1,3-Dipolar cycloadditions: Investigation of cycloadditions of C-aryl-N-(4-chlorophenyl) nitrones to N-cinnamoyl piperidines

Article abstract of DOI:10.1002/jhet.5570440122

(Chemical Equation Presented) Investigation of cycloadditions of C-aryl-N-(4-chlorophenyl)nitrones to N-cinnamoyl piperidines was carried out. Two diastereoisomeric and one regioisomeric cycloadducts, and in some cases ring-opened compounds were character

Full text of DOI:10.1002/jhet.5570440122

Jan-Feb 2007
137
1,3-Dipolar Cycloadditions: Investigation of Cycloadditions of C-
Aryl-N-(4-Chlorophenyl) Nitrones to N-Cinnamoyl Piperidines
Avijit Banerji [1]*, Pizush Kanti Biswas [1], Debasish Bandyopadhyay [1]
Maya Gupta [1], Thierry Prangé [2] and Alain Neuman[2]
[1] Centre of Advanced Studies on Natural Products including Organic Synthesis, Department of Chemistry,
University Colleges of Science and Technology, University of Calcutta, 92; Acharya Prafulla Chandra Road,
Kolkata-700009, India.
[2] Centre Universitaire, Paris-sud, Batiment 209D-BP34, 91898 Orsay Cedex, France
Received April 13, 2006
R
H
R1
Toluene
C
N
C
O
N
+
+
110 °C, 15-20 hrs, N2
_
O
Cl
R
H
R
R
H
R1
O
C
H
H
H
O
C
H
N
N
H
+
+
H
N
C+
H
N
N
O
O
C
O
N
O
Cl
Cl
Cl
R
1
R1
Investigation of cycloadditions of C-aryl-N-(4-chlorophenyl)nitrones to N-cinnamoyl piperidines was
carried out. Two diastereoisomeric and one regioisomeric cycloadducts, and in some cases ring-opened
compounds were characterized by spectroscopic and X-ray data. Molecular modelling was carried out for
conformational studies.
J. Heterocyclic Chem., 44, 137 (2007).
Subsequently, an improved microwave assisted
procedure similar to that developed by the authors for the
C-aryl-N-methyl nitrones [9] was used.
1,3-Dipolar cycloadditions of C-aryl-N-(4-chloro-
phenyl) nitrones (1-4) to N-cinnamoyl piperidines (5-8)
afforded mixture of diastereoisomeric products (types I,
II) and small amounts of regioisomeric products (type
III); in some cases ring-opened compounds (9a, 10a, 13a,
17a), were also obtained (Scheme 1).
INTRODUCTION
The 1,3-dipolar cycloaddition of nitrones to electron-
deficient olefins constitutes the best procedure for the
synthesis of isoxazolidines [1-4]. Exploiting this strategy as
the key step, several classes of biologically active compounds
as well as natural products have been synthesized [2-5]. As a
part of our investigations in this particular field [6-9], we have
recently carried out the ꢀ4s + ꢀ2s cycloaddition of C-aryl-N-
(4-chlorophenyl) nitrones to N-cinnamoyl piperidines. The
main objective of this investigation was to study the regio-
and stereochemical course of nitrone cycloaddition reaction to
1,2-disubstituted olefins as well as the substitution effect on
the aryl rings of the substrate. This communication gives a
report of this investigation.
The reactions were carried out using three-fold molar
excess of the dipolarophile, to enhance reaction rates and
hence yields, in refluxing toluene under nitrogen
atmosphere for about 15-20 hrs. At the end of this period,
only small amounts of the nitrones survived. Removal of
the solvent under reduced pressure and chromatography
over neutral alumina furnished the products. The all-trans
isomers (type I) were the major products isolated from all
the reactions in this series. The diastereoisomeric 3,4-cis-
4,5-trans (type II) 5-aryl-4-piperidinyloxoisoxazolidine
cycloadducts were isolated in some cases, the others were
RESULTS AND DISCUSSION
A new series of nitrones, viz. C-aryl-N-(4-chloro-
phenyl) nitrones, were chosen for the present cycloaddi-
tion studies. A total of seven reactions were carried out
varying the substituents on the aryl rings from electron-
donating to electron-withdrawing groups (Scheme I).
These nitrones were initially synthesized by the
conventional procedure of heating N-(4-chlorophenyl)-
hydroxylamine with the appropriate aldehydes in ethanol.
1
characterized from the H NMR spectra of the crude
reaction mixture. The regioisomeric (type III) 4-aryl-5-
1
piperidinyloxoisoxazolidines were identified from the H
NMR spectra of the crude reaction mixture. Product ratios
of the cycloadducts were determined by 1H NMR analysis

138
A. Banerji, P. K. Biswas, D. Bandyopadhyay, M. Gupta, T. Prangé and A. Neuman
Vol 44
R
H
R1
C
N
Toluene
+
C
O
N
+
1100C, 15-20 hrs, N2
_
O
Cl
(5) R1 = Cl
(6) R1 = NO2
(7) R1 = H
(1) : R = 4-NO2
(2) : R = 3-NO2
(3) : R = H
(8) R1 = OCH3
(4) : R = 4-OCH3
R
R
R
B
R
B
1
O
B
H
H
O
H
H
H
H
C
N
D
C
H
N
D
C
H
N
4
3
+
3
4
+
3
4
2
H
5
N
2
1
5
2
N
5
N
1
1
A
O
A
A
O
O
D
C
O
C
C
Cl
Cl
Cl
R 1
R 1
Type I
Type II
Type III
Major product
3,4-trans-4,5-trans
Minor product
3,4-cis-4,5-trans
Regioisomeric product
3,4-trans-4,5-trans
(9) : R = 4-NO2; R1 = Cl
(10) : R = 4-NO2; R1 = Cl*
(13) : R = 4-NO2; R1 = NO2*
(16) : R = 4-NO2; R1 = H
(19) : R = 4-NO2; R1 = -OCH3
(22) : R = 3-NO2; R1 = Cl
(25) : R = H; R1 = Cl
(11) : R = 4-NO2; R1 = Cl
(14) : R = 4-NO2; R1 = NO2
(17) : R = 4-NO2; R1 = H*
(20) : R = 4-NO2; R1 = -OCH3
(23) : R = 3-NO2; R1 = Cl
(26) : R = H; R1 = Cl
(12) : R = 4-NO2; R1 = NO2
(15) : R = 4-NO2; R1 = H
(18) : R = 4-NO2; R1 = -OCH3
(21) : R = 3-NO2; R1 = Cl
(24) : R = H; R1 = Cl
(27) : R = 4-OCH3; R1 = Cl
(28) : R = 4-OCH3; R1 = Cl
(29) : R = 4-OCH3; R1 = Cl
*corresponding ring-opened compounds (9a)
,
(10a)
,
(13a) and (17a) were obtained.
Scheme 1
of crude reaction mixture. The product ratios for the
different series of cycloadducts were found to be as
follows: 100:14:11:7 (9:10:11:9a), 100:49:17 (12:13a:14),
100:24:21 (15:16:17), 100:10:7 (18:19:20), 100:14:8
(21:22:23), 100:8:6 (24:25:26), 100:14:8 (27:28:29),
respectively.
HMBC experiments established 2-aryl-3,4,5-trisubstituted
isoxazolidine derived structures for all cycloadducts; the
sequence -O-C(5)H-C(4)H-C(3)H-N(2)Ar was found to
be present in all cases. Two-dimensional long-range
COSY experiments revealed correlations between the
benzylic proton and C(3)H for all three types of
cycloadducts. Such long-range correlations exists between
C(5)H and benzylic protons in types I and II; in type III
cycloadducts the correlation is between C(4)H and the
benzylic protons. Thus types I and II cycloadducts are 2-
(4-chlorophenyl)-3,5-diaryl-4-piperidinyloxoisoxazolidine
derivatives stereoisomeric at C(3); the relative trans-
C(4)H-C(5)H stereochemistry follows from the substrate
amide. The type III cycloadducts, on the other hand are
regioisomers, with 2-(4-chlorophenyl)-3,4-diaryl-5-piper-
idinyloxoisoxazolidine structures.
All the isolated products showed amide bands at 1600-
1650 cm-1 in their respective IR spectra. The three types
of cycloadducts (viz. type I, type II and type III) could be
1
differentiated from their H and 13C NMR characteristics.
The C(3)H doublet (in the series 9, 10, 11) appeared at ꢀ
5.37 ppm in (9) and ꢀ 4.52 ppm in (10), C(5)H was found
as a doublet at ꢀ 5.20 ppm (9) and ꢀ 4.88 ppm (10). C(4)H
resonated comparatively upfield for both (9) and (10) at ꢀ
3.65 ppm. In the regioisomeric compound (11) [type III
series], H-3 and H-5 were shielded by ~0.7 and 1.0 ppm,
respectively, compared to (9); the benzylic H-4 (double
doublet) was deshielded by ~1.0 ppm. These relationships
were typical of all the compounds belonging to the
different series. Two-dimensional 1H-1H-COSY and
The ring-opened compounds of isoxazolidine ring
system were identified from the presence of two hydroxyl
protons viz. >N-OH and 5-OH. These two hydroxyl
protons, viz. >N-OH and 5-OH, showed long-range

Jan-Feb 2007
Cycloadditions of C-Aryl-N-(4-Chlorophenyl) Nitrones to N-Cinnamoyl Piperidines
139
coupling with H-3, H-4, and H-5 protons (as well as to
each other) respectively in TOCSY spectra.
The X-Ray crystallographic analysis of a representative
compound of type I, viz (9) (R= 4-NO2; R1= Cl) showed
that the compound had all-trans stereochemistry,
including the lone pair of ring nitrogen [N2, trans to
C(3)H] (Figure 1). The relative configuration of the minor
cycloadducts followed as 3,4-cis (type II). The regio-
isomers of type III were given the relative configuration
shown, on the basis of NMR comparisons with the other
cycloadducts, and similar cycloadducts derived from C-
aryl-N-phenyl nitrones [8,9], for which the X-Ray
crystallographic analysis were performed.
Figure 2. Molecular modelling of 9 (all-trans isomer).
Figure 1. PLUTO projection of 9 (all-trans isomer).
Figure 3. Molecular modelling of 10 (3,4-cis-4,5-trans isomer).
Interest was then focused on the conformational
analysis and computer-assisted energy minimisation of
the stereoisomeric (9) and (10). Energy minimisation of
the all-trans isomer (9), and the corresponding
diastereoisomeric (10) was carried out considering the
corresponding non-chlorinated analogues by conjugate
gradient method [10,11] using DISCOVER Molecular
Simulation Program (version 2.98) running on a Silicon
Graphics O2 workstation. In these cases normal
completion of conjugate gradient was achieved in 1000
steps of energy evaluations. The derived structures are
given in Figure 2 for (9) and Figure 3 for (10). From the
relative values of potential energy it was found that the
energy content of 3,4-cis-4,5-trans isomer was about 3.6
kcal/mol greater than all-trans isomer (Table 1). This
value of potential energy reflects the overall stability of
the 3,4-trans-4,5-trans (all-trans) isomer, which was
found as a major product in this series of reactions.
The all-trans isomer is obtained by the endo-mode of
approach of the dipolarphile with respect to the carbonyl
group. Several publications have analysed the regio-
selectivity and diastereoselectivity of the 1,3-dipolar
cycloadditions of nitrones on the basis of FMO
interactions [2,12,13]. Most authors have explained the
favoured endo-mode of approach with respect to the
carbonyl group, to be due to favourable ‘Secondary
orbital interactions’, on the other hand, others have
proposed that other factors are responsible. Our
experimental results seem to indicate steric and dipolar
factors that favour the all-trans-cycloadduct, should also
play a significant role in the transition state leading to it.
In conclusion, detailed study of 1,3-dipolar cyclo-
addition of C-aryl-N-(4-chlorophenyl) nitrones to N-
cinnamoyl piperidines has been carried out including
energy calculations of cycloadducts. The major products
in all the cases are formed by endo- addition. Only small
but perceptible changes of product ratios on changing the
aryl ring substituents were observed usually. However,
when the dipolarophile was a 4-nitro derivative; the
relative proportion of the diasteroisomeric cycloadduct
(Type II) became comparatively much higher.
Table 1
Relative values of potential energy of isomer (9) and (10).
Isomer
Relative P.E. (kcal/mol)
all-trans
3,4-cis-4,5-trans
0.0
3.6

140
A. Banerji, P. K. Biswas, D. Bandyopadhyay, M. Gupta, T. Prangé and A. Neuman
Vol 44
(1H, m, HA-2ꢀ ), 3.15 (1H, m, HB-2ꢀ ), 2.65 (2H, m, H-6ꢀ ), 1.04
(2H, m, H-3ꢀ ), 1.16 (2H, m, H-4ꢀ ), 0.73 (1H, m, HA-5ꢀ ), 0.47
(1H, m, HB-5ꢀ ), 6.78 (2H, d, J=8.7, A,H-2,6), 7.12 (2H, d, J=8.7,
A,H-3,5), 7.61 (2H, d, J=8.7, B,H-2,6), 8.09 (2H, d, J=8.7, B,H-
3,5), 7.29 (2H, d, J=8.4, C,H-2,6), 7.36 (2H, d, J=8.4, C,H-3,5)
ppm; 13C NMR (CDCl3, ꢀ, 75.5 MHz): 74.9 (C-3), 63.9 (C-4),
84.5 (C-5), 43.0 (C-2ꢀ ), 25.7 (C-3ꢀ ), 24.1 (C-4ꢀ ), 26.4 (C-5ꢀ ),
46.9 (C-6ꢀ ), 165.8 (>C=O), 150.0 (A,C-1), 115.7 (A,C-2,6),
127.9 (A,C-3,5), 135.2 (A,C-4), 147.0 (B,C-1), 127.1 (B,C-2,6),
124.1 (B,C-3,5), 148.4 (B,C-4), 127.6 (C,C-1), 129.2 (C,C-2,6),
129.1 (C,C-3,5), 134.4 (C,C-4) ppm: MS(FAB): m/z = 527
(M++2), 385 (M+ - C7H5OCl), 301 (385 – C5H10NO; 18%), 283
(M+ – C12H17NO2Cl; 100% base peak), 259 (M+ – C14H17NO2Cl;
11%), 154 (266 – C6H10NO; 100% base peak), 136 (249 –
C6H4Cl – 2H•; 68%). Anal. Calcd. for C27H25N3O4Cl2: C, 61.76;
H, 4.80; N, 8.01. Found: C, 61.69 ; H, 4.72; N, 7.90.
EXPERIMENTAL
General. Melting points were recorded on a Köfler block
apparatus and are uncorrected. Neutral alumina was used for
column chromatography, and silica gel (60-120 mesh) for TLC.
Petrol refers to the petroleum ether AR (b.p. 60-80°). Analytical
samples were routinely dried over CaCl2 in vacuo at room
temperature. IR spectra were recorded in KBr pellets with a
Perkin-Elmer RX-1 FT-IR, and UV spectra in spectroscopic
grade ethanol (Merck) with a Hitachi U-3501 instrument. Mass
spectra were recorded with a JEOL JMS600 mass spectrometer.
Elemental analysis (C, H, N) were conducted using the Perkin-
Elmer 2400 Series II elemental analyser, their results were found
to be in good agreement (± 0.2%) with the calculated values for
1
C, H, N. 300 MHz H NMR, 75.5 MHz 13C NMR and two-
dimensional spectra (COSY, XHCORR) were recorded in
CDCl3 and d6-DMSO solution with a Bruker AM-300L
spectrometer (chemical shifts in ꢀ ppm and J in Hz). 500 MHz
1H NMR, 125 MHz 13C NMR and corresponding two-
dimensional correlation experiments (DQF, TOCSY, HMQC
and HMBC) were recorded with a Bruker DRX 500 NMR
spectrometer (11.7 Tesla). (A-C) refers to the respective rings
(Scheme I).
1RS-(1R*,2R*,3S*)-1´-[N-Hydroxy-N-(4-chlorophenyl)-
amino]-1´-(4-nitrophenyl)-3-[hydroxy-3-(4-chlorophenyl)]-
propanoyl piperidines, (10a; C27H27N3O5Cl2). Light brown
solid; m.p.: 236°C; yield: 0.25 g (10%) ; IR: ꢁ = 3377, 3285 (m,
-OH), 2934 -2850 (m, -CH2-), 1607 (s, amide >C=O), 830 (m, 1,
4-disubstituted benzene ring) cm-1; UV: ꢂ
(log ꢃ) = 254
max
(3.71) nm; 1H NMR (d6-DMSO, ꢀ, 500 MHz): 4.52 (1H, t,
J=8.2, H-3), 3.49 (1H, br.t, H-4), 4.88 (1H, dd, J=7.3, 3.5, H-5),
6.63 (1H, d, J=7.3, >N-OH), 5.85 (1H, d, J=3.5, 5-OH), 2.76
(4H, m, H-2ꢀ,6ꢀ ), 0.73 (2H, m, H-3ꢀ ), 1.02 (2H, m, H-4ꢀ ), 0.59
(2H, m, H-5ꢀ ), 6.33 (2H, d, J=8.8, A,H-2,6), 6.84 (2H, d, J=8.8,
A,H-3,5), 7.42 (2H, d, J=8.7, B,H-2,6), 7.90 (2H, d, J=8.7, B,H-
3,5), 7.06 (2H, d, J=8.5, C,H-2,6), 7.10 (2H, d, J=8.5, C,H-3.5)
ppm; 13C NMR (d6-DMSO, ꢀ, 125.5 MHz) 59.6 (C-3), 53.7 (C-
4), 74.4 (C-5), 42.4 (C-2ꢀ ), 25.9 (C-3ꢀ ), 24.4 (C-4ꢀ ), 26.3 (C-5ꢀ ),
47.1 (C-6ꢀ ), 167.9 (>C=O), 146.7 (A,C-1), 115.6 (A,C-2,6),
129.5 (A,C-3,5), 121.2 (A,C-4),147.3 (B,C-1),129.9 (B,C-2,6),
123.7 (B,C-3,5), 150.8 (B,C-4), 132.4 (C,C-1), 129.7 (C,C-2,6),
The compound N-(4-chlorophenyl)hydroxylamine, m.p. 89-90
°C was prepared from 4-chloronitrobenzene by adopting the
method used for obtaining N-phenylhydroxylamine from
nitrobenzene [14]. Initially the nitrones were prepared as
described in our early communications [7,8,9]. The C-aryl-N-
(4´-chlorophenyl) nitrones were also synthesised by a more
convenient method using microwave irradiation techniques from
the appropriate aromatic aldehyde and N-(4-chlorophenyl)
hydroxylamine. This improved procedure was similar to that
developed by the authors for C-aryl-N-methyl nitrones [9]. In
this procedure the aromatic aldehyde was taken with a small
excess of N-(4-chlorophenyl) hydroxylamine (1:1.2 molar ratio)
in dry dichloromethane in an Erlenmeyer flask. The reaction
mixture was subjected to microwave irradiation for periods
varying from 1-4 min. For C-phenyl-N-(4-chlorophenyl) nitrone
the yield, after 4 min was 91.5%. Similar reaction times and
yields were found for the other nitrones. At the end of the
reaction period the post-reaction mixture was worked up, and
the residue was analysed by 1H NMR. The nitrones were
crystallised from ethanol, methanol or petrol-benzene mixture
and characterised from their FT-IR, 300 MHz 1H NMR and 75.5
MHz 13C NMR spectra.
128.2 (C,C-3,5), 142.8 (C,C-4) ppm.
Anal. Calcd. for
C27H27N3O5Cl2: C, 61.80; H, 4.82; N, 9.02. Found: C, 61.65; H,
4.76; N, 7.94.
3RS-(3R*,4S*,5R*)-2-(4´-chlorophenyl)-3-(4´´-nitrophenyl)-
4-(4-chlorophenyl)-5-piperidinyl-oxoisoxazolidine (11;
C27H25N3O4Cl2). The regioisomeric cycloadduct (11) was
detected from the 1H NMR spectrum of the crude reaction
1
mixture. H NMR (CDCl3, ꢁ, 300 MHz): 5.38 (1H, d, J=7.9, H-
3), 5.00 (1H, dd, J=7.9, 6.7, H-4), 5.17 (1H, d, J=6.7, H-5).
1RS-(1R*,2R*,3S*)-1ꢀ-[N-hydroxy-N-(4-chlorophenyl)-
amino]-1ꢀ-(4-nitrophenyl) 3-[hydroxy-3-(4-chlorophenyl)]
propanoyl piperidines, (9a; C27H27N3O5Cl2). White crystalline
solid; m.p.: 170°C; yield; 0.25 g (10%); IR: ꢁ = 3421, 3346 (m, -
OH), 2934, 2861 (m, -CH2-), 1626 (s, amide >C=O), 819 (m, 1,
General Method. A hot solution of nitrones 1-4 (0.0066
mol) in anhydrous toluene (20 ml) was added to a solution of
piperidides 5-8 (3 x 0.0066 mol) in anhydrous toluene (20 ml).
The reaction mixture was refluxed under a nitrogen atmosphere
for 15-20 hrs. The reaction was monitored by TLC and by 300
MHz H NMR analyses. The solvent was removed from the
crude reaction mixture, and the mixture was chromatographed
over neutral alumina to separate the products.
4-disubstituted benzene ring) cm-1; UV: ꢂ
(log ꢃ) = 254
max
1
(4.24) nm; H NMR (CDCl3, ꢀ, 300 MHz): 4.80 (1H, d, J=7.4,
H-3), 3.20 (1H, dd, J=7.4, 4.5, H-4), 4.65 (1H, d, J=4.5, H-5),
5.39 (1H, s, >N-OH), 3.96 (1H, s, 5-OH), 3.56 (1H, m, HA-2ꢀ),
3.28 (1H, m, HB-2ꢀ), 2.99 (2H, m, H-6ꢀ), 1.50 (4H, m, H-3ꢀ,4ꢀ),
1.18 (2H, m, H-5ꢀ), 6.13 (2H, d, J=8.7 A,H-2,6), 6.92 (2H, d,
J=8.7, A,H-3,5), 7.17 (2H, d, J=8.5, B,H-2,6), 7.93 (2H, d,
J=8.5, B,H-3,5), 6.92 (2H, d, J=8.4, C,H-2,6), 7.11 (2H, d,
J=8.4, C,H-3,5) ppm. 13C NMR (CDCl3, ꢀ, 75.5 MHz): 60.4 (C-
3), 54.6 (C-4), 71.2 (C-5), 41.9 (C-2ꢀ), 26.2 (C-3ꢀ), 24.2 (C-4ꢀ),
27.9 (C-5ꢀ), 44.3 (C-6ꢀ), 172.0 (>C=O), 150.0 (A,C-1), 115.3
(A,C-2,6), 129.0 (A,C-3,5), 136.0 (A,C-4), 147.0 (B,C-1), 128.5
(B,C-2,6), 123.5 (B,C-3,5), 148.0 (B,C-4), 127.0 (C,C-1), 130.0
(C,C-2,6), 129.1 (C,C-3,5), 145.0 (C,C-4) ppm. Anal. Calcd. for
1
Reaction of C-(4-Nitrophenyl)-N-(4´-chlorophenyl) nitrone
(1) with Piperidide of 4-Chlorocinnamic acid (5). 3RS-(3R*,
4S*,5R*)-2-(4´-Chlorophenyl)-3-(4´´-nitrophenyl)-5-(4-chloro-
phenyl)-4-piperidinyl-oxoisoxazolidine (9); C27H25N3O4Cl2).
White crystals; m.p.: 164°C; yield: 1.73 g (70%); IR: ꢁ = 2937,
2860 (m, -CH2-), 1636 (s, amide >C=O), 827 (m, 1, 4-
disubstituted benzene ring); cm-1; UV:ꢂ
(log ꢃ) = 249 (4.01)
max
nm; 1H NMR (d6-DMSO, ꢀ, 500 MHz): 5.18 (1H, d, J=7.0, H-3),
3.83 (1H, dd, J=7.0, 9.3, H-4), 5.03 (1H, d, J= 9.3, H-5), 3.29

Jan-Feb 2007
Cycloadditions of C-Aryl-N-(4-Chlorophenyl) Nitrones to N-Cinnamoyl Piperidines
141
1
C27H27N3O5Cl2: C, 61.80; H, 4.82; N, 8.02. Found: C, 61.62; H,
4.74; N, 7.97.
(log ꢂ) = 250 (4.35) nm; H NMR (CDCl3, ꢃ, 500 MHz): 5.51
(1H, d, J=7.5, H-3), 3.77 (1H, dd, J=7.5, 9.5, H-4), 5.23 (1H, d,
J=9.5, H-5), 3.64 (1H, m, HA-2ꢀ), 3.40 (1H, m, HB-2ꢀ), 2.74 (2H,
m, H-6ꢀ), 1.40 (4H, m, H-3ꢀ,4ꢀ ), 0.95 (1H, m, HA-5ꢀ), 0.64 (1H,
m, HB-5ꢀ), 6.93 (2H, d, J=8.9, A,H-2,6), 7.22 (2H, d, J=8.9, A,H-
3,5), 7.73 (2H, d, J=8.7, B,H-2,6), 8.26 (2H, d, J=8.7, B,H-3,5),
7.38-7.44 (5H, m, C,H-2,3,4,5,6) ppm; 13C NMR (CDCl3, ꢃ,
125.5 MHz): 75.2 (C-3), 64.5 (C-4), 85.7 (C-5), 44.3 (C-2ꢀ),
26.1 (C-3ꢀ), 24.5 (C-4ꢀ ), 26.6 (C-5ꢀ), 47.3 (C-6ꢀ), 166.2 (>C=O),
150.5 (A,C-1), 115.9 (A,C-2,6), 129.4 (A,C-3,5), 127.5 (A,C-4),
149.3 (B,C-1), 127.4 (B,C-2,6), 124.8 (B,C-3,5), 148.1 (B,C-4),
135.6 (C,C-1), 127.1 (C,C-2,6), 129.5 (C,C-3,5), 129.8 (C,C-4)
ppm. Anal. Calcd. for C27H26N3O4Cl: C, 66.11; H, 5.34; N, 8.54.
Found: C, 65.90; H, 5.27; N, 8.47.
Reaction of C-(4-Nitrophenyl)-N-(4´-chlorophenyl) nitrone
(1) with Piperidide of 4-Nitrocinnamic acid (6). 3RS-
(3R*,4S*,5R*)-2-(4´-chlorphenyl)-3-(4´´-nitrophenyl)-5-(4-
nitrophenyl)-4-piperidinyl-oxoisoxazolidine (12, C27H25N4O6Cl).
Yellowish crystals; m.p.: 184°C; yield: 1.44 g (57%); IR: ꢀ =
2940, 2860 (m, -CH2-), 1638 (s, amide >C=O), 838 (m, 1,4-
disubstituted benzene ring) cm-1; UV: ꢁ
(log ꢂ) = 255 (4.14)
max
1
nm; H NMR (CDCl3, ꢃ, 300 MHz): 5.49 (1H,d, J=9.3, H-3),
3.73 (1H, t, J=8.6, H-4), 5.33 (1H, d, J=9.1, H-5), 3.56 (2H, m,
H-2ꢀ), 2.72 (2H, m, H-6ꢀ), 1.46 (4H, m, H-3ꢀ,4ꢀ), 0.93 (1H, m,
HA-5ꢀ), 0.81 (1H, m, HB-5ꢀ), 6.91 (2H, d, J=8.8, A,H-2,6), 7.23
(2H, d, J=8.8, A,H-3,5), 7.71 (2H, d, J=8.6, B,H-2,6), 8.29 (2H,
d, J=8.6, B,H-3,5), 7.64 (2H, d, J=8.6, C,H-2,6), 8.26 (2H, d,
J=8.6, C,H-3,5) ppm; 13C NMR (CDCl3, ꢃ, 75.5 MHz): 74.9 (C-
3), 63.3 (C-4), 83.3 (C-5), 43.7 (C-2ꢀ), 25.5 (C-3ꢀ), 23.8 (C-4ꢀ),
26.2 (C-5ꢀ), 46.7 (C-6ꢀ), 165.2 (>C=O), 149.2 (A,C-1), 115.7
(A,C-2,6), 128.9 (A,C-3,5), 147.1 (A,C-4), 147.8 (B,C-1), 124.2
(B,C-2,6), 123.8 (B,C-3,5), 148.1 (B,C-4), 127.9 (C,C-1), 126.9
(C,C-2,6), 126.6 (C,C-3,5), 143.2 (C,C-4) ppm. MS (EI): m/z =
536(M+), 409 (M+ - C6H4NCl-2H•), 276 [M+ – C14H16N2O3], 260
[M+ - C13H9N2O3Cl; 100% base peak], 385 [M+ - C7H5NO3], 150
[M+ – C20H20N3O3Cl - H•], 176 (260 – C5N10NO; 63%), 138 (259
– C6H4NO2 + H•), 125 (C6H6NCl+; 100% base peaks), 111
(C6H4Cl+), 84 (C5H10N+), 102 (150-NO2-2H•). Anal. Calcd. for
C27H25N4O6Cl: C, 60.45; H, 4.70; N, 10.45. Found: C, 60.38; H,
4.65; N, 10.40.
3RS-(3R*,4R*,5S*)-2-(4-chlorophenyl)-3-(4´-nitrophenyl)-
5-phenyl-4-piperidinyloxo-isoxazolidine (16, C27H26N3O4Cl).
White shiny crystals; m.p.: 240°C; yield: 0.25 g (24%); IR: ꢀ =
2939, 2859 (m, -CH2-), 1609 (s, amide >C=O), 858 (m, 1,4-
disubstituted benzene ring), 770, 702 (m, mono-substituted
benzene ring) cm-1; UV: ꢁ max (log ꢂ) = 252 (4.32) nm; 1H NMR
(CDCl3, ꢃ, 500 MHz): 5.08 (1H, d, J=9.5, H-3), 3.41 (1H, dd,
J=9.5, 7.1, H-4), 5.27 (1H, d, J=7.1, H-5), 3.07 (1H, m, HA-2 ),
2.94 (1H, m, HB-2ꢀ), 2.73 (1H, m, HA-6ꢀ), 2.56 (1H, m, HB-6ꢀ),
1.01 (2H, m, H-3ꢀ), 1.23 (2H, m, H-4ꢀ), 0.82 (1H, m, HA-5ꢀ), 0.62
(1H, m, HB-5ꢀ), 6.30 (2H, d, J=8.8, A,H-2,6), 7.00 (2H, d, J=8.8,
A,H-3,5), 7.61 (2H, d, J=8.7, B,H-2,6), 8.12 (2H, d, J=8.7, B,H-
3,5), 7.39 (2H, d, J=7.2, C,H-2,6), 7.32 (2H, t, J=7.3, C,H-3,5),
7.29 (1H, d, J=7.2, C,H-4) ppm; 13C NMR (CDCl3, ꢃ, 125.5
MHz): 61.2 (C-3), 54.7 (C-4), 76.7 (C-5), 42.5 (C-2ꢀ), 25.4 (C-
3ꢀ), 24.1 (C-4ꢀ), 26.0 (C-5ꢀ), 46.9 (C-6ꢀ), 177.0 (>C=O), 145.5
(A,C-1), 115.8 (A,C-2,6), 128.6 (A,C-3,5), 128.4 (A,C-4), 148.0
(B,C-1), 126.9 (B,C-2,6), 124.0 (B,C-3,5), 152.0 (B,C-4), 142.5
(C,C-1), 128.9 (C,C-2,6), 128.8 (C,C-3,5), 129.3 (C,C-4) ppm.
Anal. Calcd. for C27H26N3O4Cl: C, 66.11; H, 5.34; N, 8.54.
Found: C, 65.94; H, 5.29; N, 8.45.
1RS-(1R*,2R*,3S*)-1´-[N-hydroxy-N-(4-chlorophenyl)-
amino]-1´-(4-nitrophenyl)-3-hydroxy-3-(4-nitrophenyl)-pro-
panoyl piperidine (13a, C27H27N4O7Cl). White needle shaped
crystals; m.p.: 230°C; yield: 0.59 g (29%); IR: ꢀ = 3349, 3271
(m, -OH), 2934, 2858 (m, -CH2-), 1607 (s, amide >C=O), 856,
819 (m, 1,4-disubstituted benzene ring) cm-1; UV: ꢁmax (log ꢂ) =
1
255 (4.29) nm; H NMR (d6-DMSO, ꢃ, 300 MHz): 4.64 (1H, t,
J=7.4, H-3), 3.79 (1H, br. t, H-4), 5.24 (1H, dd, J=6.4, 3.6, H-5),
6.83 (1H, d, J=7.9, >N-OH), 6.19 (1H, d, J=3.6), 3.04 (2H, m,
H-2ꢀ), 2.86 (2H, m, H-6ꢀ), 1.20 (4H, m, H-3ꢀ,4ꢀ), 0.98 (1H, m,
HA-5ꢀ), 0.71 (1H, m, HB-5ꢀ), 6.52 (2H, d, J=8.5, A, H-2,6), 7.02
(2H, d, J=8.5, A,H-3,5), 7.58 (2H, d, J=8.5, B,H-2,6), 8.09 (2H,
d, J=8.5, B,H-3,5), 7.47 (2H, d, J=8.5, C,H-2,6), 8.06 (2H, d,
J=8.5, C,H-3,5) ppm; 13C NMR (d6-DMSO, ꢃ, 75.5 MHz): 57.4
(C-3), 51.4 (C-4), 72.1 (C-5), 40.8 (C-2ꢀ), 24.3 (C-3ꢀ), 22.7 (C-
4ꢀ), 24.7 (C-5ꢀ), 45.5 (C-6ꢀ), 166.2 (>C=O), 150.0 (A,C-1), 113.9
(A,C-2,6), 128.3 (A,C-3,5), 145.7 (B,C-1), 127.4 (B,C-2,6),
121.7 (B,C-3,5), 148.9 (B,C-4), 119.6 (C,C-1), 127.6 (C,C-2,6),
1RS-(1R*,2S*,3R*)-1´-N-hydroxy-N-(4´-chlorophenyl)-
amino]-1´-(4´-nitrophenyl)-2-phenyl-3-hydroxy-3-propan-
oylpiperidine (17a, C27H28N3O5Cl). White flakes; m.p.: 156°C;
yield: 0.12 g (12%); IR: ꢀ = 3422, 3300 (m, -OH), 2940, 2900
(m, -CH2-), 1626 (s, amide >C=O), 821 (m, 1,4-disubstituted
benzene ring), 703 (m, mono-substituted benzene ring) cm-1;
1
UV: ꢁ
(log ꢁ) = 254 (4.19) nm; H NMR (CDCl3, ꢃ, 500
max
MHz): 4.95 (1H, br.t, J ~7, H-3), 3.25 (1H, dd, J=8, 3, H-4), 4.80
(1H, dd, J= 9, H-5), 5.46 (1H, d, J=6, >N-OH), 4.00 (1H, d, J=9,
5-OH), 3.58 (1H, m, HA-2ꢀ), 3.36 (1H, m, HB-2ꢀ), 3.26 (1H, m,
HA-6ꢀ), 3.00 (1H, m, HB-6ꢀ), 1.43 (2H, m, H-3ꢀ), 1.53 (2H, m, H-
4ꢀ), 1.25 (1H, m, H-5ꢀ), 6.40 (2H, d, J=9, A,H-2,6), 7.00 (2H, d,
J=9, A,H-3,5), 7.26 (2H, d, J=8.5, B,H-2,6), 7.99 (2H, d, J=8.5,
B,H-3,5), 7.04 (2H, dd, J=7, 2.3, C,H-2,6), 7.21-7.23 (3H, m,
C,H-3,4,5) ppm; 13C NMR (CDCl3, ꢃ, 125.5 MHz): 60.7 (C-3),
55.9 (C-4), 71.3 (C-5), 44.2 (C-2ꢀ), 25.8 (C-3ꢀ), 24.4 (C-4ꢀ), 26.4
(C-5ꢀ), 47.0 (C-6ꢀ), 172.4 (>C=O), 145.2 (A,C-1), 115.4 (A,C-
2,6), 129.4 (A,C-3,5), 123.3 (A,C-4), 147.3 (B,C-1), 128.8 (B,C-
2,6), 123.7 (B,C-3,5), 149.9 (B,C-4), 139.5 (C,C-1), 128.2 (C,C-
2,6), 129.2 (C,C-3,4,5) ppm. Anal. Calcd. for C27H28N3O5Cl: C,
63.15; H, 5.36; N, 8.56. Found: C, 65.95; H, 5.39; N, 8.48.
Reaction of C-(4-Nitrophenyl)-N-(4´-chlorophenyl) nitrone
(1) with Piperidide of 4-Methoxycinnamic acid (8). 3RS-
(3R*,4S*,5R*)-2-(4-chlorophenyl)-3-(4-nitrophenyl)-5-(4-
methoxyphenyl)-4-piperidinyloxoisoxazolidine, (18,
C28H28N3O5Cl). White crystals; m.p.: 150°C; yield: 0.48 g (83
%); IR: ꢀ = 2934, 2854 (m, -CH2-), 1634 (s, amide >C=O), 829
122.0 (C,C-3,5), 144.9 (C,C-4) ppm.
Anal. Calcd. for
C27H27N4O7Cl: C, 60.47; H, 4.72; N, 10.50. Found: C, 60.33; H,
4.62; N, 10.43.
3RS-(3R*,4S*,5R*)-2-(4´-chlorophenyl)-3-(4´´-nitrophenyl)-
4-(4-nitrophenyl)-5-piperidinyl-oxoisoxazolidine
(14,
C27H25N4O6Cl). The regioisomeric cycloadduct (14) was
detected from the 1H NMR spectrum of the crude reaction
1
mixture. H NMR (CDCl3, ꢃ, 300 MHz): 5.55 (1H, d,
J=8.8, H-3), 4.95 (1H, br. t), 5.06 (1H, d, J=9.5).
Reaction of C-(4-Nitrophenyl)-N-(4´-chlorophenyl) nitrone
(1) with Piperidide of Cinnamic acid (7). 3RS-(3R*,4S*,
5R*)–2-(4-chlorophenyl)-3-(4´-nitrophenyl)-5-phenyl-4-piperi-
dinyloxo-isoxazolidine, (15, C27H26N3O4Cl). White crystals;
m.p.: 150°C; yield: 0.6 g (56%); IR: ꢀ = 2936, 2857 (m, -CH2-),
1626 (s, amide >C=O), 834 (m, 1,4-disubstituted benzene ring),
758, 699 (m, mono-substituted benzene ring) cm-1; UV: ꢁ
max

142
A. Banerji, P. K. Biswas, D. Bandyopadhyay, M. Gupta, T. Prangé and A. Neuman
Vol 44
(s, 1,4-disubstituted benzene ring), cm-1; UV: ꢀ max (log ꢁ) = 250
(4.35) nm; H NMR (CDCl3, ꢂ, 300 MHz): 5.53 (1H, d, J=7.5,
Reaction of C-Phenyl-N-(4-chlorophenyl) nitrone (3) with
Piperidide of 4-Chlorocinnamic acid (29). 3RS-(3R*,4S*,5R*)-
2-(4-chlorophenyl)-3-phenyl-5-(4-chlorophenyl)-4-piperidinyl-
oxo-isoxazolidine (24, C27H26N2O2Cl2). Pale yellow crystals;
m.p.: 120°C; yield: 0.40 g (80%); IR: ꢃ = 2937, 2859 (m, -
CH2-), 1637 (s, amide >C=O), 825 (s, 1,4-disubstituted
benzene ring), 757, 700 (m, mono-substituted benzene ring)
1
H-3), 3.76 (1H, t, J=8.5, H-4), 5.16 (1H, d, J= 9.5, H-5), 3.60
(1H, m, HA-2ꢀ), 3.44 (1H, m, HB-2ꢀ), 2.75 (2H, m, H-6ꢀ), 1.36
(4H, m, H-3ꢀ,4ꢀ ), 0.95 (1H, m, H A-5ꢀ), 0.70 (1H, m, HB-5ꢀ), 3.81
(3H, s, -OCH3), 6.91 (2H, d, J=8.5, A,H-2,6), 7.35 (2H, d, J=8.5,
A,H-3,5), 7.72 (2H, d, J=8.5, B,H-2,6), 8.27 (2H, d, J=8.5, B,H-
3,5), 7.21 (1H, d, J=8.5, C,H-2,6), 6.91 (1H, d, J=8.5, C,H-3,5)
ppm; 13C NMR (CDCl3, ꢂ, 75.5 MHz): 74.8 (C-3), 64.0 (C-4),
85.2 (C-5), 43.9 (C-2ꢀ), 25.7 (C-3ꢀ), 24.2 (C-4ꢀ ), 26.3 (C-5ꢀ),
46.9 (C-6ꢀ), 166.1 (>C=O), 55.4 (-OCH3), 150.2 (A,C-1), 115.5
(A,C-2,6), 128.2 (A,C-3,5), 147.0 (A,C-4), 147.8 (B,C-1), 127.0
(B,C-2,6), 124.3 (B,C-3,5), 149.0 (B,C-4), 126.8 (C,C-1), 129.0
(C,C-2,6), 114.5 (C,C-3,5), 160.5 (C,C-4) ppm.
1
cm-1; UV: ꢀmax (log ꢁ) = 249.5 and 225 (3.15 and 3.34) nm; H
NMR (CDCl3, ꢂ, 300 MHz): 5.14 (1H, d, J=8.2, H-3), 3.76
(1H, t, J=8.8, H-4), 5.38 (1H, d, J= 9.3, H-5), 3.50 (2H, m, H-
2ꢀ), 2.75 (2H, m, H-6ꢀ), 1.60 (2H, m, H-3ꢀ), 1.42 (1H, m, H-4ꢀ),
0.87 (1H, m, HA-5ꢀ), 0.80 (1H, m, HB-5ꢀ), 6.90 (2H, d, J=7,
A,H-2,6), 7.17 (2H, d, J=7, A,H-3,5), 7.50 (2H, d, J=7.1, B,H-
2,6), 7.30-7.40 (3H, m, B,H-3,4,5), 7.30-7.42 (4H, m, C,H-
2,6,3,5) ppm; 13C NMR (CDCl3, ꢂ, 75.5 MHz): 76.1 (C-3),
63.8 (C-4), 83.9 (C-5), 43.7 (C-2ꢀ), 25.7 (C-3ꢀ), 24.2 (C-4ꢀ),
26.0 (C-5ꢀ), 46.9 (C-6ꢀ), 167.3 (>C=O), 150.6 (A,C-1), 115.9
(A,C-2,6), 128.9 (A,C-3,5), 135.3 (A,C-4), 140.6 (B,C-1),
127.8 (B,C-2,6), 126.3 (B,C-3,5), 128.2 (B,C-4), 127.0 (C,C-
1), 129.2 (C,C-2,6), 129.0 (C,C-3,5), 134.6 (C,C-4) ppm. Anal.
Calcd. for C27H26N2O2Cl2: C, 67.42; H, 5.44; N, 5.86. Found:
C, 67.36; H, 5.55; N, 5.80.
Anal. Calcd. for C28H28N3O5Cl: C, 64.36; H, 5.41; N,
8.04. Found: C, 64.42; H, 5.37; N, 8.00.
3RS-(3R*,4R*,5S*)-2-(4-chlorophenyl)-3-(4-nitrophenyl)-
5-(4-methoxyphenyl)-4-piperidinyloxoisoxazolidine, (19,
C28H28N3O5Cl). The diastereomeric cycloadduct (19) was
detected from the 1H NMR spectrum of the crude reaction
mixture. 1H NMR (CDCl3, ꢂ, 300 MHz): 4.86 (1H, d, J=9, H-3),
4.09 (1H, br, t, H-4), 5.88 (1H, d, J=8.5, H-5).
3RS-(3R*,4R*,5S*)-2-(4-chlorophenyl)-3-phenyl-5-(4-chloro-
phenyl)-4-piperidinyloxo-isoxazolidine(25; C27H26N2O2Cl2).
3RS-(3R*,4S*,5R*)-2-(4-Chlorophenyl)-3-(4-nitrophenyl)-
4-(4-methoxyphenyl)-5-piperidinyl-oxoisoxazolidine (20,
1
The diastereomeric cycloadduct (25) was detected from the H
C28H28N3O5Cl).
The regioisomeric cycloadduct (20) was
NMR spectrum of the crude reaction mixture. 1H NMR (CDCl3,
ꢁ, 300 MHz): 6.02 (1H, d, J=9, H-3), 3.70 (1H, br. t, H-4), 4.67
(1H, d, J=10.5, H-5).
detected from the 1H NMR spectrum of the crude reaction
mixture. 1H NMR (CDCl3, ꢂ, 300 MHz): 4.89 (1H, d, J=6, H-3),
4.38 (1H, br. t, H-4), 4.51 (1H, d, J=7.5, H-5)
3RS-(3R*,4S*,5R*)-2-(4-chlorophenyl)-3-phenyl-4-(4-chloro-
phenyl)-5-piperidinyloxo-isoxazolidine (26; C27H26N2O2Cl2).
Reaction of C-(3-Nitrophenyl)-N-(4´-chlorophenyl) nitrone
(2) with Piperidide of 4-Chlorocinnamic acid (5). 3RS-
(3R*,4S*,5R*)-2-(4-Chlorophenyl)-3-(3-nitrophenyl)-5-(4-chloro-
phenyl)-4-piperidinyloxo-isoxazolidine (21; C27H25N3O4Cl2).
White crystals; m.p.: 164°C; yield: 0.43 g (82%); IR: ꢃ = 2930,
2860 (m, -CH2-), 1624 (s, amide >C=O), 823.7 (s, 1,4-
disubstituted benzene ring), 688 (m, meta-substituted benzene
ring) cm-1; UV: ꢀmax (log ꢁ) = 247.5 (3.68) nm; 1H NMR (CDCl3,
ꢂ, 300 MHz): 5.43 (1H, d, J=7.7, H-3), 3.74 (1H, dd, J=7.7, 9.4,
H-4), 5.26 (1H, d, J= 9.4, H-5), 3.56 (1H, m, H-2ꢀ), 2.78 (2H, m,
H-6ꢀ), 1.40 (4H, m, H-3ꢀ,4ꢀ ), 0.95 (1H, m, HA-5ꢀ), 0.80 (1H, m,
HB-5ꢀ), 6.90 (2H, d, J=8.8, A,H-2,6), 7.20 (2H, d, J=8.8, A,H-
3,5), 8.40 (1H, s, B,H-2), 8.20 (1H, d, J=8.2, B,H-4), 7.60 (1H, t,
J=8.0, B,H-5), 7.90 (1H, d, J=7.7, B,H-6) 7.28-7.37 (4H, m,
C,H-2,6,3,5) ppm; 13C NMR (CDCl3, ꢂ, 75.5 MHz): 75.3 (C-3),
64.2 (C-4), 84.8 (C-5), 44.3 (C-2ꢀ), 26.1 (C-3ꢀ), 24.5 (C-4ꢀ), 26.8
(C-5ꢀ), 47.4 (C-6ꢀ), 166.1 (>C=O), 149.3 (A,C-1), 115.9 (A,C-
2,6), 128.3 (A,C-3,5), 135.5 (A,C-4), 143.8 (B,C-1), 132.5 (B,C-
2), 151.9 (B,C-3), 130.6 (B,C-4), 121.5 (B,C-5), 123.4 (B,C-6),
134.3 (C,C-1), 129.6 (C,C-2,6), 129.5 (C,C-3,5), 127.7 (C,C-4)
ppm. Anal. Calcd. for C27H25N3O4Cl2: C, 61.73; H, 4.78; N,
8.00. Found: C, 61.60; H, 4.73; N, 7.92.
1
The regioisomeric cycloadduct (26) was detected from the H-
NMR spectrum of the crude reaction mixture. 1H NMR (CDCl3,
ꢁ, 300 MHz): 5.03 (1H, d, J=7, H-3), 4.86 (1H, t, J=4, H-4), 4.49
(1H, d, J=4, H-5).
Reaction of C-(4-Methoxyphenyl)-N-(4´-chlorophenyl)
nitrone (4) with Piperidide of 4-Chlorocinnamic acid (5).
3RS-(3R*,4S*,5R*)-2-(4-chlorophenyl)-3-(4-methoxyphenyl)-
5-(4-chlorophenyl)-4-piperidinyloxoisoxazolidine (27,
C28H28N2O3Cl2). White crystalline solid; m.p.: 255°C; yield: 0.38
g (74%); IR: ꢂ = 2934, 2856 (m, -CH2-), 1611 (s, amide >C=O),
827 (s, 1,4-disubstituted benzene ring) cm-1; UV: ꢃmax (log ꢄ) =
1
252.5 and 229 (3.74 and 3.88) nm; H NMR (CDCl3, ꢁ, 300
MHz): 5.25 (1H, d, J=7, H-3), 3.30 (1H, dd, J=7.5, 10, H-4),
4.94 (1H, d, J= 10, H-5), 3.02 (1H, m, H-2ꢀ), 2.69 (2H, m, H-6ꢀ),
1.25 (4H, m, H-3ꢀ,4ꢀ), 1.00 (1H, m, HA-5ꢀ), 0.80 (1H, m, HB-5ꢀ),
3.73 (3H, s, -OCH3), 6.77 (2H, d, J=8.5, A,H-2,6), 7.00 (2H, d,
J=8.5, A,H-3,5), 7.20 (2H, d, J=8.5, B,H-2,6), 6.47 (2H, d,
J=8.5, B,H-3,5), 7.20 (2H, d, J=8.5, C,H-2,6), 7.34 (2H, d,
J=8.6, C,H-3,5) ppm; 13C NMR (CDCl3, ꢁ, 75.5 MHz): 70.1 (C-
3), 62.1 (C-4), 76.1 (C-5), 42.2 (C-2ꢀ), 25.1 (C-3ꢀ), 23.9 (C-4ꢀ),
25.6 (C-5ꢀ), 46.5 (C-6ꢀ), 55.3 (C-OCH3), 182.1 (>C=O), 159.3
(A,C-1), 114.1 (A,C-2,6), 128.1 (A,C-3,5), 147.0 (A,C-4), 147.8
(B,C-1), 127.0 (B,C-2,6), 117.1 (B,C-3,5), 166.0 (B,C-4), 146.0
(C,C-1), 129.1 (C,C-2,6), 128.3 (C,C-3,5), 147.7 ( C,C-4) ppm.
Anal. Calcd. for C28H28N2O3Cl2: C, 65.75; H, 5.56; N, 5.49.
Found: C, 65.88; H, 5.50; N, 5.40.
3RS-(3R*,4R*,5S*)-2-(4-Chlorophenyl)-3-(3-nitrophenyl)-
5-(4-chlorophenyl)-4-piperidinyloxo-isoxazolidine (22;
C27H25N3O4Cl2). The diastereomeric cycloadduct (22) was
detected from the 1H NMR spectrum of the crude reaction
1
mixture. H NMR (CDCl3, ꢂ, 300 MHz): 4.89 (1H, d, J=10, H-
3), 3.80 (1H, br. t, H-4), 5.92 (1H, d, J=9, H-5)
3RS-(3R*,4S*,5R*)-2-(4-Chlorophenyl)-3-(3-nitrophenyl)-
4-(4-chlorophenyl)-5-piperidinyloxo-isoxazolidine (23;
C27H25N3O4Cl2). The regioisomeric cycloadduct (23) was
detected from the 1H NMR spectrum of the crude reaction
mixture. 1H NMR (CDCl3, ꢂ, 300 MHz): 4.88 (1H, d, J=7, H-3),
4.51 (1H, br. t, J~7-7.5, H-4), 4.68 (1H, d, J=7.5, H-5)
3RS-(3R*,4R*,5S*)-2-(4-Chlorophenyl)-3-(4-methoxy-
phenyl)-5-(4-chlorophenyl)-4-piperidinyloxoisoxazolidine
(28, C28H28N2O3Cl2). The diastereomeric cycloadduct (28) was
detected from the 1H NMR spectrum of the crude reaction
mixture. H NMR (CDCl3, ꢁ, 300 MHz): 5.97 (1H, d, J=11, H-
3), 3.99 (1H, br. t, H-4), 5.00 (1H, d, J=10, H-5)
1

Jan-Feb 2007
Cycloadditions of C-Aryl-N-(4-Chlorophenyl) Nitrones to N-Cinnamoyl Piperidines
143
[7] A. Banerji, K.K. Maiti, S. Halder, C. Mukhopadhyay, J. Banerji,
T. Prangé, A. Neuman, Monatshefte für Chem, 131, 901-911, (2000).
[8] A. Banerji, J. Banerji, S. Haldar (neé Datta), K. K. Maiti, S. Basu
(neé Sinha), T. Prangé, A. Neuman, Indian J Chem, 37B, 105-119, (1998).
[9] A. Banerji, P. K. Biswas, P. Sengupta, S. Dasgupta, M.
Gupta, Indian J Chem, 43B, 880-881, (2004).
[10] C. L. Brooks III, M. Karplus, B. M. Pettitt, Proteins: A
Theoretical Perspective of Dynamics, Structure & Thermodynamics.
Wiley, New York pp 23-31, (1987).
[11] G. H. Grant, W. G. Richard, Computational Chemistry.
Oxford Chemistry Primers, Oxford University Press, (1995).
[12] M. Joucla, F. Tonnard, D. Grée, J. Hamelin, J. Chem.
Research (S), 240; (M), 290, (1978).
3RS-(3R*,4S*,5R*)-2-(4-Chlorophenyl)-3-(4-methoxy-
phenyl)-4-(4-chlorophenyl)-5-piperidinyloxoisoxazolidine
(29, C28H28N2O3Cl2). The regioisomeric cycloadduct (29) was
detected from the 1H NMR spectrum of the crude reaction
mixture. H NMR (CDCl3, ꢀ, 300 MHz): 5.34 (1H, d, J=9.5, H-
3), 4.78 (1H, br. t, H-4), 4.60 (1H, d, J=10, H-5).
1
Acknowledgments. The authors thank the Indian Council for
Cultural Relation (ICCR) for financial assistance to P. K.
Biswas.
REFERENCES AND NOTES
[13] R. Sustmann, Tetrahedron Lett., 29, 2717, (1978)
[14] A. I. Vogel, in A Textbook of Practical Organic Chemistry,
[1] J. J. Tufariello, 1,3-Dipolar Cycloaddition Chemistry, John
Wiley and Sons, Inc.: New York (1984).
4th edition, (Longman, London), 722, (1978).
[15] The LURE DCI Synchrotron facility in Orsay, France, was
used to record the Crystal structure data for compound 9. An Image Plate
system (MAR345) was used as the detector. Recording was done under
cryotemperature condition, at –50°C. The crystals were triclinic, space
group P-1, with 1 molecule/asymmetric unit. Crystallographic Data for
compound 9 have been deposited with the Cambridge Crystallographic
Data Centre as CCDC 235163. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK (fax: +44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
[2] K. B. G. Torssell, Nitrile Oxides, Nitrones, and Nitronates in
Organic Synthesis, VCH; Weinheim, (1988).
[3] S. Kobayashi and K. A. Jørgensen, Cycloaddition Reactions
in Organic Synthesis, Wiley-VCH Verlag GmbH, Weinheim, (2002).
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(1998).
[5] M. Frederickson, Tetrahedron, 53, 403-425 (1997).
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