Unusual retention of isoxazole ring under the influence of 3-(substituted nitrophenyl)-2-isoxazoline during catalytic hydrogenation of isoxazoline-substituted isoxazole systems

Article abstract of DOI:10.1002/jhet.87

(Chemical Equation Presented) The cleavage of the isoxazole ring during the Raney-Ni-promoted catalytic hydrogenation is prevented under the influence of 3-(substituted nitrophenyl)-2-isoxazoline in isoxazoline-substituted isoxazole systems produced via 1

Full text of DOI:10.1002/jhet.87

762
Unusual Retention of Isoxazole Ring under the Influence of 3-
(Substituted nitrophenyl)-2-Isoxazoline during Catalytic
Hydrogenation of Isoxazoline-Substituted Isoxazole Systems
Vol 46
Vijay Singh,a Samiran Hutait,a Gaya P. Yadav,b Prakas R. Maulik,b and
Sanjay Batraa*
aMedicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow,
Uttar Pradesh, India
bMolecular and Structural Biology Division, Central Drug Research Institute, Lucknow,
Uttar Pradesh, India
*E-mail: batra_san@yahoo.co.uk
Received June 19, 2008
DOI 10.1002/jhet.87
Published online 14 July 2009 in Wiley InterScience (www.interscience.wiley.com).
Dedicated to Professor Raymond C. F. Jones on the occasion of his 60th birthday.
The cleavage of the isoxazole ring during the Raney-Ni-promoted catalytic hydrogenation is prevented
under the influence of 3-(substituted nitrophenyl)-2-isoxazoline in isoxazoline-substituted isoxazole sys-
tems produced via 1,3-dipolar cycloaddition either on the Baylis–Hillman derivatives or Grignard prod-
ucts. Unexpectedly, the hydrogenations in these diastereomeric compounds were observed to exclusively
yield products, wherein the methoxycarbonyl and the hydroxyl or the acetyl groups exist syn to each other.
J. Heterocyclic Chem., 46, 762 (2009).
INTRODUCTION
zonitrile oxide to the Baylis–Hillman adduct of 3-isoxazole-
carbaldehyde and subjecting it to catalytic hydrogenation in
the presence of Raney-Ni. Unexpectedly, analysis of the
product isolated after work-up of the reaction revealed that
instead of cleavage of the isoxazole ring, only the nitro
group present on the phenyl group of the isoxazoline ring
was reduced to amino group. A careful literature survey
revealed that several reports described the Pd-on-carbon-
promoted hydrogenation of the isoxazole derivatives with-
out cleavage of the ring [6], but there exists no report exem-
plifying the retention of the isoxazole ring during Raney-
Ni-promoted catalytic hydrogenation. This prompted us to
systematically investigate the catalytic hydrogenation of
derivatives wherein the isoxazole ring carry 3-(substituted
nitrophenyl)-2-isoxazoline as substituent. It was observed
that the cleavage of the isoxazole ring was invariably pre-
vented during the catalytic hydrogenation because of the
influence of 3-(substituted nitrophenyl)-2-isoxazoline in an
isoxazoline-substituted isoxazole derivative. The details of
this study are presented in this communication.
The catalytic hydrogenation of isoxazole and 2-isoxazo-
line heterocyclic systems in the presence of heterogeneous
catalysts is relatively old and well-studied subject of syn-
thetic organic chemistry [1]. Recently, we have discovered
that the 2-isoxazoline system containing a 2-,3- or 4-nitro-
phenyl group at 3-position does not undergo ring cleavage
under catalytic hydrogenation [2]. In our program to carry
out Baylis–Hillman reaction-assisted synthesis of cyclic
compounds [3], based on the aforementioned observation,
we envisaged the synthesis of the spiroisoxazoline III
from I (Figure 1). Substrate I was to be readily generated
via 1,3-dipolar cycloaddition of appropriate benzonitrile
oxide on the Baylis–Hillman adduct of substituted 3-isoxa-
zolecarbaldehyde. In principle, a Raney-Ni-promoted hy-
drogenation would result in chemoselective ring cleavage
of I to afford II, which may undergo intramolecular cycli-
zation to produce the spiro-derivative. Spiroisoxazoline
class of compounds has stimulated great interest in medic-
inal and biological chemistry [4]. Moreover, naturally
occurring spiroisoxazolines have been found useful in dif-
ferent biomedical areas [5].
RESULTS AND DISCUSSION
Therefore, we initiated the investigation by synthesizing
I via 1,3-dipolar cycloaddition of the nitro-substituted ben-
The Baylis–Hillman adducts (1a–c) of substituted 3-
isoxazolecarbaldehydes were prepared according to the
C
V
2009 HeteroCorporation

July 2009
Unusual Retention of Isoxazole Ring under the Influence of 3-(Substituted nitrophenyl)-
2-isoxazoline during Catalytic Hydrogenation of Isoxazoline-Substituted Isoxazole Systems
763
Scheme 2. Reagents and conditions: (i) (2-NO2C6H4)AC(¼NOH)Cl,
Et3N, Et2O, ꢀ78ꢁC to rt, 12 h. (ii) Raney-Ni, H2, MeOH, rt, 40 psi, 3 h.
Figure 1. Possible route to spiroisoxazoline from isoxazoline-substi-
tuted isoxazole system. [Color figure can be viewed in the online
issue, which is available at www.interscience.wiley.com.]
zole-carbaldehydes [8,9]. Accordingly, compounds 5a,b
were prepared in 83–92% yields from the Baylis–Hill-
man adduct (4a) of 3-phenyl-5-methyl-4-isoxazolecarb-
aldehyde and corresponding acetate 4b through 1,3-
dipolar cycloaddition. These compounds upon hydrogen-
ation in the presence of Raney-Ni resulted in 6a,b
(Scheme 2) as single diastereomer in 66–92% yields.
The relative stereochemistry delineated via X-ray crys-
tallographic analysis of a single crystal of compound 6b
indicated that the acetyl group is placed syn to the ester
group (Figure 2) [10].
literature procedure [7] and subjected to 1,3-dipolar
cycloaddition with 2-nitrobenzonitrile oxide. The
required benzonitrile oxide was generated in situ from
corresponding 2-nitrophenyl methylhydroximinoyl chlo-
ride by treating it with triethyl amine in dry ether. This
reaction yielded 2a–c as diastereomeric mixtures (1:1)
in 78–83% yields. Hydrogenation of 2a in the presence
of Raney-Ni in methanol on a Parr assembly led to com-
pletion of reaction in 3 h. Unexpectedly, the spectral
analysis of the isolated product (67% yield) led us to es-
tablish the structure as 3a as a single diastereomer
(Scheme 1). At this stage, the likelihood was that both
the diastereomer were formed during the reaction, but
In the next stage, the Baylis–Hillman derivatives 7a–c
and 8a afforded from substituted 5-isoxazolecarbalde-
hydes were subjected to the cycloaddition with 2-nitro-
benzonitrile oxide to furnish 9a–c and 10a, respectively,
as diastereomeric mixtures (1:1) in 82–89% yields. Hy-
drogenation of 9a–c and 10a in the presence of Raney-
Ni yielded 13a–c and 14a, respectively, in 63–71%
yields (Scheme 3).
1
we isolated only one of them. Consequently, H NMR
of the crude product was recorded. This spectrum also
indicated the presence of a single diastereomer. Assum-
ing that the period of reaction was insufficient to affect
the cleavage of the isoxazole ring, the hydrogenation
was repeated by continuing it for longer duration (ca.
24 h). The product isolated even after 24 h of the reac-
tion time, however, was found to be 3a. This led us to
examine the hydrogenation using Pd-on-carbon as the
catalyst. Interestingly, under this condition too, the com-
pound 2a was transformed to 3a in 65% yield. To evalu-
ate the outcome of these reactions with other substrates,
compounds 2b and 2c were subjected to similar reac-
tions. Both substrates behaved in an identical fashion to
furnish corresponding products 3b and 3c as a single
diastereomer in 63–66% yields.
Next, to investigate whether the position of the nitro
group in the phenyl ring has any effect on the outcome
of the product, we prepared compounds 11a and 12a
and carried out Raney-Ni-promoted hydrogenation.
This unusual observation generated interest to study
hydrogenation in similar substrates afforded from the
Baylis–Hillman adducts of substituted 4- and 5- isoxa-
Scheme 1. Reagents and conditions: (i) (2-NO2C6H4)AC(¼NOH)Cl,
Et3N, Et2O, ꢀ78ꢁC to rt, 12 h. (ii) Raney-Ni or Pd on carbon, H2,
MeOH, rt, 40 psi, 3 h.
Figure 2. Ortep diagram of compound 6b showing retention of both
isoxazole and isoxazoline ring during catalytic hydrogenation [Color
figure can be viewed in the online issue, which is available at
www.interscience.wiley.com.]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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V. Singh, S. Hutait, G. P. Yadav, P. R. Maulik, and S. Batra
Vol 46
Scheme 3. Reagents and conditions: (i) (2,3 or 4-
NO2C6H4)AC(¼NOH)Cl, Et3N, Et2O, ꢀ78ꢁC to rt, 12 h. (ii) Raney-
Ni or Pd on carbon, H2, MeOH, rt, 40 psi, 3–5 h.
Scheme 5. Reagent and conditions: (i) allyl bromide, Mg, Et2O, rt,
3 h. (ii) (2-NO2)C6H4C(¼NOH)Cl, Et3N, Et2O, ꢀ78ꢁC, 12 h. (iii)
Raney-Ni, H2, rt, 40 psi, 3–5 h. (iv) C6H5C(¼NOH)Cl, Et3N, Et2O,
ꢀ78ꢁC, 12 h.
Gratifyingly, these substrates were also transformed to
products 15a and 16a. In the absence of evidence, it is
difficult to comment on the observed stereoselectivity; it
is assumed that during hydrogenation reaction, inversion
of one of the diastereomer occurs to produce the product
with syn-stereochemistry only.
With the objective to find whether this phenomenon
was restricted to the system wherein both the rings were
separated by a methylene bridge or extend to a system
wherein the two rings are separated by ethylene spacer
compounds 23–24 were prepared. Grignard reaction of
19–20 with allylbromide resulted in the formation of
21–22 in good yields (Scheme 5). 1,3-Dipolar cycload-
dition reaction of 2-nitrobenzonitrile oxide on the double
bond of the allyl moiety furnished the required deriva-
tives 23–24. Hydrogenation of compounds 23–24 in the
presence of Raney-Ni in methanol at room temperature
in the Parr assembly yielded compounds 25–26, respec-
tively. Simultaneously, 1,3-dipolar cycloaddition of ben-
zonitrile oxide on 21 was accomplished to afford the
product 27. As expected, hydrogenation of 27 in the
presence of Raney-Ni at room temperature for 3 h led to
the cleavage of isoxazole and isoxazoline ring leading
to 28. This study further substantiate that the presence
of a 2-isoxazoline ring bearing a nitro-phenyl substitu-
tion at 3-position protect the isoxazole ring from
hydrogenolysis.
Earlier, we have observed that replacing the nitro-
substituted phenyl with phenyl group at 3-position of
the 2-isoxazoline makes it prone to ring cleavage during
the catalytic hydrogenation [2]. In view of this observa-
tion, we decided to evaluate the effect of catalytic hy-
drogenation in the system where the nitrophenyl group
was replaced by phenyl group. Hence, in a model study,
compound 17 was prepared from reaction between
compound 8a and benzonitrile oxide. The Raney-Ni-
mediated hydrogenation of 17 yielded a product, which
was analyzed to be the 2-pyrrolidone 18 (Scheme 4).
The formation of compound 18 from 17 implied that
during catalytic hydrogenation, cleavage of both the iso-
xazole and the 2-isoxazoline rings ensued. This result
made it apparent that presence of a nitro-substituted
phenyl moiety at the 3-position of the 2-isoxazoline pro-
tected the isoxazole from ring cleavage during the cata-
lytic hydrogenation of an isoxazoline-substituted isoxa-
zole system.
On suggestion from one of the reviewers that the pro-
duction of aniline derivatives during the hydrogenation
would be poisoning the catalyst to prevent further reac-
tion, hydrogenations of different substrates in the pres-
ence of aniline were investigated. Hydrogenating a sim-
pler isoxazole derivative 29 in the presence of aniline
Scheme 4. Reagents and conditions: (i) C6H5AC(¼NOH)Cl, Et3N,
Et2O, ꢀ78ꢁC to rt, 12 h. (ii) Raney-Ni, H2, MeOH, rt, 40 psi, 3 h.
Scheme 6. Reagent and conditions: (i) Aniline, Raney-Ni, H2, rt, 40
psi, 5 h. (ii) Aniline, Raney-Ni, H2, rt, 40 psi, 1 h then added 29, 5 h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
Unusual Retention of Isoxazole Ring under the Influence of 3-(Substituted nitrophenyl)-
2-isoxazoline during Catalytic Hydrogenation of Isoxazoline-Substituted Isoxazole Systems
765
(m, 8H, 2 ꢂ 4ArH), 7.60–7.68 (m, 4H, 2 ꢂ 2ArH), 7.80–7.81
(m, 4H, 2 ꢂ 2ArH), 8.06–8.11 (m, 2H, ArH); 13C NMR (deu-
teriochloroform): d 42.5, 43.3, 53.9, 69.2, 90.5, 91.8, 99.4,
124.6, 124.8, 125.3, 126.3, 127.4, 128.4, 128.8, 129.4, 130.8,
131.0, 131.5, 134.0, 134.9, 148.1, 156.6, 162.8, 170.0, 170.9;
ms: (electron sprayþ) m/z 424.2 (Mþ þ 1). Anal. Calcd for
C21H17N3O7: C, 59.57; H, 4.05; N, 9.93. Found: C, 59.48; H,
4.11; N, 9.98.
and Raney-Ni furnished 30 in 67% yield (Scheme 6).
Alternatively, a mixture of aniline and Raney-Ni was
maintained under hydrogen atmosphere for 1 h followed
by addition of 29. This reaction too resulted in the for-
mation of 30 in 5 h. Similar study was also performed
with compound 27. Here too, the hydrogenolyzed prod-
uct 28 was isolated in 62% yield. This study delineated
that the presence of aniline in the hydrogenation mixture
does not affect the activity of the catalyst.
Methyl 5-[acetoxy-(5-phenylisoxazol-3-yl)-methyl]-3-(2-
nitrophenyl)-4,5-dihydroisoxazole-5-carboxylate (2b). This
compound was obtained in 83% yield as a white solid, mp
133–135ꢁC; IR (potassium bromide): 1756 (CO2Me and OAc)
cmꢀ1
; d 2.22 (s, 3H,
1H NMR (deuteriochloroform):
CONCLUSIONS
OCOCH3), 2.25 (s, 3H, OCOCH3), 3.80–4.01 (m, 10H, 2 ꢂ
CH2 and 2 ꢂ CO2CH3), 6.67 (s, 1H, ¼¼CH), 6.68 (s, 1H,
¼¼CH), 7.40–7.49 (m, 8H, 2 ꢂ 3ArH and 2 ꢂ CHOAc), 7.60–
7.68 (m, 6H, 2 ꢂ 3ArH), 7.79–7.86 (m, 4H, 2 ꢂ 2ArH), 8.07–
8.13 (m, 2H, 2 ꢂ 1ArH); 13C NMR (deuteriochloroform): d
21.1, 21.3, 42.6, 43.3, 54.0, 54.2, 67.8, 89.3, 90.0, 102.9,
103.7, 124.6, 124.7, 125.4, 127.1, 127.4, 128.7, 128.9, 129.4,
130.5, 130.7, 131.6, 134.0, 134.2, 148.1, 156.2, 156.3, 163.1,
166.1, 166.3, 168.2, 168.8, 169.5, 169.9, 171.2; ms: (electron
sprayþ) m/z 466.1 (Mþ þ 1). Anal. Calcd for C23H19N3O8: C,
59.36; H, 4.11; N, 9.03. Found: C, 59.13; H, 4.21; N, 8.96.
Methyl 3-(2-nitrophenyl)-5-(5-phenylisoxazol-3-ylmethyl)-
4,5-dihydroisoxazole-5-carboxylate (2c). This compound was
obtained in 78% yield as yellow oil; IR (neat): 1744 (CO2Me)
In summary, we have disclosed an interesting obser-
vation wherein the cleavage of the isoxazole ring during
the catalytic hydrogenation is influenced by the substitu-
tions present on the 3-position of the 2-isoxazoline ring
in isoxazoline-substituted isoxazole systems. Further
work toward exploring applications of the intermediates
resulting from the study for the synthesis of heterocyclic
systems is underway.
EXPERIMENTAL
Melting points are uncorrected and were determined in cap-
illary tubes on an apparatus containing silicon oil. IR spectra
were recorded using Perkin Elmer’s Spectrum RX I FTIR
spectrophotometer. 1H NMR and 13C NMR spectra were
recorded either on a Bruker DPX-200 FT or Bruker Avance
DRX-300 spectrometers, using TMS as an internal standard
(chemical shifts in d values, J in Hz). The ESMS were
recorded on MICROMASS LCMS system and FABMS were
recorded on JEOL/ SX-102 spectrometer. Elemental analyses
were performed on Carlo Erba’s 108 or Elementar’s Vario EL
III microanalyzer. The HRMS spectra were recorded as EI-
HRMS. Compounds 2, 5, 9–12 existed as 1:1 diastereomeric
mixtures.
General procedure for the synthesis of compounds 2a–c,
5a–b, 9a–c, 10–12a, 17, 23–24, and 27: as exemplified for
the compound 2a. To a stirred solution of compound 1a (2.0
g, 7.7 mmol) and 2-nitrophenyl methylhydroximinoyl chloride
(1.85 g, 9.3 mmol) in anhydrous diethylether (15 mL) was
added dropwise a solution of Et3N (1.5 mL, 11.1 mmol) in an-
hydrous diethylether (5 mL) at ꢀ78ꢁC. The reaction was
allowed to continue at room temperature for 24 h. Thereafter,
the reaction mixture was quenched with water (30 mL) and
the ether layer was separated. The aqueous layer was again
extracted with diethylether. The combined organic layer was
dried over anhydrous Na2SO4 and evaporated to obtain the
crude oily residue. The crude product was then purified by col-
umn chromatography over silica gel (60–120 mesh) using hex-
ane/ethyl acetate (70:30, v/v) as the eluent to afford 2.58 g
(79%) of 2a as a brown solid.
cmꢀ1 1H NMR (deuteriochloroform): d 3.47 (d, 1H, 1H of
;
CH2, J ¼ 17.4 Hz), 3.66 (d, 2H, CH2, J ¼ 6.1 Hz), 3.86 (d,
1H, 1H of CH2, J ¼ 17.4 Hz), 3.93 (s, 3H, CO2CH3), 6.63 (s,
1H, ¼¼CH), 7.45–7.50 (m, 3H, ArH), 7.61–7.71 (m, 3H, ArH),
7.81–7.84 (m, 2H, ArH), 8.10 (d, 1H, ArH, J ¼ 7.2 Hz); 13C
NMR (deuteriochloroform) d¼ 33.5, 45.5, 53.7, 87.8, 102.6,
124.3, 124.5, 125.1, 127.0, 128.8, 129.0, 130.2, 131.2, 133.9,
147.7, 155.9, 162.9, 167.1, 167.2, 170.2; ms: (electron sprayþ)
m/z 408.1 (Mþ þ 1). Anal. Calcd for C21H17N3O6: C, 61.91;
H, 4.21; N, 10.31. Found: C, 61.78; H, 4.29; N, 10.26.
Methyl 5-[hydroxy-(5-methyl-3-phenylisoxazol-4-yl)-
methyl]-3-(2-nitrophenyl)-4,5-dihydroisoxazole-5-carboxylate
(5a). This compound was obtained in 92% yield as pale yellow
oil; IR (neat): 1744 (CO2Me), 3382 (OH) cmꢀ1 1H NMR
;
(deuteriochloroform): d 2.64 (s, 3H, CH3), 2.65 (s, 3H, CH3),
3.07 (d, 1H, 1H of CH2, J ¼ 17.4 Hz), 3.36 (d, 1H, 1H of
CH2, J ¼ 17.4 Hz), 3.45 (d, 1H, 1H of CH2, J ¼ 17.4 Hz),
3.53 (d, 1H, 1H of CH2, J ¼ 17.4 Hz), 3.61 (s, 6H, 2 ꢂ
CO2CH3), 5.26 (s, 1H, CHOH), 5.40 (s, 1H, CHOH), 7.21–
7.42 (m, 2H, 2 ꢂ 1ArH), 7.43–7.57 (m, 10H, 2 ꢂ 5ArH),
7.60–7.69 (m, 4H, 2 ꢂ 2ArH), 8.02–8.07 (m, 2H, 2 ꢂ 1ArH);
13C NMR (deuteriochloroform): d 13.0, 13.1, 41.7, 43.6, 53.2,
53.3, 67.3, 67.7, 92.7, 92.8, 110.0, 124.2, 124.9, 128.7, 128.9,
129.0, 129.2, 129.7, 130.9, 131.1, 133.7, 147.6, 155.9, 162.3,
169.5, 170.4; ms: (electron sprayþ) m/z 438.1 (Mþ þ 1).
Anal. Calcd for C22H19N3O7: C, 60.41; H, 4.38; N, 9.61.
Found: C, 60.63; H, 4.47; N, 9.49.
Methyl 5-[hydroxy-(5-phenylisoxazol-3-yl)-methyl]-3-(2-
nitrophenyl)-4,5-dihydro-isoxazole-5-carboxylate (2a). Mp
120–122ꢁC, IR (potassium bromide): 1741 (CO2Me), 3449
Methyl 5-[acetoxy-(5-methyl-3-phenylisoxazol-4-yl)-
methyl]-3-(2-nitrophenyl)-4,5-dihydroisoxazole-5-carboxylate
(5b). This compound was obtained in 83% as a pale yellow
solid, mp. 74–76ꢁC; IR (potassium bromide): 1752 (CO2Me
1
(OH) cmꢀ1; H NMR (deuteriochloroform): d 3.69 (d, 1H, 1H
1
of CH2, J ¼ 17.7 Hz), 3.81–3.93 (m, 9H, CH2, 1H of CH2 and
2 ꢂ CO2CH3), 5.49 (d, 1H, CHOH, J ¼ 5.8 Hz), 5.56 (s, 1H,
CHOH), 6.74 (s, 1H, ¼¼CH), 6.77 (s, 1H, ¼¼CH), 7.45–7.46
and OAc) cmꢀ1; H NMR (deuteriochloroform): d 2.19 (s, 3H,
OCOCH3), 2.26 (s, 3H, OCOCH3), 2.72 (s, 3H, CH3), 2.74 (s,
3H, CH3), 3.26–3.50 (m, 4H, 2 ꢂ CH2), 3.78 (s, 6H, 2 ꢂ
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V. Singh, S. Hutait, G. P. Yadav, P. R. Maulik, and S. Batra
Vol 46
CO2CH3), 6.37 (s, 1H, CHOAc), 6.42 (s, 1H, CHOAc), 7.12
(d, 1H, ArH, J ¼ 7.6 Hz), 7.47–7.54 (m, 7H, 2 ꢂ 3ArH and
ArH), 7.62–7.73 (m, 8H, 2 ꢂ 4ArH), 8.08 (d, 2H, 2 ꢂ 1ArH,
J ¼ 7.6 Hz); 13C NMR (deuteriochloroform): d 13.5, 13.7,
20.9, 21.0, 43.9, 44.1, 53.3, 53.8, 68.7, 69.3, 91.2, 91.5, 108.0,
108.7, 124.4, 125.4, 129.2, 129.6, 129.9, 130.3, 131.4, 131.7,
134.1, 134.3, 147.8, 148.2, 155.6, 162.2, 162.6, 169.7, 170.0,
171.7, 172.0; ms: (electron sprayþ) m/z 480.1 (Mþ þ 1).
Anal. Calcd for C24H21N3O8: C, 60.12; H, 4.41; N, 8.76.
Found: C, 59.98; H, 4.53; N, 8.69.
¼¼CH), 7.24–7.28 (m, 4H, 2 ꢂ 2ArH), 7.48–7.51 (m, 2H, 2 ꢂ
1ArH), 7.61–7.71 (m, 8H, 2 ꢂ 4ArH), 8.05–8.09 (m, 2H, 2 ꢂ
1ArH); 13C NMR (deuteriochloroform): d 21.8, 41.7, 43.9, 53.9,
54.0, 68.7, 69.0, 90.6, 91.5, 102.1, 102.2, 124.5, 125.3, 125.9,
126.1, 127.2, 130.0, 131.5, 131.6, 134.0, 134.2, 140.8, 148.1,
156.6, 162.8, 169.3, 169.6, 170.3; ms: (electron sprayþ) m/z
438.1 (Mþ þ 1). Anal. Calcd for C22H19N3O7: C, 60.41; H,
4.38; N, 9.61. Found: C, 60.58; H, 4.29; N, 9.70.
Methyl 5-[hydroxy-(3-phenylisoxazol-5-yl)-methyl]-3-(3-
nitrophenyl)-4,5-dihydroisoxazole-5-carboxylate (11a). This
compound was obtained in 79% as a pale yellow solid, mp
138–140ꢁC; IR (potassium bromide): 1744 (CO2Me), 3421
Methyl 5-[hydroxy(3-phenylisoxazol-5-yl)methyl]-3-(2-nitro-
phenyl)-4,5-dihydroisoxazole-5-carboxylate (9a). This com-
pound was obtained in 82% as yellow oil; IR (neat): 1744
(OH) cmꢀ1 1H NMR (deuteriochloroform): d 3.68–3.91 (m,
;
1
(CO2Me), 3336 (OH) cmꢀ1; H NMR (deuteriochloroform): d
4H, 2 ꢂ CH2), 3.92 (s, 3H, CO2CH3), 3.93 (s, 3H, CO2CH3),
5.51 (s, 1H, CHOH), 5.58 (s, 1H, CHOH), 7.08 (s, 1H, ¼¼CH),
7.14 (s, 1H, ¼¼CH), 7.38–7.42 (m, 4H, 2 ꢂ 2ArH), 7.48–7.54
(m, 6H, 2 ꢂ 3ArH), 7.61–7.66 (m, 4H, 2 ꢂ 2ArH), 7.93–7.99
(m, 2H, 2 ꢂ 1ArH), 8.03–8.05 (m, 2H, 2 ꢂ 1ArH); 13C NMR
(deuteriochloroform): d 42.3, 43.6, 53.9, 69.2, 91.2, 91.9,
104.3, 124.7, 125.3, 126.3, 127.6, 129.9, 131.5, 132.3, 134.0,
148.0, 148.2, 156.6, 162.6, 167.2, 169.9, 170.3; ms: (electron
sprayþ) m/z 424.1 (Mþ þ 1). Anal. Calcd for C21H17N3O7: C,
59.57; H, 4.05; N, 9.93. Found: C, 59.69; H, 4.19; N, 9.84.
Methyl 5-[hydroxy-(3-phenylisoxazol-5-yl)-methyl]-3-(4-
nitrophenyl)-4,5-dihydroisoxazole-5-carboxylate (12a). This
compound was obtained in 79% as pale yellow oil; IR (neat):
3.64–3.85 (m, 4H, 2 ꢂ CH2), 3.89 (s, 3H, CO2CH3), 3.93 (s,
3H, CO2CH3), 5.47 (s, 1H, CHOH), 5.56 (s, 1H, CHOH), 6.75
(s, 1H, ¼¼CH), 6.78 (s, 1H, ¼¼CH), 7.46–7.52 (m, 6H, 2 ꢂ
3ArH), 7.58–7.72 (m, 4H, 2 ꢂ 2ArH), 7.78–8.04 (m, 6H, 2 ꢂ
3ArH), 8.06–8.09 (m, 2H, 2 ꢂ 1ArH); 13C NMR (deuterio-
chloroform): d 41.7, 43.9, 53.9, 54.0, 68.7, 69.0, 90.6, 91.5,
102.2, 124.4, 125.2, 127.3, 128.8, 129.4, 130.5, 130.6, 131.5,
131.6, 134.0, 134.2, 148.2, 156.6, 162.9, 169.6, 169.9; ms:
(electron sprayþ) m/z 424.0 (Mþ þ 1). Anal. Calcd for
C21H17N3O7: C, 59.57; H, 4.05; N, 9.93. Found: C, 59.38; H,
4.17; N, 10.01.
Methyl 5-[(acetyloxy)(3-phenylisoxazol-5-yl)methyl]-3-
(2-nitrophenyl)-4,5-dihydroisoxazole-5-carboxylate (9b). This
compound was obtained in 86% as yellow oil; IR (neat): 1757
;
(CO2Me and OAc) cmꢀ1 1H NMR (deuteriochloroform): d
1742 (CO2Me), 3464 (OH) cmꢀ1 1H NMR (deuteriochloro-
;
form): d 3.71 (d, 1H, 1H of CH2, J ¼ 17.1 Hz), 3.83–3.95 (m,
9H, CH2, 1H of CH2 and 2 ꢂ CO2CH3), 5.49 (s, 1H, CHOH),
5.58 (s, 1H, CHOH), 6.76 (s, 1H, ¼¼CH), 6.79 (s, 1H, ¼¼CH),
7.46–7.53 (m, 8H, 2 ꢂ 4ArH), 7.61–7.72 (m, 4H, 2 ꢂ 2ArH),
7.79–7.82 (m, 4H, 2 ꢂ 2ArH), 8.08–8.13 (m, 2H, 2 ꢂ 1ArH);
13C NMR (deuteriochloroform): d 41.7, 43.6, 53.8, 54.1, 68.9,
69.1, 90.6, 91.3, 102.6, 103.1, 124.5, 124.7, 125.4, 127.0,
128.8, 129.2, 130.5, 130.7, 131.4, 131.7, 134.1, 134.3, 148.2,
156.9, 163.7, 169.9, 170.3; ms: (electron sprayþ) m/z 424.1
(Mþ þ 1). Anal. Calcd for C21H17N3O7: C, 59.57; H, 4.05; N,
9.93. Found: C, 59.43; H, 3.89; N, 9.97.
2.20 (s, 3H, OCOCH3), 2.25 (s, 3H, OCOCH3), 3.72–4.02 (m,
10H, 2 ꢂ CH2 and 2 ꢂ CO2CH3), 6.62 (s, 1H, CHOAc), 6.70
(s, 1H, CHOAc), 6.72 (s, 1H, ¼¼CH), 6.83 (s, 1H, ¼¼CH),
7.46–7.48 (m, 6H, 2 ꢂ 3ArH), 7.64–7.70 (m, 4H, 2 ꢂ 2ArH),
7.77–8.05 (m, 6H, 2 ꢂ 3ArH), 8.10–8.13 (m, 2H, 2 ꢂ 1ArH);
13C NMR (deuteriochloroform): d 21.0, 21.4, 42.4, 43.4, 54.1,
54.2, 67.8, 89.1, 90.0, 103.5, 103.9, 124.4, 124.5, 125.4, 127.2,
127.3, 128.6, 128.8, 129.4, 130.7, 130.8, 131.6, 134.1, 134.2,
148.2, 156.1, 156.2, 163.0, 166.1, 166.3, 168.3, 168.9, 169.5,
169.6, 171.5; ms: (electron sprayþ) m/z 466.0 (Mþ þ 1).
Anal. Calcd for C23H19N3O8: C, 59.36; H, 4.11; N, 9.03.
Found: C, 59.21; H, 4.01; N, 9.12.
Methyl 5-{hydroxy[3-(4-methylphenyl)isoxazol-5-yl]methyl}-
3-phenyl-4,5-dihydroisoxazole-5-carboxylate (17). This com-
pound was obtained in 85% as a white solid, mp. 118–120ꢁC;
1
Methyl 3-(2-nitrophenyl)-5-[(3-phenylisoxazol-5-yl)methyl]-
4,5-dihydroisoxazole-5-carboxylate (9c). This compound was
IR (potassium bromide): 1744 (CO2Me), 3438 (OH) cmꢀ1; H
NMR (deuteriochloroform): d 2.40 (s, 6H, 2 ꢂ ArCH3), 3.67–
3.95 (m, 10H, 2 ꢂ CH2 and 2 ꢂ CO2CH3), 5.55 (s, 1H,
CHOH), 5.56 (s, 1H, CHOH), 6.68 (s, 1H, ¼¼CH), 6.69 (s, 1H,
¼¼CH), 7.24–7.28 (m, 6H, 2 ꢂ 3ArH), 7.37–7.43 (m, 4H, 2 ꢂ
2ArH), 7.15–7.19 (m, 2H, 2 ꢂ 1ArH), 7.63–7.70 (m, 6H, 2 ꢂ
3ArH); 13C NMR (deuteriochloroform): d 21.8, 21.9, 38.9,
41.9; 53.8, 68.9, 69.0, 90.0, 91.0, 102.0, 126.0, 127.2, 127.4,
128.6, 128.9, 129.2, 130.1, 131.2, 140.8, 141.3, 157.9, 162.8,
169.4, 169.7; ms: (electron sprayþ) m/z 393.1 (Mþ þ 1).
Anal. Calcd for C22H20N2O5: C, 67.34; H, 5.14; N, 7.14.
Found: C, 67.47; H, 5.01; N, 7.21.
obtained in 87% as brown oil; IR (neat): 1743 (CO2Me) cmꢀ1
;
1H NMR (deuteriochloroform): d 3.45 (d, 1H, 1H of CH2, J ¼
17.4 Hz), 3.64 (s, 2H, CH2), 3.85 (d, 1H, 1H of CH2, J ¼ 17.4
Hz), 3.91 (s, 3H, CO2CH3), 6.62 (s, 1H, ¼¼CH), 7.45–7.48 (m,
4H, ArH), 7.58–7.72 (m, 2H, ArH), 7.79–7.81 (m, 2H, ArH),
8.11 (d, 1H, ArH, J ¼ 7.3 Hz); 13C NMR (deuteriochloro-
form): d 33.9, 45.6, 54.0, 88.1, 102.8, 124.6, 125.4, 127.3,
129.1, 129.4, 130.6, 131.5, 131.6, 134.2, 148.1, 156.2, 163.2,
167.4, 170.6; ms: (electron sprayþ) m/z 408.1 (Mþ þ 1).
Anal. Calcd for C21H17N3O6: C, 61.91; H, 4.21; N, 10.31.
Found: C, 62.13; H, 4.12; N, 10.39.
2-[3-(2-Nitrophenyl)-4,5-dihydroisoxazol-5-yl]-1-(3-phe-
nylisoxazol-5-yl)ethan-1-ol (23). This compound was obtained
Methyl 5-{hydroxy[3-(4-methylphenyl)isoxazol-5-yl]methyl}-3-
(2-nitrophenyl)-4,5-dihydroisoxazole-5-carboxylate (10a). This
compound was obtained in 89% as pale yellow oil; IR (neat):
;
1742 (CO2Me), 3371 (OH) cmꢀ1 1H NMR (deuteriochloro-
form): d 2.40 (s, 6H, 2 ꢂ ArCH3), 3.63–3.84 (m, 4H, 2 ꢂ CH2),
3.88 (s, 3H, CO2CH3), 3.93 (s, 3H, CO2CH3), 5.46 (s, 1H,
CHOH), 5.55 (s, 1H, CHOH), 6.72 (s, 1H, ¼¼CH), 6.74 (s, 1H,
in 69% as yellow oil; IR (neat): 3414 (OH) cmꢀ1 1H NMR
;
(deuteriochloroform): d 2.38–2.56 (m, 2H, CH2), 3.00–3.14
(m, 1H, 1H of CH2), 3.37–3.46 (m, 1H, 1H of CH2), 5.01–
5.28 (m, 1H, CHOH), 5.22–5.25 (m, 1H, CHCH2), 6.62 (s,
1H, ¼¼CH), 7.44–7.46 (m, 3H, ArH), 7.57–7.70 (m, 3H, ArH),
7.79–7.82 (m, 2H, ArH), 8.06–8.09 (m, 1H, ArH); 13C NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
Unusual Retention of Isoxazole Ring under the Influence of 3-(Substituted nitrophenyl)-
2-isoxazoline during Catalytic Hydrogenation of Isoxazoline-Substituted Isoxazole Systems
767
(deuteriochloroform): d 40.7, 42.9, 65.3, 78.4, 99.5, 124.9,
125.4, 126.8, 128.8, 129.0, 130.1, 130.8, 131.0, 141.6, 156.0,
162.4, 174.6; ms: (electron sprayþ) m/z 380.0 (Mþ þ 1).
Anal. Calcd for C20H17N3O5: C, 63.32; H, 4.52; N, 11.08.
Found: C, 63.49; H, 4.47; N, 11.34.
Methyl 5-[acetoxy-(5-phenylisoxazol-3-yl)-methyl]-3-(2-
amino-phenyl)-4,5-dihydromisoxazole-5-carboxylate (3b).
This compound was obtained in 63% as yellow oil; IR (neat):
1743 (CO2Me), 3358 (NH) cmꢀ1 1H NMR (deuteriochloro-
;
form): d 2.17 (s, 3H, OCOCH3), 3.53–3.67 (m, 3H, CH2 and
1H of CH2), 3.86 (s, 3H, CO2CH3), 4.03 (d, 1H, 1H of CH2, J
¼ 17.0 Hz), 5.59 (s, 2H, NH2), 6.56 (s, 1H, ¼¼CH), 6.69–6.75
(m, 2H, ArH), 7.12–7.23 (m, 2H, ArH), 7.45–7.47 (m, 3H,
ArH), 7.78–7.79 (m, 2H, ArH); 13C NMR (deuteriochloro-
form): d 34.0, 44.8, 53.8, 85.6, 102.4, 110.8, 116.4, 117.0,
127.2, 129.3, 130.1, 130.5, 131.7, 147.3, 158.5, 163.1, 167.6,
171.1; ms: (electron sprayþ) m/z 436.1 (Mþ þ 1). Anal. Calcd
for C23H21N3O6: C, 63.44; H, 4.86; N, 9.65. Found: C, 63.68;
H, 5.07; N, 9.56.
1-[3-(4-Methylphenyl)isoxazol-5-yl]-2-[3-(2-nitrophenyl)-
4,5-dihydroisoxazol-5-yl]ethan-1-ol (24). This compound was
obtained in 74% as pale yellow oil; IR (neat): 3382 (OH)
cmꢀ1; 1H NMR (deuteriochloroform): d 2.28–2.49 (m, 5H, CH2
and ArCH3), 2.97–3.18 (m, 1H, 1H of CH2), 3.35–3.51 (m, 1H,
1H of CH2), 5.01–5.16 (m, 1H, CHOH), 5.21–5.24 (m, 1H,
CHCH2), 6.60 (s, 1H, ¼¼CH), 7.24–7.28 (m, 1H, ArH), 7.55–
7.61 (m, 2H, ArH), 7.62–7.72 (m, 3H, ArH), 8.08 (d, 2H, ArH, J
¼ 7.7 Hz); 13C NMR (deuteriochloroform): d 21.7, 40.9, 41.3,
64.8, 79.5, 99.6, 125.0, 125.3, 126.5, 128.3, 129.2, 130.3, 130.6,
131.4, 141.2, 157.1, 162.1, 174.3; ms: (electron sprayþ) m/z
394.0 (Mþ þ 1). Anal. Calcd for C21H19N3O5: C, 64.12; H,
4.87; N, 10.68. Found: C, 63.91; H, 5.03; N, 10.47.
Methyl 3-(2-amino-phenyl)-5-[hydroxy-(5-methyl-3-phenyli-
soxazol-4-yl)-methyl]-4,5-dihydro-isoxazole-5-carboxylate
(6a). This compound was obtained in 66% as yellow oil; IR
(neat): 1731 (CO2Me), 3466 (NH and OH) cmꢀ1 1H NMR
;
(deuteriochloroform): d 2.66 (s, 3H, CH3), 3.21 (d, 1H, 1H of
CH2, J ¼ 17.0 Hz), 3.44 (d, 1H, 1H of CH2, J ¼ 17.0 Hz),
3.60 (s, 3H, CO2CH3), 5.40 (s, 1H, CHOH), 6.64–6.74 (m,
3H, ArH), 7.15–7.21 (m, 1H, ArH), 7.50–7.54 (m, 3H, ArH),
7.55–7.59 (m, 2H, ArH); 13C NMR (deuteriochloroform): d
13.2, 30.3, 43.1, 53.7, 69.4, 88.7, 107.9, 110.1, 117.4, 117.9,
129.1, 129.5, 130.6, 131.7, 133.0, 147.1, 157.4, 163.2, 169.9,
170.6; ms: (electron sprayþ) m/z 408.1 (Mþ þ 1). Anal. Calcd
for C22H21N3O5: C, 64.86; H, 5.20; N, 10.31. Found: C,
64.98; H, 5.08; N, 10.43.
2-(3-Phenyl-4,5-dihydroisoxazol-5-yl)-1-(3-phenylisoxazol-
5-yl)ethan-1-ol (27). This compound was obtained in 66% as
a white solid, mp 135–137ꢁC; IR (potassium bromide): 3380
(OH) cmꢀ1 1H NMR (deuteriochloroform): d 2.31–2.38 (m,
;
2H, CH2), 3.10–3.20 (m, 1H, 1H of CH2), 3.52–3.61 (m, 1H,
1H of CH2), 4.98–5.16 (m, 1H, CHOH), 5.25–5.28 (m, 1H,
CHCH2), 6.60 (d, 1H, ¼¼CH, J ¼ 2.1 Hz), 7.41–7.48 (m, 5H,
ArH), 7.67–7.70 (m, 3H, ArH); 7.80–7.83 (m, 2H, ArH); 13C
NMR (deuteriochloroform): d 40.8, 41.3, 64.8, 77.9, 99.7,
126.9, 127.0, 128.79, 129.0, 129.3, 129.4, 130.3, 130.5, 130.6,
157.3, 162.6, 174.8; ms: (electron sprayþ) m/z 335.0 (Mþ
þ
Methyl 5-[acetoxy-(5-methyl-3-phenylisoxazol-4-yl)-methyl]-3-
(2-amino-phenyl)-4,5-dihydro-isoxazole-5-carboxylate (6b). This
compound was obtained in 92% as a white solid, mp. 180–
182ꢁC; IR (potassium bromide) 1756 (CO2Me and OAc), 3346
1). Anal. Calcd for C20H18N2O3: C, 71.84; H, 5.43; N, 8.38.
Found: C, 71.92; H, 5.21; N, 8.55.
General procedure for the synthesis of compounds 3a–c,
6a–b, 13a–c, 14–16a, 18, 25–26, and 28: as exemplified for
the compound 3a. A mixture of compound 2a (1.5 g, 3.56
mmol) and Raney-Ni (100 mg wet) in methanol (10 mL) was
subjected to hydrogenation in the Parr assembly at 40 psi. The
reaction was allowed to continue for 3 h. Thereafter, the cata-
lyst was removed by filtration of the reaction mixture through
a celite bed with methanol. The filtrate was evaporated to
obtain an oily residue, which was taken in ethyl acetate (2 ꢂ
20 mL) and washed with water (30 mL). The organic layers
were collected, dried over anhydrous Na2SO4, and the solvent
was evaporated in vacuo to obtain a crude oily product, which
was purified by column chromatography over silica gel (60–
120 mesh). Elution with hexane: ethyl acetate (70:30, v/v)
gave 0.93 g (67%) of compound 3a as a brown solid.
The Pd-on-carbon-promoted hydrogenations were performed
in similar fashion on a Parr assembly.
Methyl 3-(2-aminophenyl)-5-[hydroxy(phenylisoxazol-3-
yl)methyl]-4,5-dihydroisoxazole-5-carboxylate (3a). Mp 83–
85ꢁC; IR (potassium bromide): 1745 (CO2Me), 3352 (NH),
;
3461 (OH) cmꢀ1 1H NMR (deuteriochloroform): d 3.81 (d,
1H, 1H of CH2, J ¼ 17.1 Hz), 3.88 (s, 3H, CO2CH3), 3.98 (d,
1H, 1H of CH2, J ¼ 17.1 Hz), 5.54 (s, 1H, CHOH), 6.67–6.74
(m, 3H, ¼¼CH and ArH), 7.16–7.24 (m, 2H, ArH), 7.45–7.48
(m, 3H, ArH), 7.78–7.83 (m, 2H, ArH); 13C NMR (deuterio-
chloroform): d 42.5, 53.9, 69.2, 91.8, 99.4, 125.3, 126.3,
127.4, 128.5, 129.4, 130.9, 131.5, 134.0, 148.1, 156.6, 162.8,
170.0, 170.9; ms: (electron sprayþ) m/z 394.2 (Mþ þ 1).
Anal. Calcd for C21H19N3O5: C, 64.12; H, 4.87; N, 10.68.
Found: C, 63.98; H, 4.95; N, 10.73.
(NH) cmꢀ1 1H NMR (deuteriochloroform): d 2.16 (s, 3H,
;
OCOCH3), 2.70 (s, 3H, CH3), 3.00 (d, 1H, 1H of CH2, J ¼
17.0 Hz), 3.39 (d, 1H, 1H of CH2, J ¼ 17.0 Hz), 3.77 (s, 3H,
CO2CH3), 5.49 (s, 2H, NH2), 6.38 (s, 1H, CHOAc), 6.62–6.71
(m, 3H, ArH), 7.15–7.20 (m, 1H, ArH), 7.53–7.55 (m, 3H,
ArH), 7.59–7.63 (m, 2H, ArH); 13C NMR (deuteriochloro-
form): d 13.4, 20.9, 30.1, 43.4, 53.7, 69.6, 88.9, 107.9, 110.1,
116.4, 116.7, 129.4, 129.6, 130.4, 131.8, 132.9, 147.2, 157.4,
162.5, 169.7, 170.6, 171.8; ms: (electron sprayþ) m/z 449.9
(Mþ þ 1). HR-EIMS Calcd for C24H23N3O6: 449.1587.
Found: 449.1566.
Methyl 3-(2-aminophenyl)-5-[hydroxy(3-phenylisoxazol-
5-yl)methyl]-4,5-dihydroisoxazole-5-carboxylate (13a). This
compound was obtained in 67% as brown oil; IR (neat): 1742
(CO2Me), 3350 (NH), 3464 (OH) cmꢀ1 1H NMR (deuterio-
;
chloroform): d 3.77–3.94 (m, 5H, CH2 and CO2CH3), 5.54
(brs, 3H, CHOH and NH2), 6.67–6.74 (m, 3H, ¼¼CH and
ArH), 7.16–7.23 (m, 2H, ArH), 7.45–7.46 (m, 3H, ArH), 7.76–
7.79 (m, 2H, ArH); 13C NMR (deuteriochloroform): d 40.6,
53.9, 69.0, 89.0, 102.0, 110.9, 116.5, 117.2, 127.3, 128.9,
129.4, 130.3, 130.7, 131.8, 147.2, 159.1, 162.8, 169.6, 170.0;
ms: (electron sprayþ) m/z 394.1 (Mþ þ 1). Anal. Calcd for
C21H19N3O5: C, 64.12; H, 4.87; N, 10.68. Found: C, 64.31; H,
4.72; N, 10.79.
Methyl 3-(2-aminophenyl)-5-{hydroxy[3-(4-methylphenyl)
isoxazol-5-yl]methyl}-4,5-dihydroisoxazole-5-carboxylate
(14a). This compound was obtained in 63% as colorless oil;
;
IR (neat): 1741 (CO2Me), 3352 (NH), 3461(OH) cmꢀ1 1H
NMR (deuteriochloroform): d 2.40 (s, 3H, ArCH3), 3.78 (d,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

768
V. Singh, S. Hutait, G. P. Yadav, P. R. Maulik, and S. Batra
Vol 46
1H, 1H of CH2, J ¼ 17.1 Hz), 3.87 (s, 3H, CO2CH3), 3.97 (d,
1H, 1H of CH2, J ¼ 17.1 Hz), 5.53 (brs, 3H, CHOH and
NH2), 6.68–6.74 (m, 3H, ¼¼CH and ArH), 7.16–7.24 (m, 4H,
ArH), 7.69 (d, 2H, ArH, J ¼ 7.8 Hz); 13C NMR (deuterio-
chloroform): d 21.8, 40.5, 53.9, 69.0, 89.1, 101.9, 110.9,
116.5, 117.2, 126.0, 127.2, 130.1, 130.3, 131.7, 140.8, 147.2,
159.1, 162.8, 169.5, 170.0; ms: (electron sprayþ) m/z 408.1
(Mþ þ 1); Anal. Calcd for C22H21N3O5: C, 64.86; H, 5.20; N,
10.31. Found: C, 64.67; H, 5.09; N, 10.43.
3.5 Hz), 6.70–6.77 (m, 2H, ArH), 7.15–7.23 (m, 2H, ArH);
7.46–7.48 (m, 3H, ArH), 7.80–7.82 (m, 2H, ArH); 13C NMR
(deuteriochloroform): d 40.8, 41.2, 64.9, 78.6, 99.6, 111.8,
116.2, 116.6, 117.0, 126.1, 126.9, 129.8, 131.0, 131.3, 140.6,
147.1, 162.5, 174.5; ms: (electron sprayþ) m/z 350.1 (Mþ þ 1).
Anal. Calcd for C20H19N3O3: C, 68.75; H, 5.48; N, 12.03.
Found: C, 68.62; H, 5.19; N, 12.28.
2-[3-(2-Aminophenyl)-4,5-dihydroisoxazol-5-yl]-1-[3-(4-meth-
ylphenyl)isoxazol-5-yl]ethan-1-ol (26). This compound was
obtained in 62% as a brown solid mp 158–160ꢁC; IR (potas-
Methyl 3-(3-aminophenyl)-5-[hydroxy-(3-phenylisoxazol-5-
yl)-methyl]-4,5-dihydro-isoxazole-5-carboxylate (15a). This
compound was obtained in 73% as a brown solid, mp. 114–
116ꢁC; IR (potassium bromide): 1721 (CO2Me), 3321 (NH),
1
sium bromide): 3374 (OH and NH2) cmꢀ1; H NMR (deuterio-
chloroform): d 2.24–2.33 (m, 2H, CH2), 2.40 (s, 3H, ArCH3),
3.19–3.29 (m, 1H, 1H of CH2), 3.56–3.69 (m, 1H, 1H of
CH2), 4.63–4.94 (m, 1H, CHOH), 5.21–5.24 (m, 1H, CHCH2),
5.63 (brs, 2H, NH2), 6.58 (d, 1H, ¼¼CH, J ¼ 1.2 Hz), 6.66–
6.76 (m, 2H, ArH), 7.13–7.19 (m, 2H, ArH); 7.22–7.28 (m,
2H, ArH), 7.69 (d, 2H, ArH, J ¼ 8.0 Hz); 13C NMR (75 MHz,
deuteriochloroform): d¼ 21.7, 40.6, 42.5, 65.2, 78.0, 99.7,
111.6, 116.1, 116.8, 116.9, 126.2, 127.0, 129.9, 131.1, 131.2,
140.5, 147.0, 158.9, 162.6, 173.9; ms: (electron sprayþ) m/z
364.1 (Mþ þ 1). HR-EIMS Calcd for C21H21N3O3: 363.1583.
Found: 363.1577.
1
3456 (OH) cmꢀ1; H NMR (deuteriochloroform): d 3.72–3.88
(m, 5H, CH2 and CO2CH3), 5.31 (s, 1H, CHOH), 5.46 (s, 2H,
NH2), 6.62–6.67 (m, 2H, ¼¼CH and ArH), 6.87–6.93 (m, 2H,
ArH), 7.06–7.12 (m, 1H, ArH), 7.31–7.38 (m, 3H, ArH), 7.69–
7.70 (m, 2H, ArH); 13C NMR (deuteriochloroform): d 40.5,
52.0, 67.6, 88.1, 100.2, 111.7, 116.2, 116.4, 125.6, 127.6, 127.7,
128.4, 128.8, 145.4, 155.9, 161.1, 168.3; ms: (electron sprayþ)
m/z 394.1 (Mþ þ 1); Anal. Calcd for C21H19N3O5: C, 64.12; H,
4.87; N, 10.68. Found: C, 64.37; H, 4.98; N, 10.49.
Methyl 3-(4-aminophenyl)-5-[hydroxy-(3-phenylisoxazol-5-
yl)-methyl]-4,5-dihydro-isoxazole-5-carboxylate (16a). This
compound was obtained in 69% as yellow oil; IR (neat): 1745
1,8-Diamino-4,6-dihydroxy-1,8-diphenyloct-1-en-3-one (28).
This compound was obtained in 63% as a brown solid, mp
118–120ꢁC; IR (potassium bromide): 3410 (OH and NH2)
;
cmꢀ1 1H NMR (deuteriochloroform): d 1.71 (brs, 1H, OH),
(CO2Me), 3345 (NH), 3442 (OH) cmꢀ1
;
1H NMR (deuterio-
chloroform): d 3.83 (d, 2H, 1H of CH2, J ¼ 17.0 Hz), 3.89 (s,
3H, CO2CH3), 4.00 (d, 2H, 1H of CH2, J ¼ 17.0 Hz), 5.55 (s,
1H, CHOH), 6.73–6.75 (m, 3H, ¼¼CH and ArH), 7.19 (d, 2H,
ArH, J ¼ 7.5 Hz), 7.47–7.49 (m, 3H, ArH), 7.80–7.85 (m, 3H,
ArH); 13C NMR (deuteriochloroform): d 41.3, 53.2, 67.9, 88.7,
101.4, 111.3, 115.1, 114.9, 125.4, 126.4, 127.0, 128.1, 128.4,
129.6, 144.7, 156.7, 161.8, 168.5, 170.2; ms: (electron sprayþ)
m/z 394.2 (Mþ þ 1). Anal. Calcd for C21H19N3O5: C, 64.12;
H, 4.87; N, 10.68. Found: C, 64.27; H, 4.73; N, 10.79.
1.79–2.06 (m, 4H, 2 ꢂ CH2), 3.71 (brs, 5H, OH and 2 ꢂ
NH2), 4.15–4.22 (m, 1H, CHOH), 4.37–4.39 (m, 1H, CHOH),
4.48–4.50 (m, 1H, CHNH2), 5.53 (s, 1H, ¼¼CH), 7.33–7.57 (m,
10H, ArH); 13C NMR (deuteriochloroform): d 29.6, 30.7, 49.5,
52.9, 90.3, 126.4, 127.6, 128.6, 128.9, 129.3, 129.6, 129.9,
130.0, 134.2, 175.2; ms: (electron sprayþ) m/z 341.1 (Mþ þ 1).
Anal. Calcd for C20H24N2O3: C, 70.56; H, 7.11; N, 8.23. Found:
C, 70.75; H, 7.03; N, 8.31.
(Z)-4-Amino-1-hydroxy-4-phenylbut-3-en-2-one (30). This
compound was obtained in 67% as yellow oil; IR (neat): 1703
(CO), 3407 (OH and NH2) cmꢀ1 1H NMR (deuteriochloro-
;
form): d 3.61 (brs, 1H, OH), 4.26 (s, 2H, CH2), 5.36 (s, 1H,
¼¼CH), 7.40–7.61 (m, 5H, ArH), 9.69 (brs, 2H, NH2); ms:
(electron sprayþ) m/z 178.1 (Mþ þ 1). Anal. Calcd for
C10H11NO2: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.83; H,
6.41; N, 7.62.
General procedure for the synthesis of compounds 21–
22: as exemplified for the compound 21. To the stirred sus-
pension of Mg (0.42 g, 17.34 mmol) in anhydrous diethyl
ether (30 mL), allyl bromide (1.5 mL, 17.34 mmol) was added
under nitrogen atmosphere at room temperature and the mix-
ture was stirred for 1 h. Thereafter, the resulting Grignard rea-
gent was added to the stirred solution of appropriate aldehydes
from 19 (1.5 g, 8.67 mmol) in anhydrous diethyl ether (40
mL) dropwise via cannula under nitrogen atmosphere, and the
reaction was continued for additional 5 h. After completion,
the reaction mixture was decomposed with cold H2O maintain-
ing the pH at 5–6 with dil. HCl. The resulting mixture was
extracted with diethyl ether (3 ꢂ 30 mL). The organic layers
were combined, dried with anhydrous Na2SO4, and evaporated
to yield crude product, which was purified via silica gel chro-
matography using hexane: EtOAc (80:20, v/v) to afford 1.4 g
(75%) of compound 21 as yellow oil.
3-[(Z)-4-Amino-1-hydroxy-4-(4-methylphenyl)-2-oxobut-3-
enyl]-3-hydroxy-5-phenylpyrrolidin-2-one (18). This compound
was obtained in 85% as a pale yellow solid, mp. 90–92ꢁC; IR
(potassium bromide): 1685 (CONH), 1721 (CO), 3426 (OH
1
and NH) cmꢀ1; H NMR (deuteriochloroform): d 2.42 (s, 6H,
2 ꢂ ArCH3), 3.48 (d, 1H, 1H of CH2, J ¼ 17.1 Hz), 3.72 (d,
1H, 1H of CH2, J ¼ 17.1 Hz), 3.83–3.96 (m, 2H, CH2), 4.26
(s, 2H, 2 ꢂ ArCH), 4.36 (brs, 1H, 1H of NH2), 4.75 (s, 1H,
CHOH), 4.82 (s, 1H, CHOH), 5.34 (brs, 1H, 1H of NH2), 5.64
(brs, 1H, 1H of NH2), 5.67 (brs, 1H, 1H of NH2), 5.74 (s, 1H,
¼¼CH), 5.81 (s, 1H, ¼¼CH), 7.37–7.51 (m, 14H, 2 ꢂ 7ArH),
7.60–7.72 (m, 4H, 2 ꢂ 2ArH), 9.89 (brs, 1H, NH), 8.96 (brs,
1H, NH); 13C NMR (deuteriochloroform): d 21.5, 21.8, 33.4,
33.5, 39.9, 41.3, 89.4, 89.5, 93.9, 94.1, 103.1, 103.4, 126.1,
126.3, 127.4, 127.8, 128.2, 128.8, 129.2, 130.3, 131.2, 140.4,
141.5, 157.6, 157.7, 162.4, 162.7, 179.3, 179.5, 190.4, 190.6;
ms: (electron sprayþ) m/z 367.1 (Mþ þ 1). Anal. Calcd for
C21H22N2O4: C, 68.84; H, 6.05; N, 7.65. Found: C, 68.69; H,
6.19; N, 7.57.
2-[3-(2-Aminophenyl)-4,5-dihydroisoxazol-5-yl]-1-(3-phe-
nylisoxazol-5-yl)ethan-1-ol (25). This compound was obtained
in 63% as a yellow solid, mp 110–112ꢁC; IR (potassium bro-
mide): 3431 (OH and NH2) cmꢀ1 1H NMR (deuteriochloro-
;
form): d 2.27–2.36 (m, 2H, CH2), 3.16–3.29 (m, 1H, 1H of
CH2), 3.60–3.69 (m, 1H, 1H of CH2), 4.90–4.96 (m, 1H,
CHOH), 5.24–5.26 (m, 1H, CHCH2), 6.62 (d, 1H, ¼¼CH, J ¼
1-(3-Phenylisoxazol-5-yl)but-3-en-1-ol (21). IR (neat):
1
3411 (OH) cmꢀ1; H NMR (deuteriochloroform): d 2.65–2.76
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
Unusual Retention of Isoxazole Ring under the Influence of 3-(Substituted nitrophenyl)-
2-isoxazoline during Catalytic Hydrogenation of Isoxazoline-Substituted Isoxazole Systems
769
Southern, P. J.; Prabhakar, J.; Lorelli, W.; Smallheer, J. M.; Mousa, S.
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2006, 79, 134; (k) Adamo, M. F. A.; Donati, D.; Duffy, E. F.;
Sarti-Fantoni, P. J Org Chem 2005, 70, 8395.
(m, 2H, CH2CH), 4.94, 4.99 (dd, 1H, CHOH, J1 ¼ 6.7 Hz, J2
¼ 16.7 Hz), 5.21–5.30 (m, 2H, ¼¼CH2), 5.73–5.93 (m, 1H,
¼¼CHCH2), 6.54 (d, 1H, ¼¼CH, J ¼ 0.9 Hz), 7.42–7.49
(m, 3H, ArH), 7.78–7.82 (m, 2H, ArH); 13C NMR (deuterio-
chloroform): d 40.7, 66.9, 98.8, 120.6, 126.2, 126.7, 127.2,
129.4, 133.0, 141.3, 162.1, 174.7; ms: (electron sprayþ) m/z
216.1 (Mþ þ 1). Anal. Calcd for C13H13NO2: C, 72.54; H,
6.09; N, 6.51. Found: C, 72.31; H, 5.97; N, 6.63.
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1-[3-(4-Methylphenyl)isoxazol-5-yl]but-3-en-1-ol (22). This
compound was obtained in 90% as pale yellow oil; IR (neat):
;
3384 (OH) cmꢀ1 1H NMR (deuteriochloroform): d 2.40 (s,
3H, ArCH3), 2.65–2.75 (m, 2H, CH2CH), 4.91–5.00 (m, 1H,
CHOH), 5.20–5.30 (m, 2H, ¼¼CH2), 5.73–5.90 (m, 1H,
¼¼CHCH2), 6.51 (d, 1H, ¼¼CH, J ¼ 1.0 Hz), 7.26 (d, 2H, ArH,
J ¼ 8.0 Hz), 7.69 (d, 2H, ArH, J ¼ 8.0 Hz); 13C NMR (deu-
teriochloroform): d 21.7, 40.5, 66.6, 99.3, 120.1, 126.3, 127.0,
129.9, 132.7, 140.4, 162.5, 174.3; ms: (electron sprayþ) m/z
230.1 (Mþ þ 1). Anal. Calcd for C14H15NO2: C, 73.34; H,
6.59; N, 6.11. Found: C, 73.19; H, 6.72; N, 6.01.
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Acknowledgments. Three of the authors (VS, SH, and GPY)
gratefully acknowledge the financial support from CSIR, N. Delhi
in the form of fellowship. This work was carried out with a grant
under the DST project. The authors thank the anonymous
reviewers for their suggestions and comments.
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M ¼ 449.45, Orthorhombic, Pna2 (1), a ¼ 18.34(3), b ¼ 9.076
3
˚
˚
(214.746(2), c ¼ 8.374(1) A, V ¼ 2264.7(6) A , Z ¼ 4, Dc ¼ 1.318 g
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet