A facile synthesis of diformylated pyrroles by dehydroxylation of N-aryl-5-hydroxy-γ-lactam derivatives under Vilsmeier reaction conditions

Article abstract of DOI:10.1007/s10593-015-1789-z

A simple and efficient methodology for the conversion of substituted trans-1,4-diaryl-5-hydroxypyrrolidin-2-ones to diformylated N-arylpyrroles by treatment with Vilsmeier-Haack reagent has been developed.

Full text of DOI:10.1007/s10593-015-1789-z

DOI 10.1007/s10593-015-1789-z
Chemistry of Heterocyclic Compounds 2015, 51(10), 869–871
Dedicated to Professor Jayanta Kumar Ray (Department of Chemistry, Indian Institute of Technology)
A facile synthesis of diformylated pyrroles
by dehydroxylation of N-aryl-5-hydroxy-γ-lactam derivatives
under Vilsmeier reaction conditions
Gopa Barman1*
1 Department of Chemistry, Berhampore Girls' College,
Berhampore 742101, India; e-mail: gopathesis@gmail.com
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2015, 51(10), 869–871
Submitted July 22, 2015
Accepted October 18, 2015
A simple and efficient methodology for the conversion of substituted trans-1,4-diaryl-5-hydroxypyrrolidin-2-ones to diformylated
N-arylpyrroles by treatment with Vilsmeier–Haack reagent has been developed.
Keywords: trans-1,4-diaryl-5-hydroxypyrrolidin-2-ones, aromaticity, dehydroxylation, Vilsmeier–Haack reagent.
Pyrroles and their derivatives are one of the most
important classes of heterocyclic compounds.1 They exhibit
diverse biological and pharmacological properties.2 Highly
functionalized pyrroles are subunits of considerable impor-
tance in heme, chlorophyll, bile pigments, vitamin B12,
and marine-derived pyrrole alkaloids.3 Since Knorr
reported the first synthesis of pyrroles,4 a lot of papers have
been published on the synthesis of substituted pyrroles.5
Although these methods provide efficient ways to construct
pyrrole cycle, it is still necessary to develop novel and
alternative methodologies so that the substitution patterns
of these important heterocyclic compounds can be
expanded.
γ-Lactams are N-containing five-membered heterocycles
and very attractive cyclic systems because they are present
in wide range of natural and nonnatural biologically active
molecules and drug candidates.1b Modification of lactam
cycle has been playing a vital role in determining the bio-
logical activities of these derivatives. Therefore, attempts
to develop new methodologies for the synthesis of
differently substituted N-heterocycles from γ-lactam
derivatives are of considerable interest from the standpoint
of the medicinal and organic chemistry. As I have reported
recently, tetra- and pentasubstituted pyrroles can be
synthesized by applying the Vilsmeier–Haack reagent to
N-aryl-γ-lactam carboxylic acid derivatives.6 The Vilsmeier–
Haack reagent is an efficient, economical, and mild reagent
for the formylation of reactive aromatic and heteroaromatic
substrates.7 It is now used as a powerful synthetic tool for
the construction of many heterocyclic compounds.8
As a part of my continued interest in conversion of
γ-lactam derivatives to other N-heterocycles9 I initiated an
investigation to find applications of the Vilsmeier–Haack
reagent to different transformations of N-aryl-γ-lactams,
and herein I wish to report on the feasibility of the
formation of N-arylformylpyrroles together with the
experimental and spectral details of my earlier results.6
I have selected trans-1,4-diaryl-5-hydroxypyrrolidin-
2-ones 1a–h as starting compounds and treated them with
Vilsmeier–Haack reagent (POCl3–DMF or PBr3–DMF) in
CHCl3, thus obtaining N-aryl-5-chloro(bromo)-3-aryl-
(hetaryl)pyrrole-2,4-dicarbaldehyde derivatives 2a–h in
good yields (Scheme 1, Table 1).
It was very difficult to perform the Vilsmeier–Haack
reaction on the γ-lactam carbonyl group, as the carbonyl
group of N-aryl-γ-lactam derivatives behaves like amide
carbonyl functionality. However, presence of an acid
functionality in N-aryl-γ-lactam ring at any position favors
the lactam carbonyl group to react with Vilsmeier–Haack
reagent.6 Here it is reported that the presence of a hydroxyl
group in lactam ring at position 2 favors the reaction of the
lactam carbonyl group with Vilsmeier–Haack reagent. It
was reasonable to hope that Vilsmeier–Haack reagent may
bring about dehydroxylation along with oxidative aroma-
tization of N-substituted pyrrolidin-2-one to produce the cor-
responding N-aryl-3,5-diformylpyrrole in one-step process.
From the literature survey one can see that γ-lactam
derivatives undergo the Vilsmeier–Haack reaction to form
diformylated pyrrole derivatives through the formation of
1,4-diaryl-1,5-dihydropyrrol-2-ones as intermediates.6 One can
0009-3122/15/5110-0869©2015 Springer Science+Business Media New York
869

Chemistry of Heterocyclic Compounds 2015, 51(10), 869–871
Scheme 1
Experimental
1H NMR spectrum of compound 2c and 13C NMR
spectra of compounds 2a,c,e were recorded on a Bruker
AC 400 spectrometer (400 and 100 MHz, respectively).
1H and 13C NMR spectra of remaining compounds were
recorded on a Bruker AC 200 spectrometer (200 and
50 MHz, respectively). Solvent – CDCl3, internal standard –
signal of the solvent (7.26 ppm for 1H nuclei, 77.0 ppm for
13C nuclei). 13C NMR spectra were recorded with complete
proton decoupling. Elemental analyses were performed on
CHN Analyzers. Chromatographic purification was
performed on a column with 60–120 mesh silica gel (SRL),
eluent petroleum ether (bp 60–80°C) – EtOAc, 40:1. For
reaction monitoring, precoated silica gel 60 F254 TLC
sheets (Merck) were used.
Table 1. Yields of diformylated N-arylpyrroles 2a–h
Com-
pound
Reaction Yield,
R
R1
R2
R3
X
time, h
3.0
%
78
82
77
79
80
78
81
76
Ph
Ph
H
H
H
Cl
Cl
H
H
H
Cl
Cl
H
F
H
H
H
H
H
Cl
H
F
Cl
Br
Cl
Cl
Br
Cl
Cl
Cl
2a
2b
2c
2d
2e
2f
4.5
The
starting
trans-1,4-diaryl-5-hydroxypyrrolidin-
Ph
5.0
2-ones 1a–h were synthesized by the known method.10
DMF used in the experiments was dried, distilled, and
stored over molecular sieves (4 Å). All reactions were
carried out with access of air.
2-Thienyl
2-Thienyl
Ph
5.5
F
6.0
Cl
Br
F
4.5
Synthesis of diformylated pyrroles 2a–h (General
method). POCl3 or PBr3 (5 mmol) was added dropwise to a
flask containing DMF (0.39 ml, 5 mmol) in anhydrous
CHCl3 (10 ml) at 0°C, and the resulting mixture was stirred
for 40 min at 25°C. Then the reaction mixture was cooled
again to 0°C, and a solution of trans-1,4-diaryl-5-hydroxy-
pyrrolidin-2-one 1a–h (1 mmol) in CHCl3 (10 ml) was
added dropwise. The resulting reaction mixture was
refluxed for 3–8 h (monitored by TLC), then cooled to
room temperature and poured into ice-cold water. Solid
NaHCO3 was carefully added to neutralize the acids, and the
mixture was extracted several times with CH2Cl2. The
combined organic extract was washed with cold water
thoroughly, dried over Na2SO4, and evaporated. Purification of
the residue was done by column chromatography. The obtained
products 2a–h are light-yellow viscous dense liquids.
Ph
5.0
2g
2h
Ph
8.0
also suppose that 1,4-diaryl-1,5-dihydropyrrol-2-one B (B')
would be formed as an intermediate and the reaction would
proceed along the mechanistic pathway proposed in Scheme 2,
resulting in the formation of the diformylated pyrrole 2.
The Vilsmeier–Haack reaction is widely used for formy-
lations and can be applied to introduce an aldehyde group into
activated aromatic compounds, but here it has been shown that
conversions of saturated heterocycles to corresponding
aromatic heterocycles can be achieved with this method.
All the compounds were characterized by spectroscopic
(1H and 13C NMR) and analytical data
In conclusion, I have demonstrated that trans-1,4-diaryl-
5-hydroxypyrrolidin-2-ones can be converted to diformylated
N-arylpyrroles with good yields in one-step process by reaction
with Vilsmeier–Haack reagent. The reagent system used is
safe, simple, and inexpensive, so the operational simplicity and
economic viability of this method will likely broaden the
perspective of further study in this field.
5-Chloro-1-(4-chlorophenyl)-3-phenylpyrrole-2,4-di-
1
carbaldehyde (2a). H NMR spectrum, δ, ppm (J, Hz):
7.24–7.26 (2H, d, J = 8.0, H Ar); 7.48–7.52 (7H, m, H Ar);
9.38 (1H, s, CHO); 9.88 (1H, s, CHO). 13C NMR spectrum,
δ, ppm: 120.7; 122.0; 125.3; 128.1; 128.5 (2C); 128.6;
128.7 (2C); 129.2; 129.6 (2C); 130.9 (2C); 133.9; 135.9
Scheme 2
870

Chemistry of Heterocyclic Compounds 2015, 51(10), 869–871
(C Ar); 178.7 (CHO); 184.7 (CHO). Found, %: C 62.66;
CHO); 9.89 (1H, s, CHO). 13C NMR spectrum, δ, ppm: 117.4;
117.5; 117.8; 118.1; 118.9; 124.30; 124.34; 128.6 (2C); 128.8;
129.4 (2C); 130.9 (2C); 132.5; 139.7 (C Ar); 178.7 (CHO);
184.4 (CHO). Found, %: C 62.12; H 3.20; N 4.20.
C18H10ClF2NO2. Calculated, %: C 62.53; H 2.92; N 4.05.
H 3.59; N 4.26. C18H11Cl2NO2. Calculated, %: C 62.81;
H 3.22; N 4.07.
5-Bromo-1-(4-chlorophenyl)-3-phenylpyrrole-2,4-di-
1
carbaldehyde (2b). H NMR spectrum, δ, ppm: 7.19–7.28
(2H, m, H Ar); 7.42–7.49 (6H, m, H Ar); 7.49–7.60 (1H,
m, H Ar); 9.32 (1H, s, CHO); 9.90 (1H, s, CHO). 13C NMR
spectrum, δ, ppm: 121.1; 121.6; 128.5 (2C); 128.8; 129.1
(2C); 129.2 (2C); 129.6 (2C); 131.0 (2C); 135.3; 136.0;
140.1 (C Ar); 178.7 (CHO); 185.1 (CHO). Found, %:
C 55.75; H 3.02; N 3.45. C18H11BrClNO2. Calculated, %:
C 55.63; H 2.85; N 3.60.
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1H NMR spectrum, δ, ppm: 7.31–7.34 (2H, m, H Ar); 7.49
(5H, s, H Ar); 7.54–7.58 (3H, m, H Ar); 9.40 (1H, s,
CHO); 9.90 (1H, s, CHO). 13C NMR spectrum, δ, ppm:
118.6; 127.5 (2C); 128.4 (2C); 128.8; 129.1; 129.3 (2C);
129.8; 130.9 (2C); 132.3; 135.4; 139.2 (C Ar); 178.7
(CHO); 184.6 (CHO). Found, %: C 69.43; H 3.80; N 4.30.
C18H12ClNO2. Calculated, %: C 69.80; H 3.90; N 4.52.
5-Chloro-1-(3-chloro-4-fluorophenyl)-3-(2-thienyl)-
pyrrole-2,4-dicarbaldehyde (2d). 1H NMR spectrum,
δ, ppm (J, Hz): 7.13–7.20 (2H, m, H Ar); 7.33–7.37 (1H, m,
H Ar); 7.52 (1H, dd, J = 1.2, J = 5.2, H Ar); 7.98 (2H, s, H Ar);
9.55 (1H, s, CHO); 9.96 (1H, s, CHO). 13C NMR spectrum,
δ, ppm: 117.5; 119.1; 127.6; 127.8 (2C); 128.3; 128.9 (2C);
129.4; 130.1; 131.2 (2C); 131.7; 135.6 (C Ar); 178.6 (CHO);
184.2 (CHO). Found, %: C 52.00; H 2.50; N 3.95.
C16H8Cl2FNO2S. Calculated, %: C 52.19; H 2.19; N 3.80.
5-Bromo-1-(3-chloro-4-fluorophenyl)-3-(2-thienyl)-
pyrrole-2,4-dicarbaldehyde (2e). 1H NMR spectrum,
δ, ppm (J, Hz): 7.15–7.21 (2H, m, H Ar); 7.24–7.26 (2H,
m, H Ar); 7.34–7.37 (1H, m, H Ar); 7.54 (1H, dd, J = 1.2,
J = 5.2, H Ar); 9.50 (1H, s, CHO); 9.95 (1H, s, CHO).
13C NMR spectrum, δ, ppm: 117.1; 117.3; 128.0 (2C);
128.1; 128.8 (2C); 129.4 (2C); 129.8 (2C); 130.1; 130.3;
130.5 (C Ar); 178.4 (CHO); 184.7 (CHO). Found, %:
C 46.20; H 2.12; N 3.03. C16H8BrClFNO2S. Calculated, %:
C 46.57; H 1.95; N 3.39.
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5-Chloro-1-(3,4-dichlorophenyl)-3-phenylpyrrole-2,4-
1
dicarbaldehyde (2f). H NMR spectrum, δ, ppm (J, Hz):
7.19 (1H, dd, J = 2.4, J = 8.6, H Ar); 7.44–7.53 (6H, m,
H Ar); 7.62 (1H, d, J = 8.4, H Ar); 9.39 (1H, s, CHO); 9.89
(1H, s, CHO). 13C NMR spectrum, δ, ppm: 117.1; 117.3;
117.9; 118.1; 118.2; 118.9; 127.6 (2C); 127.7 (2C); 128.5
(2C); 129.3; 130.0; 130.8 (2C, C Ar); 178.7 (CHO); 184.3
(CHO). Found, %: C 56.73; H 2.81; N 4.09. C18H10Cl3NO2.
Calculated, %: C 57.10; H 2.66; N 3.70.
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1-(4-Bromophenyl)-5-chloro-3-phenylpyrrole-2,4-di-
1
carbaldehyde (2g). H NMR spectrum, δ, ppm (J, Hz):
7.20 (2H, dd, J = 6.6, J = 1.8, H Ar); 7.26–7.48 (5H, m,
H Ar); 7.67 (2H, dd, J = 6.6, J = 1.8, H Ar); 9.39 (1H, s,
CHO); 9.89 (1H, s, CHO). 13C NMR spectrum, δ, ppm:
118.9; 124.1; 128.5 (2C); 128.7; 128.8; 129.2 (2C); 129.3;
130.9 (2C); 132.3; 132.6 (2C); 134.5; 139.6 (C Ar); 178.8
(CHO); 184.4 (CHO). Found, %: C 55.60; H 3.17; N 3.49.
C18H11BrClNO2. Calculated, %: C 55.63; H 2.85; N 3.60.
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1
dicarbaldehyde (2h). H NMR spectrum, δ, ppm (J, Hz):
7.07–7.15 (1H, m, H Ar); 7.19 (1H, s, H Ar); 7.24 (1H, d,
J = 2.4, H Ar); 7.32–7.49 (5H, m, H Ar); 9.39 (1H, s,
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871