Facile, regio- And diastereoselective synthesis of spiro-pyrrolidine and pyrrolizine derivatives and evaluation of their antiproliferative activities

Article abstract of DOI:10.3390/molecules190710033

A number of novel spiro-pyrrolidines/pyrrolizines derivatives were synthesized through [3+2]-cycloaddition of azomethine ylides with 3,5-bis[(E)- Arylmethylidene]tetrahydro-4(1H)-pyridinones 2a-n. Azomethine ylides were generated in situ from the reaction of 1H-indole-2,3-dione (isatin, 3) with N-methylglycine (sarcosine), phenylglycine, or proline. All compounds (50 μM) were evaluated for their antiproliferative activity against human breast carcinoma (MDA-MB-231), leukemia lymphoblastic (CCRF-CEM), and ovarian carcinoma (SK-OV-3) cells. N-α-Phenyl substituted spiro-pyrrolidine derivatives (5a-n) showed higher antiproliferative activity in MDA-MB-231 than other cancer cell lines. Among spiro-pyrrolizines 6a-n, a number of derivatives including 6a-c and 6i-m showed a comparable activity with doxorubicin in all three cell lines. Among all compounds in three classes, 6a, 6b, and 6m, were found to be the most potent derivatives showing 64%, 87%, and 74% antiproliferative activity in MDA-MB-231, SK-OV-3, and CCRF-CEM cells, respectively. Compound 6b showed an IC₅₀ value of 3.6 μM in CCRF-CEM cells. These data suggest the potential antiproliferative activity of spiro-pyrrolidines/pyrrolizines.

Full text of DOI:10.3390/molecules190710033

Molecules 2014, 19, 10033-10055; doi:10.3390/molecules190710033
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Facile, Regio- and Diastereoselective Synthesis of
Spiro-Pyrrolidine and Pyrrolizine Derivatives and Evaluation of
Their Antiproliferative Activities
Abdulrahman I. Almansour 1, Raju Suresh Kumar 1, Farzana Beevi 2, Amir Nasrolahi Shirazi 3,6,
Hasnah Osman 4, Rusli Ismail 7, Tan Soo Choon 5, Brian Sullivan 3, Kellen McCaffrey 3,
Alaa Nahhas 3, Keykavous Parang 3,6,* and Mohamed Ashraf Ali 2,5,
*
1
Department of Chemistry, College of Science, King Saud University, P.O.Box 2455, Riyadh 11451,
Saudi Arabia
2
3
New Drug Discovery Research, Department of Medicinal Chemistry, Sunrise University, Alwar,
Rajasthan-301030, India
Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode
Island, Kingston, RI 02881, USA
4
5
School of Chemical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia.
Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden 11800,
Penang, Malaysia
6
7
School of Pharmacy, Chapman University, Irvine, CA 92618, USA
Centre of Excellence for Research in AIDS, University Malaya, Kuala Lumpur 50603, Malaysia
* Authors to whom correspondence should be addressed; E-Mails: parang@chapman.edu (K.P.);
drashraf@usm.my (M.A.A.); Tel.: +1-401-874-4471 (K.P.); Fax: +1-401-874-5787 (K.P.).
Received: 29 May 2014; in revised form: 24 June 2014 / Accepted: 1 July 2014 /
Published: 10 July 2014
Abstract: A number of novel spiro-pyrrolidines/pyrrolizines derivatives were
synthesized through [3+2]-cycloaddition of azomethine ylides with 3,5-bis[(E)-
arylmethylidene]tetrahydro-4(1H)-pyridinones 2a–n. Azomethine ylides were generated
in situ from the reaction of 1H-indole-2,3-dione (isatin, 3) with N-methylglycine
(sarcosine), phenylglycine, or proline. All compounds (50 μM) were evaluated for their
antiproliferative activity against human breast carcinoma (MDA-MB-231), leukemia
lymphoblastic (CCRF-CEM), and ovarian carcinoma (SK-OV-3) cells. N-α-Phenyl
substituted spiro-pyrrolidine derivatives (5a–n) showed higher antiproliferative activity in
MDA-MB-231 than other cancer cell lines. Among spiro-pyrrolizines 6a–n, a number of
derivatives including 6a–c and 6i–m showed a comparable activity with doxorubicin in all

Molecules 2014, 19
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three cell lines. Among all compounds in three classes, 6a, 6b, and 6m, were found to be
the most potent derivatives showing 64%, 87%, and 74% antiproliferative activity in
MDA-MB-231, SK-OV-3, and CCRF-CEM cells, respectively. Compound 6b showed an
IC50 value of 3.6 μM in CCRF-CEM cells. These data suggest the potential antiproliferative
activity of spiro-pyrrolidines/pyrrolizines.
Keywords: antiproliferative activity; diastereoselective synthesis; pyrrolizine;
regio-selective synthesis; spiro-pyrolidine
1. Introduction
Multicomponent reactions (MCRs) [1–5] constitute an efficient and powerful tool for the synthesis
of novel organic compounds. MCRs take advantage of several distinct properties including low cost,
accelerated reaction time, and eco-friendly reaction conditions [6–9], and provide an expeditious and
elegant access to libraries of complex structures and diversified compounds. Thus, MCRs are widely
used in combinatorial chemistry and complicated synthetic procedures [10–15].
Functionalized pyrrolidines and pyrrolizines are the central skeleton of numerous alkaloids and
constitute classes of compounds with significant biological properties, such as anticancer activity [16–18].
Heterocycles containing piperidine sub-structures display important biological activities, such as
anticancer activity as well as being useful as synthons in the construction of alkaloid natural
products [19–21]. Dimmock et al. reported the synthesis of 3,5-bis[(E)-arylmethyl idene] tetrahydro-
4(1H)-pyridinones and their corresponding substituted analogues as potential anticancer agents with
modest to high activity [22].
Several spiro-compounds have shown very promising biologically activity with potential
applications as anticancer [21–25], antibacterial [26,27], anticonvulsant [28–30], anti-tuberculosis [31],
and anti-Alzheimer’s disease agents [31]. Spiro compounds have also been recently used as
antioxidant agents [32,33].
[3+2]-Cycloaddition of azomethine ylides with olefinic dipolarophiles has been reported as one of
the main methods for generating highly functionalized heterocyclic scaffolds as diversified chemical
libraries [33–39]. Inspired by the previously reported biological potency of spiro compounds and as a
part of our ongoing research in the construction of novel hybrid heterocycles, herein we report the
synthesis of three different classes of spiro-pyrrolidines and spiro-pyrrolizines derivatives by the
[3+2]-cycloaddition of azomethine ylides with 3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones
and evaluation of their anticancer activities.
2. Results and Discussion
2.1. Chemistry
The synthesis of the prerequisite 3,5-bis[(E)-arylmethyl idene]tetrahydro-4(1H)-pyridinones 2 was
carried out according to the previously reported procedure from the reaction of an appropriate aryl
aldehyde (2 mmol) with 4-piperidone hydrochloride monohydrate (1, 1 mmol) in acetic acid [25].

Molecules 2014, 19
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Azomethine ylides were generated in situ from the reaction of 1H-indole-2,3-dione (isatin, 3) with
(i) N-methylglycine (sarcosine); (ii) phenylglycine; and (iii) proline. The [3+2]-cycloaddition of
azomethine ylides with the exocyclic dipolarophiles (2) afforded the novel N-methyl substituted
spiro-pyrrolidines 4a–n, N-α-phenyl substituted spiro-pyrrolidine derivatives 5a–n, and spiro-pyrrolizines
6a–n, respectively, in reasonable yields. All the reactions were performed by heating the mixture of
2a–n, 1H-indole-2,3-dione (3) and N-methylglycine/phenylglycine/proline in a molar ratio 1:1.1:1.1
under reflux in methanol. All compounds were isolated as in a form of racemic mixtures in 82%–94%
(Scheme 1).
Scheme 1. Synthesis of piperidone grafted spiroheterocycles.
H
1" N O
2"
N
H
N
1
5
2
COOH
4
2'
Ar
H
3
HN
1'
6'
4'
MeOH
Reflux, 1h
5'
O
Ar
Ar
4a-n
2 ArCHO
O
HCl, CH3COOH
HN
Ar
H
1" N
2"
O
H
NH2
HCl.HN
1
Acetone:Water
K2CO3
O
N
Ph
5 Ar
H
2
4
3
1
Ph
COOH
2a-n
2'
4'
HN
1'
6'
+
MeOH
Reflux, 1h
O
5'
O
Ar
5a-n
O
N
H
3
H
1"N
2"
7
O
6
1
N
2
2, Ar: a = C6H5
f = 2-FC6H4
k = 4-ClC6H4
l = 4-BrC6H4
m = 4-FC6H4
n = 1-Naphthyl
5
COOH
N
H
4a
b = 2-MeC6H4 g = 2,4-Cl2C6H3
c = 2-OMeC6H4 h = 3-NO2C6H4
4
3
2'
4'
Ar
HN
1'
6'
H
d = 2-ClC6H4
e = 2-BrC6H4
i = 4-MeC6H4
j = 4-OMeC6H4
5'
MeOH
O
Reflux, 30 min
Ar
6a-n
For instance, the synthesis of spiro-pyrrolidine derivatives 4 and 5 by using N-methylglycine or
phenylglycine, respectively, was completed within 1 h. In comparison, the reaction with proline took
30 min to afford the corresponding spiro-pyrrolizine derivatives 6. All substrates carrying aromatic
rings with electron-withdrawing and electron-donating substituents afforded the product in high to
excellent yields within approximately similar time ranges (Table S1, Supporting Information). The
cycloaddition reaction worked well regardless of the position and electronic or steric properties of the
substituents at the aromatic rings of 2. The reaction of 1H-indole-2,3-dione with N-methylglycine,
phenylglycine, or proline afforded the corresponding azomethine ylide, which was added to one of the
exocyclic C=C bonds of the bisdipolarophile 2 to form the corresponding cycloadducts 4, 5, or 6,
respectively. The structures of cycloadducts 4–6 were characterized using elemental analysis, FT-IR,
1H, 13C and 2D-NMR spectroscopic analysis.
A proposed mechanism for the formation of spiro-pyrrolidines is shown in Scheme 2. It is
noteworthy to mention that all reactions proceeded chemoselectively since the dipole addition was

Molecules 2014, 19
10036
occurred only to the available C=C bond rather than C=O functional group of 2. All reactions were
also found to be regioselective, which can be viewed as the result of a preferential attack of the
nucleophilic carbon of the azomethine ylide to the end of the enone fragment of the dipolarophile 2 to
give 4, 5, or 6. Another significant advantage of this method is that all the above reactions proceeded
via complete stereoselectivity leading to the production of a single stereoisomer despite the presence of
many stereocenters in the cycloadducts.
Scheme 2. Mechanism for the formation of spiro-pyrrolidines.
2.2. Biological Evaluation
Starting building blocks 2a–n and three classes of synthesized compounds 3a–n, 4a–n, and 6a–n
(50 μM) were evaluated for their effect on proliferation of human ovarian adenocarcinoma (SK-OV-3),
breast adenocarcinoma (MDA-MB-231), and lymphoblastic leukemia (CCRF-CEM). Doxorubicin
(Dox) and DMSO were used as positive and negative controls, respectively.
The results for cell proliferation at 50 μM after 72 h for 3,5-bis[(E)-arylmethylidene]tetrahydro-
4(1H)-pyridinones 2a–n are shown in Figure 1. Compounds 2a–g inhibited the cell proliferation of
MDA-MB-231 cells by 85%–88%. The presence of a wide range of substituents on two side aromatic
rings was tested. The majority of derivatives containing electron donating groups including methyl and
methoxy, showed higher antiproliferative actvity than compounds with electron withdrawing groups
e.g., nitro in MDA-MB-231 cells after 72 h incubation. Compounds with substitutions on para
positions were exhibited slightly lower inhibition activity. This trend was also observed in SK-OV-3
and CCRF-CEM cells. All the compounds in this class showed higher antiproliferative activity in
MDA-MB-231 than CCRF-CEM and SK-OV-3 cells. Thus, MDA-MB-231 cells were found to be the
most sensitive cell line to these compounds among the three that have tested.
N-Methyl spiro-pyrrolidine derivatives 4a–n antiproliferative activities are shown in Figure 2.
Among all compounds in this class, 4k, 4n, and 4l showed the highest antiproliferative activity in
CCRF-CEM, MDA-MB-231, and SK-OV-3 cells by 58%, 80%, and 70% inhibition, respectively.

Molecules 2014, 19
10037
Most of the compounds showed higher antiproliferative activity in MDA-MB-231 cells than other
cancer cell lines. However, some compounds including 4i, 4k, 4l, 4m, and 4n exhibited a consistent
potency in all cell lines. The position of substituents on aromatic rings was found to be critical in
antiproliferative activity against SK-OV-3 and MDA-MB-231 cells. Compounds 4i–m with the para
substituents on the aromatic rings showed significantly higher activity when compared with
compounds 4a–h with substituents on the ortho and meta positions.
Figure 1. Antiproliferative activity of 3,5-bis[(E)-arylmethylidene] tetrahydro -4(1H)-pyridinones 2a–n.
160
CCRF-CEM
MDA-MB-231
SK-OV-3
140
120
100
80
60
40
20
0
Figure 2. Antiproliferative activity of N-methylspiro-pyrrolidine derivatives 4a–n.
160
140
120
100
80
CCRF-CEM
MDA-MB-231
SK-OV-3
60
40
20
0

Molecules 2014, 19
10038
N-α-Phenyl substituted spiro-pyrrolidines derivatives 5a–n were evaluated for their antiproliferative
potency against SK-OV-3, MDA-MB-231, and CCRF-CEM cells. All compounds showed higher
antiproliferative potency in MDA-MB-231 than other cancer cell lines (Figure 3).
Figure 3. Antiproliferative activity of N-α-phenyl substituted spiro-pyrrolidines derivatives 5a–n.
120
CCRF-CEM
MDA-MB-231
SK-OV-3
100
80
60
40
20
0
The majority of compounds showed modest to modest antiproliferative activity in MDA-MB-231 cells
by inhibiting the proliferation in a range of 59% to 87%. The potency of compound 5g was found to be
cell-specific since this compound inhibited the proliferation of MDA-MB-231, CCRF-CEM, and
SK-OV-3 by 82%, 44%, and 22%, respectively. In general, the N-α-phenyl substituted spiro-pyrrolidines
derivatives 5a–n showed higher antiproliferative activity when compared with the corresponding
N-methyl spiro-pyrrolidine derivatives 4a–n. For instance, 2-chlorosubstituted 4d did not inhibit the
proliferation of SK-OV-3 and MDA-MB-231 cells. However, after the replacement of hydrogen with a
phenyl ring at position 5 in the corresponding 2-chlorosubstituted compound 5d, the antiproliferative
potency elevated significantly by 52%, 75% in SK-OV-3 and MDA-MB-231, respectively, suggesting
that the presence of phenyl group contributes to the improvement of the antiproliferative potency of the
compound. Finally, a class of spiro-pyrrolizines derivatives was examined for their antiproliferative
activity against SK-OV-3, MDA-MB-231, and CCRF-CEM cells (Figure 4).
A number of derivatives including 6a–c and 6i–m compounds showed a comparable activity with
Dox in all three cell lines. Among all derivatives, compound 6m inhibited the proliferation of CCRF-CEM
cells by 64%. Similarly, compound 6a inhibited MDA-MB-231 proliferation by 87%. However,
compound 6b exhibited higher activity in SK-OV-3 cells by inhibiting their growth up to 74%,
respectively. The antiproliferative activity of compounds 6f, 6h and 6n were decreased significantly
when compared to their corresponding compounds 5f, 5h and 5n. The other spiro-pyrrolizines
derivatives in this class showed comparable or higher antiproliferative activity when compared with
spiro-pyrrolidines derivatives, suggesting that the less rigidity of the chemical structure contributes possibly

Molecules 2014, 19
10039
to their antiproliferative activity. Compounds 6a and 6b exhibited IC50 values of 25.2 and 3.6 μM in
CCRF-CEM cells and 38.9 and 35.8 μM in SK-OV-3 cells after 72 h incubation.
Figure 4. Antiproliferative activity of 6a–n.
160
CCRF-CEM
MDA-MB-231
SK-OV-3
140
120
100
80
60
40
20
0
3. Experimental
3.1. General Methods
1
13
The melting points were measured using open capillary tubes and are uncorrected. H, C and
two-dimensional NMR spectra were recorded on a Bruker 500, 400 and 300 MHz instruments in
CDCl3, MeOD, and DMSO using TMS as internal standard. Chemical shifts are given in parts per
million (-scale) and the coupling constants are given in Hertz. IR spectra were recorded on a JASCO
FT IR instrument (KBr pellets). Elemental analyses were performed on a Perkin Elmer 2400 Series II
Elemental CHNS analyzer. Column chromatography was performed on silica gel (230–400 mesh)
using petroleum ether-ethyl acetate as eluents.
3.2. General Procedure for the Synthesis of 3,5-bis[(E)-Arylmethylidene]tetrahydro-4(1H)-pyridinones 2
Following the literature reported procedure by Dimmock et al., an appropriate aryl aldehyde
(2 mmol) was added to a suspension of 4-piperidone hydrochloride monohydrate (1 mmol) in acetic acid
(40 mL). Dry hydrogen chloride was passed through this mixture for 30 min during which time a clear
solution was obtained and the stirring continued for 24 h. The precipitate obtained was collected and
added to a mixture of saturated aqueous potassium carbonate solution and acetone. The resultant
mixture was stirred for 30 min, the free base collected was washed with water and dried and
crystalized with ethyl acetate to afford 2 in good yield.

Molecules 2014, 19
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3.3. General Procedure for the Synthesis of 1-Methyl-4-(aryl)pyrrolo-(spiro[2.3″]oxindole)-spiro[3.3′]-
5′(arylmethylidene)-piperidin-4′-ones 4
A mixture of 3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinone (1 mmol), isatin (1.1 mmol),
and sarcosine (1.1 mmol) were dissolved in methanol (5 mL) and heated under reflux for 1 h. After
completion of the reaction as evident from TLC, the mixture was poured into water (50 mL). The
precipitated solid was filtered and washed with water to obtain the corresponding product 4 in good yield.
3.4. Spectral Data
1-Methyl-4-(phenyl)pyrrolo-(spiro[2.3″]oxindole)-spiro[3.3′]-5′-(phenylmethylidene)-piperidin-4′-one
(4a). Obtained as a pale yellow solid, (0.150 g, 92%); mp = 169–171°C; IR (KBr): 1604, 1620, 1703,
1
3407 cm−1; H-NMR (300 MHz, CDCl3): δH 2.05 (d, 1H, J = 13.2 Hz, 2ꞌ-CH2), 2.14 (s, 1H, N-CH3),
3.35 (dd, 1H, J = 7.2, 7.2 Hz, 5-CH2), 3.50–3.58 (m, 2H, 6ꞌ-CH2), 3.64 (d, 1H, J = 13.2 Hz, 2ꞌ-CH2),
3.94 (dd, 1H, J = 9.0, 8.7 Hz, 5-CH2), 4.85 (dd, 1H, J = 7.2, 7.2 Hz, 4-CH), 6.66–7.43 (m, 15H, Ar-H),
13
8.41 (s, 1H, 1ꞌꞌ-NH). C-NMR (75 MHz, CDCl3): δC 35.07, 46.43, 48.66, 50.38, 57.35, 66.75, 76.29,
109.46, 122.55, 127.22, 127.99, 128.29, 128.59, 128.66, 128.97, 129.26, 130.01, 130.24, 135.16,
135.63, 137.75, 138.97, 142.15, 178.69, 199.98. Anal. calcd for C29H27N3O2: C, 77.48; H, 6.05; N,
9.35; found: C, 77.34; H, 6.23; N, 9.28.
1-Methyl-4-(2-methylphenyl)pyrrolo-(spiro[2.3″]oxindole)-spiro[3.3′]-5′-(2-methylphenylmethylidene)
piperidin-4′-one (4b). Obtained as a pale yellow solid, (0.140 g, 90%); mp = 163–164 °C; IR (KBr):
1602, 1615, 1711, 3405 cm−1; 1H-NMR (400 MHz, CDCl3): δH 2.06–2.09 (m, 1H, 2'-CH2), 2.15 (s, 3H,
N-CH3), 2.17 (s, 3H, CH3), 2.32 (s, 3H, CH3), 3.25–3.56 (m, 4H, 5-CH2, 6'-CH2 and 2'-CH2), 4.00 (t,
1H, J = 9.2 Hz, 5-CH2), 4.98 (t, 1H, J = 8.0 Hz, 4-CH), 6.72–7.57 (m, 11H, Ar-H), 7.70 (d, 1H, J = 6.8 Hz,
13
Ar-H), 7.83 (d, 1H, J = 8.0 Hz, Ar-H), 8.23 (s, 1H, 1"-NH). C-NMR (100 MHz, CDCl3): δC 20.44,
21.55, 35.06, 42.46, 48.66, 51.44, 58.81, 64.72, 76.04, 109.60, 122.98, 125.69, 126.21, 126.99, 128.38,
128.85, 128.99, 129.18, 129.74, 129.83, 130.47, 130.56, 130.61, 131.15, 134.12, 134.54, 137.53,
138.09, 142.30, 178.21, 199.75. Anal. calcd for C31H31N3O2: C, 77.96; H, 6.54; N, 8.80; found: C,
77.81; H, 6.65; N, 8.69.
1-Methyl-4-(2-methoxyphenyl)pyrrolo-(spiro[2.3″]oxindole)-spiro[3.3′]-5′-(2-methoxyphenylmethylid
ene)piperidin-4′-one (4c). Obtained as a white solid, (0.130 g, 86%); mp = 159–160 °C; IR (KBr):
1
1599, 1617, 1705, 3410 cm−1; H-NMR (300 MHz, CDCl3): δH 2.15 (s, 3H, N-CH3), 2.30 (d, 1H,
J = 13.8 Hz, 2'-CH2), 3.24–3.71 (m, 4H, 5-CH2, 6'-CH2 and 2'-CH2), 3.73 (s, 3H, OCH3), 3.81 (s, 3H,
OCH3), 4.10 (dd, 1H, J = 9.3, 9.0 Hz, 5-CH2), 4.93 (dd, 1H, J = 8.1, 7.5 Hz, 4-CH), 6.68–7.65 (m,
13
13H, Ar-H), 8.37 (s, 1H, 1"-NH). C-NMR (75 MHz, CDCl3): δC 35.28, 40.39, 48.42, 55.07, 55.34,
55.71, 56.28, 64.03, 76.44, 109.66, 110.25, 110.94, 120.18, 120.89,122.50, 122.89, 124.90, 126.47,
127.96, 128.72, 128.98, 129.18, 130.48, 130.63, 133.59, 134.32, 142.28, 158.34, 158.48, 178.51,
199.07. Anal. calcd for C31H31N3O4: C, 73.06; H, 6.13; N, 8.25; found: C, 73.28; H, 6.29; N, 8.32.
1-Methyl-4-(2-chlorophenyl)pyrrolo-(spiro[2.3″]oxindole)-spiro[3.3′]-5′-(2-chlorophenylmethylidene)
piperidin-4′-one (4d). Obtained as a white solid, (0.137 g, 91%); mp = 168–169 °C; IR (KBr): 1598,

Molecules 2014, 19
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1
1615, 1706, 3409 cm−1; H-NMR (400 MHz, CDCl3): δH 2.03 (d, 1H, J = 14.2 Hz, 2'-CH2), 2.13 (s,
3H, N-CH3), 3.25–3.57 (m, 4H, 5-CH2, 6'-CH2 and 2'-CH2), 3.99 (t, 1H, J = 8.8 Hz, 5-CH2), 5.14 (t,
1H, J = 8.8 Hz, 4-CH), 6.72 (d, 1H, J = 7.6 Hz, Ar-H), 6.87–7.31 (m, 8H, Ar-H), 7.34 (d, 2H, J = 8.0 Hz,
Ar-H), 7.64 (s, 1H, C=CH), 8.00 (d, 1H, J = 8.0 Hz, Ar-H), 8.31 (s, 1H, 1"-NH). 13C-NMR (100 MHz,
CDCl3): δC 35.12, 43.14, 48.52, 50.83, 57.97, 64.01, 77.67, 109.62, 123.54, 126.56, 126.83, 127.12,
128.37, 128.58, 129.32, 129.59, 129.64, 130.10, 130.48, 131.29, 134.06, 135.05, 135.30, 135.61,
136.27, 137.30, 141.98, 178.20, 198.60. Anal. calcd for C29H25Cl2N3O2: C, 67.19; H, 4.86; N, 8.11;
found: C, 67.30; H, 4.70; N, 8.04.
1-Methyl-4-(2-bromophenyl)pyrrolo-(spiro[2.3ꞌꞌ]oxindole)-spiro[3.3′]-5′-(2-bromophenylmethylidene)
piperidin-4′-one (4e). Obtained as a white solid, (0.126 g, 90%); mp = 143–144 °C; IR (KBr): 1605,
1
1614, 1702, 3412 cm−1; H-NMR (400 MHz, CDCl3): δH 1.99 (d, 1H, J = 14.8 Hz, 2'-CH2), 2.13 (s,
3H, N-CH3), 3.24–3.57 (m, 4H, 5-CH2, 6'-CH2 and 2'-CH2), 3.96 (t, 1H, J = 8.8 Hz, 5-CH2), 5.08 (t,
1H, J = 8.4 Hz, 4-CH), 6.74 (d, 1H, J = 7.6 Hz, Ar-H), 6.89 (d, 1H, J = 7.2 Hz, Ar-H), 6.98–7.61 (m,
8H, Ar-H), 7.65 (s, 1H, C=CH), 7.94 (t, 1H, J = 8.8 Hz, Ar-H), 8.05 (d, 1H, J = 7.6 Hz, Ar-H), 8.42
13
(s, 1H, 1"-NH). C-NMR (100 MHz, CDCl3): δC 35.10, 46.09, 48.27, 50.78, 58.47, 63.85, 76.14,
109.68, 123.64, 125.46, 126.81, 127.19, 127.64, 127.70, 128.59, 128.69, 129.33, 130.24, 130.46,
131.73, 132.95, 133.01, 133.35, 135.85, 137.26, 139.08, 142.05, 178.22, 198.58. Anal. calcd for
C29H25Br2N3O2: C, 57.35; H, 4.15; N, 6.92; found: C, 57.52; H, 4.01; N, 6.84.
1-Methyl-4-(2-fluorophenyl)pyrrolo-(spiro[2.3″]oxindole)-spiro[3.3′]-5′-(2-fluorophenylmethylidene)
piperidin-4′-one (4f). Obtained as a white solid, (0.143 g, 92%); mp = 165–166 °C; IR (KBr): 1603,
1617, 1705, 3408 cm−1; 1H-NMR (400 MHz, CDCl3): δH 2.14 (s, 3H, N-CH3), 2.30 (d, 1H, J = 13.6 Hz,
2'-CH2), 3.27–3.55 (m, 4H, 5-CH2, 6'-CH2 and 2'-CH2), 3.98 (t, 1H, J = 9.6 Hz, 5-CH2), 5.08 (t, 1H,
J = 9.6 Hz, 4-CH), 6.68 (d, 1H, J = 7.6 Hz, Ar-H), 6.83–7.32 (m, 11H, Ar-H), 7.76 (t, 1H, J = 7.2 Hz,
Ar-H), 8.01 (s, 1H, 1"-NH). 13C-NMR (100 MHz, CDCl3): δC 35.07, 38.61, 48.80, 50.68, 56.97, 65.03,
76.89, 109.42, 115.45 (2JCF = 22.6 Hz), 116.00 (2JCF = 21.8 Hz), 122.99, 123.92, 123.96, 126.49,
127.15, 128.25, 128.59, 128.73, 129.15, 129.30, 130.68, 130.79, 130.87, 136.23, 141.90, 160.68,
162.23, 178.20, 198.37. Anal. calcd for C29H25F2N3O2: C, 71.74; H, 5.19; N, 8.65; found: C, 71.95; H,
5.08; N, 8.78.
1-Methyl-4-(2,4-dichlorophenyl)pyrrolo-(spiro[2.3″]oxindole)-spiro[3.3′]-5′-(2,4-dichlorophenylmeth
ylidene)piperidin-4′-one (4g). Obtained as a white solid, (0.127 g, 90%); mp = 171–172 °C; IR (KBr):
1
1600, 1619, 1708, 3406 cm−1; H-NMR (300 MHz, CDCl3): δH 2.11 (s, 3H, N-CH3), 2.22–2.25 (m,
1H, 2'-CH2), 3.27–3.56 (m, 4H, 6'-CH2,2'-CH2 and 5-CH2), 3.91 (t, 1H, J = 9.0 Hz, 5-CH2), 5.07 (t,
1H, J = 8.7 Hz, 4-CH), 6.69–7.44 (m, 8H, Ar-H), 7.54 (s, 1H, Ar-H), 7.86 (d, 1H, J = 8.4 Hz, Ar-H),
13
7.95 (d, 1H, J = 8.7 Hz, Ar-H), 8.77 (s, 1H, 1"-NH). C-NMR (75 MHz, CDCl3): δC 35.10, 42.65,
48.11, 49.95, 57.10, 63.92, 76.54, 109.20, 123.47, 125.93, 126.55, 127.03, 128.36, 129.34, 129.48,
130.06, 130.87, 132.36, 132.54, 133.46, 133.93, 134.41, 135.45, 135.80, 136.04, 136.78, 142.15,
178.33, 198.39. Anal. calcd for C29H23Cl4N3O2: C, 59.30; H, 3.95; N, 7.15; found: C, 59.45; H, 3.77;
N, 7.01.

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1-Methyl-4-(3-nitrophenyl)pyrrolo-(spiro[2.3″]oxindole)-spiro[3.3′]-5′-(3-nitrophenylmethylidene)
piperidin-4′-one (4h). Obtained as a pale yellow solid, (0.131 g, 89%); mp = 185–186 °C; IR (KBr):
1
1599, 1617, 1705, 3408 cm−1; H-NMR (400 MHz, MeOH): δH 2.09–2.13 (m, 1H, 2'-CH2), 2.17 (s,
3H, N-CH3), 3.44 (t, 1H, J = 7.6 Hz, 5-CH2), 3.51–3.60 (m, 2H, 6'-CH2), 3.64 (d, 1H, J = 12.8 Hz, 2'-CH2)
3.94 (t, 1H, J = 9.6 Hz, 5-CH2), 4.90 (dd, 1H, J = 7.6, 7.2 Hz, 4-CH), 6.74 (d, 1H, J = 7.6 Hz, Ar-H),
6.92–8.12 (m, 11H, Ar-H), 8.34 (s, 1H, 1"-NH). 13C-NMR (100 MHz, MeOH): δC 34.92, 45.92, 48.40,
50.39, 57.54, 66.71, 76.10, 109.75, 122.50, 122.62, 123.56, 124.40, 124.74, 127.41, 128.20, 129.59,
129.68, 129.73, 134.98, 135.67, 136.39, 137.03, 137.12, 141.23, 142.22, 148.50, 148.75, 178.18,
199.03. Anal. calcd for C29H25N5O6: C, 64.56; H, 4.67; N, 12.98; found: C, 64.68; H, 4.59; N, 12.85.
1-Methyl-4-(4-methylphenyl)pyrrolo-(spiro[2.3″]oxindole)-spiro[3.3′]-5′-(4-methylphenylmethylidene)
piperidin-4′-one (4i). Obtained as a white solid, (0.146 g, 93%); mp = 180–181 °C; IR (KBr): 1607,
1621, 1710, 3412 cm−1; 1H-NMR (400 MHz, CDCl3): δH 2.14 (s, 3H, N-CH3), 2.20 (d, 1H, J = 13.6 Hz,
2'-CH2), 2.30 (s, 3H, CH3), 2.31 (s, 3H, CH3), 3.15–3.63 (m, 4H, 5-CH2, 6'-CH2 and 2'-CH2), 3.91 (t,
1H, J = 9.6 Hz, 5-CH2), 4.80 (t, 1H, J = 9.6 Hz, 4-CH), 6.63–7.32 (m, 13H, Ar-H), 8.08 (s, 1H,
1"-NH). 13C-NMR (100 MHz, CDCl3): δC 21.43, 21.69, 35.04, 46.18, 48.73, 50.29, 57.51, 66.51,
76.40, 109.33, 122.55, 128.33, 129.19, 129.54, 129.71, 129.89, 130.16, 130.41, 132.84, 134.38,
135.83, 136.77, 137.80, 139.27, 142.02, 178.64, 200.02. Anal. calcd for C31H31N3O2: C, 77.96; H,
6.54; N, 8.80; found: C, 78.10; H, 6.46; N, 8.73.
1-Methyl-4-(4-methoxyphenyl)pyrrolo-(spiro[2.3″]oxindole)-spiro[3.3′]-5′-(4-methoxyphenylmethylidene)
piperidin-4′-one (4j). Obtained as a pale yellow solid, (0.129 g, 85%); mp = 187–188 °C; IR (KBr):
1
1600, 1615, 1706, 3410 cm−1; H-NMR (400 MHz, CDCl3): δH 2.14 (s, 3H, N-CH3), 2.21 (d, 1H,
J = 13.2 Hz, 2'-CH2), 3.35 (dd, 1H, J = 7.2, 7.2 Hz, 5-CH2), 3.55–3.76 (m, 2H, 6'-CH2), 3.77 (s, 3H,
OCH3), 3.78 (s, 3H, OCH3), 3.80–3.91 (m, 2H, 5-CH2 and 2'-CH2), 4.78 (dd, 1H, J = 7.2, 7.2 Hz,
4-CH), 6.65 (d, 1H, J = 7.6 Hz, Ar-H), 6.77–7.09 (m, 8H, Ar-H), 7.13 (d, 2H, J = 7.6 Hz, Ar-H), 7.35
(d, 2H, J = 8.8 Hz, Ar-H), 8.27 (s, 1H, 1"-NH). 13C-NMR (100 MHz, CDCl3): δC 34.61, 45.52, 48.36,
49.82, 55.18, 55.22, 57.37, 65.85, 76.12, 108.86, 113.60, 113.74, 122.05, 127.61, 127.90, 128.71,
130.58, 131.84, 132.37, 132.72, 137.27, 141.66, 158.45, 159.97, 178.22, 199.52. Anal. calcd for
C31H31N3O4: C, 73.06; H, 6.13; N, 8.25; found: C, 73.17; H, 6.01; N, 8.34.
1-Methyl-4-(4-chlorophenyl)pyrrolo-(spiro[2.3″]oxindole)-spiro[3.3′]-5′-(4-chlorophenylmethylidene)
piperidin-4′-one (4k). Obtained as a pale yellow solid, (0.140 g, 93%); mp = 169–170°C; IR (KBr):
1602, 1617, 1709, 3410 cm−1; 1H-NMR (500 MHz, CDCl3): δH 2.07–2.10 (m, 1H, 2'-CH2), 2.13 (s, 3H,
N-CH3), 3.34 (t, 1H, J = 8.0 Hz, 5-CH2), 3.48–3.54 (m, 2H, 6'-CH2), 3.60 (d, 1H, J = 13.0 Hz, 2'-CH2),
3.86 (t, 1H, J = 10.0 Hz, 5-CH2), 4.79 (dd, 1H, J = 7.5, 7.5 Hz, 4-CH), 6.67 (d, 1H, J = 8.0 Hz, Ar-H),
6.91 (d, 2H, J = 8.0 Hz, Ar-H), 6.97 (t, 1H, J = 7.5 Hz, Ar-H), 7.00 (s, 1H, C=CH), 7.07–7.13 (m, 2H,
13
Ar-H), 7.21–7.28 (m, 4H, Ar-H), 7.35 (d, 2H, J = 8.5 Hz, Ar-H), 8.45 (s, 1H, 1"-NH). C-NMR
(125 MHz, CDCl3): δC 34.60, 45.32, 48.21, 49.92, 56.99, 66.17, 75.81, 109.17, 122.15, 127.81, 128.42,
128.53, 128.78, 129.00, 130.97, 131.07, 132.69, 133.50, 134.71, 134.98, 136.16, 137.00, 141.77,
178.30, 199.24. Anal. calcd for C29H25Cl2N3O2: C, 67.19; H, 4.86; N, 8.11; found: C, 67.07; H, 4.73;
N, 8.19.

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1-Methyl-4-(4-bromophenyl)pyrrolo-(spiro[2.3″]oxindole)-spiro[3.3′]-5′-(4-bromophenylmethylidene)
piperidin-4′-one (4l). Obtained as a pale yellow solid, (0.127 g, 91%); mp = 172–173 °C; IR (KBr):
1
1598, 1619, 1710, 3409 cm−1; H-NMR (300 MHz, MeOH): δH 2.11 (s, 3H, N-CH3), 2.17 (d, 1H,
J = 13.2 Hz, 2'-CH2), 3.32–3.56 (m, 4H, 5-CH2,6'-CH2 and 2'-CH2), 3.90 (dd, 1H, J = 9.0, 9.0 Hz,
5-CH2), 4.64 (s, 1H, 1"-NH), 4.76 (dd, 1H, J = 7.5, 7.2 Hz, 4-CH), 6.72 (d, 1H, J = 7.8 Hz, Ar-H),
6.98–7.18 (m, 6H, Ar-H), 7.34 (d, 2H, J = 8.4 Hz, Ar-H), 7.45–7.48 (m, 4H, Ar-H). 13C-NMR (75 MHz,
MeOH): δC 33.86, 45.84, 48.28, 50.01, 57.10, 65.86, 76.31, 109.55, 120.81, 121.91, 122.96, 127.15,
127.74, 129.36, 131.43, 131.56, 131.69, 131.77, 134.43, 135.74, 136.13, 138.06, 143.25, 178.53, 199.78.
Anal. calcd for C29H25Br2N3O2: C, 57.35; H, 4.15; N, 6.92; found: C, 57.48; H, 4.27; N, 6.99.
1-Methyl-4-(4-fluorophenyl)pyrrolo-(spiro[2.3″]oxindole)-spiro[3.3′]-5′-(4-fluorophenylmethylidene)
piperidin-4′-one (4m). Obtained as a white solid, (0.146 g, 94%); mp = 174–175 °C; IR (KBr): 1601,
1618, 1709, 3411 cm−1; 1H-NMR (300 MHz, MeOH): δH 2.10 (s, 3H, N-CH3), 2.18 (d, 1H, J = 13.2 Hz,
2'-CH2), 3.26–3.57 (m, 4H, 5-CH2, 6'-CH2 and 2'-CH2), 3.89 (dd, 1H, J = 9.3, 9.0 Hz, 5-CH2), 4.65 (s,
1H, 1"-NH), 4.78 (dd, 1H, J = 7.5, 7.2 Hz, 4-CH), 6.73 (d, 1H, J = 7.5 Hz, Ar-H), 6.89–7.17 (m, 11H,
13
Ar-H), 7.39–7.44 (m, 1H, Ar-H). C-NMR (75 MHz, MeOH): δC 33.90, 45.73, 48.22, 50.02, 57.40,
65.75, 76.42, 109.54, 114.64 (2JCF = 21.2 Hz), 115.30 (2JCF = 21.8 Hz), 121.93, 127.22, 127.75,
129.32, 131.30 (JCF = 77.3 Hz), 131.73 (JCF = 3.3 Hz), 132.25 (JCF = 83.3 Hz), 134.64 (2JCF = 3.2 Hz),
134.87, 136.42, 143.22, 162.32 (1JCF = 242.7 Hz), 163.14 (1JCF = 247.4 Hz), 178.58, 199.98. Anal.
calcd for C29H25F2N3O2: C, 71.74; H, 5.19; N, 8.65; found: C, 71.87; H, 5.31; N, 8.59.
1-Methyl-4-(1-naphthyl)pyrrolo-(spiro[2.3″]oxindole)-spiro[3.3′]-5′-(1-naphthylmethylidene)piperidin-
4′-one (4n). Obtained as a pale yellow solid, (0.132 g, 90%); mp = 160–161 °C; IR (KBr): 1698, 1620,
1
1706, 3410 cm−1; H-NMR (300 MHz, DMSO): δH 1.66 (d, 1H, J = 12.6 Hz, 2'-CH2), 2.00 (s, 3H,
N-CH3), 3.07 (d, 1H, J = 15.8 Hz, 6'-CH2), 3.19 (d, 1H, J = 15.8 Hz, 6'-CH2), 3.35 (t, 1H,
J = 7.8 Hz, 5-CH2), 3.55 (d, 1H, J = 12.6 Hz, 2'-CH2), 4.05 (t, 1H, J = 9.3 Hz, 5-CH2), 5.50 (t, 1H,
J = 8.4 Hz, 4-CH), 6.66 (d, 1H, J = 6.6 Hz, Ar-H), 7.02–7.96 (m, 17H, Ar-H), 8.12 (d, 1H, J = 8.7 Hz,
Ar-H), 10.46 (s, 1H, 1"-NH). 13C-NMR (75 MHz, DMSO): δC 34.95, 40.63, 49.23, 51.52, 58.72,
64.93, 76.59, 109.95, 122.19, 124.48, 125.49, 125.89, 126.17, 126.33, 127.12, 127.32, 127.47, 127.61,
127.79, 128.03, 129.23, 129.36, 129.56, 129.74, 129.80, 131.64, 132.54, 133.63, 133.74, 134.37,
135.14, 135.84, 137.0, 144.41, 177.57, 199.76. Anal. calcd for C37H31N3O2: C, 80.85; H, 5.68; N, 7.64;
found: C, 80.96; H, 5.82; N, 7.55.
4,5-Diphenylpyrrolo(spiro[2.3′′]-oxindole)-spiro-[3.3′]-5′-(phenylmethylidene)piperidin-4′-one (5a).
Obtained as a white solid, (0.170 g, 93%); mp = 162–163 °C; IR (KBr): 1593, 1613, 1698, 3179,
3344 cm−1; 1H-NMR (500 MHz, CDCl3): δH 2 .31 (d, 1H, J = 13.0 Hz, 2'-CH2), 3.52 (dd, 1H, J = 14.5,
2.5 Hz, 6'-CH2), 3.64 (d, 1H, J = 15.0 Hz, 6'-CH2), 3.77 (dd, 1H, J = 13.0, 1.0 Hz, 2'-CH2), 4.73 (d,
1H, J = 11.0 Hz, 4-CH), 5.43 (d, 1H, J = 11.0 Hz, 5-CH), 6.67 (d, 1H, J = 7.5 Hz, Ar-H), 6.98–7.04
(m, 4H, Ar-H), 7.12–7.28 (m, 11H, Ar-H), 7.41 (d, 2H, J = 7.0 Hz, Ar-H), 7.53 (d, 2H, J = 7.5 Hz,
Ar-H), 7.99 (s, 1H, 1"-NH). 13C-NMR (125 MHz, CDCl3): δC 48.19, 49.74, 56.85, 64.24, 67.34, 71.82,
109.21, 122.20, 126.85, 127.02, 127.57, 127.66, 128.25, 128.33, 128.70, 128.99, 129.21, 129.89,

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129.93, 134.86, 135.12, 137.09, 137.38, 140.74, 141.00, 180.91, 200.14. Anal. calcd for C34H29N3O2:
C, 79.82; H, 5.71; N, 8.21; found: C, 79.70; H, 5.85; N, 8.15.
4-(2-Methylphenyl)-5-phenylpyrrolo(spiro[2.3″]oxindole)spiro[3.3′]-5′-(2-methylphenylmethylidene)
piperidin-4′-one (5b). Obtained as a pale yellow solid, (0.160 g, 90%); mp = 150–151 °C; IR (KBr):
1
1595, 1618, 1697, 3168, 3340 cm−1; H-NMR (300 MHz, CDCl3): δH 2.11 (s, 1H, CH3), 2.20 (s, 1H,
CH3), 2.27–2.32 (m, 1H, 2'-CH2), 3.41 (d, 1H, J = 15.3 Hz, 6'-CH2), 3.51 (dd, 1H, J = 15.3, 2.4 Hz,
6'-CH2), 3.58 (d, 1H, J = 13.2 Hz, 2'-CH2), 4.90 (d, 1H, J = 9.9 Hz, 4-CH), 5.54 (d, 1H, J = 9.9 Hz,
5-CH), 6.73 (d, 1H, J = 7.5 Hz, Ar-H), 6.82 (d, 1H, J = 7.5 Hz, Ar-H), 6.92–7.55 (m, 15H, Ar-H),
7.63 (s, 1H, C=CH), 8.42 (s, 1H, 1"-NH). 13C-NMR (75 MHz, CDCl3): δC 20.49, 21.44, 48.43, 51.42,
54.54, 65.44, 66.53, 74.25, 109.94, 122.91, 125.80, 125.98, 126.29, 126.98, 127.83, 127.91, 128.81,
128.94, 129.42, 129.64, 130.58, 130.78, 134.36, 134.54, 135.46, 135.60, 136.82, 137.44, 138.21,
138.31, 138.63, 141.79, 180.90, 201.06. Anal. calcd for C36H33N3O2: C, 80.12; H, 6.16; N, 7.79;
found: C, 80.28; H, 6.27; N, 7.70.
4-(2-Methoxyphenyl)-5-phenylpyrrolo(spiro[2.3″]oxindole)spiro[3.3′]-5′-(2-methoxyphenylmethylidene)
piperidin-4′-one (5c). Obtained as a pale yellow solid, (0.144 g, 85%); mp = 155–156 °C; IR (KBr):
1597, 1614, 1695, 3173, 3342 cm−1; 1H-NMR (300 MHz, CDCl3): δH 2.43 (d, 1H, J = 13.8 Hz, 2'-CH2),
3.26–3.62 (m, 3H, 6'-CH2 and 2'-CH2), 3.65 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 4.89 (d, 1H, J = 9.9 Hz,
4-CH), 5.74 (d, 1H, J = 9.9 Hz, 5-CH), 6.67–7.86 (m, 18H, Ar-H and C=CH), 8.02 (s, 1H, 1"-NH).
13C-NMR (75 MHz, CDCl3): δC 48.50, 49.76, 54.32, 55.41, 55.80, 63.89, 66.56, 74.29, 110.36, 111.05,
111.12, 120.31, 120.51, 121.09, 122.83, 124.72, 127.33, 127.88, 128.07, 128.31, 128.85, 129.29,
130.53, 130.88, 131.03, 133.42, 141.81, 158.23, 158.76, 180.01, 201.03. Anal. calcd for C36H33N3O4:
C, 75.64; H, 5.82; N, 7.35; found: C, 75.50; H, 5.97; N, 7.18.
4-(2-Chlorophenyl)-5-phenylpyrrolo(spiro[2.3″]oxindole)spiro[3.3′]-5′-(2-chlorophenylmethylidene)
piperidin-4′-one (5d). Obtained as a white solid, (0.155 g, 92%); mp = 151–152 °C; IR (KBr): 1590,
1
1617, 1692, 3175, 3340 cm−1; H-NMR (300 MHz, CDCl3): δH 1.97 (br s, 1H, NH), 2.41 (d, 1H,
J = 13.8 Hz, 2'-CH2), 3.27 (d, 1H, J = 13.8 Hz, 2'-CH2), 3.42 (d, 1H, J = 15.6 Hz, 6'-CH2), 3.61 (d,
1H, J = 15.6 Hz, 6'-CH2), 5.11 (d, 1H, J = 9.0 Hz, 4-CH), 5.66 (d, 1H, J = 9.0 Hz, 5-CH), 6.69 (d, 1H,
J = 7.5 Hz, Ar-H), 6.97–7.39 (m, 12H, Ar-H), 7.58–7.66 (m, 3H, Ar-H), 7.84 (s, 1H, C=CH), 8.15 (d,
13
1H, J = 7.2 Hz, Ar-H), 8.68 (s, 1H, 1"-NH). C-NMR (75 MHz, CDCl3): δC 48.52, 50.71, 55.41,
64.74, 65.74, 75.18, 109.92, 123.44, 126.66, 127.17, 127.29, 127.72, 128.12, 128.18, 128.47, 129.00,
129.51, 129.71, 130.19, 130.32, 130.52, 131.09, 133.87, 135.11, 135.33, 135.58, 136.52, 136.70,
141.22, 141.64, 179.14, 200.63. Anal. calcd for C34H27Cl2N3O2: C, 70.35; H, 4.69; N, 7.24; found: C,
70.47; H, 4.61; N, 7.16.
4-(2-Bromophenyl)-5-phenylpyrrolo(spiro[2.3″]oxindole)spiro[3.3′]-5′-(2-bromophenylmethylidene)
piperidin-4′-one (5e). Obtained as a white solid, (0.137 g, 89%); mp = 153–154 °C; IR (KBr): 1590,
1
1611, 1694, 3184, 3337 cm−1; H-NMR (300 MHz, CDCl3): δH 1.91 (br s, 1H, NH), 2.45 (d, 1H,
J = 13.8 Hz, 2'-CH2), 3.23 (d, 1H, J = 13.8 Hz, 2'-CH2), 3.40 (d, 1H, J = 15.6 Hz, 6'-CH2), 3.62 (dd,
1H, J = 15.6, 2.1 Hz, 6'-CH2), 5.06 (d, 1H, J = 9.3 Hz, 4-CH), 5.67 (d, 1H, J = 9.3 Hz, 5-CH), 6.71 (d,
1H, J = 7.8 Hz, Ar-H), 6.95–7.44 (m, 8H, Ar-H), 7.48 (d, 2H, J = 7.5 Hz, Ar-H), 7.58 (d, 2H, J = 7.2 Hz,

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Ar-H), 7.67 (d, 2H, J = 7.2 Hz, Ar-H), 7.84 (s, 1H, C=CH), 8.21(d, 1H, J = 7.8 Hz, Ar-H), 8.67 (s, 1H,
13
1"-NH). C-NMR (75 MHz, CDCl3): δC 48.28, 50.66, 58.56, 64.64, 66.37, 75.47, 110.01, 123.57,
125.76, 127.16, 127.32, 127.59, 127.93, 128.13, 128.22, 128.54, 128.83, 129.04, 129.55, 130.54,
131.49, 133.07, 133.45, 135.14, 135.62, 137.38, 138.44, 141.13, 141.68, 178.95, 200.93. Anal. calcd
for C34H27Br2N3O2: C, 61.00; H, 4.07; N, 6.28; found: C, 61.13; H, 4.26; N, 6.40.
4-(2-Fluorophenyl)-5-phenylpyrrolo(spiro[2.3″]oxindole)spiro[3.3′]-5′-(2-fluorophenylmethylidene)
piperidin-4′-one (5f). Obtained as a white solid, (0.158 g, 90%); mp = 148–149 °C; IR (KBr): 1592,
1
1618, 1694, 3178, 3345 cm−1; H-NMR (300 MHz, CDCl3): δH 2.20 (br s, 1H, NH), 2.43 (d, 1H,
J = 13.5 Hz, 2'-CH2), 3.31–3.66 (m, 3H, 2'-CH2 and 6'-CH2), 5.00 (d, 1H, J = 9.9 Hz, 4-CH), 5.57 (d,
1H, J = 9.9 Hz, 5-CH), 6.68 (d, 1H, J = 7.5 Hz, Ar-H), 6.90–7.63 (m, 16H, Ar-H), 7.87 (s, 1H,
C=CH), 8.65 (s, 1H, 1"-NH). 13C-NMR (75 MHz, CDCl3): δC 48.79, 50.39, 63.10, 64.48, 65.97, 73.65,
109.92, 115.64 (2JCF = 23.3 Hz), 116.08 (2JCF = 21.7 Hz), 122.94, 123.39, 123.57, 124.07 (JCF = 3.0 Hz),
124.48 (JCF = 3.0 Hz), 127.28, 128.01, 128.18, 128.31, 128.92, 129.41, 129.56, 130.16, 130.61,
130.80, 131.16, 136.04, 140.98, 141.59, 161.15 (1JCF = 250.6 Hz), 161.96 (1JCF = 244.1 Hz), 180.24,
199.77. Anal. calcd for C34H27F2N3O2: C, 74.57; H, 4.97; N, 7.67; found: C, 74.45; H, 4.88; N, 7.74.
4-(2,4-Dichlorophenyl)-5-phenylpyrrolo(spiro[2.3″]oxindole)spiro[3.3′]-5′-(2,4-dichlorophenyl
methylidenedichlorophenylmethylidene)piperidin-4′-one (5g). Obtained as a white solid, (0.144 g,
92%); mp = 160–161 °C; IR (KBr): 1599, 1618, 1704, 3182, 3338 cm−1; 1H-NMR (300 MHz, CDCl3):
δH 2.35 (d, 1H, J = 13.5 Hz, 2'-CH2), 3.23–3.42 (m, 2H, 2'-CH2 and 6'-CH2), 3.56 (d, 1H, J = 15.3 Hz,
6'-CH2), 5.04 (d, 1H, J = 9.3 Hz, 4-CH), 5.58 (d, 1H, J = 9.3 Hz, 5-CH), 6.69 (d, 1H, J = 7.2 Hz, Ar-H),
6.88 (d, 1H, J = 8.1 Hz, Ar-H), 6.97 (d, 1H, J = 7.5 Hz, Ar-H), 7.12–7.29 (m, 5H, Ar-H), 7.40 (s, 1H,
Ar-H), 7.54 (d, 2H, J = 7.2 Hz, Ar-H), 7.61 (d, 2H, J = 7.8 Hz, Ar-H), 7.76 (s, 1H, C=CH), 7.88 (d,
13
1H, J = 7.2 Hz, Ar-H), 8.09 (d, 1H, J = 8.1 Hz, Ar-H), 8.90 (s, 1H, 1"-NH). C-NMR (75 MHz,
CDCl3): δC 48.49, 50.62, 54.85, 64.54, 65.89, 75.09, 110.16, 123.42, 127.13, 127.47, 127.64, 128.02,
128.43, 129.12, 129.42, 129.52, 130.18, 131.16, 131.93, 132.21, 133.64, 134.12, 134.92, 135.27,
135.51, 135.71, 136.34, 137.08, 140.77, 141.75, 179.13, 200.24. Anal. calcd for C34H25Cl4N3O2: C,
62.88; H, 3.88; N, 6.47; found: C, 62.75; H, 3.97; N, 6.40.
4-(3-Nitrophenyl)-5-phenylpyrrolo(spiro[2.3″]oxindole)spiro[3.3′]-5′-(3-nirophenylmethylidene)
piperidin-4′-one (5h). Obtained as a white solid, (0.149 g, 91%); mp = 154–155 °C; IR (KBr): 1596,
1
1612, 1702, 3186, 3336 cm−1; H-NMR (300 MHz, CDCl3): δH 2.26 (d, 1H, J = 12.9 Hz, 2'-CH2),
3.43–3.85 (m, 3H, 2'-CH2 and 6'-CH2), 4.78 (d, 1H, J = 10.5 Hz, 4-CH), 5.43 (d, 1H, J = 10.5 Hz, 5-CH),
6.70 (m, 11H, Ar-H), 7.80 (s, 1H, C=CH), 7.87–8.13 (m, 4H, Ar-H), 8.20 (s, 1H, Ar-H), 8.35 (s, 1H,
Ar-H), 8.76 (s, 1H, 1"-NH). 13C-NMR (75 MHz, CDCl3): δC 48.33, 56.82, 63.88, 65.01, 67.37, 72.16,
110.16, 122.62, 123.71, 124.55, 125.02, 127.31, 127.95, 128.50, 129.01, 129.42, 129.71, 129.84,
130.17, 134.77, 135.81, 136.76, 136.88, 137.20, 140.01, 140.29, 141.81, 148.46, 148.64, 181.44,
199.69. Anal. calcd for C34H27N5O6: C, 67.88; H, 4.52; N, 11.64; found: C, 67.73; H, 4.73; N, 11.46.
4-(4-Methylphenyl)-5-phenylpyrrolo(spiro[2.3″]oxindole)spiro[3.3′]-5′-(4-methylphenylmethylidene)
piperidin-4′-one (5i). Obtained as a pale yellow solid, (0.164 g, 92%); mp = 157–158 °C; IR (KBr):
1
1597, 1615, 1690, 3181, 3340 cm−1; H-NMR (300 MHz, CDCl3): δH 2.25 (s, 1H, CH3), 2.29 (s, 1H,

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CH3), 2.34 (d, 1H, J = 13.2 Hz, 2'-CH2), 3.50 (d, 1H, J = 15.0 Hz, 6'-CH2), 3.60 (d, 1H, J = 15.0 Hz,
6'-CH2), 3.70 (d, 1H, J = 13.2 Hz, 2'-CH2), 4.68 (d, 1H, J = 10.5 Hz, 4-CH), 5.40 (d, 1H, J = 10.5 Hz,
5-CH), 6.65 (d, 1H, J = 7.5 Hz, Ar-H), 6.76 (d, 1H, J = 7.8 Hz, Ar-H), 6.91 (d, 2H, J = 8.1 Hz, Ar-H),
13
6.97–7.30 (m, 12H, Ar-H), 7.52 (d, 2H, J = 6.9 Hz, Ar-H), 8.72 (s, 1H, 1"-NH). C-NMR (75 MHz,
CDCl3): δC 21.49, 21.77, 48.63, 50.03, 57.33, 64.90, 67.44, 72.62, 109.86, 122.53, 127.31, 127.95,
128.11, 128.76, 129.24, 129.42, 129.46, 130.17, 130.58, 132.73, 134.46, 134.73, 135.52, 136.76,
137.66, 139.52, 141.30, 141.69, 181.55, 200.83. Anal. calcd for C36H33N3O2: C, 80.12; H, 6.16; N,
7.79; found: C, 80.03; H, 6.24; N, 7.85.
4-(4-Methoxyphenyl)-5-phenylpyrrolo(spiro[2.3″]oxindole)spiro[3.3′]-5′-(4-methoxyphenylmethyl
idene)piperidin-4′-one (5j). Obtained as a pale yellow solid, (0.146 g, 86%); mp = 159–160 °C; IR
(KBr): 1598, 1620, 1710, 3179, 3347 cm−1; 1H-NMR (300 MHz, CDCl3): δH 2.44 (d, 1H, J = 13.8 Hz,
2'-CH2), 3.28–3.63 (m, 3H, 6'-CH2 and 2'-CH2), 3.66 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 4.89 (d, 1H,
J = 9.9 Hz, 4-CH), 5.74 (d, 1H, J = 9.9 Hz, 5-CH), 6.69–7.87 (m, 18H, Ar-H), 8.20 (s, 1H, 1"-NH).
13C-NMR (75 MHz, CDCl3): δC 48.53, 50.07, 55.42, 55.79, 57.46, 64.93, 67.51, 72.69, 110.35, 111.05,
111.11, 120.30, 120.50, 121.09, 122.86, 124.74, 127.38, 127.87, 128.07, 128.31, 128.84, 129.41,
130.52, 130.85, 131.03, 141.81, 158.52, 158.76, 181.22, 199.93. Anal. calcd for C36H33N3O4: C, 75.64;
H, 5.82; N, 7.35; found: C, 75.78; H, 5.93; N, 7.42.
4-(4-Chlorophenyl)-5-phenylpyrrolo(spiro[2.3″]oxindole)spiro[3.3′]-5′-(4-chlorophenylmethylidene)
piperidin-4′-one (5k). Obtained as a pale yellow solid, (0.151 g, 90%); mp = 154–155 °C; IR (KBr):
1
1598, 1618, 1711, 3179, 3338 cm−1; H-NMR (300 MHz, CDCl3): δH 2.09 (s, 1H, NH), 2.27 (d, 1H,
J = 13.2 Hz, 2'-CH2), 3.46–3.60 (m, 2H, 6'-CH2), 3.72 (d, 1H, J = 13.2 Hz, 2'-CH2), 4.67 (d, 1H,
J = 10.8 Hz, 4-CH), 5.35 (d, 1H, J = 10.8 Hz, 5-CH), 6.67 (d, 1H, J = 7.2 Hz, Ar-H), 6.77 (d, 1H,
13
J = 7.2 Hz, Ar-H), 6.90–7.54 (m, 16H, Ar-H), 8.49 (s, 1H, 1"-NH). C-NMR (75 MHz, CDCl3): δC
48.52, 50.03, 56.65, 64.81, 67.43, 72.25, 109.85, 122.58, 124.35, 127.32, 127.98, 128.34, 128.76,
128.87, 129.00, 129.31, 129.53, 131.57, 132.07, 133.16, 133.79, 135.25, 135.42, 136.33, 140.72,
141.61, 181.42, 200.18. Anal. calcd for C34H27Cl2N3O2: C, 70.35; H, 4.69; N, 7.24; found: C, 70.51; H,
4.80; N, 7.31.
4-(4-Bromophenyl)-5-phenylpyrrolo(spiro[2.3″]oxindole)spiro[3.3′]-5′-(4-bromophenylmethylidene)
piperidin-4′-one (5l). Obtained as a white solid, (0.142 g, 92%); mp = 166–167 °C; IR (KBr): 1597,
1615, 1705, 3174, 3340 cm−1; 1H-NMR (300 MHz, CDCl3): δH 2.08 (s, 1H, NH), 2.27 (d, 1H, J = 12.9 Hz,
2'-CH2), 3.46–3.79 (m, 3H, 6'-CH2 and 2'-CH2), 4.66 (d, 1H, J = 10.8 Hz, 4-CH), 5.34 (d, 1H, J = 10.8 Hz,
5-CH), 6.66–6.72 (m, 2H, Ar-H), 6.84 (d, 2H, J = 8.1 Hz, Ar-H), 6.93 (s, 1H, C=CH), 6.97–7.51 (m,
13
13H, Ar-H), 8.39 (s, 1H, 1"-NH). C-NMR (75 MHz, CDCl3): δC 48.52, 50.03, 56.67, 64.73, 67.43,
72.21, 109.84, 121.36, 122.59, 123.59, 127.98, 128.24, 128.88, 129.54, 129.77, 130.18, 131.77,
131.85, 131.97, 132.27, 134.23, 135.53, 136.37, 136.79, 140.69, 141.58, 181.33, 200.14. Anal. calcd
for C34H27Br2N3O2: C, 61.00; H, 4.07; N, 6.28; found: C, 61.17; H, 4.21; N, 6.35.
4-(4-Fluorophenyl)-5-phenylpyrrolo(spiro[2.3″]oxindole)spiro[3.3′]-5′-(4-fluorophenylmethylidene)
piperidin-4′-one (5m). Obtained as a pale yellow solid, (0.164 g, 93%); mp = 159–160 °C; IR (KBr):
1
1596, 1617, 1700, 3181, 3346 cm−1; H-NMR (300 MHz, CDCl3): δH 2.13 (s, 1H, NH), 2.28 (d, 1H,

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J = 13.2 Hz, 2'-CH2), 3.48 (d, 1H, J = 14.7 Hz, 6'-CH2), 3.58 (d, 1H, J = 14.7 Hz, 6'-CH2), 3.70 (d,
1H, J = 13.2 Hz, 2'-CH2), 4.67 (d, 1H, J = 10.5 Hz, 4-CH), 5.34 (d, 1H, J = 10.5 Hz, 5-CH), 6.68 (d,
2H, J = 7.5 Hz, Ar-H), 6.89–7.55 (m, 16H, Ar-H), 8.58 (s, 1H, 1"-NH). 13C-NMR (75 MHz, CDCl3):
δC 48.50, 50.05, 56.79, 65.10, 67.27, 72.40, 109.86, 115.56 (2JCF = 21.0 Hz), 115.88 (2JCF = 21.5 Hz),
122.56, 127.33, 127.99, 128.15, 128.83, 129.41, 129.46, 130.17, 131.76, 132.30, 133.43, 134.77,
136.55, 140.93, 141.65, 162.23 (1JCF = 244.1 Hz), 163.13 (1JCF = 248.9 Hz), 181.43, 200.42. Anal.
calcd for C34H27F2N3O2: C, 74.57; H, 4.97; N, 7.67; found: C, 74.69; H, 4.90; N, 7.76.
4-(1-Naphthyl)-5-phenylpyrrolo(spiro[2.3″]oxindole)spiro[3.3′]-5′-(1-naphthylmethylidene)piperidin-
4′-one (5n). Obtained as a yellow solid, (0.142 g, 87%); mp = 164–165 °C; IR (KBr): 1590, 1619,
1
1704, 3174, 3335 cm−1; H-NMR (300 MHz, CDCl3): δH 1.94 (s, 1H, NH), 2.07 (d, 1H, J = 12.9 Hz,
2'-CH2), 3.18–3.73 (m, 3H, 6'-CH2 and 2'-CH2), 5.58 (d, 1H, J = 9.9 Hz, 4-CH), 5.80 (d, 1H, J = 9.9 Hz,
5-CH), 6.71–8.06 (m, 24H, Ar-H), 8.50 (s, 1H, 1"-NH). 13C-NMR (75 MHz, CDCl3): δC 48.70, 50.15,
56.53, 64.71, 67.46, 72.20, 109.83, 122.96, 124.46, 125.04, 125.41, 126.45, 126.73, 127.12, 127.24,
127.58, 127.84, 127.98, 128.61, 128.82, 129.05, 129.20, 129.41, 129.99, 130.16, 132.41, 132.64,
133.24, 133.84, 134.84, 135.15, 135.62, 136.91, 137.01, 144.40, 181.38, 200.13. Anal. calcd for
C42H33N3O2: C, 82.46; H, 5.44; N, 6.87; found: C, 82.39; H, 5.56; N, 6.80.
Spiro[2.3″]oxindole-spiro[3.3′]-5′-(phenylmethylidene)-tetrahydro-4′(1H)-pyridinone-4-(phenyl)
hexahydro-1H-pyrrolizine (6a). Obtained as a white solid, (0.165 g, 94%); mp = 182–188 °C; IR
1
(KBr): 1610, 1618, 1706, 3390 cm−1; H-NMR (400 MHz, CDCl3): δH 1.60–1.69 (m, 1H, 5-CH2),
1.82–2.01 (m, 2H, 6-CH2), 2.04–2.14 (m, 1H, 5-CH2), 2.33 (d, 1H, J = 13.2 Hz, 2'-CH2), 2.60 (td, 1H,
J = 8.8, 2.4 Hz, 7-CH2), 3.07–3.13 (m, 1H, 7-CH2), 3.39 (d, 1H, J = 14.8 Hz, 6'-CH2), 3.62 (d, 1H,
J = 14.8 Hz, 6'-CH2), 3.96 (d, 1H, J = 13.2 Hz, 2'-CH2), 4.38 (d, 1H, J = 11.2 Hz, 4-CH), 4.62–4.70
(m, 1H, 4a-CH), 6.73 (d, 1H, J = 6.8 Hz, Ar-H), 6.94–7.02 (m, 3H, Ar-H), 7.15–7.31 (m, 9H, Ar-H
13
and arylmethylidene), 7.37 (d, 2H, J = 7.6 Hz, Ar-H), 8.87 (s, 1H, 1"-NH). C-NMR (100 MHz,
CDCl3): δC 26.28, 29.29, 48.13, 48.35, 49.30, 53.64, 66.52, 71.88, 74.81, 109.97, 121.78, 127.23,
128.62, 128.69, 128.93, 129.36, 129.39, 130.03, 130.14, 135.58, 136.18, 136.30, 137.95, 142.06, 180.06,
200.63. Anal. calcd for C31H29N3O2: C, 78.29; H, 6.15; N, 8.84%; found: C, 78.12; H, 6.33; N, 8.95%.
Spiro[2.3″]oxindole-spiro[3.3′]-5′-(2-methylphenylmethylidene)tetrahydro-4′(1H)-pyridinone-4-(2-
methylphenyl)hexahydro-1H-pyrrolizine (6b). Obtained as a white solid, (0.154 g, 93%); mp =
1
184–185 °C; IR (KBr): 1605, 1622, 1705, 3387 cm−1; H-NMR (300 MHz, CDCl3): δH 1.58–1.70 (m,
1H, 5-CH2), 1.78–2.04 (m, 3H, 6-CH2 and 5-CH2), 2.30 (s, 3H, CH3), 2.31 (s, 3H, CH3), 2.42 (d, 1H,
J = 12.9 Hz, 2'-CH2), 2.64 (td, 1H, J = 8.1, 3.0 Hz, 7-CH2), 3.09–3.17 (m, 1H, 7-CH2), 3.61 (dd, 1H,
J = 15.0, 2.1 Hz, 6'-CH2), 3.97 (d, 1H, J = 15.0 Hz, 6'-CH2), 4.19 (d, 1H, J = 12.9 Hz, 2'-CH2), 4.62
(d, 1H, J = 10.8 Hz, 4-CH), 4.82–4.86 (m, 1H, 4a-CH), 6.62 (d, 1H, J = 7.5 Hz, Ar-H), 6.87–7.25 (m,
13
10H, Ar-H), 7.53–7.63 (m, 2H, Ar-H and arylmethylidene), 8.03 (s, 1H, 1"-NH). C-NMR (75 MHz,
CDCl3): δC 20.39, 21.12, 26.08, 28.59, 47.19, 48.92, 49.22, 53.22, 65.83, 70.05, 74.73, 110.12, 122.47,
125.78, 125.95, 127.34, 128.61, 129.30, 129.42, 129.59, 130.62, 130.80, 131.13, 133.45, 134.52,
135.11, 136.61, 138.26, 138.77, 141.61, 180.74, 202.27. Anal. calcd for C33H33N3O2: C, 78.70; H,
6.60; N, 8.34%; found: C, 78.59; H, 6.76; N, 8.25%.

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Spiro[2.3″]oxindole-spiro[3.3′]-5′-(2-methoxyphenylmethylidene)tetrahydro-4′(1H)-pyridinone-4-(2-
methoxyphenyl)hexahydro-1H-pyrrolizine (6c). Obtained as a brown solid, (0.140 g, 88%); mp =
1
187–188 °C; IR (KBr): 1603, 1619, 1702, 3389 cm−1; H-NMR (300 MHz, CDCl3): δH 1.69–2.00 (m,
4H, 5-CH2 and 6-CH2), 2.62 (d, 1H, J = 12.9 Hz, 2'-CH2), 2.83 (td, 1H, J = 8.1, 3.0 Hz, 7-CH2),
3.30–3.43 (m, 1H, 7-CH2), 3.65 (s, 3H, OCH3), 3.71–3.81 (m, 1H, 6'-CH2), 3.85 (s, 3H, OCH3), 3.99–4.15
(m, 2H, 6'-CH2 and 2'-CH2), 4.64 (d, 1H, J = 10.8 Hz, 4-CH), 4.82–4.87 (m, 1H, 4a-CH), 6.62–7.37
(m, 12H, Ar-H and arylmethylidene), 7.51 (d, 1H, J = 7.2 Hz, Ar-H), 8.02 (s, 1H, 1"-NH). 13C-NMR
(75 MHz, CDCl3): δC 25.31, 27.97, 48.65, 49.36, 50.51, 54.02, 54.97, 55.88, 65.45, 70.05, 74.18,
110.51, 111.11, 111.17, 120.49, 120.90, 122.44, 125.24, 126.17, 128.17, 128.33, 129.61, 130.69,
130.84, 131.03, 132.16, 135.25, 135.58, 142.01, 158.02, 158.79, 180.27, 201.51. Anal. calcd for
C33H33N3O4: C, 74.00; H, 6.21; N, 7.84%; found: C, 74.21; H, 6.10; N, 7.98%.
Spiro[2.3″]oxindole-spiro[3.3′]-5′-(2-chlorophenylmethylidene)tetrahydro-4′(1H)-pyridinone-4-(2-
chlorophenyl)hexahydro-1H-pyrrolizine (6d). Obtained as a pale yellow solid, (0.145 g, 92%);
1
mp = 172–173 °C; IR (KBr): 1605, 1618, 1702, 3389 cm−1; H-NMR (300 MHz, CDCl3): δH 1.79–2.19
(m, 4H, 5-CH2 and 6-CH2), 2.39 (d, 1H, J = 12.9 Hz, 2'-CH2), 2.59–2.64 (m, 1H, 7-CH2), 3.22–3.28
(m, 1H, 7-CH2), 3.45–3.66 (m, 2H, 6'-CH2), 3.95 (d, 1H, J = 12.9 Hz, 2'-CH2), 4.55–4.60 (m, 1H,
4-CH), 4.82–4.87 (m, 1H, 4a-CH), 6.61–7.74 (m, 13H, Ar-H and arylmethylidene), 8.72 (s, 1H,
1"-NH). 13C-NMR (75 MHz, CDCl3): δC 25.81, 28.35, 48.10, 48.27, 48.81, 52.20, 64.19, 70.19, 74.78,
110.10, 122.62, 126.78, 126.86, 127.54, 128.74, 130.14, 130.54, 130.85, 131.06, 132.04, 132.92,
133.34, 133.60, 133.85, 135.47, 136.42, 136.66, 137.46, 141.69, 180.46, 201.23. Anal. calcd for
C31H27Cl2N3O2: C, 68.38; H, 5.00; N, 7.72%; found: C, 68.23; H, 5.17; N, 7.61%.
Spiro[2.3″]oxindole-spiro[3.3′]-5′-(2-bromophenylmethylidene)tetrahydro-4′(1H)-pyridinone-4-(2-
bromophenyl)hexahydro-1H-pyrrolizine (6e). Obtained as a light brown solid, (0.134 g, 92%);
1
mp = 164–165 °C; IR (KBr): 1604, 1619, 1700, 3391 cm−1; H-NMR (300 MHz, CDCl3): δH 1.67–2.14
(m, 4H, 5-CH2 and 6-CH2), 2.24–2.28 (m, 1H, 2'-CH2), 2.52–2.65 (m, 1H, 7-CH2), 3.22–3.29 (m, 1H,
7-CH2), 3.46–3.61 (m, 2H, 6'-CH2), 3.92 (d, 1H, J = 12.9 Hz, 2'-CH2), 4.55–4.60 (m, 1H, 4-CH), 4.80–4.90
(m, 1H, 4a-CH), 6.60 (d, 1H, J = 7.2 Hz, Ar-H), 6.76–7.655 (m, 11H, Ar-H and arylmethylidene), 7.75
13
(d, 1H, J = 7.2 Hz, Ar-H), 8.99 (s, 1H, 1"-NH). C-NMR (75 MHz, CDCl3): δC 25.75, 28.46, 47.89,
48.09, 48.61, 51.55, 64.19, 70.91, 75.32, 110.23, 122.47, 125.66, 127.39, 127.50, 127.61, 129.09,
130.68, 130.87, 131.06, 133.32, 133.54, 134.05, 134.64, 135.58, 135.68, 135.93, 136.27, 137.16,
141.84, 180.50, 201.21. Anal. calcd for C31H27Br2N3O2: C, 58.79; H, 4.30; N, 6.63%; found: C, 58.93;
H, 4.12; N, 6.75%.
Spiro[2.3″]oxindole-spiro[3.3′]-5′-(2-fluorophenylmethylidene)-tetrahydro-4′(1H)-pyridinone-4-(2-
fluorophenyl)hexahydro-1H-pyrrolizine (6f). Obtained as a white solid; mp = 198–199 °C; IR (KBr):
1
1606, 1620, 1703, 3392 cm−1; H-NMR (500 MHz, CDCl3): δH 1.65–1.72 (m, 1H, 5-CH2), 1.82–1.88
(m, 1H, 6-CH2), 1.99–2.13 (m, 2H, 6-CH2 and 5-CH2), 2.35 (d, 1H, J = 13.0 Hz, 2'-CH2), 2.62 (td, 1H,
J = 8.0, 2.0 Hz, 7-CH2), 3.31–3.36 (m, 1H, 7-CH2), 3.42–3.50 (m, 2H, 6'-CH2), 3.87 (d, 1H, J = 13.0 Hz,
2'-CH2), 4.64 (d, 1H, J = 10.5 Hz, 4-CH), 4.81–4.85 (m, 1H, 4a-CH), 6.72 (d, 1H, J = 7.5 Hz, Ar-H),
6.88 (t, 1H, J = 7.0 Hz, Ar-H), 6.96–7.04 (m, 4H, Ar-H), 7.12 (d, 1H, J = 8.0 Hz, Ar-H), 7.15 (d, 1H,

Molecules 2014, 19
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J = 8.0 Hz, Ar-H), 7.18 (s, 1H, arylmethylidene), 7.20–7.25 (m, 3H, Ar-H), 7.29 (d, 1H, J = 8.0 Hz,
13
Ar-H), 7.59 (t, 1H, J = 7.0 Hz, Ar-H), 8.74 (s, 1H, 1"-NH). C-NMR (125 MHz, CDCl3): δC 25.16,
28.59, 47.30, 47.87, 48.32, 49.88, 65.78, 69.35, 74.86, 109.50, 115.45 (2JCF = 18.0 Hz), 115.59
(2JCF = 17.0 Hz), 121.73, 123.10 (JCF = 10.0 Hz), 123.58 (JCF = 3.0 Hz), 123.96 (JCF = 3.0 Hz), 124.87
(JCF = 12.0 Hz), 126.08, 128.36 (123.10 (JCF = 7.0 Hz), 128.95, 129.22, 129.65 (JCF = 3.0 Hz), 130.36
(JCF =2.0 Hz), 130.48 (JCF =8.0 Hz), 130.76 (JCF = 4.0 Hz), 136.29, 141.62, 160.60 (1JCF = 200.0 Hz),
161.86 (1JCF = 196.0 Hz), 179.57, 199.06. Anal. calcd for C31H27F2N3O2: C, 72.78; H, 5.32; N, 8.21%;
found: C, 72.96; H, 5.51; N, 8.09%.
Spiro[2.3″]oxindole-spiro[3.3′]-5′-(2,4-chlorophenylmethylidene)tetrahydro-4′(1H)-pyridinone-4-(2,4-
chlorophenyl)hexahydro-1H-pyrrolizine (6g). Obtained as a pale yellow solid, (0.141 g, 95%);
1
mp = 210–211 °C; IR (KBr): 1604, 1620, 1702, 3391 cm−1; H-NMR (300 MHz, CDCl3): δH 1.73–2.29
(m, 4H, 5-CH2 and 6-CH2), 2.60 (d, 1H, J = 12.3 Hz, 2'-CH2), 2.64–2.79 (m, 1H, 7-CH2), 3.21–3.30
(m, 1H, 7-CH2), 3.52–3.68 (m, 1H, 6'-CH2), 3.97 (d, 1H, J = 15.6 Hz, 6'-CH2), 4.14 (d, 1H, J = 12.3 Hz,
2'-CH2), 4.54–4.60 (m, 1H, 4-CH), 4.83–4.89 (m, 1H, 4a-CH), 6.62–7.92 (m, 11H, Ar-H and
13
arylmethylidene), 8.75 (s, 1H, 1"-NH). C-NMR (75 MHz, CDCl3): δC 25.82, 28.51, 48.14, 48.54,
49.25, 52.23, 65.17, 70.21, 74.73, 110.29, 122.77, 127.23, 127.31, 128.37, 130.10, 130.30, 130.73,
130.87, 131.48, 131.68, 132.26, 132.59, 133.93, 135.49, 135.90, 136.34, 137.15, 141.75, 180.37, 201.14.
Anal. calcd for C31H25Cl4N3O2: C, 60.70; H, 4.11; N, 6.85%; found: C, 60.87; H, 4.23; N, 6.64%.
Spiro[2.3″]oxindole-spiro[3.3′]-5′-(3-nitrophenylmethylidene)tetrahydro-4′(1H)-pyridinone-4-(3-
nitrophenyl)hexahydro-1H-pyrrolizine (6h). Obtained as a pale yellow solid, (0.144 g, 93%);
mp = 204–205 °C; IR (KBr): 1608, 1621, 1707, 3386 cm−1; 1H-NMR (300 MHz, CDCl3): δH 1.58–2.02
(m, 4H, 5-CH2 and 6-CH2), 2.27 (d, 1H, J = 12.6 Hz, 2'-CH2), 2.60–2.63 (m, 1H, 7-CH2), 3.06–3.15
(m, 1H, 7-CH2), 3.46–3.51 (m, 1H, 6'-CH2), 3.62 (d, 1H, J = 14.7 Hz, 6'-CH2), 4.01 (d, 1H, J = 12.6 Hz,
2'-CH2), 4.48 (d, 1H, J = 10.8 Hz, 4-CH), 4.65–4.73 (m, 1H, 4a-CH), 6.70–8.25 (m, 13H, Ar-H and
13
arylmethylidene), 9.10 (s, 1H, 1"-NH). C-NMR (75 MHz, CDCl3): δC 26.10, 29.10, 48.13, 48.86,
49.07, 51.06, 63.20, 71.89, 74.04, 110.72, 122.78, 123.02, 123.99, 124.68, 125.03, 125.41, 125.90,
127.47, 129.68, 130.04, 133.91, 135.68, 136.30, 136.93, 137.33, 137.90, 141.92, 148.45, 148.61,
180.54, 201.06. Anal. calcd for C31H27N5O6: C, 65.83; H, 4.81; N, 12.38%; found: C, 65.69; H, 4.94;
N, 12.47%.
Spiro[2.3″]oxindole-spiro[3.3′]-5′-(4-methylphenylmethylidene)tetrahydro-4′(1H)-pyridinone-4-(4-
methylphenyl)hexahydro-1H-pyrrolizine (6i). Obtained as a brown solid, (0.156 g, 94%); mp =
1
168–169 °C; IR (KBr): 1611, 1623, 1704, 3392 cm−1; H-NMR (300 MHz, CDCl3): δH 1.60–2.03 (m,
4H, 5-CH2 and 6-CH2), 2.29 (d, 1H, J = 12.9 Hz, 2'-CH2), 2.36 (s, 3H, CH3), 2.38 (s, 3H, CH3), 2.58–2.63
(m, 1H, 7-CH2), 3.10–3.16 (m, 1H, 7-CH2), 3.49 (d, 1H, J = 15.3 Hz, 6'-CH2), 3.78 (d, 1H, J = 15.3 Hz,
6'-CH2), 3.99–4.03 (m, 1H, 2'-CH2), 4.36 (d, 1H, J = 11.7 Hz, 4-CH), 4.50–4.55 (m, 1H, 4a-CH), 6.66
(d, 1H, J = 7.5 Hz, Ar-H), 6.84–7.54 (m, 12H, Ar-H and arylmethylidene), 8.56 (s, 1H, 1"-NH). 13C-NMR
(75 MHz, CDCl3): δC 21.3, 21.8, 26.07, 28.83, 48.50, 48.78, 49.35, 53.42, 65.96, 71.84, 74.06, 110.25,
122.61, 126.02, 129.33, 129.66, 129.74, 130.51, 131.01, 131.04, 132.11, 132.78, 135.12, 136.49,

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136.97, 139.82, 141.96, 181.00, 202.06. Anal. calcd for C33H33N3O2: C, 78.70; H, 6.60; N, 8.34%;
found: C, 78.84; H, 6.42; N, 8.42%.
Spiro[2.3″]oxindole-spiro[3.3′]-5′-(4-methoxyphenylmethylidene)tetrahydro-4′(1H)-pyridinone-4-(4-
methoxyphenyl)hexahydro-1H-pyrrolizine (6j). Obtained as a brown solid, (0.135 g, 85%); mp =
1
204–205 °C; IR (KBr): 1610, 1623, 1703, 3394 cm−1; H-NMR (300 MHz, CDCl3): δH 1.58–2.05 (m,
4H, 5-CH2 and 6-CH2), 2.32 (d, 1H, J = 12.6 Hz, 2'-CH2), 2.57–2.65 (m, 1H, 7-CH2), 3.08–3.15 (m,
1H, 7-CH2), 3.48 (d, 1H, J = 15.3 Hz, 6'-CH2), 3.62 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 3.82 (d, 1H,
J = 15.3 Hz, 6'-CH2), 3.97–4.06 (m, 1H, 2'-CH2), 4.38 (d, 1H, J = 11.4 Hz, 4-CH), 4.52–4.56 (m, 1H,
13
4a-CH), 6.65–7.54 (m, 13H, Ar-H and arylmethylidene), 8.52 (s, 1H, 1"-NH). C-NMR (75 MHz,
CDCl3): δC 26.12, 28.86, 47.50, 48.18, 49.63, 53.13, 55.20, 55.31, 64.41, 70.34, 74.39, 110.12, 113.45,
113.92, 122.64, 127.42, 127.86, 129.51, 130.57, 132.21, 132.98, 137.44, 141.53, 158.33, 159.85, 181.03,
201.06. Anal. calcd for C33H33N3O4: C, 74.00; H, 6.21; N, 7.84%; found: C, 74.26; H, 6.14; N, 7.76%.
Spiro[2.3″]oxindole-spiro[3.3′]-5′-(4-chlorophenylmethylidene)tetrahydro-4′(1H)-pyridinone-4-(4-
chlorophenyl)hexahydro-1H-pyrrolizine (6k). Obtained as a pale yellow solid, (0.150 g, 95%);
mp = 175–176 °C; IR (KBr): 1610, 1621, 1703, 3387 cm−1; 1H-NMR (300 MHz, CDCl3): δH 1.56–2.04
(m, 4H, 5-CH2 and 6-CH2), 2.29 (d, 1H, J = 12.9 Hz, 2'-CH2), 2.58–2.62 (m, 1H, 7-CH2), 3.07–3.15
(m, 1H, 7-CH2), 3.49 (d, 1H, J = 15.6 Hz, 6'-CH2), 3.76 (dd, 1H, J = 15.6, 2.1 Hz, 6'-CH2), 4.05–4.16
(m, 1H, 2'-CH2), 4.35 (d, 1H, J = 11.4 Hz, 4-CH), 4.51–4.56 (m, 1H, 4a-CH), 6.68 (d, 1H, J = 7.8 Hz,
13
Ar-H), 6.88–7.55 (m, 12H, Ar-H and arylmethylidene), 8.66 (s, 1H, 1"-NH). C-NMR (75 MHz,
CDCl3): δC 26.08, 28.96, 48.29, 48.85, 49.20, 53.41, 63.99, 71.86, 74.04, 110.43, 122.84, 125.96,
128.03, 128.82, 129.21, 129.29, 131.73, 132.07, 132.11, 133.63, 133.88, 135.37, 135.49, 136.05,
141.85, 180.74, 201.55. Anal. calcd for C31H27Cl2N3O2: C, 68.38; H, 5.00; N, 7.72%; found: C, 68.59;
H, 5.15; N, 7.60%.
Spiro[2.3″]oxindole-spiro[3.3′]-5′-(4-bromophenylmethylidene)tetrahydro-4′(1H)-pyridinone-4-(4-
bromophenyl)hexahydro-1H-pyrrolizine (6l). Obtained as a pale yellow solid, (0.136 g, 93%);
mp = 207–208 °C; IR (KBr): 1612, 1619, 1702, 3389 cm−1; 1H-NMR (300 MHz, CDCl3): δH 1.52–2.07
(m, 4H, 5-CH2 and 6-CH2), 2.29 (d, 1H, J = 13.2 Hz, 2'-CH2), 2.58–2.62 (m, 1H, 7-CH2), 3.06–3.14
(m, 1H, 7-CH2), 3.47 (d, 1H, J = 15.6 Hz, 6'-CH2), 3.75 (dd, 1H, J = 15.6, 2.1 Hz, 6'-CH2), 4.05–4.15
(m, 1H, 2'-CH2), 4.33 (d, 1H, J = 11.1 Hz, 4-CH), 4.51–4.56 (m, 1H, 4a-CH), 6.69 (d, 1H, J = 7.8 Hz,
13
Ar-H), 6.81–7.55 (m, 12H, Ar-H and arylmethylidene), 8.60 (s, 1H, 1"-NH). C-NMR (75 MHz,
CDCl3): δC 26.10, 28.98, 48.35, 48.76, 49.25, 53.28, 64.98, 71.85, 74.12, 110.41, 121.80, 122.84,
123.92, 128.06, 129.83, 131.64, 131.77, 131.92, 132.17, 132.25, 132.39, 134.32, 135.44, 136.23,
141.81, 180.70, 201.52. Anal. calcd for C31H27Br2N3O2: C, 58.79; H, 4.30; N, 6.63%; found: C, 58.96;
H, 4.47; N, 6.51%.
Spiro[2.3″]oxindole-spiro[3.3′]-5′-(4-fluorophenylmethylidene)tetrahydro-4′(1H)-pyridinone-4-(4-
fluorophenyl)hexahydro-1H-pyrrolizine (6m). Obtained as a pale yellow solid, (0.154 g, 94%);
mp = 192–193 °C; IR (KBr): 1611, 1620, 1701, 3390 cm−1; 1H-NMR (500 MHz, CDCl3): δH 1.50–2.03
(m, 4H, 5-CH2 and 6-CH2), 2.30 (d, 1H, J = 13.5 Hz, 2'-CH2), 2.57–2.65 (m, 1H, 7-CH2), 3.03–3.12
(m, 1H, 7-CH2), 3.37 (d, 1H, J = 15.0 Hz, 6'-CH2), 3.77 (d, 1H, J = 15.0, 2.1 Hz, 6'-CH2), 4.06–4.13

Molecules 2014, 19
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(m, 1H, 2'-CH2), 4.36 (d, 1H, J = 11.0 Hz, 4-CH), 4.52–4.55 (m, 1H, 4a-CH), 6.61–7.54 (m, 13H, Ar-H
13
and arylmethylidene), 8.62 (s, 1H, 1"-NH). C-NMR (125 MHz, CDCl3): δC 25.67, 28.54, 47.84,
48.47, 48.70, 52.83, 64.51, 69.60, 74.93, 109.99, 115.12 (2JCF = 20.0 Hz), 115.80 (2JCF = 21.25 Hz),
122.41, 125.59, 127.73, 128.70, 130.40, 131.71, 132.13, 132.52, 133.61, 135.17, 141.52, 161.95
(1JCF = 245.0 Hz), 163.01 (1JCF =250.0 Hz), 180.62, 201.19. Anal. calcd for C31H27F2N3O2: C, 72.78;
H, 5.32; N, 8.21%; found: C, 72.92; H, 5.54; N, 8.04%.
Spiro[2.3″]oxindole-spiro[3.3′]-5′-(1-naphthylmethylidene)tetrahydro-4′(1H)-pyridinone-4-(1-
naphthyl)hexahydro-1H-pyrrolizine (6n). Obtained as a yellow solid, (0.139 g, 91%); mp = 158–159 °C;
1
IR (KBr): 1607, 1619, 1705, 3391 cm−1; H-NMR (300 MHz, CDCl3): δH 1.82–2.09 (m, 4H, 5-CH2
and 6-CH2), 2.65–2.68 (m, 1H, 7-CH2), 2.78 (d, 1H, J = 12.9 Hz, 2'-CH2), 3.30–3.35 (m, 1H, 7-CH2),
3.44 (d, 1H, J = 15.6 Hz, 6'-CH2), 3.87 (d, 1H, J = 15.6 Hz, 6'-CH2), 4.22 (d, 1H, J = 12.6 Hz, 2'-CH2),
4.44–4.50 (m, 1H, 4-CH), 4.68–4.73 (m, 1H, 4a-CH), 6.27 (s, 1H, arylmethylidene), 6.41–8.07 (m,
13
18H, Ar-H), 9.02 (s, 1H, 1"-NH). C-NMR (75 MHz, CDCl3): δC 25.99, 28.74, 48.00, 48.68, 49.30,
51.14, 64.58, 70.98, 75.04, 110.30, 122.63, 124.62, 125.05, 125.30, 125.45, 125.75, 126.77, 127.16,
127.59, 127.91, 128.20, 128.85, 129.08, 129.22, 129.39, 129.64, 130.05, 132.45, 132.48, 133.64,
133.70, 133.96, 134.46, 134.90, 136.90, 137.73, 138.82, 141.09, 181.13, 202.63. Anal. calcd for
C39H33N3O2: C, 81.37; H, 5.78; N, 7.30%; found: C, 81.59; H, 5.60; N, 7.43%.
3.5. Cell Culture and Cell Proliferation Assay
3.5.1. Cell Culture
Human ovarian adenocarcinoma cell line (SK-OV-3, ATCC no. HTB-77), human breast carcinoma
(MDA-MB-231, ATCC no. HTB-26), and human lymphoblastic leukemia cell line (CCRF-CEM,
ATCC no. CCL-119) obtained from American Type Culture Collection. The cells were grown on 75 cm2
cell culture flasks with RPMI-16 medium for CCRF-CEM cells and EMEM (Eagle’s minimum
essential medium) for SK-OV-3 and MDA-MB-231 cells, and supplemented with 10% fetal bovine
serum, and 1% penicillin/streptomycin solution (10,000 units of penicillin and 10 mg of streptomycin
in 0.9% NaCl) in a humidified atmosphere of 5% CO2, 95% air at 37 °C.
3.5.2. Cell Proliferation Assay
The cell proliferation assay was carried out using CellTiter 96 aqueous one solution cell proliferation
assay kit (Promega, Madison, WI, USA). Briefly, upon reaching about 75%–80% confluency, SK-OV-3
(5,000 cells/well), MDA-MB-231 (5,000 cells/well), or CCRF-CEM (40,000 cells/well) were plated in
96-well microplate in 100 µL media. After seeding for 24 h, the cells were treated with 50 µM
compound in triplicate. Doxorubicin (10 µM) was used as the positive control. At the end of the
sample exposure period (72 h), CellTiter 96 aqueous solution (20 µL) was added. The plate was
returned to the incubator for 1 h in a humidified atmosphere at 37 °C. The absorbance of the formazan
product was measured at 490 nm using a microplate reader. The blank control was recorded by
measuring the absorbance at 490 nm with wells containing medium mixed with CellTiter 96 aqueous
solution but no cells. Results were expressed as the percentage of the control (without compound set at

Molecules 2014, 19
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100%). The percentage of cell survival was calculated as [OD value of cells treated with the test
compound − OD value of culture medium]/[(OD value of control cells − OD value of culture
medium)] × 100%.
3.5.3. IC50 Determination Assay
IC50 determination assay was performed by CellTiter 96 aqueous one solution cell proliferation
assay kit (Promega). Briefly, SK-OV-3 (5,000 cells/well) and CCRF-CEM (40,000 cells/well) were
seeded in 96-well plate in media (100 µL). After 24 h, the cells were treated with various
concentrations of compounds (1–100 µM) in triplicate. After 72 h of incubation, 20 µL CellTiter 96
aqueous solution was added to wells. The plate was kept in the incubator for 1 h in a humidified
atmosphere at 37 °C. The absorbance of the formazan product was measured at 490 nm using
microplate reader. The blank control was recorded by measuring the absorbance at 490 nm with wells
containing medium mixed with CellTiter 96 aqueous solution but no cells. The IC50 values were
extrapolated from concentration–effect curves using non-linear regression analysis in GraphPad
Prism®, version 5.03.
4. Conclusions
In conclusion, azomethine ylides generated via an in situ reaction between 1H-indole-2,3-dione
with N-methylglycine, phenylglycine, or proline underwent [3+2]-cycloaddition with 3,5-bis[(E)-
arylmethylidene]tetrahydro-4(1H)-pyridinones to afford different classes of spiropyrrolidines/pyrrolizines.
A number of compounds exhibited antiproliferative activity against MDA-MB-231, CCRF-CEM, and
SK-OV-3 cells. In general, most of the spiro-pyrrolizines derivatives showed higher antiproliferative
activity when compared with N-methyl spiro-pyrrolidines and N-α-phenyl substituted spiro-pyrrolidines
derivatives. Compounds 6a, 6b, and 6m were found to be the most potent derivatives showing
64%, 87%, and 74% antiproliferative activity in MDA-MB-231, SK-OV-3, and CCRF-CEM cells,
respectively. These lead compounds will be studied for their stereochemistry properties and have the
potential as antiproliferative agents after further optimization.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/19/7/10033/s1.
Acknowledgments
We thank National Center for Research Resources, NIH, and Grant Number and Grant Number 8
P20 GM103430-12 for sponsoring the core facility. The authors acknowledge the Deanship of
Scientific Research at King Saud University for the Research Grant RGP-VPP-026.
Author Contributions
The contributions of the respective authors are as follows: R.K., F.B., H.O., R.I., T.S.C.,A.I.A.,
AND M.A.A. design and synthesis of compounds and A.S., B.S., K.M., A.N., and K.P. performed
cell-based assays and provide SAR. The manuscript was written by K.P., M.A.A., and A. S.

Molecules 2014, 19
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Conflicts of Interest
The authors declare no conflict of interest.
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