also developed by the same group through a sequential AgOTfcatalyzed cyclization of N′-(2-alkynylbenzylidene)-tosylhydrazides 4-111 to generate N-tosylisoquinolinium imides 4-112 and an aryne 1,3-dipolar cycloaddition reaction, affording indazolo[3,2-a]-isoquinolines 4-113 in modest to high yields (Scheme 39b).309 In 2018, Sharma and co-workers reported an aryne [3 + 2] cycloaddition reaction with N-benzoyl protected quinolinium imides 4-114, giving rise to four-ring-fused N,N′heterocyclic compounds 4-115 in moderate to high yields (Scheme 39c).310 Different from the reaction with N3910 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR tosylpyridinium imides 4-108, the benzoyl-protecting group on the products 4-115 did not eliminate after the [3 + 2] cycloaddition reaction. 4.2.8. With Cyclic 1,3-Dipoles. Cyclic 1,3-dipoles could also be employed in aryne [3 + 2] cycloaddition reactions. Several mesoionic dipoles, such as sydnones, münchnones, and 1,3-dithiolium-4-olates (DTOs), were investigated in aryne cycloaddition reactions. In 2010, Larock, Shi, and co-workers first utilized sydnones 4-116 as 1,3-dipoles to react with arynes. 2H-Indazoles 4-118 were obtained in good to excellent yields (Scheme 40a).311,312 After the aryne 1,3-dipolar cycloaddition Review Scheme 41. Aryne 1,3-Dipolar Cycloaddition Reactions with DTOs and Thiadiazoles Scheme 40. Aryne 1,3-Dipolar Cycloaddition Reactions with Sydnones and Münchnone (Scheme 42a).321 In 2014, Hu and co-workers developed an unprecedented strategy toward enantiopure cyclic sulfoxiScheme 42. Reactions with Other 1,3-Dipoles reaction, extrusion of CO2 occurred on the cycloadducts 4-117 to afford 2H-indazole derivatives 4-118. Synthetic applications based on this protocol were then explored by different research groups.153,313−316 Münchnones are isoelectronic with sydnones and have been utilized as cyclic 1,3-dipoles as well. In 2014, the groups of Larock and Shi317 and Gribble318 independently demonstrated an aryne [3 + 2] cycloaddition reaction with münchnones 4-119, producing isoindoles 4-121318 after extrusion of CO2 from the cycloadducts 4-120 (Scheme 40b). Recently, Audisio, Taran, and co-workers prepared a series of 1,3-dithiolium-4-olates (DTOs) 4-122 and studied their reactivity with strained alkynes.319 As shown in Scheme 41a, various benzo[c]thiophenes 4-124 were facilely prepared through an aryne [3 + 2] cycloaddition/extrusion of carbonyl sulfide (COS) sequence via intermediate 4-123. Another type of cyclic 1,3-dipole is thiadiazole. In 2015, Willis and Chen disclosed that both 3,4-dichloro-1,2,5-thiadiazole and unsymmetrical thiadiazoles 4-125, such as 3-hydroxy-4-aminothiadiazoles, could react with o-silylaryl triflates to furnish benzo[d]isothiazoles 4-127 in modest to excellent yields (Scheme 41b).320 Cyanic acid can be then extruded from the cycloadduct 4-126 after the 1,3-dipolar cycloaddition reaction. 4.2.9. With Other 1,3-Dipoles. Other 1,3-dipoles as aryne [3 + 2] cycloaddition partners have been investigated. In 2007, Huang et al. reported a 1,3-dipolar cycloaddition of Kobayashi benzyne precursor with 1,3-bis(2,4,6-trimethylphenyl)-2-Nphenylthiocarbamoyl imidazolinium inner salt (4-130), prepared from the reaction between N-heterocyclic carbene 4-128 and 2-tolyl isothiocyanate (4-129), resulting in the formation of spiro(imidazolidine-2,3′-benzo[b]thiophene) (4-131) mines, in which N-tert-butanesulfinyl imines 4-132 as quasi1,3-dipoles could participate in aryne 1,3-dipolar cycloaddition reaction to produce cycloadducts 4-133 in good to high yields (Scheme 42b).322 In this study, the presence of the PhSO2CF2 group was the key for the success of this transformation, allowing both high efficiency and excellent stereoselectivity in the [3 + 2] cycloaddition reaction. In 2018, Singh and Garg demonstrated that 2,3-disubstuted benzo[b]thiophenes 4-136 could be obtained in the aryne 1,3dipolar cycloaddition reaction with acyl ketene dithioacetals 4134 (Scheme 43a).323 Notably, this study unraveled the dipole character of acyl ketene dithioacetals 4-134 conveyed by their resonance structure 4-135, furnishing 4-136 through a sequential [3 + 2] cycloaddition reaction and extrusion of an ethylene moiety via either path a or path b. In the same year, Ko and co-workers utilized azomethine ylides 4-137 as 1,33911 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 43. Aryne 1,3-Dipolar Cycloaddition Reactions with Acyl Ketene Dithioacetals, Azomethine Ylides, and αHaloamides Review Scheme 44. Aryne [2 + 2] Cycloaddition Reactions with CS and CSe Bonds structure of which was otherwise hard to be accessed (Scheme 44c).328 In 2009, Hsung and co-workers demonstrated a [2 + 2] cycloaddition reaction between enamides 4-148 and benzyne, furnishing cycloadducts 4-149 in moderate to excellent yields (Scheme 45a).329 A similar aryne [2 + 2] cycloaddition Scheme 45. Aryne [2 + 2] Cycloaddition Reactions with Enamides dipoles to react with arynes and obtained spirooxindole-3,2′pyrrolidine derivatives 4-138 in moderate to excellent yields (Scheme 43b).324 Fluoride ion in this transformation served as both the activating reagent for o-silylaryl triflates and the base to deprotonate ketimine species. Meanwhile, Singh et al. revealed that N-alkoxy oxindoles 4-141 could be readily prepared via a formal [3 + 2] cycloaddition reaction between arynes and α-haloamides 4-139, which can be seen as putative aza-oxyallyl cation synthons 4-140 (Scheme 43c).325 Notably, N-alkoxy substituents on α-haloamides were necessary for the success of this transformation, which was reasoned by their stabilizing ability to the aza-oxyallyl cation 4-140. reaction with N,N-bis(Boc)-protected dehydroalanine 4-150 was recently reported by Ramtohul et al., in which α,αdisubstituted benzocyclobutene amino acids 4-151 were readily prepared (Scheme 45b).330 Notably, a simple modification on the N-protecting group of the substrates could result in the formation of either indoline or isoquinoline products (see section 6).331,332 In 2014, Yu, Liu, and co-workers examined aryne [2 + 2] cycloaddition reactions with a series of olefins (Scheme 46a).333 Among them, norbornadiene, norbornene, vinyl butyl ether, and alkyl acrylate could all afford benzocyclobutenes 4-152 in high yields. Subsequently, Lakshman and coworkers systematically investigated the reaction between osilylaryl triflates and cyclic enol ethers 4-153, such as analogues of 2,3-dihydrofuran, 2,3-dihydro-3H-pyran, and 1,4-dioxene. All of them could produce the corresponding benzocyclobutenes 4-154 in moderate to high yields with excellent stereoselective control (Scheme 46b).334 Similar to 2,3-dihydro-3H-pyran, tetrahydropyridines were reported as well. In 2017, Wang, Lu, and co-workers demonstrated that the [4 + 2] cycloadducts 4-155 between 4.3. [2 + 2] Cycloaddition Reactions In comparison with intensively investigated as well as broadly utilized [4 + 2] and 1,3-dipolar cycloaddition reactions, formal [2 + 2] cycloaddition with o-silylaryl triflates received much less attention. In 1998, Okuma and co-workers first employed Kobayashi benzyne precursor in the benzyne [2 + 2] cycloaddition reaction with thiopivalophenone 4-142, giving rise to 2-tert-butyl-2-p-tolyl-2H-benzo[b]thiete (4-143), albeit in low yield (Scheme 44a).326 By using thiofenchone (4-144) as the substrate, a mixture of [2 + 2] cycloadducts 4-145 was obtained (Scheme 44b).327 In 2001, the same group demonstrated that benzoselenete 4-147 could be efficiently prepared through a benzyne [2 + 2] cycloaddition reaction with 1,1,3,3-tetramethylindane-2-selone (4-146), the product 3912 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 46. Aryne [2 + 2] Cycloaddition Reactions with Olefins Review Scheme 48. Aryne [n + 2] Cycloaddition Reactions allene ketones and 1-azadienes could participate in a further aryne [2 + 2] cycloaddition reaction to yield 4-156 (Scheme 47a).335 Later in 2018, another [4 + 2]/[2 + 2] cycloaddition Scheme 47. Other Aryne [2 + 2] Cycloaddition Reactions In 2010, Cossı ́o et al. carried out both computational and experimental studies on the reaction between imidazo[1,2a]pyridines/pyrimidines 4-166 and arynes, which led to the formation of benzo[a]imidazo-[5,1,2-cd]indolizines (X = CH) and 2,3,9c-triazocyclopenta[j,k]fluorenes (X = N) 4-167 via a [8 + 2] cycloaddition reaction/dehydrogenative aromatization process (Scheme 48c).126 Microwave irradiation was found to promote the reaction, whereas classical heating only produced trace amounts of the products. Their computational study revealed that both the [8 + 2] cycloaddition step and the aromatization step were concerted. In addition, the nonlinear optical properties of coumarin derivatives340 and the excited state intramolecular proton transfer property of this class of molecules341 were investigated. Recently, Cheng, Zhai, and coworkers demonstrated that pyridinium 1,4-zwitterionic thiolates 4-168 could serve as 1,5-dipoles and reacted with osilylaryl triflates to produce 12aH-benzo[f ]pyrido[1,2-d][1,4]thiazepines 4-169 (Scheme 48d).342 Meanwhile, benzo[b]thiophenes were also obtained as side products, the formation of which was through a [3 + 2] cycloaddition/elimination of the pyridine process. reaction process was reported by Wang and co-workers, in which the generated [4 + 2] cycloadducts 4-159 from compounds 4-157 could react with arynes to afford 4-158 via the [2 + 2] cycloaddition reaction (Scheme 47b).336 Other [2 + 2] cycloaddition reactions between o-silylaryl triflates and simple olefins were also explored.337,338 4.4. [n + 2] Cycloaddition Reactions Along with Shi’s study on aryne 1,3-dipolar cycloaddition with 3-oxidopyridinium species (X = O) 4-160, they observed the formation of benzofuran derivatives 4-161, the generation of which was through a sequential aryne [7 + 2] cycloaddition reaction/pyridine ring-opening process (Scheme 48a).254 By employing 3-amidopyridinium species (X = NR2) 4-162 as the substrates, indole scaffold 4-163 could be obtained via the same process. In 2007, Xu and co-workers reported an aryne [8 + 2] cycloaddition reaction with indolizines and annulated indolizines 4-164, affording indolizino[3,4,5-ab]isoindoles and benzo[6,7]pyrrolizino[3,4,5-ab]isoquinolines 4-165 after rearomatization (Scheme 48b).339 Both the fluorescence and electrochemical properties of these compounds were then investigated. 4.5. Ene Reactions The employment of Kobayashi’s method provides mild conditions for aryne ene reactions. The first aryne ene reaction with o-silylaryl triflates was reported by Cheng and co-workers. In 2006, they found that alkynes could participate in the ene 3913 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review reaction, they identified that the trityl group (Tr) could serve as an ideal protecting group on various anilines 4-178 (Scheme 51a). Consequently, the aryne heteroene reaction proceeded reaction with arynes under mild conditions, affording arylallene derivatives 4-170 in moderate to good yields (Scheme 49a).343 Scheme 49. Aryne Ene Reactions with Alkynes Scheme 51. Other Aryne Ene Reactions In 2014, Ma and Yuan observed an intramolecular aryne ene reaction as the first step in a Pd-catalyzed cascade transformation (Scheme 49b).344 In this transformation, the generated aryne 4-172 from o-silylaryl triflates 4-171 proceeds through an intramolecular ene reaction to generate allene intermediate 4-173, which then reacts with arylpalladium species to afford benzofurans 4-174. Olefins could also serve as ene arynophiles. Several intermolecular aryne ene reactions with olefins have been recently elaborated, whereas with aryne precursors other than Kobayashi’s.345−347 Although the aryne ene reaction of osilylaryl triflates with alkenes was accidentally discovered by Okuma and co-workers in their aryne three-component coupling reactions,348 Yin, Liu, and co-workers systematically investigated this transformation with respect to various olefins, producing allyl arenes 4-175 in good to high yields (Scheme 50a).349 In 2016, He et al. also reported an aryne ene reaction smoothly to yield 2-arylanilines 4-179 in moderate to excellent yields with high functional group tolerance. Based on the fact that only ortho-arylated products were obtained and with their deuterium-labeling experiment, a concerted aryne ene reaction mechanism was proposed. Recently, Jones and co-workers applied an aryne ene reaction on Hantzsch esters 4-180 to realize either C2 or C3 arylated products 4-181 and 4-182, respectively, in regioselective manner (Scheme 51b).353,354 They reasoned that the formation of C3 arylated products 4182 was the result of steric repulsion by the bulky group on the C4-position of Hantzsch esters 4-180b. Both the experimental studies and the DFT calculations suggested a concerted aryne ene process. Moreover, examples of aryne ene reactions involved in cascade transformations were reported.241,355,356 5. NUCLEOPHILIC ADDITION REACTIONS Scheme 50. Aryne Ene Reactions with Olefins The electrophilic nature of aryne species makes them excellent reaction partners with respect to a variety of nucleophiles. In a study carried out by Garg et al., they quantitatively determined the electrophilicity of benzyne by using the diffusion-clock method.357 This study revealed that benzyne is only 1 order of magnitude less electrophilic than bis(4-methoxyphenyl)methylium ion. More importantly, nucleophiles could trigger or initiate different modes of aryne transformations, such as nucleophilic addition/annulation reactions, insertion reactions, and multicomponent reactions. Among them, the primary reaction mode is nucleophilic addition to arynes, which includes a protonation on the vicinal position of the arene ring. In this transformation, arynes serve as efficient arylation synthons under transition-metal-free conditions. Therefore, it can be seen as an alternate to the prevailingly investigated transition-metal-catalyzed arylation strategies. Particularly, various nucleophiles, especially those with heteroatom and/ or inert ones, have been found to be efficient arynophiles, further underlining the merit of aryne arylation strategy. with an α,β-unsaturated cyclic ketone 4-176, affording compounds 4-177 in good to excellent yields (Scheme 50b).350 Moreover, an example of the aryne ene reaction with allene species was exhibited by Lee et al.351 In 2012, a distinct aryne heteroene reaction of N-substituted anilines was disclosed by Greaney and co-workers.352 After searching for solutions to prevent the competing N-arylation 3914 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR 5.1. N-Arylation Reactions Review conditions. Unsubstituted primary or N-alkyl amides, however, were inert under arylation conditions, which was reasoned by their weak nucleophilicity. In 2011, Lynch and co-workers reported an efficient N-arylation reaction on acetanilides 5-5 with o-silylaryl triflates (Scheme 53b).362 The reaction employed TBAT as the fluoride source, producing N-arylated products 5-6 in good to high yields. Furthermore, Jin et al. could solve the inactivity problem of N-alkyl amides by using N-alkoxy amides 5-7 as the substrates, which allowed a smooth formation of N-arylated products 5-8 with high functional group tolerance (Scheme 53c).363 Particularly, this arylation transformation exhibited a distinct chemoselectivity on Nalkoxy amides over other functionalized N−H bonds, such as N-Ac, N-Cbz, N-Boc, and even N-Ts moieties, when hydroxamic acids derived from N-protecting amino acids and peptides were utilized. It was reasoned that the presence of the N-alkoxy group results in a decreased pKa value on the amide N−H bond. In 2017, Shen, Xu, and co-workers reported that N-arylation of cyclic 2-benzoxazolinones (X = O) and 2-benzimidazolinones (X = NMe) 5-9 with arynes proceeded smoothly with no observation of aryne insertion into the N−CO bond on the substrates (Scheme 54a).364 Subsequently, Li, Wang, and co- Nitrogen is an efficient nucleophilic element in aryne chemistry, which is also one of the most investigated arynophiles with o-silylaryl triflates. In 2002, Yoshida, Kunai, and co-worker first demonstrated a N-arylation reaction of Nalkyl substituted imidazoles 5-1 with o-silylaryl triflates, affording N-alkyl-N′-arylimidazolium salts 5-2 in modest to good yields (Scheme 52).358 Scheme 52. N-Arylation Reactions with N-Alkyl Substituted Imidazoles Subsequently, Larock et al. systematically investigated the arylation reactions of o-silylaryl triflates with amines (R2 = aryl, alkyl), sulfonamides (R2 = R′SO2), carbamates (R2 = CO2Et), and benzamides (R2 = ArCO) (Scheme 53a).359,360 Depending Scheme 53. N-Arylation Reactions with Amides Scheme 54. N-Arylation Reactions with 2-Benzoxazolinone and Oxadiazolones on the stoichiometry of aryne precursors, either monoarylated products 5-3 or diarylated products 5-4 could be obtained in moderate to excellent yields. Moreover, Jung and co-workers found that the N-arylation reaction of aromatic amines with benzyne proceeded smoothly in the presence of either 2,5dimethoxytetrahydrofuran or 1,3-diacetone dicarboxylic acid.361 Different from the copper-mediated Ullmann reaction and the palladium-catalyzed Buchwald−Hartwig C−N coupling reaction, this method is under transition-metal-free workers showed that 3-aryl-1,2,4-oxadiazolones 5-11 underwent a facile N-arylation reaction with arynes, furnishing compounds 5-12 in good to excellent yields (Scheme 54b).365 In 2019, Shanmugam et al. investigated the reaction between (het)aryl amino amides 5-13 and o-silylaryl triflates and observed the chemoselective formation of N-monoarylated products 5-14 and N,N-diarylated products 5-15 on amine nitrogen with no observation of N-arylated products on amide nitrogen (Scheme 55a).366 They also applied this protocol in the preparation of triaryl amine derivatives, which are blue and red emissive with high quantum yields. In 2018, Nilsson and co-workers developed a unique N-arylation protocol on amino sugars 5-16 (Scheme 55b).367 In this study, both N-mono- and N,N-diarylated products 5-17 could be achieved by varying the stoichiometry of o-silylaryl triflates. Notably, unprotected carbohydrate amines showed excellent chemoselectivity, furnishing N-arylated products with no observation of the Oarylation reaction. In the presence of carbohydrate diamines, a selective N-monoarylation reaction could be manipulated. Tertiary amines can serve as efficient nucleophiles in arylation reactions. In 2013, Biju and co-workers demonstrated 3915 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review Isocyanates could serve as N-nucleophiles to react with arynes as well. In 2012, Hsieh and co-workers reported a double arylation protocol of isocyanates 5-22 with arynes. As shown in Scheme 57a, they found that both water and a Scheme 55. N-Arylation Reactions with Primary Amines Scheme 57. N-Arylation Reactions with Isocyanates a monoselective N-arylation reaction of aromatic tertiary amines, leading to the formation of diaryl amines 5-18 after demethylation (Scheme 56a).368 Ammonium bicarbonate was Scheme 56. N-Arylation Reactions with Tertiary Amines catalytic amount of pyridine derivatives were needed in order to reach high yields.371 Mechanistically, they proposed that pyridine could attack isocyanate 5-22 to generate zwitterion 524 first, which is followed by a nucleophilic addition to aryne to produce unstable carbamic acid 5-25 in the presence of water. Decarboxylation on intermediate 5-25 would occur to afford amine 5-26, which then undergoes the N-arylation reaction with a second aryne to give products 5-23. Similarly, Ko and co-workers developed both monoarylation372 and diarylation reactions373 on tosyl and aryl isocyanates (Scheme 57b). In these studies, they proposed that isocyanate hydrolysis takes place first to release primary amines before N-arylation. The N-arylation reaction with arynes turns out to be a general scenario with respect to various N-nucleophiles. In 2015, Yao reported an efficient N-arylation reaction with amidines 5-27 and N,N-disubstituted amidines 5-29, affording the corresponding N-arylated products 5-28 and 5-30, respectively (Scheme 58a).374 In the same year, Singh et al. revealed a N-arylation reaction by using NH-sulfoximines 5-31 as the substrates (Scheme 58b).375 There are two features for this transformation: (1) no aryne insertion into either the S O or SN bond was reported; (2) substrates with chiral centers could be tolerated under the reaction conditions. In 2017, Cheng, Zhai, and co-workers demonstrated a chemoselective N-arylation reaction of 2-aminopyridine derivatives 533 to produce compound 5-34, in which the pyridine nitrogen served as the sole nucleophile (Scheme 58c).204 In 2016, Mhaske et al. found that, in the presence of a catalytic amount of water, sodium nitrite could attack arynes and produce nitrobenzenes 5-35 (Scheme 59a).376 Subsequently, Cheng, Zhai, and co-workers employed Mitsunobu reagent 5-36 as the N-nucleophile to realize a N-arylation reaction with arynes, giving rise to arylhydrazides 5-37 in modest to high yields (Scheme 59b).377 Furthermore, diverse found to be the key additive for the success of this transformation. Moreover, no diarylation product was detected even in the presence of an excess amount of o-silylaryl triflates, which was reasoned by the delocalization of the lone pair electrons on nitrogen between two benzene rings after the first N-arylation reaction. Similar transformation was also realized by Ko et al. using N-methyl morpholine (5-19) as the nucleophile and obtained tertiary anilines 5-20 after demethylation (Scheme 56b).369 In 2016, Diesendruck and co-workers reported a straightforward N-arylation protocol with tertiary amines, affording various quaternary ammonium salts 5-21, such as trialkylaryl, dialkyldiaryl, triarylalkyl, and Nchiral ammonium salts (Scheme 56c).370 In this study, methanol was added as both the cosolvent and proton source to prevent Hoffman elimination. Although this transformation had a broad substrate scope, it was not applicable to triarylamines. 3916 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review 5.2. O-Arylation Reactions Scheme 58. N-Arylation Reactions with Other NNucleophiles In comparison with N-nucleophiles, there are limited examples of O-arylation transformations. Almost at the same moment with their N-arylation study, the Larock group investigated Oarylation reactions as well.360,378,396 In 2004, they reported facile O-arylation reactions on both phenols and aromatic carboxylic acids with arynes, affording the corresponding Oarylated products 5-40 and 5-41 in good to excellent yields with high functional group tolerance (Scheme 60a).396 Scheme 60. O-Arylation Reactions with Phenols and Carboxylic Acids Raminelli et al. applied this method in the O-arylation of sterically hindered 2,6-dihalophenols.397 In addition, Oarylation of phenols was also reported by other groups.398,399 Unfortunately, the Larock’s method was not applicable to both alcohols and aliphatic carboxylic acids at the moment. Until 2015, Chen, Zhang, and co-workers could solve this inactivity problem on aliphatic carboxylic acids. As shown in Scheme 60b, they noticed that sodium carboxylates, generated from NaOH and aliphatic carboxylic acids, have enhanced nucleophilicity over their acid form.400 Consequently, a combination of aliphatic carboxylic acid and its sodium salt in the reaction with arynes could furnish the corresponding products 5-42 along with a small amount of C−OH bond insertion products. The inactivity problem with alcohols was then solved by Biju and co-workers. In 2016, they found that under low reaction temperature (−20 °C), a number of linear, O-tethered, and branched aliphatic alcohols could all react with arynes to exclusively produce the corresponding O-arylated products 543 (Scheme 61a).401 In the presence of both tertiary and primary alcohols on the same substrate, selective arylation on the primary alcohol occurred. In this study, they also observed a temperature dependent reaction behavior, the details of which will be discussed in Scheme 140c. Recently, Mukherjee and co-workers demonstrated an intriguing O-arylation protocol of carbohydrates 5-44, which could furnish O-arylated products 5-45 selectively (Scheme 61b).402 Notably, this transformation prefers not only primary over secondary alcohols but also equatorial over axial ones. Besides, an uncommon O-nucleophile was also examined. In 2008, Kolomeitsev et al. applied trifluoromethanolate salt 5-46, readily prepared from trifluoromethyl triflate and 5-47, as a trifluoromethoxy group carrier in the reaction with Kobayashi benzyne precursor, affording both phenyl trifluoromethyl ether (5-48) and fluorobenzene (Scheme 61c).403 Scheme 59. N-Arylation Reactions with Sodium Nitrite and Mitsunobu Reagents nitrogen-containing heterocycles could be prepared through one-pot processes under either Fisher indole synthesis conditions or through condensation with 1,3-diones. They proposed that 1,3-zwitterion 5-38 should be first formed from Mitsunobu reagent 5-36 and PPh3, which then attacks aryne to produce 1,5-zwitterion 5-39. Upon protonation and removal of triphenylphosphine oxide, arylhydrazides 5-37 could be obtained. An alternative mechanistic pathway would be the generation of hydrazide first from 5-38 and water, which in turn attacks aryne to give 5-37. Moreover, these N-arylation protocols have become general methods with many synthetic applications.378−395 5.3. C-Arylation Reactions Carbon nucleophiles are quite different from heteroatom nucleophiles in arylation reactions with arynes, because aryne 3917 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review Scheme 63. Asymmetric C-Arylation Reaction of β-Enamino Esters Scheme 61. O-Arylation with Other O-Nucleophiles unprecedented study, C-arylated products 5-54 with stereodefined quaternary centers were obtained in up to 96% enantiomeric excess (ee) after hydrolytic workup. In addition, a one-pot transformation of a β-ketoester substrate to the corresponding arylated product was demonstrated. Chirality transfer from the N-bound chiral auxiliary to the final product was studied by their computations as well. Recently, another distinct asymmetric C-arylation reaction was achieved by Luo et al. by using electrochemical method to generate arynes from 1-aminobenzotriazoles, which will not be discussed here.408 This C-arylation strategy was further expanded to βdicarbonyl compounds, such as malonamide esters409 and secondary β-keto amides.410 In 2012, Mhaske and co-workers demonstrated that α-arylation of α-substituted/unsubstituted N-arylmalonamide esters 5-55 with o-silylaryl triflates could produce compounds 5-56 and 5-57 containing benzylic quaternary stereocenters (Scheme 64a).409 In particular, by using N-aryl-N-methyl malonamide ester as the substrate, only insertion into various carbon-based bonds, i.e., C−C and C− heteroatom bonds, has been well-known as the following step after nucleophilic addition of carbanions to arynes (see section 7). In order to prevent insertion reactions, a quick protonation operation is normally necessary, and the structure of the substrate plays an essential role for the selection of this reaction mode. In 2007, Ramtohul and co-worker disclosed that β-enamino esters/ketones 5-49 could readily participate in C-arylation reaction with arynes, affording a variety of substituted aromatic β-enamino compounds 5-50 in moderate to excellent yields (Scheme 62a).404 Particularly, there was no observation of Scheme 64. C-Arylation Reactions with β-Dicarbonyl Compounds Scheme 62. C-Arylation with β-Enamino Compounds both N-arylation and C−C bond insertion products on 5-49. Their deuterium-labeling experiments suggested that an intramolecular proton transfer is responsible for quenching the generated aryl anion after nucleophilic addition. Recently, Gogoi el al. applied this method in the C-arylation reaction of 4-aminocoumarins 5-51 and furnished 4-amino-3-arylcoumarin derivatives 5-52 (Scheme 62b).405 This protocol was also utilized by Cheng et al.406 Of particular interest was a recent achievement on asymmetric C-arylation of β-enamino esters 5-53 developed by Houk, Garg, and co-workers (Scheme 63).407 In this 3918 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR monoarylated products were observed. Meanwhile, Coquerel, Rodriguez, and co-worker reported a C-arylation reaction of secondary β-keto amides 5-58 with arynes, furnishing products 5-59 in good to excellent yields (Scheme 64b).410 The preferential formation of C-arylated products in this transformation was reasoned by the proper acidity of the N−H bond on secondary β-keto amides, which could interrupt the undesired C−C bond insertion reaction. In 2017, Mohanan et al. realized a decarboxylative C-arylation reaction of fluoromalonamates 5-60 (R1 ≠ t-Bu) with arynes, affording α-aryl-α-fluoroamides 5-61 in good to excellent yields (Scheme 64c).411 The employment of tert-butyl ester of fluoromalonamate 5-60 (R1 = t-Bu) could prevent the decarboxylation reaction and produced the arylated fluoromalonamates 5-62 instead. They reasoned that the decarboxylation step could be promoted by the increased electrophilicity of the α-carbon after arylation reaction. Other than β-keto amides, Chen, Du, and co-workers revealed that malonates 5-63 could also undergo a mono Carylation reaction with arynes to afford compounds 5-64, whereas other 1,3-diketone compounds preferred the C−C σbond insertion pathway (Scheme 64d).412 Although in Yoshida’s previous study, malonates were found to proceed through the C−C σ-bond insertion pathway with arynes,413 this different reactivity was reasoned by the employment of more acidic acetonitrile as the solvent, which could facilitate the protonation of aryl anion and yields the C-arylated products 5-64. Oxindoles were found to be suitable substrates for Carylation reactions. In 2016, Srihari, Mehta, and co-workers disclosed that 3,3-disubstituted oxindoles 5-66 and 5-67 could be obtained through C-arylation of oxindoles 5-65 with arynes at room temperature (Scheme 65a).414 It was also found that Review Based on a previous observation by Hu and co-workers, the introduction of phenylsulfonyl group on fluorinated carbanions could make them better nucleophiles. Consequently, they realized a nucleophilic fluoroalkylation of arynes with fluorobis(phenylsulfonyl)methane (5-68) furnished fluorobis(phenylsulfonyl)methylated arenes 5-69 in good to high yields (Scheme 65b).416 In 2018, Burtoloso and co-workers revealed that the C-arylation reaction of readily accessible βketosulfoxonium ylides 5-70 with arynes furnished α-aryl-βketosulfoxonium ylides 5-71, which could be further converted to α-aryl ketones after desulfurization (Scheme 65c).417 5.4. S-Arylation Reactions In their study on both N- and O-arylation reactions with osilylaryl triflates, Larock and co-worker also demonstrated two S-arylation examples by using arenethiols 5-72 as nucleophiles, furnishing diaryl sulfides 5-73 in good yields (Scheme 66a).360 Scheme 66. S-Arylation Reactions with Thiolates In addition, Kolomeitsev et al. showed that trifluoromethanethiolate salt, the TDAE2+2CF3S− (or Me4N+CF3S−)/CsF system, could serve as an S-nucleophile to attack benzyne and afforded phenyl(trifluoromethyl)sulfane (5-74) in 83% yield (Scheme 66b).403 In 2014, the groups of Mhaske418 and Singh419 independently reported a highly efficient S-arylation protocol of alkyl/ aryl sodium sulfinates with o-silylaryl triflates. In Mhaske’s study, they employed aryl/alkyl/heteroaryl sodium sulfinates 5-75 as the S-nucleophiles to react with arynes, furnishing diaryl sulfones, aryl alkyl sulfones, and aryl heteroaryl sulfones 5-76, respectively (Scheme 67a).418 Similar results were Scheme 65. Other C-Arylation Reactions Scheme 67. S-Arylation Reactions with Sodium Sulfinates under elevated temperature (90 °C), a C−C bond insertion reaction occurred, which will be discussed in Scheme 100b. In a study carried out by Shanmugam et al. on the reactivity of isatin-based Morita−Baylis−Hillman (MBH) adducts, they reported a similar C-arylation reaction with arynes, which contained a small amount of [3 + 2] spiroannulation products as well.415 obtained by Singh et al., where unsymmetrical biaryl sulfones, aryl vinyl sulfones, and aryl alkyl sulfones could be conveniently prepared (Scheme 67a).419 One difference between these two systems is the utilization of different fluoride sources. In 2018, Shibata and co-workers prepared trifluoromethanesulfonyl arenes 5-77, namely, aryl triflones, 3919 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR through a trifluoromethanesulfonylation of arynes with sodium trifluoromethanesulfinate (NaSO2CF3) (Scheme 67b).420 In this study, 15-c-5 was employed in order to increase the solubility of the sodium salts. In 2017, Peng et al. reported a mild protocol toward the preparation of triarylsulfonium salts 5-79 via an S-arylation reaction of diarylsulfides 5-78 with o-silylaryl triflates (Scheme 68a).421 This transformation furnished triarylsulfonium salts 5- Review Scheme 69. P-Arylation Reactions with Phosphines Scheme 68. S-Arylation Reactions with Other SNucleophiles Scheme 70. P-Arylation Reactions with Alkoxyphosphines affording aromatic oxophosphorus compounds 5-88 in good to excellent yields.135 Notably, steric repulsion played a determining role in terms of regioselective control in this study. Moreover, the deuterium labeling experiment suggested that the hydrated TBAF served as the proton source. In Mhaske’s study, they could readily prepare aryl phosphonates, aryl phosphinates, and aryl phosphine oxides from trialkyl phosphites, diethyl phenylphosphonite, and diphenylphosphinite, respectively (Scheme 70).426 In this work, the proton source was acetonitrile. In 2016, the P-arylation reactions of both dialkylphosphites and secondary phosphine oxides with arynes were realized independently by the groups of Chen427 and Zhang428 (Scheme 71). In Chen’s study, they could obtain dialkyl arylphosphonates and tertiary phosphine oxides 5-90 from 79 with high functional group tolerance. Meanwhile, Shen, Xu and co-workers demonstrated that the S-arylation reaction proceeded selectively and smoothly on cyclic 2-oxazolidinethiones 5-80 with arynes to afford S-arylated dihydrooxazoles 5-81 (Scheme 68b).364 Both the N-arylation reaction and aryne insertion into the thiocarbonyl group were not detected with these substrates. Recently, Yao, Tan, and co-workers revealed a chemoselective S-arylation reaction of thiooxindoles 5-82, affording 2-(arylthio)indolenines 5-83 in good to excellent yields (Scheme 68c).422 5.5. P-Arylation Reactions P-Nucleophiles were studied behind other nucleophiles with osilylaryl triflates. In 2010, Jugé et al. first realized a P-arylation reaction of phosphines with arynes, giving rise to both achiral and chiral quaternary phosphonium salts 5-84 (Scheme 69a).423 Particularly, when chiral phosphines were employed with either P-chirality or chirality on the carbon backbone, phosphonium triflates could be synthesized in an enantio- or diastereomerically pure form. In order to tune the physicochemical properties of 1,3-diphosphacyclobutane-2,4diyls, Ito and co-workers applied the P-arylation protocol onto both sterically encumbered 1-tert-butyl-424 and 1-amino-1,3diphosphacyclobuten-4-yl anions 5-85,425 which could afford the corresponding P-arylated products 5-86 (Scheme 69b). It was found that the incorporated aromatic substituent could influence the open-shell character of 5-86. Moreover, the potential of 5-86 as the HF detector was investigated. In 2013, the groups of Hosoya135 and Mhaske 426 independently reported a P-arylation reaction of various alkoxyphosphines 5-87 with o-silylaryl triflates (Scheme 70). In Hosoya’s study, they demonstrated a P-arylation protocol through the Michaelis−Arbuzov-type reaction with arynes, Scheme 71. P-Arylation with Dialkyl Phosphites and Secondary Phosphine Oxides 3920 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review 6. NUCLEOPHILIC ANNULATION REACTIONS Along with the studies on arylation reactions with o-silylaryl triflates, different types of nucleophile-induced aryne transformations have also been developed, affording various 1,2difunctionalized arenes. A step further from arylation protocols is to tether an electrophile (E) and a nucleophile (Nu) together with a linker, so that the generated aryl anion from nucleophilic addition to the aryne could react with the tethered electrophilic component intramolecularly (Scheme 73). In this dialkyl phosphites and secondary phosphine oxides 5-89, respectively, in good to excellent yields under mild conditions.427 The employment of Cs2CO3 was believed to both enhance the nucleophilicity of the substrate and increase the concentration of the P(III) form through tautomerization of the P(V) phosphinylidene (Scheme 71). Moreover, their deuterium labeling experiments suggested that trace amounts of water in hygroscopic CsF/Cs2CO3 served as the proton source. Meanwhile, Zhang and co-workers demonstrated that P-arylation of diarylphosphine oxides and dialkyl phosphites could furnish various arylphosphorus compounds in good to excellent yields (Scheme 71).428 Scheme 73. General Scheme for Aryne Nucleophilic Annulation Reactions 5.6. With B-Nucleophile In a study carried out by Takita, Uchiyama, and co-workers toward the preparation of borylzincate species 5-91 from dialkylzinc and diboron, they applied this borylzincate species 5-91 in the reaction with arynes, generated from o-haloiodobenzene. Among those substrates, they showed one example with Kobayashi benzyne precursor, giving rise to Barylated products 5-92 in 66% yield (Scheme 72a).429 way, an overall aryne annulation transformation could be realized through this sequential intermolecular nucleophilic addition/intramolecular bond-forming process. This section will be elaborated on based on the types of nucleophiles as well as the types of electrophiles. Scheme 72. Aryne Reactions with B- and F-Nucleophiles 6.1. With O-Nucleophiles The first nucleophilic annulation reaction of this type with osilylaryl triflates employed O-nucleophiles. In 2005, Larock and Zhao demonstrated that salicylates 6-1 (X = O) could participate in a tandem nucleophilic addition/electrophilic cyclization process with arynes to afford xanthones 6-2 in modest to high yields (Scheme 74a).436,437 Notably, the employment of CsF in THF could promote intramolecular cyclization over intermolecular proton abstraction. Moreover, methyl thiosalicylate 6-1 (X = S) could produce the corresponding thioxanthones as well. This method was recently utilized by Cichewicz et al.438 In 2009, Okuma and co-workers revealed that aldehyde could serve as an electrophile in this transformation. When salicylaldehydes 6-3 reacted with benzyne, both xanthenes 6-4 and xanthones 6-5 were obtained, whereas under basic conditions 9-hydroxyxanthenes 6-6 could be achieved in moderate to high yields (Scheme 74b).439 Mechanistically, xanthenes 6-4 and xanthones 6-5 are formed through disproportionation of 9-hydroxyxanthenes 6-6. To prevent a disproportionation reaction, Yuan, He, and coworkers employed 2-trifluoroacetylphenols 6-7 as the substrates and harvested trifluoromethylated xanthenes 6-8 in moderate to excellent yields with no observation of xanthenes and xanthones (Scheme 74c).440 N-tosylimines could also serve as electrophiles in this type of transformations. In this context, the groups of He441 and Lu442 independently reported an efficient preparation of 9-aminoxanthenes 6-10 from salicyl N-tosylimines 6-9 and arynes (Scheme 74d). Recently, Yoshida et al. disclosed that the reaction between S-(2hydroxyaryl) 4-toluenethiosulfonates 6-11 (X = O) and osilylaryl triflates could furnish phenoxathiins 6-12 (X = O) (Scheme 74e).443 Notably, the optimal conditions employed triglyme as an uncommon solvent, which was found to give higher yields than those in THF. In this study, they also demonstrated that phenothiazines could be obtained from S(2-aminoaryl) 4-toluenethiosulfonates 6-11 (X = NH). Michael acceptors were also employed as the electrophiles in this type of transformation. In 2010, Huang and Zhang demonstrated a nucleophilic addition/Michael addition process between 4-(2-hydroxyphenyl)but-3-(E)-en-2-one ana- 5.7. With F-Nucleophile Although arynes have been utilized as efficient synthons in many types of transformations, nucleophilic fluorination on aryne has been rarely reported using either Kobayashi’s method403 or other aryne generation methods.430−432 The reasons are both poor nucleophilicity of a fluoride ion and the reversibility of a fluorination reaction.433 In 2014, Ikawa, Akai and co-workers first achieved a highly efficient nucleophilic fluorination reaction using a modified Kobayashi’s method.434 In this study, they prepared 2-(trialkylsilyl)phenyl nonafluorobutanesulfonates 5-94 from 2-(trialkylsilyl)phenols 593 and nonafluorobutanesulfonyl fluoride (NfF). A strongly nucleophilic fluoride salt, Bu4NF(t-BuOH)4, was then added in one-pot fashion to afford fluoroarenes 5-95 in moderate to good yields (Scheme 72b).434 It was also found that fluorination with 3-silylbenzyne preferred a meta-selectivity, suggesting that solvation with fluoride ion might make it a bulkier nucleophile. Subsequently, they further enhanced the reaction efficiency by employing the microflow technique and reached higher yields than those under batch conditions.435 They reasoned that the highly efficient mixing under microflow conditions allows both quick fluoride addition and immediate protonation, hence, resulting in high reaction yields. 3921 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review 6.2. With N-Nucleophiles Scheme 74. Aryne Nucleophilic Annulation with ONucleophiles Although N-nucleophiles were employed behind O-nucleophiles, they have become the most investigated nucleophiles in this subfield of aryne chemistry. Along with the study on salicylates and thiosalicylates by Larock et al., they demonstrated that methyl 2-aminobenzoate derivatives 6-17 could proceed through a nucleophilic annulation reaction with arynes to afford acridones 6-18 (Scheme 76a).437 In 2009, the Scheme 76. Aryne Nucleophilic Annulation with NNucleophiles and Esters logues 6-13 and arynes, which could lead to the preparation of xanthenes 6-14 in moderate to excellent yields (Scheme 75a).444 Subsequently, Larock and co-workers reported a similar transformation with an expanded scope of substrates.445 In 2018, Mei, Shi, and co-workers investigated the reactivity of ortho-hydroxyphenyl-substituted para-quinone methides 6-15 with Kobayashi benzyne precursor, giving rise to xanthene scaffold 6-16 (Scheme 75b).446 Soon after this work, He et al. also reported the same transformation.447 groups of Larock448 and Ramtohul449 independently reported the reaction between indole-2-carboxylate esters 6-19 and arynes, which led to the formation of polycyclic indoleindolone ring systems 6-20 under mild conditions (Scheme 76b). Besides, Ramtohul disclosed that both pyrrole- and imidazole-2-carboxylate esters 6-21 could afford the corresponding polycyclic products 6-22 as well (Scheme 76c).449 In 2011, Okuma and co-workers revealed the preparation of 2phenylindolin-3-ones 6-24 from amino acid methyl esters 6-23 (Scheme 76d).450 Mechanistically, this transformation proceeds through a nucleophilic annulation reaction with an additional C-arylation reaction. In 2013, Argade and Vaidya reported an efficient transformation between substituted 1,3quinazolin-4-ones 6-25 and o-silylaryl triflates, furnishing fused quinazolinone scaffolds 6-26 in moderate to excellent yields (Scheme 76e).451 Notably, a variety of functional groups, such as ester, Weinreb amide, ketone, acid chloride, and α,βunsaturated ester, worked well as the electrophiles. Moreover, Scheme 75. Aryne Nucleophilic Annulation with ONucleophiles and Michael Acceptors 3922 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR they applied this method in the total syntheses of several bioactive quinazolinone-based natural products. This nucleophilic annulation protocol was also utilized by Chen et al. in their study.452 In 2011, Larock and Rogness reported that N-arylisatins 628 could be readily prepared from 2-oxo-2-(arylamino)acetates 6-27 and arynes in modest to excellent yields under mild conditions (Scheme 77).453 In this study, NaHCO3 was found Review Scheme 78. Aryne Nucleophilic Annulation with NNucleophiles and Ketones Scheme 77. Aryne Nucleophilic Annulation with 2-Oxo-2(arylamino)acetates Scheme 79. Formation of Indolines 6-39, Tetrahydroquinolines 6-41, and Benzimidazoles 6-43 to be necessary and served as the optimal base to promote this transformation. As shown in Scheme 77, two plausible reaction pathways were proposed after nucleophilic addition: (1) direct annulation via intermediate 6-29 (path a); (2) C−N σ-bond insertion through four-membered ring intermediate 6-30 and annulation on 6-31 (path b). Singh et al. also reported the same transformation promoted by heterogeneous catalysts under microwave irradiation.454 α-Aminoketones and their analogues were utilized in this type of transformation as well. In 2013, Zhu et al. demonstrated that N-aryl-α-aminoketones 6-32 could react with arynes through a successive nucleophilic addition/ annulation/dehydration process, affording N-aryl-2,3-disubstituted indoles 6-33 in moderate to high yields (Scheme 78a).455 This transformation is regiospecific, which is in contrast with the classic Bischler−Möhlau reaction that usually gives a mixture of two regioisomers. Similar transformations were also studied by other groups.456,457 In 2014, Zhu and co-workers employed this nucleophilic annulation protocol in an efficient preparation of 5,6-dihydroindolo[1,2-a]-quinolines 6-35 from 2-acyl substituted tetrahydroquinolines 6-34 (Scheme 78b).458 These 2-acyl substituted tetrahydroquinolines were readily synthesized through a Lewis acid-catalyzed three-component Povarov reaction of α-oxo aldehydes, anilines, and dienophiles. Recently, Dai, He and co-workers reported a nucleophilic annulation reaction between carbocyclic β-aminoketones 6-36 and arynes, furnishing hexahydrophenanthridines 6-37 in modest to high yields (Scheme 78c).459 In 2014, He, Dai and co-workers revealed that the dehydration step could be prohibited by avoiding acidic workup in the transformation with α-aminoketones. When αaminoketones 6-38 were employed to react with arynes, multisubstituted indolines 6-39 could be obtained with synselectivity (Scheme 79a).460 In the cases with β-aminoketones 6-40, N-aryl tetrahydroquinolines 6-41 were achieved with anti-selectivity. In 2018, Song et al. realized a convenient preparation of N-heterocyclic benzimidazoles 6-43 from benzimidazole derivatives 6-42 via the nucleophilic annulation protocol (Scheme 79b).461 When indole and indazole scaffolds were used, a strong base Cs2CO3 was employed to replace K2CO3 in order to ensure the success of the reactions. In 2012, Larock and co-workers reported two aryne annulation approaches, both of which combined N-nucleophiles with accompanying imine electrophiles (Scheme 80).462,463 They first employed 2-substituted pyridines to realize a nucleophilic annulation reaction with arynes. When imines 6-44 generated from 2-pyridinecarboxaldehyde were treated with arynes, N-aryl-2-pyrido[1,2-a]indoles 6-45 were obtained (Scheme 80a).462 Mechanistically, this transformation involves a sequential N-nucleophilic addition, cyclization with imine, and N-arylation with a second molecule of aryne. 3923 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review unsubstituted indole 6-49 (path a) or to carbon to give intermediate 6-52 (path b). At 60 °C, 1,3-hydrogen shift could occur on 6-52 to produce 6-49; whereas at −10 °C, an aryne ene reaction would convert 6-52 to N-arylindole 6-50. Michael acceptors were employed as annulation partners associated with N-nucleophilic addition. In 2008, Stoltz and co-workers first demonstrated a protocol toward convenient preparation of functionalized indolines 6-54 by using N-Bocprotected dehydroalanine esters 6-53 (Scheme 82a).331 TBAT Scheme 80. Aryne Nucleophilic Annulation with NNucleophiles and Imines Scheme 82. Aryne Nucleophilic Annulation with NNucleophiles and Michael Acceptors In this study, they also achieved a one-pot three-component transformation of 2-pyridinecarboxaldehyde, t-BuNH2, and Kobayashi benzyne precursor, affording the same product in good yield. Meanwhile, they demonstrated that 1-methyl-1Hindazoles 6-47 could be obtained in modest to high yields from o-silylaryl triflates and 1,1-dimethylhydrazones 6-46 (Scheme 80b).463 Two preparation procedures were employed in order to reach 6-47: (1) a one-pot NCS-chlorination/aryne annulation (condition A) and (2) an Ac2O-acylation/ deprotection/aromatization process (condition B). In 2016, Biju et al. studied the reactions between 2H-azirines 6-48 and arynes and disclosed a temperature-dependent reaction behavior (Scheme 81). 464 In this study, NScheme 81. Aryne Nucleophilic Annulation with 2HAzirines was found to be an ideal fluoride source in this transformation. Subsequently, Huang and Zhang treated anilines 6-55 containing an α,β-unsaturated ketone moiety on the ortho position with arynes and obtained 9-functionalized acridines 656 (Scheme 82b).444 Along with the study on the aryne nucleophilic annulation reaction using N-pyridin-2-yl-methanimines as the substrates, Larock et al. also examined the reaction of 2-(pyridin-2-yl-methylene)malonates 6-57 with arynes, which could yield pyrido[1,2-a]indole derivatives 6-58 (Scheme 82c).462 In 2017, Sedalia et al. demonstrated a highly diastereoselective synthesis of chiral 2,3-disubstituted indolines 6-60 from γ-amino-α,β-unsaturated esters 6-59, which could be readily prepared from α-amino acids (Scheme 83a).465 A similar work was also reported by Ikawa, Akai, and co-workers.466 Meanwhile, She and co-workers accomplished an efficient synthesis of indole-fused hydrocarbazoles 6-62 through a formal [3 + 2] annulation reaction of protected p-quinamines 6-61 and o-silylaryl triflates (Scheme 83b).467 Notably, when 4 Å molecular sieves (4 Å MS) were used as the additive, the reaction could reach the highest yield. In 2018, Mhaske and Pandya reported a transformation between carbamoylpropiolates 6-63 and arynes, which could produce various (E)oxindolylidene acetates 6-64 with high functional group tolerance (Scheme 83c).468 unsubstituted 2,3-diarylindoles 6-49 were preferentially formed at 60 °C; whereas at −10 °C, the selectivity switched to the formation of 1,2,3-triarylindoles 6-50. Mechanistically, they proposed that after a formal [2 + 2] cycloaddition reaction of aryne with the CN bond to construct intermediate 6-51, a 1,2-hydrogen shift takes place either to nitrogen to produce N- 6.3. With C-Nucleophiles In Stoltz’s study on the preparation of functionalized indolines from N-Boc protected dehydroalanine esters, they disclosed that a simple modification on dehydroalanine esters 6-65 from 3924 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review 72 in moderate to good yields (Scheme 85a).470 In addition, Shanmugam et al. also observed the formation of small Scheme 83. Other Reactions with N-Nucleophiles and Michael Acceptors Scheme 85. Aryne Nucleophilic Annulation with Other CNucleophiles N-Boc to the N-acyl group could efficiently furnish polyfunctionalized isoquinolines 6-66 (Scheme 84a).331 amounts of spiroannulation products along with the Carylation products when isatin based Morita−Baylis−Hillman (MBH) adducts reacted with arynes.415 In 2016, He and coworkers disclosed that carbazolequinones 6-74 could be obtained in moderate to high yields through a nucleophilic annulation reaction of 2-amino-1,4-naphthoquinones 6-73 with arynes (Scheme 85b).471 Primary amines worked better than secondary amines, whereas tertiary amine did not react at all. Mechanistically, this transformation was proposed to proceed through a sequential C-nucleophilic addition to generate intermediate 6-75/addition of aryl anion to iminium nitrogen to produce 6-76/oxidative dehydrogenation process. They reasoned that the electron-withdrawing ability of naphthalenedione makes the iminium nitrogen electrophilic, although there might be other possibilities. Scheme 84. Aryne Nucleophilic Annulation with Dehydroalanine Esters and N-(1-Arylvinyl)acetamides 6.4. With S- and Se-Nucleophiles Sulfur is a less investigated nucleophile in aryne chemistry, which is usually accompanied by the study on O-nucleophiles. In Larock’s early study on O-nucleophilic annulation protocol, they also showed examples with respect to S-nucleophiles (Scheme 74a).436,437 In 2006, Okuma et al. investigated the reactivity of 3,3-di-tert-butylthiirane-2-thione (6-77) with Kobayashi benzyne precursor and obtained an annulation product 2-(2,2,4,4-tetramethylpentan-3-ylidene)benzo[d][1,3]dithiole (6-78) in 90% yield via intermediate 6-79 (Scheme 86a).472 Subsequently, the same group examined the chemical behavior of 5-isopropylidene-4,4-dimehtyl-1,2dithiolane-3-thione (6-80) and found that this compound could react with benzyne to generate benzo-1,3-dithiole 6-81 in 85% yield, the mechanistic pathway of which experiences the formation and recombination of a betaine intermediate 6-82 (Scheme 86b).473 In 2015, Werz and co-workers prepared a series of amphiphilic benzodithioloimines 6-83 containing both positively and negatively polarized sulfur (Scheme 87).474 When these benzodithioloimines 6-83 reacted with arynes, thianthrene derivatives 6-84 were achieved in modest to excellent Mechanistically, the overall process involves a sequential Cnucleophilic addition of enamine to aryne to produce 6-67/ annulation/dehydrative aromatization on intermediate 6-68. Moreover, they applied this methodology in the total synthesis of opiate alkaloid papaverine. Similar work was also reported by Ramtohul et al.332 In a study carried out by Guan and coworkers on the coupling reaction of N-(1-arylvinyl)acetamides 6-69 with alkynes and arynes, they reported a facile construction of isoquinolines 6-70 as well (Scheme 84b).469 In 2017, Srihari, Mehta, and co-workers realized a spiroannulation reaction between substituted N-methyl-3(carbethoxymethyl)oxindoles 6-71 and arynes, which could produce the corresponding indano-spirooxindole scaffolds 63925 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 86. Aryne Nucleophilic Annulation with SNucleophiles Review Scheme 88. Aryne Nucleophilic Annulation with SeNucleophiles the OAc group by the generated aryl anion might be possible to account for the formation of 6-87. 6.5. With P-Nucleophiles Recently, Tobisu and co-workers revealed a unique dearylative annulation process between triarylphosphine 6-90 and arynes.477 As shown in Scheme 89, a pentacoordinated Scheme 89. Aryne Nucleophilic Annulation with PNucleophiles Scheme 87. Aryne Nucleophilic Annulation with Benzodithioloimines tetraarylfluorophosphorane 6-91 was first produced through a sequential nucleophilic addition of triarylphosphine 6-90 to aryne and an intramolecular SNAr reaction on an aryl fluoride moiety. Subsequent dearylation reaction from fluorophosphorane 6-91 could furnish fluorinated dibenzophosphole derivatives 6-92 in a convergent manner. yields. Furthermore, benzo[d]pyrrolo[2,1-b]thiazole was obtained in moderate yield from 2-thiocyanatopyrrole and the Kobayashi benzyne precursor. Mechanistically, this transformation proceeds through a S-nucleophilic addition to benzyne with concomitant opening of the dithioloimine ring to generate intermediate 6-85, which is followed by cyclization on the electrophilic sulfur bearing the newly generated nitrile group to afford thianthrene 6-84. In 2002, Biehl et al. investigated the reaction between Barton esters and arynes. Following their early study on Barton esters with arynes generated from anthranilic acids,475 they reported a reaction between acetic acid 2-selenoxo-2H-pyridin1-yl esters 6-86, namely, Barton 2-selenoxo esters and arynes generated from different precursors (Scheme 88).476 Among them, the reactions with o-silylaryl triflates could afford benzo[b]seleno[2,3-b]pyridines (6-87) in moderate yields. Based on their study, an unprecedented mechanism involving single electron transfer (SET) was proposed: selenium atom attacks aryne via SET produces radical adduct 6-88, which would then undergo annulation reaction to generate intermediate 6-89. Product 6-87 could be obtained after aromatization. Despite this mechanistic pathway proposed by Biehl, an alternative mechanism via a sequential Senucleophilic addition to aryne and SN2′-type displacement of 7. INSERTION REACTIONS When a nucleophile and an electrophile are covalently bonded via either single or double bond, aryne insertion into this covalent bond is a natural extension to nucleophilic aryne transformations under transition-metal-free conditions. A wide range of σ- and π-bonds could be “inserted” by arynes, those of which include C−C, C−heteroatom, and heteroatom− heteroatom bonds. Normally, this type of transformations proceeds through either a four-membered ring transition state or direct 1,3-migration of the covalently bonded electrophile after nucleophilic addition on arynes (Scheme 90). With the extensive employment of Kobayashi’s method, since early 2000, aryne insertion reaction has become a convenient means in preparing a broad spectrum of vicinal difunctionalized arenes.91,478 This section will be divided by the types of Scheme 90. General Scheme for Aryne Insertion Reactions 3926 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR chemical bonds that could be “inserted” by aryne intermediates. Review Scheme 92. Aryne Insertion into the C−N σ-Bond of Amides 7.1. Insertion into C−N σ-Bonds The first type of σ-bond inserted by arynes, generated from osilylaryl triflates, was the N−CO σ-bond of substituted ureas. In 2002, Shirakawa, Hiyama, and co-workers disclosed that arynes could insert into the N−CO bond of ureas 7-1 under transition-metal-free conditions (Scheme 91).479 Various 1,4Scheme 91. Aryne Insertion into the C−N σ-Bond of Ureas benzodiazepines, 1,5-benzodiazocines, and 2-aminobenzamides 7-2 were readily achievable in this transformation, some of which are otherwise hardly accessible through conventional methods. Moreover, when substituted arynes, such as 3-methoxybenzyne, 3-phenylbenzyne, and 1,2-naphthalyne, were utilized, excellent regioselective control was observed. Mechanistically, this transformation involves a first nucleophilic addition of the urea nitrogen to aryne, which is followed by an intramolecular aryl anion cyclization to form a four-membered ring intermediate 7-3. After ring-opening, the insertion products 7-2 could be obtained. Recently, Ikawa, Akai, and co-workers also applied this protocol in the reaction between N-(p-toluenesulfonyl)imidazolidin-2-ones and 3-triflyloxybenzynes, giving rise to the C−N insertion product in a highly regioselective manner.480 This outstanding discovery by Shirakawa and Hiyama commenced a new research direction in aryne chemistry, namely, aryne insertion reactions. In 2005, Larock and Liu demonstrated that arynes could insert into the C−N bond of N-aryltrifluoroacetamides 7-4 under transition-metal-free conditions, furnishing vicinal difunctionalized arenes 7-5 in moderate to high yields (Scheme 92a).481 Two plausible pathways were proposed and the difference between them resides in the nucleophile, either an anionic nitrogen or a neutral one. This method, however, was restricted by the fact that only the C−N σ-bond of trifluoacetyl-protected anilines could be inserted. In 2014, Yamazaki and co-workers employed this method in a double C−CN bond insertion of pphenylenebis(perfluoroalkanamides) by benzyne, where the perfluoroalkyl group can be either CF3 or C2F5.482 The restriction on trifluoacetyl-protected anilines in Larock’s study was then broken by Greaney et al. in 2010, whereby the N− CO bond of both pivoloyl (piv)- and benzoyl-protected anilines 7-6 could be inserted by arynes, giving rise to aminobenzophenones 7-7 in good to excellent yields (Scheme 92b).483 In this study, biologically active acridones and acridines were then prepared in a one-pot fashion. In 2016, Stoltz and co-workers further expanded the substrate scope for C−N σ-bond insertion to acetylacetamide analogues 7-8 and afforded products 7-9, which were capable of undergoing further conversion to prepare quinolones, indoles, and ketoanilines (Scheme 93a).484 In an aim to Scheme 93. Aryne Insertion into the C−N σ-Bond of Imides readily prepare 3,4-dioxygenated quinolin-2-one natural products, Heretsch, Christmann, and co-workers examined Stoltz’s method by treating arynes with unsymmetrical imides 7-10 (Scheme 93b).485 Conventional methods, however, only afforded the C−N insertion product 7-11 in low yields. By applying the flow process in this transformation, the reaction yields were significantly enhanced. Consequently, a family of quinolinone alkaloids could be readily prepared (see section 14). Beside these previous achievements on aryne insertion into the C(sp2)−N bonds of ureas, amides, and imides, Jones et al. recently accomplished a formal aryne insertion reaction into the C(sp3)−N bond of 1,3-diaza-heterocycles 7-12, which led to the construction of benzofused medium-ring N-heterocycles 7-13 (Scheme 94).486 This transformation proceeds through a sequential N-arylation with aryne to generate zwitterion 7-14 that is in equilibrium with a ring-opened form 7-15 and an 3927 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review reported a similar work on aryne insertion into the C−C σbond of β-dicarbonyl species 7-18 to produce 7-19 (Scheme 95b).413 Applications on this β-dicarbonyl approach were then reported.412,490,491 These two early studies stimulated an active field of aryne insertion reaction with the construction of two C−C bonds. Langer could utilize this method to prepare various fluorinated 1,5-dicarbonyl compounds from fluorinated 1,3-dicarbonyl substrates.492 Phthalazines were prepared through a three-step sequence of aryne C−C bond insertion/diazo transfer reaction/Diaza−Wittig reaction.493 2,3-Benzodiazepines were constructed via a one-pot, two-step process, which led to the syntheses of biologically active molecules, such as tofisopam, girisopam, and nerisopam.494 Beside β-dicarbonyl species as effective substrates for C−C σ-bond insertion, variations on different substrate frameworks were then explored as well. In 2005, Yoshida, Kunai, and coworkers revealed an aryne insertion into the C−C σ-bond of αcyanocarbonyl compounds 7-20, furnishing compounds 7-21a in moderate to excellent yields along with small amount of further C-arylation products 7-21b (Scheme 96a).495 In 2007, Scheme 94. Aryne Insertion into the C−N σ-Bond of 1,3Diaza-heterocycles intramolecular cyclization to afford benzofused N-heterocycle 7-13. 7.2. Insertion into C−C σ-Bonds Although carbon−carbon σ-bond insertion of dimethylmalonate by aryne was first achieved by Shair and Danishefsky in their total synthesis of dynemicin A,487,488 the harsh aryne generation conditions by treating aryl bromide with lithium tetramethylpiperidide (LiTMP) restricted the application of this protocol. Since the first employment of o-silylaryl triflates in C−C σ-bond insertion transformations independently by the groups of Stoltz489 and Yoshida/Kunai,413 it has become the most studied as well as broadly applied insertion protocol in aryne chemistry. In general, a key factor for the success of this aryne transformation is the effective formation of carbanion nucleophiles from activated C−H bonds by electron-withdrawing groups. In 2005, Stoltz and co-workers first demonstrated that an acyl-alkylation of aryne occurred on β-ketoesters 7-16 via a σbond insertion event, giving rise to 7-17 in moderate to excellent yields (Scheme 95a).489 This transformation is mild and highly efficient with a broad substrate scope, allowing the concomitant formation of two new C−C bonds in one operation. Distinctively, benzannulated skeletons were readily achieved from cyclic β-ketoesters through a ring-expansion operation. Subsequently, Yoshida, Kunai, and co-workers Scheme 96. Aryne C−C Bond Insertion with NitrileContaining Molecules Scheme 95. Aryne Insertion into the C−C σ-Bond of βDicarbonyl Compounds the same group accomplished double aryne insertion cascade processes from either α-Ts nitrile or dinitrile compounds 7-22, which led to the formation of diarylmethane skeleton 7-23 through a sequential C−CN bond insertion/C-arylation via intermediates 7-24 and 7-25, respectively (Scheme 96b).496 Recently, Wang and co-workers demonstrated that aryne alkylcyanation could take place with N,N-disubstituted aminomalononitriles 7-26, giving rise to 2-substituted benzonitriles 7-27 in moderate to high yields (Scheme 96c).497 β-Keto sulfones were found to be suitable substrates for this C−C bond insertion protocol as well. In 2008, the groups of Huang498 and Hu416 independently demonstrated that β-keto sulfones 7-28 could participate in aryne insertion reaction to 3928 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review 39 were obtained by Mhaske et al. from α-SCF3 ketones 7-38 (Scheme 98c).503 Notably, all the aforementioned C−C σ-bond insertion reactions require two strong EWGs in order to enhance the acidity of the target C−H bond and, consequently, permit the generation of the corresponding carbanion. Beyond these successes, efforts have also been tried by employing substrates bearing a less acidic C−H bond for C−C bond insertion reactions. In this context, Yoshida and co-workers disclosed that compounds 7-41 could be achieved via acylfluorenylation of arynes from fluorene derivative 7-40 (Scheme 99a).504 This afford compounds 7-29 through a preferential C−C bond insertion reaction (Scheme 97a). In Hu’s study, 2-fluoro-2Scheme 97. Aryne Insertion into the C−C σ-Bond of β-Keto Sulfones Scheme 99. Aryne C−C Bond Insertion with 2-Aryl Ketones (phenylsulfonyl)acetophenone (7-30) was employed to produce acyl-fluoroalkylated arenes 7-31 in good to high yields (Scheme 97a).416 This method was also utilized in a study by Hammond and Xu.499 Later in 2009, Huang et al. disclosed an aryne insertion into the C−C σ-bond of αsulfonyl cyclic ketones 7-32, delivering medium- and largesized benzannulated cyclic ketones 7-33 (Scheme 97b).500 In 2009, Liang, Li and co-workers reported an aryne C−C bond insertion into β-ketophosphonates 7-34, leading to the formation of o-acylbenzylphosphonates 7-35 that could be further elaborated on to afford olefins via the Wittig reaction (Scheme 98a).501 Recently, aryne insertion into the C−C bond of α-nitroketones 7-36 was realized by Zheng et al. to afford 2nitromethyl aromatic ketones 7-37 (Scheme 98b).502 In 2017, o-methyl trifluoromethyl sulfide substituted benzophenones 7Scheme 98. Aryne C−C Bond Insertion with Substrates Containing Heteroatom EWGs reaction was made possible by the aromatic stabilization ability of fluorenyl anion 7-42 after deprotonation. In 2011, the same group disclosed that benzyl trifluoromethyl ketones 7-43 could serve as suitable substrates for C−C σ-bond insertion reaction as well, giving rise to compounds 7-44 (Scheme 99b).505 It was found that the acidity of the benzylic C−H bond could be sufficiently enhanced by using the CF3 group. In 2016, Zeng et al. revealed that 2-benzylphenyl ketones 7-46 could be readily accessed via aryne C−C bond insertion reaction on 2phenylacetophenones 7-45, the transformation of which was promoted by the electron-deficient aryl group on the substrate (Scheme 99c).506 In 2016, Zeng and co-workers unraveled a ring expansion reaction via aryne insertion into the C−C σ-bond of α-aryl cycloketones 7-47, where products 7-48 containing mediumsized rings could be readily synthesized (Scheme 100a).507 Two types of product skeletons could be obtained, depending on the position of the α-aryl group, either imbedded in or attached outside of the cycloketone ring. Meanwhile, in a study carried out by Srihari and Mehta on C-arylation of oxindoles 3929 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 100. Aryne C−C Bond Insertion with α-Aryl Cycloketones Review Scheme 102. Aryne C−O Bond Insertion with Epoxides and Oxaziridines with arynes, they disclosed a temperature-controlled C−C σbond insertion transformation on 7-49, constructing dibenzo[b,e]azepin-6-one derivatives 7-50 under elevated temperatures (Scheme 100b).414 Moreover, they developed a concise synthesis toward potent antiulcer agent darenzepine. Although 2-arylacetates are inert due to the reduced acidity of the benzyl C−H bond, Chandrasekhar and co-workers revealed that both N-tosylacetimidates (X = O) and Ntosylacetimidamides (X = NH) 7-51 could serve as effective substrates for the aryne C−C σ-bond insertion reaction to produce compounds 7-52 (Scheme 101).508 In addition, the employment of cyclic 2-sulfonyliminoindolines 7-53 furnished either the ring-expansion product 7-54 or the arylation product, depending on the solvent.508 Mechanistically, this transformation proceeds through intermediates 7-62 and 7-63. Cyclization on 7-63 produces 7-60 (path a); whereas intramolecular 1,4-hydrogen migration affords 7-61 (path b). Although carboxylic acid has been known to normally participate in the O-arylation reaction with arynes,396 aryne insertion into the C−O σ-bond of carboxylic acids 7-64 was realized by Larock et al. to construct o-hydroxyaryl ketones 765 in modest to high yields (Scheme 103).512 Subsequent Scheme 101. Aryne C−C Bond Insertion with NTosylacetimidamides and Cyclic 2-Sulfonyliminoindolines Scheme 103. Aryne C−O Bond Insertion with Carboxylic Acids 7.3. Insertion into C−O σ-Bonds In comparison with aryne insertion into the C−N and C−C σbonds, there are limited examples on the C−O σ-bond insertion. In 2007, Peña and co-workers reported a selective aryne insertion into the C−O bond of styrene oxide (7-55) (Scheme 102a).509 Although this study proved the feasibility of aryne insertion into the σ-bond of strained epoxides, the low yield of 7-56 associated with several side-products impeded its further application. In 2010, Larock and Kivrak reported an aryne insertion into the C−O bond of oxaziridines 7-57, furnishing dihydrobenzisoxazoles 7-58 with high functional group tolerance (Scheme 102b).510 In this study, they ruled out the possibility of aryne 1,3-dipolar cycloaddition reaction with the in situ generated nitrone intermediates via isomerization of oxaziridines. In 2018, Vankar and Dubbu applied aryne insertion reaction on 1,2-anhydrosugars 7-59 and achieved both 1,2-dihydrobenzofuran-fused C-aryl glycosides 7-60 and C2-O-phenolic glycals 7-61 (Scheme 102c).511 transformation on in situ generated phenolate anion could give rise to xanthones, 4-chromanones, and flavones.513 The keys for the success of this transformation reside in high reaction temperature (125 °C), dilute reaction media, and an excess amount of aryne and CsF. 7.4. Insertion into Other σ-Bonds Aryne insertion into other element−element σ-bonds has shown to be a convenient and highly diverse approach to incorporate various elements as well as substituents on the arene ring. In 2005, Yoshida, Kunai, and co-workers reported an aryne insertion into the C−P bond of cyanomethyldiphenylphosphine oxide (7-66a) (R1 = CN) and harvested compounds 7-67 (Scheme 104a).514 By employing ethyl (diphenylphosphinyl)acetate (7-66b) (R1 = CO2Et) as the substrate, two products via aryne insertion into either the C−P bond or the C−C bond of 7-66b were obtained in a 1:1 ratio. 3930 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 104. Aryne Insertion into Carbon-Based σ-Bonds Review Scheme 105. NHC-Catalyzed Aryne Insertion into the C−H Bond of Aldehydes Subsequently, the same group developed two types of aryne insertion reactions into carbon−halogen σ-bonds. In 2007, they disclosed that aryne could insert into the C−X (X = Cl, Br) bond of acid halides 7-68 to afford compounds 7-69, where both aryl and aliphatic acyl functional groups were found to be effective (Scheme 104b).515 Moreover, this transformation was highly regioselective when substituted aryne precursors were employed. In 2009, they exhibited that aryne could insert into the C−Cl bond of dichlorotriazines 770 to produce 7-71, albeit in low to moderate yields (Scheme 104c).516 In 2010, a prominent N-heterocyclic carbene (NHC)catalyzed formal insertion of aryne into the Cformyl−H bond of aldehydes was achieved by Glorius and Biju.517 As shown in Scheme 105, after screening for different NHC precursors, they identified catalyst 7-72 as an ideal carbene precursor. Products 7-73, such as benzophenones, α,β-unsaturated ketones, and other aryl ketones, were readily achievable via this aryne hydroacylation protocol. Mechanistically, they proposed that the generated Breslow intermediate 7-74 attacks aryne to produce alkoxide intermediate 7-77 through either Carylated intermediate 7-75 or a concerted transition state 7-76, which could then realize the formation of products 7-73 along with regeneration of the NHC catalyst 7-72. In 2017, Xu et al. reported that aryl triflones 7-79 could be achieved via an aryne insertion into the C−S bond of CF3SO2containing carbon nucleophiles 7-78 (Scheme 106a).518 Electron-withdrawing substituents on the aryl group of the substrates were necessary for this transformation. In addition, β-triflyl esters could work as well, albeit in low yields. Recently, Mhaske and co-workers demonstrated that aryne could insert into the C−S σ-bond of sulfonium ylides to afford osubstituted thioanisole derivatives 7-80 (Scheme 106b).519 Although both ketone and nitrile groups were effective electron-withdrawing groups on sulfonium salts to promote this reaction, the ester group was found to be inert. Aryne insertion into nitrogen-based σ-bonds has also been intensively investigated, the success of which is mainly attributed to the high nucleophilic character of nitrogen Scheme 106. Aryne Insertion into C−S σ-Bonds nucleophiles. In 2005, Yoshida, Kunai, and co-workers reported a facile insertion reaction of arynes into the N−Si bond of aminosilanes 7-81, which could afford 2-silylanilines 782 (Scheme 107a).520 Notably, the silyl groups on the 2silylaniline products 7-82 could not be further removed by fluoride ion in the reaction. In 2013, Wang et al. demonstrated that o-haloaminoarenes 7-84 were obtained through a one-pot protocol by inserting arynes into the N-halogen bond of the in situ generated N-haloamines 7-83 (Scheme 107b).521 Their mechanistic study revealed that, after nucleophilic addition to aryne by 7-83, an aryl radical might partially account for the formation of 7-84.522 In 2013, aryne N−P bond insertion was realized by Zhang and co-workers, in which N-aryl diphenylphospinic amides 7-85 served as effective substrates and the products 7-86 could be potentially utilized as bidentate aminophosphine ligands (Scheme 107c).523 Subsequently, this protocol was applied in the P−N bond insertion of enantiopure P-stereogenic diarylphosphinic amides with retention of the configuration at the P-center.524 In 2014, Zeng and Rao realized an aminocyanation reaction through 3931 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 107. Aryne Insertion into Nitrogen-Based σ-Bonds Review Notably, trifluoromethyl group was found to be essential for the efficient construction of products 7-92. Recently, Biju and co-workers revealed that aryne can insert into the S−N σ-bond of sulfenamides 7-93, giving rise to 2-sulfanylanilines 7-94 (Scheme 108b).527 Mechanistically, N-nucleophile on 7-93 attacks aryne first, which is followed by a 1,3-migration of Smoiety to the ortho position of the nitrogen substituent. This study was also applied in a convenient preparation of antidepressant drug vortioxetine. Sulfur can serve as a nucleophile, leading to aryne insertion reactions into S-based σ-bonds. In 2004, Yoshida, Kunai, and co-workers demonstrated that aryne insertion into the S−Sn bonds of stannyl sulfides 7-95 proceeded smoothly to produce compounds 7-96 (Scheme 109a).528 Moreover, Murafuji and Scheme 109. Aryne Insertion into Other Sulfur-Based σBonds aryne insertion into the N−CN σ-bond of N-aryl cyanamides 7-87, producing 2-aminobenzonitriles 7-88 with broad substrate scope (Scheme 107d).525 Later, Wang and Chen disclosed that aryne could efficiently insert into the N−OH bond of hydroxyindolinones 7-89 to afford sterically congested 2-aminophenols 7-90 (Scheme 107e).526 They reasoned that the structural rigidity of the substrates could prohibit a competing [3,3]-sigmatropic rearrangement reaction, the process of which was observed by using N-hydroxyindoles. Along with the study on aryne insertion into N−COCF3 bond, Larock et al. also accomplished an insertion reaction into the N−SOCF3 bond of compounds 7-91 (Scheme 108a).481 Chen applied aryne insertion protocol on the S−Bi σ-bond of 7-97, furnishing o-arylthio triarylbismuthanes 7-98 (Scheme 109b).529 In 2017, 1,2-bis(trifluoromethylthio)arenes 7-100 were obtained from bis(trifluoromethyl)disulfide 7-99 by Daugulis and Mesgar via an aryne S−S bond insertion pathway (Scheme 109c).530 Similarly, selenium-based σ-bonds could be inserted by arynes as well. In 2007, Raminelli et al. reported a direct benzyne insertion into the Se−Se bond of 7-101, affording o-bis(organochalcogenide)benzenes 7-102 in modest to good yields (Scheme 110a).531 Subsequently, the same group achieved an aryne selenostannylation reaction via aryne insertion into the Se−Sn bond of tributyl(phenylselanyl)stannane 7-103, which could give the corresponding products 7-104 (Scheme 110b).532 In 2011, Kazmaier and co-workers demonstrated a catalystfree hydrostannation protocol to synthesize compounds 7-105 Scheme 108. Aryne Insertion into N−S σ-Bonds Scheme 110. Aryne Insertion into Selenium-Based σ-Bonds 3932 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review phosphines 7-112 was realized by Hirano, Miura, and coworkers through an aryne insertion into the P−P bond of 7112 (Scheme 112b).536 For ease of handling, the diphosphinated products 7-113 were further converted to phosphine sulfides 7-114 with S8. In 2014, Taniguchi and Curran accomplished a first and distinct hydroboration protocol on arynes (Scheme 113a).537 through an aryne insertion into the Sn−H bond of Bu3SnH (Scheme 111a).129 Similar results were also reported by Moses Scheme 111. Aryne Insertion into the F−Sn Bond of Bu3SnF Scheme 113. Aryne Insertion into Other σ-Bonds et al.533 A distinct aryne insertion into the F−Sn bond of Bu3SnF was disclosed by Yoshida and co-workers, affording compounds 7-106 via the simultaneous formation of a C−F and a C−Sn bond in highly regioselective manner (Scheme 111b).534 Their mechanistic investigation revealed that a difluorotributylstannate (Bu3SnF2−) species 7-107 was responsible for the overall conversion. The nucleophilic addition of 7107 to aryne would form intermediate 7-108, which then converts to 7-109 via a 1,3-migration of Bu3SnF. At last, fluoride dissociation on 7-109 could produce 7-106. This study also led to the preparation of the anti-inflammatory drug flurbiprofen. In 2016, Guo, He, and co-workers demonstrated an aryne insertion reaction into the P−OH σ-bond of diarylphosphinic acid 7-110, giving rise to o-hydroxy-substituted arylphosphine oxides 7-111 in modest to high yields (Scheme 112a).535 The employment of TBAT as a less basic fluoride source suppressed the undesired O-arylation side-reaction on the phenol oxygen of 7-111. Their mechanistic study favored a Onucleophilic attack/Fries rearrangement pathway on the P− OH bond over a [2 + 2] cycloaddition/ring-opening process on the PO bond. Aryne diphosphination with tetraaryldi- In this study, they employed stable N-heterocyclic carbene boranes (NHC-borane) 7-115 to react with arynes, affording B-aryl NHC-boranes 7-116 in modest to high yields. Furthermore, they could convert the product to the corresponding pinacol borane or phenylboronic acid.538 Besides, aryne insertion into the I−I σ-bond was also realized by Pérez, Guitián, and co-workers, and o-diiodoarenes 7-117 were obtained in modest to high yields (Scheme 113b).539 7.5. Insertion into π-Bonds Aryne insertion into π-bonds, i.e., CS, CC, PN, PO, SO, and SN bonds, has also been achieved. In 2011, Greaney et al. uncovered a distinct aryne insertion protocol into the CS bond of thioureas 7-118, which could afford functionalized amidines 7-119 in modest to high yields (Scheme 114a).540 In contrast to the aryne reaction with ureas, in which a C−N σ-bond was inserted by arynes,479 the reaction of arynes with thioureas exhibited completely different Scheme 114. Aryne Insertion into CS and CC Bonds Scheme 112. Aryne Insertion into P-Based σ-Bonds 3933 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR chemoselectivity. In 2013, Shi et al. reported a reaction between o-silylaryl triflates and vinylogous amides 7-120 containing no free N−H bonds, furnishing 2-substituted benzaldehydes or ketones 7-121 in modest to high yields (Scheme 114b).541 This overall CC bond insertion transformation proceeds through a [2 + 2] cycloaddition reaction and a subsequent ring-opening on intermediate 7-122 to generate an iminium inner salt 7-123, which could then be trapped by methanol to afford aminal 7-124. Upon hydrolysis, 1,2-difunctionalized arenes 7-121 can be obtained. In 2014, Lopez-Leonardo, López-Ortiz, Alajarin, and coworkers disclosed that P-(2-arylamino)phenyl phosphonium triflates 7-126 could be accessed through the reaction of iminophosphoranes 7-125 with o-silylaryl triflates (Scheme 115a).542 This transformation proceeds through a [2 + 2]/ Review Scheme 116. Aryne Insertion into the SO Bond of DMSO Scheme 115. Aryne Insertion into PN and PO Bonds component to capture the generated phenolate ion and yielded 7-130 (Scheme 116b).545 A similar transformation was recently achieved by Gogoi et al. by using both allyl bromides and vinyl bromides as the alkylation components.546 In 2015, Wang and co-workers reported a similar transformation, which could produce compounds 7-131a and 7131b (Scheme 117a).547 Their mechanistic study revealed that Scheme 117. Aryne Insertion into the SO Bond of Diaryl Sulfoxides retro [2 + 2] cycloaddition reaction sequence, which was followed by either N-protonation or N-arylation in the presence of excess aryne. In this study, P-(2-phenylthio)phenyl phosphonium triflates were also obtained in good yields from phosphane sulfides. Recently, Gogoi et al. realized an aryne insertion into the PO bond of phosphine oxides 7-127, giving rise to o-aryloxotriphenylphosphonium triflates 7-128 in moderate to good yields with high functional group tolerance (Scheme 115b).543 A sequential formal aryne [2 + 2] cycloaddition and O-arylation with a second molecule of aryne was proposed as the reaction mechanism. In 2014, Chen, Xiao, and co-workers first demonstrated an aryne insertion protocol into the SO bond of DMSO with concomitant formation of C−S and C−O bonds on the vicinal positions of a benzene ring (Scheme 116a).544 Mechanistically, this transformation includes an aryne insertion into the SO bond, O-alkylation with α-bromo carbonyl compounds, and demethylation of sulfonium ion to produce products 7-129. In 2019, Gogoi et al. employed activated alkynes as the third the formation of 7-131a might proceed through a sulfonium ylide intermediate 7-132; whereas, 7-131b should be realized via an intramolecular 1,4-migration of the R2 group. When diaryl sulfoxides 7-133 were employed, a different reaction mode was discovered. Peng et al. found that o-aryloxy triarylsulfonium salts 7-134 could be obtained from sulfoxides 7-133 at room temperature (Scheme 117b).548 In 2015, Hosoya et al. demonstrated an unprecedented preparation of o-sulfanylanilines 7-136 from arynes and sulfilimines 7-135 (Scheme 118a).549 The mechanism for this transformation involves a sequential regioselective [2 + 2] cycloaddition reaction of aryne with the SN bond to 3934 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review component (E). Meanwhile, the positive charge on Nu can be captured by a fourth, nucleophilic component (Nu′) or that from the E end to realize a benzannulated scaffold. Alternatively, anionic nucleophiles that are compatible with electrophilic components in the reaction system could also be employed in this strategy to realize three-component coupling reactions. Scheme 118. Aryne Insertion into SN Bonds 8.1. Isocyanide-Triggered MCRs Yoshida, Kunai, and co-workers first accomplished a series of three-component coupling reactions of arynes with isocyanides. In 2004, they reported that diverse benzannulated iminofurans 8-4 could be readily assembled through the MCR of o-silylaryl triflates, isocyanides 8-1, and aldehydes (Scheme 120a).553 The mechanism for this transformation proceeds Scheme 120. Aryne Three-Component Coupling Reactions with Isocyanides generate intermediate 7-137/S−N bond cleavage on 7-137/ intramolecular ipso-substitution at the more electron-deficient aryl group on intermediate 7-138. In this study, they also found that when sulfilimine contains a methyl group, o-arylthio aniline could be obtained. This transformation was then applied in the preparation of diaryl sulfides 7-140 by using S(o-bromoaryl)-S-methylsulfilimines 7-139 as the substrates (Scheme 118b).550 A subsequent intramolecular Buchwald− Hartwig amination operation was able to convert 7-140 to phenothiazine. Moreover, they disclosed that the SN bond of sulfoximines 7-141 could be inserted by arynes (Scheme 118c).551 Their computational calculations suggested a similar mechanistic pathway to that of diarylsulfoxides. In particular, the reaction modes were highly dependent on the substrates. When S,S-diarylsulfoximines were employed, o-sulfinylanilines 7-142 could be achieved in a regioselective manner, whereas N-arylation products 7-143 were obtained from both S-alkyl-Saryl- and S, S-dialkylsulfoximines. 8. MULTICOMPONENT REACTIONS (MCRs) Another aryne reaction mode is multicomponent reaction (MCR).552 The general scheme for this transformation begins with nucleophilic addition of neutral nucleophiles (Nu) to highly electrophilic aryne species to generate a zwitterionic intermediate (Scheme 119). The strongly nucleophilic aryl anion on this zwitterion would then attack a third, electrophilic through a nucleophilic addition of isocyanide 8-1 to aryne to generate a zwitterion 8-2, which in turn reacts with aldehyde to afford a formal [3 + 2] cycloadduct 8-4 after annulation from intermediate 8-3. Subsequently, the same group disclosed that aldehydes could be replaced by imines,554 ketones,555 benzoquinones,555 or sulfonylimines,555 giving rise to derivatives of iminoisoindolines or iminodihydroisobenzofurans. In 2011, Stoltz and co-workers discovered that the combination of o-silylaryl triflates, isocyanides, and phenyl esters 8-5 could deliver iminoisobenzofurans 8-6 as well in good to excellent yields (Scheme 120b).556 By employing aqueous oxalic acid to hydrolyze the iminoisobenzofuran products, they developed a one-pot, two-step transformation to produce o-ketobenzamides 8-7. Further exploration unraveled that electron-deficient alkynes 8-8 could serve as efficient third components in the Scheme 119. General Scheme for Multicomponent Reactions 3935 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR MCR of arynes and isocyanide, furnishing carbocyclic iminoindenones 8-9 in moderate to high yields (Scheme 120c).556 In 2009, Huang and Sha revealed a MCR of arynes, isocyanides, and terminal alkynes, affording polysubstituted pyridines 8-10 and isoquinolines 8-11 under mild conditions in highly chemo- and regioselective manners (Scheme 121).557,558 After nucleophilic addition of isocyanide to Review Scheme 122. Aryne MCRs with Isocyanides and 3Substituted Propynes Scheme 121. Aryne MCRs with Isocyanides and Terminal Alkynes Scheme 123. Aryne MCRs with Isocyanides and Organic Bromides aryne, the generated zwitterionic intermediate 8-12′ can be trapped by terminal alkyne to produce imide intermediate 813. A 1,5-hydride shift on imide 8-13 then occurs to yield an allenyl imine species 8-14. Consequently, this allenyl imine intermediate 8-14 could take part in a further aza-Diels−Alder reaction/aromatization to afford either polysubstituted pyridines 8-10 with alkynes or isoquinoline derivatives 8-11 with arynes. Overall, this protocol allows a ready assembly of four components through two uniquely ordered sequences. In 2013, Sha, Wu, and co-workers demonstrated an interesting multicomponent transformation of arynes, isocyanides, and 3-substituted propynes 8-15 (Scheme 122).559 Disubstituted pyridines 8-16 (R2 = H) could be obtained in moderate to high yields by using 3-bromopropyne (8-15a) as the third component, whereas the employment of 3acetoxypropynes (8-15b) led to the formation of trisubstituted pyridines (R2 = aryl). Mechanistically, this transformation involves a 1,3-hydride shift from N-allenyl imine 8-17 to generate azatriene 8-18, which then participates in an intramolecular pericyclization and aromatization through the extrusion of either HBr or HOAc. In 2011, Yoshida et al. developed a three-component coupling reaction of arynes, isocyanides, and organic bromides 8-19, leading to the production of bromoarenes 8-20 (Scheme 123).560 In this MCR, either alkynyl bromides or polyfluoroaryl bromides served as the sources of electrophilic bromide to react with zwitterion 8-2. Meanwhile, the departed anionic part from 8-19 could back attack intermediate 8-21 to furnish product 8-20. In 2014, Biju and co-workers reported a threecomponent coupling reaction of arynes and isocyanides using either CO2 or water as the third component (Scheme 124).561 When CO2 was utilized, N-substituted phthalimides 8-22 were obtained. The plausible mechanistic pathway for this transScheme 124. Aryne MCRs with Isocyanides and CO2/Water 3936 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR formation might proceed through a fluoride-induced ring opening of iminoisobenzofuranone species 8-23, generated from 8-2 and CO2 via either a concerted or stepwise manner, and further cyclization to afford phthalimide derivatives 8-22. In the presence of water, benzamide derivatives 8-24 could be obtained after trapping the zwitterion intermediate 8-2 with water. Similar work was also reported by the groups of Wang/ Ji562 and Pirali.563 Review (SO2F2) could be efficiently trapped in the MCR of arynes and secondary amines to afford various 2-aminoarenesulfonyl fluoride derivatives 8-28 in modest to high yields with high functional group tolerance (Scheme 125d).568 Besides, Mhaske and Dhokale found that sodium nitrite (NaNO2) could serve as a nucleophile. After trapping the generated aryl anion with aldehyde, (2-nitrophenyl)methanol derivatives 8-29 were achieved through a three-component coupling reaction of arynes, NaNO2, and aldehydes (Scheme 125e).376 In 2019, Tian et al. reported a MCR of o-silylaryl triflates, tertiary amines, and organohalides, leading to the formation of diverse tertiary 2-haloanilines 8-30 (Scheme 126a).569 Beside 8.2. N-Nucleophile-Triggered MCRs Nitrogen nucleophiles are versatile arynophiles in aryne MCRs. In 2006, Yoshida, Kunai, and co-workers first accomplished a three-component coupling reaction of arynes, imines, and CO2, furnishing six-membered benzoxazinone derivatives 8-25 in modest to high yields (Scheme 125a).564 Subsequently, they Scheme 126. Tertiary Amine-Triggered Aryne MCRs Scheme 125. N-Nucleophile-Triggered Aryne MCRs carbon tetrachloride, carbon tetrabromide, carbon tetraiodide, hexachloroethane, fluorotribromomethane, NCS, NBS, and NIS could all serve as effective organohalides. As proposed, the departed anionic moieties from organohalides served as nucleophiles in the dealkylation step on ammonium salt intermediate. Meanwhile, Biju and co-workers also disclosed a MCR of arynes and tertiary amines with either aryl selenium bromide or diaryl diselenide as the third component (Scheme 126b).570 2-Selanyl aniline derivatives 8-31 could be facilely prepared in modest to high yields. In a study carried out by Biju et al., they revealed an interesting aryl to aryl amino-group migration event. As shown in Scheme 127a, this MCR involved o-silylaryl triflates, aromatic tertiary amines 8-32, and aldehydes, which could produce 2-functionalized tertiary amines 8-33.571 Distinctively, an aryl to aryl tertiary amino group migration via intermediates 8-34 and 8-35 was observed through the SNAr mechanism in this transformation. They reasoned that the formation of electron-deficient quaternary ammonium intermediate 8-34 might be the key for this aryl migration event. Moreover, activated ketones, such as N-methylisatin, trifluoroacetophenone, and benzil, could also serve as effective third components in this reaction. In 2016, the same group reported a MCR of arynes, aromatic tertiary amines, and CO2 (Scheme 127b).572 A switchable selectivity was observed. When aromatic tertiary amines containing an electron-deficient substituent on the arene ring were utilized, an aryl to aryl amino-group migration occurred to afford 2-aminoaryl benzoates 8-36. In contrast, in the presence of electron- reported another MCR of arynes, secondary amines, and CO2, where anthranilic acid derivatives 8-26 were readily prepared (Scheme 125b).565 Moreover, the same group developed two types of three-component coupling reactions of arynes and aminosilanes with either aldehydes566 or sulfonylimines,567 giving rise to the corresponding 2-aminobenzhydrols (X = O) and 2-aminobenzhydrylamines (X = NTs) 8-27, respectively (Scheme 125c). In these studies, a catalytic amount of benzoic acid was found to be essential to promise the high reaction efficiency. According to their mechanistic investigation, they proposed that a secondary amine could be formed in situ from aminosilane and benzoic acid, which is the actual active species for the following three-component coupling transformations. Recently, Kim and Kwon demonstrated that sulfuryl fluoride 3937 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 127. Tertiary Amine-Triggered Aryne MCRs Involving Aryl Migration Review Scheme 128. N-Heteroaromatic-Triggered Aryne MCRs species 8-42 could abstract a proton from the terminal alkyne to generate an acetylide anion 8-45, which would then attack the N-arylated quinolinium/pyridinium cation 8-43 to afford 8-44. Ketones with no α-hydrogens were employed as the third component. In 2013, Biju et al. demonstrated a MCR of arynes, N-heterocycles, and isatins 8-46 (Scheme 129a).576 When isoquinolines were employed, spirooxazino isoquinoline donating or neutral groups, 2-arylamino benzoates 8-37 were obtained via a nitrogen to oxygen alkyl group migration pathway. Similar aryl to aryl amino-group migration was reported by Okuma and co-workers in their preparation of both 9- and 10-membered N,O-containing heterocycles 8-39 via a MCR of arynes, aldehydes, and substituted indolines (n = 1) or tetrahydroquinolines (n = 2) 8-38 (Scheme 127c).573 N-Heteroaromatic compounds were found to be effective triggers in aryne multicomponent reactions. In 2006, Cheng and Jeganmohan first demonstrated a three-component coupling reaction of arynes, N-heteroaromatics 8-40 (e.g., pyridines, quinolines, and isoquinolines), and nitriles, affording the corresponding N-arylated 1,2-dihydro-2-pyridinyl, 1,2dihydro-2-quinolinyl, and 1,2-dihydro-1-isoquinolinyl nitriles 8-41, respectively (Scheme 128a).574 A representative mechanistic pathway was proposed by using pyridine as the N-heteroaromatic substrate: (1) 1,4-dipole 8-42, generated from N-nucleophilic addition to aryne, abstracts an α-hydrogen from nitrile; (2) the nitrile anion would then attack cation 8-43 to realize 8-41. The discovery by using acetonitrile as an efficient third component is particularly noteworthy because the reactions with o-silylaryl triflates are normally carried out in acetonitrile. In 2010, Cheng et al. reported that various Nheteroaromatics 8-40, such as quinolines, isoquinolines, and pyridines could participate in the MCRs with arynes and terminal alkynes to assemble 8-44 in good to high yields (Scheme 128b).575 Similar to their previous study, zwitterionic Scheme 129. Quinoline-Triggered Aryne MCRs 3938 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR derivatives 8-47 could be produced in moderate to high yields. Subsequently, the groups of Biju577 and Lei/Hu578 independently reported a similar MCR of arynes, quinolines, and aldehydes/ketones, giving rise to products 8-48 (Scheme 129b). When pyridines were utilized as the nucleophilic triggers, an unexpected reaction pathway involving the formation of pyridine carbenes 8-49 was disclosed by Biju et al. through labeling experiments (Scheme 130).576 Mechanis- Review Scheme 131. Other N-Heteroaromatic-Triggered Aryne MCRs Scheme 130. Aryne MCRs with Pyridines and Isatins tically, pyridine carbene 8-49 can be generated from 8-42, which then attacks isatin 8-46 to form 8-50. A subsequent intramolecular aryl transfer through an SNAr pathway with the formation of a σ-complex intermediate 8-51 would take place to enable the production of indolin-2-one derivatives 8-52. This mechanistic proposal was later supported by Rodriguez, Coquerel, and co-workers through their theoretical calculations.579 Hydrogen abstraction from the third component, i.e., solvent molecules, was found to be a common tactic in Nheteroaromatic-triggered MCRs. In 2016, Chenoweth and Suh reported that both DCM and MeCN could participate in the MCRs with benzyne and phthalazine (8-53), affording the corresponding products 8-54 and 8-55, respectively, albeit in low yields (Scheme 131a).580 The dual roles of DCM and MeCN in these transformations are both the proton sources and the subsequent nucleophiles. In the same year, Dai, He, and co-workers disclosed that dialkylphosphites 8-56 could be utilized as the third component as well to produce 8-57, and N-heteroaromatics 8-40 were found to be quinolines, isoquinolines, phenanthrolines, and acridines (Scheme 131b).581 Chloroform could also participate in this type of transformation to give 8-58 in modest to excellent yields (Scheme 131c).582 In 2018, Tian, Yu and co-workers disclosed a MCR of o-silylaryl triflates, electron-deficient N-heteroaromatics 8-59, and carbon tetrachloride, furnishing the corresponding products 8-60 in good to high yields (Scheme 131d).583 In this study, both the control experiment and the DFT calculations indicated that chlorine transfer from CCl4 was favored over either intramolecular 1,4-proton transfer or proton abstraction from MeCN. Like the CN double bonds on N-heteroaromatics, imines could serve as efficient nucleophilic triggers in aryne multicomponent reactions as well. In 2017, Tian and coworkers demonstrated a three-component carboarylation reaction of arynes, imines, and various carbon nucleophiles, such as chloroform, acetonitrile, and methyl propiolate, and obtained products 8-61 (Scheme 132a).584 Meanwhile, Scheme 132. Imine-Triggered MCRs 3939 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Voskressensky et al. synthesized cyanomethyl-substituted tetrahydroisoquinolines and tetrahydrothieno[3,2-c]pyridines 8-63 through the MCR of the dihydro analogues of isoquinoline and pyridine 8-62 with benzyne and acetonitrile (Scheme 132b).585 A four-component reaction was also developed through the in situ generation of imines from primary amines and aldehydes.586 In a study carried out by Tian, Yu, and co-workers on the MCRs of arynes with electron-deficient N-heteroaromatics, they also realized similar transformations with imines using carbon tetrachloride as the third component, giving rise to products 8-64 (Scheme 132c).583 Recently, Peng et al. disclosed that oxazolines 8-65 could serve as nucleophilic triggers in the aryne threecomponent coupling reaction with chloroform, furnishing products 8-66 in modest to high yields (Scheme 132d).587 Intriguingly, after screening various chiral auxiliaries, isopropyl group (i-Pr) was found to be the superior auxiliary (Aux) and trichloromethylated chiral oxazolidines 8-66 could be prepared in good to excellent diastereoselectivities. In a rare case, Wu and co-workers reported a preparation of cinnolines 8-68 through a MCR of arynes, tosylhydrazine (TsNHNH2), and α-bromo ketones 8-67 (Scheme 133).588 Review Scheme 134. Aziridine/Azetidine-Triggered Aryne MCRs unsuitable. Wu, Sha, and co-workers later developed a MCR of arynes, aziridines 8-74 with 2-carbonyl substituents, and TBAF hydrate as a fluorinating reagent, which led to the formation of α-fluoro-β-amino acid derivatives 8-75 in moderate to excellent yields (Scheme 134b).591 A small amount of water was found to be crucial for the success of this transformation, the role of which was proposed to protonate the aryl anion on zwitterion intermediate. A similar reaction was recently observed when Yudin, Studer, and co-workers studied the reactivity between vinylaziridines and o-silylaryl triflates; whereas arynes, generated under Knochel’s conditions by using o-haloaryl sulfonates as the aryne precursors and Grignard reagent as the activating reagent, proceeded through a formal [5 + 2] cycloaddition reaction pathway with vinylaziridines.592 In 2015, Biju et al. noticed that trifluoroacetic acid (TFA) could promote the MCR of arynes, N-substituted aziridines 870, and water, affording N-aryl β-amino alcohol derivatives 876 in moderate to high yields (Scheme 135a).593 Moreover, four-membered azetidines were found to be good substrates Scheme 133. Aryne MCRs with Tosylhydrazine and αBromo Ketones Based on their mechanistic investigation, a plausible mechanism was proposed: a formal [2 + 2 + 2] cycloaddition of arynes, α-bromo ketones, and diazene, generated from tosylhydrazine and CsF, could furnish intermediate 8-69, which then converts to cinnolines 8-68 after elimination of water. Because diazene is short-lived and would reduce the aryne intermediate, another possible reaction pathway might involve a direct reaction of tosylhydrazine with aryne. The reaction of N-substituted aziridines with arynes to generate zwitterionic species could be traced back to 1972, in which Giumanini studied their reaction with benzyne by using fluorobenzene as the precursor.589 This benzyne generation method, however, only afforded the desired product in low efficiency. Along with the development of Kobayashi’s method, N-substituted aziridines were recently employed in aryne MCRs. In 2013, Larionov and co-workers first demonstrated that the MCR of arynes, aziridines 8-70, and acetonitrile could produce N-aryl γ-aminobutyronitriles 8-71 in good to excellent yields (Scheme 134a).590 Mechanistically, this three-component transformation includes (1) N-nucleophilic addition of aziridine 8-70 to aryne to form zwitterionic species 8-72; (2) the aryl anion on 8-72 abstracts a proton from acetonitrile; (3) the deprotonated acetonitrile attacks the three-membered ring on intermediate 8-73 to furnish 8-71. Although fourmembered azetidine could be utilized in this reaction as well, both five- and six-membered cyclic amines were found to be Scheme 135. Other Aziridine/Azetidine-Triggered Aryne MCRs 3940 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review fluoride, and 2,4-pentanedione were all employed as nucleophiles in this transformation. Recently, they reported the same type of MCR by using nitrogen nucleophile as the third component.596 In 2017, Tian et al. achieved an aryne MCR with enantioenriched tertiary benzylic amines 8-88 and various nucleophiles, such as benzenethiol, thiolate, thiocarboxylic acid, sulfinic acid, sodium sulfinate, selenol, malononitrile, and azidosilane, furnishing structurally diverse benzylic compounds 8-89 in moderate to excellent yields (Scheme 137b).597 An overall stereospecific nucleophilic substitution with inversion of the configuration and excellent retention of enantiopurity occurred via an SN2 reaction pathway on the in situ generated ammonium salt. for this MCR as well to afford the corresponding N-aryl γamino alcohols. Their detailed mechanistic studies clearly revealed that water is responsible for the protonation of aryl anion 8-77 and TFA is the actual nucleophile in the SN2-type ring-opening reaction on 8-78. After hydrolysis of intermediate 8-79, N-aryl β-amino alcohols 8-76 could be obtained. Subsequently, the same group reported a MCR of arynes and carboxylic acids with either aziridines or azetidines, producing the corresponding N-aryl β-amino alcohols and Naryl γ-amino alcohols 8-80, respectively (Scheme 135b).594 In 2016, a unique aryne MCR was disclosed by Biju and coworkers, where N-substituted electron-deficient aziridines 8-81 were employed and N-aryl α-amino epoxides 8-82 could be obtained in good yields with good diastereoselectivity (Scheme 136). 595 Both variations on aziridines 8-81 and the 8.3. Other Nucleophile-Triggered MCRs Multicomponent reactions of arynes, activated carbonyl compounds, and electron-deficient alkenes/alkynes were developed. In general, these transformations involve a sequential aryne insertion into a C−C σ-bond, an annulation reaction with alkene or alkyne, and elimination to afford polysubstituted naphthalenes. In 2007, Huang and Xue first demonstrated a MCR of arynes, β-keto sulfones 8-90, and electron-deficient alkenes to produce polysubstituted naphthols 8-91 and naphthalenes 8-92 in moderate to good yields (Scheme 138a).598 In 2018, Shu, Wu, and co-workers Scheme 136. Aryne MCRs with Electron-Deficient Aziridines and Aldehydes Scheme 138. MCRs via Aryne C−C σ-Bond Insertion replacement of aldehydes with N-substituted isatins were found to be efficient in this transformation. A mechanistic pathway was proposed: after a sequential aziridine-triggered formation of zwitterion 8-83 and intramolecular 1,4-proton abstraction, a strained aziridinium ylide 8-84 can be generated, which could add to aldehyde to give an alkoxide anion 8-85; this alkoxide then opens the aziridinium ring to furnish αamino epoxides 8-82. In 2018, Ko and co-workers demonstrated that 1,4diazabicyclo[2.2.2]octane (DABCO) (8-86) could serve as a cyclic amine trigger in aryne MCR in combination with various nucleophiles, which could yield 2-(4-phenylpiperazin-1-yl)ethan-1-amine-containing derivatives 8-87 (Scheme 137a).369 Other than thiols, methyl acrylate, allyl acetate, methyl acetate, Scheme 137. Other N-Nucleophile-Triggered Aryne MCRs accomplished two types of three-component σ-bond insertion/benzannulation transformations of arynes and alkynoates 8-93 with either α-cyanoacetophenones (R2 = CN) or 1,3diketones (R2 = COAr), affording various polysubstituted naphthalene derivatives 8-94a and 8-94b, respectively (Scheme 138b).599 When 1,3-diketones were employed, a decarbonalytion reaction occurred to produce 8-94b. Beside the aforementioned mechanism, a combination of these three components could proceed through different reaction pathway. In 2016, Shu, Wu, and co-workers reported a 3941 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR formal [2 + 2 + 2] cycloaddition reaction involving arynes, 1,3dicarbonyl compounds 8-95, and alkynoates 8-93, affording naphthalene derivatives 8-96 in moderate to high yields (Scheme 139).600 Mechanistically, they proposed that Review Scheme 140. O-Nucleophile-Triggered Aryne MCRs Scheme 139. Formal [2 + 2 + 2] Cycloaddition Reaction of Arynes, 1,3-Dicarbonyl Compounds, and Alkynoates deprotonated 8-95 attacks alkynoates 8-93 first to generate 8-97, which in turn reacts with aryne in an annulation fashion to produce the final product after dehydration on intermediate 8-98. O-Nucleophiles were also utilized in aryne MCRs with osilylaryl triflates, albeit with limited application. Since 2008, the Okuma group has investigated the MCRs of cyclic ethers and active methines with different aryne precursors.348,601,602 Among these studies, they demonstrated a MCR of epoxides 8-99, chloroform, and Kobayashi benzyne precursor, furnishing isomeric mixtures of trichloroalkyl phenyl ethers 8-100a and 8-100b, albeit in low efficiency (Scheme 140a).348 In Yoshida’s investigation on the MCRs of arynes, isocyanides, and alkynyl bromides, they noticed that the oxygen atom on both THF and oxetane could attack aryne to generate the corresponding 1,3-dipoles 8-101, which then reacted with either alkynyl bromides or polyfluoroaryl bromides to produce benzo[b]oxepine derivatives 8-102 in moderate to high yields (Scheme 140b).560 In 2016, Biju and co-workers reported a temperature dependent switchable reactivity of arynes with aliphatic alcohols. At 60 °C, THF could serve as an efficient nucleophilic trigger in the MCR with arynes and aliphatic alcohols to produce ethers 8-103 (Scheme 140c);401 whereas at low temperature, direct aryne insertion into the O−H bond of alcohols occurred (see Scheme 61a). Recently, Qi, Jiang, and co-workers employed precursors of 3-triflyloxybenzyne 8104 in a four-component coupling reaction with cyclic ethers, CO2, and amines, giving rise to functionalized carbamate derivatives 8-105 in modest to high yields (Scheme 140d).603 Mechanistically, this transformation initiates with a cyclic ether-triggered formation of zwitterion 8-106, followed by protonation with in situ generated ammonium cation of carbamate 8-107 from diethylamine and CO2, which could then furnish products 8-105 after ring opening reaction. In 2018, Hu and co-workers prepared trifluoromethyl benzoate (TFBz) (8-108) as an unprecedented trifluoromethoxylation reagent and employed this reagent in a threecomponent reaction with arynes and various halogen sources, furnishing o-haloaryl trifluoromethyl ethers 8-109 in modest to high yields (Scheme 141a).604 Those halogen sources were phenylethynyl bromide for “Br”, C6F5I for “I”, and CCl4 for Scheme 141. Aryne MCRs with Trifluoromethoxylation Reagents “Cl”. In this study, they also identified that a thermally stable trifluoromethoxide salt [K(cis-dicyclohexano-18-c-6)]+CF3O− was responsible for the success of this transformation. Recently, Lei, Zhu, and co-workers reported a new class of trifluoromethoxylation reagent, trifluoromethyl aryl sulfonates (TFMS) 8-110, and applied them in the trifluoromethoxylation-iodination of arynes, yielding products 8-111 (Scheme 141b).605 In this study, they systematically screened the crown ether, fluoride salts, solvent effect, and “I” sources. 3942 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Sulfonium ylides could be generated from the reaction of certain S-containing molecules with o-silylaryl triflates, which would then participate in the subsequent transformations. In 2014, Xu, Shen, and co-workers demonstrated a MCR of thioethers, arynes, and isatins, furnishing various spiroepoxy oxindoles 8-112, albeit with no diastereoselectivity (Scheme 142a).606 In this study, sulfonium ylide 8-114 could be Review Scheme 143. Cyclic Thioether-Triggered Aryne MCRs Scheme 142. MCRs via Benzyne-Induced Sulfonium Ylides could protonate the sulfonium ylide intermediate. Meanwhile, He et al. disclosed a similar MCR by employing both inorganic salts, i.e., KF, KCl, KBr, and KSCN, and silylated reagents, i.e., TMSCN, TMSN3, and TMSCl, as nucleophiles (Scheme 143c).610 Phosphines were examined in aryne MCRs as well. In this context, Biju et al. reported several MCRs of arynes, phosphines, and carbonyl compounds.611,612 In 2014, they first exhibited that stable pentacovalent phosphoranes 8-121 based on the benzooxaphosphole scaffold could be obtained in good to high yields from the MCR of arynes, phosphines, and aldehydes (Scheme 144a).611 Two plausible mechanistic pathways were proposed to capture aldehydes after the initial formation of 1,3-phosphonium zwitterion intermediate 8-122 through either a stepwise manner (path a) or a formal [3 + 2] cycloaddition reaction (path b). Subsequently, they demon- generated through a sequential nucleophilic addition of thioether to aryne and an immediate intramolecular 1,4-proton shift on 8-113. Subsequently, the reaction of 8-114 with isatin produces product 8-112 via intermediate 8-115. In 2016, Zhang, Wang, and co-workers discovered that sulfonium ylide 8-116 could be generated via a successive benzyne insertion into the SO bond of sulfoxides/O-arylation/proton abstraction pathway (Scheme 142b).607 Consequently, they developed a MCR of sulfoxides, benzyne, and carbonyl electrophiles, such as N-methyl isatins and activated aromatic aldehydes, giving rise to the corresponding epoxide products 8117a and 8-117b, respectively. Recently, saturated sulfur heterocycles were employed to serve as nucleophilic triggers in aryne three-component coupling reactions in combination of various nucleophiles as the third components. In 2018, Tan, Xu, and co-workers systematically investigated the reactivity of saturated sulfur heterocycles 8-118 in the MCRs with arynes and different nucleophiles, which led to the preparation of products 8-119 (Scheme 143a).608,609 They found that four- to six-membered cyclic thioethers could all participate in ring-opening reactions upon activation with arynes, and the nucleophilic components could be C-, O-, S-, and N-based nucleophiles.608 Moreover, they disclosed that this protocol could be applied in a ringopening fluorination reaction by using KF as the fluorine source, affording products 8-120 in modest to high yields (Scheme 143b).609 In this transformation, 2,3-dimethylindole was found to serve as a non-nucleophilic proton mediator that Scheme 144. Phosphine-Triggered Aryne MCRs 3943 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review iodine ate complex 8-131, which then converts to the orthoiodinated aryl fluoride 8-132 upon proton abstraction. This work not only provides a facile aryne fluorination maneuver but also represents an unprecedented example in catalytic aryne transformations under transition metal-free conditions.517 In addition, inorganic salts were developed to serve as active nucleophiles to attack arynes. In 2019, Jiang and co-workers reported a three-phase, four-component coupling reaction of arynes, KCl, CO2, and chloroalkanes 8-133 (Scheme 147a).616 strated that different kinds of acyclic and cyclic activated carbonyl compounds 8-123 could participate in the same kind of transformation through a formal [3 + 2] cycloaddition fashion, leading to the formation of substituted (spiro)benzoxaphosphole derivatives 8-124 in moderate to high yields (Scheme 144b).612 Recently, the groups of Biju613 and Cai/ He614 independently employed CO2 as the third component and prepared zwitterionic phosphonium benzoates 8-125 (Scheme 144c). No annulated benzooxaphosphol-3(1H)ones were formed in this reaction system. In 2018, Biju et al. discovered that a combination of phosphines and base, such as Cs2CO3, could convert arynes into aryl anion equivalents (Scheme 145).615 Both aldehydes and isatins were used to Scheme 147. Inorganic Salts-Triggered Aryne MCRs Scheme 145. Formation of Benzyl Alcohols via PhosphineTriggered Aryne MCR capture the aryl anions and afforded the corresponding benzyl alcohols 8-126. They proposed that after the nucleophilic addition of phosphine to aryne and protonation, the generated tetraaryl phosphonium salt 8-127 could be attacked by a base, either Cs2CO3 or CsOH, to produce a pentavalent phosphorus intermediate 8-128. Consequently, aryl anion would be released from 8-128, which then attacks either aldehyde or isatin to afford 8-126. Along with their study on fluorination/trifluoroalkylation of arynes, Hu and co-workers achieved a distinct diphenyliodonium-catalyzed vicinal fluorination-iodination of arynes by using CsF as the fluorine source and C4F9I (RfI) as the electrophile (Scheme 146).433 Based on their experimental studies, they proposed the formation of an adduct 8-129 from Ph2I+OTf− and fluoride ion, which possesses higher reactivity toward arynes than the classical fluoride ion. The generated ofluoroaryl anion 8-130 could be captured by RfI to generate an In this study, KCl was utilized as a chloride source to attack arynes in the presence of 18-c-6, resulting in 2-chloroaryl anion species 8-134 that was trapped by CO2. The generated 2chlorobenzoate 8-135 could then react with chloroalkanes to afford 2-chlorobenzoates 8-136. Recently, Biju et al. revealed that KI could serve as an efficient nucleophile in aryne MCR with aldehydes (Scheme 147b).617 2-Iodobenzyl alcohols 8137 were facilely obtained with good functional group tolerance. In this study, they also disclosed that both KBr and KCl could be employed and the electrophiles were replaceable by N-methylisatin and CO2. Moreover, Jiang and co-workers discovered an aryne MCR with allyl bromides 8-138 and CO2 and obtained orthobrominated aryl esters 8-139 in moderate to high yields (Scheme 148).618 Depending on the electronic nature of the Scheme 148. Aryne MCRs with Allyl Bromides and CO2 Scheme 146. Diphenyliodonium-Catalyzed FluorinationIodination of Arynes 3944 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR allyl bromides, they proposed two possible mechanisms. For those substrates containing electron-rich or electron-neutral groups (path a), an allylic cation 8-140 and bromide anion might be generated, the latter of which undergoes a sequential nucleophilic addition to aryne and then to CO2 by the generated aryl anion. The resulting 2-bromobenzoate intermediate 8-141 could then combine with allylic cation 8-140 to yield product 8-139. For those electron-deficient substrates (path b), allyl bromide could serve as a nucleophile to generate a 1,3-zwitterion 8-142, which was followed by the formation of 1,5-zwitterion 8-143 by capturing CO2 and a subsequent intramolecular allyl group shift to furnish allyl 2-bromobenzoates 8-139. Review Scheme 150. Aryne MCRs with DMF 8.4. DMF-Involved MCRs Those aforementioned MCRs are normally triggered by certain nucleophiles to generate zwitterionic intermediates or aryl anions, which could in turn react with various electrophilic components. Beside these typical approaches, MCRs involving an aryne insertion into the CO bond represent a unique tactic. Although aryne insertion into the CO bond of aldehydes was first discovered by Yoshida, Kunai, and coworkers in 2004,619 DMF was then found to be a more amenable and versatile reagent. As shown in Scheme 149, a Scheme 149. General Scheme for Aryne Insertion into the CO Bond of DMF high yields by trapping o-quinone methide 8-145 with zinc enolates of α-chlorinated methines 8-150 (Scheme 151).626,627 formal [2 + 2] cycloaddition of aryne with the CO bond of DMF could produce a benzoxetene intermediate 8-144, the ring strain of which would then allow a selective ring-opening to afford an ortho-quinone methide intermediate 8-145. Subsequent Michael addition on 8-145 with a nucleophilic substrate as the third component occurs to regenerate the benzene ring. In 2010, Miyabe and co-workers first discovered that oquinone methide 8-145 could be trapped by organozinc reagents (Scheme 150a).620,621 Subsequently, the same group developed an unprecedented MCR of arynes, DMF, and active methylenes from 1,3-diketones or β-keto esters (Scheme 150b).622 This transformation involves the generation of oquinone methide 8-145 and a subsequent annulation with active methylene species to form cyclic products 2Hchromenes 8-146 from 1,3-diketones and coumarins 8-147 from β-keto esters. In marked contrast, direct aryne insertion into the C−C σ-bond of those active methylenes as a plausible competing reaction was prohibited. Meanwhile, Yoshida et al. reported a similar MCR of arynes, DMF, and active methylene compounds, i.e., arylacetic acids or arylacetonitriles, furnishing coumarin scaffolds in moderate to excellent yields.623 By employing N,S-keteneacetals as the third component, 2aryliminochromene derivatives were also achieved in good yields.624 Furthermore, Miyabe et al. developed a one-pot, four-component coupling reaction by trapping the coupling product 8-149 with thiols through an SN2′ pathway, producing xanthene derivatives 8-148 in moderate to high yields (Scheme 150c).625 In 2013, Miyabe and co-workers demonstrated that dihydrobenzofurans 8-151 could be obtained in modest to Scheme 151. Trapping o-Quinone Methide with Zinc Enolates of α-Chlorinated Methines Mechanistically, Michael addition on 8-145 with zinc enolate 8-153 would generate intermediate 8-154, which could cyclize to produce dihydrobenzofurans 8-151. Additional diethyl zinc (Et2Zn) was found to promote the decarboxylation of 8-151 and resulted in the formation of benzofurans 8-152.627 3945 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review reaction. In addition, Jiang et al. noticed that diaryliodonium salts 8-163 could serve as electrophiles to react with o-quinone methide 8-145, furnishing ortho-formyl diaryl ethers 8-164 in good to excellent yields (Scheme 153b).631 Similar to this work, Gogoi and Sharma revealed that aryl sulfonyl chlorides 8-165 were able to capture the oxygen on 8-145 and produced 2-formylarylsulfonates 8-166 in high efficiency with high functional group tolerance (Scheme 153c).632 Moreover, Gogoi and co-workers developed two protocols using either 2-bromoacetophenones633 or activated alkenes634 as the electrophilic components in the reactions with oquinone methide. When 2-bromoacetophenones 8-167 were employed, 2-aroyl benzofurans 8-155 were achieved in good to high yields via an O-alkylation on 8-145 to form 8-168/ annulation/aromatization process (Scheme 154a).633 This In 2018, Chandrasekhar and co-workers reported an efficient synthesis of 2-aroyl benzofurans 8-155 from 8-145 and sulfonium ylides 8-156 through a [4 + 1] annulation pathway (Scheme 152a).628 The sulfonium ylide 8-156 served as both a Scheme 152. Trapping o-Quinone Methide with Sulfonium Ylides and Diesters of Acetylenedicarboxylic Acid Scheme 154. Trapping o-Quinone Methide with Alkyl/Allyl Bromides and Allenes nucleophile and an electrophile in the annulation step via intermediate 8-157. In 2014, Miyabe and co-workers revealed that o-quinone methide 8-145 could be efficiently trapped by diesters of acetylenedicarboxylic acid 8-158, producing the [4 + 2] cycloadducts 8-159 (Scheme 152b).629 In addition, the nucleophilic feature of o-quinone methide 8145 was disclosed by several groups. In 2014, Lu, Wang, and co-workers realized a preparation of α-amino-α-aryl carbonitriles 8-161 via the MCR of arynes, DMF, and aroyl cyanides 8-160 (Scheme 153a).630 In this study, they employed aroyl cyanides 8-160 as nontoxic cyanide sources, which could slowly release cyanide anion from intermediate 8-162 in the Scheme 153. Nucleophilic Feature of o-Quinone Methide transformation is mechanistically different from those previously reported benzofuran formation strategies.626−628 Subsequently, they also demonstrated that allyl bromides were able to capture o-quinone methide 8-145 and produced 2formyl substituted allyl aryl ethers 8-169; whereas 2-methyl-3(arylsulfonyl)-2H-chromen-2-ol scaffolds 8-171 were obtained from 2-bromoallylsulfones 8-170. The mechanistic pathway for the formation of 8-171 was proposed to proceed through the addition of 8-145 to the in situ generated sulfonyl allene 8-172 and a subsequent annulation on intermediate 8-173 (Scheme 154b).634 In a rare case, Zhang et al. discovered a MCR of arynes, carbodiimides 8-174, and terminal alkynes or haloalkynes, furnishing 2-aminoaryl alkynyl imines 8-175 in good to excellent yields (Scheme 155).635 Mechanistically, carbodiimides participates in an aryne [2 + 2] cycloaddition reaction to 3946 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review tion, which in turn participates in aryne [3 + 2] cycloaddition reactions. In 2013, Shi and co-workers disclosed an in situ production of nitrones 8-181 from hydroxylamines and acetylenedicarboxylates, which could then undergo aryne [3 + 2] cycloaddition reaction to afford functionalized dihydrobenzisoxazoles 8-182 (Scheme 156b).638 This threecomponent reaction took advantage of the in situ generation of nitrones with pot efficiency. In 2014, Wu et al. demonstrated a silver triflate (AgOTf)catalyzed MCR of arynes, tosylhydrazine, and 2-alkynylbenzaldehyde 8-183 for the efficient production of H-pyrazolo[5,1-a]isoquinolines 8-184 (Scheme 157a).639 As proposed, Scheme 155. Carbodiimide-Involved Aryne MCRs Scheme 157. Other MCRs via Aryne [3 + 2] Cycloaddition Reaction produce an azetine species 8-176, the high ring strain of which then leads to a selective ring-opening to generate intermediate 8-177. At this stage, a terminal alkyne or a haloalkyne then adds to 8-177 through a six-membered ring transition state to assemble 8-178. After N-arylation or C−Z bond insertion with the second aryne species, products 8-175 could be obtained. Particularly, this study revealed an unusual reconnection pattern on one of the CN bonds of carbodiimides. 8.5. MCRs via Aryne [3 + 2] Cycloaddition Reaction Several studies were reported involving the in situ assembly of active 1,3-dipoles for aryne [3 + 2] cycloaddition reactions. The groups of Zhang636 and Huang637 independently reported a MCR of arynes, pyridines, and 2-bromoacetophenones, furnishing pyrido[2,1-a]isoindoles 8-179 (Scheme 156a). Mechanistically, 1,3-dipolar species 8-180 can be generated through a sequential N-alkylation of pyridine and deprotonaScheme 156. MCRs via Aryne [3 + 2] Cycloaddition Reaction this transformation involves a facile formation of isoquinolinium-2-yl amide 8-185 via a AgOTf-catalyzed 6-endo cyclization of N′-(2-alkynylbenzylidene)hydrazide intermediate, which was generated from 8-183 and tosylhydrazine. The following aryne [3 + 2] cycloaddition reaction could yield Hpyrazolo[5,1-a]isoquinolines 8-184 in a one-pot fashion. 3947 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Recently, Chandaluri, Kumar, Singh, Sawant, and co-workers revealed that azomethine imines 8-186 could be generated via a Pd-catalyzed MCR with azidobenzaldehyde, isocyanide, and 4-chlorophenylsulfonyl hydrazide, which were then captured in situ by arynes to afford fluorescent indazolo[2,3-c]quinazolines 8-187 in good to high yields (Scheme 157b).640 In a study carried out by Ramana et al. on the chemical behavior of the Ohira−Bestmann reagent (dimethyl diazo-2-oxopropylphosphonate, OBR) (8-188), they discovered a fluoride-mediated dephosphonylation of OBR to furnish α-diazocarbonyl intermediate 8-189. Consequently, 8-189 could participate in a sequential aryne [3 + 2] cycloaddition reaction and Michael addition with either acrylate or acrylonitrile, giving rise to products 8-190 (Scheme 157c).641 Review Scheme 158. Aryne [4 + 2] Cycloaddition-Initiated Cascade Reactions 9. CASCADE OR TANDEM REACTIONS Beyond those aforementioned typical aryne reaction modes, aryne-involved cascade/tandem reactions have also shown significant potential along with the advances of Kobayashi’s method. On one hand, reactive intermediates could be generated in an aryne-involved reaction step, such as through a pericyclic reaction or by activating an inert functional group, to ensure the following cascade steps. On the other hand, tandem processes could also be achieved by properly incorporating different types of aryne transformations in consecutive manners. These cascade processes not only possess the atom- and step-economy advantages but also could rapidly build-up complexity for the construction of challenging structural motifs. 9.1. Cycloaddition Reaction-Initiated Cascade Reactions 9.1.1. Initiated by Diels−Alder Reaction. In 2007, Zhang and Xie disclosed that N-substituted imidazoles 9-1 could undergo tandem reaction with benzyne to afford aryl amines 9-2 containing the anthracene scaffold (Scheme 158a).642 Although Yoshida and Kunai previously demonstrated that N-arylation occurred preferentially in the presence of excess amount of N-substituted imidazoles,358 this study revealed that by increasing the stoichiometry of the Kobayashi benzyne precursor, the anthracene framework could be obtained. Mechanistically, this tandem transformation proceeds through a benzyne Diels−Alder reaction with substituted imidazole, followed by the extrusion of nitrile on intermediate 9-3 via a retro Diels−Alder reaction, to afford intermediate 94. After a sequential Diels−Alder reaction with the second benzyne to produce 9-5/N-arylation with the third benzyne/ rearrangement, aryl amines 9-2 could be realized. In 2015, Chenoweth and co-workers reported a tandem triple arynetetrazine reaction, giving rise to a class of dibenzo[de,g]cinnolines 9-7 (Scheme 158b).643,644 The overall process includes (1) [4 + 2] cycloaddition reaction of aryne with tetrazine 9-6 and subsequent extrusion of nitrogen gas to afford phthalazine heterocycle 9-8; (2) N-arylation-proton transfer to generate s-cis diene intermediate 9-9; (3) formation of 9-10 via either Diels−Alder reaction with the second molecule of aryne or through a nonconcerted pathway; and (4) dehydrogenative aromatization to yield 9-7. Accompanied with the research on the preparation of polycyclic aromatic hydrocarbons (PAHs), Peña, Guitián, and co-workers demonstrated a cascade furan cycloaddition transformation. As shown in Scheme 159, a tandem [4 + 2]/ [4 + 2] cycloaddition process occurred between bisfurans 9-11 and arynes, affording exo,exo-9-12 with a stereoselective Scheme 159. Cascade Furan Cycloaddition Reactions formation of six adjacent stereocenters.645,646 Extended PAHs could then be obtained by treating 9-12 with HCl in EtOH. Moreover, trisfuran 9-13 was found to participate in a cascade [4 + 2]/[4 + 2]/[4 + 2] cycloaddition process with benzyne to construct exo,exo,exo,exo-9-14 with a concomitant formation of 10 adjacent stereocenters.646 In 1997, Guitián and co-workers examined the reaction between 1,8-diethynylnaphthalene (9-15) and benzyne (Scheme 160).647 Unexpectedly, they observed the formation of benzo[a]pyrene (9-16) among other possibilities. Based on 3948 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review More Diels−Alder reaction-triggered cascade processes were reported as well. In 2014, Biju and co-workers demonstrated a cascade [4 + 2] cycloaddition/ene reaction process between styrenes and arynes (Scheme 162a).241 9-Aryl-9,10-dihydro- Scheme 160. Cascade Diels−Alder Reaction with 1,8Diethynylnaphthalene Scheme 162. Aryne [4 + 2] Cycloaddition/C-Arylation Cascades their experimental result, they proposed that this transformation proceeds through a benzyne Diels−Alder reaction with arylacetylene to afford a cyclic allene species 9-17, a further cyclization with the other alkyne group to generate a σ,π-diradical intermediate 9-18, and the formation of benzo[a]pyrene (9-16) after hydrogen migration. In a study carried out by Biju et al. on the reaction between indene/benzofuran 9-19 and arynes, a tandem [4 + 2]/[2 + 2] cycloaddition process was discovered, which led to the formation of dihydrobenzocyclobutaphenanthrene derivatives 9-20 in excellent diastereoselectivity (Scheme 161a).337 In Scheme 161. Aryne [4 + 2]/[2 + 2] Cycloaddition Cascade Reactions phenanthrene derivatives 9-24 were readily achievable. In the same year, Liu et al. employed functionalized benzylidenephthalans 9-25 as the substrates to react with arynes and obtained phenanthro[10,1-bc]furans 9-26 in moderate to high yields (Scheme 162b).648 They proposed that after aryne Diels− Alder reaction with 9-25, a fluoride-induced deprotonation on the cycloadduct occurs to generate anion 9-27, which then undergoes a C-arylation reaction with another molecule of aryne. Based on Biju’s study in Scheme 162a, a concerted ene reaction pathway might also account for the formation of the above products. Meanwhile, Jia, Li, and co-workers reported the synthesis of compounds 9-29 from arylidenoxindoles 9-28, in which a tandem [4 + 2] cycloaddition/C-arylation reaction took place (Scheme 162c).649 Recently, Yennam and co-workers reported an unusual cascade process by treating 2-arylidene-1,3-indandiones 9-30 bearing electron-rich functional groups with arynes, affording dibenz[a,c]anthracene-9,14-dione derivatives 9-31 through a Diels−Alder reaction/ring expansion process (Scheme 2017, Wang, He, and co-workers disclosed a new [4 + 2]/[2 + 2] cycloaddition process between N-sulfonyl ketimines 9-21 and arynes, furnishing dihydrocyclobutaquinoline derivatives 9-23 in moderate to high yields with high functional group tolerance (Scheme 161b).233 The overall transformation proceeds through an inverse electron-demand aza Diels− Alder reaction and a [2 + 2] cycloaddition on intermediate 922. 3949 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review Scheme 163. Cascade Reactions of Arynes with 2-Arylidene-1,3-indandiones Scheme 164. Aryne Cascade Reactions with Pyridine NOxides 163).650 Mechanistically, after the Diels−Alder reaction to generate cycloadduct 9-32, alcohol intermediate 9-33 could be formed via an intramolecular nucleophilic addition on 9-32, which then experiences a retro-aldol reaction to furnish product 9-31. Interestingly, when R1 is an electron-poor substituent on 9-30, a C−C bond insertion/ring expansion transformation occurred, affording dibenzo[a,d]cycloheptanoid analogues 9-34 in moderate to high yields. The mechanism for this transformation involves (1) Michael addition of fluoride ion to 9-30 to form intermediate 9-35, (2) [2 + 2] cycloaddition reaction of 9-35 with aryne to generate intermediate 9-36, and (3) ring expansion to produce 9-34 (Scheme 163). 9.1.2. Initiated by [3 + 2] Cycloaddition Reaction. In 1974, Abramovitch et al. first explored the reactions of pyridine N-oxides 9-37 with benzyne, generated via various methods other than Kobayashi’s, which led to the formation of a mixture of 3- and 2-(2-hydroxyphenyl)pyridines in low yields.651 In 2006, Larock and co-workers revisited this reaction by using o-silylaryl triflates and discovered a regioselective coupling reaction, furnishing substituted 3-(2hydroxyphenyl)pyridines 9-38 (Scheme 164a).139 Mechanistically, after aryne [3 + 2] cycloaddition reaction with pyridine N-oxide 9-37 to generate cycloadduct 9-39, intermediate 9-40 could be formed via a further rearrangement. It was rationalized that hydrogen Ha on intermediate 9-40 is more acidic than Hb. Hence, 3-(2-hydroxyphenyl)pyridines 9-38 could be obtained upon preferential deprotonation of hydrogen Ha. This transformation was also employed on 3siylbenzynes with a detailed mechanistic study.130,652 In 2012, Liu et al. disclosed a different regioselective outcome from Larock’s system by simply modifying the reaction conditions. 6 5 3 As shown in Scheme 164b, 2-(2hydroxyphenyl)pyridines 9-41 were obtained from pyridine N-oxides and arynes in a highly regioselective manner. They reasoned that an excess amount of N-oxides and fluoride could promote a deprotonation on intermediate 9-39, giving rise to 2-substituted pyridines 9-41 exclusively. In addition, they noticed that the presence of propiolates switches the regioselectivity to deliver 3-substituted pyridines 9-43 via the interception of cyclopropyl ketone intermediate 9-42. Subsequently, this transformation was extended to quinoline Noxides654,655 and acridine N-oxides.655 In 2011, Wu and co-workers reported an unprecedented cascade process by using 2-alkynylbenzaldoximes 9-44, arynes, and a catalytic amount of silver triflate, giving rise to 2-oxa-6azabicyclo[3.2.2]nona-6,8-diene derivatives 9-45 in modest to high yields (Scheme 165).656 Based on their mechanistic study, they proposed that silver triflate catalyzes the formation of isoquinoline-N-oxides 9-46 from 2-alkynylbenzaldoximes 9-44, which then undergoes a [3 + 2] cycloaddition reaction with aryne to afford fused 1,2-dihydroisoquinolines 9-47. A 3950 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review In 2016, Studer et al. investigated the reaction behavior of vinyl sulfides 9-56 with arynes and achieved highly substituted alkenes 9-57 and 9-58 in high stereoselectivity.659 As shown in Scheme 167a, benzannulated sulfonium ylides 9-59 could be Scheme 165. Silver-Catalyzed, Aryne [3 + 2] CycloadditionInvolved Cascade Reaction Scheme 167. Aryne Cascade Processes with Vinyl Sulfides subsequent rearrangement involving a N−O bond cleavage on 9-47 and an intramolecular radical addition on 9-48 could result in the formation of 9-45. In the same year, Hwu et al. demonstrated a benzyneinduced conversion of β-amino alcohols to olefins in a stereospecific manner.657 As shown in Scheme 166a, 1,3Scheme 166. Other Aryne [3 + 2] Cycloaddition-Initiated Cascade Reactions generated after aryne [3 + 2] cycloaddition reaction with vinyl sulfides. Consequently, a proton transfer with a following βelimination could furnish products 9-57; whereas, in the cases of α-ester- and α-acyl-substituted vinyl sulfides (R1 = COR′) 9-56, a successive C-arylation/1,4-proton transfer/β-elimination process occurred to yield products 9-58. A similar transformation was then independently reported by the groups of Yu/Zhang/Meng660 and Li/Chen,661 in which 2-methylenebenzothiophene-3-ones 9-60 reacted with arynes to furnish eight-membered cyclic sulfides 9-61 (Scheme 167b). The mechanism for this transformation involves a tandem [3 + 2] cycloaddition reaction/1,2-proton transfer/C−S bond cleavage process. In 2018, Mo et al. reported a formal [7 + 2] cycloaddition reaction between N-vinyl-α,β-unsaturated nitrones 9-62 and arynes, giving rise to 9-membered benzoxazonines 9-64 (Scheme 168a).662 A cascade [3 + 2] cycloaddition reaction/ [3,3] sigmatropic rearrangement via intermediate 9-63 accounted for the formation of 9-64. Recently, Anderson and co-workers demonstrated a distinct cascade process between N-alkenylnitrones 9-65 and o-silylaryl triflates, furnishing spirocyclic pyrroline cyclohexadienones 9-67 in moderate to excellent yields (Scheme 168b).663 Mechanistically, this transformation commences with a 1,3-dipolar cycloaddition reaction to produce cycloadduct 9-66, which then undergoes a dearomative [3,3]-sigmatropic rearrangement to afford spirocyclic pyrrolines 9-67. 9.1.3. Initiated by [2 + 2] Cycloaddition Reaction. In 2004, Yoshida, Kunai, and co-workers revealed a unique tandem process between aldehydes and arynes. Diverse 9arylxanthene derivatives 9-69 were synthesized through a sequential formal [2 + 2] cycloaddition reaction/isomerization to o-quinone methide 9-68/Diels−Alder reaction with another thiazolidine-2-thiones 9-50, readily prepared from β-amino alcohols 9-49 with DBU and carbon disulfide, underwent a [3 + 2] cycloaddition reaction with benzyne to give intermediate 9-51, which then released olefin 9-52 and byproduct 9-53 via a retro [3 + 2] cycloaddition reaction. This protocol also led to the syntheses of (−)-1-deoxy-D-fructose,657 and iminosugars.658 In 2014, Larock, Shi, and co-worker reported a tandem [3 + 2]/retro [4 + 2]/[4 + 2] cycloaddition process between stable münchnones 9-54 and arynes, affording 9,10dihydro-9,10-epiminoanthracenes 9-55 in good to excellent yields (Scheme 166b).317 3951 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review further developed a tandem [2 + 2] cycloaddition reaction/ pericyclic ring-opening/intramolecular [4 + 2] cycloaddition process to produce nitrogen heterocycles 9-75 in a highly stereoselective manner (Scheme 170).329 This work also led to the total syntheses of chelidonine and norchelidonine, which will be elaborated on in section 15.665 Scheme 168. Aryne [3 + 2] Cycloaddition-Initiated Rearrangement Reactions Scheme 170. Cascade Reactions Triggered by Aryne [2 + 2] Cycloaddition with Enamides In 2013, Studer and co-workers demonstrated a facile preparation of carbazole scaffolds 9-77 in the reaction between nitrosoarenes 9-76 and arynes.666 As depicted in Scheme 171a, Scheme 171. Other [2 + 2] Cycloaddition-Initiated Cascade Reactions molecule of aryne (Scheme 169a).619 This protocol was also employed by Werz et al. on cyclopropenones, furnishing Scheme 169. Cascade Reaction-Triggered by Aryne [2 + 2] Cycloaddition with Aldehydes either NH-carbazoles or N-arylated carbazoles 9-77 were achievable by varying the fluoride source and the solvent. Mechanistically, after the aryne [2 + 2] cycloaddition reaction with nitrosoarenes 9-76 and a cycloreversion, o-quinone derivative 9-78 was generated, which then undergoes an intramolecular electrophilic aromatic substitution and a C− OH bond cleavage by a nucleophile or other pathway on the resulting intermediate 9-79 to afford 9-80. Either protonation or N-arylation on 9-80 could yield the corresponding products spirocyclic xanthene-cyclopropenes.664 In 2012, Wu and coworkers disclosed a tandem reaction between enals 9-70 and arynes, in which 2H-chromenes 9-73 were readily achieved through a successive [2 + 2] cycloaddition reaction/thermal electrocyclic ring-opening on cycloadduct 9-71/6e-electrocyclization of 9-72 process (Scheme 169b).240 In a study carried out by Hsung and co-workers on the aryne [2 + 2] cycloaddition reaction with enamides 9-74, they 3952 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR 9-77. Recently, He et al. reported that the reaction between fluorene-derived N-arylimines 9-81 and arynes could construct spiroacridines 9-82 in modest to good yields, the mechanistic pathway of which includes a successive [2 + 2] cycloaddition reaction/ring-opening/electrocyclization reaction sequence (Scheme 171b).246 9.1.4. Initiated by Other Cycloaddition Reaction. In 2017, Yoo and co-workers disclosed that pyridinium zwitterions 9-83 could serve as unprecedented 1,5-dipoles, which reacted with arynes to yield polycyclic 1,4-benzodiazepines 9-85 (Scheme 172).667 This transformation proceeds Review Scheme 173. Aryne [8 + 2] Cycloaddition-Initiated Cascade Reactions Scheme 172. Aryne [5 + 2] Cycloaddition-Initiated Cascade Reactions through a cascade [5 + 2]/[2 + 2] cycloaddition process involving two molecules of arynes. Their mechanistic studies revealed that the [5 + 2] cycloadduct 9-84 would undergo an immediate [2 + 2] cycloaddition reaction with another molecule of aryne. In 2018, Wang, He, and co-worker undertook a systematic study on the reaction between azaheptafulvenes 9-86 and osilylaryl triflates (Scheme 173a).355 Both cyclohepta[b]indoles 9-87 and polycyclic oxacyclohepta[b]indoles 9-88 were obtained, depending on the stoichiometry of arynes. Mechanistically, cyclohepta[b]indoles 9-87 could be produced through a tandem [8 + 2] cycloaddition/ene reaction sequence; whereas oxacyclohepta[b]indoles 9-88 are assembled via a further [6 + 2] cycloaddition reaction with a third molecule of aryne. Meanwhile, they found that when heteroazulenes 9-89 were employed, a mixture of 9-90a and 990b were obtained, the formation of which followed a similar pathway to that of 9-87 (Scheme 173b).355 Scheme 174. Aryne-Induced Claisen Rearrangements 9.2. Nucleophilic Addition-Initiated Rearrangements 9.2.1. Claisen Rearrangements. Another cascade/ tandem reaction mode is aryne-induced rearrangement transformations.93 In 2009, Greaney and co-workers discovered an aryne aza-Claisen rearrangement of tertiary allylamines 9-91 to yield products 9-92, the mechanistic pathway of which involves a tandem N-arylation of allylamines 9-91/protonation of zwitterion intermediate 9-93 with solvent/aza-Claisen rearrangement on 9-94 (Scheme 174a).668 An alternative pathway including the 6-endo SN2′ reaction of zwitterion intermediate 9-93 was ruled out by using unsymmetrically substituted aryne precursors. This protocol was also applied to cyclic tertiary allylamines, affording benzannulated medium-ring amines through a ring-expansion operation. Subsequently, Saito and co-workers applied this ring-expansion protocol on 2-vinylazetidines 9-95 and furnished benzazocine derivatives 9-96 in 3953 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR modest to high yields (Scheme 174b).669 In 2018, Karunakar et al. reported that secondary allylamines 9-97 could react with arynes to afford ortho-allyl-substituted N-arylanilines 9-98, those of which were further converted to aryl-fused mediumsized heterocyclic molecules via a ring-closing metathesis operation (Scheme 174c).670 9.2.2. [2,3]/[1,2] Sigmatropic Rearrangements. Recent studies revealed that arynes can promote the formation of both quaternary ammonium and sulfonium ylides from tertiary amines and thioethers, respectively, which could in turn induce the following sigmatropic rearrangements. One of the advantages for this strategy on aryne-promoted formation of onium ylides over traditional approaches is its strong-base-free conditions. In 2016, the groups of Gu/Tian671 and Biju672 independently demonstrated an aryne-induced [2,3] Stevens rearrangement transformation on tertiary allylamines 9-99 bearing electron-withdrawing groups, which led to the formation of homoallylic amines 9-100 and 9-101 in modest to high yields with high functional group tolerance (Scheme 175). No aza- Review Scheme 176. Other Aryne Reaction-Induced [2,3] Stevens Rearrangements Scheme 175. Aryne Reaction-Induced [2,3] Stevens Rearrangement terminal or internal ones, the corresponding conjugated dienes 9-109 or amino-substituted allenes 9-110 were obtained, respectively. Recently, Biju and co-workers demonstrated an aryneinduced Sommelet−Hauser rearrangement of tertiary benzylamines 9-111, producing α-aryl amino acid derivatives 9-112 (Scheme 177).676 After the formation of ammonium ylide 9Scheme 177. Aryne Reaction-Induced Sommelet−Hauser Rearrangement Claisen rearrangement was observed in both studies. This transformation follows a sequential nucleophilic addition of tertiary amine to aryne, a proton transfer on intermediate 9102 to furnish a quaternary ammonium ylide 9-103, and a [2,3] Stevens rearrangement. Moreover, both groups examined this protocol on optically active tertiary allylamines and obtained quaternary stereocenters with a retention of enantiopurity and an inversion of configuration. In 2017, Sweeney and co-workers applied this aryne-induced [2,3] Stevens rearrangement protocol on N-(2-malonyl) tetrahydropyridines 9-104 and furnished 3-substituted Naryl-2-acylpyrrolidines 9-105 in modest to excellent yields (Scheme 176a).673 Moreover, Liu et al. employed 1,2,3,4tetrahydroisoquinolines 9-106 as the substrates to readily prepare (E)-3-aryl-2,3,4,5-tetrahydro-1H-3-benzazonines 9107 in highly stereospecific manner (Scheme 176b).674 In 2018, Tian and co-workers reported an aryne-induced [2,3] Stevens rearrangement with tertiary propargylic amines 9-108 bearing electron-withdrawing groups (Scheme 176c).675 Depending on the structure of the propargyl groups, either 113, a [2,3] sigmatropic rearrangement occurred to furnish a dearomatized intermediate 9-114. Upon a 1,3-protron shift, αaryl amino acid 9-112 was generated. This transformation was found to be temperature dependent, preferring the Sommelet− Hauser rearrangement at low temperature, whereas a [1,2] Stevens rearrangement took place at 70 °C. Beside ammonium ylides, sulfonium ylides could also be facilely generated from arynes and thioethers upon S-arylation and deprotonation. In 2017, the groups of Biju677 and Tan/ Xu678 independently reported an aryne-induced [2,3] Stevens rearrangement with allylthioethers 9-115, affording function3954 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR alized β-keto arylthioethers 9-116 and 9-117 in modest to high yields with high functional group tolerance (Scheme 178). In the study carried out by Tan, Xu, and co-workers, propargyl thioethers were also examined.678 Review obtained, albeit in low yields. Notably, their mechanistic studies revealed that both 3-aryl-3-benzazepine 9-122 and the C-arylated product could be formed from a common ammonium ylide intermediate 9-123. Similar transformations were also reported by Voskressensky686 and Guranova.687 9.2.3. Other Rearrangements. In 2011, Greaney et al. realized an aryne Fischer-indole synthesis by using N-tosyl hydrazones 9-124 and o-silylaryl triflates, furnishing Ntosylindoles 9-125 in moderate to high yields (Scheme 180a).688 After N-arylation on 9-124, a one-pot addition of Scheme 178. Aryne Reaction-Induced [2,3] Stevens Rearrangement with Allylthioethers Scheme 180. Other Aryne Reaction-Induced Rearrangement Reactions Aryne-induced [1,2] Stevens rearrangement was reported by Boekelheide and Otsubo in 1975 using anthranilic acid as a benzyne precursor.679 In 2017, Guo, He, and co-workers disclosed a convenient preparation of multisubstituted β-keto thioethers 9-119 from arynes and benzyl thioethers 9-118 bearing β-keto groups (Scheme 179a).680 Upon generation of Scheme 179. Aryne Reaction-Induced [1,2] Sigmatropic Rearrangements BF3·OEt2 promoted the Fischer cyclization reaction. In 2016, the same group demonstrated a unique aryne Truce−Smiles rearrangement, which was triggered by the nucleophilic addition of aryl sulfonamides 9-126 to arynes and afforded biaryls 9-127 under transition-metal-free conditions (Scheme 180b).689 Sterically hindered tri- and tetra-ortho-substituted biaryls could be achieved. Mechanistically, a Smiles-type ipso substitution on intermediate 9-128 occurs to produce Meisenheimer complex 9-129, which in turn undergoes an extrusion of SO2 to produce biaryls 9-127. In 2017, a nucleophilic addition-triggered Fries rearrangement on osilylaryl triflates 9-130 was revealed by Bronner et al., giving rise to 2,3-disubstituted phenols 9-131 in moderate to high yields (Scheme 180c).690 In 2018, Palakodety and co-workers demonstrated a basemediated cyclization of propargylic alcohols 9-132 with arynes, affording 3-benzofuranyl-2-oxindoles 9-133 along with the formation of 3-spirooxindole benzofurans 9-134 as minor products (Scheme 181).691 It was found that the nature of the R2 group on 9-132 could influence the reaction outcome. Mechanistically, O-arylated intermediate 9-135 undergoes a propargyl Claisen rearrangement to generate an allene species sulfonium ylide 9-120, a [1,2] sigmatropic rearrangement occurred to produce the product 9-119. Inspired by Boekelheide’s early study,679 o-silylaryl triflates were recently utilized in ring-contraction transformations with thioethers via the [1,2] Stevens rearrangement pathway.681−684 In 2018, Liu and Pan reported that substituted 1,2,3,4-tetrahydroisoquinolines 9-121 could participate in the aryne-induced [1,2] Stevens rearrangement, affording 3-aryl-3-benzazepines 9-122 in moderate to high yields (Scheme 179b).685 In addition, under reduced temperature, α-arylated products were 3955 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review enantioenriched α-chiral alkanoyl hydrazides were used, complete retention of the configuration was observed. Besides, water, amines, alkoxyamine, and thiophenol could all serve as efficient nucleophiles in this transformation. Scheme 181. Aryne Cascade Reactions with Propargylic Alcohols 9.3. Nucleophilic Addition-Triggered Other Cascade Reactions Aryne arylation reaction could trigger subsequent cascade/ tandem reactions as well. In 2015, Hwu and co-workers accomplished an unprecedented aryne-induced tandem Narylation/[3 + 2] cycloaddition process using 2 equiv of Schiff bases 9-141, furnishing imidazolidines 9-142 in good to high yields (Scheme 183).693 Mechanistically, after an aryneScheme 183. Tandem N-Arylation/[3 + 2] Cycloaddition Reaction induced formation of ylide species 9-143 from the Schiff base, a subsequent [3 + 2] cycloaddition reaction with another molecule of the Schiff base takes place to construct 9-142 in high diastereoselectivity. In addition, electron-deficient alkenes were also utilized as the third component in this transformation, giving rise to highly substituted pyrrolidines. Meanwhile, Voskressensky et al. investigated aryne-induced arylation−Hoffman cleavage processes.694,695 In 2014, they studied the reaction between arynes and 10-carbamoylsubstituted benzo[b][1,6]naphthyridines 9-144 and obtained 2-vinylquinolines 9-146, albeit in low to moderate yields (Scheme 184a).694 After nucleophilic addition to aryne, a Hoffman-type fragmentation occurred on intermediate 9-145. In 2018, the same group realized a similar cascade process by using tetrahydropyrido[4,3-d]pyrimidin-4-ones 9-147 condensed with isoxazole, thiazole, thiadiazole, or triazole rings as the substrates, furnishing 6-vinyl-substituted pyrimidones 9148 fused with the corresponding azole rings via a Hofmann cleavage of the tetrahydropyridine moiety (Scheme 184b).695 In a study carried out by Hoye et al. on the reaction of hexadehydro-Diels−Alder (HDDA) aryne with natural products, they showed one example between tropinone (9-149) and Kobayashi benzyne precursor, leading to the formation of product 9-150 in 66% yield (Scheme 184c).167 In 2015, Voskressensky and co-workers studied the reaction between 4-hydroxymethylisoindolines 9-151 and o-silylaryl triflates and obtained 4-aminomethyl-substituted dihydroisobenzofuran derivatives 9-152 in good to high yields. This transformation involves a nucleophilic addition to aryne by the tertiary amine and a subsequent intramolecular recyclization via intermediate 9-153 (Scheme 185a).696 In 2018, in a derivatization study on the natural product lycorine, Hergenrother et al. observed an unusual reaction behavior of 9-154 with benzyne, which involves a benzyne-induced N- 9-136, which is followed by a 5-exo-dig cyclization to give intermediate 9-137. Upon protonation, product 9-133 could be obtained. Meanwhile, a small portion of intermediate 9-135 participates in an intramolecular nucleophilic addition on alkyne, producing 3-spirooxindole benzofurans 9-134 after protonation. In 2018, Tian et al. accomplished a benzyne-induced Curtius-type rearrangement with N′-methyl-N′-phenyl acyl hydrazides 9-138 in the presence of various nucleophiles (Scheme 182).692 An isocyanate intermediate 9-140 was proposed from the reaction of benzyne and acyl hydrazide 9138, which could then react with alcohols to yield carbamates 9-139 (NuH = ROH) in modest to excellent yields. When Scheme 182. Benzyne-Induced Curtius-Type Rearrangement 3956 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review In 2018, Guranova and co-workers reported their study on thieno[2,3-c]pyrrolines 9-156 bearing a branched substituent on the nitrogen atom and discovered the formation of thienylaziridines 9-157 (Scheme 186).687 Mechanistically, the Scheme 184. N-Arylation−Hoffman Cleavage Cascades Scheme 186. Aryne Cascade Reaction with Thieno[2,3c]pyrrolines generated ammonium ylide 9-158 participates in a 6πelectrocyclic opening to give intermediate 9-159, which then undergoes an intramolecular 1,6-hydrogen shift to produce the resonance-stabilized azomethine ylide 9-160. A subsequent 4πelectrocyclization would yield thienylaziridines 9-157. Recently, Almqvist and co-workers reported an aryneinduced cascade formation of 6-arylthio-substituted-N-alkenyl 2-pyridones 9-162 from bicyclic thiazolino-2-pyridones 9-161 (Scheme 187).698 Although the classical Kobayashi benzyne Scheme 185. N-Arylation-Triggered Cascade Reactions Scheme 187. S-Arylation-Triggered Cascade Reactions precursor only gave the corresponding products in low to moderate yields, the employment of the 3-methoxybenzyne precursor could significantly enhance the reaction efficiency with distinct regioselective control. Notably, this process preferred a thioether ring-opening pathway over a potentially competing [4 + 2] cycloaddition reaction. Tandem reactions involving C-arylation with arynes were reported. In 2011, Peña, Guitián, and co-workers revealed a formal aryne insertion into the C(sp)−O σ-bond of ethoxyacetylene (9-163), giving rise to 2-ethoxyethynylaryl derivatives 9-164 (Scheme 188).699 Both the experimental observation with 3-methoxybenzyne and computational studies suggested that, instead of a nucleophilic addition of the oxygen atom to aryne, this transformation initiates with a nucleophilic addition by the triple bond carbon to generate zwitterionic structure 9-165, which could cyclize to produce intermediate arylation of 9-154 and a ring rearrangement process to yield 9155 in 41% yield (Scheme 185b).697 3957 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review cleavage/cyclization process, although other mechanistic pathways might not be excluded. In 2017, Gogoi et al. accomplished an aryne-induced isomerization from coumarin to isocoumarin (Scheme 190a).702 3-Substituted isocoumarins 9-177 were readily Scheme 188. Aryne Reaction with Ethoxyacetylene Scheme 190. C-Nucleophile-Triggered Aryne Cascade Reactions 9-166. Consequently, 9-166 would convert to products 9-164 via a concomitant 1,2-hydrogen migration and ring-opening. Despite this proposed mechanistic pathway, there might be other possibilities. In 2016, Pirali and co-workers revealed that the reaction of secondary α,α′-disubstituted α-isocyanoacetamides 9-167 with arynes could afford 2-arylimidazolones 9-168, whereas those of α-nonsubstituted and α-monosubstituted isocyanoacetamides only yielded complex mixtures (Scheme 189a).700 MechanisScheme 189. Isocyano Group-Triggered Aryne Cascade Reactions prepared from 4-hydroxycoumarins 9-173 and o-silylaryl triflates with high functional group tolerance. Mechanistically, a four-membered ring intermediate 9-175 could be first generated from anion 9-174, which then undergoes a ringopening to form ketene intermediate 9-176. Upon ring closure, isocoumarin product 9-177 could be obtained. Recently, John, Hopf, and co-workers reported another C-arylation/cyclization process between 4-haloacetoacetates 9-178 and arynes, affording 4-aryl-3-(2H)-furanones 9-179 in moderate to good yields (Scheme 190b).703 9.4. Nucleophilic Annulation-Induced Cascade Reactions Cascade processes involving nucleophilic annulation with osilylaryl triflates were reported. In 2008, Liang, Li, and coworkers demonstrated a facile preparation of benzofurans 9181 from arynes and iodonium ylides 9-180 (Scheme 191a).704 They proposed that this cascade process occurs through a nucleophilic addition of zwitterion intermediate 9182 to benzyne to generate intermediate 9-183, which undergoes an intramolecular cycloaddition to give either intermediate 9-184 or 9-185. A subsequent reductive elimination could construct benzofurans 9-181. In 2010, Lin, Wang, and co-workers disclosed an efficient synthesis of indole scaffolds 9-187 from 2-azidoacrylates 9-186 and o-silylaryl triflates in the presence of PPh 3 (Scheme 191b). 705 Mechanistically, this transformation commences with a nucleophilic double cyclization of iminophosphoranes 9-188, generated from 2-azidoacrylates 9-186 and PPh3, with benzyne to produce 9-189. Hydrolysis on intermediate 9-189 will give intermediate 9-190, which could then be converted to indole product 9-187 after dehydrogenative oxidation. tically, a 1,4-zwitterion 9-169 is first proposed after nucleophilic addition. After intramolecular proton abstraction from amide, the generated intermediate 9-170 could then cyclize to yield 2-arylimidazolone 9-168. In 2018, Chen, Li, and co-workers reported a domino reaction between 2isocyanophenyloxyacrylates 9-171 and arynes, furnishing compounds 9-172 by installing an olefin and a benzoxazole on the vicinal positions of a benzene ring (Scheme 189b).701 They proposed that this cascade process proceeds through a successive nucleophilic addition/Michael addition/C−O bond 3958 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 191. Aryne Nucleophilic Annulation-Induced Cascade Reactions Review Scheme 192. Aryne Cascade Reactions with Hydrazones and Hydrazides Scheme 193. Aryne Cascade Reactions with Aziridines and 3,4-Dihydroisoquinolines Hydrazones and hydrazides were also employed in cascade aryne transformations. In 2011, Larock et al. revealed that o(dimethylamino)aryl ketones 9-192 could be achieved in moderate to excellent yields from the reaction of 1,1dimethylhydrazones of aldehydes 9-191 with arynes, the mechanism of which involves a nucleophilic annulation to afford dihydroindazole intermediate 9-193 and a subsequent ring opening pathway (Scheme 192a).706 Moreover, acridones were obtained from o-halobenzaldehyde hydrazones, the formation of which included an additional intramolecular SNAr reaction and demethylation. Recently, Chudasama and co-workers reported a preparation of 2-hydrazobenzophenones 9-195 from arynes and readily achievable acyl hydrazides 9194 (Scheme 192b).707,708 Three plausible pathways were proposed for this transformation, all of which could lead to the formation of 9-195. The 2-hydrazobenzophenone products 9195 could be further converted to 1H-/2H-indazoles707 and 2aminobenzophenones.708 In a study carried out by Wu, Sha, and co-workers on the reaction between 2-carboxylic acid ester substituted aziridines 9-196 and arynes, they found that indole spiro-derivatives 9197 were obtained under anhydrous conditions (Scheme 193a).591 Mechanistically, ammonium salt 9-198 could be formed via an aryne nucleophilic annulation reaction, which is then converted to 1-benzyl-2-methyleneindolin-3-ones 9-199 through ring-opening. Next, dimerization via the Diels−Alder reaction occurs on 9-199 to yield products 9-197. In 2016, Voskressensky et al. revealed a unique aryne-induced aryl anion migration event in the reaction of arynes with 1-aroyl3,4-dihydroisoquinolines 9-200 (Scheme 193b).709 The formation of 12a-aryl substituted indoxylisoquinolines 9-201 was proposed to proceed through the reformation of the carbonyl group on oxy-anion 9-202 with a concomitant aryl group migration. In 2016, He and co-workers realized a cascade process between aza-Morita−Baylis−Hillman (AMBH) adducts 9-203 3959 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR and o-silylaryl triflates, furnishing 4-quinolone derivatives 9204 in moderate to high yields with a broad substrate scope (Scheme 194a).350 This transformation involves an aryne Review Scheme 195. Aryne C−C Bond Insertion-Initiated Cascade/ One-Pot Reactions Scheme 194. Aryne Cascade Reactions with Allyl Amines and Carbamoylpropiolates 195b).712 Moreover, 4-aryl-2-naphthols 9-212a prepared through this protocol were utilized in the synthesis of binaphtols.712−715 In order to solve the lack of regioselectivity problem in Okuma’s study,712 Suzuki and co-workers proposed to use ketodioxinones 9-213 as the substrate in a tandem aryne acylalkylation/intramolecular aldol condensation process, which could yield functionalized β-hydroxynaphthoate derivatives 9214 in a highly regioselective manner (Scheme 196a).716 Mechanistically, after nucleophilic addition to form intermediate 9-215, the generated aryl anion preferentially attacks the more electrophilic ketone carbonyl group, hence, exclusively affording intermediate 9-216. In 2019, Muthukrishnan et al. accomplished a benzannulation reaction of 1,3oxopentanedioates 9-217 with o-silylaryl triflates, giving rise to highly functionalized naphthalene derivatives 9-218 in moderate to high yields (Scheme 196b).717 Furthermore, they converted the naphthalene derivatives into a series of rhodamine dye analogues. Meanwhile, Pabbaraja, Mehta, and co-workers disclosed a cascade process to produce 9-220a and 9-220b, when unsubstituted dimethylacetonedicarboxylates (9-219) (R1 = H) reacted with arynes (Scheme 196c).718 Interestingly, when C2-substituted dimethylacetonedicarboxylates 9-221 (R1 ≠ H) were employed, the aldol condensation step became highly selective, leading to the formation of compounds 9-222 in good to high yields. This preferred cyclization pathway was attributed by the stereoelectronic factors with respect to the R1 group. In addition, Okuma et al. examined the reaction of trifluoromethylated β-diketones 9-223 with arynes.719,720 As shown in Scheme 197, polysubstituted isocoumarins 9-224 were obtained in moderate to good yields, the formation of which proceeds through an extrusion of CF3 anion after a C−C bond insertion/cyclization process. This study also led to the preparation of natural products thunberginol A and xyridine A.719 Other interesting cascade processes initiated by aryne acylalkylation were recently reported. Huang, Fu, Huang, and coworkers discovered an unusual cascade process between arynes and α,γ-diketo esters 9-225, which led to the formation of highly functionalized indanes 9-226 in modest to high yields (Scheme 198a).721 Based on their theoretical study, a nucleophilic annulation reaction to generate intermediate 9205 and a subsequent ene reaction with another molecule of aryne. Similarly, in a study carried out by Mhaske et al. on the aryne nucleophilic annulation reaction with carbamoylpropiolates 9-206, they observed the formation of spirooxindolopyrrolidones 9-207, which was realized through a Michael addition/annulation event on oxindolylidene acetate 9-208 with another molecule of carbamoylpropiolate 9-206 (Scheme 194b).468 9.5. Insertion Reaction-Triggered Cascade Reactions 9.5.1. Through C−C Bond Insertion. The uniqueness of carbon−carbon σ-bond insertion by arynes is its ready assembly of two new C−C bonds on the arene ring, which could then be converted to different useful frameworks, such as natural products bearing polycyclic ring systems. Along with the study carried out by Stoltz and co-workers on aryne insertion into the C−C σ-bonds of β-ketoesters, they developed two one-pot procedures for aryne acyl-alkylation/ condensation, which could further convert the aryne insertion products to either 3-hydroxyisoquinolines 9-209 or 2-hydroxy1,4-naphthoquinones 9-210 (Scheme 195a).710 This protocol was also applied in the total syntheses of (−)-jorunnamycin A and (−)-jorumycin,711 unraveling its great potential toward polycyclic ring systems. Subsequently, Okuma et al. employed aroylacetones 9-211 as the substrates and realized a tandem aryne insertion/intramolecular aldol reaction/dehydration process, furnishing 4-aryl-2-naphthols 9-212a and 3-aryl-1naphthols 9-212b, albeit in poor regioselectivity (Scheme 3960 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 196. Aryne Cascade Reactions with Analogues of Acetonedicarboxylate Review Scheme 198. Other Aryne C−C Bond Insertion-Initiated Cascade Reactions produced, respectively (Scheme 199a).512 The mechanism for this reaction includes an aryne insertion into the C−O σ-bond of carboxylic acids and an intramolecular Michael addition on 9-235 to furnish the annulated products 9-234. Subsequently, Ma and co-workers demonstrated that 2,3-allenoic acids 9-236 could react with arynes through a sequential C−O σ-bond insertion and intramolecular Michael addition on intermediate 9-238, which could afford chromone derivatives 9-237 in moderate to excellent yields (Scheme 199b).723 In 2017, Mhaske et al. reported a sequential aryne insertion into the C− O bond of silyl-protected acid 9-239 and the intramolecular Michael addition reaction, giving cyclohexenone-fused spirobenzofuran-3-one analogues 9-240 that share the same core structure with natural product leptosphaerin C (Scheme 199c).724 In 2012, the groups of Larock and Shi725 and Stoltz726 independently reported the reaction between β-lactams and arynes (Scheme 200). N-Unsubstituted β-lactams 9-241 (R1 = H) were found to react with arynes to afford acridones 9-242. Mechanistically, this cascade transformation involves (1) aryne insertion into the strained C−N σ-bond of β-lactams to form 2,3-dihydroquinolin-4-ones 9-243; (2) nucleophilic annulation reaction with another molecule of aryne to generate 9-244; (3) extrusion of ethylene; (4) N-arylation with another molecule of aryne to give acridones 9-242 (R′ = Ar). Moreover, Larock, Shi, and co-workers found that N-alkyl dihydroquinolinone 9241 (R1 = alkyl) could furnish acridones 9-242 (R′ = alkyl) with arynes; whereas N-phenyl dihydroquinolinone gave only a trace amount of the desired product.725 In 2011, Alajarin, Lopez-Leonardo, and co-workers revealed an aryne insertion into the PN bond of both P-alkynyl-λ5phosphazenes 9-245 and P-alkenyl-λ5-phosphazenes 9-247, Scheme 197. Preparation of Isocoumarins from Trifluoromethylated β-Diketones mechanism was suggested: after nucleophilic addition of 9-225 to aryne, aryl anion 9-227 could be converted to 9-229 via the ring-opening of benzocyclobutene intermediate 9-228; subsequent cyclization on 9-229 would then furnish product 9226. Another example was reported by Ramachary et al., in which benzannulated bicyclo[3.3.0]octanes 9-231 were readily achieved from lawsones 9-230 and o-silylaryl triflates in a highly selective manner (Scheme 198b).722 It was reasoned that, after the formation of tertiary alkoxide 9-232, an alkoxideinduced C−C bond rearrangement could happen to produce 9-231. 9.5.2. Through Other Insertion Reactions. Along with the study carried out by Larock on aryne insertion into the C− OH σ-bond of carboxylic acids, they disclosed that when both acrylic and propiolic acids 9-233 were utilized, the corresponding 4-chromanones and flavones 9-234 could be 3961 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 199. Cascade Reactions via Aryne C−O Bond Insertion/Michael Addition Pathway Review Scheme 201. Cascade Reaction Initiated by Aryne Insertion into PN Bond Scheme 202. Aryne Cascade Reaction with Allyl Sulfoxides Scheme 200. Aryne Cascade Reaction with β-Lactam 1,2,3-trisubstituted arenes 9-253 in a highly selective manner. Three chemical bonds, namely, C−S, C−O, and C−C bonds, were assembled on the consecutive positions of a benzene ring. By using substituted aryne precursors, up to pentasubstituted arenes could be conveniently prepared. In 2017, Yoshida, Hosoya, and co-workers disclosed that oarylthio-substituted diaryl ethers 9-256 could be obtained from arynes and diaryl sulfoxides by conducting the reaction at high temperature, the mechanism of which involves an intramolecular migratory O-arylation via intermediates 9-254 and 9-255 (Scheme 203a).729 In 2017, Studer and Li reported an unprecedented transformation between arynes and vinyl sulfoxides 9-257, affording o-sulfinylaryl vinyl ethers 9-258 (Scheme 203b).730 It was proposed that after the formation of 9-259, a stereospecific S to O vinyl group migration occurred to produce products 9-258. They also observed that water was an essential additive to suppress fluoride-mediated disproportionation of sulfoxide. Recently, Peng and co-workers revealed two desulfurization reactions between benzyne and diaryl/ heteroaryl sulfoxides, producing biaryls 9-260 and desulfurized heteroarenes 9-261, respectively (Scheme 203c).731 Both their mechanistic study and theoretical calculations suggested the leading to the formation of the corresponding 1,4-benzazaphosphorinium triflates 9-246 and 9-248, respectively, in good to excellent yields (Scheme 201).727 Mechanistically, the overall transformation involves a successive formal [2 + 2] cycloaddition reaction to generate 9-249/retro [2 + 2] cycloaddition reaction to produce 9-250/6π-electrocyclization to afford 9-251/protonation process. In 2016, Li and co-workers realized a cascade threecomponent coupling reaction of arynes, aryl allyl sulfoxides 9-252, and an electrophile (Scheme 202).728 This transformation proceeds through a unique combination of aryne insertion into the SO bond of sulfoxides with a subsequent C−H bond functionalization via rearrangement, furnishing 3962 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review dented radical mechanism was proposed: a biradical intermediate 9-265 can be first generated from the reaction between thioaldehyde 9-263 and benzyne, which is followed by a proton abstraction to form intermediate 9-266 and an internal combination to afford 9-264. In 2013, Hwu et al. demonstrated a unique and efficient transition-metal-free preparation of phenanthrenes 9-268 from allenylsilanes 9-267 and o-silylaryl triflates (Scheme 205).733 Scheme 203. Other Cascade Reactions via Aryne Insertion into SO Bonds Scheme 205. Aryne Cascade Reactions with Allenylsilanes Notably, the stabilizing ability of the β-silyl group through the hyperconjugation was proposed to promote the formation of zwitterionic adducts 9-269. Annulation of 9-269 with another molecule of aryne could produce intermediate 9-270, which then undergoes oxidation to give products 9-268. In 2018, Jones et al. revealed a transition-metal-free cross-dehydrogenative coupling reaction on o-silylaryl triflates 9-271, furnishing α-functionalized heterocyclic and aliphatic tertiary amines 9272 (Scheme 206).734 Their deuterium labeling studies Scheme 206. Aryne Cascade Reactions via Intramolecular 1,5-Hydride Transfer generation of a common tetraaryl(heteroaryl) sulfurane species 9-262 that could proceed through two disassembly pathways to give either 9-260 or 9-261, the formation of which was determined by the electronic property of the substrates. 9.6. Other Cascade Reactions In a study carried out by Okuma and co-workers on the reaction between benzyne, generated from different precursors, and a sterically congested thione 2,4,6-tri-tert-butylthiobenzaldehyde (9-263), they obtained 5,7-di-tert-butyl-3,3-dimethylindan-1-yl phenyl sulfide (9-264) in 86% yield with the Kobayashi benzyne precursor (Scheme 204).732 An unpreceScheme 204. Aryne Cascade Reaction with Sterically Congested Thione suggested that the cleavage of the α-C−H bond of amine via an intramolecular 1,5-hydride transfer on aryne 9-273 accounts for the formation of aryl anion 9-274, which could then deprotonate a range of “pronucleophiles”, such as acetonitrile, chloroform, nitromethane, and phenylacetylene. Consequently, those nucleophiles would in turn attack the iminium ion and yield products 9-272. In a study carried out by Li, Lai, Kira, and co-workers on the reaction of stable monomeric dialkylstannylene 9-275 with benzyne, they observed the formation of 9-276 in 75% yield (Scheme 207).735 A plausible mechanism was proposed: (1) 3963 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review Scheme 207. Aryne Cascade Reaction with Dialkylstannylene Scheme 208. Pd-Catalyzed [2+ 2 + 2] Cyclotrimerization of Arynes initially formed stannacyclopropene 9-277 transforms to zwitterion 9-278; (2) one of the silyl groups on 9-278 then migrates to aryl anion to generate stannene 9-279; (3) insertion of the CSn bond into a C−H bond of the migrated TMS group could afford product 9-276. combination of Pd(PPh3)4 and o-silylaryl triflates worked well. In contrast, the employment of 1,2-dibromobenzene as the benzyne precursor and n-BuLi as the activating reagent afforded triphenylene only in low yield. Notably, symmetrically substituted aryne gave symmetric triphenylene derivative, whereas 3-methoxybenzyne afforded a mixture of isomers 10-2a and 10-2b in a 93:7 ratio. Based on these observations, they proposed a preferential formation of complex 10-3. Since then, they employed the Pd-catalyzed [2 + 2 + 2] cyclotrimerization strategy in the preparation of a variety of polycyclic aromatic hydrocarbons, which will be discussed in section 15.110,744−746 In addition, Don et al. disclosed that a Pd(II)−Pb(II) bimetallic metal−organic framework (MOF) using N-heterocyclic dicarbene ligand could serve as an efficient heterogeneous catalyst in aryne cyclotrimerization.747 As shown in Scheme 209, a general mechanism for this cyclotrimerization was proposed. Sequential complexation of 10. TRANSITION-METAL-CATALYZED REACTIONS Transition metal π-complexes with arynes have long been studied since several decades ago. During the early era of this field, both early transition metals (Ti, Zr, Nb, Mo, W, Re, V, etc.) and late transition metals (Ni, Pt, Ru, and Pd) were investigated.736−742 One property of the transition metal πcomplexes with arynes is that this coordination mode can release part of the ring strain on those angle-strained arynes, leading to the formation of stable complexes. These early studies, however, mainly focused on the coordination of transition metal with arynes using stoichiometric amounts of metal reagents, whereas only limited synthetic applications with zirconium-aryne complexes were reported.736,739,740 Not until the end of 1990s were transition-metal-catalyzed aryne transformations commenced. Because of the mild generation conditions with respect to Kobayashi’s method and its tunable aryne generation rate, this method was found to be well suited for transition metal catalysis. Consequently, there has been a rapid development in this field of aryne chemistry in the past 2 decades.73,77,90,98 Here in this section, transition metalcatalyzed aryne transformations will be classified by metals. Scheme 209. Proposed Mechanism for Pd-Catalyzed [2+ 2 + 2] Cyclotrimerization 10.1. Palladium-Catalyzed Reactions Palladium is the earliest as well as the most investigated transition metal compatible with o-silylaryl triflates in catalytic aryne chemistry. Since the first discovery by Guitián, Pérez, and co-workers in 1998,743 Pd-catalyzed aryne transformations have been broadly explored. Based on the type of active palladium intermediates involved in catalytic cycles, these Pdcatalyzed aryne transformations could be classified into [2 + 2 + 2] cyclotrimerization, π-allylpalladium-involved reactions, arylpalladium-involved reactions, alkyl/vinylpalladium-involved reactions, azapalladium-involved reactions, and Pd-catalyzed aryne insertion into element−element σ-bonds. 10.1.1. (Co)cyclotrimerization. The earliest investigated reaction mode was Pd-catalyzed aryne [2 + 2 + 2] cyclotrimerization. In 1998, Pérez, Guitián, and co-workers reported the first Pd-catalyzed [2 + 2 + 2] cyclotrimerization of arynes that could readily prepare triphenylene derivatives 10-1 (Scheme 208).743 In this study, they examined various Pdcatalysts as well as aryne precursors and found that the Pd(0) catalyst with two benzynes furnishes complex 10-4, which then leads to the formation of a five-membered palladacycle 10-5. After binding with benzyne intermediate, triphenylene can be produced from 10-6 along with the regeneration of Pd(0) catalyst. It can be envisioned that the replacement of one or two arynes with other unsaturated bonds, such as alkynes, alkenes, and allenes, in this [2 + 2 + 2] cycloaddition strategy would construct more versatile and useful frameworks other than 3964 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review threne derivatives 10-13 in moderate to excellent yields (Scheme 212a).752 Similar type of reaction was later reported triphenylene scaffolds. The efficiency of this strategy, however, would be affected by the production of complex mixtures due to a lack of chemoselectivity. Pleasingly, by carefully varying the reaction conditions, this problem could be solved. In 1999, Pérez, Guitián and co-workers found that dimethyl acetylenedicarboxylate (DMAD) could participate in a chemoselective cocyclotrimerization with arynes in the presence of palladium catalysts (Scheme 210).748−750 By simply switching the choice Scheme 212. Pd-Catalyzed Aryne Cocyclotrimerization of Arynes with Olefins Scheme 210. Aryne Cocyclotrimerization with DMAD of appropriate Pd-catalyst, two types of products, phenanthrenes 10-7 via aryne−aryne−alkyne cyclization and naphthalenes 10-8 via aryne−alkyne−alkyne cyclization, were obtained in this reaction. The employment of Pd(PPh3)4 afforded substituted phenanthrenes 10-7 as the major products; whereas Pd2(dba)3 led to the preferential formation of naphthalenes 10-8. In this study, an experimental evidence suggested complex 10-9 from Pd(PPh3)4 and DMAD; while Pd2(dba)3 was expected to form palladacycle 10-10 with DMAD. Polycyclic aryne precursors were also examined, which showed the same reaction behavior.750 One drawback on Pérez and Guitián’s system is that electron-rich alkynes normally give phenanthrenes in low yields.748 Right after this early investigation, Yamamoto and co-workers reported an alternative Pd(OAc)2/(o-tol)3P system for an efficient cocyclotrimerization of alkynes with benzyne to exclusively produce phenanthrenes 10-11 (Scheme 211).751 Various electron-rich alkynes could be employed to efficiently furnish phenanthrene skeletons in good yields. by Lee et al. by using oxadisilole fused oxabicyclic alkenes 1014 to obtain exo-adducts 10-15 (Scheme 212b).753 In 2006, Peña, Pérez, and co-workers revealed that electron-deficient alkenes could participate in this Pd-catalyzed cocyclotrimerization reaction, which led to the production of dihydrophenanthrenes 10-16 by using PPh3 as the ligand or ortho-olefinated biaryls 10-17 in the presence of P(o-tol)3 ligand (Scheme 212c).754 In 2018, Peña et al. employed diiodo compound 1018 as the precursor of pyramidalized alkene and achieved cyclotrimerized products 10-19 with arynes (Scheme 212d).755 Allenes have also been utilized as the third component in aryne cocyclotrimerization reactions. In 2009, Liang, Li, and co-workers first applied allenes 10-20 in a Pd-catalyzed cocyclotrimerization reaction with arynes, affording phenanthrene analogues 10-21 in modest to good yields (Scheme 213a).756 In 2013, Ma et al. reported a Pd-catalyzed preparation of phenanthrene derivatives 10-23 from propargylic carbonates 10-22 and Kobayashi benzyne precursor (Scheme 213b).757 In this study, an allenylic palladium species 10-24 was proposed to be first generated from 10-22, which could then react with two molecules of benzyne to produce phenanthrene derivatives 10-23 after annulation. Another type of Pd-catalyzed [2 + 2 + 2] cocyclotrimerization employs only one aryne, and the other two components can be either alkenes or alkynes. In 2003, Pérez, Guitián, and co-workers demonstrated a Pd-catalyzed [2 + 2 + 2] Scheme 211. Pd-Catalyzed Cocyclotrimerization of Arynes with Electron-Rich Alkynes Along with the study on alkyne-aryne cocyclotrimerization, people also revealed that olefins could serve as efficient partners with a broad spectrum of applications. One prevailingly investigated approach was to assemble two arynes and one olefin together to a central 6-membered ring under Pd-catalyzed conditions, which can be seen as an aryne−arynealkene cocyclotrimerization reaction mode. In 2004, Cheng and co-workers demonstrated a Pd-catalyzed cocyclotrimerization of bicyclic alkenes 10-12 and o-silylaryl triflates, furnishing the corresponding norbornane anellated 9,10-dihydrophenan3965 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 213. Pd-Catalyzed Cocyclotrimerization of Arynes with Allenes Review Scheme 215. Pd-Catalyzed Aryne Reaction with Conjugated Dienes cocyclotrimerization of arynes with benzodiynes 10-25, which could achieve benzo[b]fluorenones 10-26 (Scheme 214a).758 Scheme 214. Pd-Catalyzed Aryne-Alkyne-Alkyne Cocyclotrimerization intermediate 10-31. Upon reductive elimination and oxidative aromatization, naphthalene derivatives 10-30 could be obtained (Scheme 215). 10.1.2. With π-Allylpalladium Species. The aforementioned Pd-catalyzed cyclotrimerization strategies normally employ three π-bond-containing components, those of which include either three arynes or arynes with various stoichiometric amounts of alkynes/alkenes. Other than those π-bondcontaining species, π-allylpalladium as a relatively stable species was found to be an efficient intermediate in Pd-catalyzed aryne transformations. In 2000, Yamamoto and co-workers first revealed a Pd-catalyzed annulation reaction between o-silylaryl triflates and allyl chlorides 10-32 via a controlled sequential incorporation of two arynes onto π-allylpalladium species (Scheme 216).762,763 In the presence of [Pd2(dba)3]·CHCl3 as the catalyst, a combination of Kobayashi benzyne precursor with allyl chloride could construct phenanthrene derivatives 10-37 along with 10-37′ as the minor products. As shown in Scheme 216, a proposed mechanism involves the insertion of benzyne into π-allylpalladium species 10-33 to give 10-34. After another benzyne insertion, intermediate 10-35 could be generated. Subsequent intramolecular carbopalladation on 1035 produces intermediate 10-36, which then undergoes βhydride elimination and alkene isomerization to afford phenanthrene products 10-37. Recently, Dong et al. also revealed that a Pd(II)−Pb(II) bimetallic metal−organic framework (MOF) using N-heterocyclic dicarbene ligand could catalyze the coupling reaction of aryne with various allyl halides, giving rise to phenanthrene products.764 Since Yamamoto’s initial success on the π-allylpalladiuminvolved aryne annulation reaction, this protocol has received much attention. In the same year, Yamamoto et al. reported a 1,2-diallylation of benzyne through bis-π-allylpalladium complex 10-38, which was generated from allyl chloride and allyltributylstannane (Scheme 217a).765 This in situ generated In this study, they noticed that both the steric and electronic properties of a diyne species could significantly affect the reaction outcome. This reaction mode was further examined by Sato, Mori, and co-workers in their preparation of arylnaphthalene derivatives 10-28 from diynes 10-27 (Scheme 214b).759,760 Notably, those diynes containing a Weinreb amide moiety could deliver 10-28 in the highest yields. This method was also used in the total syntheses of taiwanins C & E759 and dehydrodesoxypodophyllotoxin,760 which will be elaborated on in section 14. One interesting discovery was reported by Argade et al. in 2013, where they employed an unsymmetrically conjugated dienes 10-29 to react with arynes in the presence of Pd-catalyst (Scheme 215).761 Naphthalene derivatives 10-30 were obtained. Control experiments revealed that this reaction cannot proceed through a straightforward Diels−Alder reaction pathway due to the steric repulsion of the aryl group on diene. Instead, Pd-catalyzed cyclopalladation of aryne with the first alkene, followed by an intramolecular insertion of the second alkene, could afford seven-membered palladacycle 3966 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 216. π-Allylpalladium-Involved Aryne Carbocyclization Reactions Review Scheme 217. π-Allylpalladium-Involved Aryne ThreeComponent Coupling Reactions bis-π-allylpalladium species 10-38 is amphiphilic, permitting an ortho double allylation on benzyne to produce 10-39. Subsequently, Cheng and co-workers utilized this protocol to develop several unique transformations. They first demonstrated two similar transformations using either alkynylstannanes766 or allenylstannanes767 as the third components to couple with π-allylpalladium species, furnishing the corresponding products 10-40 (Scheme 217b) and 10-41 (Scheme 217c), respectively. In 2005, they realized a Pd-catalyzed threecomponent coupling reaction of allyl halides, arynes, and arylboronic acids, leading to the formation of o-allylbiaryl derivatives 10-42 in good to high yields (Scheme 217d).768 In 2008, the same group reported a Pd-catalyzed MCR of osilylaryl triflates, allylic acetates/halides, and terminal alkynes in the presence of catalytic amount of CuI, which could produce 1-allyl-2-alkynylbenzene derivatives 10-43 in good to excellent yields (Scheme 217e).769 Variations of this reaction mode were reported as well. In 2009, Li, Liang, and co-workers realized a Pd-catalyzed aryne coupling reaction using allylic alkynoates 10-44 as the source of both allyl and alkynyl moieties, which yielded 1-allyl-2ethynylbenzenes 10-45 (Scheme 218a).770 This transformation was enabled by a Pd-catalyzed decarboxylative activation of 1044. In 2015, Werz et al. demonstrated a Pd-catalyzed threecomponent coupling reaction of arynes, terminal alkynes, and vinyl cyclopropane dicarboxylate (10-46), furnishing 1-allyl-2alkynylbenzenes 10-47 in moderate to good yields (Scheme 218b).771 In this study, a π-allylpalladium species 10-48 was proposed to be generated from vinyl cyclopropane dicarboxylate 10-46 through the ring opening of vinyl cyclopropane with Pd(0). Scheme 218. Other π-Allylpalladium-Involved Aryne Reactions with Alkynes In 2001, Chatani, Murai, and co-workers disclosed that πallylpalladium species could participate in a MCR of benzyne, allyl acetates, and CO, and the generated 2-methyleneindanone derivatives 10-49 could be reached via a carbopalladation of 3967 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review reactions through either oxidative addition of Pd(0) to aryl halides or directing-group assisted C−H bond activation. One challenge for the success of this strategy is how to manipulate the reaction of highly reactive arylpalladium species with transient aryne intermediates in a tunable manner. 10.1.3.1. Six-Membered Carbocycles. In 2005, Larock et al. demonstrated the first Pd-catalyzed annulation reaction of arynes with 2-halobiaryls 10-54, giving rise to fused polycyclic aromatics 10-55 (Scheme 220a).775,776 It was found that the the benzyne/CO insertion/intramolecular Heck reaction sequence (Scheme 219a).772 In 2010, Liang, Li, and coScheme 219. Aryne Annulation Reactions via πAllylpalladium Species Scheme 220. Pd-Catalyzed Aryne Annulation Reactions with 2-Halobiaryls and 1-(2-Bromophenyl)-1H-indoles key factor for the success of this transformation was to control a slow aryne generation rate. A number of heterocycles, such as benzofuran, indole, and chromone, could furnish the corresponding products. In 2007, Zhang and co-workers reported a Pd-catalyzed annulation protocol between arynes and heterocyclic halobiaryls, 1-(2-bromophenyl)-1H-indoles 10-56, leading to the formation of indolo[1,2-f ]phenanthridines 10-57 in moderate to excellent yields (Scheme 220b).777 This protocol was then applied by Kang, Ko, and co-workers in the preparation of indolo[1,2f ]phenanthridine-based organic sensitizers.778 In 2006, Cheng and co-workers reported a Pd-catalyzed carbocyclization reaction using 2-fold arynes and one aryl halides 10-58, furnishing triphenylene derivatives 10-59 in good to high yields (Scheme 221).779 In this study, thallium Scheme 221. Pd-Catalyzed Aryne Carbocyclization Reaction with Aryl Halides workers developed a Pd-catalyzed cyclocarbonylation reaction of arynes with allyl carbonates and CO, furnishing 2benzylidene-2,3-dihydro-1H-inden-1-ones 10-49 and 2-methylene-3-substituted-2,3-dihydro-1H-inden-1-ones 10-50 (Scheme 219b).773 Notably, the formation of the preferred products depended on the choice of ligands. In 2018, Cheng, Zhai, and co-workers revealed an unprecedented decarboxylative approach from vinyl benzoxazinanones 10-51 and constructed cis-5,5a,6,10b-tetrahydroindeno[2,1-b]indoles 1052 in modest to high yields (Scheme 219c).774 Mechanistically, after the generation of a π-allylpalladium species from 1051, a further conversion occurs to generate a four-membered palladacycle intermediate 10-53, which could then capture arynes to assemble 10-52. 10.1.3. With Arylpalladium Species. Arylpalladium species are the most investigated in Pd-catalyzed aryne transformations. These species could be obtained in the acetate Tl(OAc) was found to be necessary for the success of this transformation. Alternatively, either in the absence of Tl(OAc) or by using various silver salts as additives only yielded product 10-59 in low efficiency. They hypothesized that thallium salt could assist the removal of halide on palladium intermediate. Similar transformation was also achieved in Larock’s study, in which Pd(OAc)2/dppf complex was found to be the ideal catalyst.776 In comparison with 3968 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Cheng’s work,779 this catalytic system did not need thallium salt, albeit with slightly lower yields. In 2006, Cheng et al. accomplished another Pd-catalyzed aryne carboannulation reaction of bicyclic alkenes 10-60, aryl iodides 10-61, and o-silylaryl triflates, furnishing 9,10dihydrophenanthrene derivatives 10-62 in moderate to excellent yields (Scheme 222a).780 When oxabenzonorborna- Review Scheme 223. Pd-Catalyzed Aryne Annulation Reactions Involving Intramolecular Heck Reactions Scheme 222. Arylpalladium-Involved Aryne Carbocyclization Reactions with Bicyclic Alkenes and Alkynes construct complex molecular frameworks.785−788 In 2012, Cheng and co-workers first demonstrated a Pd-catalyzed cascade annulation reaction of arynes with alkyne-tethered aryl halides 10-70 and 10-72, furnishing isochromen-6-ones 10-71 and phenanthro[1,10-bc]oxepines 10-73, respectively, in good to high yields through a Pd-catalyzed biscarbocyclization cascade process (Scheme 224).785 A mechanism was proposed for these transformations: (1) insertion of alkyne into the Pd− C bond of palladium π-complex 10-74 generates vinylpalladium 10-75; (2) cyclopalladation on 10-75 through intramolecular C−H bond activation affords five-membered palladacycle 10-76; (3) aryne cyclopalladation could produce seven-membered palladacycle 10-77; and (4) reductive elimination furnishes the polycyclic product 10-71. In 2016, Garcıá -López and co-workers achieved an unprecedented Pd-catalyzed cascade reaction of o-silylaryl triflates with 10-78, giving rise to heterospirocyclic compounds 10-79 in moderate to excellent yields (Scheme 225).786 Similar to the mechanism in Cheng’s study,785 this cascade process includes an intramolecular Heck arylation via 5-exo-trig cyclization to generate alkylpalladium species 10-80, which is followed by intermolecular aryne carbopalladation and C−H activation (or vice versa) to produce seven-membered palladacycles 10-81 or 10-82. Reductive elimination on either 10-81 or 10-82 could afford product 10-79. Meanwhile, Lautens and co-workers independently discovered a similar Pd-catalyzed cascade spirocyclization process (Scheme 226a).787 Two types of frameworks, namely, spirooxindole and spirodihydrobenzofuran 10-84, could be readily accessed from 10-83 in moderate to excellent yields. Although it is generally difficult to determine whether the C− H activation step to form five-membered or seven-membered palladacycle occurs first on alkylpalladium species after Heck arylation, their mechanistic study clearly indicated that the reaction through a seven-membered palladacycle is unfavorable. In 2017, Yao et al. reported a Pd-catalyzed cascade process that proceeds through the same mechanistic pathway, which could produce heterocycle-fused 9,10-dihydrophenan- dienes were utilized as the coupling partners, the products could be further converted to polyaromatic hydrocarbons. In this study, Pd(dba)2/P(2-furyl)3 complex was found to be the best catalyst of the choice. The high regio- and stereoselectivity in this transformation was reasoned by (1) insertion of bicyclic alkene into arylpalladium species is favored over that of aryne; (2) C−H activation on the arene ring of aryl iodide preferentially proceeds on the less hindered site. Moreover, Larock and co-workers disclosed a similar Pd-catalyzed threecomponent coupling transformation of arynes, aryl halides, and alkynes to yield substituted phenanthrenes 10-63, the mechanistic pathway of which also follows a sequential insertion of alkyne and then aryne into arylpalladium intermediate (Scheme 222b).781 In this study, they found that Tl(OAc) was crucial for the success of this reaction. This transformation could readily assemble polycyclic aromatic compounds in a highly regioselective manner. In 2009, Larock et al. disclosed that o-halo allylic benzenes 10-64 could undergo Pd-catalyzed annulation reaction with arynes to afford 9,10-phenanthrenes 10-65 (Scheme 223a).782 In 2016, Yao, Zhang, and co-workers developed another annulation reaction of arynes with 2-halostyrenes 10-66, producing phenanthrene derivatives 10-67 in modest to excellent yields with broad functional group tolerance (Scheme 223b).783 The mechanism of this transformation includes a sequential oxidative addition of Pd(0) to aryl iodide/aryne insertion/intramolecular endo-Heck reaction. In a recent study carried out by Sridharan et al., they reported one example on Pd-catalyzed annulation reaction of benzyne with compound 10-68, giving rise to product 10-69 in 55% yield (Scheme 223c).784 In addition to Pd-catalyzed carbocyclization among arynes, arylhalides, and alkynes/alkenes to build six-membered rings, distinct cascade processes were also developed by using alkyne/alkene-tethered arylhalides as the substrates to 3969 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 224. Pd-Catalyzed Aryne Annulation Reactions with Alkyne-Tethered Aryl Halides Review Scheme 226. Other Pd-Catalyzed Aryne Annulation Reactions with Alkene-Tethered Aryl Iodides Scheme 227. Pd-Catalyzed Aryne Annulation Reaction with Ketone-Tethered Aryl Iodides Later in 2012, Larock et al. disclosed that 2-halobenzamides 10-89 were able to serve as efficient annulation partners with arynes (Scheme 228a).790 The employment of this approach readily accessed N-substituted phenanthridinone derivatives 10-90 with a concomitant formation of C−C and C−N bonds. It was noticed that mono N-substituted amide is essential for Scheme 225. Pd-Catalyzed Aryne Annulation Reaction with Alkene-Tethered Aryl Bromides Scheme 228. Pd-Catalyzed Formation of Phenanthridinone Derivatives threnes 10-86 from 10-85 (Scheme 226b).788 Depending on the length of the linker, products via both 5-exo-trig or 6-exotrig Heck cyclization could be obtained. 10.1.3.2. Six-Membered Heterocycles. Beside the formation of all carbon six-membered rings via arylpalladium-involved aryne annulation processes, six-membered heterocyclic rings could also be constructed. In 2010, Liang, Li, and co-workers employed substrates 10-87 bearing a tethered aryl iodide and ketone to achieve a Pd-catalyzed annulation reaction with arynes, affording 6H-benzo[c]-chromenes 10-88 with good functional group tolerance (Scheme 227).789 Mechanistically, this transformation involves an α-arylation of ketones, which was the first example of this kind in aryne chemistry. 3970 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review efficient with respect to various substituents, including electron deficient N-methoxybenzamides (condition B).794 Moreover, DMSO was found to be crucial for this transformation and a KIE value of 4.7 suggested that the key step in this catalytic cycle should be the C−H activation step. In 2019, Li, Wang, and co-workers combined photoredox catalysis with palladium catalyst in an annulation reaction of N-methoxybenzamides with arynes by using molecular oxygen as a terminal oxidant in replacement of K2S2O8 or Cu(OAc)2 (Scheme 229b).795 Phenanthridinone derivatives 10-98 were facilely prepared under mild conditions. This Pd-catalyzed C−H activation strategy was then expanded to other directing groups. In 2014, Sha et al. discovered that aryl ketone O-acetyloximes 10-99 could serve as effective substrates in Pd-catalyzed annulation reaction with arynes, affording phenanthridine derivatives 10-100 (Scheme 230a).796 Their mechanistic study suggested that the reaction the success of the reaction. In contrast, the employment of 2halobenzamides containing either the absence of N-substituent or N,N-dimethyl group did not observe any desired products. In a study carried out by Harmata et al. on the preparation of benzofused benzothiazines from o-halo sulfoximines, they also reported Pd-catalyzed annulation examples, albeit in low yields.791 Recently, Meng, Xu, and co-workers achieved a Pdcatalyzed decarbonylative annulation of phthalimides 10-91 with o-silylaryl triflates, affording phenanthridinones 10-92 with good functional group tolerance (Scheme 228b).792 Mechanistically, the catalytic cycle involves (1) oxidative addition of Pd(0) into an imide N−CO bond to generate intermediate 10-93; (2) decarbonylation to give a fivemembered palladacycle 10-94; (3) aryne insertion to form a seven-membered palladacycle 10-95; and (4) reductive elimination to yield 10-92 along with the regeneration of Pd(0) species. An alternative strategy to generate arylpalladium species is through direct C−H bond activation. This protocol, however, encountered difficulty when efforts were tried to combine C− H bond activation with aryne transformations. A plausible reason to account for this problem can be a mismatch between harsh C−H activation conditions and highly active, unstable aryne intermediates. Until 2014, two distinct Pd-catalyzed annulation reactions of arynes with N-methoxybenzamides 1096 were independently reported by the groups of Jeganmohan793 and Xu,794 which could construct tricyclic phenanthridinone derivatives 10-97 (Scheme 229a). Although both Scheme 230. Pd-Catalyzed C−H Bond Activation Protocols with Other Directing Groups Scheme 229. Formation of Phenanthridinones via PdCatalyzed C−H Bond Activation Protocol initiates with an ortho C−H activation directed by the oxime group. Besides, Li, Wei, and co-workers employed N-alkoxy benzsulfonamides 10-101 as the substrates in a Pd-catalyzed C−H activation/aryne insertion/annulation process, giving rise to various dibenzosultams 10-102 in good to excellent yields (Scheme 230b).797 An excess amount of Cu(OAc)2 was needed for this transformation, so it was reasoned that the copper salt might be responsible for the removal of the R2 group in the reaction. Recently, Chikhalia et al. revealed a Pdcatalyzed annulation reaction of N-methyl-benzylamines 10103 with arynes, which led to the construction of various 5,6dihydrophenanthridine derivatives 10-104 in moderate to high yields (Scheme 230c).798 Moreover, benzyne insertion into the six-membered palladacycles was also investigated by SauraLlamas, Vicente, and co-workers.799−801 Others have attempted to construct six-membered heterocyclic rings via the arylpalladium-aryne annulation protocol. In 2014, Liang and co-workers reported an efficient Pd-catalyzed annulation of arynes and N-substituted-N-(2-iodophenyl)- studies employed an amide-directed ortho-activation of the C(sp2)−H bond to generate the desired five-membered palladacycle intermediate, their reaction conditions were quite different. In Jeganmohan’s study, they found that both 1-adamantanecarboxylic acid (Adm-1-CO2H) and K2S2O8 were crucial for the success of this transformation (condition A).793 In addition, N-methybenzamides worked as well. NMethoxybenzamides 10-96 bearing halogens and EWGs on the benzene ring, however, only furnished N-arylated products, suggesting that the C−H activation step is the rate-limiting step. Notably, Xu et al. revealed another catalytic system by using Pd(OAc)2, Cu(OAc)2, TBAB, and CsF in a binary solvent of DMSO and dioxane, which was found to be highly 3971 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR formamides 10-105 (Scheme 231).802 This transformation could furnish phenanthridinone derivatives 10-106 in moder- Review aryne generation conditions, phenanthridinones 10-108 were obtained exclusively by using CsF/TBAI/MeCN with 10% H2O; (b) using dppm as the ligand and under slow aryne releasing conditions, acridones 10-109 could be achieved preferentially. It was reasoned that both the steric and electrondonating effects of the dppm ligand could prevent the coordination of aryne with palladium, hence, allowing a preferential CO binding event. Subsequently, a modification was realized by the same group by using anilines 10-110 to replace 2-iodoanilines, which required an ortho C−H activation step to generate an arylpalladium intermediate (Scheme 232b).804 Phenanthridinone derivatives 10-111 were achieved with no formation of acridone alkaloid scaffold. In this study, they found that CuF2 was crucial for the success of this threecomponent annulation reaction. Based on their experimental study, the mechanism involves a dimeric palladium intermediate from palladation of aniline under a CO atmosphere. 10.1.3.3. Five-Membered Rings. Other than the formation of six-membered rings, methods toward the construction of five-membered rings via an arylpalladium species have also been achieved by Larock and others. In 2005, Larock and coworkers demonstrated that fluoren-9-one scaffold 10-113 could be readily constructed from o-halobenzaldehydes 10112 via a Pd-catalyzed annulation reaction with arynes (Scheme 233).805,806 This transformation provided an efficient Scheme 231. Pd-Catalyzed Aryne Annulation Reactions with N-(2-Iodophenyl)formamides ate to excellent yields via an arylation-annulation process. Two possible pathways might be involved on arylpalladium intermediate 10-107 after the insertion of aryne to arylpalladium species: (a) insertion of carbonyl group to Pd−C bond and a β-hydride elimination and (b) oxidative addition of palladium to the amide C−H bond and reductive elimination. There was no clear evidence, however, on which pathway is the real one. A distinct Pd-catalyzed three-component annulation reaction of arynes, CO, and anilines was realized by Jiang et al. (Scheme 232).803,804 In 2015, they first reported a ligand controlled regiodivergent preparation of both phenanthridinones 10-108 and acridone alkaloids 10-109 through Pdcatalyzed coupling of arynes, CO, and 2-iodoanilines (Scheme 232a).803 In particular, the regioselective control could be realized by simply altering both the ligand and aryne generation rate: (a) in the absence of ligand and under fast Scheme 233. Pd-Catalyzed Aryne Annulation Reactions with o-Halobenzaldehydes Scheme 232. Pd-Catalyzed Aryne Annulation Reactions with Anilines and CO solution for the expeditious preparation of fluoren-9-one derivatives from readily available starting materials. After aryne insertion into the Pd−C bond of arylpalladium species, there are two plausible mechanistic pathways to account for the formation of final products from intermediate 10-114: (1) addition to the carbonyl group with following a β-hydride elimination on intermediate 10-115 (path a); (2) oxidative C− H insertion to form a Pd(IV) intermediate 10-116 and a reductive elimination (path b). Later in 2009, Larock et al. also disclosed that o-halostyrenes 10-117 could undergo Pd-catalyzed annulation reactions with arynes to produce 9-fluorenylidenes 10-118 in good to excellent yields (Scheme 234).782,807 This synthetic protocol involves the generation of two new C−C bonds under mild conditions with broad functional group compatibility. The formation of 9-fluorenylidene scaffold from o-halostyrenes 10117 was distinctly different from the work carried out by Yao and Zhang, where phenanthrenes were obtained.783 It was noticed that the substrates in the study by Yao, Zhang, and coworkers would prohibit β-hydride elimination after 5-exo-trig 3972 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 234. Pd-Catalyzed Aryne Annulation with oHalostyrenes Review Scheme 236. Other Pd-Catalyzed Aryne Annulation Reactions Heck cyclization with an arylpalladium intermediate. Consequently, the phenanthrene framework was formed then.783 Arynes can be also utilized in Pd-catalyzed annulation reactions with anilines, furnishing carbazole frameworks. In a study carried out by Jiao and co-workers on Pd-catalyzed annulation of anilines and electron-deficient alkynes, they exhibited one example by using the Kobayashi benzyne precursor to reach carbazole (10-119) in 60% yield (Scheme 235a).808 Their mechanistic study suggested a sequential 10.1.3.4. Other Arylpalladium-Involved Reaction. In 2007, Greaney and co-workers realized a three-component Heck coupling reaction of aryl iodides, arynes, and electron-deficient olefins, furnishing highly functionalized biaryls 10-126 in modest to high yields (Scheme 237).812 Scheme 235. Pd-Catalyzed Aryne Reactions to Construct Carbazole Frameworks Scheme 237. Pd-Catalyzed Aryne Reaction with Aryl Iodides and Electron-Deficient Olefins 10.1.4. With Alkylpalladium and Vinylpalladium. In addition to π-allylpalladium and arylpalladium species, both alkylpalladium and vinylpalladium have been investigated in aryne transformations. In 2006, Greaney et al. reported an unprecedented Pd-catalyzed three-component coupling reaction of aryne, methyl bromoacetate/benzyl bromides, and acrylates, furnishing products 10-127 in moderate to excellent yields (Scheme 238).813 The mechanistic pathway of this aminopalladation of aryne, arene C−H bond activation, and reductive elimination, although it could not exclude a possible direct ortho C−H activation on anilines with Pd(0) to form dimeric arylpalladium intermediate as postulated by Jiang.804 In 2012, Larock and co-workers reported a similar annulation reaction between arynes and 2-haloacetanilides 10-120, affording N-acylcarbazoles 10-121 (Scheme 235b).809 It was found that strong electron-withdrawing groups on these substrates disfavor the nucleophilic addition of nitrogen to arylpalladium intermediate in the ring-closing step. Recently, Luan and co-workers discovered a Pd-catalyzed cascade process between arynes and naphthalene-based biaryls 10-122, furnishing spirofluorene scaffold 10-123 (Scheme 236a).810 This unprecedented dearomatization/[3 + 2] spiroannulation process includes a successive aryne insertion into the arylpalladium species/Heck-type dearomative 5-exotrig cyclization/hydride elimination sequence. Notably, this process is distinctively different from the prior Larock’s report, which resulted in an exclusive formation of triphenylene framework by using 2-halobiaryls.775,776 Phosphine as a cyclization acceptor was also reported by Tobisu, Chatani, and co-workers (Scheme 236b).811 In their study on Pdcatalyzed intramolecular formation of dibenzofused sixmembered phosphacycles from triphenylphosphine derivatives, they exhibited one example for the construction of 10-125 between bromide 10-124 and Kobayashi benzyne precursor in 24% yield. Scheme 238. Alkylpalladium-Involved Aryne Reaction transformation involves an aryne carbopalladation on the alkylpalladium intermediate followed by an intermolecular Heck reaction. Notably, it was found that the replacement of allyl chloride with methyl bromoacetate could prohibit the aryne−aryne−alkene [2 + 2 + 2] cocyclotrimerization reaction mode. Efforts have been make to realize alkenylpalladium-involved aryne transformations. Along with Larock’s study on 2halobiaryls, they also reported the Pd-catalyzed annulation reactions of arynes with vinylic halides/triflates 10-128, which could yield phenanthrenes 10-129 (Scheme 239a).775,776 In 2010, Huang and co-workers demonstrated a Pd-catalyzed 3973 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review transformation involves an oxidative insertion of Pd(0) to C−S bond, aryne insertion, and a subsequent reductive elimination on intermediate 10-136 to produce 10-135. It was noticed that the formation of methanethiol or ethanethiol byproduct in the catalytic cycle required an equivalent of sacrificing aryne. Subsequently, Gogoi et al. reported a Pdcatalyzed aryne annulation reaction with 4-hydroxycoumarins 10-137, which could furnish coumestans 10-138 in moderate to high yields (Scheme 240b).816 It was proposed that the reaction first generates an anion species 10-139, which could then transform to intermediate 10-140. After aryne insertion, the generated intermediate 10-141 would undergo a reductive elimination to produce coumestans 10-138 in the presence of a base. Moreover, this methodology was applied to the synthesis of natural product flemichapparin C, which will be discussed in section 14. In 2018, Chen, Xiao, and co-workers reported a Pd-catalyzed formal [2 + 2 + 2] annulation reaction of arynes and various vinyl triflates 10-142, producing phenanthrene scaffolds 10143 in moderate to excellent yields with a broad substrate scope (Scheme 241).817 The catalytic cycle of this trans- Scheme 239. Vinylpalladium-Involved Aryne Reactions Scheme 241. Pd-Catalyzed Formation of Phenanthrenes from Arynes and Vinyl Triflates carboannulation reaction of arynes with either allyl-substituted iodocycloenones 10-130 or iodofuranones 10-132, leading to the formation of substituted naphthalene derivatives 10-131 and 10-133, respectively, in moderate to good yields (Scheme 239b).814 In 2014, a distinct Pd-catalyzed annulation reaction of arynes with α-carbamoyl ketene dithioacetals 10-134 was realized by Liu, Wang, and co-workers, giving rise to 2quinolinones 10-135 in modest to excellent yields with broad substrate scope (Scheme 240a).815 Mechanistically, this formation involves a 2-fold aryne insertion into the vinylpalladium species, a 6-endo-Heck cyclization, and a 1,3-hydride migration. Particularly, the addition of LiOPiv was found to be crucial for the success of this transformation, which could prefer a 6-endo-Heck reaction mode over a competing 5-exoHeck cyclization. 10.1.5. With Azapalladium Species. Azapalladium was also employed in aryne transformations. In 2009, Neuville, Zhu, and co-workers demonstrated the first annulation transformation of arynes with azapalladium intermediate, generated from acyloximes 10-144 via an oxidative addition of Pd(0) complex, which led to the generation of phenanthridines scaffold 10-145 (Scheme 242).818 Butyronitrile with a high boiling point was the optimal solvent for this transformation. They proposed that the reaction mechanism includes (1) oxidative insertion of Pd(0) into an acyloxime N− O bond to generate azapalladium 10-146; (2) aryne insertion to produce 10-147; (3) intramolecular C−H activation to form a seven-membered palladacycle 10-148; (4) reductive elimination to produce 10-145 along with the regeneration of Pd(0) species. Alternatively, cyclopalladation to generate fivemembered palladacycle from azapalladium 10-146, followed by aryne insertion and reductive elimination, would be another plausible pathway. In 2015, Ma, Xu, and co-workers reported a Pd-catalyzed annulation reaction of arynes with acrylamides 10-149 and harvested quinolinone derivatives 10-150 (Scheme 243).819 In this work, they conducted an intermolecular KIE experiment and obtained a KIE value of 1.7, suggesting that the C−H bond cleavage on acrylamide is not the rate-determining step. With the perception that C−H activation on electron-deficient Scheme 240. Other Vinylpalladium-Involved Aryne Reactions 3974 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review not be directly inserted by arynes in the absence of palladium catalyst. A general mechanistic scheme includes the oxidative addition of a Pd(0) species to those σ-bonds to generate the Pd(II) intermediate, which then gives rise to vicinal difunctionalized arenes after aryne insertion and reductive elimination. In 2001, Shirakawa, Hiyama and co-workers reported the first example of this kind by activating either alkynyl- or vinylstannane with Pd-catalyst, giving rise to 10-154 (Scheme 245a).822 The generated C−Sn bond on 10-154 could be Scheme 242. Pd-Catalyzed Formation of Phenanthridines from Arynes and Acyloximes Scheme 245. Pd-Catalyzed Aryne Insertion into C−Sn and Sn−Sn σ-Bonds Scheme 243. Pd-Catalyzed Formation of Quinolinones from Arynes and Acrylamides further converted to a variety of a C−C bond through crosscoupling manipulation. In 2004, Yoshida, Kunai, and coworkers accomplished a Pd-catalyzed distannylation of arynes to give 10-155 in modest to good yields (Scheme 245b).823 Subsequently, the same group revealed a Pd-catalyzed distannylation of arynes, which could furnish a mixture of 10-156 and 10-157 (Scheme 245c).824 These divergent transformations were realized by switching the ligands and varying the reaction stoichiometry. In 2005, Yoshida, Kunai, and co-workers discovered an unprecedented catalytic transformation, where bissilylation of aryne could be reached from cyclic disilanes 10-158 to form 10-159 (Scheme 246a).825−827 Both five- and six-membered cyclic disilanes 10-158 worked well in this reaction. In 2015, Werz and co-workers found that palladium could efficiently activate aryl thiocyanates 10-160 and furnished 1,2-thiobenzonitriles 10-161 (Scheme 246b).828 In particular, molecular oxygen was found to be necessary for the success of this process, the role of which was assumed to stabilize an intermediate in the catalytic cycle. Moreover, C−C bond insertion on the three-membered ring of 10-162 by Pd(0) species was also reported by Wu and co-workers, which could proceed through a further [3 + 2] cycloaddition reaction with arynes to afford products 10-163 in good to excellent yields (Scheme 246c).829 acrylamide is difficult, they proposed that aryne insertion into the acyclic azapalladium species was the favorable pathway over that of the five-membered palladacycle. 10.1.6. Other Palladium-Catalyzed Reactions. Nishihara and co-workers reported a Pd(II)-catalyzed threecomponent coupling reaction of aryne, isocyanides 10-151, and cyanoformates 10-152, furnishing iminoisobenzofuran derivatives 10-153 (Scheme 244).820,821 It was found that cationic palladium catalyst played an essential role in this three-component coupling transformation. 10.1.7. Insertion into Element−Element σ-Bonds. Aryne insertion into element−element σ-bonds could be enabled by palladium complexes, those of which will otherwise Scheme 244. Pd-Catalyzed Formation of Iminoisobenzofurans 3975 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 246. Pd-Catalyzed Aryne Insertion into Other σBonds Review ones. Besides, Sato et al. also reported nickel-catalyzed [2 + 2 + 2] cocyclotrimerization reactions of 3,4-pyridyne with either diynes832 or alkynes,833 which will be discussed in section 12. In 2009, Sato and co-workers investigated a Ni-catalyzed cocyclotrimerization of 1,6-dienes 10-168 with arynes (Scheme 248).834 Unexpectedly, they did not obtain products Scheme 248. Ni-Catalyzed [2 + 2 + 2] Cocyclotrimerization of Arynes with 1,6-Dienes 10.2. Nickel-Catalyzed Reactions In comparison with Pd-catalyzed aryne transformations, nickel catalysis has received much less attention. In the past 2 decades, there are only a few reports on Ni-catalyzed aryne transformations. In 2004, Cheng and co-workers revealed the first nickelcatalyzed chemoselective [2 + 2 + 2] cocyclotrimerization of arynes with allenes 10-164 (Scheme 247a).830 This transScheme 247. Ni-Catalyzed [2 + 2 + 2] Cocyclotrimerization of Arynes with Allenes and Diynes via the aryne-alkene-alkene cyclization reaction mode. Instead, an aryne−aryne−alkene cyclization reaction was observed to afford 9,10-dihydrophenanthrenes 10-169. NHC ligand SIMes·HBF4 10-170 was found to be the ideal ligand for this transformation. In this study, the employment of diene moiety was crucial for the success of this reaction, so it was reasoned that both double bonds are needed in order to form a sufficiently stable nickel-diene complex. Mechanistically, there are two plausible pathways that could account for the formation of a seven-membered nickelacycle 10-173: (1) formation of five-membered nickelacycle 10-171 with one aryne and an olefin, followed by insertion of a second aryne (path a) and (2) formation of five-membered nickelacycle 10172 with two aryne species, followed by insertion of an olefin. Upon reductive elimination on intermediate 10-173, 9,10dihydrophenanthrenes 10-169 were generated. In 2011, Lautens and co-workers developed a Ni-catalyzed cocyclotrimerization of enynes 10-174 and o-silylaryl triflates, furnishing compounds 10-175 in modest to excellent yields (Scheme 249a).835 This transformation was under ligand-free conditions. In particular, when the olefin contains an adjacent substituent (R4 ≠ H), products 10-175 with excellent transstereoselectivity were obtained. In 2009, Xie and Qiu also revealed a Ni-catalyzed three-component [2 + 2 + 2] cocyclotrimerization reaction of arynes, alkynes, and alkenes, formation belongs to an aryne−aryne−allene cyclization mode, which furnished 10-methylene-9,10-dihydrophenanthrenes 10165 in a highly chemoselective manner. The internal double bond of allenes participated in the reaction, and the resulting exocyclic double bond on the product did not isomerize to form a phenanthrene skeleton. The proposed mechanistic pathway is close to that in palladium catalyzed transformations. In 2005, the same group demonstrated another Ni-catalyzed aryne cocyclotrimerization transformation (Scheme 247b).831 Naphthalene derivatives 10-167 containing 5- to 7-membered fused-ring were achieved between arynes and diynes 10-166. It was noticed that this transformation is sensitive to the structure of diynes with terminal diynes the most reactive 3976 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 249. Other Ni-Catalyzed Aryne Reactions Review Scheme 250. Ni-Catalyzed Aryne [4 + 2] Cycloaddition Reaction with Styrenes undergoes a ring-expansion to give nickelacycle 10-183 (path b). Rearomatization on 10-183 could yield intermediate 10185, which then undergoes a reductive elimination to afford 10-182. affording dihydronaphthalene derivatives 10-176 (Scheme 249b).836 In order to avoid the aryne−aryne−alkyne cycloaddition side reaction, activated alkenes, i.e., methyl acrylate, were necessary. Excellent regioselectivity was observed when unsymmetrical alkynes were utilized in this reaction. Other than cocyclotrimerization, more reaction modes were also developed. In 2007, Cheng et al. reported an efficient Nicatalyzed three-component coupling reaction of arynes, boronic acids 10-177, and alkenes 10-178, affording the coupling products 10-179 in moderate to excellent yields (Scheme 249c).837 It was noticed that organoboronic acids played a dual role in this reaction, serving as both the proton sources and the C-nucleophiles. In 2018, Cheng and coworkers discovered a new Ni-catalyzed aryne reaction mode. Phenanthridinone derivatives 10-181 could be achieved from 1,2,3-benzotriazin-4-(3H)-ones 10-180 and arynes in good to excellent yields via a Ni(0)/dppm-catalyzed denitrogenative annulation process (Scheme 249d).838 This transformation has a broad substrate scope with high functional group tolerance. Recently, Ichikawa et al. revealed a Ni-catalyzed formal [4 + 2] cycloaddition reaction between styrenes and arynes, producing 9,10-dihydrophenanthrenes 10-182 in good to excellent yields with broad substrate scope (Scheme 250).839 This transformation was distinctly different from Biju’s previous study on cycloaddition reaction of styrenes with arynes,241 in which a successive ene reaction with a second molecule of aryne occurred on the [4 + 2] cycloadduct, except for those styrenes bearing a strong electron-withdrawing substituent on the 4-position. Mechanistically, after the coordination of styrene and benzyne with nickel, sevenmembered nickelacycle 10-183 was generated via an oxidative cyclization pathway (path a). Alternatively, five-membered nickelacycle 10-184 might be formed as well, which then 10.3. Copper-Catalyzed/Mediated Reactions Cu-catalyzed aryne transformations were studied behind that of palladium and nickel. Moreover, the reaction modes involved in Cu-catalyzed aryne reactions are quite different from those in palladium catalysis. For instance, there was only one example on Cu-catalyzed [2 + 2 + 2] cyclotrimerization of benzyne to produce triphenylene product in Zhang’s study;840 whereas copper acetylide species have been broadly employed as the key intermediates in aryne transformations. Copper acetylide intermediates can be facilely generated from terminal alkynes, which then undergo efficient nucleophilic addition to arynes. Consequently, the generated arylcopper species could couple with various third components. In 2008, Zhang and co-workers reported the first Cucatalyzed coupling reactions between terminal alkynes and arynes.840 As shown in Scheme 251, in the absence of ligand, the coupling product 10-186 was produced in good to high yields. Meanwhile, a three-component coupling reaction was achieved by using allyl chlorides as the third component and CuI/dppe as the catalyst, giving rise to 1,6-enyne products 10187. In the latter transformation, K2CO3 was found to suppress the protonation step. Mechanistically, the generated copper acetylide species 10-188 attacks aryne to form a carbocopper intermediate 10-189, which could undergo protonation to produce 10-186 (path a). In the presence of allyl chloride, a subsequent oxidative addition on 10-189 occurs, furnishing the 1,6-enyne products 10-187 after reductive elimination (path b). Alternatively, a direct nucleophilic addition of carbocopper 10-189 to allyl chloride might take place to directly furnish 10187. Subsequently, Biehl et al. applied microwave conditions in 3977 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review Scheme 251. Cu-Catalyzed Aryne Reactions with Terminal Alkynes arynes before protonation (Scheme 252b).842 Diverse 2alkynylbiaryls 10-191 were readily prepared. In 2012, Pineschi et al. employed alkenyl aziridines 10-192 in a Cu-catalyzed three-component coupling reaction of alkynes and arynes, affording products 10-193 in moderate to high yields (Scheme 252c).843 In this study, CuI/PPh3 was utilized as the catalyst and both cyclic and acyclic alkenyl aziridines could serve as efficient third components. In 2009, Cheng and co-workers accomplished a highly regioand chemoselective three-component coupling reaction of arynes, allylic epoxides 10-194, and terminal alkynes to assemble compounds 10-195, where copper and palladium served as cooperative catalysts in this transformation (Scheme 253).844 Mechanistically, an oxidative addition of Pd(0) with Zhang’s Cu-catalyzed alkyne-aryne coupling reaction, yielding both symmetrical and unsymmetrical diaryl alkynes in much shorter reaction time.125 At almost the same time with Zhang’s discovery on Cucatalyzed aryne transformations, Cheng et al. demonstrated a three-component coupling reaction of arynes, terminal alkynes, and activated alkenes (Scheme 252a).841 In this study, CuI/ PCy3 in binary solvents was found to be the optimal conditions, which could furnish 1-alkyl-2-alkynylbenzenes 10190 in moderate to high yields. In 2009, Yoshida and coworkers revealed a Cu-catalyzed 2:1 coupling reaction of arynes with terminal alkynes, in which copper acetylide participated in a sequential nucleophilic addition to two Scheme 252. Cu-Catalyzed Coupling Reactions with Arynes and Terminal Alkynes Scheme 253. Cooperative Cu- and Pd-Catalyzed Reactions of Arynes, Terminal Alkynes, and Allylic Epoxides 3978 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR allylic epoxide could generate a π-allylpalladium complex 10196, which is then attacked by carbocopper species 10-189 to produce product 10-195 with regeneration of both Cu- and Pd-catalysts. In 2014, Kobayashi and co-workers employed carbon dioxide to capture carbocopper intermediate 10-189, which led to the formation of isocoumarins 10-197 via a Cu-catalyzed three-component coupling reaction of arynes, terminal alkynes, and CO2 (Scheme 254a).845 The employment of [(IPr)CuCl] Review Scheme 255. Aryne Coupling Reactions Involving Cu(III) Intermediates Scheme 254. Cu-Catalyzed Coupling Reactions of Arynes, Terminal Alkynes, and CO2 oxazoles, and O-benzoylhydroxylamines was achieved, affording o-(benz)oxazolyl anilines 10-207. The success of the latter transformation was based on the fact that the active hydrogen on (benz)oxazoles is sufficiently acidic to be removed by a base. Subsequently, Xiao et al. realized a Cu-catalyzed threecomponent iodoalkynylation reaction of arynes, terminal alkynes, and NIS, giving rise to o-alkynyl aryl iodides 10-208 in moderate to high yields (Scheme 255b).848 Based on their mechanistic study, they proposed that copper is involved in two key steps in this transformation: (1) formation of 1-iodo2-arylacetylene (10-209) via an alkynylcopper(III) intermediate from copper acetylide 10-188 and NIS; (2) insertion of aryne into the C(sp)−I bond of 10-209. The exact reaction pathway, however, was not addressed. Very recently, Xie and co-workers reported a Cu-catalyzed oxidative 1:2 coupling reaction of arynes with terminal alkynes under aerobic conditions, which led to the formation of arenediynes 10210 in modest to excellent yields (Scheme 255c).849 Their mechanistic study suggested the formation of an aryl-Cu(III) intermediate 10-211 via the oxidation of carbocopper 10-189, which could be attacked by another copper acetylide 10-188 to furnish arenediynes 10-210 and regenerate Cu(I) species. Inspired by the work on Pd-catalyzed ortho-C−H activation/ aryne insertion annulation strategy,793,794 Zhang and coworkers reported a series of Cu-catalyzed transforma- (IPr = 1,3-bis(diisopropyl)-phenylimidazol-2-ylidene) (10198) as the NHC-copper catalyst was the key for the success of this transformation. Mechanistically, the generated carbocopper intermediate 10-189 attacks CO2 to produce a copper carboxylate 10-199, which then undergoes a 6-endo-dig cyclization to furnish endocyclic copper heterocycle 10-200. After protonation, isocoumarin 10-197 was obtained. In 2016, Xu and co-workers developed a Cu-catalyzed three-component coupling reaction of arynes, terminal alkynes, and benzenesulfonothioates 10-201, giving rise to o-alkynyl arylsulfides 10202 in moderate to high yields (Scheme 254b). 846 Benzenesulfonothioates 10-201 were found to be efficient electrophiles to capture the carbocopper intermediate 10-189 in this transformation. In 2019, Chen, Xiao, and co-workers found that Obenzoylhydroxylamines 10-203 could serve as the third component as well, furnishing o-alkynyl anilines 10-204 in modest to high yields (Scheme 255a).847 The role of Obenzoylhydroxylamines 10-203 was proposed to react with carbocopper 10-189 to generated an aryl-Cu(III) intermediate 10-205, which could then convert to 10-204 along with the regeneration of Cu(I) species. Furthermore, by altering terminal alkynes to (benz)oxazoles 10-206, a Cu-catalyzed three-component carboamination reaction of arynes, (benz)3979 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR tions.850−852 In 2017, they first realized a Cu-catalyzed direct ortho-C−H/N−H annulation of N-quinolylbenzamides 10212 with arynes, furnishing phenanthridinones 10-213 in modest to excellent yields with broad substrate scope (Scheme 256).850 Mechanistically, after ligation with N,N-bidentate Review Scheme 257. Other Cu-Catalyzed ortho-C−H/N−H Annulation Transformations Scheme 256. Cu-Catalyzed Formation of Phenanthridinones via ortho-C−H/N−H Annulation Process Scheme 258. Cu-Catalyzed Formal Aryne Insertion into σBonds directing group, an intramolecular C−H activation occurs to give a five-membered complex 10-214. Upon carbocupration with aryne to afford 10-215 and a subsequent reductive elimination, phenanthridinones 10-213 could be produced. Moreover, their KIE study suggested that Cu-catalyzed C−H activation is the rate-limiting step. Later in 2018, they applied this Cu-catalyzed ortho-C−H/N−H annulation strategy in the reaction of arynes with indolocarboxamides 10-216 and 10218, furnishing the corresponding polyheterocyclic indolo[3,2-c]/[2,3-c]quinolines 10-217 and 10-219, respectively (Scheme 257a).851 In addition, 2-quinolinones 10-221 were obtained in modest to excellent yields from electron-deficient acrylamides 10-220 through this protocol (Scheme 257b).852 Cu-catalyzed aryne insertion reactions into σ-bonds were also explored. In 2010, Yoshida et al. first disclosed that aryne could insert into the C(sp)−Br σ-bond of bromoalkynes 10222 in the presence of CuBr2 (Scheme 258a).853 A mixture of 2-bromo-2′-(phenylethynyl)biphenyls 10-223 and 1-bromo-2(phenylethynyl)benzenes 10-224 were obtained under the same conditions. Mechanistically, this transformation involves the insertion of one or two arynes into a Cu−Br bond of CuBr2 first and a subsequent nucleophilic coupling of arylcopper species with bromoalkyne. Subsequently, the same group demonstrated that diborylation of both alkynes and o-silylaryl triflates could be realized by using (PPh3)3CuOAc as an efficient catalyst (Scheme 258b).854 In this transformation, a borylcopper species 10-226 was proposed to be first generated, which was followed by an aryne insertion into the Cu−B bond to produce arylcopper intermediate 10-227. A σ-bond metathesis of 10-227 with another diboron substrate could afford diboralated products 10-225 in moderate to good yields. In 2016, Chen and co-workers revealed a Cu-catalyzed Parylation of secondary phosphine oxides 10-228 with arynes, giving rise to phosphine oxides 10-229 in good to excellent yields (Scheme 258c).855 This reaction proceeds through a 3980 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR sequential formation of R12P(O)Cu species 10-230/aryne insertion/protonation to yield 10-229 along with the regeneration of copper catalyst. In 2017, Yoshida and co-workers reported two types of Cucatalyzed aryne σ-bond insertion reactions with tributyltin cyanide (10-231) and alkynyl tributylstannanes 10-233 (Scheme 259a).856 These C−Sn bonds could be readily Review single or double insertion of arynes into arylstannanes, respectively. In recent years, Tsui and co-workers developed several Cumediated trifluoromethylation reactions of arynes. In 2018, they demonstrated a Cu-mediated vicinal trifluoromethylationallylation of arynes by using Grushin’s fluoroform-derived [CuCF3] reagent (generated from CuCl/t-BuOK/CF3H) and allyl bromides, furnishing trifluoromethylated allylarenes 10242 (Scheme 260a).859 Mechanistically, aryne insertion into Scheme 259. Cu-Catalyzed Aryne Insertion into C−Sn σBonds Scheme 260. Cu-Mediated Vicinal TrifluoromethylationAllylation of Arynes Cu−CF3 bond, followed by an oxidative addition to allyl bromide, will produce a π-allylcopper species 10-243. Upon reductive elimination, trifluoromethylated allylarenes 10-242 could be obtained. Moreover, they applied this method in the synthesis of CF3-containing analogue of the antispasmodic drug papaverine. The same group then realized a Cu-mediated 1,2-bis(trifluoromethylation) of arynes with Grushin’s fluoroform-derived [CuCF 3 ] as well, furnishing 1,2-bis(trifluoromethyl)arenes 10-244 (Scheme 260b).860 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) was found to be an efficient oxidant for this transformation. Their mechanistic studies suggested that the formation of an o-trifluoromethyl aryl radical 10-245 is through a CF3 group transfer from [CuCF3] to aryne. In addition, a Cu-catalyzed aryne polymerization was realized by Mikami, Uchiyama, and coworker, which will be discussed in section 15.861 inserted by arynes, furnishing ortho-cyanoarylstannanes 10-232 and alkynylstannylated arenes 10-234, respectively. In these transformations, CuCN was used as the catalyst with no need for ligand. It was proposed that the cyano- or alkynylstannylation initiates with the formation of potassium cyanocuprate(I) 10-235 and tributyltin fluoride (10-236) from fluoride ion and an organostannane. Compound 10-235 then adds to arynes to generate an arylcuprate(I) 10-237. After nucleophilic addition to tributyltin fluoride (10-236), the corresponding products could be produced. Recently, Tsuchimoto et al. combined this Cu-catalyzed alkynylstannylation protocol with a Zn-catalyzed stannylation of terminal alkynes.857 In 2019, Yoshida et al. revealed a Cu-catalyzed arylstannylation of arynes with electron-deficient arylstannanes 10-238 (Scheme 259b).858 By using copper(I) 2-thiophenecarboxylate (CuTC) (10-239) as the catalyst, both substituted ortho-stannylbiaryls 10-240 and teraryls 10-241 could be prepared, the mechanistic pathway of which involves either a 10.4. Silver-Catalyzed/Mediated Reactions In 2013, Hu and co-workers revealed an unprecedented Agmediated vicinal trifluoromethylation-iodination of arynes using AgCF3, facilely prepared from TMSCF3 and AgF, and 1-iodophenylacetylene (10-246), affording substituted otrifluoromethylated iodoarenes 10-247 in modest to high yields (Scheme 261a). 862 2,2,6,6-Tetramethylpiperidine (TMP) was found to play an essential role in this transformation. With their in-depth mechanistic study, they proposed a plausible mechanism: (1) AgCF3·TMP complex attacks aryne to generate intermediate 10-248 first; (2) after binding with another molecule of TMP to produce 10-249, deprotonation will happen to furnish anionic intermediate 10250; (3) 10-250 coordinates with iodophenylacetylene via halogen bonding to give 10-251; (4) ate complex 10-252 is 3981 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 261. Ag-Catalyzed/Mediated Aryne Reactions Review Scheme 262. Au-Catalyzed Aryne Reactions Karunakar et al., where gold did not directly interact with aryne in the reaction.869 10.6. Platinum-Catalyzed Reactions formed through intramolecular nucleophilic addition, which is then converted to product 10-247. Subsequently, the same group demonstrated a Ag-mediated trifluoromethylthiolationiodination of arynes with trifluoromethylthiosilver (AgSCF3) and 1-iodophenylacetylene (10-246), which led to the formation of o-trifluoromethylthiolated arenes 10-253 (Scheme 261b).863 Moreover, they realized a Ag-catalyzed formal insertion of arynes into the Rf−I bond of 10-254 (Rf = CF3 , C 2 F5 ) via an ionic atom-/group-transfer of R fI compounds to yield o-perfluoroalkyl iodoarenes 10-255 (Scheme 261c).864 In this work, 1,10-phenanthroline (phen) served as an efficient ligand. Some other Ag-catalyzed aryneinvolved transformations were also reported, where silver catalysts did not directly interact with arynes.365,656,865,866 In 2010, Yoshida and co-workers accomplished a platinumcatalyzed diborylation reaction of arynes, affording 1,2diborylarenes 10-225 in modest to high yields (Scheme 263).870 A Pt-isocyanide catalyst was found to be ideal for the Scheme 263. Pt-Catalyzed Diborylation Reaction of Arynes 10.5. Gold-Catalyzed Reactions success of this transformation. The 1,2-diborylarene products could be converted to ortho-terphenyls via a further SuzukiMiyaura coupling reaction. This protocol was also applied on indolynes, which will be discussed in section 12.871 Besides, Gagné and co-workers employed Kobayashi benzyne precursor in the reaction with (triphos)Pt-CH3+ 10259 to synthesize a π-complex 10-260 (Scheme 264).872 Thermolysis of complex 10-260 furnished (triphos)Pt(otolyl)+ 10-261, while protonolysis of this complex gave rise to toluene. In 2015, a gold-catalyzed [2 + 2 + 2] cyclotrimerization of osilylaryl triflates was realized by Zhang, Chen and co-workers, furnishing triphenylenes in moderate to high yields (Scheme 262a).867 Ph3PAuCl was used as the catalyst and the reaction mechanism was proposed to be the same with that in Pdcatalyzed cyclotrimerization reactions. In 2008, Zhang et al. reported a gold- and copper-catalyzed tandem reaction between terminal alkynes and arynes, giving rise to alkynylated biphenyl derivatives 10-256 (Scheme 262b).868 A cooperative Au- and Cu-catalyzed process was proposed: complex 10-257 can be first formed between gold catalyst and aryne; next, carbocopper intermediate 10-189 reacts with complex 10-257 to afford organogold intermediate 10-258. Upon protodemetalation, alkynylated biphenyl derivatives 10-256 were generated. In addition, a Au-catalyzed cyclization of Npropargylic β-enaminones with arynes was reported by 10.7. Cobalt-Catalyzed Reaction In 2001, in an early study carried out by Chatani, Murai, and co-workers, they examined various transition metal catalysts in carbonylation reactions with o-silylaryl triflates. By using Co2(CO)8 as the catalyst, anthraquinones 10-262 were obtained in good yields (Scheme 265).772 In this study, they 3982 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review Scheme 264. Transformations of Pt-Benzyne π-Complex Scheme 265. Cobalt-Catalyzed Formation of Anthraquinones with Arynes Figure 5. 1,4-Benzdiyne, 1,3-benzdiyne, and 1,2-benzdiyne. 2) as the 1,4-benzdiyne equivalent via triflation of hydroquinone 11-1 in pyridine (Scheme 266).873 In the presence of Scheme 266. Heptacene 11-4 from 1,4-Benzdiyne proposed that the insertion of a CO molecule on intermediate 10-263 could produce 10-264, which then undergoes a sequential incorporation of another molecule of aryne and reductive elimination to furnish the anthraquinone products 10-262. 11. BENZDIYNE CHEMISTRY The extensive exploration on o-silylaryl triflates not only significantly expanded the realm for the preparation of 1,2disubstituted benzenes as well as benzannulated scaffolds but also has been applied in the facile preparation of polysubstituted arenes and polycyclic aromatic hydrocarbons (PAHs) via equivalents of polyarynes.89 Those polyarynes can be classified into benzdiynes (i.e., 1,4-benzdiyne, 1,3-benzdiyne, and 1,2-benzdiyne), naphthodiynes, and other diynes with larger aromatic systems. Although these polyarynes started to be used as early as in the 1980s,89 the introduction of Kobayashi’s method significantly stimulated the recent advances in this subfield of aryne chemistry. In this section, we will focus on the methodology development on the equivalents of 1,4-benzdiyne, 1,3-benzdiyne, and 1,2-benzdiyne, which could sequentially generate two triple bonds on a benzene ring in the course of polyaryne transformations (Figure 5). Because naphthodiynes have shown distinct applications in the preparation of PAHs, they will be discussed in section 15. Moreover, Suzuki et al. employed 1,3,5benztriyne strategy to prepare a series of hexasubstituted benzenes.163−165 Because o-haloaryl triflates were utilized as the aryne precursors in their studies, these works will not be covered here. TBAF, “twistacene” 11-4 with a seven linear polyacene core was obtained in 22% yield via a double [4 + 2] cycloaddition reaction/extrusion of CO process between 11-2 and pyranodiphenylcyclopentadienone (11-3). This heptacene 11-4 possesses a stable nonpropeller twist topology, causing only marginal changes in electronic properties and reversible redox character. In 2015, Pavliček, Peña, and co-workers treated 1,4benzdiyne equivalent 11-2 with iodine and perylene (11-5) in a two-step transformation, which could afford diiodoarene 11-6 as a new aryne precursor (Scheme 267).874 By using lowtemperature scanning tunneling microscopy and atomic force microscopy techniques, they observed the generation of Scheme 267. Preparation of Diiodoarene 11-6 and the Observation of Individual Polycyclic Aryne 11-7 11.1. 1,4-Benzdiyne Chemistry The earliest and most widely investigated polyaryne is 1,4benzdiyne, which has found useful applications in the preparation of PAHs. In 2003, Wudl and co-workers first synthesized 1,4-bis(trimethylsilyl)phenyl-2,5-bis(triflate) (113983 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review products 11-15 was developed through the differential generation of 1,2-aryne 11-13 at 0 °C and then 4,5-aryne 11-15 at 45 °C. individual polycyclic aryne intermediate 11-7 from 11-6 through a tip-induced dissociation of iodine on an ultrathin insulating film. Based on bond-order analysis, the dominant constitution of 11-7 was suggested to be a cumulene resonance structure. Meanwhile, the same group reported an efficient preparation of polyphenyl aryne precursors through a controlled reaction of 1,4-benzdiyne equivalent 11-2 with cyclopentadienones 118, giving rise to new set of aryne precursors 11-9 (Scheme 268a).875 Both the proportion of solvent and the stoichiometry 11.2. 1,3-Benzdiyne Chemistry In comparison with 1,4-benzdiyne, the study of 1,3-benzdiyne equivalents has received much less attention, especially those with Kobayashi’s generation method. An interesting aspect for 1,3-benzdiyne transformations is its potential to construct angularly fused acenes. In order to rapidly prepare unsymmetrical and multiring fused heterocyclic compounds, Ikawa, Akai, and co-workers designed two Kobayashi equivalents of 1,3-benzdiyne 11-16 and 11-17 (Scheme 269).877 When Scheme 268. Double Annulation Strategies with Equivalents of 1,4-Benzdiyne Scheme 269. Study on 1,3-Benzdiyne by Ikawa and Akai compound 11-16 was treated with fluoride, only aryne 11-18 was generated. This result was attributed to the fact that the TMS group between the two electron-withdrawing OTf groups is more vulnerable to the activating reagent. In contrast, two aryne intermediates, namely, 1,2-aryne 11-19 and 3,4-aryne 11-20, could be released chemoselectively in a stepwise manner from aryne precursor 11-17, which was explained by the higher stability of the TBS group. Through the employment of different arynophiles, unsymmetrical, multisubstituted aromatic compounds 11-21 were readily achieved. Along with the study on 1,4-benzdiyne precursors, Kitamura et al. also prepared a new type of 1,3-benzdiyne equivalent [3,6-bis(trimethylsilyl)-2-(triflyloxy)phenyl](phenyl)iodonium triflate (11-24) (Scheme 270).878 The preparation of 11-24 commenced with the reaction of sodium 2,3,6-trichlorophenoxide (11-22) with TMSCl, Mg, CuCl, and LiCl in DMI at 55 °C and afforded compound 11-23 in 98% yield. After a successive iodination/hydrolysis/triflation/oxidation, 1,3-benzdiyne equivalent 11-24 could be produced in overall moderate yield. By treating 11-24 with fluoride ion, they observed a chemoselective generation of 1,2-aryne intermediate 11-25 from the phenyliodonio/TMS part. Bis-cycloadducts 11-27 could then be obtained by trapping 1,2-aryne 11-25 and 3,4aryne 11-26 with different arynophiles. of fluoride salts were the key factors that could avoid the generation of the second aryne. These polyphenyl aryne precursors have potential for the use in the synthesis of various acene, phene, and starphene derivatives. Meanwhile, Seliverstov et al. demonstrated a method to prepare ring-fused aryne precursors 11-10, which could be further utilized in the synthesis of unsymmetrical adducts 11-11 (Scheme 268b).876 In 2016, Ikawa, Akai, and co-workers discovered that 1,4benzdiyne equivalent 11-2 could release two aryne species, namely, 1,2-benzyne and 4,5-benzyne, at different time. Various arynophiles were then employed in a one-pot fashion at two aryne stages, leading to a convenient assembly of a set of unsymmetrical multiannulated products 11-11 (Scheme 268c).877 In 2017, Kitamura and co-workers further modified the structure of 1,4-benzdiyne equivalent 11-2 and prepared [2,5-bis(trimethylsilyl)-4-(triflyloxy)phenyl](phenyl)iodonium triflate (11-12) (Scheme 268d).878 It was found that the phenyliodonio/TMS part on 11-12 exhibits high reactivity toward fluoride ion, which allows a chemoselective generation of 1,2-benzyne intermediate 11-13. Consequently, a one-pot procedure for the preparation of various doubly cyclized 3984 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review position. When TPBT reagent 11-28 was treated with protected benzothioamides, both 2,4-disubstituted benzothiazoles 11-32a and 2-substituted benzothiazoles 11-32b could be obtained, the selectivity of which was determined by the structure of the protecting groups. Mechanistically, after the formation of 2,3-aryne 11-30, an intramolecular cyclization generates zwitterion 11-31. Depending on whether the R2 group contains an α-hydrogen or not, either 1,3-carbonyl migration on 11-31a or 1,5-hydrogen shift on 11-31b occurred to produce the corresponding products 11-32a and 11-32b, respectively. Later in 2016, Li and co-workers realized two diamination reactions with TPBT 11-28 (Scheme 272). When N-aromatic Scheme 270. Study on 1,3-Benzdiyne by Kitamura Scheme 272. Domino Aryne Diamination Reactions 11.3. 1,2-Benzdiyne Chemistry There is a common feature for the above 1,4-benzdiyne and 1,3-benzdiyne transformations: two sets of formal triple bonds occupy four positions on the same benzene ring. In contrast, two aryne intermediates, namely, 1,2-aryne and 2,3-aryne, share a common C2 position in a 1,2-benzdiyne process (Figure 5). Therefore, a maximum of trisubstituted benzenes should be realized. Although seemingly disadvantageous for forming less substituted benzenes comparing with 1,4- and 1,3benzdiyne processes, the chemistry of 1,2-benzdiyne has a distinctive feature in terms of regioselective control. Because the 2,3-aryne intermediate can only be generated after the consumption of 1,2-aryne in a 1,2-benzdiyne process, this strict mechanistic requirement offers a unique platform for chemoand regioselective 1,2-benzdiyne transformations. In 2015, Li and co-workers synthesized a Kobayashi 1,2benzdiyne precursor, 2-(trimethylsilyl)-1,3-phenylene bis(trifluoromethanesulfonate) (TPBT) (11-28), which is now known as the domino aryne reagent (Scheme 271).879 Upon activation, this TPBT reagent could generate 3-triflyloxybenzyne (11-29), which allows the nucleophile to attack its C1 or N-aliphatic sulfamides 11-33 reacted with TPBT 11-28, vicinal diamination occurred to furnish 1,2-diaminobenzenes 11-34 (Scheme 272a).880 The SO2 group on the substrates serves as both the linker and the electron-tuning factor. When Tf-protected anilines reacted with TPBT 11-28, 1,3diaminobenzenes 11-35 were obtained (Scheme 272b).881 Due to the electron-withdrawing inductive effect of the nitrogen substituent at the 2,3-aryne stage, a high level of regioselective control was observed in this transformation. Moreover, by using toluene as the solvent and K2CO3 as the activating reagent, an intramolecular thia-Fries rearrangement of a Tf group from NTf took place, furnishing 1,2,3trisubstituted 1,3-diaminobenzenes 11-36. Because two aryne species are generated in consecutive manner in a domino 1,2-benzdiyne process, combinations of different types of arynophiles might be plausible beyond two nucleophiles. To this end, Li et al. realized a domino aryne nucleophilic-ene process, affording benzo-fused N-heterocyclic compounds 11-39 from 11-38 (Scheme 273a).882 Notably, distinct chemoselectivity was observed at two aryne stages: an intermolecular nucleophilic addition proceeds faster than the ene reaction on 1,2-aryne 11-40; whereas the intramolecular ene reaction takes place exclusively on 2,3-aryne 11-41. In addition, a new domino aryne precursor TTPM 11-37 with an OTs group to replace one of the two OTf groups was found to be the key for the success of this transformation. It was explained that the retarded departure tendency of the OTs Scheme 271. Reaction of Domino Aryne Precursor 11-28 with Protected Benzothioamides 3985 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 273. Domino Aryne Annulation Reactions Review Scheme 274. 3-Silylbenzyne as Equivalent of 1,2-Benzdiyne activation, aryne precursors 11-51 could generate the corresponding 2,3-aryne species, which was then trapped by various arynophiles and furnished polysubstituted arenes containing pyridine substituent in good yields and excellent regioselectivity. In addition to the above transformations, 1,3-bis(triflyloxy)2-iodoarenes 11-54 was also employed as a 1,2-benzdiyne precursor by Yoshida, Hosoya, and co-workers (Scheme 275).884,885 In the presence of trimethylsilylmethyl Grignard Scheme 275. 1,2-Benzdiyne Processes with N-Silyl Amines and N-Silyl Sulfides group would defer the generation of 2,3-aryne 11-41, hence, favoring an intramolecular ene reaction. Moreover, domino aryne nucleophilic/Diels−Alder reaction processes were independently realized by the groups of Hoye883 and Li.356 As shown in Scheme 273b, Hoye et al. demonstrated that substrate 11-42 could participate in domino aryne nucleophilic addition, intramolecular hexadehydroDiels−Alder (HDDA) reaction with either TPBT 11-28 or TTPM 11-37 to generate a naphthalyne intermediate 11-43, which was then trapped by various arynophiles to afford polysubstituted naphthalenes 11-44.883 On the other hand, Li and co-workers disclosed that cinnamyl sulfonamides 11-46 could also realize a nucleophilic, Diels−Alder reaction cascade process, furnishing a variety of [6,n,6,6]-tetracyclic and [6,5,6,6,6]-pentacyclic ring structures 11-47 in a highly efficient manner (Scheme 273c).356 In this study, a series of domino aryne precursors 11-45 were systematically investigated, and 11-45 with a 2,6-difluorophenylsulfonate (Ar = 2,6-difluorophenyl) as the second LG was identified to serve as an ideal domino aryne precursor. A synthetic effort toward the construction of ergot alkaloid framework was reported, which will be discussed in section 14. In 2018, Li and co-workers developed an aryne 1,2,3trifunctionalization protocol from 2,6-bis(silyl)aryl triflates 1148, where the generated 3-silylaryne intermediate 11-49 could react with pyridine N-oxides 11-50 or N-hydroxylamides 1152 in a highly regioselective manner to afford the corresponding o-silylaryl triflates/tosylates 11-51 and 11-53, respectively, in one-pot fashion (Scheme 274).652 Upon reagent, the generated 3-triflyloxybenzynes 11-29 could insert into the N−Si bond of N-silylamines884 (Scheme 275a) and the S−Si bond of silyl sulfides885 (Scheme 275b) regioselectively to afford the corresponding o-silylaryl triflates 11-55 and 11-57, respectively, as 2,3-aryne precursors. Upon activation and trapping with various arynophiles, polysubstituted arenes 11-56 and 11-58 could be obtained from these 2,3-aryne precursors. 12. HETARYNE CHEMISTRY When a formal C−C triple bond is positioned within a heterocyclic aromatic framework, the structure can be seen as a heterocyclic aryne or hetaryne. Akin to the history of benzyne chemistry, the early precursors of hetarynes also required harsh generation conditions, which restricted their synthetic application. Along with the widespread application of Kobayashi’s method in benzyne chemistry, this generation 3986 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR method has been extended to hetaryne chemistry as well.83,100 In this section, we wish to summarize the preparation and the reactivity study on Kobayashi precursors of various hetarynes, those of which include pyridynes (2,3-pyridyne, 3,4-pyridine), 2,3-quinolyne, indolynes (4,5-indolyne, 5,6-indolyne, 6,7indolyne), 4,5-benzofuranyne, and 6,7-thienobenzyne (Figure 6). Review Scheme 276. Preparation of 2,3-Pyridyne Precursors with furan; whereas a mixture of 12-11a and 12-11b were obtained in a 3:1 ratio with 2-methylfuran (Scheme 277a).889 Figure 6. Hetarynes with preferred site of attack. Scheme 277. Cycloaddition Reactions with 2,3-Pyridynes 12.1. Pyridynes and 2,3-Quinolyne Pyridynes are the most widely studied hetarynes. According to the location of the formal triple bond on a pyridine ring, pyridynes can be classified into 2,3-pyridyne and 3,4-pyridyne. DFT studies on both pyridynes indicated that although the structure of 3,4-pyridyne is consistent with a formal triple bond moiety, the cumulenic structure of 2,3-pyridyne seems to be more favorable (Figure 6).886,887 This cumulenic resonance structure not only confers greater electrophilic character at the C2 position but also makes 2,3-pyridyne extreme reactive, resulting in low reaction efficiency due to the unexpected side reactions. In addition, while the reaction of 2,3-pyridyne can normally yield the corresponding products in satisfactory regioselectivity, those with unsubstituted 3,4-pyridyne lack regioselective control. 12.1.1. 2,3-Pyridyne. In 1991, Effenberger and Daub prepared two Kobayashi precursors of 2,3-pyridyne with the TMS and OTf groups on the opposite positions of the pyridine ring. They first treated pyridin-2(1H)-one (12-1) with LDA and TMSCl to prepare 3-(trimethylsilyl)-2-((trimethylsilyl)oxy)pyridine (12-2), which could then be converted to 2,3pyridyne precursor 12-3 (Scheme 276a).888 The same protocol was also employed to synthesize 2,3-pyridyne precursor 12-5 from pyridin-3-ol (12-4). This study was the first preparation of Kobayashi precursors of 2,3-pyridyne. Their further investigation on the [4 + 2] cycloaddition reaction of both 12-3 and 12-5 with furan, however, failed to produce the desired cycloadducts. In 1995, Walters and Shay demonstrated a five-step preparation of 5-methoxy-2,3-pyridyne precursor 12-9.889 As shown in Scheme 276b, this synthetic route commenced with the replacement of the nitro group on 4nitropyridine 1-oxide (12-6) with sodium methoxide via SNAr mechanism and a subsequent production of pyridone 12-7 in refluxing acetic anhydride. Pyridone 12-8 was then prepared through silylation of 12-7, which was converted to the 2,3pyridyne precursor 12-9 after triflation. With compound 12-9 in hand, Walters and Shay examined its [4 + 2] cycloaddition reaction with furans through dropwise addition of compound 12-9 into the reaction media. Cycloadduct 12-10 (R = H) was produced in 41% yield Subsequently, they examined the Diels−Alder reaction of 2,3pyridyne precursor 12-3 with furans by using anhydrous CsF as the activating reagent (Scheme 277b).890 Unfortunately, these reactions only furnished the cycloadducts 12-12 in low yields. In addition, [4 + 2] cycloaddition reactions of 2,3pridynes have also been used by Lautens.891 In 2014, Saito, Sato, and co-workers reported a [3 + 2] cycloaddition reaction between organic azides and 2,3-pyridyne precursors 12-3 and 12-9, affording cycloadducts 12-13 as the only regioisomer (Scheme 277c).892 Although 4-methoxy-2,3-pyridyne exhibits the same regioselective preference with that of simple 2,3pyridyne, the reactions with 12-9 normally give higher yields. Other types of [3 + 2] cycloaddition reactions with 2,3pyridyne have also been reported by Gribble.318 In addition to pericyclic reactions, nucleophiles were also examined. In 2012, Larock studied the reactions of 2,3pyridyne with organic amines and o-aminobenzoates (Scheme 3987 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR 278a).893 2-Aminopyridines 12-14 were obtained from primary and secondary amines, while benzonaphthyridinones 12-16 Review 12-22 was obtained through Fries rearrangement on 12-20b by treating it with LDA and a subsequent triflation. In 2013, Garg et al. reported the preparation of three Kobayashi precursors of 3,4-pyridyne (Scheme 280).152 Scheme 278. Reactions of 2,3-Pyridynes with Nucleophilic Arynophiles Scheme 280. Preparation of 3,4-Pyridyne Precursors by Garg could be achieved from secondary and tertiary o-aminobenzoates 12-15. Both transformations were realized in excellent regioselectivity. In this study, slow addition of pyridyne precursor was found to prevent unwanted side reactions. Later in 2013, Saito, Minami, Sato, and co-workers investigated the reaction of 2,3-pyridyne precursors with compounds 12-17, such as N,N-dimethylimidazolidone (DMI) (X = NMe, n = 1), DMPU (X = NMe, n = 2), and 1-methyl-2-oxazolidone (X = O, n = 1), affording the corresponding C−N σ-bond insertion products 12-18 in moderate to excellent yields (Scheme 278b).894 In 2016, Garg et al. examined the reactivity of 2,3-pyridyne with Nnucleophiles, 1,3-dipoles, and DMI as well.895 In addition, Kobayashi precursors of 2,3-pyridyne have also been utilized as hetaryne substrates in benzyne transformations.318,417,536,668 12.1.2. 3,4-Pyridyne. In 1992, Snieckus and Tsukazaki first employed the directed ortho metalation strategy to prepare Kobayashi precursors of 3,4-pyridyne.896 As shown in Scheme 279, starting from 3-pyridyl carbamate (12-19), silylation with trialkylsilyl chloride could yield compounds 12-20 in good to excellent yields. After reductive removal of the carbamate group and triflation, 3,4-pyridyne precursor 12-21 could be produced from 12-20a. Alternatively, 3,4-pyridyne precursor Starting from 3-hydroxypyridine (12-23), silylcarbamates 1224 could be obtained through carbamoylation and a C4selective silylation procedure (Scheme 280a). 3,4-Pyridyne precursor 12-25 was prepared from 12-24a via a one-pot deprotection of the R1 group and triflation. Alternatively, compound 12-24b could be converted to 12-26 in two steps in 53% yield. As shown in Scheme 280b, compound 12-28 was prepared from benzyl ether 12-27 through sulfamoylation and C4 silylation, which was then readily converted to 3,4-pyridyne precursor 12-29 after deprotection and triflation. Gram quantities of these three 3,4-pyridyne precursors were prepared by using the protocols in Scheme 280. After the preparation of Kobayashi precursors of 3,4pyridyne 12-21 and 12-22, Snieckus and Tsukazaki examined their reactivity with furan and 1,3-diphenylisobenzofuran, which led to the formation of the corresponding cycloadducts 12-30 and 12-31, respectively, in low to moderate yields (Scheme 281).896 Tetracyclone could also serve as diene arynophile. Notably, when benzenethiol was used as the nucleophile, a 1:1 mixture of 12-32a and 12-32b was obtained from the reaction with 12-21; whereas the reaction with 12-22 gave rise to 12-33 in 55% yield as the only isomer. A distinct regioselectivity study on the reaction of different 3,4-pyridyne precursors was carried out by Garg and co-workers.147,152 Both the 5-bromo group on 12-26 and the sulfamate group on 1229 could serve as effective EW inductive substituents, leading to regioselective transformations with respect to both 3,4pyridyne precursors 12-26 and 12-29. The details on this study have been discussed in Scheme 12. More [4 + 2] cycloaddition reactions with the Kobayashi precursor of 3,4-pyridyne were also reported by the groups of Coudert897 and Carroll.898 In 2009, Sato and Iwayama demonstrated a Ni(0)-catalyzed [2 + 2 + 2] cocyclotrimerization of diynes and 3,4-pyridynes, furnishing isoquinoline derivatives 12-35 (Scheme 282).832 In this study, intramolecular [2 + 2 + 2] cocyclotrimerization of Scheme 279. Preparation of 3,4-Pyridyne Precursors by Snieckus 3988 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 281. Reactivity Study on 3,4-Pyridynes by Snieckus Review Scheme 283. Ni-Catalyzed Cocyclotrimerization of 3,4Pyridyne with Alkynes Scheme 284. Silver-Catalyzed Tandem Reaction with 3,4Pyridynes Scheme 282. Ni-Catalyzed [2 + 2 + 2] Cocyclotrimerization of Diynes and 3,4-Pyridines 12-34 with tethered diyne and pyridyne moiety was also achieved. Mechanistically, they proposed that oxidative addition of diyne to nickel(0) complex could afford nickelacyclopentadiene intermediate 12-36 (Scheme 282). Insertion of 3,4-pyridyne to 12-36 generates seven-membered nickelacycle 12-37a or 12-37b, which then undergoes reductive elimination to produce isoquinoline 12-35. Subsequently, the same group realized a Ni(0)-catalyzed [2 + 2 + 2] cocyclotrimerization of 3,4-pyridyne with two molecules of 2-butyn-1,4-diol derivatives 12-38 and 1,3-diynes 12-40, affording isoquinoline derivatives 12-39 and 12-41, respectively (Scheme 283).833 They reasoned that the reactivity and selectivity in this transformation originates from the coordination of the oxygen at the propargylic position in nickel complex 12-42. In 2012, Fang, Wu, and co-workers reported a silver triflatecatalyzed tandem reaction of N′-(2-alkynylbenzylidene)hydrazide 12-43 with 3,4-pyridyne precursor 12-21 (Scheme 284).899 As previously demonstrated with arynes by the same group,656 this transformation was proposed to proceed through a [3 + 2] cycloaddition reaction between 3,4-pyridyne and isoquinolinium-2-yl amide 12-44, furnishing pyridinyl-fused Hpyrazolo[5,1-a]isoquinolines 12-45a and 12-45b after eliminative aromatization on the [3 + 2] cycloadducts. By employing 2-chloro-3,4-pyridyne (12-46) in this transformation, products 12-49 were obtained, the formation of which was proposed to proceed through a sequential N−N bond cleavage on cycloadduct 12-47 and an intramolecular recombination on radical intermediate 12-48. Along with their study on the C−N bond insertion reactions with 2,3-pyridyne, Saito, Minami, Sato, and co-workers also investigated the reactivity of 3,4-pyridyne with DMI, DMPU, and 1-methyl-2-oxazolidone, which led to the formation of 1250a and 12-50b as mixtures of regioisomers (Scheme 285a).894 In addition, the same group examined the [3 + 2] cycloaddition reactions of 3,4-pyridyne with organic azides, furnishing the corresponding cycloadducts 12-51a and 12-51b as well (Scheme 285b).892 Moreover, Kobayashi precursors of 3,4-pyridyne have also been utilized as hetaryne substrates in benzyne transformations.369,474,537,783,788,835 12.1.3. 2,3-Quinolyne. 2,3-Quinolyne was normally seen as the analogue of 2,3-pyridyne and has been only employed along with the study on 2,3-pyridyne.892−894 3989 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 285. Other 3,4-Pyridyne Transformations Review Scheme 287. Preparation of Indolyne Precursors by Garg 12.2. Indolynes In 2009, Buszek and co-workers developed a Fischer indole synthesis strategy to prepare Kobayashi precursors of 4,5-, 5,6-, and 6,7-indolynes.900 As shown in Scheme 286, hydrazine indolyne precursor 12-64. The same protocol was also applied in the preparation of 6,7-indolyne precursor 12-66 from carbamate 12-65 (Scheme 287). In this study, both Nunprotected and N-Boc-protected analogues of these three types of indolynes as well as 3-substituted 4,5-indolyne precursors were also prepared.150 Moreover, direct functionalization on the framework of indolyne precursors was demonstrated by the groups of Pilarski117,118 and Yoshida.902 As has been discussed in Figure 4, Houk, Garg, and coworkers employed a distortion/interaction model to rationalize the selectivity issue in either nucleophilic addition reactions or other transformations with polar arynophiles with respect to 4,5-, 5,6-, and 6,7-indolynes.144,145,148−150 This model suggests that whenever the internal angle difference between triple bond carbons is larger than 4°, a substantial degree of regioselectivity could be envisioned. As depicted in Figure 6, 6,7-indolyne prefers its C6-position and 4,5-indolyne prefers its C5-position. 5,6-Indolyne, however, does not show an obvious preference on which site is more electrophilic. These theoretical studies were then examined with polar arynophiles, the regioselectivity of which was highly consistent with their prediction.150 In 2015, Oestreich and co-workers reported a platinum(0)catalyzed insertion reaction of indolynes into the B−B bond of bis(pinacolato)diboron (pinB)2, furnishing products 12-67, 12-68, and 12-69 in moderate yields (Scheme 288).871 Among those products, 6,7-bis[(pinacolato)boryl]indole 12-67 could undergo C7-selective Suzuki−Miyaura cross coupling reactions to afford 12-70. Moreover, Kobayashi precursors of indolynes Scheme 286. Preparation of Indolyne Precursors by Buszek hydrochloride salt 12-53 could be prepared in 51% overall yield from 4-nitro-2-(trimethylsilyl)phenol (12-52), which was then subjected to Fischer’s cyclization conditions with phenylacetaldehyde to afford indole products 12-54 and 1255 in a 1:5 ratio. After methylation, Kobayashi precursors of 4,5-indolyne 12-56 and 5,6-indolyne 12-57 were prepared. Meanwhile, starting from 2-nitro-6-(trimethylsilyl)phenol (1258), the corresponding 6,7-indolyne precursor 12-59 was synthesized by employing the same preparation procedure. In addition, [4 + 2] cycloaddition reactions of 12-56, 12-57, and 12-59 with 2-tert-butylfuran were examined, all of which afforded the corresponding cycloadducts in high yields. In the same year, Garg et al. provided an efficient protocol toward Kobayashi precursor of 4,5-indolyne,901 which was then expanded to the preparation of both 5,6-indolyne and 6,7indolyne precursors (Scheme 287).150 Carbamate 12-60 was synthesized from commercially available 5-benzyloxyindole, which was then converted to silyl carbamate 12-61 in 84% yield via a selective silylation operation. Meanwhile, carbamate 12-62 was obtained in 10% yield along with the formation of 12-61. Next, a one-pot deprotection/triflation on both carbamates gave 4,5-indolyne precursor 12-63 and 5,6- Scheme 288. Pt-Catalyzed Insertion of Boron−Boron Bond 3990 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review have been extensively utilized as hetaryne substrates along with benzyne transformations.135,236,365,407,415,424,433,471,521,522,526,549,550,604,864,903,904 12.3. Other Hetarynes 12.3.1. 4,5-Benzofuranyne. In 2016, Garg and coworkers prepared the Kobayashi precursor of 4,5-benzofuranyne 12-71 from 5-hydroxybenzofuran (Scheme 289a).153 Figure 7. Structures of cyclohexynes, 1,2-cyclohexadienes, and 1,2,3cyclohexatriene. Scheme 289. 4,5-Benzofuranyne and 6,7-Thienobenzyne 13.1. Preparation Methods Because the preparation for Kobayashi precursors of cyclohexyne, 1,2-cyclohexadiene, and 1,2,3-cyclohexatriene mainly follow similar synthetic protocols or from the same key intermediates, these procedures will be discussed together. In 1990, Johnson and Shakespeare reported a preparation of the Kobayashi precursor of 1,2,3-cyclohexatriene 13-3.908 As shown in Scheme 290a, starting from 2-bromocyclohexenone Scheme 290. Preparation Procedures via 2(Trimethylsilyl)cyclohexenone (13-2) Upon activation with CsF, the generated 4,5-benzofuranyne intermediate 12-72 were then trapped by various arynophiles to afford the corresponding products 12-73 in good to excellent yields. Based on their distortion/interaction model, the C5-position of 4,5-benzofuranyne is the more electrophilic site in the reactions with polar arynophiles. Moreover, this model also suggested that the regioselectivity in the reaction with 4,5-benzofuranyne (7° internal angel difference) should be higher than those with 4,5-indolyne (4° internal angle difference). 12.3.2. 6,7-Thienobenzyne. In 2018, Yoshida, Hosoya, and co-workers reported the preparation of a series of 2,3disubstituted 6,7-thienobenzyne precursors 12-74 (Scheme 289b).905 The corresponding 6,7-thienobenzynes 12-75 could be trapped by arynophiles, furnishing the desired products 1276 in modest C6 regioselectivity. In addition, Kobayashi precursors of 3,4-furanyne906 and 4,5-pyrimidyne895 were also synthesized. Unfortunately, efforts to capture the desired hetaryne intermediates from these precursors with various arynophiles were found to be unfruitful. (13-1), 2-(trimethylsilyl)cyclohexenone (13-2) could be prepared in three steps. Enolization of compound 13-2 with LDA, followed by triflation with PhNTf2 afforded 1,2,3cyclohexatriene precursor 13-3 in 50% yield. Enone 13-2 was then employed as a common building block for the preparation of both cyclohexyne and 1,2-cyclohexadiene precursors. In 1998, Guitián et al. reported a facile preparation of cyclohexyne precursor 13-5 from compound 13-2 (Scheme 290b).909 A two-step one-pot operation was successfully developed, which includes a hydride conjugate addition to enone 13-2 with L-Selectride and a subsequent triflation on intermediate 13-4, furnishing cyclohexyne precursor 13-5 in 78% yield. In 2009, the same group employed enone 13-2 to prepare Kobayashi precursors of 1,2cyclohexadiene 13-7.910 As shown in Scheme 290c, Michael addition on enone 13-2 with L-Selectride afforded either compound 13-6a after aqueous workup or compound 13-6b by trapping with iodomethane. Further enolization and triflation on 13-6 could produce the corresponding 1,2cyclohexadiene precursors 13-7a and 13-7b. In 2016, West and co-workers reported an efficient and scalable synthesis of 1,2-cyclohexadiene precursors.911 As 13. CYCLOHEXYNE, 1,2-CYCLOHEXADIENE, AND 1,2,3-CYCLOHEXATRIENE Beside arynes and hetarynes, six-membered angle-strained cyclic alkynes/allenes have also been studied along with the advances of aryne chemistry.78,141,907 There are three aliphatic active species bearing a parent six-membered ring, namely, cyclohexyne, 1,2-cyclohexadiene, and 1,2,3-cyclohexatriene, which also include heteroatom-imbedded analogues (Figure 7). Although owning great synthetic potential, these transient intermediates remain largely unexplored.78 Along with the employment of Kobayashi’s method as the generation conditions for these species, more and more applications were reported in the past decade. 3991 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR shown in Scheme 291, a copper-mediated conjugate addition of dimethylphenylsilyllithium to enol triflate derivative 13-8, Review Scheme 293. Preparation Methods Developed by Garg Scheme 291. Preparation of 1,2-Cyclohexadiene Precursors by West protocol was also employed by the same group in the preparation of 3,4-oxacyclohexyne precursor.153 In 2018, Kwon et al. reported an unusual preparation of substituted cyclohexyne precursors 13-28 via alkenyl cation intermediate 13-27 (Scheme 294).915 Mechanistically, cation readily prepared from cyclohexane-1,2-dione, could generate intermediate 13-9, which was then trapped by acetic anhydride to furnish an acetoxy-substituted 1,2-cyclohexadiene precursor 13-10. Alternatively, tosylate 13-11 could be prepared from enone 13-8 via 1,2-reduction and protection with tosyl chloride, which was then subjected to a copper-mediated allylic substitution with dimethylphenylsilyllithium to afford 1,2-cyclohexadiene precursor 13-12. In 2018, Okano and co-workers developed a method to reach both Kobayashi precursors of cyclohexynes and 1,2cyclohexadienes in a regiocontrolled manner.912,913 As shown in Scheme 292, the treatment of silyl enol ether 13-13 with a Scheme 294. Preparation Method Developed by Kwon Scheme 292. Preparation Methods Developed by Okano 13-26 could be generated by treating silylalkynols 13-25 with triflic acid, which then cyclizes to produce alkenyl cation 1327. Subsequently, triflate anion combines with 13-27 to afford Kobayashi precursors of either cyclohexyne or 1,4-dihydronaphalyne 13-28. A unique property of this method is its ease to introduce various substituents at the C3-position of the cyclohexyne scaffold. In 2014, Danheiser and Tlais reported a preparation of Ntosyl-3-azacyclohexyne precursor 13-32 (Scheme 295).916 In this study, they started with α-bromination of lactam 13-29 to afford dibromide 13-30, which was then converted to α-silyl lactam 13-31 by using an excess amount of n-BuLi and TMSCl. Furthermore, α-deprotonation on 13-31 and triflation combination of LDA and t-BuOK resulted in a silyl group migration (retro-Brook rearrangement) to generate α-silyl enolate 13-14, which was then trapped by Comins’ reagent 1315 to produce 1,2-cyclohexadiene precursors 13-16. Moreover, α-silyl enolate 13-14 could isomerize to intermediate 13-17 in the presence of a stoichiometric amount of water, yielding cyclohexyne precursors 13-18 upon triflation. In this study, various silyl groups, such as TES, TBS, TIPS, and TBDPS, were found to be effective. In 2019, Garg et al. demonstrated a concise protocol to prepare both cyclohexyne and 1,2-cyclohexadiene precursors (Scheme 293).914 Starting from α-bromocyclohexanone (1319), silyl enol ether 13-20 was readily prepared using DABCO and triethylchlorosilane (TESCl). Upon treatment of 13-20 with sec-BuLi, a metal−halogen exchange and retro-Brook rearrangement occurred to generate intermediate 13-21. Onepot triflation of 13-21 with PhNTf2 furnished cyclohexyne precursor 13-22; while quenching 13-21 with aqueous sodium bicarbonate produced α-silyl ketone 13-23, which was then converted to 1,2-cyclohexadiene precursor 13-24. This Scheme 295. Preparation Method Developed by Danheiser 3992 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR could readily prepare N-tosyl-3-azacyclohexyne precursor 1332. In 2015, Houk, Garg, and co-workers demonstrated an efficient preparation of 3,4-piperidyne precursor 13-36 (Scheme 296a).155 The synthesis commenced with ortho Review Scheme 297. Reactions on Cyclohexyne by Pérez and Guitián Scheme 296. Preparation of 3,4-Piperidyne and Aza-1,2cyclohexadiene Precursors In 2014, Houk, Garg, and co-workers systematically investigated the reaction between cyclohexynes and various 1,3-dipoles, furnishing 5-membered heterocycles 13-46 (Scheme 298).154 A variety of trapping agents, i.e., azide, Scheme 298. Reactions on Cyclohexyne by Houk and Garg silylation of 4-methoxypyridine (13-33) to afford silylpyridine 13-34 in 77% yield. Next, one-pot reductive carbamoylation and hydrolysis yielded vinylogous amide 13-35 in high yield. At last, a conjugate reduction/triflation operation on 13-35 furnished a protected 3,4-piperidyne precursor 13-36. With this protocol in hand, they accomplished the synthesis of a series of aza-1,2-cyclohexadiene precursors.157 As shown in Scheme 296b, vinylogous amide 13-37, prepared from 4methoxypyridine (13-33) through a similar preparation procedure to that in Scheme 296a, was converted to either ketone 13-38a or 13-38b after 1,4-reduction with L-Selectride and followed with protonation or methylation, respectively. After triflation, o-silyl triflates 13-39 were obtained. Alternatively, ketones 13-38 could be transformed to enols 13-40, which then underwent triflation to yield o-silyl triflates 13-41. diazo compound, N-phenylpyrazole, nitrone, and nitrile oxide, were effective with respect to cyclohexyne. In addition, they employed 3-benzyloxycyclohexyne (13-47) in the reactions with both imidazole and benzyl azide, which could afford the corresponding products in good to high regioselectivity. These regioselectivities were predicted by their distortion/interaction model as well. In 2014, Danheiser et al. examined the reactivity of N-tosyl3-azacyclohexyne (13-32) in the presence of various arynophiles, i.e., tetracyclone, benzyl azide, and Bu3SnH, all of which could afford the corresponding products 13-48 in moderate to high yields with excellent regioselectivity (Scheme 299a).916 Subsequently, Bräse and co-workers reported the cycloaddition reactions of compound 13-32 with sydnones 1349, furnishing fused amino-substituted pyrazole scaffolds 1350a and 13-50b (Scheme 299b).919 In 2015, Houk, Garg, and co-workers studied the reactivity of 3,4-piperidyne precursor 13-36 with different arynophiles (Scheme 299c).155 Based on their distortion/interaction model calculations, they predicted 13.2. Cyclohexyne Reactions In 2002, Pérez, Guitián, and co-workers reported a transitionmetal-catalyzed cyclotrimerization of cyclohexyne, affording dodecahydrotriphenylene (13-42) in moderate yield (Scheme 297a).917 Both Pd(PPh3)4 and Pt(PPh3)4 were found to be active catalysts in this transformation. Later in 2006, Peña examined a Pd-catalyzed [2 + 2 + 2] cocyclotrimerization of cyclohexynes with alkynes, which could furnish octahydrophenanthrenes 13-43 in moderate yields (Scheme 297b).918 In addition, they also studied the reactivity of cyclohexyne precursor in the presence of catalytic amount of Ni(COD)2 and obtained 13-45 in 27% yield, along with 10% of 13-42 (Scheme 297c).918 It was proposed that the formation of 1345 was from the Diels−Alder reaction of two molecules of dimer 13-44. 3993 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 299. Reactions on Aza/Oxo-Cyclohexynes Review Scheme 300. Preparation of Heteroatom-Containing PAHs by Garg than that of oxadiazinone 13-53. Meanwhile, Yoshida, Hosoya, and co-workers reported a chemoselective preparation of similar compounds from the reaction of oxadiazinone 13-53 with precursors of cyclohexyne and arynes.189 Besides, those Kobayashi precursors of cyclohexynes have also been utilized along with the studies on arynes, such as distannylation,823 acyl-alkylation/condensation,710 cycloaddition,134 the reaction with sulfoxonium ylides,417 and asymmetric C-arylation of chiral enamines.407 In 2018, Li and co-workers developed a facile preparation toward cyclohexenynone precursors as equivalents of polysubstituted cyclohexynes.920 As shown in Scheme 301a, oxidative dearomatization of o-silylaryl triflates 13-57 and that the C4 position is more electrophilic in the reactions with nucleophiles and unsymmetrical cycloaddition partners. In 2016, the same group also investigated the reactivity of 3,4oxacyclohexyne precursor 13-51 with various arynophiles.153 As shown in Scheme 299d, their distortion/interaction model calculation indicated that the C4 position of 3,4-oxacyclohexyne (13-52) is more electrophilic, which was then confirmed by their experimental results. Recently, Garg and co-workers applied 3,4-piperidyne precursor 13-36 in the preparation of heteroatom-containing PAHs (Scheme 300).903 In this study, oxadiazinone 13-53 was utilized to trap 3,4-piperidyne intermediate, affording pyrones 13-54a and 13-54b as a mixture of regioisomers. The isolated 13-54a was then subjected to a second Diels−Alder reaction with various arynes and cyclic alkynes, resulting in the modular syntheses of PAHs 13-55a and 13-55b (Scheme 300a). In this study, a three-component coupling reaction was also realized by using equal molar concentrations of 3,4-piperidyne precursor 13-36, Kobayashi benzyne precursor, and oxadiazinone 13-53, giving rise to 13-56 as the only product (Scheme 300b). They reasoned that 3,4-piperidyne is more readily generated from its precursor 13-36 than that of benzyne. In contrast, the reaction of oxadiazinone 13-53 with benzyne only obtained double cycloaddition product, which could be explained by the higher reactivity of the benzopyrone intermediate generated after the first Diels−Alder reaction Scheme 301. Cyclohexenynone Precursors 3994 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review 13-59 containing a phenol moiety was utilized to access two types of cyclohexenynone precursors 13-58 and 13-60, respectively. Moreover, both 13-58 and 13-60 could be converted to a variety of densely functionalized cyclohexyne precursors by further manipulating the carbonyl, olefin, and methoxy groups. A study on these cyclohexenynone precursors with different arynophiles revealed that they could readily participate in cycloaddition reactions and nucleophilic additions to produce the corresponding products in moderate to high yields. In this study, they also demonstrated that the reaction of these densely substituted cyclohexyne precursors with aryl allyl sulfoxides 13-61 could afford 2,2-disubstituted 1,3-cyclohexadiones 13-63, which was formed via a [2,3] sigmatropic rearrangement on an allyl sulfonium ylide intermediate 13-62 (Scheme 301b). Scheme 303. Reactions on 1,2-Cyclohexadiene and Azacyclic Allenes by Houk and Garg 13.3. 1,2-Cyclohexadiene Reactions preferential formation of the endo products. In addition, their DFT calculations explained that the regioselective control is through either the stepwise or concerted reaction pathway. Meanwhile, West et al. examined the reaction of 1,2cyclohexadiene with various 1,3-dipoles, such as nitrones, nitrile oxides, and azomethine imines, all of which could furnish the corresponding products in high regio- and stereoselectivity.911 In 2018, the same group reported an indepth study on azacyclic allenes.157 As shown in Scheme 303b, azacyclic allene precursors 13-39 (R = H) and 13-41 (R = CO2Me) were subjected to the Diels−Alder reactions with furans and N-phenylpyrrole, affording cycloadducts 13-72 in moderate to excellent yields. It was observed that the site of cycloaddition was distal to the methyl group and proximal to the ester group on 13-39 and 13-41. Their DFT calculations suggested a concerted asynchronous endo transition state. Moreover, they exhibited that the stereochemical information could be transferred from enantioenriched precursor 13-39 and 13-41 to the cycloadducts 13-72. In 2009, Peña, Guitián, and co-workers investigated the reactivity of 1,2-cyclohexadiene in both the [4 + 2] cycloaddition reaction and Pd-catalyzed [2 + 2 + 2] cocyclotrimerization with alkyne.910 As shown in Scheme 302a, the [4 + 2] cycloaddition reaction of 13-7a with both Scheme 302. Reactions on 1,2-Cyclohexadiene 13.4. 1,2,3-Cyclohexatriene Reactions In comparison with the study on cyclohexynes and 1,2cyclohexadienes, there are only a few reports on 1,2,3cyclohexatriene with respect to the Kobayashi-type precursor. In 1990, Johnson et al. treated 1,2,3-cyclohexatriene precursor 13-3 with CsF in the presence of diphenylisobenzofuran and obtained cycloadduct 13-73, albeit in 24% yield (Scheme 304a).908 In 1994, Paquette and Hickey carried out the Scheme 304. Reactions on 1,2,3-Cyclohexatriene furan and tropone (13-64) afforded mixtures of endo- and exocycloadducts 13-65 and 13-66, respectively, with excellent endo-selectivity. Moreover, Pd-catalyzed [2 + 2 + 2] cocyclotrimerization of 1,2-cyclohexadiene with DMAD yielded compounds 13-67 and 13-68, albeit in low yields (Scheme 302b). Mechanistically, after Pd-catalyzed trimerization of 13-69, a fluoride-induced deprotonation/rearomatization could generate anion 13-70. Consequently, both protonation and nucleophilic addition to DMAD would happen to yield 13-67 and 13-68, respectively. In 2016, Houk, Garg, and co-workers systematically investigated the reaction behavior of 1,2-cyclohexadiene with nitrones.156 As shown in Scheme 303a, the reaction between 1,2-cyclohexadiene precursor 13-7a and nitrones occurred in regioselective manner to afford isoxazolidines 13-71 with reaction of compound 13-3 with cyclopentadiene and achieved cycloadduct 13-74 in 74% yield, which was converted to compound 13-75 for further study (Scheme 304b).921,922 3995 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR 14. SYNTHESES OF NATURAL PRODUCTS AND BIOACTIVE MOLECULES Along with the advances of Kobayashi’s method, it has also been applied in the preparation of natural products as well as bioactive molecules. There are several previous reviews on aryne-involved synthesis of natural products, which include not only Kobayashi’s method but also those from different precursors.78,79,92 This section will focus on the examples related to o-silylaryl triflates. Review of tert-butyl 6-(furan-3-yl)-2,3-dimethoxybenzoate (14-8) and aryne precursor 14-7, furnishing cycloadduct 14-9. After an acid-promoted regiospecific lactonization and dehydration, arnottin I 14-10 was obtained. Further saponification on arnottin I, followed by a hypervalent iodide-mediated spirocyclization, achieved the synthesis of racemic arnottin II 14-11. In the same year, Raminelli et al. accomplished the syntheses of a series of aporphine alkaloids (Scheme 307).926,927 The key 14.1. Cycloaddition Strategies Scheme 307. Total Syntheses of Aporphine Alkaloids In 1998, Guitián and co-workers accomplished a concise total synthesis of ellipticine (14-6) by employing a regioselective [4 + 2] cycloaddition reaction between 1,3-dimethyl-4-(phenylsulfonyl)-4H-furo[3,4-b]indole (14-1) and 2-chloro-3,4-pyridyne (14-3), generated from pyridyne precursor 14-2, as the key step (Scheme 305).923 This transformation gave a mixture Scheme 305. Concise Total Synthesis of Ellipticine step for the construction of the aporphine core 14-13 is an aryne [4 + 2] cycloaddition reaction with 1-methyleneisoquinolines 14-12, which is followed by rearomatization via a hydrogen migration event. Upon further modifications, (R)aporphine 14-14, lysicamine 14-15, (±)-nuciferine 14-16, (±)-nornuciferine 14-17, (±)-zanthoxyphylline iodide 14-18, (±)-O-methylisothebaine 14-19, and (±)-trimethoxynoraporphine 14-20 were successfully prepared. Particularly, the preparation of (±)-zanthoxyphylline iodide 14-18, (±)-Omethylisothebaine 14-19, and (±)-trimethoxynoraporphine 14-20 proceeded through a highly regioselective aryne Diels−Alder reaction by using 3-methoxybenzyne.927 In 2015, Rodriguez, Coquerel, and co-workers developed an aryne aza-Diels−Alder reaction, which was applied in the total synthesis of benzo[c]phenanthridine alkaloid nornitidine 1425 (Scheme 308).236 This synthetic route contains two aryne [4 + 2] cycloaddition reactions. First, Diels−Alder reaction of N-Boc-pyrrole 14-21 with aryne precursor 14-7 afforded cycloadduct 14-22 in 88% yield. A sequential rhodiumcatalyzed ring opening on 14-22, deprotection of the Boc group, and dehydration with DMF could readily prepare 2-azadiene 14-23. An aryne aza-Diels−Alder reaction with aryne precursor 14-24 then occurred with a concomitant extrusion of dimethylamine to realize the synthesis of nornitidine (14-25). Nornitidine (14-25) was achieved in five steps with an overall yield of 22%. In 2017, Jeganmohan and Reddy developed a two-step procedure to construct aristolactam alkaloid skeleton and employed this strategy to realize the facile total syntheses of caldensine (14-30), sauristolactam (14-31), N-methyl piperolactam A (14-32), aristolactam FI (14-33), cepharanone B (14-34), norcepharanone (14-35), and piperolactam C (14- of regioisomers 14-4 and 14-5 in a 1:2.4 ratio. The isolated cycloadduct 14-5 then proceeded through a reductive cleavage of the ether bridge with a following hydrogenolysis to produce ellipticine 14-6. Subsequently, they further investigated the [4 + 2] cycloaddition reaction of 14-1 with a series of halosubstituted 3,4-pyridyne precursors and revealed that both 2bromo- and 2-fluoro-3,4-pyridynes yielded the corresponding regioisomers in an ∼1:1 ratio.924 In addition, the reaction with 5-chloro-3,4-pyridyne gave no regioselective control as well. In 2015, Lewis and co-workers reported the concise total syntheses of arnottin I 14-10 and arnottin II 14-11 (Scheme 306).925 The synthetic route involves a Diels−Alder reaction Scheme 306. Total Syntheses of Arnottin I and II 3996 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 308. Total Synthesis of Nornitidine Review Scheme 310. Total Synthesis of Clausenawalline D resulting N-arylbenzotriazole 14-40 was subjected to photolysis conditions to furnish clausenawalline D (14-41) in 22% yield along with the formation of its regioisomer in the same amount. Aryne [2 + 2] cycloaddition reaction was also employed in natural product synthesis. In 2012, Hsung et al. developed a unique tandem process involving a successive aryne [2 + 2] cycloaddition reaction with enamide 14-42/pericyclic ringopening/intramolecular Diels−Alder reaction process (Scheme 311).665 Starting from aryne precursor 14-7 and enamide 1442, compound 14-43 was obtained in 65% overall yield through this tandem transformation. Upon hydroborationoxidation on compound 14-43, a 1:1 mixture of 14-44-cis and 14-44-trans could be obtained in 70% yield. The isolated 14- 36) (Scheme 309).245 In this study, a ruthenium-catalyzed oxidative cyclization of benzamides 14-26 with vinyl sulfone Scheme 309. Total Syntheses of Aristolactam Alkaloids Scheme 311. Total Syntheses of (±)-Chelidonine and (±)-Norchelidonine 14-27 afforded 3-methyleneisoindolin-1-ones 14-28, which then participated in an aryne [4 + 2] cycloadditiondesulfonylation transformation to furnish the aristolactam core 14-29. In the same year, Bochet and co-workers achieved a total synthesis of an antimalarial alkaloid clausenawalline D (1441).928 As shown in Scheme 310, the [3 + 2] cycloaddition reaction of aryne precursor 14-37 with aromatic azide 14-38 gave a 1:1 mixture of regioisomers 14-39a and 14-39b in 82% yield. Upon deprotection of the benzyl group on 14-39b, the 3997 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR 44-cis was then converted to (±)-chelidonine (14-45) and (±)-norchelidonine (14-46). Review Scheme 313. Total Syntheses of Indolactam Alkaloids 14.2. Nucleophilic Annulation Strategies In 2008, along with the study on the preparation of isoquinolines through aryne nucleophilic annulation protocol, Stoltz and co-workers demonstrated its application in an expeditious total synthesis of papaverine (14-49).331 As shown in Scheme 312a, starting from enamine 14-47, a dehydrative Scheme 312. Total Syntheses of Papaverine and (−)-Quinocarcin aryne annulation reaction with 14-24 took place to afford isoquinoline 14-48. After saponification and decarboxylation on compound 14-48, papaverine (14-49) was obtained. This strategy was also utilized by Stoltz et al. in the asymmetric total synthesis of (−)-quinocarcin (14-54) (Scheme 312b).929 The reaction between aryne precursor 14-50 and enamine 14-51 could produce isoquinoline 14-52 in 60% yield, which was then converted to compound 14-53 in four steps. After saponification on the methyl ester, oxazolidine ring could be constructed via partial reduction of the lactam with lithium in liquid ammonia and an acid promoted cyclization, leading to the formation of (−)-quinocarcin (14-54). In 2011, Garg and co-workers accomplished a concise total synthesis of indolactam V 14-61 via indolyne intermediate.151 As shown in Scheme 313a, they proposed to use Kobayashi precursor of 6-bromo-4,5-indolyne 14-55, because the generated 6-bromo-4,5-indolyne (14-57) exhibited preferential C4 regioselectivity in nucleophilic reactions. In comparison, a typical 4,5-indolyne (14-56) prefers C5 regioselectivity. With this understanding in mind, they commenced a total synthesis toward indolactam V (14-61). Nucleophilic addition of peptide 14-58 to the C4 position of 6-bromo-4,5-indolyne (14-57) could afford compound 14-59 in 62% yield with high regioselectivity. Consequently, unsaturated ester 14-60 was obtained after debromination and dehydration. An annulation approach with ZrCl 4 in DCM, followed by further modification, achieved the synthesis of indolactam V (1461). In 2014, the same group optimized several key steps and achieved the total synthesis of (−)-indolactam V. 930 Furthermore, they developed a late-stage functionalization on the C7 position of indolactam V (14-61) via a Pd-catalyzed cross-coupling reaction, allowing the assembly of a quaternary carbon center on this site.930 As shown in Scheme 313b, compound 14-62 was obtained from indolactam V (14-61) in two steps, which could then be transformed to 14-63 in 61% yield through an alkylative coupling strategy. After three-step 3998 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review be prepared, which was then subjected to Claisen rearrangement conditions with a subsequent universal removal of benzyl protecting groups, giving rise to toxyloxanthone B (14-76) in 64% yield. In 2016, He et al. developed a formal [3 + 2] cycloaddition strategy between arynes and 2-aminoquinones to afford the calothrixin framework, the mechanistic pathway of which proceeds through a C-nucleophilic addition to aryne and cyclization to form a C−N bond.471 Subsequently, they employed 2-aminophenanthridinedione (14-77) as the substrate to react with benzyne and obtained an indolo[3,2j]phenanthridine alkaloid calothrixin B (14-79) in 26% yield via intermediate 14-78, although there might be other mechanistic possibilities (Scheme 316a).932 Further oxidation of 14-79 with m-CPBA furnished calothrixin A (14-80) in 71% yield. In 2017, Guo, He, and co-workers accomplished the modular syntheses of dictyodendrins F, G, H, and I by using the same protocol.933 As shown in Scheme 316b, pyrrolinone 14-82 was prepared in six steps from aminoquinone 14-81, modification, (−)-pendolmycin (14-64) was prepared. Similarly, both (−)-lyngbyatoxin A (14-65) and (−)-teleocidin A2 (14-66) were synthesized using this strategy as well. In 2013, Argade and Vaidya developed a nucleophilic annulation reaction between arynes and substituted 1,3quinazolin-4-ones 14-67 and applied this protocol in the facile syntheses of tryptanthrin, phaitanthrins, and cruciferane (Scheme 314).451 The reaction of compound 14-67 with Scheme 314. Total Syntheses of Tryptanthrin, Phaitanthrins, and Cruciferane Scheme 316. Total Syntheses of Calothrixins and Dictyodendrins benzyne afforded tryptanthrin (14-68) in excellent yield. Next, K2CO3-induced aldol condensation of 14-68 with acetone gave phaitanthrin A (14-69) in 79% yield. Alternatively, phaitanthrin B (14-70) was prepared by treating 14-68 with methyl acetate and LDA. Subsequent borohydride-induced induced reductive intramolecular cyclization on 14-70 constructed (±)-cruciferane (14-71) in 82% yield. In 2014, Moody and co-workers accomplished a total synthesis of toxyloxanthone B (14-76).931 As shown in Scheme 315, this synthesis involves an aryne nucleophilic annulation reaction between methyl salicylate 14-72 and o-silylaryl triflate 14-73, furnishing the xanthone framework 14-74 in regioselective manner. Consequently, compound 14-75 could Scheme 315. Total Synthesis of Toxyloxanthone B 3999 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR which was then subjected to the reaction with o-silylaryl triflate 14-50 to afford annulated product 14-83 in 40% yield. Universal removal of the methyl groups on 14-83 with BBr3 completed the synthesis of dictyodendrin F (14-84) in 54% yield. Similar synthetic procedure on modified substrates led to the preparation of dictyodendrins G, H, and I. In 2018, Zhu and co-workers demonstrated an aryne annulation protocol with α-amino imides, furnishing 2,2disubstituted indolin-3-ones with direct incorporation of 2aminoethyl or 2-aminopropyl substituents. By employing this methodology, they realized an enantioselective total synthesis of marine alkaloid (+)-hinckdentine A (14-91) (Scheme 317). 934 This synthesis commenced with a catalytic Review Scheme 318. Enantioselective Total Synthesis of (+)-Amurensinine Scheme 317. Enantioselective Total Synthesis of (+)-Hinckdentine A produced (−)-14-95 in 90% ee (path a, Scheme 318). This (−)-14-95 was then converted to (+)-amurensinine (14-96) in four steps. Alternatively, they transformed (±)-14-95 to hydroxysilane (±)-14-97 first and subjected it to oxidative kinetic resolution conditions to produce (−)-14-97 in 47% yield and higher than 99% ee (path b, Scheme 318). After a few steps, (+)-amurensinine (14-96) was achieved in 99% ee from hydroxysilane (−)-14-97. In 2010, Stoltz et al. reported a concise enantioselective total synthesis of benzannulated macrolactone natural product (−)-curvularin using this aryne C−C σ-bond insertion protocol as the key step.937 As shown in Scheme 319, the synthesis started with acetate 14-98, which could be converted to β-ketolactone 14-99 in four steps. The insertion reaction of 14-99 with aryne precursor 14-73 furnished benzannulated macrolactone 14-100 in 30% yield. After deprotection of the benzyl groups, (−)-curvularin (14-101) was obtained in 8% overall yield from acetate 14-98. Moreover, this aryne insertion enantioselective Michael addition of methyl α-(2-nitrophenyl)-α-isocyanoacetate (14-85) to phenyl vinyl selenone (1486), affording (S)-14-87 in moderate ee. After four-step manipulation, imide 14-88 was prepared, which then participated in a nucleophilic annulation reaction with benzyne to produce indolin-3-one 14-89. Further five-step modification furnished compound 14-90. After selective bromination and oxidation with NMO, (+)-hinckdentine A (14-91) was afforded. Scheme 319. Enantioselective Total Synthesis of (−)-Curvularin 14.3. Insertion Reaction Strategies Accompanied with the discovery on aryne insertion into the C−C bond of β-ketoester,489 Stoltz and co-workers employed this methodology to realize a convergent and enantioselective total synthesis of (+)-amurensinine (14-96).935,936 As shown in Scheme 318, β-ketoester 14-93 was readily prepared in six steps from (3,4-dimethoxyphenyl)acetic acid (14-92), which then participated in a C−C σ-bond insertion reaction with aryne precursor 14-7 to afford ketoester (±)-14-94 in 57% yield. The reduced hydroxyester (±)-14-95 was subjected to oxidative kinetic resolution using Pd(sparteine)Cl2 and O2 and 4000 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR strategy has also been employed in the facile preparation of cytosporone B and phomopsin C,938 isocoumarins thunberginol A and xyridine A,719 tofisopam,939 and turkiyenine940 by other groups. In 2016, Chandrasekhar and co-workers employed aryne insertion strategy as the key step to achieve a formal total synthesis of pentacyclic alkaloid (±)-cephalotaxine (14-107) (Scheme 320).941 Starting from β-ketoester 14-102, a C−C σ- Review Scheme 321. Syntheses of Radermachol and Darenzepine Scheme 320. Total Synthesis of (±)-Cephalotaxine Scheme 322. Total Synthesis of Cossonidine bond insertion with aryne precursor 14-7 yielded 14-103 in 72% yield. The Wacker oxidation of 14-103 afforded 14-104 in 70% yield, which was converted to spiro pyrrolidine 14-105 as a crude intermediate. Upon removal of the Boc group and lactam formation, pentacyclic compound 14-106 could be assembled. After five-step modification from 14-106, (±)-cephalotaxine (14-107) was achieved. In the same year, Srihari, Mehta and co-workers employed aryne insertion protocol to construct benzannulated mediumrings, which was used in the preparation of pentacyclic natural product radermachol (14-111)942 and potent antiulcer agent darenzepine (14-114).414 As shown in Scheme 321a, the reaction between aryne precursor 14-108 and indan-1,3-dione (14-109) could readily access benzannulated cycloheptanedione 14-110 in 78% yield. Subsequent three-step transformations realized the synthesis of radermachol (14-111).942 Meanwhile, darenzepine (14-114) was readily prepared through a benzyne insertion into the C−C σ-bond of compound 14-112 to furnish N-Boc-dibenzoazepinenone 14113 and a following three-step manipulation (Scheme 321b).414 In 2018, Kisunzu, Sarpong and co-workers demonstrated a total synthesis of hetisine-type natural product cossonidine (14-121) by using the aryne insertion reaction as one of the key steps (Scheme 322).943 The reaction between β-ketoester 14-116 and aryne precursor 14-115 assembled tricyclic compound 14-117 in 38−45% yield, which was then converted to compound 14-118 in five steps. Chemoselective reduction of the nitrile group with cobalt boride and borane t-butylamine complex on 14-118 was the next key step to reach tertiary amine 14-119 after a further LiAlH4 reduction and photochemical hydroamination. A sequential Birch reduction/ intramolecular Diels−Alder reaction could set up the [2.2.2] bicycle on heptacyclic compound 14-120, which was transformed to the target natural product cossonidine (14-121) in six steps. In 2019, Slamon, Stoltz, and co-workers accomplished the total syntheses of (−)-jorunnamycin A (14-130) and (−)-jorumycin (14-131).711 As shown in Scheme 323, by employing their previously developed one-pot aryne acylalkylation/condensation protocol,710 3-hydroxy-isoquinoline 4001 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 323. Total Syntheses of (−)-Jorunnamycin A and (−)-Jorumycin Review Scheme 324. Total Synthesis of (±)-Galanthamine (±)-galanthamine (14-137) was synthesized in seven steps from compound 14-136. Recently, Dai and co-workers reported their efforts toward the synthesis of hamigeran natural products, the structures of which contain a common 6−7−5 tricyclic carbon skeleton (Scheme 325).945 This synthesis commenced with the reaction Scheme 325. Synthesis toward the 6−7−5 Tricyclic Core of Hamigerans 14-123 was obtained in 45% yield from aryne precursor 14122 and methyl acetoacetate through an in situ condensation procedure. After triflation, the generated compound 14-124 was then coupled with isoquinoline N-oxide 14-125 using modified Fagnou’s method, furnishing bis-isoquinoline 14-126 in 93% yield. After further transformations, compound 14-127 was prepared, which was subjected to the key asymmetric hydrogenation reaction. After optimization, they found that pentacycle 14-128 could be obtained in 83% yield with >20:1 dr and 88% ee by using [Ir(cod)Cl]2 and (S,RP)-BTFMXyliphos (14-129) as the chiral ligand, leading to the formation of four new stereocenters and a central C-ring lactam. After five-step modification, (−)-jorunnamycin A (14130) was achieved. In addition, (−)-jorunnamycin A (14-130) could be readily transformed to (−)-jorumycin (14-131) in a single operation. In the same year, Chandrasekhar et al. reported a total synthesis of (±)-galanthamine (14-137) employing aryne insertion into the C−C σ-bond of γ-amino butyric acid as the key step.944 As shown in Scheme 324, the reaction of β-formyl ester 14-133 with aryne precursor 14-132 produced compound 14-134 in a regioselective manner. Benzofuranone 14-135 was then prepared from 14-134 in three steps, which was further converted to tetracyclic lactol 14-136. Finally, of β-ketoester 14-139 with aryne precursor 14-138 and furnished C−C σ-bond insertion product 14-140 in 60% yield. A six-step manipulation on bicyclic compound 14-140 could prepare dienone 14-141, which was subjected to Nazarov cyclization conditions to construct tricyclic compound 14-142. Next, they could introduce an all-carbon quaternary center via either a Ni-catalyzed conjugate methyl addition (path a) or a Corey−Chaykovsky reaction (path b), leading to the formation of the corresponding compounds 14143 and 14-144, respectively. Both 14-143 and 14-144 were converted to an advanced intermediate 14-145, which was expected to be transformed to hamigeran natural products. 4002 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review In 2018, Heretsch, Christmann, and co-workers realized the syntheses of a series of 3,4-dioxygenated quinolin-2-one natural products, including (±)-peniprequinolone, (±)-aflaquinolones E and F, (±)-quinolinones A and B, and (±)-aniduquinolone C (Scheme 326a).485 In this study, the key step was a were prepared from the corresponding precursors 14-153 and 14-154, respectively, via a successive Claisen rearrangement and Grubbs’ olefin cross metathesis (Scheme 326b).485 Very recently, the same group realized the concise syntheses of yaequinolones J1 (14-157) and J2 (14-158) through a similar synthetic procedure (Scheme 326c).946 Scheme 326. Syntheses of 3,4-Dioxygenated Quinolin-2-one Natural Products 14.4. Cascade Reaction and MCR Strategies In 2011, Hwu and Hsu accomplished a total synthesis of bioactive (−)-1-deoxy-D-fructose (14-163) via a benzyneinduced olefination of β-amino alcohol (Scheme 327).657 In Scheme 327. Total Synthesis of (−)-1-Deoxy-D-fructose this study, they started with D-(+)-glucose (14-159) and converted it to compound 14-160 in three steps. By treating compound 14-160 with benzyne, a cascade process took place to afford enol acetate 14-162 in 75% yield, the mechanistic pathway of which includes a benzyne [3 + 2] cycloaddition reaction to generate a tricyclic intermediate 14-161 and a retro [3 + 2] cycloaddition process. After saponification and in situ cyclization, the synthesis of (−)-1-deoxy-D-fructose (14-163) was realized. Moreover, this benzyne-induced olefination methodology was also applied in the preparation of various deoxy and iminosugars.658 In 2019, Chudasama et al. disclosed a synthesis of neurological medicine phenazepam (14-167).708 As shown in Scheme 328, the reaction of acyl hydrazide 14-164, generated from 2-chlorobenzaldehyde and diisopropyl azodicarboxylate (DIAD), with benzyne produced 2-hydrazobenzophenone 14165 in 67% yield through a benzyne-based molecular Scheme 328. Synthesis of Phenazepam regioselective aryne insertion into the C−N σ-bond of unsymmetrical imides 14-146, which could afford N-glycolated 2-aminobenzophenones 14-147 under continuous flow conditions. An intramolecular aldol reaction would then assemble 3,4-dioxygenated quinoline-2-ones 14-148. This procedure was applied to the syntheses of (±)-aflaquinolone E (14-149), (±)-aflaquinolone F (14-150), (±)-quinolinone A (14-151), and (±)-quinolinone B (14-152). Furthermore, (±)-aniduquinolone C (14-155) and (±)-peniprequinolone (14-156) 4003 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review Wilkinson’s catalyst, which could furnish taiwanin C (14-176) in 64% yield. Alternatively, taiwanin E (14-177) was obtained through Baeyer−Villiger oxidation of 14-175 and subsequent hydrolysis. This strategy was also applied in the total synthesis of dehydrodesoxypodophyllotoxin by the same group.760 In 2013, Argade and Patel developed a Pd-catalyzed [2 + 2 + 2] cocyclotrimerization of unsymmetrical conjugated dienes and arynes, which could be applied in the concise syntheses of justicidin B (14-181) and retrojusticidin B (14-182).761 As shown in Scheme 331, arylnaphthalene 14-179 was prepared transformation process. Compound 14-166 was then obtained from 14-165. Subsequent bromination and alkylation-cyclization on compound 14-166 afforded phenazepam (14-167) in 77% yield. Along with the study carried out by Yoshida et al. on threecomponent coupling reaction of arynes, cyclic ethers, and organic halides, they also applied this protocol in the synthesis of a benzo[b]oxepine-based nonsteroidal estrogen (Scheme 329).560 The reaction of oxetane, aryne precursor 14-168, and Scheme 329. Total Synthesis of Benzoxepine Scheme 331. Syntheses of Justicidin B and Tetrojusticidin B (4-benzyloxyphenyl)ethynyl bromide (14-169) afforded 14170 in a regioselective manner. A platinum-catalyzed diborylation reaction on the triple bond of 14-170 produced vicinal diborylalkene 14-171, which was then converted to benzoxepine (14-172) via a Suzuki−Miyaura coupling/baseinduced proto-deborylation/dechlorination pathway. 14.5. Transition-Metal-Catalyzed Strategies In 2004, Sato, Mori, and co-worker applied a Pd-catalyzed [2 + 2 + 2] cocyclotrimerization of diynes and arynes in the total syntheses of taiwanins C and E.759 As shown in Scheme 330, Pd-catalyzed reaction of aryne precursor 14-7 with diyne 14173 facilely assembled arylnaphthalene 14-174 in 61% yield. After four-step manipulation, compound 14-175 was obtained. Decarbonylation of 14-175 was realized by treating it with in 66% yield from aryne precursor 14-24 and 14-178 by using this protocol, which was then converted to acid 14-180 via a selective saponification on the less-hindered ester group. Chemoselective reduction reactions on 14-180 were realized, affording justicidin B (14-181) by using borane dimethyl sulfide complex as the reductant as well as retrojusticidin B (14-182) through the reduction with lithium borohydride. In 2015, Jiang and co-workers employed their regiodivergent approach on the Pd-catalyzed three-component coupling reaction of arynes, 2-iodoanilines, and CO to synthesize both phenanthridinone and acridone alkaloids (Scheme 332a).803 When aryne precursor 14-7 and N-methyl-2-iodoaniline (14183) (R = Me) were subjected to a Pd(OAc)2/dppm catalytic system, acridone alkaloid 2,3-methylenedioxy-10-methyl-9acridanone (14-184) was achieved in 55% yield. Alternatively, several phenanthridinone alkaloids 14-185 could be obtained under ligand-free conditions. In 2016, Gogoi et al. accomplished a Pd-catalyzed cascade reaction of 4-hydroxycoumarins 14-186 with 14-7, which led to a facile synthesis of flemichapparin C (14-187) (Scheme 332b).816 In 2016, a total synthesis of biologically active alkaloid (±)-tylophorine was reported by Yao, Zhang, and coworker.783 As shown in Scheme 333a, α,β-unsaturated ester 14-189 was prepared in four steps from amine 14-188, which Scheme 330. Total Syntheses of Taiwanins C and E 4004 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review Scheme 334, the generated 1,2-aryne intermediate 14-195 from 1,3-benzdiyne equivalent 14-194 reacted with chloro- Scheme 332. Syntheses of Acridone Alkaloid, Phenanthridinone Alkaloids, and Flemichapparin C Scheme 334. Synthesis of Risperidone Scheme 333. Syntheses of (±)-Tylophorine and Callosumin oxime 14-196 to produce cycloadduct 14-197 in 52% yield as a single regioisomer. Next, 3,4-aryne intermediate 14-198 could be generated from 14-197 and captured by fluoride ion, giving rise to compound 14-199. Upon deprotection of the Boc group and alkylation, risperidone (14-200) was successfully prepared. In 2018, Li et al. applied their domino aryne nucleophilicene cascade protocol in the preparation of ibutamoren mesylate (14-206), which is used for the treatment of growth hormone deficiency.882 As shown Scheme 335a, the reaction of domino aryne precursor 14-201 with compound 14-202 constructed indoline 14-203 in 56% yield. Upon hydrogenation, compound 14-204 was obtained. Selective amide hydrolysis on compound 14-204 produced 14-205, which was then converted to ibutamoren mesylate (14-206). In 2019, the same group developed a domino aryne nucleophilic, [4 + 2] cycloaddition reaction strategy and employed it to the construction of an ergot alkaloid skeleton.356 As shown in Scheme 335b, the synthesis commenced with the reaction of 14-201 with 3-(pyridin-2-yl)allyl sulfonamide 14-207, furnishing tetracyclic compound 14-208 in 40% yield. Piperidine 14209 could be achieved in 91% yield via a one-pot, two-step operation from 14-208. After deprotection of the Ts group and oxidative dehydration on 14-209, compound 14-210 was obtained in 81% yield, the structure of which shares an identical core skeleton with that of lysergine. In 2019, Ohmori, Suzuki, and co-workers accomplished an enantioselective total synthesis of actinorhodin (14-218) by employing 1,4-benzdiyne chemistry.947 As shown in Scheme 336, 1,4-benzdiyne equivalent 14-211 was employed, the structure of which contains a Suzuki precursor with a I/OTs pair and a Kobayashi precursor with a TMS/OTf pair. Upon activation with n-BuLi at low temperature (Suzuki’s activation conditions), 1,2-aryne 14-212 was selectively generated and captured by furan to afford cycloadduct 14-213 in excellent yield. Next, 4,5-aryne 14-214 was released under Kobayashi’s conditions, which then participated in a regioselective alkyl- was then subjected to a Pd-catalyzed annulation reaction with aryne precursor 14-24 to construct phenanthrene 14-190 in 46% yield. Subsequently, a three-step operation including deprotection of the Boc group/intramolecular cyclization/ lactam reduction could afford (±)-tylophorine (14-191). Along with a study carried out by Ichikawa et al. on Nicatalyzed [4 + 2] cycloaddition reaction of styrenes with osilylaryl triflates, they exhibited a concise preparation of a naturally occurring stilbenoid callosumin (14-193) between 3,5-dimethoxystyrene (14-192) and aryne precursor 14-24 (Scheme 333b).839 14.6. Benzdiyne Strategies Along with the study on 1,3-benzdiyne equivalent 14-194, Ikawa, Akai, and co-workers reported a convergent synthesis of antipsychotic drug risperidone (14-200).877 As shown in 4005 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 335. Syntheses of Ibutamoren Mesylate and Ergot Alkaloid Skeleton Review Scheme 336. Total Synthesis of Actinorhodin Scheme 337. General Scheme for Pd-Catalyzed [2 + 2 + 2] Cyclotrimerization acylation reaction with methyl acetoacetate to produce ketone 14-215. With ketone 14-215 in hand, further manipulation afforded naphthol 14-216 in four steps. Dimerization of 14216 under Laatsch conditions (Ag2O, Et3N), followed by reduction and protection of phenol, could furnish compound 14-217 in excellent yield. Finally, actinorhodin (14-218) was synthesized in seven steps from compound 14-217. 15. PAHs, POLYMER CHEMISTRY, AND MATERIALS SCIENCE Along with the blooming advances of Kobayashi’s method in the past 2 decades, people sought for its interdisciplinary applications, whereby exciting progress was achieved in the fields of polycyclic aromatic hydrocarbons (PAHs),81,99,948−951 polymer chemistry, and materials science. Particularly, as one of the classical aryne reaction modes, [4 + 2] cycloaddition reaction has been extensively utilized in this field. fruitful achievements in the past 2 decades. Particularly, some of those PAHs are otherwise inaccessible through traditional methods, further underlining the power and essential role of aryne chemistry in the field of PAHs. In 1999, Pérez, Guitián, and co-workers reported Pdcatalyzed cyclotrimerization of 1,2-naphthalyne and 9,10phenanthryne (Scheme 338).744 In this study, the reaction of unsymmetrical 1,2-naphthalyne yielded a mixture of trimers 15-1a and 15-1b in a 2.7:1 ratio. In addition, cyclotrimerization of symmetrical 9,10-phenanthryne built compound 15-2, a highly twisted molecular propeller, which was later proven to be C2-symmetric.745 Subsequently, Cobas, Pérez, Guitián, and co-workers further investigated the reactivity of unsymmetrical arynes. They found that both 3,4-phenanthryne and 1,2-triphenylyne could yield unsymmetrical products as well. With the employment of the Kobayashi precursor of 3,4-phenanthryne, a double helicene 15-3 constituted by a [5]helicene and a [7]helicene unit with two rings in common was obtained, the relative configuration of which was established by their 1H NMR data and 15.1. Preparation of PAHs 15.1.1. Through Pd-Catalyzed Cyclotrimerization. Pdcatalyzed [2 + 2 + 2] (co)cyclotrimerization of arynes has shown to be a powerful and convenient strategy to construct structurally complex PAHs from relatively simple and readily achievable o-silylaryl triflates. As shown in Scheme 337, various PAHs bearing a common triphenylene core could be assembled through Pd-catalyzed [2 + 2 + 2] cyclotrimerization of arynes. Soon after the first discovery of this methodology, the groups of Pérez, Peña, and Guitián commenced their exploration toward the preparation of PAHs and accomplished 4006 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review Scheme 338. PAHs via Pd-Catalyzed Cyclotrimerization Scheme 339. More Cyclotrimerized PAHs twist.953 In 2009, Chi, Wu, and co-workers first prepared hexamethyltriphenylene 15-6 from 4,5-dimethylbenzyne, which was then converted to electron-deficient trinaphthylene carboximides 15-7.954 Moreover, they observed a long-range columnar stacking on 15-7, which might be used as n-type semiconductors in electronic devices. More exciting applications on this Pd-catalyzed cyclotrimerization protocol were reported by different research calculations.746 In 2008, Pd-catalyzed cyclotrimerization of 1,2triphenylyne was also examined, giving rise to nonplanar polycyclic arene 15-4 in 10% yield.952 Cyclotrimerization of both 3,6-dimethylbenzyne and 4,5dimethylbenzyne were studied. In 2007, Mount, Galow et al. prepared 1,4,5,8,9,12-hexamethyltriphenylene 15-5 from 3,6dimethylbenzyne, the crystal structure of which is C2symmetric and highly distorted with a 53° end-to-end 4007 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review Scheme 340. Cyclotrimerization of Indolynes Scheme 341. PAHs via On-Surface Cyclodehydrogenation Reactions which prefers a highly nonplanar “twist” conformation of C1 symmetry.958 Since 2012, Peña and co-workers have systematically synthesized a series of nanographene structures by employing this cyclotrimerization protocol. They first demonstrated that hexaphenyl-substituted [16]cloverphene 15-12 could be prepared in 22% yield, which is a cata-condensed PAH with a C3-symmetric conformation.959 The presence of six phenyl groups could induce distortion from planarity and, hence, enhance the solubility. Subsequently, they synthesized two new types of nanographenes: a 3-fold symmetric molecule 15-13 with 22 fused benzene rings960 and 15-14 with a 19 groups, and the structural complexity of the corresponding triphenylene-based products has been significantly enhanced (Scheme 339). In 2004, Pérez, Vollhardt, and co-workers employed biphenylynes to assemble C3-symmetric trimers 158,110 which was later found to reversibly and selectively add onto a semiconductor surface via Diels−Alder reaction.955 Both substituted 2,3-triphenylynes956 and 2,3-naphthalynes957 were able to trimerize to furnish the corresponding 15-9 and 15-10, respectively. In 2011, Sygula et al. examined a Pdcatalyzed cyclotrimerization of corannulyne and obtained a crowded PAH 15-11 with a formula of C60H24, the structure of 4008 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review Scheme 342. Study on Isobenzofuran Trimer 15-29 cata-fused benzene rings distributed within six branches.961 Due to the extreme insolubility of the products, however, conventional characterization methods were not applicable. In this context, they employed scanning probe microscopy techniques, both noncontact atomic force microscopy (ncAFM) and scanning tunneling microscopy (STM), with atomic resolution to characterize these PAHs. In 2017, Garg, Houk, and co-workers demonstrated a Pdcatalyzed cyclotrimerization of indolynes (Scheme 340).962 Kobayashi precursors of 4,5-indolyne 15-15, 5,6-indolyne 1517, and 6,7-indolyne 15-19 were examined, each of which produced a pair of indole-based conjugated trimers. Their computational study also described the structural and photophysical properties of these compounds. In the same year, Tsurusaki, Kamikawa, and co-workers subjected aryne precursor 15-21 to Pd-catalyzed cyclotrimerization conditions and obtained hexapole helicenes 1522 with six [5]helicene subunits (Scheme 341a).963,964 Both their experimental study963 and theoretical examination964 suggested a first formation of saddle-like C2-symmetic 15-22a in the Pd-catalyzed cycloaddition step, which could be quantitatively converted to more stable propeller-like D3symmetic structure 15-22b under thermal conditions. In 2019, Godlewski, Peña, and co-workers further subjected 15-22b to on-surface Au-promoted cyclodehydrogenation conditions, furnishing nanographene 15-23 with 3-fold symmetry.965 This PAH was characterized by scanning probe microscopy with atomic resolution. Recently, Godlewski, Peña, and coworkers were able to further convert PAH 15-25, prepared from aryne precursor 15-24, to trigonal porous nanographene on the gold surface in two on-surface cyclodehydrogenation reactions (Scheme 341b).966 At 300 °C on the gold surface, compound 15-26 was first formed; while heating at 370 °C, triporous nanographene 15-27 could be produced, the structure of which contains 102 sp2 carbon atoms. In addition, nc-AFM and STM techniques were utilized to analyze these structures. Besides, Hamura et al. demonstrated that the cyclotrimerized product 15-28 from the corresponding o-silylaryl triflates could serve as an equivalent of isobenzofuran trimer 15-29. Under thermal conditions, a retro Diels−Alder reaction occurred to extrude three tetraphenylcyclopentadienone molecules and generate intermediate 15-29. Subsequent cycloaddition of 15-29 with naphthoquinone 15-30 afforded the Y-shaped polycyclic aromatic ketone 15-31 (Scheme 342).967 15.1.2. Through Pd-Catalyzed Cocyclotrimerization. As has been discussed in section 10, alkynes are efficient components in Pd-catalyzed cocyclotrimerization reactions. There are two types of reaction modes: aryne−aryne−alkyne cyclotrimerization mode (path a) and aryne−alkyne−alkyne cyclotrimerization mode (path b) (Scheme 343). Scheme 343. General Scheme for Pd-Catalyzed Cocyclotrimerization of Arynes with Alkynes In an early study carried out by Pérez, Guitián, and coworkers, they found that the employment of Pd(PPh3)4 as the catalyst normally results in the phenanthrene framework; whereas in the presence of Pd2(dba)3, the reaction favors naphthalene derivatives (Scheme 210).749 In 2004, they reported the preparation of both 15-32a and 15-32b using this protocol (Scheme 344).110 Subsequently, they examined cocyclotrimerization of 7-methoxy-1,2-didehydronaphthalene with DMAD and obtained compounds 15-33a, 15-33b, and 15-33c in a 5.9:8.6:1 ratio.968 Furthermore, an asymmetric version was examined, which could reach pentahelicene 15-33a with up to 76% ee. Although the enantioselectivity in this reaction was not high, it was claimed to be the first transitionmetal-catalyzed enantioselective cycloaddition reaction with arynes. When cycloaddition of 2,3-triphenylynes with DMAD was examined, compounds 15-34a and 15-34b were obtained.956 Further study on 15-34b analogues revealed that they could self-assemble and form ordered mesophases.969 In 2008, both 3,4-phenanthryne and 1,2-triphenylyne were studied, affording the corresponding sterically congested PAHs 15-35 and 15-36, respectively.952 Similarly, PAHs 15-37959 and 15-38961 were also prepared from more complex aryne precursors along with the study on aryne cyclotrimerization (Scheme 344). Recently, Tsurusaki, Kamikawa, and co-workers demonstrated a distinct Pd-catalyzed enantioselective cross-cyclotrimerization of two helicenyl arynes with dialkyl acetylenedi4009 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review Scheme 344. PAHs from Pd-Catalyzed Cocyclotrimerization with Alkynes 15.1.4. Benzdiyne and Naphthodiyne Strategies. A common strategy is to perform 2-fold Diels−Alder reactions between equivalents of benzdiyne/naphthodiyne and dienes containing polycyclic aromatic rings. This strategy has the advantage that those polyaryne precursors can quickly expand the aromatic system through simple operations. 15.1.4.1. 1,4-Benzdiyne Strategies. As shown in Scheme 346a, 1,4-benzdiyne equivalent 15-47 has been extensively utilized as a unique building block to reach linear PAHs 15-48 via a 2-fold Diels−Alder reaction process. After Wudl’s first example on preparing heptacene from pyrano-diphenylcyclopentadienone and 15-47 (Scheme 266),873 Sygula et al. accomplished the synthesis of bis-corannulenoanthracene 1550 from isocorannulenofuran 15-49 and 15-47 (Scheme 346b).975 Further Diels−Alder reaction of 15-50 with maleic anhydride harnessed compound 15-51, the angularly fused structure of which could allow two benzocorannulene pincers to capture C60 with strong affinity. In 2017, Itami, Yamaguchi, and co-worker demonstrated a concise preparation of multiply arylated anthracenes 15-56a and 15-56b.976 As shown in Scheme 347, aryne [4 + 2] cycloaddition reaction of 15-52 as a precursor of 15-47 with tetraarylthiophene S-oxide 15-53 yielded tetraarylnaphthalyne precursor 15-54 as a mixture of regioisomers after triflation. carboxylate, yielding optically active triple helicenes 15-39 with an enantiomeric ratio of up to 98:2 by using (S)-QUINAP as the ligand (Scheme 344).970 Their DFT calculations indicated that the enantioselectivity originates from the dynamic kinetic resolution of a five-membered palladacycle intermediate. In 2011, Kitamura et al. reported the preparation of tetracene octaesters 15-40 via a Pd-catalyzed 2-fold [2 + 2 + 2] cocyclotrimerization with dialkyl acetylenedicarboxylates.971 15.1.3. Through Pd-Catalyzed Annulation Reactions. Since the first report by Larock et al. on Pd-catalyzed annulation reaction of arynes with 2-halobiaryls 15-41 to produce fused polycyclic aromatics 15-42,775,776 this protocol has been employed by Mü llen and co-workers in the preparation of core-expanded rylenebis(dicarboximide) dyes (Scheme 345). In 2007, Müllen et al. revealed the synthesis of dibenzocoronene bis(dicarboximide) 15-43 and core-modified quaterrylenebis(dicarboximide) (QDI) 15-44, both of which possess significant hypsochromic shifts of absorption, excellent photostabilities, and high fluorescence quantum yields.972 Subsequently, the same group achieved core-expanded perylene tetracarboxdiimide 15-45973 and terrylene tetracarboxdiimide 15-46974 as well and investigated their optical properties (Scheme 345). 4010 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review Scheme 345. PAHs via Pd-Catalyzed Annulation Reactions Scheme 346. PAHs via 1,4-Benzdiyne Chemistry supported the resonance structure predicted by the Clar model. 15.1.4.2. 2,6-Naphthodiyne Strategies. 2,6-Naphthodiyne equivalent 15-63 received more attention than 1,4-benzdiyne 15-47, which could afford various polycyclic aromatic frameworks 15-64 after double Diels−Alder reactions (Scheme 349a). Since 2007, Kitamura and co-workers prepared a series of 1,4,7,10-tetraalkyltetracenes 15-65 from the reaction of 1563 with 2,5-disubstituted furans and a subsequent deoxygenative aromatization, those of which exhibited different solid-state optical properties (Scheme 349b).979−982 In 2016, Moresco, Peña and co-workers reported that the double cycloadduct of 15-63 with furan could be converted to tetracene (15-66) via on-surface reduction.983,984 This 2,6naphthodiyne equivalent 15-63 was also employed in the preparation of various PAHs via double [4 + 2] cycloaddition reactions with cyclopentadienones, giving rise to 6,9,16,19tetraphenyl-1.20,4.5,10.11,14.15-tetrabenzooctatwistacene Consequently, a second [4 + 2] cycloaddition reaction of 1554 with tetraarylthiophene S-oxide 15-55 took place to afford octaarylanthracenes 15-56a and 15-56b in 46% overall yield. In a study carried out by Peña, Pascual, and co-workers on on-surface production of planar nanographenes, they prepared 12-ring dibromo polycyclic aromatic compound 15-60 from 15-47 (Scheme 348a).977 The first Diels−Alder reaction of 1547 with compound 15-57 assembled aryne precursor 15-58 in 37% yield, which then underwent a second Diels−Alder reaction with tetraphenylcyclopentadienone (15-59) to produce 15-60 in 61% yield. Recently, Peña, Pérez, and coworkers reported a modified synthesis of kekulene (15-62) from the key intermediate 5,6,8,9-tetrahydrobenzo[m]tetraphene (15-61), readily prepared from 15-47 and styrene (Scheme 348b).978 The structure of individual kekulene (1562) was resolved by ultrahigh-resolution AFM and was simulated by their computational study. These studies 4011 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review Scheme 347. Preparation of PAHs 15-56 via 1,4-Benzdiyne Chemistry Scheme 348. Other PAHs via 1,4-Benzdiyne Chemistry (15-67)985 and other large acenes 15-68 to 15-71 (Scheme 349b).986 A unique procedure was developed to prepare hexacene (1577) from 2,6-naphthodiyne equivalent 15-63. Inspired by the method developed by Hamura et al. toward the isobenzofuran scaffold from the cycloadduct of benzyne with furan,987 Peña, Moresco, and co-workers first synthesized cycloadduct 15-72 from 15-47 (Scheme 350a). Upon treatment of 15-72 with 3,6-di(2-pyridyl)-1,2,4,5-tetrazine (15-73), isobenzofuran 1574 was generated and reacted in situ with 15-63 to afford a mixture of regioisomers 15-75. Further Diels−Alder reaction of 15-75 with furan produced 15-76 as a mixture of four diastereomers, which was subjected to the surface-assisted deoxygenation reaction on Au(111) to yield hexacene (1577).988 Subsequently, this on-surface strategy was also applied to the preparation of decacene (15-78),989 dodecacene (1579),990 and tetraepoxy[10]cyclacene 15-80 (Scheme 350b).991 15.1.4.3. 1,7-Naphthodiyne Strategy. In 2016, Pérez et al. employed compound 15-81 as 1,7-naphthodiyne equivalent to readily prepare angularly fused acene derivatives 15-82, those of which include benzo[c]phenanthrene (15-83), sterically congested polyarenes octaphenyl-benzo[c]-phenanthrene (1584), and 5,10,15,16-tetraphenylnaphtho[2,3-a]tetraphene (1585) (Scheme 351a).992 15.1.4.4. 1,5-Naphthodiyne Strategy. In 2019, Uno et al. prepared 1,5-naphthodiyne equivalent 15-86 and subjected it to the Diels−Alder reactions with cyclopentadiene and 1,3cyclohexadiene, obtaining cycloadducts 15-87 and 15-88, respectively (Scheme 351b).993 Both reactions resulted in 1:1 mixtures of syn- and anti-isomers. Furthermore, cycloadduct 15-87 could be converted to PAH 15-90; while synoriented diethanochrysene-connected bisporphyrin syn-15-89 was prepared from 15-88. The 1:1 complex of syn-15-89 with C60 or C70 was determined by X-ray diffraction analysis. 4012 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review Scheme 349. PAHs via 2,6-Naphthodiyne Chemistry Scheme 350. Other PAHs via 2,6-Naphthodiyne Protocols 15.1.5. Other Cycloaddition Strategies. The Diels− Alder cycloaddition reaction has also been extensively utilized in the preparation of other PAHs. In 2005, Kunai et al. prepared a trisaryne equivalent 15-91 containing a 1,3,5-triaryl benzene core, which was then subjected to triple aryne transformation to afford 1,3,5-tris(9,10-diphenyl-2-anthryl)benzene (15-92) and other related compounds (Scheme 352). 994 In 2008, Sygula and co-workers synthesized corannulyne precursor 15-93 and obtained cycloadducts 1594, 15-95, and 15-96 in the reactions with various diene arynophiles.995 Subsequently, they reported the preparation of corannulene-based molecular clip 15-97996 and a highly nonplanar hydrocarbon C80H32 15-98997 from corannulyne precursor 15-93 as well. In a study carried out by Itami, Yamaguchi, and co-workers toward hexaarylbenzenes of different substituents, they accomplished the preparation of tetraarylnaphthalene 15-99 via Diels−Alder reaction of tetraarylthiophene S-oxide with benzyne.998 In 2016, Mastalerz and co-workers demonstrated a synthesis of conformationally highly stable contorted hexabenzoovalene 15-101 containing two peripheral triptycene units and six tert-butyl substituents with improved solubility.999,1000 In this structure, two phenylene blades of the peripheral triptycene units are almost coplanar. A double [4 + 2] cycloaddition reaction with triptycene-based aryne precursor 15-100 was involved in the synthetic procedure. In 2018, Peña, Wornat, Gross, and co4013 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review Scheme 351. PAHs from 1,7- and 1,5-Naphthodiyne 15.2. Polymer Chemistry workers developed a method that can integrate AFM with other analytical tools to identify PAHs from complex molecular mixtures, which led to the detection of a seven-ring PAH benz[l]indeno[1,2,3-cd]pyrene (15-103).1001 Consequently, PAH 15-103 was synthesized from 9,10-phenanthryne precursor 15-102. In addition, PAHs 15-1041002 and 15105904,1003 were readily prepared via a sequential [4 + 2] cycloaddition reaction with various o-silylaryl triflates and oxidative aromatization. In 2004, Katz et al. prepared Kobayashi precursors bearing [6]- and [7]-helicene skeletons.1004 Upon activation with fluoride, the generated aryne species underwent an intramolecular Diels−Alder reaction to the other ring on the frameworks, giving rise to bridged derivatives 15-106, 15-107, and their analogues. Recently, Jancarik, Gourdon and co-workers developed a facile strategy to prepare various long acenes by using tetraene 7,7-dimethoxy-2,3,5,6-tetramethylenebicyclo[2.2.1]heptane (15-108) as the key synthon.1005,1006 As shown in Scheme 353a, double [4 + 2] cycloaddition reaction of 15-108 with various o-silylaryl triflates could afford the desired acenes after a few step manipulations. Consequently, heptacene (15-109), benzo[a]hexacene (15-110), cis-dibenzopentacene (15-111), and trans-dibenzopentacene (15-112) were readily prepared through this protocol. In 2019, Audisio et al. demonstrated the first approach to [4]-, [5]-, [6]-, and [7]-helicenes 15-115 containing pyrazole moiety through regioselective 1,3-dipolar cycloaddition reaction of o-silylaryl triflates 15-113 and sydnones 15-114 (Scheme 353b).315 This transformation was regioselective with preferential formation of more sterically constrained heterohelicenes. Their DFT calculations indicated that the origin of selectivity was controlled by primary orbital interactions and C−H···π dispersive interactions. o-Silylaryl triflates have also been employed in polymer chemistry, which could be divided to aryne (co)polymerization and modification on polymers. In 2005, Ihara, Inoue, and coworkers reported a polymerization of o-silylaryl triflates, affording polymer 15-116 via an alternating copolymerization of aryne with pyridine (Scheme 354a).1007 However, there was no observation of direct polymerization of arynes in this study. In 2015, Mikami, Uchiyama, and co-worker accomplished the first Cu-catalyzed direct polymerization of o-silylaryl triflates, furnishing poly(ortho-phenylene)s 15-117 of up to ∼100-mer size in a straightforward manner (Scheme 354b).861 In this transformation, Lipshutz-type cuprate, nBu2Cu(CN)Li2, and a broad range of monovalent copper salts were found to be essential for the success of this polymerization. Moreover, both radical species and light were not able to initiate or promote this polymerization. In 2015, Craig et al. demonstrated their single-molecule force spectroscopy (SMFS) studies on the forbidden ringopening reactions of a series of polymers containing either benzocyclobutene or cyclopropane units.1008 Among those polymers, polymer 15-121 was prepared via copolymerization of benzocyclobutene 15-119 with monoepoxidized cyclooctadiene 15-120 (Scheme 355a). Benzocyclobutene 15-119 was obtained from [2 + 2] cycloaddition reaction of (E, Z)-1,5cyclooctadiene 15-118 with benzyne. Subsequently, polymer 15-124 was prepared by the same group starting from benzocyclobutene 15-123 that was synthesized from 1,3cyclooctadiene (15-122) and benzyne (Scheme 355a).1009 In 2017, Maynard, Garg, and co-workers reported a concise and practical synthesis of air-stable benzonorbornadiene polymers 15-126, which was realized through the ring opening metathesis polymerization (ROMP) of the [4 + 2] cyclo4014 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review Scheme 352. PAHs via Other Aryne [4 + 2] Cycloaddition Reactions (Scheme 356).1022 In addition, modifications on carbon nanotubes, 1023−1025 carbon nanohorn, 1026 and graphene1027−1029 with o-silylaryl triflates have also been reported. adducts 15-125 of benzyne with either cyclopentadiene or furans (Scheme 355b). 1010 Meanwhile, Gidron et al. demonstrated an efficient protocol to transform long oligofurans 15-127 to oligoarenes in a highly selective manner.1011,1012 As shown in Scheme 355c, [4 + 2] cycloaddition reaction of benzyne with oligofurans 15-127 containing up to six units afforded the corresponding cycloadducts 15-128, which could be converted to the desired oligonaphthalenes 15-129 through a subsequent deoxygenation operation. Besides, triptycene moieties, generated from the Diels−Alder reaction of anthracene with o-silylaryl triflates, have also been utilized in polymer chemistry.1013,1014 16. CONCLUSIONS In this review, we describe the history and development of Kobayashi aryne precursors over the past 2 decades. As arynes have to be released in situ from their precursors in any aryne transformation, chemists have endeavored to search for “ideal” aryne generation methods since the early era of aryne chemistry. Among them, Kobayashi’s method has been recognized as one of the best protocols in modern aryne chemistry, primarily due to its mild generation conditions that well accommodate a broad spectrum of functional groups as well as different types of aryne reactions. In this context, this protocol not only significantly enhanced the efficiency of traditional aryne transformations, i.e., pericyclic reactions and nucleophilic reactions, but also provided a platform for continuing discovery toward new synthetic strategies. For instance, insertion reactions and multicomponent reactions emerged along with the study on o-silylaryl triflates. Because of the supreme compatibility advantage of this mild generation protocol, it has also been applied in a variety of distinct cascade or tandem reactions, some of which are otherwise hard to be reached through other aryne generation methods. Particularly, the employment of o-silylaryl triflates commenced a new 15.3. Materials Science 15.3.1. Triptycene-Based Materials. Triptycenes generated via the [4 + 2] cycloaddition reaction of anthracenes with o-silylaryl triflates have been found useful in materials science. Some of those applications include triptycene-based self-assembled thin films1015−1017 and the preparation of supramolecular scaffolds.1018−1021 15.3.2. Nanotube and Graphene. In 2016, Pérez, ́ and co-workers found that 1,4-benzdiyne equivalent Martin, 15-47 could add to C60 to prepare a C60-aryne precursor 15130, which could in turn connect with a second C60 or the fewlayered graphene (FLG) unit to assemble compound 15131 and FLG−C60 nanoconjugate 15-132, respectively 4015 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Scheme 353. Other PAHs via Aryne Cycloaddition Protocols Review Scheme 355. Aryne-Involved Polymer Chemistry Scheme 354. Aryne (Co)polymerization Scheme 356. 1,4-Benzdiyne as the Linker for C60 and Fewlayered Graphene research field on transition-metal-catalyzed aryne transformations, which also shows a great potential to incorporate uncommon substituents or functional groups via transition metal catalysis. Besides, Kobayashi precursors of polyarynes have been extensively utilized to access various polysubstituted arenes, especially in the expeditious construction of PAHs. With the recent resurgence in aryne chemistry, there is no doubt that more and more synthetic strategies as well as applications will be developed in the future to further expand the boundary of aryne chemistry. Meanwhile, some new research fields might be unraveled with the discovery of a yet unexplored reactivity/property of arynes, especially by incorporating transition metals in aryne reactions. Although it is traditionally difficult to imagine how to reach asymmetric aryne transformations, a few recent examples suggested possible solutions on how to realize asymmetric aryne reactions, such as through the preparation of chiral nonplanar PAHs and in asymmetric arylation reactions. In addition, the chemistry of hetarynes has not been sufficiently explored yet, 4016 https://dx.doi.org/10.1021/acs.chemrev.0c01011 Chem. Rev. 2021, 121, 3892−4044 Chemical Reviews pubs.acs.org/CR Review ACKNOWLEDGMENTS The authors gratefully acknowledge research support of this work by the Basic and Frontier Research Project of Chongqing (Grants cstc2018jcyjAX0357 and cstc2019jcyj-bshX0021), Fundamental Research Funds for the Central Universities (Grant 2018CDXZ0003), and NSFC (Grants 21971028, 21772017, and 21901025). J.S. was funded by the China Postdoctoral Science Foundation (Grant 2018M640897). the success of which could assemble useful heterocyclic aromatic compounds. Another exciting subfield would be the application of this generation protocol in angle-strained aliphatic cyclic alkynes/allenes. Beyond traditional aryne transformations, unprecedented reaction modes as well as asymmetric transformations should be developed associated with Kobayashi precursors of cyclohexynes and 1,2-cyclohexadienes. For instance, an excellent work on nickel-catalyzed asymmetric reaction of 1,2-cyclohexadiene was reported by Houk, Garg, and co-workers after we finished this review.1030 In view of the substantial body of evidence represented by the myriad successes captured in this review, it is certain that with the assistance of Kobayashi’s mild generation method, both the intrinsic properties and synthetic potentials of aryne as highly reactive, while synthetically important building blocks, will be further explored and exploited. There is an undoubtedly bright future for this protocol. ABBREVIATIONS Ac acetyl acac acetylacetonate BHT 2,6-di-tert-butyl-4-methylphenol Bn benzyl B2(pin)2 bis(pinacolato)diboron Boc tert-butyloxycarbonyl 2,2′-bpy 2,2′-bipyridine Cp cyclopentadienyl Cy cyclohexyl cod 1,5-cyclooctadiene coe cyclooctene 18-c-6 18-crown-6 DABCO 1,4-diazabicyclo[2.2.2]octane DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCB 1,2-dichlorobenzene DCE 1,2-dichloroethane DCM dichloromethane DDQ 2,3-dichloro-5,6-dicyanobenzoquinone DIPEA N, N-diisopropylethylamine DMAP 4-dimethylaminopyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxide dba dibenzylideneacetone dppb 1,4-bis(diphenylphosphino)butane dppe 1,2-bis(diphenylphosphino)ethane dppf 1,1′-bis(diphenylphosphino)ferrocene dppm 1,1-bis(diphenylphosphino)methane dppp 1,3-bis(diphenylphosphino)propane dr diastereomeric ratio dtbpy 4,4′-di-tert-butyl-2,2′-dipyridyl EDC N-(3-(dimethylamino)propyl)-N′-ethylcarbodiimide ETPO 4-ethyl-2,6,7-trioxa-1-phosphabicyclo-[2.2.2]octane ee enantiomeric excess Het heteroaryl HFIP hexafluoroisopropanol HMDS hexamethyldisilazane HMPA hexamethylphosphoramide HOBt 1-hydroxybenzotriazole IMes 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene IPr 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene i-Pr isopropyl KHMDS potassium bis(trimethylsilyl)amide LDA lithium diisopropylamide L-Selectride lithium tri-sec-butylborohydride Me methyl Mes 2,4,6-trimethylphenyl Mes* 2,4,6-tri-tert-butylphenyl MOM methoxymethyl Ms methanesulfonyl AUTHOR INFORMATION Corresponding Author Yang Li − School of Chemistry and Chemical Engineering, Chongqing University, Chongqing, P. R. China 400030; orcid.org/0000-0002-0090-2894; Email: y.li@ cqu.edu.cn Authors Jiarong Shi − School of Chemistry and Chemical Engineering, Chongqing University, Chongqing, P. R. China 400030; orcid.org/0000-0001-5723-6514 Lianggui Li − School of Chemistry and Chemical Engineering, Chongqing University, Chongqing, P. R. China 400030 Complete contact information is available at: https://pubs.acs.org/10.1021/acs.chemrev.0c01011 Author Contributions † J. Shi and L. Li contributed equally to this work. Notes The authors declare no competing financial interest. Biographies Jiarong Shi was born in Jiangsu Province, China, in 1991. He received his B.Sc. (2013) and Ph.D. (2018) degrees from Chongqing University under the guidance of Professor Yang Li. As a student, his research interests were on multiaryne chemistry. He is now an Assistant Research Fellow at Chongqing University and is working on the development of new aryne transformations. Lianggui Li was born in Guangxi Province, China, in 1993. He received his B.Sc. degree in Chemistry from Guangxi Normal University in 2017. He joined Professor Yang Li’s group in 2017 as a Ph.D. student. His research interest is the study on new reaction modes in aryne chemistry. Yang Li was born in Jilin Province, China, in 1978. In 2000, he received his B.Sc. degree from Jilin University, China, with Professor Ruren Xu and Professor Jihong Yu. In 2006, he obtained his Ph.D. degree from the University of Georgia under the guidance of Professor George Majetich. From 2006 to 2009, he was a Postdoctoral Fellow with Professor Vy M. Dong and Professor Datong Song at the University of Toronto. From 2009 to 2012, he was a Postdoctoral Fellow with Professor Stephen J. Lippard at Massachusetts Institute of Technology. In 2012, he joined Chongqing University, China. 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