Investigations on regio- and stereoselectivities in cycloadditions involving α- (3-pyridyl)-N-phenylnitrone: Development of an efficient route to novel nicotine analogs

Article abstract of DOI:10.1002/jhet.5570420603

Thermal reactions of hitherto α-(3-pyridyl)-N-phenylnitrone (1) with mono-substituted electron-rich and electron-neutral dipolarophiles are regio-, and stereo-selective (exo-selective), controlled by LUMO-dipole - HOMO-dipolarophile interaction, and furnish syn-5-substituted-3-(3-pyridyl)- isoxazolidines (5) in high yields. With electron deficient dipolarophiles such as acrylonitrile there is observed a loss of regioselectivity as well as stereoselectivity and the regioselectivity is reversed in reactions with methyl vinyl ketone and methyl acrylate, due to intervention of HOMO-dipole - LUMO-dipolarophile interaction, affording 4-substituted-3-(3-pyridyl)- isoxazolidines (7) as major products. Reactions of nitrone (1) with disubstituted dipolarophiles such as methyl methacrylate and ethyl coronate furnish methyl syn-5-methy-3-pyridyl-1-phenyl-isoxazolidine-5-carboxylate (8) and ethyl anti-5-methy-3-pyridyl-1-phenyl-isoxazolidine-4-carboxylate (10), respectively, in high yields. Reaction with N-Phenylmaleimide affords novel isoxazolidino-pyrrolidinediones bearing a 3-pyridyl moiety (11, 12). A mechanistic rationalization of the obtained results in terms of electronic, steric and secondary interactions is proffered.

Full text of DOI:10.1002/jhet.5570420603

Sep-Oct 2005
Investigations on Regio- and Stereoselectivities in Cycloadditions
Involving α- (3-Pyridyl)-N-phenylnitrone: Development of an Efficient
Route to Novel Nicotine Analogs
1047
*
Gurpinder Singh, M. P. S. Ishar , Navdeep K. Girdhar and Lakhwinder Singh
Department of Pharmaceutical Sciences, Guru Nanak Dev University,
Amritsar 143 005, Punjab, India
Fax +91-183-2258820; email: mpsishar@yahoo.com
Received September 7, 2004
Thermal reactions of hitherto α-(3-pyridyl)-N-phenylnitrone (1) with mono-substituted electron-rich and
electron-neutral dipolarophiles are regio-, and stereo-selective (exo-selective), controlled by LUMO – dipole
-
HOMO- dipolarophile interaction, and furnish syn-5-substituted-3-(3-pyridyl)-isoxazolidines (5) in high
yields. With electron deficient dipolarophiles such as acrylonitrile there is observed a loss of regioselectivity
as well as stereoselectivity and the regioselectivity is reversed in reactions with methyl vinyl ketone and
methyl acrylate, due to intervention of HOMO-dipole - LUMO-dipolarophile interaction, affording 4-substi-
tuted-3-(3-pyridyl)-isoxazolidines (7) as major products. Reactions of nitrone (1) with disubstituted dipo-
larophiles such as methyl methacrylate and ethyl coronate furnish methyl syn-5-methy-3-pyridyl-1-phenyl-
isoxazolidine-5-carboxylate (8) and ethyl anti-5-methy-3-pyridyl-1-phenyl-isoxazolidine-4-carboxylate
(
10), respectively, in high yields. Reaction with N-Phenylmaleimide affords novel isoxazolidino-pyrro-
lidinediones bearing a 3-pyridyl moiety (11, 12). A mechanistic rationalization of the obtained results in
terms of electronic, steric and secondary interactions is proffered.
J. Heterocyclic Chem., 42, 1047 (2005).
Introduction.
understanding of existence of subtypes of endogenous
nAChRs with structural variation, tissues specific localization
and function [5a]. Therefore, synthesis of nicotine/ epibati-
dine analogues, both agonists and antagonists, with improved
biological/pharmacological properties, and for the characteri-
zation of receptor sub-types, is drawing considerable interest
Cognizant of the well established synthetic potential of the
nitrone 1,3-dipolar cycloadditions, in affording
precursors/scaffolds for the synthesis of a variety of molecu-
lar frameworks [1], the chemists are showing increasing inter-
est in synthetic [2], mechanistic/theoretical [3] investigations
of 1,3-dipolar cycloadditions, involving a variedly substituted
nitrones. As a part of our continuing interest in nitrone chem-
istry [4], we have presently investigated the regio- and stere-
oselectivities in the reactions of hitherto α-(3-pyridyl)-N-
phenylnitrone (1) with a variety of dipolarophiles. The inves-
tigations were of particular interest because cycloadditions of
the nitrone (1) were to furnish novel isoxazolidine analogs of
nicotine (2). Design and development of newer ligands for
nicotinic–acetylcholine-receptors (nAChRs) is drawing con-
siderable attention due to their potential applications in the
treatment of a variety of conditions such as Alzheimer’s dis-
ease, Depression, Parkinson’s and Tourette’s syndromes, as
antinociceptives (analgesics), as cognition enhancers, and for
treatment of addiction to smoking [5]. The recent hectic activ-
ity in this area has been spurred by the isolation of epibatidine
[5,7].
It is pertinent to mention here that a large number of
nicotine analogs have been designed by making a rational
start with nicotine itself, however, there are very few
examples wherein N-methylpyrrolidine moiety of nicotine
has been replaced with other five – membered - hetero-
cyclic systems, though, very recently isoxazolylmethyli-
dene-quinuclidines (4) have been synthesized and shown
to possess broad range of affinities for nicotinic, and cen-
tral muscarinic receptors [8]. Molecular modeling
(MOPAC) of nicotine (2) and corresponding N-phenyl/
methyl-isoxazolidine analogs (A, B) revealed (Figure 2)
that isoxazolidine moiety in these molecules shall have
nearly identical stereochemical features as pyrrolidine ring
in nicotine with a similar disposition of pyridyl moiety.
However, the targeted analogs will possess additional spa-
tial (steric) and binding (electronic) components, and are
anticipated to possess useful pharmacological properties.
(3), a natural analog of nicotine, having useful non-opiod-
antinociceptive activity [6], and by the advancement in the
Figure 1

1
048
G. Singh, M. P. S. Ishar, N. K. Girdhar and L. Singh
Vol. 42
Results and Discussion.
in particular, NMR spectral data with the data reported for
isoxazolidines obtained by 1,3-dipolar cycloadditions of
nitrones to a variety of dipolarophiles [4d,9], clearly indi-
cated that the presently obtained cycloadducts are also
derived from 1,3-dipolar cycloadditions. The assigned
α-(3-Pyridyl)-N-Phenylnitrone (1) was obtained by
reacting 3-formylpyridine with N-phenyhydroxylamine in
dry benzene and characterized spectroscopically. Initially,
the reactions of nitrone were carried out with mono-substi-
tuted dipolarophiles by refluxing equimolar solutions of
the addends in dry toluene. After completion of the reac-
tion (tlc) the residues obtained on removal of solvent under
vacuum were resolved by column chromatography over
silica gel. The results are summarized in Scheme 1 and
Table 1.
1
regiochemistry of addition in (5) and (6) is based on H
NMR couplings, which clearly indicated that C4-Hs are
vicinal to both C3-H and C5-H; this is also corroborated by
1
3
the C NMR chemical shifts of the various carbons of the
isoxazolidines moiety [4d]. The syn – stereochemistry in 5
involving pyridyl group and substituent-X at C5 is based
1
Table 1
on H NMR couplings involving C3-H, C4-H, and C5-H
1
Reaction Time and Yields (%) of the Products (5-7)
and follows from the premise that the cis - vicinal H cou-
pling constants are always higher than trans in case of
isoxazolidines and related heterocycles [4d,9,10]. The H
*
Serial
no.
X
Reaction
time (h)
Yield (%) of various products
5:6:7
1
chemical shift and coupling constant, involving C3-H, C5-
1
2
3
4
5
6
7
8
-OEt
-OisoButyl
-Ph
4-Pyridyl
-CH(OMe)2
-CN
30
12
24
24
24
18
10
15
5a (90)
5b (90)
5c (90)
5d (87)
5e (75)
5f (40)
5g (10)
5h (15)
6a(traces) 7a(--)
6b(traces) 7b(--)
H, C4-H and C4-H , and variation in their values in going
a
b
6c(<5)
6d(--)
6e(--)
6f(30)
6g(~10)
6h(15)
7c(--)
7d(--)
7e(--)
7f(20)
7g(70)
7h(60)
from syn (5) to anti-adducts (6f-h) form the bases of the
assigned stereochemistry in the case of latter [4d,9,10]; the
stereochemistry and relative proportion of 6g in a mixture
fraction were ascertained through a doublet at δ 5.12 (J =
6.1 Hz, C5-H) and an unresolved dd at δ 4.37 (J ~ 7.0 Hz,
C3-H) cf. [4d]. The assigned stereochemistry in the case of
-COMe
-CO Me
2
1
*
Based on isolated pure products along with, in some cases, H NMR
1
spectral analysis of mixture fractions from column chromatography.
5a,d,e is further corroborated through H nOe enhance-
1
ments observed by recording H nOe diffrence spectra on
The assigned structures are based on detailed spectro-
scopic analysis (IR, H NMR, C NMR and Mass) and
micro-analytical data. A comparison of the spectroscopic,
saturating C3-H, C4-Ha, C4-Hb and C5-H resonances, and
the established connectivities are shown in Figure 3. The
assigned reversed regiochemistry of cycloaddition in
1
13

Sep-Oct 2005
Investigations on Regio- and Stereoselectivities in Cycloadditions
1049
adducts (7 f-h), is based on H and 13C NMR spectral data.
For instance in case of (7h) the methylene-Hs (C5-Hs) are
located as multiplet at δ 4.41-4.23 and this downfield
1
[11]. The regioselectivity of addition is reversed in case of
reactions of the nitrone (1) with electron deficient dipo-
larophiles leading to formation of adducts 7g,h.
Surprisingly, this reversal of regioselectivity of addition,
which is a consequence of change in the nature of involved
frontier molecular orbital interaction, and which is gener-
ally observed in reactions of nitrones with highly electron
deficient dipolarophiles like nitro-alkenes [11a-c], occurs
rather early in present series as far as the electron defi-
ciency of the involved dipolarophiles is concerned. The
stereo-selectivity of addition leading to higher relative pro-
portions of syn- (5a-e) than the corresponding anti-
cycloadducts (6) can be rationalized in terms of preferred
exo- mode of addition of nitrone in its Z-form [11d,12];
such exo-selectivity has been observed earlier also and has
1
shifted position vis-à-vis the H NMR chemical shift of
methylene hydrogen atoms in the regioisomeric adducts
5, 6), is indicative of the attachement of methylene carbon
to oxygen in 7h; these conclusions are corroborated by the
observed proton connectivities and C NMR chemical
shift assignments [4d,9,10]. Here, the assigned trans-
arrangement of substituents at C3 and C4 is based on the
lower value of coupling constant J3,4 5-6 Hz only [4d,9,10]
and further corroborated by non observation of any
mutual H nOe enhancement in the H nOe difference
spectra recorded after saturating C3-H and C4-H reso-
nances (Figure 3).
(
1
3
1
1
The regiochemistry of addition leading to adducts (5)
and (6) can be rationalized in terms of the frontier molecu-
lar orbital control of the cycloaddition, i.e., in terms of
LUMO (dipole) – HOMO (dipolarophiles) interaction
been attributed to steric factors [4d]. In general any signif-
icant endo-mode of addition is observed only in case of
substituents which are capable of undergoing secondary
interaction [4d,13]. However, it may be mentioned here

1
050
G. Singh, M. P. S. Ishar, N. K. Girdhar and L. Singh
Vol. 42
that a variety of interactions have been invoked to explain
stereoselectivities in 1,3-dipolar cycloadditions, in particu-
lar, and cycloaddition in general, though, the question of
secondary orbital or secondary interaction is still far from
settled and steric factors appear to play an overwhelming
role [13]. Recently, preferred endo-orientation [13b,c] of
alkoxy groups, even in the presence of an ester function
[
13c], has been reported.
Subsequently, the investigations were extended to disub-
stituted and cyclic dipolarophiles such as methyl
methacrylate, ethyl crotonate and N-phenylmaleimide
with the data reported for cycloadducts derived from addi-
tion of nitrones to crotonates [4d,10f,g]. The assigned
regiochemistry of addition is easily discerned from the
chemical shift value of C5-H (δ 4.39); the C5-H resonance
could be easily identified from its multiplicity (dq). Here
the trans - relationship between C3-H and C4-H is based
on J3,4 = 6.7 Hz as it is still lower than the J4,5 = 8.9 Hz;
the latter hydrogens are anticipated to be trans as a conse-
quence of concerted cycloaddition to trans-crotonate cf.
(
Scheme 2).
Reaction of nitrone (1) with methyl methacrylate in
refluxing toluene afforded a major product (8, 70 %) along
with a minor product (9, < 5%); the latter was detected
only in some mixture fractions. The stereochemistry, i.e.,
the cis relationship between pyridyl moiety and ester func-
1
tion in 8 is based on the H NMR chemical shifts and cou-
pling constants values for C3-H, C4-H and C4-H . Here
a
b
[
10f,g]. The assigned trans stereochemistry is further cor-
C4-H appeared as dd at δ 3.54 and its downfield shifted
a
1
roborated by H nOe investigations (Figure 5). Though,
the regiochemistry of addition was anticipated in the light
of literature reports [4d,1b,11], however, the important
aspect of the present results is obtained complete regio-
and stereo-selectivity, which can be rationalized in terms
of addition of nitrone in Z - form with ester moiety being
endo-oriented in the transition state (approach E) for steric
reasons (Figure 5).
position vis-à-vis C4-H (dd at δ 2.39), indicated that it is
b
cis to ester function [10c]. Again, lower value of coupling
constant J4a,3 7.7 Hz as compared to J4b,3 8.4 Hz, indicated
that C -H is trans to C -H, which is also corroborated by
4
a
3
1
13
comparison of the overall H and C NMR spectral data
with the data reported for cycloadducts derived from addi-
tion of various nitrones to methyl methacrylate [4d,10c].
The cis relationship between C3-H, C4-H and C5-Me is
b
ascertained through spatial proximity established by
1
recording H nOe difference spectra after saturating C3-H
and C5-Me resonances (Figure 4). The other isomer (9)
could be detected only in trace amount in some column
fractions.
Similar, reaction of nitrone (1) with N-phenylmaleimide
under identical conditions afforded two compounds (11)
and (12). The major compound (11) displayed, interalia, a
1
H singlet at δ 5.71, which was attributed to C3-H and sig-
nified its trans – relationship with C4-H; such lack of any
observable coupling between trans- vicinal-hydrogen
atoms in case of isoxazolidines, particularly, in case of
rigid systems derived from addition of nitrones to cyclic-
dipolarophiles has precedent [4d]. Both C4-H and C5-H
were present as 1H doublets at δ 3.91 and δ 5.30, respec-
tively, displaying a mutual splitting of 7.5 Hz. The minor
cycloadduct (12) on the other hand displayed C3-H reso-
nance as a doublet (1H, J = 8.7 Hz), C5-H as a doublet at δ
4.84 (1H, J = 9.9 Hz) and C4 - H as an unresolved double
doublet at δ 3.92. Mechanistically, the compound (11) can
The obtained major mode of addition can be rationalized
as exo-addition as far as ester function is concerned with
nitrone reacting in Z - form (C) or endo-orientation of ester
function with nitrone reacting in E-form (D) cf. [4d]; pre-
ferred endo-selectivity of α-methyl groups for steric rea-
sons has also been observed in the case of some Diels-
Alder reactions [13d].
A similar reaction of nitrone (1) with ethyl crotonate
afforded a single product, which has been characterized as
cycloadduct (10) by comparison of the spectroscopic data

Sep-Oct 2005
Investigations on Regio- and Stereoselectivities in Cycloadditions
1051
be described as the endo – and 12 as the corresponding exo
adduct derived from addition of nitrone in Z - form.
Reaction of Nitrone (1) with Ethyl Vinyl Ether.
–
Reaction of nitrone (1, 300 mg)) with ethyl vinyl ether (109
mg) and column chromatography of the residue (hexane:ethyl
acetate 9:1 eluent) afforded syn-5-ethoxy-2-phenyl-3-(3-
pyridyl)-isoxazolidine (5a) as light brown viscous oil (370 mg);
ir (chloroform): 3032, 2976, 1599, 1489, 1427, 1326, 1271, 1201
Conclusion.
In summary the regio- and stereo-selectivities in
cycloadditions of hitherto α-(3-pyridyl)-N-phenylni-
trone have been investigated. The cycloadditions have
provided an easy access to a variety of substituted
mono- and bicyclic - isoxazolidine analogs of nicotine,
which are anticipated to display useful biological
activities.
-1 1
cm ; H nmr (duteriochloroform): δ 1.28(t, 3H, J = 7.1 Hz,
CH ), 2.33(dd, 1H, J = 11.2 Hz & J = 5.5 Hz, 4-Hb), 3.00(ddd,
3
gem
1
H, Jgem = 11.2 & J = 9.8, 5.8 Hz, 4-Ha), 3.59(qd, 1H, Jgem
=
1
1.7 & J = 7.1 Hz, OCH ), 3.98(qd, 1H, J
= 11.7 & J = 7.1
2
gem
Hz, OCH ), 4.38(dd, 1H, J = 9.8 & 5.5 Hz, 3-H), 5.38(d, 1H, J =
2
5
&
.8 Hz, 5-H), 6.87-6.98 (m, 3H, Ar-Hs), 7.14-7.40 (m, 3H, Ar-Hs
5′-H), 7.97(d, 1H, J = 7.8 Hz, 4′-H), 8.53(d, 1H, J = 4.1 Hz, 6′-
1
3
H), 8.63 (s, 1H, 2′-H); C nmr (duteriochloroform): δ
EXPERIMENTAL
1
5
1
4.72(CH ), 45.21(C-4), 63.04(OCH2), 65.92(C-3), 100.32(C-
3
), 115.86 (CH), 122.31(CH), 123.39(C-5′), 128.20(CH),
Bruker AC-200 (200 MHz) and JEOL-AL-300FT NMR spec-
34.94(C-4′), 137.04(C-3′), 148.24 (q), 148.29 & 149.54(C-2′ &
1
13
trometers were used to record H NMR, and C NMR (50 MHz)
+
C-6′); EI-MS: m/z (rel. int.) = 270(M , 6), 183(30), 182(30),
181(25), 162(55), 134(55), 93(45), 91(40), 77(100).
spectra in CDCl as solvent. Chemical shifts (δ) are reported as
3
downfield displacements from tetramethylsilane (TMS) used as
internal standard. IR spectra were recorded on Shimadzu DR-
Anal. Calcd. for C H N O (270): C, 71.09; H, 6.71; N,
1
6 18 2 2
1
0.36. Found: C, 70.97; H, 6.75; N, 10.25.
2
001 FT-IR spectrophotometer as thin film with chloroform
Reaction of Nitrone (1) with Isobutyl Vinyl Ether.
(
CHCl ) or as Potassium bromide (KBr) pellets. Mass spectra, EI
3
and ESI-methods, were recorded on Shimadzu GCMS-QP-
000A and Bruker Daltonics Esquire 300 mass spectrometers,
Reaction of nitrone (1, 300 mg) with isobutyl vinyl ether (152 mg)
and column chromatography of the residue (hexane:ethyl acetate 9:1
eluent) afforded syn-5-isobutoxy-2-phenyl-3-(3-pyridyl)-isoxazoli-
dine (5b) as light yellow viscous oil (410 mg); ir (chloroform):
2
respectively. Elemental Analysis was carried out on a Perkin-
Elmer 240C elemental analyzer and are reported in percent
atomic abundance. All melting points are uncorrected and mea-
sured in open glass-capillaries on a Precision (make) MP-D digi-
tal melting point apparatus.
-1
1
3080(sh), 3019, 2961, 2874, 1599, 1489, 1428, 1216 cm ; H nmr
(
duteriochloroform): δ 0.93 (d, 6H, J = 6.7 Hz, 2 × CH ). 1.76-
3
2.19(m, 1H, CH), 2.35(ddd, 1H, J = 12.2 Hz & J = 5.1 &1.2 Hz, 4-
gem
Hb), 2.99(ddd, 1H, Jgem = 12.2 & J 9.9 & 5.8 Hz, 4-Ha), 3.27(dd, 1H,
C-(3-Pyridyl)-N-phenylnitrone (1).
Jgem = 9.2 & J = 6.6 Hz, OCH ), 3.69(dd, 1H, J = 9.2 & J = 6.7 Hz,
2
gem
3
-Formylpyridine (3.0 g, 2.8 mmol) was dissolved in dry
OCH ), 4.42(dd, J = 9.9 & 5.1 Hz, 3-H), 5.36(dd, 1H, J = 5.8 & 1.2
2
benzene (30 ml) and to the clear solution was added N-phenyl-
hydroxylamine hydrochloride (4.08 g, 2.8 mmol) and the con-
tents were allowed to stand at room temperature. After 30 min-
utes nitrone (1) separated out as a light yellow solid, which was
collected by filtration (5.2 g, 95%); mp 88-89 °C (benzene:
hexane, 1:1); ir (potassium bromide): 3065, 3019, 2925, 1591,
Hz, 5-H), 6.87-6.94(m, 3H, Ar-Hs), 7.15-7.32 (m, 3H, Ar-Hs & 5′-
H), 7.97(dt, 1H, J = 6.0 & ~1.8 Hz, 4′-H), 8.54(dd, 1H, J = 4.7 & 1.5
13
Hz, 6′-H), 8.65(d, 1H, J = 1.8 Hz, 2′-H); C nmr (duteriochloro-
form): δ 19.35(CH ), 28.35(CH), 45.37(C-4), 66.05(C-3),
3
7
4.78(OCH ), 101.16(C-5), 116.04(CH), 122.50 (CH), 123.66(C-5′),
2
1
28.60(CH), 135.12(C-4′), 137.62(C-3′), 148.71(overlapping C-6′ &
-
1 1
1
555, 1485, 1460, 1424, 1411, 1216 cm ; H nmr (duteri-
+
q arom.), 150.10 (C-2′); EI MS: m/z (rel. int.) = 300(M +2, 0.5),
ochloroform): δ 7.42 -7.52 (m, 4H, Ar-Hs & 5-H), 7.81(m, 2H,
+
+
299(M +1,1.5), 298(M , 45), 190(30), 134(100).
Ar-Hs), 8.0(s, 1H, α−H), 8.65(d, 1H, J = 4.2 Hz, 6-H), 9.07(s,
Anal. Calcd. for C H N O (298) : C, 72.46; H, 7.43; N,
1
8 22 2 2
1
3
1
H, 2-H), 9.27(d, 1H, J = 8.1 Hz, 4-H); C nmr (duteriochlo-
9
.39. Found: C, 72.36; H, 7.31; N, 9.26.
roform): δ 121.31(CH), 123.52(C-5), 127.32(C-α),
Reaction of Nitrone (1) with Styrene.
1
1
1
7
28.97(CH), 130.12(CH), 131.18(C-3), 135.14(C-4),
48.26(C-6), 149.93(q), 151.58(C-2); EI MS: m/z (rel. int.) =
99(M +1, 5), 198(M , 25), 197(M -1,12), 182(40), 91(90),
8(30), 77(100).
Reaction of nitrone (1, 300 mg)) with styrene (158 mg) and
column chromatography of the residue (hexane:ethyl acetate 9:1
eluent) afforded syn-2,5-diphenyl-3-(3-pyridyl)-isoxazolidine
(5c) as light brown viscous oil (415 mg); ir (chloroform): 3081,
+
+
+
Anal. Calcd. for C12H10N O (198): C, 72.71; H, 5.08; N,
2
-
1 1
1
4.13. Found: C, 72.63; H, 5.00; N, 14.02.
3019, 1598, 1488, 1426, 1362, 1220 cm ; H nmr (duteriochlo-
roform): δ 2.48(ddd, 1H, J = 12.2 & J = 9.5 & 7.6 Hz, 4-Ha),
gem
General Procedure for the Reaction of Nitrone (1) with Various
Dipolarophiles.
3
.25 (ddd, 1H, J
= 12.2 & J = 8.1 , 6.0 Hz, 4-Hb), 5.01(dd, 1H,
gem
J = 8.1 & 7.6 & Hz, 3-H), 5.23(dd, 1H, J = 9.5 & 6.0 Hz, 5-H),
6.97-7.10(m, 3H, Ar-Hs), 7.18-7.42(m, 8H, Ar-Hs and 5′-H),
7.97(d, 1H, J = 7.8 Hz, 4′-H), 8.59(d, 1H, J = 3.6 Hz, 6′-H),
To a solution of nitrone (300 mg) in dry toluene (50 ml) was
added the dipolarophile (1 molar equivalent) and the solution was
refluxed with stirring. After the completion of the reaction (tlc),
the solvent was removed under reduced pressure. The products
were purified by column chromatography (silica gel 60-120
mesh, 20 g, column packed in hexane). The reported yields were
based on isolated pure products and the relative proportions were
1
3
8.77(bs, 1H, 2′-H); C nmr (duteriochloroform): δ 48.06(C-4),
66.95(C-3), 80.53(C-5), 114.01(CH), 121.85(CH), 123.86(C-5′),
126.79(CH), 128.66(CH), 128.73(CH), 129.17(CH),
134.16(C-4′), 137.51(q), 138.63(C-3′), 148.05(q), 148.52(C-6′),
+
+
151.97(C-2′); EI MS m/z(rel. int.) = 304(M +2, 1), 303(M +1,
1
determined in mixtures by H NMR spectroscopy.
3.5), 302(M+, 70), 194(35), 183(30), 105(40), 91(60), 77(100).

1052
G. Singh, M. P. S. Ishar, N. K. Girdhar and L. Singh
Vol. 42
Anal. Calcd. for C H N O (302) : C, 79.44; H, 6.00; N, 9.26.
Found: C, 79.42; H, 5.92; N, 9.17.
93(35), 91(60), 77(100).
Anal. Calcd. for C H N O (251) : C, 71.70; H, 5.21; N,
2
0 18 2
1
5 13 3
1
6.72. Found C, 71.59; H, 5.18; N, 16.6.
Reaction of Nitrone (1) with 4-Vinyl Pyridine.
A mixture (~ 1:1) of 5f with corresponding anti- isomer (6f,
Reaction of nitrone (1, 300 mg)) with 4-vinylpyridine (160
mg) and column chromatography of the residue (hexane:ethyl
acetate 7:3 eluent) afforded syn-2-phenyl-3-(3-pyridyl)-5-(4-
pyridyl)-isoxazolidine (5d) as light brown viscous oil (400 mg);
ir (chloroform): 3065, 3055, 2924, 1599, 1559, 1541, 1488, 1418
1
13
1
230 mg), Critical H and C nmr features of 6f: H nmr (duteri-
ochloroform): δ 2.67-2.77(m, 4-Hb), 2.90-3.06(m, 4-Ha),
4
Hz, 3-H), 7.86(d, J = 8.1 Hz, 4′-H); C nmr (duteriochloroform):
δ 43.45(C-4), 65.02(C-5), 68.60(C-3), 115.61(CH), 117.78(CN),
.59(dd, 1H, J = 9.1 & 5.5 Hz, 5-H), 5.08(dd, 1H, J = 8.2 & 3.4
13
-1 1
cm ; H nmr (duteriochloroform): δ = 2.35-2.21(m, 1H, 4-Hb),
1
22.21(CH), 124.09(C-5′), 128.18(CH), 134.83(C-4′), 135.87(C-
3
1
6
5
2
.20(td, 1H, J
= 11.6 & J = 7.5 Hz, 4-Ha), 4.85(unresolved dd,
gem
3′), 148.53(q), 149.25(C-6′), 151.35(C-2′). anti-2-phenyl-3-(3-
pyridyl)-isoxazolidine-4-carbonitrile (7f) as yellowish viscous
H, J ~ 7.5 Hz, 3-H), 5.14(unresolved dd,1H, J ~7.7 Hz, 5-H),
.85-6.95(m, 3H, Ar-Hs), 7.21-7.09(m, 5H, Ar-Hs & 5′-H, 3′′-H,
′′-Hs), 7.89(dd, 1H, J = 6.4 & 1.9 Hz, 4′-H), 8.43-8.50(m, 3H,
mass (75 mg); ir (chloroform): 3025, 2238, 1599, 1490, 1465,
1426, 1386, 1320, 1265 cm-1; 1H nmr (duteriochloroform): δ
1
3
′′-H, 6′-H & 6′′-H), 8.58 (bs, 1H, 2′-H); C nmr (duteriochloro-
3.46(. ddd, 1H, J = 5.8 ,7.1 & 8.5 Hz, 4-H), 4.32(dd, 1H, J
=
gem
form): δ 47.21(C-4), 66.40(C-3), 78.22(C-5), 114.39(CH),
10.4 & J 7.1 Hz, 5-H), 4.35(dd, 1H, Jgem = 10.4 & J = 8.5 Hz, 5-
H), 4.93(d, 1H, J = 5.8 Hz, 3-H), 7.10-6.93(m, 3H, Ar-Hs), 7.20-
1
1
6
3
21.01 (CH), 122.71(C-3′′ & C-5′′), 123.73(C-5′), 129.07(CH),
34.03(C-4′), 137.58(C-3′), 147.59(C-4′′), 148.24(q), 149.05(C-
′), 149.83(C-2′′ & C-6′′), 151.05(C-2′); EI MS m/z(rel. int.) =
7.38(m, 3H, Ar-Hs and 5′-H), 7.82(d, 1H, J = 7.9 Hz, 4′-H), 8.50-
8.65 (br, 2H, 2′-H & 6′-H); 13C nmr (duteriochloroform): δ
+
+
+
03(M , 5), 302(M -1, 15), 301(M -2, 78), 283(30), 171(90),
12(70), 94(30), 83(55), 71(100), 70(90).
Anal. Calcd. for C H N O (303): C, 75.23; H, 5.65; N,
44.71(C-4). 66.37(C-5), 71.52(C-3), 115.68(CH), 117.18 (CN),
123.80(C-5′), 121.53 (CH), 129.20(CH), 134.19(C-4′), 135.04
(C-3′), 147.85(q), 149.46 (C-6′), 149.63(C-2′); EIMS m/z (rel.
1
1
9 17 3
+
1
3.85. Found: C, 75.14; H, 5.57; N, 13.78.
int.) = 251(M , 20,), 182(40), 144(25), 92(20), 91(67), 77(100).
Anal. Calcd. for C H N O (251): C, 71.70; H, 5.21; N,
6.72. Found C, 71.62; H, 5.12; N, 16.59.
1
5 13 3
Reaction of Nitrone (1) with Acroleindimethylacetal.
1
Reaction of nitrone (1, 300 mg) with acroleindimethylacetal
Reaction of Nitrone (1) with Methyl Vinyl Ketone.
(
(
155 mg) and column chromatography of the residue
hexane:ethyl acetate 9:1 eluent) afforded syn-5-
Reaction of nitrone (1, 300 mg)) with methyl vinyl ketone
(107 mg) and column chromatography of the residue
(hexane:ethyl acetate 9:1 eluent) afforded, in order of elution:
syn-5-acetyl-2-phenyl-3-(3-pyridyl)-isoxazolidine (5g) as yellow
viscous oil (~60 mg); ir (chloroform): 3019, 1718, 1600, 1522,
dimethoxymethyl-2-phenyl-3-(3-pyridyl)-isoxazolidine (5e) as
brown viscous oil (340 mg); ir (chloroform): 3019, 1600, 1521,
-
1 1
1
1
3
424, 1216 cm ; H nmr (duteriochloroform): δ 2.35-2.16(m,
H, 4-Hb), 2.60-2.80(m, 1H, 4-Ha), 3.26(s, 3H, OCH ), 3.38(s,
H, OCH ), 4.22-4.30(m, 2H, 5-H & OCH), 4.71(dd, 1H, J = 7.9
3
-
1 1
1476, 1423, 1216 cm ; H nmr (duteriochloroform): δ = 2.34(s,
3
&
5.9 Hz, 3-H), 6.93-6.83(m, 3H, Ar-Hs), 7.11-7.19(m, 3H, Ar-
3H, CH ). 2.63(dt, 1H, J = 12.7 & J = 5.1 Hz, 4-Hb),
3
gem
Hs & 5-H), 7.79(d, 1H, J = 7.8 Hz, 4′-H), 8.44(d, 1H, J = 4.2 Hz,
2.98(ddd, Jgem = 12.7 & J = 9.2, 7.0 Hz, 4-Ha), 4.58(dd, 1H, J =
9.2 & 5.1 Hz, 3-H), 4.69(dd, 1H, J = 7.0 & 5.1 Hz, 5-H), 6.80-
7.03(m, 3H, Ar-Hs), 7.15-7.40(m, 3H, Ar-Hs & 5′-H), 7.74(br d,
1H, J = 8.0 Hz, 4′-H), 8.50-8.62 (br, 2H, 2′-H & 6′-H). 13C nmr
1
3
6
4
5
5
′-H), 8.60 (bs, 1H, 2′-H); C nmr (duteriochloroform): δ
0.37(C-4). 54.09(OCH ), 54.70(OCH ), 67.53(C-3), 78.11(C-
3
3
), 104.16[CH-(OCH) ], 114.64 (CH), 121.14(CH), 123.46(C-
3
′), 128.82(CH), 134.37(C-4′), 137.96(C-3′), 149.26(q), 150.49
(duteriochloroform): δ 25.67(CH ). 40.12(C-4), 67.15(C-3),
3
+
(
3
C-6′), 150.93(C-2′); EIMS m/z(rel. int.) = 302(M +2, 2),
81.54(C-5), 116.67(CH), 123.64(CH), 126.57(C-5′),
128.83(CH), 134.31(C-4′), 138.53(C-3′), 148.59(q), 149.18(C-
6′), 151.53(C-2′), 201.35 (C=O). EI MS m/z(rel. int.) =
+
+
01(M +1, 10), 300(M , 40), 183(40), 182(43), 181 (48),
20(25), 104(30).
1
+
+
+
Anal. Calcd. for C H N O (300): C, 67.98; H, 6.71; N,
270(M +2, 2), 269(M +1, 4), 268(M , 12), 187(10), 170(15),
111(65), 71(100).
1
7 20 2 3
9
.33. Found C, 67.86; H, 6.65; N, 9.28.
Anal. Calcd. for C H N O (268) : C, 71.62; H, 6.01; N,
1
6 16 2 2
Reaction of Nitrone (1) with Acrylonitrile.
1
0.44. Found C, 71.55; H, 5.94, N, 10.31.
Reaction of nitrone (1, 300 mg)) with acrylonitrile (81 mg) and
column chromatography of the residue (hexane:ethyl acetate 95:5
eluent) afforded, in order of elution: syn-2-phenyl-3-(3-pyridyl)-
isoxazolidine-5-carbonitrile (5f) as light brown viscous oil (38
mg); ir (chloroform): 3043, 2922, 2246, 1596, 1489, 1453.9,
anti-4-Acetyl-2-phenyl-3-(3-pyridyl)-isoxazolidine (7g) as
yellowish viscous material (285 mg). ir (chloroform): 3019,
-
1 1
1716, 1598, 1521, 1489, 1428, 1215 cm . H nmr (duteriochlo-
roform): δ 2.16(s, 3H, CH ), 3.64(ddd, 1H, J = 8.4, 7.5 & 5.7 Hz,
3
4-H), 4.14(dd, 1H, J
= 8.1 & J = 7.5 Hz, 5-H), 4.45(dd, 1H,
gem
-1 1
1
427, 1322, 1261 cm ; H nmr (duteriochloroform): δ 2.58(ddd,
Jgem = 8.1 & J = 8.4 Hz, 5-H), 5.06(d, 1H, J = 5.7 Hz, 3-H), 6.91-
6.98(m, 3H, Ar-Hs), 7.15-7.33(m, 3H, Ar-Hs & 5′-H), 7.84(dt,
1H, J = 8.7 & ~1.4 Hz, 4′-H), 8.55(dd, 1H, J = 4.6 & 1.2 Hz, 6′-
Jgem = 12.9 and J = 3.4 & 5.5 Hz, 4-Hb), 3.17(unresolved ddd,
Jgem = 12.9 & J ~ 9.0 Hz 4-Ha), 4.90(dd, J = 8.9 & 5.5 Hz, 5′-H),
1
3
4
7
8
4
1
3
2
.98(dd, J = 9.3 & 3.4 Hz, 3-H), 6.94-7.09(m, 3H, Ar-Hs), 7.21-
H), 8.69(d, 1H, J = 1.4 Hz, 2′-H); C nmr (duteriochloroform): δ
.39(m, 3H, Ar-Hs & 5-H), 7.91(d, 1H, J = 8.1 Hz, 4′-H), 8.32-
29.56(CH ), 66.75(C-4), 68.40(overlapping C-3 & C-5 resolved
3
1
3
.55(m, 2H, 2′-H & 6′-H); C nmr (duteriochloroform): δ
4.03(C-4′), 63.96(C-5′), 69.13(C-3′), 115.86(CH), 117.23 (CN),
23.80(CH), 124.47(C-5′), 128.95(CH), 134.76(C-4′), 135.52(C-
′), 148.02(q), 148.57(C-6′), 149.63(C-2′); EI MS m/z(rel. int.) =
by DEPT), 115.10(CH), 123.80(CH), 126.67(C-5′), 128.95(CH),
134.42(C-4′), 137.15(C-3′), 148.32(C-6′), 149.16(C-2′),
+
149.94(q), 203.11(C=O); EI MS m/z(rel. int.) = 270(M +2, 2),
+
+
269(M +1, 7), 268(M , 13), 169(100).
+
+
52(M +1, 5), 251(M , 25), 183(20), 182(40), 181(42), 104(25),
Anal. Calcd. for C H N O (268): C, 71.62; H, 6.01; N,
1
6 16 2 2

Sep-Oct 2005
Investigations on Regio- and Stereoselectivities in Cycloadditions
1053
1
0.44. Found C, 71.49; H, 5.96; N, 10.34.
A 2:1 mixture of 8 with methyl anti-5-methyl-2-phenyl-3-(3-
pyridyl)-isoxazolidine-5-carboxylate (9, 68 mg); Critical 1
3
C
Reaction of Nitrone (1) with Methyl Acrylate.
nmr spectral features of 9: δ 174.01(C = O), 148.57(C-2′),
Reaction of nitrone (1, 300 mg)) with methyl acrylate (131
mg) and column chromatography of the residue (hexane:ethyl
acetate 9:1 eluent) afforded a mixture (1:1) of methyl syn/anti-2-
phenyl-3-(3-pyridyl)-isoxazolidine-5-carboxylate (5h & 6h) as
135.06(C-3′), 123.89(C-5′), 82.04(C-5), 52.64(OCH ), 48.20(C-
3
4), 22.70(CH ).
3
Reaction of Nitrone (1) with Ethyl Crotonate.
brownish viscous material (130 mg); ir (chloroform): 2984, 1740,
Reaction of nitrone (1, 300 mg) with ethyl crotonate (170 mg)
and column chromatography of the residue (hexane:ethyl acetate
9:1 eluent) afforded ethyl anti-5-methyl-2-phenyl-3-(3-pyridyl)-
isoxazolidine-4-carboxylate (10) as yellow oil (400 mg); ir (chlo-
-
1
.
&
605, 1581, 1496, 1474, 1421, 1414, 1316, 1315, 1224, 1211 cm
H nmr (duteriochloroform): δ 2.38(ddd, 1H, J = 12.7, 5.2 Hz
2.0 Hz, 4-Hb in 5h), 2.50-2.80(m, 2H, 4-Ha and 4-Hb in 6h),
1
1
-1 1
2
&
.98(unresolved ddd, 1H, J = 12.7 & ~7.2 Hz , 4-Ha in 5h), 3.67
3.73(singlets 3H each, -OCH in 5h & 6h), 4.52(unresolved
roform): 3020, 1732, 1598, 1488, 1429, 1216 cm ; H nmr (deu-
teriochloroform): δ 1.22 (t, 3H, J = 7.2 Hz, CH3), 1.50(d, 3H, J =
5.9 Hz, 5-CH3), 3.08(dd, 1H, J = 8.9 & 6.7 Hz, 4-H), 4.14(q, 2H,
J = 7.1 Hz, OCH2), 4.39 (dq, 1H, J = 8.9 & 5.9 Hz, 5-H), 5.18(d,
1H, J = 6.7 Hz, 3-H), 6.87-6.94(m, 3H, Ar-Hs), 7.10-7.32(m, 3H,
Ar-Hs & 5′-H), 7.90(d, 1H, J = 7.9 Hz, 4′-H), 8.53(d, 1H, J = 4.1
3
dd, 1H, J ~ 7.4 Hz, 3-H in 6h), 4.72(dd, 1H, J = 8.4 Hz, 5.2, 3-H
in 5h), 5.16(dd, 1H, J = 7.9 & 2.0 Hz, 5-H in 5h), 5.25 (br d, 1H,
J = 6.8 Hz, 5-H in 6h), 6.90-7.00(m, 6H, Ar-Hs in, 5h & 6h),
7
7
5
.15-7.40(m, 6H, Ar-Hs & 5′-H, in 5h & 6h), 7.84(br d, 2H, J ~
1
3
.9 Hz, 4′-H, in 5h & 6h), 8.70-8.77(overlapping ds, 2H, 6′-H in
Hz, 6′-H), 8.71(s, 1H, 2′-H). C nmr (duteriochloroform): δ
13.98(CH ), 17.36(C5-CH ), 61.54(-OCH ), 65.12(C-4),
1
3
h & 6h), 8.97 (br s, 2H, 2′-H in 5h & 6h). C nmr (duteriochlo-
3
3
2
roform): δ 41.57 & 41.69 (C-4 in 5h and 6h), 51.86(OMe in 6h),
71.07(C-3), 76.60(C-5), 115.78(CH), 121.84(CH), 123.90(C-5′),
5
5
1
1
2.76(OMe in 5h), 66.67 (C-3 in 5h), 67.30(C-3 in 6h), 75.37(C-
in 5h), 75.75(C-5 in 6h), 115.66, 116.15, 123.11, 124.75,
26.50, 126.63, 128.63, 129.18, 134.38, 134.57, 135.91, 136.90,
129.02 (CH), 134.48(C-4′), 137.76(C-3′), 147.72(q), 149.15(C-
+
6′), 151.05(C-2′), 169.75(C=O). ESI MS m/z = 352(M + K) .
Anal. Calcd. for: C18H20N2O3 (312): C, 69.21; H, 6.45; N,
48.31, 148.97, 149.67, 150.77, 151.29, 151.86, 170.49 & 169.40
8.97. Found C, 69.15; H, 6.40; N, 8.89.
+
(
ester C=O in 5h & 6h); ESI-MS m/z = 324(M + K) . Methyl
Reaction of Nitrone (1) with N-Phenylmaleimide.
anti-2-phenyl-3-(3-pyridyl)-isoxazolidine-4carboxylate (7h) as
light yellow oil (260 mg); ir (chloroform): 3020, 1739, 1599,
Reaction of nitrone (1, 300 mg) with N-phenylmaleimide (263
mg) and column chromatography of the residue (hexane:ethyl
acetate 90:10 to 85:15, eluent) afforded: endo-cycloadduct (11)
as brown solid (430 mg); mp 183-185 °C (diethyl ether). ir
-
1 1
1
3
5
7
1
521, 1426, 1216cm ; H nmr (duteriochloroform): δ 3.47-
.57(m, 1H, 4-H), 3.68(s, 3H, OCH ), 4.23-4.41 (m, 2H, 5-Hs),
.05(d, 1H, J = 5.5 Hz, 3-H), 6.92-7.02(m, 3H, Ar-Hs), 7.18-
.42(m, 3H. Ar-Hs & 5′-H), 7.87(d, 1H, J = 7.8 Hz, 4′-H), 8.71(d,
H, J = 4.3 Hz, 6′-H), 8.97(s, 1H, 2′-H); C nmr (duteriochloro-
form): δ 52.55(OMe), 56.05(C-4), 68.75(C-3), 69.61(C-5),
15.03(CH), 123.78(CH), 126.49(C-5′), 128.93(CH), 134.38(C-
′), 136.50(C-3′), 148.30(q), 149.12 (C-6′), 149.96 (C-2′),
70.84(C=O); EI MS m/z(rel. int.) = 284(M , 10), 283(M -1,
0), 169(90), 111(75), 94(40), 71(100), 70(90).
3
(
potassium bromide): 3060, 2962, 1712, 1592, 1498, 1488, 1453,
-
1 1
1
3
1425, 1387, 1327, 1243 cm ; H nmr (duteriochloroform): δ
3
1
7
.91(d, 1H, J = 7.5 Hz, 4-H), 5.03(d, 1H, J = 7.5 Hz, 5-H), 5.71(s,
H, 3-H), 6.54(dd, 2H, J = 6.9 & 1.8 Hz, Ar-Hs), 6.97(t, 1H, J =
.2 Hz, Ar-H), 7.12(d, 2H, J = 7.5 Hz, Ar-Hs), 7.19-7.28(m. 6H,
1
4
1
3
+
+
Ar-Hs & 5′-H), 7.56(d, 1H, J = 8.2 Hz, 4′-H), 8.55(broad, 1H, 6′-
1
3
H), 8.75(broad, 1H, 2′-H); C nmr (duteriochloroform): δ
5
1
1
1
6.65(C-4), 67.60(C-3), 77.06(C-5), 114.47(CH), 122.48(CH),
23.21(C-5′), 125.99(CH), 128.90(CH), 129.40(C-4′), 130.74(q),
34.29(C-4′), 137.51(C-3′), 148.20 (q aromatic), 148.16(C-6′),
Anal. Calcd. For C H N O (284): C, 67.59; H, 5.67; N,
1
6 16 2 3
9
.85. Found C, 67.66; H, 5.69; N, 9.74.
Reaction of Nitrone (1) with Methyl Methacrylate.
49.45(C-2′), 172.01(C=O), 173.41(C=O); (ESI) m/z = 394(M +
+
Na) .
Reaction of nitrone (1, 300 mg)) with methyl methacrylate
Anal. Calcd. for C H N O (371): C, 71.15; H, 4.61; N,
(
(
152 mg) and column chromatography of the residue
hexane:ethyl acetate, 90:10 eluent) afforded in order of elution
22 17 3 3
11.31. Found C, 71.02; H, 4.57; N, 11.20.
Exo-cycloadduct (12) as light brown solid, (120 mg); mp 215-
17 °C (diethyl ether). ir (potassium bromide): 3064, 2922,
methyl syn-5-methyl-2-phenyl-3-(3-pyridyl)-isoxazolidine-5-
carboxylate (8) as light brown viscous oil (295 mg); ir (chloro-
form): 3059, 3034, 2995, 2952, 1735, 1597, 1489, 1454, 1429,
2
1
-
1 1
700, 1598, 1541, 1498, 1384, 1315 cm ; H nmr (duteriochlo-
-
1
1
roform): δ 3.92(dd, 1H, J = 9.9 & 8.7 Hz, 4-H), 4.84(d, 1H, J =
1
281, 1203 cm ; H nmr (duteriochloroform): δ 1.74(s, 3H, 5-
9
.9 Hz, 5-H), 5.64(d, 1H, J = 8.7 Hz, 3-H), 6.63-6.73(m, 3H, Ar-
Me), 2.39(dd, 1H, J =12.2 & J = 8.4 Hz, 4-Hb), 3.54(dd, 1H,
gem
Hs), 7.10-7.27(m, 4H, Ar-Hs), 7.41-7.48(m, 4H, Ar-Hs & 5′-H),
Jgem = 12.2 & J = 7.7 Hz, 4-Ha), 3.67(s, 3H, OCH ), 4.98(dd, 1H,
3
7
.88(d, 1H, J = 7.8 Hz, 4′-H), 8.45(d, 1H, J = 4.0 Hz, 6′-H), 8.61
J = 8.4 &7.7 Hz, 3-H), 6.95-7.07(m, 3H, Ar-Hs), 7.27(t, 2H, J =
+
(
br, 1H, 2′-H). (ESI) m/z = 394 (M + Na) .
7
.6 Hz, Ar.-Hs), 7.40(dd, 1H, J = 8.1 & 5.3 Hz, 5′-H), 7.94(d, 1H,
Anal. Calcd. for C H N O (371): C, 71.15, H, 4.61, N,
J = 7.9 Hz, 4′-H), 8.64(d, 1H, J = 3.8 Hz, 6′-H), 8.78(s, 1H, 2′-H);
22 17
3 3
1
3
11.31. Found C, 71.01, H, 4.53, N, 11.21.
C nmr (duteriochloroform): δ 22.21(CH ), 48.96(C-4),
3
5
1
6
3
1
2.32(OCH ), 67.06(C-3), 83.39(C-5), 114.49(CH), 121.79(CH),
3
23.94(C-5′), 128.52(CH), 134.53(C-3′), 147.87(q), 148.60(C-
REFERENCES AND NOTES
′), 150.44(C-2′), 172.97(ester C=O); EI MS m/z(rel. int.) =
+
+
+
00(M +2, 5), 299(M +1, 10), 298(M , 35), 181(30), 130(30),
06(50), 91(100), 77(95).
[
1a] W. R., Carruthers, Cycloadditions in Organic Synthesis,
Pergamon Press, London, 1990, Chapter 6, p 269; [b] D. S. C. Black, R.
F. Cozier and V. C. Davis, Synthesis, 205 (1975); [c] J. J. Tuffariello, in
Nitrones in 1,3-Dipolar Cycloaddition Chemistry; ed, A. Padwa, Wiley
Anal. Calcd. for C H N O (298): C, 68.44; H, 6.08; N,
1
7 18 2 3
9
.39. Found C, 68.32; H, 5.97; N, 9.29.

1054
G. Singh, M. P. S. Ishar, N. K. Girdhar and L. Singh
Vol. 42
Interscience, New York, 1984, Vol. 2, p 1; [d] L. A. Paquette,
Comprehensive Organic Synthesis, eds, B.M. Trost and I. Fleming,
Pergamon, Oxford, 1991, Vol. 5, Chapter 3; [e] M. Frederickson,
Tetrahedron, 53, 403 (1997); [f] K. V. Gothelf and K. A. Jorgensen,
Chem. Rev., 98, 863 (1998).
[b] C. Hedberg, P. Pinho, P. Roth and P. G. Andersson, J. Org. Chem., 65,
2810 (2000); [c] D. M. Hodgson, C. R. Maxwell, R. Wisedale, I. R.
Matthews, K. J. Carpenter, A. H. Dickenson and S. Wonnacott, J. Chem.
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