Sodium borohydride-iodine mediated reduction of γ-lactam carboxylic acids followed by DDQ mediated oxidative aromatisation: a simple approach towards N-aryl-formylpyrroles and 1,3-diaryl-formylpyrroles

Article abstract of DOI:10.1016/j.tet.2007.01.058

A simple methodology for the conversion of substituted N-aryl-γ-lactam 2/3-carboxylic acids to substituted N-aryl-2/3-formyl-pyrroles has been developed. Several N-aryl-γ-lactam 2/3-carboxylic acids were reduced to substituted (N-aryl-pyrroliden-2/3-yl)-m

Full text of DOI:10.1016/j.tet.2007.01.058

Tetrahedron 63 (2007) 3049–3056
Sodium borohydride–iodine mediated reduction of g-lactam
carboxylic acids followed by DDQ mediated oxidative
aromatisation: a simple approach towards N-aryl-
formylpyrroles and 1,3-diaryl-formylpyrroles
*
Pranab Haldar, Gopa Barman and Jayanta K. Ray
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, West Bengal, India
Received 26 September 2005; revised 11 January 2007; accepted 25 January 2007
Available online 30 January 2007
Abstract—A simple methodology for the conversion of substituted N-aryl-g-lactam 2/3-carboxylic acids to substituted N-aryl-2/3-formyl-
pyrroles has been developed. Several N-aryl-g-lactam 2/3-carboxylic acids were reduced to substituted (N-aryl-pyrroliden-2/3-yl)-methanols
in good yields by using the NaBH4–I2 system. Aromatisation and in situ oxidation of these alcohols using DDQ produced N-aryl-2/3-formyl-
pyrroles, which act as key starting material and intermediates in the synthesis of several bioactive compounds.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
N
N
N
F
F
F
MeO2S
The pyrrole ring constitutes a basic heteroaromatic structure.
Some substituted pyrroles are highly biologically active
compounds, which make up an important class of synthetic
pharmaceuticals1a and natural products with fungicidal1b
and insecticidal1c activities. They also constitute the vital
building blocks of the porphyrin ring systems present in
chlorophyll, haeme, vitamin B12 and the bile pigments.2
Additionally, there are a number of pyrrole-containing small
molecules that exhibit interesting biological activities,3a–d
for example, 3-substituted N-arylpyrroles act as potent
aldose reductase (AR) inhibitors.3e
SO2NH2
SO2Me
ii
i
iii
HIV-1 protease inhibitors with an N-aryl-pyrrole-containing
moiety in the P3 position I have excellent antiviral potency
with improved aqueous solubility.7 3-(1H-Pyrrol-1-yl)-2-
oxazolidinones II show antimycobacterial activity,8 and
N-phenyl-3-(aminomethyl)-pyrroles III act as potential
antipsychotic agents.9 In all cases (Fig. 1) the key synthetic
intermediate was 3-formyl-N-phenyl pyrrole IV.7–9 Gener-
ally N-arylpyrroles were prepared by the Clauson-Kaas reac-
tion with 2,5-dimethoxytetrahydrofuran in refluxing acetic
acid from commercially available anilines. But the reaction
of pyrrole with the Vilsmeir reagent gave a mixture of 2-
formyl-1-arylpyrroles and 3-formyl-1-aryl-pyrroles. Among
them most 3-substituted arylpyrroles showed a higher 5-HT7
affinity than the 2-substituted compounds.10
Among the substituted pyrroles, mono- and bi-arylpyrrole
derivatives are of special interests to both chemists as well
as biologists due to their remarkable bioactivities.4 1,5-Di-
arylpyrrole-3-acetic acids and esters act as potent and highly
selective cyclooxygenase-2 inhibitors.5
1,2-Diarylpyrrole i is an excellent inhibitor of COX-2 with an
IC50 of 14 nm. Pyrrole iii is also a very potent (COX-2, IC50¼
60 nm) and selective (COX-1/COX-2>1700) inhibitor.
Similarly, pyrrole ii inhibited COX-2 with an IC50¼0.5 mm
while showing no inhibition of COX-1 at 100 mM.6
Although there are a number of potentially useful methods
for the synthesis of N-arylpyrroles, 3-substituted N-arylpyr-
roles are the most difficult to synthesise since most electro-
philic aromatic substitution reactions, as well as lithiation
reactions, of N-substituted pyrroles occur at the 2-position,11
and so functionalisation at the 3-position of pyrrole is a
challenging goal in synthetic research.
Keywords: Lactam; Pyrrole; Reduction; Oxidative aromatisation.
* Corresponding author. Tel.: +91 3222 283326; fax: +91 3222 282252;
e-mail: jkray@chem.iitkgp.ernet.in
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.058

3050
P. Haldar et al. / Tetrahedron 63 (2007) 3049–3056
To further examine the generality of the reaction, N-aryl-5-
N
oxo-pyrrolidine-3-carboxylic acids 10 were synthesised by
the condensation of substituted arylamines with methylene-
succinic acid (itaconic acid).17 Now on treatment with
NaBH4–I2 in dry THF at 0–78 ꢀC, g-lactam 10 afforded
(N-aryl-pyrrolidin-3-yl)-methanol 2 in very good yield
(Scheme 2 and Table 2).
OH
OH
H
N
N
N
O
O
O
NH
P3
N
CF3
I
NHCHOCH3
Table 2
O
N
CHO
5-Oxo-N-aryl-pyrrolidine- Ar
3-carboxylic acid
N-aryl-pyrrolidin- Yield
(%)
O
N
3-ylmethanol
N
10a
10b
10c
10d
10e
4-CH3–C6H4
4-Br–C6H4
4-Cl–C6H4
3,4-Cl,Cl–C6H3 2d
3-Cl,4-F–C6H3 2e
2a
2b
2c
91
94
96
88
85
N
N
N
N
II
IV
III
Figure 1.
In this case, the starting material itaconic acid is cheaper and
air-stable than 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-
dione, but the reduction step in Scheme 2 is slower than
that in Scheme 1. g-Lactam carboxylic acids 1 were reduced
to 2 at room temperature within 2 h, whereas nearly 3.5–4 h
was required for the complete conversion of 10 to 2 at room
temperature. However, under refluxing condition (78 ꢀC), N-
aryl-5-oxo-pyrrolidine-3-carboxylic acids 10 were reduced
to (N-aryl-pyrrolidin-3-yl)-methanol 2 within 30 min, and
the yield of alcohol 2 in Scheme 2 is better than that in
Scheme 1.
As a part of our continued interest in selective reductions,12
we initiated an investigation to find applications of the
NaBH4–I2 reagent system13 on N-aryl-g-lactam derivatives,
and discovered an efficient method14 for the conversion of
N-aryl-g-lactam carboxylic acids15 to the desired N-aryl-
formylpyrrole derivatives. A part of this result has been
reported recently in a communication,14 and we wish to
present here a comparative study of the effect of this reagent
system on three different types of N-aryl-g-lactam carb-
oxylic acids, feasibility of the formation of N-arylformylpyr-
roles together with the experimental and spectral details of
our earlier results.
(1-Substituted pyrrolidin-3-yl)methanols and their corre-
sponding chlorides18 are useful intermediates for the prepa-
ration of a number of physiologically active compounds of
therapeutic value.
2. Results and discussion
We hoped that DDQ19 might bring about oxidative aromati-
sation of N-substituted pyrrolidin-3-ylmethanols to produce
N-aryl-3-formylpyrroles, and this proved to be the case.
N-Aryl-2-oxo-pyrrolidine-3-carboxylic acids 1 were syn-
thesised at room temperature by the reaction of substituted
arylamines and 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-
4,8-dione.16 g-Lactam 1 upon treatment with NaBH4–I2 in
dry THF at room temperature furnished (N-aryl-pyrrolidin-
3-yl)-methanol 2 in good yield (Scheme 1,Table 1).
Aromatisation followed by in situ oxidation of 2 by DDQ
furnished the desired compound 3 in one step and in good
yield (Scheme 3, Table 3).
O
Ar
Ar
O
O
O
N
N
NaBH4/I2
+
Ar
Ar NH2
Ar
N
N
DDQ
Dry THF, 0-25 °C
O
CH2OH
2
CO2H
1
dry Benzene,
80 °C
CHO
3
CH2OH
2
Scheme 1.
Scheme 3.
Table 1
2-Oxo-N-aryl-pyrrolidine- Ar
3-carboxylic acid
N-aryl-pyrrolidin- Yield
3-ylmethanol
A recent study showed that N-aryl-2-formylpyrroles could
act as key starting materials for the synthesis of isotactic-
polypropylene (IPP) catalysts20 and certain pyrrole Mannich
bases that act as antipsychotic agents.21
(%)
1a
1b
1c
1d
1e
4-CH3–C6H4
4-Br–C6H4
4-Cl–C6H4
3,4-Cl,Cl–C6H3 2d
3-Cl,4-F–C6H3 2e
2a
2b
2c
76
81
82
80
78
The above reports and the pleasing outcome of the above re-
actions (Schemes 1–3) prompted us to extend this method to
Ar
Ar
O
NaBH4/I2
N
N
Ar NH2 HO C
+
2
Dry THF, 0-78 °C
CO2H
CH2OH
CO2H
1'
2
Scheme 2.

P. Haldar et al. / Tetrahedron 63 (2007) 3049–3056
3051
Table 3
reaction temperature, rate and yield of the reduction.
Furthermore, the reagent system used is safe, simple and in-
expensive. We have also determined that DDQ is an efficient
reagent for the oxidative aromatisation of N-arylpyrrolidin-
3-ylmethanols in good yields, providing a simple and novel
approach for the conversion of both N-aryl-2-oxo-pyrroli-
dine-3-carboxylic acids and N-aryl-5-oxo-pyrrolidine-3-
carboxylic acids into N-aryl-3-formylpyrroles, which play
a central role as key intermediates in the synthesis of several
bioactive compounds.7–9 This methodology has been suc-
cessfully applied to the synthesis of a range of N-aryl-2-
formylpyrroles. The operational simplicity and economic
viability of this method definitely broaden the preview of
further study in this area.
Pyrrolidin-3-
ylmethanol
Ar
3-Formylpyrrole
Yield
(%)
2a
2b
2c
2d
2e
4-CH3–C6H4
4-Br–C6H4
4-Cl–C6H4
3,4-Cl,Cl–C6H3
3-Cl,4-F–C6H3
3a
3b
3c
3d
3e
62
64
65
62
60
the synthesis of N-aryl-2-formylpyrroles. We selected N-
aryl-5-oxo-3-aryl/heteroaryl-pyrrolidine-2-carboxylic acids
415 to investigate the generality of the reaction, and assess
the effect of steric crowding surrounding the carboxylic
acid group at the 2-position of g-lactam 4. While the reduc-
tion was successful, it was much slower than those reported
in Tables 1 and 2; it took nearly 2–3 h for the complete con-
version of 4 to provide 5 in refluxing THF (Scheme 4, Table
4). But the rate of DDQ mediated oxidative aromatisation of
(1,3-diaryl-pyrrolidine-2-yl)-methanols 5 to afford N-aryl-2-
formyl-3-aryl/heteroaryl-pyrroles 6 (Scheme 4 and Table 5)
is little faster than those reported in Table 3.
4. Experimental
4.1. General remarks
1H NMR (200 MHz) spectra were recorded on a BRUKER-
AC 200 MHz spectrometer. Chemical shifts are reported in
parts per million from tetramethylsilane with the solvent
resonance as the internal standard (deuterochloroform:
7.26 ppm). Data are reported as follows: chemical shifts,
multiplicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet,
br¼broad, m¼multiplet), coupling constant (Hz). 13C
NMR (50 MHz) spectra were recorded on a BRUKER-AC
200 MHz spectrometer with complete proton decoupling.
Chemical shifts are reported in parts per million from
tetramethylsilane with the solvent resonance as the internal
standard (deuterochloroform: 77.0 ppm). IR spectra were
recorded on Perkin–Elmer 883 and Shimadzu FTIR-8300
infrared spectrometers. EIMS (70 eV) spectra were taken
using a VG Autospec M mass spectrometer and ESI-MS
spectra were taken using Waters LCT mass spectrometer.
Elemental analysis was carried out by using an Elemental
Analyzer VARIOEL instrument.
Ar
Ar
Ar
CH2OH
Ar'
CO2H
Ar'
CHO
Ar'
NaBH4/I2
DDQ
dry Benzene,
80 °C
N
N
N
dry THF,
0-78 °C
O
4
5
6
Scheme 4.
Table 4
g-Lactam-
carboxylic acid
Ar
Ar0
Pyrrolidin-2- Yield
ylmethanol
(%)
4a
4b
4c
4d
4e
4-Cl–C6H4
2-Thienyl 5a
79
83
85
82
80
4-CH3–C6H4
4-Cl–C6H4
3,4-F,F–C6H3
Phenyl
Phenyl
Phenyl
5b
5c
5d
5e
3-Cl,4-F–C6H3 Phenyl
All reactions were carried out under an argon atmosphere.
Chromatographic purification was done with either 60–120
or 100–200 mesh silica gel (SRL). For reaction monitoring,
precoated silica gel 60 F254 TLC sheets (Merck) were used.
Petroleum ether refers to the fraction boiling in the range
60–80 ꢀC. Tetrahydrofuran was freshly distilled over benzo-
phenone-sodium.
Table 5
Pyrrolidin-2- Ar
ylmethanol
Ar0
2-Formylpyrrole Yield
(%)
5a
5b
5c
5d
5e
4-Cl–C6H4
2-Thienyl 6a
67
70
72
68
69
4-CH3–C6H4
4-Cl–C6H4
3,4-F,F–C6H3
Phenyl
Phenyl
Phenyl
6b
6c
6d
6e
4.2. General procedure for the synthesis of N-aryl-2-oxo-
pyrrolidine-3-carboxylic acids 116
3-Cl,4-F–C6H3 Phenyl
To
6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione
(10 mmol) was added substituted arylamine (30 mmol).
The mixture became a homogeneous solution after 20 min
and was allowed to stir at room temperature for 11–14 h.
The resulting crystalline mass was diluted with 150 mL of
chloroform, washed three times with aqueous 10% hydro-
chloric acid (15 mL), washed once with brine (50 mL) and
dried over anhydrous Na2SO4. Evaporation of solvent by ro-
tavac furnished the crude acid, which was recrystallised
from chloroform–hexane to afford 1 in 80–86% yield.
All the compounds were characterised by interpretation of
the usual spectroscopic and analytical data.
3. Conclusion
In conclusion we have disclosed that NaBH4–I2 can
effectively reduce both the lactam carbonyl and the labile
(b-carbonyl) carboxylic acid groups of N-aryl-2-oxo-pyrro-
lidine-3-carboxylic acids at room temperature and investi-
gated the positional effect of carboxylic acid groups on the
4.2.1. 2-Oxo-1-(p-tolyl)-pyrrolidine-3-carboxylic acid
(1a). Colourless solid; yield 80%; mp 132–134 ꢀC (ethanol).

3052
P. Haldar et al. / Tetrahedron 63 (2007) 3049–3056
IR (KBr) nmax 1726.7, 1685.4 cmꢁ1
;
1H NMR (CDCl3,
condenser. After that, the molten mass was cooled in
200 MHz): d 2.33 (s, 3H), 2.35–2.55 (m, 2H), 3.46–3.52
(t, 1H, Jw9.2 Hz), 3.73–3.97 (m, 2H), 7.13 (d, 2H,
Jw8.2 Hz), 7.34 (d, 2H, Jw6.9 Hz). 13C NMR (50 MHz,
DMSO-d6+CDCl3) d 21.0, 47.2, 47.7, 120.6, 129.6, 135.4,
135.9, 169.8, 170.9. Anal. Calcd for C12H13NO3: C, 65.74;
H, 5.98; N, 6.39. Found: C, 65.63; H, 6.01; N, 6.32%. ESI-
MS for C12H13NO3 [M], [M+H]+¼220.10.
ice-cold water and then dissolved in sodium bicarbonate
solution, treated with charcoal, filtered and the filtrate was
acidified with ice-cold dilute hydrochloric acid. The precip-
itated acid 10 was recrystallised from aqueous ethanol.
4.3.1. 5-Oxo-1-(p-tolyl)-pyrrolidine-3-carboxylic acid
(10a). White solid; yield 90%; mp 186–188 ꢀC (ethanol).
IR (KBr) nmax 1702.3, 1685.4 cmꢁ1 1H NMR (CDCl3,
;
4.2.2. 1-(4-Bromophenyl)-2-oxopyrrolidine-3-carboxylic
acid (1b). White solid; yield 73%; mp 147–150 ꢀC (etha-
200 MHz): d 2.35 (s, 3H), 2.87–2.98 (m, 2H), 3.19–3.26
(m, 1H), 3.98–4.24 (m, 2H), 7.14–7.18 (m, 2H), 7.31–7.38
(m, 2H). 13C NMR (50 MHz, DMSO-d6+CDCl3) d 20.8,
35.4, 35.7, 50.6, 120.6, 129.3, 134.4, 136.2, 171.8, 174.3.
Anal. Calcd for C12H13NO3: C, 65.74; H, 5.98; N, 6.39.
Found: C, 65.82; H, 5.95; N, 6.34%. ESI-MS for
C12H13NO3 [M], [M+H]+¼220.12.
nol). IR (KBr) nmax 1718.9, 1685.9 cmꢁ1
;
1H NMR
(CDCl3, 300 MHz): d 2.38–2.59 (m, 2H), 3.63–3.69 (t, 1H,
Jw9.4 Hz), 3.87–3.92 (m, 2H), 7.47–7.54 (m, 4H). 13C
NMR (50 MHz, DMSO-d6+CDCl3): d 21.6, 46.7, 49.5,
117.1, 121.1, 131.3, 137.6, 169.3, 170.7. Anal. Calcd for
C11H10NO3Br: C, 46.50; H, 3.55; N, 4.93. Found: C,
46.65; H, 3.52; N, 4.87%. ESI-MS for C11H10NO3Br [M],
[M+H]+¼283.97 (79Br), 285.97 (81Br).
4.3.2. 1-(4-Bromophenyl)-5-oxopyrrolidine-3-carboxylic
acid (10b). White solid; yield 78%; mp 172–174 ꢀC (etha-
nol). IR (KBr) nmax 1701.8, 1685.8, 1654.9 cmꢁ1 1H
;
4.2.3. 1-(4-Chlorophenyl)-2-oxopyrrolidine-3-carboxylic
acid (1c). White solid; yield 83%; mp 136–138 ꢀC (ethanol).
NMR (CDCl3, 200 MHz): d 2.72–2.88 (m, 2H), 3.20–3.27
(m, 1H), 3.86–4.05 (m, 2H), 7.30–7.45 (m, 4H). 13C NMR
(50 MHz, DMSO-d6+CDCl3): d 35.0, 35.1, 49.8, 116.7,
120.9, 131.2, 137.6, 171.5, 173.6. Anal. Calcd for
C11H10NO3Br: C, 46.50; H, 3.55; N, 4.93. Found: C,
46.59; H, 3.51; N, 4.90%. ESI-MS for C11H10NO3Br [M],
[M+H]+¼283.97 (79Br), 285.97 (81Br).
IR (KBr) nmax 1719.5, 1685.8 cmꢁ1 1H NMR (CDCl3,
;
200 MHz): d 2.30–2.54 (m, 2H), 3.52–3.60 (t, 1H,
Jw8.7 Hz), 3.71–3.96 (m, 2H), 7.27 (d, 2H, Jw8 Hz), 7.53
(d, 2H, Jw8.5 Hz). 13C NMR (50 MHz, DMSO-d6+CDCl3):
d 21.6, 46.6, 49.4, 120.7, 128.2, 129.2, 137.1, 169.2, 170.7.
Anal. Calcd for C11H10ClNO3: C, 55.13; H, 4.21; N, 5.84.
Found: C, 55.22; H, 4.19; N, 5.80%. ESI-MS for
C11H10ClNO3 [M], [M+H]+¼240.05 (35Cl,35Cl), 242.05
(35Cl,37Cl).
4.3.3. 1-(4-Chlorophenyl)-5-oxopyrrolidine-3-carboxylic
acid (10c). White solid; yield 92%; mp 150–152 ꢀC (etha-
nol). IR (KBr) nmax 1702.5, 1686.1, 1655.2 cmꢁ1 1H
;
NMR (CDCl3, 200 MHz): d 2.75–3.01 (m, 2H), 3.25–3.34
(m, 1H), 3.92–4.13 (m, 2H), 7.22–7.31 (m, 2H), 7.49–7.55
(m, 2H). 13C NMR (50 MHz, DMSO-d6+CDCl3) d 35.3,
35.3, 50.2, 120.9, 128.5, 128.9, 137.4, 171.8, 173.5. Anal.
Calcd for C11H10ClNO3: C, 55.13; H, 4.21; N, 5.84. Found:
C, 55.24; H, 4.23; N, 5.81%. ESI-MS for C11H10ClNO3 [M],
[M+H]+¼240.03 (35Cl,35Cl), 242.03 (35Cl,37Cl).
4.2.4. 1-(3,4-Dichlorophenyl)-2-oxopyrrolidine-3-car-
boxylic acid (1d). White solid; yield 81%; mp 145–147 ꢀC
1
(ethanol). IR (KBr) nmax 1718.7, 1685.5 cmꢁ1; H NMR
(CDCl3, 200 MHz): d 2.29–2.51 (m, 2H), 3.48–3.56 (t, 1H,
Jw9.1 Hz), 3.66–3.91 (m, 2H), 7.29–7.44 (m, 2H), 7.76
(d, 1H, Jw2.4 Hz). 13C NMR (50 MHz, DMSO-d6+CDCl3):
d 21.9, 46.9, 49.8, 116.9, 121.4, 127.8, 130.2, 132.4, 138.4,
169.8, 170.9. Anal. Calcd for C11H9NO3Cl2: C, 48.20; H,
3.31; N, 5.11. Found: C, 48.29; H, 3.33; N, 5.06%. ESI-MS
for C11H9NO3Cl2 [M], [M+H]+¼274.00 (35Cl,35Cl), 276.00
(35Cl,37Cl), 278.00 (37Cl,37Cl).
4.3.4. 1-(3,4-Dichlorophenyl)-5-oxopyrrolidine-3-car-
boxylic acid (10d). White solid; yield 91%; mp 139–
1
142 ꢀC (ethanol). IR (KBr) nmax 1701.9, 1685.9 cmꢁ1; H
NMR (CDCl3, 200 MHz): d 2.76–2.97 (m, 2H), 3.18–3.28
(m, 1H), 3.96–4.14 (m, 2H), 7.28–7.45 (m, 3H). 13C NMR
(50 MHz, DMSO-d6+CDCl3) d 34.9, 35.1, 49.8, 118.6,
120.9, 126.6, 130.3, 131.7, 138.3, 171.9, 173.7. Anal. Calcd
for C11H9NO3Cl2: C, 48.20; H, 3.31; N, 5.11. Found: C,
48.12; H, 3.34; N, 5.15%. ESI-MS for C11H9O3NCl2 [M],
[M+H]+¼274.00 (35Cl,35Cl), 276.00 (35Cl,37Cl), 278.00
(37Cl,37Cl).
4.2.5. 1-(3-Chloro-4-fluorophenyl)-2-oxopyrrolidine-3-
carboxylic acid (1e). White solid; yield 78%; mp 154–
1
157 ꢀC (ethanol). IR (KBr) nmax 1719.2, 1685.6 cmꢁ1; H
NMR (CDCl3, 200 MHz): d 2.24–2.54 (m, 2H), 3.49–3.57
(t, 1H, Jw9.2 Hz), 3.67–3.89 (m, 2H), 7.01–7.10 (t, 1H,
Jw8.7 Hz), 7.35–7.43 (m, 1H), 7.70 (dd, 1H, Jw2.6 Hz and
6.4 Hz). 13C NMR (50 MHz, DMSO-d6+CDCl3) d 21.7,
46.9, 49.6, 115.9, 116.1, 116.3, 119.3, 119.4, 1231.8,
135.5, 135.5, 142.4, 149.6, 156.8, 169.4, 170.9. Anal. Calcd
for C11H9O3NFCl: C, 51.28; H, 3.52; N, 5.44. Found: C,
51.41; H, 3.48; N, 5.36%. ESI-MS for C11H9O3NFCl [M],
[M+H]+¼258.03 (35Cl), 260.03 (37Cl).
4.3.5. 1-(3-Chloro-4-fluorophenyl)-5-oxopyrrolidine-3-
carboxylic acid (10e). White solid; yield 87%; mp 132–
134 ꢀC (ethanol). IR (KBr) nmax 1703.2, 1686.5,
1
1655.4 cmꢁ1; H NMR (CDCl3, 200 MHz): d 2.75–2.83
(m, 2H), 3.19–3.27 (t, 1H, Jw9.2 Hz), 3.84–4.01 (m, 2H),
7.03 (t, 1H, Jw8.8 Hz), 7.31–7.39 (m, 1H), 7.63–7.68 (m,
1H). 13C NMR (50 MHz, DMSO-d6+CDCl3): d 35.1, 35.3,
50.3, 116.0, 116.5, 121.9, 125.7, 127.8, 135.8, 145.8,
152.1, 156.9, 171.9, 173.8. Anal. Calcd for C11H9O3NFCl:
C, 51.28; H, 3.52; N, 5.44. Found: C, 51.41; H, 3.48; N,
5.36%. ESI-MS for C11H9O3NFCl [M], [M+H]+¼258.03
(35Cl), 260.03 (37Cl).
4.3. General procedure for the synthesis of N-aryl-5-oxo-
pyrrolidine-3-carboxylic acids 10
17
To itaconic acid (10 mmol) substituted arylamine (10 mmol)
was added and the dry reactants were maintained at the
fusion point for 20 min in a flask attached to a reflux

P. Haldar et al. / Tetrahedron 63 (2007) 3049–3056
3053
4.4. General procedure for the synthesis of N-arylpyr-
rolidin-3-ylmethanols 2 from N-aryl-2-oxo-pyrrolidine-
3-carboxylic acids 1
4.5.3. [1-(4-Chlorophenyl)pyrrolidin-3-yl]methanol 2c.
Colourless, viscous oily material; yield 82% from 1c, 96%
1
from 10c. IR (neat) nmax 3359.4, 2924.3 cmꢁ1; H NMR
(CDCl3, 200 MHz): d 1.79–1.86 (m, 1H), 2.12–2.16 (m,
1H), 2.55–2.59 (m, 1H), 3.07–3.13 (m, 1H), 3.25–3.39
(m, 3H), 3.63–3.69 (m, 2H), 6.44–6.52 (m, 2H), 7.14–7.25
(m, 2H). 13C NMR (50 MHz, CDCl3): d 27.8, 40.9, 47.3,
50.6, 65.1, 112.7, 120.5, 128.8, 146.4. Anal. Calcd for
C11H14NOCl: C, 62.41; H, 6.67; N, 6.62. Found: C, 62.53;
H, 6.65; N, 6.56%. ESI-MS for C11H14NOCl [M],
[M+H]+¼212.07 (35Cl), 214.07 (37Cl).
To a stirred solution of NaBH4 (6 mmol) in dry THF (20 mL)
a solution of iodine (3 mmol) in dry THF (5 mL) was added
dropwise under argon at 0 ꢀC over 45 min. Next, lactam-
monoacid 1 (2 mmol) in dry THF (8 mL) was added and
the mixture was stirred at room temperature (25 ꢀC) for
2 h. The mixture was then cooled to 0 ꢀC and the excess
hydride was carefully destroyed by dropwise addition of
methanol (10 mL). The solvents were removed under vac-
uum and the residue was taken up in 30 mL of 20% aqueous
KOH and the mixture was extracted three times with ether
(80 mL). The ether layer was washed with sodium thiosul-
fate solution and then with brine and dried over anhydrous
Na2SO4. The solvent was evaporated and the crude product
2 was purified by column chromatography [silica gel/petro-
leum ether (60–80 ꢀC)–ethyl acetate (40:1)].
4.5.4. [1-(3,4-Dichlorophenyl)pyrrolidin-3-yl]methanol
2d. Colourless, viscous oily material; yield 80% from 1d,
88% from 10d. IR (neat) nmax 3357.4, 2925.1 cmꢁ1 1H
;
NMR (CDCl3, 200 MHz): d 1.77–1.87 (m, 1H), 2.06–2.19
(m, 1H), 2.22–2.27 (br s, 1H), 2.53–2.60 (m, 1H), 3.04–
3.12 (m, 1H), 3.22–3.42 (m, 3H), 3.59–3.72 (m, 2H),
6.34–6.40 (dd, 1H, Jw2.7 Hz and 8.8 Hz), 6.59 (d, 1H,
Jw2.7 Hz), 7.20 (d, 1H, Jw8.8 Hz). 13C NMR (50 MHz,
CDCl3) d 27.8, 40.9, 47.2, 50.5, 64.8, 111.3, 112.9, 118.2,
130.3, 132.6, 147.1. Anal. Calcd for C10H13Cl2NO: C,
53.68; H, 5.32; N, 5.69. Found: C, 53.53; H, 5.34; N,
5.73%. ESI-MS for C11H13Cl2NO [M], [M+H]+¼246.03
(35Cl), 248.03 (35Cl and 37Cl), 250.03 (37Cl).
4.5. General procedure for the synthesis of N-arylpyr-
rolidin-3-ylmethanols 2 from N-aryl-5-oxo-pyrrolidine-
3-carboxylic acids 10
To a stirred solution of NaBH4 (6 mmol) in dry THF (20 mL)
a solution of iodine (3 mmol) in dry THF (5 mL) was added
dropwise under argon at 0 ꢀC over 45 min. Next, lactam-
monoacid 10 (2 mmol) in dry THF (8 mL) was added and
the mixture was stirred at room temperature (25 ꢀC) for
10 min. Then the mixture was refluxed for 30 min, cooled to
0 ꢀC and the excess hydride was carefully destroyed by drop-
wise addition of methanol (10 mL). The solvents were re-
moved under vacuum and the residue was taken up in 20%
aqueous KOH (30 mL) and the mixture was extracted three
times with ether (80 mL). The ether layer was washed with
sodium thiosulfate solution and then with brine and dried
over anhydrous Na2SO4. The solvent was evaporated and
the crude product 2 was purified by column chromatography
[silica gel/petroleum ether (60–80 ꢀC)–ethyl acetate (40:1)].
4.5.5. [1-(3-Chloro-4-fluorophenyl)pyrrolidin-3-yl]-
methanol 2e. Colourless, viscous oily material; yield 78%
from 1e, 85% from 10e. IR (neat) nmax 3364.3,
2924.0 cmꢁ1 1H NMR (CDCl3, 200 MHz): d 1.80–1.91
;
(m, 1H), 2.11–2.17 (m, 1H), 2.45–2.57 (m, 1H), 3.05–3.12
(m, 1H), 3.26–3.41 (m, 3H), 3.62–3.71 (m, 2H), 6.48–6.55
(m, 2H), 6.68–6.75 (m, 1H), 6.98–7.04 (m, 1H). 13C NMR
(50 MHz, CDCl3) d 27.8, 40.9, 47.6, 50.9, 64.9, 110.6,
110.7, 112.7, 116.4, 116.9, 120.6, 121.0, 144.9, 147.7,
152.4. Anal. Calcd for C11H13NOClF: C, 57.52; H, 5.71;
N, 6.10. Found: C, 57.63; H, 5.66; N, 6.06%. ESI-MS for
C11H13NOClF [M], [M+H]+¼230.07 (35Cl), 232.07 (37Cl).
4.6. General procedure for the synthesis of N-aryl-3-
formylpyrroles 3
4.5.1. [1-(p-Tolyl)pyrrolidin-3-yl]methanol 2a. Colour-
less, viscous oily material; yield 76% from 1a, 91% from
10a. IR (neat) nmax 3394.5, 2921.4 cmꢁ1; 1H NMR (CDCl3,
200 MHz): d 1.76–1.85 (m, 1H), 2.02–2.11 (m, 1H), 2.33
(s, 3H), 2.42–2.49 (m, 1H), 3.08–3.15 (m, 1H), 3.27–3.45
(m, 3H), 3.57–3.68 (m, 2H), 6.64 (d, 2H, Jw8.4 Hz), 7.05
(d, 2H, Jw8.3 Hz). 13C NMR (50 MHz, CDCl3) d 20.3,
27.9, 40.8, 47.5, 50.9, 65.3, 112.1, 125.3, 128.2, 146.0.
Anal. Calcd for C12H17NO: C, 75.35; H, 8.96; N, 7.32.
Found: C, 75.48; H, 8.92; N, 7.26%. ESI-MS for
C12H17NO [M], [M+H]+¼192.12.
Compound 2 (1.4 mmol) was heated at reflux with DDQ
(8 mmol) in dry benzene [caution: carcinogenic] (40 mL)
for 8 h. After completion of the reaction, the organic layer
was washed with aqueous NaHCO3 solution, dried over an-
hydrous Na2SO4, the solvent was evaporated and the desired
aldehyde 3 was purified by column chromatography [neutral
alumina/petroleum ether (60–80 ꢀC)–ethyl acetate (60:1)].
4.6.1. 1-(p-Tolyl)-3-formylpyrrole 3a. Colourless, viscous
oily material; yield 62%. IR (neat) nmax 1673.2 cmꢁ1; H
1
4.5.2. [1-(4-Bromophenyl)pyrrolidin-3-yl]methanol 2b.
Colourless, viscous oily material; yield 81% from 1b, 94%
NMR (CDCl3, 200 MHz): d 2.35 (s, 3H), 6.78 (d, 1H,
Jw2.7 Hz), 7.03 (d, 1H, Jw2.7 Hz), 7.28–7.41 (m, 4H), 7.60
(s, 1H), 9.84 (s, 1H). 13C NMR (50 MHz, CDCl3) d 22.6,
110.1, 117.8, 120.1, 121.9, 129.8, 134.1, 137.9, 185.3.
Anal. Calcd for C12H11NO: C, 77.81; H, 5.99; N, 7.56.
Found: C, 77.72; H, 5.96; N, 7.61%. ESI-MS for
C12H11NO [M], [M+H]+¼186.09.
1
from 10b. IR (neat) nmax 3365.6, 2924.9 cmꢁ1; H NMR
(CDCl3, 200 MHz): d 1.78–1.86 (m, 1H), 2.12–2.18 (m,
1H), 2.51–2.58 (m, 1H), 3.11–3.16 (m, 1H), 3.23–3.44
(m, 3H), 3.61–3.70 (m, 2H), 6.49–6.54 (m, 2H), 7.16–7.24
(m, 2H). 13C NMR (50 MHz, CDCl3) d 27.9, 40.8, 47.2,
50.6, 64.9, 107.5, 113.3, 131.7, 146.7. Anal. Calcd for
C11H14NOBr: C, 51.58; H, 5.51; N, 5.47. Found: C, 51.49;
H, 5.55; N, 5.50%. ESI-MS for C11H14NOBr [M],
[M+H]+¼256.03 (79Br), 258.03 (81Br).
4.6.2. 1-(4-Bromophenyl)-3-formylpyrrole 3b. Colour-
less, viscous oily material; yield 64%. IR (neat) nmax
1
1672.6 cmꢁ1; H NMR (CDCl3, 200 MHz): d 6.81 (d, 1H,

3054
P. Haldar et al. / Tetrahedron 63 (2007) 3049–3056
Jw2.7 Hz), 7.05 (d, 1H, Jw2.8 Hz), 7.28–7.32 (m, 2H), 7.58–
7.61 (m, 2H), 7.63 (s, 1H), 9.85 (s, 1H). 13C NMR (50 MHz,
CDCl3) d 110.1, 120.8, 122.1, 122.6, 126.8, 128.5, 132.9,
138.6, 185.4. Anal. Calcd for C11H8NOBr: C, 52.83; H,
3.22; N, 5.60. Found: C, 52.95; H, 3.20; N, 5.64%. ESI-
MS for C11H8NOBr [M], [M+H]+¼249.98 (79Br), 251.97
(81Br).
3.76; N, 4.35. Found: C, 56.08; H, 3.74; N, 4.39%. ESI-
MS for C15H12ClNO3S [M], [M+H]+¼321.02 (35Cl),
323.02 (37Cl).
4.7.2. 5-Oxo-3-phenyl-1-(p-tolyl)pyrrolidine-2-carbox-
ylic acid 4b. White solid; yield 91%; mp 170–172 ꢀC (etha-
nol). IR (KBr) nmax 1739.5, 1654.7 cmꢁ1; 1H NMR (DMSO-
d6+CDCl3, 200 MHz): d 2.19 (s, 3H), 2.55 (dd, 1H, Jw3.2 Hz
and 17.2 Hz), 3.15 (dd, 1H, Jw9.2 Hz and 17.1 Hz), 3.53–
3.59 (m, 1H), 4.46 (d, 1H, Jw2.6 Hz), 7.02–7.05 (m, 2H),
7.13–7.35 (m, 7H). 13C NMR (50 MHz, CDCl3): d 20.8,
38.6, 41.3, 69.3, 121.9, 126.4, 127.5, 129.1, 129.5, 135.2,
135.6, 142.6, 172.9, 173.4. Anal. Calcd for C18H17NO3: C,
73.20; H, 5.80; N, 4.74. Found: C, 73.27; H, 5.84; N,
4.72%. ESI-MS for C18H17NO3 [M], [M+H]+¼296.12.
4.6.3. 1-(4-Chlorophenyl)-3-formylpyrrole 3c. Colourless,
viscous oily material; yield 65%. IR (neat) nmax
1
1671.9 cmꢁ1; H NMR (CDCl3, 200 MHz): d 6.80 (d, 1H,
Jw2.8 Hz), 7.05 (d, 1H, Jw2.7 Hz), 7.33–7.48 (m, 4H),
7.62 (s, 1H), 9.84 (s, 1H). 13C NMR (50 MHz, CDCl3):
d 109.9, 122.2, 122.3, 126.8, 128.4, 129.9, 133.1, 138.1,
185.4. Anal. Calcd for C11H8NOCl: C, 64.23; H, 3.89; N,
6.81. Found: C, 64.12; H, 3.84; N, 6.87%. ESI-MS for
C11H8NOCl [M], [M+H]+¼206.01 (35Cl), 208.01 (37Cl).
4.7.3. 1-(4-Chlorophenyl)-5-oxo-3-phenylpyrrolidine-2-
carboxylic acid 4c. White solid; yield 92%; mp 209–
1
4.6.4. 1-(3,4-Dichlorophenyl)-3-formylpyrrole 3d. Col-
ourless, viscous oily material; yield 62%. IR (neat) nmax
212 ꢀC (ethanol). IR (KBr) nmax 1734.3, 1654.6 cmꢁ1; H
NMR (DMSO-d6+CDCl3, 200 MHz): d 2.64 (dd, 1H,
Jw3.5 Hz and 17.4 Hz), 3.15 (dd, 1H, Jw9.1 Hz and
17.3 Hz), 3.60–3.69 (m, 1H), 4.53 (d, 1H, Jw2.8 Hz), 7.21–
7.34 (m, 7H), 7.41–7.46 (m, 2H). 13C NMR (50 MHz,
DMSO-d6+CDCl3) d 38.4, 40.9, 68.8, 122.6, 126.1, 127.4,
128.7, 128.9, 130.3, 136.6, 142.0, 172.3, 173.3. Anal. Calcd
for C17H14NO3Cl: C, 64.67; H, 4.47; N, 4.44. Found: C,
64.79; H, 4.44; N, 4.41%. ESI-MS for C17H14NO3Cl [M],
[M+H]+¼316.07 (35Cl), 318.07 (37Cl).
1
1672.2 cmꢁ1; H NMR (CDCl3, 200 MHz): d 6.81–6.83
(m, 1H), 7.03–7.06 (m, 1H), 7.29–7.31 (m, 1H), 7.54–7.58
(m, 2H), 7.63 (d, 1H, Jw1.9 Hz), 9.84 (s, 1H). 13C NMR
(50 MHz, CDCl3) d 110.1, 117.9, 120.9, 122.4, 123.8,
123.8, 127.0, 128.5, 185.35. Anal. Calcd for C11H7NOCl2:
C, 55.03; H, 2.94; N, 5.83. Found: C, 55.17; H, 2.96; N,
5.78%. ESI-MS for C11H7NOCl2 [M], [M+H]+¼239.98
(35Cl), 241.98 (35Cl and 37Cl).
4.6.5. 1-(3-Chloro-4-fluorophenyl)-3-formylpyrrole 3e.
Colourless, viscous oily material; yield 60%. IR (neat)
nmax 1670.6 cmꢁ1; 1H NMR (CDCl3, 200 MHz): d 6.78 (d,
1H, Jw1.8 Hz), 6.95–7.00 (m, 2H), 7.30–7.35 (m, 2H),
7.56–7.58 (t, 1H, Jw1.9 Hz), 9.83 (s, 1H). 13C NMR
(50 MHz, CDCl3) d 109.9, 122.2, 122.3, 126.9, 128.4,
129.9, 133.1, 138.1, 185.4. Anal. Calcd for C11H7NOClF:
C, 59.08; H, 3.16; N, 6.26. Found: C, 58.96; H, 3.18; N,
6.21%. ESI-MS for C11H7NOClF [M], [M+H]+¼224.02
(35Cl), 226.02 (37Cl).
4.7.4. 1-(3,4-Difluorophenyl)-5-oxo-3-phenylpyrrolidine-
2-carboxylic acid 4d. White solid; yield 84%; mp 186–
1
189 ꢀC (ethanol). H NMR (DMSO-d6+CDCl3, 200 MHz):
d 2.67 (dd, 1H, Jw3.4 Hz and 17.3 Hz), 3.17 (dd, 1H,
Jw9.1 Hz and 17.3 Hz), 3.61–3.69 (m, 1H), 4.52 (d, 1H,
Jw2.8 Hz), 7.05–7.11 (m, 1H), 7.20–7.37 (m, 5H), 7.46–
7.62 (m, 2H). 13C NMR (50 MHz, DMSO-d6+CDCl3)
d 38.4, 40.9, 68.6, 110.9, 111.3, 116.7, 117.1, 120.0,
126.7, 127.3, 128.6, 128.9, 133.6, 142.7, 144.6, 146.9,
151.9, 172.0, 173.2. Anal. Calcd for C17H13NO3F2: C,
64.35; H, 4.13; N, 4.41. Found: C, 64.43; H, 4.11; N,
4.44%. ESI-MS for C17H13NO3F2 [M], [M+H]+¼318.09.
4.7. General procedure for the synthesis of N-aryl-5-oxo-
3-aryl/heteroaryl-pyrrolidine-2-carboxylic acids 415
4.7.5. 1-(3-Chloro-4-fluorophenyl)-5-oxo-3-phenylpyrro-
lidine-2-carboxylic acid 4e. White solid; yield 88%; mp
158–161 ꢀC (ethanol). 1H NMR (DMSO-d6+CDCl3,
200 MHz): d 2.71 (dd, 1H, Jw3.5 Hz and 17.3 Hz), 3.16
(dd, 1H, Jw9.2 Hz and 17.5 Hz), 3.56–3.65 (m, 1H), 4.53
(d, 1H, Jw2.8 Hz), 7.08–7.24 (m, 2H), 7.27–7.45 (m, 5H),
7.62 (dd, 1H, Jw2.7 Hz and 6.4 Hz). 13C NMR (50 MHz,
DMSO-d6+CDCl3) d 37.4, 40.4, 68.1, 115.6, 116.0, 119.7,
120.1, 120.6, 123.3, 125.6, 126.8, 128.3, 134.2, 141.2,
151.9, 156.9, 171.4, 172.7. Anal. Calcd for C17H13NO3ClF:
C, 61.18; H, 3.93; N, 4.20. Found: C, 61.29; H, 3.90; N,
4.24%. ESI-MS for C17H13NO3ClF [M], [M+H]+¼334.06
(35Cl), 336.06 (37Cl).
To a solution of 1-aryl-2,2-dicarbethoxy-5-oxo-3-aryl/hetero-
aryl-pyrrolidine (8 mmol) in ethanol (40 mL), a solution of
KOH (17 mmol) in 10–15 mL water was added and refluxed
for 5 h. Excess ethanol was distilled out and the residue was
diluted further with 20 mL ice-cold water. It was then acid-
ified with ice-cold dilute hydrochloric acid. The precipitate
was dissolved in sodium bicarbonate solution and extracted
with ether to remove neutral matter. The aqueous layer was
again acidified with ice-cold dilute hydrochloric acid. The
precipitated acid 4 was recrystallised from aqueous ethanol.
4.7.1. 1-(4-Chlorophenyl)-5-oxo-3-(2-thienyl)pyrroli-
dine-2-carboxylic acid 4a.15b White solid; yield 82%; mp
216–217 ꢀC (ethanol). IR (KBr) nmax 1736.1, 1648.8 cmꢁ1
;
4.8. General procedure for the synthesis of (1,3-diaryl-
pyrrolidine-2-yl)-methanols 5
1H NMR (DMSO-d6+CDCl3, 200 MHz): d 2.72 (dd, 1H,
Jw3.7 Hz and 17.1 Hz), 3.16 (dd, 1H, Jw8.8 Hz and
17.0 Hz), 3.78–3.86 (m, 1H), 4.61 (d, 1H, Jw2.9 Hz), 6.90
(d, 2H, Jw3.5 Hz), 7.18–7.21 (m, 1H), 7.29 (dd, 2H,
Jw2.4 Hz and 6.7 Hz), 7.39 (dd, 2H, Jw2.4 Hz and
6.8 Hz). Anal. Calcd for C15H12ClNO3S: C, 55.99; H,
To a stirred solution of NaBH4 (6 mmol) in dry THF (20 mL)
a solution of iodine (3 mmol) in dry THF (5 mL) was added
dropwise under argon at 0 ꢀC over 45 min. Next, lactam-
monoacid 4 (2 mmol) in dry THF (8 mL) was added and

P. Haldar et al. / Tetrahedron 63 (2007) 3049–3056
3055
the mixture was stirred at room temperature (25 ꢀC) for
10 min. Then the mixture was heated at reflux for 2–3 h,
cooled to 0 ꢀC and the excess hydride was carefully de-
stroyed by dropwise addition of methanol (10 mL). The sol-
vents were removed under vacuum and the residue was taken
up in 30 mL of 20% aqueous KOH and the mixture was ex-
tracted three times with ether (80 mL). The ether layer was
washed with sodium thiosulfate solution and then with brine
and dried over anhydrous Na2SO4. The solvent was evapo-
rated and the crude product 5 was purified by column chro-
matography [silica gel/petroleum ether (60–80 ꢀC)–ethyl
acetate (50:1)].
H, 5.87; N, 4.82%. EIMS m/z: 289 (M+, 48.4%), 258
(M+ꢁC2H5, 100%).
4.8.5. [1-(3-Chloro-4-fluorophenyl)-3-phenyl-pyrrolidin-
2-yl]methanol 5e. Colourless, viscous oily material; yield
1
80%. IR (liquid film) nmax 3334.0, 2930.6 cmꢁ1; H NMR
(CDCl3, 200 MHz): d 2.40–2.58 (m, 2H), 3.27–3.39 (q,
1H, Jw7.5 Hz), 3.45–3.55 (m, 2H), 3.70–3.79 (m, 2H),
3.85–3.91 (m, 1H), 6.50–6.58 (m, 1H), 6.69–6.74 (q, 1H,
Jw2.9 Hz), 6.98 (s, 1H), 7.02–7.10 (m, 2H), 7.18–7.33 (m,
3H). 13C NMR (50 MHz, CDCl3): 31.9, 46.7, 49.0, 62.2,
67.1, 111.6, 113.7, 116.6, 117.0, 121.0, 121.4, 126.6,
126.9, 128.7, 143.8, 144.2, 148.3, 153.0. Anal. Calcd for
C17H17ClFNO: C, 66.78; H, 5.60; N, 4.58. Found: C,
66.69; H, 5.63; N, 4.56%. EIMS m/z: 305 (M+, 21.3%),
274 (M+ꢁC2H5, 100%).
4.8.1. [1-(4-Chlorophenyl)-3-(2-thienyl)-pyrrolidin-2-yl]-
methanol 5a. Colourless, viscous oily material; yield 79%.
IR (liquid film) nmax 3357.5, 2931.1 cmꢁ1; 1H NMR (CDCl3,
200 MHz): d 2.0–2.08 (br s, 1H), 2.44–2.54 (m, 1H), 3.34–
3.57 (m, 3H), 3.73–3.92 (m, 4H), 6.61 (d, 2H, Jw8.8 Hz),
6.74 (d, 1H, Jw3.1 Hz), 6.86–6.91 (dd, 1H, Jw3.4 Hz and
4.9 Hz), 7.11 (d, 1H, Jw5.0 Hz), 7.18 (d, 2H, Jw8.8 Hz).
13C NMR (50 MHz, CDCl3) d 32.2, 42.0, 48.3, 62.1, 67.6,
113.5, 121.5, 123.4, 123.5, 126.0, 129.0, 145.8, 147.2.
Anal. Calcd for C15H16ClNOS: C, 61.32; H, 5.49; N, 4.77.
Found: C, 61.44; H, 5.46; N, 4.73%. EIMS m/z: 293 (M+,
25.5%), 262 (M+ꢁC2H5, 100%).
4.9. General procedure for the synthesis of 1,3-diaryl-
2-formylpyrroles 6
Compound 5 (1.4 mmol) was heated at reflux with DDQ
(8 mmol) in dry benzene [caution: carcinogenic] (40 mL)
for 5–6 h. After completion of the reaction, the organic layer
was washed with aqueous NaHCO3 solution, dried over an-
hydrous Na2SO4, the solvent was evaporated and the desired
aldehyde 6 was purified by column chromatography [neutral
alumina/petroleum ether (60–80 ꢀC)–ethyl acetate (70:1)].
4.8.2. [3-Phenyl-1-(p-tolyl)-pyrrolidin-2-yl]methanol 5b.
Colourless, viscous oily material; yield 83%. IR (liquid
film) nmax 3392.8, 2931.4 cmꢁ1
;
1H NMR (CDCl3,
4.9.1. 1-(4-Chlorophenyl)-2-formyl-3-(2-thienyl)pyrrole
6a. Colourless, viscous oily material; yield 67%. IR (neat)
nmax 1655.0 cmꢁ1; 1H NMR (CDCl3, 200 MHz): d 6.52 (d,
1H, Jw2.7 Hz), 6.99 (d, 1H, Jw2.8 Hz), 7.11–7.14 (m, 1H),
7.27–7.31 (m, 3H), 7.36–7.45 (m, 3H), 9.83 (s, 1H). 13C
NMR (50 MHz, CDCl3) d 111.6, 126.5, 127.3, 127.5, 127.8,
129.1, 130.8, 135.3, 180.0. Anal. Calcd for C15H10ClNOS: C,
62.61; H, 3.50; N, 4.87. Found: C, 62.75; H, 3.48; N, 4.83%.
EIMS m/z: 287 (M+, 99.9%), 258 (M+ꢁCHO, 59.6%).
200 MHz): d 1.97–2.03 (m, 1H), 2.28 (s, 3H), 2.38–2.52
(m, 1H), 3.37–3.49 (m, 1H), 3.53–3.63 (m, 2H), 3.66–3.72
(m, 1H), 3.78–3.81 (m, 1H), 3.86–3.92 (m, 1H), 6.66 (d,
2H, Jw8.5 Hz), 7.06–7.13 (m, 4H), 7.12–7.35 (m, 3H). 13C
NMR (50 MHz, CDCl3) d 21.01, 31.99, 46.66, 49.24,
60.38, 62.08, 114.16, 126.66, 127.00, 128.78, 129.21,
143.67, 145.48. Anal. Calcd for C18H21NO: C, 80.86; H,
7.92; N, 5.24. Found: C, 81.01; H, 7.87; N, 5.21%. EIMS
m/z: 267 (M+, 15.5%), 236 (M+ꢁC2H5, 100%).
4.9.2. 1-(p-Tolyl)-2-formyl-3-phenylpyrrole 6b. Colour-
less, viscous oily material; yield 70%. IR (neat) nmax
4.8.3. [1-(4-Chlorophenyl)-3-phenyl-pyrrolidin-2-yl]-
methanol 5c. Colourless, viscous oily material; yield 85%.
1
1655.4 cmꢁ1; H NMR (CDCl3, 200 MHz): d 2.34 (s, 3H),
IR (liquid film) nmax 3376.8, 2930.1 cmꢁ1
;
1H NMR
6.53 (d, 1H, Jw2.8 Hz), 7.12 (d, 1H, Jw2.9 Hz), 7.27–7.29
(m, 2H), 7.43–7.57 (m, 5H), 7.99 (d, 2H, Jw7.6 Hz), 9.67
(s, 1H). 13C NMR (50 MHz, CDCl3) 20.9, 111.3, 126.5,
127.4, 128.3, 128.7, 129.2, 129.8, 130.3, 130.7, 134.4,
136.5, 139.7, 179.9. Anal. Calcd for C18H15NO: C, 82.73;
H, 5.79; N, 5.36. Found: C, 82.89; H, 5.75; N, 5.33%.
EIMS m/z: 261 (M+, 100%).
(CDCl3, 200 MHz): d 2.34–2.52 (m, 2H), 3.31–3.40 (q,
1H, Jw7.5 Hz), 3.48–3.57 (m, 2H), 3.68–3.80 (m, 2H),
3.83–3.89 (m, 1H), 6.54–6.62 (m, 2H), 7.08–7.16 (m, 2H),
7.20–7.34 (m, 5H). 13C NMR (50 MHz, CDCl3) d 32.0,
46.9, 48.7, 62.5, 66.8, 113.7, 121.6, 126.6, 127.0, 128.8,
129.1, 144.1, 145.8. Anal. Calcd for C17H18NOCl: C,
70.95; H, 6.30; N, 4.87. Found: C, 71.07; H, 6.27; N,
4.86%. ESI-MS for C17H18NOCl [M], [M+H]+¼288.11
(35Cl), 290.11 (37Cl).
4.9.3. 1-(4-Chlorophenyl)-2-formyl-3-phenylpyrrole 6c.
Colourless, viscous oily material; yield 72%. IR (neat)
nmax 1658.3 cmꢁ1; 1H NMR (CDCl3, 200 MHz): d 6.49 (d,
1H, Jw2.8 Hz), 7.01 (d, 1H, Jw2.9 Hz), 7.22–7.28 (m, 3H),
7.43–7.49 (m, 6H), 9.64 (s, 1H). 13C NMR (50 MHz,
CDCl3): d 111.8, 121.2, 125.6, 127.1, 127.3, 127.6, 128.1,
128.6, 128.8, 129.5, 129.7, 130.3, 131.8, 132.6, 136.2,
140.9, 179.7. Anal. Calcd for C17H12ClNO: C, 72.47; H,
4.29; N, 4.97. Found: C, 72.58; H, 4.27; N, 4.93%. EIMS
m/z: 205 (M+, 100%).
4.8.4. [1-(3,4-Difluorophenyl)-3-phenyl-pyrrolidin-2-yl]-
methanol 5d. Colourless, viscous oily material; yield
1
82%. IR (liquid film) nmax 3393.4, 2931.2 cmꢁ1; H NMR
(CDCl3, 200 MHz): d 2.0–2.11 (m, 1H), 2.30–2.57 (m,
2H), 3.30–3.42 (q, 1H, Jw8.1 Hz), 3.49–3.60 (m, 2H), 3.75
(d, 1H, Jw4.9 Hz), 3.87–3.91 (m, 1H), 6.38–6.43 (m, 1H),
6.50–6.60 (m, 1H), 7.05–7.16 (m, 2H), 7.27–7.38 (m, 4H).
13C NMR (50 MHz, CDCl3) d 32.0, 46.7, 49.3, 59.2, 62.2,
67.4, 111.8, 114.0, 116.7, 117.1, 121.1, 121.5, 126.7,
126.9, 128.8, 143.7, 144.1, 148.5, 153.2. Anal. Calcd for
C17H17F2NO: C, 70.57; H, 5.92; N, 4.84. Found: C, 70.71;
4.9.4. 1-(3,4-Difluorophenyl)-2-formyl-3-phenylpyrrole
6d. Colourless, viscous oily material; yield 68%. IR (neat)
nmax 1655.1 cmꢁ1 1H NMR (CDCl3, 200 MHz): d 6.48
;

3056
P. Haldar et al. / Tetrahedron 63 (2007) 3049–3056
T.; Feng, D.; Ponpipom, M.; Girotra, N.; Liang, G.-B.; Qian,
X.; Bugianesi, R.; Simeone, J.; Chang, L.; Gurnett, A.;
Liberator, P.; Dulski, P.; Leavitt, P. S.; Crumley, T.; Misura,
A.; Murphy, T.; Rattray, S.; Samaras, S.; Tamas, T.; Mathew,
J.; Brown, C.; Thompson, D.; Schmatz, D.; Fisher, M.;
Wyvratt, M. Bioorg. Med. Chem. Lett. 2005, 15, 3296.
5. Biava, M.; Porretta, G. C.; Cappelli, A.; Vomero, S.; Manetti,
F.; Botta, M.; Sautebin, L.; Rossi, A.; Makovec, F.; Anzini,
M. J. Med. Chem. 2005, 48, 3428.
6. Khanna, I. K.; Weier, R. M.; Yu, Y.; Collins, P. W.; Miyashiro,
J. M.; Koboldt, C. M.; Veenhuizen, A. W.; Currie, J. L.; Seibert,
K.; Isakson, P. C. J. Med. Chem. 1997, 40, 1619.
7. Kevin, N. J.; Duffy, J. L.; Kirk, B. A.; Chapman, K. T.; Schleif,
W. A.; Olsen, D. B.; Stahlhut, M.; Rutkowski, C. A.; Kuo,
L. C.; Jin, L.; Lin, J. H.; Emini, E. A.; Tata, J. R. Bioorg.
Med. Chem. Lett. 2003, 13, 4027.
(d, 1H, Jw2.9 Hz), 7.01 (d, 1H, Jw 3.0 Hz), 7.14–7.17 (m,
2H), 7.21–7.24 (m, 1H), 7.42–7.52 (m, 5H), 9.64 (s, 1H).
13C NMR (50 MHz, CDCl3): d 111.6, 115.8, 116.9, 117.3,
122.5, 127.5, 128.1, 128.6, 129.6, 130.0, 130.8, 133.2,
136.4, 140.8, 179.8. Anal. Calcd for C17H11F2NO: C,
72.08; H, 3.91; N, 4.94. Found: C, 72.21; H, 3.87; N,
4.87%. EIMS m/z: 283 (M+, 100%).
4.9.5. 1-(3-Chloro-4-fluorophenyl)-2-formyl-3-phenyl-
pyrrole 6e. White solid; yield 69%; mp 154–157 ꢀC (etha-
nol). IR (KBr) nmax 1657.5 cmꢁ1 1H NMR (CDCl3,
;
200 MHz): d 6.49 (d, 1H, Jw2.8 Hz), 7.01 (d, 1H,
Jw2.9 Hz), 7.22–7.28 (m, 2H), 7.43–7.49 (m, 6H), 9.64 (s,
1H). 13C NMR (50 MHz, CDCl3): d 111.6, 116.5, 121.1,
126.1, 127.5, 128.0, 128.2, 128.4, 128.6, 129.6, 130.0, 130.8,
133.2, 136.2, 140.8, 179.6. Anal. Calcd for C17H11NOClF: C,
68.11; H, 3.67; N, 4.67. Found: C, 67.98; H, 3.75; N, 4.73%.
ESI-MS for C17H11NOClF [M], [M+H]+¼300.14 (100%)
(35Cl), 302.14 (33.2%) (37Cl).
8. Sbardella, G.; Mai, A.; Artico, M.; Loddo, R.; Setzu, M. G.;
Colla, P. L. Bioorg. Med. Chem. Lett. 2004, 14, 1537.
9. Thurkauf, A.; Yuan, J.; Chen, X.; Wasley, J. W. F.; Meade, R.;
Woodruff, K. H.; Huston, K.; Ross, P. C. J. Med. Chem. 1995,
38, 4950.
10. Paillet-Loilier, M.; Fabis, F.; Lepailleur, A.; Bureau, R.; Butt-
Gueulle, S.; Dauphin, F.; Delarue, C.; Vaudry, H.; Rault, S.
Bioorg. Med. Chem. Lett. 2005, 15, 3753.
11. Anderson, H. J.; Loader, C. E.; Xu, R. X.; Le, N.; Gogan, N. J.;
McDonald, R.; Edwards, L. G. Can. J. Chem. 1985, 63, 896.
12. (a) Haldar, P.; Ray, J. K. Tetrahedron Lett. 2003, 44, 8229; (b)
Haldar, P.; Ray, J. K. Org. Lett. 2005, 7, 4341.
Acknowledgements
Financial support from DST (New Delhi) and CSIR (New
Delhi) (for a fellowship to P.H.) is gratefully acknowledged.
References and notes
13. (a) McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm, M.
J. Org. Chem. 1993, 58, 3568; (b) Prasad, A. S. B.; Kanth,
J. V. B.; Periasamy, M. Tetrahedron 1992, 48, 4623; (c)
Kanth, J. V. B.; Periasamy, M. J. Org. Chem. 1991, 56, 5964;
(d) Karimi, B.; Zareyee, D. Synthesis 2003, 335; (e)
Periasamy, M.; Sivakumar, S.; Reddy, M. N. Synthesis 2003,
1965.
14. Haldar, P.; Guin, J.; Ray, J. K. Tetrahedron Lett. 2005, 46, 1071.
15. (a) Ray, J. K.; Sami, I.; Kar, G. K.; Roy, B. C.; Brahma, N. K.
Bioorg. Med. Chem. 1994, 2, 1417; (b) Kar, G. K.; Roy, B. C.;
Adhikari, S. D.; Ray, J. K.; Brahma, N. K. Bioorg. Med. Chem.
1998, 6, 2397; (c) Haldar, P.; Kar, G. K.; Ray, J. K. Tetrahedron
Lett. 2003, 44, 7433.
16. Danishefsky, S.; Singh, R. K. J. Am. Chem. Soc. 1975, 97,
3239.
17. Paytash, P. L.; Sparrow, E.; Gathe, J. C. J. Am. Chem. Soc.
1950, 72, 1415.
18. Wu, Y. H.; Feldkamp, R. F. J. Org. Chem. 1961, 26, 1519.
19. Walker, D.; Hiebert, J. D. Chem. Rev. 1967, 67, 153.
20. Ewen, J. A.; Elder, M. J.; Jones, R. L.; Rheingold, A. L.;
Liable-Sands, L. M.; Sommer, R. D. J. Am. Chem. Soc. 2001,
123, 4763.
1. (a) Lehuede, J.; Fauconneau, B.; Barrier, L.; Ourakow, M.;
Piriou, A.; Vierfond, J. M. Eur. J. Med. Chem. 1999, 34, 991;
(b) Ueda, A.; Kojima, S.; Nishikawa, H.; Yasuda, Y.;
Ookuma, K.; Nakada, A. Jpn. Kokai Tokkyo Koho JP
56079672, 1981, 5; (c) Fugmann, B.; Lieb, F.; Moeschler, H.;
Naumann, K.; Wachendorff, U. Chem. Unserer Zeit 1991,
25, 317.
2. (a) Battersby, A. R. Angew. Chem. 1995, 107, 421; Angew.
Chem., Int. Ed. Engl. 1995, 34, 383; (b) Kitamura, C.;
Yamashita, Y. J. Chem. Soc., Perkin Trans. 1 1997, 1443.
3. (a) Unverferth, K.; Engel, J.; Hofgen, N.; Rostock, A.; Gunther,
R.; Lankau, H. J.; Menzer, M.; Rolfs, A.; Liebscher, J.; Muller,
B.; Hofmann, H. J. J. Med. Chem. 1998, 41, 63; (b) Dannhardt,
G.; Kiefer, W.; Kraemer, G.; Maehrlein, S.; Nowe, U.; Fiebich,
B. Eur. J. Med. Chem. 2000, 35, 499; (c) Rango, R.; Marshall,
G. R.; Santo, R. D.; Costi, R.; Massa, S.; Rompei, R.; Artico,
M. Bioorg. Med. Chem. 2000, 8, 1423; (d) Massa, S.; Artico,
M.; Corelli, F.; Mai, A.; Di Santo, R.; Cortes, S.; Marongiu,
M. E.; Pani, A.; La Colla, P. J. Med. Chem. 1990, 33, 2845;
(e) Nicolaou, I.; Zika, C.; Demopoulos, V. J. J. Med. Chem.
2004, 47, 2706.
21. Scott, M. K.; Martin, G. E.; DiStefano, D. L.; Fedde, C. L.;
Kukla, M. J.; Barrett, D. L.; Baldy, W. J.; Elgin, R. J.;
Kesslick, J. M.; Mathiasen, J. R.; Shank, R. P.; Vaught, J. L.
J. Med. Chem. 1992, 35, 552.
4. (a) Artico, M.; Di Santo, R.; Costi, R.; Massa, S.; Retico, A.;
Artico, M.; Apuzzo, G.; Simonetti, G.; Strippoli, V. J. Med.
Chem. 1995, 38, 4223; (b) Jana, G. H.; Jain, S.; Arora, S. K.;
Sinha, N. Bioorg. Med. Chem. Lett. 2005, 15, 3592; (c) Biftu,