A facile synthesis of functionalized dispirooxindole derivatives via a three-component 1,3-dipolar cycloaddition reaction

Article abstract of DOI:10.3390/molecules18055142

An efficient synthesis of novel dispirooxindoles has been achieved through three-component 1,3-dipolar cycloaddition of azomethine ylides generated in situ by the decarboxylative condensation of isatin and an α-amino acid with the dipolarophile 5-benzylid

Full text of DOI:10.3390/molecules18055142

Molecules 2013, 18, 5142-5154; doi:10.3390/molecules18055142
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
A Facile Synthesis of Functionalized Dispirooxindole Derivatives
via a Three-Component 1,3-Dipolar Cycloaddition Reaction
Jun He 1,†, Guang Ouyang 2,†, Zhixiang Yuan 3, Rongsheng Tong 2, Jianyou Shi 2,* and
Liang Ouyang 1,*
1
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University,
Chengdu 610041, China
2
Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital,
Chengdu 610072, China
3
Institute of Pharmacy, Sichuan Academy of Chinese Medicine Sciences, Chengdu 610041, China
†
These authors contributed equally to this work.
* Authors to whom correspondence should be addressed; E-Mails: shijianyoude@126.com (J.S.);
ouyangliang@scu.edu.cn (L.O.); Tel.: +86-028-8739-3234 (J.S.); Fax: +86-028-8550-3817 (L.O.).
Received: 3 April 2013; in revised form: 26 April 2013 / Accepted: 27 April 2013 /
Published: 3 May 2013
Abstract: An efficient synthesis of novel dispirooxindoles has been achieved through
three-component 1,3-dipolar cycloaddition of azomethine ylides generated in situ by the
decarboxylative condensation of isatin and an α-amino acid with the dipolarophile
5-benzylideneimidazolidine-2,4-dione. The improved procedure features mild reaction
conditions, high yields, high diastereoselectivities, a one-pot procedure and operational
simplicity.
Keywords: multicomponent reactions; 1,3-dipolar cycloaddition; azomethine ylide;
dispirooxindole
1. Introduction
Nowadays, conventional one-pot, multicomponent reactions (MCRs) are considered to be one of
the most efficient strategies in organic and medical chemistry for synthesizing structurally diverse
compounds and biologically active natural products, usually in a stereoselective-manner [1]. The

Molecules 2013, 18
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highly effective one-pot procedure of MCRs exhibits many advantages, including atom economy,
facile synthesis, convergence, productivity and easy execution [2]. MCRs were a common method for
building molecular diversities with complex scaffolds and had broad applications in combinatorial
chemistry, which allowed a rapid access to identify a promising lead molecule in drug candidate
discovery [3–5].
The 1,3-dipolar cycloaddition of azomethine ylides with olefinic and acetylenic dipolarophiles is
one of the most useful MCRs for providing an useful approach to building nitrogen-containing five-
membered ring heterocycles, such as pyrroline, pyrrolidine, pyrrolizidine or spirooxindole
derivatives [6–9], which served as useful molecular scaffolds for the exploration and exploitation of
pharmacophore space via diversity-oriented synthesis [10–13]. Among of them, dispirooxindole ring
systems possess more interesting structural properties and have been reported to exhibit strong
bioactivity profiles including antimicrobial [14], antitumoral [15], anti-inflammatory [16], anti-HIV [17]
and potent non-peptide inhibition of the p53–MDM2 interaction [18].
Hydantoin derivatives are widely used in malignant hyperthermia, neuroleptic malignant syndrome,
spasticity, and anticonvulsants [19–22], especially the spirohydantoins, which are considered to be a
novel aldose reduetase inhibitor to treat for diabetes [23]. Significant efforts have been focused on
developing a general synthetic route to access those compounds. However, to the best of our
knowledge, only a few methods were reported to synthesize the spiropyrrolidine bisoxindoles [24,25],
and a general method to prepare dispirooxindole hydantoin derivatives is still lacking. Thus, in order to
extend our interest in cycloaddition reactions of novel spiro compounds and nitrogen heterocycles with
biological activities [26–28], we report herein the efficient synthesis in excellent yields of a series of
novel dispirooxindole derivatives by the three-component 1,3-dipolar cycloaddition reaction of
nonstabilized azomethine ylides generated in situ by the decarboxylative condensation of isatin and
primary α-amino acid with the Knoevenagel adduct derivatives (preformed by reaction of hydantoin
with substituted benzaldehydes).
2. Results and Discussion
In our initial endeavor, the Knoevenagel adducts 3 were synthesized via a method involving
condensation of commercially available hydantoin and substituted benzaldehydes in water using
ethanolamine as catalyst. After work-up, the crude reaction mixtures were purified by recrystallization
in ethanol/water (40:60) to afford 63-99% total yields of the target products (Scheme 1). Melting point,
NMR and mass spectrometry data were consistent with those reported in the literature [29].
Scheme 1. The synthetic route to compounds 3.
R3
HN
HN
Ethanolamine
CHO
R3 = Ph
= 3,4-Cl2C6H3
+
R3
O
O
O
O
H2O
N
N
H
H
= 4-BrC6H4
= 3-ClC6H4
= 4-CF3C6H4
= 3-OCH3C6H4
63%-99%
3

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From the mechanistic perspective, the azomethine ylides, a powerful class of reagents, have
featured in a number of 1,3-dipolar cycloaddition reactions. In combination with the experiences from
our previous work, we envisaged that an azomethine ylide could be generated in situ from isatin (1a)
and L-proline (2a), and then trapped with Knoevenagel adduct 5-benzylideneimidazolidine-2,4-dione (3a)
acting as dipolarophile, to afford spiropyrrolizidine oxindole 4a. Hence, the 1,3-dipolar cycloaddition
reaction would be facilitated in one-pot with two steps. Although the azomethine ylides, generated
from the reaction of isatin and L-proline, have two nucleophilic carbons potentially resulting in two
regioisomers. However, high regioselectivity was observed in the formation of the product (see
below). It may resulted from the more stable transition state (Inta) leading to the observed products
(4a). Meanwhile, the other possible one (Intb) would be less stable because of steric interactions
between the aryl ring of Knoevenagel adducts and isatin backbone (Scheme 2).
Scheme 2. Possible reaction mechanism for the synthesis of dispirooxindole hydantoin
derivatives.

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In an effort to identify the reaction parameters of this one-pot process, the three-component reaction
of isatin, L-proline and 5-benzylideneimidazolidine-2,4-dione was carried out as model reaction.
Firstly, various solvents were examined under 80 °C，and the results were summarized in Table 1.
Acetonitrile and ether solvents such as dioxane and THF gave moderate yields (entries 1–3), and with
toluene as solvent, a poor yield resulted (entry 4). To our delight, the alcohol solvent methanol gave
promising yields, and ethanol afforded even better results (entries 5–6). Ethanol may facilitate the
production of the azomethine ylide by accelerating the formation of an iminium species between isatin
and L-proline. Then the reaction temperature, mixed solvent and time were further investigated, the
desired product was finally obtained as a single regioisomer in almost quantitative yield (95%) after 10
hours at 50 °C (entries 7–9). Consequently, we chose these conditions for the rest of our studies.
Table 1. Optimization of reaction conditions a.
Entry
Solvent
1,4-dioxane
THF
Temp (°C)
Yield b (%)
1
80
33
42
31
17
57
68
55
74
95
2
80
3
CH3CN
80
4
Toluene
Methanol
Ethanol
80
5
reflux
80
6
7
Ethanol/H2O
Ethanol
100
50
8
9 c
Ethanol
50
a Unless indicated otherwise, the reaction was performed with 3a (0.5 mmol), 1a isatin (0.5 mmol), and
b
L-proline (0.5 mmol) in different solvents (10.0 mL) and temperatures for 5 h. Isolated yield based on
isatin. c 10 h.
With the optimized reaction conditions in hand, various structurally diverse 5-benzyli-
deneimidazolidine-2,4-diones 3 were investigated. Gratifyingly, the corresponding spiro-pyrrolidine
products 4a–4m were obtained as single diastereoisomers in high yields. As shown in Table 2,
different substitutents on the aryl ring, such as bromo, chloro, CF3 and OCH3 groups at the meta or
para positons all gave corresponding products 4e, 4i, 4l and 4m in high yields ranging from 85% to
90% (entries 5, 9, 12 and 13). Furthermore, different substituents in the isatin such as 5-F, -Cl or -Br
also reacted smoothly to generate the desired products in high yields (entries 3, 6, 7 and 10). More
interestingly, the unprotected isatin gave even better results (entry 1 vs. 2), which opens a door to
further functionalize the products in future medicinal chemistry studies.
We also studied the cycloaddition reaction of the different amino acid thioproline 2b, wbereby the
reaction between isatin 1, 2b and 3 happened smoothly to afford the desired spirothiopyrrolidine 4n as
a single diastereoisomer in 90% yield (Scheme 3).

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Table 2. Scope of the reaction.
R3
R3
O
O
R2
HN
N
NH
Ethanol
50 oC
COOH
O
R2
+
+
N
O
O
N
R1
HN
O
N
H
H
O
N
R1
4a-4m
2a
3
1
Entry 1
3
4
Yield (%)
1
2
3
4
R1 = R2 = H
R3 = Ph
R3 = Ph
R3 = Ph
4a
4b
4c
4d
93
89
92
83
R1 = CH2C6H4, R2 = H
R1 = H, R2 = Br
R1 = CH2C6H4, R2 = H
R1 = R2 = H
R3 = 3,4-Cl2C6H3
5
6
7
8
9
10
11
R1 = H, R2 = F
R3 = 4-BrC6H4
R3 = Ph
R3 = Ph
4e
4f
4g
4h
4i
90
91
84
95
88
93
89
R1 = H, R2 = Cl
R1 = CH3, R2 = H
R1 = R2 = H
R1 = H, R2 = Cl
R1 = CH2C6H4, R2 = H
R1 = H R2 = H
R3 = Ph
R3 = 3-ClC6H4
R3 = 3-ClC6H4
R3 = 3-ClC6H4
4j
4k
R1 = H R2 = H
12
13
R3 = 4-CF3C6H4
R3 = 4-OCH3C6H4
4l
4m
85
82
Scheme 3. MCRs of thioproline 2b.
To further confirm the structure, diastereoselectivity and regioselectivity, detailed NMR spectral
and X-ray analyses were carried out. The structures proposed for all products were in agreement with
their NMR spectra, as discussed for compound 4b as an example In the 1H-NMR spectrum of 4b, the
pyrrolidine ring proton of C-5 exhibited a multiplet (m) peak at δ 4.48 (m, 1H). The C-4 proton which
was attached to the aryl group appeared as a doublet at δ 3.77 (d, J = 10.3 Hz, 1H). The aromatic
protons were distributed in the δ 7.41–6.24 region. The NH proton appeared as a singlet at δ 8.37 and δ
10.37. Based on the calculation of the coupling constant (J-based configuration analysis, J > 10 Hz),
the relative configuration of this structure should be as same as compound 4b shown in Figure 1 and
the configuration was further confirmed by the X-ray study of a single crystal of compound 4b (Figure 1b).
The results revealed that the pyrrolidine ring adopted an envelope form with the spiro carbon being out
of plane. The 13C-NMR of compound 4b supported the proposed structure as well. The pyrrolidine ring
carbons resonated in the δ 67.67 ppm region. The carbonyl carbon resonated at δ 154.93 ppm,
respectively.

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1
Figure 1. (a) Selected H- and 13C-NMR chemical shifts of 4b. (b) Single crystal
X-ray diffraction study of compound 4b.
The regioselectivity in formation of 4 can be explained by considering the secondary orbital
interaction (SOI) mechanism proposed in Scheme 4 [30]. The reaction proceeds through the generation
of azomethine ylide via the condensation of isatin with L-proline and decarboxylation. The
dipolarophile 3 regioselectively reacts with azomethine ylides in ethanol to give the desired products
compounds 4. The X-ray structure of the product 4b reflects that the cycloaddition proceeds via an
exo’-transition state (Scheme 4, path B). This can be explained by the fact that the corresponding
endo’-transition state (A) would require more free energy of activation than the exo’-transition state (B)
leading to 4a as the former would result in electrostatic repulsion between the cis carbonyls increasing
the free energy of activation. Accordingly, the observed regioisomer 4 via path B is more favorable
because of the SOI which is not possible in path A [31].
Scheme 4. Plausible mechanism for the formation of compound 4.

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3. Experimental
3.1. General
All reagents were purchased from commercial sources and used without further purification.
1
Melting points are corrected. H-NMR spectra were determined on a Bruker Avance III 400MHz
spectrometer in DMSO-d6 solution. J values are in Hz. Chemical shifts are expressed in ppm downfield
from internal standard TMS. HRMS data were obtained using Bruker micrOTOF-Q instrument or TOF-MS
instrument. The starting compounds 3 were prepared according to the previously reported procedures.
3.2. General Procedure for the Synthesis of Dispirooxindoles 4
A dry 50 mL flask was charged with istain derivatives 1(0.5 mmol), L-proline, L-thioproline 2a or
2b (0.5 mmol), and imidazolidin-2-one derivatives 3 (0.5 mmol), and ethanol (10 mL). The mixture
was stirred at 50 °C for 10 h. After completion of the reaction (monitored by TLC), the solvent was
cooled, then was filtrated and washed by 10 mL of ethanol twice to give solid. The solid was dried at
80 °C for 4h under vacuum to give compounds 4. The structures of the products were identified by
13
1H-NMR, C{1H}-NMR and HRMS spectra. The structure and regiochemistry of the products were
assigned on the basis of their spectroscopic analysis.
1-Phenylhexahydro-1H-pyrrolizine-2-spiro-5'-imidazolidine-2',4'-dione-3-spiro-3''-indoline-2''-one
1
(4a). White solid; m.p. 196–198 °C; H-NMR (DMSO-d6): δ (ppm) 1.56–1.69 (m, 1H, CH2),
1.73–2.06 (m, 3H, CH2), 2.81–2.95 (m, 1H, CH2), 3.70 (d, J = 10.3 Hz, 1H, CH), 4.31–4.52 (m, 1H,
CH), 6.80 (d, J = 7.6 Hz, 1H, ArH), 6.98–7.07 (m, 1H, ArH), 7.19–7.34 (m, 4H, ArH), 7.36 (d,
J = 7.1 Hz, 2H, ArH), 7.50 (d, J = 7.5 Hz, 1H, ArH), 8.10 (s, 1H, NH), 10.33 (s, 1H, NH), 10.42 (s,
1H, NH); 13C{1H}-NMR (DMSO-d6): δ 27.19, 29.56, 46.43, 55.99, 56.79, 67.50, 76.79, 79.47,
109.78, 120.98, 124.21, 127.36, 128.20, 128.32, 129.31, 129.66, 134.80, 154.93, 172.39, 176.38;
+
HRMS: calcd. for C22H20N4O3 [M+H]+: 389.1613, found: 389.1614.
1-Phenylhexahydro-1H-pyrrolizine-2-spiro-5'-imidazolidine-2',4'-dione-3-spiro-3''-N-benzylindoline-
1
2''-one (4b). White solid; m.p. 187–189 °C; H-NMR (DMSO-d6): δ (ppm) 1.51–1.73 (m, 1H, CH2),
1.75–2.10 (m, 3H, CH2), 2.81–2.92 (m, 1H, CH2). 3.77 (d, J = 10.3 Hz, 1H, CH), 4.33–4.41 (brs, 1H,
CH2), 4.43–4.53 (m, 1H, CH), 4.72 (d, J = 15.9 Hz, 1H, CH2), 5.05 (d, J = 15.9 Hz, 1H, CH2), 6.82 (d,
J = 7.7 Hz, 1H, ArH), 7.01–7.14 (m, 1H, ArH), 7.18–7.35 (m, 9H, ArH), 7.36–7.46 (d, J = 6.9 Hz, 2H,
ArH), 7.59 (d, J = 7.2 Hz, 1H, ArH), 8.37 (s, 1H, NH), 10.37 (s, 1H, NH); 13C{1H}-NMR (DMSO-d6):
δ 27.47, 29.67, 42.75, 46.49, 56.06, 67.67, 76.71, 79.78, 109.35, 121.77, 123.69, 126.96, 127.35,
127.51, 128.28, 128.31, 129.4, 129.78, 134.67, 136.12, 142.46, 154.93, 172.15, 174.95; HRMS: calcd.
+
for C29H26N4O3 [M+H]+: 479.2080, found: 479.2083.
1-Phenylhexahydro-1H-pyrrolizine-2-spiro-5'-imidazolidine-2',4'-dione-3-spiro-3''-5-bromoindoline-
1
2''-one (4c). White solid; m.p. 175–177 °C; H-NMR (DMSO-d6): δ (ppm) 1.57–1.70 (m, 1H, CH2),
1.75–2.08 (m, 3H, CH2), 2.73–2.90 (m, 1H, CH2 ), 3.66 (d, J = 10.5 Hz, 1H, CH), 4.34–4.46 (m, 1H,
CH), 6.75 (d, J = 8.3 Hz, 1H, ArH), 7.23–7.34 (m, 3H, ArH), 7.37 (d, J = 7.0 Hz, 2H, ArH), 7.45 (dd,
J = 8.3, 1.5 Hz, 1H, ArH), 7.60 (s, 1H, ArH), 8.29 (s, 1H, NH), 10.44 (s, 1H, NH), 10.59 (s, 1H, NH);

Molecules 2013, 18
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13C{1H}-NMR (DMSO-d6): δ 27.35, 29.52, 46.45, 56.74, 67.50, 76.87, 79.65, 111.79, 112.98, 126.70,
127.48, 128.24, 129.71, 130.67, 132.28, 134.55, 141.52, 154.85, 172.34, 175.93; HRMS: calcd. for
+
C22H19BrN4O3 [M+H]+: 467.0728, found: 467.0719.
1-(3,4-Dichloro)phenylhexahydro-1H-pyrrolizine-2-spiro-5'-imidazolidine-2',4'-dione-3-spiro-3''-N-
1
benzylindoline-2''-one (4d). White solid; m.p. 160–162 °C; H-NMR (DMSO-d6): δ (ppm) 1.53–1.67
(m, 1H, CH2), 1.68-1.80 (m, 1H, CH2), 1.95–2.11 (m, 2H, CH2), 2.62 (t, J = 7.2 Hz, 1H, CH2),
3.45–3.55 (m, 1H, CH2), 4.25 (d, J = 8.0 Hz, 1H, CH), 4.66–4.79 (m, 2H, 1/2CH2, CH), 5.05 (d,
J = 15.7 Hz, 1H, CH2), 6.84 (d, J = 7.8 Hz, 1H, ArH), 7.01–7.10 (m, 1H, ArH), 7.21–7.31 (m, 4H,
ArH), 7.34 (d, J = 7.1 Hz, 2H, ArH), 7.53 (dd, J = 8.4, 2.3 Hz, 2H, ArH), 7.63 (d, J = 2.2 Hz, 1H,
13
ArH), 7.87 (s, 1H, ArH), 7.98 (d, J = 8.6 Hz, 1H, ArH), 10.68 (s, 1H, NH); C{1H}-NMR (DMSO-
d6): δ 25.05, 29.22, 42.62, 47.58, 53.38, 68.27, 76.75, 78.47, 109.57, 122.27, 123.31, 127.42, 127.84,
128.47, 128.64, 130.04, 132.49, 132.63, 133.20, 135.48, 135.83, 143.65, 155.35, 174.80, 175.40;
HRMS: calcd. for C29H24Cl2N4O3 [M+H]+: 547.1300, found: 547.1304.
+
1-(4-Bromo)phenylhexahydro-1H-pyrrolizine-2-spiro-5'-imidazolidine-2',4'-dione-3-spiro-3''-indoline-
1
2''-one (4e). White solid; m.p. 222–224 °C; H-NMR (DMSO-d6): δ (ppm) 1.59–1.70 (m, 1H, CH2),
1.72–2.05 (m, 3H, CH2), 2.83–2.96 (m, 1H, CH2), 3.70 (d, J = 10.3 Hz, 1H, CH), 4.32–4.40 (m, 1H,
CH), 6.80 (d, J = 7.6 Hz, 1H, ArH), 6.97–7.06 (m, 1H, ArH), 7.19–7.28 (m, 1H, ArH), 7.33 (d, J = 8.5
Hz, 2H, ArH), 7.43–7.59 (m, 3H, ArH), 8.21 (s, 1H, NH), 10.41 (s, 1H, NH), 10.45 (s, 1H, NH);
13C{1H}-NMR (DMSO-d6): δ 27.13, 29.46, 46.52, 56.26, 67.60, 76.78, 79.40, 109.86, 120.86, 121.06,
124.13, 128.37, 129.44, 131.16, 131.92, 134.34, 142.22, 155.01, 172.46, 176.34; HRMS: calcd. for
+
C22H19BrN4O3 [M+H]+: 467.0718, found: 467.0719.
1-Phenylhexahydro-1H-pyrrolizine-2-spiro-5'-imidazolidine-2',4'-dione-3-spiro-3''-5-fluoroindoline-
1
2''-one (4f). White solid; m.p. 196–197 °C; H-NMR (DMSO-d6): δ (ppm) 1.59–1.74 (m, 1H, CH2),
1.76–1.94 (m, 2H, CH2), 1.95–2.071 (m, 1H, CH2), 2.72–2.83 (m, 1H, CH2), 3.71 (d,
J = 10.4 Hz, 1H, CH), 4.33–4.43 (m, 1H, CH), 6.79 (dd, J = 8.5, 4.6 Hz, 1H, ArH), 7.06–7.14 (m, 1H,
ArH), 7.22–7.33 (m, 3H, ArH), 7.34–7.43 (m, 3H, ArH), 8.35 (s, 1H, NH), 10.37 (s, 1H, NH), 10.43
13
(s, 1H, NH); C{1H}-NMR (DMSO-d6): δ 27.74, 29.63, 46.26, 56.35, 67.52, 77.11, 79.72, 110.45,
110.53, 115.71, 115.95, 116.21, 126.02, 126.10, 127.48, 128.19, 129.73, 134.60, 138.25, 154.89,
+
156.72, 158.62, 171.89, 176.34; HRMS: calcd. for C22H19FN4O3 [M+H]+: 407.1520, found: 407.1519.
1-Phenylhexahydro-1H-pyrrolizine-2-spiro-5'-imidazolidine-2',4'-dione-3-spiro-3''-5-chloroindoline-
1
2''-one (4g). White solid; m.p. 193–195 °C; H-NMR (DMSO-d6): δ (ppm) 1.56–1.71 (m, 1H, CH2),
1.76–1.95 (m, 2H, CH2), 1.96–2.06 (m, 1H, CH2), 2.76–2.87(m, 1H, CH2), 3.67 (d, J = 10.4 Hz, 1H,
CH), 4.32–4.44 (m, 1H, CH), 6.82 (d, J = 8.3 Hz, 1H, ArH), 7.22–7.34 (m, 4H, ArH), 7.33–7.41 (m,
2H, ArH), 7.49 (d, J = 1.9 Hz, 1H, ArH), 8.30 (s, 1H, NH), 10.42 (s, 1H, NH), 10.57 (s, 1H, NH);
13C{1H}-NMR (DMSO-d6): δ 27.50, 29.58, 46.42, 56.67, 67.53, 76.94, 79.70, 111.29, 125.25, 126.33,
127.51, 128.09, 128.25, 129.43, 129.73, 134.56, 141.09, 154.89, 172.24, 176.10; HRMS: calcd. for
+
C22H19ClN4O3 [M+H]+: 423.1225, found: 423.1224.

Molecules 2013, 18
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1-Phenylhexahydro-1H-pyrrolizine-2-spiro-5'-imidazolidine-2',4'-dione-3-spiro-3''-N-methylindoline-
1
2''-one (4h). White solid; m.p. 199–201 °C; H-NMR (DMSO-d6): δ (ppm) 1.58–1.71 (m, 1H, CH2),
1.73–2.09 (m, 3H, CH2), 2.80–2.93 (m, 1H, CH2), 3.10 (s, 3H,CH3), 3.74 (d, J = 10.4 Hz, 1H, CH),
4.38–4.50 (m, 1H, CH), 7.00 (d, J = 7.8 Hz, 1H, ArH), 7.06–7.16 (m, 1H, ArH), 7.22–7.43 (m, 6H,
ArH), 7.57 (d, J = 7.5 Hz, 1H, ArH), 8.18 (s, 1H, NH), 10.34 (s, 1H, NH), 13C{1H}-NMR (DMSO-d6):
δ 26.29, 27.28, 29.61, 46.53, 57.04, 67.59, 76.57, 79.58, 108.79, 121.74, 123.65, 127.48, 128.03,
+
128.28, 129.54, 129.74, 134.78, 143.63, 154.92, 172.40, 174.69; HRMS: calcd. for C23H22N4O3
[M+H]+: 403.1767, found: 403.1770.
1-(3-Chloro)phenylhexahydro-1H-pyrrolizine-2-spiro-5'-imidazolidine-2',4'-dione-3-spiro-3''-indoline-
1
2''-one (4i). White solid; m.p. 156–128 °C; H-NMR (DMSO-d6): δ (ppm) 1.58–1.71 (m, 1H, CH2),
1.74–7.97 (m, 3H, CH2), 2.79–2.91 (m, 1H, CH2), 3.74 (d, J = 10.3 Hz, 1H, CH), 4.31–4.44 (m, 1H,
CH), 6.80 (d, J = 7.7 Hz, 1H, ArH), 6.95–7.07 (m, 1H, ArH), 7.15–7.28 (m, 1H, ArH), 7.29–7.40 (brs,
3H, ArH), 7.45 (s, 1H, ArH), 7.52 (d, J = 7.5 Hz, 1H, ArH), 8.32 (s, 1H, NH), 10.40 (s, 1H, NH),
10.43 (s, 1H, NH); 13C{1H}-NMR (DMSO-d6): δ 27.29, 29.48, 46.44, 56.19, 67.57, 76.76, 79.47,
109.85, 121.03, 124.07, 127.50, 128.46, 129.40, 129.49,130.02, 132.89, 137.46, 142.13, 154.98,
+
172.21, 176.27; HRMS: calcd. for C22H19ClN4O3 [M+H]+: 423.1224, found: 423.1224.
1-(3-Chloro)phenylhexahydro-1H-pyrrolizine-2-spiro-5'-imidazolidine-2',4'-dione-3-spiro-3''-5-
1
chloroindoline-2''-one (4j). White solid; m.p. 161–163 °C; H-NMR (DMSO-d6): δ (ppm) 1.64–1.75
(m, 1H, CH2), 1.76–1.94 (m, 2H, CH2), 1.95–2.06 (m, 1H, CH2), 2.71–2.83 (m, 1H, CH2), 3.74 (d,
J = 10.4 Hz, 1H, CH), 4.31–4.38 (m, 1H, CH), 6.82 (d, J = 8.3 Hz, 1H, ArH), 7.28–7.39 (m, 4H, ArH),
7.46 (s, 1H, ArH), 7.55 (d, J = 1.7 Hz, 1H, ArH), 8.50 (s, 1H, NH), 10.47 (s, 1H, NH), 10.57 (s, 1H,
13
NH); C{1H}-NMR (DMSO-d6): δ 27.73, 29.87, 46.88, 56.56, 68.02, 77.02, 80.05, 109.77, 122.27,
123.78, 127.26, 128.77, 129.08, 129.88, 130.52, 133.36, 136.29, 137.46, 142.70, 155.46, 172.43,
+
175.26; HRMS: calcd. for C22H18Cl2N4O3 [M+H]+: 457.0831, found: 457.0834.
1-(3-Chloro)phenylhexahydro-1H-pyrrolizine-2-spiro-5'-imidazolidine-2',4'-dione-3-spiro-3''-N-
1
benzylindoline-2''-one (4k). White solid; m.p. 216–218 °C; H-NMR (DMSO-d6): δ (ppm) 1.62–1.75
(m, 1H, CH2), 1.76–2.04 (m, 3H, CH2), 2.79–2.91 (m, 1H, CH2), 3.82 (d, J = 10.4 Hz, 1H, CH),
4.40–4.50 (m, 1H, CH), 4.72 (d, J = 15.9 Hz, 1H, CH2), 5.05 (d, J = 15.9 Hz, 1H, CH2), 6.83 (d,
J = 7.8 Hz, 1H, ArH), 7.04–7.13 (m, 1H, ArH), 7.12–7.42 (m, 9H, ArH), 7.50 (s, 1H, ArH), 7.62 (d,
J = 7.5 Hz, 1H, ArH), 8.55 (s, 1H, NH), 10.46(s, 1H, NH); 13C{1H}-NMR (DMSO-d6): δ 27.68, 29.84,
43.13, 46.86, 56.63, 68.00, 77.00, 80.02, 109.74, 122.25, 123.76, 127.23, 127.78, 128.03, 128.67,
128.82, 129.06, 129.78, 129.92, 130.49, 133.35, 136.27, 137.45, 142.69, 155.43, 172.43, 175.24;
+
HRMS: calcd. for C29H25ClN4O3 [M+H]+: 513.1693, found: 513.1693.
1-(4-Trifluoromethy)phenylhexahydro-1H-pyrrolizine-2-spiro-5'-imidazolidine-2',4'-dione-3-spiro-3''-
indoline-2''-one (4l). White solid; m.p. 239–241 °C; 1H-NMR (DMSO-d6): δ 1.60–1.72 (m, 1H, CH2),
1.73–1.87 (m, 1H, CH2), 1.87–2.06 (m, 2H, CH2), 2.87–2.98 (m, 1H, CH2), 3.82 (d, J = 10.3 Hz, 1H,
CH), 4.41–4.51 (m, 1H, CH), 6.81 (d, J = 7.7 Hz, 1H, ArH), 6.98–7.06 (m, 1H, ArH), 7.21–7.30 (m,
1H, ArH), 7.52 (d, J = 7.6 Hz, 1H, ArH), 7.60 (d, J = 8.2 Hz, 2H, ArH), 7.69 (d, J = 8.2 Hz, 2H, ArH),
13
8.30 (s, 1H, NH), 10.45 (s, 1H, NH), 10.48 (s, 1H, NH); C{1H}-NMR (DMSO-d6): δ 27.02, 29.38,

Molecules 2013, 18
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46.55, 56.55, 67.65, 76.82, 79.50, 109.87, 121.08, 122.92, 124.05, 125.06, 125.62, 127.86, 128.18,
128.35, 129.50, 129.81, 130.59, 139.88, 142.27, 154.97, 172.52, 176.28; HRMS: calcd. for
+
C23H19F3N4O3 [M+H]+: 457.1486, found: 457.1488.
1-(3-Methoxy)phenylhexahydro-1H-pyrrolizine-2-spiro-5'-imidazolidine-2',4'-dione-3-spiro-3''-indoline-
1
2''-one (4m). Yellow solid; m.p. 177–179 °C; H-NMR (400 MHz, DMSO-d6): δ (ppm) 1.57–1.70
(m, 1H, CH2), 1.72–1.87 (m, 1H, CH2), 1.87–2.04 (m, 2H, CH2), 2.83–2.95 (m, 1H, CH2), 3.67 (d,
J = 10.3 Hz, 1H, CH), 4.35–4.46 (m, 1H, CH), 6,77–6.86 (m, 2H, ArH), 6.89 (d, J = 7.6 Hz, 1H, ArH),
6.97–7.06 (m, 2H, ArH), 7.16–7.28 (m, 2H, ArH), 7.49 (d, J = 7.5 Hz, 1H, ArH), 8.07 (s, 1H, NH),
13
10.34 (s, 1H, NH), 10.40 (s, 1H, NH); C{1H}-NMR (100 MHz, DMSO-d6): δ 27.16, 29.63, 46.50,
54.93, 56.85, 59.75, 67.50, 76.83, 79.45, 109.82, 112.82, 115.22, 121.01, 121.95, 124.25, 128.34,
+
129.25, 136.42, 142.21, 155.00, 159.07, 172.55, 176.43; HRMS: calcd. for C23H22N4O4 [M+H]+:
419.1718, found: 419.1719.
7-Phenyl-5-spiro-3'-indoline-2'-one-hexahydropyrrolo[1,2-c]thiazole-6-spiro-5''-imidazolidine-2'',4''-
dione (4n). White solid; m.p. 200–202 °C; 1H-NMR (DMSO-d6): δ (ppm) 2.87 (dd, J = 11.2, 4.1 Hz,
1H, CH2). 3.07 (dd, J = 11.1, 6.8 Hz, 1H, CH2), 3.54 (d, J = 9.4 Hz, 1H, CH), 3.71–3.80 (m, 2H, CH2),
4.63 (m, 1H, CH), 6.79 (d, J = 7.7 Hz, 1H, ArH), 7.01 (m, 1H, ArH), 7.21–7.35 (m, 4H, ArH), 7.40 (d,
J = 6.6 Hz, 1H, ArH), 7.73 (d, J = 7.6 Hz, 1H, ArH), 8.58 (s, 1H, NH), 10.30 (s, 1H, NH), 10.48 (s,
1H, NH); 13C{1H}-NMR (DMSO-d6): δ 34.80, 51.90, 55.13, 70.18, 77.11, 78.29, 109.70, 120.70,
122.78, 127.84, 128.31, 129.21, 129.67, 129.83, 133.78, 141.79, 154.84, 170.67, 175.45; HRMS:
calcd. for C21H18N4O3S+ [M+H]+: 407.1176, found: 407.1178.
3.3. Crystallographic Data and Molecular Structure of Compound 4b [32]
C29H26N4O3•C2H6O, M = 524.61, triclinic, a = 9.8656(7) Å, b = 11.0707(8) Å, c = 13.5643(10) Å, α
= 98.6770(10)°, β = 110.6190(10)°, γ = 103.4270(10)°, V = 1303.90(16) Å3, T = 100(2) K, space
group P1¯ , Z = 2, μ(MoKα) = 0.090 mm-1, 18612 reflections measured, 7266 independent reflections
(Rint = 0.0225). The final R1 values were 0.0436 (I > 2σ(I)). The final wR(F2) values were 0.1160
(I > 2σ(I)). The final R1 values were 0.0560 (all data). The final wR(F2) values were 0.1250 (all data).
The goodness of fit on F2 was 1.021.
4. Conclusions
In conclusion, we have successfully developed an efficient method for the synthesis of potentially
biologically active a series of novel dispirocycloadducts via a three-component 1,3-dipolar
cycloaddition reaction of azomethine ylides. This method has the advantages of convenient operation,
the availability of starting materials, mild reaction conditions employed, high yields and high
efficiency, as well as the complete regio- and stereoselectivity observed. Further studies to acquire more
information about the pharmacological activity of these compounds are in progress in our laboratory.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/18/5/5142/s1.

Molecules 2013, 18
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Acknowledgments
We are grateful to Zhiyan Huang (Nanyang Technological University) for his critical reviews on
this manuscript. We also thank Xiaonian Li (Kunming Institute of Botany) and Jian Yang (Kunming
University of Science and Technology) for their helpful assistance with the single crystal X-ray
diffraction analysis. Financial support from Natural Science Foundation of China (No. 81102325),
China Postdoctoral Science Foundation (No. 2012T50781), Young Teachers Fund of Sichuan
University (No. 2011SCU11108) and Sichuan Provincial Health Department Research Project
(No. 110173) is gratefully acknowledged.
Conflict of Interest
The authors declare no conflict of interest.
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© 2013 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).