NaBH4-I2 mediated chemoselective reduction of γ-lactam and thio-γ-lactam in presence of gem-dicarboxylates: An easy access to 1,3-diaryl pyrrolidines

Article abstract of DOI:10.1002/jhet.542

Substituted pyrrolidine derivatives were synthesized in high yield by NaBH₄/I₂ mediated chemoselective reduction of N-aryl-γ-lactam and N-aryl-thio-γ-lactam-2,2-dicarboxylate. With excess NaBH₄/I₂, carbonyl func

Full text of DOI:10.1002/jhet.542

March 2011
NaBH4-I2 Mediated Chemoselective Reduction of c-Lactam and
Thio-c-lactam in Presence of Gem-dicarboxylates: An Easy
Access to 1,3-Diaryl Pyrrolidines
463
Gopa Barman, Pranab Haldar, Neelanjan Dutta, and Jayanta K. Ray*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
*E-mail: jkray@chem.iitkgp.ernet.in
Received February 25, 2010
DOI 10.1002/jhet.542
Published online 10 December 2010 in Wiley Online Library (wileyonlinelibrary.com).
Substituted pyrrolidine derivatives were synthesized in high yield by NaBH4/I2 mediated chemoselec-
tive reduction of N-aryl-c-lactam and N-aryl-thio-c-lactam-2,2-dicarboxylate. With excess NaBH4/I2,
carbonyl functionality of the ester groups remained unchanged.
J. Heterocyclic Chem., 48, 463 (2011).
INTRODUCTION
RESULTS AND DISCUSSION
Heterocycles are abundant in nature and are of great
significance to life because their structural subunits exist
in many natural products such as vitamins, hormones,
antibiotics, and alkaloids, as well as pharmaceuticals,
herbicides, dyes, and many more compounds. Among
them, substituted pyrrolidines are found in numerous nat-
ural products and biologically active compounds as
structural motifs [1]. Depending on the substitution pat-
tern and functionalization, different substituted pyrroli-
dines have been shown to be effective antibacterials or
fungicides agents and glycosidase inhibitors. A potent
class of cis- and trans-di-aryl pyrrolidines that inhibit
biosynthetic pathways, specially the synthesis of leuko-
triene-B4, can be useful for treatment of asthma, arthri-
tis, inflammatory bowel disease, and psoriasis [2]. A
series of alkaloids broussonetines A–L and broussoneti-
nines A and B extracted from the branches of Broussone-
tia kazinoki (Oriental tree, termed ‘‘himekouzo’’ in
Japan) have a common functionalized pyrrolidine ring
system. All these compounds are strong inhibitors of a-
and b-glucosidase, b-galactosidase, and a- and b-manno-
sidase enzymes. These compounds display different selec-
tivity toward different enzymes [3]. Medicinal chemistry
program investigated that pyrrolidines bearing an aro-
matic or heteroaromatic substituent at the C-3 position
acts as central nervous system (CNS) stabilizers [1b].
Several strategies have also been developed for the
synthesis of pyrrolidines. To utilize the synthetic c-lac-
tams (prepared in our laboratory), we are eager to de-
velop a chemoselective methodology to reduce the
lactam carbonyl group in presence of gem-dicarboxy-
lates for the synthesis of a pyrrolidine moiety. Chemo-
selective methods for the reduction of lactams to amines
have also been achieved using diisobutyl aluminium
hydride, diborane, sodium borohydride, and rhodium
catalyzed hydrosilation [4].
As part of our on going interest in selective reduction
[5] on c-lactam derivatives, we choose NaBH4/I2 rea-
gent system to investigate its application [6] on N-aryl-
thio-c-lactam derivatives [7] which are prepared from
N-aryl-c-lactam derivatives.
The starting material N-aryl-c-lactam diesters 1a–f
was prepared following the general method [5,8,9]. The
thio-c-lactam diesters 2a–f are prepared by refluxing the
lactam with P4S10 [10] in dry THF for 6 h (Scheme 1
and Table 1).
Some thio-lactams have also been found to be CNS
active. These compounds cause clonic and tonic convul-
sions in mice a few seconds after ip (intraperitoneal)
injection. The five-membered thio-lactam can cause
mild sedation at lower doses (500 mg/kg) and convul-
sions at higher doses (1000 mg/kg) [11].
C
V
2010 HeteroCorporation

464
G. Barman, P. Haldar, N. Dutta, and J. K. Ray
Vol 48
Scheme 1
Scheme 2
Formation of BH3: THF in situ by the reaction of
NaBH4 with I2 in dry THF has already been reported
[12] and when we treated the resulting lactams with
NaBH4/I2 in dry THF which furnished substituted pyrro-
lidines 3a–f in good yields (Scheme 2 and Table 2).
In presence of excess NaBH4/I2 in dry THF, carbonyl
functionality of the ester groups remain unchanged.
As the mechanism of the reaction is uncertain and as
we are unable to isolate the intermediate, the plausible
mechanism may be written as depicted in Scheme 3
[12].
200 MHz and 400 MHz Spectrometer with complete proton
decoupling. IR spectra were recorded on a Perkin-Elmer 883
and Shimadzu FTIR-8300 infrared spectrometers. EIMS (70
eV) spectra were taken using a VG Auto spec M mass spec-
trometer, and ESI-MS spectra were taken using Waters LCT
mass spectrometer. All reagents and solvents are obtained
from commercial suppliers.
Chromatographic purification was done with either 60–120
or 100–200 mesh silica gels (SRL). Petroleum ether refers to
the fraction boiling in the range 60–80ꢀC. Tetrahydrofuran
was freshly distilled over sodium-benzophenone.
All the compounds were characterized by interpreta-
tion of the usual spectroscopic and analytical data.
General procedure for synthesis of diethyl N-aryl-5-thioxo-
3-aryl/heteroaryl-pyrrolidine-2,2-dicarboxylates 2a–f. To
a
stirred solution of c-lactam diester (1 mmol) in dry THF (30
mL), P4S10 (3 mmol) was added under argon atmosphere, and
the reaction mixture was refluxed for 5 h. Solvent was evapo-
rated under vacuum, and the residue basified with ammonia
solution. The aqueous layer then extracted with CHCl3 and the
combined organic layer was washed with brine and followed
by water several times, dried over anhydrous Na2SO4 and con-
centrated in vacuum. Light yellow solid appeared. The product
was purified by column chromatography.
Diethyl 1-(4-fluorophenyl)-5-thioxo-3-phenyl-pyrrolidine-
2,2-dicarboxylate 2a. White solid; yield 85%; mp 105–106ꢀC
(from ethyl acetate-petroleum ether); (Found: C, 63.94; H,
5.43; N, 3.21. Calculated for C22H22FNO4S: C, 63.61; H, 5.30;
N. 3.37%); mmax (liquid film)/cm 1729.70, 1508.41; 1H NMR
(200 MHz; CDCl3; Me4Si): d 0.78 (t, 3H, J ¼ 7.2 Hz,
OCH2CH3), 0.96 (t, 3H, J ¼ 7.1 Hz, OCH2CH3), 3.48–3.6 (m,
3H, NCSCH2, OC(H)HCH3), 3.85–3.95 (m, 2H, OCH2CH3),
4.08–4.17 (m, 1H, OC(H)HCH3), 4.74 (t, 1H, J ¼ 9.3 Hz,
CONCLUSION
Thus 1,3-diaryl pyrrolidine can be prepared by che-
moselective reduction of carbonyl and thio carbonyl
group of N-aryl-c-lactam and N-aryl-thio c-lactam by
NaBH4-I2 in dry THF. Here we successfully disclose the
applicability of NaBH4-I2 reagent system on lactam-car-
bonyl group as well as thio-lactam carbonyl group in
dry THF. As pyrrolidine is the precursor of pyrrole this
methodology has been successfully applied to the syn-
thesis of a range of N-aryl-pyrroles.5
EXPERIMENTAL
1H NMR spectra were recorded in CDCl3 with TMS as the
internal standard on a BRUKER-AC 200 MHz and 400 MHz
spectrometer. Chemical shifts are reported in ppm. Data are
reported as follows: chemical shifts, multiplicity (s ¼ singlet,
d ¼ doublet, t ¼ triplet, q ¼ quartet, br ¼ broad, m ¼ multip-
let), coupling constant (Hz). 13C NMR (50 MHz) and 13C
NMR (100 MHz) spectra were recorded on a BRUKER-AC
Table 2
Synthesis of 1,3-diaryl-pyrrolidine-2,2-dicarboxylates 3(a-f).
Substrate
5-oxo-/5-thio-oxo
pyrolidine
Yield
Product (%)
Ar
Ar0
Table 1
1a
2a
1b
2b
1c
2c
1d
2d
1e
2e
1f
4-F-C6H4
4-F-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-CH3-C6H4 Phenyl
4-CH3-C6H4 Phenyl
3,4-F,F-C6H3 Phenyl
3,4-F,F-C6H3 Phenyl
4-F-C6H4
4-F-C6H4
4-F-C6H4
4-F-C6H4
Phenyl
Phenyl
Phenyl
Phenyl
3a
3a
3b
3b
3c
3c
3d
3d
3e
3e
3f
84
82
83
80
77
65
83
81
78
62
82
86
Synthesis of 1,3-diaryl-5-thioxopyrrolidine-2,2-dicarboxylates 2(a–f)
from 1,3-diaryl-2,2-dicarbethoxy-5-oxo-pyrrolidine 1(a–f).
Substrate
5-oxo-pyrolidine
5-thiooxo- Yield
pyrolidine (%)
Ar
Ar0
1a
1b
1c
1d
1e
1f
4-F-C6H4
4-Cl-C6H4
4-CH3-C6H4 Phenyl
3,4-F,F-C6H3 Phenyl
Phenyl
Phenyl
2a
2b
2c
2d
2e
2f
85
83
77
90
78
80
2-Thienyl
2-Thienyl
2-Furyl
2-Furyl
4-F-C6H4
4-F-C6H4
2-Thienyl
2-Furyl
2f
3f
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011
NaBH4-I2 Mediated Chemoselective Reduction of c-Lactam and Thio-c-lactam
in Presence of Gem-dicarboxylates: An Easy Access to 1,3-Diaryl Pyrrolidines
465
mmax (liquid film)/cm 1736.14, 1509.61; 1H NMR (200 MHz;
CDCl3; Me4Si): d 0.77 (t, 3H, J ¼ 7.2 Hz, OCH2CH3), 1.00 (t,
3H, J ¼ 7.2 Hz, OCH2CH3), 3.48–3.56 (dd, 2H, J ¼ 8.8, 22.4
Hz, NCSCH2), 3.84–3.91 (m, 1H, OCH2CH3), 3.92–4.00 (1H,
m, OCH2CH3)), 4.11–4.21 (1H, m, OCH2CH3), 4.24–4.29 (1H,
m, OCH2CH3)), 4.72 (t, 1H, J ¼ 9.2 Hz, C(3)HPh), 6.94–7.04
(m, 1H, Ar-H)), 7.17–7.21 (m, 2H, Ar-H), 7.24–7.31 (m, 5H,
Ar-H). dC (100 MHz; CDCl3; Me4Si) 13.29, 13.55 (2ꢁ
OCH2CH3), 47.76 (NCSCH2), 47.92 (C(3)Ph), 62.41, 62.85
(2ꢁ OCH2CH3), 85.37 (C(2)), 117.44, 117.62, 17.81, 118.83,
119.01, 125.78, 125.81, 128.41, 128.45, 128.67, 135.52,
135.58, 165.60 (ArC), 166.06, 167.31 (2ꢁ COOCH2CH3),
207.51 (NCS). C22H21NO4F2S [M],[M þ Hþ]:434.19.
Scheme 3
Diethyl 1-(4-fluoro phenyl)-5-thioxo-3-(2-thienyl)-pyrro-
lidine-2,2-dicarboxylate 2e. Light yellow crystalline solid;
yield 78%; mp 112–1116ꢀC (from ethyl acetate-petroleum
ether ); (Found: C, 57.03; H, 4.87; N. 3.29. Calculated for
C20H20NO4FS2: C, 57.04; H, 4.78; N. 3.32%); mmax (liquid
film)/cm 1733.14, 1498.88; 1H NMR (400 MHz; CDCl3;
Me4Si): d 0.92 (t, 3H, J ¼ 7.2 Hz, OCH2CH3), 0.98 (t, 3H, J
¼ 7.2 Hz, OCH2CH3), 3.55–3.78 (m, 2H, NCSCH2 ), 3.91–
3.97 (m, 1H, OCH2CH3), 4.00–4.04 (m, 2H, OCH2CH3), 4.05–
4.16 (m, 1H, OCH2CH3), 4.96–5.01 (dd, 1H, J ¼ 8.4, 11.2 Hz,
C(3)H), 6.99–7.04 (m, 2H, Ar-H), 7.08–7.15 (m, 2H, Ar-H),
7.24–7.29 (m, 3H, Ar-H). 13C NMR (100 MHz; CDCl3;
Me4Si): d 13.40 (2ꢁ OCH2CH3), 43.38 (NCSCH2), 48.46
(C(3)), 62.42, 62.61 (2ꢁ OCH2CH3), 84.89 (C(2)), 116.13,
116.36, 125.55, 126.56, 126.90, 130.40, 130.48, 135.30,
135.33, 137.42, 161.22, 163.70 (ArC), 165.17, 165.90 (2ꢁ
COOCH2CH3), 206.12 (NCS). C20H20NO4FS2 [M],[M þ Hþ]:
422.16.
Diethyl 1-(4-fluorophenyl)-5-thioxo-3-(2-furyl)-pyrrolidine-
2,2-dicarboxylate 2f. Light yellow crystalline solid; yield 80%;
mp 133–134ꢀC (from ethyl acetate-petroleum ether); (Found:
C, 57.62; H, 4.85; N, 3.31. Calculated for C20H20NO5FS: C,
56.99; H, 4.78; N. 3.32%); mmax (liquid film)/cm 1735.85,
1508.40; 1H NMR (400 MHz; CDCl3; Me4Si): d 0.92 (t, 3H,
J ¼ 7.2 Hz, OCH2CH3), 1.00 (t, 3H, J ¼ 7.2 Hz, OCH2CH3),
3.43–3.74 (m, 2H, NCSCH2), 3.76–3.81 (m, 1H, OCH2CH3),
3.85–4.05 (m, 1H, OCH2CH3), 4.06–4.12 (m, 2H, OCH2CH3),
4.76–4.81 (dd, 1H, J ¼ 8.8, 11.6 Hz, C(3)H), 6.28–6.33 (dd,
2H, J ¼ 2.8, 19.2 Hz, Ar-H), 6.96–7.09 (m, 2H, Ar-H), 7.11–
727 (m, 2H, Ar-H), 7.37 (s, 1H, Ar-H). 13C NMR (100 MHz;
C(3)HPh), 7.07–7.17 (m, 2H, Ar-H), 7.22–7.37 (m, 7H, Ar-H).
13C NMR (50 MHz; CDCl3; Me4Si): d 13.26, 13.42 (2ꢁ
OCH2CH3), 47.70 (NCSCH2), 47.87 (C(3)Ph), 62.14, 62.63
(2ꢁ OCH2CH3), 85.42 (C(2)), 115.92, 116.38, 128.29, 128.36,
128.56, 130.65, 130.83, 135.36, 135.61, 160.01 (ArC), 165.71,
166.06 (2ꢁ COOCH2CH3), 207.29 (NCS).
Diethyl 1-(4-chlorophenyl)-5-thioxo-3-phenyl-pyrrolidine-
2,2-dicarboxylates 2b. Light yellow crystalline solid; yield
83%; mp 135–136ꢀC (from ethylacetate-petroleum ether);
(Found: C, 61.04; H, 4.97; N, 3.16. Calculated for
C22H22ClNO4S: C, 61.18; H, 5.09; N, 3.24%) mmax (liquid
film)/cm 1733.14, 1490.68; 1H NMR (200 MHz; CDCl3;
Me4Si): d 0.77 (t, 3H, J ¼ 7.2 Hz, OCH2CH3), 0.96 (t, 3H, J
¼
7.2 Hz, OCH2CH3), 3.47–3.59 (m, 3H, NCSCH2,
OC(H)HCH3), 3.84–3.96 (m, 2H, OCH2CH3), 4.09–4.14 (m,
1H, OC(H)HCH3), 4.72 (t, 1H, J ¼ 9.3 Hz, C(3)HPh), 7.19–
7.42 (m, 9H, Ar-H). 13C NMR (50 MHz; CDCl3; Me4Si): d
13.25, 13.40 (2ꢁ OCH2CH3), 47.73 (NCSCH2), 47.97
(C(3)Ph), 62.17, 62.68 (2ꢁ OCH2CH3), 85.34 (C(2)), 128.34,
128.55, 129.40, 130.28, 134.91,135.59, 138.00 (ArC), 165.65,
166.00 (2ꢁ COOCH2CH3), 207.15 (NCS). ESI-MS for
C22H22NO4SCl [M],[M þ Hþ]: 432.10 (35Cl); 434.10 (37Cl).
Diethyl
1-(p-tolyl)-5-thioxo-3-phenyl-pyrrolidine-2,2-di-
carboxylate 2c. White crystalline solid; yield 77%; mp 118–
120ꢀC (from ethyl acetate-petroleum ether); (Found: C, 67.52;
H, 6.05; N, 3.44. Calculated for C23H25NO4S: C, 67.15; H,
6.08; N, 3.40); mmax (liquid film)/cm 1729.83, 1511.40; 1H
NMR (200 MHz; CDCl3; Me4Si): d 0.78 (t, 3H, J ¼ 7.1 Hz,
OCH2CH3), 0.92 (3H, t, J ¼ 7.1 Hz, OCH2CH3), 2.36 (3H, s,
ArCH3), 3.49–3.60 (m, 3H, NCSCH2, OC(H)HCH3), 3.61–3.94
(m, 2H, OCH2CH3), 3.98–4.14 (m, 1H, OCH2CH3), 4.74 (t,
1H, J ¼ 9.3 Hz, C(3)HPh)), 7.1–7.25 (m, 5H, Ar-H), 7.28–
7.42 (m, 4H, Ar-H). 13C NMR (50 MHz; CDCl3; Me4Si): d
13.27, 13.30 (2ꢁ OCH2CH3), 21.22 (ArCH3), 47.69
(NCSCH2), 47.89 (C(3)Ph), 61.98, 62.51 (2ꢁ OCH2CH3),
85.47 (C(2)), 128.18, 128.28, 128.34, 128.49, 129.80, 135.73,
136.86, 138.90 (ArC), 165.78, 166.04 (2ꢁ COOCH2CH3),
206.83 (NCS). ESI-MS for C23H25NO4S [M],[M þ Hþ]:
412.13.
CDCl3; Me4Si):
d
13.46, 13.52 (2ꢁ OCH2CH3), 42.26
(NCSCH2), 45.84 (C(3)), 62.74, 62.78 (2ꢁ OCH2CH3), 83.68
(C(2)), 109.08, 110.60, 115.95, 116.09, 130.50, 130.58,
135.03, 135.06, 142.69, 148.68, 161.20, 163.28 (ArC), 164.98,
165.89 (2ꢁ COOCH2CH3), 205.91 (NCS). C20H20NO5FS
[M],[M þ Hþ]: 406.17.
General procedure for the synthesis of 1-aryl-2,2-dicar-
bethoxy-3-aryl/heteroarylpyrrolidine 3(a–f) from diethyl
1,3-diaryl-5-oxo-pyrrolidine-2,2-dicarboxylates 1(a–f). To a
stirred solution of NaBH4 (4 mmol) in dry THF (20 mL), a so-
lution of iodine (3 mmol) in dry THF (5 mL) was added drop
wise under an argon atmosphere at 0ꢀC over 45 min. Next c-
lactam diester (1 mmol) in dry THF (5 mL) was added to the
reagent mixture, which was stirred at 25–30ꢀC for 2 h. Then
the mixture was refluxed for 20 min, cooled to 0ꢀC, and the
excess hydride was carefully destroyed with dilute HCl solu-
tion and then neutralized with dilute NaOH solution. The or-
ganic layer was separated, and the aqueous layer was extracted
Diethyl 1-(3,4-difluoro phenyl)-5-thioxo-3-phenyl-pyrro-
lidine-2,2-dicarboxylate 2d. Light yellow crystalline solid;
yield 90%; mp 78–83ꢀC (from ethyl acetate-petroleum ether);
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

466
G. Barman, P. Haldar, N. Dutta, and J. K. Ray
Vol 48
with ether. The combined organic extracts were washed with
sodium thiosulfate solution and then with brine and dried over
anhydrous Na2SO4. The solvent was evaporated, and the crude
products were purified by column chromatography. Colorless
viscous oily materials were identified by spectroscopic
methods.
7.27–7.32 (m, 5H, Ar-H). 13C NMR (50 MHz; CDCl3; Me4Si):
d 13.35, 13.78 (2ꢁ OCH2CH3), 20.15 (ArCH3), 28.81 (C(4)),
49.74 (C(5)), 54.80 (C(3)), 60.94, 61.38 (2ꢁ OCH2CH3),
114.25 (C(2)), 126.69, 127.35, 127.97, 128.29, 128.82, 138.02,
143.21 (ArC), 168.11, 169.60 (2ꢁ COOCH2CH3).
1-(3,4-Difluorophenyl)-2,2-dicarbethoxy-3-phenyl pyrro-
lidine 3d. Yellow viscous oily material; yield (83% from 1d;
81% from 2d); (Found: C, 65.62; H, 5.73; N, 3.50. Calculated
for C22H23F2NO4: C, 65.50; H, 5.75; N, 3.47 %.); 1H NMR
(200 MHz; CDCl3; Me4Si): d 0.85 (t, 3H, J ¼ 7.2 Hz,
OCH2CH3), 1.16 (t, 3H, J ¼ 7.1 Hz, OCH2CH3), 2.38–2.47
(m, 2H, C(4)H2), 3.61–3.91 (m, 4H, OCH2CH3), 4.14–4.25 (m,
3H, C(5)H2, C(3)H), 6.26–6.33 (m, 1H, Ar-H), 6.43–6.55 (m,
1H, Ar-H), 6.87–7.02 (m, 1H, Ar-H ), 7.19–7.33 (m, 5H, Ar-H
). 13C NMR (50 MHz; CDCl3; Me4Si): d 13.45, 13.93 (2ꢁ
OCH2CH3), 28.87 (C(4)), 50.35 (C(5)), 54.97 (C(3)), 61.47,
61.92 (2ꢁ OCH2CH3), 103.35, 103.78, 109.49, 109.55 (ArC),
116.40 (C(2)), 116.74, 127.70, 128.24, 128.39, 137.75, 140.80,
141.06, 142.52, 142.72, 145.52, 145.78, 147.51, 147.78,
152.36, 152.63 (ArC), 167.79, 169.22 (2ꢁ COOCH2CH3).
1-(4-Fluorophenyl)-2,2-dicarbethoxy-3-(2-thienyl) pyrro-
lidine 3e. Yellow viscous oily material; yield (78% from 1e;
62% from 2e); (Found: C, 61.48; H, 5.63; N, 3.56. Calculated
for C20H22FNO4S: C, 61.37; H, 5.66; N, 3.58%); mmax (liquid
General procedure for the synthesis of 1-aryl-2,2-dicar-
bethoxy-3-aryl/heteroarylpyrrolidine 3(a–f) from diethyl
N-aryl-5-thioxo-3-aryl/heteroaryl-pyrrolidine-2,2-dicarbox-
ylates (2a–f). To a stirred solution of NaBH4 (3 mmol) in dry
THF (20 mL), solution of iodine (2 mmol) in dry THF (5 mL)
was added drop by drop, under an argon atmosphere at 0ꢀC. The
thio-c-lactam diester (1 mmol) in dry THF (5 mL) was added to
the mixture and next the resulting reaction mixture was stirred
for 3–5 h at room temperature (25–30ꢀC). After completion, the
reaction (checking by TLC), the reaction mixture was cooled to
0ꢀC, and excess hydride was carefully destroyed by adding
dilute HCl solution. Then it was neutralized with dilute NaOH
solution. The organic layer was evaporated out under reduced
pressure and the aqueous layer was extracted with ether. The
combined organic layer was washed with sodium thiosulfate so-
lution and then with brine and dried over anhydrous Na2SO4.
The solvent was evaporated, and the crude products were puri-
fied by column chromatography. Colorless viscous oily materi-
als were identified by spectroscopic methods.
1
film)/cm 1726.40; H NMR (200 MHz; CDCl3; Me4Si): d 0.97
(t, 3H, J ¼ 6.9 Hz, OCH2CH3), 1.17 (t, 3H, J ¼ 6.9 Hz,
OCH2CH3), 2.46–2.54 (m, 2H, C(4)H2), 3.69–3.82 (m, 2H,
OCH2CH3), 3.86–3.99 (m, 2H, OCH2CH3), 4.14–4.25 (m, 2H,
C(5)H2), 4.45 (dd, 1H, J ¼ 7.5, 9.8 Hz, C(3)H), 6.57–6.64 (m,
2H, Ar-H), 6.83–6.96 (m, 4H, Ar-H), 7.19–7.22 (m, 1H, Ar-
H). 13C NMR (50 MHz; CDCl3; Me4Si): d 13.64, 13.95 (2ꢁ
OCH2CH3), 30.64 (C(4)), 50.10 (C(5)), 50.23 (C(3)), 61.55,
61.84 (2ꢁ OCH2CH3), 114.64 (C(2)), 115.08, 115.39, 115.54,
124.73, 126.38, 126.57, 140.45, 142.13, 142.16, 153.73,
158.43 (ArC), 168.15, 169.15 (2ꢁ COOCH2CH3).
1-(4-Fluorophenyl)-2,2-dicarbethoxy-3-phenyl pyrrolidine
3a. Yellow viscous oily material; yield (84% from 1a; 82%
from 2a); (Found: C, 68.66; H, 6.25; N, 3.61. Calculated for
C22H24FNO4: C, 68.56; H, 6.28; N, 3.63%); mmax (liquid film)/
cm 1726.24; 1H NMR (200 MHz; CDCl3; Me4Si): d 0.85 (t,
3H, J ¼ 7.2 Hz, OCH2CH3), 1.12 (t, 3H, J ¼ 7.1 Hz,
OCH2CH3), 2.42–2.51 (m, 2H, C(4)H2), 3.63–3.86 (m, 4H,
OCH2CH3), 4.09–4.25 (m, 3H, C(5)H2, C(3)H), 6.58–6.65 (m,
2H, Ar-H), 6.84–6.93 (m, 2H, Ar-H), 7.20–7.35 (m, 5H, Ar-
H). 13C NMR (50 MHz; CDCl3; Me4Si): d 13.869, 14.117 (2ꢁ
OCH2CH3), 29.61 (C(4)), 50.31(C(5)), 54.85 (C(3)), 61.20,
61.62 (2ꢁ OCH2CH3), 114.58 (C(2)), 115.020, 115.59, 115.74,
153.79, 158.48 (ArC), 168.18, 169.43 (2ꢁ COOCH2CH3).
1-(4-Chlorophenyl)-2,2-dicarbethoxy-3-phenyl pyrrolidine
3b. Yellow viscous oily material; yield (83% from 1b; 80%
from 2b); (Found: C, 65.68; H, 5.99; N, 3.51. Calculated for
C22H24ClNO4: C, 65.75; H, 6.02; N, 3.49%); mmax (liquid
1-(4-Fluorophenyl)-2,2-dicarbethoxy-3-(2-furyl) pyrroli-
dine 3f. Yellow viscous oily material; yield (82% from 1f;
86% from 2f); (Found: C, 64.07; H, 5.88; N, 3.75. Calculated
for C20H22FNO5: C, 63.99; H, 5.91; N, 3.73%); mmax (liquid
1
film)/cm 1736.16; H NMR (200 MHz; CDCl3; Me4Si): d 1.02
(t, 3H, J ¼ 7.2 Hz, OCH2CH3), 1.14 (t, 3H, J ¼ 7.2 Hz,
OCH2CH3), 2.34–2.52 (m, 2H, C(4)H2), 3.67–3.74 (m, 2H,
OCH2CH3), 3.80–4.01 (m, 2H, OCH2CH3), 4.12–4.34 (m, 3H,
C(5)H2, C(3)H), 6.18 (d, 1H, J ¼ 3 Hz, Ar-H), 6.30 (t, 1H, J
¼ 1.9 Hz, Ar-H), 6.55–6.62 (m, 2H, Ar-H), 6.83–6.91 (2H, m,
Ar-H), 7.34 (d, 1H, J ¼ 1.8 Hz, Ar-H). 13C NMR (50 MHz;
CDCl3; Me4Si): d 13.69, 13.86 (2ꢁ OCH2CH3), 27.59 (C(4)),
48.75 (C(5)), 49.89 (C(3)), 61.59, 61.82 (2ꢁ OCH2CH3),
107.62, 110.24, 114.61 (C(2)), 115.05, 115.12,115.27,
141.92, 151.63, 153.67, 158.37 (ArC), 168.22, 169.07 (2ꢁ
COOCH2CH3).
1
film)/cm 1729.25; H NMR (200 MHz; CDCl3; Me4Si): d 0.87
(t, 3H, J ¼ 7.1 Hz, OCH2CH3), 1.16 (t, 3H, J ¼ 7.2 Hz,
OCH2CH3), 2.38–2.57 (m, 2H, C(4)H2), 3.64–3.91(m, 4H,
OCH2CH3), 4.14–4.24 (3H, m, C(5)H2, C(3)H), 6.54–6.62 (m,
2H, Ar-H), 7.09–7.17 (m, 2H, Ar-H), 7.21–7.34 (m, 5H, Ar-
H). 13C NMR (50 MHz; CDCl3; Me4Si): d 13.49, 13.97 (2ꢁ
OCH2CH3), 28.94 (C(4)), 50.07 (C(5)), 55.06 (C(3)), 61.37,
61.84 (2ꢁ OCH2CH3), 115.47 (C(2)), 122.78, 128.22,
128.30, 128.46, 137.88, 144.31 (ArC), 167.87, 169.40 (2ꢁ
COOCH2CH3).
1-(p-Tolyl)-2,2-dicarbethoxy-3-phenyl pyrrolidine 3c. Yellow
viscous oily material; yield (77% from 1c; 65% from 2c);
(Found: C, 72.51; H, 7.10; N, 3.65. Calculated for C23H27NO4:
C,72.42; H, 7.13; N, 3.67%); mmax (liquid film)/cm 1735.17;
1H NMR (200 MHz; CDCl3; Me4Si): d 0.90 (t, 3H, J ¼ 7.2
Hz, OCH2CH3), 1.17 (t, 3H, J ¼ 7.1 Hz, OCH2CH3), 2.27 (s,
3H, Ar-CH3), 2.41–2.57 (m, 2H, C(4)H2), 3.66–3.95 (m, 4H,
OCH2CH3), 4.20 (q, 3H, J ¼ 7.4 Hz, C(5)H2, C(3)H), 6.63 (d,
2H, J ¼ 8.4 Hz, Ar-H), 7.01–7.05 (d, 2H, J ¼ 8.1 Hz, Ar-H),
Acknowledgments. Financial support from DST and CSIR
(New Delhi) is gratefully acknowledged.
REFERENCES AND NOTES
[1] (a) Zhongze, M.; Yoshio, H.; Feng, Q.; Yingjie, C.; Taro,
¨
N. Tetrahedron Lett 2004, 45, 3263; (b) Sonesson, C.; Wikstrom, H.;
Smith, M. W.; Svensson, K.; Carlsson, A.; Waters, N. Bioorg Med
Chem Lett 1997, 7, 241.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011
NaBH4-I2 Mediated Chemoselective Reduction of c-Lactam and Thio-c-lactam
in Presence of Gem-dicarboxylates: An Easy Access to 1,3-Diaryl Pyrrolidines
467
[2] Yee, N. K.; Nummy, L. J.; Byrne, D. P.; Smith, L. L.;
[8] (a) Kar, G. K.; Ramesh, D.; Chatterjee, B. G.; Ray, J. K. J
Chem Res (M) 1997, 568; (b) Kar, G. K.; Ramesh, D.; Chatterjee, B.
G.; Ray, J. K. J Chem Res (S) 1997, 80.
Roth, G. P. J Org Chem 1998, 63, 326.
[3] O’Hagan, D. Nat Prod Rep 2000, 17, 435.
[4] Flaniken, J. M.; Collins, C. J.; Lanz, M.; Singaram, B. Org
Lett 1999, 1, 799.
[9] (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.; Das
Adhikari, S.; Ray, J. K.; Brahma, N. K. Bioorg Med Chem 1998, 6,
2397; (c) Chatterjee, B. G.; Sahu, D. P. J Org Chem 1977, 42, 3162.
[10] Polshettiwar, V.; Kaushik, M. P. Tetrahedron Lett 2004, 45,
6255.
[5] (a) Haldar, P.; Ray, J. K. Org Lett 2005, 7, 4341; (b) Hal-
dar, P.; Ray, J. K. Tetrahedron Lett 2003, 44, 8229.
[6] (a) Haldar, P.; Guin, J.; Ray, J. K. Tetrahedron Lett 2005,
46, 1071; (b) Haldar, P.; Barman, G.; Ray, J. K. Tetrahedron 2007,
63, 3049.
[11] Lien, E. J.; Tong, G. L. J Med Chem 1971, 14, 846.
[12] Prasad, A. S. B.; Kanth, J. V. B.; Periasamy, M. Tetrahe-
dron 1992, 48, 4623.
[7] Sabeena, M. S.; Pakrashi, S. C.; Giri, V. S.; Mandal, S. B.
J Org Chem 1988, 53, 4236.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet