A New Synthesis of Pyrrole-2-Carboxylic Acids

LETTER 1271
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
b 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: nyerges.oct@chem.bme.hu
Received 3 May 1999
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 5,6
H-NMR data of similar compounds.
Scheme 1 Reagents and conditions: i. AgOAc, Et 3N, 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
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, H 2O 2; ii. (a)
NaOMe, MeOH (b) H + ; iii. ClCOOMe, pyridine, CH 2Cl 2, r.t;
Table 1 Conversion of 2-carboethoxy-4-nitropyrrolidines 3 into pyrrole-2-carboxylic
acids using H 2O 2
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 ISSN 0936-5214 © Thieme Stuttgart · New York

1272 C. S. Pak, M. Nyerges LETTER
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. CS 2, Et 3N, CH 3CN, 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
Synlett 1999, No. 8, 1271–1273 ISSN 0936-5214 © Thieme Stuttgart · New York
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 CH 3OH
(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 o C 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 CH 2Cl 2,
washed with water, dried over MgSO 4 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: 1 H-NMR (CDCl 3, 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); 13 C-NMR (CDCl 3, 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 (CH 2), 55.3 (OMe),
54.9 (CH), 14.1 (CH 3); m/z (rel. intensity, %): 371 (M +1 , 1.2),
324 (1.8), 250 (24), 223 (base peak), 145 (11), 117 (24); IR

LETTER A New Synthesis of Pyrrole-2-Carboxylic Acids 1273
(KBr, cm -1 ): 3451, 3031, 2838, 1747, 1610, 1550, 1368, 1303,
1185, 1033; Compound 4c: 1 H-NMR (DMSO-d 6, 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); 13 C-NMR (CDCl 3, 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: 1 H-NMR (CDCl 3, 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); 13 C-NMR (CDCl 3, 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 (CH 2), 55.2 (OMe),
53.2 (OMe), 47.8 (CH), 14.0 (Me); m/z (rel. intensity, %): 428
(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: 1 H-
NMR (DMSO-d 6, 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); 13 C-NMR (75 MHz, DMSO d6): 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 (CH 2), 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 © Thieme Stuttgart · New York