Facile synthesis of β-lactam-grafted spirooxindolopyrrolidine through regioselective 1,3-dipolar cycloaddition reaction

Article abstract of DOI:10.1080/00397911.2010.515351

One-pot synthesis of novel β-lactam-grafted spiropyrrolidines has been accomplished in good yield via a facile [3+2] cycloaddition reaction of azomethine ylides, derived from β-lactam aldehyde and sarcosine, with various p-substituted (E)-2-oxoindoline-3-

Full text of DOI:10.1080/00397911.2010.515351

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Facile Synthesis of β-Lactam-Grafted
Spirooxindolopyrrolidine Through
Regioselective 1,3-Dipolar Cycloaddition
Reaction
Natarajan Arumugam a & Raghavachary Raghunathan a
a Department of Organic Chemistry, University of Madras, Guindy
Campus, Chennai, India
Version of record first published: 29 Jun 2011
To cite this article: Natarajan Arumugam & Raghavachary Raghunathan (2011): Facile Synthesis of β-
Lactam-Grafted Spirooxindolopyrrolidine Through Regioselective 1,3-Dipolar Cycloaddition Reaction,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 41:18, 2747-2755
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Synthetic Communications1, 41: 2747–2755, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.515351
FACILE SYNTHESIS OF b-LACTAM-GRAFTED
SPIROOXINDOLOPYRROLIDINE THROUGH
REGIOSELECTIVE 1,3-DIPOLAR CYCLOADDITION
REACTION
Natarajan Arumugam and Raghavachary Raghunathan
Department of Organic Chemistry, University of Madras, Guindy Campus,
Chennai, India
GRAPHICAL ABSTRACT
Abstract One-pot synthesis of novel b-lactam-grafted spiropyrrolidines has been
accomplished in good yield via a facile [3 þ 2] cycloaddition reaction of azomethine ylides,
derived from b-lactam aldehyde and sarcosine, with various p-substituted (E)-2-
oxoindoline-3-ylidene acetophenone derivatives as dipolarophiles. The reaction gave
excellent yields of the products when carried out under microwave irradiation.
Keywords Azomethine ylide; b-lactam; cycloaddition; microwave; spiropyrrolidine
INTRODUCTION
The 1,3-dipolar cycloaddition of azomethine ylides with olefinic and acetylenic
dipolarophiles has resulted in a number of novel heterocyclic scaffolds, which are
particularly useful for the creation of diverse chemical libraries of druglike molecules
for biological screening.[1,2] Functionalized pyrrolidines and oxindoles are the central
skeletons for numerous alkaloids and constitute classes of compounds with signifi-
cant biological activity.[3,4] Derivatives of spirooxindole find very wide biological
applications as antimicrobials; anti-inflammatory, antitumoral, and antibiotic
agents, and inhibitors of human NK-1 receptors.[5] They are also found to be potent
Received April 27, 2010.
Address correspondence to Raghavachary Raghunathan, Department of Organic Chemistry,
University of Madras, Guindy Campus, Chennai 600 025, India. E-mail: ragharaghunathan@yahoo.com
2747

2748
N. ARUMUGAM AND R. RAGHUNATHAN
aldose reductase inhibitors (ARIs), which help to treat and prevent diabetic
complications arising from elevated levels of sorbitol.[6] Spiropyrrolidinyloxindole
ring systems are found in a number of alkaloids such as horsifiline, spirotryprosta-
tine A and B, and elacomine.[7]
b-Lactam forms a class of antibiotic characterized by the presence of an
azetidine-2-one ring, with biological activity.[8] The azetidine-2-one ring system is
a common structural feature of a number of broad-spectrum b-lactam antibiotics
such as pencillins, cephalosporins, carbapenems, nocardicins, and monobactams,
which have been widely used as chemotherapeutic agents for treating microbial
diseases.[9] It also shows many other interesting biological properties, such as chol-
esterol absorption inhibitory,[10] human cytomegalovirus protease inhibitory,[11]
thrombin inhibitory,[12] antihyperglycemic,[13] antitumor,[14] anti-HIV,[15] anti-
inflammatory, and analgesic activities.[16] Hence, there has been renewed interest
in the synthesis of b-lactam-based heterocycles.
Our research group has been largely involved in the synthesis of spiropyrroli-
dine subsitituted oxindole and b-lactam heterocycles[17–20] by 1,3-dipolar cycloaddi-
tion, which are found in many naturally occurring alkaloids with significant
biological activity. We had recently reported the synthesis of macrocyclic bis-b-
lactam[21] through [2 þ 2] Staudinger reaction and the synthesis of b-lactam-substi-
tuted spiropyrrolidine=pyrrolizidines.[22] And, also we reported the synthesis of
b-lactam-substituted pyrroloisoquinoline and indolizinoindole ring system by inter-
molecular 1,3-dipolar cycloaddition.[23]
In continuation of our efforts[24] and in anticipation of the high bioactive
potential of pyrrolidine-based heterocycles, we herein report the synthesis of some
spirooxindolopyrrolidine with b-lactam moiety. Although there are reports available
for the synthesis of substituted spiropyrrolidine, there seem to be no reports for the
synthesis of b-lactam-grafted spiropyrrolidine with oxindole derivative. Conse-
quently, integration of the b-lactam moiety with spirooxindolopyrrolidine deriva-
tives may increase their biological activities or create new medicinal properties.
RESULTS AND DISCUSSION
In a one-pot cycloaddition reaction, the azomethine ylide generated from b-lac-
tam and sarcosine was reacted with (E)-2-oxoindoline-3-ylidene acetophenones 3a–e
in refluxing toluene to afford a series of spiropyrrolidine 4a–e with overall yield of
45–50% (Scheme 1). The required dipolarophile (E)-2-oxoindoline-3-ylidene aceto-
phenones 3a–e were prepared by the base-catalyzed condensation of isatin with
various acetophenones according to the literature procedure.[25]
The cycloadducts 4a–e were confirmed by spectroscopic techniques and
elemental analysis.
The infrared (IR) spectrum of compound 4d exhibited a peak at 3192 cmꢀ1
characteristic of oxindole NH stretch. The presence of an amide carbonyl group
was confirmed by an absorption band at 1706 cmꢀ1. The absorption bands at
1739 cmꢀ1 and 1630 cmꢀ1 showed the presence of b-lactam carbonyl and benzoyl
1
carbonyl groups respectively. The H NMR spectrum of compound 4d showed a
sharp singlet at d 2.24 ppm due to N-methyl protons, and the N-CH2 protons of
the pyrrolidine ring appeared as two doublets at d 2.92 ppm (J ¼ 10.3 Hz) and

b-LACTAM-GRAFTED SPIROOXINDOLOPYRROLIDINE
2749
Scheme 1. Synthesis of spiropyrrolidines.
d 3.53 (J ¼ 10.3 Hz). The Ha proton exhibited a doublet at d 5.15 ppm (J ¼ 2.1 Hz).
The Hb proton resonated as a doublet of doublets in the range d 4.40–4.42 ppm
(J ¼ 4.8, 2.4 Hz). The Hc proton exhibited a doublet of doublet at d 4.22–4.26 ppm
(J ¼ 8.1, 4.8 Hz). The Hd proton appeared as doublet at d 4.53 ppm (J ¼ 8.4 Hz),
which clearly showed the regiochemistry of the cycloaddition. The NH proton of
the oxindole appeared as a singlet at d 8.14. If the other possible regio-isomer 5d
had been formed, a triplet for Hd proton would have been observed.
The 13C NMR spectrum of cycloadduct 4d showed peaks at 195.62 ppm and
181.29 ppm due to the benzoyl carbonyl carbon and oxindole amide carbonyl carbon
respectively. b-Lactam amide carbonyl carbon showed a peak at d 166.17 ppm. The
N-methyl carbon exhibited a peak at d 40.99 ppm. The spirocarbon showed a peak at
d 68.50 ppm. The mass spectrum of 4d showed a peak at m=z 571.25 (Mþ), which
confirmed the structure of the cycloadduct. The regioselective cycloaddition of the
dipoles is shown in Scheme 2.
Finally, the regio- and stereochemical outcome of the cycloaddition reaction
was unambiguously ascertained by single-crystal x-ray diffraction analysis of the
[26]
cycloadduct 4d and 4e (Figs. 1and 2). The crystal structure has been deposited
at the Cambridge Crystallographic Data Centre and allocated the deposition number
Scheme 2. Regioselective cycloaddition of the dipoles.

2750
N. ARUMUGAM AND R. RAGHUNATHAN
Figure 1. ORTEP diagram of 4d.
Figure 2. ORTEP diagram of 4e.

b-LACTAM-GRAFTED SPIROOXINDOLOPYRROLIDINE
Table 1. Synthesis of spirooxindolopyrrolodines (5a–e)
2751
Conventional method
yield in 4 h (%)
Microwave method in toluene
in 10 min yield (%)
Entry
Compounds
R
1
2
3
4
5
6a
6b
6c
6d
6e
H
Cl
50
52
45
55
54
86
89
87
85
84
Br
Me
OMe
CCDC 271093 for compound 4d. In the molecular structure of 4d, the pyrrolidine
ring adopts a twist conformation. The molecular structure is stabilized by intramol-
ecular CꢀH ꢁ ꢁ ꢁ O interaction, and the crystal packing also involves weak Cꢀ
H ꢁ ꢁ ꢁ O interactions. The b-lactam ring is planar with its internal angles in the range
85.7(1) to 94.5(1)ꢂ. The oxindole moiety is planar, is nearly orthogonal to the pyrroli-
dine and the b-lactam rings, and makes a dihedral angle of 67.3(1)ꢂ with the benzoyl
plane.
To achieve greater yield of the cycloadducts, reactions were carried out under
two different conditions. Thus, the reaction of b-lactam aldehyde and sarcosine,
when reacted with dipolarophiles in toluene under reflux, afforded cycloadducts
4a–e in moderate yields in all cases but required long reaction times and higher tem-
perature. When the same reactions were carried out under microwave irradiation in a
toluene solvent, there was a dramatic increase in the yields of the products with a
decrease in reaction time. Under these conditions, cycloadducts were obtained in
good yields (84–89%) with high regio- and stereoselectivity. The results are summar-
ized in Table 1.
CONCLUSION
In conclusion, the synthesis of a series of b-lactam-grafted spirooxindolopyrro-
lidines has been accomplished in a simple one-pot reaction with high regioselectivity.
Microwave irradiation was found to be synthetically useful in achieving good yields
of the products with reduced reaction time as compared to the conventional method.
The bioactive studies on the synthesized b-lactam-grafted spiropyrrolidines are in
progress.
EXPERIMENTAL
All melting points are uncorrected. IR spectra were recorded on a Shimadzu
1
IR-8300 series Fourier transform (FT)-IR spectrophotometer. H NMR and 13C
NMR spectra were recorded on Jeol 300 instruments in CDCl3 solvent with tetra-
methylsilane (TMS) as a standard. Mass spectra were recorded by Jeol-DX303
HF mass spectrophotometer. Elemental analyses were carried out on a Perkin-Elmer
CHNS 2400 instrument. Single-crystal x-ray diffraction analyses were performed by

2752
N. ARUMUGAM AND R. RAGHUNATHAN
a Bruker Smart Apex CCD area–detector diffractometer and Bruker Smart Apex II
CCD area–detector diffractometer.
Column chromatography was performed on silica gel (ACME, 100–200 mesh).
Routine monitoring of the reaction was done using thin-layer chromatography
(TLC) developed on glass plates coated with silica gel G (ACME) 25 mm thick
and visualized with iodine.
General Procedure for Synthesis of Cycloadducts (4a–e)
A solution of cis-4-formyl-2 azetidinones (200 mg, 0.71 mmol), sarcosine
(63 mg, 0.71 mmol), and 4-(E)-3-phenacylidene oxindole (176 mg, 0.71 mmol) was
refluxed in dry toluene for 12 h at 110 ꢂC using a Dean–Stark apparatus. After the
completion of reaction as indicated by TLC, toluene was evaporated under reduced
pressure. The crude product was purified by column chromatography using hexane–
EtOAc (8:2) as eluent. The product was recrystallized from EtOAc to reveal the
cycloadduct as colorless crystals.
General Procedure for Synthesis of Cycloadducts Under Microwave
Method (4a–e)
A mixture of cis-4-formyl-2 azetidinones (200 mg, 0.71 mmol), sarcosine
(63 mg, 0.71 mmol), and 4-(E)-phenacylideneoxindole (176 mg, 0.71 mmol) in toluene
was subjected to microwave irradiation for 10 min. After completion of the reaction
as evidenced by TLC analysis, the crude product was subjected to column chroma-
tography using petroleum ether=EtOAc (8:2) as eluent. The cycloadduct was
obtained exclusively.
Selected Data
1-N-Methyl-2-[1’-N-(p-methoxyphenyl)-3’-phenylazetidine-2’-one]-3-
benzoyl spiro[4.300]oxindole pyrrolidine, 4a. White solid, 86% (0.45 g); mp
1
238–240 ꢂC; IR (KBr): 1738, 1708 and 1626 cmꢀ1; H NMR (CDCl3, 300 MHz): d
2.24 (s, 3H, NCH3), 2.87 (d, 1H, NCH2, J ¼ 10.3 Hz), 3.49 (d, J ¼ 10.3 Hz, 1H,
NCH2), 3.78 (s, 3H, OCH3), 4.20–4.24 (dd, 1H, J ¼ 8.1, 4.8 Hz), 4.38–4.40 (dd,
13
1H, J ¼ 4.8, 2.4 Hz), 4.52 (d, 1H, J ¼ 8.4 Hz), 5.13 (d, 1H, J ¼ 2.1 Hz), 6.50–7.44
(m, Ar-H, 18H), 8.20 (s, 1H, N-H);
C NMR (CDCl3, 75 MHz): d 40.75, 52.98,
54.36, 55.38, 55.64, 60.84, 68.29, 68.47, 109.41, 114.02, 118.83, 122.45, 126.39,
127.27, 127.66, 128.12, 128.38, 128.81, 128.79, 130.67, 134.20, 135.76, 140.26,
143.69, 156.12, 166.15, 181.25 and 195.58. Mass spectrum (EI, 70 eV): m=z, 557.23
(Mþ). Anal. calcd. for C35H31N3O4: C, 75.38; H, 5.60; N, 7.54%. Found: C, 75.48;
H, 5.68; N, 7.45%.
1-N-Methyl-2-[1’-N-(p-methoxyphenyl)-3’-phenylazetidine-2’-one]-3-(p-
chlorobenzoyl) spiro[4.300]oxindolo pyrrolidine, 4b. White solid, 87% (0.5 g);
mp: 282–285 ꢂC; IR (KBr): 1739, 1708 and 1628 cmꢀ1
;
1H NMR (CDCl3,
300 MHz): d 2.26 (s, 3H, NCH3), 2.91 (d, 1H, NCH2, J ¼ 10.3 Hz), 3.54 (d, 1H,
NCH2, J ¼ 10.3 Hz), 3.78 (s, 3H, OCH3), 4.25–4.29 (dd, 1H, J ¼ 8.1, 4.8 Hz),

b-LACTAM-GRAFTED SPIROOXINDOLOPYRROLIDINE
2753
4.39–4.41 (dd, 1H, J ¼ 4.8, 2.4 Hz), 4.55 (d, 1H, J ¼ 8.4 Hz), 5.17 (d, 1H, J ¼ 2.1 Hz),
6.58–7.40 (m, Ar-H, 17H), 8.24 (s, 1H, N-H); 13 C NMR (CDCl3, 75 MHz): d 41.97,
53.48, 54.36, 55.40, 55.68, 61.09, 68.35, 68.45, 109.17, 114.07, 118.95, 122.53, 126.36,
127.35, 127.68, 128.05, 128.47, 128.96, 129.02, 130.69, 134.31, 135.78, 140.38, 143.94,
156.26, 166.25, 181.32 and 195.74. Mass spectrum (EI, 70 eV): m=z 591.19 (Mþ).
Anal. calcd. for C35H30ClN3O4: C, 71.00; H, 5.11; N, 7.10%. Found: C, 71.16;
H, 5.20; N, 7.02%.
1-N-Methyl-2-[1’-N-(p-methoxyphenyl)-3’-phenylazetidine-2’-one]-3-(p-
bromobenzoyl) spiro[4.300]oxindolo pyrrolidine, 4c. White solid, 85% (0.54 g);
mp 265–267 ꢂC; IR (KBr): 1738, 1708 and 1625 cmꢀ1
;
1H NMR (CDCl3,
300 MHz): d 2.21 (s, 3H, NCH3), 2.95 (d, 1H, NCH2, J ¼ 10.3 Hz), 3.57 (d, 1H,
NCH2, J ¼ 10.3 Hz), 3.79 (s, 3H, OCH3), 4.23–4.27 (dd, 1H, J ¼ 8.1, 4.8 Hz),
4.41–4.43 (dd, 1H, J ¼ 4.8, 2.4 Hz), 4.56 (d, 1H, J ¼ 8.4 Hz), 5.15 (d, 1H, J ¼ 2.1 Hz),
6.57–7.37 (m, Ar-H, 17H), 7.85 (s, 1H, N-H); 13 C NMR (CDCl3, 75 MHz): d 42.26,
53.52, 54.36, 55.49, 55.83, 60.03, 68.26, 68.55, 109.57, 114.04, 119.06, 122.61, 126.21,
127.22, 127.34, 128.04, 128.30, 128.90, 129.74, 130.77, 132.58, 137.09, 140.47, 143.89,
156.17, 166.27, 181.39 and 195.60. Mass spectrum (EI, 70 eV): m=z 635.14 (Mþ).
Anal. calcd. for C35H30BrN3O4: C, 66.04; H, 4.75; N, 6.60%; Found: C, 66.12;
H, 4.68; N, 6.69%.
1-N-Methyl-2-[1’-N-(p-methoxyphenyl)-3’-phenylazetidine-2’-one]-3-(p-
methylbenzoyl) spiro[4.300]oxindolo pyrrolidine, 4d. Colorless crystals, 75%
1
(0.42 g); mp 263–265 ꢂC; IR (KBr): 1739, 1706 and 1630 cmꢀ1; H NMR (CDCl3,
300 MHz): d 2.24 (s, 3H, NCH3), 2.43 (s, 3H, CH3), 2.92 (d, 1H, NCH2, J ¼ 10.3 Hz),
3.53 (d, 1H, NCH2, J ¼ 10.3 Hz), 3.75 (s, 3H, OCH3), 4.22–4.26 (dd, 1H, J ¼ 8.1,
13
4.8 Hz), 4.40–4.42 (dd, 1H, J ¼ 2.4, 4.8 Hz), 4.53 (d, 1H, J ¼ 8.4 Hz), 5.15 (d, 1H,
J ¼ 2.1 Hz), 6.56–7.41 (m, Ar-H, 17H), 8.14 (s, 1H, N-H);
C NMR (CDCl3,
75 MHz): d 21.53, 40.99, 53.42, 54.38, 55.42, 55.73, 60.94, 68.24, 68.50, 109.37,
113.93, 118.93, 122.52, 126.31, 127.37, 127.76, 128.00, 128.37, 128.82, 128.98,
130.77, 134.21, 135.73, 140.31, 143.86, 156.16, 166.17, 181.29 and 195.62. Mass spec-
trum (EI, 70 eV): m=z 571.25 (Mþ). Anal. calcd. for C36H33N3O4: C, 75.64; H, 5.82;
N, 7.35%. Found: C, 75.73; H, 5.96; N, 7.27%.
1-N-Methyl-2-[1’-N-(p-methoxyphenyl)-3’-phenylazetidine-2’-one]-3-(p-
methoxybenzoyl) spiro[4.300]oxindolo pyrrolidine, 4e. Colorless crystals, 84%
1
(0.42 g); mp 255–258 ꢂC; IR (KBr): 1738, 1708 and 1626 cmꢀ1; H NMR (CDCl3,
300 MHz): d 2.44 (s, 3H, NCH3), 2.95 (d, 1H, NCH2, J ¼ 10.3 Hz), 3.56 (d, 1H,
J ¼ 10.3 Hz), 3.72 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 4.26–3.30 (dd, 1H, J ¼ 8.1,
4.8 Hz), 4.42–4.44 (dd, 1H, J ¼ 4.8, 2.4 Hz), 4.53 (d, 1H, J ¼ 8.4 Hz), 6.49–7.41 (m,
Ar-H, 17H), 9.15 (s, 1H, N-H); 13C NMR (CDCl3, 75 MHz): d 40.98, 52.87,
54.57, 55.27, 55.42, 56.57, 60.84, 68.31, 68.71, 109.67, 113.92, 118.88, 122.52,
126.34, 127.42, 127.82, 128.09, 128.34, 128.48, 128.85, 129.98, 130.67, 133.56,
135.72, 140.57, 156.31, 166.18, 181.97 and 194.28. Mass spectrum (EI, 70 eV): m=z
587.24 (Mþ). Anal. calcd. for C36H33N3O5: C, 73.58; H, 5.66; N, 7.15%. Found:
C, 73.65; H, 5.78; N, 7.06%.

2754
N. ARUMUGAM AND R. RAGHUNATHAN
ACKNOWLEDGMENTS
The authors thank the Council of Scientific and Industrial Research (CSIR),
New Delhi, India, for financial support. One of the authors, N. A., thanks CSIR,
New Delhi, for the award of junior and senior research fellowships.
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