Enno Wotthuis Downloaded via ESCUELA SUPER POLITECNICA D LITORAL on July 26, 2021 at 02:48:24 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. Calvin College Grand Rapids, Michigan 49506 The Synthesis of Heterocyclic Compounds Some laboratory experiments The increasing significance of heterocycles is generally not apparent in the teaching and laboratory practice in the average college organic chemistry course. All too often this subject is considered only superficially, and then only if time permits. This situation is regrettable, especially in the case of many pre-professional students who may not be exposed to more organic chemistry in their undergraduate curricula but who must encounter many heterocyclic compounds in their professional training and practice. this deficiency? It has been How should one overcome suggested that an advanced course on heterocycles be given (7). Unfortunately, this solution does not fit into many curricula. As an alternative, we sincerely believe that the subject in the introductory should be introduced in some manner course, no doubt at the expense of some other aspects of organic chemistry. Furthermore, some “hands on” experience with heterocycles can be realized by including a limited number of experiments dealing with them. Such exercises may be assigned to all students, but at least be made available to all, and recommended particularly to students majoring in chemistry and/or seeking honors credit for the course. It is this laboratory treatment of heterocycles with which this paper is concerned. Ideally, laboratory work in heterocycles should include syntheses and reactions, preferably in that order. Where time is limited (and where is it not?), we suggest that at least a few experiments be included. From time to time this Journal has published recommended experiments on the subject (2-4). Some of these are very good; others require more time than the average laboratory period allows, and/or require chemicals or equipment not generally available. Organic Syntheses includes a large number of excellent preparations, but, of course, these are not designed particularly for use by the average student in organic chemistry. Our object, then, was to review the literature on the synthesis of heterocycles, to choose those procedures which could most likely be used as such, or be modified and simplified to fit into the normal three- or four-hour laboratory period, and then to develop those procedures for student use, employing common reagents and equipment. For the present we have chosen only five- and six-member heterocycles containing only nitrogen and/or oxygen. We present only those syntheses which give reasonably good yields. The references cited provided the bases for our modifications. Experiments Preparation of 2,5-Dimethyl-l-plienylpyrrole (5). (Time, 3^4 hr.) Charge a 100-ml round bottomed flask with 9.3 g aniline, 11.4 g 2,5-hexanedione, 2 drops concentrated hydrochloric acid, and a boiling stone. Attach a condenser for refluxing, and boil gently for one hour. Pour the hot solution into a beaker containing 50 ml water and 3 ml concentrated hydrochloric acid. Filter the product and wash it with a total of about 50 ml water. Recrystallize the moist product from 50 ml methanol and about 5 ml water, and dry it at 30-40°C. Yield: about 12 g (70 percent), mp 50-51°C. Preparation of 1,2,3,4-Tetrahydrocarbazole (6) and Carbazole (7) (Time, 3 hr. each) Measure 3.7 g phenylhydrazine hydrochloride and 20 ml of glacial acetic acid into a 100-ml round bottomed flask, add a boiling stone, attach a condenser for refluxing, and heat to boiling. Insert a longstem glass funnel through the top of the condenser, and add through it, during 3-5 minutes, 2.5 ml cyclohexanone. The reaction is quite exothermic. Reflux the mixture one hour more. While still hot, transfer the solution to a beaker containing 20 ml hot glacial acetic acid. Again heat to boiling and stir in about 25 ml water to make the solution slightly turbid. Cool to about 20° C, filter, and wash the residue, first with a solution of 20 ml acetic acid and 15 ml water, then with only water to remove the acid, and dry the product at about 80°C. Yield: about 3.8 g (91%), mp 116-117°C. If desired, the crude product may be recrystallized from a small volume of methanol; however, the crude product can be used for dehydrogenation. Dehydrogenation to Carbazole This is most easily accomplished by the procedure in the reference cited (7). We have found'that mesitylene as solvent may be substituted for p-cymene. Preparation of Benzimidazole (2,8) (Time, 3 hr.) Add 5.4 g o-phenylenediamine and 10 ml 90% formic acid to a 100-ml round-bottomed flask, mix well, add a boiling stone, attach a reflux condenser, and heat the mixture one hour with a boiling-water bath. Rinse the dark solution into a beaker with about 5 ml water, cool to 20°C, and stir in about 15 ml concentrated ammonium hydroxide to precipitate the product in a weakly alkaline solution. Cool the suspension to 5-10°C, filter with suction, and wash the residue with 30 ml cold water. Dissolve the moist solid in 75 ml boiling water, add about a gram of Norit, boil one minute, and filter through a steam funnel. The funnel must be kept hot. Rinse the beaker and filter with about 25-ml hot water. Cool the combined filtrate and washes to 510° C, filter the precipitate with suction, wash the product with 20 ml ice-cold water, and dry the product at about 100°C. Yield: about 4.7 g (80%), mp 172-3°C. Preparation of Benzofurazan-l-oxide(3,9,10,11 (Time, 2 hr.) Measure 35 ml methanol into a 250-ml Erlenmeyer flask. While swirling the flask, add a solution of 2.5 g sodium hydroxide in 3 ml water (or its equivalent as 50% (technical) solution), and 2.0 g o-nitroaniline. Warm the mixture to dissolve both base and amine. Insert a thermometer into the flask and cool the mixture to 5°C with an ice-water bath. While agitating well (by swirling or with a magnetic bar), add from a dropping funnel 40 ml Chlorox or its equivalent during 20-25 min. (about 1 drop per 2 sec), while holding the temperature at 5-10°C. Stir 10 min. longer at 5-10°C, then filter, wash the yellow residue with three 20-ml portions of water, followed by 20 ml 1-2% hydrochloric acid, and finally 20 ml water. Dry the product at 40-50°C. Yield: about 1.6 g (81%), mp 68-9°C. If desired, the product may be recrystallized from a small volume of methanol to obtain a pure product of mp 72-3°C. Preparation of Ethyl 2-oxo-2H-1 -benzopyran-3-carboxylate (12) (Time, 3 hr.) (3-Carbethoxycoumarin) Put into a 100-ml round bottomed flask 6.1 g saticylaldehyde, 8.8 g diethyl malonate, 20 ml ethanol, 10 drops piperidine, and 2 drops glacial acetic acid. Add a boiling stone, attach a reflux condenser, and boil the mixture 2 hr. Rince the hot solution into a beaker with 5 ml ethanol, then wjth 35 ml water. If turbid, heat the solution to 50-60°C, then allow it to cool without agitation until crystals begin to form. Finally cool with stirring to 5-10 °C, filter with suction, wash the crystals twice with a total of 40 ml ethanol-water mixture (35/60, v/v) and dry the product at 60-70°C. Yield: about 9.0 g (82.5%), mp 923°C. Preparation of 4-Methyl-2(lH)-quinoline (13-15) (Time, 3 hr.) (4-Methylcarbostyril) Measure 20 ml concentrated sulfuric acid into a 125-ml Erlenmeyer flask, insert a thermometer, and warm to 75°C. During 8-10 minutes at 70-90°C, and, with good agitation, add 17.7 g acetoacetanilide through a wide-stern funnel. Cool with a water bath to control the exothermic reaction within that temperature range. When the temperature no longer rises due to the heat of reaction, heat 30 min longer on a hot plate or steam bath. Allow the solution to cool to about 60°C Volume 56, Number 5, May 1979 / 343 and pour it into 500 ml water, rinse the flask with a little water also. Cool the suspension to 20°C, filter with suction, and wash the product with 400 ml water in several portions until free of acid, then twice with a total of 40 ml methanol (to facilitate drying). Dry the product at about 100°C. Yield: about 14.0 g (88%), mp 224-6°C. Preparation of 2,4,6(lH,3Hi5H)-Pyrimidinetrione (16). (Time, 3-4 hr.) (Barbituric acid) Note: in this preparation it is important to employ very good agitation. Magnetic stirring is preferred. Charge a 200-ml round-bottomed flask with 35 ml anhydrous ethanol and 1.2 g sodium, in small pieces. Attach a condenser for refluxing and stir until all the sodium has reacted, moderating the reaction rate with a water bath. Meanwhile, prepare a solution of 3.0 g urea in 25 ml warm anhydrous ethanol. While the sodium ethoxide solution is still hot, add 8 ml diethyl malonate, then the urea solution, rinsing the latter into the flask with 5 ml ethanol. Again attach the condenser and agitate well while heating to boiling. Reflux the mixture for two hours. While the solution is still hot, pour it into a beaker and rinse the flask with 60 ml hot water. Stir the suspension while adding 5 ml concentrated hydrochloric acid, or enough to dissolve the pre- 344 / Journal of Chemical Education cipitate at about pH 4. Cool to 0-5°C, with stirring, filter the crystals, wash them twice with a total of 20 ml ice-cold water, and dry at about 100°C. Yield: about 4.2 g(66%), mp 250°d. Literature Cited (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) Katritsky, A. R., J. CHEM. EDUC., 42,636 (1965). Wagner, E, C. and Simons, .3. K., J. CHEM. EDUC., 13, 265 (1936). Schimelpfenig, C. W., J. CHEM. EDUC. 36,570 (1959). Rose, N. C. and Rome, S„ J. CHEM. EDUC., 47, 649 (1970). 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