1,3-dipolar cycloaddition reactions leading to the synthesis of new 2,3,5-triaryl-4h,2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-diones

Article abstract of DOI:10.1002/jhet.1838

Cycloaddition of C,N-diphenylnitrones 1 to N-aryl maleimides 2 afforded two diastereomeric isoxazolidines with high selectivity. The structure and steric configuration of the adducts have been assigned on the basis of ¹H NMR, ¹H NMR COSY, ¹³C NMR and IR spectroscopy. The π-π stacking interactions between maleimide's and nitrone's aromatic rings during the 1,3-dipolar cycloaddition were assumed to control the exo-endo selectivity of the reaction. Thus, the exo-endo ratio depends upon the position of the substituent present on the C-phenyl ring of the C,N-diphenylnitrones.

Full text of DOI:10.1002/jhet.1838

Month 2014
1,3-Dipolar Cycloaddition Reactions Leading to the Synthesis of New 2,3,
5-Triaryl-4H,2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-diones
*
Anjandeep Kaur and Baldev Singh
Department of Chemistry, Punjabi University, Patiala 147002, Punjab, India
*
E-mail: drbaldev.chem@yahoo.com
Received June 3, 2012
DOI 10.1002/jhet.1838
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
Cycloaddition of C,N-diphenylnitrones 1 to N-aryl maleimides 2 afforded two diastereomeric isoxazolidines
with high selectivity. The structure and steric configuration of the adducts have been assigned on the basis of 1H
NMR, 1H NMR COSY, 13C NMR and IR spectroscopy. The p–p stacking interactions between maleimide’s
and nitrone’s aromatic rings during the 1,3-dipolar cycloaddition were assumed to control the exo–endo
selectivity of the reaction. Thus, the exo–endo ratio depends upon the position of the substituent present on
the C-phenyl ring of the C,N-diphenylnitrones.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
asymmetric synthesis [6]. Mechanistically, the nitrone
cycloaddition is a [4p + 2p]-type concerted process similar
to the Diels–Alder reaction. One of the reasons for the
success of the synthetic application of nitrones is that,
contrary to the majority of other 1,3-dipoles, most nitrones
are stable compounds that do not require in situ formation.
Their 1,3-dipolar cycloaddition reactions have a nearly
singular capability of establishing large number of stereo-
chemical centers in one synthetic step [7]. The ability to
utilize nitrone cycloaddition in organic synthesis depends
heavily on understanding the factors that determine the
stereochemistry of the reaction. In our work, we investigated
the effects of substituents on C-phenyl group of nitrones on
the exo–endo selectivity of cycloaddition reactions with
variously substituted maleimides. This could ensure an entry
to the control of the stereochemistry of cycloaddition, where
the p–p stacking interactions may play a crucial role.
The 1,3-dipolar cycloaddition reaction is one of the
most useful reactions for the synthesis of heterocyclic
compounds [1]. It has a nearly singular capability of establish-
ing large numbers of stereochemical centers in one synthetic
step [2]. In this line, an impressive effort has been devoted
to the synthetic application of the cycloaddition of nitrones.
Among a plethora of functional groups, the nitrone
functionality has etched a place of distinction in organic
synthesis [3]. Remarkable regioselectivity, stereoselectivity,
face selectivity, and chemoselectivity along with efficient
incorporation of multiple stereocenters have made nitrone
cycloaddition reactions an attractive and efficient key step
in the synthesis of a great many natural products of biological
interest such as isoxazolidines [4]. Isoxazolidine hetero-
cycles are commonly found in polycyclic compounds with
biological activity, and there are also numerous examples
of these N,O-heterocycles being used as key building blocks
in the total synthesis of natural and unnatural compounds [5].
The 1,3-dipolar cycloaddition reaction of nitrones with
alkenes in particular has received considerable attention in
RESULTS AND DISCUSSION
The starting compounds, azomethine N-oxides 1(Scheme 1)
and maleimides 2 (Scheme 2) were synthesized by
© 2014 HeteroCorporation

A. Kaur and B. Singh
Vol 000
Scheme 1
following similar procedure as reported in literature [8].
Equimolar quantities of 1 and 2 upon refluxing in toluene
gave a mixture of diastereoisomers (Scheme 3) of 2,3,5-
triaryl-4H,2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-
4,6-dione derivatives 3a–i (Table 1), which were separated
through fractional crystallization into two diastereomers
3-A and 3-B and characterized through 1H NMR and
1H NMR COSY (Figs 1 and 2) spectral data. The isomers
showing C3–H and C6a–H as doublets and C3a–H as doublet
of doublet on coupling with both protons C3–H and C6a–H
were assigned as cis geometry, and the isomers showing
C3–H as singlet and C3a–H and C6a–H as doublets in their
1H NMR spectra were assigned as trans geometry.
Scheme 2
In their IR spectra, these derivatives exhibit a strong
absorption band (nmax) in the range 1712–1720 cmꢀ1 and a
shoulder band in the range 1781–1795cmꢀ1 due to imide
carbonyl groups. However, in the 1H NMR spectra,
cis-3,5-bis(4-methoxyphenyl)-2-phenyl-4H-2,3,3a,5,6,
6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-dione (3a-A) displays
a pair of singlets at d 3.77 and 3.80 (3H each for two –OCH3
groups), a doublet of doublet at d 4.06 (1H, H3a) due to
coupling with both H3 and H6a (J = 9.06 and 7.84 Hz), a
doublet at d 4.85 (1H, H3) due to coupling with proton H3a
(J = 9.16Hz), a another doublet at d 5.36 (1H, H6a) due to
coupling with H3a (J= 7.72 Hz), and multiplet signal at
d 6.86–7.34 (13H, Ar–H), whereas the 1H NMR spectrum of
trans-3,5-bis(4-methoxyphenyl)-2-phenyl-4H-2,3,3a,5,6,
6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-dione (3a-B)
displays a pair of singlets at d 3.77 and 3.81 (3H each for
two –OCH3 groups), a partially resolved doublet of doublet
Scheme 3
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Synthesis of New Hexahydropyrrolo[3,4-d]isoxazole-4,6-diones
Table 1
Synthesis of 2,3,5-triaryl-4H,2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-dione derivatives (3).
Yield (%)
Melting point (ꢁC)
Compounds
X
Y
A
B
A:B
A
B
3a
3b
3c
3d
3e
3f
3g
3h
3i
4-OCH3
4-OCH3
4-OCH3
3-OCH3
3-OCH3
3-OCH3
2-OCH3
2-OCH3
2-OCH3
OCH3
CH3
Cl
OCH3
CH3
Cl
OCH3
CH3
Cl
56.4
11.5
15.1
10.8
57.4
63.6
60.8
66.6
61.2
65.5
83:17
82:18
85:15
18:82
14:86
20:80
17:83
15:85
16:84
218–220
204–206
217–219
198–201
200–202
196–198
198–200
200–202
209–211
178–180
185–187
175–177
178–180
176–178
173–175
177–179
155–157
182–185
68.8
61.2
12.5
10.2
14.9
13.4
10.7
12.6
In their 1H NMR NOESY spectra, it is evident that in cis
isomer 3a-A (Figs 3 and 4), the proton H3a shows cross
peaks with H3 and H6a but no correlation with the protons
of C-phenyl ring, which signifies the “anti” geometry of H3
and C-phenyl ring and “syn” nature of H3, H3a, and H6a
protons. whereas in case of trans isomer 3a-B (Figs 5 and 6),
cross peaks of H3a with H3, H6a, and C-200, C-600of C-phenyl
ring are evident, which signifies the “syn” geometry of H3a
and C-phenyl ring and the “anti” geometry of H3a and H3
protons. Besides this, in both the isomers, the proton H3
shows cross peak with proton H3a and has also correlation
with the aromatic hydrogens both on C-phenyl ring at C-200,
C-600 and N-phenyl ring at C-20, C-60, and cross peaks were
also observed between protons H6a and H3a, showing their
correlation. Also in these isomers, the –OCH3 group present
at C-4000 of succinimide moiety shows correlation with the
aromatic protons at position C-3000 and C-5000, while the
–OCH3 group at C-400 of C-phenyl ring showed cross
peaks with the protons at C-300 and C-500.
Figure 1. 400 MHz 1H NMR COSY spectrum of 3a-A in CDCl3.
The stereochemistry of 1,3-dipolar cycloaddition reactions
of nitrones and maleimides originates from the transition
state of the reactants. The cis/trans selectivity in these
reactions is primarily controlled by the substituent on C-styryl
moiety because the most stable configuration for the
azomethine N-oxides derived from aromatic aldehydes is
“trans” in which the C-phenyl ring is “anti” to the
at d 3.96 (1H, H3a) due to coupling with H6a (J =7.44Hz) and
minor coupling with H3, a doublet at d 5.10 (1H, H6a) due to
coupling with H3a (J= 7.44 Hz), a singlet at d 5.69 (1H, H3),
and multiplet signal at d 6.51–7.47 (equivalent to 13H, Ar–H).
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A. Kaur and B. Singh
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Figure 4. Structure of compound 3a-A and NOE correlation.
Figure 2. 400 MHz 1H NMR COSY spectrum of 3a-B in CDCl3.
Figure 5. 400 MHz 1H NMR NOESY spectrum of 3a-B in CDCl3.
Figure 3. 400 MHz 1H NMR NOESY spectrum of 3a-A in CDCl3.
azomethinic oxygen because of the smaller number of
nonbonded steric interactions between the C-phenyl and
N-phenyl nuclei as compared with the “cis” configuration
where the C-phenyl is “syn” to the N-phenyl nucleus of
azomethine N-oxide (Fig. 7).
In the present 1,3-dipolar cycloaddition reactions stud-
ied, two stereoisomers (cis-A and trans-B) have been
obtained in ratio of 80:20. The preferred orientation of
the azomethine N-oxides at the transition state seems to
be “anti” one where steric interactions are minimum, so
Figure 6. Structure of compound 3a-B and NOE correlation.
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Synthesis of New Hexahydropyrrolo[3,4-d]isoxazole-4,6-diones
for cis isomer (A) as nonbonded steric interaction are
completely absent in this transition state.
The trans isomer (B) also arises from the “anti” form of
the azomethine N-oxide, but in this case, the attack by the
dipolarophile maleimide occurs from the azomethine
N-oxide molecule. In the transition state, accumulation of
the double bonds again plays a dominant role, but it is not
so marked as in the previous case. In this case, N-phenyl
nucleus of the dipole rather than the C-phenyl ring comes
in a plane nearly parallel to the unsaturation of the carbonyl
group of the imide because these are separated by two atoms
(O and C on one side and C and C atoms on the other)
rather than by one atom as in the previous transition state;
this secondary interaction is, therefore smaller in this
transition state, which leads to the formation of the minor
trans isomer B.
A study of the Drieding models of the trans isomer (Fig. 9)
also indicates that this is the most favored transition state
leading to this favored conformation as this has the least
number of nonbonded steric interaction.
But in case of o-OCH3 and m-OCH3 groups on C-phenyl
ring, the cis–trans isomeric ratio is found to be the reverse.
In these cases, the closer approach of methoxy group to the
oxygen atom of carbonyl moiety leads to steric interaction
and thus leading to the dominance of trans over the cis isomer
(Figs 10 and 11).
Figure 7. Configuration of azomethine N-oxides.
as the dipole and dipolarophile approach each other, there
are p–p interactions between the two substrates. This more
favored orientation of the azomethine N-oxide results in
the formation of cis isomer as the major one, perhaps
because of the steric requirement alone. Moreover, “anti”
form of the azomethine N-oxide is thermodynamically
more stable, which leads to the formation of the major cis
product. The transition state seems to follow the “endo ad-
dition rule.” In the endo or cis transition state, there is a
“maximum accumulation of double bonds” of the dipole
as well as that of the dipolarophile. At the transition state,
C-phenyl nucleus of dipole and one carbonyl group of
the imide nucleus come parallel to each other in addition
to the p-electron overlap of the reacting atoms. From a
study of the Drieding models of the cis isomers (Fig. 8),
it has been found that this is the most favored conformation
Figure 8. Drieding model of cis isomer.
Figure 9. Drieding model of trans isomer.
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A. Kaur and B. Singh
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Figure 10. Drieding model of cis isomer with o-OCH3 on C-phenyl ring.
Figure 11. Drieding model of cis isomer with m-OCH3 on C-phenyl ring.
synthesis of product was confirmed by TLC and further by recording
the melting points of the nitrones obtained.
EXPERIMENTAL
General.
Melting points are uncorrected. IR spectra were
General procedure for synthesis of maleimide. Equimolar
quantities of p-substituted aniline and maleic anhydride were stirred in
toluene at room temperature for 1 h to yield maleimic acid. The
maleimic acid thus obtained was further cyclized to maleimide
(Scheme 2) in acetic anhydride in the presence of anhydrous sodium
acetate by refluxing on hot water bath for 1.5 h and then pouring the
contents in ice cold water and keeping it overnight to afford the solid
that was filtered and washed with water to give the maleimide 2.
General procedure for cycloadditions. An oven-dried flask
was cooled under a stream of nitrogen and charged with azomethine
N-oxide 1 (5mmol), maleimide 2 (5 mmol) and sodium dried
toluene (25mL). The flask was equipped with a reflux condenser,
and the mixture was refluxed for 6 h (Scheme 3) until the
substrates were consumed as judged by TLC. On completion, the
reaction mixture was concentrated, and the precipitated compound
was filtered. The crude product was subjected to fractional
crystallization to obtain cis and trans isomers.
recorded on a Perkin Elmer RXIFT infrared spectrophotometer
(Manufactured at Buckinghamshire, England) using KBr pellets.
1H NMR, 1H NMR COSY, and 1H NMR NOESY were recorded
at 400MHz on Bruker spectrometer (Manufactured at Fallanden,
Switzerland) using TMS as internal standard. The 13C NMR
spectra were recorded at 300 MHz on Bruker spectrometer
(Manufactured at Fallanden, Switzerland) using TMS as internal
standard. Mass spectra were recorded on Waters Micromass Q-T
of Micro (ESI) spectrometer (Manufactured at Vernon Hills,
USA). TLC plates were coated with silica-G suspended in
methanol–chloroform. Elemental analysis was carried out using
Elementar vario MICRO cube CHN analyzer.
General procedure for synthesis of azomethine N-oxide.
The mixture of nitrobenzene (4.2 mL, 41 mmol) and ammonium
chloride (2.5 g, 46 mmol) in 100 mL of water was stirred for 1 h with
slow addition of zinc dust (5.9 g, 83 mmol) with the help of a
mechanical stirrer. The rate of addition of zinc dust was such that rise
in temperature was not more than 65–70ꢁC. After complete addition
of zinc, the stirring was continued for further 15 min to complete the
reduction, which was observed by decrease in temperature of the
reaction mixture. The resulting solution was filtered and washed with
warm water (100 mL). The filtrate was extracted with chloroform to
which was added stoichiometric amount of aromatic aldehyde and
then stirred the mixture till the solid precipitated out (Scheme 1). The
cis-3,5-bis(4-Methoxyphenyl)-2-phenyl-4H-2,3,3a,5,6,6a-
hexahydropyrrolo[3,4-d]isoxazole-4,6-dione (3a-A). Compound
obtained as white solid (1.20 g, 56.4%), mp 218–220ꢁC; IR (KBr
1
pellets): 1719, 1795 cmꢀ1 (C═O); H NMR (400 MHz, CDCl3):
d
H 3.77 (s, 3H), 3.80 (s, 3H), 4.06 (dd, 1H, J= 9.06, 7.84 Hz), 4.85
(d, 1H, J= 9.16 Hz), 5.36 (d, 1H, J= 7.72 Hz), 6.86–7.34 (m, 13H);
13C NMR (300 MHz, CDCl3): d 54.29 (C-3a), 54.79 (400-OCH3),
55.10 (4000-OCH3), 70.46 (C-6a), 76.91 (C-3), 113.69 (C-300, 500),
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113.86 (C-3000, 5000), 118.97 (C-100), 124.02 (C-20, 60), 124.32 (C-40),
126.60 (C-30, 50), 127.35 (C-2000, 6000), 128.33 (C-200, 600), 128.58
(C-1000), 147.36 (C-10), 158.90 (C-4000), 159.00 (C-400), 171.87
(C-4, C═O), 174.13 (C-6, C═O); MS: m/z: 430 [M]+, 431
[M + 1]+, Anal. Calcd for C25H22N2O5: C, 69.76; H, 5.11; N,
6.51, found: C, 69.91; H, 5.13; N, 6.48.
trans-3,5-bis(4-Methoxyphenyl)-2-phenyl-4H-2,3,3a,5,6,6a-
hexahydropyrrolo[3,4-d]isoxazole-4,6-dione (3a-B). Compound
obtained as white solid (0.24 g, 11.5%), mp 178–180ꢁC; IR
(KBr pellets): 1719, 1791cmꢀ1 (C═O); 1H NMR (400 MHz,
CDCl3): dH 3.77 (s, 3H), 3.81 (s, 3H), 3.96 (d, 1H, J = 7.44Hz),
5.10 (d, 1H, J = 7.44Hz), 5.69 (s, 1H), 6.51–7.47 (m, 13H); 13C
NMR (300 MHz, CDCl3): d 55.37 (C-3a), 55.46 (400-OCH3),
57.25 (4000-OCH3), 69.56 (C-6a), 76.73 (C-3), 114.25 (C-300, 500),
114.33 (C-3000, 5000), 114.48 (C-100), 122.84 (C-20, 60), 123.45
(C-40), 127.38 (C-30, 50), 127.82 (C-2000, 6000), 129.36 (C-200, 600),
130.65 (C-1000), 148.82 ( C-10), 159.38 (C-4000), 159.76 (C-400),
172.98 (C-4, C═O), 174.48 (C-6, C═O); MS: m/z: 430 [M]+,
431 [M + 1]+, Anal. Calcd for C25H22N2O5: C, 69.76; H, 5.11;
N, 6.51, found: C, 69.91; H, 5.12; N, 6.53.
trans-5-(4-Chlorophenyl)-3-(4-methoxyphenyl)-2-phenyl-
4H-2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-dione
(3c-B). Compound obtained as white solidꢀ(10.23 g, 10.8%), mp
1
175–177ꢁC; IR (KBr pellets): 1713, 1782 cm (C═O); H NMR
(400 MHz, CDCl3): dH 3.79 (s, 1H), 3.94 (d, 1H, J =7.48 Hz),
5.11 (d, 1H, J = 7.52 Hz), 5.72 (s, 1H), 6.52–7.35 (m, 13H);
13C NMR (300 MHz, CDCl3): d 55.28 (C-3a), 55.85 (400-OCH3),
69.89 (C-6a), 76.72 (C-3), 113.40 (C-300, 500), 118.97 (C-100),
121.44 (C-20, 60), 125.21 (C-40), 127.26 (C-30, 50), 128.31 (C-3000,
5000), 129.59 (C-2000, 6000), 129.78 (C-200, 600), 134.21 (C-4000), 138.93
(C-1000), 148.72 (C-10), 159.86 (C-400), 172.76 (C-4, C═O), 174.86
(C-6, C═O); MS: m/z: 434 [M]+, 436 [M + 2]+, Anal. Calcd for
C24H19N2O4Cl: C, 66.28; H, 4.37; N, 6.44, found: C, 66.37; H,
4.36; N, 6.47.
cis-3-(3-Methoxyphenyl)-5-(4-methoxyphenyl)-2-phenyl-
4H-2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-dione
(3d-A).
Compound obtained as white solid (0ꢀ.216 g, 12.5%),
1
mp 198–201ꢁC; IR (KBr pellets): 1717, 1780 cm (C═O); H
NMR (400 MHz, CDCl3): dH 3.76 (s, 3H), 3.82 (s, 3H), 4.03
(dd, 1H, J = 9.06, 7.88 Hz), 4.88 (d, 1H, J = 9.06), 5.26 (d, 1H,
J = 7.84 Hz), 6.54–7.32 (m, 13H); 13C NMR (300 MHz,
CDCl3): d 55.32 (C-3a), 55.78 (4000-OCH3), 57.21 (300-OCH3),
69.71 (C-6a), 76.72 (C-3), 111.58 (C-400), 112.33 (C-200), 114.10
(C-3000), 119.32 (C-600), 123.09 (C-20, 40, 60), 123.24 (C-2000, 6000),
126.10 (C-30, 50), 128.88 (C-500), 131.03 (C-100), 139.68 (C-1000),
148.25 (C-10), 159.01 (C-4000), 160.23 (C-300), 171.68 (C-4,
C═O), 173.57 (C-6, C═O); MS: m/z: 430 [M]+, 431 [M + 1]+,
Anal. Calcd for C25H22N2O5: C, 69.76; H, 5.11; N, 6.51, found:
C, 69.59; H, 5.13; N, 6.53.
cis-3-(4-Methoxyphenyl)-5-(4-methylphenyl)-2-phenyl-4H-
2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-dione (3b-A).
Compound obtained as white solid (1.41 g, 68.8%), mp 204–206ꢁC;
1
IR (KBr pellets): 1715, 1792 cmꢀ1 (C═O); H NMR (400 MHz,
CDCl3): dH 2.34 (s, 3H), 3.78 (s, 3H), 4.01 (dd, 1H, J=8.92,
8.00 Hz), 4.85 (d, 1H, J= 9.04 Hz), 5.24 (d, 1H, J=7.84Hz),
13
6.86–7.36 (m, 13H); C NMR (CDCl3): d 21.23 (4000-CH3), 54.58
(C-3a), 55.25 (400-OCH3), 71.19 (C-6a), 76.74 (C-3), 114.40 (C-300,
500), 118.42 (C-100), 124.75 (C-4000), 125.78 (C-2000, 6000), 126.26
(C-20, 60), 128.49 (C-40), 128.76 (C-3000, 5000), 128.79 (C-30, 50),
129.83 (C-200, 600), 138.91 (C-1000), 147.44 (C-10), 159.80 (C-400),
171.67 (C-4, C═O), 173.76 (C-6, C═O); MS: m/z: 434 [M]+,
436 [M + 2]+, Anal. Calcd for C25H22N2O4: C, 72.46; H, 5.31;
N, 6.76, found: C, 72.27; H, 5.32; N, 6.78.
trans-3-(3-Methoxyphenyl)-5-(4-methoxyphenyl)-2-phenyl-
4H-2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-dione
(3d-B). Compound obtained as white solid (1.22ꢀg1, 57.4%),
mp 178–180ꢁC; IR (KBr pellets): 1715, 1781 cm (C═O);
1H NMR (400 MHz, CDCl3): dH 3.76 (s, 3H), 3.82 (s, 3H),
3.98 (d, 1H, J = 7.32 Hz), 5.07 (d, 1H, J = 7.48 Hz), 5.72
(s, 1H), 6.47–7.25 (m, 13H); 13C NMR (300 MHz, CDCl3):
d 55.40 (C-3a), 55.45 (4000-OCH3), 57.29 (300-OCH3), 69.87
(C-6a), 76.73 (C-3), 112.05 (C-400), 113.68 (C-200), 114.32
(C-3000), 118.68 (C-600), 122.88 (C-20, 40, 60), 123.040 3 (C-2000,
6000), 127.36 (C-30, 50), 129.42 (C-500), 130.08 (C-1 ), 140.33
(C-1000), 148.94 (C-10), 159.77 (C-4000), 160.10 (C-300), 172.88
(C-4, C═O), 174.37 (C-6, C═O); MS: m/z: 430 [M]+, 431
[M + 1]+, Anal. Calcd for C25H22N2O5: C, 69.76; H, 5.11;
N, 6.51, found: C, 69.88; H, 5.12; N, 6.45.
cis-3-(3-Methoxyphenyl)-5-(4-methylphenyl)-2-phenyl-4H-
2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-dione
(3e-A). Compound obtained as white solid (0.21 g, 10.2%), mp
200–202ꢁC; IR (KBr pellets): 1713, 1787cmꢀ1 (C═O); 1H NMR
(400 MHz, CDCl3): dH 2.33 (s, 3H), 3.83 (s, 3H), 4.03 (dd, 1H,
J = 9.08, 7.82Hz), 4.85 (d, 1H, J = 9.10Hz), 5.26 (d, 1H,
J = 7.82 Hz), 6.82–7.38 (m, 13H); 13C NMR (300 MHz, CDCl3):
d 21.23 (4000-CH3), 54.79 (C-3a), 55.92 (300-OCH3), 69.25 (C-6a),
76.73 (C-3), 112.68 (C-400), 113.68 (C-200), 119.58 (C-600), 123.06
(C-4000), 124.05 (C-6000), 125.58 (C-20, 60), 126.77 (C-40), 128.43
(C-3000, 5000), 129.33 (C-30, 50), 130.19 (C-500), 130.83 (C-100),
138.36 (C-1000), 149.26 (C-10), 160.01 (C-300), 172.22 (C-4, C═O),
174.31 (C-6, C═O); MS: m/z: 414 [M]+, 415 [M+ 1]+, Anal.
Calcd for C25H22N2O4: C, 72.46; H, 5.31; N, 6.76, found: C,
72.65; H, 5.33; N, 6.71.
trans-3-(4-Methoxyphenyl)-5-(4-methylphenyl)-2-phenyl-
4H-2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-dione
(3b-B). Compound obtained as white solidꢀ(10.31 g, 15.1%), mp
1
185–187ꢁC; IR (KBr pellets): 1714, 1789 cm (C═O); H NMR
(400 MHz, CDCl3): dH 2.30 (s, 3H), 3.77 (s, 1H), 3.98 (d, 1H,
J= 7.48 Hz), 5.09 (d, 1H, J = 7.56 Hz), 5.68 (s, 1H), 6.54–7.45
(m, 13H); 13C NMR (300 MHz, CDCl3): d 21.20 (4000-CH3), 54.72
(C-3a), 55.21 (400-OCH3), 70.21 (C-6a), 76.72 (C-3), 112.24(C-300,
500), 117.32 (C-100), 124.21 (C-4000), 126.25 (C-2000, 6000), 126.78
(C-20, 60), 128.22 (C-40), 128.68 (C-3000, 5000), 128.91 (C-30, 50),
130.28 (C-200, 600), 138.97 (C-1000), 147.35 (C-10), 160.05
(C-400), 171.92 (C-4, C═O), 174.13 (C-6, C═O); MS: m/z: 414
[M]+, 415 [M + 1]+, Anal. Calcd for C25H22N2O4: C, 72.46; H,
5.31; N, 6.76, found: C, 72.21; H, 5.33; N, 6.80.
cis-5-(4-Chlorophenyl)-3-(4-methoxyphenyl)-2-phenyl-4H-
2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-dione
(3c-A). Compound obtained as white solid (1.32 g, 61.2%), mp
217–219ꢁC; IR (KBr pellets): 1712, 1785 cmꢀ1 (C═O); 1H NMR
(400 MHz, CDCl3): dH 3.79 (s, 3H), 4.03 (dd, 1H, J = 9.04,
7.80 Hz), 4.88 (d, 1H, J = 9.04 Hz), 5.26 (d, 1H, J = 7.76Hz),
6.86–7.38 (m, 13H); 13C NMR (300 MHz, CDCl3): d 54.42
(C-3a), 55.21 (400-OCH3), 70.13 (C-6a), 76.33 (C-3), 112.84
(C-3000, 500), 119.17 (C-100), 121.03 (C-20, 60), 124.72 (C-40), 127.52
(C-3 , 50), 128.88 (C-3000, 5000), 130.15 (C-2000, 6000), 130.98
(C-200, 600), 134.01 (C-4000), 139.42 (C-1000), 147.93 (C-10), 160.05
(C-400), 171.66 (C-4, C═O), 174.08 (C-6, C═O); MS: m/z: 434
[M]+, 436 [M + 2]+, Anal. Calcd for C24H19N2O4Cl: C, 66.28; H,
4.37; N, 6.44, found: C, 66.10; H, 4.38; N, 6.49.
trans-3-(3-Methoxyphenyl)-5-(4-methylphenyl)-2-phenyl-
4H-2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-dione
(3e-B). Compound obtained as white solid (1.31 g, 63.6%), mp
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Kaur and B. Singh
Vol 000
176–178ꢁC; IR (KBr pellets): 1714, 1787 cmꢀ1 (C═O); 1H NMR
(400 MHz, CDCl3): dH 2.32 (s, 3H), 3.83 (s, 3H), 4.01 (d, 1H,
J = 7.48Hz), 5.10 (d, 1H, J = 7.76Hz), 5.73 (s, 1H), 6.45–7.35
(C-500), 124.68 (C-20, 60), 125.92 (C-40), 126.79 (C-30, 50),
128.25 (C-2000, 6000), 128.91 (C-400), 129.28 (C-600), 131.21
(C-1000), 149.32 (C-10), 158.37 (C-4000), 159.88 (C-200), 171.34
(C-4, C═O), 173.67 (C-6, C═O); MS: m/z: 430 [M]+, 431
[M + 1]+, Anal. Calcd for C25H22N2O5: C, 69.76; H, 5.11; N,
6.51, found: C, 69.76; H, 5.09; N, 6.56.
13
(m, 13H); C NMR (300 MHz, CDCl3): d 21.20 (4000-CH3),
55.56 (C-3a), 55.78 (300-OCH3), 70.18 (C-6a), 76.78 (C-3), 113.02
(C-400), 114.78 (C-200), 119.08 (C-600), 122.68 (C-4000), 125.09
(C-6000), 126.28 (C-20, 60), 127.48 (C-40), 128.49 (C-3000, 5000), 129.53
(C-30, 50), 129.88 (C-500), 130.28 (C-100), 139.91 (C-1000), 148.92
(C-10), 159.76 (C-300), 171.57 (C-4, C═O), 174.03 (C-6, C═O);
MS: m/z: 414 [M]+, 415 [M+1]+, Anal. Calcd for C25H22N2O4: C,
72.46; H, 5.31; N, 6.76, found: C, 72.67; H, 5.32; N, 6.72.
cis-3-(2-Methoxyphenyl)-5-(4-methylphenyl)-2-phenyl-4H-
2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-dione
(3h-A). Compound obtained as white solid (0.22 g, 10.7%), mp
200–202ꢁC; IR (KBr pellets): 1713, 1786 cmꢀ1 (C═O); 1H NMR
(400 MHz, CDCl3): dH 2.29 (s, 3H), 3.96 (s, 3H), 4.08 (dd, 1H,
J = 9.02, 7.56 Hz), 4.88 (d, 1H, J = 9.02 Hz), 5.24 (d, 1H,
J = 7.72 Hz), 6.35–7.56 (m, H); 13C NMR (300 MHz, CDCl3):
d 21.23 (4000-CH3), 55.44 (C-3a), 55.78 (200-OCH3), 66.03
(C-6a), 76.73 (C-3), 111.23 (C-300), 113.04 (C-100), 121.39
(C-500), 123.49 (C-4000), 126.21 (C-2000, 6000), 126.82 (C-20, 60),
127.33 (C-40), 128.88 (C-3000, 5000), 129.82 (C-30, 50), 129.08
(C-400), 130.31 (C-600), 139.35 (C-1000), 148.62 (C-10), 157.38
(C-200), 172.49 (C-4, C═O), 174.59 (C-6, C═O); MS: m/z:
414 [M]+, 415 [M + 1]+, Anal. Calcd for C25H22N2O4: C,
72.46; H, 5.31; N, 6.76, found: C, 72.18; H, 5.29; N, 6.79.
trans-3-(2-Methoxyphenyl)-5-(4-methylphenyl)-2-phenyl-
4H-2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-dione
(3h-B). Compound obtained as white solidꢀ(11.26 g, 61.2%), mp
cis-5-(4-Chlorophenyl)-3-(3-methoxyphenyl)-2-phenyl-4H-
2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-dione
(3f-A). Compound obtained as white solidꢀ(01.32 g, 14.9%), mp
1
196–198ꢁC; IR (KBr pellets): 1718, 1785 cm (C═O); H NMR
(400 MHz, CDCl3): dH 3.83 (s, 3H), 4.07 (dd, 1H, J= 9.18,
7.84 Hz), 4.88 (d, 1H, J = 9.16 Hz), 5.27 (d, 1H, J= 7.84 Hz),
6.52–7.36 (m, 13H); 13C NMR (300 MHz, CDCl3): d 54.61(C-3a),
55.41 (300-OCH3), 69.90 (C-6a), 76.72 (C-3), 111.68 (C-400),
113.12 (C-200), 114.26 (C-600), 118.64 (C-20, 60), 118.94 (C-40),
122.48 (C30, 50), 124.17 (C-3000), 129.05 (C-2000, 6000), 130.13
(C-50), 135.23 (C-100), 135.72 (C4000), 139.66 (C-1000), 147.23
(C-10), 159.72 (C-300), 171.02 (C-4, C═O), 173.29 (C-6, C═O);
MS: m/z: 434 [M]+, 436 [M+ 2]+, Anal. Calcd for C24H19N2O4Cl:
C, 66.28; H, 4.37; N, 6.44, found: C, 66.49; H, 4.38; N, 6.46.
trans-5-(4-Chlorophenyl)-3-(3-methoxyphenyl)-2-phenyl-
4H-2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-dione
(3f-B). Compound obtained as white solidꢀ(11.31 g, 60.8%), mp
1
155–157ꢁC; IR (KBr pellets): 1712, 1784 cm (C═O); H NMR
(400 MHz, CDCl3): dH 2.29 (s, 3H), 3.94 (s, 3H), 3.97 (d, 1H,
J = 7.60 Hz), 4.98 (d, 1H, J = 7.52 Hz), 6.06 (s, 1H), 6.36–7.57
(m, 13H); 13C NMR (300 MHz, CDCl3): d 21.22 (4000-CH3), 55.57
(C-3a), 55.73 (200-OCH3), 65.51 (C-6a), 76.80 (C-3), 110.39
(C-300), 114.14 (C-100), 120.77 (C-500), 122.68 (C-4000), 125.95
(C-2000, 6000), 126.79 (C-20, 60), 127.24 (C-40), 128.39
(C-3000, 5000), 129.43 (C-30, 50), 129.46 (C-400), 129.60 (C-600),
138.97 (C-1000), 149.55 (C-10), 156.31 (C-200), 173.12 (C-4, C═O),
174.33 (C-6, C═O); MS: m/z: 414 [M]+, 415 [M+1]+, Anal. Calcd
for C25H22N2O4: C, 72.46; H, 5.31; N, 6.76, found: C, 72.24; H,
5.32; N, 6.78.
1
173–175ꢁC; IR (KBr pellets): 1717, 1788 cm (C═O); H NMR
(400 MHz, CDCl3): dH 3.83 (s, 3H), 4.02 (d, 1H, J= 7.52 Hz),
5.10 (d, 1H, J= 7.84 Hz), 5.74 (s, 1H), 6.50–7.40 (m, 13H); 13C
NMR (300 MHz, CDCl3): d 55.26 (C-3a), 57.32 (300-OCH3),
71.30 (C-6a), 76.820 (C-3), 112.08 (C-400), 113.70 (C-200), 114.26
(C-600), 118.64 (C-2 , 60), 119.67 (C-40), 123.01 (C30, 50), 124.88
(C-3000), 129.56 (C-2000, 6000), 130.20 (C-50), 134.93 (C-100), 135.96
(C4000), 140.09 (C-1000), 148.85 (C-10), 160.12 (C-300), 172.35
(C-4, C═O), 173.88 (C-6, C═O); MS: m/z: 434 [M]+, 436
[M + 2]+, Anal. Calcd for C24H19N2O4Cl: C, 66.28; H, 4.37;
N, 6.44, found: C, 66.53; H, 4.36; N, 6.47.
cis-5-(4-Chlorophenyl)-3-(2-methoxyphenyl)-2-phenyl-4H-
2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-dione
(3i-A).
Compound obtained as white solid (0.27ꢀg1, 12.6%),
cis-3-(2-Methoxyphenyl)-5-(4-methoxyphenyl)-2-phenyl-4H-
2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-dione
mp 209–211ꢁC; IR (KBr pellets): 1712, 1786 cm (C═O);
1H NMR (400 MHz, CDCl3): dH 3.97 (s, 3H), 4.09 (dd, 1H,
J = 9.04, 7.78 Hz), 4.86 (d, 1H, J = 9.11 Hz), 5.26 (d, 1H,
J = 7.72 Hz), 6.42–7.38 (m, 13H); 13C NMR (300 MHz,
CDCl3): d 55.49 (C-3a), 56.21 (200-OCH3), 67.26 (C-6a),
76.71 (C-3), 111.58 (C-300), 114.67 (C-100), 120.21 (C-500),
123.09 (C-20, 60), 126.59 (C-40), 127.05 (C-30, 50), 127.88
(C-3000, 5000), 128.91 (C-2000, 6000), 129.42 (C-600), 129.78
(C-400), 130.25 (C-4000), 135.18 (C-1000), 150.01 (C-10), 156.72
(C-200), 172.98 (C-4,C═O), 173.48 (C-6, C═O); MS: m/z:
434 [M]+, 436 [M + 2]+, Anal. Calcd for C24H19N2O4Cl: C,
66.28; H, 4.37; N, 6.44, found: C, 66.39; H, 4.36; N, 6.47.
trans-5-(4-Chlorophenyl)-3-(2-methoxyphenyl)-2-phenyl-
4H-2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-dione
(3g-A).
Compound obtained as white solid (0.28 g, 13.4%), mp
198–200ꢁC; IR (KBr pellets): 1720, 1790 cmꢀ1 (C═O); H NMR
(400 MHz, CDCl3): dH 3.74 (s, 3H), 3.97 (s, 3H), 4.14 (dd, 1H,
J= 9.08, 7.72 Hz), 5.00 (d, 1H, J= 9.16 Hz), 5.23 (d, 1H, J=7.48Hz),
6.39–7.36 (m, 13H); 13C NMR (300 MHz, CDCl3): d 54.20 (C-3a),
55.21 (4000-OCH3), 55.47 (200-OCH3), 68.29 (C-6a), 76.93 (C-3),
112.32 (C-300), 115.82 (C-3000, 5000), 118.10 (C-100), 121.02 (C-500),
125.12 (C-20, 60), 125.68 (C-40), 126.62 (C-30, 50), 127.58 (C-2000, 6000),
129.10 (C-400), 129.38 (C-600), 130.24 (C-1000), 148.35 (C-10), 157.92
(C-4000), 158.39 (C-200), 172.21 (C-4, C═O), 174.32 (C-6, C═O); MS:
m/z: 430 [M]+, 431 [M+1]+, Anal. Calcd for C25H22N2O5: C, 69.76;
H, 5.11; N, 6.51, found: C, 70.01; H, 5.09; N, 6.47.
1
trans-3-(2-Methoxyphenyl)-5-(4-methoxyphenyl)-2-phenyl-
4H-2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-dione
(3i-B).
Compound obtained as white solidꢀ(11.41 g, 65.5%), mp
1
182–185ꢁC; IR (KBr pellets): 1713, 1786 cm (C═O); H NMR
(400 MHz, CDCl3): dH 3.98 (s, 3H), 4.02 (d, 1H, J= 7.44 Hz), 5.03
(d, 1H, J= 7.72 Hz), 6.08 (s, 1H), 6.45–7.38 (m, 13H); 13C NMR
(300 MHz, CDCl3): d 55.60 (C-3a), 55.80 (200-OCH3), 65.62 (C-6a),
76.79 (C-3), 110.44 (C-300), 114.18 (C-100), 120.83 (C-500), 122.80
(C-20, 60), 126.59 (C-40), 127.25 (C-30, 50), 127.47 (C-3000, 5000),
129.10 (C-2000, 6000), 129.17 (C-600), 129.48 (C-400), 129.56 (C-4000),
134.78 (C-1000), 149.50 (C-10), 156.31 (C-200), 172.70 (C-4, C═O),
(3g-B).
Compound obtained as white solid (1.42 g, 66.6%),
mp 177–179ꢁC; IR (KBr pellets): 1718, 1792 cmꢀ1 (C═O); 1H
NMR (400 MHz, CDCl3): dH 3.74 (s, 3H), 3.94 (s, 3H), 3.97 (d,
1H, J= 7.64Hz), 4.99 (d, 1H, J = 7.52), 6.06 (s, 1H), 6.39–7.35
(m, 13H); 13C NMR (300 MHz, CDCl3): d 55.04 (C-3a), 55.79
(4000-OCH3), 56.09 (200-OCH3), 70.21 (C-6a), 76.33 (C-3),
113.25 (C-300), 114.72 (C-3000, 5000), 119.12 (C-100), 121.24
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of New Hexahydropyrrolo[3,4-d]isoxazole-4,6-diones
173.95 (C-6, C═O); MS: m/z: 434 [M]+, 436 [M+ 2]+, Anal. Calcd
for C24H19N2O4Cl: C, 66.28; H, 4.37; N, 6.44, found: C, 66.44; H,
4.38; N, 6.50.
[4] (a) Black, D. St. C.; Crozier, R. F.; Davis, V. C. Synthesis
1975, 4, 205; (b) Banerji, A.; Sahu, A. J Scient Indus Res 1986, 45,
355; (c) Banerji, A.; Basu, S. Tetrahedron 1992, 48, 3335; (d) Green,
M. J.; Tiberi, R. L.; Friary, R.; Lutsky, B. N.; Berkenkoph, J.;
Monahan, M. J Med Chem 1982, 25, 1492; (e) Loh, B.; Vozzolo,
L.; Mok, B. J.; Lee, C. C.; Fitzmaurice, R. J.; Caddick, S.; Fassati, A.
Chem Biol Drug Des 2010, 75, 461.
[5] (a) Confalone, P. N.; Huie, E. M. Org react 1988, 36, 1; (b)
Gothelf K. V.; Jorgensen, K. A. Chem Rev, 1998, 98, 863.
[6] Frederickson, M. Tetrahedron, 1997, 53, 403.
REFRENCES AND NOTES
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Benaglia, M. Eur J Org Chem 2001, 6, 1033; (d) Nair, V.; Suja, T. D.
Tetrahedron 2007, 63, 12247; (e) Pellissier, H. Tetrahedron 2007, 63, 3235;
(f) Stanley, L. M.; Sibi, M. P. Chem Rev 2008, 108, 2887; (g) Kissane, M.;
Maguire, A. R. Chem Soc Rev 2010, 39, 845.
[2] Hamadi, N. B.; Msaddek, M. C R Chimie 2011, 14, 891.
[3] Tufariello, J. J. 1,3 Dipolar Cycloaddition Chemistry, Padwa,
A., Ed.; Wiley Interscience: New York, 1984; Vol. 2, pp. 83–168.
[7] Torssell, K. B. G. Nitrile Oxides, Nitrones and Nitronates in Or-
ganic Synthesis, VCH: Weinheim, 1988, pp. 75–93.
[8] (a) Searle, N. E. U. S. Patent 2,444,536, 1948; Chem Abst
1948, 42, 7340; (b) Furniss, B. S.; Hannaford, A. J.; Rogers, V.;
Smith, P. W. G.; Tatchell, A. R. Vogel’s Textbook of Practical
Organic Chemistry, 5th ed. Longman Scientific and Technical: Essex,
UK, 1991, 955.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet