Diastereoselective synthesis of novel spiro-isoxazolidines via [3 + 2] cycloaddition

Article abstract of DOI:10.1080/00397911.2011.622063

In this protocol, synthesis of novel 2,5-diphenyl-3,3-spiropentamethylene- 5H-2,3,3a,6a-tetrahydropyrrolo[3,4-d]isoxazole-4,6-diones through [3 + 2] cycloaddition of N-cyclohexylidene N-phenyl nitrones with cyclic dipolarophiles is described. 1,3-Dipolar

Full text of DOI:10.1080/00397911.2011.622063

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Diastereoselective Synthesis of
Novel Spiro-Isoxazolidines via [3 + 2]
Cycloaddition
Sakshi Shah a , Rahul Badru a & Baldev Singh a
a Department of Chemistry, Punjabi University, Patiala, Punjab, India
Accepted author version posted online: 22 Feb 2012.Version of
record first published: 07 Jan 2013.
To cite this article: Sakshi Shah , Rahul Badru & Baldev Singh (2013): Diastereoselective Synthesis
of Novel Spiro-Isoxazolidines via [3 + 2] Cycloaddition, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 43:7, 1073-1082
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Synthetic Communications1, 43: 1073–1082, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.622063
DIASTEREOSELECTIVE SYNTHESIS OF NOVEL
SPIRO-ISOXAZOLIDINES VIA [3 þ 2] CYCLOADDITION
Sakshi Shah, Rahul Badru, and Baldev Singh
Department of Chemistry, Punjabi University, Patiala, Punjab, India
GRAPHICAL ABSTRACT
Abstract In this protocol, synthesis of novel 2,5-diphenyl-3,3-spiropentamethylene-5H-
2,3,3a,6a-tetrahydropyrrolo[3,4-d]isoxazole-4,6-diones through [3 þ 2] cycloaddition of
N-cyclohexylidene N-phenyl nitrones with cyclic dipolarophiles is described. 1,3-Dipolar
cycloaddition of nitrones with substituted N-arylmaleimides gives exclusively endo-diaster-
eoisomers of spiro-isoxazolidines and their stereochemistry was assigned using 1H NMR and
1H-1H correlation spectroscopic studies.
Keywords [3 þ 2] Cycloaddition; N-arylmaleimides; N-cyclohexylidene n-phenyl nitrone;
spiro-isoxazolidines
INTRODUCTION
Spiro compounds having cyclic structures fused at a central carbon are of cur-
rent interest because of their interesting conformational features and their structural
implications on biological systems. The asymmetric characteristic of the molecule
due to the chiral spiro carbon is one of the significant factors for the biological
activities. Spiro compounds exhibit prominent pharmacological activities and have
been used in the chemistry of natural products as more complex heterocycles.[1–3]
These can be synthesized through cycloaddition of 1,3-dipoles obtained from
cyclic ketones, namely, nitrones and olefins.[4] Nitrones occupy a special position
in 1,3-dipoles and dipolar cycloaddition reactions because of their greater stability,
isolatability, and regioselective behavior in comparison to other 1,3-dipoles.[5,6]
Isoxazolidines are synthesized through 1,3-dipolar cycloaddition reactions
[7,8]
of 1,3-dipoles and dipolarophiles
in a single concerted step with two or more
Received July 11, 2011.
Address correspondence to Sakshi Shah, Department of Chemistry, Punjabi University, Patiala 147
002, Punjab, India. E-mail: sakshishah29@gmail.com
1073

1074
S. SHAH, R. BADRU, AND B. SINGH
stereogenic centers[9,10] and are potential precursors for the synthesis of extremely
useful natural products such as sugar derivatives, b-lactams, amino acids, and
alkaloids.[11–16] They can be further explored into polyfunctional cyclic or acyclic
bioactive molecules with complete control of relative stereochemistry.[17]
The biological applications of spiro-compounds and (spiro) isoxazolidines[18–20]
prompted us to synthesize spiro-isoxazolidines. In the present study synthesis of
novel 2,5-diphenyl-3,3-spiropentamethylene-5H-2,3,3a,6a-tetrahydropyrrolo[3,4-
d]isoxazole-4,6-diones by reacting substituted N-arylmaleimides and N-cyclohexyl-
diene N-phenyl nitrones is described.
RESULTS AND DISCUSSION
For these [3 þ 2] cycloaddition reactions, an equimolar mixture of freshly
prepared N-cyclohexyldiene N-phenyl nitrones (prepared from condensation of
cyclohexanone 1 with phenylhydroxyamine, Scheme 1) 3 with N-phenylmaleimide
4 was refluxed in toluene to provide single endo-diastereoisomers 5 in good yields
(Scheme 1, Table 1), which were characterized as substituted 3-spiro-isoxazolidines
1
through their spectral analysis (i.e., IR, H NMR, mass, etc). In their IR spectra,
these derivatives show carbonyl stretching vibrations of succinimide moiety and
strong absorption bands in the range of 1690–1786 cmꢀ1
.
In 1H NMR spectrum of 2-phenyl-5-p-tolyl-3,3-spiropentamethylene-5H-
2,3,3a,6a-tetrahydropyrrolo[3,4-d]isoxazole-4,6-dione (5b), two doublets at d 3.76
and d 4.97 were observed for cis-protons C3a-H and C6a-H with coupling constants
1
J ¼ 7.44 Hz.(J3a-6a) for each proton. This was also supported by their H-1H corre-
lation spectrum (COSY, Fig. 1) of product 5b, which assigned them to H-3a and
H-6a, respectively. A multiplet equivalent to 10 protons at d 1.02–2.04 has been
assigned to 10 methylenic protons of the cyclohexylidene moiety and another multi-
plet at d 7.16–7.36 has been assigned to N-aryl protons. Proton C6a-H shows a slight
downfield chemical shift as compared to proton C3a-H, due to the presence of an
electronegative oxygen atom at 1-position and carbonyl group at 6-position. In its
13C NMR spectrum, compound 5b displays a signal at d 21.3, which has been
assigned to the methyl group. A multiplet signal at d 23.1–32.2 has been assigned
to five methylenic carbons of cyclohexyl moiety, while a signal at d 53.0 has been
Scheme 1. Stereoselective synthesis of various 3-spiro-isoxazolidines.

NOVEL SPIRO-ISOXAZOLIDINES
1075
Table 1. Synthesis of spiro-isoxazolidines with stereo-isomeric excess
Entry
Nitrone
Dipolarophile
Productsa Time (h) Yieldb (%) Mp (ꢁC)
1
5a
5b
4.5
70
72
198–199
195–197
2
3
4
5
5
5c
5d
5e
5.5
6.5
6.5
75
69
65
210–215
190–192
201–202
6
5f
5
69
200–202
7
5 g
5.5
65
193–195
(Continued )

1076
S. SHAH, R. BADRU, AND B. SINGH
Table 1. Continued
Entry
Nitrone
Dipolarophile
Productsa Time (h) Yieldb (%) Mp (ꢁC)
8
5 h
6
67
64
72
183–184
230–232
194–195
9
5i
6.5
10
5j
4.5
11
5k
6.5
62
205–207
12
5 l
6
61
185–187
aThe products were characterized by spectral techniques like IR, 1H NMR, 13CNMR, and mass.
bIsolated yields after recrystallization.
assigned to the C3-carbon. Another two signals at d 72.4 and d 74.4 have been
assigned to C3a and C6a carbon atoms respectively. A multiplet signal at d 123.0–
143.2 has been assigned to aromatic carbon while two other signals at d 173.9 and
d 174.3 have been assigned to two carbon atoms of the carbonyl group.
The only single isolated diastereoisomer seems to arise through endo transition
state (TS 2, Scheme 2) where one of the carbonyl groups of succinimide moiety
comes parallel to the N-phenyl moiety of nitrone during their approach to each
other, thus stabilizing the endo transition state through maximum accumulation of

NOVEL SPIRO-ISOXAZOLIDINES
1077
Figure 1. 1H-1H-COSY correlation spectrum of product 5b.
double bond of dipole and dipolarophile as compared to the exo transition state (TS
1, Scheme 2) where the N-phenyl maleimide approaches from the other side of
nitrone and no secondary interaction stabilization occurs. Thus, these 1,3-dipolar
cycloadditions reported here are regioselective in nature, following the cis-endo
addition rule.
Scheme 2. Possible transition state (TS).

1078
S. SHAH, R. BADRU, AND B. SINGH
In conclusion, the present method is facile, efficient, and catalyst-free for the
synthesis of spiro-isoxazolidines cycloadduct with one endo-diastereoisomer. The
employed N-oxide of cyclohexanone is very stable and affords end products in good
yields. The attractive feature is the generation of only one stereoisomer without
adopting any vigorous reaction conditions or chiral-catalyst=bio catalyst.
EXPERIMENTAL
Melting points reported are uncorrected. IR spectra were recorded on a Perkin
1
Elmer RXIFT IR spectrophotometer using KBr pellets. H NMR, 13C NMR, and
1H-1H-COSY spectra were recorded on a 400-MHz Bruker spectrometer using
tetramethylsilane (TMS) as internal standard. Mass spectra were recorded on Waters
Micromass Q-T of Micro (ESI) spectrometer. Elemental analysis was carried out
using an Elementar Vario Micro cube CHN analyzer. Thin-layer chromatographic
(TLC) plates were coated with silica gel G suspended in methanol–chloroform.
General Procedure for the Synthesis of 3-Spiro-isoxazolidines
Nitrones 3a–c (10 mmol) and substituted N-aryl maleimides 4a–e (10 mmol)
were refluxed in toluene (20 ml) for 4.5–6.5 h (Table 1). Reaction completion was
monitored by TLC using mobile phase (ethyl acetate–petroleum ether; 1:9). After
the completion of the reaction, excess solvent was pulled off under vacuum, provid-
ing crude products, which were purified using silica-gel column chromatography
employing ethyl acetate–petroleum ether (1:9) as eluent and recrystallized from a
mixture of ethyl acetate–petroleum ether to provide only cis products in 61–75%
yields (Table 1).
2,5-Diphenyl-3,3-spiropentamethylene-5H-2,3,3a,
6a-tetrahydropyrrolo[3,4-d]isoxazole-4,6-diones (5a)
IR (KBr): nmax ¼ 1786, 1697, 1610, 1410–1220 cmꢀ1
;
1H NMR (CDCl3): d
1.01–2.07 (m, 10H), 3.71 (d, 3a-H, 1H, J ¼ 7.58 Hz), 4.93 (d, 6a-H, 1H, J ¼ 7.58 Hz),
7.16–7.51 (m, Ar-H, 10H) ppm;13C NMR (CDCl3): d 23.3, 23.5, 25.7, 28.6, 32.5, 53.2,
72.5, 74.7, 123.1, 124.2, 126.0, 126.2, 128.1, 128.9, 137.2, 143.4, 174.0, 174.5 ppm; MS:
m=z: 362 [M]þ. Anal. calcd. for C22H22N2O3: C, 72.93; H, 6.08; N, 7.74. Found: C,
72.82; H, 6.18; N, 7.66.
2-Phenyl-5-p-tolyl-3,3-spiropentamethylene-5H-2,3,3a,
6a-tetrahydropyrrolo[3,4-d]isoxazole-4,6-diones (5b)
IR (KBr): nmax ¼ 1785, 1692, 1600, 1410–1220 cmꢀ1
;
1H NMR (CDCl3): d
1.02–2.04 (m, 10H), 2.38 (s, 3H), 3.76 (d, 3a-H, 1H, J ¼ 7.48 Hz), 4.97 (d, 6a-H,
1H, J ¼ 7.44 Hz), 7.16–7.36 (m, Ar-H, 9H) ppm;13C NMR (CDCl3): d 21.3, 23.1,
23.5, 25.4, 28.9, 32.2, 53.0, 72.4, 74.4, 123.0, 126.0, 126.2, 128.1, 128.9, 129.9,
139.0, 143.2, 173.9, 174.3 ppm; MS: m=z: 376 [M]þ. Anal. calcd. for C23H24N2O3:
C, 73.40; H, 6.38; N, 7.45. Found: C, 73.48; H, 6.26; N, 7.53.

NOVEL SPIRO-ISOXAZOLIDINES
1079
2-Phenyl-5-p-anisyl-3,3-spiropentamethylene-5H-2,3,3a,
6a-tetrahydropyrrolo[3,4-d]isoxazole-4,6-diones (5c)
IR (KBr): nmax ¼ 1783, 1706, 1605, 1410–1225 cmꢀ1
;
1H NMR (CDCl3): d
1.02–2.05 (m, 10H), 3.8 (s, 3H), 4.1 (d, 3a-H, 1H, J ¼ 7.46 Hz), 5.3 (d, 6a-H, 1H,
J ¼ 7.46 Hz), 7.10-7.43 (m, Ar-H, 9H) ppm;13C NMR (CDCl3): d 23.0, 23.3, 25.6,
29.0, 32.5, 53.5, 55.6, 72.2, 74.7, 113.8, 123.5, 126.2, 128.2, 128.1, 133.4, 139.4,
158.3, 173.7, 174.8 ppm; MS: m=z: 392 [M]þ. Anal. calcd. for C23H24N2O4: C,
70.41; H, 6.12; N, 7.14. Found: C, 70.35; H, 6.27; N, 7.22.
2-Phenyl-5-p-cl-phenyl-3,3-spiropentamethylene-5H-2,3,3a,
6a-tetrahydropyrrolo[3,4-d]isoxazole-4,6-diones (5d)
IR (KBr): nmax ¼ 1766, 1700, 1610, 1210–1070 cmꢀ1
;
1H NMR (CDCl3): d
1.01–2.04 (m, 10H), 4.2 (d, 3a-H, 1H, J ¼ 7.40 Hz), 5.4 (d, 6a-H, 1H, J ¼ 7.41 Hz),
7.25–7.55 (m, Ar-H, 9H) ppm; 13C NMR (CDCl3): d 22.8, 24.0, 25.3, 28.7, 32.2,
53.7, 72.7, 74.9, 123.8, 124.2, 126.0, 126.7, 128.1, 135.0, 139.6, 143.7, 174.2,
174.8 ppm; MS: m=z: 397 [M]þ. Anal. calcd. for C22H21N2O3Cl: C, 66.58; H, 5.30;
N, 7.06. Found: C, 66.61; H, 5.24; N, 7.19.
2-Phenyl-5-m-nitro-phenyl-3,3-spiropentamethylene-5H-2,3,3a,
6a-tetrahydropyrrolo[3,4-d]isoxazole-4,6-diones (5e)
IR (KBr): nmax ¼ 1784, 1699, 1610, 1410–1060 cmꢀ1
;
1H NMR (CDCl3): d
1.03–2.06 (m, 10H), 4.25 (d, 3a-H, 1H, J ¼ 7.45), 5.5 (d, 6a-H, 1H, J ¼ 7.45 Hz),
7.26–7.87 (m, Ar-H, 9H) ppm; 13C NMR (CDCl3): d 23.1, 23.5, 25.4, 28.9, 32.2,
53.0, 72.4, 74.4, 120.1, 123.6, 125.5, 126.1, 127.1, 128.3, 132.9, 137.2, 143.2, 148.6,
173.9, 174.3 ppm; MS: m=z: 407 [M]þ. Anal. calcd. for C22H21N3O5: C, 64.86; H,
5.16; N, 10.32. Found: C, 64.75; H, 5.31; N, 10.41.
2,5-p-Ditolyl-3,3-spiropentamethylene-5H-2,3,3a,
6a-tetrahydropyrrolo[3,4-d]isoxazole-4,6-diones (5f)
IR (KBr): nmax ¼ 1783, 1702, 1600, 1200–1030 cmꢀ1
;
1H NMR (CDCl3): d
1.02–2.03 (m, 10H), 2.46 (s, 6H), 3.7 (d, 3a-H, 1H, J ¼ 7.56 Hz), 4.6 (d, 6a-H, 1H,
J ¼ 7.56 Hz), 7.16–7.36 (m, Ar-H, 8H) ppm; 13C NMR (CDCl3): d 21.3, 21.8, 23.1,
23.2, 25.7, 28.8, 32.6, 53.4, 72.8, 74.7, 126.0, 126.4, 128.1, 128.6, 129.4, 129.7,
138.7, 142.9, 174.9, 175.3 ppm; MS: m=z: 390 [M]þ. Anal. calcd. for C24H26N2O3:
C, 73.85; H, 6.67; N, 7.18. Found: C, 73.77; H, 6.71; N, 7.27.
2-Tolyl-5-p-anisyl-3,3-spiropentamethylene-5H-2,3,3a,
6a-tetrahydropyrrolo[3,4-d]isoxazole-4,6-diones (5g)
IR (KBr): nmax ¼ 1776, 1700, 1610, 1225–1035 cmꢀ1
;
1H NMR (CDCl3): d
1.03–2.05 (m, 10H), 3.6 (d, 3a-H, 1H, J ¼ 7.49 Hz), 4.8 (d, 6a-H, 1H, J ¼ 7.49 Hz),
2.53 (s, 3H), 3.87 (s, OCH3, 3H), 7.12–7.45 (m, Ar-H, 8H) ppm;13C NMR (CDCl3):
d 22.0, 23.1, 23.0, 25.6, 29.0, 32.3, 53.3, 55.4, 72.4, 74.5, 113.5, 126.5, 127.3, 128.5,

1080
S. SHAH, R. BADRU, AND B. SINGH
129.5, 133.6, 139.5, 158.2, 173.7, 174.6 ppm; MS: m=z: 406 [M]þ. Anal. calcd. for
C24H26N2O4: C, 70.94; H, 6.40; N, 6.90. Found: C, 71.06; H, 6.32; N, 6.98.
2-Tolyl-5-p-cl-phenyl-3,3-spiropentamethylene-5H-2,3,3a,
6a-tetrahydropyrrolo[3,4-d]isoxazole-4,6-diones (5h)
IR (KBr): nmax ¼ 1784, 1699, 1610, 1200–1070 cmꢀ1
;
1H NMR (CDCl3): d
1.06–2.07 (m, 10H), 2.83 (s, 3H), 3.9 (d, 3a-H, 1H, J ¼ 7.44 Hz), 5.2 (d, 6a-H, 1H,
J ¼ 7.44 Hz), 7.16–7.65 (m, Ar-H, 8H) ppm;13CNMR (CDCl3): d 21.8, 23.7, 23.9,
25.6, 28.8, 32.7, 53.8, 72.6, 74.4, 126.1, 126.4, 127.9, 128.5, 129.0, 134.9, 139.6,
143.2, 174.1, 174.7 ppm; MS: m=z: 411 [M]þ. Anal. calcd. for C23H23N2O3Cl: C,
67.24; H, 5.60; N, 6.82. Found: C, 67.36; H, 5.48; N, 6.87.
2-Tolyl-5-m-nitro-phenyl-3,3-spiropentamethylene-5H-2,3,3a,
6a-tetrahydropyrrolo[3,4-d]isoxazole-4,6-diones (5i)
IR (KBr): nmax ¼ 1786, 1677, 1600, 1210–1170 cmꢀ1
;
1H NMR (CDCl3): d
1.05–2.12 (m, 10H), 2.77 (s, 3H), 4.20 (d, 3a-H, 1H, J ¼ 7.49), 5.43 (d, 6a-H, 1H,
J ¼ 7.48 Hz), 7.16–7.67 (m, Ar-H, 8H) ppm; 13C NMR (CDCl3): d 21.4, 23.2, 23.5,
25.7, 28.7, 32.25, 53.3, 73.0, 74.3, 120.8, 126.0, 126.6, 127.9, 128.1, 129.6, 132.9,
139.0, 142.7, 146.2, 173.6, 174.3 ppm; MS: m=z 421 [M]þ. Anal. calcd. for
C23H23N3O5: C, 65.56; H, 5.46; N, 9.98. Found: C, 65.42; H, 5.58; N, 10.09.
2-Cl-5-phenyl-3,3-spiropentamethylene-5H-2,3,3a,
6a-tetrahydropyrrolo[3,4-d]isoxazole-4,6-diones (5j)
IR (KBr): nmax ¼ 1783, 1694, 1600, 1210–1070 cmꢀ1
;
1H NMR (CDCl3) d
1.07–2.09 (m, 10H), 4.1(d, 3a-H, 1H, J ¼ 7.55 Hz), 5.3 (d, 6a-H, 1H, J ¼ 7.55 Hz),
7.32–7.76 (m, Ar-H, 9H) ppm; 13CNMR (CDCl3): d 22.9, 23.5, 25.4, 27.9, 33.0,
52.9, 73.0, 74.2, 123.3, 124.2, 126.3, 126.9, 128.4, 135.5, 138.9, 143.6, 174.3,
175.0 ppm; MS: m=z: 397 [M]þ. Anal. calcd. for C22H21N2O3Cl: C, 66.58; H, 5.30;
N, 7.06. Found: C, 66.65; H, 5.21; N, 7.17.
2-Cl-phenyl-5-m-nitro-phenyl-3,3-spiropentamethylene-5H-2,3,3a,
6a-tetrahydropyrrolo [3,4-d]isoxazole-4,6-diones (5k)
IR (KBr): nmax ¼ 1765, 1690, 1600, 1400–1150 cmꢀ1
;
1H NMR (CDCl3): d
1.03–2.06 (m,10H), 4.22 (d, 3a-H, 1H, J ¼ 7.48), 5.53 (d, 6a-H, 1H, J ¼ 7.48 Hz),
7.19–7.77 (m, Ar-H, 8H) ppm; 13C NMR (CDCl3): d 23.4, 23.2, 24.4, 28.6, 32.7,
53.0, 72.4, 74.4, 120.4, 123.0, 126.0, 126.2, 128.1, 128.9, 129.9, 132.8, 139.0, 143.2,
149.3, 174.9, 175.7 ppm; MS: m=z: 442 [M]þ. Anal. calcd. for C22H20N3O5Cl: C,
59.80; H, 4.53; N, 9.51. Found: C, 59.73; H, 4.66; N, 9.62.
2,5-p-Dichloro-diphenyl-3,3-spiropentamethylene-5H-2,3,3a,
6a-tetrahydropyrrolo[3,4-d]isoxazole-4,6-diones (5l)
IR (KBr): nmax ¼ 1776, 1695, 1600, 1200–1040 cmꢀ1
;
1H NMR (CDCl3):
1.09–2.10 (m, 10H), 4.2 (d, 3a-H, 1H, J ¼ 7.57 Hz), 5.4 (d, 6a-H, 1H, J ¼ 7.57 Hz),

NOVEL SPIRO-ISOXAZOLIDINES
1081
7.35–7.65 (m, 8H) ppm;13CNMR (CDCl3): d 23.8, 23.7, 25.4, 28.9, 33.2, 52.9, 72.4,
73.8, 126.3, 126.5, 127.8, 128.0, 135.3, 135.6, 142.9, 143.2, 173.3, 174.6 ppm; MS: m=
z: 431 [M]þ. Anal. calcd. for C22H20N2O3Cl2: C, 61.25; H, 4.64; N, 6.50. Found: C,
61.41; H, 4.57; N, 6.63.
ACKNOWLEDGMENTS
The authors are thankful to the University Grant Commission (UGC), New
Delhi, for financial assistance and the Sophisticated Analytical Instrumentation
Facility (SAIF), Panjab University, Chandigarh, for spectral analysis.
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