Synthesis of isoxazoline N -oxides via [hydroxy(tosyloxy)iodo]benzene (HTIB)-mediated oxidative N-O coupling

Article abstract of DOI:10.1021/jo1018393

An HTIB mediated oxidative N-O coupling strategy for the synthesis of some isoxazoline N-oxide derivatives from β-hydroxyketoximes is described, along with a comparative study of the efficiency of N-O coupling in two different solvents. A plausible mechanism for the conversion is proposed.

Full text of DOI:10.1021/jo1018393

pubs.acs.org/joc
Synthesis of Isoxazoline N-Oxides via [Hydroxy(tosyloxy)iodo]benzene
(HTIB)-Mediated Oxidative N-O Coupling
Mustafa J. Raihan, Veerababurao Kavala, Pateliya Mujjamil Habib, Qiao-Zhi Guan,
Chun-Wei Kuo, and Ching-Fa Yao*
Department of Chemistry, National Taiwan Normal University, 88, Sec. 4, Tingchow Road, Taipei,
Taiwan 116, Republic of China
cheyaocf@ntnu.edu.tw
Received September 17, 2010
An HTIB mediated oxidative N-O coupling strategy for the synthesis of some isoxazoline N-oxide
derivatives from β-hydroxyketoximes is described, along with a comparative study of the efficiency of
N-O coupling in two different solvents. A plausible mechanism for the conversion is proposed.
Introduction
On the other hand, despite the immense synthetic and
medicinal utility of oxa-aza heterocycles with N-O bonds,
methods for producing a bond between nitrogen and oxygen
atoms remain limited.2 Examples of N-O bond formation in
the literature involve either the displacement of a leaving group,
attached to nitrogen, in an SN2 reaction2a or the oxidation of
2-aminoacetophenone,2e 2-hydroxyacetophenoneoxime,3 and
glyoxime2b,c derivatives. Among these, the oxidation of 2-hy-
droxyacetophenoneoxime and glyoxime derivatives is the more
frequently utilized method, primarily because the starting ma-
terials are readily accessible.2b,c,3 However, in many instances,
the oxidation of oximes is accompanied by deoximation.4 As a
result, the selection of a suitable reagent and conditions that
The longstanding goal of “on water” organic transforma-
tions, as an economic and environmentally friendly protocol,
has been utilized to produce a diverse array of pharmaceu-
tically active and synthetically useful substances.1 The pro-
tocol eliminates the difficulties associated with the workup
procedures that arise when homogeneous media are involved
and also enhances the rate and selectivity of the reactions.1c
It is generally believed and has been proven in some situa-
tions that a homogeneous medium is the optimal system for
chemical transformations. Notwithstanding the possible use
of toxic organic solvents, a homogeneous medium is the most
frequently utilized medium in organic synthesis.
(1) For selected recent publications, see: (a) Zheng, Z.; Perkins, B. L.; Ni,
B. J. Am. Chem. Soc. 2010, 132, 50. (b) Duplais, C.; Krasovskiy, A.;
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Soc. 2006, 128, 9687. (c) Nath, U.; Das, S. S.; Deb, D.; Das, P. J. New J.
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424 J. Org. Chem. 2011, 76, 424–434
Published on Web 12/22/2010
DOI: 10.1021/jo1018393
r
2010 American Chemical Society

Raihan et al.
JOCArticle
new source of starting materials and a more diverse protocol
is needed. In this context, β-hydroxy ketoxime derivatives
have the potential to serve as ideal alternative synthons for
accessing five-membered cyclic nitronates, since they are
readily obtained from β-hydroxy ketones.6 Although proto-
cols for the synthesis of chiral and achiral derivatives of these
ketones have been extensively explored in the literature,7,8 to
the best of our knowledge, they have not been applied to
access isoxazoline N-oxides. On the other hand, previous
studies reported on the synthesis of benzoisoxazole N-oxide
derivatives from 2-hydroxyacetophenone oximes used either
Pb(OAc)4 or NaBO3.3 The limitation associated with Pb-
(OAc)4 is that it is a toxic reagent.11a In the case of NaBO3,
the product yield is poor at room temperature and glacial
acetic acid is typically used as the solvent.3b One more
notable fact is that, in spite of the multifarious utilities of
the nitro group as a functional group,9 isoxazoline N-oxide
derivatives with nitro functionalities have not been exten-
sively explored. Furthermore, to our knowledge, no general
protocol is available in the literature for accessing both
isoxazoline N-oxides and benzoisoxazole N-oxides.
Keeping all these facts in view, in a continuation of our
ongoing project on the development of green synthetic
protocols based on “on water” concepts,10 we wish to report
herein on the first HTIB-mediated oxidative N-O coupling
strategy, leading to the synthesis of both isoxazoline N-oxide
and benzoisoxazole N-oxide derivatives. In addition, we also
report on a comparative study of the efficiency of N-O
coupling in two different media. It is noteworthy that, as an
oxidizing agent, HTIB has a diverse array of applications in
synthetic chemistry.4d,e,10a,11
FIGURE 1. Applications of isoxazoline N-oxides.
permit the oxidation of oximes to be controlled in favor of N-O
bond formation can be a challenge.
In the family of 2,1-oxa-aza heterocycles, isoxazoline
N-oxides are well-known precursors in the synthesis of a variety
of organic compounds of biomedical and synthetic importance
(Figure 1).5 Synthetic applications cover areas that include the
synthesis of bicyclic isoxazolines, isoxazolines, amino alcohols,
amino acids, and clausenamide derivatives and the asymmetric
synthesis of carbanucleosides.5 In addition, Ioffe and co-workers
recently reported on the C-C coupling of isoxazoline N-oxide
derivatives with silyl ketene acetals.5d
In spite of this, only nitroalkanes and nitroalkenes have
been utilized as sources of these five-membered nonaromatic
nitronates during the past few decades.5 A wide variety of
methods for preparing chiral and achiral isoxazoline N-oxide
derivatives from these precursors have been documented in
the literature.5 However, all of these protocols involve the
use of various organic solvents. Moreover, since the starting
materials are similar, the scope of the reaction is limited.
Hence, to introduce further diversity and expand this area, a
Results and Discussion
We recently reported on the HTIB-mediated rapid and mild
“on water” oxidation of 2-allyloxy and 2-propargyloxy aldox-
imes in preparing chromeno isoxazoles and isoxazolines.10a At
the same time, Patel et al. disclosed a protocol for the oxidation
of aldoximes to N-hydroxyamides using the same λ3-iodane.11a
In the two instances, the substrates have two different environ-
ments around the in situ formed nitrile oxide moiety. In our case,
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A. S.; Khomutova, Y. A.; Ioffe, S. L.; Tartakovsky, V. A. Eur. J. Org. Chem.
2009, 3066. (e) Zhu, C.-Y.; Deng, X.-M.; Sun, X.-L.; Zheng, J.-C.; Tang, Y.
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J. Org. Chem. Vol. 76, No. 2, 2011 425

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TABLE 1. Optimization of the Reaction with Various Solvents and
Reagents
was characterized by H NMR, 13C NMR, DEPT-135, mass
spectral analysis, and elemental analysis. The structure was
confirmed by single-crystal X-ray analysis (Figure 2a and the
Supporting Information), which showed that the N2-O4 bond
length is almost equal to the N-O bond length of a nitro group,
whereas the N2-O3 bond is longer than N2-O4. The 1HNMR
spectrum (Figure 1b) of the compound showed splitting of the
benzylic proton (H1; Figure 2c) due to both allylic coupling and
long-range coupling, as evidenced by COSY and HMQC
(Supporting Information).
In general, most organic reactions proceed efficiently in a
homogeneous medium.1c Hence, in order to compare the
efficacy of our reaction in different types of homogeneous and
heterogeneous media, we ran the reactions in various organic
solvents in addition to water (Table 1). For this purpose, we
used nonpolar (CH2Cl2, toluene, diethyl ether) as well as polar
aprotic (DMF, acetonitrile, THF) and polar protic (methanol,
ethanol, tert-butyl alcohol) solvents. Poor yields were obtained
in all of the nonpolar solvents (entries 1-3). However, when
polar aprotic solvents were used, moderate yields were obtained
(entries 4-6). Polar protic solvents were found to be the most
effective for this conversion (entries 7-10). Water and methanol
produced comparable yields (entries 7 and 10). From a mecha-
nistic viewpoint (Scheme 5), the solvent effect can be explained by
considering the fact that more polar and coordinating solvents
provide better stabilization of the in situ formed hydroxy-
(phenyl)iodonium ion (PhIþOH) via coordination (Scheme 1).
1
entry
solvent
reagenta
HTIB
HTIB
HTIB
HTIB
HTIB
HTIB
HTIB
HTIB
HTIB
HTIB
CAN
chloramine-T
iodine
H2O2
NaOCl
DIB
DIB/CF3COOH
DMP
time (h)
yield (%)b
1
2
3
toluene
CH2Cl2
Et2O
0.50
0.50
0.50
0.50
0.50
0.50
0.50
0.50
0.50
0.75
24
24
24
24
24
24
1
1.5
25
33
18
44
52
77
88
75
81
87
4
5
6
CH3CN
DMF
THF
7
8
9
MeOH
EtOH
t-BuOH
H2O
H2O
H2O
H2O
H2O
H2O
H2O
10
11c
12c
13c
14c
15d
16c
17
18
18
H2O
H2O
55
trace
a1.1 equiv of reagent was used. bIsolated yields. cStarting material was
recovered. d2.5 equiv of NaOCl was used.
the resulting nitrile oxide underwent an intramolecular [3 þ 2]
cycloaddition due to the presence of a neighboring dienophile.
However, in the case of Patel et al., the attack of an external
nucleophile occurred on a similar unstable intermediate due to
the absence of a neighboring dienophile. Moreover, with respect
to hypervalent iodine mediated N-X (X = N, C) bond
formation, Dong et al. reported on the oxidative cyclization of
1-carbamoyl-1-oximoylcycloalkanes in the design of spiro-fused
pyrazolin-5-one N-oxides (N-N bond formation)12a and Ag-
garwal et al. synthesized 2,4-diphenylquinoxaline-1-oxides from
benzyl-R-arylimino oximes (N-C bond formation).12b Intri-
gued by these reports, we anticipated the formation of five-
membered cyclic nitronates from various β-hydroxyketoximes
via oxidative N-O coupling.
In our attempts to prepare the desired N-oxides, our efforts
started with 2-(hydroxy(2-nitrophenyl)methyl)cyclohex-2-en-
one oxime (1; Table 1), derived from the corresponding Baylis-
Hillman adduct (BHA). We tested our assumption by treating
this β-hydroxy ketoxime (1; Table 1) with HTIB under on water
conditions and found that the five-membered cyclic nitronate
was formed in excellent yield (entry 10, Table 1). The product
SCHEME 1. Coordination of the Solvent Molecule at the Cat-
ionic Center of the Active Species
After choosing suitable solvents, we examined a series of mild,
moderate, and strong oxidizing agents in order to find a better
alternative to HTIB (Table 1). Among the oxidants tested,
CAN, chloramine-T, iodine, H2O2, and DIB proved to be
ineffective for this transformation (entries 11-14 and 16).
However, a poor yield of the desired N-oxide was obtained with
NaOCl (entry 15). On the other hand, in the presence of a
catalytic amount of trifluoroacetic acid, DIB produced the
isoxazoline N-oxide 1a in moderate yield (entry 17). Only trace
amounts of the desired product were obtained when DMP was
used (entry 18). On the basis of these results, we concluded that
HTIB was the optimal oxidant for this conversion.
FIGURE 2. (a) Crystal structure, (b) 1H NMR, and (c) type of coupling in the 1H NMR of 1a.
426 J. Org. Chem. Vol. 76, No. 2, 2011

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TABLE 2. Synthesis of Various Carbocycle Fused Isoxazoline
N-Oxides from Oximes of the Baylis-Hillman Adducts
TABLE 3. Synthesis of Various Carbocyclic Fused Isoxazoline
N-Oxides from Oximes of Aldol Adducts
aReactions performed on a 1.0 mmol scale. bIsolated yield. c17% of
starting material was recovered with water. dWith water, the starting
e
material was recovered. With MeOH, 10% of β-hydroxy ketone was
formed via deoximation. With H2O, 14% of the starting material was
recovered.
With the optimized conditions in hand, we explored the
scope and limitations of our methodology. In this regard, we
first focused on oximes derived from Baylis-Hillman adducts
(BHAs) (Table 2). The corresponding BHAs were synthesized
from substituted or unsubstituted benzaldehydes and different
cyclic or acyclic ketones, as previously reported in the litera-
ture.13 In the course of the experiments, we found that the
reaction yield varies with the nature of the substituent on the
benzene ring, when cyclohex-2-enone oxime derivatives were
subjected to HTIB treatment in two different media (entries
1-5). In the homogeneous medium, the presence of a strongly
electron withdrawing group such as a nitro group resulted in the
formation of the corresponding isoxazoline N-oxide derivatives
in good yields (entries 1 and 2). Unsubstituted as well as mildly
electron withdrawing halide-substituted ketoximes produced
moderate yields of the expected product (entries 3-5). Under
“on water” conditions, the efficiencies of the reactions were
comparable to those for an organic medium in cases of nitro-
substituted and unsubstituted ketoximes (entries 1 and 5).
However, it is surprising that reactions with halide-substituted
ketoximes failed to produce the desired product under “on
water” conditions and the starting materials were recovered
(entries 3 and 4). While the cyclopent-2-enone oxime derivative
aReactions performed on a 0.5 mmol scale. bIsolated yield. cWith
MeOH, 76% of the corresponding β-hydroxyketone was formed via
deoximation. With H2O, 44% of the starting material was recovered.
dWith water, starting material was recovered.
was converted into the corresponding β-hydroxy ketones via
deoximation in methanol and under “on water” conditions, no
conversion was detected (entry 6). On the other hand, the
reactions of acyclic ketoxime produced a moderate yield of
the product in both methanol and water (entry 7).
Encouraged by the successful syntheses of isoxazoline
N-oxides from various oximes of Baylis-Hillman adducts,
we turned our attention to ketoximes, produced from aldol
adducts (Scheme 2). In this particular scheme, our goals were
the synthesis of different carbocycle fused isoxazoline N-
oxide derivatives and the study of the influence of ring size
and stereochemistry on N-O coupling. In this regard, we
followed the corresponding literature citations in preparing
(12) (a) Wang, K.; Fu, X.; Liu, J.; Liang, Y.; Dong, D. Org. Lett. 2009, 11,
1015. (b) Aggarwal, R.; Sumran, G.; Saini, A.; Singh, S. P. Tetrahedron Lett.
2006, 47, 4969.
(13) (a) Luo, S.; Wang, P. G.; Cheng, J.-P. J. Org. Chem. 2004, 69, 555. (b)
Shi, M.; Jiang, J.-K.; Li, C.-Q. Tetrahedon Lett. 2002, 43, 127.
J. Org. Chem. Vol. 76, No. 2, 2011 427

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SCHEME 2. Synthetic Strategy for β-Hydroxyketoximes via an Aldol Reaction
TABLE 4. Synthesis of 3,5-Disubstituted Isoxazoline N-Oxides from
Oximes of Aldol Adducts
the aldol adducts from m-nitrobenzaldehyde and different
cyclic ketones to produce a mixture of two diastereomers.14b
These isomers were separated by silica gel column chromatog-
raphy, and the corresponding ketoximes were then synthesized
(Scheme 2 and also the Supporting Information).
The aldol ketoximes were reacted under optimized reac-
tion conditions in both water and methanol, and the results
are shown in Table 3. Here, it is noteworthy that, irrespective
of ring size, the anti diastereomers were more prone to
undergo cyclization than the syn diastereomers. In homo-
geneous medium (methanol solvent) with cyclohexanone
oxime derivatives, the anti diastereomer produced a poor
yield of the expected product (entry 1), while the syn diaste-
reomer failed to form the desired N-oxide (entry 2). A better
result was obtained with the anti isomer when the reaction
was carried out under “on water” conditions (entry 1). Under
these conditions, the desired product was formed, even in
the case of the syn isomer (entry 2). On the other hand, the
reaction of the anti isomer of the cycloheptanone oxime
derivative produced the corresponding isoxazoline N-oxide
in excellent yield in both methanol and water (entry 3).
However, the syn isomer afforded the cycloheptane fused
five-membered cyclic nitronate in lower yield with water
than with methanol (entry 4). The reaction of cyclooctanone
oxime derivatives resulted in an outcome that was different
from those for the other cyclic ketoximes. In methanol, an
excellent yield of the N-oxide was obtained from the anti
isomer (entry 5), while under “on water” conditions a good
yield of the desired product was obtained from the syn
isomer (entry 6). It is noteworthy that our protocol was even
suitable for preparing an isoxazoline N-oxide fused with a
cyclododecane moiety (entries 7 and 8). Here, methanol was
a superior solvent, in comparison to water. The syn and anti
diastereomers of an isoxazoline N-oxide fused with cyclo-
heptane (10a and 11a) and cyclododecane (14a and 15a)
moieties were characterized by single-crystal X-ray analysis
(Supporting Information). A close look at the data revealed
that the N-O bonds of the isoxazoline ring of the syn
isomers is longer than the corresponding bonds for the anti
isomers. Presumably, due to the longer bond lengths, the syn
isomers were less efficient toward N-O coupling than the
anti isomers. In addition to the 3-nitro derivatives, the
aReactions performed on a 1.0 mmol scale. bIsolated yields. cDeoxima-
tion: 16% with MeOH and 19% with water. dDeoximation: 19% with
MeOH and 21% with water. 22% of the starting materials was recovered
f
with water. e25% of the starting material was recovered with water. 23%
deoximation with water. The starting material was recovered with methanol.
desired isoxzoline N-oxides were obtained in good to ex-
cellent yields from the 4-nitro derivatives (entries 9 and 10).
After successfully accomplishing the preparation of car-
bocycle fused isoxazoline N-oxides from oximes of various
aldol adducts of cyclic ketones, we focused our attention on
aldol adducts, generated from acyclic ketones (Table 4).14a In
this category, although the phenyl derivatives underwent
efficient cyclization in methanol, the reactions were less
efficient in water (entries 1-3). Notably, the reactions of
ketoximes, generated from acetone, resulted in the formation
of substantial amounts of β-hydroxy ketone via deoximation
(entries 1 and 2). This can be attributed to the presence of a
sterically less hindered carbonyl center. Under these circum-
stances, an external nucleophile (solvent) competes with the
(14) (a) Chimni, S. S.; Mahajan, D. Tetrahedron 2005, 61, 5019. (b)
Dimmock, J. R.; Jha, A.; Kumar, P.; Zello, G. A.; Quail, J. W.; Oloo,
E. O.; Oucharek, J. J.; Pasha, M. K.; Seitz, D.; Sharma, R. K.; Allen, T. M.;
Santos, C. L.; Manavathu, E. K.; Clercq, E. D.; Balzarini, J.; Stables, J. P.
Eur. J. Med. Chem. 2002, 37, 35.
428 J. Org. Chem. Vol. 76, No. 2, 2011

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TABLE 5. Synthesis of 4-Methylene Isoxazoline N-Oxide Derivatives
FIGURE 3. Crystal structure of 23a.
TABLE 6. Synthesis of Benzoisoxazole N-Oxides
aReaction performed on a 0.5 mmol scale. bIsolated yields. cWith
water, 19% of the starting material was recovered.
neighboring group. However, the outcome was interesting in
the case of a pyridine derivative (entry 4). Although the
reaction failed with methanol, the expected nitronate was
obtained in water. In this case, the oxime was solubilized in
water after addition of the reagent. The overall result could
be explained by considering the fact that water is a better
proton donor than methanol.15 Hence, water would proton-
ate the pyridine, thus preventing the N center of pyridine
from coordinating with hydroxy(phenyl)iodonium ion
(PhIþOH).
Except for 9a and 21a, the isoxazoline N-oxide derivatives
described here are stable in air and moisture. However, even
on storage in a refrigerator (at 4 °C), compounds 9a and 21a
decomposed to the corresponding β-hydroxy ketones.
At this point, the oxidative N-O coupling reactions have
been confined to β-hydroxy ketoximes, containing a steri-
cally crowded hydroxyl group (Tables 2-4). To observe the
effect of the environment at the hydroxyl counterpart, we
used primary hydroxyl containing ketoximes in the N-O
coupling reaction (Table 5). We prepared 2-acetylcinnamyl
alcohol derivatives,16 and the corresponding ketoximes were
then synthesized (Supporting Information). These ketoximes
were then subjected to HTIB treatment in water and metha-
nol (Table 5). The results for methanol were excellent in all of
the cases (entries 1-4). These efficient N-O couplings are
due to the presence of sterically less crowded primary alcohol
moieties as the neighboring group. Under “on water” con-
ditions, the outcome was comparable to the results for
methanol in cases of mononitro-substituted derivatives
(entries 1 and 4). In water, however, the halo-substituted
ketoximes were found to be less efficient toward the cycliza-
tion than the others (entries 2 and 3). The isoxazoline
aReaction performed on a 1.0 mmol scale. bIsolated yields.
counterparts of these types of molecules have already been
reported,17 but to the best of our knowledge the N-oxide
derivatives are the new entities in the isoxazoline N-oxide
family. The structure of compound 23a was confirmed by
single-crystal X-ray analysis (Figure 3).
In addition to isoxazoline N-oxide derivatives, our proto-
col has also proved to be suitable for the synthesis of
benzoisoxazole N-oxide derivatives (Table 6). Various 2-hy-
droxyacetophenone oximes underwent smooth cyclization
with good yields in both water and methanol (entries 1-3). A
substrate with an electron-donating group (entry 2) pro-
duced lower yields than a substrate with an electron-with-
drawing group (entry 3).
The effect of medium appeared to be more important in
the case of a bis-oxime (29; Scheme 3). Here, methanol, being
a better nucleophile than water, produced a mixture of three
products, two of which were produced by deoximation (29b,
c). The yield of the desired nitronate was poor (38% of 29a).
In contrast, under “on water” conditions, the desired bis
benzoisoxazole N-oxide (29a) was obtained as the sole
product in good yield.
In order to extend the scope of our methodology further,
we utilized 3-acetyl-4-hydroxyquinolone oxime (30; Scheme 4)
to synthesize a quinoline fused isoxazole derivative (31). The
desired product was not produced, and the starting material
was recovered. This may be because 3-acetyl-4-hydroxyquino-
lone oxime (30) is hyperconjugated and generates a more
nucleophilic substituted hydroxylamine center and the oxygen
of this hydroxylamine attacks the cationic active species more
quickly than the oxime oxygen.
(15) (a) Tarnopolsky, A.; Hoz, S. Org. Biomol. Chem. 2007, 5, 3801. (b)
€
Nurminen, E.; Lonnberg, H. J. Phys. Org. Chem. 2004, 17, 1.
(16) (a) Lee, K. Y.; Kim, J. M.; Kim, J. N. Tetrahedron 2003, 59, 385. (b)
Kim, H. S.; Kim, T. Y.; Lee, K. Y.; Chung, Y. M.; Lee, H. J.; Kim, J. N.
Tetrahedron Lett. 2000, 41, 2613. (c) Basavaiah, D.; Kumaragurubaran, N.;
Padmaja, K. Synlett 1999, 1630. (d) To be submitted for publication.
(17) (a) Dunn, P. J.; Graham, A. B.; Grigg, R.; Higginson, P.; Sridharan,
V.; Pett, M. T. Chem. Commun. 2001, 1968. (b) Broggini, G.; Rosa, C. L.;
Zecchi, G. Synlett 1995, 1208.
(18) (a) Dale, T. J., Jr.; Rebek, J. Angew. Chem., Int. Ed. 2009, 48, 7850.
(b) Ren, Y.; Yamataka, H. J. Org. Chem. 2007, 72, 5660. (c) Richter, H. W.;
Cherry, B. R.; Zook, T. Z.; Koser, G. F. J. Am. Chem. Soc. 1997, 119, 9614.
(d) Klopman, G.; Tsuda, K.; Louis, J. B.; Davis, R. E. Tetrahedron 1970, 26,
4549. (e) Edwards, J. O.; Pearson, R. G. J. Am. Chem. Soc. 1962, 84, 16. (f )
Jencks, W. P.; Carriuolo, J. J. Am. Chem. Soc. 1960, 82, 1778.
J. Org. Chem. Vol. 76, No. 2, 2011 429

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SCHEME 3. Reaction of a Bis Oxime with HTIB
literature reports,18 we envisage that the hydroxyphenylio-
donium ion (PhIþOH) acts as an active species in the
oxidative N-O coupling reactions (Scheme 5). Here, we
assume that the initiation of the reaction may occur in a
manner similar to our previous proposal to form intermedi-
ate B and the mechanism is similar up to the formation of
intermediate D. It should be noted that the formation of an
N-oxonitrenium ion (D) from an oxime was postulated ear-
lier by Dong et al., in explaining the formation of an N-N
bond, mediated by PIFA/TFA in dichloromethane.12a As
this ion (intermediate D) possesses a nucleophilic alcoholic
oxygen at the β-position, we assume an N-O coupling.
Actually, in this circumstance, there are two electrophillic
centers available for the neighboring alcoholic oxygen.
Those electrophilic centers are the carbon and nitrogen
centers of the N-oxonitrenium ion moiety. If the neighboring
nucleophile attacks the carbon center (pathway a), then an
unstable four-membered ring (E) would be formed, whereas
if it attacks the nitrogen center (pathway b) the result would
be the formation of a stable five-membered ring (G). This
would drive the reaction toward N-O coupling (pathway b).
The formation of the deoximation product can be rationa-
SCHEME 4. Probable Explanation for the Failure of the Re-
action between 3-Acetyl-4-hydroxyquinolone Oxime and HTIB
After examining the scope and limitations of our protocol,
we focused our attention on possible mechanisms for the
reaction. In our previous report, we proposed a mechanism
for the HTIB-mediated oxidation of an aldoxime into a
nitrile oxide.10a On the basis of our earlier results10a and
SCHEME 5. Plausible Mechanistic Pathway for the Formation of Isoxazoline N-Oxide Derivatives
430 J. Org. Chem. Vol. 76, No. 2, 2011

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Additional applications of isoxazoline N-oxide derivatives will
be reported in due course.
SCHEME 6. Reaction of (6-(Hydroxyimino)cyclohex-1-enyl)-
(2-nitrophenyl)methyl Acetate with HTIBa,b
Conclusions
In summary, we have described a novel route to the synthe-
sisis of isoxazoline N-oxides via oxidative intramolecular N-O
coupling and verified that this methodology is also applicable to
the synthesis of benzoisoxazole N-oxide derivatives. This is the
first report of an “on water” protocol for the synthesis of the
five-membered cyclic nitronates. Our protocol is mild and
efficient, and the substrates are easily accessible. In most cases,
the product is insoluble in both water and methanol and hence is
precipitated at the bottom of the reaction vessel. A simple
filtration is sufficient to isolate the pure product in such cases.
A mechanism for the oxidative N-O coupling, which is
supported by experimental evidence as well as literature reports,
is proposed. The utility of these new types of isoxazoline N-
oxides was further explored by synthesizing a substituted
cinnamaldehyde derivative. Finally, we conclude that, apart
from the existing nitroalkane- and nitroalkene-oriented proto-
cols, the oxidation of ketoximes has the potential to serve as an
equally sustainable alternative route to accessing a wide range
of new and novel nitronates.
a1.1 equiv of reagent used. bIsolateyield.
lized by considering the participation of an external nucleo-
phile (pathway c).
In order to support our assumption, we carried out an
NMR experiment in D2O and the outcome was similar to
that in a previous report (see Supporting Information).10a
Moreover, when we blocked the β-hydroxy group of the
ketoxime with an acetyl group (32), the ketone (32a) was
obtained as the predominant product (Scheme 6). The reason
for this is the unavailability of a neighboring group. In this
situation, the external nucleophile attacks at the carbonyl
center, resulting in the formation of the deoximation product.
Methanol, being more nucleophilic than water, results in a
better yield of the deoximation product than an aqueous
medium. This result indirectly supports an intramolecular
N-O coupling at the last step (pathway b, Scheme 5) and rules
out the possibility of an SN2 substitution after oxidation of the
oxime to a nitro functionality.4f In addition, it also proves that
the solvent methanol is more prone to cause deoximation than
water. Notably, under “on water” conditions, a significant
amount of the starting oxime was recovered.
Once we explored the scope, limitations, and a plausible
mechanism for the N-O coupling strategy, we evaluated the
utility of our novel types of isoxazoline N-oxides (Scheme 7). In
this context, (Z)-3-methyl-4-(2-nitrobenzylidene)-4,5-dihydroi-
soxazole 2-oxide (22a) was transformed into (2Z)-3-(hydroxy-
imino)-2-(2-nitrobenzylidene)butanal (33) on treatment with
triethylamine in DMSO. Compound 33 was obtained as a
mixture of syn and anti oximes in a ratio of 2:1. The acyl-
substituted o-nitrocinnamaldehyde derivative 33 is a new com-
pound and is quite unique, in that it contains a ketoxime group
as well as a free aldehyde group. Later, considering the diverse
utility of conjugated enones in synthetic chemistry,19 we con-
ducted a Knoevenagel condensation of this cinamaldehyde
derivative with 5,5-dimethyl-1,3-cyclohexanedione under “on
water” conditions to prepare a conjugated enone (34).
Experimental Section
General Information. Reagents and solvents were purchased
from various commercial sources and used directly without any
further purification unless otherwise stated. Column chroma-
tography was performed on 63-200 mesh silica gel. 1H and 13
C
NMR spectra were recorded at 400 and 100 MHz, respectively.
Chemical shifts are reported in parts per million (δ) using TMS
as an internal standard, and coupling constants are expressed in
hertz. IR spectra were recorded on an FT-IR spectrometer and
are reported in cm-1. Melting points were recorded using an
Electro Thermal capillary melting point apparatus and are
uncorrected. Sonication was conducted at 42 kHz with a power
of 100 W. 26a and 28a are known compounds.3b,d,e
General Procedure for the Oxidative N-O Coupling. Proce-
dure A. To a 50 mL beaker containing the oxime derivative
(0.5 mmol) in 5 mL of methanol was added [hydroxy(tosyloxy)-
iodo]benzene (0.55 mmol) in small portions with continuous
stirring over a period of 25 min, and the stirring was then
continued for an additional 5 min. An equal amount of water
was then added. If the solid product precipitated at the bottom of
the beaker, the precipitate was isolated on the filter and washed
with 60% methanol in water to give the pure product. In cases
where the product did not precipitate, an additional 10 mL of water
was added to the reaction mixture and the organic compound was
isolated by extraction with ethyl acetate (15 mL ꢀ 3). The
combined organic layers were dried over magnesium sulfate and
SCHEME 7. Synthesis of Conjugated Enonea
aIsolated yield.
J. Org. Chem. Vol. 76, No. 2, 2011 431

Raihan et al.
JOCArticle
concentrated under vacuum. The resulting residue was further
purified by flash column chromatography.
(Mþ, 100), 215 (4), 214 (20), 183 (26), 156 (17). HRMS (m/z): calcd
for C13H1279BrNO2 (Mþ) 293.0046, found 293.0028 and calcd for
C13H1281BrNO2 (Mþ) 295.0025, found 295.0004.
Procedure B. To a 50 mL beaker containing the oxime derivative
(0.5 mmol) in 5 mL of water was added [hydroxy(tosyloxy)-
iodo]benzene (0.55 mmol) in small portions with continuous
stirring over a period of 45 min. After the completion of the
addition, the stirring was continued for an additional 5 min. The
precipitated crude product was isolated by filtration and washed
with water. In the case of an oily product, the reaction mixture was
extracted with ethyl acetate (2 ꢀ 10 mL). The organic layers were
separated, dried over magnesium sulfate, and concentrated under
vacuum. The resulting residue was further purified by flash column
chromatography.
3-Phenyl-3,5,6,7-tetrahydrobenzo[c]isoxazole 1-Oxide (5a).
Yellow gummy solid. IR (KBr, cm-1): 3063, 3033, 2945, 1653,
1631, 1451, 1355, 1266. 1H NMR (400 MHz, CDCl3): δ
7.43-7.35 (m, 5H), 6.02 (m, 1H), 5.60 (dd, J = 6.9, 4.3 Hz,
1H), 2.64 (t, J = 6.6 Hz, 2H), 2.31-2.14 (m, 2H), 1.91-1.80 (m,
2H). 13C NMR (100 MHz, CDCl3): δ 138.3, 137.5, 129.1, 129.0,
126.9, 121.2, 116.2, 80.6, 24.9, 21.1, 20.7. MS (m/z (relative
intensity)): 216 (Mþ þ 1, 45), 215 (Mþ, 100), 198 (9), 185 (5),
169 (22), 157 (14), 141 (22), 129 (10), 105 (33). HRMS (m/z): calcd
for C13H13NO2 (Mþ) 215.0941, found 215.0948.
3-Methyl-4-methylene-5-(2-nitrophenyl)-4,5-dihydroisoxazole
2-Oxide (7a). Yellow solid, mp 115-117 °C. IR (KBr, cm-1):
3077, 2863, 1646, 1606, 1528, 1351, 1263. 1H NMR (400 MHz,
CDCl3): δ 8.08 (d, J = 8.2 Hz, 1H), 7.72 (t, J = 7.4 Hz, 1H), 7.65
(d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 6.83 (t, J = 2.5 Hz,
1H), 5.13 (m, 2H), 2.11 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
147.9, 144.7, 134.4, 133.8, 129.9, 128.7, 125.2, 115.6, 106.8, 75.7,
8.9. MS (m/z (relative intensity)): 235 (Mþ þ 1, 11), 234 (Mþ,
100), 203 (5), 187 (17), 171 (5), 158 (38), 130 (33), 103 (45), 93
(14), 79 (36), 76 (23). HRMS (m/z): calcd for C11H10N2O4 (Mþ)
234.0635, found 234.0639.
3-(3-Nitrophenyl)-3,3a,4,5,6,7-hexahydrobenzo[c]isoxazole
1-Oxide (Anti) (8a). Colorless solid, mp 152-154 °C. IR (KBr,
cm-1): 3080, 2930, 2855, 1655, 1532, 1345, 1270, 1236. 1H NMR
(400 MHz, CDCl3): δ 8.24 (s, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.74
(d, J = 7.6 Hz, 1H), 7.59 (t, J = 7.9 Hz, 1H), 5.20 (d, J = 9.4 Hz,
1H), 3.19-3.13 (m, 1H), 2.81 (dd, J = 15.7, 4.3 Hz, 1H), 2.22-
2.14 (m, 2H), 1.99-1.90 (m, 2H), 1.56-1.41 (m, 2H), 1.40-1.27
(m 1H). 13C NMR (100 MHz, CDCl3): δ 148.6, 140.2, 132.1,
130.2, 123.8, 121.1, 116.7, 82.4, 51.6, 30.9, 24.0, 23.9, 23.6. MS
(m/z (relative intensity)): 262 (Mþ, 52), 245 (45), 170 (1), 150 (15),
111 (28), 81 (100). HRMS (m/z): calcd for C13H14N2O4 (Mþ)
262.0948, found 262.0960.
3-(3-Nitrophenyl)-3,3a,4,5,6,7-hexahydrobenzo[c]isoxazole
1-Oxide (Syn) (9a). Colorless gummy solid. IR (KBr, cm-1):
2934, 2860, 1703, 1661, 1530, 1448, 1350, 1282, 1231. 1H NMR
(400 MHz, CDCl3): δ 8.18 (d, J = 8.2 Hz, 1H), 8.14 (s, 1H), 7.69
(d, J = 7.7 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 5.82 (d, J = 10.2 Hz,
1H), 3.70-3.62 (m, 1H), 2.88-2.83 (m, 1H), 2.25-2.18 (m, 1H),
1.92-1.88 (m, 1H), 1.80-1.73 (m, 1H), 1.55-1.50 (m, 1H),
1.32-1.19 (m, 2H), 0.76-0.66 (m, 1H). 13C NMR (100 MHz,
CDCl3): δ 148.6, 138.9, 131.9, 130.1, 123.5, 121.1, 115.4, 77.2,
47.9, 28.4, 24.4, 24.1, 24.0.
3-(3-Nitrophenyl)-3a,4,5,6,7,8-hexahydro-3H-cyclohepta[c]iso-
xazole 1-Oxide (Anti) (10a). Pale yellow solid, mp 101-103 °C.
IR (KBr, cm-1): 3077, 2930, 2856, 1639, 1532, 1451, 1347, 1274,
1241, 1211. 1H NMR (400 MHz, CDCl3): δ 8.27 (s, 1H), 8.25 (d,
J = 8.2 Hz, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.62 (t, J = 7.9 Hz,
1H), 5.16 (d, J = 8.1 Hz, 1H), 3.35-3.30 (m, 1H), 2.70-2.65 (m,
1H), 2.57-2.49 (m, 1H), 2.04-1.92 (m, 4H), 1.79-1.68 (m, 1H),
1.52-1.34 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 148.7, 140.6,
132.2, 130.3, 123.9, 121.3, 120.3, 81.6, 55.5, 32.9, 30.2, 28.9, 27.7,
25.3. MS (m/z (relative intensity)): 276 (Mþ, 37), 259 (25), 176 (2),
150 (11), 125 (13), 95 (100). HRMS (m/z): calcd for C14H16N2O4
(Mþ) 276.1105, found 276.1114.
3-(2-Nitrophenyl)-3,5,6,7-tetrahydrobenzo[c]isoxazole 1-Oxide
(1a). Pale yellow solid, mp 156-158 °C. IR (KBr, cm-1): 3079,
2928, 2835, 1652, 1628, 1524, 1435, 1353, 1269, 1246, 1188, 1165.
1H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 8.0 Hz, 1H),
7.75-7.69 (m, 2H), 7.57-7.51 (m, 1H), 6.80-6.79 (m, 1H), 5.87
(dd, J = 6.8, 4.4 Hz, 1H), 2.71-2.56 (m, 2H), 2.31-2.23 (m, 1H),
2.18-2.11 (m, 1H), 1.89-1.73 (m, 2H). 13C NMR (100 MHz,
CDCl3): δ 147.3, 136.2, 134.8, 134.5, 129.4, 128.2, 125.2, 123.2,
115.2, 75.3, 25.1, 21.2, 20.4. MS (m/z (relative intensity)): 261
(Mþ þ 1, 12), 260 (Mþ, 100), 231 (16), 214 (48), 197 (61), 182
(14), 168 (20), 158 (22). HRMS (m/z): calcd for C13H12-
N2O4 (Mþ) 260.0792, found 260.0807. Anal. Calcd for C13H12-
N2O4: C, 60.00; H, 4.65; N, 10.76. Found: C, 59.96; H, 4.63;
N, 10.72.
3-(2-Nitro-5-chlorophenyl)-3,5,6,7-tetrahydrobenzo[c]isoxazole
1-Oxide (2a). Yellow solid, mp 172-174 °C. IR (KBr, cm-1):
3099, 2947, 2864, 1656, 1628, 1527, 1343, 1270, 1256, 1183, 1110.
1H NMR (400 MHz, CDCl3): δ 8.09 (d, J = 8.8 Hz, 1H), 7.72 (d,
J = 2.2 Hz, 1H), 7.48 (dd, J = 8.8, 2.3 Hz, 1H), 6.83 (dd, J = 5.6,
2.8 Hz, 1H), 5.88-5.85 (m, 1H), 2.71-2.58 (m, 2H), 2.31-2.18
(m, 1H), 2.18-2.11 (m, 1H), 1.87-1.76 (m, 2H). 13C NMR (100
MHz, CDCl3): δ 145.4, 141.6, 136.9, 135.8, 129.7, 128.3, 126.9,
123.7, 114.9, 74.8, 25.2, 21.3, 20.4. MS (m/z (relative intensity)):
296 (Mþþ2, 23), 294 (Mþ, 83), 248 (100), 231 (73), 192 (26), 167
(18), 126 (8), 95 (4). HRMS (m/z): calcd for C13H11ClN2O4 (Mþ)
294.0402, found 294.0416 and calcd for C13H1137ClN2O4 (Mþ)
296.0372, found 296.0389.
3-(2,4-Dichlorophenyl)-3,5,6,7-tetrahydrobenzo[c]isoxazole
1-Oxide (3a). Brown solid, mp 63-65 °C. IR (KBr, cm-1): 3070,
2945, 2834, 1657, 1624, 1587, 1561, 1472, 1451, 1381, 1355, 1263.
1H NMR (400 MHz, CDCl3): δ 7.44 (d, J = 1.8 Hz, 1H), 7.40 (d,
J = 8.4 Hz, 1H), 7.30 (dd, J = 8.4, 1.8 Hz, 1H), 6.44 (d, J = 2.6
Hz, 1H), 5.80 (d, J = 2.4, 1H), 2.65-2.61 (m, 2H), 2.29-2.19 (m,
2H), 1.86-1.79 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 136.4,
135.3, 135.0, 133.2, 129.9, 129.0, 128.0, 121.9, 115.6, 76.5, 24.9,
21.2, 20.5. MS (m/z (relative intensity)): 283 (Mþ, 100), 248 (17),
218 (5), 173 (13), 159(2). HRMS(m/z):calcdfor C13H1135Cl2NO2
(Mþ) 283.0161, found 283.0164 and calcd for C13H11Cl137ClNO2
(Mþ) 285.0132, found 285.0136.
3-(2-Bromophenyl)-3,5,6,7-tetrahydrobenzo[c]isoxazole 1-Oxide
(4a). Colorless solid, mp 93-95 °C. IR (KBr, cm-1): 3063, 2930,
2834, 1657, 1628, 1469, 1439, 1355, 1266. H NMR (400 MHz,
1
CDCl3): δ 7.59 (d, J = 8.0 Hz, 1H), 7.44 (dd, J = 7.8, 1.4 Hz, 1H),
7.36 (t, J = 7.7 Hz, 1H), 7.24-7.20 (m, 1H), 6.49 (dd, J = 5.8, 2.9
Hz, 1H), 5.84 (dd, J = 7.2, 4.4 Hz, 1H), 2.70-2.57 (m, 2H), 2.30-
2.12 (m, 2H), 1.87-1.77 (m, 2H). 13C NMR (100 MHz, CDCl3): δ
138.0, 136.7, 133.4, 130.4, 128.3, 128.2, 122.1, 121.8, 115.8, 79.1,
25.0, 21.2, 20.6. MS (m/z (relative intensity)): 296(Mþ þ 3, 13), 293
3-(3-Nitrophenyl)-3a,4,5,6,7,8-hexahydro-3H-cyclohepta[c]iso-
xazole 1-Oxide (Syn) (11a). Pale yellow solid, mp 105-107 °C. IR
(KBr, cm-1): 2930, 2856, 1639, 1532, 1451, 1351, 1277, 1218,
1203. 1H NMR (400 MHz, CDCl3): δ 8.21 (d, J = 8.2 Hz, 1H),
8.18 (s, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H),
5.77 (d, J = 9.0 Hz, 1H), 3.64-3.59 (m, 1H), 2.74-2.69 (m, 1H),
2.58-2.49 (m, 1H), 2.05-1.94 (m, 2H), 1.82-1.79 (m, 1H), 1.50-
1.47 (m, 1H), 1.30-1.26 (m, 1H), 1.22-1.13 (m, 2H), 1.12-1.05
(m, 1H). 13C NMR (100 MHz, CDCl3): δ 148.5, 137.6, 132.5,
130.0, 123.6, 121.6, 120.8, 79.0, 50.4, 30.2, 29.6, 29.1, 27.5, 25.3.
(19) For selected recent publications, see: (a) Basavaiah, D.; Aravindu,
K.; Kumar, K. S.; Reddy, K. R. Eur. J. Org. Chem. 2010, 1843. (b) Goswami,
P.; Das, B. Tetrahedron Lett. 2009, 50, 897. (c) Basavaiah, D.; Aravindu, K.
Org. Lett. 2007, 9, 2453. (d) Guo, H.-C.; Ma, J. A. Angew. Chem., Int. Ed.
2006, 45, 354. (e) Takao, K.-i.; Munakata, R.; Tadano, K.-i. Chem. Rev.
2005, 105, 4779.
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MS (m/z (relative intensity)): 276 (Mþ, 39), 259 (20), 231 (4), 176
(3), 150 (9), 125 (14), 95 (100), 67 (17). HRMS (m/z): calcd for
C14H16N2O4 (Mþ) 276.1105, found 276.1112.
(KBr, cm-1): 3079, 2929, 2855, 1640, 1606, 1519, 1451, 1382,
1348, 1278. 1H NMR (400 MHz, CDCl3): δ 8.25 (d, J = 8.6 Hz,
2H), 7.51(d, J = 8.6 Hz, 2H), 5.75(d, J = 9.0 Hz, 1H), 3.65-3.59
(m, 1H), 2.73-2.68 (m, 1H), 2.57-2.48 (m, 1H), 2.03-1.94 (m,
2H), 1.81-1.78 (m, 1H), 1.53-1.44 (m, 1H), 1.29-1.21 (m, 1H),
1.16 (dd, J = 22.6, 11.4 Hz, 2H), 1.10-0.99 (m, 1H). 13C NMR
(100 MHz, CDCl3): δ 148.2, 142.7, 127.5, 124.0, 120.7, 79.0, 50.5,
30.1, 29.6, 29.2, 27.5, 25.3. MS (m/z (relative intensity)): 276 (Mþ,
46), 259 (16), 184 (5), 150 (8), 125 (14), 95 (100), 67 (13). HRMS
(m/z): calcd for C14H16N2O4 (Mþ) 276.1105, found 276.1102.
3-Methyl-5-(4-nitrophenyl)-4,5-dihydroisoxazole 2-Oxide (18a).
Colorless solid, mp 123-125 °C. IR (KBr, cm-1): 3107, 2922,
2849, 1653, 1598, 1513, 1351. 1H NMR (400 MHz, CDCl3): δ 8.28
(d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 5.69 (dd, J = 9.4, 7.1
Hz, 1H), 3.63 (dd, J= 17.0, 9.8 Hz, 1H), 3.03 (dd, J= 17.0, 6.6 Hz,
1H), 2.04 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 148.3, 146.6,
126.4, 124.5, 111.1, 73.9, 42.5, 11.9. MS (m/z (relative intensity)):
223 (Mþ þ 1, 23), 222 (Mþ, 100), 205 (7), 175 (18), 150 (44), 146
(7), 84 (4), 71 (39), 55 (7). HRMS (m/z): calcd for C10H10N2O4
(Mþ) 222.0635, found 222.0644.
3-(3-Nitrophenyl)-3,3a,4,5,6,7,8,9-octahydrocycloocta[c]isoxa-
zole 1-Oxide (Anti) (12a). Colorless solid, mp 98-100 °C. IR
(KBr, cm-1): 3085, 2922, 2863, 1635, 1532, 1462, 1347, 1292. 1H
NMR (400 MHz, CDCl3): δ 8.24-8.22 (m, 2H), 7.80 (d, J = 7.7
Hz, 1H), 7.61 (t, J = 8.6 Hz, 1H), 5.29 (d, J = 6.8 Hz, 1H), 3.30
(dd, J = 11.5, 7.2 Hz, 1H), 2.76-2.69 (m, 1H), 2.34-2.27 (m,
1H), 2.09-2.05 (m, 1H), 1.92-1.84 (m, 4H), 1.71-1.66 (m, 2H),
1.63-1.57 (m, 1H), 1.55-1.42 (m, 2H). 13C NMR (100 MHz,
CDCl3): δ 148.8, 141.3, 131.7, 130.3, 123.8, 120.8, 119.2, 79.9,
53.9, 29.2, 26.3, 25.6, 25.5, 24.0, 23.6. MS (m/z (relative inten-
sity)): 290 (M þ, 44), 273 (14), 244 (5), 162 (3), 150 (9), 109 (100),
67 (57). HRMS (m/z): calcd for C15H18N2O4 (Mþ) 290.1261,
found 290.1269.
3-(3-Nitrophenyl)-3,3a,4,5,6,7,8,9-octahydrocycloocta[c]isoxa-
zole 1-Oxide (Syn) (13a). Pale yellow solid, mp 130-132 °C. IR
(KBr, cm-1): 3092, 2929, 2858, 1630, 1529, 1463, 1443, 1349. 1H
NMR(400 MHz, CDCl3): δ8.22 (d, J = 7.3Hz, 1H), 8.20(s,1H),
7.73 (d, J = 7.7 Hz, 1H), 7.62-7.58 (m, 1H), 5.82 (d, J = 7.9 Hz,
1H), 3.45-3.39 (m, 1H), 2.68-2.58 (m, 2H), 2.04-1.99 (m, 1H),
1.72-1.61 (m, 2H), 1.58-1.46 (m, 3H), 1.32-1.26 (m, 3H),
1.18-1.11 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 148.5,
136.9, 132.3, 129.9, 123.5, 121.9, 121.4, 80.3, 48.9, 28.7, 27.5,
26.1, 25.9, 23.9, 22.7. MS (m/z (relative intensity)): 290 (Mþ, 39),
273 (48), 150 (100), 109 (65). HRMS (m/z): calcd for C15H18N2O4
(Mþ) 290.1267, found 290.1262.
3-(3-Nitrophenyl)-3,3a,4,5,6,7,8,9,10,11,12,13-dodecahydrocy-
clododeca[c]isoxazole 1-Oxide (Anti) (14a). Colorless solid, mp
113-115 °C. IR (KBr, cm-1): 2932, 2863, 1637, 1531, 1469, 1444,
1351. 1H NMR (400 MHz, CDCl3): δ 8.22-8.20 (m, 2H), 7.76 (d,
J = 7.7 Hz, 1H), 7.63-7.58 (m, 1H), 5.29 (d, J = 5.6 Hz, 1H),
3.32 (dd, J = 10.0, 4.8 Hz, 1H), 2.53-2.46 (m, 1H), 2.43-2.36(m,
1H), 1.94-1.75 (m, 3H), 1.61-1.46 (m, 5H), 1.46-1.25 (m, 10H).
13C NMR (100 MHz, CDCl3): δ 148.8, 142.2, 131.5, 130.4, 123.8,
120.6, 117.2, 79.3, 54.6, 29.7, 25.7, 25.1, 24.3, 24.2, 23.6, 23.3, 23.2,
22.3. MS (m/z (relative intensity)): 346 (Mþ, 100), 329 (53), 299
(34), 230 (5), 216 (9), 202 (14), 163 (23), 150 (15), 95 (30), 83 (55).
HRMS (m/z): calcd for C19H26N2O4 (Mþ) 346.1893, found
346.1885.
5-(2-(Allyloxy)-5-nitrophenyl)-3-methyl-4,5-dihydroisoxazole
2-Oxide (19a). Yellow solid, mp 85-87 °C. IR (KBr, cm-1):
3086, 2923, 1659, 1652, 1613, 1593, 1520, 1488, 1338, 1271. 1H
NMR (400 MHz, CDCl3): δ 8.43 (d, J = 2.7 Hz, 1H), 8.22 (dd,
J = 9.0, 2.8 Hz, 1H), 6.98 (d, J = 9.1 Hz, 1H), 6.09-5.99 (m,
1H), 5.81 (dd, J = 10.0, 2.8 Hz, 1H), 5.45-5.37 (m, 2H),
4.74-4.65 (m, 2H), 3.65-3.57 (m, 1H), 3.00-2.94 (m, 1H),
2.01 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 159.9, 141.7, 131.6,
129.4, 125.8, 122.1, 119.3, 111.9, 111.7, 70.6, 70.0, 41.3, 11.9. MS
(m/z (relative intensity)): 278 (Mþ, 5), 261 (8), 221 (7), 209 (11),
206 (100), 191 (39), 166 (20), 96 (10), 73 (8). HRMS (m/z): calcd
for C13H14N2O5 (Mþ) 278.0897, found 278.0887.
3,5-Diphenyl-4,5-dihydroisoxazole 2-Oxide (20a). Colorless
solid, mp 76-78 °C. IR (KBr, cm-1): 3048, 2937, 1613, 1591,
1498, 1447, 1384, 1226. 1H NMR (400 MHz, CDCl3): δ 7.93 (d,
J = 7.7 Hz, 2H), 7.46-7.35 (m, 8H), 5.73 (t, J = 8.5 Hz, 1H),
3.92 (dd, J = 16.2, 9.5 Hz, 1H), 3.55 (dd, J = 16.2, 7.7 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ 138.9, 129.7, 129.2, 129.1,
128.9, 126.9, 126.4, 125.9, 114.1, 75.9, 40.5. MS (m/z (relative
intensity)): 239 (Mþ, 100), 192 (10), 117 (4), 105 (12), 103 (18).
HRMS (m/z): calcd for C15H13N1O2 (Mþ) 239.0941, found
239.0944.
3-(3-Nitrophenyl)-3,3a,4,5,6,7,8,9,10,11,12,13-dodecahydrocy-
clododeca[c]isoxazole 1-Oxide (Syn) (15a). Colorless solid, mp
118-120 °C. IR (KBr, cm-1): 3091, 2934, 2864, 1651, 1634, 1538,
1531, 1469, 1445, 1348. 1H NMR (400 MHz, CDCl3): δ
8.23-8.20 (m, 2H), 7.72 (d, J = 7.7 Hz, 1H), 7.61 (t, J = 7.8
Hz, 1H), 5.79 (d, J = 8.6 Hz, 1H), 3.59 (dd, J = 13.6, 5.8 Hz, 1H),
2.63-2.55 (m, 1H), 2.47-2.40 (m, 1H), 1.76-1.70 (m, 1H),
1.68-1.62 (m, 1H), 1.53-1.47 (m, 2H), 1.43-1.35 (m, 7H),
3-Methyl-5-(pyridin-2-yl)-4,5-dihydroisoxazole 2-Oxide (21a).
Brown oil. IR (KBr, cm-1): 3057, 3012, 2922, 1713, 1652, 1593,
1573, 1475, 1438, 1395, 1352, 1259. 1H NMR (400 MHz, CDCl3):
δ 8.59 (d, J = 4.2 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.61 (d, J =
7.8 Hz, 1H), 7.29-7.26 (m, 1H), 5.64 (dd, J = 9.9, 5.4 Hz, 1H),
3.63-3.56 (m, 1H), 3.39 (dd, J = 17.4, 4.0 Hz, 1H), 2.01 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 158.4, 149.8, 137.4, 123.6, 120.6,
112.4, 74.9, 40.3, 11.9.
1.29-1.20 (m, 4H), 1.18-1.11 (m, 2H), 1.01-0.97 (m, 1H). 13
C
NMR (100 MHz, CDCl3): δ 148.5, 137.2, 132.4, 129.9, 123.6,
121.6, 120.4, 79.1, 48.2, 25.9, 25.8, 24.5, 24.2, 23.7, 23.6, 23.4, 22.9,
22.8. MS (m/z (relative intensity)): 346 (Mþ, 100), 329 (77), 298
(11), 228 (3), 222 (8), 178 (11), 163 (20), 95 (30), 83 (61). HRMS
(m/z): calcd for C19H26N2O4 (Mþ) 346.1893, found 346.1885.
3-(4-Nitrophenyl)-3a,4,5,6,7,8-hexahydro-3H-cyclohepta[c]iso-
xazole 1-Oxide (Anti) (16a). Colorless solid, mp 135-137 °C. IR
(KBr, cm-1): 3079, 2928, 2855, 1640, 1607, 1521, 1451, 1349,
1275. 1H NMR (400 MHz, CDCl3): δ 8.28-8.25 (m, 2H), 7.62-
7.59 (m, 2H), 5.16 (d, J = 7.8 Hz, 1H), 3.30-3.25 (m, 1H), 2.67-
2.62 (m, 1H), 2.57-2.49 (m, 1H), 1.99-1.91 (m, 4H), 1.79-1.70
(m, 1H), 1.47-1.40 (m, 1H), 1.36-1.32 (m, 2H). 13C NMR (100
MHz, CDCl3): δ 148.4, 145.7, 126.9, 124.4, 120.1, 81.5, 55.6, 33.2,
30.1, 28.9, 27.7, 25.3. MS (m/z (relative intensity)): 276 (Mþ, 39),
259 (6), 230 (2), 176 (2), 125 (14), 95 (100), 67 (10). HRMS (m/z):
calcd for C14H16N2O4 (Mþ) 276.1105, found 276.1111.
3-Methyl-4-(2-nitrobenzylidene)-4,5-dihydroisoxazole 2-Oxide
(22a). Yellow solid, mp 128-130 °C. IR (KBr, cm-1): 1641,
1595, 1509, 1361, 1269. 1H NMR (400 MHz, CDCl3): δ 8.04 (dd,
J = 8.2, 1.1 Hz, 1H), 7.66-7.62 (m, 1H), 7.47-7.43 (m, 1H), 7.27
(d, J=7.6, 1H), 6.78 (t, J =3.1 Hz, 1H), 5.29 (d, J =3.1 Hz, 2H),
2.16 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 148.2, 138.5, 133.5,
130.4, 128.8, 128.5, 125.6, 117.5, 113.6, 68.3, 9.1. MS (m/z
(relative intensity)): 235 (Mþ þ 1, 12), 234 (Mþ, 100), 158 (15),
146 (11), 130 (11), 119 (22), 104 (6), 92 (36). HRMS (m/z): calcd
for C11H10N2O4 (Mþ) 234.0635, found 234.0640.
3-Methyl-4-(5-chloro-2-nitrobenzylidene)-4,5-dihydroisoxazole
2-Oxide (23a). Yellow solid, mp 129-131 °C. IR (KBr, cm-1):
3109, 3070, 2923, 1644, 1600, 1578, 1517, 1334, 1279. 1H NMR
(400 MHz, CDCl3): δ 8.03 (d, J = 8.8 Hz, 1H), 7.41 (dd, J = 8.8,
2.0 Hz, 1H), 7.22 (d, J = 1.7 Hz, 1H), 6.74 (t, J = 3.0 Hz, 1H),
5.31 (d, J = 3.0 Hz, 2H), 2.15 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 146.3, 139.9, 139.8, 132.4, 128.6, 128.4, 127.2, 117.4,
112.4, 68.1, 9.2. MS (m/z (relative intensity)): 270 (Mþ þ 2, 25),
3-(4-Nitrophenyl)-3a,4,5,6,7,8-hexahydro-3H-cyclohepta[c]iso-
xazole 1-Oxide (Syn) (17a). Colorless solid, mp 95-97 °C. IR
J. Org. Chem. Vol. 76, No. 2, 2011 433

Raihan et al.
JOCArticle
268 (Mþ, 100), 208 (6), 192 (20), 153 (38), 125 (46), 90 (6), 55 (6).
HRMS (m/z): calcd for C11H9ClN2O4 (Mþ) 268.0245, found
268.0257 and calcd for C11H937ClN2O4 (Mþ) 270.0216, found
270.0225.
magnesium sulfate, and concentrated under vacuum. The re-
sulting residue was further purified by flash column chroma-
tography (15% EA in hexane). The product was obtained as a
nonseparable mixture of syn and anti oximes in a ratio of 2:1 as a
yellow solid; mp 130-132 °C. IR (KBr, cm-1): 3276, 2922, 2849,
3-Methyl-4-(5-bromo-2-nitrobenzylidene)-4,5-dihydroisoxazole
2-Oxide (24a). Yellow solid, mp 125-127 °C. IR (KBr, cm-1):
3092, 3070, 1642, 1580, 1517, 1336, 1274. 1H NMR (400 MHz,
CDCl3): δ 7.92 (d, J = 8.8 Hz, 1H), 7.56 (dd, J = 8.7, 1.9 Hz, 1H),
7.39 (d, J = 1.7 Hz, 1H), 6.73 (t, J = 3.1 Hz, 1H), 5.30 (d, J = 3.1
Hz, 2H), 2.15 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 146.8,
139.8, 132.4, 131.6, 131.4, 128.4, 127.2, 117.4, 112.3, 68.1, 9.2. MS
(m/z (relativeintensity)): 314 (Mþ þ 2, 81), 312 (Mþ, 100), 297 (3),
266 (8), 210 (36), 199 (52), 171 (72), 145 (13), 130 (7), 90 (18), 55
(13). HRMS (m/z): calcd for C11H9BrN2O4 (Mþ) 311.9740,
found 311.9745 and calcd for C11H981BrN2O4 (Mþ) 313.9720,
found 313.9728.
3-Methyl-4-(4-nitrobenzylidene)-4,5-dihydroisoxazole 2-Oxide
(25a). Yellow solid, mp 184-186 °C. IR (KBr, cm-1): 1635,
1603, 1570, 1508, 1340, 1273. 1H NMR (400 MHz, CDCl3): δ8.27
(d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H), 6.38 (t, J = 3.1 Hz,
1H), 5.44 (d, J = 3.0 Hz, 2H), 2.17 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 146.3, 142.1, 139.1, 128.8, 124.6, 117.6, 116.5, 69.0, 9.2.
MS (m/z (relative intensity)): 235 (Mþ þ 1, 11), 234 (Mþ, 100),
205 (5), 176 (8), 150 (5), 130 (4), 84 (5). HRMS (m/z): calcd for
C11H10N2O4 (Mþ) 234.0635, found 234.0643.
6-Methoxy-3-methylbenzo[d ]isoxazole 2-Oxide (27a). Color-
less solid, mp 113-115 °C. IR (KBr, cm-1): 2974, 2834, 1599,
1504, 1427. 1H NMR (400 MHz, CDCl3): δ 7.29 (d, J = 8.5 Hz,
1H), 6.88 (dd, J = 8.6, 2.2 Hz, 1H), 6.72 (d, J = 2.1 Hz, 1H), 3.86
(s, 3H), 2.39 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 161.7,
151.6, 119.9, 116.3, 113.8, 112.9, 92.2, 55.9, 9.5. MS (m/z
(relative intensity)): 179 (Mþ, 100), 150 (4), 149 (54), 121 (52),
91 (5), 77 (4). HRMS (m/z): calcd for C9H9NO3 (Mþ) 179.0577,
found 179.0587.
Bis Isoxazoline N-Oxide Derivative 29a. Colorless solid, mp
176-178 °C. IR (KBr, cm-1): 1601, 1459, 1412, 1365, 1259,
1220. 1H NMR (400 MHz, CDCl3): δ 7.37 (s, 1H), 7.03 (d, J =
0.4 Hz, 1H), 2.48 (s, 6H). 13C NMR (100 MHz, DMSO): δ 150.2,
117.9, 115.2, 111.5, 86.9, 9.1. MS (m/z (relative intensity)): 220
(Mþ, 100), 190 (9), 148 (13), 131 (16), 122(13). HRMS (m/z):
calcd for C10H8N2O4 (Mþ) 220.0484, found 220.0483.
Preparation of (2Z )-3-(Methylimino)-2-(2-nitrobenzylidene)-
butanal (33). To a stirred solution of 3-methyl-4-(2-nitroben-
zylidene)-4,5-dihydroisoxazole 2-oxide (2 mmol) in 1.6 mL of
DMSO was added triethylamine (4.4 mmol), and the reaction
was monitored by TLC. After 0.5 h, the reaction mixture was
transferred into 50 mL of water in a beaker and the solution
extracted with ethyl acetate (50 mL ꢀ 3). The combined organic
layers were washed with a brine solution (50 mL ꢀ 2), dried over
1
1686, 1522, 1342. H NMR (400 MHz, CDCl3): δ (for major
peaks) 9.76 (s, 1H), 8.20 (d, J = 8.2 Hz, 1H), 7.99 (s, 1H), 7.87 (s,
1H), 7.69 (dd, J = 16.2, 7.36 Hz, 1H), 7.65-7.56 (m, 1H), 7.41
(d, J = 7.6 Hz, 1H), 1.89 (s, 3H); δ (for minor peaks) 9.76 (s, 1H),
8.27 (d, J = 8.1 Hz, 1H), 7.99 (s, 1H), 7.98 (s, 1H), 7.69 (dd, J =
16.2, 7.36 Hz, 1H), 7.65-7.56 (m, 1H), 7.41 (d, J = 7.6 Hz, 1H),
2.18 (s, 3H). 13C NMR (100 MHz, CDCl3): δ (for major peaks)
191.8, 151.6, 147.5, 147.4, 139.5, 134.1, 133.3, 130.6, 129.9,
125.2, 13.1; δ (for minor peaks) 190.5, 154.7, 147.4, 143.3,
137.5, 133.8, 133.3, 130.9, 129.9, 125.6, 15.1. MS (m/z (relative
intensity)): 233 (Mþ - 1, 14), 205 (44), 170 (55), 130 (100), 103
(92). HRMS (m/z): calcd for C11H9N2O4 (Mþ - 1) 233.0562,
found 233.0563.
Synthesis of 2-(3-(Hydroxyimino)-2-(2-nitrobenzylidene)butyli-
dene)-5,5-dimethylcyclohexane-1,3-dione (34). To (2Z)-3-(methyl-
imino)-2-(2-nitrobenzylidene)butanal (0.5 mmol) and 5,5-di-
methyl-1,3-cyclohexanedione (0.6 mmol) in a 20 mL vial was
added 5 mL of water, and the mixture was stirred for 5 min. It was
then sonicated for 18 h. The solid was isolated on a filter, and the
resulting residue was further purified by flash column chromatog-
raphy to give a yellow solid; mp 212-214 °C. IR (KBr, cm-1): 3284,
2959, 2871, 1630, 1590, 1531, 1399, 1359, 1264. 1H NMR (400 MHz,
CDCl3): δ 7.81 (d, J = 7.7 Hz, 1H), 7.51-7.43 (d, 3H), 7.35 (d, J =
7.5 Hz, 1H), 7.16 (s, 2H), 2.35-2.17 (m, 4H), 2.09 (s, 3H), 1.03 (s,
3H), 0.97 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 194.9, 171.5,
153.8, 149.3, 132.9, 129.8, 129.1, 124.6, 122.9, 118.9, 110.9, 72.4,
50.5, 42.1, 32.6, 29.3, 27.6, 9.5. MS (m/z (relative intensity)): 358
(Mþ þ 2, 2), 356 (Mþ, 56), 339 (66), 293 (64), 292 (45), 280 (16), 235
(5), 222 (30), 188 (35), 169 (100), 158 (43), 83 (16). HRMS (m/z):
calcd for C19H20N2O5 (Mþ) 356.1372, found 356.1376.
Acknowledgment. We wish to express our sincere grati-
tude to the National Science Council of the Republic of
China and National Taiwan Normal University (Grant No.
99T3030-2 and 99-D) for providing financial support for
the pursuit of this work. M.J.R. is grateful to the MOFA for
a Taiwan Scholarship.
Supporting Information Available: Text, figures, and tables
giving experimental procedures and spectroscopic data for all
compounds and tables, figures, and CIF files giving crystal
structure data for 1a, 10a, 11a, 14a, 15a, and 23a. This material
is available free of charge via the Internet at http://pubs.acs.org.
434 J. Org. Chem. Vol. 76, No. 2, 2011