In the Laboratory
A Convenient Synthesis of the Tetrasubstituted Pyrrole An Undergraduate Heterocyclic Laboratory Experiment Patrik Kolar* and Miha Tiˇsler Department of Organic Chemistry, University of Ljubljana, SLO-1000 Ljubljana, Slovenia
Practical courses in basic and advanced organic chemistry usually involve little or no amino acid chemistry because of the time-consuming procedures during peptide synthesis. Some efficient and relatively short dipeptide syntheses were published in this Journal (1–3) to overcome this problem and to increase the popularity of the amino acid transformations in undergraduate laboratories. Although amino acids have also been successfully used as synthons for various heterocycles for almost a century (4), this aspect of amino acid chemistry unfortunately receives much less attention in the lecture room and laboratory than it truly deserves. Since 1915, when probably the first synthesis of a pyrrole from an amino acid derivative (ethyl glycinate) was reported (5), this heterocyclic system has been prepared by several acid- or base-catalyzed cyclizations of αamino acid ester enamines (6–10). Many of these methods are not very suitable for laboratory experiments because of the long reaction times required, relatively expensive reagents, or chromatographic separations that cannot be performed successfully in a reasonable time by less experienced students. Recently we developed an efficient synthesis of tetrasubstituted pyrroles from esters of alkyl, aryl, and heteroaryl substituted α-amino acids (I), which is presented in the Figure (11). α-Amino acid esters (Fig. 1, I) react easily with dimethyl acetylenedicarboxylate (DMAD) in methanol at 0– 20 °C and form mixtures of (E) and (Z)-enamines (Fig. 1, II). The addition reaction proceeds quantitatively (according to TLC evidence) and is completed in 15 min to 2 h. The enamines (II) can be transformed into pyrroles (Fig. 1, III) by a sodium methoxide–catalyzed Dieckmann-like condensation similarly to the enamines prepared from αamino acid esters and 1,3-dicarbonyl compounds (6, 9, 10). The cyclization does not give any side products in noticeable amounts and the pyrroles are precipitated as TLCpure products after the acidification of reaction mixtures by a 10% solution of acetic acid. The reaction time for cyclization into pyrroles depends on the radical R of the amino acid residue in enamines (II). It ranges from 0.5 h for R = benzyl to 24 h for R = methyl. Because of the high rate of cyclization and satisfactory yield of product (about 65%), the preparation of pyrrole from L -phenylalanine ethyl ester (I, R = benzyl, R1 = ethyl) seems to be the most convenient for use as a preparative experiment. The preparation of pyrrole (III, R = benzyl) is simple and rapid; together with the preparation of L -phenylalanine ethyl ester from its hydrochloride, the whole synthesis takes about 3 h. The synthesis can also be applied to larger-scale preparations (starting with up to 15 g of L*Corresponding author.
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phenylalanine ethyl ester) without any additional difficulties, giving the product in approximately the same yield (63–72%). Because usually only two pyrrole preparations (the Knorr and the Paal-Knorr synthesis) are included in undergraduate organic chemistry (12, 13), we believe that the synthesis described here represents an attractive alternative to these classical pyrrole syntheses. Experimental Procedure Melting point was determined on a Kofler micro hot stage. IR spectra were recorded on a Perkin-Elmer 1310 spectrometer and 1H NMR spectra were recorded on a Varian 360L spectrometer vs. TMS. Analytical TLC Silicagel plates (0.2 mm) with a 254-nm fluorescent indicator (FLUKA, Switzerland). A mixture of chloroform and methanol (7:3) as a mobile phase was used for monitoring the transformation of L -phenylalanine ethyl ester (Rf = 0.65) with DMAD into its enamine (Rf = 0.9). The same mobile phase was used for checking the purity of the crude pyrrole (R f = 0.75). L-Phenylalanine
ethyl ester (I, R = benzyl, R1 = ethyl)
Commercially available L -phenylalanine ethyl ester hydrochloride (2.57 g) was dissolved in 25 mL of water, cooled on ice bath to 0 °C, and neutralized with a solution of 0.45 g of sodium hydroxide in 10 mL of water. The neu-
Figure 1. A two-step synthesis of tetrasubstituted pyrroles from α-amino acid esters.
Journal of Chemical Education • Vol. 73 No. 10 October 1996
In the Laboratory
tralized solution was extracted 4–5 times with 15-mL portions of diethyl ether, and combined extracts were dried with anhydrous sodium sulfate and evaporated in vacuo to give the colorless oily product (1.89 g, 88%). The resulting L-phenylalanine ethyl ester was used immediately, without further purification, in the next reaction steps.
5-Benzyl-4-hydroxy-2,3-di(methoxycarbonyl)pyrrole (III, R = benzyl) L-Phenylalanine ethyl ester (1.89 g) was dissolved in 7 mL of methanol and cooled to 0 °C, and 1.40 g of DMAD was added dropwise with stirring. Stirring was continued for one more hour and the reaction mixture was then evaporated in vacuo to remove the excess of DMAD. The resulting enamine, obtained as a yellow oil, was dissolved in 6 mL of methanol and a freshly prepared solution of sodium methoxide, prepared from 0.23 g of sodium and 6 mL of anhydrous methanol, was added dropwise at room temperature. The stirring was continued for the next 25– 30 minutes. After this period the thick mass of the sodium salt of hydroxypyrrole precipitated. The reaction mixture was diluted with 10 mL of water and the precipitate dissolved completely. The resulting solution was neutralized with 15 mL of 10% acetic acid and the precipitated pyrrole was filtered and washed with aqueous methanol, giving a yield of 1.85 g (65%) of the product as a TLC-pure, almost colorless solid. This was further purified by crystallization from methanol to give the analytically pure pyrrole as colorless crystals, mp = 140–141 °C (uncorrected). CAUTION: Sodium must be handled with great care according to the safety instructions in the literature (14). During the preparation of sodium methoxide solution, safety glasses should be worn and the reaction should always be performed in a well ventilated hood to minimize
the fire hazard due to the hydrogen produced. Alternatively, inexpensive commercially available solutions of sodium methoxide can be used to avoid handling the elemental sodium.1
Analytical data:2 IR (KBr): 3290, 1660, 1500, 1460, 1340, 1300, 1195, 1080 cm–1. 1H NMR (60 MHz, DMSO-d ) δ: 3.57 (6H,s,two 6 COOMe), 3.73 (2H,s,CH2), 6.96 (5H, broad s, Ph), 7.91 (1H,s,OH), 11.45 (1H, broad s,NH).
Notes 1. 25 wt % solution of sodium methoxide in methanol ($15.30 per liter) is available from Aldrich Chemicals, Milwaukee, WI. 2. Elemental analysis and the intensity of molecular ion in mass spectra can be found in ref 11.
Literature Cited 1. Young, P. E.; Campbell, A. J. Chem. Educ. 1982, 59, 701–702. 2. Lindeberg, G. J. Chem. Educ. 1987, 64, 1062–1064. 3. Blatchly, R. A.; Allen, T. R.; Bergstrom, D. T.; Shiozaki,Y. J. Chem. Educ. 1989, 66, 965–967. 4. For recent reviews on the subject, see: Kleemann, A. Chem. Ztg. 1982, 106, 151– 167; Ottenheijm, H. C. J. Chimia 1985, 39, 89–98. 5. Hale, W. J.; Hoyt, W. V. J. Am. Chem. Soc. 1915, 37, 2538–2552. 6. Treibs, A.; Ohorodnik, A. Liebigs Ann. Chem. 1958, 611, 139–149. 7. Gupta, S. K. Synthesis 1975, 726–727. 8. Mataka, S.; Takahashi, K.; Tsuda, Y.; Tashiro, M. Synthesis 1982, 157–159. 9. Walizei, G. H.; Breitmaier, E. Synthesis 1989, 337–340. 10. Hombrecher, H. K.; Horter, G. Synthesis 1990, 389–391. 11. Kolar, P.; Tiˇsler, M. Synth. Commun. 1994, 24(13), 1887–1893. 12. Vogel’s Textbook of Practical Organic Chemistry, 5th ed.; Longman: London, 1989; p 1151. 13. Wolthuis, E. J. Chem. Educ. 1979, 56, 343–344. 14. Ref 12, pp 462–463.
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