1,3-Dipolar cycloaddition of nitrile oxides to (R)-1-(1-phenylethyl)-3-[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones: synthesis of enantiomerically pure spiro heterocycles

Article abstract of DOI:10.1016/j.tetasy.2007.01.015

The 1,3-dipolar cycloaddition of (R)-1-(1-phenylethyl)-3-[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones to nitrile oxides proceeds chemo-, regio-, and stereoselectively affording moderate yields of enantiomerically pure spiro heterocycles comprising pi

Full text of DOI:10.1016/j.tetasy.2007.01.015

Tetrahedron: Asymmetry 18 (2007) 170–180
1,3-Dipolar cycloaddition of nitrile oxides to
(R)-1-(1-phenylethyl)-3-[(E)-arylmethylidene]tetrahydro-4(1H)-
pyridinones: synthesis of enantiomerically pure spiro heterocycles
Raju Suresh Kumar,a Subbu Perumal,a,* Henri B. Kaganb and Regis Guillotb
aDepartment of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
bInstitut de Chimie Mole´culaire et des Mate´riaux d’Orsay (CNRS-UMR 8182), Universite´ Paris-Sud, 91405 Orsay, France
Received 2 November 2006; accepted 12 January 2007
Abstract—The 1,3-dipolar cycloaddition of (R)-1-(1-phenylethyl)-3-[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones to nitrile oxides
proceeds chemo-, regio-, and stereoselectively affording moderate yields of enantiomerically pure spiro heterocycles comprising piperi-
dine and isoxazoline/dioxazole rings.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
of enantiomerically pure spiro heterocycles comprising
both piperidine and isoxazoline or dioxazole ring systems
through the 1,3-dipolar cycloaddition of nitrile oxides to
(R)-1-(1-phenylethyl)-3-[(E)-arylmethylidene]tetrahydro-
4(1H)-pyridinones 2 and we report the results in this paper.
Further, it would also be of interest to unearth the factors
that are underlying the stereoselectivity of these cyclo-
additions, as the dipolarophiles could exist in the form of
diastereomeric conformations arising from ring flip and
N-inversion. Recently, we have reported the 1,3-dipolar
cycloaddition of nitrones to 3,5-bis(arylidene)-1-methyl-
piperidin-4-ones.12 The present work constitutes the first
investigation on the 1,3-dipolar cycloaddition of (R)-1-
(1-phenylethyl)-3-[(E)-arylmethylidene]tetrahydro-4(1H)-
pyridinones.
1,3-Dipolar cycloadditions offer a convenient one-step
route for the construction of five-membered heterocycles
with multiple stereogenic centers.1,2 Isoxazolines are versa-
tile intermediates for the synthesis of a variety of bifunc-
tional building blocks and bioactive compounds.3–5
Isoxazolines, belonging to a class of unique pharmaco-
phores, are found in many therapeutic agents such as
GPII/IIIa inhibitors and human leukocyte elastase (HLE)
inhibitors.6 The piperidine ring systems are of great interest
in the pharmaceutical industry as they exhibit a wide range
of biological activities.7
The construction of chiral molecules is essential to explore
new medicines and agrochemicals. It is obvious that the
design of a specific chiral environment utilizing chiral
auxiliaries provides a useful protocol to prepare optically
active substances. a-Phenylethylamine is one of the most
promising and less expensive chiral auxiliaries,8 both
enantiomers of which are readily available.
2. Results and discussion
The (R)-1-(1-phenylethyl)tetrahydro-4(1H)-pyridinone 1
was obtained by a literature procedure.14 The (R)-1-
(1-phenylethyl)-3-[(E)-arylmethylidene]tetrahydro-4(1H)-
The biological activities of the isoxazoline and piperidine
rings and our continued interest in the synthesis of novel
heterocycles9–13 prompted us to investigate the synthesis
pyridinones
2 were synthesized in moderate yields
(58–72%) through a solvent-free reaction of pyridinone 1
with aromatic aldehydes in the presence of pyrrolidine
under microwave irradiation (Scheme 1). All the five
(R)-1-(1-phenylethyl)-3-[(E)-arylmethylidene]tetrahydro-
4(1H)-pyridinones 2 obtained as viscous liquids are new
*
Corresponding author. Tel./fax: +91 452 2459845; e-mail: subbu.perum@
gmail.com
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.01.015

R. S. Kumar et al. / Tetrahedron: Asymmetry 18 (2007) 170–180
171
always contaminated with small amounts of 3, from which
the isolation of 4 in a pure state proved difficult.
O
N
O
Ar
Pyrrolidine
MWI
ArCHO
+
The predominant formation of 3 in all the reactions shows
that the cycloaddition proceeds (i) chemoselectively, with
the nitrile oxide preferring to react with the C@C and
not with C@O bond of 2, (ii) regioselectively, the oxygen
of the nitrile oxide adding over the a-carbon of the C@C
bond of 2, and (iii) stereoselectively, affording only one
of the stereoisomers of the isoxazoline (3) as the
major product. The cycloadducts were characterized by
1H, 13C, and 2D NMR spectroscopic techniques (H,H-
COSY, C,H-COSY, and HMBC). Selected HMBC correla-
tions of 3b are given in Figure 2. The 1H and 13C chemical
shifts of 3b and 4b, assigned by straightforward consider-
ations, are depicted in Figure 3. The structure and stereo-
chemistry of 3 has been fully elucidated from an X-ray
crystallographic study of a single crystal of 3b (Fig. 4).
N
R
R
H
H
Ph
Ph
H3C
H3C
1
2
Irradiation Yield
time (min.)
Comp.
2a
Ar
(%)
58
C6H5
3.5
2b
p-ClC6H4
p-MeC6H4
o-ClC6H4
1-naphthyl
3.0
3.5
3.0
4.0
65
68
72
63
2c
2d
2e
The H and 13C chemical shifts of 3b and 4b differ a little.
1
Scheme 1.
This suggests that the structures 3 and 4 probably possess a
mirror-image relationship, if one ignores the configuration
of N-a-phenylethyl group (inclusive of which points to a
diastereomeric relationship). The other possible structures
for 4 with the oxygen of the isoxazoline ring oriented axi-
ally (denoted as 4b0 and 4b00) are excluded on the basis that
only small differences exist between the chemical shifts of
3b and 4b. For instance, the carbonyl chemical shift for
structures 4b0 or 4b00 might probably be anticipated to differ
significantly from that of 3b (probably more upfield), due
to the steric interaction between the benzylic proton and
the carbonyl function in 4b0 or 4b00, contrary to the almost
identical chemical shift observed for the carbonyl carbons,
204.3 and 204.1 ppm of 3b and 4b, respectively.
compounds and their structures are in good agreement
with their 1H, 13C, and 2D NMR spectroscopic data
(Fig. 1). All compounds of series 2 were obtained as viscous
liquids and hence X-ray crystallographic studies could not
be performed to unambiguously determine the configura-
tion of the C@C bond. Energy minimization of 2a employ-
ing AM1 calculations (Hyperchem software) suggests that
the (E)-form is more stable than the (Z)-form as is evident
from the heat of formation of (E)- and (Z)-forms,
ꢀ4649.61 and ꢀ4645.98 kcal/mol, respectively. The stereo-
chemistry of the cycloaddition products is also in accord
with the (E)-form of 2 (vide infra).
A comparison of the chemical shifts of the 6-CH2 and
8-CH2 of 3b and 4b is noteworthy. The proton, H-8ax of
3b, appears more upfield (2.75–2.87 ppm) than H-8ax
(2.92–3.02 ppm) of 4b, while the H-8eq of 3b appears more
downfield (2.49–2.67 ppm) than H-8eq (2.31–2.43 ppm) of
4b. This can be explained as follows. All the three
conformations of 3b, viz. 3b, 3b0, and 3b00 depicted in
Figure 5, are likely to suffer from steric interactions
between the groups of a-phenylethyl group and the piperi-
done ring hydrogens, viz. methyl and H-8eq in 3b, phenyl
and H-8eq as well as methyl and H-6eq in 3b0 and methyl
The 1,3-dipolar cycloaddition of nitrile oxide, generated
in situ from 4-chlorobenzohydroximoyl chloride and trieth-
ylamine15 to (R)-1-(1-phenylethyl)-3-[(E)-arylmethylid-
ene]tetrahydro-4(1H)-pyridinones 2 (Scheme 2), afforded
two spiroisoxazolines, 3 and 4, in 52–56% and 8–10%,
respectively. In the case of 2 with an o-chlorophenyl ring,
dispiro compound, 5g and 5h, in 6% and 7% yields, respec-
tively, were also obtained. Flash column chromatographic
separation of the cycloadducts on silica gel using petroleum
ether–ethyl acetate led to pure 3 and 5. Cycloadduct 4 is
7.48, s
H
O
H
O
134.2
Ar
7
39.3
198.6
7
H
H
3
4
4
2.59, t, J=6.2 Hz
Ar
3
2
5
5
133.3
H
H 2.72-2.80, m
H
H
2
H
H
6
3.57-3.62, m
6
1
2.85-2.93, m
H
1
N
H
3.81, d, J=14.7 Hz
47.0
52.7
N
3.68, q, J=6.9 Hz
63.5
H
H
Ph
Ph
H C
19.2
1.42, d, J=6.9 Hz
3
H3C
7.20-7.35, m, aromatic
Figure 1. Selected HMBC correlations and 1H and 13C chemical shifts of 2b.

172
R. S. Kumar et al. / Tetrahedron: Asymmetry 18 (2007) 170–180
O
Ar
N
R
H
H3C
Ph
Cl
2
OH
Et3N
Benzene, RT
N
Ar'
Ar'
Ar'
N
Ar
H
Ar'
R
Ar
H
Ar
R
S
H
H
N
O
CH3
H
H
N
6
R
N
H
H3C
+
6
6
N
H
H3C
N
H
+
S
O
S
O
O
R
R
R
Ph
8
H
S
Ph
Ph
N
8
8
H
O
O
O
H
Ar'
3
5
4
Comp.
Ar
Ar’
3a
4b
8
5a
-
a
b
c
d
e
f
C6H5
C6H5
C6H5
56
54
54
55
54
53
52
53
54
52
p-ClC6H4
C6H5
10
8
-
p-ClC6H4
p-ClC6H4
p-MeC6H4
-
p-ClC6H4
C6H5
9
-
10
8
-
p-MeC6H4 p-ClC6H4
-
g
h
i
o-ClC6H4
o-ClC6H4
1-naphthyl
C6H5
p-ClC6H4
C6H5
8
6
7
-
8
10
9
j
1-naphthyl p-ClC6H4
-
a Isolated yields of pure 3 and pure 5.
b Yield from 1 H NMR signal intensities of 3 and 4 from the isolated 4 containing
small amounts of 3.
Scheme 2. Synthesis of spiroisoxazolines and spirodioxazoles.
with both H-8ax and H-6ax in 3b00 diminishing the stability
of all these conformations. The conformation, 3B in Figure
6 with the p-plane of the phenyl ring moved close to H-8ax
and the methyl moved away from the H-8eq relative to 3b
(Fig. 5) is likely to be the most stable conformation with
minimum steric interaction. By similar considerations, the
phenyl ring of the a-phenylethyl group in the most stable
conformation of 4b, viz. 4B (Fig. 6), would be closer to
H-6ax. The aryl ring of 3B being proximate to H-8ax
would shield it and deshield H-8eq relative to the corre-
sponding protons in 4B. Similarly, the proximity of the
phenyl ring to H-6ax in 4B would shield H-6ax
(2.16 ppm) and deshield H-6eq (2.74 ppm) relative to the
corresponding protons in 3B (Fig. 6), which has chemical
shift values of 2.37 ppm for H-6ax and 2.49–2.67 ppm for
H-6eq. The above trends in the chemical shifts of 3b and
4b support the stereochemical relationship between 3 and
4.
Cl
Ar
H
4
3
N
2
H
5
H
H
7
N
H
6
H3C
O
1
9
Ph
10
H
H
8
O
H
Ar = C6H5
Figure 2. Selected HMBC correlations of 3b.

R. S. Kumar et al. / Tetrahedron: Asymmetry 18 (2007) 170–180
173
Aromatic protons
7.13-7.52, m
Aromatic protons
7.11-7.51, m
H-6eq, H-8eq and H-9eq,
2.49-2.67, m
Ar'
Ar'
5.10, s
H
2.74,dd,
Ar
Ar
5.16, s
H
J=12.8,2.2 Hz
3
3
158.2
4
54.4
2.94-3.08, m
158.0
1.15, d,
J=6.8 Hz
18.1 CH3
3.44, q,
4 55.0
3.04-3.14, m
J=6.7 Hz
2N
N
7
N
7
2
H
H
90.9
H
91.3
H
H
N
56.0
55.6
5
H
H C
O
18.8
3
O
5
1
1
6
1.08, d,
6
62.9
62.9
3.49, q,
J=6.8 Hz
Ph
9
9
H
J=6.7 Hz
H
10
204.1
8
Ph
204.3
38.4
38.1
H
49.4
2.31-2.43, m
8
49.7
H
H
10
H
O
O
2.46-2.54, m
H
H
2.75-2.87, m
2.37,d, J=12.6 Hz
2.16,d,
J=12.8 Hz
2.92-3.02, m
4b
3b
Figure 3. 1H and 13C chemical shifts of 3b and 4b.
formed, or during the cycloaddition itself, although this
reaction could be expected to be slow.
The formation of 3 and 4 in preference to 4b0 and 4b00
(Fig. 7) suggests that the transition states leading to 4b0
and 4b00 by attack of the dipole from the topside of 2A
and 2B requires higher free energy of activation than those
leading to 3b and 4b. This may probably be ascribed to (i)
the repulsion between the nitrogen lone pair of 2A or 2B
and the electron pairs of oxygen of the nitrile oxide, and
(ii) the steric interaction between the benzylic hydrogen
and the carbonyl group in the transition state leading to
4b0 and 4b00. The formation of 4 as the minor product
may presumably be ascribed to the possibly greater steric
interaction between the aryl group at the 4-position of
the isoxazoline with the methyl group of the a-phenylethyl
in 4 as well as 6 than the interaction between the 4-aryl and
hydrogen of the a-phenylethyl in 3.
Figure 4. X-ray structure of 3b.
Ar'
Ar'
Ph
H
Ph
R
R
The formation of 3b and 4b from the cycloaddition of
nitrile oxide over 2 can be rationalized if one considers
the conformational equilibrium of 2 arising from ring flip
and N-inversion (Scheme 3), involving three conforma-
tional diastereomers 2A, 2B, and 2C, each with different
reactivity toward the cycloaddition. The reaction of the
nitrile oxides from the bottom side of the general plane
of 2A and 2C would explain the formation of products 3
and 4, respectively. The reaction of 2B could also lead to
the formation of 4, after N-inversion of 6 either after it is
H3C
H
N
O
CH3
H 6
6
N
N
H
N
H
R
S
O
S
O
R
8
H
H 8
O
H
Ar' = p-ClC6H4
H-6ax shielded
H-8ax shielded
3B
4B
Figure 6. Most stable conformations of 3b and 4b.
Ar'
Ar
Ar'
Ar'
N
Ph
H
R
Ph
H
R
R
H
H3C
Ph
H
Ph
N
N
6
N
H3C
6
6
N
H
N
H
S
O
H
S
S
O
H
O
R
R
R
8
Ph
O
8
8
H
O
O
H3C
H
H
H
Ar' = p-ClC6H4
3b
3b''
3b'
Figure 5. Conformational equilibrium of 3b.

174
R. S. Kumar et al. / Tetrahedron: Asymmetry 18 (2007) 170–180
H
Ar
Ar
Ph
Me
180o
O
Ph
R
Ph
N
N-inversion
ring flip
N
N
O
R
O
O
H
H
R
N
Me
Me
R
Ph
2A
2B
Ar
2C
2B
Me
Ar
+
O-
H
C N
Ar'
+
+
O-
O-
Ar' C N
Ar' C N
Ar'
Ar
H
R
Ar'
N
Ph
Ar
Me
Ar'
H
S
4
H
H
H
H
N
S
4
Ar
R
N
H
Me
N-inversion
6
N
Me
N
H
S
O
H
N
R
R
R
Ph
O
Ph
8
R
O
O
O
O
H
H
H
6
3
4
Scheme 3. Formation of monospiroheterocycles, 3 and 4.
ray study (Fig. 9). The structure of 5h (Fig. 9) shows that
the configuration at the stereocenters of isoxazoline is the
same in 5h and 3h. This suggests that 5h is presumably
formed from further cycloaddition of the nitrile oxide over
the C@O of 3h. This is also confirmed by the formation of
5h as the major product in a separate reaction of 3h with
nitrile oxide. The stereochemistry of 5h shows that the
nitrile oxide adds on the less hindered side of the C@O
(viz. on the side of the oxygen of the isoxazoline) of 3h
leading to facial diastereoselectivity.
N
N
O
O
Ar'
Ar'
Ar
H
CH3
H
6
N
6
H3C
N
Ar
H
H
R
Ph
R
H
O
H
O
Ph
8
8
H
H
4b''
4b'
Figure 7.
The structure of 5 is found to be in accord with its NMR
An explanation for the formation of 5, viz. 5g and 5h, only
in the case of nitrile oxide cycloaddition of 2d with o-
ClC6H4 is furnished below on the basis of electronic and
steric interactions in the corresponding spiroisoxazolines,
3g and 3h, which undergo further cycloaddition to give
1
spectroscopic data. Selected HMBC correlations and H
and 13C chemical shifts of 5h assigned by straightforward
considerations are given in Figure 8. The stereochemistry
of 5h has been fully elucidated from a single crystal X-
Cl
Cl
7.04-7.73, m, aromatic
2.40, d, J=11.7 Hz, Hax
5.50, s
H
Ar
Ar
9
2.84-3.05, m,
Heq
158.3
N 8
9
H
10
52.9
89.8
10
12
2.84-3.05, m
12
H
N 8
H
H
H
H
H
6
N
52.3
7
O
N
H C
20.3
0.63, d, J=3.6 Hz
3
O
6
H3C
7
1
O
64.3
11
32.2
11
1
O
14
H
5
13
H
Ph
14
Ph
47.5
H
116.1
H
H
H
5
13
2
N
2
N
H
O
H
O
4
4
158.6
3
3
2.68-2.81, m, Hax
2.00-2.25, m, Heq
2.49-2.54, m, Hax
2.00-2.25, m, Heq
Cl
Cl
Figure 8. Selected HMBC correlations and 1H and 13C chemical shifts of 5h.

R. S. Kumar et al. / Tetrahedron: Asymmetry 18 (2007) 170–180
175
CDCl3 using TMS as an internal standard. Chemical shifts
are given in parts per million (d-scale) and the coupling
constants are given in Hertz. IR spectra were recorded on
a JASCO FT IR instrument (KBr pellet in case of solids
and CHCl3 in case of liquids). The single crystal X-ray data
set for 3b and 5h was collected on Bruker Kappa X8
˚
APPEX II diffractometer with MoKa (k = 0.71073 A)
radiation. Scan range was 2.22° 6 h 6 33.00°. Elemental
analyses were performed on a Perkin Elmer 2400 Series
II Elemental CHNS analyser. Column chromatography
was performed on silica gel (230–400 mesh) using petro-
leum ether–ethyl acetate as eluent. Optical rotation values
were measured using an autopol IV automatic polarimeter
at sodium D line at 25 °C.
4.2. Preparation of 1-[(R)-1-phenylethyl]-3-[(E)-arylmethyl-
idene]tetrahydro-4(1H)-pyridinones 2a–e
4.2.1. General procedure. A mixture of 1 (1 mmol) and
pyrrolidine (1 mmol) was mixed well in a semi-micro-
boiling tube and irradiated for 0.5 min at maximum
power level (600 W) in a microwave oven. Then aromatic
aldehyde (1 mmol) is added to the mixture and again
irradiated for appropriate time (2.5–3.5 min) at the same
power level. The progress of the reaction was monitored
intermittently after every 1 minute of irradiation by thin
layer chromatography with petroleum ether–ethyl acetate
(4:1 v/v mixture) as eluent. After completion of the
reaction as evident from TLC, the resulting mixture is
extracted with CH2Cl2 and subjected to column chroma-
tography to obtain 2.
Figure 9. X-ray structure of 5h.
5g and 5h. The chlorine in o-ClC6H4 group of 3g and 3h
can interact electronically with the proximal C@N–O func-
tionality of the isoxazoline ring, while the o-chlorophenyl
ring at C-10 and the aryl ring linked to the imino carbon
(C-9) may interact sterically. These steric interactions be-
tween the aryl rings could alter their rotameric preferences
in 3g and 3h relative to the other compounds of series 3
with p-substituted aryl at C-4. These electronic and steric
interactions in 3g and 3h probably influence the electron
distribution of the C@N–O functionality, which, in turn,
can alter the electron distribution and polarity of the car-
bonyl through either spatial interactions or by the overlap
of orbitals. These changes in the carbonyl originating from
o-chlorophenyl presumably favor the second cycloaddition
of 3g and 3h to afford 5g and 5h, respectively.
4.2.2. 1-[(R)-1-Phenylethyl]-3-[(E)-phenylmethylidene]tetra-
hydro-4(1H)-pyridinone 2a. Obtained as a viscous liquid;
[a]D = +27.4 (c 0.25, CHCl3); IR (CHCl3): 1679, 1643,
1594, 1448, 1078 cmꢀ1 1H NMR (300 MHz, CDCl3): d
;
1.42 (d, 3H, J = 6.6 Hz, CH3), 2.59 (t, 2H, J = 6.2 Hz, H-
5a and H-5b), 2.69–2.78 (m, 1H, H-6a), 2.85–2.93 (m,
1H, H-6b), 3.62–3.69 (m, 2H, H-2a and CH), 3.90 (d,
1H, J = 15.0 Hz, H-2b), 7.22–7.41 (m, 10H, aromatic),
7.56 (s, 1H, CHAr). 13C NMR (75 MHz, CDCl3): d 19.2
(CH3), 39.3 (C-5), 46.9 (C-6), 52.8 (C-2), 63.5 (CH),
127.1, 127.3, 128.3, 128.4, 128.9, 130.3, 133.6 (C-3),
134.8, 135.6, 143.0 (aromatic), 198.8 (C-4). Anal. Calcd
for C20H21NO: C, 82.44; H, 7.26; N, 4.81. Found: C,
82.40; H, 7.32; N, 4.76.
3. Conclusion
The present investigation describes a facile access to the
enantiomerically pure novel dipolarophiles. The 1,3-di-
polar cycloaddition of these dipolarophiles with nitrile
oxides occurs chemo-, regio-, and stereoselectively to
provide enantiomerically pure spiro heterocycles contain-
ing nitrogen and oxygen. The synthetic potential of the
cycloaddition of the chiral dipolarophiles, described in this
work, with other 1,3-dipoles is being currently explored in
our research group.
4.2.3. 3-[(E)-(4-Chlorophenyl)methylidene]-1-[(R)-1-phenyl-
ethyl]tetrahydro-4(1H)-pyridinone 2b. Obtained as a vis-
cous liquid; [a]D = +19.3 (c 0.21, CHCl3); IR (CHCl3):
1
1675, 1641, 1592, 1490, 1091 cmꢀ1; H NMR (300 MHz,
CDCl3): d 1.42 (d, 3H, J = 6.9 Hz, CH3), 2.59 (t, 2H,
J = 6.2 Hz, H-5a and H-5b), 2.72–2.80 (m, 1H, H-6a),
2.85–2.93 (m, 1H, H-6b), 3.57–3.62 (m, 1H, H-2a), 3.68
(q, 1H, J = 6.9 Hz, CH), 3.81 (d, 1H, J = 14.7 Hz, H-2b),
7.20–7.35 (m, 9H, aromatic), 7.48 (s, 1H, CHAr). 13C
NMR (75 MHz, CDCl3): d 19.2 (CH3), 39.3 (C-5), 47.0
(C-6), 52.7 (C-2), 63.5 (CH), 127.2, 127.3, 128.4, 128.7,
131.5, 133.3 (C-3), 134.1, 134.2, 134.9, 142.9 (aromatic),
198.6 (C-4). Anal. Calcd for C20H20ClNO: C, 73.72; H,
6.19; N, 4.30. Found: C, 73.76; H, 6.15; N, 4.34.
4. Experimental
4.1. General methods
Melting points were taken using open capillary tubes and
are uncorrected. 1H, 13C, and two-dimensional NMR spec-
tra were recorded on a Bruker 300 MHz instrument in

176
R. S. Kumar et al. / Tetrahedron: Asymmetry 18 (2007) 170–180
4.2.4. 3-[(E)-(4-Methylphenyl)methylidene]-1-[(R)-1-phenyl-
ethyl]tetrahydro-4(1H)-pyridinone 2c. Obtained as a vis-
cous liquid; [a]D = +42.6 (c 0.19, CHCl3); IR (CHCl3):
4.3.2. (4R,5S)-3,4-Diphenyl-7-[(R)-1-phenylethyl]-1-oxa-2,7-
diazaspiro[4.5]dec-2-en-10-one 3a. Obtained as colorless
crystals; mp = 168–169 °C; [a]D = ꢀ232.0 (c 0.20, CHCl3);
1
1
1678, 1647, 1597, 1490, 1075 cmꢀ1; H NMR (300 MHz,
IR (KBr): 1724, 1490, 1448, 1332, 1187, 1012 cmꢀ1; H
CDCl3): d 1.42 (d, 3H, J = 6.8 Hz, CH3), 2.37 (s, 3H,
CH3), 2.58 (t, 2H, J = 6.0 Hz, H-5a and H-5b), 2.67–2.76
(m, 1H, H-6a), 2.84–2.92 (m, 1H, H-6b), 3.61–3.63 (m,
1H, H-2a), 3.66 (q, 1H, J = 6.8 Hz, CH), 3.91 (d, 1H,
J = 14.7 Hz, H-2b), 7.17–7.34 (m, 9H, aromatic), 7.54 (s,
1H, CHAr). 13C NMR (75 MHz, CDCl3): d 19.8 (CH3),
21.8 (CH3), 39.8 (C-5), 47.5 (C-6), 53.4 (C-2), 64.1 (CH),
127.6, 127.8, 128.8, 129.7, 131.0, 132.6, 133.2 (C-3),
136.3, 139.7, 143.6 (aromatic), 199.2 (C-4). Anal. Calcd
for C21H23NO: C, 82.58; H, 7.59; N, 4.59. Found: C,
82.63; H, 7.54; N, 4.62.
NMR (300 MHz, CDCl3): d 1.07 (d, 3H, J = 6.9 Hz,
CH3), 2.40 (d, 1H, J = 12.9 Hz, H-6ax), 2.53–2.64 (m,
3H, H-6eq, H-8eq and H-9eq), 2.74–2.83 (m, 1H, H-8ax),
2.95–3.06 (m, 1H, H-9ax), 3.44 (q, 1H, J = 6.9 Hz, CH),
5.13 (s, 1H, H-4), 7.14–7.59 (m, 15H, aromatic). 13C
NMR (75 MHz, CDCl3): d 18.8 (CH3), 38.1 (C-9), 49.7
(C-8), 55.3 (C-4), 55.6 (C-6), 62.9 (CH), 91.2 (C-5), 127.1,
127.2, 127.4, 128.1, 128.2, 128.3, 128.5, 128.9, 130.0,
132.9, 142.5 (aromatic), 158.9 (C-3), 204.6 (C-10). Anal.
Calcd for C27H26N2O2: C, 79.00; H, 6.38; N, 6.82. Found:
C, 78.96; H, 6.42; N, 6.79.
4.2.5. 3-[(E)-(2-Chlorophenyl)methylidene]-1-[(R)-1-phenyl-
ethyl]tetrahydro-4(1H)-pyridinone 2d. Obtained as a vis-
cous liquid; [a]D = +31.9 (c 0.16, CHCl3); IR (CHCl3):
4.3.3. (4S,5R)-3,4-Diphenyl-7-[(R)-1-phenylethyl]-1-oxa-2,7-
diazaspiro[4.5]dec-2-en-10-one 4a.16 Obtained as a color-
less viscous liquid; IR (CHCl3): 1725, 1580, 1459, 1338,
1
1671, 1654, 1590, 1474, 1080 cmꢀ1; H NMR (300 MHz,
1120, 1065 cmꢀ1 1H NMR (300 MHz, CDCl3): d 1.14
;
CDCl3): d 1.37 (d, 3H, J = 7.0 Hz, CH3), 2.61 (t, 2H,
J = 6.0 Hz, H-5a and H-5b), 2.75–2.83 (m, 1H, H-6a),
2.90–2.97 (m, 1H, H-6b), 3.50 (d, 1H, J = 15.2 Hz, H-2a),
3.60–3.68 (m, 1H, CH), 3.83 (d, 1H, J = 15.2 Hz, H-2b),
7.04–7.43 (m, 9H, aromatic), 7.66 (s, 1H, CHAr). 13C
NMR (75 MHz, CDCl3): d 19.2 (CH3), 39.3 (C-5), 47.2
(C-6), 52.1 (C-2), 62.9 (CH), 126.3, 127.2, 127.3, 128.3,
129.8, 130.1, 132.3, 133.3 (C-3), 134.7, 135.3, 143.0 (aro-
matic), 198.8 (C-4). Anal. Calcd for C20H20ClNO: C,
73.72; H, 6.19; N, 4.30. Found: C, 73.67; H, 6.23; N, 4.27.
(d, 3H, J = 6.9 Hz, CH3), 2.18 (d, 1H, J = 12.9 Hz, H-
6ax), 2.46–2.64 (m, 3H, H-6eq, H-8eq, and H-9eq), 2.71–
2.82 (m, 1H, H-8ax), 3.07–3.14 (m, 1H, H-9ax), 3.48 (q,
1H, J = 6.9 Hz, CH), 5.19 (s, 1H, H-4), 7.14–7.59 (m,
15H, aromatic). 13C NMR (75 MHz, CDCl3): d 18.1
(CH3), 38.4 (C-9), 49.5 (C-8), 54.5 (C-4), 56.0 (C-6), 62.9
(CH), 90.8 (C-5), 127.2, 127.4, 127.5, 128.1, 128.2, 128.4,
128.5, 128.8, 128.9, 130.0, 133.0, 141.6 (aromatic), 159.1
(C-3), 204.3 (C-10).
4.3.4.
phenylethyl]-1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-one
(4R,5S)-3-(4-Chlorophenyl)-4-phenyl-7-[(R)-1-
3b.
4.2.6. 3-[(E)-1-Naphthylmethylidene]-1-[(R)-1-phenylethyl]-
tetrahydro-4(1H)-pyridinone 2e. Obtained as a viscous
liquid; [a]D = +31.0 (c 0.20, CHCl3); IR (CHCl3): 1684,
1656, 1580, 1440, 1045 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d 1.29 (d, 3H, J = 6.6 Hz, CH3), 2.64 (t, 2H, J = 6.0 Hz, H-
5a and H-5b), 2.72–2.77 (m, 1H, H-6a), 2.88–2.94 (m, 1H,
H-6b), 3.51 (d, 1H, J = 14.6 Hz, H-2a), 3.58 (q, 1H,
J = 6.6 Hz, CH), 3.73 (d, 1H, J = 14.6 Hz, H-2b), 7.22–
7.99 (m, 12H, aromatic), 8.13 (s, 1H, CHAr). 13C NMR
(75 MHz, CDCl3): d 19.1 (CH3), 39.4 (C-5), 47.3 (C-6),
52.4 (C-2), 63.1 (CH), 124.6, 124.9, 126.2, 126.5, 126.7,
127.1, 127.3, 128.2, 128.3, 128.5, 129.2, 131.9, 133.4 (C-
3), 133.6, 135.5, 142.8 (aromatic), 198.9 (C-4). Anal. Calcd
for C24H23NO: C, 84.42; H, 6.79; N, 4.10. Found: C, 84.45;
H, 6.83; N, 4.06.
Obtained as colorless crystals; mp = 189–190 °C;
[a]D = ꢀ256.0 (c 0.20, CHCl3); IR (KBr): 1772, 1490,
1452, 1330, 1191, 1093 cmꢀ1
;
1H NMR (300 MHz,
CDCl3): d 1.08 (d, 3H, J = 6.7 Hz, CH3), 2.37 (d, 1H,
J = 12.6 Hz, H-6ax), 2.49–2.67 (m, 3H, H-6eq, H-8eq,
and H-9eq), 2.75–2.87 (m, 1H, H-8ax), 2.94–3.08 (m, 1H,
H-9ax), 3.44 (q, 1H, J = 6.7 Hz, CH), 5.10 (s, 1H, H-4),
7.13–7.52 (m, 14H, aromatic). 13C NMR (75 MHz,
CDCl3): d 18.8 (CH3), 38.1 (C-9), 49.7 (C-8), 55.0 (C-4),
55.6 (C-6), 62.9 (CH), 91.3 (C-5), 126.9, 127.1, 127.2,
128.2, 128.3, 128.6, 128.8, 129.0, 132.7, 136.0, 142.4 (aro-
matic), 158.0 (C-3), 204.3 (C-10). Anal. Calcd for
C27H25ClN2O2: C, 72.88; H, 5.66; N, 6.30. Found: C,
72.83; H, 5.62; N, 6.34.
4.3. Cycloaddition of benzohydroximoyl chloride with
1-[(R)-1-phenylethyl]-3-[(E)-arylmethylidene]tetrahydro-
4(1H)-pyridinones
4.3.5. (4S,5R)-3-(4-Chlorophenyl)-4-phenyl-7-[(R)-1-phenyl-
ethyl]-1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-one 4b.16 Ob-
tained as a colorless viscous liquid; IR (CHCl3): 1722,
1
4.3.1. General procedure. [(R)-1-Phenylethyl]-3-[(E)-aryl-
methylidene]tetrahydro-4(1H)-pyridinone 2 (1 mmol) was
dissolved in benzene (15 mL). To this solution, benzohydr-
oximoyl chloride (1.5 mmol) was added and the mixture
stirred at room temperature. Triethylamine (1.5 mmol)
was dissolved in benzene (10 mL) and was added dropwise
to the above mixture and stirring continued for 9–12 h. The
reaction mixture was filtered to remove the triethylamine
hydrochloride and the solvent was evaporated in vacuo.
The residue was subjected to flash column chromatography
on silica gel (10:1 petroleum ether–ethyl acetate).
1580, 1459, 1340, 1139, 1057 cmꢀ1; H NMR (300 MHz,
CDCl3): d 1.15 (d, 3H, J = 6.8 Hz, CH3), 2.16 (d, 1H,
J = 12.8 Hz, H-6ax), 2.31–2.43 (m, 1H, H-8eq), 2.46–2.54
(m, 1H, H-9eq), 2.74 (dd, 1H, J = 12.8, 2.2 Hz, H-6eq),
2.92–3.02 (m, 1H, H-8ax), 3.04–3.14 (m, 1H, H-9ax), 3.49
(q, 1H, J = 6.8 Hz, CH), 5.16 (s, 1H, H-4), 7.11–7.51 (m,
14H, aromatic). 13C NMR (75 MHz, CDCl3): d 18.1
(CH3), 38.4 (C-9), 49.4 (C-8), 54.4 (C-4), 56.0 (C-6), 62.9
(CH), 90.9 (C-5), 126.9, 127.1, 127.2, 127.5, 128.2, 128.3,
128.7, 128.8, 129.0, 132.7, 136.0, 141.5 (aromatic), 158.2
(C-3), 204.1 (C-10).

R. S. Kumar et al. / Tetrahedron: Asymmetry 18 (2007) 170–180
177
4.3.6. (4R,5S)-4-(4-Chlorophenyl)-3-phenyl-7-[(R)-1-phenyl-
ethyl]-1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-one 3c. Ob-
4.3.10. (4R,5S)-4-(4-Methylphenyl)-3-phenyl-7-[(R)-1-
phenylethyl]-1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-one 3e.
tained as colorless crystals; mp = 96–97 °C; [a]D = ꢀ182.0
Obtained as colorless crystals; mp = 147–148 °C;
[a]D = ꢀ212.5 (c 0.20, CHCl3); IR (KBr): 1775, 1496,
1452, 1360, 1192, 1061 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d 1.08 (d, 3H, J = 6.6 Hz, CH3), 2.30 (s, 1H, CH3), 2.43 (d,
1H, J = 12.6 Hz, H-6ax), 2.48–2.64 (m, 3H, H-6eq, H-8eq
and H-9eq), 2.73–2.81 (m, 1H, H-8ax), 2.90–3.03 (m, 1H,
H-9ax), 3.45 (q, 1H, J = 6.6 Hz, CH), 5.09 (s, 1H, H-4),
7.14–7.52 (m, 14H, aromatic). 13C NMR (75 MHz,
CDCl3): d 18.7 (CH3), 21.1 (CH3), 38.0 (C-9), 49.6 (C-8),
54.9 (C-4), 55.6 (C-6), 62.8 (CH), 91.1 (C-5), 127.0, 127.2,
127.3, 128.1, 128.2, 128.3, 128.4, 129.5, 129.8, 129.9,
137.8, 142.7 (aromatic), 159.0 (C-3), 204.6 (C-10). Anal.
Calcd for C28H28N2O2: C, 79.22; H, 6.65; N, 6.60. Found:
C, 79.26; H, 6.69; N, 6.53.
(c 0.20, CHCl3); IR (KBr): 1779, 1498, 1450, 1342, 1170,
1
1073 cmꢀ1; H NMR (300 MHz, CDCl3): d 1.13 (d, 3H,
J = 6.8 Hz, CH3), 2.33 (d, 1H, J = 12.6 Hz, H-6ax), 2.51–
2.62 (m, 3H, H-6eq, H-8eq and H-9eq), 2.82–2.87 (m,
1H, H-8ax), 2.96–3.06 (m, 1H, H-9ax), 3.45 (q, 1H,
J = 6.8 Hz, CH), 5.14 (s, 1H, H-4), 7.19–7.47 (m, 14H, aro-
matic). 13C NMR (75 MHz, CDCl3): d 18.5 (CH3), 37.9 (C-
9), 49.5 (C-8), 54.2 (C-4), 55.7 (C-6), 62.9 (CH), 90.9 (C-5),
127.0, 127.1, 127.2, 127.3, 127.9, 128.1, 128.5, 128.9, 130.1,
131.5, 134.0, 142.2 (aromatic), 158.6 (C-3), 204.1 (C-10).
Anal. Calcd for C27H25ClN2O2: C, 72.88; H, 5.66; N,
6.30. Found: C, 72.91; H, 5.62; N, 6.36.
4.3.7. (4S,5R)-4-(4-Chlorophenyl)-3-phenyl-7-[(R)-1-phenyl-
ethyl]-1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-one 4c.16 Ob-
tained as a colorless viscous liquid; IR (CHCl3): 1729,
4.3.11.
(4S,5R)-4-(4-Methylphenyl)-3-phenyl-7-[(R)-1-
phenylethyl]-1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-one 4e.16
1
1589, 1446, 1354, 1142, 1046 cmꢀ1; H NMR (300 MHz,
Obtained as a colorless viscous liquid; IR (CHCl3): 1721,
1572, 1456, 1369, 1146, 1030 cmꢀ1; H NMR (300 MHz,
1
CDCl3): d 1.19 (d, 3H, J = 6.8 Hz, CH3), 2.17 (d, 1H,
J = 12.6 Hz, H-6ax), 2.38–2.49 (m, 1H, H-8eq), 2.50–2.58
(m, 1H, H-9eq), 2.72 (dd, 1H, J = 12.6, 1.8 Hz, H-6eq),
2.95–2.99 (m, 1H, H-8ax), 3.03–3.13 (m, 1H, H-9ax), 3.51
(q, 1H, J = 6.8 Hz, CH), 5.18 (s, 1H, H-4), 7.11–7.56 (m,
14H, aromatic). 13C NMR (75 MHz, CDCl3): d 18.1
(CH3), 38.3 (C-9), 49.5 (C-8), 53.8 (C-4), 55.9 (C-6), 62.9
(CH), 90.6 (C-5), 127.2, 127.3, 127.4, 127.9, 128.2, 128.6,
129.2, 130.2, 130.5, 131.6, 134.1, 141.5 (aromatic), 158.9
(C-3), 204.0 (C-10).
CDCl3): d 1.15 (d, 3H, J = 6.6 Hz, CH3), 2.20 (d, 1H,
J = 12.6 Hz, H-6ax), 2.31 (s, 1H, CH3), 2.37–2.48 (m,
1H, H-8eq), 2.52–2.64 (m, 1H, H-9eq), 2.78 (dd, 1H,
J = 12.6, 1.8 Hz, H-6eq), 2.90–2.99 (m, 1H, H-8ax), 3.02–
3.11 (m, 1H, H-9ax), 3.48 (q, 1H, J = 6.6 Hz, CH), 5.15
(s, 1H, H-4), 7.09–7.59 (m, 14H, aromatic). 13C NMR
(75 MHz, CDCl3): d 18.1 (CH3), 21.1 (CH3), 38.4 (C-9),
49.6 (C-8), 54.3 (C-4), 56.0 (C-6), 62.9 (CH), 90.7 (C-5),
127.1, 127.2, 127.4, 127.5, 128.1, 128.2, 128.4, 129.6,
129.8, 129.9, 137.8, 141.8 (aromatic), 159.2 (C-3), 204.4
(C-10).
4.3.8. (4R,5S)-3,4-Bis(4-chlorophenyl)-7-[(R)-1-phenylethyl]-
1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-one 3d. Obtained as
colorless crystals; mp = 101–102 °C; [a]D = ꢀ162.5 (c
0.20, CHCl3); IR (KBr): 1769, 1490, 1445, 1350, 1184,
4.3.12. (4R,5S)-3-(4-Chlorophenyl)-4-(4-methylphenyl)-7-
[(R)-1-phenylethyl]-1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-one
3f. Obtained as colorless crystals; mp = 156–157 °C;
[a]D = ꢀ197.0 (c 0.20, CHCl3); IR (KBr): 1770, 1490,
1459, 1348, 1199, 1056 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d 1.08 (d, 3H, J = 6.3 Hz, CH3), 2.31 (s, 1H, CH3), 2.41 (d,
1H, J = 12.9 Hz, H-6ax), 2.53–2.58 (m, 2H, H-8eq and H-
9eq), 2.62 (d, 1H, J = 12.9 Hz, H-6eq), 2.75–2.82 (m, 1H,
H-8ax), 2.93–3.00 (m, 1H, H-9ax), 3.45 (q, 1H,
J = 6.3 Hz, CH), 5.07 (s, 1H, H-4), 7.10–7.52 (m, 13H, aro-
matic). 13C NMR (75 MHz, CDCl3): d 18.6 (CH3), 21.1
(CH3), 38.0 (C-9), 49.5 (C-8), 54.7 (C-4), 55.5 (C-6), 62.8
(CH), 91.3 (C-5), 126.8, 127.0, 127.2, 127.4, 128.0, 128.1,
128.6, 128.7, 129.4, 129.6, 138.0, 142.5 (aromatic), 158.0
(C-3), 204.4 (C-10). Anal. Calcd for C28H27ClN2O2: C,
73.27; H, 5.93; N, 6.10. Found: C, 73.31; H, 5.90; N, 6.05.
1
1065 cmꢀ1; H NMR (300 MHz, CDCl3): d 1.15 (d, 3H,
J = 6.9 Hz, CH3), 2.27 (d, 1H, J = 12.6 Hz, H-6ax), 2.50–
2.63 (m, 3H, H-6eq, H-8eq and H-9eq), 2.87–2.92 (m,
1H, H-8ax), 2.99–3.10 (m, 1H, H-9ax), 3.46 (q, 1H,
J = 6.9 Hz, CH), 5.11 (s, 1H, H-4), 7.06–7.49 (m, 13H, aro-
matic). 13C NMR (75 MHz, CDCl3): d 18.5 (CH3), 38.1 (C-
9), 49.6 (C-8), 54.0 (C-4), 55.9 (C-6), 62.9 (CH), 91.1 (C-5),
126.5, 127.2, 128.3, 128.6, 128.9, 129.2, 130.4, 131.2, 134.3,
136.2, 142.2 (aromatic), 157.8 (C-3), 204.0 (C-10). Anal.
Calcd for C27H24Cl2N2O2: C, 67.65; H, 5.05; N, 5.84.
Found: C, 67.60; H, 5.09; N, 5.81.
4.3.9. (4S,5R)-3,4-Bis(4-chlorophenyl)-7-[(R)-1-phenylethyl]-
1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-one 4d.16 Obtained
as
a
colorless viscous liquid; IR (CHCl3): 1732,
4.3.13. (4S,5R)-3-(4-Chlorophenyl)-4-(4-methylphenyl)-7-
[(R)-1-phenylethyl]-1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-one
4f.16 Obtained as a colorless viscous liquid; IR (CHCl3):
1578, 1451, 1362, 1153, 1038 cmꢀ1; H NMR (300 MHz,
CDCl3): d 1.19 (d, 3H, J = 6.9 Hz, CH3), 2.15 (d, 1H,
J = 12.9 Hz, H-6ax), 2.39–2.49 (m, 1H, H-8eq), 2.50–2.63
(m, 1H, H-9eq), 2.72 (dd, 1H, J = 12.9, 1.8 Hz, H-6eq),
2.99–3.04 (m, 1H, H-8ax), 3.08–3.14 (m, 1H, H-9ax), 3.52
(q, 1H, J = 6.9 Hz, CH), 5.15 (s, 1H, H-4), 7.15–7.49 (m,
13H, aromatic). 13C NMR (75 MHz, CDCl3): d 18.2
(CH3), 38.3 (C-9), 49.5 (C-8), 53.7 (C-4), 56.0 (C-6), 62.9
(CH), 90.9 (C-5), 126.5, 127.2, 127.4, 128.2, 128.6, 128.9,
129.3, 131.3, 134.4, 136.3, 141.5 (aromatic), 158.0 (C-3),
203.8 (C-10).
1
1728, 1580, 1449, 1353, 1140, 1046 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 1.15 (d, 3H, J = 6.6 Hz, CH3), 2.20
(d, 1H, J = 12.6 Hz, H-6ax), 2.31 (s, 1H, CH3), 2.53–2.58
(m, 3H, H-6eq, H-8eq, and H-9eq), 2.75–2.82 (m, 1H, H-
8ax), 3.02–3.10 (m, 1H, H-9ax), 3.47 (q, 1H, J = 6.6 Hz,
CH), 5.12 (s, 1H, H-4), 7.10–7.52 (m, 13H, aromatic).
13C NMR (75 MHz, CDCl3): d 18.0 (CH3), 21.1 (CH3),
38.3 (C-9), 49.4 (C-8), 54.1 (C-4), 55.8 (C-6), 62.8 (CH),
90.8 (C-5), 126.8, 127.0, 127.1, 127.3, 128.0, 128.1, 128.5,

178
R. S. Kumar et al. / Tetrahedron: Asymmetry 18 (2007) 170–180
128.7, 129.4, 129.5, 135.8, 141.7 (aromatic), 158.2 (C-3),
204.1 (C-10).
J = 6.9 Hz, CH), 5.74 (s, 1H, H-4), 7.14–7.55 (m, 13H, aro-
matic). 13C NMR (75 MHz, CDCl3): d 17.9 (CH3), 38.2 (C-
9), 49.8 (C-8), 50.7 (C-4), 54.5 (C-6), 62.9 (CH), 90.8 (C-5),
126.5, 127.1, 127.4, 127.9, 128.1, 128.5, 128.9, 129.0, 130.1,
130.5, 130.9, 134.0, 136.2, 143.6 (aromatic), 158.2 (C-3),
203.2 (C-10). Anal. Calcd for C27H24Cl2N2O2: C, 67.65;
H, 5.05; N, 5.84. Found: C, 67.61; H, 5.02; N, 5.89.
4.3.14. (4R,5S)-4-(2-Chlorophenyl)-3-phenyl-7-[(R)-1-phen-
ylethyl]-1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-one 3g. Ob-
tained as colorless crystals; mp = 165–166 °C; [a]D =
ꢀ242.0 (c 0.20, CHCl3); IR (KBr): 1768, 1484, 1452,
1360, 1190, 1042 cmꢀ1 1H NMR (300 MHz, CDCl3): d
;
1.09 (d, 3H, J = 6.9 Hz, CH3), 2.38 (d, 1H, J = 12.3 Hz,
H-6ax), 2.48–2.56 (m, 1H, H-8eq), 2.62–2.65 (m, 1H, H-
9eq), 2.67 (d, 1H, J = 12.3 Hz, H-6eq), 2.87–2.92 (m, 1H,
H-8ax), 2.95–3.07 (m, 1H, H-9ax) 3.50 (q, 1H,
J = 6.9 Hz, CH), 5.78 (s, 1H, H-4), 6.99–7.61 (m, 14H, aro-
matic). 13C NMR (75 MHz, CDCl3): d 18.0 (CH3), 38.2 (C-
9), 49.9 (C-8), 50.9 (C-4), 54.7 (C-6), 63.0 (CH), 90.7 (C-5),
127.2, 127.3, 127.5, 127.9, 128.2, 128.7, 129.5, 130.0, 130.2,
130.7, 131.3, 134.0, 141.6 (aromatic), 159.2 (C-3), 203.4 (C-
10). Anal. Calcd for C27H25ClN2O2: C, 72.88; H, 5.66; N,
6.30. Found: C, 72.85; H, 5.62; N, 6.27.
4.3.18. (4S,5R)-4-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-[(R)-
1-phenylethyl]-1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-one
4h.16 Obtained as a colorless viscous liquid; IR (CHCl3):
1720, 1572, 1440, 1359, 1148, 1058 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 0.96 (d, 3H, J = 6.6 Hz, CH3), 2.52
(d, 1H, J = 12.5 Hz, H-6ax), 2.62–2.63 (m, 2H, H-8eq and
H-9eq), 2.69 (d, 1H, J = 12.5 Hz, H-6eq), 2.74–2.82 (m,
2H, H-8ax and H-9ax), 3.28 (q, 1H, J = 6.6 Hz, CH), 5.64
(s, 1H, H-4), 6.97–7.72 (m, 13H, aromatic). 13C NMR
(75 MHz, CDCl3): d 19.3 (CH3), 37.9 (C-9), 49.7 (C-8),
51.8 (C-4), 55.1 (C-6), 63.3 (CH), 91.3 (C-5), 126.4, 127.1,
127.5, 127.9, 128.3, 128.5, 129.0, 129.7, 130.0, 130.5, 131.0,
134.1, 136.3, 142.7 (aromatic), 158.0 (C-3), 203.8 (C-10).
4.3.15. (4S,5R)-4-(2-Chlorophenyl)-3-phenyl-7-[(R)-1-phenyl-
ethyl]-1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-one 4g.16 Ob-
tained as a colorless viscous liquid; IR (CHCl3): 1727,
4.3.19. (4R,5S,10S)-10-(2-Chlorophenyl)-3,9-bis(4-chloro-
phenyl)-12-[(R)-1-phenylethyl]-1,4,7-trioxa-2,8,12-triazadi-
spiro[4.0.4.4]tetradeca-2,8-diene 5h. Obtained as colorless
crystals; mp = 181–182 °C; [a]D = ꢀ50.0 (c 0.10, CHCl3);
1
1587, 1454, 1346, 1128, 1078 cmꢀ1; H NMR (300 MHz,
CDCl3): d 0.96 (d, 3H, J = 6.6 Hz, CH3), 2.53 (d, 1H,
J = 12.2 Hz, H-6ax), 2.59–2.65 (m, 2H, H-8eq and H-
9eq), 2.70 (d, 1H, J = 12.2 Hz, H-6eq), 2.79–2.86 (m, 1H,
H-8ax), 2.89–3.04 (m, 1H, H-9ax), 3.29 (q, 1H,
J = 6.6 Hz, CH), 5.68 (s, 1H, H-4), 6.95–7.57 (m, 14H, aro-
matic). 13C NMR (75 MHz, CDCl3): d 19.3 (CH3), 37.9 (C-
9), 49.8 (C-8), 51.9 (C-4), 55.1 (C-6), 63.3 (CH), 91.1 (C-5),
127.0, 127.1, 127.2, 127.5, 127.9, 128.3, 128.6, 129.5, 129.9,
130.2, 130.6, 131.3, 134.2, 142.8 (aromatic), 158.9 (C-3),
203.9 (C-10).
1
IR (KBr): 3012, 2412, 1518, 1424, 1229 cmꢀ1; H NMR
(300 MHz, CDCl3): d 0.63 (d, 3H, J = 3.6 Hz, CH3),
2.00–2.25 (m, 2H, H-13eq and H-14eq), 2.40 (d, 1H,
J = 11.7 Hz, H-11ax), 2.49–2.54 (m, 1H, H-14ax), 2.68–
2.81 (m, 1H, H-13ax), 2.84–3.05 (m, 2H, CH and H-
11eq), 5.50 (s, 1H, H-10), 7.04–7.73 (m, 17H, aromatic).
13C NMR (75 MHz, CDCl3): d 20.3 (CH3), 32.2 (C-14),
47.5 (C-13), 52.3 (C-11), 52.9 (C-10), 64.3 (CH), 89.8 (C-
6), 116.1 (C-5), 121.2, 126.6, 127.0, 127.3, 128.2, 128.3,
128.5, 128.8, 128.9, 129.4, 129.9, 130.7, 132.1, 134.8,
136.0, 137.6, 143.7 (aromatic), 158.3 (C-9), 158.6 (C-3).
Anal. Calcd for C34H28Cl3N3O3: C, 64.52; H, 4.46; N,
6.64. Found: C, 64.55; H, 4.49; N, 6.59.
4.3.16. (4R,5S,10S)-10-(2-Chlorophenyl)-3,9-diphenyl-12-[(R)-
1-phenylethyl]-1,4,7-trioxa-2,8,12-triazadispiro[4.0.4.4]tetra-
deca-2,8-diene 5g. Obtained as colorless crystals;
mp = 172–173 °C; [a]D = ꢀ62.0 (c 0.10, CHCl3); IR
(KBr): 3018, 2400, 1521, 1417, 1220 cmꢀ1 1H NMR
;
(300 MHz, CDCl3): d 0.59 (d, 3H, J = 6.5 Hz, CH3),
2.17–2.20 (m, 1H, H-14eq), 2.60–2.71 (m, 3H, H-11ax, H-
13eq, and H-14ax), 2.98 (q, 1H, J = 6.5 Hz, CH), 3.17 (d,
1H, H-13ax, J = 10.2 Hz), 3.69 (d, 1H, H-11eq,
J = 12.6 Hz), 5.57 (s, 1H, H-10), 6.84–7.84 (m, 19H, aro-
matic). 13C NMR (75 MHz, CDCl3): d 20.1 (CH3), 32.2
(C-14), 49.7 (C-13), 52.4 (C-11), 52.9 (C-10), 64.5 (CH),
89.8 (C-6), 115.2 (C-5), 122.9, 127.1, 127.2, 127.3, 128.2,
128.3, 128.5, 128.6, 128.7, 129.2, 129.7, 130.0, 130.8,
131.2, 133.5, 133.8, 135.2, 143.6 (aromatic), 158.5 (C-9),
160.2 (C-3). Anal. Calcd for C34H30ClN3O3: C, 72.40; H,
5.36; N, 7.45. Found: C, 72.37; H, 5.32; N, 7.49.
4.3.20. (4R,5S)-4-(1-Naphthyl)-3-phenyl-7-[(R)-1-phenylethyl]-
1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-one 3i. Obtained as
colorless crystals; mp = 138–139 °C; [a]D = ꢀ187.5 (c
0.20, CHCl3); IR (KBr): 1769, 1480, 1458, 1384, 1164,
1
1052 cmꢀ1; H NMR (300 MHz, CDCl3): d 1.00 (d, 3H,
J = 6.6 Hz, CH3), 1.94 (d, 1H, J = 12.9 Hz, H-6ax), 2.15–
2.27 (m, 1H, H-8eq), 2.45–2.51 (m, 1H, H-9eq), 2.78 (dd,
1H, J = 12.9, 2.4 Hz, H-6eq), 2.98–3.02 (m, 1H, H-8ax),
3.17–3.22 (m, 1H, H-9ax), 3.26 (q, 1H, J = 6.6 Hz, CH),
6.27 (s, 1H, H-4), 6.96–8.19 (m, 17H, aromatic). 13C
NMR (75 MHz, CDCl3): d 18.7 (CH3), 38.6 (C-9), 48.4
(C-4), 49.8 (C-8), 56.2 (C-6), 62.8 (CH), 91.0 (C-5), 122.8,
125.4, 125.9, 126.9, 127.1, 127.2, 127.4, 127.9, 128.0,
128.3, 128.5, 128.6, 129.1, 129.2, 129.9, 131.7, 134.0,
141.9 (aromatic), 159.4 (C-3), 204.5 (C-10). Anal. Calcd
for C31H28N2O2: C, 80.84; H, 6.13; N, 6.08. Found: C,
80.81; H, 6.10; N, 6.11.
4.3.17. (4R,5S)-4-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-[(R)-
1-phenylethyl]-1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-one 3h.
Obtained as colorless crystals; mp = 152–153 °C;
[a]D = ꢀ210.5 (c 0.20, CHCl3); IR (KBr): 1775, 1474,
1446, 1372, 1182, 1049 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d 1.08 (d, 3H, J = 6.9 Hz, CH3), 2.37 (d, 1H, J = 12.5 Hz,
H-6ax), 2.49–2.55 (m, 1H, H-8eq), 2.56–2.62 (m, 1H, H-
9eq), 2.67 (d, 1H, J = 12.5 Hz, H-6eq), 2.85–2.90 (m, 1H,
H-8ax), 2.92–3.03 (m, 1H, H-9ax), 3.50 (q, 1H,
4.3.21. (4S,5R)-4-(1-Naphthyl)-3-phenyl-7-[(R)-1-phenylethyl]-
1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-one 4i.16 Obtained
as a colorless viscous liquid; IR (CHCl3): 1722, 1581,
1452, 1348, 1157, 1050 cmꢀ1; 1H NMR (300 MHz, CDCl3):

R. S. Kumar et al. / Tetrahedron: Asymmetry 18 (2007) 170–180
179
d 0.87 (d, 3H, J = 6.8 Hz, CH3), 2.24 (d, 1H, J = 12.8 Hz,
H-6ax), 2.37–2.45 (m, 1H, H-8eq), 2.52–2.59 (m, 1H, H-
9eq), 2.63 (dd, 1H, J = 12.8, 2.1 Hz, H-6eq), 2.81–2.86
(m, 1H, H-8ax), 3.10–3.19 (m, 1H, H-9ax), 3.37 (q, 1H,
J = 6.8 Hz, CH), 6.19 (s, 1H, H-4), 6.83–8.20 (m, 17H, aro-
matic). 13C NMR (75 MHz, CDCl3): d 18.4 (CH3), 38.3 (C-
9), 48.9 (C-4), 49.8 (C-8), 55.3 (C-6), 62.3 (CH), 91.6 (C-5),
122.9, 125.4, 125.9, 126.9, 127.0, 127.1, 127.3, 127.8, 128.0,
128.3, 128.5, 128.6, 129.1, 129.2, 130.0, 131.7, 134.0, 142.4
(aromatic), 159.3 (C-3), 204.7 (C-10).
and refined by full matrix least squares on SHELXL 97 for all
nonhydrogen atoms for 3b and 5h. All hydrogen atoms
were placed in calculated positions.
4.4.1. Compound 3b. C27H25ClN2O2, M = 444.94, Dc =
3
˚
1.212 g/cm , triclinic, space group P1, a = 6.2709(4) A,
3
˚
˚
˚
b = 7.7719(5) A, c = 11.5241(7) A, V = 542.16(6) A , Z =
1, F(000) = 234, l = 0.204 mmꢀ1. The reflections collected
were 17,939 of which 6531 unique [R(int) = 0.0493]; 6531
reflections I > 2r(I), R1 = 0.0251 and wR2 = 0.0673 for
6531 [I > 2r(I)] and R1 = 0.0247 and wR2 = 0.0669 for
all (6607) intensity data. Goodness of fit = 1.080, residual
electron density in the final Fourier map was 0.316 and
4.3.22. (4R,5S)-3-(4-Chlorophenyl)-4-(1-naphthyl)-7-[(R)-1-
phenylethyl]-1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-one
3j.
ꢀ0.262 e Aꢀ3. CCDC number is 623332.
˚
Obtained as colorless crystals; mp = 146–147 °C;
[a]D = ꢀ173.0 (c 0.20, CHCl3); IR (KBr): 1770, 1474,
1450, 1379, 1136, 1059 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d 1.00 (d, 3H, J = 6.8 Hz, CH3), 1.93 (d, 1H, J = 12.8 Hz,
H-6ax), 2.15–2.23 (m, 1H, H-8eq), 2.45–2.52 (m, 1H, H-
9eq), 2.79 (dd, 1H, J = 12.8, 2.4 Hz, H-6eq), 2.98–3.03
(m, 1H, H-8ax), 3.16–3.23 (m, 1H, H-9ax), 3.27 (q, 1H,
J = 6.8 Hz, CH), 6.23 (s, 1H, H-4), 6.94–8.11 (m, 17H, aro-
matic). 13C NMR (75 MHz, CDCl3): d 18.7 (CH3), 38.6 (C-
9), 48.2 (C-4), 49.7 (C-8), 56.1 (C-6), 62.7 (CH), 91.2 (C-5),
122.7, 125.4, 125.7, 126.1, 126.8, 126.9, 127.2, 127.3, 127.8,
128.0, 128.3, 128.6, 128.8, 129.1, 131.7, 134.0, 135.9, 141.8
(aromatic), 158.5 (C-3), 204.2 (C-10). Anal. Calcd for
C31H27ClN2O2: C, 75.22; H, 5.50; N, 5.66. Found: C,
75.19; H, 5.54; N, 5.62.
4.4.2. Compound 5h. C34H28Cl3N3O3, M = 632.94,
Dc = 1.212 g/cm3, orthorhombic, space group P212121,
˚
˚
˚
˚
a = 7.1329(4) A, b = 18.5932(11) A, c = 22.9836(14) A,
3
-1
V = 3048.2(3) A , Z = 4, F(000) = 1312, l = 0.341 mm .
The reflections collected were 57,890 of which 14097
unique [R(int) = 0.0249]; 14,097 reflections I > 2r, R1 =
0.0496 and wR2 = 0.0937 for 14,097 [I > 2r] and
R1 = 0.0370 and wR2 = 0.0881 for all (16,620) intensity
data. Goodness of fit = 1.034, residual electron density in
-3
˚
the final Fourier map was 0.477 and ꢀ0.334 e A . CCDC
number is 623333.
Acknowledgments
4.3.23. (4S,5R)-3-(4-Chlorophenyl)-4-(1-naphthyl)-7-[(R)-1-
phenylethyl]-1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-one 4j.16
Obtained as a colorless viscous liquid; IR (CHCl3): 1728,
S.P. thanks the Department of Science and Technology,
New Delhi, for a major research project and for funds
under (i) IRHPA programme for the purchase of a high
resolution NMR spectrometer and (ii) FIST programme
and the University Grants Commission, New Delhi, for
funds under the DRS and ASIST programmes. The
X-ray measurements on 3b and 5h were carried out at
1
1574, 1442, 1359, 1150, 1062 cmꢀ1; H NMR (300 MHz,
CDCl3): d 0.88 (d, 3H, J = 6.6 Hz, CH3), 2.21 (d, 1H,
J = 12.9 Hz, H-6ax), 2.37–2.44 (m, 1H, H-8eq), 2.53–2.59
(m, 1H, H-9eq), 2.63 (d, 1H, J = 12.9 Hz, H-6eq), 2.79–
2.87 (m, 1H, H-8ax), 3.10–3.20 (m, 1H, H-9ax), 3.37 (q,
1H, J = 6.6 Hz, CH), 6.15 (s, 1H, H-4), 6.83–8.16 (m,
17H, aromatic). 13C NMR (75 MHz, CDCl3): d 18.4
(CH3), 38.3 (C-9), 48.8 (C-4), 49.7 (C-8), 55.3 (C-6), 62.4
(CH), 91.8 (C-5), 122.8, 125.4, 126.0, 126.8, 126.9, 127.1,
127.3, 127.7, 127.9, 128.0, 128.1, 128.8, 128.9, 129.2, 131.7,
134.0, 135.9, 142.3 (aromatic), 158.4 (C-3), 204.5 (C-10).
´
´
ICMMO (Institut de Chimie Moleculaire et des Materiaux
d’Orsay, France) diffractometer service.
References
1. (a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565–
598; (b) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2,
633–645.
4.4. X-ray crystallographic determination of compounds 3b
and 5h
2. (a) For selected reviews: 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; Wiley: New York, 1984; (b) Gothelf, K. V.;
Jorgensen, K. A. Chem. Rev. 1998, 98, 863–909; (c) Torssell,
K. B. G. Nitrile Oxides, Nitrones and Nitronates in Organic
Synthesis; VCH: Weinheim, 1988; (d) Cycloaddition Reactions
in Organic Synthesis; Kobayashi, S., Jorgensen, K. A., Eds.;
Wiley-VCH: Weinheim, 2002.
3. Kanemasa, S.; Tsuge, O. Heterocycles 1990, 30, 719–736.
4. (a) Fuller, A. A.; Chen, B.; Minter, A. R.; Mapp, A. K. J.
Am. Chem. Soc. 2005, 127, 5376–5383; (b) Bode, J. W.;
Fraefel, N.; Muri, D.; Carreira, E. M. Angew. Chem., Int. Ed.
2001, 40, 2082–2085.
5. (a) Jager, V.; Buss, V.; Schwab, W. Tetrahedron Lett. 1978,
19, 3133–3136; (b) Curran, D. P. J. Am. Chem. Soc. 1982,
104, 4024–4026.
6. (a) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555–
600; (b) Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D.
Spiroisoxazoline 3b and spirodioxazole 5h were recrystal-
lized from petroleum ether–ethyl acetate (1:1) mixture. X-
ray diffraction data for 3b and 5h were collected using a
Bruker Kappa X8 APPEX II diffractometer with graph-
˚
ite-monochromated MoKa radiation k = 0.71073 A. The
temperature of the crystal was maintained at the selected
value (100 K) by means of a 700 series Cryostream cooling
device to within an accuracy of 1. The data collection,
integration, and data reduction for 3b and 5h were per-
formed using Bruker SMART and Bruker SAINT programs.
An empirical absorption correction was applied using psi
scan method. The unit cell parameters were determined
by a least square fitting of randomly selected strong reflec-
tions by SADABS program. The structure was solved by di-
rect methods (SHELXS 97) and subsequent Fourier synthesis

180
R. S. Kumar et al. / Tetrahedron: Asymmetry 18 (2007) 170–180
Tetrahedron 1996, 52, 4527–4554; (c) Booth, S.; Hermkens, P. 10. Savitha Devi, N.; Perumal, S. Tetrahedron 2006, 62, 5931–
H. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron 1998, 54,
5936.
15385–15443.
11. Srinivasan, M.; Perumal, S.; Selvaraj, S. Chem. Pharm. Bull.
2006, 54, 795–801.
12. Ranjith Kumar, R.; Perumal, S.; Kagan, H. B.; Guillot, R.
Tetrahedron 2006, 62, 12380–12391.
13. Indumathi, S.; Ranjith Kumar, R.; Perumal, S. Tetrahedron
2007, 63, 1411–1416.
14. Kuehne, M. E.; Matson, P. A.; Bornmann, W. G. J. Org.
Chem. 1991, 56, 513–528.
7. (a) Puder, C.; Krastel, P.; Zeeck, A. J. Nat. Prod. 2000, 63,
1258–1260; (b) Gurevich, A. I.; Kolosov, M. N.; Korobko, V.
G.; Onoprienko, V. V. Tetrahedron Lett. 1968, 9, 2209–2212;
(c) Monti, S. A.; Schmidt, R. R.; Shoulders, B. A.; Lochte, H.
L. J. Org. Chem. 1972, 37, 3834–3838; (d) Guengerich, F. P.;
DiMari, S. J.; Broquist, H. P. J. Am. Chem. Soc. 1973, 95,
2055–2056.
8. Juaristi, E.; Leon-Romo, J. L.; Reyes, A.; Escalante, J.
Tetrahedron: Asymmetry 1999, 10, 2441–2495.
9. Alex Raja, V. P.; Perumal, S. Tetrahedron 2006, 62, 4892–
4899.
15. Christl, M.; Huisgen, R. Chem. Ber. 1973, 106, 3345–3367.
16. For 4a–j, elemental analysis data and specific rotations are
not given, as pure 4 could not be isolated from 3; 4 is always
obtained along with some small amounts of 3.