Studies on the reduction of the nitro group in 3-aryl-2-methylene-4-nitro-alkanoates afforded by the Baylis-Hillman adducts: synthesis of 4-aryl-3-methylene-2-pyrrolidinones and 3-(1-alkoxycarbonyl-vinyl)-1H-indole-2-carboxylates

Article abstract of DOI:10.1016/j.tet.2006.08.045

The formation of substituted 2-pyrrolidinones and indoles by the reduction of the secondary nitro group in appropriate 3-aryl-2-methylene-4-nitroalkanoates afforded by Baylis-Hillman chemistry via different reducing agents is described. The 3-aryl-2-methy

Full text of DOI:10.1016/j.tet.2006.08.045

Tetrahedron 62 (2006) 10100–10110
Studies on the reduction of the nitro group in 3-aryl-2-methylene-
4-nitro-alkanoates afforded by the Baylis–Hillman adducts:
synthesis of 4-aryl-3-methylene-2-pyrrolidinones and
3-(1-alkoxycarbonyl-vinyl)-1H-indole-2-carboxylates*
Vijay Singh,a Sanjeev Kanojiyab and Sanjay Batraa,
*
aMedicinal Chemistry Division, Central Drug Research Institute, PO Box 173, Lucknow 226001, Uttar Pradesh, India
bSAIF Division, Central Drug Research Institute, PO Box 173, Lucknow 226001, Uttar Pradesh, India
Received 6 June 2006; revised 29 July 2006; accepted 11 August 2006
Available online 1 September 2006
Abstract—The formation of substituted 2-pyrrolidinones and indoles by the reduction of the secondary nitro group in appropriate 3-aryl-
2-methylene-4-nitroalkanoates afforded by Baylis–Hillman chemistry via different reducing agents is described. The 3-aryl-2-methylene-4-
nitroalkanoate obtained from SN2 nucleophilic reaction between the acetate of Baylis–Hillman adducts and ethyl nitroacetate upon reduction
with indium–HCl furnishes a mixture of cis and trans substituted phenyl-3-methylene-2-pyrrolidinones. In contrast, similar reductions of anal-
ogous substrates derived from nitroethane stereoselectively furnished only the trans substituted phenyl-3-methylene-2-pyrrolidinones. On the
other hand the SnCl2$2H2O-promoted reductions of substrates derived from nitro ethylacetate give oxime derivatives while the ones obtained
from nitroethane yield a mixture of cis and trans 4-aryl-3-methylene-2-pyrrolidinones. Alternatively, the SnCl2$2H2O-promoted reduction of
substituted 2-nitrophenyl-2-methylene-alkanoate furnished from ethyl nitroacetate yield 3-(1-alkoxycarbonyl-vinyl)-1H-indole-2-carboxyl-
ate while indium-promoted reaction of this substrate leads to a complex mixture. Analogous reactions with SnCl2$2H2O of substituted 2-nitro-
phenyl-2-methylene-alkanoate obtained from nitroethane yield 4-alkyl-3-methylene-2-quinolones in moderate yields.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
obtained by SN2 nucleophilic reaction of the acetate of the
Baylis–Hillman products with nitroalkanes, should in princi-
ple offer opportunities for constructing highly substituted
3-methylene-2-pyrrolidinones provided the nitro group is
chemoselectively reduced and the resulting amine could be
made to undergo intramolecular cyclization. Recently, Kim
and co-workers have reported the synthesis of 2-amino-
2,3-dihydrobenzofuran derivatives via oxidation of simi-
lar nitro compounds afforded via SN20 reaction of ethyl
nitroacetate on the allyl bromides afforded by the Baylis–
Hillman adducts.6 In addition, several groups have accom-
plished the facile synthesis of different heterocyclic
compounds employing nitro derivatives afforded via Baylis–
Hillman adducts.7,8 In order to investigate our envisaged
strategy, we have carried out selective reduction of the
nitro group in nitroalkanoates with In to afford the 4-aryl-
3-methylene-2-pyrrolidinones in good yields. Interestingly,
we have observed that reduction of the secondary nitro group
via SnCl2$2H2O in these compounds occurs only partially
leading to the oxime derivatives. This unique observation
has led us to formulate a simple synthesis of substituted
indoles from the nitroalkanoates obtained from the Baylis–
Hillman adducts of 2-nitrobenzaldehyde. The details of the
results of our studies are described herein.
Nitrogen-heterocycles are structural units of several natural
products and represent compounds of pharmacological sig-
nificance. Their prevalence and medicinal utility perhaps
are the major driving force for attracting organic and medic-
inal chemists to formulate their diverse syntheses via novel,
convenient, and efficient methods. The propensity of the
Baylis–Hillman reaction to afford products with multifunc-
tional backbone, which could be tailored further, has found
profound application toward the construction of an array
of useful synthons, heterocycles, and natural products.1 In
order to expand the synthetic utility of this reaction, for
the last couple of years our group has been involved in a
program to carry out convenient and efficient syntheses of
diverse heterocyclic systems utilizing the Baylis–Hillman
chemistry.2,3 Based on our previous work in this area and
on the results reported by Janecki et al.4 and Yus et al.5 we
reasoned that the 3-aryl-2-methylene-4-nitroalkanoates,
*
CDRI communication no. 6919.
Keywords: Baylis–Hillman; Nitroalkanoate; 2-Pyrrolidinone; 1H-Indole-2-
carboxylate; Indium; SnCl2$2H2O.
* Corresponding author. Tel.: +91 522 2262411/18ꢀ4368; fax: +91 522
2623405/2623938; e-mail: batra_san@yahoo.co.uk
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.08.045

V. Singh et al. / Tetrahedron 62 (2006) 10100–10110
10101
Table 1. Results of optimization study for the synthesis of 4-aryl-3-methyl-
ene-2-pyrrolidinones
2. Results and discussion
The preparation of the starting materials in our synthetic
sequence (Scheme 1), the acetates 2a–g, was accomplished
by acetylating Baylis–Hillman adducts 1a–g, which in turn
were afforded from substituted benzaldehydes following
the literature procedure.9 The SN2 nucleophilic substitution
of the acetate 2a–g with ethyl nitroacetate in the presence of
DABCO in a THF–water system yielded the nitroalkanoates
3a–g in 4–6 h in 68–79% yields as diastereoisomeric mix-
tures. This observation is in contrast to the reactions carried
out by Kim et al. who have reported the synthesis of similar
derivatives after 2 days.10 In the next step the products 3a–g
were subjected to chemoselective reduction of the nitro
group without affecting the double bond. In a model reac-
tion, the reduction of the nitro group of compound 3b was
examined with metallic In, Sn, Zn, and Fe in the presence
of HCl or AcOH and SnCl2$2H2O.11 The selection of these
reagents was based on the fact that they are inexpensive,
readily available, and do not require any elaborate reaction
conditions. Results of our evaluation in this direction are
illustrated in Table 1. The highest yield of the expected
substituted 3-methylene-2-pyrrolidinone 4b was achieved
when the reaction was carried out in the presence of In using
HCl in a THF–H2O system at room temperature. Conse-
quently all the substituted 3-methylene-2-pyrrolidinones
5a–g were prepared by reducing the required nitro com-
pound with In in the presence of aq HCl. In all cases these
compounds were obtained as a mixture of cis and trans
products. Our attempts to separate these diastereoisomers
via silica gel column chromatography were successful
Entry Metal/
metal salt
Condition
Product Yield
(%)
1
2
3
4
5
In
In/HCl in THF–H2O for 2 h at rt 5b
64
42
39
45
78
Sn
Zn
Fe
Sn/HCl for 2 h at reflux
Zn/HCl in EtOH for 24 h at rt
Fe/AcOH for 2 h at rt
5b
5b
5b
7b
SnCl2$2H2O SnCl2$2H2O in MeOH
for 2 h at reflux
with compounds 5a and 5b, whereas for compounds 5c–g
these could not be separated. The NOESY experiment of
the polar isomer of compound 5b indicated it to be the trans
isomer.
However the reduction of compound 3b with SnCl2$2H2O,
instead of yielding the expected pyrrolidinone 5b, gave the
oxime 7b (entry 5, Table 1). This was found to be the general
course of reaction as substrates 3a–g also furnished the
corresponding oximes 7a–g when subjected to the SnCl2
reductive conditions. The spectroscopic data supported the
structure assignments. Further support for the assigned struc-
tures of the oximes was made on the basis of an alternate syn-
thesis. It is reported in the literature that the tin complexes
generated from SnCl2$2H2O in the presence of thiophenol
and triethylamine reduces secondary aliphatic nitro com-
pound to the corresponding oxime.12 On the basis of this
report, the compound 3a was treated with SnCl2$2H2O,
thiophenol, and triethylamine to yield a product, which was
similar in all respect to the oxime 7a. As would be expected,
Scheme 1. Reagents and conditions: (i) AcCl, Pyridine, CH2Cl2, rt, 3 h; (ii) DABCO, R1CH2NO2, THF–H2O, rt, 4–7 h; (iii) In, HCl, THF–H2O, rt, 2 h; (iv)
SnCl2$2H2O, MeOH, reflux, 1.5 h; (v) SnCl2$2H2O, MeOH, reflux, 24 h; (vi) MeI, Ag2O, neat, reflux, 1 h; (vii) TsCl, Et3N, CH2Cl2, rt, 3 h; and (viii) DBU,
CH2Cl2, rt, 330 min.

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V. Singh et al. / Tetrahedron 62 (2006) 10100–10110
the methylation of the oximes 7b, c using methyl iodide in the
presence of silver oxide furnished the methyl derivatives
8b, c.13 Although, the SnCl2$2H2O-promoted reduction of
nitroalkenes to the corresponding oximes is documented,14
the ability of SnCl2$2H2O alone to transform the secondary
aliphatic nitro compound to the oxime derivative is
unreported.
steps.15 In order to investigate such possibility with the
oxime 7 generated during the present study, compounds 7b,
d were treated with tosyl chloride in the presence of triethyl-
amine in dichloromethane at room temperature to yield the
corresponding tosyl derivatives 9b, d. Reaction of com-
pounds 9b, d with DBU in dichloromethane gave a complex
mixture of products. The column chromatography of this
mixture led to isolation of a pure product in low yield, the
structure of which was established as substituted pyrroles
10a, d. The formation of the pyrroles can be explained on
the basis of the mechanism as shown in Figure 2.
The next phase of the study was aimed at determining the
driving force responsible for the formation of the oximes.
One possibility was the presence of the carboethoxy group
on the a-carbon of the nitroalkane derivative as illustrated
in Figure 1. In order to validate this concept experimentally,
the SN2 reaction of acetates 2a–c, f, g with nitroethane in
the presence of DABCO in a THF–H2O system to afford
products 4a–c, f, g was accomplished. The nitro group in
compound 4c in the presence of SnCl2$2H2O underwent
reduction followed by cyclization to give 3-methylene-2-
pyrrolidinones 6c as a diastereoisomeric mixture, although
the reaction took more than 24 h for completion. This sup-
ported our assumption that the presence of carboethoxy
group was responsible for the formation of the oxime proba-
bly by the formation of an oximino intermediate. In order to
establish that oxime was not the intermediate for the pyrrol-
idinone, in a model reaction the oxime 7c was treated with
SnCl2$2H2O for more than 24 h. But this reaction failed
indicating that the presence of the ester moiety stabilizes
the oximes. Nevertheless, the reduction of the nitro group in
compounds 4a–c,f, g in the presence of In was complete in
2 h in a highly diastereoselective fashion to furnish the trans
isomer of 4-aryl-5-methyl-3-methylene-2-pyrrolidinones
6a–c, f, g exclusively in 53–64% yields.
Having demonstrated the utility of substrates such as 3a–g
and 4a–c, f, g for the generation of the 3-methylene-2-pyr-
rolidinone system and oximes via selective reduction, we
decided to explore the synthetic utility of similar substrates
derived from 2-nitrophenyl benzaldehyde, such as 11a–c
(Scheme 2) for the following reasons. It is well established
that the Baylis–Hillman derivatives obtained from 2-nitro-
benzaldehyde and acrylates, upon reduction of the nitro moi-
ety to amine invariably results in the formation of quinoline
derivatives through an in situ intramolecular cyclization be-
tween the amino group on the phenyl ring and the ester group
of the side chain.16 However, in view of the findings of the
present study, if compounds 11a–c and 12 are reduced in
the presence of SnCl2$2H2O, the aromatic nitro group will
be chemoselectively reduced to an amino group, which
will then compete for the two ester moieties for the intra-
molecular cyclization. Consequently compound 11a was
synthesized and reacted with SnCl2$2H2O in methanol
under reflux conditions. This reaction proceeded smoothly
to be completed in 1.5 h to give a product, the structure of
which was established as substituted 3-(1-methoxycar-
bonyl-vinyl)-1H-indole-2-carboxylic acid ethyl ester 14a
(Scheme 2). Subsequently other analogs 11b, c and 12
were prepared and subjected to reaction with SnCl2$2H2O.
Of particular relevance to 7, it has been very recently re-
ported that oximes obtained from a-aryl ketones can be
transformed to indoles by an intermediate azirine in two
Figure 1. Mechanism for the formation of oximes.
Figure 2. Mechanism for the formation of pyrroles.
Scheme 2. Reagents and conditions: (i) SnCl2$2H2O, MeOH, reflux, 1.5–2 h.

V. Singh et al. / Tetrahedron 62 (2006) 10100–10110
10103
Figure 3. Mechanism for the formation of indole derivatives.
All these substrates afforded the respective indole deriva-
tives 14b, c and 15 indicating the general nature of this reac-
tion and implying that this transformation invariably
eliminates the aliphatic nitro group, presumably after reduc-
tion to the oxime. The expected mechanism for the forma-
tion of the indole derivative is shown in Figure 3. Unlike
compounds 11 and 12, compounds 13a, b upon reduction
in the presence of SnCl2$2H2O yielded the corresponding
substituted 2-quinolones 16a, b in 2 h in moderate yields.
The formation of 16 was understandable since it has been
previously observed that the aliphatic nitro group is reduced
to an amino group only when the reaction is prolonged
beyond 24 h. These results provoked us to evaluate the reac-
tions of compounds 11 and 13a, b with In in the presence of
HCl in aqueous medium. However, this reaction led to a
complex mixture, which could not be purified in all cases.
compound, 50:50, v/v) was added DABCO (1.5 equiv) at
room temperature and the reaction was allowed to continue
for 20 min. Thereafter ethyl nitroacetate or nitroethane
(1.2 equiv) was added to the reaction mixture and the reac-
tion was allowed to proceed at room temperature for 4 h.
The THF was removed from the reaction mixture via rotary
evaporation and the residue was diluted with water (100 mL)
and extracted with EtOAc (3ꢀ40 mL). The organic layers
were pooled, washed with brine (50 mL), dried (anhyd
Na2SO4), and evaporated to yield a residue, which was puri-
fied via silica gel chromatography employing hexane–
EtOAc (80:20, v/v) to afford products as oils or solids.
4.2.1. 2-Methylene-4-nitro-3-phenylpentanedioic acid
5-ethyl ester 1-methyl ester (3a). Colorless oil 77%
(1.0 g); nmax (Neat) 1723 (CO2Et), 1751 (CO2Me) cmꢁ1
;
1H NMR (200 MHz, CDCl3) d¼0.97 (t, 3H, J¼7.1 Hz,
CH3CH2), 1.27 (t, 3H, J¼7.1 Hz, CH3CH2), 3.71 (s, 3H,
CO2CH3), 3.73 (s, 3H, CO2CH3), 3.99 (q, 2H, J¼7.1 Hz,
CH2CH3), 4.26 (q, 2H, J¼7.1 Hz, CH2CH3), 4.89 (d, 1H,
J¼12.0 Hz, CHAr), 4.95 (d, 1H, J¼12.0 Hz, CHAr), 5.80
(s, 1H, ]CH), 5.86 (s, 1H, ]CH), 5.87 (d, 1H,
J¼12.0 Hz, CHCO2Et), 6.05 (d, 1H, J¼12.0 Hz, CHCO2Et),
6.34 (s, 1H, ]CH), 6.38 (s, 1H, ]CH), 7.28–7.30 (m, 10H,
2ꢀ5ArH); mass (ES+) m/z 330.0 (M++Na); Anal. Calcd for
C15H17NO6: C, 58.63; H, 5.58; N, 4.56. Found: C, 58.38;
H, 5.76; N, 4.64.
3. Conclusions
In summary, we demonstrated the scope of 3-aryl-2-methyl-
ene-4-nitroalkanoates obtained from the Baylis–Hillman
chemistry for the generation of 4-aryl-3-methylene-2-pyrro-
lidinones and 3-(1-alkoxycarbonyl-vinyl)-1H-indole-2-car-
boxylates by the reduction of the secondary nitro group
using different reducing conditions. The mechanistic details
to account for the formation of different heterocyclic systems
have also been proposed. All the synthetic achievements de-
scribed herein were operationally simple and diversity ori-
ented. We believe that the lactam and the indole derivatives
described in this paper will serve as useful building blocks
for the synthesis of compounds belonging to these classes.
4.2.2. 2-Methylene-4-nitro-3-p-tolylpentanedioic acid 5-
ethyl ester 1-methyl ester (3b). Colorless oil 68% (1.4 g);
1
nmax (Neat) 1724 (CO2Et), 1751 (CO2Me) cmꢁ1; H NMR
(200 MHz, CDCl3) d¼1.00 (t, 3H, J¼7.1 Hz, CH3CH2),
1.27 (t, 3H, J¼7.1 Hz, CH3CH2), 2.30 (s, 6H, 2ꢀArCH3),
3.70 (s, 3H, CO2CH3), 3.72 (s, 3H, CO2CH3), 4.01 (q, 2H,
J¼7.1 Hz, CH2CH3), 4.25 (q, 2H, J¼7.1 Hz, CH2CH3),
4.85 (d, 1H, J¼12.0 Hz, CHAr), 4.91 (d, 1H, J¼12.0 Hz,
CHAr), 5.79 (s, 1H, ]CH), 5.83 (s, 1H, ]CH), 5.82 (d,
1H, J¼12.0 Hz, CHCO2Et), 6.02 (d, 1H, J¼12.0 Hz,
CHCO2Et), 6.32 (s, 1H, ]CH), 6.35 (s, 1H, ]CH), 7.08–
7.22 (m, 8H, 2ꢀ4ArH); 13C NMR (50.32 MHz, CDCl3)
d¼13.9, 14.2, 21.4, 48.2, 48.6, 52.6, 63.3, 63.6, 90.1, 90.7,
125.6, 127.5, 128.2, 129.0, 129.9, 130.0, 132.2, 133.5,
138.3, 138.4, 139.0, 163.5, 163.7, 166.1; mass (ES+) m/z
344.0 (M++Na); Anal. Calcd for C16H19NO6: C, 59.81; H,
5.96; N, 4.36. Found: C, 59.48; H, 5.82; N, 4.26.
4. Experimental
4.1. General
Melting points were recorded on a hot stage melting point ap-
paratus and are uncorrected. The IR spectra were recorded on
1
a FTIR spectrophotometer. The H and 13C NMR spectra
were recorded on 200 MHz or 300 MHz spectrometer using
TMS as an internal standard. The mass spectra were recorded
as FAB or LCMS having ES probe. The HRMS spectra were
recorded as EIHRMS. All the solvents and chemicals were
used as procured from the suppliers. The compounds 3a–g,
4a–c, f, g, 5c–g, 11a–c, 12, 13a, b, and 16a, b were obtained
as diastereoisomeric mixtures. All yields indicated herein are
the isolated yields after column chromatography.
4.2.3. 3-(2-Chlorophenyl)-2-methylene-4-nitro-pentane-
dioic acid 5-ethyl ester 1-methyl ester (3c). Colorless oil
79% (2.5 g); nmax (Neat) 1724 (CO2Et), 1751
1
(CO2Me) cmꢁ1; H NMR (200 MHz, CDCl3) d¼1.03 (t,
4.2. General procedure for the preparation of
compounds 3a–g and 4a–c, f, g
3H, J¼7.1 Hz, CH3CH2), 1.27 (t, 3H, J¼7.1 Hz, CH3CH2),
3.71 (s, 3H, CO2CH3), 3.73 (s, 3H, CO2CH3), 4.05 (q, 2H,
J¼7.1 Hz, CH2CH3), 4.24 (q, 2H, J¼7.1 Hz, CH2CH3),
5.34 (d, 1H, J¼12.1 Hz, CHAr), 5.40 (d, 1H, J¼12.1 Hz,
CHAr), 5.98 (s, 1H, ]CH), 5.99 (s, 1H, ]CH), 6.14
To the stirred solution of appropriate compound from 2a–g
(1.0 equiv) in THF–H2O (10 mL for approx. 1.5 g of

10104
V. Singh et al. / Tetrahedron 62 (2006) 10100–10110
(d, 1H, J¼12.1 Hz, CHCO2Et), 6.31 (d, 1H, J¼12.1 Hz,
CHCO2Et), 6.39 (s, 1H, ]CH), 6.42 (s, 1H, ]CH), 7.20–
7.25 (m, 4H, ArH), 7.36–7.41 (m, 3H, ArH), 7.48–7.52 (m,
1H, ArH); mass (FAB+) m/z 342 (M++1); Anal. Calcd for
C15H16ClNO6: C, 52.72; H, 4.72; N, 4.14. Found: C, 53.08;
H, 4.93; N, 4.24.
1H, J¼12.0 Hz, CHCO2Et), 6.34 (s, 1H, ]CH), 6.38
(s, 1H, ]CH), 7.14–7.22 (m, 4H, 2ꢀ2ArH), 7.42–7.57
(m, 4H, 2ꢀ2ArH); mass (ES+) m/z 386.2 (M++1); Anal.
Calcd for C15H16BrNO6: C, 46.65; H, 4.18; N, 3.63. Found:
C, 46.98; H, 4.25; N, 3.71.
4.2.8. 2-Methylene-4-nitro-3-phenylpentanoicacidmethyl
ester (4a). Colorless oil 96% (2.35 g); nmax (Neat) 1721
4.2.4. 3-(2-Fluorophenyl)-2-methylene-4-nitro-pentane-
dioic acid 5-ethyl ester 1-methyl ester (3d). Colorless oil
73% (1.4 g from 1.5 g); nmax (Neat) 1724 (CO2Et), 1753
1
(CO2Me) cmꢁ1; H NMR (200 MHz, CDCl3) d¼1.40 (d,
3H, J¼6.6 Hz, CH3CH), 1.61 (d, 3H, J¼6.6 Hz, CH3CH),
3.73 (s, 6H, CO2CH3), 4.37 (d, 1H, J¼12.0 Hz, CHAr),
4.44 (d, 1H, J¼12.0 Hz, CHAr), 5.19–5.28 (m, 1H,
CHCH3), 5.42–5.60 (m, 1H, CHCH3), 5.81 (s, 1H, ]CH),
5.91 (d, 1H, J¼1.8 Hz, ]CH), 6.34 (s, 1H, ]CH), 6.36 (s,
1H, ]CH), 7.28–7.35 (m, 10H, 2ꢀ5ArH); 13C NMR
(50.32 MHz, CDCl3) d¼19.3, 19.5, 51.5, 52.5, 52.7, 85.5,
86.0, 125.2, 128.0, 128.2, 129.1, 129.4, 131.1, 137.8,
139.6, 139.9, 166.3, 166.6; mass (ES+) m/z 272.1
(M++Na); Anal. Calcd for C13H15F3NO5: C, 62.64; H,
6.07; N, 5.62. Found: C, 62.97; H, 5.99; N, 5.53.
1
(CO2Me) cmꢁ1; H NMR (200 MHz, CDCl3) d¼1.02 (t,
3H, J¼7.1 Hz, CH3CH2), 1.28 (t, 3H, J¼7.1 Hz,
CH3CH2), 3.72 (s, 3H, CO2CH3), 3.74 (s, 3H, CO2CH3),
4.04 (q, 2H, J¼7.1 Hz, CH2CH3), 4.28 (q, 2H, J¼7.1 Hz,
CH2CH3), 5.10–5.19 (m, 2H, CHAr), 5.92 (d, 1H,
J¼1.0 Hz, ]CH), 5.95 (s, 1H, ]CH), 6.08 (d, 1H,
J¼12.0 Hz, CHCO2Et), 6.23 (d, 1H, J¼12.0 Hz, CHCO2Et),
6.38 (s, 1H, ]CH), 6.41 (s, 1H, ]CH), 7.03–7.39 (m, 8H,
2ꢀ4ArH); mass (ES+) m/z 326.4 (M++1); Anal. Calcd for
C15H16FNO6: C, 55.38; H, 4.96; N, 4.31. Found: C, 55.89;
H, 5.21; N, 4.52.
4.2.9. 2-(2-Nitro-1-p-tolylpropyl)-acrylic acid methyl
ester (4b). Colorless oil 88% (0.73 g); nmax (Neat) 1721
4.2.5. 3-(4-Chlorophenyl)-2-methylene-4-nitro-pentane-
dioic acid 5-ethyl ester 1-methyl ester (3e). Pale yellow
solid 78% (1.23 g), mp 96–98 ꢂC; nmax (KBr) 1724
1
(CO2Me) cmꢁ1; H NMR (300 MHz, CDCl3) d¼1.42 (d,
3H, J¼6.0 Hz, CH3CH), 1.62 (d, 3H, J¼6.0 Hz, CH3CH),
2.30 (s, 3H, ArCH3), 2.34 (s, 3H, ArCH3), 3.70 (s, 3H,
CO2CH3), 3.75 (s, 3H, CO2CH3), 4.36 (d, 1H, J¼12.0 Hz,
CHAr), 4.43 (d, 1H, J¼12.0 Hz, CHAr), 5.19–5.25 (m, 1H,
CHCH3), 5.44–5.50 (m, 1H, CHCH3), 5.81 (s, 1H, ]CH),
5.91 (d, 1H, J¼3.0 Hz, ]CH), 6.34 (s, 1H, ]CH), 6.36 (s,
1H, ]CH), 7.09–7.20 (m, 8H, 2ꢀ2ArH); 13C NMR
(50.32 MHz, CDCl3) d¼19.3, 19.5, 21.4, 51.2, 52.4,
52.5, 52.6, 85.6, 86.1, 125.0, 127.7, 128.3, 129.0, 130.1,
134.0, 134.8, 137.9, 138.1, 139.8, 140.0, 166.4, 166.7;
mass (ES+) m/z 286.1 (M++Na); Anal. Calcd for
C14H17NO4: C, 63.87; H, 6.51; N, 5.32. Found: C, 64.23;
H, 6.89; N, 5.21.
(CO2Et), 1751 (CO2Me) cmꢁ1
;
1H NMR (200 MHz,
CDCl3) d¼1.04 (t, 3H, J¼7.1 Hz, CH3CH2), 1.26 (t, 3H,
J¼7.1 Hz, CH3CH2), 3.71 (s, 3H, CO2CH3), 3.73 (s, 3H,
CO2CH3), 4.04 (q, 2H, J¼7.1 Hz, CH2CH3), 4.26 (q, 2H,
J¼7.1 Hz, CH2CH3), 4.86 (d, 1H, J¼12.1 Hz, CHAr), 4.91
(d, 1H, J¼12.1 Hz, CHAr), 5.81 (s, 1H, ]CH), 5.86 (s,
1H, ]CH), 5.87 (d, 1H, J¼12.1 Hz, CHCO2Et), 6.02 (d,
1H, J¼12.1 Hz, CHCO2Et), 6.35 (s, 1H, ]CH), 6.38 (s,
1H, ]CH), 7.24–7.38 (m, 8H, 2ꢀ4ArH); mass (FAB+)
m/z 342 (M++1); Anal. Calcd for C15H16ClNO6: C, 52.72;
H, 4.72; N, 4.14. Found: C, 53.28; H, 4.54; N, 4.35.
4.2.6. 3-(4-Fluorophenyl)-2-methylene-4-nitro-pentane-
dioic acid 5-ethyl ester 1-methyl ester (3f). Pale yellow
solid 72% (1.56 g), mp 82–84 ꢂC; nmax (KBr) 1723
4.2.10. 3-(2-Chlorophenyl)-2-methylene-4-nitro-penta-
noic acid methyl ester (4c). Pale yellow oil 85% (1.8 g);
(CO2Et), 1750 (CO2Me) cmꢁ1
;
1H NMR (200 MHz,
nmax (Neat) 1726 (CO2Me) cmꢁ1 1H NMR (200 MHz,
;
CDCl3) d¼1.00 (t, 3H, J¼7.1 Hz, CH3CH2), 1.27 (t, 3H,
J¼7.1 Hz, CH3CH2), 3.72 (s, 3H, CO2CH3), 3.73 (s, 3H,
CO2CH3), 4.03 (q, 2H, J¼7.1 Hz, CH2CH3), 4.26 (q, 2H,
J¼7.1 Hz, CH2CH3), 4.85 (d, 1H, J¼12.0 Hz, CHAr), 4.98
(d, 1H, J¼12.0 Hz, CHAr), 5.80 (s, 1H, ]CH), 5.86 (s,
1H, ]CH), 5.87 (d, 1H, J¼12.0 Hz, CHCO2Et), 6.01 (d,
1H, J¼12.0 Hz, CHCO3Et), 6.35 (s, 1H, ]CH), 6.38 (s,
1H, ]CH), 6.96–7.04 (m, 4H, 2ꢀ2ArH), 7.21–7.30 (m,
4H, 2ꢀ2ArH); mass (FAB+) m/z 326 (M++1); Anal. Calcd
for C15H16FNO6: C, 55.38; H, 4.96; N, 4.31. Found: C,
55.98; H, 5.11; N, 4.52.
CDCl3) d¼1.45 (d, 3H, J¼6.6 Hz, CH3CH), 1.63 (d, 3H,
J¼6.6 Hz, CH3CH), 3.68 (s, 3H, CO2CH3), 3.74 (s, 3H,
CO2CH3), 4.93 (d, 1H, J¼11.0 Hz, CHAr), 5.08 (d, 1H,
J¼11.0 Hz, CHAr), 5.21–5.28 (m, 1H, CHCH3), 5.64–5.73
(m, 1H, CHCH3), 5.95 (s, 1H, ]CH), 5.97 (s, 1H, ]CH),
6.39 (s, 1H, ]CH), 6.41 (s, 1H, ]CH), 7.17–7.25 (m, 4H,
2ꢀ2ArH), 7.33–7.37 (m, 2H, 2ꢀ1ArH), 7.53–7.58 (m, 2H,
2ꢀ1ArH); mass (ES+) m/z 284.6 (M++1); Anal. Calcd for
C13H14ClNO4: C, 55.04; H, 4.97; N, 4.94. Found: C,
54.78; H, 5.08; N, 4.86.
4.2.11. 3-(4-Fluorophenyl)-2-methylene-4-nitro-penta-
noic acid methyl ester (4f). Pale yellow oil 85% (1.5 g);
4.2.7. 3-(4-Bromophenyl)-2-methylene-4-nitro-pentane-
dioic acid 5-ethyl ester 1-methyl ester (3g). Colorless oil
72% (1.5 g); nmax (Neat) 1721 (CO2Et), 1750
nmax (Neat) 1721 (CO2Me) cmꢁ1 1H NMR (200 MHz,
;
CDCl3) d¼1.40 (d, 3H, J¼6.6 Hz, CH3CH), 1.61 (d, 3H,
J¼6.6 Hz, CH3CH), 3.70 (s, 3H, CO2CH3), 3.74 (s, 3H,
CO2CH3), 4.35 (d, 1H, J¼11.2 Hz, CHAr), 4.43 (d, 1H,
J¼11.2 Hz, CHAr), 5.18–5.25 (m, 1H, CHCH3), 5.40–5.49
(m, 1H, CHCH3), 5.83 (s, 1H, ]CH), 5.90 (s, 1H, ]CH),
6.34 (s, 1H, ]CH), 6.37 (s, 1H, ]CH), 6.92–7.06 (m, 4H,
2ꢀ2ArH), 7.21–7.30 (m, 4H, 2ꢀ2ArH); 13C NMR
(50.32 MHz, CDCl3) d¼19.3, 19.5, 51.5, 52.5, 52.7, 85.5,
1
(CO2Me) cmꢁ1; H NMR (200 MHz, CDCl3) d¼1.04 (t,
3H, J¼7.1 Hz, CH3CH2), 1.26 (t, 3H, J¼7.1 Hz,
CH3CH2), 3.71 (s, 3H, CO2CH3), 3.73 (s, 3H, CO2CH3),
4.05 (q, 2H, J¼7.1 Hz, CH2CH3), 4.26 (q, 2H, J¼7.1 Hz,
CH2CH3), 4.85 (d, 1H, J¼12.0 Hz, CHAr), 4.89 (d, 1H,
J¼12.0 Hz, CHAr), 5.81 (s, 1H, ]CH), 5.86 (s,
1H, ]CH), 5.87 (d, 1H, J¼12.0 Hz, CHCO2Et), 6.02 (d,

V. Singh et al. / Tetrahedron 62 (2006) 10100–10110
10105
86.0, 125.2, 128.0, 128.2, 129.1, 129.4, 131.1, 137.8, 139.6,
139.9, 166.3, 166.6; mass (FAB+) m/z 268 (M++1); Anal.
Calcd for C13H14FNO4: C, 58.42; H, 5.28; N, 5.24. Found:
C, 58.01; H, 5.52; N, 5.20.
4.3.3. 4-Methylene-5-oxo-3-p-tolylpyrrolidine-2-carbox-
ylic acid ethyl ester (5b)-(cis). Total yield 64% (0.268 g)
as a white solid, mp 123–125 ꢂC; nmax (KBr) 1695 (CONH),
1738 (CO2Et), 3445 (NH) cmꢁ1 1H NMR (200 MHz,
;
CDCl3) d¼1.28 (t, 3H, J¼7.1 Hz, CH3CH2), 2.35 (s, 3H,
ArCH3), 4.15–4.27 (m, 4H, CH2CH3, CHAr and CHCO2Et),
5.25 (d, 1H, J¼1.8 Hz, ]CH), 6.20 (d, 1H, J¼2.6 Hz,
]CH), 6.62 (s, 1H, NH), 7.17 (s, 4H, ArH); mass (FAB+)
m/z 260 (M++1); HREIMS calculated for C15H17NO3
259.1208, found, 259.1208.
4.2.12. 3-(4-Bromophenyl)-2-methylene-4-nitro-penta-
noic acid methyl ester (4g). Colorless oil 92% (2.4 g);
nmax (Neat) 1725 (CO2Me) cmꢁ1 1H NMR (200 MHz,
;
CDCl3) d¼1.41 (d, 3H, J¼6.6 Hz, CH3CH), 1.61 (d, 3H,
J¼6.6 Hz, CH3CH), 3.68 (s, 3H, CO2CH3), 3.73 (s, 3H,
CO2CH3), 4.32 (d, 1H, J¼11.5 Hz, CHAr), 4.41 (d, 1H, J¼
11.5 Hz, CHAr), 5.14–5.22 (m, 1H, CHCH3), 5.41–5.47 (m,
1H, CHCH3), 5.81 (s, 1H, ]CH), 5.90 (s, 1H, ]CH), 6.35
(s, 1H, ]CH), 6.37 (s, 1H, ]CH), 7.13–7.19 (m, 4H,
2ꢀ2ArH), 7.39–7.48 (m, 4H, 2ꢀ2ArH); 13C NMR
(50.32 MHz, CDCl3) d¼19.3, 19.4, 51.1, 52.4, 52.6, 52.8,
85.0, 85.7, 122.3, 125.6, 128.3, 130.1, 130.8, 132.3, 132.5,
136.1, 136.9, 139.1, 139.4, 166.1, 166.4; mass (FAB+) m/z
328 (M++1); Anal. Calcd for C13H14BrNO4: C, 47.58; H,
4.30; N, 4.27. Found: C, 46.71; H, 4.53; N, 4.41.
4.3.4. 4-Methylene-5-oxo-3-p-tolylpyrrolidine-2-carbox-
ylic acid ethyl ester (5b)-(trans). Total yield 64%
(0.268 g) as a white solid, mp 162–164 ꢂC; nmax (KBr)
1
1695 (CONH), 1738 (CO2Et), 3442 (NH) cmꢁ1; H NMR
(300 MHz, CDCl3) d¼0.85 (t, 3H, J¼7.3 Hz, CH3CH2),
2.30 (s, 3H, ArCH3), 3.57–3.64 (m, 1H, CHAr), 3.74–3.77
(m, 1H, CHAr), 4.46–4.54 (m, 2H, CH2CH3), 5.29 (d, 1H,
J¼3.0 Hz, ]CH), 6.22 (d, 1H, J¼3.0 Hz, ]CH), 6.57 (s,
1H, NH), 7.04–7.10 (m, 4H, ArH); 13C NMR (50.32 MHz,
CDCl3) d¼13.9, 21.4, 48.0, 59.8, 61.6, 119.4, 129.3,
129.5, 135.5, 137.9, 142.4, 170.4, 171.4; mass (FAB+) m/z
260 (M++1); HREIMS calculated for C15H17NO3
259.1208, found, 259.1208.
4.3. General procedure for the reduction of 3a–g and
4a–c, f, g with indium
To the stirred solution of appropriate compound from 3a–g
and 4a–c, f, g (1.0 equiv) in THF–H2O (5 mL for approx.
0.5 g of compound, 1:3, v/v) was added In powder
(4.0 equiv) followed by 6 N HCl (6.0 equiv). The reaction
was allowed to proceed at room temperature and was mon-
itored via TLC. On completion, approximately 2 h, THF
was evaporated and the pH of the residue was made alkaline
with saturated NaHCO3 solution. The solution was diluted
with EtOAc and filtered through a bed of Celite. The filtrate
was then extracted with EtOAc (3ꢀ25 mL) and the com-
bined organic layers were dried (Na2SO4) and concentrated.
The residue was purified by column chromatography over
silica gel using hexane–EtOAc (30:70, v/v) to yield products
5a–g and 6a–c, f, g.
4.3.5. 3-(2-Chlorophenyl)-4-methylene-5-oxo-pyrrol-
idine-2-carboxylic acid ethyl ester (5c). White solid 56%
(0.37 g), mp 110–112 ꢂC; nmax (KBr) 1710 (CONH), 1728
1
(CO2Et), 3412 (NH) cmꢁ1; H NMR (200 MHz, CDCl3)
d¼0.82 (t, 3H, J¼7.1 Hz, CH3CH2), 1.27 (t, 3H, J¼7.1 Hz,
CH3CH2), 3.49–3.62 (m, 1H, CHHCH3), 3.67–3.79 (m,
1H, CHHCH3), 4.17–4.31 (m, 2H, CH2CH3), 4.68 (d, 2H,
J¼9.0 Hz, 2ꢀCHAr), 5.13 (d, 2H, J¼9.0 Hz, 2ꢀCHCO2Et),
5.23 (s, 1H, ]CH), 5.35 (s, 1H, ]CH), 6.16 (d, 1H,
J¼2.4 Hz, ]CH), 6.31 (d, 1H, J¼2.6 Hz, ]CH), 6.69 (br
s, 2H, 2ꢀ1NH), 7.20–7.27 (m, 6H, 2ꢀ3ArH), 7.40–7.41
(m, 2H, 2ꢀ1ArH); 13C NMR (50.32 MHz, CDCl3) d¼13.9,
14.4, 44.2, 46.1, 58.2, 60.5, 61.1, 62.4, 119.1, 119.7, 127.4,
127.9, 129.4, 129.7, 130.0, 130.3, 130.4, 134.2, 135.9,
138.8, 140.9, 142.1, 170.0, 170.4, 171.2; mass (ES+) m/z
280.1 (M++1), 282.1 (M++3); HREIMS calculated for
C14H14ClNO3 279.0662, found, 279.0664.
4.3.1. 4-Methylene-5-oxo-3-phenylpyrrolidine-2-carbox-
ylic acid ethyl ester (5a)-(cis). Total yield 68% (0.54 g) as
a white solid, mp 122–124 ꢂC; nmax (KBr) 1692 (CONH),
1746 (CO2Et), 3400 (NH) cmꢁ1 1H NMR (200 MHz,
;
CDCl3) d¼1.27 (t, 3H, J¼7.1 Hz, CH3CH2), 4.18–4.27 (m,
4H, CH2CH3, CHAr and CHCO2Et), 5.26 (s, 1H, ]CH),
6.22 (s, 1H, ]CH), 6.56 (s, 1H, NH), 7.29–7.38 (m, 5H,
ArH); 13C NMR (50.32 MHz, CDCl3) d¼14.5, 48.9, 61.9,
62.3, 119.8, 128.0, 128.4, 129.4, 141.7, 142.9, 170.1,
171.3; mass (ES+) m/z 246.1 (M++1); HREIMS calculated
for C14H15NO3 245.1052, found, 245.1052.
4.3.6. 3-(2-Fluorophenyl)-4-methylene-5-oxo-pyrrol-
idine-2-carboxylic acid ethyl ester (5d). White solid 57%
(0.12 g), mp 105–107 ꢂC; nmax (KBr) 1704 (CONH), 1743
1
(CO2Et), 3332 (NH) cmꢁ1; H NMR (200 MHz, CDCl3)
d¼0.85 (t, 3H, J¼7.2 Hz, CH3CH2), 1.29 (t, 3H, J¼7.2 Hz,
CH3CH2), 3.48–3.61 (m, 2H, CH2CH3), 4.23–4.39 (m, 5H,
CH2CH3, 2ꢀCHAr and CHCO2Et), 4.71–4.84 (m, 1H,
CHCO2Et), 5.28 (d, 1H, J¼1.3 Hz, ]CH), 5.36 (d, 1H,
J¼0.6 Hz, ]CH), 6.20 (d, 1H, J¼1.1 Hz, ]CH), 6.38 (d,
1H, J¼1.0 Hz, ]CH), 7.04–7.30 (m, 8H, 2ꢀ4ArH); 13C
NMR (50.32 MHz, CDCl3) d¼13.9, 14.4, 40.0, 43.0, 58.8,
60.8, 61.7, 61.9, 115.3, 115.7, 116.1, 116.5, 119.7, 119.8,
124.7, 125.0, 125.1, 125.7, 129.8, 130.0, 130.2, 130.3,
138.9, 140.8, 142.0, 169.9, 170.2, 171.0, 171.5; mass (ES+)
m/z 264.3 (M++1); HREIMS calculated for C14H14FNO3
263.0958, found, 263.0954.
4.3.2. 4-Methylene-5-oxo-3-phenylpyrrolidine-2-carbox-
ylic acid ethyl ester (5a)-(trans). Total yield 68% (0.54 g)
as a white solid, mp 160–162 ꢂC; nmax (KBr) 1692
(CONH), 1738 (CO2Et), 3445 (NH) cmꢁ1
;
1H NMR
(300 MHz, CDCl3) d¼0.83 (t, 3H, J¼6.0 Hz, CH3CH2),
3.57–3.63 (m, 1H, CHAr), 3.75–3.81 (m, 1H, CHCO2Et),
4.52–4.61 (m, 2H, CH2CH3), 5.33 (s, 1H, ]CH), 6.26 (s,
1H, ]CH), 6.76 (s, 1H, NH), 7.18–7.29 (m, 5H); 13C
NMR (50.32 MHz, CDCl3) d¼13.9, 48.2, 59.7, 61.6, 119.6,
128.2, 128.9, 129.4, 138.6, 142.3, 170.4, 171.4; mass (ES+)
m/z 246.1 (M++1); HREIMS calculated for C14H15NO3
245.1052, found, 245.1052.
4.3.7. 3-(4-Chlorophenyl)-4-methylene-5-oxo-pyrrol-
idine-2-carboxylic acid ethyl ester (5e). White solid 61%
(0.174 g), mp 106–108 ꢂC; nmax (KBr) 1713 (CONH),

10106
V. Singh et al. / Tetrahedron 62 (2006) 10100–10110
1748 (CO2Et), 3445 (NH) cmꢁ1
;
1H NMR (200 MHz,
(50.32 MHz, CDCl3) d¼18.3, 21.4, 50.9, 62.9, 117.9,
CDCl3) d¼0.88 (t, 3H, J¼7.2 Hz, CH3CH2), 1.29 (t, 3H,
J¼7.2 Hz, CH3CH2), 3.51–3.92 (m, 2H, 2ꢀCHAr), 4.14–
4.27 (m, 4H, 2ꢀCH2CH3), 4.40–4.68 (m, 2H, 2ꢀCHCO2Et),
5.25 (d, 1H, J¼1.9 Hz, ]CH), 5.31 (d, 1H, J¼1.6 Hz,
]CH), 6.22 (d, 1H, J¼2.9 Hz, ]CH), 6.26 (d, 1H,
J¼2.6 Hz, ]CH), 6.98 (s, 2H, 2ꢀNH), 7.11–7.37 (m, 8H,
2ꢀ4ArH); 13C NMR (50.32 MHz, CDCl3) d¼14.0, 14.5,
47.5, 48.2, 59.6, 61.8, 61.9, 62.6, 119.5, 120.1, 129.0,
129.6, 129.7, 129.8, 130.8, 133.9, 134.2, 137.1, 138.9, 140.0,
141.9, 142.6, 169.9, 170.1, 171.0, 171.3; mass (ES+) m/z
280.1 (M++1); HREIMS calculated for C14H14ClNO3
279.0662, found, 279.0658.
128.7, 130.0, 137.3, 137.7, 163.8; mass (ES+) 188.2
(M++1); HREIMS calculated for C13H15NO 201.1155,
found, 201.1148.
4.3.12. 4-(2-Chlorophenyl)-5-methyl-3-methylenepyr-
rolidin-2-one (6c). Brown solid 58% (0.09 g), mp 117–
1
119 ꢂC; nmax (KBr) 1684 (CONH), 3433 (NH) cmꢁ1. H
NMR (300 MHz, CDCl3) d¼0.76 (d, 3H, J¼6.0 Hz,
CH3CH), 4.20–4.25 (m, 1H, CHAr), 4.85–4.90 (m, 1H,
CHCH3), 5.33 (d, 1H, J¼3.0 Hz, ]CH), 6.30 (d, 1H,
J¼3.0 Hz, ]CH), 7.18–7.25 (m, 2H, ArH), 7.38–7.44 (m,
2H, ArH); mass (ES+) 222.1 (M++1); HREIMS calculated
for C12H12ClNO 221.0607, found, 221.0606.
4.3.8. 3-(4-Fluorophenyl)-4-methylene-5-oxo-pyrrol-
idine-2-carboxylic acid ethyl ester (5f). White solid 63%
(0.315 g), mp 114–116 ꢂC; nmax (KBr) 1705 (CONH), 1743
4.3.13. 4-(2-Chlorophenyl)-5-methyl-3-methylenepyr-
rolidin-2-one (6c) (diastereoisomeric mixture as obtained
from reaction of SnCl2$2H2O). Brown solid 54% (0.13 g),
1
(CO2Et), 3214 (NH) cmꢁ1; H NMR (200 MHz, CDCl3)
d¼1.21–1.39 (m, 6H, 2ꢀCH3CH2), 3.70–3.98 (m, 2H, 2ꢀ
CHAr), 4.05–4.38 (m, 6H, 2ꢀCH2CH3 and 2ꢀCHCO2Et),
5.27–5.32 (m, 2H, 2ꢀ]CH), 6.23–6.28 (m, 2H, 2ꢀ]CH),
7.01–7.43 (m, 8H, 2ꢀ4ArH); 13C NMR (50.32 MHz,
CDCl3) d¼14.0, 14.5, 44.3, 45.8, 62.0, 62.6, 66.2, 67.9,
115.7, 116.1, 116.2, 116.7, 120.0, 120.3, 129.8, 130.0,
131.5, 131.7, 136.1, 139.2, 139.7, 142.0, 160.3, 164.7,
165.2, 168.2, 169.8; mass (FAB+) m/z 264 (M++1); HREIMS
calculated for C14H14FNO3 263.0958, found, 263.0958.
mp 96–98 ꢂC; nmax (KBr) 1670 (CONH), 3415 (NH) cmꢁ1
;
1H NMR (200 MHz, CDCl3) d¼0.77 (d, 3H, J¼6.5 Hz,
CH3CH), 0.89 (d, 3H, J¼6.5 Hz, CH3CH), 3.60–3.65 (m,
1H, CHAr), 4.22–3.29 (m, 1H, CHAr), 4.35–4.39 (m, 1H,
CHCH3), 4.87–4.92 (m, 1H, CHCH3), 5.26 (s, 1H, ]CH),
5.37 (d, 1H, J¼2.5 Hz, ]CH), 6.14 (s, 1H, ]CH), 6.34 (d,
1H, J¼2.5 Hz, ]CH), 6.96 (br s, 2H, 2ꢀNH), 7.17–7.27
(m, 6H, 2ꢀ3ArH), 7.33–7.45 (m, 2H, 2ꢀ1ArH); mass
(FAB+) 222 (M++1); HREIMS calculated for C12H12ClNO
221.0607, found, 221.0608.
4.3.9. 3-(4-Bromophenyl)-4-methylene-5-oxo-pyrrol-
idine-2-carboxylic acid ethyl ester (5g). White solid 55%
(0.21 g), mp 159–161 ꢂC; nmax (KBr) 1712 (CONH), 1750
4.3.14. 4-(4-Fluoro-phenyl)-5-methyl-3-methylenepyr-
rolidin-2-one (6f). White solid 53% (0.13 g), mp 162–
1
1
(CO2Et), 3430 (NH) cmꢁ1; H NMR (200 MHz, CDCl3)
164 ꢂC; nmax (KBr) 1667 (CONH), 3413 (NH) cmꢁ1; H
d¼0.88 (t, 3H, J¼7.1 Hz, CH3CH2), 1.29 (t, 3H, J¼7.1 Hz,
CH3CH2), 3.60–3.91 (m, 2H, 2ꢀCHAr), 4.21–4.27 (m, 4H,
2ꢀCH2CH3), 4.38–4.60 (m, 2H, 2ꢀCHCO2Et), 5.25 (d,
1H, J¼2.0 Hz, ]CH), 5.30 (d, 1H, J¼1.7 Hz, ]CH), 6.22
(d, 1H, J¼2.9 Hz, ]CH), 6.25 (d, 1H, J¼2.5 Hz, ]CH),
6.66 (br s, 2H, 2ꢀNH), 7.06–7.57 (m, 8H, 2ꢀ4ArH); 13C
NMR (50.32 MHz, CDCl3) d¼14.0, 14.5, 47.5, 48.3, 59.4,
61.8, 62.4, 120.0, 122.0, 122.3, 130.2, 131.1, 131.5, 132.0,
132.5, 134.4, 137.7, 140.6, 141.9, 142.6, 170.2, 171.1, 171.9;
mass (ES+) m/z 324.1 (M++1), 326.1 (M++3); HREIMS
calculated for C14H14BrNO3 323.0157, found, 323.0155.
NMR (200 MHz, CDCl3) d¼1.45 (d, 3H, J¼6.2 Hz,
CH3CH), 3.54–3.57 (m, 1H, CHAr), 3.75–3.84 (m, 1H,
CHCH3), 5.12 (d, 1H, J¼2.3 Hz, ]CH), 6.08 (d, 1H,
J¼2.8 Hz, ]CH), 6.99–7.08 (m, 2H, ArH), 7.14–7.21 (m,
2H, ArH); 13C NMR (50.32 MHz, CDCl3) d¼18.3, 50.5,
63.1, 116.1, 116.5, 118.0, 130.2, 130.4, 131.4, 136.1,
141.8, 165.0; mass (ES+) m/z 206.1 (M++1); HREIMS calcu-
lated for C12H12FNO 205.0903, found, 205.0905.
4.3.15. 4-(4-Bromophenyl)-5-methyl-3-methylenepyr-
rolidin-2-one (6g). Yellow oil 64% (0.23 g); nmax (Neat)
1688 (CONH), 3427 (NH) cmꢁ1 1H NMR (200 MHz,
;
4.3.10. 5-Methyl-3-methylene-4-phenylpyrrolidin-2-one
(6a). An off white solid 62% (0.144 g), mp 118–120 ꢂC;
CDCl3) d¼1.44 (d, 3H, J¼6.2 Hz, CH3CH), 3.53–3.58 (m,
1H, CHAr), 3.76–3.86 (m, 1H, CHCH3), 5.13 (d, 1H,
J¼2.4 Hz, ]CH), 6.07 (d, 1H, J¼2.9 Hz, ]CH), 7.08 (d,
2H, J¼8.4 Hz, ArH), 7.48 (d, 2H, J¼8.4 Hz, ArH); 13C
NMR (50.32 MHz, CDCl3) d¼18.5, 51.2, 62.8, 117.9,
128.9, 130.2, 137.3, 137.9, 164.5; mass (ES+) m/z 266.0
(M++1); HREIMS calculated for C12H12BrNO 265.0102,
found, 265.0108.
nmax (KBr) 1674 (CONH), 3413 (NH) cmꢁ1 1H NMR
;
(200 MHz, CDCl3) d¼1.45 (d, 3H, J¼6.2 Hz, CH3CH),
3.55–3.58 (m, 1H, CHAr), 3.82–3.88 (m, 1H, CHCH3),
5.13 (d, 1H, J¼2.4 Hz, ]CH), 6.09 (d, 1H, J¼3.0 Hz,
]CH), 7.19 (m, 5H, ArH); 13C NMR (50.32 MHz, CDCl3)
d¼18.4, 51.2, 63.0, 117.8, 128.0, 128.8, 129.3, 140.4,
163.6; mass (ES+) 188.2 (M++1); HREIMS calculated for
C12H13NO 187.0997, found, 187.0991.
4.4. General procedure for reduction of compounds
3a–g with SnCl2$2H2O
4.3.11. 5-Methyl-3-methylene-4-p-tolylpyrrolidin-2-one
(6b). Brown solid 60% (0.107 g), mp 155–157 ꢂC; nmax
To the solution of compounds from 3a–g (1.0 equiv) in
methanol (10 mL) was added SnCl2$2H2O (5.0 equiv) and
the reaction mixture was heated at reflux with stirring at
80 ꢂC for 1.5 h in a nitrogen atmosphere. On completion,
methanol was evaporated and the residue was made alkaline
with saturated NaHCO3 and then EtOAc (100 mL) was
added. The suspension was passed through a bed of Celite
(KBr) 1686 (CONH), 3431 (NH) cmꢁ1
;
1H NMR
(200 MHz, CDCl3) d¼1.32 (d, 3H, J¼6.0 Hz, CH3CH),
2.35 (s, 3H, ArCH3), 3.54 (d, 1H, J¼2.7 Hz, CHAr), 3.68
(t, 1H, J¼6.1 Hz, CHCH3), 5.12 (s, 1H, ]CH), 6.08 (d,
1H, J¼2.7 Hz, ]CH), 6.92 (s, 1H, NH), 7.11 (d, 2H,
J¼8.0 Hz, ArH), 7.17 (d, 2H, J¼8.0 Hz, ArH); 13C NMR

V. Singh et al. / Tetrahedron 62 (2006) 10100–10110
10107
and the filtrate was partitioned in a separating funnel. The
organic layer was separated, dried (Na2SO4), and concen-
trated to afford a residue, which was purified by silica
gel chromatography using hexane–EtOAc (90:10, v/v) or
(20:80, v/v) as eluent to yield products 7a–g as oils.
mass (FAB+) m/z 326; HREIMS calculated for
C15H16ClNO5 325.0717, found, 325.0718.
4.4.6. 3-(4-Fluorophenyl)-2-hydroxyimino-4-methylene-
pentanedioic acid 1-ethyl ester 5-methyl ester (7f). Color-
less oil 87% (0.24 g); nmax (Neat) 1628 (C]N), 1722 (CO2Et
and CO2Me), 3367 (OH) cmꢁ1; 1H NMR (200 MHz, CDCl3)
d¼1.27 (t, 3H, J¼7.1 Hz, CH3CH2), 3.75 (s, 3H, CO2CH3),
4.23 (q, 2H, J¼7.1 Hz, CH2CH3), 5.32 (d, 1H, J¼1.6 Hz,
]CH), 5.45 (s, 1H, CHAr), 6.35 (d, 1H, J¼1.6 Hz, ]CH),
6.97–7.09 (m, 2H, ArH), 7.29–7.33 (m, 2H, ArH), 9.35
(br s, 1H, OH); mass (ES+) m/z 310.0; HREIMS calculated
for C15H16FNO5 309.1013, found, 309.1016.
4.4.1. 2-Hydroxyimino-4-methylene-3-phenylpentane-
dioic acid 1-ethyl ester 5-methyl ester (7a). Pale yellow
oil 73% (0.83 g); nmax (Neat) 1630 (C]N), 1735 (CO2Me
and CO2Et), 3425 (OH) cmꢁ1
;
1H NMR (200 MHz,
CDCl3) d¼1.26 (t, 3H, J¼7.2 Hz, CH3CH2), 3.75 (s, 3H,
CO2CH3), 4.21 (q, 2H, J¼7.2 Hz, CH2CH3), 5.32 (d, 1H,
J¼2.1 Hz, ]CH), 5.48 (s, 1H, CHAr), 6.35 (s, 1H, ]CH),
7.31 (s, 5H, ArH), 9.20 (br s, 1H, OH); mass (ES+) m/z
291.9 (M++1); HREIMS calculated for C15H17NO5
291.1107, found, 291.1110.
4.4.7. 3-(4-Bromophenyl)-2-hydroxyimino-4-methylene-
pentanedioic acid 1-ethyl ester 5-methyl ester (7g). Pale
yellow oil 73% (0.7 g from 1.0 g); nmax (Neat) 1633
1
4.4.2. 2-Hydroxyimino-4-methylene-3-p-tolylpentane-
dioic acid 1-ethyl ester 5-methyl ester (7b). 78%
(1.48 g); nmax (Neat) 1631 (C]N), 1731 (CO2Me and
(C]N), 1722 (CO2Et and CO2Me), 3450 (OH) cmꢁ1; H
NMR (200 MHz, CDCl3) d¼1.27 (t, 3H, J¼7.2 Hz,
CH3CH2), 3.75 (s, 3H, CO2CH3), 4.23 (q, 2H, J¼7.2 Hz,
CH2CH3), 5.34 (d, 1H, J¼1.9 Hz, ]CH), 5.43 (s, 1H,
CHAr), 6.37 (d, 1H, J¼1.6 Hz, ]CH), 7.19 (d, 2H,
J¼8.4 Hz, ArH), 7.45 (d, 2H, J¼8.4 Hz, ArH), 9.26 (br s,
1H, OH); 13C NMR (50.32 MHz, CDCl3) d¼14.3, 44.8,
52.7, 62.4, 127.3, 131.7, 132.2, 141.8, 144.6, 152.2, 164.3,
166.7; mass (ES+) m/z 370.2 (M++1); HREIMS calculated
for C15H16BrNO5 369.0212, found, 369.0210.
CO2Et), 3425 (OH) cmꢁ1 1H NMR (CDCl3, 200 MHz)
;
d¼1.19–1.30 (m, 3H, CH3CH2), 2.33 (s, 3H, ArCH3), 3.75
(s, 3H, CO2CH3), 4.07–4.28 (m, 2H, CH2CH3), 5.32 (d,
1H, J¼1.2 Hz, ]CH), 5.42 (s, 1H, CHAr), 6.33 (d, 1H,
J¼1.2 Hz, ]CH), 7.13 (d, 2H, J¼8.2 Hz, ArH), 7.20 (d,
2H, J¼8.2 Hz, ArH), 9.20 (br s, 1H, OH); 13C NMR
(50.32 MHz, CDCl3) d¼14.2, 21.5, 45.1, 52.5, 62.2, 126.9,
129.8, 134.2, 137.4, 137.4, 140.4, 151.5, 163.6, 167.5;
mass (FAB+) m/z 306 (M++1); HREIMS calculated for
C16H19NO5 305.1263, found, 305.1249.
4.5. Reaction of 3a with Sn(SPh)2 complex
To a stirred solution of SnCl2$2H2O (0.81 g, 3.61 mmol) in
MeCN (5 mL), PhSH (1.12 mL, 12.1 mmol) and Et3N
(1.67 mL, 12.1 mmol) were added at room temperature.
4.4.3. 3-(2-Chlorophenyl)-2-hydroxyimino-4-methylene-
pentanedioic acid 1-ethyl ester 5-methyl ester (7c). Color-
less oil 79% (0.45 g); nmax (Neat) 1627 (C]N), 1726
Subsequently
a solution of compound 3a (0.74 g,
(CO2Et and CO2Me), 3497 (OH) cmꢁ1
;
1H NMR
2.25 mmol) in MeCN (2 mL) was added and the reaction
was allowed to continue for 30 min. Thereafter, the reaction
mixture was concentrated and the residue was purified by
column chromatography over silica gel using hexane–
EtOAc (90:10, v/v) as an eluent to give compound (0.42 g)
(60%) 7a as a pale yellow oil.
(200 MHz, CDCl3) d¼1.27–1.29 (m, 3H, CH3CH2), 3.75
(s, 3H, CO2CH3), 4.11–4.28 (m, 2H, CH2CH3), 5.29 (s,
1H, ]CH), 5.86 (s, 1H, CHAr), 6.40 (s, 1H, ]CH), 7.20–
7.34 (m, 3H, ArH), 7.38–7.41 (m, 1H, ArH), 9.21 (br s,
1H, OH); mass (FAB+) m/z 326 (M++1); HREIMS calcu-
lated for C15H16ClNO5 325.0717, found, 325.0717.
4.6. General procedure for the preparation of methyl
derivatives 8b, c
4.4.4. 3-(2-Fluorophenyl)-2-hydroxyimino-4-methylene-
pentanedioic acid 1-ethyl ester 5-methyl ester (7d). Color-
less oil 77% (0.73 g); nmax (Neat) 1630 (C]N), 1724 (CO2Et
and CO2Me), 3452 (OH) cmꢁ1; 1H NMR (200 MHz, CDCl3)
d¼1.26 (t, 3H, J¼7.0 Hz, CH3CH2), 3.76 (s, 3H, CO2CH3),
4.24 (q, 2H, J¼7.0 Hz, CH2CH3), 5.31 (s, 1H, ]CH), 5.77
(s, 1H, CHAr), 6.38 (s, 1H, ]CH), 7.01–7.10 (m, 2H,
ArH), 7.14–7.32 (m, 2H, ArH), 9.26 (br s, 1H, OH); mass
(ES+) m/z 310.1 (M++1); HREIMS calculated for
C15H16FNO5 309.1013, found, 309.1015.
To the flask charged with oxime 7b or 7c (1.0 equiv) and
Ag2O (1.0 equiv) was added MeI (5 mL for approx. 0.3 g
substrate) with stirring at room temperature. After the initial
exothermic reaction has subsided, the reaction mixture was
heated at reflux for 1 h. The reaction mixture was cooled
to room temperature and filtered through a bed of Celite
with the help of CHCl3. The combined filtrates were evapo-
rated and the residue was purified via silica gel column chro-
matography. Elution with hexane–EtOAc (90:10, v/v) gave
pure 8b or 8c.
4.4.5. 3-(4-Chlorophenyl)-2-hydroxyimino-4-methylene-
pentanedioic acid 1-ethyl ester 5-methyl ester (7e). Color-
less oil 75% (0.47 g); nmax (Neat) 1627 (C]N), 1722 (CO2Et
and CO2Me), 3341 (OH) cmꢁ1; 1H NMR (200 MHz, CDCl3)
d¼1.26 (t, 3H, J¼7.2 Hz, CH3CH2), 3.75 (s, 3H, CO2CH3),
4.07–4.29 (m, 2H, CH2CH3), 5.33 (d, 1H, J¼1.8 Hz,
]CH), 5.45 (s, 1H, CHAr), 6.36 (d, 1H, J¼1.6 Hz, ]CH),
7.22–7.33 (m, 4H, ArH), 9.28 (br s, 1H, OH); 13C NMR
(50.32 MHz, CDCl3) d¼14.2, 44.8, 52.6, 62.4, 127.2,
129.2, 131.3, 133.7, 135.8, 139.7, 151.3, 163.3, 167.3;
4.6.1. 2-Methoxyimino-4-methylene-3-p-tolylpentane-
dioic acid 1-ethyl ester 5-methyl ester (8b). Pale yellow
oil 80% (0.25 g); nmax (Neat) 1625 (C]N), 1735 (CO2Me
1
and CO2Et) cmꢁ1; H NMR (200 MHz, CDCl3) d¼1.25 (t,
3H, J¼7.1 Hz, CH3CH2), 2.32 (s, 3H, ArCH3), 3.74 (s,
3H, CO2CH3), 3.98 (s, 3H, NCH3), 4.23 (q, 2H, J¼7.1 Hz,
CH2CH3), 5.32 (d, 1H, J¼1.5 Hz, ]CH), 5.39 (s, 1H,
CHAr), 6.30 (s, 1H, ]CH), 7.12 (s, 4H, ArH); mass

10108
V. Singh et al. / Tetrahedron 62 (2006) 10100–10110
(FAB+) m/z 320 (M++1); EIHRMS calculated for
C17H21NO5 319.1420, found, 319.1421.
column chromatography using hexane–EtOAc (85:15, v/v)
to give the pyrroles in low yields.
4.6.2. 3-(2-Chlorophenyl)-2-methoxyimino-4-methylene-
pentanedioic acid 1-ethyl ester 5-methyl ester (8c). Color-
less oil 68% (0.05 g); nmax (Neat) 1627 (C]N), 1728 (CO2Et
and CO2Me) cmꢁ1; 1H NMR (200 MHz, CDCl3) d¼1.24 (t,
3H, J¼7.1 Hz, CH3CH2), 3.74 (s, 3H, CO2CH3), 3.97 (s, 3H,
NCH3), 4.23 (q, 2H, J¼7.1 Hz, CH2CH3), 5.29 (d, 1H,
J¼1.5 Hz, ]CH), 5.80 (s, 1H, CHAr), 6.37 (s, 1H, ]CH),
7.18–7.25 (m, 3H, ArH), 7.37–7.40 (m, 1H, ArH); 13C
NMR (50.32 MHz, CDCl3) d¼14.4, 43.4, 52.6, 62.3, 63.8,
127.3, 129.0, 130.0, 130.6, 134.7, 135.8, 138.2, 151.1,
163.4, 167.0; mass (FAB+) m/z 340 (M++1); HREIMS calcu-
lated for C16H18ClNO5 339.0871, found, 339.0868.
4.8.1. 3-p-Tolyl-1H-pyrrole-2,4-dicarboxylic acid 2-ethyl
ester 4-methyl ester (10b). White solid 28% (0.11 g), mp
150–152 ꢂC; nmax (KBr) 1730 (CO2Et and CO2Me), 3429
1
(NH) cmꢁ1; H NMR (200 MHz, CDCl3) d¼1.37 (t, 3H,
J¼7.2 Hz, CH3CH2), 2.40 (s, 3H, ArCH3), 3.77 (s, 3H,
CO2CH3), 4.33 (q, 2H, J¼7.2 Hz, CH2CH3), 7.25 (d, 2H,
J¼7.8 Hz, ArH), 7.38 (d, 1H, J¼2.8 Hz, ]CH), 7.52 (d,
2H, J¼7.8 Hz, ArH), 9.36 (s, 1H, NH); mass (FAB+) m/z
288 (M++1); HREIMS calculated for C16H17NO4
287.1158, found, 287.1146.
4.8.2. 3-(4-Fluorophenyl)-1H-pyrrole-2,4-dicarboxylic
acid 2-ethyl ester 4-methyl ester (10d). White solid 25%
(0.023 g), mp 156–158 ꢂC; nmax (KBr) 1728 (CO2Et and
4.7. General procedure for the preparation of tosyl
derivatives 9b, d
1
CO2Me), 3441 (NH) cmꢁ1; H NMR (200 MHz, CDCl3)
d¼1.38 (t, 3H, J¼7.2 Hz, CH3CH2), 3.77 (s, 3H, CO2CH3),
4.32 (q, 2H, J¼7.2 Hz, CH2CH3), 7.10–7.18 (m, 2H, ArH),
7.38 (d, 1H, J¼2.8 Hz, ]CH), 7.59–7.65 (m, 2H, ArH),
9.38 (s, 1H, NH); mass (ES+) m/z 292.0 (M++1); HREIMS
calculated for C15H14FNO4 291.0907, found, 291.0919.
To the stirred solution of appropriate oxime from 7b,
d (1.0 equiv) in dry dichloromethane (10 mL) was added
Et3N (1.5 mmol). The reaction mixture was brought to 0 ꢂC
via ice-bath and to it was added tosyl chloride (1.1 equiv)
and the reaction was continued for 2 h at room temperature.
Thereafter, the mixture was extracted with water and
dichloromethane. The organic layer was separated, dried
(Na2SO4), and evaporated to dryness to yield the crude prod-
uct, which was purified by silica gel column chromatography
using hexane–EtOAc (80:20, v/v) to yield pure products.
4.9. General procedure for the preparation of
compounds 11a–c, 12, and 13a, b
The compounds 11a–c, 12, and 13a, b were prepared follow-
ing the procedure as described for compounds 3a–g and the
reactions were worked up after 1 h.
4.7.1. 2-Tosyloxyimino-4-methylene-3-p-tolylpentane-
dioic acid 1-ethyl ester 5-methyl ester (9b). Yellow oil
75% (0.61 g); nmax (Neat) 1628 (C]N), 1732 (CO2Et and
4.9.1. 2-Methylene-4-nitro-3-(2-nitrophenyl)-pentane-
dioic acid 5-ethyl ester 1-methyl ester (11a). An off white
solid 72% (1.36 g), mp 116–118 ꢂC; nmax (KBr) 1721
CO2Me) cmꢁ1
;
1H NMR (200 MHz, CDCl3) d¼1.25 (t,
3H, J¼7.2 Hz, CH3CH2), 2.34 (s, 3H, ArCH3), 2.44 (s, 3H,
ArCH3), 3.69 (s, 3H, CO2CH3), 4.17 (q, 2H, J¼7.2 Hz,
CH2CH3), 5.35 (two s merged, 2H, CHAr and ]CH), 6.37
(s, 1H, ]CH), 7.09 (s, 4H, ArH), 7.27 (d, 2H, J¼8.0 Hz,
ArH), 7.69 (d, 2H, J¼8.0 Hz, ArH); mass (ES+) m/z 460.2
(M++1); HREIMS calculated for C23H25NO7S 459.1352,
found, 459.1364.
(CO2Et), 1755 (CO2Me) cmꢁ1 1H NMR (200 MHz,
;
CDCl3) d¼1.07 (t, 3H, J¼7.1 Hz, CH3CH2), 3.68 (s, 3H,
CO2CH3), 4.09 (q, 2H, J¼7.1 Hz, CH2CH3), 5.53 (d, 1H,
J¼11.5 Hz, CHAr), 5.99 (s, 1H, ]CH), 6.08 (d, 1H,
J¼11.5 Hz, CHCO2Et), 6.46 (s, 1H, ]CH), 7.42–7.49 (m,
1H, ArH), 7.52–7.58 (m, 2H, ArH), 7.82–7.84 (d, 1H,
J¼7.6 Hz, ArH); 13C NMR (50.632 MHz, CDCl3) d¼13.8,
42.9, 52.8, 63.8, 89.3, 125.4, 128.5, 129.5, 130.1, 130.8,
133.2, 137.0, 150.5, 163.0, 165.7; mass (ES+) m/z 375.0
(M++Na); HREIMS calculated for C15H16N2O6 352.0907,
found, 352.0909.
4.7.2. 3-(4-Fluorophenyl)-2-hydroxyimino-4-methylene
pentanedioic acid 1-ethyl ester 5-methyl ester (9d). Yel-
low oil 78% (0.20 g); nmax (Neat) 1630 (C]N), 1729
1
(CO2Et and CO2Me) cmꢁ1; H NMR (200 MHz, CDCl3)
d¼1.23 (t, 3H, J¼7.1 Hz, CH3CH2), 2.45 (s, 3H, ArCH3),
3.70 (s, 3H, CO2CH3), 4.20 (q, 2H, J¼7.1 Hz, CH2CH3),
5.33 (two s merged, 2H, CHAr and ]CH), 6.39 (d, 1H,
J¼1.3 Hz, ]CH), 7.11–7.15 (m, 2H, ArH), 7.23–7.34 (m,
4H, ArH), 7.64–7.68 (m, 2H, ArH); mass (ES+) m/z 464.1
(M++1); HREIMS calculated for C22H22FNO7S 463.1101,
found, 463.1124.
4.9.2. 2-Methylene-4-nitro-3-(6-nitrobenzo[1,3]dioxol-5-
yl)-pentanedioic acid 5-ethyl ester 1-methyl ester (11b).
Yellow solid 68% (0.42 g), mp 148–150 ꢂC; nmax (KBr)
1
1722 (CO2Et), 1749 (CO2Me) cmꢁ1; H NMR (300 MHz,
CDCl3) d¼1.17 (t, 3H, J¼7.2 Hz, CH3CH2), 3.71 (s, 3H,
CO2CH3), 4.15 (q, 2H, J¼7.2 Hz, CH2CH3), 5.63 (d, 1H,
J¼12.0 Hz, CHAr), 5.99 (d, 1H, J¼12.0 Hz, CHCO2Et),
6.02 (s, 1H, ]CH), 6.12 (s, 2H, CH2), 6.47 (s, 1H, ]CH),
6.93 (s, 1H, ArH), 7.38 (s, 1H, ArH); 13C NMR
(50.32 MHz, CDCl3) d¼14.2, 42.8, 52.9, 63.9, 89.3, 103.7,
106.4, 109.3, 126.3, 128.4, 137.2, 144.7, 148.0, 151.8,
163.0, 165.8; mass (ES+) m/z 419.0 (M++Na); HREIMS cal-
culated for C16H16N2O10 396.0805, found, 396.0806.
4.8. General procedure for the reaction of 9b, d with
DBU
To the stirred solution of appropriate tosyl derivatives from
9b, d (1.0 mmol) in dry dichloromethane (5 mL), a solution
of DBU (1.2 mmol) in dichloromethane (4.0 mL) was added
dropwise at room temperature. After 30 min, organic layer
was washed with water, dried (anhyd Na2SO4), and evapo-
rated to furnish a residue, which was purified via silica gel
4.9.3. 3-(5-Chloro-2-nitro phenyl)-2-methylene-4-nitro-
pentanedioic acid 5-ethyl ester 1-methyl ester (11c).
Brown solid 75% (0.80 g), mp 130–132 ꢂC; nmax (KBr)

V. Singh et al. / Tetrahedron 62 (2006) 10100–10110
10109
1
1725 (CO2Et), 1750 (CO2Me) cmꢁ1; H NMR (200 MHz,
hexane–EtOAc (80:20, v/v) as an eluent to yield the final
products.
CDCl3) d¼1.12 (t, 3H, J¼7.1 Hz, CH3CH2), 3.70 (s, 3H,
CO2CH3), 4.12 (q, 2H, J¼7.1 Hz, CH2CH3), 5.56 (d, 1H,
J¼11.6 Hz, CHAr), 6.00–6.06 (m, 2H, CHCO2Et and
]CH), 6.49 (s, 1H, ]CH), 7.39–7.44 (m, 1H, ArH), 7.52
(d, 1H, J¼2.1 Hz, ArH), 7.83 (d, 1H, J¼8.7 Hz, ArH);
mass (ES+) m/z 409.0 (M++Na); HREIMS calculated for
C15H15ClN2O8 386.0517, found, 386.0515.
4.10.1. 3-(1-Methoxycarbonyl-vinyl)-1H-indole-2-car-
boxylic acid ethyl ester (14a). Yellow oil 56% (0.183 g);
nmax (Neat) 1723 (CO2Et and CO2Me), 3315 (NH) cmꢁ1
;
1H NMR (200 MHz, CDCl3) d¼1.36 (t, 3H, J¼7.1 Hz,
CH3CH2), 3.75 (s, 3H, CO2CH3), 4.40 (q, 2H, J¼7.1 Hz,
CH2CH3), 5.93 (s, 1H, ]CH), 6.66 (s, 1H, ]CH), 7.16–
7.19 (m, 1H, ArH), 7.34–7.41 (m, 1H, ArH), 7.54–7.61
(m, 2H, ArH), 10.64 (s, 1H, NH); 13C NMR (50.32 MHz,
CDCl3) d¼14.4, 52.5, 61.7, 110.1, 114.2, 119.6, 120.9,
121.8, 126.4, 129.4, 133.3, 133.9, 164.3, 167.9; mass
(ES+) m/z 274.0 (M++1); HREIMS calculated for
C15H15NO4 273.1001, found, 273.1004.
4.9.4. 2-Methylene-4-nitro-3-(2-nitrophenyl)-pentane-
dioic acid diethyl ester (12). Yellow solid 71% (0.44 g),
mp 90–92 ꢂC; nmax (KBr) 1728 (CO2Et) cmꢁ1; H NMR
1
(200 MHz, CDCl3) d¼1.03–1.30 (m, 6H, 2ꢀCH3CH2),
4.03–4.28 (m, 4H, 2ꢀCH2CH3), 5.52–5.59 (m, 2H,
2ꢀCHAr), 5.96 (two s merged, 2H, ]CH), 5.08 (d, 1H,
J¼11.5 Hz, CHCO2Et), 6.29 (d, 1H, J¼11.5 Hz, CHCO2Et),
6.41 (s, 1H, ]CH), 6.47 (s, 1H, ]CH), 7.44–7.49 (m, 2H,
2ꢀ1ArH), 7.55–7.58 (m, 4H, 2ꢀ2ArH), 7.68–7.71 (m, 1H,
ArH), 7.85 (d, 2H, J¼7.8 Hz, ArH); mass (ES+) m/z 389.0
(M++Na); HREIMS calculated for C15H16N2O8 366.1063,
found, 366.1059.
4.10.2. 3-(1-Methoxycarbonyl-vinyl)-5H-[1,3]diox-
olo[4,5-f]indole-6-carboxylic acid ethyl ester (14b). Pale
yellow solid 58% (0.093 g), mp 116–118 ꢂC; nmax (KBr)
1732 (CO2Et and CO2Me), 3308 (NH) cmꢁ1 1H NMR
;
(200 MHz, CDCl3) d¼1.23–1.36 (m, 3H, CH3CH2), 3.73
(s, 3H, CO2CH3), 4.31 (q, 2H, J¼7.2 Hz, CH2CH3), 5.85
(t, 1H, J¼2.8 Hz, ]CH), 5.97 (s, 2H, CH2), 6.60 (t, 1H,
J¼4.1 Hz, ]CH), 6.85 (two s merged, 2H, ArH), 8.92
(s, 1H, NH); 13C NMR (50.32 MHz, CDCl3) d¼14.6, 52.5,
62.5, 100.3, 102.7, 106.2, 115.3, 115.8, 120.4, 128.9,
136.9, 148.1, 151.6, 165.2, 168.3; mass (ES+) m/z 318.0
(M++1), 340.1 (M++Na); HREIMS calculated for
C16H15NO6 317.0899, found, 317.0899.
4.9.5. 2-Methylene-4-nitro-3-(2-nitrophenyl)-pentanoic
acid methyl ester (13a). Brown solid 65% (0.58 g), mp
110–112 ꢂC; nmax (KBr) 1722 (CO2Me) cmꢁ1; H NMR
1
(200 MHz, CDCl3) d¼1.56 (d, 3H, J¼6.6 Hz, CH3CH),
1.63 (d, 3H, J¼6.6 Hz, CH3CH), 3.63 (s, 3H, CO2CH3),
3.75 (s, 3H, CO2CH3), 5.08 (d, 1H, J¼11.0 Hz, CHAr),
5.21–5.35 (m, 2H, CHAr and CHCO2Et), 5.64–5.68 (m,
1H, CHCO2Et), 5.96 (s, 1H, ]CH), 6.00 (s, 1H, ]CH),
6.41 (two s merged, 2H, 2ꢀ]CH), 7.34–7.47 (m, 4H,
2ꢀ2ArH), 7.57 (t, 2H, J¼7.2 Hz, 2ꢀ1ArH), 7.79 (t, 2H,
J¼7.2 Hz, 2ꢀ1ArH); mass (ES+) m/z 395.1 (M++1);
HREIMS calculated for C15H15ClN2O8 294.0852, found,
294.0853.
4.10.3. 5-Chloro-3-(1-methoxycarbonyl-vinyl)-1H-in-
dole-2-carboxylic acid ethyl ester (14c). Yellow oil 62%
(0.103 g); nmax (Neat) 1723 (CO2Et and CO2Me), 3372
1
(NH) cmꢁ1; H NMR (200 MHz, CDCl3) d¼1.36 (t, 3H,
J¼7.1 Hz, CH3CH2), 3.75 (s, 3H, CO2CH3), 4.40 (q, 2H,
J¼7.1 Hz, CH2CH3), 5.91 (s, 1H, ]CH), 6.67 (s, 1H,
]CH), 7.36 (s, 1H, ArH), 7.48–7.65 (m, 2H, ArH), 10.72
(s, 1H, NH); 13C NMR (50.32 MHz, CDCl3) d¼13.8, 52.5,
61.8, 124.4, 125.6, 127.2, 130.6, 131.1, 131.4, 136.2,
141.7, 145.9, 165.2, 167.3; mass (ES+) m/z 308.0 (M++1);
HREIMS calculated for C15H14ClNO4 307.0611, found,
307.0612.
4.9.6. 3-(5-Chloro-2-nitrophenyl)-2-methylene-4-nitro-
pentanoic acid methyl ester (13b). Brown solid 66%
(0.50 g), mp 104–106 ꢂC; nmax (KBr) 1724 (CO2Me) cmꢁ1
;
1H NMR (200 MHz, CDCl3) d¼1.57 (d, 3H, J¼6.6 Hz,
CH3CH), 1.63 (d, 3H, J¼6.6 Hz, CH3CH), 3.65 (s, 3H,
CO2CH3), 3.77 (s, 3H, CO2CH3), 5.06 (d, 1H, J¼11.1 Hz,
CHAr), 5.24–5.34 (m, 2H, CHAr and CHCO2Et), 5.63–
5.68 (m, 1H, CHCO2Et), 5.99 (s, 1H, ]CH), 6.04 (s, 1H,
]CH), 6.45 (two s merged, 2H, 2ꢀ]CH), 7.30–7.31
(m, 2H, 2ꢀ1ArH), 7.38–7.44 (m, 2H, 2ꢀ1ArH), 7.76–7.83
(m, 2H, 2ꢀ1ArH); mass (ES+) m/z 329.1 (M++1); HREIMS
calculated for C15H15ClN2O8 328.0462, found, 328.0458.
4.10.4. 3-(1-Ethoxycarbonyl-vinyl)-1H-indole-2-carb-
oxylic acid ethyl ester (15). Brown solid 59% (0.10 g),
mp 104–106 ꢂC; nmax (KBr) 1713 (CO2Et), 3331
(NH) cmꢁ1; 1H NMR (200 MHz, CDCl3) d¼1.14–1.47 (m,
6H, 2ꢀCH3CH2), 4.10–4.44 (m, 4H, 2ꢀCH2CH3), 5.92 (s,
1H, ]CH), 6.66 (s, 1H, ]CH), 7.12–7.23 (m, 1H, ArH),
7.34–7.41 (m, 1H, ArH), 7.54–7.62 (m, 2H, ArH), 10.60
(s, 1H, NH); 13C NMR (50.32 MHz, CDCl3) d¼14.4, 14.6,
61.4, 62.3, 110.1, 112.3, 114.2, 121.0, 121.7, 126.4, 129.1,
133.2, 134.2, 164.5, 167.7; mass (ES+) m/z 288.0 (M++1);
HREIMS calculated for C16H17NO4 287.1158, found,
287.1156.
4.10. General procedure for the preparation of
compounds 14a–c, 15, and 16a, b
To the solution of appropriate compounds from 11a–c, 12,
and 13a, b (1.0 equiv) in methanol (10 mL) was added
SnCl2$2H2O (10 equiv) and the reaction mixture was heated
at reflux with stirring at 80 ꢂC for 1 h in a nitrogen atmo-
sphere. After completion, methanol was evaporated and
the residue was made basic with saturated NaHCO3 and
taken up in EtOAc (100 mL). The suspension formed was
filtered through a bed of Celite and the filtrate was parti-
tioned in a separating funnel. The organic layer was sepa-
rated, dried (Na2SO4), and concentrated to give a residue,
which was purified by silica gel chromatography using
4.10.5. 3-Methylene-4-(1-nitro-ethyl)-3,4-dihydro-1H-
quinolin-2-one (16a). White solid 53% (0.062 g), mp 166–
1
168 ꢂC; nmax (KBr) 1664 (CONH), 3218 (NH) cmꢁ1; H
NMR (200 MHz, CDCl3) d¼1.47 (d, 3H, J¼4.7 Hz,
CH3CH), 1.50 (d, 3H, J¼4.7 Hz, CH3CH), 4.15 (d, 1H,
J¼7.6 Hz, CHAr), 4.23 (d, 1H, J¼7.6 Hz, CHAr), 4.61–
4.72 (m, 2H, 2ꢀCHCH3), 5.68 (two s merged, 2H,

10110
V. Singh et al. / Tetrahedron 62 (2006) 10100–10110
Tetrahedron 2006, 62, 4342–4348; (m) Coelho, F.; Veronese,
D.; Pavam, C. H.; de Paula, V. I.; Buffon, R. Tetrahedron
2006, 62, 4563–4572; (n) Gowrisankar, S.; Lee, K. Y.; Kim,
J. N. Tetrahedron 2006, 62, 4052–4058.
2ꢀ]CH), 6.41 (s, 1H, ]CH), 6.49 (s, 1H, ]CH), 6.89–6.94
(m, 2H, 2ꢀ1ArH), 7.01–7.08 (m, 2H, 2ꢀ1ArH), 7.14–7.17
(m, 2H, 2ꢀ1ArH), 7.23–7.33 (m, 2H, 2ꢀ1ArH), 8.95 (s,
1H, NH), 9.10 (s, 1H, NH); 13C NMR (50.32 MHz, CDCl3)
d¼19.3, 19.4, 51.2, 52.4, 85.6, 86.1, 124.9, 127.7, 128.3,
129.0, 129.8, 130.1, 134.0, 134.8, 137.9, 138.1, 139.8,
140.0, 166.4, 166.7; mass (FAB+) m/z 233 (M++1); HREIMS
calculated for C12H12N2O3 232.0848, found, 232.0848.
2. (a) Singh, V.; Saxena, R.; Batra, S. J. Org. Chem. 2005, 70,
353–356; (b) Pathak, R.; Roy, A. K.; Batra, S. Synlett 2005,
848–850; (c) Pathak, R.; Roy, A. K.; Kanojiya, S.; Batra, S.
Tetrahedron Lett. 2005, 46, 5289–5292; (d) Pathak, R.; Batra,
S. OCCB-2006, PN-102, CSIR–ACS conference at NCL,
Pune, Jan 7–9, 2006.
3. Singh, V.; Batra, S. Synthesis 2006, 63–72.
4. Blaszczyk, E.; Krawczyk, H.; Janecki, T. Synlett 2004, 2685–
2688.
5. Choudhury, P. K.; Foubelo, F.; Yus, M. J. Org. Chem. 1999, 64,
3376–3378.
6. Lee, K. Y.; Seo, J.; Kim, J. N. Tetrahedron Lett. 2006, 47, 3913–
3917.
7. (a) Basavaiah, D.; Rao, J. S. Tetrahedron Lett. 2004, 45, 1621–
1625; (b) Bauchet, R.; Le Rouille, E.; Foucad, A. Bull. Soc.
Chim. Fr. 1991, 128, 267–271; (c) Chamakh, A.; M’hirsi, M.;
Villieras, J.; Lebreton, J.; Amri, H. Synthesis 2000, 295–299.
8. (a) Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M.
Chem. Rev. 2005, 105, 933–972; (b) Ballini, R.; Petrini, M.
Tetrahedron 2004, 60, 1017–1047.
4.10.6. 6-Chloro-3-methylene-4-(1-nitro-ethyl)-3,4-dihy-
dro-1H-quinolin-2-one (16b). Pale yellow solid 48%
(0.116 g), mp>250 ꢂC; nmax (KBr) 1672 (CONH), 3391
1
(NH) cmꢁ1; H NMR (200 MHz, CDCl3) d¼1.46 (d, 3H,
J¼4.6 Hz, CH3CH), 1.52 (d, 3H, J¼4.6 Hz, CH3CH), 4.14
(d, 1H, J¼7.8 Hz, CHAr), 4.22 (d, 1H, J¼7.8 Hz, CHAr),
4.60–4.74 (m, 2H, 2ꢀCHCH3), 5.69 (two s merged, 2H,
2ꢀ]CH), 6.42 (s, 1H, ]CH), 6.47 (s, 1H, ]CH), 6.90–
6.95 (m, 2H, 2ꢀ1ArH), 7.06–7.09 (m, 2H, 2ꢀ1ArH), 7.16–
7.17 (m, 2H, 2ꢀ1ArH), 8.93 (s, 1H, NH), 9.08 (s, 1H, NH);
mass (ES+) m/z 266.9 (M++1), 289.0 (M++Na); HREIMS
calculated for C13H14N2O3 266.0458, found, 266.0455.
Acknowledgements
9. (a) Cai, J.; Zhou, Z.; Zhao, G.; Tang, C. Org. Lett. 2002, 4,
4723–4725; (b) Patra, A.; Batra, S.; Kundu, B.; Joshi, B. S.;
Roy, R.; Bhaduri, A. P. Synthesis 2001, 276–281.
10. (a) Kim, M. K.; Im, Y. J.; Kim, T. H.; Kim, J. N. Bull. Korean
Chem. Soc. 2002, 23, 657–658; (b) Lee, M. J.; Lee, K. Y.;
Gowrisankar, S.; Kim, J. N. Tetrahedron Lett. 2006, 47,
1355–1358.
One of the authors (V.S.) acknowledges the financial support
from the DST, New Delhi in the form of fellowship. This
work was supported by a financial grant from DST. The
authors acknowledge Drs. R. Roy and A. Arora for carrying
out the NOESY experiments.
References and notes
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Synthesis 2001, 81–84; (b) For Sn: Vogel’s Textbook of
Practical Organic Chemistry, 5th ed.; Furniss, B. S.,
Hannaford, A. J., Smith, P. W. G., Tatchell, A. R., Eds.;
Pearson Education: Singapore (Indian branch), 2004 (with
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Synthesis 2006, 1021–1027.
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