Unusual Regioselectivity of the Dipolar Cycloaddition Reactions of Nitrile Oxides and Tertiary Cinnamides and Crotonamides

Article abstract of DOI:10.1021/jo9807621

Benzonitrile oxides undergo 1,3-dipolar cycloaddition reactions with methyl cinnamate to produce the 5-phenyl and 4-phenyl regioisomers in approximately an 80:20 ratio. However, use of N,N-diethylcinnamide as the dipolarophile unexpectedly resulted in the formation of the 5-phenyl and 4-phenyl regioisomers in a 23:77 ratio. Studies have shown that this phenomena occurs only for tertiary cinnamides. In addition, it has been demonstrated that the phenyl group of tertiary cinnamides is not essential for the reversal of regioselectivity since crotonamides produce the same results and trends as the cinnamides. However, since acrylates and acrylamides both produce the 5-carbonyl regioisomers, it can be concluded that the β-substituent is playing a key role for the unexpected results by possibly increasing steric interactions between the dipole and dipolarophile in the transition state. Transition state energies were calculated for the regioisomeric cycloadduct pairs derived from several crotonamides as well as methyl crotonate. These calculations indicate that steric factors are indeed responsible for the reversal of regioselectivity.

Full text of DOI:10.1021/jo9807621

J . Org. Chem. 1998, 63, 6319-6328
6319
Un u su a l Regioselectivity of th e Dip ola r Cycloa d d ition Rea ction s
of Nitr ile Oxid es a n d Ter tia r y Cin n a m id es a n d Cr oton a m id es1
Michele A. Weidner-Wells,*,† Stephanie A. Fraga-Spano, and Ignatius J . Turchi2
Drug Discovery, The R.W. J ohnson Pharmaceutical Research Institute, 1000 Route 202, P.O. Box 300,
Raritan, New J ersey 08869
Received April 22, 1998
Benzonitrile oxides undergo 1,3-dipolar cycloaddition reactions with methyl cinnamate to produce
the 5-phenyl and 4-phenyl regioisomers in approximately an 80:20 ratio. However, use of N,N-
diethylcinnamide as the dipolarophile unexpectedly resulted in the formation of the 5-phenyl and
4-phenyl regioisomers in a 23:77 ratio. Studies have shown that this phenomena occurs only for
tertiary cinnamides. In addition, it has been demonstrated that the phenyl group of tertiary
cinnamides is not essential for the reversal of regioselectivity since crotonamides produce the same
results and trends as the cinnamides. However, since acrylates and acrylamides both produce the
5-carbonyl regioisomers, it can be concluded that the â-substituent is playing a key role for the
unexpected results by possibly increasing steric interactions between the dipole and dipolarophile
in the transition state. Transition state energies were calculated for the regioisomeric cycloadduct
pairs derived from several crotonamides as well as methyl crotonate. These calculations indicate
that steric factors are indeed responsible for the reversal of regioselectivity.
In tr od u ction
Nitrile oxides, generated by dehydrohalogenation of
hydroximinoyl acid chlorides (chloro oximes), undergo
1,3-dipolar cycloaddition reactions with a wide variety
of olefins to produce 4,5-dihydroisoxazoles in a stereospe-
cific manner.3 Cycloadditions with monosubstituted ole-
fins proceed rapidly and regioselectively to yield the
5-substituted dihydroisoxazole (eq 1). For example, the
use of styrene (1) as the dipolarophile results in the
formation of the 5-phenyl isomer 2 and the 4-phenyl
isomer 3 in a 99:1 ratio.3
(2)
acterized by spectral properties. Huisgen and Christl4
have reported that the differences in chemical shifts
between the H4 and H5 methine protons clearly distin-
guishes between the two regioisomers. In addition,
DeSarlo and co-workers6 have shown for the cycloadducts
derived from cinnamaldehyde that the 5-phenyl isomer
exhibits a large MH+ - 106 peak in the mass spectrum
corresponding to loss of benzaldehyde.
(1)
On the other hand, reaction of nitrile oxides with 1,2-
disubstituted olefins tends to be slower and have reduced
regioselectivity. For example, trans methyl cinnamate
(4) undergoes cycloaddition with phenyl nitrile oxide (5)
to form the 5- and 4-phenyl trans substituted isomers 6
and 7 in an 80:20 ratio, respectively (eq 2).4,5 Monforte5
distinguished between the regioisomers by subjecting
each isomer to hydrolysis/decarboxylation conditions. In
recent years, the regioisomers 6 and 7 have been char-
During the course of our studies, it was desired to
replace the ester functionality of each regioisomer 6 and
7 with various amide moieties.7 Instead of preparing
both amides via the corresponding acids, the cycloaddi-
tion reaction was accomplished using the appropriate
cinnamide 9 as the dipolarophile to produce the desired
compounds 10 and 11 directly in one step (eq 3). This
route was very attractive since large quantities of chloro
oximes 8 and cinnamides 9 with diverse substitution
patterns could be easily prepared and, therefore, numer-
ous permutations of 8 and 9 in the cycloaddition reaction
would rapidly produce the corresponding two isomers 10
and 11 required for biological testing.
† E-mail: mwells@prius.jnj.com.
(1) This work was presented in part at the ACS National Meeting
in Chicago, IL, in August 1995.
(2) Department of Process Chemistry.
(3) (a) Quilico, A. In Five and Six Membered Compounds with
Nitrogen and Oxygen; Wiley, R. H., Ed.; Interscience Publishers: New
York, 1962. (b) Torssell, K. Nitrile Oxides, Nitrones and Nitronates in
Organic Synthesis; VCH: New York, 1988. (c) Caramella, P.; Gru¨nanger,
P. In 1,3-Dipolar Cycloaddition Chemistry, Vol. 1; Padwa, A., Ed.;
Wiley: New York, 1984. (d) Gru¨nanger, P.; Vita-Finzi, P. Isoxazoles-
Part 1; Vol. 49 of Chemistry of Heterocyclic Compounds; Wiley: New
York, 1991 and references cited therein.
(6) DeSarlo, F.; Guarna, A.; Brandi, A. J . Heterocycl. Chem. 1983,
20, 1505.
(7) Weidner-Wells, M. A.; Fraga, S. A.; Demers, J . P. Tetrahedron
Lett. 1994, 35, 6473.
(4) (a) Huisgen, R.; Christl, M. Chem. Ber. 1973, 106, 3275. (b)
Huisgen, R.; Christl, M. Chem. Ber. 1973, 106, 3345.
(5) Monforte, F. Gazz. Chim. Ital. 1952, 82, 130.
S0022-3263(98)00762-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/18/1998

6320 J . Org. Chem., Vol. 63, No. 18, 1998
Weidner-Wells et al.
Ta ble 1. Regioisom er ic Ra tios of Dih yd r oisoxa zoles 10
a n d 11a
X of
nitrile
entry oxide 8
Z of
dipolarophile
5-phenyl 4-phenyl yield (%)
(3)
isomer
isomer
of cyclo-
adducts
9
10
11
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
H
4-Cl
4-MeO OMe
3-NO2 OMe
4-Cl
H
4-MeO NEt2
3-NO2 NEt2
4-Cl
4-Cl
4-Cl
H
4-Cl
4-Cl
4-Cl
H
4-Cl
4-Cl
OMe
OMe
80
78
81
82
23
28
25
29
18
51
45
52
47
35
73
74
78
31
20
22
19
18
77
72
75
71
82
49
55
48
53
65
27
26
22
69
84
85
64
Resu lts
70 (88)b
95
NEt2
NEt2
The chloro oximes 8 were synthesized in two steps from
the corresponding benzaldehyde (eq 4). The intermediate
oximes were chlorinated with N-chlorosuccinimide in
DMF.8 The resulting chloro oximes 8 were not contami-
nated with ring chlorinated products, require no purifica-
tion, and may be stored for several months without any
decomposition. The nitrile oxides were generated in situ,
by dehydrohalogenation of the chloro oxime with triethy-
lamine.4
83
40
63
85
piperidinyl
NHPh
54 (71)b
88
NHPh(4-OMe)
NHPh(4-OMe)
NHPh(4-NO2)
NMe(Ph)
NH(c-C5H9)
NH(c-C5H9)
NH2
88
66
54
79
76
80
85
NMe2
a
Determined by integration of the C4 and C5 methines in the
b
(4)
NMR of the crude reaction mixture. Yield based on recovered
starting material in parentheses.
Sch em e 1
Reaction of nitrile oxide 8e (X ) 4-Cl) and N,N-
diethylcinnamide (9e) (eq 3 and Table 1, entry e) unex-
pectedly led to a reversal of regioselectivity to yield the
5-phenyl 10e and the 4-phenyl 11e cycloadducts in a 23:
77 ratio as determined by the integration of the C-4 and
C-5 isoxazoline methine protons in the NMR of the crude
reaction mixture. The structures were initially assigned
on the basis of the relative chemical shifts and coupling
constants of the C-4 and C-5 methine doublets. Major
isomer 11e exhibits two closely spaced doublets (δ 5.12
and 5.64) similar to that found for the 4-phenyl-5-
carbomethoxy adduct 11b (δ 4.97 and 5.02), while minor
isomer 10e exhibits two largely spaced doublets (δ 4.64
and 5.73), similar to that for the corresponding ester 10b
(δ 4.43 and 6.00). The H4-H5 coupling constants for the
pair of isomers of 10e and 11e are 9.3 and 5.7 Hz,
respectively, indicating a trans relationship9 in the
cycloadducts (cis coupling ∼11-12 Hz). These values are
similar to the reported values4 for 10a and 11a (6.2 and
4.1 Hz). More importantly, the mass spectrum of amide
10e exhibits a peak corresponding to the loss of benzal-
dehyde (MH+ - 106), thus indicating that the phenyl
group is attached to the 5-position of the dihydroisoxazole
ring. This same regiochemistry was observed when
piperidinyl amide 9i was used as the dipolarophile in the
reaction.
Confirmation of the structural assignments was
achieved by independent synthesis of several adducts
from the ester intermediates 10b or 11b (Scheme 1) via
acid 12 or acid 13, respectively.
As is evident from Table 1, the regioselectivity of the
reaction using either an ester (entries a-d) or an amide
(entries e-h) dipolarophile is independent of the elec-
tronic nature of the substituents on the phenyl ring of
the benzonitrile oxide. (4-Nitrobenzonitrile oxide was not
used since it dimerizes to the furoxane faster than it
undergoes cycloaddition with cinnamates.)
We initially proposed that the difference in electronics
between an ester carbonyl and an amide carbonyl may
be responsible for altering the dipolarophilic nature of
the olefin leading to a reversal of selectivity. To this end,
the aniline amides 9j-m were prepared. These cycload-
dition reactions were found to be nonregioselective with
the products being formed in approximately equal
amounts. However, when the tertiary aniline amide 9n
was the dipolarophile, the ratio of cycloadducts was
similar to that of the other tertiary cinnamides, thus
ruling out electronic effects due to the difference in the
type of carbonyl.
With the cinnamides studied to this point, reversal of
regiochemistry occurred with the tertiary amides, thus
hinting that steric factors may be playing an important
role. Less bulky amides such as cyclopentyl amide 9o
and cinnamide (9q) were investigated. Interestingly,
both cases afford the 5-phenyl 10o or 10q and the
4-phenyl 11o or 11q cycloadducts in approximately the
same ratio as for methyl cinnamate! Since cinnamide
(8) Liu, K.; Shelton, B.; Howe, R. K. J . Org. Chem. 1980, 45, 3916.
(9) Sustmann, R.; Huisgen, R.; Huber, H. Chem. Ber. 1967, 100,
1802.

Dipolar Cycloaddition Reactions of Nitrile Oxides
J . Org. Chem., Vol. 63, No. 18, 1998 6321
Ta ble 2. Regiosiom er ic Ra tios of Dih yd r oisoxa zoles 15
a n d 16a
Discu ssion
From these studies, we have shown that primary and
secondary cinnamides and crotonamides produce the
cycloadducts with the opposite regiochemistry as the
analogous tertiary amides. One difference between these
types of amides is the presence or absence of the amide
hydrogen which can function as a hydrogen bond donor
which may lead to a templating effect and, hence, affect
the regiochemistry of the reaction. Curran has reported
that allylic secondary amides can alter the regio- and
diastereoselectivity of nitrile oxide cycloadditions.10 The
authors proposed that the amide hydrogen forms a
hydrogen bond with the oxygen of the nitrile oxide, thus
leading to a preponderance (90:10 ratio) of the 5-substi-
tuted cycloadduct. However, when this model is applied
to the secondary cinnamides/crotonamides, one would
predict that the major adduct would be the 5-carboxam-
ide product 11 or 16. Since this is not the case, then this
type of templating effect is miminal in the cinnamide/
crotonamide system.
Fronter molecular orbital (FMO) theory has enjoyed
considerable success in rationalizing the regiochemistry
of Diels-Alder reactions.11 In many cases, FMO theory
is inadequate for the treatment of 1,3-dipolar cycloaddi-
tions. This is due to, in simple FMO theory, the
disregard of steric and electrostatic effects as well as the
effects of interactions of other high-energy filled orbitals
with low-energy unfilled orbitals. Often in dipolar cy-
cloadditions it is difficult to determine if the reaction is
dipole HOMO or LUMO controlled in cases where the
HOMO-LUMO gaps are of similar energy.
X of
nitrile dipolarophile
entry oxide 8 14
Z of
5-methyl 4-methyl yield (%)
isomer
isomer
of cyclo-
adducts
15
16
a
b
c
d
e
f
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
OMe
NEt2
piperidinyl
NH2
66
16
23
59
60
3
34
84
77
41
40
97
65
86
83
65
69
74
NH(c-C5H9)
TMPb
a
Determined by integration of the C4 and C5 methines in the
b
NMR of the crude reaction mixture. TMP ) 2,2,6,6-tetrameth-
ylpiperidinyl.
(9q) did not result in a reversal of regioselectivity and
N,N-diethylcinnamide (9e) did, the smallest tertiary
cinnamide, N,N-dimethylcinnamide (9r ), was subjected
to the cycloaddition reaction. This dipolarophile did
reverse the regioselectivity of the reaction, producing the
isomeric isoxazolines 10r and 11r in a 31:69 ratio.
The effect of the â-substituent of the dipolarophile was
next investigated (eq 5, Table 2). The first dipolarophile
(5)
examined was where the â-substituent was a methyl
group, thus eliminating the possibility of any electronic
effects, due to conjugation, between the phenyl ring and
the olefinic ester (or amide) portions of the molecule. The
crotonate/crotonamide series of compounds produced the
same results and trends as those for cinnamides. The
extremely bulky N-2,2,6,6-tetramethylpiperidinyl cro-
tonamide (14f) furnished the 4-methyl isomer 16f with
excellent regioselectivity. These results also indicate that
sterics of the amide moiety could be responsible for this
unusual regiochemistry. Examination of the coupling
patterns for the C-4 and C-5 methines in the proton NMR
and the fragmentation pattern in the mass spectrum
differentiated between the two regioisomers for the ester
and the amide pairs.
Kamimura and Hori reported that the choice of car-
bonyl protecting group reverses the regioselectivity in the
nitrile oxide cycloadditions to cinnamaldehyde and cro-
tonaldehyde derivatives 20.12 Acetals provide a majority
of the C-4 acetal cycloadducts 21 whereas the dithioacetal
affords mainly the C-5 dithioacetal adduct 22 (eq 7). The
(7)
The third dipolarophile examined was the unsubsti-
tuted example where the â-substituent was a hydrogen
(eq 6). Ethyl acrylate (17a ) produced the 5-carboethox-
ydihydroisoxazole 19a along with only trace amounts of
the 4-carboethoxy isomer 18a .3 N,N-Diethylacrylamide
(17b) exclusively forms the 5-carboxamide adduct 19b
with no trace of isomer 18b being observed in the crude
NMR. Interestingly, there is no reversal in the regiose-
lectivity with this dipolarophile. These results indicate
that the â-substituent of the dipolarophile is also playing
an important role along with the amide moiety in
determining the regiochemistry of the reaction.
authors invoke FMO theory to rationalize the regio-
chemical outcome of the cycloaddition with acetals and
steric factors to rationalize the opposite outcome with the
dithioacetals. MNDO calculations indicated that the
steric interaction between the C-3 phenyl group and the
1,3-dithiolane ring at C-4 raises the energy of the adduct
21 by 4.2 kcal/mol, thus leading to a majority of 22 being
preferentially formed. However, these calculations failed
to correctly predict the regioselectivity of the acetal
derivatives, even though the authors note that the steric
biases of the acetal and thioacetal groups are similar.
Likewise, the FMO theory failed to correctly predict the
regioselectivity for the dithioacetals.
(10) Curran, D. P.; Choi, S.-M.; Gothe, S. A.; Lin, F.-T. J . Org. Chem.
1990, 55, 3710.
(11) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley: New York, 1976.
(12) Kamimura, A.; Hori, K. Tetrahedron 1994, 50, 7969.
(6)

6322 J . Org. Chem., Vol. 63, No. 18, 1998
Weidner-Wells et al.
We applied FMO theory to the cycloaddition of ben-
zonitrile oxide with N,N-dimethylcrotonamide (23h ) (eq
8). The geometry optimization of each was performed
(8)
at the RHF/3-21G and AM113 levels of theory. Using the
ab initio eigenvalues it was determined that the reaction
was dipole LUMO controlled and this orbital interacts
with the (HOMO-1) of the dipolarophile, which is cen-
tered on the olefinic carbon atoms. The LUMO dipole-
(HOMO-1) dipolarophile gap is 12.04 eV. The HOMO
dipole-LUMO dipolarophile gap is 12.86 eV. The larger
LUMO coefficient of benzonitrile oxide is on the carbon
of the dipole and the larger (HOMO-1) coefficient of the
dipolarophile is on the carbon bearing the amide (both
inner and outer coefficients for each). This leads to the
prediction that 5-methyl-4-carboxamide isomer 24h would
be the preferred regioisomer. This is contrary to the
experimental results. Using the AM1 calculated eigen-
values, the HOMO dipole-LUMO dipolarophile gap was
nearly the same as the LUMO dipole-(HOMO-1) dipo-
larophile gap, and therefore, no clear regiochemical
preference is apparent.
F igu r e 1. Transition structures (RHF/3-21G top; AM1 bot-
tom) for the cycloaddition of benzonitrile oxide with N,N-
dimethylcrotonamide (23h ) leading to the 5- and 4-methyl-
isoxazolines 24 (left) and 25 (right).
dition of formonitrile oxide with N,N-dimethylcrotona-
mide (23h ) leading to the 4-carbonyl 5-methyl regioiso-
mer are 2.073 and 2.330 Å, respectively, a difference of
only 0.26 Å. The AM1 transition structures leading to
the 4-carbonyl regioisomer 24 are much more synchro-
nous with the C-O bond being shorter than the C-C
bond by only 0.08 Å on average. The AM1 calculated
C-O and C-C bond lengths for the transition structures
for the cycloaddition of formonitrile oxide with N,N-
dimethylcrotonamide (23h ) leading to the 4-carbonyl-5-
methyl regioisomer are 2.186 and 2.080 Å, respectively.
In this case the C-O bond is longer than the C-C bond
by 0.11 Å.
The failure of FMO theory to correctly predict the
regiochemical course of the nitrile oxide cycloaddition
with N,N-dimethylcrotonamide (23h ) led us to apply
semiempirical (AM1),13 ab initio, and density functional
theory (DFT) methods to examine the regioisomeric
transition structures, thus allowing for a quantitative
comparison of ∆E and ∆H for these reactions. Because
of the large size of the systems under study, geometry
optimizations were performed at the AM1 and RHF/3-
21G levels of theory. Since the regiochemical outcome
of these cycloadditions is independent of the substituent
on the phenyl ring of the benzonitrile oxide (vide supra),
only benzonitrile oxide was examined as the dipole for
the theoretical studies.
Figure 1 shows the RHF/3-21G and AM1 transition
structures (TS) for the cycloaddition of benzonitrile oxide
with N,N-dimethylcrotonamide (23h ). Table 3 shows the
lengths of the forming bonds in the cycloadditions of
benzonitrile oxide with methyl acrylate (23a ), methyl
crotonate (23b), the acrylamides 23c-e and the crotona-
mides 23f-i calculated at the RHF/3-21G and AM1
levels.
The RHF/3-21G transition structures leading to the
5-carbonyl regioisomers 25 are more synchronous than
those leading to the 4-carbonyl regioisomers 24. The
C-O bond is shorter than the C-C bond by 0.13 Å on
average while for the AM1 transition structures, the C-O
bond is longer than the C-C bond by 0.07 Å on average.
Houk14 reported that in the RHF/3-21G transition struc-
ture for the reaction of formonitrile oxide with ethylene,
the forming bonds are nearly the same length; the C-O
bond is 2.281 Å and the C-C bond is 2.265 Å. We
obtained similar results for the cycloaddition of formoni-
trile oxide with N,N-dimethylcrotonamide (23h ) leading
to the 5-carbonyl-4-methyl regioisomer. In this case, the
RHF/3-21G transition structure is nearly synchronous.
The C-O bond length is 2.197 Å, and the C-C bond
length is 2.192 Å. The bond lengths for the AM1
transitions structure are 2.205 Å for the C-O bond and
2.032 Å for the C-C bond.
These results suggest that there are unfavorable steric
(and possibly electrostatic) repulsions between the phenyl
ring of the nitrile oxide and the ester or amide function-
alities of the dipolarophiles in the transition structures
of the 4-carbonyl regioisomers 24. These interactions can
be partially overcome by the asynchronicity of the transi-
tion structures with the forming C-O bond being shorter
than the forming C-C bond. The bulkier the amide
portion is, the more unfavorable steric interactions are
in the transition structure, therefore favoring the 4-
The most striking feature derived from these calcula-
tions is the asynchronicity in the RHF/3-21G transition
structures leading to the 4-carbonyl regioisomer 24 with
the C-O bond being shorter than the C-C bond by 0.53
Å on average. The RHF/3-21G calculated C-O and C-C
bond lengths for the transition structures for the cycload-
(13) Dewar, M. J . S.; Zoenison, E. G.; Healy, E. F. J . Am. Chem.
Soc. 1985, 107, 3902.
(14) Brown, F. K.; Singh, U. C.; Kollman, P. A.; Raimondi, L.; Houk,
K. N.; Bock, C. W. J . Org. Chem. 1992, 57, 4862.

Dipolar Cycloaddition Reactions of Nitrile Oxides
J . Org. Chem., Vol. 63, No. 18, 1998 6323
Ta ble 3. RHF /3-21G a n d AM1 Bon d Len gth s for th e F or m in g Bon d s in th e Tr a n sition Str u ctu r es Lea d in g to
Regioisom er s 24 a n d 25
RHF/3-21G for isomer 24
AM1 for isomer 24
RHF/3-21G for isomer 25
AM1 for isomer 25
dipolarophile 23
RCsC
RCsO
RCsC
RCsO
RCsC
RCsO
RCsC
RCsO
a
b
c
d
e
f
g
h
i
2.439
2.438
2.433
2.426
2.428
2.433
2.427
2.426
2.427
1.891
1.899
1.894
1.906
1.902
1.902
1.914
1.913
1.924
2.193
2.152
2.169
2.167
2.181
2.122
2.123
2.133
2.136
2.020
2.070
2.067
2.064
2.038
2.122
2.123
2.086
2.084
2.207
2.200
2.215
2.215
2.214
2.206
2.207
2.205
2.198
2.087
2.073
2.071
2.072
2.082
2.074
2.075
2.086
2.087
2.049
2.078
2.047
2.049
2.050
2.073
2.074
2.075
2.075
2.144
2.087
2.173
2.164
2.166
2.112
2.106
2.106
2.105
Ta ble 4. Ca lcu la ted Activa tion En er gies a n d Activa tion En th a lp ies (k ca l/m ol) for th e Cycloa d d ition of Ben zon itr ile
Oxid e w ith Dip ola r op h iles a n d Differ en ces in th e Activa tion En er gies a n d Activa tion En th a lp ies for th e F or m a tion of
th e Regioisom er s 24 a n d 25
product
Eq a
∆Eq e
Eq b
∆Eq e
∆Hq c
∆∆Hq e
Eq d
∆Eq e
24a
25a
24b
25b
24c
25c
24d
25d
24e
25e
24f
25f
24g
25g
24h
25h
24i
19.57
24.27
20.49
27.46
19.57
23.34
19.69
23.35
19.52
22.26
20.47
25.87
20.59
25.85
20.45
24.74
26.08
29.17
16.86
15.24
18.97
19.61
17.22
16.29
17.36
16.36
17.20
15.80
19.21
18.85
19.30
18.94
19.25
18.33
19.24
17.79
16.67
17.31
13.30
15.02
16.83
15.10
16.95
16.38
17.28
16.08
12.88
12.88
19.47
20.66
13.31
13.60
23.54
21.48
15.47
13.18
15.80
18.12
15.91
12.62
16.21
15.79
15.67
11.44
16.91
16.99
17.16
20.23
17.17
16.25
24.06
18.17
-4.70
-6.97
-3.77
-3.66
-2.74
-5.40
-5.26
-4.29
-3.09
1.62
-0.64
0.93
-0.64
-1.72
1.73
2.29
-2.32
3.29
1.00
0.57
0.42
1.40
1.20
4.23
0.36f
0.36g
0.92
0.00
-0.08
-3.07
0.92
-1.19
-0.29
2.06
25i
1.45
5.89
a
b
RHF/3-21G//RHF/3-21G+ZPE (scaled by 0.8929). B3LYP/6-31G(d)//RHF/3-21G+ZPE (scaled by 0.8929). c AM1//AM1 (no ZPE).
B3LYP/6-31G(d)//AM1 (no ZPE). e ∆Eq ) (Etransition structure - Eseparated reactants); ∆∆Hq ) (∆Htransition structure - ∆Hseparated reactants); a negative
d
value for ∆Eq or ∆∆Hq means that the 4-regioisomer is preferred. f B3LYP/6-311+G(2d,p)//RHF/3-21G; ∆Eq ) -0.24. B3LYP/6-
g
311+G(2d,p)//RHF/3-21G; ∆Eq ) 0.17.
methyl regioisomer 25 since the steric interaction of the
methyl groups of methyl crotonate and the tertiary
crotonamides with the phenyl ring of the nitrile oxide
should be smaller. For esters and less bulky amides, the
steric interaction for the carbonyl moiety and the phenyl
ring of the nitrile oxide is less than that between the
â-substituent and the phenyl ring yielding the 5-methyl
adduct 24 as the major product. However, for the
acrylate/acrylamide series, the ester/amide is always
oriented toward the oxygen of the nitrile oxide and the
â-hydrogen is close to the phenyl ring of the nitrile oxide
so as to miminize steric interactions leading to almost
exclusive formation of the 5-substituted isomers 25a and
25c-e.
The calculated activation energies (ab initio and DFT)
and enthalpies of activation (AM1) for the cycloaddition
of benzonitrile oxide to methyl acrylate (23a ), methyl
crotonate (23b), the acrylamides 23c-e, and crotona-
mides 23f-i are given in Table 4 as well as the ∆Eq (ab
initio and DFT) and ∆∆Hq (AM1) for the formation of the
4-carbonyl regioisomer 24 and 5-carbonyl regioisomers
25 (∆Eq ) Eq(24) - Eq(25); ∆∆Hq ) ∆Hq(24) - ∆Hq(25);
i.e., when ∆Eq (or ∆∆Hq) < 0 kcal/mol, regioisomer 24 is
favored). The RHF/3-21G activation energies are in each
case higher than the B3LYP/6-31G(d)//RHF/3-21G acti-
vation energies as well as the AM1 activation enthalpies.
This is generally the case for Hartree-Fock calculated
activation energies for cycloadditions since Coulomb
correlation effects are neglected.15 Correlation effects are
partially included in semiempirical methods in the
experimental parameters. Solely on the basis of the
calculated ∆Eq, RHF/3-21G predicts that only the 4-car-
bonyl regioisomer 24 will be formed exclusively in these
reactions.16,17 This is contrary with the experimental
results. The ∆Eqs calculated by the B3LYP/6-31G(d)//
RHF/3-21G and the B3LYP/6-31G(d)//AM1 procedures
and the AM1 calculated ∆∆Hqs are much smaller and
predict that mixtures of regioisomers should arise from
these cycloadditions. The B3LYP/6-31G(d)//RHF/3-21G
method even predicts the predominant regioisomer in all
but two cases, i.e., the cycloaddition of benzonitrile oxide
with crotonamide 23f and N-methylcrotonamide 23g.
However, use of a larger basis set in the calculation
(B3LYP/6-311+G(2d,p)//RHF/3-21G) correctly predicts
that regioisomer 24f will predominate in the cycloaddi-
tion with crotonamide 23f. It should be mentioned that
for each of these two cases the experimental results
indicate a small preference for the 5-methyl cycloadducts
24, thereby making the theoretical predictions more
(15) Houk, K. N.; Li, Y.; Evanseck, J . D. Angew. Chem., Int. Ed.
Engl. 1992, 31, 682.
(16) The calculated (RHF/3-21G and AM1) ∆∆Sq for the 4- and
5-regioisomers are <2 eu.
(17) RHF/6-31G(d)//RHF/3-21G single-point calculated energies give
only slightly better results than the RHF/3-21G calculations with the
4-regioisomer predominating in each case while MP2/6-31G(d)//RHF/
3-21G single-point calculations predict that the 5-regioisomers pre-
dominate in each case.

6324 J . Org. Chem., Vol. 63, No. 18, 1998
Weidner-Wells et al.
Ta ble 5. Ca lcu la ted En er gies a n d En th a lp ies of
Rea ction (k ca l/m ol) for th e Cycloa d d ition of Ben zon itr ile
Oxid e w ith Dip ola r op h iles of th e Regioisom er s 24 a n d 25
â-substitutent of the dipolarophile as well as the amide
functionality is responsible for the regioselectivities
observed.
a
b
c
d
product
Er
Er
∆Hr
Er
Semiempirical (AM1) and ab initio calculations were
performed on a series of crotonate/crotonamide and
acrylate/acrylamide dipolarophiles. These results indi-
cate that the RHF/3-21G transition structures of the
4-carbonyl isomers 24 are highly asynchronous such that
the C-C bond is approximately 0.5 Å longer than the
C-O bond. However, the RHF/3-21G transition struc-
tures of the 5-carbonyl isomers 25 are more synchronous.
This is most likely due to steric interactions between the
phenyl group of the nitrile oxide and the ester or amide
portion of the molecule. The larger tertiary amide directs
the formation of 25 while the more sterically congested
transition state leads to 24.
24a
25a
24b
25b
24c
25c
24d
25d
24e
25e
24f
25f
24g
25g
24h
25h
24i
-46.69
-46.48
-47.53
-44.04
-45.31
-54.63
-45.64
-54.88
-45.20
-52.59
-48.13
-52.81
-46.47
-53.09
-45.89
-50.36
-39.35
-46.55
-36.89
-38.98
-35.72
-33.53
-36.75
-44.47
-36.89
-44.80
-36.41
-42.91
-37.26
-39.74
-36.30
-40.21
-35.62
-37.62
-33.55
-37.30
-36.02
-35.31
-30.84
-29.35
-38.20
-39.71
-38.15
-39.83
-35.59
-38.67
-32.98
-33.72
-32.94
-33.78
-30.52
-32.73
-27.86
-29.93
-33.61
-34.95
-32.74
-28.93
-33.86
-39.51
-33.61
-34.95
-31.12
-38.77
-33.24
-34.37
-32.74
-34.45
-30.13
-33.11
-25.31
-30.83
In addition, ab initio and DFT activation energies were
calculated. The ∆Eqs calculated by the B3LYP/6-31G (d)//
RHF/3-21G method correctly predicts the predominate
regioisomer in all cases but one.
25i
a
b
RHF/3-21G//RHF/3-21G+ZPE (scaled by 0.8929). B3LYP/6-
31G(d)//RHF/3-21G+ZPE (scaled by 0.8929). c AM1//AM1 (no ZPE).
d
Exp er im en ta l Section
B3LYP/6-31G(d)//AM1 (no ZPE). Er ) Eproducts - Eseparated reactants
;
∆Hr ) ∆Hproducts - ∆Hseparated reactants
.
Melting points are uncorrected. Proton NMR spectra were
recorded at 300 MHz using tetramethylsilane as an internal
standard. Carbon NMR were recorded at 75 MHz using either
chloroform-d or dimethyl sulfoxide-d6 as an internal standard.
Carbon multiplicities were assigned by either DEPT experi-
ments or HETCORR experiments. Reported NMR data were
obtained in chloroform-d unless otherwise noted.
Chloro oximes 8 were prepared according to the literature
procedure8 from the corresponding oximes and NCS in DMF
at 0-20 °C for activated rings and at ∼45 °C for deactivated
rings and had physical properties identical to those reported.
The corresponding nitrile oxides were generated in situ by
dehydrohalogenation with triethylamine.
Gen er a l P r oced u r e for th e P r ep a r a tion of Cin n a -
m id es 9, Cr oton a m id es 14, or Acr yla m id es 17. To cin-
namoyl chloride, crotonyl chloride, or acryoyl chloride (15
mmol) in CH2Cl2 (50 mL) at 0 °C was added the appropriate
amine (30 mmol) in CH2Cl2 (50 mL) over 30 min. After being
stirred at room temperature for 2 h, the reaction mixture was
poured into 1 N HCl (50 mL) and extracted. The organic layer
was washed with water (50 mL), dried (MgSO4), filtered, and
evaporated. If necessary, the amides were purified by recrys-
tallization or column chromatography generally using ethyl
acetate/hexanes.
difficult since the corresponding differences in energies
is smaller than for the tertiary crotonamides which
exhibit a large preference for the 4-methyl isomer 25.
Table 5 gives the energies (ab initio and DFT) and
enthalpies of reaction for the cycloadditions. As expected
the reactions are very exothermic with the RHF/3-21G
giving higher Ers than the DFT and AM1 values.
Recently, Houk and co-workers published several
reports of the successful application of DFT, especially
the hybrid HF-DFT gradient corrected methods, to the
study of pericyclic reactions.18 On the basis of our
experimental results, we have shown that the B3LYP
energies with a moderately sized basis set using the RHF/
3-21G optimized geometries gives excellent estimates of
the ratios of regioisomers in the cycloaddition of ben-
zonitrile oxide with methyl acrylate (23a ), methyl cro-
tonate (23b), and various acrylamides and crotonamides.
Interestingly, the semiempirical AM1 method gives
significantly better results than the ab initio RHF/3-21G
method.
N,N-Dieth ylcin n a m id e (9e): mp ) 66.5-67.5 °C (white
needles from ether/hexanes) (lit.19 mp ) 68-69 °C).
P ip er id in ylcin n a m id e (9i): mp ) 114-116 °C (white
needles from ether/hexanes) (lit.19 mp ) 119-120 °C).
N-P h en ylcin n a m id e (9j): mp ) 168-172 °C (lit.20 mp )
174 °C).
Con clu sion s
Methyl cinnamate (9a ) and methyl crotonate (14a )
undergo a [3 + 2] cycloaddition reaction with phenyl
nitrile oxides to predominantly afford the 5-phenyl or the
5-methyl isoxazoline 10 or 15, respectively. However,
utilization of tertiary cinnamides or tertiary crotonamides
as the dipolarophile unexpectedly resulted in a reversal
of regioselectivity such that the 4-phenyl or 4-methyl
isoxazoline 11 or 16 is the major cycloadduct. The
primary or secondary cinnamides and crotonamides
produce the regioisomeric adducts with the same selec-
tivity as the parent ester, except for the secondary
anilides amides that yield approximately 1:1 ratios.
Interestingly, all acrylamides exhibit the same selectivity
as ethyl acrylate (17a ), yielding the 5-substituted isox-
azolines 19. These experimental results indicate that the
N-(4-Meth oxyp h en yl)cin n a m id e (9k ): mp ) 165-167 °C
(gray solid from EtOAc/hexanes) (lit.20 mp ) 185 °C).
N-(4-Nitr op h en yl)cin n a m id e (9m ): mp ) 216-219 °C
(yellow solid from EtOAc) (lit.21 mp ) 208 °C).
N-Meth yl-N-p h en ylcin n a m id e (9n ): mp ) 68-70 °C
(lit.22 mp ) 71.5-72.5 °C).
N-Cyclop en tylcin n a m id e (9o): mp ) 142-143 °C (lit.23
mp ) 145-146 °C).
N,N-Dim eth ylcin n a m id e (9r ): mp ) 91-93 °C (lit.24 mp
) 94-95 °C).
N,N-Dieth ylcr oton a m id e (14b): oil, ref 25.
(19) Delaney, A. D.; Currie, D. J .; Holmes, H. L. Can. J . Chem. 1969,
47, 3273.
(20) Fahmy, A. F.; Sayed, G. H.; Hamed, A. A. Ind. J . Chem. Soc. B
1978, 16B, 869.
(21) Yamaguchi, K. Nippon Kagaku Zasshi 1957, 78, 1236; Chem.
Abstr. 1958, 13540.
(22) Coates, R. M.; J ohnson, E. F. J . Am. Chem. Soc. 1971, 93, 4016.
(23) Currie, D. J .; Holmes, H. L. Can. J . Chem. 1970, 48, 1340.
(18) (a) Yoo, H. Y.; Houk, K. N. J . Am. Chem. Soc. 1997, 119, 2877.
(b) Wiest, O. Houk, K. N. Top. Curr. Chem. 1996, 183 (Density
Functional Theory IV), 1.

Dipolar Cycloaddition Reactions of Nitrile Oxides
J . Org. Chem., Vol. 63, No. 18, 1998 6325
N-P ip er id in ylcr oton a m id e (14c): oil, ref 26.
Calcd for C18H17NO4: C, 69.44; H, 5.50; N, 4.50. Found: C,
69.38; H, 5.43; N, 4.59.
N-Cyclop en tylcr oton a m id e (14e): mp ) 107-108 °C
(white solid from ether/hexanes); 1H NMR δ 6.82 (dq, J ) 15.0,
6.8 Hz, 1H), 5.76 (dq, J ) 15.0, 1.5 Hz, 1H), 5.41 (br s, 1H),
4.23-4.33 (m, 1H), 1.97-2.04 (m, 2H), 1.84 (dd, J ) 6.8, 1.5
Hz, 3H), 1.56-1.74 (m, 4H), 1.35-1.42 (m, 2H); IR 3265, 1623
cm-1; MS m/z 154 (MH+). Anal. Calcd for C9H15NO: C, 70.55;
H, 9.87; N, 9.14. Found: C, 70.18; H, 9.48; N, 8.97.
tr a n s-Meth yl 3-(4-Meth oxyp h en yl)-4,5-d ih yd r o-4-p h e-
n ylisoxa zole-5-ca r boxyla te (11c). This was isolated as a
mixture of 10c and 11c: 1H NMR δ 7.67 (d, J ) 8.7 Hz, 2H),
7.30-7.38 (m, 5H), 6.80 (d, J ) 8.7 Hz, 2H), 5.01 (d, J ) 4.0
Hz, 1H), 4.94 (d, J ) 4.0 Hz, 1H), 3.93 (s, 3H), 3.79 (s, 3H).
tr a n s-Meth yl 3-(3-n itr op h en yl)-4,5-d ih yd r o-5-p h en yl-
isoxa zole-4-ca r boxyla te (10d ) (70% yield both isomers; 88%
yield based on recovered starting material): mp ) 88-90.5
°C; 1H NMR δ 8.55 (t, J ) 2.1 Hz, 1H), 8.27 (ddd, J ) 8.1, 2.1,
1.0 Hz, 1H), 8.11 (ddd, J ) 8.1, 2.1, 1.0 Hz, 1H), 7.61 (t, J )
8.1 Hz, 1H), 7.34-7.44 (m, 5H), 6.10 (d, J ) 6.3 Hz, 1H), 4.51
(d, J ) 6.3 Hz, 1H), 3.81 (s, 3H); IR 1735 cm-1; MS m/z 327
(MH+), 221 (MH+ - PhCHO). Anal. Calcd for C17H14N2O5:
C, 62.58; H, 4.32; N, 8.58. Found: C, 62.55; H, 4.29; N, 8.97.
tr a n s-Meth yl 3-(3-n itr op h en yl)-4,5-d ih yd r o-4-p h en yl-
isoxa zole-5-ca r boxyla te (11d ): mp ) 123-124 °C; 1H NMR
δ 8.42 (t, J ) 2.2 Hz, 1H), 8.18 (ddd, J ) 8.1, 2.2, 1.0 Hz, 1H),
7.99 (ddd, J ) 8.1, 2.2, 1.0 Hz, 1H), 7.50 (t, J ) 8.1 Hz, 1H),
7.28-7.41 (m, 5H), 5.09 (d, J ) 4.4 Hz, 1H), 5.06 (d, J ) 4.4
Hz, 1H), 3.87 (s, 3H); IR 1743 cm-1; MS m/z 327 (MH+). Anal.
Calcd for C17H14N2O5: C, 62.58; H, 4.32; N, 8.58. Found: C,
62.77; H, 4.38; N, 8.62.
tr a n s-N,N-Diet h yl 3-(4-ch lor op h en yl)-4,5-d ih yd r o-5-
p h en ylisoxa zole-4-ca r boxa m id e (10e) (95% yield both iso-
mers): mp ) 123-124.5 °C; 1H NMR δ 7.54 (d, J ) 8.7 Hz,
2H), 7.33-7.52 (m, 7H), 5.73 (d, J ) 9.3 Hz, 1H), 4.64 (d, J )
9.3 Hz, 1H), 3.13-3.50 (3m, 4H), 1.14 (t, J ) 7.1 Hz, 3H), 0.96
(t, J ) 7.2 Hz, 3H); 13C NMR δ 167.7, 154.8, 138.6, 135.9, 129.1
(CH), 129.0 (CH), 128.9 (CH), 127.8 (CH), 127.5, 126.2 (CH),
89.0 (CH), 59.9 (CH), 42.3 (CH2), 40.9 (CH2), 14.5 (CH3), 12.6
(CH3); IR 2975, 1638, 1598 cm-1; MS m/z 357, 359 (MH+), 251,
253 (MH+ - PhCHO). Anal. Calcd for C20H21ClN2O2: C,
67.32; H, 5.93; N, 7.85. Found: C, 67.47; H, 5.91; N, 7.96.
tr a n s-N,N-Diet h yl 3-(4-ch lor op h en yl)-4,5-d ih yd r o-4-
p h en ylisoxa zole-5-ca r boxa m id e (11e): mp ) 116-118 °C;
1H NMR δ 7.53 (d, J ) 8.7 Hz, 2H), 7.25-7.35 (m, 7H), 5.64
(d, J ) 5.7 Hz, 1H), 5.12 (d, J ) 5.7 Hz, 1H), 3.38-3.50 (2m,
4H), 1.23 (t, J ) 7.1 Hz, 3H), 1.16 (t, J ) 7.1 Hz, 3H); 13C
NMR δ 166.2, 158.1, 138.2, 135.8, 129.3 (CH), 128.7 (CH),
128.6 (CH), 127.9 (CH), 127.8 (CH), 126.6, 87.3 (CH), 55.7
(CH), 41.9 (CH2), 40.6 (CH2), 14.2 (CH3), 12.5 (CH3); IR 2975,
1645, 1598 cm-1; MS m/z 357, 359 (MH+). Anal. Calcd for
2,2,6,6-Tetr am eth ylpiper idin ylcr oton am ide (14f): white,
waxy solid, mp ) 39-40 °C; 1H NMR δ 6.65 (dq, J ) 15.0, 6.8
Hz, 1H), 6.22 (dq, J ) 15.0, 1.5 Hz, 1H), 1.85 (dd, J ) 6.8, 1.5
Hz, 3H), 1.76 (s, 6H), 1.40-1.50 (br m, 12H); IR 1623 cm-1
;
MS m/z 210 (MH+). Anal. Calcd for C13H23NO: C, 74.59; H,
11.07; N, 6.69. Found: C, 74.49; H, 10.97; N, 6.62.
N,N-Dieth yla cr yla m id e (17b): oil, ref 27.
Gen er a l P r oced u r e for th e Cycloa d d ition Rea ction s.
To hydroximinoyl acid chloride 8 (10 mmol) and dipolarophile
9, 14, or 17 (8 mmol) in EtOAc (100 mL) was added triethy-
lamine (10 mmol) in EtOAc (25 mL) dropwise over a period of
30-45 min. The reaction was stirred at room temperature
overnight and then examined by TLC. Usually, for reactions
with cinnamides and crotonamides, the TLC indicated the
presence of starting olefin. An additional amount of hydrox-
iminoyl acid chloride 8 (10 mmol) was added, followed by the
dropwise addition of triethylamine (10 mmol) in EtOAc (25
mL). After being stirred overnight, the reaction mixture was
washed with water (3 × 200 mL), dried (MgSO4), filtered, and
evaporated. The ratio of cycloadducts was determined by
integration of H4 and H5 protons of each product in the crude
NMR. Most of the major isomer was isolated by fractional
recrystallization from EtOAc/hexanes or ether/hexanes. The
remaining mother liquor was chromatographed using 10-15%
EtOAc/hexanes to yield an additional amount of the major
isomer and the minor isomer.
tr a n s-Meth yl 3,5-d ip h en yl-4,5-d ih yd r oisoxa zole-4-ca r -
boxyla t e (10a ) (84% yield both isomers): mp ) 83-85 °C
1
(lit.4a mp ) 83-84 °C); H NMR δ 7.70-7.73 (m, 2H), 7.33-
7.41 (m, 8H), 5.98 (d, J ) 6.2 Hz, 1H), 4.46 (d, J ) 6.2 Hz,
1H), 3.77 (s, 3H); IR 3031, 2952, 1733 cm-1; MS m/z 282 (MH+),
176 (MH+ - PhCHO). Anal. Calcd for C17H15NO3: C, 72.58;
H, 5.37; N, 4.98. Found: C, 72.61; H, 5.39; N, 5.03.
tr a n s-Meth yl 3,4-d ip h en yl-4,5-d ih yd r oisoxa zole-5-ca r -
boxyla te (11a ): mp ) 106-109 °C (lit.4a mp ) 108-110 °C);
1H NMR δ 7.60-7.63 (m, 2H), 7.27-7.42 (m, 8H), 5.05 (d, J )
4.1 Hz, 1H), 4.97 (d, J ) 4.1 Hz, 1H), 3.84 (s, 3H); IR 2965,
1752 cm-1; MS m/z 282 (MH+). Anal. Calcd for C17H15NO3:
C, 72.58; H, 5.37; N, 4.98. Found: C, 72.61; H, 5.50; N, 5.15.
tr a n s-Meth yl 3-(4-ch lor op h en yl)-4,5-d ih yd r o-5-p h en yl-
isoxa zole-4-ca r boxyla te (10b) (85% yield both isomers): mp
C
20H21ClN2O2: C, 67.32; H, 5.93; N, 7.85. Found: C, 67.12;
H, 5.80; N, 7.61.
tr a n s-N,N-Dieth yl 3,5-d ip h en yl-4,5-d ih yd r oisoxa zole-
4-ca r boxa m id e (10f) (83% yield both isomers): mp ) 94-
96 °C; 1H NMR δ 7.58-7.63 (m, 2H), 7.33-7.43 (m, 8H), 5.74
(d, J ) 9.2 Hz, 1H), 4.68 (d, J ) 9.2 Hz, 1H), 3.10-3.54 (4m,
4H), 1.13 (t, J ) 7.1 Hz, 3H), 0.97 (t, J ) 7.2 Hz, 3H); IR 2976,
1626 cm-1; MS m/z 323 (MH+), 217 (MH+ - PhCHO). Anal.
Calcd for C20H22N2O2: C, 74.51; H, 6.88; N, 8.69. Found: C,
74.29; H, 6.82; N, 8.67.
1
) 87-88 °C; H NMR δ 7.65 (d, J ) 8.7 Hz, 2H), 7.34-7.42
(m, 7H), 6.00 (d, J ) 6.2 Hz, 1H), 4.43 (d, J ) 6.2 Hz, 1H),
3.78 (s, 3H); IR 2985, 1732 cm-1; MS m/z 316, 318 (MH+), 210,
212 (MH+ - PhCHO). Anal. Calcd for C17H14ClNO3: C, 64.67;
H, 4.47; N, 4.44. Found: C, 64.71; H, 4.67; N, 4.45.
tr a n s-N,N-Dieth yl 3,4-d ip h en yl-4,5-d ih yd r oisoxa zole-
tr a n s-Meth yl 3-(4-ch lor op h en yl)-4,5-d ih yd r o-4-p h en yl-
isoxa zole-5-ca r boxyla te (11b): mp ) 80-82 °C; 1H NMR δ
7.54 (d, J ) 8.7 Hz, 2H) 7.24-7.36 (m, 7H), 5.02 (d, J ) 4.3
Hz, 1H), 4.97 (d, J ) 4.3 Hz, 1H), 3.85 (s, 3H); 13C NMR δ
170.1, 157.2, 137.5, 136.3, 129.5 (CH), 128.9 (CH), 128.8 (CH),
128.4 (CH), 127.5 (CH), 126.5, 86.8 (CH), 58.0 (CH), 52.8 (CH3);
IR 2991, 1761 cm-1; MS m/z 316, 318 (MH+). Anal. Calcd for
1
5-ca r boxa m id e (11f): mp ) 118-119 °C; H NMR δ 7.60-
7.64 (m, 2H), 7.23-7.35 (m, 8H), 5.67 (d, J ) 5.6 Hz, 1H), 5.11
(d, J ) 5.6 Hz, 1H), 3.67 (q, J ) 7.1 Hz, 2H), 3.42 (q, J ) 7.1
Hz, 2H), 1.23 (t, J ) 7.1 Hz, 3H), 1.16 (t, J ) 7.1 Hz, 3H); IR
2969, 1644 cm-1; MS m/z 323 (MH+). Anal. Calcd for
C
20H22N2O2: C, 74.51; H, 6.88; N, 8.69. Found: C, 74.56; H,
6.88; N, 8.58.
C
17H14ClNO3: C, 64.67; H, 4.47; N, 4.44. Found: C, 64.61; H,
4.43; N, 4.46.
tr a n s-N,N-Dieth yl 3-(4-m eth oxyp h en yl)-4,5-d ih yd r o-5-
p h en ylisoxa zole-4-ca r b oxa m id e (10g) (40% yield both
tr a n s-Meth yl 3-(4-m eth oxyp h en yl)-4,5-d ih yd r o-5-p h e-
n ylisoxa zole-4-ca r b oxyla t e (10c) (64% yield both iso-
1
isomers): mp ) 107-108 °C; H NMR δ 7.54 (d, J ) 8.8 Hz,
2H), 7.35-7.41 (m, 5H), 6.88 (d, J ) 8.8 Hz, 2H), 5.72 (d, J )
9.2 Hz, 1H), 4.64 (d, J ) 9.2 Hz, 1H), 3.82 (s, 3H), 3.10-3.53
(4m, 4H), 1.14 (t, J ) 7.1 Hz, 3H), 0.96 (t, J ) 7.1 Hz, 3H); IR
2970, 1632 cm-1; MS m/z 353 (MH+), 247 (MH+ - PhCHO).
Anal. Calcd for C21H24N2O3: C, 71.57; H, 6.86; N, 7.94.
Found: C, 71.22; H, 6.72; N, 7.76.
1
mers): mp ) 80-81 °C; H NMR δ 7.65 (d, J ) 8.8 Hz, 2H),
7.32-7.38 (m, 5H), 6.91 (d, J ) 8.8 Hz, 2H), 5.95 (d, J ) 6.0
Hz, 1H), 4.43 (d, J ) 6.0 Hz, 1H), 3.83 (s, 3H), 3.77 (s, 3H); IR
1733 cm-1; MS m/z 312 (MH+), 206 (MH+ - PhCHO). Anal.
(24) Chan, S.O.; Wells, E. J . Can. J . Chem. 1967, 45, 2123.
(25) Tung, C. C.; Speziale, A. J . J . Org. Chem. 1964, 29, 1577.
(26) Mitsudo, T.; Suzuki, N.; Kondo, T.; Watanabe, Y. J . Org. Chem.
1994, 59, 7759.
tr a n s-N,N-Dieth yl 3-(4-m eth oxyp h en yl)-4,5-d ih yd r o-4-
p h en ylisoxa zole-5-ca r boxa m id e (11g): mp ) 85-86 °C; 1H
NMR δ 7.55 (d, J ) 8.9 Hz, 2H), 7.25-7.32 (m, 5H), 6.78 (d, J
) 8.9 Hz, 2H), 5.64 (d, J ) 5.6 Hz, 1H), 5.07 (d, J ) 5.6 Hz,
(27) Maier, L. Helv. Chim. Acta 1973, 56, 1252.

6326 J . Org. Chem., Vol. 63, No. 18, 1998
Weidner-Wells et al.
1H), 3.76 (s, 3H), 3.47 (q, J ) 7.1 Hz, 2H), 3.42 (q, J ) 7.1 Hz,
2H), 1.23 (t, J ) 7.1 Hz, 3H), 1.15 (t, J ) 7.1 Hz, 3H); IR 2973,
1645 cm-1; MS m/z 353 (MH+). Anal. Calcd for C21H24N2O3:
C, 71.57; H, 6.86; N, 7.95. Found: C, 71.60; H, 6.92; N, 7.99.
tr a n s-N,N-Dieth yl 3-(3-n itr op h en yl)-4,5-d ih ydr o-5-p h e-
n ylisoxa zole-4-ca r boxa m id e (10h ) (63% yield both iso-
mers): mp ) 124-125 °C; 1H NMR δ 8.18-8.28 (m, 3H), 7.60
(t, J ) 7.9 Hz, 1H), 7.40-7.45 (m, 5H), 5.80 (d, J ) 9.6 J z,
1H), 4.74 (d, J ) 9.6 Hz, 1H), 3.19-3.60 (3m, 4H), 1.16 (t, J )
7.1 Hz, 3H), 1.04 (t, J ) 7.2 Hz, 3H); IR 1638 cm-1; MS m/z
Anal. Calcd for C23H19ClN2O3: C, 67.90; H, 4.71; N, 6.89.
Found: C, 67.46; H, 4.81; N, 6.96.
tr a n s-N-(4-Meth oxyp h en yl) 3,5-d ip h en yl-4,5-d ih yd r o-
isoxa zole-4-ca r boxa m id e (10l) (88% yield both isomers): mp
) 166-167.5 °C; 1H NMR δ 7.77-7.82 (m, 2H), 7.30-7.47 (m,
11H), 6.83 (d, J ) 9.0 Hz, 2H), 6.02 (d, J ) 4.8 Hz, 1H), 4.40
(d, J ) 4.8 Hz, 1H), 3.77 (s, 3H); IR 3271, 1650 cm-1; MS m/z
373 (MH+), 267 (MH+
C
-
PhCHO). Anal. Calcd for
23H20N2O3: C, 74.18; H, 5.41; N, 7.52. Found: C, 73.94; H,
5.31; N, 7.43.
368 (MH+), 262 (MH+ - PhCHO). Anal. Calcd for C20H21
-
tr a n s-N-(4-Meth oxyp h en yl) 3,4-d ip h en yl-4,5-d ih yd r o-
isoxa zole-5-ca r boxa m id e (11l): mp ) 183-184 °C; 1H NMR
δ 8.46 (br s, 1H), 7.62-7.66 (m, 2H), 7.51 (d, J ) 9.1 Hz, 2H),
7.28-7.40 (m, 8H), 6.87 (d, J ) 9.1 Hz, 2H), 5.21 (d, J ) 3.3
Hz, 1H), 4.98 (d, J ) 3.3 Hz, 1H), 3.79 (s, 3H); IR 3352, 1677,
1513 cm-1; MS m/z 373 (MH+). Anal. Calcd for C23H20N2O3:
C, 74.18; H, 5.41; N, 7.52. Found: C, 74.04; H, 5.32; N, 7.51.
N3O4: C, 65.38; H, 5.76; N, 11.44. Found: C, 65.33; H, 5.71;
N, 11.80.
tr a n s-N,N-Dieth yl 3-(3-n itr op h en yl)-4,5-d ih ydr o-4-ph e-
n ylisoxa zole-5-ca r boxa m id e (11h ): mp ) 85-87 °C; 1H
NMR δ 8.48 (t, J ) 1.9 Hz, 1H), 8.15 (ddd, J ) 8.0, 1.9, 1.0
Hz, 1H), 7.91 (ddd, J ) 8.0, 1.9, 1.0 Hz, 1H), 7.46 (t, J ) 8.0
Hz, 1H), 7.28-7.42 (m, 5H), 5.68 (d, J ) 5.4 Hz, 1H), 5.20 (d,
J ) 5.4 Hz, 1H), 3.48 (q, J ) 7.1 Hz, 2H), 3.43 (q, J ) 7.1 Hz,
2H), 1.24 (t, J ) 7.1 Hz, 3H), 1.16 (t, J ) 7.1 Hz, 3H); IR 1645
cm-1; MS m/z 368 (MH+). Anal. Calcd for C20H21N3O4: C,
65.38; H, 5.76; N, 11.44. Found: C, 64.99; H, 5.75; N, 11.50.
tr a n s-1-[3-(4-Ch lor op h en yl)-4,5-d ih yd r o-5-p h en ylisox-
a zole-4-ca r bon yl]p ip er id in e (10i) (85% yield both iso-
mers): mp ) 128-130 °C; 1H NMR δ 7.55 (d, J ) 8.7 Hz, 2H),
7.34-7.42 (m, 7H), 5.70 (d, J ) 8.3 Hz, 1H), 4.75 (d, J ) 8.3
Hz, 1H), 3.65-3.80 (m, 1H), 3.45-3.55 (m, 1H), 3.32 (t, J )
5.5 Hz, 2H), 1.23-1.70 (m, 6H); IR 2968, 1628 cm-1; MS m/z
369, 371 (MH+), 263, 265 (MH+ - PhCHO). Anal. Calcd for
tr a n s-N-(4-Nitr op h en yl) 3-(4-ch lor op h en yl)-4,5-d ih y-
d r o-5-p h en ylisoxa zole-4-ca r boxa m id e (10m ) (66% yield
both isomers): mp ) 188-190 °C; 1H NMR δ 8.21 (d, J ) 9.2
Hz, 2H), 7.85 (br s, 1H), 7.66-7.74 (m, 5H), 7.36-7.44 (m, 6H),
6.04 (d, J ) 4.4 Hz, 1H), 4.44 (d, J ) 4.4 Hz, 1H); IR 3356,
1677 cm-1; MS m/z 422, 424 (MH+), 316, 318 (MH+ - PhCHO).
tr a n s-N-(4-Nitr op h en yl) 3-(4-ch lor op h en yl)-4,5-d ih y-
d r o-4-p h en ylisoxa zole-5-ca r boxa m id e (11m ): mp ) 169-
1
170.5 °C; H NMR δ 8.83 (br s, 1H), 8.25 (d, J ) 9.1 Hz, 2H),
7.81 (d, J ) 9.1 Hz, 2H), 7.56 (d, J ) 8.6 Hz, 2H), 7.28-7.41
(m, 7H), 5.19 (d, J ) 3.3 Hz, 1H), 5.04 (d, J ) 3.3 Hz, 1H); 13
C
NMR δ 168.9, 159.0, 144.0, 142.2, 136.9, 136.8, 129.5 (CH),
C
21H21ClN2O2: C, 68.38; H, 5.74; N, 7.59. Found: C, 68.50;
129.1 (CH), 128.8 (CH), 128.4 (CH), 127.2 (CH), 125.5, 125.0
H, 5.51; N, 7.33.
(CH), 119.4 (CH), 87.1 (CH), 58.2 (CH); IR 3359, 1694 cm-1
;
tr a n s-1-[3-(4-Ch lor op h en yl)-4,5-d ih yd r o-4-p h en ylisox-
a zole-5-ca r bon yl]p ip er id in e (11i): mp ) 163-165.5 °C; 1H
NMR δ 7.54 (d, J ) 8.7 Hz, 2H), 7.22-7.36 (m, 7H), 5.66 (d, J
) 5.6 Hz, 1H), 5.15 (d, J ) 5.6 Hz, 1H), 3.61-3.80 (m, 2H),
MS m/z 422, 424 (MH+). Anal. Calcd for C22H16ClN3O4 (was
performed on a mixture of both isomers): C, 62.64; H, 3.82;
N, 9.96. Found: C, 62.68; H, 3.77; N, 10.01.
tr a n s-N-Meth yl-N-p h en yl 3-(4-ch lor op h en yl)-4,5-d ih y-
d r o-5-p h en ylisoxa zole-4-ca r boxa m id e (10n ) (54% yield
both isomers): mp ) 178-179 °C; 1H NMR δ 7.50 (d, J ) 8.6
Hz, 2H), 7.37 (d, J ) 8.6 Hz, 2H), 7.16-7.36 (m, 8H), 6.80 (br
s, 2H), 5.81 (d, J ) 9.3 Hz, 1H), 4.46 (d, J ) 9.3 Hz, 1H), 3.31
(s, 3H); 13C NMR δ 168.6, 154.8, 142.1, 137.7, 135.9, 129.8
(CH), 129.0 (CH), 128.9 (CH), 128.7 (CH), 128.3 (CH), 127.8
(CH), 127.3, 126.8 (CH), 126.7 (CH), 89.2 (CH), 59.8 (CH), 38.0
(CH3); IR 1653 cm-1; MS m/z 391, 393 (MH+), 285, 287 (MH+
- PhCHO). Anal. Calcd for C23H19ClN2O2: C, 70.68; H, 4.90;
N, 7.17. Found: C, 70.53; H, 4.83; N, 7.13.
3.39-3.47 (m, 2H), 1.58-1.75 (m, 6H); IR 2948, 1647 cm-1
;
MS m/z 369, 371 (MH+). Anal. Calcd for C21H21ClN2O2: C,
68.38; H, 5.74; N, 7.59. Found: C, 68.56; H, 5.86; N, 7.51.
tr a n s-N-P h en yl 3-(4-ch lor op h en yl)-4,5-d ih yd r o-5-p h e-
n ylisoxa zole-4-ca r boxa m id e (10j) (54% yield both isomers;
71% based on recovered starting material): mp ) 244-245
°C; 1H NMR (DMSO-d6) δ 10.62 (br s, 1H), 7.73 (d, J ) 8.6
Hz, 2H), 7.29-7.57 (m, 11H), 7.09-7.12 (m, 1H), 5.92 (d, J )
7.0 Hz, 1H), 4.82 (d, J ) 7.0 Hz, 1H); 13C NMR (DMSO-d6) δ
165.9, 152.9, 138.8, 137.1, 134.5, 127.8 (CH), 127.7 (CH), 127.6
(CH), 127.5 (CH), 126.9 (CH), 126.3, 124.8 (CH), 123.1 (CH),
118.6 (CH), 87.0 (CH), 62.1 (CH); IR 3340, 1654 cm-1; MS m/z
377, 379 (MH+), 271, 273 (MH+ - PhCHO). Anal. Calcd for
tr a n s-N-Meth yl-N-p h en yl 3-(4-ch lor op h en yl)-4,5-d ih y-
d r o-4-p h en ylisoxa zole-5-ca r boxa m id e (11n ): mp ) 144-
1
145.5 °C; H NMR δ 7.48 (d, J ) 8.6 Hz, 2H), 7.08-7.37 (m,
C
22H17ClN2O2: C, 70.12; H, 4.55; N, 7.43. Found: C, 69.96;
12H), 5.36 (d, J ) 5.7 Hz, 1H), 4.84 (d, J ) 5.7 Hz, 1H), 3.34
(s, 3H); 13C NMR δ 167.7, 157.5, 142.1, 137.5, 135.7, 129.6
(CH), 129.1 (CH), 128.6 (CH), 128.4 (CH), 128.1 (CH), 127.8
(CH), 127.7 (CH), 127.4 (CH), 126.6, 85.7 (CH), 56.9 (CH), 38.2
(CH3); IR 1661 cm-1; MS m/z 391, 393 (MH+). Anal. Calcd
for C23H19ClN2O2: C, 70.68; H, 4.90; N, 7.17. Found: C, 70.51;
H, 4.75; N, 7.12.
H, 4.44; N, 7.33.
tr a n s-N-P h en yl 3-(4-ch lor op h en yl)-4,5-d ih yd r o-4-p h e-
n ylisoxa zole-5-ca r boxa m id e (11j): mp ) 163-165 °C; 1H
NMR δ 8.53 (br s, 1H), 7.55-7.62 (m, 4H), 7.27-7.39 (m, 9H),
7.15-7.17 (m, 1H), 5.19 (d, J ) 3.4 Hz, 1H), 5.01 (d, J ) 3.4
Hz, 1H); 13C NMR δ 168.2, 158.9, 137.4, 136.8, 136.7, 129.5
(CH), 129.1 (CH), 128.9 (CH), 128.4 (CH), 127.4 (CH), 125.9,
125.0 (CH), 119.8 (CH), 87.4 (CH), 58.3 (CH); IR 3354, 1683
cm-1; MS m/z 377, 379 (MH+), 256, 258 (MH+ - C(O)NHPh).
Anal. Calcd for C22H17ClN2O2: C, 70.12; H, 4.55; N, 7.43.
Found: C, 70.02; H, 4.43; N, 7.38.
tr a n s-N-(4-Meth oxyp h en yl) 3-(4-ch lor op h en yl)-4,5-d i-
h yd r o-5-p h en ylisoxa zole-4-ca r boxa m id e (10k ) (88% yield
both isomers): mp ) 222-224 °C; 1H NMR δ 7.72 (d, J ) 8.7
Hz, 2H), 7.25-7.40 (m, 10H), 6.84 (d, J ) 9.0 Hz, 2H), 6.02 (d,
J ) 5.0 Hz, 1H), 4.36 (d, J ) 5.0 Hz, 1H), 3.78 (s, 3H); IR
3269, 1653, 1513 cm-1; MS m/z 407, 409 (MH+), 301, 303 (MH+
- PhCHO). Anal. Calcd for C23H19ClN2O3: C, 67.90; H, 4.71;
N, 6.89. Found: C, 67.52; H, 4.81; N, 6.85.
tr a n s-N-Cyclop en tyl 3-(4-ch lor op h en yl)-4,5-d ih yd r o-5-
p h en ylisoxa zole-4-ca r b oxa m id e (10o) (79% yield both
1
isomers): mp ) 220-221 °C; H NMR δ 7.65 (d, J ) 8.5 Hz,
2H), 7.32-7.64 (m, 7H), 5.86 (d, J ) 5.4 Hz, 1H), 5.56 (br d, J
) 7.0 Hz, 1H), 4.15-4.24 (m, 1H), 4.20 (d, J ) 5.4 Hz, 1H),
1.87-2.02 (m, 2H), 1.51-1.62 (m, 4H), 1.17-1.39 (2m, 2H);
13C NMR δ 167.5, 154.4, 139.2, 136.7, 129.1 (CH), 128.8 (CH),
128.5 (CH), 128.1 (CH), 126.5, 125.1 (CH), 87.7 (CH), 64.1
(CH), 51.7 (CH), 32.7 (CH2), 23.4 (CH2); IR 3290, 2961, 1638
cm-1; MS m/z 369, 371 (MH+), 263, 265 (MH+ - PhCHO). Anal.
Calcd for C21H21ClN2O2: C, 68.38; H, 5.74; N, 7.59. Found:
C, 68.42; H, 5.79; N, 7.55.
tr a n s-N-Cyclop en tyl 3-(4-ch lor op h en yl)-4,5-d ih yd r o-4-
p h en ylisoxa zole-5-ca r boxa m id e (11o): mp ) 137.5-140 °C;
1H NMR δ 7.55 (d, J ) 8.7 Hz, 2H), 7.27-7.36 (m, 7H), 6.72
(br d, J ) 7.5 Hz, 1H), 5.10 (d, J ) 3.5 Hz, 1H), 4.85 (d, J )
3.5 Hz, 1H), 4.20 (sextet, J ) 7.5 Hz, 1H), 1.95-2.05 (m, 2H),
1.58-1.70 (m, 4H), 1.35-1.44 (m, 2H); IR 3306, 2962, 1667
tr a n s-N-(4-Meth oxyp h en yl) 3-(4-ch lor op h en yl)-4,5-d i-
h ydr o-4-ph en ylisoxazole-5-car boxam ide (11k): mp ) 155-
1
157 °C; H NMR δ 8.43 (br s, 1H), 7.56 (d, J ) 8.7 Hz, 2H),
7.50 (d, J ) 9.0 Hz, 2H), 7.27-7.39 (m, 7H), 6.87 (d, J ) 9.0
Hz, 2H), 5.19 (d, J ) 3.4 Hz, 1H), 5.00 (d, J ) 3.4 Hz, 1H),
3.79 (s, 3H); IR 3369, 1678, 1528 cm-1; MS m/z 407, 409 (MH+).

Dipolar Cycloaddition Reactions of Nitrile Oxides
J . Org. Chem., Vol. 63, No. 18, 1998 6327
cm-1; MS m/z 369, 371 (MH+). Anal. Calcd for C21H21
ClN2O2: C, 68.38; H, 5.74; N, 7.59. Found: C, 68.14; H, 5.77;
N, 7.40.
-
3H); 13C NMR δ 170.7, 159.5, 136.4, 129.2 (CH), 128.5 (CH),
126.2, 85.1 (CH), 52.8 (CH3), 46.7 (CH), 18.0 (CH3); IR 1740
cm-1; MS m/z 254, 256 (MH+). Anal. Calcd for C12H12ClNO3:
C, 56.82; H, 4.77; N, 5.52. Found: C, 56.68; H, 4.84; N, 5.48.
tr a n s-N,N-Dieth yl 3-(ch lor op h en yl)-4,5-d ih yd r o-5-m e-
th ylisoxa zole-4-ca r boxa m id e (15b) (86% yield both iso-
mers): mp ) 105-107 °C (white crystals from EtOAc/hexane);
1H NMR δ 7.53 (d, J ) 8.7 Hz, 2H), 7.33 (d, J ) 8.7 Hz, 2H),
4.91 (dq, J ) 7.4, 6.3 Hz, 1H), 4.27 (d, J ) 7.4 Hz, 1H), 3.30-
3.55 (m, 4H), 1.53 (d, J ) 6.3 Hz, 3H), 1.25 (t, J ) 7.2 Hz,
3H), 1.12 (t, J ) 7.2 Hz, 3H); 13C NMR δ 167.8, 154.8, 135.9,
129.0 (CH), 127.8 (CH), 126.0, 83.0 (CH), 58.7 (CH), 42.2 (CH2),
tr a n s-N-Cyclopen tyl 3,5-diph en yl-4,5-dih ydr oisoxazole-
4-ca r boxa m id e (10p ) (76% yield both isomers): mp ) 195-
197 °C; 1H NMR δ 7.71-7.75 (m, 2H), 7.29-7.47 (m, 8H), 5.88
(d, J ) 5.2 Hz, 1H), 5.58 (br d, J ) 6.9 Hz, 1H), 4.25 (d, J )
5.2 Hz, 1H), 4.16-4.23 (m, 1H), 1.84-2.04 (m, 2H), 1.45-1.62
(m, 4H), 1.17-1.38 (2m, 2H); IR 3263, 3076, 1641 cm-1; MS
m/z 335 (MH+), 229 (MH+ - PhCHO). Anal. Calcd for
C21H22N2O2: C, 75.42; H, 6.63; N, 8.38. Found: C, 75.17; H,
6.61; N, 8.26.
tr a n s-N-Cyclopen tyl 3,4-diph en yl-4,5-dih ydr oisoxazole-
40.9 (CH2), 20.7 (CH3), 14.9 (CH3), 12.7 (CH3); IR 1633 cm-1
;
5-ca r boxa m id e (11p ): mp ) 123-125 °C; H NMR δ 7.61-
MS m/z 295, 297 (MH+), 251, 253 (MH+ - MeCHO). Anal.
Calcd for C15H19ClN2O2: C, 61.12; H, 6.50; N, 9.50. Found:
C, 60.87; H, 6.22; N, 9.36.
1
7.64 (m, 2H), 7.27-7.35 (m, 8H), 6.75 (br d, J ) 6.0 Hz, 1H),
5.13 (d, J ) 3.4 Hz, 1H), 4.84 (d, J ) 3.4 Hz, 1H), 4.20 (sextet,
J ) 6.0 Hz, 1H), 1.95-2.06 (m, 2H), 1.55-1.68 (m, 4H), 1.32-
1.50 (m, 2H); IR 3359, 2964, 1667 cm-1; MS m/z 335 (MH+).
Anal. Calcd for C21H22N2O2: C, 75.42; H, 6.63; N, 8.38.
Found: C, 75.08; H, 6.68; N, 8.46.
tr a n s-N,N-Diet h yl 3-(4-ch lor op h en yl)-4,5-d ih yd r o-4-
1
m eth ylisoxa zole-5-ca r boxa m id e (16b): pale yellow oil; H
NMR δ 7.64 (d, J ) 8.5 Hz, 2H), 7.38 (d, J ) 8.5 Hz, 2H), 4.92
(d, J ) 5.3 Hz, 1H), 4.52 (dq, J ) 5.3, 7.3 Hz, 1H), 3.46-3.59
(m, 2H), 3.40 (q, J ) 7.1 Hz, 2H), 1.33 (d, J ) 7.3 Hz, 3H),
1.29 (t, J ) 7.1 Hz, 3H), 1.15 (t, J ) 7.1 Hz, 3H); 13C NMR δ
166.8, 160.9, 136.1, 129.1 (CH), 128.6 (CH), 126.8, 85.9 (CH),
44.1 (CH), 42.0 (CH2), 40.7 (CH2), 17.3 (CH3), 14.4 (CH3), 12.7
(CH3); IR 1645 cm-1; MS m/z 295, 297 (MH+). Anal. Calcd
for C15H19ClN2O2: C, 61.12; H, 6.50; N, 9.50. Found: C, 61.03;
H, 6.54; N, 9.11.
tr a n s-N-[3-(4-Ch lor op h en yl)-4,5-d ih yd r o-5-m eth ylisox-
a zole-4-ca r bon yl]p ip er id in e (15c) (83% yield both iso-
mers): mp ) 123-125 °C (off-white solid); 1H NMR δ 7.56 (d,
J ) 8.7 Hz, 2H), 7.35 (d, J ) 8.7 Hz, 2H), 4.90 (dq, J ) 7.1,
6.2 Hz, 1H), 4.35 (d, J ) 7.1 Hz, 1H), 3.45-3.66 (m, 4H), 1.45-
1.67 (m, 9H with a 3H doublet (J ) 6.2 Hz) at δ 1.52); 13C
NMR δ 166.8, 154.8, 136.0, 129.1 (CH), 127.8 (CH), 127.7, 82.6
(CH), 59.4 (CH), 46.9 (CH2), 43.8 (CH2), 26.6 (CH2), 25.5 (CH2),
24.3 (CH2), 20.9 (CH3); IR 1637 cm-1; MS m/z 307, 309 (MH+).
Anal. Calcd for C16H19ClN2O2: C, 62.64; H, 6.24; N, 9.13.
Found: C, 62.36; H, 6.29; N, 9.00.
tr a n s-N-[3-(4-Ch lor op h en yl)-4,5-d ih yd r o-4-m eth ylisox-
a zole-5-ca r bon yl]p ip er id in e (16c): clear oil; 1H NMR δ 7.64
(d, J ) 8.7 Hz, 2H), 7.38 (d, J ) 8.7 Hz, 2H), 4.95 (d, J ) 5.3
Hz, 1H), 4.55 (dq, J ) 5.3, 7.3 Hz, 1H), 3.70-3.77 (m, 2H),
3.33-3.53 (m, 2H), 1.57-1.72 (m, 6H), 1.33 (d, J ) 7.3 Hz,
3H); 13C NMR δ 165.7, 160.9, 136.1, 129.1 (CH), 128.5 (CH),
126.7, 85.8 (CH), 47.0 (CH2), 43.8 (CH2), 43.7 (CH), 26.5 (CH2),
25.5 (CH2), 24.5 (CH2), 17.3 (CH3); IR 1645 cm-1; MS m/z 307,
309 (MH+). Anal. Calcd for C16H19ClN2O2: C, 62.64; H, 6.24;
N, 9.13. Found: C, 62.57; H, 6.24; N, 9.13.
tr a n s-3-(4-Ch lor op h en yl)-4,5-d ih yd r o-5-m et h ylisox-
a zole-4-ca r boxa m id e (15d ) (65% yield of both isomers): mp
) 212-214 °C (white solid from EtOAC/hexanes); 1H NMR
(DMSO-d6) δ 7.96 (br s, 1H), 7.78 (br s, 1H), 7.66 (d, J ) 8.5
Hz, 2H), 7.54 (d, J ) 8.5 Hz, 2H), 4.83 (dq, J ) 7.0, 6.4 Hz,
1H), 4.19 (d, J ) 7.0 Hz, 1H), 1.38 (d, J ) 6.4 Hz, 3H); 13C
NMR (DMSO-d6) δ 170.3, 154.3, 134.4, 128.8 (CH), 128.1, 128.0
(CH), 82.8 (CH), 60.0 (CH), 20.4 (CH3); IR 3395, 3171, 1666
cm-1; MS m/z 239, 241 (MH+), 197, 197 (MH+ - MeCHO).
Anal. Calcd for C11H11ClN2O2: C, 55.36; H, 4.65; N, 11.74.
Found: C, 55.41; H, 4.64; N, 11.46.
tr a n s-3-(4-Ch lor op h en yl)-4,5-d ih yd r o-5-p h en ylisox-
a zole-4-ca r boxa m id e (10q) (80% yield both isomers): mp )
1
245-246 °C; H NMR (DMSO-d6) δ 7.99 (br s, 1H), 7.72 (d, J
) 8.6 Hz, 2H), 7.54 (d, J ) 8.6 Hz, 2H), 7.48 (br s, 1H), 7.37-
7.46 (m, 5H), 5.77 (d, J ) 7.4 Hz, 1H), 4.58 (d, J ) 7.4 Hz,
1H); 13C NMR (DMSO-d6) δ 171.7, 156.0, 141.4, 136.5, 130.7
(CH), 130.5 (CH), 130.3 (CH), 130.1 (CH), 129.3, 127.9 (CH),
89.3 (CH), 62.9 (CH); IR 3420, 3179, 1656 cm-1; MS m/z 301,
303 (MH+), 195, 197 (MH+ - PhCHO). Anal. Calcd for C16H13
-
ClN2O2: C, 63.90; H, 4.36; N, 9.31. Found: C, 63.59; H, 4.30;
N, 9.24.
tr a n s-3-(4-Ch lor op h en yl)-4,5-d ih yd r o-4-p h en ylisox-
a zole-5-ca r boxa m id e (11q): mp ) 163-165 °C; 1H NMR
(DMSO-d6) δ 7.71 (br s, 1H), 7.68 (d, J ) 8.6 Hz, 2H), 7.53 (br
s, 1H), 7.43 (d, J ) 8.6 Hz, 2H), 7.27-7.40 (m, 5H), 5.24 (d, J
) 4.2 Hz, 1H), 4.89 (d, J ) 4.2 Hz, 1H); 13C NMR (DMSO-d6)
δ 172.9, 159.3, 140.3, 136.7, 130.9 (CH), 130.8 (CH), 130.7
(CH), 129.5 (CH), 129.2 (CH), 128.4, 89.0 (CH), 58.2 (CH); IR
3453, 1678 cm-1; MS m/z 301, 303 (MH+). Anal. Calcd for
C
16H13ClN2O2: C, 63.90; H, 4.36; N, 9.31. Found: C, 63.86;
H, 4.38; N, 9.21.
tr a n s-N,N-Dim eth yl 3-(4-ch lor op h en yl)-4,5-d ih yd r o-5-
p h en ylisoxa zole-4-ca r boxa m id e (10r ) (85% yield both iso-
mers): mp ) 221-223 °C; 1H NMR δ 7.52 (d, J ) 8.6 Hz, 2H),
7.38-7.41 (m, 5H), 7.35 (d, J ) 8.6 Hz, 2H), 5.73 (d, J ) 8.4
Hz, 1H), 4.75 (d, J ) 8.4 Hz, 1H), 3.02 (s, 3H), 2.93 (s, 3H);
13C NMR δ 168.5, 154.6, 139.1, 136.1, 129.1 (CH), 129.0 (CH),
128.9 (CH), 127.9 (CH), 127.4, 126.0 (CH), 88.2 (CH), 60.3
(CH), 37.6 (CH3), 36.4 (CH3); IR 1646 cm-1; MS m/z 329, 331
(MH+). Anal. Calcd for C18H17ClN2O2: C, 65.78; H, 5.21; N,
8.52. Found: C, 65.38; H, 5.11; N, 8.43.
tr a n s-N,N-Dim eth yl 3-(4-ch lor op h en yl)-4,5-d ih yd r o-4-
p h en ylisoxa zole-5-ca r boxa m id e (11r ): mp ) 127-129 °C;
1H NMR δ 7.53 (d, J ) 8.7 Hz, 2H), 7.22-7.35 (m, 7H), 5.63
(d, J ) 5.6 Hz, 1H), 5.17 (d, J ) 5.6 Hz, 1H), 3.16 (s, 3H), 3.01
(s, 3H); 13C NMR δ 167.0, 158.2, 138.2, 136.0, 129.4 (CH), 128.8
(CH), 128.7 (CH), 128.0 (CH), 127.9 (CH), 126.7, 87.3 (CH),
55.6 (CH), 37.3 (CH3), 36.2 (CH3); IR 1652 cm-1; MS m/z 329,
331 (MH+). Anal. Calcd for C18H17ClN2O2: C, 65.78; H, 5.21;
N, 8.52. Found: C, 65.47; H, 5.24; N, 8.43.
tr a n s-3-(4-Ch lor op h en yl)-4,5-d ih yd r o-4-m et h ylisox-
a zole-5-ca r boxa m id e (16d ): mp ) 174-176 °C (white solid
tr a n s-Meth yl 3-(4-ch lor op h en yl)-4,5-d ih yd r o-5-m eth -
ylisoxa zole-4-ca r boxyla te (15a ) (65% yield both isomers):
1
from EtOAc/hexanes); H NMR (DMSO-d6) δ 7.74 (d, J ) 8.6
1
clear oil; H NMR δ 7.62 (d, J ) 6.5 Hz, 2H), 7.36 (d, J ) 6.5
Hz, 2H), 7.59 (br s, 1H), 7.52 (d, J ) 8.6 Hz, 2H), 7.42 (br s,
1H), 4.69 (d, J ) 4.4 Hz, 2H), 4.00 (dq, J ) 4.4, 7.2 Hz, 1H),
1.23 (d, J ) 7.2 Hz, 3H); 13C NMR (DMSO-d6) δ 171.9, 159.6,
134.9, 129.1 (CH), 128.8 (CH), 126.6, 85.7 (CH), 45.7 (CH), 17.9
(CH3); IR 3437, 3175, 1688 cm-1; MS m/z 239, 241 (MH+). Anal.
Calcd for C11H11ClN2O2: C, 55.36; H, 4.65; N, 11.74. Found:
C, 55.55; H, 4.75; N, 11.43.
Hz, 2H), 5.10 (quintet, J ) 6.3 Hz, 1H), 4.05 (d, J ) 6.3 Hz,
1H), 3.64 (s, 3H), 1.46 (d, J ) 6.3 Hz, 3H); 13C NMR δ 169.6,
152.8, 136.2, 129.1 (CH), 128.0 (CH), 127.3, 82.5 (CH), 59.8
(CH3), 53.0 (CH), 20.8 (CH3); IR 1740 cm-1; MS m/z 254, 256
(MH+), 210, 212 (MH+ - CH3CHO). Anal. Calcd for C12H12
-
ClNO3: C, 56.82; H, 4.77; N, 5.52. Found: C, 56.57; H, 4.80;
N, 5.61.
tr a n s-N-Cyclop en tyl 3-(4-ch lor op h en yl)-4,5-d ih yd r o-5-
m eth ylisoxa zole-4-ca r boxa m id e (15e) (69% yield of both
isomers): mp ) 198-200 °C (white solid); 1H NMR δ 7.68 (d,
J ) 8.6 Hz, 2H), 7.39 (d, J ) 8.6 Hz, 2H), 5.46-5.48 (br m,
1H), 4.99 (dq, J ) 4.3, 6.5 Hz, 1H), 4.10-4.19 (m, 1H), 3.86
(d, J ) 4.3 Hz, 1H), 1.81-1.98 (m, 2H), 1.51-1.59 (m, 4H),
tr a n s-Meth yl 3-(4-ch lor op h en yl)-4,5-d ih yd r o-4-m eth -
ylisoxa zole-5-ca r boxyla te (16a ): mp ) 66.5-68 °C (white
solid from EtOAc/hexanes); 1H NMR δ 7.62 (d, J ) 8.7 Hz,
2H), 7.38 (d, J ) 8.7 Hz, 2H), 4.80 (d, J ) 4.1 Hz, 1H), 3.95
(dq, J ) 4.1, 7.1 Hz, 1H), 3.80 (s, 3H), 1.41 (d, J ) 7.1 Hz,

6328 J . Org. Chem., Vol. 63, No. 18, 1998
Weidner-Wells et al.
1.41 (d, J ) 6.5 Hz, 3H), 1.26-1.34 (m, 1H), 1.13-1.18 (m,
1H); IR 3333, 1640 cm-1; MS m/z 307, 309 (MH+), 263 (MH+
- CH3CHO). Anal. Calcd for C16H19ClN2O2: C, 62.64; H, 6.24;
N, 9.13. Found: C, 62.24; H, 6.19; N, 8.91.
tr a n s-N-Cyclop en tyl 3-(4-ch lor op h en yl)-4,5-d ih yd r o-4-
m eth ylisoxa zole-5-ca r boxa m id e (16e): mp ) 135-136 °C
(light beige solid); 1H NMR δ 7.62 (d, J ) 8.4 Hz, 2H), 7.40 (d,
J ) 8.4 Hz, 2H), 6.67 (br d, J ) 6.9 Hz, 1H), 4.67 (d, J ) 3.4
Hz, 1H), 4.15-4.17 (m, 1H), 4.01 (dq, J ) 3.4, 7.3 Hz, 1H),
1.89-2.03 (m, 2H), 1.55-1.68 (m, 4H), 1.40 (d, J ) 7.3 Hz,
3H), 1.25-1.40 (m, 2H); IR 3330, 1643 cm-1; MS m/z 307, 309
(MH+). Anal. Calcd for C16H19ClN2O2: C, 62.64; H, 6.24; N,
9.13. Found: C, 62.28; H, 6.10; N, 8.97.
Gen er a l P r oced u r e for Con ver sion of Acid 12 (or 13)
in to Am id e 10 (or 11). Acid 12 (or 13) (∼0.50 mmol) and
carbonyldiimidazole (∼100 mg; 0.6 mmol) in anhydrous DMF
(3 mL) were stirred at room temperature for 2 h under a
nitrogen atmosphere. Either piperidine, p-methoxyaniline, or
cyclopentylamine (2-3 equiv) was added and the reaction
stirred at room temperature overnight. The reaction was
poured into water (30 mL) and extracted with EtOAc (2 × 25
mL). The combined organic layers were washed with water
(3 × 25 mL), dried (MgSO4), filtered, and evaporated. The
crude amides 10 (or 11) were purified by recrystallization. All
spectral data and physical properties were identical to those
of the amides prepared in the cycloaddition reaction.
tr a n s-N-[3-(4-Ch lor op h en yl)-4,5-d ih yd r o-4-m eth ylisox-
azole-5-car bon yl]-2,2,6,6-tetr am eth ylpiper idin e (16f) (74%
yield): mp ) 114-117 °C (white solid from EtOAc/hexanes);
1H NMR δ 7.61 (d, J ) 8.4 Hz, 2H), 7.37 (d, J ) 8.4 Hz, 2H),
5.08 (d, J ) 6.0 Hz, 1H), 4.07 (dq, J ) 6.0, 7.3 Hz, 1H), 1.76-
1.88 (m, 6H), 1.53 (s, 6H), 1.50 (s, 6H), 1.36 (d, J ) 7.3 Hz,
3H); IR 1637 cm-1; MS m/z 363, 365 (MH+). Anal. Calcd for
Com p u ta tion a l Deta ils
The programs GAUSSIAN-94 and SPARTAN 4.1 were used
for the ab initio and DFT calculations.28,29 The CAChe (v. 3.8)
worksystem30 was used for the AM1 calculations. Optimized
geometries were obtained at the AM1 and RHF/3-21G levels
of theory. All stationary points (minima and transition
structures) were characterized by calculation of their harmonic
vibrational frequencies at the corresponding level (AM1 or
RHF/3-21G). All minima had no negative eigenvalues of the
Hessian and no imaginary frequencies. All first-order saddle
points (transition structures) had one negative eigenvalue of
the Hessian and one imaginary frequency. Single-point ener-
gies were calculated using the Becke three-parameter hybrid
Hartree-Fock-DFT method31 with a 6-31G(d) basis set (un-
less noted otherwise). ZPE corrections scaled by 0.8929 were
applied to the RHF/3-21G calculated energies. RHF/3-21G
ZPE corrections (scaled by 0.8929) were also applied to the
B3LYP/6-31G(d)//RHF3-21G calculated energies. No ZPE
corrections were made to the AM1 calculated enthalpies of
formation.
C
20H27ClN2O2: C, 66.19; H, 7.50; N, 7.72. Found: C, 66.18;
H, 7.48; N, 7.51.
Eth yl 3-(4-ch lor op h en yl)-4,5-d ih yd r oisoxa zole-5-ca r -
boxyla te (19a ) (95% yield): mp ) 64-65.5 °C; 1H NMR δ
7.61 (d, J ) 8.6 Hz, 2H), 7.39 (d, J ) 8.6 Hz, 2H), 5.18 (dd, J
) 10.7, 7.7 Hz, 1H), 4.28 (q, J ) 7.2 Hz, 2H), 3.58-3.65 (m,
2H), 1.33 (t, J ) 7.2 Hz, 3H); IR 1753 cm-1; MS m/z 254, 256
(MH+). Anal. Calcd for C12H12ClNO3: C, 56.82; H, 4.77; N,
5.52. Found: C, 56.84; H, 4.54; N, 5.34.
N,N-Dieth yl 3-(4-ch lor op h en yl)-4,5-d ih yd r oisoxa zole-
5-ca r boxa m id e (19b) (83% yield): mp ) 110-112 °C; 1H
NMR δ 7.65 (d, J ) 8.6 Hz, 2H), 7.40 (d, J ) 8.6 Hz, 2H), 5.35
(dd, J ) 11.2, 7.9 Hz, 1H), 4.18 (dd, J ) 16.8, 7.9 Hz, 1H),
3.40-3.63 (2m, 4H), 3.34 (dd, J ) 16.8, 11.2 Hz, 1H), 1.29 (t,
J ) 7.1 Hz, 3H), 1.16 (t, J ) 7.1 Hz, 3H); IR 1637 cm-1; MS
m/z 281, 283 (MH+). Anal. Calcd for C19H17ClN2O2: C, 59.89;
H, 6.10; N, 9.98. Found: C, 59.51; H, 6.05; N, 9.84.
Ack n ow led gm en t. We wish to thank Dr. Dennis J .
Hlasta and Dr. William V. Murray from RWJ PRI and
Professor Dennis Liotta of Emory University for helpful
discussions and for critiquing the manuscript.
tr a n s-3-(4-Ch lor op h en yl)-4,5-d ih yd r o-5-p h en ylisox-
a zole-4-ca r boxylic Acid (12). 5-Phenyl ester 10b (11.76 g;
37.23 mmol) and NaOH (1N, 75 mL) in ethanol (100 mL) were
heated at reflux for 6 h (prolonged heating results in decar-
boxylation). After cooling, the ethanol was evaporated. The
residue was diluted with water (200 mL), cooled to 0 °C, and
acidified to pH ) 1 with concentrated HCl. A yellowish gum
formed, and the mixture was extracted with CH2Cl2 (3 × 250
mL). The combined organic layers were washed with water
(2 × 100 mL), dried (MgSO4), filtered, and evaporated to a pale
yellow powder (11.14 g, 99% yield): mp ) 124-125 °C; 1H
NMR (DMSO-d6) δ 13.50 (br s, 1H), 7.77 (d, J ) 8.7 Hz, 2H),
7.54 (d, J ) 8.7 Hz, 2H), 7.36-7.43 (m, 5H), 5.97 (d, J ) 6.1
Hz, 1H), 4.82 (d, J ) 6.1 Hz, 1H); IR 2800-3200 (br), 1698
cm-1; MS m/z 302, 304 (MH+), 258, 260 (MH+ - CO2H), 196,
198 (MH+ - PhCHO). Anal. Calcd for C16H12ClNO3: C, 63.69;
H, 4.01; N, 4.64. Found: C, 63.81; H, 3.82; N, 4.60.
tr a n s-3-(4-Ch lor op h en yl)-4,5-d ih yd r o-4-p h en ylisox-
a zole-5-ca r boxylic a cid (13) was prepared as above using
ester 11b (snow-white crystals, 79% yield) for acid 12. 13: mp
) 188-190 °C (EtOAc/hexanes); 1H NMR (DMSO-d6) δ 13.40
(br s, 1H), 7.67 (d, J ) 8.7 Hz, 2H), 7.42 (d, J ) 8.7 Hz, 2H),
7.24-7.40 (m, 5H), 5.32 (d, J ) 4.3 Hz, 1H), 5.01 (d, J ) 4.3
Hz, 1H); IR 2800-3200 (br), 1737 cm-1; MS m/z 302, 304
(MH+). Anal. Calcd for C16H12ClNO3: C, 63.69; H, 4.01; N,
4.64. Found: C, 63.58; H, 3.98; N, 4.53.
Su p p or tin g In for m a tion Ava ila ble: The Cartesian co-
ordinates for starting materials, transition structures, and
product geometries as well as the corresponding energies (90
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O9807621
(28) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Gill, P. M. W.;
J ohnson, B. G.; Robb, M. A.; Cheeseman, J . R.; Keith, T.; Petersson,
G. Al-Laham, M. A.; Zakrzewski, V. G.; Ortiz, J . V.; Foresman, J . B.;
Cioslowski, J .; Stefanov, B. B.; Nanayakkara, A.; Challacombe, M.;
Peng, C. Y.; Ayala, P. Y.; Chen, W.; Wong, M. W.; Andres, J . L.;
Replogle, E. S.; Gomperts, R.; Martin, R. L.; Fox, D. J .; Binkley, J . S.;
Defrees, D. J .; Baker, J .; Stewart, J . P.; Head-Gordon, M.; Gonzalez,
C.; Pople, J . A. Gaussian 94, Revision E.1; Gaussian, Inc.: Pittsburgh,
PA, 1995.
(29) SPARTAN (v. 4.1), Wavefunction, Inc., Irvine, CA.
(30) CAChe Scientific, Oxford Molecular, Beaverton, OR.
(31) Becke, A. D. J . Chem. Phys. 1993, 98, 5648.