A new synthesis of pyrrole-2-carboxylic acids

Article abstract of DOI:10.1055/s-1999-2797

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.

Full text of DOI:10.1055/s-1999-2797

LETTER
1271
A New Synthesis of Pyrrole-2-Carboxylic Acids
*
a
*b
Chwang Siek Pak , Miklós Nyerges
aKorea Research Institute of Chemical Technology, P.O.Box 107, Yusung, Taejon 305-606, Korea
bResearch 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
To our surprise we found that after several hours stirring
Abstract: A new two-step synthesis of pyrrole-2-carboxylic acids
at room temperature a light brown material began to pre-
is described, steps via 1,3 dipolar cycloaddition of azomethine
cipitate from the solution which was shown to be the pyr-
ylides to nitro-styrenes and oxidation of the resulting pyrrolidines
with alkaline hydrogen peroxide.
8
role derivative. 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 work-
up, a 1:1 mixture of pyrrolidine isomers of 3i and 5i re-
spectively, was isolated. (Scheme 2).
Key words: pyrroles, 1,3-dipolar cycloaddition, azomethine ylids
The biological importance of pyrrole-containing natural
products, such as heme, chlorophyll and vitamin B has
1
2
stimulated extensive research on the synthesis and reac-
1
tivity of pyrrole derivatives. There are many methods for
2
the synthesis of these important heterocycles, including
the 1,3-dipolar cycloaddition of azomethine ylides to
alkynes, followed by aromatization of the intermediate
3
pyrrolines. However, the preparation of pyrroles by de-
hydrogenation of pyrrolidines has found little application
due to the lack of general methods, and to the forcing con-
4
ditions required in most cases. We now report that a va-
riety 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 2-
aryl-nitroethylenes 2 in the presence of silver acetate
5
(
Scheme 1). The stereochemistry of the exclusive syn- Scheme 2 Reagents and conditions: i. NaOMe, MeOH, H O ; ii. (a)
2
2
+
endo cycloadducts was deduced by comparison with the NaOMe, MeOH (b) H ; iii. ClCOOMe, pyridine, CH
H-NMR data of similar compounds.
Cl
, r.t;
2
2
1
5,6
Table 1 Conversion of 2-carboethoxy-4-nitropyrrolidines 3 into pyr-
role-2-carboxylic acids using H O
2
2
Scheme 1 Reagents and conditions: i. AgOAc, Et N, toluene, r.t.
3
We originally attempted to find a feasible method for the
Nef-type conversion of highly substituted nitro-pyrro-
lidines, in connection with our studies on the synthesis of
biologically active pyrrolidine alkaloids. After several
standard methods failed in our hands we turned our atten- No aromatization occurred in the case of the N-protected
tion to the oxidation of the corresponding nitronate anion derivatives 5. It is also interesting to note that when the so-
by hydrogen peroxide, which was first described by Olah lution of the nitronate derived from 5 was treated directly
7
and co-workers.
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

1
272
C. S. Pak, M. Nyerges
LETTER
after work-up of the reaction treated with hydrogen perox- Acknowledgement
ide only a single isomer 6 was obtained. The stereochem-
Financial support from the Ministry of Science of Technology as a
Programme for Hungarian Visiting Scientist is gratefully acknow-
ledged.
istry 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
9
References and Notes
room temperature. After 4 hours reaction time only pyr-
rolidine 6 was isolated, while after 72 hours the oxime 8
was formed in good yield (Scheme 3).
(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.
Scheme 3 Reagents and conditions: i. CS , Et N, CH CN, r.t.;
2
3
3
4) (a) Southwick, P. L.; Sapper, D. I.; Pursglove, L. A. J. Am.
Chem. Soc. 1950, 72, 4940. (b) Cossy, J.; Pete, J.-P.;
The nitro group of any nitro-alkene generally fails to serve
as a leaving group in ionic base-catalysed elimination re-
actions since the reaction of primary and secondary nitro
alkanes with base results in the formation of stable nitr-
onate anions. However, with electron-withdrawing
groups at the β-position to the nitro group the base-in-
duced elimination of nitrous acid takes place smoothly to
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.
1
0
give alkenes in good yield.
Our results suggest that the first step in this aromatization
is a dehydrogenation leading to the formation of the pyr-
roline 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 al-
kaline hydrolysis of the ester group (Scheme 4). The elim-
ination step is similar to that proposed by Barton and co-
(
(
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 nitro-
pyrrolidine derivative (1.0 mmol) was suspended in CH OH
3
(
10 mL) and sodium methylate was added (0.108 g, 2.0
1
1
mmol). When the reaction mixture became homogeneous it
workers in their pyrrole synthesis. In the reaction of sim-
ilar cycloadducts, lacking the carboethoxy functionality,
with alkaline potassium permanganate only nitro-pyrro-
o
was cooled down to 0 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 Cl ,
1
2
line formation was observed, which further supports our
observations.
2
2
washed with water, dried over MgSO and evaporated to yield
4
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,
1
990.
11) Barton, D. H. R.; Kervagoret, J.; Zard, S. Z. Tetrahedron
990, 46, 7587.
(
1
(
(
12) Bajpai, K. L.; Bhaduri, A. P. Synth. Commun. 1998, 28, 181.
13) Selected spectroscopical data for representative compounds:
1
Compound 3c: H-NMR (CDCl , 200 MHz): 7.35 (s, 5H),
3
7
3
.22 (d, 2H, J 8.8 Hz), 6.92 (d, 2H, J 8.8 Hz), 5.25 (dd, 1H, J
.4 and 6.4 Hz), 4.90 (d, 1H, J 6.6 Hz), 4.39-4.04 (m, 4H) 3.82
1
3
Scheme 4
(s, 3H), 1.26 (t, 3H, J 7.0 Hz); C-NMR (CDCl , 75 MHz):
3
1
1
9
5
3
71.3 (q), 159.2 (q), 134.5 (q), 130.5 (q), 128.7 (2xCH),
28.65 (CH), 128.6 (2xCH), 126.4 (2xCH), 114.5 (2xCH),
7.1 (CH), 67.6 (CH), 67.5 (CH), 61.6 (CH ), 55.3 (OMe),
2
+1
4.9 (CH), 14.1 (CH ); m/z (rel. intensity, %): 371 (M , 1.2),
3
24 (1.8), 250 (24), 223 (base peak), 145 (11), 117 (24); IR
Synlett 1999, No. 8, 1271–1273 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
KBr, cm ): 3451, 3031, 2838, 1747, 1610, 1550, 1368, 1303,
A New Synthesis of Pyrrole-2-Carboxylic Acids
1273
-
1
+
(
(M , 3), 381 (17), 322 (11), 308 (base peak), 276 (10), 248 (8),
1
-1
1
8
4
185, 1033; Compound 4c: H-NMR (DMSO-d , 300 MHz):
115 (6); IR (KBr, cm ): 3019, 2960, 1790, 1741, 1613, 1556,
6
1
.07 (dd, 2H, J 1.7 and 8.4 Hz), 7.85 (t, 1H, J 8.4 Hz), 7.44 (m,
H), 7.27 (d, 2H, J 8.5 Hz), 6.96 (s, 1H), 6.83 (d, 2H, J 8.5
1451, 1367, 1254, 1186, 1131, 1031, 774; Compound 6: H-
NMR (DMSO-d , 300 MHz): 7.69 (d, 2H, J 6.4 Hz), 7.42 (t,
6
1
3
Hz), 3.77 (s, 3H, OMe); C-NMR (CDCl , 125 MHz): 160.9
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
3
(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),
1
3
1
%
13.2 (2xCH), 112.6 (CH), 55.4 (OMe); m/z (rel. intensity,
): 294 (M , 7), 278 (52), 261 (27), 249 (11), 235 (16), 217
(s, 3H), 1.06 (t, 3H); C-NMR (75 MHz, DMSO ): 171.0 (q),
d6
+
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
(
20), 204 (64), 176 (53), 151 (36), 102 (54), 89 (78), 77 (base
-
1
peak), 63 (70), 51 (80); IR (KBr, cm ): 2511, 1610, 1427,
1
(CH), 64.5 (CH), 62.4 (CH), 61.2 (CH ), 55.1 (Me), 53.1
2
1
311, 1250, 1221, 1032; Compound 5: H-NMR (CDCl , 200
(Me), 49.6 (CH), 13.9 (Me); MS m/z (rel. intensity, %): 428
3
+
MHz): 7.66 (dd, 2H, J 1.4 and 8.1 Hz), 7.35 (m, 3H), 7.19 (d,
H, 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,
(M , 2), 382 (45), 355 (13), 336 (50), 308 (base peak), 294
2
(32), 276 (18), 249 (18), 232 (17), 115 (31), 59 (48); IR (KBr,
-
1
(
cm ): 2980, 2911, 1738, 1712, 1612, 1554, 1515, 1447, 1350,
1252, 1133, 1028.
1
3
3
1
1
H), 3.64 (br s, 3H), 1.21 (t, 3H); C-NMR (CDCl , 75 MHz):
3
70.4 (q), 159.7 (q), 155.1 (br, q), 135.0 (br, q), 128.8 (3xCH),
28.7 (2xCH), 128.6 (q), 126.9 (2xCH), 114.5 (2xCH), 90.8
(
5
br, CH), 64.2 (CH), 62.6 (br CH), 61.6 (CH ), 55.2 (OMe),
3.2 (OMe), 47.8 (CH), 14.0 (Me); m/z (rel. intensity, %): 428
Article Identifier:
1437-2096,E;1999,0,08,1271,1273,ftx,en;G13299ST.pdf
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Synlett 1999, No. 8, 1271–1273 ISSN 0936-5214 © Thieme Stuttgart · New York