Synthesis of novel trispiroheterocycles through 1,3-dipolar cycloaddition of azomethine ylides and nitrile oxide

Article abstract of DOI:10.1002/cjoc.201090092

The 1,3-dipolar cycloaddition of an azomethine ylide generated by a decarboxylative route from sarcosine and isatin to 1-benzyl-3,5-diarylmethylidene-piperidin-4-ones afforded novel di-spiro-indolo/pyrrolidino/piperidines in moderate yields. Further cycloaddition of these di-spiro compounds to nitrile oxide afforded tri-spiro-indolo/pyrrolidino/piperadino/isoxazolines in moderate yields with high regio- and stereoselectivity.

Full text of DOI:10.1002/cjoc.201090092

FULL PAPER
Synthesis of Novel Trispiroheterocycles through 1,3-Dipolar
Cycloaddition of Azomethine Ylides and Nitrile Oxide
Li, Xiaofanga,b(李筱芳)
Yu, Xianyonga(于贤勇)
Yi, Pinggui*,a(易平贵)
a Key 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
b School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
The 1,3-dipolar cycloaddition of an azomethine ylide generated by a decarboxylative route from sarcosine and
isatin to 1-benzyl-3,5-diarylmethylidene-piperidin-4-ones afforded novel di-spiro-indolo/pyrrolidino/piperidines in
moderate yields. Further cycloaddition of these di-spiro compounds to nitrile oxide afforded tri-spiro-indolo/
pyrrolidino/piperadino/isoxazolines in moderate yields with high regio- and stereoselectivity.
Keywords spiroheterocycle, 1,3-dipolar cycloaddition, azomethine ylide, nitrile oxide
Introduction
Due to the importance of pyrrolidines, isoxazolines
and piperidines, we investigate the synthesis of novel
spiro-pyrrolidines via azomethine ylide cycloaddition to
1-benzyl-3,5-diarylmethylidene-piperidin-4-one and their
subsequent cycloaddition to nitrile oxide to obtain novel
tri-spiro heterocycles (Scheme 1). Recently, Perumal15
reported a tandem azomethine ylide/nitrile oxide
Pyrrolidine,1-3 isoxazoline4-6 and piperidine7-9 sub-
structures exhibit important biological activities. The
1,3-dipolar cycloaddition of nitrile oxides to azomethine
ylide to alkenes affords pyrrolidines and isoxazolines.
Spiroheterocycles with pyrrolidine or isoxazoline sub-
structures are an important class of organic compounds
based on their biological activities,10-12 which are motifs
in many pharmacologically relevant alkaloids.13,14 One
of the most widely used methods for the synthesis of
these compounds is via the intermolecular 1,3-dipolar
cycloaddition reaction to exocyclic double bonds.
cycloaddition
to
1-methyl-3,5-diarylmethylidene-
piperidin-4-one, which only obtained cycloreversion
mono-spiro-isoxazoline compounds. The present work
is the first report on the synthesis of tri-spiro-indolo/
pyrrolidino/piperadino/isoxazolines.
Scheme 1
*
E-mail: fine_chem@163.com, yqfeng@tju.edu.cn
Received August 24, 2009; revised October 27, 2009; accepted November 17, 2009.
Project supported by the National Natural Science Foundation of China (Nos. 20971041, 20803020), Scientific Research Fund of Hunan Provincial
Education Department (No. B30907) and Doctoral Science Foundation of Hunan University of Science and Technology (No. E50839).
434
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 434— 438

Synthesis of Novel Trispiroheterocycles through 1,3-Dipolar Cycloaddition
Experimental
7.56 (bs, 1H); 13C NMR (CDCl3, 125 MHz) δ: 34.60,
45.61, 53.82, 57.03, 57.13, 62.23, 65.43, 76.07, 108.95,
122.12, 127.13, 127.18, 127.75, 128.15, 128.42, 128.53,
128.67, 128.97, 131.04, 131.08, 132.74, 133.32, 133.42,
134.70, 136.54, 136.62, 136.96, 141.99, 177.48, 199.72;
Materials and instruments
2,6-Dichloro-benzonitrile oxide16 and 1-benzyl-3,5-
diarylmethylidene-piperidin-4-one (1)17 were prepared
according to the reported procedures. All NMR spectra
were recorded on a Bruker AV-II 500 MHz NMR spec-
－1
IR (KBr) ν: 1712.9, 1693.6 cm ; ESI MS m/z: 608 [M
＋H]＋. Anal. calcd for C36H31Cl2N3O2: C 71.05, H 5.13,
1
trometer, operating at 500 MHz for H, and 125 MHz
N 6.90; found C 70.94, H 5.23, N 6.82.
for 13C, TMS was used as an internal reference for H
1
1"-Benzyl-5"-(2-chlorobenzylidene)-4'-(2-chloroph-
enyl)-1'-methyl-2,3-dihydro-1H-indole-3-spiro-2'-
and 13C chemical shifts, and CDCl3 used as solvent.
Elemental analysis was conducted on an Elementar
analyzer (varioEL II). MS data were measured on a Fin-
nigan LCQ Advantage MAX mass spectrometer. IR
spectra were recorded on a Perkin-Elmer spectrometer
(Spectrum one). Melting points were measured by a
Yanaco MP500 melting points apparatus and uncor-
rected.
pyrrolidine-3'-spiro-3"-piperidine-2,3"-dione
(2c)
1
White solid, yield 81%; m.p. 246—248 ℃; H NMR
(CDCl3, 500 MHz) δ: 1.95 (d, J＝12.5 Hz, 1H), 2.12 (s,
3H), 2.77 (dd, J＝2.5, 14.5 Hz, 1H), 3.07 (d, J＝13.5
Hz, 1H), 3.18 (dd, J＝2.0, 13.0 Hz, 1H), 3.24 (d, J＝
14.5 Hz, 1H), 3.44—3.50 (m, 2H), 3.98 (dd, J＝9.5,
10.5 Hz, 1H), 5.15 (dd, J＝7.5, 10.5 Hz, 1H), 6.71 (d,
J＝7.5 Hz, 2H), 6.86—6.87 (m, 2H), 6.96—7.01 (m,
2H), 7.10—7.22 (m, 7H), 7.29 (d, J＝7.5 Hz, 1H), 7.33—
7.37 (m, 2H), 7.40 (s, 1H), 7.65 (bs, 1H), 8.01 (d, J＝
7.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ: 34.78,
42.68, 54.38, 57.39, 57.76, 62.62, 63.24, 108.88, 122.94,
126.13, 126.52, 126.71, 126.94, 127.99, 128.11, 128.45,
128.66, 129.26, 129.59, 129.64, 129.68, 130.94, 133.52,
133.83, 134.90, 135.02, 135.99, 136.79, 137.16, －141.90,
General procedure for the synthesis of 4'-aryl-
5"-arylmethylidene-1"-benzyl-1'-methyl-2,3-dihydro-
1H-indole-3-spiro-2'-pyrrolidine-3'-spiro-3"-piperidi-
ne-2,4"-dione (2a—2f)
A mixture of 1 (1 mmol), isatin (1 mmol) and sarco-
sine (1 mmol) was dissolved in methanol (40 mL) and
heated to reflux for 24 h. After completion of the reac-
tion as evidented by TLC, The solvent was evaporated
in vacuum. The residue was purified by column chro-
matography employing petroleum ether/ethyl acetate
mixture (4∶1, V/V) as eluent to obtain 2.
1
176.85, 197.59; IR (KBr) ν: 1703.3, 1689.8 cm ; ESI
MS m/z: 608 [M＋H]＋. Anal. calcd for C36H31Cl2N3O2:
C 71.05, H 5.13, N 6.90; found C 70.84, H 5.16, N 6.97.
1"-Benzyl-5"-(2,4-dichlorobenzylidene)-4'-(2,4-di-
chlorophenyl)-1'-methyl-2,3-dihydro-1H-indole-3-
spiro-2'-pyrrolidine-3'-spiro-3"-piperidine-2,3"-dione
1"-Benzyl-5"-benzylidene-1'-methyl-4'-phenyl-2,3-
dihydro-1H-indole-3-spiro-2'-pyrrolidine-3'-spiro-3"-
piperidine-2,3"-dione (2a) White solid, yield 80%;
m.p. 207—208 ℃; 1H NMR (CDCl3, 500 MHz) δ: 1.88
(d, J＝12.5 Hz, 1H), 2.16 (s, 3H), 2.78 (dd, J＝3.0, 14.5
Hz, 1H), 3.16 (d, J＝13.5 Hz,1H), 3.36—3.41 (m, 2H),
3.47 (dd, J＝2.0, 12.5 Hz, 1H), 3.62 (d, J＝13.0 Hz,
1H), 3.97 (dd, J＝9.0, 10.5 Hz, 1H), 4.83 (dd, J＝7.0,
11.0 Hz, 1H), 6.64 (d, J＝7.5 Hz, 1H), 6.91—6.99 (m,
5H), 7.09—7.20 (m, 8H), 7.24—7.26 (m, 3H), 7.32 (t,
J＝7.5 Hz, 3H), 7.45 (bs, 1H); 13C NMR (CDCl3, 125
MHz) δ: 34.67, 46.35, 53.95, 57.00, 57.07, 62.18, 65.68,
76.12, 108.81, 122.16, 126.90, 127.01, 127.37, 127.84,
128.05, 128.21, 128.27, 128.62, 128.73, 128.85, 129.74,
129.94, 133.14, 135.04, 136.83, 137.80, 138.48, －141.94,
1
(2d) White solid, yield 80%; m.p. 221—222 ℃; H
NMR (CDCl3, 500 MHz) δ: 1.90 (d, J＝12.5 Hz, 1H),
2.11 (s, 3H), 2.72 (dd, J＝2.5, 15 Hz, 1H), 3.06 (d, J＝
13.5 Hz, 1H), 3.16 (dd, J＝2.5, 13.0 Hz, 1H), 3.21 (d,
J＝14.5 Hz, 1H), 3.46—3.51 (m, 2H), 3.89 (t, J＝9.0
Hz, 1H), 5.09 (t, J＝9.0 Hz, 1H), 6.62 (d, J＝8.5 Hz,
1H), 6.72 (d, J＝7.5 Hz, 1H), 6.86—6.88 (m, 2H), 6.94—
6.99 (m, 2H), 7.10 (d, J＝7.5 Hz, 1H), 7.15—7.19 (m,
4H), 7.32—7.38 (m, 4H), 7.56 (bs, 1H), 7.97 (d, J＝8.5
Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ: 34.71, 42.13,
54.18, 57.45, 57.85, 62.70, 63.15, 77.25, 109.14, 122.89,
126.31, 126.59, 127.03, 127.10, 127.99, 128.10, 128.40,
128.84, 129.04, 129.62, 130.32, 131.86, 133.10, 133.94,
134.10, 134.90, 135.51, 135.65, 136.54, 136.93, －142.07,
1
177.45, 199.07; IR (KBr) ν: 1699.6, 1682.0 cm ; ESI
MS m/z: 540 [M＋H]＋. Anal. calcd for C36H33N3O2: C
80.12, H 6.16, N 7.79; found C 80.00, H 6.26, N 7.58.
1"-Benzyl-5"-(4-chlorobenzylidene)-4'-(4-chloroph-
enyl)-1'-methyl-2,3-dihydro-1H-indole-3-spiro-2'-
1
177.25, 197.25; IR (KBr) ν: 1707.1, 1678.2 cm ; ESI
MS m/z: 677 [M＋H]＋. Anal. calcd for C36H29Cl4N3O2:
C 63.83, H 4.31, N 6.20; found C 63.94, H 4.27, N 6.24.
1"-Benzyl-5"-(4-methoxybenzylidene)-4'-(4-meth-
oxyphenyl)-1'-methyl-2,3-dihydro-1H-indole-3-spiro-
2'-pyrrolidine-3'-spiro-3"-piperidine-2,3"-dione (2e)
pyrrolidine-3'-spiro-3"-piperidine-2,3"-dione
(2b)
1
White solid, yield 82%; m.p. 211—212 ℃; H NMR
(CDCl3, 500 MHz) δ: 1.85 (d, J＝13.0 Hz, 1H), 2.13 (s,
3H), 2.73 (dd, J＝2.5, 14.5 Hz, 1H), 3.15 (d, J＝13.0
Hz, 1H), 3.33—3.38 (m, 2H), 3.44 (dd, J＝2.0, 12.5 Hz,
1H), 3.63 (d, J＝13.0 Hz, 1H), 3.89 (dd, J＝9.0, 10.5 Hz,
1H), 4.78 (dd, J＝7.5, 10.5 Hz, 1H) , 6.68 (d, J＝7.5 Hz,
1H), 6.83 (d, J＝8.5 Hz, 2H), 6.92—6.98 (m, 3H), 7.06—
7.12 (m, 3H), 7.16 (d, J＝8.5 Hz, 2H), 7.19—7.23 (m,
3H), 7.28 (d, J＝8.0 Hz, 2H), 7.39 (d, J＝8.0 Hz, 2H),
1
White solid, yield 85%; m.p. 215—216 ℃; H NMR
(CDCl3, 500 MHz) δ: 1.92 (d, J＝13.0 Hz, 1H), 2.13 (s,
3H), 2.80 (dd, J＝2.5, 14.5 Hz, 1H), 3.14 (d, J＝13.0
Hz, 1H), 3.35—3.38 (m, 2H), 3.42 (dd, J＝2.0, 13.0 Hz,
1H), 3.64 (d, J＝13.5 Hz, 1H), 3.75 (s, 3H), 3.81 (s, 3H),
3.90 (dd, J＝9.0, 11 Hz, 1H), 4.78 (dd, J＝7.5, 11.0 Hz,
1H), 6.67 (d, J＝7.5 Hz, 1H), 6.72 (d, J＝9.0 Hz, 2H),
Chin. J. Chem. 2010, 28, 434— 438
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
435

Li, Yu & Yi
FULL PAPER
6.85 (d, J＝9.0 Hz, 2H), 6.91 (t, J＝7.5 Hz, 1H), 6.94 (d,
J＝7.5 Hz, 2H), 6.99—7.01 (m, 2H), 7.07—7.12 (m,
2H), 7.16—7.22 (m, 4H), 7.38 (d, J＝8.5 Hz, 2H), 7.68
(bs, 1H); 13C NMR (CDCl3, 125 MHz) δ: 34.65, 45.77,
54.41, 55.24, 55.26, 57.17, 57.39, 62.53, 65.18, 76.38,
108.78, 113.60, 113.78, 122.06, 126.97, 127.42, 127.77,
128.07, 128.69, 130.59, 130.73, 130.90, 132.12, 137.11,
137.73, 142.01, 158.47, 160.00, 177.63, 199.00; IR
109.93, 122.77, 127.13, 127.43, 127.48, 127.53, 127.98,
128.21, 128.66, 129.03, 129.30, 129.36, 129.94, 130.36,
131.24, 132.12, 136.19, 137.57, 137.95, 143.26, －156.31,
1
177.67, 202.99; IR (KBr) ν: 1714.8, 1699.0 cm ; ESI
MS m/z: 727 [M＋H]＋. Anal. calcd for C43H36Cl2N4O3:
C 70.97, H 4.99, N 7.70; found C 70.91, H 5.12, N 7.58.
1'-Benzyl-4,4"-bis-(4-chlorophenyl)-3-(2,6-dichloro-
phenyl)-1"-methyl-4,5,2''',3'''-tetrahydro-1'''H-isoxa-
zole-5-spiro-3'-piperidine-5'-spiro-3"-pyrrolidine-2"-
spiro-3'''-indole-2",4'-dione (3b) White solid, yield
80%; m.p. 242—244 ℃; 1H NMR (CDCl3, 500 MHz) δ:
1.58 (d, J＝14.0 Hz, 1H), 2.13 (s, 3H), 2.29 (d, J＝14.0
Hz, 1H), 2.67 (d, J＝13.0 Hz, 1H), 3.04 (d, J＝13.0 Hz,
1H), 3.22 (d, J＝13.5 Hz 1H), 3.43—3.47 (m, 2H), 3.93
(t, J＝10.0 Hz, 1H), 4.39 (dd, J＝8.0, 10.0 Hz, 1H),
5.84 (s, 1H), 6.64—6.66 (m, 1H), 6.76—6.79 (m, 3H),
6.98—7.00 (m, 2H), 7.02—7.05 (m, 1H), 7.11—7.19 (m,
6H), 7.26—7.31 (m, 5H), 7.44 (d, J＝8.5 Hz, 2H), 7.68—
7.69 (m, 1H); 13C NMR (CDCl3, 125 MHz) δ: 34.41,
48.74, 52.94, 54.89, 57.52, 58.11, 62.47, 66.07, 76.83,
88.75, 109.57, 122.28, 126.58, 126.95, 127.44, 127.90,
128.35, 128.39, 128.61, 129.01, 130.15, 130.74, 131.07,
131.22, 132.91, 134.16, 135.67, 136.00, 136.86, 142.66,
－1
(KBr) ν: 1709.0, 1693.6 cm ; ESI MS m/z: 600 [M＋
H]＋. Anal. calcd for C38H37N3O4: C 76.10, H 6.22, N
7.01; found C 76.17, H 6.10, N 7.08.
1"-Benzyl-5"-[4-(methylthio)benzylidene]-4'-[4-
(methythio)phenyl]-1'-methyl-2,3-dihydro-1H-indole-
3-spiro-2'-pyrrolidine-3'-spiro-3"-piperidine-2,3"-
dione (2f) White solid, yield 85%; m.p. 198—200 ℃
1H NMR (CDCl3, 500 MHz) δ: 1.90 (d, J＝12.5 Hz, 1H),
2.14 (s, 3H), 2.43 (s, 3H), 2.48 (s, 3H), 2.79 (dd, J＝2.5,
14.5 Hz, 1H), 3.15 (d, J＝13.0 Hz, 1H), 3.34—3.39 (m,
2H), 3.43 (dd, J＝2.0, 13.0 Hz, 1H), 3.64 (d, J＝13.0
Hz, 1H), 3.91 (dd, J＝11.0, 10.5 Hz, 1H), 4.77 (dd, J＝
7.5, 11.0 Hz, 1H), 6.65 (d, J＝7.5 Hz, 1H), 6.88 (d, J＝
8.0 Hz, 2H), 6.92 (t, J＝7.5 Hz, 1H), 6.98—7.00 (m,
2H), 7.04 (d, J＝8.5 Hz, 2H), 7.08—7.10 (m, 2H), 7.15
(s, 1H), 7.18—7.22 (m, 5H), 7.38 (d, J＝8.5 Hz, 2H),
7.43 (bs, 1H); 13C NMR (CDCl3, 125 MHz) δ: 15.01,
15.98, 34.62, 45.96, 54.22, 57.10, 57.13, 62.42, 65.31,
76.30, 108.96, 122.08, 125.37, 126.54, 127.07, 127.26,
127.74, 128.13, 128.69, 128.86, 130.24, 130.62, 131.44,
132.20, 135.46, 136.72, 136.89, 137.45, 140.33, －142.12,
－1
155.49, 176.88, 202.28; IR (KBr) ν＋: 1716.3, 1696.7 cm ;
ESI MS m/z: 795 [M ＋ H] . Anal. calcd for
C43H34Cl4N4O3: C 64.84, H 4.30, N 7.03; found C 64.99,
H 4.38, N 6.89.
1'-Benzyl-4,4"-bis-(2-chlorophenyl)-3-(2,6-dichlo-
rophenyl)-1"-methyl-4,5,2''',3'''-tetrahydro-1'''H-isoxa-
zole-5-spiro-3'-piperidine-5'-spiro-3"-pyrrolidine-2"-
spiro-3'''-indole-2''',4'-dione (3c) White solid, yield
78%; m.p. 238—240 ℃; 1H NMR (CDCl3, 500 MHz) δ:
1.50 (d, J＝14.0 Hz, 1H), 2.13 (s, 3H), 2.45 (d, J＝14.0
Hz, 1H), 2.87 (d, J＝13.0 Hz, 1H), 3.10 (d, J＝13.0 Hz,
1H), 3.27 (d, J＝13.0 Hz, 1H), 3.46—3.50 (m, 2H), 3.92
(t, J＝9.5 Hz, 1H), 5.01 (dd, J＝8.5, 9.5 Hz, 1H), 6.66 (d,
J＝7.5 Hz, 1H), 6.71 (s, 1H), 6.80—6.81 (m, 2H), 6.89—
6.92 (m, 1H), 6.95—6.99 (m, 2H), 7.06—7.20 (m, 8H),
7.23—7.26 (m, 2H), 7.39 (dd, J＝7.5, 1 Hz, 1H), 7.44
(d, J＝8.5 Hz, 2H), 7.69 (bs, 1H), 8.08 (d, J＝7.5 Hz,
1H); 13C NMR (CDCl3, 125 MHz) δ: 34.55, 44.94,
53.08, 53.81, 54.52, 58.43, 63.01, 64.38, 77.87, 89.65,
109.32, 123.38, 125.84, 126.31, 126.80, 126.89, 126.96,
127.17, 127.85, 127.99, 128.05, 128.43, 128.56, 128.64,
128.74, 129.35, 129.46, 129.64, 129.67, 130.92, 131.10,
131.56, 134.48, 135.71, 135.93, 136.45, 137.42, 142.26,
1
177.81, 198.86; IR (KBr) ν: 1702.8, 1689.8 cm ; ESI
MS m/z: 632 [M＋H]＋. Anal. calcd for C38H37N3O2S2:
C 72.23, H 5.90, N 6.65; found C 72.10, H 5.99, N 6.60.
General procedure for the synthesis of 4,4"-diaryl-1'-
benzyl-3-(2,6-dichlorophenyl)-1"-methyl-4,5,2''',3'''-
tetrahydro-1'''H-isoxazole-5-spiro-3'-piperidine-2"-
spiro-3"-indole-4',2"-diones (3a— 3f)
A mixture of 2 (1 mmol) and 2,6-dichloro-benzonitrile
oxide (1.5 mmol) was dissolved in dry benzene (30 mL)
and heated to reflux for 24 h. After completion of the
reaction as evident from TLC, the solvent was evapo-
rated in vacuum. The residue was purified by column
chromatography employing petroleum ether/ethyl ace-
tate mixture (5∶1, V/V) as eluent to obtain 3.
1'-Benzyl-3-(2,6-dichlorophenyl)-1"-methyl-4,4"-
diphenyl-4,5,2''',3'''-tetrahydro-1'''H-isoxazole-5-spiro-
3'-piperidine-5'-spiro-3"-pyrrolidine-2"-spiro-3'''-1-
indole-2''',4'-dione (3a) White solid, yield 83%; m.p.
－1
155.51, 177.25, 201.05; IR ＋(KBr) ν: 1698.6, 1692.9 cm ;
ESI MS m/z: 795 [M＋H] . Anal. calcd for C43H34Cl4-
N4O3: C 64.84, H 4.30, N 7.03; found C 64.93, H 4.25,
N 7.15.
1
225—226 ℃; H NMR (CDCl3, 500 MHz) δ: 1.56 (d,
J＝14.0 Hz, 1H), 2.13 (s, 3H), 2.31 (d, J＝14.0 Hz, 1H),
2.71 (d, J＝13.0 Hz, 1H), 3.07 (d, J＝13.0 Hz, 1H),
3.19 (d, J＝13.0 Hz, 1H), 3.42—3.49 (m, 2H), 4.01 (t,
J＝10.0 Hz, 1H), 4.46 (dd, J＝8.0, 10.0 Hz, 1H), 5.87 (s,
1H), 6.62 (d, J＝6.0 Hz, 1H), 6.65—6.78 (m, 2H), 6.83—
6.86 (m, 2H), 6.98—7.10 (m, 9H), 7.12—7.18 (m, 5H),
7.24—7.36 (m, 1H), 7.51 (d, J＝6.0 Hz, 2H), 7.70 (bs,
1H); 13C NMR (CDCl3, 125 MHz) δ: 34.87, 49.33,
52.90, 54.84, 57.52, 58.73, 62.51, 66.23, 76.84, 88.95,
1'-Benzyl-4,4"-bis-(2,4-dichloro)phenyl-3-(2,6-di-
chlorophenyl)-1"-methyl-4,5,2''',3'''-tetrahydro-1'''H-
isoxazole-5-spiro-3'-piperidine-5'-spiro-3"-pyrrolidine-
2"-spiro-3'''-indole-2''',4'-dione (3d)
White solid,
1
yield 70%; m.p. 250—251 ℃; H NMR (CDCl3, 500
MHz) δ: 1.51 (d, J＝14.0 Hz, 1H), 2.12 (s, 3H), 2.40 (d,
J＝14.0 Hz, 1H), 2.83 (d, J＝12.5 Hz, 1H), 3.07 (d, J＝
12.5 Hz, 1H), 3.28 (d, J＝13.0 Hz, 1H), 3.47—3.51 (m,
436
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 434— 438

Synthesis of Novel Trispiroheterocycles through 1,3-Dipolar Cycloaddition
2H), 3.85 (t, J＝9.5 Hz, 1H), 4.92 (t, J＝9.5 Hz, 1H),
6.64 (s, 1H), 6.68—6.71 (m, 1H), 6.81—6.82 (m, 2H),
6.91—6.97 (m, 2H), 7.06—7.18 (m, 8H), 7.26—7.30 (m,
3H), 7.39—7.40 (m, 1H), 7.55 (bs, 1H), 8.01 (d, J＝8.5
Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ: 34.51, 44.53,
52.97, 53.35, 54.57, 58.41, 62.96, 67.08, 77.78, 89.46,
109.40, 123.32, 126.38, 126.46, 126.71, 127.03, 127.11,
127.98, 128.02, 128.56, 128.87, 129.32, 129.56, 131.17,
132.01, 132.13, 133.17, 134.35, 134.72, 135.86, 137.01,
137.20, 142.19, 155.24, 176.90, 200.81; IR (KBr) ν:
Results and discussion
The 1,3-dipolar cycloaddition of the azomethine
ylide generated in situ from isatin and sarcosine to
1-benzyl-3,5-diarylmethylidene-piperidin-4-one 1a—1f
afforded novel di-spiropyrrolidines 2a—2f in moderate to
good yields (80%—85%) (Scheme 1). This cycloaddi-
tion reaction proceeds with high stereo- and regioselec-
tivity to afford only one isomer, which was evidenced
1
from TLC and H NMR of the crude reaction mixture.
－1
The 1H NMR spectrum of 2b demonstrates the presence
of three CH2 doublets at δ 1.85, 3.15, 3.63; two doublets
of doublets of methylene proton at δ 2.73, 3.44, 3.89 and
4.78 and two singlets at δ 2.13 and 7.56 assignable to
the NCH3 and NH respectively. The 13C NMR spectrum
of 2b demonstrates the presence of two spiro carbon
atoms at δ 65.43 and 76.07, two carbonyl carbon atoms
at δ 177.48 and 199.72. Further, the structure of the
product was confirmed by X-ray diffraction analysis of
2a18 (Figure 1).
＋
1703.2, 1696.4 cm ; ESI MS m/z: 863 [M＋H] . Anal.
calcd for C43H32Cl6N4O3: C 59.67, H 3.73, N 6.47; found
C 59.57, H 3.90, N 6.61.
1'-Benzyl-4,4"-bis-(4-methoxyphenyl)-3-(2,6-di-
chlorophenyl)-1"-methyl-4,5,2''',3'''-tetrahydro-1'''H-
isoxazole-5-spiro-3'-piperidine-5'-spiro-3"-pyrrolidine-
2"-spiro-3'''-indole-2''',4'-dione (3e) White solid, yield
73%; m.p. 220—221 ℃; 1H NMR (CDCl3, 500 MHz) δ:
1.60 (d, J＝14.0 Hz, 1H), 2.12 (s, 3H), 2.29 (d, J＝14.0
Hz, 1H), 2.69 (d, J＝13.0 Hz, 1H), 3.04 (d, J＝13.0 Hz,
1H), 3.20 (d, J＝13.5 Hz, 1H), 3.40—3.46 (m, 2H), 3.65
(s, 3H), 3.81 (s, 3H), 3.94 (t, J＝9.5 Hz, 1H), 4.40 (dd,
J＝8.0, 10.5 Hz, 1H), 5.81 (s, 1H), 6.52 (d, J＝8.5 Hz,
2H), 6.65 (d, J＝7.5 Hz, 1H), 6.75 (d, J＝8.5 Hz, 2H),
6.79—6.80 (m, 2H), 6.87 (d, J＝8.5 Hz, 2H), 7.03—
7.06 (m, 1H), 7.10—7.17 (m, 6H), 7.25—7.27 (m, 2H),
7.43 (d, J＝8.5 Hz, 2H), 7.58 (bs, 1H); 13C NMR
(CDCl3, 125 MHz) δ: 34.51, 48.74, 53.11, 55.07, 55.25,
57.75, 58.16, 62.59, 66.30, 76.92, 88.84, 109.43, 113.44,
113.63, 122.31, 123.67, 126.72, 127.11, 127.21, 127.52,
127.82, 128.70, 128.85, 128.95, 129.61, 130.68, 130.81,
130.93, 135.81, 137.34, 142.69, 156.04, 158.61, －159.21,
1
176.99, 202.90; IR (KBr) ν: 1711.3, 1698.9 cm ; ESI
MS m/z: 787 [M＋H]＋. Anal. calcd for C45H40Cl2N4O5:
C 68.61, H 5.12, N 7.11; found C 68.39, H 5.34, N 6.95.
1'-Benzyl-4,4"-bis-[4-(methylthio)phenyl]-3-(2,6-
dichlorophenyl)-1"-methyl-4,5,2''',3'''-tetrahydro-1'''H-
isoxazole-5-spiro-3'-piperidine-5'-spiro-3''-pyrrolidine-
2"-spiro-3'''-indole-2''',4'-dione (3f) White solid, yield
Figure 1 Molecular skeleton structure of compound 2a.
The spiro-pyrrolidines 2 were subsequently reacted
with nitrile oxide (Scheme 1) and tri-spiroheterocycles 3
were obtained in 70%—83% yields. The stereo- and
regioselectivity of this cycloaddition reaction was evi-
1
70%; m.p. 234—235 ℃; H NMR (DMSO-d6, 500
MHz) δ: 1.63 (d, J＝14.0 Hz, 1H), 2.13 (s, 3H), 2.30 (d,
J＝14.0 Hz, 1H), 2.35 (s, 3H), 2.49 (s, 3H), 2.70 (d, J＝
13.0 Hz, 1H), 3.05 (d, J＝13.0 Hz, 1H), 3.22 (d, J＝
13.5 Hz, 1H), 3.42—3.44 (m, 2H), 3.95 (t, J＝10.0 Hz,
1H), 4.39 (dd, J＝8.0, 10.0 Hz, 1H), 5.81 (s, 1H), 6.63
(d, J＝7.5 Hz, 1H), 6.75 (d, J＝8.0 Hz, 2H), 6.79—6.81
(m, 2H), 6.86 (d, J＝8.0 Hz, 2H), 7.04—7.06 (m, 2H),
7.13—7.17 (m, 5H), 7.22 (d, J＝8.5 Hz, 2H), 7.26—
7.28 (m, 3H), 7.43 (d, J＝8.0 Hz, 2H), 7.47 (bs, 1H);
13C NMR (CDCl3, 125 MHz) δ: 15.32, 15.94, 34.50,
49.00, 52.98, 55.04, 57.52, 58.34, 62.50, 66.25, 88.87,
109.46, 122.31, 125.72, 126.54, 126.84, 126.91, 127.10,
127.55, 127.86, 128.23, 128.69, 128.93, 129.01, 130.39,
130.94, 134.44, 135.79, 136.91, 137.18, 142.64, －155.78,
1
denced from TLC and H NMR of the crude reaction
mixture. In the molecular structure of 2a, the oxindole
ring is located above the double bond plane of aryl-
methylidene, the 2,6-dichloro-benzonitrile oxide (PNO)
can only attack the double bond plane of aryl-
methylidene from the other side which is less sterically
hindered. This induced the stereoselectivity of the reac-
tion (Figure 2). The structure of 3a—3f was elucidated
using NMR spectroscopic data and the part HMBC dia-
gram of 3b is shown in Figure 3. The complete stereo-
chemistry of 3a was obtained from corresponding single
crystal X-ray diffraction research of 3a19 (Figure 4).
1
Conclusion
176.73, 202.61; IR (KBr) ν: 1707.4, 1697.2 cm ; ESI
MS m/z: 819 [M＋H]＋. Anal. calcd for C45H40Cl2N4O3S2:
A facile and novel synthesis of tri-spiroheterocycles
was accomplished by the 1,3-dipolar cycloaddition of
C 65.92, H 4.92, N 6.83; found C 65.71, H 4.79, N 6.90.
Chin. J. Chem. 2010, 28, 434— 438
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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437

Li, Yu & Yi
FULL PAPER
to 1-benzyl-3,5-diarylmethylidene-piperidin-4-ones in
moderate to good yields. The stereo- and regioselectivi-
ties of these reactions were demonstrated by single
crystal X-ray diffraction.
References
1
2
3
4
5
6
7
Cravotto, G.; Giovenzana, G. B.; Pilati, T.; Sisti, M.;
Palmisano, G. J. Org. Chem. 2001, 66, 8447.
Onishi, T.; Sebahar, P. R.; Williams, R. M. Org. Lett. 2003,
5, 3135.
Grigg, R.; Millington, E. L.; Thornton-Pett, M. Tetrahedron
Lett. 2002, 43, 2605.
Diana, G. D.; McKinlay, M. A.; Brisson, C. J.; Zalay, E. S.;
Miralles, J. V. J. Med. Chem. 1985, 28, 748.
Lepage, F.; Tombert, F.; Cuvier, G.; Marivain, A.; Gillardin,
J. M. Eur. J. Med. Chem. 1992, 27, 581.
Ryng, S.; Machon, Z.; Wieczorek, Z.; Zimecki, M.; Mok-
rosz, M. Eur. J. Med. Chem. 1998, 33, 831.
Mai, A.; Cheng, D.; Bedford, M. T.; Valente, S.; Nebbioso,
A.; Perrone, A.; Brosch, G.; Sbardella, G.; Bellis, F. D.;
Miceli, O. M.; Altucci, L. J. Med. Chem. 2008, 51, 2279.
Kumar, R. R.; Perumal, S.; Senthilkumar, P.; Yogeeswari,
P.; Sriram, D. J. Med. Chem. 2008, 51, 5731.
Figure 2 Stereoselectivity mechanism of 3.
Figure 3 Part HMBC diagram of 3b.
8
9
Metwally, K. A.; Dukat, M. J. Med. Chem. 1998, 41, 5084.
10 Kumar, R. R.; Perumal, S.; Senthilkumar, P.; Yogeeswari,
P.; Sriram, D. Tetrahedron 2008, 64, 2962.
11 Sebahar, P. R.; Williams, R. M. J. Am. Chem. Soc. 2000,
122, 5666.
12 Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209.
13 Nicholas, G. M.; Eckman, L. L.; Newton, G. L. Bioorg. Med.
Chem. 2003, 11, 601.
14 Patrizia, C.; Carmela, D.; Ernesto, F. J. Nat. Prod. 1999, 62,
590.
15 Kumar, R. R.; Perumal, S. Tetrahedron 2007, 63, 12220.
16 Grundamann, C.; Dean, J. M. J. Org. Chem. 1965, 30, 2810.
17 Buu-Hoi, N. P.; Roussel, M. O. Bull. Soc. Chem. Fr. 1964,
3096.
18 Li, X. F.; Feng, Y. Q.; Hu, X. F.; Xu, M. Acta Crys. 2003,
E59, 711.
Figure 4 Molecular skeleton structure of compound 3a.19
nitrile oxide with di-spiropyrrolidines, which were ob-
tained by 1,3-dipolar cycloaddition of azomethine ylide
19 Li, X. F.; Feng, Y. Q.; Hu, X. F.; Xu, M. Acta Cryst. 2003,
E59, 1280.
(E0908242 Cheng, F.; Zheng, G.)
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 434— 438