Synthesis of highly substituted pyrrolidines through 1,3-dipolar cycloaddition reaction of N-metalated azomethine ylides with triarylideneacetylacetone as dipolarophile using titanocene dichloride

Article abstract of DOI:10.1080/00397910802621723

The 1,3-dipolar cycloaddition reaction of tryarylideneacetyacetone derivatives with N-metalated azomethine ylides in the presence of titanocene dichloride and triethylamine has been investigated. This two-step synthetic sequence is very efficient and yielded the highly substituted pyrrolidines in good yields. The structure and stereochemistry of one of the products has been established by single-crystal x-ray structure and spectroscopic techniques.

Full text of DOI:10.1080/00397910802621723

This article was downloaded by: [Korea University]
On: 08 January 2015, At: 01:56
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Synthesis of Highly Substituted
Pyrrolidines Through 1,3-
Dipolar Cycloaddition
Reaction of N-Metalated
Azomethine Ylides with
Triarylideneacetylacetone as
Dipolarophile Using Titanocene
Dichloride
a
b
Ramalingam Murugan , R. Raghunathan & S.
a
Sriman Narayanan
a
Department of Analytical Chemistry , University of
Madras, Guindy Campus , Chennai, India
b
Department of Organic Chemistry , University of
Madras, Guindy Campus , Chennai, India
Published online: 27 Apr 2009.
To cite this article: Ramalingam Murugan , R. Raghunathan & S. Sriman Narayanan
(2009) Synthesis of Highly Substituted Pyrrolidines Through 1,3-Dipolar Cycloaddition
Reaction of N-Metalated Azomethine Ylides with Triarylideneacetylacetone
as Dipolarophile Using Titanocene Dichloride, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 39:11,
1936-1948, DOI: 10.1080/00397910802621723
To link to this article: http://dx.doi.org/10.1080/00397910802621723

PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views
expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

1
Synthetic Communications , 39: 1936–1948, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802621723
Synthesis of Highly Substituted Pyrrolidines
Through 1,3-Dipolar Cycloaddition Reaction of
N-Metalated Azomethine Ylides with
Triarylideneacetylacetone as Dipolarophile Using
Titanocene Dichloride
1
Ramalingam Murugan, R. Raghunathan, and
2
1
S. Sriman Narayanan
1
Department of Analytical Chemistry, University of Madras,
Guindy Campus, Chennai, India
2
Department of Organic Chemistry, University of Madras,
Guindy Campus, Chennai, India
Abstract: The 1,3-dipolar cycloaddition reaction of tryarylideneacetyacetone
derivatives with N-metalated azomethine ylides in the presence of titanocene
dichloride and triethylamine has been investigated. This two-step synthetic
sequence is very efficient and yielded the highly substituted pyrrolidines in good
yields. The structure and stereochemistry of one of the products has been estab-
lished by single-crystal x-ray structure and spectroscopic techniques.
Keywords: Azomethine ylides, cycloaddition, pyrrolidines, titanocene dichloride,
triarylideneacetylacetone
INTRODUCTION
[
1]
The intermolecular 1,3-dipolar cycloaddition, also known as the
Huisgen cycloaddition, is a classic reaction in organic chemistry consist-
ing of the reaction of dipolarophile with a 1,3-dipolar compound that
Received September 21, 2008.
Address correspondence to S. Sriman Narayanan, Department of Analytical
Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India.
E-mail: sriman55@yahoo.com
1
936

Pyrrolidines by 1,3-Dipolar Cycloaddition
1937
[
2,3]
allows the production of various five-membered heterocycles.
[
These
reactions have been investigated by Kanemasa and Gothelf and
4]
[
Jorgensen. Moreover, the more general transition-metal complexation
in these reactions has been updated by Broggini et al., and the stereo-
selective intramolecular 1,3-dipolar cycloaddition was investigated by
Namboothiri and Hassner. The chemistry of the azomethine ylide has
gained importance in recent years for the construction of nitrogen-
containing five-membered heterocycles, which are often the central ring
systems of numerous alkaloids and physiologically active compounds.
The AgOAc-catalyzed 1,3-dipolar cycloaddition of arylidine glycine
imines and a variety of chiral acrylamides have been studied by Nyerges
5]
[
6]
[7]
[8]
[9]
[
10,11]
et al. This new methodology represented a new method for the
synthesis of highly substituted pyrrrolidines, which constitute the main
[12,13]
building blocks of many natural products.
Garner has reported
stereoselective AgOAc-catalyzed dipolar cycloaddition of chiral a-amino
azomethine ylides applied to the bioxalomycin family of antibiotics.
[
14]
[
15]
[16]
Ormeloxifene
and bepridil hydrochloride,
which are recent drugs
with pyrrolidine moieties, are used for selective estrogen receptor modu-
lators (SERM) and antiproliferative activity respectively. Similarly, the
chalcone derivatives such as curcumin act as anti-oxidant and cancer che-
[17]
mopreventive agents. The anticancer property and the HIV-1 integrase
18,19]
inhibitors based on chalcone pharmacophore have been studied.
[
Hitherto, the alkene unit of triarylideneacetylacetone (1a–f) has not been
used as a dipolarophile in 1,3-dipolar cycloaddition reactions. The
interesting chemistry involved in this dipolarophile is the cleavage of
the cinnamoyl group during the formation of the pyrrolidine ring. The
cleavage of cinnamoyl group in 1a–f has been studied in the synthesis
[
20]
of piperidone.
dines through 1,3-dipolar cycloaddition of azomethine ylides with triary-
We herein report the facile synthesis of novel pyrroli-
[
21]
lideneacetylacetone (1a–f) using titanocene dichloride as a catalyst
Fig. 1). This addition is decidedly regioselective and gives a single pro-
duct in each of the cases that we have studied. The required dipolaro-
(
philes (1a–f) chosen for our study were prepared by the base-catalyzed
Figure 1. Titanocene dichloride.

1938
R. Murugan, R. Raghunathan, and S. S. Narayanan
reaction of acetyl acetone with various benzaldehydes, in accordance with
prior literature.
[22]
RESULTS AND DISCUSSION
Treatment of aromatic aldehydes with glycine ethyl ester in the presence
of anhyd. MgSO in dry dichloromethane at room temperature afforded
4
the imines 2a–c almost in quantitative yield as evidenced by a doublet at
.75 ppm (J ¼ 7.6 Hz) (CH¼N) and a singlet at 4.25 ppm (N-CH ) in the
7
2
1
H NMR spectra. The chemical reaction of triarylideneacetylacetone
1a–f) with N-metalated azomethine ylides derived from imines of glycine
(
ethyl ester with three different aromatic aldehydes at ambient tempera-
ture gave a single cycloadduct in all cases, as evidenced by thin-layer
chromatography (TLC) and mass spectral studies (Scheme 1, Table 1).
The reactions afforded a series of novel pyrrolidine derivatives through
regioselective cycloaddition of azomethine ylides to the p-deficient alkene
[
23]
of the triarylideneacetylacetone in all cases.
The cycloaddition proce-
eded stereo- and regiospecifically in acetonitrile at room temperature to
afford syn-endo cycloadduct (3a–n) with the loss of the cinnamoyl group
from triarylideneacetylacetone. The stereochemistry of 3a–n is based on
Scheme 1. Synthesis of pyrrolidine derivatives through 1,3-dipolar cycloaddition.

Pyrrolidines by 1,3-Dipolar Cycloaddition
1939
Table 1. 1,3-Dipolar cycloaddition reactions between triarylideneacetylacetone
1a–f) and N-metalated azomethine ylides derived from imines (2a–c) in the pre-
sence of titanocene dichloride
(
1
2
Entry (%) Product
R
R
Time (h) Yield
1
2
3
4
5
6
7
8
9
0
1
2
3
4
3a
3b
3c
3d
3e
3f
Thiophen-2-yl 3,4,5-OMe
4-Me-1,3-thiazole-5-yl 3,4,5-OMe
1.5
1.0
2.0
2.5
2.5
2.0
2.0
2.5
2.5
3.0
3.0
2.5
3.0
4.0
82
88
92
92
94
93
88
87
90
90
90
88
88
88
Ph
2-Cl Ph
4-F Ph
4-Me Ph
Thiophen-2-yl
4-Me-1,3-thiazole-5-yl
Ph
3,4,5-OMe
3,4,5-OMe
3,4,5-OMe
3,4,5-OMe
H
H
3g
3h
3i
H
1
1
1
1
1
3j
2-Cl Ph
4-F Ph
H
H
3k
3l
4-Me Ph
Ph
2-Cl Ph
H
4-Cl
4-Cl
3m
3n
the usual facial selectivity and endo-transition state observed for metallo-
[24]
azomethine ylide cycloadditions.
The products were characterized on the basis of their elemental analysis
1
as well as infrared (IR), H NMR, C NMR, and mass spectral (MS) ana-
13
ꢀ1
lysis. Thus the IR spectrum of 3b exhibited peaks at 1687 cm
ꢀ
and
695 cm due to the two carbonyl groups. In the H NMR spectrum of
1
1
1
3
b, the ethylene protons appeared as two doublets at d 6.54 (J ¼ 16.51 Hz)
and d 7.51 (J¼ 16.51 Hz). The aromatic proton of 4-methyl-1,3-thiazole-5-
yl of 3b that was directly attached to the pyrrolidine ring appeared as a sing-
let at d 8.78, and the other proton of 4-methyl-1,3-thiazole-5-yl that was
attached to ethylene carbon appeared as a singlet at d 9.03. One quartet
1
appeared at 4.18 for CH proton of ethyl ester in the H NMR spectrum.
The stereochemistry of the cycloadducts (3a–n) was deduced on the basis
2
1
of H NOESY studies (Scheme 1). Schiff bases formed from the reaction
13
of glycine ethyl ester with Ph CHO showed singlet resonances for the imine
carbon around 160–165ppm, which on cycloaddition were replaced by the
[
25,26] 13
resonance of C-5 of the pyrrolidine ring at ꢁ60–70 ppm.
C NMR
3
spectra of 3b showed two carbonyl carbons, 11 sp carbons, and two sp car-
bons. Distortionless enhancement by polarization transfer (DEPT) 135
2
ꢂ
showed the negative peak for the methylene carbon of ethyl ester and the
aromatic carbons, which confirmed the proposed structure. No trace of
the other regioisomers (4a–n) was detected. Also, the loss of the
cinnamoyl group during the formation of cycloadduct and the structure

1940
R. Murugan, R. Raghunathan, and S. S. Narayanan
of the product 3b were confirmed by mass spectrometry, which showed a
[27]
peak m=z 558.2 (M þ 1). Finally, x-ray analysis (Fig. 2) confirmed the
structure of 3c with the proposed regiochemistry.
The cycloaddition reaction proceeded rapidly when electron-
donating groups were present in the aryl ring of triarylideneacetylacetone
rather than the electron-withdrawing groups, whereas the yields of the
cycloadducts were found to be slightly more when electron-withdrawing
groups were present in the aryl ring (Table 1). Changing the solvent from
acetonitrile to methanol and tetrahydrofuran (THF) did not enhance
yield of the cycloadducts. The catalytic activity of the titanocene dichlor-
ide and the yield of the cycloadducts were not affected by concentration
of the catalyst. When the reaction was carried out in dibutylamine (DBU)
as base instead of Et N, only a low yield of cycloadduct was obtained,
3
whereas in the presence of pyridine no characteristic product was
obtained. When the same reaction was carried out in toluene as solvent,
it afforded the cycloadduct in poor yield.
To the best of our knowledge, to date there has been no report on
cycloaddition reactions of N-metalated azomethine ylides derived from
glycine ethyl ester and aromatic aldehyde with triarylideneacetylacetone
as dipolarophiles using titanocene dichloride as a catalyst. This catalyst
offers several advantages including mild reaction conditions, cleaner
reaction profiles, shorter reaction times, better yields, and high degrees
of regio- and stereoselectivities. In fact, all the cycloadducts were
Figure 2. ORTEP diagram of 3c.

Pyrrolidines by 1,3-Dipolar Cycloaddition
1941
obtained in high yields (80–95%). After completion of the reaction as
determined by thin-layer chromatography (TLC), the reaction mixture
was filtered through a celite pad, washed with saturated aqueous solution
of NH Cl, and then extracted and purified. Identical results were
4
obtained with other derivatives of triarylideneacetylacetone.
In conclusion, titanocene dichloride was used as an efficient catalyst
in the [3 þ 2] cycloaddition reaction between N-metalated azomethine
ylides and triarylideneacetylacetone for the efficient synthesis of a series
of novel pyrrolidine derivatives. The bioactivity of the recently synthe-
sized compounds will be published elsewhere.
EXPERIMENTAL
All melting points were uncorrected. IR spectra were recorded on a
Shimadzu Fourier-transform–infrared (FT-IR) 8300 instrument. MS were
1
recorded on a PE SCIEX 3000 spectrometer. H NMR and 13C NMR
spectra were recorded on a Bruker 400-MHz instrument. Elemental
analysis were carried out on a CEST 1106 instrument.
General Procedure for the Synthesis of Highly Substituted Pyrrolidine
Cycloadducts (3a–n)
Triethylamine (1 mmol), triarylideneacetylacetone (1mmol), and then tita-
nocene dichloride (0.10 equiv.) were added to a solution of benzylidenegly-
cine ethyl ester (1 mmol) in dry acetonitrile (10 ml). After completion of the
reaction as determined by TLC, the reaction mixture was filtered through a
celite pad, washed with saturated aqueous solution of NH Cl, and then
4
extracted with CH Cl (2 ꢃ 20 mol). The combined organic layers were
2
2
washed with brine and then dried (MgSO ). After evaporation of the solvent
4
in vacuo, the residue was purified by column chromatography on C18
column (250 ꢃ 20mm, 20m) with water=acetonitrile (6:4) as an eluent. Flow
rate was 20 ml=min, and the UV detection was done at 254 nm to afford the
cycloadduct, which was lyophilized and then crystallized from ethanol.
Data
Ethyl-5-(3,4,5-trimethoxyphenyl)-3-(thiophen-2-yl)-4-((E)-3-(thiphen-
2
-yl)acryloyl)pyrrolidine-2-carboxylate (3a)
1
Yield: 82%; H NMR: d 1.30 (t, J ¼ 7.1 Hz, 3H), 3.22 (t, J ¼ 8.3 Hz, 1H),
3
.65 (t, J ¼ 8.5 Hz, 1H), 3.73 (s, 9H), 4.01 (d, J ¼ 8.8 Hz, 1H), 4.13 (q,

1942
R. Murugan, R. Raghunathan, and S. S. Narayanan
J ¼ 13.8 Hz, 2H), 4.40 (d, J ¼ 8.7 Hz, 1H), 6.11 (m, 2H), 6.54 (d,
J ¼ 16.5 Hz, 1H), 6.63–7.01 (m, 3H), 7.51 (d, J ¼ 16.5 Hz, 1H), 7.61–
1
3
7
1
1
.70 (m, 3H); C NMR: d 13.5, 42.3, 53.5, 55.2, 60.0, 62.1, 64.7, 106.1,
23.2, 125.4, 126.3, 127.5, 128.3, 130.4, 132.8, 133.1, 135.1, 136.4,
38.4, 145.4, 150.8, 172.4, 203.4 ppm. Mass m=z: 528.2 (M þ 1). Anal.
calcd. for C H NO S : C, 61.46; H, 5.54; N, 2.65. Found: C, 61.47;
2
7
29
6 2
H, 5.56; N, 2.62.
Ethyl-5-(3,4,5-trimethoxyphenyl)-3-(4-methylthiazol-5-yl)-4-((E)-3-
(4-methylthiazol-5-yl)acryloyl)pyrrolidine-2-carboxylate (3b)
1
Yield: 88%; H NMR: d 1.31 (t, J ¼ 7.1 Hz, 3H), 2.48 (s, 6H), 3.23 (t,
J ¼ 8.3 Hz, 1H), 3.66 (t, J ¼ 8.5 Hz, 1H), 3.76 (s, 9H), 4.11 (d, J ¼ 8.8 Hz,
Hz, 1H), 4.18 (q, J ¼ 13.8 Hz, 2H), 4.52 (d, J ¼ 8.7 Hz, 1H), 6.11 (m, 2H),
6
.54 (d, J ¼ 16.5 Hz, 1H), 7.51 (d, J ¼ 16.5 Hz, 1H), 8.78 (s, 1H), 9.03
1
3
(s, 1H); C NMR: d 11.5, 11.7, 13.5, 42.2, 53.4, 55.3, 60.0, 62.1, 64.7,
1
06.1, 123.2, 125.3, 126.2, 127.5, 128.3, 130.1, 135.1, 136.5, 138.2, 145.6,
1
C H N O S : C, 58.15; H, 5.60; N, 7.53. Found: C, 58.14; H, 5.61;
50.8, 172.3, 203.5 ppm. Mass m=z: 558.2 (M þ 1). Anal. calcd. for
2
7
31
3
6 2
N, 7.55.
Ethyl-5-(3,4,5-trimethoxyphenyl)-3-phenyl-4-((E)-3-phenylacryloyl)-
pyrrolidine-2-carboxylate (3c)
1
Yield: 92%; H NMR: d 1.30 (t, J ¼ 7.1 Hz, 3H), 3.23 (t, J ¼ 8.3 Hz, 1H),
3
.64 (t, J ¼ 8.5 Hz, 1H), 3.73 (s, 9H), 4.05 (d, J ¼ 8.8 Hz, 1H), 4.14 (q,
J ¼ 13.8 Hz, 2H), 4.38 (d, J ¼ 8.7 Hz, 1H), 6.12 (m, 2H), 6.86 (d,
1
3
J ¼ 16.5 Hz, 1H), 6.63–7.30 (m, 10H), 7.62 (d, J ¼ 16.5 Hz, 1H);
C
NMR: d 13.6, 42.3, 53.5, 55.2, 60.0, 62.1, 64.7, 106.1, 123.2, 125.4,
1
1
26.3, 126.7, 126.8, 127.5, 128.2, 128.9, 135.1, 136.4, 138.4, 145.4,
50.8, 172.4, 203.9 ppm. Mass m=z: 516.2 (M þ 1). Anal. calcd. for
C H NO : C, 72.21; H, 6.45; N, 2.72. Found: C, 72.19; H, 6.43; N, 2.77.
3
1
33
6
Ethyl-3-(2-chlorophenyl)-4-((E)-3-(2-chlorophenyl)acryloyl-5-(3,4,5-
trimethoxyphenyl)pyrrolidine-2-carboxylate (3d)
1
Yield: 92%; H NMR: d 1.30 (t, J ¼ 7.1 Hz, 3H), 3.21 (t, J ¼ 8.3 Hz, 1H),
3
.58 (t, J ¼ 8.5 Hz, 1H), 3.71 (s, 9H), 4.05 (d, J ¼ 8.8 Hz, 1H), 4.14 (q,
J ¼ 13.8 Hz, 2H), 4.34 (d, J ¼ 8.7 Hz, 1H), 6.11 (m, 2H), 6.75 (d,
1
3
J ¼ 16.5 Hz,1H), 6.63–7.30 (m, 8H), 7.55 (d, J ¼ 16.5 Hz, 1H);
C
NMR: d 13.6, 42.3, 53.5, 55.2, 60.0, 62.1, 64.7, 106.1, 123.2, 125.4, 126.3,

Pyrrolidines by 1,3-Dipolar Cycloaddition
1943
1
2
6
26.7, 126.8, 127.5, 128.2, 128.9, 135.1, 136.4, 138.4, 145.4, 150.8, 172.4,
03.9 ppm. Mass m=z: 584.2 (M þ 1). Anal. calcd. for C H Cl NO : C,
3
1
31
2
6
3.70; H, 5.35; N, 2.40. Found: C, 63.73; H, 5.35; N, 2.42.
Ethyl-3-(4-fluorophenyl)-4-((E)-3-(4-fluorophenyl)acryloyl-5-(3,4,5-
trimethoxyphenyl)pyrrolidine-2-carboxylate (3e)
1
Yield: 94%; H NMR: d 1.30 (t, J ¼ 7.1 Hz, 3H), 3.21 (t, J ¼ 8.3 Hz, 1H),
3
.58 (t, J ¼ 8.5 Hz, 1H), 3.71 (s, 9H), 4.05 (d, J ¼ 8.8 Hz, 1H), 4.14 (q,
J ¼ 13.8 Hz, 2H), 4.34 (d, J ¼ 8.7 Hz, 1H), 6.11 (m, 2H), 6.75 (d,
1
3
J ¼ 16.5 Hz, 1H), 6.63–7.30 (m, 8H), 7.55 (d, J ¼ 16.5 Hz, 1H);
C
NMR: d 13.6, 42.3, 53.5, 55.2, 60.0, 62.1, 64.7, 106.1, 123.2, 125.4,
1
1
26.3, 126.7, 126.8, 127.5, 128.2, 128.9, 131.2, 135.1, 136.4, 138.4,
45.4, 150.8, 160.2, 162.3, 172.4, 204.5 ppm. Mass m=z: 552.2 (M þ 1).
Anal. calcd. for C H F NO : C, 67.50; H, 5.66; N, 2.54. Found: C,
3
1
31
2
6
6
7.52; H, 5.63; N, 2.56.
Ethyl-5-(3,4,5-trimethoxyphenyl)-3-p-tolyl-4-((E)-3-p-tolylacryloyl)-
pyrrolidine-2-carboxylate (3f)
1
Yield: 93%; H NMR: d 1.31 (t, J ¼ 7.1 Hz, 3H), 2.38 (s, 6H), 3.21 (t,
J ¼ 8.3 Hz, 1H), 3.58 (t, J ¼ 8.5 Hz, 1H), 3.71 (s, 9H), 4.05 (d, J ¼ 8.8 Hz,
Hz, 1H), 4.14 (q, J ¼ 13.8 Hz, 2H), 4.34 (d, J ¼ 8.7 Hz, 1H), 6.11 (m, 2H),
6
.75 (d, J ¼ 16.5 Hz, 1H), 6.63–7.30 (m, 8H), 7.55 (d, J ¼ 16.5 Hz, 1H);
C NMR: d 12.3, 13.6, 24.6, 42.3, 53.5, 55.2, 60.0, 62.1, 64.7, 106.1,
23.2, 125.4, 126.3, 126.7, 126.8, 127.5, 128.2, 128.9, 131.2, 135.1,
36.4, 137.4, 138.4, 145.4, 150.8, 172.4, 204.5. Mass m=z: 544.3
1
3
1
1
(
C, 72.91; H, 6.84; N, 2.55.
M þ 1). Anal. calcd. for C H NO : C, 72.91; H, 6.86; N, 2.58. Found:
3
3
37
6
Ethyl-5-phenyl-3-(thiophen-2-yl)-4-((E)-3-(thiophen-2-yl)acryloyl)-
pyrrolidine-2-carboxylate (3g)
1
Yield: 93%; H NMR: d 1.30 (t, J ¼ 7.1 Hz, 3H), 3.24 (t, J ¼ 8.3 Hz, 1H),
3
4
7
1
1
.66 (t, J ¼ 8.5 Hz, 1H), 4.08 (d, J ¼ 8.8 Hz, 1H), 4.17 (q, J ¼ 13.8 Hz, 2H),
.51 (d, J ¼ 8.7 Hz, 1H), 6.54 (d, J ¼ 16.5 Hz, 1H), 6.63–7.65 (m, 11H),
1
3
.81 (d, J ¼ 16.5 Hz, 1H); C NMR: d 14.1, 46.2, 55.2, 60.0, 62.1, 64.7,
23.2, 125.4, 126.3, 127.5, 128.3, 131.4, 132.8, 133.1, 135.1, 137.4,
38.4, 145.4, 150.8, 171.8, 203.8 ppm. Mass m=z: 438.1 (M þ 1). Anal.
calcd. for C H NO S : C, 65.88; H, 5.30; N, 3.20. Found: C, 65.87;
2
4
23
3 2
H, 5.31; N, 3.24.

1944
R. Murugan, R. Raghunathan, and S. S. Narayanan
Ethyl-3-(4-methylthiozol-5-yl)-4-((E)-3-(4-methylthiozol-5-yl)acryloyl)-
5
-phenylpyrrolidine-2-carboxylate (3h)
1
Yield: 87%; H NMR: d 1.30 (t, J ¼ 7.1 Hz, 3H), 2.47 (s, 6H), 3.24 (t,
J ¼ 8.3 Hz, 1H), 3.68 (t, J ¼ 8.5 Hz, 1H), 4.08 (d, J ¼ 8.8 Hz, 1H), 4.15
(
q, J ¼ 13.8 Hz, 2H), 4.40 (d, J ¼ 8.7 Hz, 1H), 6.55 (d, J ¼ 16.5 Hz, 1H),
6
.63–7.01 (m, 5H), 7.67 (d, J ¼ 16.5 Hz, 1H), 8.78 (s, 1H), 9.03 (s, 1H);
C NMR: d 12.2, 14.1, 46.2, 55.2, 60.0, 62.1, 64.7, 123.2, 125.4, 126.3,
27.5, 128.3, 131.4, 132.8, 133.1, 135.1, 137.4, 138.4, 145.4, 150.8,
51.9, 152.8, 171.7, 203.9 ppm. Mass m=z: 468.1 (M þ 1). Anal. calcd.
1
3
1
1
for C H N O S : C, 61.65; H, 5.39; N, 8.99. Found: C, 61.63; H,
2
4
25
3
3 2
5
.43; N, 8.95.
Ethyl-3,5-diphenyl-4-((E)-3-phenylacryloyl)-pyrrolidine-2-carboxylate
3i)
(
1
Yield: 90%; H NMR: d 1.30 (t, J ¼ 7.1 Hz, 3H), 3.21 (t, J ¼ 8.3 Hz, 1H),
3
4
7
1
1
.58 (t, J ¼ 8.5 Hz, 1H), 4.03 (d, J ¼ 8.8 Hz, 1H), 4.14 (q, J ¼ 13.8 Hz, 2H),
.43 (d, J ¼ 8.7 Hz, 1H), 6.56 (d, J ¼ 16.5 Hz, 1H), 6.63–7.23 (m, 15H),
1
3
.51 (d, J ¼ 16.5 Hz, 1H); C NMR: d 14.2, 43.2, 53.2, 62.3, 64.7,
26.1, 126.3, 126.4, 128.4, 128.6, 136.4, 138.4, 140.5, 145.4, 150.8,
71.5, 203.6 ppm. Mass m=z: 426.2 (M þ 1). Anal. calcd. for
C H NO : C, 79.03; H, 6.40; N, 3.29. Found: C, 79.02; H, 6.41; N, 3.27.
2
8
27
3
Ethyl-3-(2-chlorophenyl)-4-((E)-3-(2-chlorophenyl)acryloyl)-
5
-phenylpyrrolidine-2-carboxylate (3j)
1
Yield: 90%; HNMR: d 1.30 (t, J ¼ 7.1 Hz, 3H), 3.21 (t, J ¼ 8.3 Hz, 1H),
3
4
7
1
1
.58 (t, J ¼ 8.5 Hz, 1H), 4.03 (d, J ¼ 8.8 Hz, 1H), 4.14 (q, J ¼ 13.8 Hz, 2H),
.43 (d, J ¼ 8.7 Hz, 1H), 6.56 (d, J ¼ 16.5 Hz, 1H), 6.63–7.23 (m, 13H),
1
3
.51 (d, J ¼ 16.5 Hz, 1H); C NMR: d 14.2, 42.4, 53.2, 62.3, 64.7,
26.1, 126.4, 128.4, 128.6, 131.3, 133.6, 136.4, 138.4, 140.5, 145.4,
50.8, 171.5, 203.6 ppm. Mass m=z: 494.1 (M þ 1). Anal. calcd. for
C H Cl NO : C, 68.02; H, 5.10; N, 2.83. Found: C, 68.00; H, 5.12;
2
8
25
2
3
N, 2.78.
Ethyl-3-(4-fluorophenyl)-4-((E)-3-(4-fluorophenyl)acryloyl)-
5
-phenylpyrrolidine-2-carboxylate (3k)
1
Yield: 90%; H NMR: d 1.10 (t, J ¼ 6.91 Hz, 3H), 3.31 (t, J ¼ 8.2 Hz, 1H),
3
.65 (t, J ¼ 8.4 Hz, 1H), 3.95 (d, J ¼ 8.7 Hz, 1H), 4.11 (q, J ¼ 13.9 Hz, 2H),

Pyrrolidines by 1,3-Dipolar Cycloaddition
1945
4
.25 (d, J ¼ 8.2 Hz, 1H), 6.54 (d, J ¼ 15.8 Hz, 1H), 6.8–7.3 (m, 13H), 7.54
1
3
(
d, J ¼ 15.8 Hz, 1H); C NMR: d 14.2, 42.4, 53.2, 62.3, 64.7, 115.6, 126.2,
1
2
7
26.4, 128.4, 128.6, 131.3, 134.5, 140.5, 145.4, 150.8, 160.2, 162.2, 171.5,
03.6 ppm. Mass m=z: 462.2 (M þ 1). Anal. calcd. for C H F NO : C,
2
8
25
2
3
2.87; H, 5.46; N, 3.04. Found: C, 72.85; H, 5.46; N, 3.08.
Ethyl-5-phenyl-3-p-tolyl)-4-((E)-3-p-tolylacryloyl)pyrrolidine-
2
-carboxylate (3l)
1
Yield: 88%; H NMR: d 1.28 (t, J ¼ 6.91 Hz, 3H), 2.35 (s, 6H); 3.31 (t,
J ¼ 8.2 Hz, 1H), 3.65 (t, J ¼ 8.4 Hz, 1H), 3.95 (d, J ¼ 8.7 Hz, 1H), 4.11
(
q, J ¼ 13.9 Hz, 2H), 4.25 (d, J ¼ 8.2 Hz, 1H), 6.54 (d, J ¼ 15.8 Hz, 1H),
1
3
6
4
1
.8–7.3 (m, 13H), 7.54 (d, J ¼ 15.8 Hz, 1H); C NMR: d 14.2, 24.3,
2.4, 53.2, 62.3, 64.7, 126.1, 126.4, 128.4, 128.6, 129.2, 132.3, 135.4,
37.6, 140.5, 145.4, 150.8, 171.5, 203.6 ppm. Mass m=z: 454.2 (M þ 1).
Anal. calcd. for C H NO : C, 79.44; H, 6.89; N, 3.09. Found: C,
3
0
31
3
7
9.42; H, 6.89; N, 3.13.
Ethyl-5-(4-chlorophenyl)-3-phenyl-4-((E)-3-phenyl)acryloyl)pyrrolidine-
2
-carboxylate (3m)
1
Yield: 88%; H NMR: d 1.28 (t, J ¼ 7.01 Hz, 3H), 3.31 (t, J ¼ 7.9 Hz, 1H),
3
2
1
6
1
.69 (t, J ¼ 8.1 Hz, 1H), 4.05 (d, J ¼ 7.8 Hz, 1H), 4.21 (q, J ¼ 12.88 Hz,
H), 4.79 (d, J ¼ 8.2 Hz, 1H), 6.57 (d, J ¼ 15.2 Hz, 1H), 6.62–7.22 (m,
1
3
4H), 7.52 (d, J ¼ 15.2 Hz, 1H). C NMR: d 14.2, 42.3, 55.4, 61.3, 62.5,
6.1, 126.4, 128.2, 128.6, 129.0, 129.4, 129.6, 131.6, 135.7, 138.2, 138.7,
39.1, 143.3, 171.6, 203.9 ppm. Mass m=z: 460.2 (M þ 1). Anal. calcd.
for C H ClNO : C, 73.11; H, 5.70; N, 3.05. Found: C, 73.12; H,
2
8
26
3
5
.67; N, 3.05.
Ethyl-3-(2-chlorophenyl)-5-(4-chlorophenyl)-4-((E)-3-(2-chlorophenyl)-
acryloyl)pyrrolidine-2-carboxylate (3n)
1
Yield: 88%; H NMR: d 1.22 (t, J ¼ 7.01 Hz, 3H), 3.31 (t, J ¼ 7.9 Hz, 1H),
3
2
1
6
1
.72 (t, J ¼ 8.1 Hz, 1H), 4.01 (d, J ¼ 7.8 Hz, 1H), 4.24 (q, J ¼ 12.88 Hz,
H), 4.85 (d, J ¼ 8.2 Hz, 1H), 6.90 (d, J ¼ 15.2 Hz, 1H), 7.0–7.22 (m,
1
3
2H), 7.82 (d, J ¼ 15.2 Hz, 1H). C NMR: d 14.2, 42.3, 55.4, 61.3, 62.5,
6.1, 126.4, 127.0, 127.5, 127.8, 128.7, 128.8, 129.0, 129.4, 129.6, 131.0,
31.5, 133.1, 132.0,133.1, 133.4, 133.7, 139.1, 143.3, 172.1, 203.1 ppm.
Mass m=z: 528.1 (M þ 1). Anal. calcd. for C H Cl NO : C, 63.59; H,
2
8
24
3
3
4
.57; N, 2.65. Found: C, 63.58; H, 4.56; N, 2.63.

1946
R. Murugan, R. Raghunathan, and S. S. Narayanan
ACKNOWLEDGMENTS
One of the authors, R. M., thanks Dr. Raghavendra Rao, managing
director of Orchid Research Laboratories Limited, Chennai, India, for
consent to perform the part-time research.
REFERENCES
1
2
. Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; Wiley: New York, 1984;
vols. 1 and 2.
. Grigg, R.; Sarker, M. A. B. Silver-catalysed azomethine ylide cycloaddition—
The synthesis of spiro homoserine lactone analogues. Tetrahedron 2006, 62,
10332–10343.
3
. Groselj, U.; Bevk, D.; Jakse, R.; Meden, A.; Stanovnik, B.; Svete, J.
Stereoselective additions to the exocyclic C¼C bond of some a-alkylidene-
(
þ)-camphor derivatives. Tetrahedron: Asymmetry 2006, 17, 1217–1237.
4
5
. Kanemasa, S. Metal-assisted stereocontrol of 1,3-dipolar cycloaddition.
Synlett 2002, 1371–1387.
. Gothelf, K. V.; Jorgensen, K. A. Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Towards Heterocycles and Natural Products;
A. Padwa and W. H. Pearson (Eds.), John Wiley, New York, 2002.
. Broggini, G.; Molteni, G.; Terraneo, A.; Zecchi, G. Transition metal com-
plexation in 1,3-dipolar cycloadditions. Heterocycles 2003, 59, 823–858.
. Namboothiri, I. N. N.; Hassner, A. Stereoselective intramolecular 1,3-dipolar
cycloadditions. Top. Curr. Chem. 2001, 216, 1.
6
7
8
9
. Southon, I. W.; Buckingham, J. Dictionary of Alkaloids; Chapman and Hall:
New York, 1989.
. Li, Q.; Chu, D. T. W.; Claiborne, A.; Cooper, C. S.; Lee, C. M.; Raye, K.;
Berst, K. B.; Donner, P.; Wang, W.; Hasvold, L.; Fung, A.; Ma, Z.; Tufano,
M.; Flamm, R.; Shen, L. L.; Baranowski, J.; Nilius, A.; Alder, J.; Meulbroek,
J.; Marsh, K.; Crowell, D. A.; Hui, Y.; Seif, L.; Melcher, L. M.; Henry, R.;
Spanton, S.; Faghih, R.; Klein, L. L.; Tanaka, S. K.; Plattner, J. J. Synthesis
and structure activity relationships of 2-pyridones: A novel series of potent
DNA gyrase inhibitors as antibacterial agents. J. Med. Chem. 1996, 39,
3070–3088.
1
1
1
0. Nyerges, M.; Bendell, D.; Arany, A.; Hibbs, D. E.; Coles, S. J.; Hurthouse,
M. B.; Groundwater, P. W.; Meth-Cohn, O. Silver acetate catalysed asym-
metric 1,3-dipolar cyloadditions of imines and chiral acrylamides. Synlett
2003, 947–950.
1. Nyerges, M.; Bendell, D.; Arany, A.; Hibbs, D. E.; Coles, S. J.; Hurthouse,
M. B.; Groundwater, P. W.; Meth-Cohn, O. Silver acetate catalysed asym-
metric 1,3-dipolar cyloadditions of imines and chiral acrylamides. Tetra-
hedron 2005, 61, 3745–3753.
2. Waldmann, H. Amino acid esters: Versatile chiral auxiliary groups for the
asymmetric synthesis of nitrogen heterocycles. Synlett 1995, 133–141.

Pyrrolidines by 1,3-Dipolar Cycloaddition
1947
1
3. Daly, J. W.; Spande, T. W.; Whittaker, N.; Highet, R. J.; Feigl, D.;
Noshimori, N.; Tokuyama, T.; Meyers, C. W. Alkaloids from dendrobatid
frogs: Structures of two o-hydroxy congeners of 3-butyl-5-propylindolizidine
and occcurrence of 2,5-disubstituted pyrrolidines and a 2,6-disubstituted
piperidine. J. Nat. Prod. 1986, 49 (2), 265–280.
1
1
4. Garner, P.; Kaniskan, H. U. A stereodivergent cascade imine!azomethine
ylide!1,3-dipolar cycloadditive approach to a-chiral pyrrolidines. Tetra-
hedron Lett. 2005, 46, 5181–5185.
5. Maker, A.; Bansode, F. W.; Srivastava, V. M.; Singh, M. M. Antioxidant
defense system during endometrial receptivity in the guinea pig: Effect of
ormeloxifene, a selective estrogen receptor modulator. J. Endocrinol. 2006,
188 (1), 121–134.
1
6. Marian, T.; Szabo-Peli, J.; Nemeth, E.; Tron, L.; Friedlander, E.; Szabo, A.;
Balkay, L.; Veress, G.; Krasznai, Z. Naþ=Caþ exchanger inhibitors modify
the accumulation of tumor-diagnostic PET tracers in cancer cells. Eu. J.
Pharm. Sci. 2007, 30 (1), 56–63.
1
7. Khairia, Y. M.; Magda, E.-S. A.; Faiza, E.-S. S.; Hassan, F. A.; Omar, A.-D.
A.; Sit Albanat, A. A. Synthesis of curcumin analogues as potential antioxi-
dant, cancer chemopreventive agents. Arch. Pharm. (Weinheim, Ger.) 2004,
337 (1), 42–54.
1
8. Modzelewska, A.; Pettit, C.; Achnta, G.; Davidson, N. E.; Huang, P.; Khan,
S. R. Anticancer activities of novel chalcone and bis-chalcone derivatives.
Bioorg. Med. Chem. 2006, 14 (10), 3491–3495.
1
9. Deng, J.; Sanchez, T.; Al-Mawsawi, Q.; Ayam, R.; Yunes, R. A; Garofalo,
A.; Bologer, M. B.; Neamati, N. Discovery of structurally diverse HIV-1 inte-
grase inhibitors based on a chalcone pharmacophore. Bioorg.Med. Chem.
2007, 15 (14), 4985–5002.
2
2
2
0. Vijayabaskar, V.; Perumal, S.; Devanathan, V. C. An efficient synthesis
of cis-2,6-diaryl-1-methyl-4-piperidones. Indian. J. Chem. 1995, 34B,
649–651.
1. Barr, D. A.; Grigg, R.; Sridharan, V. Ti(IV) mediated transesterification and
regio-and stereo-specific cycloaddition of imines of a-amino esters: Reversal
of normal regiochemistry. Tetrahedron Lett. 1989, 30, 4727–4730.
2. Ishii, Y.; Hasegawa, S.; Kimura, S.; Itoh, K. Novel trinuclear
palladium(0) complexes: Tris (tribenzylideneacetylacetone) tripalladium
(
4
solvent) complexes and their reactions. J. Organomet. Chem. 1974, 73,
11–418.
2
3. Mirari, A.; Arrieta, A.; Cossio, F. P. Stereocontrolled synthesis of highly
substituted proline esters via [3 þ 2] cycloaddition between N-metalated
azomethine ylides and nitroalkanes: Orgins of the metal effect on the stereo-
chemical outcome. J. Org. Chem. 1998, 63, 1795–1805.
2
4. Huisgen, R. In Advances in Cycloaddition; D. P. Curran (Ed.); JAI: London,
1988, vol. 1, pp. 1–31.
2
5. Subramaniyan, G.; Raghunathan, R. Synthesis of highly substituted
spiropyrrolidines via 1,3-dipolar cycloaddition reaction of N-metalated
azomethine ylides. Tetrahedron 2001, 57, 2909–2913.

1948
R. Murugan, R. Raghunathan, and S. S. Narayanan
26. Subramaniyan, G.; Raghunathan, R.; Martin Castro, A. M. 3-Arylidene-
4-flavanones acting as 2p components in an intermolecular 1,3-dipolar
cycloaddition reaction of azomethine ylides. Synthesis 2002, 16, 2440–2444.
7. Ramesh, P.; Murugavel, S.; Subbiah Pandi, A.; Murugan, R.; Sriman
Narayanan, S. Ethyl 3-phenyl-4-[ (Z)-3-phenylacryloyl] 5-(3,4,5-trimethoxy-
phenyl) pyrrolidine-2-carboxylate. Acta Cryst. 2007, E63, o4873.
2