A novel access to bisformylated pyrroles via decarboxylation of N-aryl-γ-lactam-carboxylic acids under Vilsmeier reaction conditions

Article abstract of DOI:10.1016/j.tetlet.2009.11.005

A simple methodology for the conversion of substituted N-aryl-γ-lactam 2/3-carboxylic acids to substituted N-aryl-diformylated pyrroles has been developed. Several γ-lactam 2/3-carboxylic acids were subjected to Vilsmeier reagent and substituted diformylated pyrroles are isolated in one-step process.

Full text of DOI:10.1016/j.tetlet.2009.11.005

Tetrahedron Letters 51 (2010) 297–300
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel access to bisformylated pyrroles via decarboxylation
of N-aryl-
c-lactam-carboxylic acids under Vilsmeier reaction conditions
*
Gopa Barman, Jayanta K. Ray
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple methodology for the conversion of substituted N-aryl-
c
-lactam 2/3-carboxylic acids to substi-
Received 12 August 2009
Revised 28 October 2009
Accepted 2 November 2009
Available online 5 November 2009
tuted N-aryl-diformylated pyrroles has been developed. Several
c-lactam 2/3-carboxylic acids were sub-
jected to Vilsmeier reagent and substituted diformylated pyrroles are isolated in one-step process.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Vilsmeier reagent
Diformylated pyrrole
c
-Lactam 2/3-carboxylic acids
Aromaticity
Decarboxylation
Highly substituted pyrroles are important structural features of
many natural products and pharmaceutically active substances.1
Moreover they are widely used in material science.2 Pyrroles can
be found in a large range of bioactive molecules, including the
blockbuster drug atrovastatin calcium, as well as important antif-
lamatants, antitumor agents, and immunosuppressants.3 This util-
ity has driven the search for efficient methods to construct
pyrroles. Several methods, such as the Knorr,4 Paal-Knorr,5 and
Hantzsch synthesis6 including multicomponent and metal-cata-
lyzed routes7 have been reported for the synthesis of pyrroles.
But these above-said methodologies require the correctly substi-
tuted precursor(s) prior to cyclization, which can complicate both
the synthesis and structural modification of substituted pyrroles.
We have recently reported that N-aryl-3-formylpyrroles can be
substituted oxazolidin-5-ones in 30–38% yields. Recently, we re-
ported that 4-chloro indanone under went bisformylation with
Vilsmeier reagent.10 Becher et al. showed that vicinal chloro-pyr-
role-carboxaldehydes could be prepared by chloroformylation of
arylpyrrol-5-ones.11
The starting materials for our work, 1,3-diaryl-5-oxopyrrolidin-
2-carboxylic acids 1, were synthesized following the general
method12,8 developed in our laboratory. We selected N-aryl-5-oxo-
3-aryl/heteroaryl-pyrrolidine-2-carboxylic acids and treated this
compound with Vilsmeier reagent (POCl3/DMF or PBr3/DMF) in
CHCl3 to get the N-aryl-5-chloro/bromo-3-aryl/heteroaryl-pyrrole-
2,4-dicarbaldehyde derivatives 2 in good yield (Scheme 1, Table 1).
It was very difficult to perform the Vilsmeier reaction on the
lactam carbonyl group, as it behaves like amide. However in above
synthesized from N-aryl-
c
-lactam carboxylic acid derivatives by
cases we saw that the presence of an acid functionality in N-aryl-c-
the successive treatment of NaBH4–I2 in THF and DDQ in benzene
in two-step process.8 Herein, we report a conceptually new syn-
thetic approach to tetra- and penta-substituted pyrroles utilizing
lactams at C-2 favors the lactam carbonyl group to react with
Vilsmeier reagent on
c-lactam carboxylic acid derivatives. In
R1
R1
1993 Balasundaram et al. have reported that N-glycine on treat-
ment with Vilsmeier reagent at 90 °C led to the formation of
diformylated product namely 2,4-dichloro-3,5-diformylpyrrole in
good yield (82%)9 but the procedure has some limitation. When
they subjected N-acetyl amino acids like valine, leucine, and glu-
tamic acids to Vilsmeier reagent at 80–90 °C, all these compounds
gave mono formylated products namely 2-formylmethylene-4-
R2
R2
R3
POCl3 /DMF
CHO
or
COOH
Ar/
R3
N
PBr3/DMF
N
Ar/
X
O
CHO
2
1
* Corresponding author. Tel.: +91 3222 283326; fax: +91 3222 282252.
E-mail address: jkray@chem.iitkgp.ernet.in (J.K. Ray).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.005

298
G. Barman, J. K. Ray / Tetrahedron Letters 51 (2010) 297–300
Table 1
Table 2
Synthesis of N-aryl-bisformylated pyrrole 2 from
c
-lactam-2-carboxylic acids 1a
Synthesis of N-aryl-bisformylated pyrrole (4) from c
-lactam-3-carboxylic acids (3)a
Substrate
N-Aryl-
Ar0
X
Products
N-Aryl-
Yield (%)
Substrate
N-Aryl-
X
Products
N-Aryl-
Yield (%)
c
-
c
-
lactam-2-
carboxylic
acid
bisformylated
pyrrole
lactam-3-
carboxylic
acid
bisformylated
pyrrole
1a
1b
1c
1d
1e
1f
R
R
R
R
1 = R3 = H, R2 = Cl Phenyl
1 = R3 = H, R2 = Cl Phenyl
1 = R3 = H, R2 = Br Phenyl
Cl 2a
Br 2b
Cl 2c
Cl 2d
Cl 2e
92
80
83
80
90
76
3a
3b
3c
3d
3e
R
R
R
R
1 = H, R2 = Cl
1 = H, R2 = OCH3
1 = H, R2 = Br
1 = R2 = Cl
Cl
Cl
Cl
Cl
Br
4a
4b
4c
4d
4e
87
83
70
79
70
1 = H, R3 = R2 = F
Phenyl
Phenyl
2-Thienyl Cl 2f
R1 = R3 = R2 = H
R1 = H, R2 = Br
R
R
1 = Cl, R2 = F,
3 = H
a
Reagents and conditions: All the reactions were carried out with 6 equiv of DMF
R1 = Cl, R2 = F,
2-Thienyl Br 2g
76
78
and 6 equiv of POCl3 or PBr3 in anhydrous CHCl3 (10 mL) at 0 °C, then after stirring
for 40 min 1 equiv of compounds was added by dissolving in CHCl3 and the
resulting mixture was refluxed at 80–90 °C for 3–8 h.
1g
1h
R
R
3 = H
1 = H, R3 = R2 = Cl Phenyl
Cl 2h
a
Reagents and conditions: All the reactions were carried out with 6 equiv of DMF
and 6 equiv of POCl3 or PBr3 in anhydrous CHCl3 (10 mL) at 0 °C, then after stirring
for 40 min 1 equiv of compounds was added by dissolving in CHCl3 and the
resulting mixture was refluxed at 80–90 °C for 3–8 h.
R2
R2
POCl3/DMF
CHO
R1
or
N
R1
N
PBr3/DMF
R2
O
R2
R1
X
CHCl
POCl3/DMF
CHO
CHO
COOH
5
or
R1
PBr3/DMF
N
4
N
X
3
COOH
Scheme 3.
O
CHO
4
3
poor yield (Scheme 6). In this case the starting materials mostly re-
main unchanged under the reaction conditions.
Scheme 2.
Are the intermediates of the types 6 and 7 actually formed in
the reaction mixture and then it undergoes the Vilsmeier reaction
to form the bisformylated pyrrole derivatives? To prove this, we
performed the Vilsmeier reaction on a lactam derivatives (8) and
surprisingly here also we isolated the same bisformylated pyrrole
derivatives (2) (Table 4, Scheme 7). This is a strong proof in favor
of the proposed mechanism as depicted in Schemes 4–6.
The lactam derivative 1,4-diphenyl-1,5-dihydropyrrole-2-one
(8) has been prepared from trans-5-hydroxy-1,4-diarylpyrrolidin-
2-ones (9)15 by treatment with InCl3 or ZnCl2 in refluxing CH3CN
(Scheme 8).16
We also verify the effect of N-substituted phenyl ring on lactam
derivatives to undergo the Vilsmeier reaction and in the absence of
the N-substituted phenyl ring under the same conditions the reac-
tion does not occur. Thus the lactam derivatives 10 remain un-
changed under the reaction conditions (Scheme 9).
Vilsmeier reagent. To further examine the generality of the reac-
tion we chose the -lactams with varied position of the acid group.
These lactam carboxylic acid derivatives were then subjected to
Vilsmeier reaction condition and observed that the results were
in conformity with the previous observations.
c
Thus N-aryl-5-oxo-pyrrolidine-3-carboxylic acids (3) were re-
fluxed with Vilsmeier reagent in CHCl3 and we isolated the N-
aryl-5-chloro/bromo-pyrrole-2,4-dicarbaldehyde (4) in good yields
(Scheme 2, Table 2).13
But, the N-aryl-2-oxo-pyrrolidine-3-carboxylic acids8 (5) with
Vilsmeier reagent produce the N-aryl-5-chloro/bromo-pyrrole-
2,4-dicarbaldehyde (4) in very poor yield (10–15%) after a long per-
iod of heating (Scheme 3, Table 3).
In all the above cases we saw that the lactam carbonyl group
participate in Vilsmeier reaction and the compounds were con-
verted to the bisformylated pyrrole derivatives that is, decarboxy-
lative bisformylation occurred along with aromatization at the
same reaction conditions. The above-mentioned observation and
literature survey9,14 have led us to propose a plausible mechanism
of the above said reactions (Scheme 4).
In conclusion, we have disclosed that N-aryl-bisformylated-pyr-
roles can be prepared from c-lactam-carboxylic acids by the reac-
tion with Vilsmeier reagent in one-step process with good yields.
Thus this demonstrates that the Vilsmeier reagent can be used
The lone pair of nitrogen atom helps for the decarboxylation
and the intermediate 6 is formed, which is then bisformylated
and converted to aromatic bisformylated pyrrole derivatives.
But for the lactam carboxylic acid derivatives 3 and 5 where the
acid groups are not at the carbon atom vicinal to nitrogen atom, the
decarboxylation occurs but not via the involvement of lone pair of
Table 3
Synthesis of N-aryl-bisformylated pyrrole 4 from c
-lactam-3-carboxylic acids 5a
Substrate
N-Aryl-
lactam-3-
carboxylic
acid
X
Products
N-Aryl-
Yield (%)
c
-
bisformylated
pyrrole
nitrogen atom. In case of acid 3 the a-hydrogen atom of lactam car-
bonyl group takes part for decarboxylation and intermediate 7 is
formed and by the same mechanistic pathway we got the bis-
formylated products (Scheme 5).
However in case of acid 5 due to less acidity of b-hydrogen
atoms the intermediate 7 is formed in very small amount in the
reaction mixture and we obtain the bisformylated pyrrole in very
5a
5b
R1 = H, R2 = Cl
R1 = H, R2 = OCH3
Cl
Cl
4a
4b
10
15
a
Reagents and conditions: All the reactions were carried out with 6 equiv of DMF
and 6 equiv of POCl3 or PBr3 in anhydrous CHCl3 at 0 °C, stirred for 40 min then
1 equiv of compounds was added by dissolving in CHCl3 and the resulting mixture
was refluxed at 80–90 °C for 3–8 h.

G. Barman, J. K. Ray / Tetrahedron Letters 51 (2010) 297–300
299
Scheme 4.
Table 4
Ar
O
.
.
Ar
O
Synthesis of N-aryl-bisformylated pyrrole 2 from 1,4-diphenyl-1,5-dihydro-pyrrole-
N
N
POCl2
2-one 8a
POCl3
COOH
O
CO2
-
Substrate
Ar0
Products
N-Aryl-
bisformylated
pyrrole
Yield (%)
C
H
3
H
O
1,4-Diphenyl-
1,5-dihydro-
pyrrole-2-one
Ar
CHO
Ar
N
N
Vilsmeier reagent
8a
8b
8c
8d
8e
R1 = R3 = R2 = H
Phenyl
2a
2b
2c
2d
87
76
70
80
76
R1 = H, R3 = Cl, R2 = F Phenyl
Cl
O
R1 = R3 = H, R2 = Br
R1 = H, R3 = R2 = F
Phenyl
Phenyl
7
CHO
R1 = Cl, R2 = F, R3 = H 2-Thienyl 2f
Scheme 5.
a
Reagents and conditions: All the reactions were carried out with 6 equiv of DMF
and 6 equiv of POCl3 or PBr3 in anhydrous CHCl3 at 0 °C, stirred for 40 min then
1 equiv of compounds was added by dissolving in CHCl3 and the resulting mixture
was refluxed at 80–90 °C for 3–8 h.
Ar
Ar
O
N
H
H
O
N
POCl3
CO
R1
O
H
-
2
C
O
R2
R3
R1
COOH
5
OPCl2
R2
R3
CHO
Ar
N
Ar
O
CHO
Ar
N
N
Vilsmeier reagent
/
N
X
Cl
/
CHCl3
Ar
OHC
O
7
CHO
X- Cl or Br
8
2
in small amount
Scheme 6.
Scheme 7.

300
G. Barman, J. K. Ray / Tetrahedron Letters 51 (2010) 297–300
Int. Ed. 2003, 42, 2681; (g) Shiraishi, H.; Nishitani, T.; Sakaguchi, S.; Ishii, Y. J.
R1
R1
Org. Chem. 1998, 63, 6234; (h) Gorin, D. J.; Davis, N. R.; Toste, D. F. J. Am. Chem.
Soc. 2005, 127, 11260; (i) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem.
Soc. 2001, 123, 2074; (j) Declerk, V.; Ribiere, P.; Martinez, J.; Lamaty, F. J. Org.
Chem. 2004, 69, 8372; (k) Kamijo, S.; Kanazawa, C.; Yamamoto, Y. J. Am. Chem.
Soc. 2005, 127, 9260; (l) Larionov, O. V.; de Meijere, A. Angew. Chem., Int. Ed.
2005, 44, 5664.
R2
R3
R2
R3
OH
InCl3/ ZnCl2
CH3CN
N
N
/
Ar
O
/
8. Haldar, P.; Barman, G.; Ray, J. K. Tetrahedron 2007, 63, 3049.
9. (a) Balasundaram, B.; Venugopal, M.; Perumaf, P. T. Tetrahedron Lett. 1993, 34,
4249; (b) Zaytsev, A. V.; Anderson, R. J.; Meth-Cohn, O.; Groundwater, P. W.
Tetrahedron 2005, 61, 5831.
O
Ar
9
8
Scheme 8.
10. Mahato, K. T.; Pan, D.; Mal, K. S.; Ray, J. K. J. Indian Chem. Soc. 2003, 80, 969.
11. Becher, J.; Jmgensen, P. L.; Pluta, K.; Krake, N. J.; Fat-Hansen, B. J. Org. Chem.
1992, 57, 2127–2134.
12. (a) Ray, J. K.; Kar, G. K.; Roy, B. C.; Brahma, N. K. Bioorg. Med. Chem. 1994, 2,
1417; (b) Ray, J. K.; Kar, G. K.; Adhikari, S. D.; Ray, J. K.; Brahma, N. K. Bioorg.
Med. Chem. 1998, 6, 2397–2403.
POCl3/DMF
13. General procedure for the synthesis of bisformylated pyrroles (2) and (4).
or
CHO
Ar
H
X
General procedure for the synthesis of bisformylated pyrroles (2b) from
lactam-carboxylic acids (1b).
To a flask containing DMF (5 mmol) in anhydrous CHCl3 (10 mL) at 0 °C POCl3
or PBr3 (5 mmol) was added drop by drop and the resulting mixture was stirred
for 40 min at room temp (25 °C). The reaction mixture was then cooled down
c-
PBr3/DMF
COOH
H
N
N
/
CHCl3
No reaction
/
O
Ar
to 0 °C and
a solution of c-lactam-carboxylic acids (1 mmol, 0.316 g) in
CHO
X= Cl, Br
chloroform (10 mL) was added drop-wise. The resulting reaction mixture was
refluxed at 80–90 °C for 3–8 h (monitored by TLC) and then cooled to room
temperature. The reaction mixture was then poured into ice-cold water and
solid sodium bicarbonate was carefully added to neutralize the acids and the
mixture was extracted several times (3–4 times) with 10 mL dichloromethane.
The organic part was then washed with cold water thoroughly, dried with
anhydrous sodium sulfate, and evaporated. Purification of the residue was
done by silica gel (60–120 mesh) column chromatography [petroleum ether
(60–80 °C)–ethylacetate (20:1)].
10
Scheme 9.
for decarboxylation as well as formylating reagent. These N-aryl-
bisformylated-pyrroles can be used for the synthesis of pyrrole
core bioactive products.
Physical properties and spectral data of representative compounds.
Compound 2b, 1-(4-chlorophenyl)-3-phenyl-5-bromopyrrole-2,4-dicarbalde-
hyde.
Light yellow viscous liquid, 1H NMR (CDCl3, 200 MHz) d: 7.19–7.28 (m, 2H),
7.48 (s, 6H), 7.49–7.60 (m, 1H), 9.32 (s, 1H), 9.90 (s, 1H); 13C NMR (CDCl3,
50 MHz) d: 121.09, 121.61, 128.50 (2C), 128.75, 129.11 (2C), 129.23 (2C),
129.63 (2C),130.95 (2C), 135.34, 135.95, 140.12, 178.71, 185.06. Anal. Calcd for
C18H11BrClNO2: C, 55.63; H, 2.85; N, 3.60. Found: C, 55.75; H, 3.02; N, 3.45.
Compound 4b, 1-(p-methoxy)-5-chloropyrrole-2,4-dicarbaldehyde.
Light yellow solid; mp 128–131 °C. 1H NMR (CDCl3, 200 MHz) d: 3.87 (s, 3H),
6.97–7.06 (m, 2H), 7.23–7.30 (m, 2H), 7.47 (s, 1H), 10.17 (s, 1H), 10.29 (s, 1H);
13C NMR (CDCl3, 100 MHz) d: 55.69, 114.83 (2C), 120.19, 124.37, 127.45 (2C),
127.96, 128.29, 128.60, 160.52, 185.33, 186.25. Anal. Calcd for C13H10ClNO2: C,
59.22; H, 3.82; N, 5.31. Found: C, 58.79; H, 3.68; N, 5.31.
Acknowledgments
Financial support from DST and CSIR (New Delhi) is gratefully
acknowledged.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.11.005.
14. Marson, C. M. Tetrahedron 1992, 48, 3659–3726.
15. (a) Haldar, P.; Ray, J. K. Tetrahedron Lett. 2008, 49, 3659–3662; (b) Barman, G.;
Roy, M.; Ray, J. K. Tetrahedron Lett. 2008, 49, 1405.
16. General procedure for the synthesis of 1,4-diphenyl-1,5-dihydro-pyrrole-2-one
derivatives (8e).
References and notes
1. (a) Sundberg, R. J.. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.,
Rees, C. W., Scriven, E. F. V., Eds.; Elsevier: Oxford, UK, 1996; Vol. 2, p 119; (b)
O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435; (c) Jendralla, H.; Baader, E.; Bartmann,
W.; Beck, G.; Bergmann, A.; Granzer, E.; Kerekjarto, B. v.; Kesseler, K.; Krause,
R.; Schubert, W.; Wess, G. J. Med. Chem. 1990, 33, 61.
2. Lee, C.-F.; Yang, L.-M.; Hwu, T.-Y.; Feng, A.-S.; Tseng, J.-C.; Luh, T.-Y. J. Am. Chem.
Soc. 2000, 122, 4992.
3. (a) Muchowski, J. M. Adv. Med. Chem. 1992, 1, 109; (b) Cozzi, P.; Mongelli, N.
Curr. Pharm. Des. 1998, 4, 181; (c) Furstner, A.; Szillat, H.; Gabor, B.; Mynott, R. J.
Am. Chem. Soc. 1998, 120, 8305.
4. Knorr, L. Chem. Ber. 1884, 17, 1635.
5. Paal, C. Chem. Ber. 1885, 18, 367.
6. Hantzsch, A. Ber. Dtsch. Chem. Ges. 1890, 23, 1474.
7. (a) Balme, G. Angew. Chem., Int. Ed. 2004, 43, 6238; (b) Nair, V.; Vinod, A. U.;
Rajesh, C. J. Org. Chem. 2001, 66, 4427; (c) Bharadwaj, A. R.; Scheidt, K. A. Org.
Lett. 2004, 6, 2465; (d) Tejedor, D.; Gonzalez-Cruz, D.; Garcia-Tellado, F.;
Marrero-Tellado, J. J.; Rodriguez, M. L. J. Am. Chem. Soc. 2004, 126, 8390; (e)
Braun, R. U.; Zietler, K.; Mu€ller, T. J. J. Org. Lett. 2001, 3, 3297; (f) Nishibayashi,
Y.; Yoshikawa, M.; Inada, Y.; Milton, M. D.; Hidai, M.; Uemura, S. Angew. Chem.,
To a flask containing 1-(3-chloro-4-fluoro-phenyl)-5-hydroxy-4-(2-thienyl)-
pyrrolidine-2-one (1 mmol, 0.3 g) in acetonitrile, (10 mL) catalytic amount of
InCl3 or ZnCl2 was added. The resulting mixture was refluxed for 6–8 h
(monitored by TLC) and then cooled to room temperature. The solvent was
evaporated under reduced pressure and the residue was extracted with 20 mL
CH2Cl2. The combined organic layer was washed with brine. After drying the
organic layer with anhydrous Na2SO4, the solvent was evaporated under
reduced pressure. The product thus obtained was purified by silica gel (60–120
mesh) column chromatography [petroleum ether (60–80 °C)–ethylacetate
(18:1)].
Compound 8e, 1-(3-chloro-4-fluoro-phenyl)-4-(2-thienyl)-1,5-dihydro-pyr-
role-2-one.
Yellow viscous liquid; 1H NMR (CDCl3, 200 MHz) d: 4.73 (d, J = 1.2 Hz, 2H), 6.32
(s, 1H), 7.03–7.15 (m, 2H), 7.19–7.35 (m, 1H), 7.49 (dd, J = 1, 5 Hz, 1H) 7.6–7.68
(m, 1H), 7.84 (dd, J = 2.6, 6.4 Hz, 1H); 13C NMR (CDCl3, 50 MHz) d: 53.05,
116.97, 117.22, 118.11, 118.24, 119.30, 120.64, 126.41, 127.13, 128.34, 134.82,
135.75, 147.70, 170.09 Anal. Calcd for C14H9ClFNOS: C, 57.24; H, 3.09; N, 4.77.
Found: C, 56.66; H, 3.30; N, 4.97.