A New Synthesis of Pyrrole-2-Carboxylic Acids

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A New Synthesis of Pyrrole-2-Carboxylic Acids Chwang Siek Pak*a, Miklós Nyerges*b a

Korea Research Institute of Chemical Technology, P.O.Box 107, Yusung, Taejon 305-606, Korea Research Group of the Hungarian Academy of Sciences, Department of Organic Chemical Technology, Technical University of Budapest, H-1521 Budapest P.O.B. 91, Hungary Fax (+361) 46 33 648; E-mail: [email protected] Received 3 May 1999

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Abstract: A new two-step synthesis of pyrrole-2-carboxylic acids is described, steps via 1,3 dipolar cycloaddition of azomethine ylides to nitro-styrenes and oxidation of the resulting pyrrolidines with alkaline hydrogen peroxide. Key words: pyrroles, 1,3-dipolar cycloaddition, azomethine ylids

The biological importance of pyrrole-containing natural products, such as heme, chlorophyll and vitamin B12 has stimulated extensive research on the synthesis and reactivity of pyrrole derivatives.1 There are many methods for the synthesis of these important heterocycles,2 including the 1,3-dipolar cycloaddition of azomethine ylides to alkynes, followed by aromatization of the intermediate pyrrolines.3 However, the preparation of pyrroles by dehydrogenation of pyrrolidines has found little application due to the lack of general methods, and to the forcing conditions required in most cases.4 We now report that a variety of substituted nitro-pyrrolidines can be converted into pyrroles using alkaline hydrogen peroxide to promote a cascade oxidation-elimination process. The highly substituted pyrrolidines were prepared in high yield by the stereoselective 1,3-dipolar cycloaddition of azomethine ylides (generated from the imines 1) with 2aryl-nitroethylenes 2 in the presence of silver acetate (Scheme 1).5 The stereochemistry of the exclusive synendo cycloadducts was deduced by comparison with the 1 H-NMR data of similar compounds.5,6

To our surprise we found that after several hours stirring at room temperature a light brown material began to precipitate from the solution which was shown to be the pyrrole derivative.8 In all cases the reactions, using two equivalents of base, were complete after stirring for 1 day, giving the diarylpyrrole-2-carboxylic acids 4 in virtually quantitative yield. The results are summarised in Table 1. In the absence of base no reaction occurred (Entry 4), while in the absence of hydrogen peroxide, after the workup, a 1:1 mixture of pyrrolidine isomers of 3i and 5i respectively, was isolated. (Scheme 2).

Scheme 2 Reagents and conditions: i. NaOMe, MeOH, H2O2; ii. (a) NaOMe, MeOH (b) H+; iii. ClCOOMe, pyridine, CH2Cl2, r.t; Table 1 Conversion of 2-carboethoxy-4-nitropyrrolidines 3 into pyrrole-2-carboxylic acids using H2O2

Scheme 1 Reagents and conditions: i. AgOAc, Et3N, toluene, r.t.

We originally attempted to find a feasible method for the Nef-type conversion of highly substituted nitro-pyrrolidines, in connection with our studies on the synthesis of biologically active pyrrolidine alkaloids. After several standard methods failed in our hands we turned our attention to the oxidation of the corresponding nitronate anion by hydrogen peroxide, which was first described by Olah and co-workers.7

No aromatization occurred in the case of the N-protected derivatives 5. It is also interesting to note that when the solution of the nitronate derived from 5 was treated directly with acid a 1:1 isomeric mixture of 5i was obtained, while

Synlett 1999, No. 8, 1271–1273

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© Thieme Stuttgart · New York

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C. S. Pak, M. Nyerges

after work-up of the reaction treated with hydrogen peroxide only a single isomer 6 was obtained. The stereochemistry of these pyrrolidines was confirmed by HH-COSY and NOE experiments. This epimerization also takes place as the first step in the reduction of the nitro-group using carbon disulfide and an excess of triethylamine at room temperature.9 After 4 hours reaction time only pyrrolidine 6 was isolated, while after 72 hours the oxime 8 was formed in good yield (Scheme 3).

Scheme 3 Reagents and conditions: i. CS2, Et3N, CH3CN, r.t.;

The nitro group of any nitro-alkene generally fails to serve as a leaving group in ionic base-catalysed elimination reactions since the reaction of primary and secondary nitro alkanes with base results in the formation of stable nitronate anions. However, with electron-withdrawing groups at the β-position to the nitro group the base-induced elimination of nitrous acid takes place smoothly to give alkenes in good yield.10 Our results suggest that the first step in this aromatization is a dehydrogenation leading to the formation of the pyrroline derivative 9. This intermediate can then eliminate a nitronate ion through a vinylogous E1CB mechanism to give pyrrole-2-carboxylic acids, after aromatization through a [1,5] sigmatropic shift of hydrogen and the alkaline hydrolysis of the ester group (Scheme 4). The elimination step is similar to that proposed by Barton and coworkers11 in their pyrrole synthesis. In the reaction of similar cycloadducts, lacking the carboethoxy functionality, with alkaline potassium permanganate only nitro-pyrroline formation was observed,12 which further supports our observations.

Scheme 4

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Acknowledgement Financial support from the Ministry of Science of Technology as a Programme for Hungarian Visiting Scientist is gratefully acknowledged.

References and Notes (1) Jones, R.A.; Bean, G.P.; The Chemistry of Pyrroles Academic Press, London, 1977. (2) (a) Sundberg, R.J. In Comprehensive Heterocyclic Chemistry; Katritzky, A.; Rees, C.W.; Eds.; Pergamon: Oxford, 1984, Vol. 4, 313. (b) For two recent examples on the synthesis of pyrrole-2-carboxylates: Uno, H.; Tanaka, M.; Inoue, T.; Ono, N. Synthesis 1999, 471.; Selic, L.; Stanovnik, B. Synthesis 1999, 479. (3) (a) La Porta, P.; Capuzzi, L.; Bettarini, F.; Synthesis 1994, 287. (b) DeShong, P.; Kell, D. A.; Sidler, D. R. J. Org. Chem. 1985, 50, 2309. (c) Padwa, A.; Norman, B. H. J. Org. Chem. 1990, 55, 4801. (4) (a) Southwick, P. L.; Sapper, D. I.; Pursglove, L. A. J. Am. Chem. Soc. 1950, 72, 4940. (b) Cossy, J.; Pete, J.-P.; Tetrahedron Lett. 1978, 4941. (c) Cervinka, O. Chem. Ind. (London) 1959, 1129. (d) Oussaid, B.; Garrigues, B.; Soufiaoui, M. Can. J. Chem. 1994, 72, 2483. (e) Bonnaud, B.; Bigg, D. C. H.; Synthesis 1994, 465. (d) Gupta, P.; Bhaduri, A.P. Synth. Commun. 1998, 28, 3151. (5) (a) Nyerges, M.; Bitter, I.; Kádas, I.; Tóth, G.; Tõke, L. Tetrahedron Lett. 1994. 34, 4413. (b) Nyerges, M.; Bitter, I.; Kádas, I.; Tóth, G.; Tõke, L. Tetrahedron 1995, 51, 11489. (c) For typical procedure see: Nyerges, M.; Rudas, M.; Tóth, G.; Herényi, B. Bitter, I.; Tõke, L. Tetrahedron 1995, 51, 13321. (6) Ayerbe, M.; Arrieta, M.; Cossio, F. P.; Linden, A. J. Org. Chem. 1998, 63, 1795. (7) (a) Olah, G. A.; Arvanaghi, M.; Vankar, Y. D.; Prakash, G.K.S.; Synthesis 1980, 662. (b) Lui, K. H.; Sammes, M. P. J. Chem. Soc. Perkin Trans. 1 1990, 457. (8) General procedure for the preparation of pyrroles: The nitropyrrolidine derivative (1.0 mmol) was suspended in CH3OH (10 mL) and sodium methylate was added (0.108 g, 2.0 mmol). When the reaction mixture became homogeneous it was cooled down to 0 oC and 30 % hydrogen peroxide solution (2 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight. Then the solution was acidified with diluted HCl, and the precipitated pyrrole was filtered off. The residue was evaporated, dissolved in CH2Cl2, washed with water, dried over MgSO4 and evaporated to yield a further quantities of the product. (9) Barton, D.H.R.; Fernandez, I.; Richard, C. S.; Zard, S.Z. Tetrahedron, 1987, 43, 551. (10) Excellent review on the nitro function as a leaving group by Ono, N.; In Nitro Compounds, Recent Advences in Synthesis and Chemistry Feuer, H.; Nielsen, A.T. Eds.; VCH New York, 1990. (11) Barton, D. H. R.; Kervagoret, J.; Zard, S. Z. Tetrahedron 1990, 46, 7587. (12) Bajpai, K. L.; Bhaduri, A. P. Synth. Commun. 1998, 28, 181. (13) Selected spectroscopical data for representative compounds: Compound 3c: 1H-NMR (CDCl3, 200 MHz): 7.35 (s, 5H), 7.22 (d, 2H, J 8.8 Hz), 6.92 (d, 2H, J 8.8 Hz), 5.25 (dd, 1H, J 3.4 and 6.4 Hz), 4.90 (d, 1H, J 6.6 Hz), 4.39-4.04 (m, 4H) 3.82 (s, 3H), 1.26 (t, 3H, J 7.0 Hz); 13C-NMR (CDCl3, 75 MHz): 171.3 (q), 159.2 (q), 134.5 (q), 130.5 (q), 128.7 (2xCH), 128.65 (CH), 128.6 (2xCH), 126.4 (2xCH), 114.5 (2xCH), 97.1 (CH), 67.6 (CH), 67.5 (CH), 61.6 (CH2), 55.3 (OMe), 54.9 (CH), 14.1 (CH3); m/z (rel. intensity, %): 371 (M+1, 1.2), 324 (1.8), 250 (24), 223 (base peak), 145 (11), 117 (24); IR


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A New Synthesis of Pyrrole-2-Carboxylic Acids

(KBr, cm-1): 3451, 3031, 2838, 1747, 1610, 1550, 1368, 1303, 1185, 1033; Compound 4c: 1H-NMR (DMSO-d6, 300 MHz): 8.07 (dd, 2H, J 1.7 and 8.4 Hz), 7.85 (t, 1H, J 8.4 Hz), 7.44 (m, 4H), 7.27 (d, 2H, J 8.5 Hz), 6.96 (s, 1H), 6.83 (d, 2H, J 8.5 Hz), 3.77 (s, 3H, OMe); 13C-NMR (CDCl3, 125 MHz): 160.9 (q), 158.2 (q), 133.3 (q), 131.0 (q), 130.2 (CH), 129.9 (2xCH), 129.5 (2xCH), 129.4 (q), 128.6 (q), 128.5 (2xCH), 113.9 (q), 113.2 (2xCH), 112.6 (CH), 55.4 (OMe); m/z (rel. intensity, %): 294 (M+, 7), 278 (52), 261 (27), 249 (11), 235 (16), 217 (20), 204 (64), 176 (53), 151 (36), 102 (54), 89 (78), 77 (base peak), 63 (70), 51 (80); IR (KBr, cm-1): 2511, 1610, 1427, 1311, 1250, 1221, 1032; Compound 5: 1H-NMR (CDCl3, 200 MHz): 7.66 (dd, 2H, J 1.4 and 8.1 Hz), 7.35 (m, 3H), 7.19 (d, 2H, J 8.8 Hz), 6.87 (d, 2H, J 8.7 Hz), 5.60 (broad s, 1H), 5.43 (t, 1H, J 10.6 Hz), 4.47 (d, 1H, J 10 Hz), 4.25 (m, 3H), 3.78 (s, 3H), 3.64 (br s, 3H), 1.21 (t, 3H); 13C-NMR (CDCl3, 75 MHz): 170.4 (q), 159.7 (q), 155.1 (br, q), 135.0 (br, q), 128.8 (3xCH), 128.7 (2xCH), 128.6 (q), 126.9 (2xCH), 114.5 (2xCH), 90.8 (br, CH), 64.2 (CH), 62.6 (br CH), 61.6 (CH2), 55.2 (OMe), 53.2 (OMe), 47.8 (CH), 14.0 (Me); m/z (rel. intensity, %): 428

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(M+, 3), 381 (17), 322 (11), 308 (base peak), 276 (10), 248 (8), 115 (6); IR (KBr, cm-1): 3019, 2960, 1790, 1741, 1613, 1556, 1451, 1367, 1254, 1186, 1131, 1031, 774; Compound 6: 1HNMR (DMSO-d6, 300 MHz): 7.69 (d, 2H, J 6.4 Hz), 7.42 (t, 2H, J 6.4 Hz), 7.35 (t, 1H, J 6.4 Hz), 7.22 (d, 2H, J 8.6 Hz), 6.83 (d, 2H, J 8.6 Hz), 5.72 (s, 1H), 5.82 (d, 1H, J 6 Hz), 4.85 (d, 1H, J 10 Hz), 4.12 (m, 3H), 3.72 (s, 3H), 3.67 (s, 3H), 3.55 (s, 3H), 1.06 (t, 3H); 13C-NMR (75 MHz, DMSOd6): 171.0 (q), 159.2 (q), 155.1 (q), 138.7 (q), 129.2 (2xCH), 128.6 (2xCH), 127.9 (CH), 125.6 (2xCH), 122.9 (q), 114.0 (2xCH), 95.5 (CH), 64.5 (CH), 62.4 (CH), 61.2 (CH2), 55.1 (Me), 53.1 (Me), 49.6 (CH), 13.9 (Me); MS m/z (rel. intensity, %): 428 (M+, 2), 382 (45), 355 (13), 336 (50), 308 (base peak), 294 (32), 276 (18), 249 (18), 232 (17), 115 (31), 59 (48); IR (KBr, cm-1): 2980, 2911, 1738, 1712, 1612, 1554, 1515, 1447, 1350, 1252, 1133, 1028.

Article Identifier: 1437-2096,E;1999,0,08,1271,1273,ftx,en;G13299ST.pdf

Synlett 1999, No. 8, 1271–1273

ISSN 0936-5214
