One-pot regioselective synthesis of novel 1-N-methyl-spiro[2,3']oxindole-spiro[3,3"]-1"-N-arylpyrrolidine-2",5"-dione-4-arylpyrrolidines through multicomponent 1,3-dipolar cycloaddition reaction of azomethine ylide

Article abstract of DOI:10.1002/jhet.2199

An atom economic and facile synthesis of novel dispiro-oxindole-pyrrolidines has been achieved via a three-component tandem cycloaddition of azomethine ylide generated in situ from isatin and sarcosine by decarboxylative condensation with N-aryl-3-benzylidene-pyrrolidine-2,5-dione derivatives as dipolarophiles. The salient features of synthetic procedure are characterized by the mild reaction conditions, high yields, high regioselectivity and stereoselectivity, one-pot procedure, and operational simplicity. This regioselectivity was assumed to be under the influence of π-π stacking interactions between the aromatic rings of azomethine ylide and N-aryl-3-benzylidene-pyrrolidine-2,5-diones that further control the exo-endo selectivity of the reaction 1,3-dipolar cycloaddition. The regiochemistry and structures of the cycloadducts were determined with spectroscopic data.

Full text of DOI:10.1002/jhet.2199

Month 2014
One-pot Regioselective Synthesis of Novel 1-N-Methyl-spiro[2,3′]
oxindole-spiro[3,3″]-1″-N-arylpyrrolidine-2″,5″-dione-4-arylpyrrolidines
through Multicomponent 1,3-Dipolar Cycloaddition Reaction of
Azomethine Ylide
*
Anjandeep Kaur, Manpreet Kaur and Baldev Singh
Department of Chemistry, Punjabi University, Patiala 147002, India
*
E-mail: drbaldev.chem@yahoo.com
Received October 26, 2013
DOI 10.1002/jhet.2199
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
An atom economic and facile synthesis of novel dispiro–oxindole–pyrrolidines has been achieved via a
three-component tandem cycloaddition of azomethine ylide generated in situ from isatin and sarcosine by
decarboxylative condensation with N-aryl-3-benzylidene-pyrrolidine-2,5-dione derivatives as
dipolarophiles. The salient features of synthetic procedure are characterized by the mild reaction conditions,
high yields, high regioselectivity and stereoselectivity, one-pot procedure, and operational simplicity. This
regioselectivity was assumed to be under the influence of π–π stacking interactions between the aromatic
rings of azomethine ylide and N-aryl-3-benzylidene-pyrrolidine-2,5-diones that further control the exo–endo
selectivity of the reaction 1,3-dipolar cycloaddition. The regiochemistry and structures of the cycloadducts
were determined with spectroscopic data.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
the syntheses of bioactive compounds [9]. MCRs leading
to interesting heterocyclic scaffolds are particularly useful
for the creation of diverse chemical libraries of “drug-like”
molecules for biological screening [10,11]. Multicomponent
1,3-dipolar cycloaddition reactions are fundamental
processes in organic chemistry [12], and their asymmetric
version offers a powerful and reliable synthetic methodology
to access five-membered heterocyclic rings in
regiocontrolled and stereocontrolled fashion [13–15]. In-
deed, the 1,3-dipolar cycloaddition reaction has been
described as “the single most important method for the con-
struction of heterocyclic five-membered rings in organic
chemistry” [16]. The 1,3-dipolar cycloaddition of ylidic spe-
cies such as azomethine ylides with dipolarophiles provides
an efficient and convergent approach for constructing
pyrrolidine rings that are classes of compounds with
Exploring novel pharmacological agents with minimum
number of synthetic steps and less time is a major
challenge for chemists [1,2]. In general, the conventional
approach involves the use of multistep reaction sequences
that are typically associated with low yields, high cost,
and tedious isolation and purification of the resulting
products. However, as a significant strategy superior to
the conventional one, multicomponent reactions (MCRs)
offer a valuable solution for such a situation [3–7]. The
highly effective one-pot procedure of MCRs exhibits many
advantages, including atom economy, facile synthesis,
convergence, productivity, and easy execution [8]. MCRs
have emerged as a powerful tool for delivering the molec-
ular diversity needed in the combinatorial approaches for
© 2014 HeteroCorporation

A. Kaur, M. Kaur, and B. Singh
Vol 000
significant biological activities [17–24]. While the cycload-
dition of these dipoles to the exocyclic olefins results in the
formation of spiro-pyrrolidines [25] that are endowed with
a wide range of pharmacological activities [26–34]. The ease
of generation of azomethine ylides coupled with the highly
regioselective and stereoselective nature of their cycloaddi-
tion reactions has resulted in a number of syntheses that uti-
lize such a reaction as the key step.
The ability to utilize azomethine ylide cycloaddition in
organic synthesis depends heavily on understanding the
factors that determine the stereochemistry of the reaction.
As part of our ongoing research program directed toward
the cycloaddition reactions [35], we report herein the
regioselective and stereoselective synthesis of dispiro–
oxindole–pyrrolidine derivatives through 1,3-dipolar
cycloaddition reaction of an azomethine ylide generated by
decarboxylative condensation reaction of isatin 8 and
sarcosine 9, with olefinic segment of N-aryl-3-benzylidene-
pyrrolidine-2,5-diones, which makes possible the simulta-
neous formation of three stereocenters in the cycloadducts.
In our work, we investigated the effect of approach of the
dipolarophiles toward the azomethine ylide on the exo–endo
selectivity of their cycloaddition reactions. This could ensure
an entry to the control of the regiochemistry and stereochem-
istry of cycloaddition, where the π–π stacking interactions
may play a significant role.
variously substituted dipolarophiles [36]. With a view to
synthesize novel dispiro heterocyclic derivatives, we
herein report the 1,3-dipolar cycloaddition reaction of
variously substituted N-aryl-3-benzylidene-pyrrolidine-2,5-
dione derivatives as 2π components with the unstabilized
azomethine ylides generated in situ. In this reaction, we
prepared variously substituted N-aryl-3-benzylidene-
pyrrolidine-2,5-dione (dipolarophile) 7a–i employing Wittig
reaction between a variety of substituted benzaldehydes 6ac
and
N-aryl-3-(triphenylphosphinylidene)pyrrolidine-2,5-
diones 5a–c. The compound 5 itself was synthesized by
refluxing triphenylphosphine and variously substituted
maleimides 4a–c. Subsequently, the Wittig reaction of 5 with
variously substituted aromatic aldehydes proceeded
smoothly under reflux conditions in methanol, giving 7a–i
in good yields (Scheme 1). The 1,3-dipolar cycloaddition
of azomethine ylide 10 generated in situ via decarboxylative
condensation of isatin 8 and sarcosine 9 with the exocyclic
double bond of N-aryl-3-benzylidene-pyrrolidine-2,5-diones
7a–i in methanol at reflux temperature yielded (Scheme 2) a
series of dispiro–oxindole–pyrrolidines 11a–i in good yields
(Table 1). The reaction afforded only one diastereomer
exclusively in all cases, as evidenced by TLC showing the
regioselectivity of these 1,3-dipolar cycloadditions.
The preferred orientation of azomethine ylide 10 in the
transition state seems to be the more thermodynamically
stable “anti” one where nonbonding steric interactions are
minimum as compared to the “syn-ylide” where the unfa-
vorable steric repulsion between the carbonyl group of
oxindole and methyl group of sarcosine raises the energy
of this moiety (Fig. 1). As the dipole and dipolarophile
approach each other, there occur secondary along with
the primary interactions between the two substrates. The
RESULT AND DISCUSSION
As a part of our endeavor to synthesize novel heterocy-
cles via cycloaddition reactions and their screening for bi-
ological activities prompted us to investigate 1,3-dipolar
cycloaddition reactions of azomethine ylides with
Scheme 1. Schematic diagram describing the steps in the synthesis of N-aryl-3-benzylidene-pyrrolidine-2,5-diones from differently substituted aniline
derivatives.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
One-pot Regioselective Synthesis of Novel Dispiro–oxindole–pyrrolidines through
Multicomponent 1,3-Dipolar Cycloaddition Reaction of Azomethine Ylide
Scheme 2. Schematic diagram describing the synthesis of dispiro–oxindole–pyrrolidines from azomethine ylide and differently substituted N-aryl-3-
benzylidene-pyrrolidine-2,5-diones.
Table 1
transition state seems to follow the “endo addition rule”
where state there is a “maximum accumulation of double
bonds” of the dipole and that of the dipolarophile. In this
transition state, the benzene ring of oxindole nucleus of
dipole and N-phenyl nucleus of the imide moiety of
dipolarophile come parallel to each other that seems to sta-
bilize the transition state. From a study of the Drieding
models of the regioisomer 11 (Fig. 2), it has been found
that this is the most favored conformation as nonbonded
steric interaction are completely absent while secondary
orbital interactions are present in this state, as compared
with the other transition state, that is, the exo one where
there are no such secondary interactions present (Fig. 3).
This leads to the complete absence of the regioisomer 12;
hence, only one set of regioisomers 11a–i was obtained.
Structural elucidation of the 1-N-Methyl-spiro[2,3′]
oxindole-spiro[3,3″]-1″-N-arylpyrrolidine-2″,5″-dione-4-
arylpyrrolidines was unambiguously accomplished by
using one and two dimensional spectroscopic techniques
Synthesis of 1-N-methyl-spiro[2,3′]oxindole-spiro[3,3″]-1″-N-
arylpyrrolidine-2″,5″-dione-4-arylpyrrolidines (11a–i).
Melting
point (°C)
Percentage
yield
Entry Products
X
Y
1
2
3
4
5
6
7
8
9
11a
11b
11c
11d
11e
11f
11g
11h
11i
OCH3
CH3
Cl
OCH3
CH3
Cl
OCH3
CH3
Cl
H
H
H
Cl
Cl
Cl
OCH3
OCH3
OCH3
214–216
228–230
189–190
208–210
216–218
224–226
212–214
224–226
228–230
69
75
81
72
80
87
65
72
78
(IR, H-NMR, 13C-NMR, H-1H COSY, NOESY, ESI-
MS) and elemental analyses data as described for 11a.
The IR spectrum of 1-N-methyl- spiro[2,3′]oxindole-spiro
[3,3′]-1″-N-(4-methoxyphenyl)pyrrolidine-2″,5″-dione-4-
phenylpyrrolidines (11a) revealed the presence of carbonyl
stretching intense vibration band (νmax) at 1777 cmÀ1 due
to mergence of carbonyl stretch bands of oxindole moiety
and one carbonyl group of succinimide ring while a shoul-
der band at frequency 1708cmÀ1 was assigned to the sec-
ond carbonyl group of succinimide ring. Absorption band
1
1
Figure 1. Configuration of azomethine ylide.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Kaur, M. Kaur, and B. Singh
Vol 000
Figure 2. Drieding model of regioisomers 11a–i.
Figure 4. 400 MHz 1H,1H-COSY spectrum of 11a CDCl3.
Figure 3. Drieding model of regioisomers 12a–i.
the 1H-NMR spectrum, assigning the more downfield dou-
blet of doublet in aliphatic region to benzylic proton He of
pyrrolidine ring triggers the assignment of all the
at 3468 cmÀ1 was assigned to the ―NH stretch of oxindole
moiety. The H-NMR spectrum of 11a revealed one sharp
1
singlet at δ 2.28 due to the N-methyl protons. The two gem-
inal protons Ha and Hb at carbon C-4″ emerged as separate
signals, that is, proton Ha appeared as doublet at δ 2.47 due
to coupling with proton Hb (J = 19.00 Hz) where as the pro-
ton Hb appeared downfield as doublet at δ 2.74
(J = 18.96 Hz) due to coupling with Ha. Out of these two
geminal protons, the proton Hb experienced a downfield
shift as compared with proton Ha because of orientation of
carbonyl group of oxindole moiety. As a result, proton Hb
comes in deshielding zone of the π-bond electron cloud of
the carbonyl group. Also, the two geminal protons at carbon
C-5 exhibited separate signals. The proton Hc appeared as
triplet at δ 3.62 on coupling with protons Hd and He
(J = 8.60 Hz); another triplet at δ 4.06 was assigned to pro-
ton Hd on coupling with protons Hc and He (J = 9.64 Hz).
The proton Hd shows downfield shift among these two gem-
inal protons as Hd comes in the deshielding zone of the π-
ring cloud of the phenyl ring present at carbon C-4 proving
the syn-geometry of Hd with this phenyl ring. A fine singlet
at δ 3.77 was assigned to methoxy protons present at the
phenyl ring of succinimide moiety. The proton He exhibited
a doublet of doublet at δ 4.52 on coupling with protons Hc
and Hd (J = 8.32 and 9.80 Hz). The aromatic protons
appeared as multiplet in the region of δ 6.64–7.50, and a
broad singlet appeared at δ 7.70 due to ―NH proton of
oxindole moiety.
1
connected protons in the ring by its H,1H-COSY spectral
analysis. From the 1H,1H-COSY correlations of He (off diag-
onal cross-peaks at δ 4.52/3.62 and δ 4.52/4.06), the triplets
at δ 3.62 and 4.06 were assigned to the protons Hc and Hd,
respectively. The δ 3.62 and 4.06 showed clean splitting
pattern with J values large enough (JHc-He = 8.60 Hz and
JHd-He = 9.64Hz) to identify Hc and Hd as neighboring
protons. The off diagonal cross-peaks at δ 3.62/4.06 proved
the correlation of geminal protons Hc and Hd.
In the NOESY (Figs 5 and 6) spectrum of 11a, there
exist correlation cross-peaks from protons Ha/(H-2‴, H-6‴)
Further confirmation of the structure comes from their
two-dimensional 1H,1H-COSY spectrum (Fig. 4). The
geminal protons Ha and Hb at carbon C-4″ show the
1H,1H-COSY correlation as evident from the off diagonal
cross-peaks at δ 2.47/2.74 having coupling constant
J ≈ 19.00 Hz proving their geminal nature. As evident from
Figure 5. 400 MHz NOESY spectrum of 11a in CDCl3.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
One-pot Regioselective Synthesis of Novel Dispiro–oxindole–pyrrolidines through
Multicomponent 1,3-Dipolar Cycloaddition Reaction of Azomethine Ylide
regioselectively across the exocyclic double bonds of the
dipolarophiles to give novel spiroheterocycles that indicates
the high endo-diastereoselectivity due to stabilization
by the secondary π-orbital interactions in the endo-approach
of the transition state.
EXPERIMENTAL
Figure 6. Structure of compound 11a and NOE correlation.
General. Unless otherwise indicated, all common reagents were
used as obtained from commercial suppliers (SIGMA-ALDRICH
CORPORATION, Bangalore, India) without further purification,
and the solvents were dried before use. All melting points were
recorded on Gallenkamp apparatus and are uncorrected. IR
spectra were recorded on a Perkin Elmer RXIFT infrared
spectrophotometer (manufactured at Buckinghamshire, England)
using KBr pellets. 1H-NMR, 1H,1H-COSY, and NOESY were
recorded at 400 MHz on BRUKER spectrometer (manufactured at
Fallanden, Switzerland) using tetramethylsilane as internal
standard. The 13C-NMR spectra were recorded at 100MHz on
BRUKER spectrometer using tetramethylsilane as internal
standard. Mass spectra were recorded on Waters Micromass Q-T
of Micro (ESI) spectrometer (manufactured at Vernon Hills, IL,
USA). Elemental analysis was carried out using Elementar Vario
MICRO cube CHN analyzer (Frankfurt, Germany). TLC analysis
was carried out on glass plates coated with silica gel-G (Loba
Chemie Pvt. Ltd, Mumbai, Maharashtra, India) suspended in
methanol–chloroform. Column chromatography was performed
at δ 2.47/7.50 and Hd/(H-2‴, H-6‴) at δ 4.06/7.50 revealing
the spatial proximity of protons Ha and Hd with the phenyl
ring protons at carbon C-4, which signifies the same planar-
ity of Ha, Hd, and C4-phenyl ring. No NOESY correlation
among Hc, H-2‴, and H-6‴ protons demonstrated the
trans-stereochemistry of protons Hc and phenyl ring at C-4.
Further, the stronger correlation cross-peaks for protons Hc/He
at δ 3.62/4.52 than the protons Hd/He at δ 4.06/4.52 affirmed
the syn-geometry of Hc and He protons and anti-geometry
of Hd and He protons. Further, the NOESY experiment
denoted the spatial interactions due to close proximity of
protons Hc and Hd with N-methyl protons, as evident from
the cross-peaks at δ 3.62/2.28 and δ 4.06/2.28. The
―OCH3 group present at C-4‴ carbon of N-phenyl ring of
succinimide moiety also exhibited the correlation with the ar-
omatic protons H-3‴ and H-5‴ through space as affirmed by
the off diagonal cross-peaks at δ 3.77/6.84.
using silica gel (100–200 mesh, Loba Chemie Pvt. Ltd).
General procedure for synthesis of maleimide (4a–c).
The off-resonance decoupled 13C-NMR spectrum of 11a
exhibited a signal at δ 35.10 due to carbon C-4 while a
signal at δ was assigned to carbon C-4″. The N-CH3 and
N-CH2 carbons exhibited the signals at δ 49.77 and δ
59.03 because of presence of adjacent N-atom. The two
peaks at δ 61.67 and 78.56 correspond to the two spiro
carbons C-3 and C-2, respectively. Suitable signals due to
aromatic carbons were assigned to the region of δ
110.15–159.54, and the imide carbonyl carbons C-2′, C-5″,
and C-2″ resonated at δ 174.24, 177.80, and 178.82, respec-
tively. Each of the succinimide carbonyl carbon exhibited a
downfield shift as compared with carbonyl carbon of
oxindole moiety because of the more deshielding effect of
the two carbonyl groups present in the succinimide ring.
The mass spectrum of 11a revealed the molecular ion peak
[M+ + 1] at m/z 468, and similar peak pattern was obtained
with other derivatives of 1-N-Methyl-spiro[2,3′]oxindole-
spiro[3,3″]-1″-N-arylpyrrolidine-2″,5″-dione-4-
Equimolar quantities of p-substituted aniline 1a–c and maleic
anhydride 2 were stirred in toluene at room temperature for 1 h to
yield maleamic acid 3a–c. The maleamic acid thus obtained was
further cyclized to maleimide (Scheme 1) in acetic anhydride
in the presence of anhydrous sodium acetate under reflux for
one and half hour and then pouring the contents in ice cold
water and keeping it overnight to afford the solid that was
filtered and washed with water to give the maleimide 4a–c.
General procedure for the synthesis of N-aryl-3-benzylidene-
pyrrolidine-2,5-diones (7a–i).
Stoichiometric amounts of
maleimide 4a–c and triphenylphosphine in anhydrous acetone
were refluxed until the substrates were consumed as judged by
TLC (Scheme 1). After cooling, the precipitates formed were
filtered through a Buchner funnel, and the filter cake was
washed with cold acetone (10 mL). Drying under reduced
vacuum
afforded
N-aryl-3-(triphenylphosphanylidene)
pyrrolidine-2,5-diones 5a–c as a white solid. The solid was used
for the next step without further purification.
A suspension of substituted benzaldehydes 6a–c and N-aryl-3-
(triphenylphosphanylidene)pyrrolidine-2,5-diones
5
in their
equimolar amounts in MeOH were refluxed. Before the tempera-
ture reached the boiling point of methanol, the reaction mixture
generally became a clear solution. During reflux, the precipitates
were formed and filtered through a Buchner funnel after cooling.
The filter cake was washed with methanol and proper solvents,
depending on the property of the substituted benzaldehydes used
for the reaction, to give the title product. The product precipitated
out in this manner was characterized by melting point and TLC.
arylpyrrolidines.
CONCLUSION
In conclusion, we have successfully developed the
regioselective version of bioactive pyrrolidines ring
containing oxindole group in a one-pot, three-component
cycloaddition reaction. It was observed that the unstabilized
azomethine ylide generated, added stereoselectivity and
The crude product obtained was recrystallized from toluene.
General procedure for the synthesis of dispiro–oxindole–
pyrrolidine derivatives (11a–i).
An oven-dried flask was
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Kaur, M. Kaur, and B. Singh
Vol 000
cooled under a stream of nitrogen and charged with mixture of
isatin (1 mmol), sarcosine (1 mmol), and N-aryl-3-
177.05 (C-5″, C═O), 177.31 (C-2″, C═O); MS: m/z: 472
[M+ + 1], 473 [M+ + 2] Anal. Calcd for C27H22ClN3O3:
C, 68.71; H, 4.66; N, 8.90, found: C, 68.89; H, 4.67; N,
8
9
benzylidene-pyrrolidine-2,5-diones 7a–i (1 mmol) methanol (25 mL).
The flask was equipped with a reflux condenser, and the mixture
was refluxed (Scheme 2) until the substrates were consumed as
judged by TLC. On completion, the reaction mixture was
concentrated, and the precipitated compound was filtered. The
solvent was removed under vacuo, and the crude product was
subjected to column chromatography using hexane:ethyl acetate
(8 : 2) as an eluent to afford pure dispiro–oxindole–pyrrolidines
8.87.
1-N-Methyl-spiro[2,3′]oxindole-spiro[3,3″]-1″-N-(4-methoxy-
phenyl)pyrrolidine-2″,5″-dione-4-(4-clorophenyl)pyrrolidine
(11d). Compound obtained as white solid (0.36 g, 72 %), mp
208–210°C; IR (KBr pellets, νmax/cmÀ1): 1615 (C═C), 1707,
1
1780 (C═O), 3466 (N―H); H-NMR (400 MHz, CDCl3): δH
2.25 (s, 3H, ―NCH3), 2.43 (d, 1H, J = 18.92 Hz, Ha), 2.72
(d, 1H, J = 18.88 Hz, Hb), 3.60 (dd, 1H, J = 8.24, 8.96 Hz,
Hc), 3.77 (s, 3H, OCH3), 3.97 (t, 1H, J = 9.40 Hz, Hd), 4.47
(dd, 1H, J = 8.16, 9.76 Hz, He), 6.65–7.47 (m, 12H, ArH),
7.86 (s, 1H, ―NH); 13C-NMR (100 MHz, CDCl3): δ 35.71
(4-CH3), 37.04 (C-4″), 49.04 (―NCH3), 55.45 (4″″―OCH3),
59.25 (C-5), 61.60 (C-3), 78.50 (C-2), 110.15 (C-3a′), 114.32
(C-3″″, 5″″), 123.50 (C-7′), 123.91 (C-2″″, 6″″), 124.91 (C-5′),
127.37 (C-3‴, 5‴), 127.84 (C-6′), 129.30 (C-4′), 130.33 (C-2‴,
6‴), 131.62 (C-1‴), 133.82 (C-4‴), 136.38 (C-7a′), 141.46 (C-1″
″), 159.58 (C-4″″), 173.90 (C-2′, C═O), 177.60 (C-5″, C═O),
178.64 (C-2″, C═O); MS: m/z: 502 [M+ + 1], 503 [M+ + 2], Anal.
Calcd for C28H24ClN3O4: C, 67.00; H, 4.78; N, 8.37, found: C,
11a–i.
1-N-Methyl-spiro[2,3′]oxindole-spiro[3,3″]-1″-N-(4-methoxy-
phenyl)pyrrolidine-2″,5″-dione-4-phenylpyrrolidine (11a).
Compound obtained as white solid (0.32 g, 69 %), mp 214–216°C;
IR (KBr pellets, νmax/cmÀ1): 1619 (C═C), 1708, 1777 (C═O),
3468 (N―H); 1H-NMR (400 MHz, CDCl3): δH 2.28 (s, 3H,
―NCH3), 2.47 (d, 1H, J= 19.00 Hz, Ha), 2.74 (d, 1H, J=18.96Hz,
Hb), 3.62 (t, 1H, J=8.60Hz, Hc), 3.77 (s, 3H, ―OCH3), 4.06
(t, 1H, J=9.64Hz, Hd), 4.52 (dd, 1H, J= 8.32, 9.80 Hz, He), 6.64–
7.50 (m, 13H, ArH), 7.70 (brs, 1H, ―NH); 13C-NMR (100 MHz,
DMSO-d6): δ 35.19 (C-4), 37.07 (C-4″), 49.77 (―NCH3), 55.45
(4″″―OCH3), 59.03 (C-5), 61.76 (C-3), 78.56 (C-2), 110.15 (C-3a
′), 114.31 (C-3″″, 5″″), 123.38 (C-7′), 124.02 (C-2″″, 6″″), 125.12
(C-5′), 127.44 (C-2‴, 4‴, 6‴), 127.89 (C-3‴, 5‴), 129.15 (C-6′),
130.19 (C-4′), 130.22 (C-1‴), 137.76 (C-7a′), 141.58 (C-1′‴),
159.54 (C-4‴′), 174.24 (C-2′, C═O), 177.80 (C-5″, C═O), 178.82
(C-2″, C═O); MS: m/z: 468 [M+ +1], Anal. Calcd for
C28H25N3O4: C, 71.94; H, 5.35; N, 8.99, found: C, 72.09; H, 5.33;
67.25; H, 4.76; N, 8.39.
1-N-Methyl-spiro[2,3′]oxindole-spiro[3,3″]-1″-N-(4-methyl-
phenyl)pyrrolidine-2″,5″-dione-4-(4-chlorophenyl)pyrrolidine
(11e). Compound obtained as white solid (0.39 g, 80 %), mp
216–218°C; IR (KBr pellets, νmax/cmÀ1): 1613 (C═C), 1715,
1783 (C═O), 3469 (N―H);1H-NMR (400 MHz, CDCl3): δH
2.18 (s, 3H, ―CH3), 2.25 (s, 3H, ―NCH3), 2.36 (d, 1H,
J = 18.96 Hz, Ha), 2.65 (d, 1H, J = 18.92 Hz, Hb), 3.53 (dd,
1H, J = 8.36, 8.88 Hz, Hc), 3.90 (t, 1H, J = 9.48 Hz, Hd),
4.40 (dd, 1H, J = 8.16, 9.80 Hz, He), 6.54–7.40 (m, 12H,
ArH), 7.57 (s, 1H, ―NH); 13C-NMR (100 MHz, CDCl3): δ
21.19 (4″″―CH3), 35.10 (C-4), 37.07 (C-4″), 49.06
(N―CH3), 59.23 (C-5′), 61.62 (C-3), 78.46 (C-2), 110.09
(C-3a′), 123.53 (C-7′), 124.89 (C-2″″, 6″″), 126.41 (C-5′),
127.41 (C-2‴, 6‴), 128.68 (C-6′), 129.30 (C-4′), 129.67
(C-3‴, 5‴), 130.31 (C-3′′′′, 5′′′′), 131.62 (C-1‴), 133.82
(C-4‴), 136.37 (C-4′′′′), 138.84 (C-7a′), 141.38 (C-1′′′′),
173.74 (C-2′, C═O), 177.44 (C-5″, C═O), 178.50 (C-2″,
C═O); MS: m/z: 486 [M+ + 1], 487 [M+ + 2] Anal. Calcd
for C28H24ClN3O3: C, 69.20; H, 4.94; N, 8.65, found: C,
N, 9.02.
1-N-Methyl-spiro[2,3′]oxindole-spiro[3,3″]-1″-N-(4-methyl-
phenyl)pyrrolidine-2″,5″-dione-4-phenylpyrrolidine (11b).
Compound obtained as white solid (0.33 g, 75 %), mp 228–230°C;
IR (KBr pellets, νmax/cmÀ1): 1620 (C═C), 1708, 1719, 1781
(C═O), 3475 (N―H); 1H-NMR (400MHz, CDCl3): δH 2.27
(s, 3H, ―CH3), 2.32 (s, 3H, ―NCH3), 2.48 (d, 1H, J = 19.04 Hz,
Ha), 2.73 (d, 1H, J = 19.04Hz, Hb), 3.61 (t, 1H, J = 8.52Hz, Hc),
4.05 (t, 1H, J=9.56Hz, Hd), 4.51 (dd, 1H, J= 8.12, 9.84 Hz, He), 6.62–
7.51 (m, 13H, ArH), 7.73 (brs, 1H, ―NH); 13C-NMR (100MHz,
DMSO-d6): δ 21.22 (4″″―CH3), 35.20 (C-4), 37.11 (C-4″), 49.78
(―NCH3), 59.03 (C-5), 61.77 (C-3), 78.48 (C-2), 110.06 (C-3a′),
123.47 (C-7′), 125.04 (C-2″″, 6″″), 126.47 (C-5′), 127.49 (C-2‴,
4‴, 6‴), 127.91 (C-3‴, 5‴), 128.74 (C-6′), 129.16 (C-4′), 129.69
(C-3″″, 5″″), 130.20 (C-4″″), 137.72 (C-1‴), 138.81 (C-7a′),
141.41 (C-1″″), 174.09 (C-2′, C═O), 177.60 (C-5″, C═O),
178.68 (C-2″, C═O); MS: m/z: 452 [M+ + 1], Anal. Calcd for
C28H25N3O3: C, 74.50; H, 5.54; N, 9.31, found: C, 74.70; H,
68.97; H, 4.93; N, 8.68.
1-N-Methyl-spiro[2,3′]oxindole-spiro[3,3″]-1″-N-(4-chloro-
phenyl)pyrrolidine-2″,5″-dione-4-(4-chlorophenyl)pyrrolidine
(11f). Compound obtained as white solid (0.44 g, 87 %), mp
224–226°C; IR (KBr pellets, νmax/cmÀ1): 1620 (C═C), 1716,
1789 (C═O), 3471 (N―H); 1H-NMR (400 MHz, CDCl3): δH
2.25 (s, 3H, ―NCH3), 2.43 (d, 1H, J = 18.92 Hz, Ha), 2.74
(d, 1H, J = 18.92 Hz, Hb), 3.60 (t, 1H, J = 8.48 Hz, Hc), 3.96 (t,
1H, J = 9.52 Hz, Hd), 4.46 (dd, 1H, J = 8.16, 9.72 Hz, He),
6.70–7.46 (m, 12H, ArH), 7.67 (s, 1H, ―NH); 13C-NMR
5.52; N, 9.33.
1-N-Methyl-spiro[2,3′]oxindole-spiro[3,3″]-1″-N-(4-chloro-
phenyl)pyrrolidine-2″,5″-dione-4-phenylpyrrolidine (11c).
Compound obtained as white solid (0.38 g, 81 %), mp 189–190°C;
IR (KBr pellets,
ν
max/cmÀ1): 1615 (C═C), 1710, 1782
1
(C═O), 3470 (N―H); H-NMR (400 MHz, CDCl3): δH 2.15
(s, 3H, ―NCH3), 2.36 (d, 1H, J = 18.44 Hz, Ha), 2.69 (d, 1H,
J = 18.36 Hz, Hb), 3.49 (t, 1H, J = 8.52 Hz, Hc), 3.90 (t, 1H,
J = 9.24 Hz, Hd), 4.39 (t, 1H, J = 9.40 Hz, He), 6.74–7.50
(m, 13H, ArH), 10.71 (s, 1H, ―NH); 13C-NMR (100 MHz,
CDCl3): δ 34.52 (C-4), 36.74 (C-4″), 48.36 (―NCH3),
58.62 (C-5), 61.16 (C-3), 77.61 (C-2), 109.89 (C-3a′), 121.84
(C-2″″, 6″″), 124.73 (C-7′), 126.08 (C-5′), 127.18 (C-2‴, 4‴,
6‴), 128.11 (C-3‴, 5‴), 128.42 (C-6′), 129.70 (C-4′),
129.87 (C-1‴), 130.03 (C-3″″, 5″″), 133.07 (C-4″″),
137.76 (C-7a′), 142.75 (C-1″″), 172.53 (C-2′, C═O),
(100 MHz, CDCl3):
δ 35.08 (C-4), 37.10 (C-4″), 48.90
(―NCH3), 59.26 (C-5), 61.79 (C-3), 78.45 (C-2), 110.20 (C-3a′),
123.53 (C-7′), 124.81 (C-2′′′′, 6′′′′), 127.19 (C-5′), 127.81
(C-2‴, 6‴), 129.19 (C-3‴, 5‴), 129.34 (C-3′′′′, 5′′′′), 129.73
(C-6′), 130.43 (C-4′), 131.59 (C-1‴), 133.91 (C-4′′′′),
134.57 (C-4‴), 136.21 (C-7a′), 141.37 (C-1′′′′), 173.20 (C-2′,
C═O), 177.37 (C-5″, C═O), 178.12 (C-2″, C═O); MS: m/z: 507
[M+ + 1], 508 [M+ + 2], 510 [M+ + 4] Anal. Calcd for
C27H21Cl2N3O3: C, 64.03; H, 4.15; N, 8.30, found: C, 64.12; H,
4.16; N, 8.32.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
One-pot Regioselective Synthesis of Novel Dispiro–oxindole–pyrrolidines through
Multicomponent 1,3-Dipolar Cycloaddition Reaction of Azomethine Ylide
1-N-Methyl-spiro[2,3′]oxindole-spiro[3,3″]-1″-N-(4-methoxy-
phenyl)pyrrolidine-2″,5″-dione-4-(4-methoxyphenyl)pyrrolidine
(11g). Compound obtained as white solid (0.32 g, 65 %), mp
212–214°C; IR (KBr pellets, νmax/cmÀ1): 1613 (C═C), 1707,
1727, 1780 (C═O), 3471 (N―H); 1H-NMR (400 MHz,
CDCl3): δH 2.26 (s, 3H, ―NCH3), 2.51 (d, 1H,
J = 19.00 Hz, Ha), 2.72 (d, 1H, J = 18.96 Hz, Hb), 3.59
(t, 1H, J = 8.72 Hz, Hc), 3.77 (s, 3H, ―OCH3), 3.82 (s, 3H,
―OCH3), 3.99 (t, 1H, J = 9.52 Hz, Hd), 4.46 (dd, 1H,
J = 8.24, 9.84 Hz, He), 6.66–7.43 (m, 12H, ArH), 7.93
(brs, 1H, ―NH); 13C-NMR (100MHz, CDCl3): δ 35.21 (C-4),
36.99 (C-4″), 49.21 (―NCH3), 55.34 (4‴―OCH3), 55.46
(4′′′′―OCH3), 59.17 (C-5), 61.71 (C-3), 78.47 (C-2), 110.10
(C-3a′), 114.31 (C-3‴, 5‴), 114.48 (C-3′′′′, 5′′′′), 123.40
(C-7′), 124.01 (C-2′′′′, 6′′′′), 125.09 (C-5′), 127.48 (C-2‴,
6‴), 127.89 (C-6′), 129.58 (C-4′), 130.22 (C-1‴), 131.27 (C-
7a′), 141.49 (C-1′′′′), 159.15 (C-4′′′′), 159.51 (C-4‴),
174.33 (C-2′, C═O), 177.66 (C-5″, C═O), 178.94 (C-2″,
C═O); MS: m/z: 498 [M+ + 1], Anal. Calcd for
C28H24ClN3O4: C, 70.02; H, 5.43; N, 8.45, found: C, 70.21;
H, 5.44; N, 8.47.
1-N-Methyl-spiro[2,3′]oxindole-spiro[3,3″]-1″-N-(4-methyl-
phenyl)pyrrolidine-2″,5″-dione-4-(4-methoxyphenyl)pyrrolidine
(11h). Compound obtained as white solid (0.34 g, 72 %), mp
224–226°C; IR (KBr pellets, νmax/cmÀ1): 1619 (C═C), 1712,
1783 (C═O), 3472 (N―H); 1H-NMR (400 MHz, CDCl3): δH
2.25 (s, 3H, ―CH3), 2.32 (s, 3H, ―NCH3), 2.51 (d, 1H,
J = 18.96 Hz, Ha), 2.71 (d, 1H, J = 19.00 Hz, Hb), 3.58
(t, 1H, J = 8.24 Hz, Hc), 3.81 (s, 3H, ―OCH3), 3.99 (t, 1H,
J = 9.48 Hz, Hd), 4.46 (dd, 1H, J = 8.16, 9.88 Hz, He),
6.63–7.43 (m, 12H, ArH), 7.95 (s, 1H, ―NH); 13C-NMR
(100 MHz, CDCl3): δ 21.19 (4′′′′―CH3), 35.16 (C-4), 37.02
(C-4″), 49.24 (―NCH3), 55.32 (4‴―OCH3), 59.14 (C-5),
61.75 (C-3), 78.48 (C-2), 110.05 (C-3a′), 114.49 (C-3‴, 5‴),
123.39 (C-7′), 125.13 (C-2′′′′, 6′′′′), 126.46 (C-5′), 127.50
(C-6′), 128.81 (C-4′), 129.61 (C-2‴, 6‴), 129.66 (C-3′′′′, 5′′
′′), 130.16 (C-1‴), 131.26 (C-4′′′′), 138.15 (C-7a′), 141.51
(C-1′′′′), 159.17 (C-4‴), 174.16 (C-2′, C═O), 177.70 (C-5″,
C═O), 178.81 (C-2″, C═O); MS: m/z: 482 [M+ + 1], Anal.
Calcd for C29H27N3O4: C, 72.34; H, 5.61; N, 8.73, found:
C, 72.46; H, 5.62; N, 8.70.
Acknowledgments. The authors acknowledge the financial
support from University Grant Commission (UGC) New Delhi and
are grateful to the Department of Chemistry, Punjabi University,
Patiala, and the Sophisticated Analytical Instrumentation Facility
(SAIF) Panjab University, Chandigarh, for spectral analysis.
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1-N-Methyl-spiro[2,3′]oxindole-spiro[3,3″]-1″-N-(4-chloro-
phenyl)pyrrolidine-2″,5″-dione-4-(4-methoxyphenyl)pyrrolidine
(11i).
Compound obtained as white solid (0.39g, 78 %), mp
228–230°C; IR (KBr pellets, νmax/cmÀ1): 1619 (C═C), 1710,
1776 (C═O), 3469 (N―H); 1H-NMR (400 MHz, CDCl3): δH
2.25 (s, 3H, ―NCH3), 2.50 (d, 1H, J = 18.96 Hz, Ha), 2.73
(d, 1H, J = 18.96 Hz, Hb), 3.58 (t, 1H, J = 8.64 Hz, Hc), 3.81
(s, 3H, OCH3), 3.98 (t, 1H, J = 9.48 Hz, Hd), 4.45 (dd, 1H,
J = 8.16, 9.88 Hz, He), 6.71–7.41 (m, 12H, ArH), 7.73
(s, 1H, ―NH); 13C-NMR (100 MHz, CDCl3): δ 35.14 (C-4),
37.05 (C-4″), 49.09 (―NCH3), 55.32 (4‴―OCH3), 59.16
(C-5), 61.94 (C-3), 78.42 (C-2), 110.10 (C-3a′), 114.52
(C-3‴, 5‴), 123.17 (C-7′), 125.07(C-2′′′′, 6′′′′), 127.32
(C-5′), 127.85 (C-6′), 129.17 (C-4′), 129.43 (C-2‴, 6′′′),
129.88 (C-3′′′′, 5′′′′), 130.27 (C-1‴), 131.22 (C-4′′′′),
134.47 (C-3a′), 141.40 (C-1′′′′), 159.23 (C-4′′′), 173.60
(C-2′, C═O), 177.49 (C-5″, C═O), 178.40 (C-2″, C═O);
MS: m/z: 502 [M+ + 1], 503 [M+ + 2]Anal. Calcd for
C28H24ClN3O4: C, 67.00; H, 4.78; N, 8.37, found: C,
67.16; H, 4.79; N, 8.39.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet