Synthesis of trispiro[oxindole-pyrrolidine]-cyclopentanone-isoxazolines by 1,3-dipolar cycloaddition

Article abstract of DOI:10.1002/jhet.443

(Chemical Equation Presented) The 1,3-dipolar cycloaddition of an azomethine ylide generated by a decarboxylative route from sarcosine and isatin to 2,5-bis(arylmethylidene)-cyclopentanones afforded novel dispiro oxindole/pyrrolidines in moderate yields. Further cycloaddition of these dispiro oxindole/pyrrolidines with nitrile oxide afforded trispiro[oxindole- pyrrolidine]-cyclopentanone-isoxazolines in moderate yields with high regioand stereoselectivity.

Full text of DOI:10.1002/jhet.443

September 2010
Synthesis of Trispiro[oxindole-pyrrolidine]-cyclopentanone-
isoxazolines by 1,3-Dipolar Cycloaddition
1157
Xiaofang Li,a,b Aiting Zheng,a Bin Liu,a Xianyong Yu,a and Pinggui Yia*
aKey Laboratory of Theoretical Chemistry and Molecular Simulation of Ministry of Education,
Hunan Province College Key Laboratory of QSAR/QSPR, School of Chemistry and Chemical
Engineering, Hunan University of Science and Technology, Xiangtan, Hunan 411201, China
bSchool of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
*E-mail: pgyi@hnust.edu.cn
Received December 27, 2009
DOI 10.1002/jhet.443
Published online 26 July 2010 in Wiley Online Library (wileyonlinelibrary.com).
The 1,3-dipolar cycloaddition of an azomethine ylide generated by a decarboxylative route from sar-
cosine and isatin to 2,5-bis(arylmethylidene)-cyclopentanones afforded novel dispiro oxindole/pyrroli-
dines in moderate yields. Further cycloaddition of these dispiro oxindole/pyrrolidines with nitrile oxide
afforded trispiro[oxindole-pyrrolidine]-cyclopentanone-isoxazolines in moderate yields with high regio-
and stereoselectivity.
J. Heterocyclic Chem., 47, 1157 (2010).
INTRODUCTION
In the present work, we report the results of a tandem
azomethine ylide/nitrile oxide cycloaddition of 2,5-
bis(arylmethylidene)-cyclopentanone to obtain trispiro-
[oxindole-pyrrolidine]-cyclopentanone-isoxazoline com-
pound 4 (Scheme 1).
Spiro-compounds are an important class of organic
compounds based on their biological activities [1],
which are motifs in many pharmacologically important
alkaloids, as typified by rhyncophylline, corynoxeine,
mitraphylline, horsifiline, and spirotryprostatins [2].
Therefore, the synthesis of spiro-compounds has recently
attracted the interest of organic chemists.
RESULTS AND DISCUSSION
On the other hand, one of the most widely used meth-
ods for the synthesis of these compounds is via the
intermolecular 1,3-dipolar cycloaddition reaction to exo-
cyclic double bonds [3,4]. Therefore, the substrate with
two exocyclic double bonds could be transformed to dif-
ferent spiro-groups by appropriate methods. Kumar and
Perumal [5] used 1-methyl-3,5-bis[(E)-arylmethylidene]-
The 1,3-dipolar cycloaddition of the azomethine ylide
generated in situ from isatin and sarcosine to 2,5-bis(ar-
ylmethylidene)-cyclopentanone (1a–g) afforded novel
dispiroheterocycles (2a–g) in moderate to good yields
(80–85%) (Scheme 1). This cycloaddition reaction pro-
ceeded with high stereo- and regioselectivity to afford
only one isomer, which was evidenced from TLC and
1H-NMR of the crude reaction mixture. The 1H-NMR
spectrum of 2a demonstrated the presence of four mul-
tiplet of cyclopentanone CH2 at d 1.23–1.30, 2.12–2.16,
2.17–2.21, 2.35–2.40: one doublet of doublets at d 4.37
tetrahydro-4(1H)-pyridinones through
a tandem se-
quence comprising nitrile oxide cycloaddition to obtain
cycloreversion mono-spiro-isoxazoline compounds other
than the presumed tri-spiro product.
C
V
2010 HeteroCorporation

1158
X. Li, A. Zheng, B. Liu, X. Yu, and P. Yi
Vol 47
Scheme 1
EXPERIMENTAL
and two triplets at d 3.60, 3.99 assigned as pyrrolidine
protons, and two singlets at d 2.25 and 8.31 assignable
to the ANCH3 and ANH, respectively. The 13C-NMR
spectrum of 2a demonstrated the presence of two spiro
carbons at d 65.61 and 77.73, two carbonyl carbons at d
178.99 and 206.90.
1 [7] and 3 [8] were prepared according to the reported pro-
cedures. All NMR spectra were recorded on a Bruker AV-II
500 MHz NMR spectrometer, operating at 500 MHz for 1H,
and 125 MHz for 13C. TMS was used as an internal reference
for 1H and 13C chemical shifts. CDCl3 was as solvent. Ele-
mental analysis was measured by an Elementar analyzer (vari-
oELII). MS was measured by a Finnigan LCQ Advantage
MAX mass spectrometer; IR spectra were recorded on Perkin-
Elmer spectrometer. Melting points were measured by a
Yanaco MP500 melting points apparatus and uncorrected.
General procedure for the synthesis of spirooxindoles
(2a–g). A solution of isatin (1mmol), sarcosine (1mmol),
and 2,5-diarylidene-cyclopentanone 1 (1mmol) in methanol
(30 mL) was refluxed overnight. Completion of the reaction
was evidenced by TLC analysis. The solvent was removed
in vacuo. The crude product was subjected to column chroma-
tography using petroleum ether-ethyl acetate (v/v 5:1) as elu-
ent to afford the corresponding 2.
The dispiroheterocycles 2 were reacted subsequently
with nitrile oxide (Scheme 1) and tri-spiroheterocycles 3
were obtained in 70–85% yields. The stereo- and regio-
selectivity of this cycloaddition reaction was evidenced
1
from TLC and H-NMR of the crude reaction mixture.
The structures of 4a–g were confirmed by IR, NMR,
elemental analyses together with X-ray. For example,
the IR spectrum of 4a exhibited two carbonyl peaks
locating at 1746.7 and 1709.8 cmꢀ1, which was assigned
to the carbonyl group in cyclopentanone ring and the
carbonyl group of lactam, respectively. What is more,
the mass spectrum of 4a showed a molecular ion peak
at m/z 623 (Mþ1), which confirmed the addition of 3 to
the exocyclic double bonds of 2a.
1
The H-NMR spectrum of 4a revealed a singlet at d
2.15 resulting from NACH3, four multiplets in the range
of d 0.99–1.02, 1.37–1.40, 1.53–1.55, and 1.66–1.70
resulting from the CH2 in cyclopentanone ring, a triplet
at d 4.20 for CH and two triplets at d 3.55 and 3.97 for
CH2 in pyrrole ring and a characterize singlet at d 4.69
for PhCH. The 13C-NMR spectrum of the product 4a
exhibited the presence of methyl carbon at d 34.8; two
CH2 in cyclopentanone ring at d 28.6 and 28.8; three
spiro carbons at d 92.4, 77.4, and 65.5; NACH2 at d
59.4; benzylic carbons at d 58.2 and 51.6, respectively;
and carbonyl carbons at d 177.7 and 213.4. Further, the
structure of the product was confirmed by X-ray diffrac-
tion analysis of 4a [6] (Fig. 1).
Figure 1. ORTEP diagram of 4a (H atoms have been omitted for
clarity).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010
Synthesis of Trispiro[oxindole-pyrrolidine]-cyclopentanone-isoxazolines
by 1,3-Dipolar Cycloaddition
1159
1-N-Methyl-spiro[2.30]oxindole-spiro[3.200]500-benzylidenecy-
clopentanone-4-phenyl-pyrrolidine (2a). White solid, yield
85%; mp: 206–208ꢁC; 1H-NMR (CDCl3, 500 MHz): d 1.23–
1.30 (m, 1H), 2.12–2.16 (m, 1H), 2.17–2.21 (m, 1H), 2.25 (s,
3H), 2.35–2.40 (m, 1H), 3.60 (t, J ¼ 8.0 Hz, 1H), 3.99 (t, J ¼
10.0 Hz, 1H), 4.37 (dd, J ¼ 8.0, 10.0 Hz, 1H), 6.79–6.84 (m,
1H), 6.91 (t, J ¼ 7.5 Hz, 1H), 7.10–7.13 (m, 1H), 7.18–7.20 (m,
3H), 7.22–7.27 (m, 5H), 7.31 (t, J ¼ 8.0 Hz, 2H), 7.53 (d, J ¼
6.5 Hz, 2H), 8.31 (s, 1H); 13C-NMR (CDCl3, 125 MHz) d:
26.21, 30.70, 35.00, 49.15, 59.95, 65.61, 77.73, 109.21, 122.96,
125.99, 126.88, 127.78, 128.34, 128.48, 129.19, 129.38, 130.18,
130.38, 133.53, 135.37, 135.52, 139.59, 141.32, 178.99, 206.90;
IR (KBr) v: 1721.4, 1704.3 cmꢀ1; MS(ESI) m/z: 435 [MþH]þ.
Anal. Calcd. for C29H26N2O2: C 80.16, H 6.03, N 6.45; found
C 80.06, H 6.17, N 6.49.
1-N-Methyl-spiro[2.30]oxindole-spiro[3.200]500-(4-chloro)benzyli-
denecyclopentanone-4-(4-chloro)phenyl-pyrrolidine (2b). White
solid, yield 85%; mp: 224–226ꢁC; 1H-NMR (CDCl3, 500
MHz): d 1.20–1.27 (m, 1H), 2.08–2.14 (m, 1H), 2.20 (s, 3H),
2.19–2.22 (m, 1H), 2.33–2.38 (m, 1H), 3.58 (t, J ¼ 8.5 Hz, 1H),
3.92 (t, J ¼ 9.5 Hz, 1H), 4.31 (dd, J ¼ 8.5, 9.5 Hz, 1H), 6.77
(d, J ¼ 7.5 Hz, 1H), 6.89 (t, J ¼ 7.5 Hz, 1H), 7.11–7.14(m,
4H), 7.19–7.21 (m, 1H), 7.23–7.28 (m, 4H), 7.45 (d, J ¼ 8.0
Hz, 2H), 8.14 (bs, 1H); 13C-NMR (CDCl3, 125 MHz) d: 26.11,
30.62, 34.92, 48.40, 59.99, 65.43, 77.52, 109.26, 122.99,
125.72, 127.70, 128.50, 128.82, 129.51, 131.29, 131.72, 132.33,
132.74, 133.71, 135.25, 135.72, 138.07, 141.24, 178.44, 206.48;
IR (KBr) v: 1720.5, 1708.1 cmꢀ1; MS(ESI) m/z: 503 [MþH]þ.
Anal. Calcd. for C29H24Cl2N2O2: C 69.19, H 4.81, N 5.56;
found C 69.37, H 4.92, N 5.48.
1-N-Methyl-spiro[2.30]oxindole-spiro[3.200]500-(3,4,5-trime-
thoxy)benzylidenecyclopentanone-4-(3,4,5-trimethoxy)phenyl-
1
pyrrolidine (2e). White solid, yield 82%; mp: 222–224ꢁC; H-
NMR (CDCl3, 500 MHz): d 1.26–1.38 (m, 1H), 2.05–2.14 (m,
1H), 2.20 (s, 3H), 2.21–2.25 (m, 1H), 2.45–2.50 (m, 1H), 3.63
(t, J ¼ 8.5 Hz, 1H), 3.78 (s, 6H), 3.84 (s, 6H), 3.87 (s, 6H),
3.96 (t, J ¼ 9.0 Hz, 1H), 4.26 (dd, J ¼ 8.5, 9.0 Hz, 1H), 6.46
(s, 2H), 6.77–6.92 (m, 4H), 7.11–7.18 (m, 2H), 7.23 (s, 1H),
8.44 (bs,1H); 13C-NMR (CDCl3, 125 MHz) d: 26.16, 30.66,
34.98, 49.61, 56.06, 60.21, 60.45, 60.80, 60.90, 65.52, 77.69,
107.18, 107.61, 109.18, 122.84, 125.76, 127.64, 129.44,
130.84, 133.97, 134.64, 135.53, 163.50, 139.33, 141.55,
152.94, 152.99, 178.54, 207.10; IR (KBr) v: 1715.8, 1692.3
cmꢀ1
;
MS(ESI) m/z: 615 [MþH]þ. Anal. Calcd. for
C35H38N2O8: C 68.39, H 6.23, N 4.56; found C 68.54, H 6.32,
N 4.71.
1-N-Methyl-spiro[2.30]oxindole-spiro[3.200]500-(2-chloro)ben-
zylidenecyclopentanone-4-(2-chloro)phenyl-pyrrolidine (2f).
White solid, yield 85%; mp: 234–236ꢁC; 1H-NMR (CDCl3,
500 MHz): d 1.16–1.23 (m, 1H), 1.99–2.06 (m, 2H), 2.22 (s,
3H), 2.24–2.29 (m, 1H), 3.60 (t, J ¼ 8.5 Hz, 1H), 4.05 (t, J ¼
9.0 Hz, 1H), 4.94 (t, J ¼ 9.0 Hz, 1H), 6.79–6.81 (m, 1H),
6.86–6.87 (m, 1H), 6.93–6.96 (m, 1H), 7.06–7.09 (m, 1H),
7.14–7.20 (m, 4H), 7.26–7.34 (m, 3H), 7.60 (s, 1H), 8.09 (d, J
¼ 7.5 Hz, 1H), 8.19 (s, 1H); 13C-NMR (CDCl3, 125 MHz) d:
25.97, 30.32, 35.04, 43.61, 58.68, 64.81, 77.67, 109.24,
123.23, 125.55, 126.28, 126.87, 127.93, 128.00, 129.16,
129.45, 129.65, 129.77, 129.81, 129.87, 131.37, 133.85,
135.51, 135.86, 137.31, 137.64, 141.42, 178.48, 205.36; IR
(KBr) v: 1715.7, 1702.5 cmꢀ1; MS(ESI) m/z: 503 [MþH]þ.
Anal. Calcd. for C29H24Cl2N2O2: C 69.19, H 4.81, N 5.56;
found C 69.06, H 5.02, N 5.78.
1-N-Methyl-spiro[2.30]oxindole-spiro[3.200]500-(4-methoxy)-
benzylidenecyclopentanone-4-(4-methoxy)phenyl-pyrrolidine
(2c). White solid, yield 83%; mp: 188–190ꢁC; 1H-NMR
(CDCl3, 500 MHz): d 1.24–1.35 (m, 1H), 2.06–2.17 (m, 2H),
2.20 (s, 3H), 2.31–2.36 (m, 1H), 3.56 (t, J ¼ 8.5 Hz, 1H), 3.78
(s, 6H), 3.93 (t, J ¼ 9.5 Hz, 1H), 4.29 (t, J ¼ 9.0 Hz, 1H), 6.74
(d, J ¼ 7.5 Hz, 1H), 6.79 (d, J ¼ 8.5 Hz, 2H), 6.84 (d, J ¼ 8.5
Hz, 2H), 6.89 (t, J ¼ 7.5 Hz, 1H), 7.09 (t, J ¼ 7.5 Hz, 2H), 7.17–
7.22 (m, 3H), 7.43 (d, J ¼ 7.5 Hz, 2H), 7.96 (bs, 1H); 13C-NMR
(CDCl3, 125 MHz) d: 26.3, 30.6, 35.1, 48.5, 55.2, 55.3, 60.2,
65.5, 77.87, 109.3, 113.7, 114.1, 114.3, 122.9, 126.1, 127.8,
128.1, 129.3, 131.4, 131.7, 132.1, 132.6, 133.2, 133.5, 141.6,
1-N-Methyl-spiro[2.30]oxindole-spiro[3.200]500-(4-methylsul-
fanyl)benzylidenecyclopentanone-4-(4-methylsulfanyl)phenyl-
1
pyrrolidine (2g). White solid, yield 85%; mp: 203–204ꢁC; H-
NMR (CDCl3, 500 MHz): d 1.26–1.33 (m, 1H), 2.08–2.14 (m,
1H), 2.20 (s, 3H), 2.18–2.22 (m, 1H), 2.32–2.37 (m, 1H), 2.43
(s, 3H), 2.45 (s, 3H), 3.57 (t, J ¼ 8.5 Hz, 1H), 3.95 (t, J ¼
9.5, Hz, 1H), 4.31 (dd, J ¼ 8.5, 9.5 Hz, 1H), 6.79 (d, J ¼ 7.5
Hz, 1H), 6.88 (t, J ¼ 7.5 Hz, 1H), 7.08–7.13 (m, 4H), 7.16–
7.20 (m, 3H), 7.26–7.28 (m, 1H), 7.45 (d, J ¼ 8.0 Hz, 2H),
7.52 (d, J ¼ 8.5 Hz, 1H), 8.57 (bs, 1H); 13C-NMR (CDCl3,
125 MHz) d: 15.03, 15.87, 26.31, 30.64, 35.02, 48.71, 59.96,
65.54, 77.73, 109.30, 122.91, 125.59, 125.86, 125.95, 126.55,
127.75, 129.40, 130.62, 130.88, 131.14, 131.80, 132.35,
133.20, 133.40, 134.55, 136.54, 136.61, 136.78, 140.99,
141.16, 141.45, 178.82, 206.82; IR (KBr) v: 1719.4, 1702.3
158.5, 160.5, 179.2, 207.1; IR (KBr) v: 1718.6, 1704.7 cmꢀ1
;
MS(ESI) m/z: 495 [MþH]þ. Anal. Calcd. for C31H30N2O4: C
75.28, H 6.11, N 5.66; found C 75.34, H 6.21, N 5.45.
1-N-Methyl-spiro[2.30]oxindole-spiro[3.200]500-(2,4-dichloro)-
benzylidenecyclopentanone-4-(2,4-dichloro)phenyl-pyrrolidine
(2d). White solid, yield 80%; mp: 239–241ꢁC; 1H-NMR
(CDCl3, 500 MHz): d 1.16–1.18 (m, 1H), 1.99–2.05 (m, 2H),
2.20 (s, 3H), 2.23–2.26 (m, 1H), 3.59 (t, J ¼ 8.5 Hz, 1H),
3.96 (t, J ¼ 9.0 Hz, 1H), 4.87 (t, J ¼ 9.0 Hz, 1H), 6.77–6.80
(m, 2H), 6.92 (t, J ¼ 7.5 Hz, 1H), 7.06–7.09 (m, 1H), 7.14–
7.18 (m, 2H), 7.27–7.30 (m, 1H), 7.33–7.36 (m, 2H), 7.52 (s,
1H), 7.83 (s, 1H), 8.03 (d, J ¼ 9.0 Hz, 1H); 13C-NMR
(CDCl3, 125 MHz) d: 25.93, 30.28, 34.96, 43.09, 58.70, 64.68,
77.49, 109.26, 123.26, 125.32, 126.79, 127.27, 127.93, 128.75,
128.84, 129.57, 129.74, 130.23, 132.29, 132.36, 133.01,
135.18, 135.96, 136.24, 136.36, 137.79, 141.28, 178.07,
204.96; IR (KBr) v: 1716.6, 1685.9 cmꢀ1; MS(ESI) m/z: 571
[MþH]þ. Anal. Calcd. for C29H22Cl4N2O2: C 60.86, H 3.87,
N 4.89; found C 60.97, H 3.81, N 4.99.
cmꢀ1
;
MS(ESI) m/z: 527 [MþH]þ. Anal. Calcd. for
C31H30N2O2S2: C 70.69, H 5.74, N 5.32; found C 70.53, H
5.47, N 5.50.
General procedure for the synthesis of trispiro[oxindole-
pyrrolidine]-cyclopentanone-isoxazoline (4a–g). A solution
of 2 (1mmol), 3 (1mmol) in dioxane (30 mL) was refluxed
overnight. Completion of the reaction was evidenced by TLC
analysis. The solvent was removed in vacuo. The crude prod-
uct was subjected to column chromatography using petroleum
ether-ethyl acetate (v/v 5:1) as eluent to afford the correspond-
ing 4.
3000-(2,6-Dichlorophenyl)-10-methyl-40,4000-diphenyl-4000,5000-
dihydroindole-3-spiro-20-pyrrolidine-30-spiro-100-cyclopentane-300-
spiro-5000-[1,2]oxazole-2(3H),200-dione (4a). White solid, yield
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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X. Li, A. Zheng, B. Liu, X. Yu, and P. Yi
Vol 47
83%; mp: 250–251ꢁC; 1H-NMR (CDCl3, 500 MHz): d 0.99–
1.02 (m, 1H), 1.37–1.40 (m, 1H), 1.53–1.55 (m, 1H), 1.66–
1.70 (m, 1H), 2.15 (s, 3H), 3.55 (t, J ¼ 9.0 Hz, 1H), 3.97 (t, J
¼ 9.0 Hz, 1H), 4.20 (t, J ¼ 8.0 Hz, 1H), 4.69 (s, 1H), 6.54–
6.55 (m, 2H), 6.77 (d, J ¼ 8.0 Hz, 1H), 6.99–7.02 (m, 2H),
7.04–7.07 (m, 1H), 7.10–7.13 (m, 1H), 7.22–7.25 (m, 4H),
7.32–7.38 (m, 4H), 7.49 (d, J ¼ 7.5Hz, 2H), 7.74 (br, 1H); 13C-
NMR (CDCl3, 125 MHz) d: 28.59, 28.82, 34.80, 51.58, 58.17,
59.44, 65.46, 77.42, 92.37, 109.75, 123.43, 126.90, 127.06,
127.24, 128.01, 128.08, 128.35, 128.51, 128.74, 128.78, 129.46,
129.89, 130.29, 130.80, 132.73, 135.74, 138.18, 142.09, 155.16,
177.69, 213.37; IR (KBr) v: 1746.7, 1709.8 cmꢀ1; ESI MS m/z:
623 [MþH]þ. Anal. Calcd. for C36H29Cl2N3O3: C 69.46, H
4.70, N 6.75; found C 69.32, H 4.59, N 6.91.
3000-(2,6-Dichlorophenyl)-10-methyl-40,4000-bis-(4-chlorophenyl)-
4000,5000-dihydroindole-3-spiro-20-pyrrolidine-30-spiro-100-cyclo-
pentane-300-spiro-5000-[1,2]oxazole-2(3H),200-dione (4b). White
solid, yield 85%; mp: 203–206ꢁC; 1H-NMR (CDCl3, 500
MHz): d 0.97–0.99 (m, 1H), 1.46–1.54 (m, 2H), 1.77–1.84 (m,
1H), 2.12 (s, 3H), 3.54 (t, J ¼ 8.5 Hz, 1H), 3.90 (t, J ¼ 9.5 Hz,
1H), 4.18 (t, J ¼ 9.0 Hz, 1H), 4.71 (s, 1H), 6.51–6.52 (m, 2H),
6.77–6.78 (m, 1H), 7.00–7.02 (m, 2H), 7.15–7.17 (m, 1H),
7.23–7.30 (m, 6H), 7.33–7.35 (m, 1H), 7.42–7.43 (m, 2H), 8.01
(br, 1H); 13C-NMR (CDCl3, 125 MHz) d: 28.75, 29.18, 34.67,
50.65, 57.33, 59.46, 65.48, 92.04, 109.97, 123.34, 126.67,
126.75, 128.31, 128.50, 128.67, 128.86, 129.96, 130.70, 131.04,
131.24, 131.56, 133.07, 134.14, 135.62, 136.81, 142.17, 155.00,
177.76, 212.72; IR (KBr) v: 1739.8, 1717.7 cmꢀ1; MS(ESI) m/
z: 691 [MþH]þ. Anal. Calcd. for C36H27Cl4N3O3: C 62.53, H
3.94, N 6.08; found C 62.47, H 3.98, N 6.16.
3000-(2,6-Dichlorophenyl)-10-methyl-40,4000-bis-(4-methoxy-
phenyl)-4000,5000-dihydroindole-3-spiro-20-pyrrolidine-30-spiro-100-
cyclopentane-300-spiro-5000-[1,2]oxazole-2(3H),200-dione (4c).
White solid, yield 80%; mp: 175–177ꢁC; 1H-NMR (CDCl3,
500 MHz): d 1.09–1.09 (m, 1H), 1.35–1.38 (m, 1H), 1.55–1.63
(m, 2H), 2.13 (s, 3H), 3.52 (t, J ¼ 8.5 Hz, 1H), 3.65 (s, 3H),
3.79 (s, 3H), 3.90 (t, J ¼ 9.5 Hz, 1H), 4.15 (t, J ¼ 9.0 Hz, 1H),
4.63 (s, 1H), 6.46–6.54 (m, 4H), 6.80–6.82 (m, 1H), 6.86–6.87
(m, 2H), 7.11–7.12 (m, 1H), 7.21–7.26 (m, 3H), 7.34–7.37 (m,
2H), 7.41–7.43 (m, 2H), 8.30 (s, 1H); 13C-NMR (CDCl3, 125
MHz) d: 28.46, 28.52, 34.77, 51.00, 55.01, 55.22, 57.59, 59.56,
65.26, 77.51, 92.33, 109.85, 113.30, 113.80, 123.36, 124.55,
126.86, 127.12, 128.63, 128.73, 129.81, 130.13, 130.64,
130.74, 131.28, 135.67, 142.23, 155.22, 158.69, 159.18,
178.15, 213.82; IR (KBr) v: 1743.5, 1717.1 cmꢀ1; MS(ESI) m/
z: 683 [MþH]þ. Anal. Calcd. for C38H33Cl2N3O5: C 66.86, H
4.87, N 6.16; found C 67.01, H 4.78, N 6.27.
3000-(2,6-Dichlorophenyl)-10-methyl-40,4000-bis-(2,4-dichlor-
ophenyl)-4000,5000-dihydroindole-3-spiro-20-pyrrolidine-30-spiro-
100-cyclopentane-300-spiro-5000-[1,2]oxazole-2(3H),200-dione (4d).
White solid, yield 76%; mp: 188–190ꢁC; 1H-NMR (CDCl3,
500 MHz): d 1.09–1.14 (m, 1H), 1.42–1.45 (m, 1H), 1.55–1.58
(m, 1H), 1.70–1.73 (m, 1H), 2.15 (s, 3H), 3.54 (t, J ¼ 8.5 Hz,
1H), 3.84 (t, J ¼ 8.5 Hz, 1H), 4.72 (t, J ¼ 9.0 Hz, 1H), 5.26
(s, 1H), 6.76 (d, J ¼ 7.5 Hz, 1H), 7.04–7.13 (m, 4H), 7.20–
7.24 (m, 5H), 7.28–7.30 (m, 1H), 7.41–7.42 (m, 2H), 8.03 (br,
1H); 13C-NMR (CDCl3, 125 MHz) d: 27.33, 27.82, 34.82,
47.06, 52.66, 59.65, 62.72, 77.92, 92.84, 109.74, 124.12,
125.81, 126.38, 126.97, 127.15, 128.66, 128.75, 129.00,
129.13, 129.19, 129.22, 129.85, 131.19, 132.89, 132.96,
133.54, 134.36, 134.42, 143.82, 135.89, 136.80, 142.15,
154.93, 177.78, 211.60; IR (KBr) v: 1750.7, 1717.8 cmꢀ1
;
MS(ESI) m/z: 760 [MþH]þ. Anal. Calcd. for C36H25Cl6N3O3:
C 56.87, H 3.31, N 5.53; found C 56.84, H 3.17, N 5.40.
3000-(2,6-Dichlorophenyl)-10-methyl-40,4000-bis-(3,4,5-trime-
thoxyphenyl)-4000,5000-dihydroindole-3-spiro-20-pyrrolidine-30-
spiro-100-cyclopentane-300-spiro-5000-[1,2]oxazole-2(3H),200-dione
(4e). White solid, yield 70%; mp: 206–208ꢁC; 1H-NMR
(CDCl3, 500 MHz): d 1.12–1.17 (m, 1H), 1.55–1.60 (m, 1H),
1.68–1.71 (m, 1H), 1.83–1.88 (m, 1H), 2.15 (s, 3H), 3.57 (t, J
¼ 8.5 Hz, 1H), 3.70 (s, 6H), 3.72 (s, 3H), 3.83 (s, 3H), 3.87 (s,
6H), 3.94 (t, J ¼ 9.5 Hz, 1H), 4.13 (t, J ¼ 9.5 Hz, 1H), 4.61 (s,
1H), 6.78 (d, J ¼ 7.5 Hz, 2H), 7.15–7.21 (m, 4H), 7.28–7.30
(m, 3H), 7.35 (d, J ¼ 7.5 Hz, 2H), 8.19 (br, 1H); 13C-NMR
(CDCl3, 125 MHz) d: 28.26, 28.98, 34.74, 52.06, 56.12, 56.22,
57.91, 59.52, 60.65, 60.80, 65.35, 92.50, 106.64, 109.86,
123.01, 126.88, 128.36, 128.54, 129.00, 129.71, 130.98, 134.08,
135.69, 136.78, 137.78, 142.46, 152.78, 153.05, 155.65, 177.65,
213.16; IR (KBr) v: 1742.0, 1713.1 cmꢀ1; MS(ESI) m/z: 803
[MþH]þ. Anal. Calcd. for C42H41Cl2N3O9: C 62.84, H 5.15, N
5.23; found C 62.94, H 5.28, N 5.15.
3000-(2,6-Dichlorophenyl)-10-methyl-40,4000-bis-(2-chlorophenyl)-
4000,5000-dihydroindole-3-spiro-20-pyrrolidine-30-spiro-100-cyclopen-
tane-300-spiro-5000-[1,2]oxazole-2(3H),200-dione (4f). White solid,
yield 70%; mp: 195–196ꢁC; 1H-NMR (DMSO-d6, 500 MHz): d
1.03–1.07 (m, 1H), 1.27–1.32 (m, 1H), 1.36–1.39 (m, 1H),
1.62–1.64 (m, 1H), 2.01 (s, 3H), 3.39 (t, J ¼ 9.0 Hz, 1H), 3.74
(t, J ¼ 9.0 Hz, 1H), 4.50 (t, J ¼ 9.0 Hz, 1H), 5.20 (s, 1H), 6.75
(d, J ¼ 8.0 Hz, 1H), 7.02 (t, J ¼ 8.0 Hz, 1H), 7.17–7.25 (m,
6H), 7.36–7.41 (m, 2H), 7.42–7.45 (m, 3H), 7.47–7.49 (m, 1H),
8.07–8.08 (m, 1H), 10.72 (s, 1H); 13C-NMR (DMSO-d6, 125
MHz) d: 26.46, 27.13, 34.10, 47.13, 52.75, 59.07, 61.85, 77.08,
92.66, 109.64, 122.63, 125.42, 125.62, 126.95, 127.12, 128.00,
128.98, 129.02, 129.11, 129.38, 129.41, 129.65, 130.24, 131.95,
131.99, 132.42, 132.71, 134.74, 135.20, 143.81, 154.01, 176.97,
212.13; IR (KBr) v: 1746.3, 1701.1 cmꢀ1; MS(ESI) m/z: 691
[MþH]þ. Anal. Calcd. for C36H27Cl4N3O3: C 62.53, H 3.94, N
6.08; found C 62.62, H 4.02, N 6.01.
3000-(2,6-Dichlorophenyl)-10-methyl-40,4000-bis-(4-methylsulfa-
nylphenyl)-4000,5000-dihydroindole-3-spiro-20-pyrrolidine-30-spiro-
100-cyclopentane-300-spiro-5000-[1,2]oxazole-2(3H),200-dione (4g).
White solid, yield 74%; mp: 195–196ꢁC; 1H-NMR (CDCl3,
500 MHz): d 1.01–1.06 (m, 1H), 1.42–1.46 (m, 1H), 1.53–1.60
(m, 1H), 1.72–1.77 (m, 1H), 2.14 (s, 3H), 2.37 (s, 3H), 2.47
(s, 3H), 3.52 (t, J ¼ 8.5 Hz, 1H), 3.92 (t, J ¼ 9.5 Hz, 1H),
4.17 (t, J ¼ 8.0 Hz, 1H), 4.66 (s, 1H), 6.46–6.48 (m, 2H),
6.75–6.76 (m, 1H), 6.87–6.88 (m, 2H), 7.11–7.14 (m, 1H),
7.21–7.24 (m, 5H), 7.33–7.35 (m, 2H), 7.41 (d, J ¼ 8.0 Hz,
2H), 7.52 (br, 1H); 13C-NMR (CDCl3, 125 MHz) d: 15.07,
15.83, 28.61, 29.07, 34.76, 51.05, 57.64, 59.38, 65.44, 77.41,
92.26, 109.96, 123.38, 125.36, 126.65, 126.85, 126.96, 128.59,
128.83, 129.13, 129.83, 129.91, 130.71, 130.89, 135.08,
135.70, 137.22, 138.74, 142.25, 155.13, 178.06, 213.29; IR
(KBr) v: 1732.6, 1713.1 cmꢀ1; MS(ESI) m/z: 715 [MþH]þ.
Anal. Calcd. for C38H33Cl2N3O3S2: C 63.86, H 4.65, N 5.88;
found C 63.65, H 4.56, N 6.04.
Acknowledgments. This research was supported by National
Natural Science Foundation of China (No. 20772027, 20803020,
and 20971041) and A Project Supported by Scientific Research
Fund of Hunan Provincial Education Department (09K081,
B30907).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010
Synthesis of Trispiro[oxindole-pyrrolidine]-cyclopentanone-isoxazolines
by 1,3-Dipolar Cycloaddition
1161
(c) Hiromitsu, T.; Yuhshin, T.; Mariko, K. J Org Chem 1994, 59,
4381.
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