A facile one-pot synthesis of 3,5-disubstituted isoxazole derivatives using hydroxy (tosyloxy) iodobenzene

Article abstract of DOI:10.1002/jhet.1556

Hydroxy (tosyloxy) iodobenzene (HTIB), a hypervalent iodine reagent, has been extensively used for oxidative transformations. We have developed a one-pot synthesis wherein aldoximes when reacted with alkynes in the presence of HTIB result in the direct formation of isoxazoles. This simple and straightforward reaction allows for ease of purification while leading to the formation of high purity 3,5-disubstituted isoxazoles in moderate yields.

Full text of DOI:10.1002/jhet.1556

774
A Facile One-Pot Synthesis of 3,5-Disubstituted Isoxazole Derivatives
Using Hydroxy (Tosyloxy) Iodobenzene
Vol 50
*
Ravindra D. Jadhav, Hitesh D. Mistry, Hashim Motiwala, Kishorkumar S. Kadam, Shivaji Kandre, Amol Gupte,
Ashok K. Gangopadhyay, and Rajiv Sharma
Department of Medicinal Chemistry, Piramal Life Sciences Limited, Goregaon (E), Mumbai 400 063, Maharashtra, India
*
E-mail: amol.gupte@piramal.com
Received August 14, 2011
DOI 10.1002/jhet.1556
Published online 24 June 2013 in Wiley Online Library (wileyonlinelibrary.com).
Hydroxy (tosyloxy) iodobenzene (HTIB), a hypervalent iodine reagent, has been extensively used for oxidative
transformations. We have developed a one-pot synthesis wherein aldoximes when reacted with alkynes in the
presence of HTIB result in the direct formation of isoxazoles. This simple and straightforward reaction
allows for ease of purification while leading to the formation of high purity 3,5-disubstituted isoxazoles in
moderate yields.
J. Heterocyclic Chem., 50, 774 (2013).
INTRODUCTION
of asymmetric 3,5-disubstituted isoxazoles involves a two-
step synthetic protocol necessitating an additional base treat-
ment and the need for temperature control to optimize reaction
yields. Direct oxidizing agents such as ceric ammonium
nitrate, lead (IV) acetate, potassium ferricyanide, magtrieve
(CrO2), and manganese dioxide have also been used to yield
asymmetric 3,5-disubstituted isoxazoles [17]. However these
reagents also suffer from certain disadvantages that include
harsh reaction conditions, leading to the formation of signifi-
cant amounts of corresponding aldehydes from aldoximes
thereby lowering the overall yields of this reaction.
The hypervalent iodine reagent diacetoxy iodobenzene
(DIB) has been reported to react with several substituted
aldoximes resulting in the formation of their corresponding
nitrile oxide intermediates that in turn have been used to
synthesize isoxazolines following a reaction with alkenes
and isoxazoles following a reaction with alkynes [18].
However, hypervalent iodine reagents also have the poten-
tial to induce deoximation of aldoximes, thereby suppres-
sing the formation of nitrile oxides [19]. The scope of a
hypervalent iodine reagent hydroxy (tosyloxy) iodoben-
zene (HTIB), also known as Koser’s reagent, for the in situ
formation of nitrile oxide and its intramolecular dipolar
cycloaddition for the preparation of isoxazole and
isoxazoline derivatives has been recently explored by Yao
and co-workers [20]. We have explored and report the scope
of this reagent, for the conversion of aldoximes to nitrile
oxides followed by their subsequent reactivity with a
substituted alkyne resulting in the intermolecular synthesis
of 3,5-disubstituted isoxazoles. Our results demonstrate the
applicability and identify limitations of this HTIB-mediated
formation of 3,5 disubstituted isoxazoles.
Aromatic heterocycles such as isoxazoles are valuable
synthetic templates in organic and medicinal chemistry.
Several isoxazoles have been used as key intermediates for
the synthesis of complex organic molecules. The isoxazole
moiety is a part of several commercial drugs including anti-
depressants [1], anti-inflammatory agents [2], antibiotics
[3], and antifungal agents [4]. Because of the commercial
applications of isoxazoles, there has been an immense inter-
est in developing convenient methodologies for the synthesis
of this heterocycle. A few prominently reported methods for
the synthesis of asymmetric 3,5-disubstituted isoxazoles
include the condensation of 1,3-dicarbonyl compounds
with hydroxylamine [5], solid phase methods that involve
anchoring a nitrile oxide precursor onto resins [6], and
1,3-dipolar cycloaddition reactions that use 1,1-disubstituted
bromoalkenes as alkyne equivalents for regioselective
synthesis [7]. However the disadvantages of these methods
include low yields, formation of side products, and
nonselective synthesis of regioisomers.
A commonly used approach for isoxazole synthesis
involves the 1,3-dipolar cycloaddition reaction of nitrile
oxides with terminal alkynes [8]. Aldoximes that serve as
established precursors for obtaining nitrile oxides can be
conveniently generated using reported methodologies [9]
that either utilize halogenating reagents [10], direct oxidizing
reagents [11], or hypervalent iodine reagents [12].
Conventional methods use halogenating reagents such
as N-bromosuccinimide [13], N-chlorosuccinimide [14],
sodium hypochlorite [15], and tert-butyl hypochlorite [16].
However, the use of halogenating reagents for the synthesis
© 2013 HeteroCorporation

July 2013
A Facile One-Pot Synthesis of 3,5-Disubstituted Isoxazole Derivatives
Using Hydroxy (Tosyloxy) Iodobenzene
775
RESULTS AND DISCUSSION
In an attempt to explore the feasibility of this methodol-
ogy with aliphatic alkynes, the nitrile oxide intermediates
obtained from aromatic aldoximes, following a treatment
with HTIB, were reacted with mono-substituted and
di-substituted alkynes to produce di-substituted and tri-
substituted isoxazoles in moderate yields (45–60%,
Table 2, entries 1–3). The use of a heteroaromatic aldoxime
(Table 2, entry 4) also resulted in the formation of a tri-
substituted product (Table 2, compound 8d) when reacted
with dimethyl-2-butynedioate.
We have also explored the feasibility of this HTIB-
mediated methodology for studying the reactivity of
para-substituted benzaldoxime with para-substituted phe-
nyl alkynes resulting in the formation of 3,5-disubstituted
isoxazoles (Table 3, entries 1–10). It was observed that
the nature of a para-substituent on the aldoxime influenced
its reactivity. The presence of an electron donating benzy-
loxy substituent (Table 3, entry 10) on the aldoxime gave a
low 9% yield of the corresponding isoxazole. However,
electron-withdrawing substituents (Table 3, entries 1–9)
on the aldoxime yielded products (12a–12i) ranging from
30 to 57%. This study thus highlights that the formation
of a reactive nitrile oxide intermediate from aromatic
aldoximes appears to be suppressed in the presence of
electron-donating substituents.
A convenient one-pot protocol describing the synthesis
of 3,5-disubstituted isoxazoles has been developed. In this
reaction, nitrile oxide intermediates are obtained from
aromatic aldoximes following a treatment with HTIB
and are further reacted in situ with substituted alkynes to
obtain 3,5-disubstituted isoxazoles. We investigated the
feasibility of this HTIB-mediated generation of nitrile
oxides from substituted aromatic aldoximes (Table 1,
entries 1–10) and validated it following the subsequent
trapping of these reactive intermediates using ethyl
propiolate to yield several ethyl 3-(substituted phenyl)
isoxazole-5-carboxylates (Table 1, compounds 4a–4j).
The effect of electron-withdrawing and electron-donating
substituents on the reactivity of the aldoxime was also
studied. Five different electron-withdrawing substituents
(Table 1, entries 1–5) on the aldoxime yielded cor-
responding isoxazole products (4a–4e) in moderate yields
ranging from 50 to 64%. However, the presence of
electron-donating substituents (Table 1, entries 6 and 7)
displayed either negligible (4f) or no product (4g) forma-
tion. In the case of disubstitution (Table 1, entries
8 and 9), the presence of an electron-withdrawing sub-
stituent appears to override the effects of an electron-
donating substituent (4h), thereby yielding around 65%
of the 3,5-disubstituted isoxazoles. The formation of a
corresponding 3,5-disubstituted isoxazole product (4j)
following the use of a heterocyclic aldoxime (Table 1,
entry 10) also highlights the utility of this method for
such substituents.
The reaction condition thus developed can be used to
synthesize, in moderate yields, 3,5-disubstituted isoxazoles
that possess electron-withdrawing substituents on the
aromatic aldoxime. It is possible that the moderate yields
observed were a result of a competing in situ alkynyl
iodinium species formation [21]. Deoximation of the
Table 1
HTIB-mediated synthesis of 3,5-disubstituted isoxazoles using ethyl propiolate.
Entry
X
R1
Product
Yielda
1
2
3
4
5
6
7
8
9
10
–CH–
–CH–
–CH–
–CH–
–CH–
–CH–
–CH–
–CH–
–CH–
–N–
4–F
4–CI
4a
4b
4c
4d
4e
4f
4g
4h
4i
62
56
64
50
60
14
4–CF3
4–NO2
4–NO2
4–OCH2Ph
4–OCH3
2–OCH3, 4–NO2
3–F, 4–NO2
–H
No product
65
74
55
4j
aIsolated yields.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

776
R. D. Jadhav, H. D. Mistry, H. Motiwala, K. S. Kadam, S. Kandre,
A. Gupte, A. K. Gangopadhyay, and R. Sharma
Vol 50
Table 2
HTIB-mediated synthesis of 3,5-disubstituted isoxazoles/3,4,5-trisubstituted isoxazoles using substituted alkynes.
Entry
X
R1
R2
R3
Product
Yield (%)a
1
2
3
4
–CH–
–CH–
–CH–
–N–
4–CI
4–F
4–CI
–H
–H
–COOCH3
–H
–CH2OH
–COOCH3
–COCH3
8a
8b
8c
8d
45
60
55
50
–COOCH3
–COOCH3
aIsolated yields.
Table 3
HTIB-mediated synthesis of 3,5-disubstituted isoxazoles using substituted aromatic alkynes.
Entry
R
R1
Product
Yield (%)a
1
2
3
4
5
6
7
8
9
10
–NO2
–NO2
–NO2
–F
–CF3
–CI
–NO2
–NO2
–NO2
–OCH2Ph
–H
–F
–CF3
–CF3
–CF3
–CF3
–CH3
–OCH3
–C(CH3)3
–H
12a
12b
12c
12d
12e
12f
12g
12h
12i
45
44
47
35
55
57
30
49
36
9
12j
aIsolated yields.
starting aldoximes in the presence of hypervalent iodine
reagents [19] resulting in the reduction of nitrile oxide
formation can provide yet another explanation for the
moderate yields of the resulting 3,5-disubstituted isoxazoles.
This reaction condition, utilizing HTIB, appears to have
limited utility for synthesizing 3,5-disubstituted isoxazoles
possessing electron-donating substituents on the aromatic
aldoxime. However, a detailed study to gauge the scope of
electron-donating substituents is warranted because of the
limited number of examples covered herein.
subsequently obtained solid in ethanol and eventually con-
ducting a simple filtration to obtain the desired isoxazoles
as a solid. The yields reported herein are those following this
simplified workup that does not necessitate any column
chromatographic purification. The structures of all the
synthesized isoxazoles were established from their spectral
(1H NMR, 13C NMR, and HRMS) data. Interestingly, in
each case only the 3,5-disubstituted regioisomer was
obtained, as is evident from the 1H NMR data.
The advantage of this simplistic HTIB protocol for the
synthesis of 3,5-disubstituted isoxazoles lies in the ease of
reaction workup that involves a sequential evaporation
of the solvent used, followed by a trituration of the
CONCLUSIONS
In summary, an alternate intermolecular one-pot
synthesis of 3,5-disubstituted isoxazoles has been
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2013
A Facile One-Pot Synthesis of 3,5-Disubstituted Isoxazole Derivatives
Using Hydroxy (Tosyloxy) Iodobenzene
777
Procedure A: preparation of aromatic aldoximes.
To a
achieved. This reaction proceeds via a reactive nitrile oxide
intermediate synthesized in situ by reacting a substituted
aromatic aldoxime with HTIB, which on subsequent
coupling with either an aliphatic or aromatic alkyne leads
to the formation of corresponding 3,5-disubstituted isoxa-
zole. The presence of an electron-withdrawing substituent
on the aromatic aldoxime leads to moderate yields of the
corresponding isoxazoles. However, aromatic aldoximes
possessing electron-donating substituents exhibit poor
reactivity and negligible yields. The reagent, HTIB, used
in this reaction is readily available, stable, and can be
handled without any special care.
solution of the aromatic aldehyde (1.0equiv) in ethanol, pyridine
(1.5equiv) and hydroxylamine hydrochloride (2.0equiv) were
added sequentially, and the reaction mixture was refluxed
overnight. The reaction mixture was concentrated in vacuo, and
the residue was taken in water and extracted using ethyl acetate.
The organic layer was dried over sodium sulfate and evaporated
in vacuo to yield a solid product that was subsequently
recrystallized from ethyl acetate and petroleum ether to afford the
desired aromatic aldoxime.
Procedure B: preparation of 3,5-disubstitured isoxazoles.
Hydroxy (tosyloxy) iodobenzene (1.3equiv) was added to a
solution of the aromatic aldoxime (1.0 equiv) in acetonitrile, and
the mixture was stirred at 80ꢀC for 5 min. Subsequently the
alkyne (2.0equiv) was added to this reaction mixture and stirred
for an additional 2 h at 80ꢀC. Following completion of this
reaction, the solvent was removed under reduced pressure, the
residue was subsequently triturated with ethanol, and the resulting
solid was filtered and dried under vacuum to yield the title
compounds (4a–4j, 8a–8d, and 12a–12j).
Ethyl 3-(4-fluorophenyl)isoxazole-5-carboxylate (4a).
Reaction with 4-fluorobenzaldehyde oxime (0.50 g, 3.59 mmol)
and ethyl propiolate (0.72 mL, 7.18mmol) afforded compound 4a
(0.52g, 62%) as a white solid, mp 126–128ꢀC; 1H NMR
(300 MHz, DMSO-d6): d 7.82 (d, J= 9.0 Hz, 2H, phenyl), 7.21
(s, 1H, isoxazole), 7.16 (d, J= 9.0 Hz, 2H, phenyl), 4.46
(q, J=6.0Hz, 2H, CH2), 1.43 (t, J= 6.0 Hz, 3H, CH3); 13C NMR
(75 MHz, CDCl3) d 165.8, 162.5, 161.2, 156.8, 129.0, 128.9,
124.4, 116.5, 116.2, 107.3, 62.5, 14.3; HRMS (ESI+) calcd.
for C12H11FNO3 [M + H]+ 236.0717, found 236.0707 (error
4.23 ppm); HPLC: retention time 5.18 min, purity
95.73% (method A).
Ethyl 3-(4-chlorophenyl)isoxazole-5-carboxylate (4b). Reaction
with 4-chlorobenzaldehyde oxime (0.50g, 3.21mmol) and ethyl
propiolate (0.65 mL, 6.42 mmol) afforded compound 4b (0.45 g,
56%) as a white solid, mp 135–137ꢀC (lit [17]: 136–138ꢀC);
1H NMR (300 MHz, DMSO-d6): d 7.77 (d, J = 9.0Hz, 2H.
phenyl), 7.46 (d, J = 9.0 Hz, 2H, phenyl), 7.22 (s, 1H, isoxazole),
4.46 (d, J = 6.0 Hz, 2H, CH2), 1.43 (t, J = 7.2 Hz, 3H, CH3); 13C
NMR (75MHz, CDCl3) d 162.1, 161.3, 156.8, 136.8, 129.5
(2C), 128.2 (2C), 126.6, 107.3, 62.5, 14.3; HRMS (ESI+)
calcd. for C12H11ClNO3 [M+ H]+ 252.0422, found 252.0420
(error 0.79 ppm); HPLC: retention time 5.84 min, purity
99.27% (method A).
EXPERIMENTAL
Unless mentioned otherwise, all reactions were performed
under atmosphere. Unless otherwise specified, all reagents were
obtained from Aldrich (St. Louis, MO) and solvents were
obtained from Thomas Baker (Mumbai, India) and used without
further purification. 1H NMR and 13C NMR spectra were
recorded on a Bruker spectrometer (300 MHz; Billerica, MA)
1
operating at 300 and 75 MHz for H and 13C, respectively using
either CDCl3 or DMSO-d6 as the solvent. Chemical shifts, d, are
reported in parts per million (ppm) relative to solvent resonance:
CDCl3, d 7.26 (1H NMR), and 77.3 (13C NMR); DMSO-d6, d
2.50 (1H NMR), and 40.2 (13C NMR). Multiplicities are indicated
by s (singlet), d (doublet), dd (doublet of doublets), t (triplet), q
(quartet), and m (multiplet). Coupling constants, J, are reported in
Hertz. High resolution mass spectra were obtained on Bruker
Daltonics ESI-QTOF instrument equipped with an ESI interface.
Melting points have been determined on a manually operated
Veego (VMP-1; Mumbai, India) melting point apparatus and are
reported uncorrected. Analytical HPLC was obtained on a Waters
Alliance 2695 HPLC system (Milford, MA) fitted with a PDA
detector using either method A or method B as follows:
HPLC solvents
A1: acetonitrile
B1: 0.01 M NH4OAc + 0.5% TEA, pH 5.0 with AcOH
B2: 0.1% trifluoroacetic acid
HPLC columns
Ethyl 3-(4-(trifluoromethyl)phenyl)isoxazole-5-carboxylate
(4c). Reaction with 4-(trifluoromethyl)benzaldehyde oxime (0.5 g,
2.64mmol) and ethyl propiolate (0.53mL, 5.28 mmol) afforded
Column 1: Ascentis TM Express (50 Â 4.6 mm I.D.), 2.7 mm
operated at 1 mL/min, detection at 288 nm
Column 2: Kromasil 250 Â 4.6 mm, 3.5 mm, C18 operated at
1 mL/min, detection at 276 nm
1
compound 4c (0.48g, 64%) as a white solid, mp 124–126ꢀC; H
NMR (300 MHz, DMSO-d6): d 7.95 (d, J = 9.0 Hz, 2H, phenyl),
7.73 (d, J = 9.0 Hz, 2H, phenyl), 7.28 (s, 1H, isoxazole), 4.44
(d, J = 7.2 Hz, 2H, CH2), 1.43 (t, J = 7.2 Hz, 3H, CH3); 13C NMR
(75 MHz, CDCl3) d 161.9, 161.6, 156.6, 132.7, 132.3, 131.5,
127.3 (2C), 126.2, 126.1, 107.3, 62.6, 14.2; HRMS (ESI+)
calcd. for C13H11F3NO3 [M + H]+ 286.0686, found 286.0676
(error 3.49 ppm); HPLC: retention time 6.02 min, purity
99.16% (method A).
Ethyl 3-(4-nitrophenyl)isoxazole-5-carboxylate (4d). Reaction
with 4-nitrobenzaldehyde oxime (0.5 g, 3.01 mmol) and ethyl
propiolate (0.61 mL, 6.02 mmol) afforded compound 4d (0.39 g,
50%) as a white solid, mp 152–154ꢀC; 1H NMR (300 MHz,
CDCl3): d 8.35 (d, J= 9.0 Hz, 2H, phenyl), 8.03 (d, J=9.0Hz, 2H,
phenyl), 7.32 (s, 1H, isoxazole), 4.47 (q, J= 6.0 Hz, 2H, CH2), 1.44
HPLC methods
Method A: Elution with 20–80% linear gradient of A1 in 6 min
followed by 20–80% linear gradient of B1 in 1 min that is continued
using an isocratic elution with 80% B1 for 3 min using Column 1.
Method B: Elution with 10–90% linear gradient of A1 in 20 min
followed by 10–90% linear gradient of B2 in 2 min that is continued
using an isocratic elution with 90% B2 for 8 min using Column 2.
The aldoximes used for synthesis were prepared in-house
using a reported procedure and characterized completely using
1H NMR and mass spectrometry. General procedures used for
the synthesis of these aromatic aldoximes (procedure A) and its
subsequent conversion to 3,5-disubstitured isoxazoles (procedure
B) are provided in the following sections.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

778
R. D. Jadhav, H. D. Mistry, H. Motiwala, K. S. Kadam, S. Kandre,
A. Gupte, A. K. Gangopadhyay, and R. Sharma
Vol 50
(t, J= 6.0 Hz, 3H, CH3); 13C NMR (75MHz, CDCl3) d 161.4, 160.7,
155.9, 148.6, 133.5, 127.4 (2C), 123.9 (2C), 106.8, 62.2, 13.7;
HRMS (ESI+) calcd. for C12H11N2O5 [M + H]+ 263.0662, found
263.0668 (error 2.28 ppm); HPLC: retention time 4.98 min, purity
99.61% (method A).
1.34 (t, J = 7.0 Hz, 3H, CH3); 13C NMR (75 MHz, DMSO-d6)
d 164.0, 161.2, 156.6, 150.6, 146.9, 138.2, 126.1, 122.2, 108.5,
62.7, 14.4; HRMS (ESI+) calcd. for C11H11N2O3 [M + H]+
219.0764, found 219.0757 (error 3.19ppm); HPLC: retention time
3.75min, purity 99.11% (method A).
Ethyl 3-(3-nitrophenyl)isoxazole-5-carboxylate (4e). Reaction
with 3-nitrobenzaldehyde oxime (0.5g, 3.01 mmol) and
ethyl propiolate (0.61mL, 6.02 mmol) afforded compound 4e
(0.47 g, 60%) as a white solid, mp 125–127ꢀC; 1H NMR
(300MHz, CDCl3): d 8.65 (s, 1H, phenyl), 8.34 (dd, J = 9.0,
6.0 Hz, 1H, phenyl), 8.21 (d, J = 6.0 Hz, 1H, phenyl), 7.70
(t, J = 9.0 Hz, 1H, phenyl), 7.34 (s, 1H, isoxazole), 4.47
(q, J = 6.0Hz, 2H, CH2), 1.44 (t, J = 6.0 Hz, 3H, CH3); 13C NMR
(75 MHz, CDCl3) d 161.9, 161.2, 156.5, 148.8, 132.6, 130.5,
129.9, 125.2, 121.9, 107.2, 62.7, 14.2; HRMS (ESI+) calcd.
for C12H11N2O5 [M+ H]+ 263.0662, found 263.0671 (error
(3-(4-chlorophenyl)isoxazol-5-yl)methanol (8a). Reaction with
4-chlorobenzaldehyde oxime (0.25 g, 1.60 mmol) and propargyl
alcohol (0.18 mL, 3.20 mmol) afforded compound 8a (0.15 g, 45%)
as a white solid, mp 98–100ꢀC (lit [22]: 98–100ꢀC); 1H NMR
(300 MHz, DMSO-d6): d 7.72 (d, J= 9.0 Hz, 2H, phenyl), 7.43
(d, J= 9.0 Hz, 2H, phenyl), 6.54 (s, 1H, isoxazole), 4.82 (s, 2H,
CH2); 13C NMR (75MHz, CDCl3) d 172.3, 161.7, 136.3, 131.7,
129.4, 129.0, 128.2, 127.4, 100.0, 56.7; HRMS (ESI+) calcd. for
C10H9ClNO2 [M + H]+ 210.0316, found 210.0319 (error 1.42 ppm);
HPLC: retention time 3.43 min, purity 97.25% (method A).
Dimethyl 3-(4-fluorophenyl)isoxazole-4,5-dicarboxylate (8b).
Reaction with 4-fluorobenzaldehyde oxime (0.25 g, 1.79 mmol) and
dimethyl-2-butynedioate (0.43 mL, 3.58 mmol) afforded compound
8b (0.33g, 60%) as a white solid, mp 110–112ꢀC; 1H NMR
(300 MHz, DMSO-d6): d 7.71 (d, J = 9.0 Hz, 2H, phenyl), 7.39
(m, 2H, phenyl), 3.94 (s, 3H, CH3), 3.84 (s, 3H, CH3); 13C NMR
(75 MHz, DMSO-d6) d 165.2, 163.1, 161.5, 160.4, 156.4, 130.9,
130.8, 123.2, 116.9, 116.7, 115.6, 54.1, 53.8; HRMS (ESI+)
calcd. for C13H11FNO5 [M + H]+ 280.0616, found 280.0620 (error
3.42 ppm);
HPLC:
retention
time
5.03min,
purity
96.11% (method A).
Ethyl 3-(4-(benzyloxy)phenyl)isoxazole-5-carboxylate (4f).
Reaction with 4-(benzyloxy)benzaldehyde oxime (0.2 g,
2.20 mmol) and ethyl propiolate (0.44 mL, 4.40 mmol) afforded
compound 4f (0.04 g, 14%) as an off-white solid, mp 112–114ꢀC;
1H NMR (300 MHz, DMSO-d6): d 7.79 (d, J = 9.0 Hz, 2H,
phenyl), 7.41 (m, 5H, phenyl), 7.28 (s, 1H, isoxazole), 7.08
(d, J = 9.0 Hz, 2H, phenyl), 5.14 (s, 2H, OCH2), 4.47
(d, J = 6.0Hz, 2H, CH2), 1.45 (t, J = 6.0 Hz, 3H, CH3); 13C NMR
(75 MHz, CDCl3) d 162.5, 160.7, 160.6, 156.9, 136.4, 128.7 (2C),
128.3 (2C), 128.2, 127.5 (2C), 120.7, 115.4 (2C), 107.2, 70.1,
62.3, 14.2; HRMS (ESI+) calcd. for C19H18NO4 [M+ H]+
324.1230, found 324.1242 (error 3.70ppm); HPLC: retention time
6.38 min, purity 95.79% (method A).
Ethyl 3-(2-methyl-4-nitrophenyl)isoxazole-5-carboxylate (4h).
Reaction with 2-methyl-4-nitrobenzaldehyde oxime (0.5 g,
2.20 mmol) and ethyl propiolate (0.44 mL, 4.40 mmol) afforded
compound 4h (0.49g, 65%) as a white solid, mp 92–94ꢀC; 1H
NMR (300 MHz, DMSO-d6): d 8.26 (d, J= 1.5 Hz, 1H, phenyl),
8.14 (dd, J= 2.1, 8.4 Hz, 1H, phenyl), 7.90 (d, J= 8.7 Hz, 1H,
phenyl), 7.80 (s,1H, isoxazole), 4.40 (q, J= 6.9 Hz, 2H, CH2), 2.55
(s, 3H, Ar-CH3), 1.33 (t, J= 6.9 Hz, 3H, CH3); 13C NMR (75MHz,
DMSO-d6) d 162.7, 160.7, 156.7, 148.7, 139.7, 134.0, 131.7,
126.2, 121.7, 110.9, 62.8, 21.3, 14.5; HRMS (ESI+) calcd. for
C13H13N2O5 [M + H]+ 277.0819, found 277.0829 (error 3.60 ppm);
HPLC: retention time 5.42 min, purity 98.10% (method A).
1.42ppm);
HPLC:
retention
time
4.84min,
purity
99.41% (method A).
1-(3-(4-Chlorophenyl)isoxazol-5-yl)ethanone (8c). Reaction with
4-chlorobenzaldehyde oxime (0.25 g, 1.60 mmol) and 3-butyne-2-
one (0.25 mL, 3.20 mmol) afforded compound 8c (0.19 g, 55%) as
a white solid, mp 133–135ꢀC (lit [23]: 134–136ꢀC); 1H NMR
(300 MHz, DMSO-d6): d 7.99 (m, 3H, 2H-phenyl, 1H-isoxazole),
7.63 (d, J= 8.4 Hz, 2H, phenyl), 2.61 (s, 3H, CH3); 13C NMR
(75 MHz, DMSO-d6) d 186.9, 166.9, 162.3, 135.9, 129.8 (2C),
128.9 (2C), 126.9, 107.5, 27.9; HRMS (ESI+) calcd. for
C11H9ClNO2 [M + H]+ 222.0316, found 222.0324 (error 3.60 ppm);
HPLC: retention time 4.92 min, purity 99.35% (method A).
Dimethyl 3-(pyridin-2-yl)isoxazole-4,5-dicarboxylate (8d).
Reaction with picolinaldehyde oxime (0.25 g, 2.04 mmol) and
dimethyl-2-butynedioate (0.23 mL, 4.08 mmol) afforded compound
8d (0.29 g, 50%) as a white solid, mp 90–92ꢀC; 1H NMR
(300 MHz, DMSO-d6): d 8.67 (m, 1H, phenyl), 8.02 (m, 2H,
phenyl), 7.57 (m, 1H, phenyl), 3.94 (s, 3H, CH3), 3.84 (s, 3H,
CH3); 13C NMR (75 MHz, DMSO-d6) d 161.8, 161.1, 158.3,
156.1, 150.6, 145.9, 138.5, 126.5, 122.7, 117.1, 54.1, 53.6; HRMS
(ESI+) calcd. for C12H11N2O5 [M + H]+ 263.0662, found 263.0671
(error 4.18 ppm); HPLC: retention time 3.66 min, purity
99.97% (method A).
Ethyl 3-(3-fluoro-4-nitrophenyl)isoxazole-5-carboxylate (4i).
Reaction with 3-fluoro-4-nitrobenzaldehyde oxime (0.5 g,
2.72 mmol) and ethyl propiolate (0.55 mL, 5.44 mmol) afforded
1
compound 4i (0.56 g, 74%) as a white solid, mp 144–146ꢀC; H
NMR (300 MHz, DMSO-d6): d 8.30 (t, J= 9.0 Hz, 1H, phenyl),
8.18 (d, J= 9.0 Hz, 1H, phenyl), 8.04 (d, J= 9.0 Hz, 1H, phenyl),
8.00 (s, 1H, isoxazole), 4.45 (q, J= 6.0 Hz, 2H, CH2), 1.38
(t, J= 6.0 Hz, 3H, CH3); 13C NMR (75 MHz, DMSO-d6) d 161.2,
160.7, 155.9, 153.2, 137.8, 134.7, 127.3, 123.2, 117.1, 108.5, 62.4,
13.9; HRMS (ESI+) calcd. for C12H10FN2O5 [M + H]+ 281.0568,
found 281.0576 (error 2.84 ppm); HPLC: retention time 5.07 min,
purity 98.09% (method A).
Ethyl 3-(pyridin-2-yl)isoxazole-5-carboxylate (4j). Reaction
with picolinaldehyde oxime (0.5 g, 4.09 mmol) and ethyl
propiolate (0.82 mL, 8.18mmol) afforded compound 4j
(0.49 g, 55%) as a yellow solid, mp 70–72ꢀC; 1H NMR
(300MHz, DMSO-d6): d 8.73 (d, J = 4.8 Hz, 1H, phenyl), 8.09
(d, J = 8.1 Hz, 1H, phenyl), 7.99 (m, 1H, phenyl), 7.66 (s, 1H,
isoxazole), 7.55 (m, 1H, phenyl), 4.39 (q, J = 7.0 Hz, 2H, CH2),
3-(4-Nitrophenyl)-5-phenylisoxazole (12a). Reaction with
4-nitrobenzaldehyde
oxime
(0.25 g,
1.50 mmol)
and
phenylacetylene (0.32 mL, 3.00 mmol) afforded compound 12a
(0.18 g, 45%) as a white solid, mp 224–226ꢀC (lit [24]: 226–
228ꢀC); 1H NMR (300 MHz, DMSO-d6): d 8.42 (d, J=9.0Hz,
2H, phenyl), 8.22 (d, J= 9.0 Hz, 2H, phenyl), 7.95 (m, 2H, phenyl)
7.80 (s, 1H, isoxazole), 7.60 (m, 3H, phenyl); 13C NMR (75MHz,
CDCl3) d 169.5, 161.2, 148.6, 134.6, 128.0 (2C), 127.8, 126.7,
126.2 (2C), 125.4 (2C), 124.3 (2C), 98.9; HRMS (ESI+) calcd. for
C15H11N2O3 [M + H]+ 267.0764, found 267.0776 (error 4.49 ppm);
HPLC: retention time 6.09 min, purity 97.46% (method A).
5-(4-Fluorophenyl)-3-(4-nitrophenyl)isoxazole (12b). Reaction
with 4-nitrobenzaldehyde oxime (0.25 g, 1.50 mmol) and 4-
fluorophenylacetylene (0.34 mL, 3.00 mmol) afforded compound
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2013
A Facile One-Pot Synthesis of 3,5-Disubstituted Isoxazole Derivatives
Using Hydroxy (Tosyloxy) Iodobenzene
779
12b (0.18 g, 45%) as a white solid, mp 206–208ꢀC; 1H NMR
(300 MHz, DMSO-d6): d 8.38 (d, J= 8.7 Hz, 2H, phenyl), 8.07
(d, J= 8.7 Hz, 2H, phenyl), 7.87 (m, 2H, phenyl), 7.23 (m, 2H,
phenyl), 6.87 (s, 1H, isoxazole); 13C NMR (75 MHz, CDCl3) d
170.5, 165.7, 161.3, 148.7, 135.1, 128.1, 127.9, 127.7 (2C), 124.3
(2C), 123.3, 116.6, 116.3, 97.3; HRMS (ESI+) calcd. for
C15H10FN2O3 [M + H]+ 285.0670, found 285.0682 (error 4.20 ppm);
HPLC: retention time 6.18 min, purity 98.54% (method A).
Ar-CH3); 13C NMR (75MHz, DMSO-d6) d 171.1, 161.6, 148.8,
141.2, 135.1, 130.3 (2C), 128.3 (2C), 126.0 (2C), 124.8 (2C),
124.3, 98.9, 21.5; HRMS (ESI+) calcd. for C16H13N2O3 [M + H]+
281.0921, found 281.0931 (error 3.55 ppm); HPLC: retention time
20.52 min, purity 99.89% (method B).
5-(4-Methoxyphenyl)-3-(4-nitrophenyl)isoxazole (12h).
Reaction with 4-nitrobenzaldehyde oxime (0.25 g, 1.50 mmol)
and 4-ethynyl anisole (0.39 mL, 3.00 mmol) afforded compound
12h (0.21 g, 49%) as a white solid, mp 173–175ꢀC (lit [24]:
3-(4-Nitrophenyl)-5-(4-(trifluoromethyl)phenyl)isoxazole (12c).
Reaction with 4-nitrobenzaldehyde oxime (0.25 g, 1.50mmol)
and 4-trifluoromethylphenylacetylene (0.49 mL, 3.00mmol)
afforded compound 12c (0.23 g, 47%) as an off-white solid, mp
172–175ꢀC); 1H NMR (300 MHz, DMSO-d6):
d
8.36
(d, J = 8.7 Hz, 2H, phenyl), 8.06 (d, J = 8.7 Hz, 2H, phenyl),
7.81 (d, J = 8.7 Hz, 2H, phenyl), 7.04 (d, J = 8.7 Hz, 2H,
phenyl), 6.79 (s, 1H, isoxazole), 3.90 (s, 3H, OCH3); 13C NMR
(75 MHz, CDCl3) d 169.8, 162.4, 162.1, 148.8, 133.8, 127.6,
127.5, 127.0, 124.2 (2C), 123.6, 114.5 (2C), 114.2, 96.1, 55.4;
HRMS (ESI+) calcd. for C16H13N2O4 [M + H]+ 297.0870,
found 297.0872 (error 0.67 ppm); HPLC: retention time
6.08 min, purity 97.63% (method A).
186–188ꢀC; 1H NMR (300MHz, DMSO-d6):
d
8.38
(d, J = 9.0 Hz, 2H, phenyl), 8.08 (d, J = 9.0 Hz, 2H, phenyl), 8.00
(d, J = 8.1 Hz, 2H, phenyl), 7.80 (d, J = 8.4 Hz, 2H, phenyl), 7.03
(s, 1H, isoxazole); 13C NMR (75 MHz, CDCl3) d 169.8, 161.4,
148.8, 134.8, 132.6, 132.1, 129.9, 127.7 (2C), 126.2 (3C), 125.4,
124.3 (2C), 98.9; HRMS (ESI+) calcd. for C16H10F3N2O3
[M+ H]+ 335.0638, found 335.0641 (error 0.89 ppm); HPLC:
retention time 6.85min, purity 97.24% (method A).
3-(4-Fluorophenyl)-5-(4-(trifluoromethyl)phenyl)isoxazole
(12d). Reaction with 4-fluorobenzaldehyde oxime (0.25 g,
1.79 mmol) and 4-trifluoromethylphenylacetylene (0.29mL,
3.58 mmol) afforded compound 12d (0.19 g, 35%) as a white
solid, mp 112–114ꢀC; 1H NMR (300 MHz, DMSO-d6): d 8.13
(d, J = 9.0 Hz, 2H, phenyl), 7.97 (m, 4H, phenyl), 7.84 (s, 1H,
isoxazole), 7.44 (d, J = 9.0 Hz, 2H, phenyl); 13C NMR (75MHz,
DMSO-d6) d 168.7, 162.4, 162.1, 130.9, 130.8, 130.5, 129.5,
129.4, 126.8 (2C), 126.1, 125.3, 122.7, 116.9, 116.6, 100.9;
HRMS (ESI+) calcd. for C16H10F4NO [M+ H]+ 308.0693, found
308.0696 (error 0.97ppm); HPLC: retention time 6.97 min, purity
99.72% (method A).
3,5-bis(4-(Trifluoromethyl)phenyl)isoxazole (12e). Reaction
with 4-(trifluoromethyl) benzaldehyde oxime (0.25g, 1.32mmol)
and 4-trifluoromethylphenylacetylene (0.21 mL, 2.64mmol)
afforded compound 12e (0.26g, 55%) as a white solid, mp
154–156ꢀC; 1H NMR (300MHz, DMSO-d6): d 8.15 (m, 4H,
phenyl), 7.96 (m, 5H, 4 H-phenyl, 1H-isoxazole); 13C NMR
(75 MHz, DMSO-d6) d 169.1, 162.2, 132.6, 131.8, 131.3, 130.6,
127.9 (2C), 126.8 (4 C), 126.7 (2C), 126.4, 125.1, 101.2; HRMS
(ESI+) calcd. for C17H10F6NO [M+ H]+ 358.0661, found
358.0674 (error 3.63ppm); HPLC: retention time 5.70 min, purity
99.04% (method A).
5-(4-(tert-Butyl)phenyl)-3-(4-nitrophenyl)isoxazole (12i).
Reaction with 4-nitrobenzaldehyde oxime (0.25 g, 1.50 mmol) and
4-(tert-butyl)phenylacetylene (0.54 mL, 3.00 mmol) afforded
1
compound 12i (0.17g, 36%) as a white solid, mp> 230ꢀC; H
NMR (300 MHz, CDCl3): d 8.41 (d, J = 9.0 Hz, 2H, phenyl), 8.21
(d, J = 8.7 Hz, 2H, phenyl), 7.86 (d, J = 8.4 Hz, 2H, phenyl), 7.74
(s,1H, isoxazole), 7.62 (d, J = 8.4 Hz, 2H, phenyl), 1.33 (s, 9H,
(CH3)3); 13C NMR (75 MHz, DMSO-d6) d 169.3, 162.0, 151.3,
147.9, 134.3, 128.3 (2C), 126.6 (2C), 125.9 (2C), 124.9
(2C), 122.5, 100.9, 34.3, 31.3 (3 C); HRMS (ESI+) calcd.
for C19H19N2O3 [M+ H]+ 323.1390, found 323.1387 (error
0.92ppm); HPLC: retention time 22.13 min, purity
99.89% (method B).
3-(4-(Benzyloxy)phenyl)-5-(4-(trifluoromethyl)phenyl)isoxazole
(12j). Reaction with 4-(benzyloxy)benzaldehyde oxime (0.25 g,
1.10 mmol) and phenylacetylene (0.24 mL, 2.20 mmol) afforded
compound 12j (0.038 g, 9%) as an off-white solid, mp 144–146ꢀC;
1H NMR (300MHz, DMSO-d6): d 7.91 (dd, J = 1.5, 8.1 Hz, 2H,
phenyl), 7.87 (d, J= 9.0 Hz, 2H, phenyl), 7.56 (m, 3H, phenyl),
7.49 (d, J= 6.9 Hz, 2H, phenyl), 7.38 (m, 4H, 3H-phenyl,
1H-isoxazole) 7.19 (d, J = 8.7 Hz 2H, phenyl), 5.19 (s, 2H, CH2);
13C NMR (75 MHz, CDCl3) d 170.2, 162.6, 160.2, 136.6, 130.2,
128.9 (2C), 128.7 (2C), 128.2 (2C), 128.1 (2C), 127.5 (2C), 125.8
(2C), 121.9, 115.2 (2C), 97.3, 70.1; HRMS (ESI+) calcd. for
C22H18NO2 [M + H]+ 328.1332, found 328.1329 (error 0.91 ppm);
HPLC: retention time 7.22 min, purity 99.76% (method A).
3-(4-Chlorophenyl)-5-(4-(trifluoromethyl)phenyl)isoxazole
(12f).
Reaction with 4-chlorobenzaldehyde oxime (0.25 g,
1.60 mmol) and 4-trifluoromethylphenylacetylene (0.26mL,
3.20 mmol) afforded compound 12f (0.29g, 57%) as a white
solid, mp 120–122ꢀC; 1H NMR (300 MHz, DMSO-d6): d 8.13
(d, J = 8.1 Hz, 2H, phenyl), 7.96 (d, J = 8.4 Hz, 4H, phenyl), 7.86
(s, 1H, isoxazole), 7.65 (d, J = 8.4Hz, 2H, phenyl); 13C NMR
(75 MHz, DMSO-d6) d 168.8, 162.4, 135.6, 130.9, 130.7, 130.5,
129.8 (2C), 128.8 (2C), 127.6, 126.8 (2C), 126.1, 122.5, 100.9;
HRMS (ESI+) calcd. for C16H10ClF3NO [M + H]+ 324.0399,
found 324.0398 (error 0.30 ppm); HPLC: retention time
22.55 min, purity 98.97% (method B).
3-(4-Nitrophenyl)-5-(p-tolyl)isoxazole (12g). Reaction with
4-nitrobenzaldehyde oxime (0.25 g, 1.50mmol) and 4-
methylphenylacetylene (0.35g, 3.00 mmol) afforded compound
12g (0.12g, 30%) as a white solid, mp 178–180ꢀC; 1H NMR
(300MHz, DMSO-d6): d 8.41 (d, J = 8.7 Hz, 2H, phenyl), 8.19
(d, J = 8.7 Hz, 2H, phenyl), 7.82 (d, J = 8.1 Hz, 2H, phenyl), 7.72
(s, 1H, isoxazole), 7.40 (d, J = 8.4 Hz, 2H, phenyl), 2.39 (s, 3H,
Acknowledgments. Analytical support provided by the Discovery
Analytical Sciences Department at Piramal Life Sciences Limited is
gratefully acknowledged. Part of this work has been presented at the
14th ISCB International Conference held at Central Drug Research
Institute, Lucknow, India, in January 2010.
REFERENCES AND NOTES
[1] Fiedorowicz, J. G.; Swartz, K. L. J Psychiatr Pract 2004, 10, 239.
[2] Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Koboldt,
C. M.; Masferrer, J. L.; Perkins, W. E.; Rogers, R. S.; Shaffer, A. F.; Zhang,
Y. Y.; Zweifel, B. S.; Seibert, K. J Med Chem 2000, 43, 775.
[3] Yang, S.; Xiong, Y. Q.; Boyle-Vavra, S.; Daum, R.; Jones, T.;
Bayer, A. S. Antimicrob Agents Chemother 2010, 54, 3161.
[4] Bormann, A. M.; Morrison, V. A. Drug Design Dev Ther
2009, 3, 295.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

780
R. D. Jadhav, H. D. Mistry, H. Motiwala, K. S. Kadam, S. Kandre,
A. Gupte, A. K. Gangopadhyay, and R. Sharma
Vol 50
[5] Katritzky, A. R.; Wang, M.; Zhang, S.; Voronkov, M. V. J Org
[15] Lee, G. A. Synthesis 1982, 6, 508.
Chem 2001, 66, 6787.
[16] Ye, Y.; Zheng, Y.; Xu, G.; Liu, L. Heteroatom Chem 2003, 14,
[6] (a) Shen, D.; Shu, M.; Chapman, K. T. Org Lett 2000, 2, 2789;
(b) Shankar, B. B.; Yang, D. Y.; Girton, S.; Ganguly, A. K. Tetrahedron
Lett 1998, 39, 2447.
254.
[17] Bhosale, S.; Kurhade, S.; Prasad, U. V.; Palle, V. P.; Bhuniya,
D. Tetrahedron Lett 2009, 50, 3948.
[7] Dadiboyena, S.; Xu, J.; Hamme, A. T. Tetrahedron Lett 2007,
48, 1295.
[18] Mendelsohn, B. A.; Lee, S.; Kim, S.; Teyssier, F.; Aulakh,
V. S.; Ciufolini, M. A. Org Lett 2009, 11, 1539.
[8] Kanemasa, S.; Tsuge, O. Heterocycles 1990, 30, 719.
[9] Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247.
[10] (a) Sammelson, R. E.; Miller, R. B.; Kurth, M. J. J Org Chem
2000, 65, 2225; (b) Rodrigues, R. C.; Aguiar, A. P. Synth Commun 2001,
31, 3075; (c) Toker, J. D.; Tremblay, M. R.; Yli-Kauhaluoma, J.;
Wentworth, A. D.; Zhou, B.; Wentworth, P.; Janda, K. D. J Org Chem
2005, 70, 7810; (d) Rai, K. M. L.; Hassner, A. Synth Commun 1997,
27, 467; (e) Kumar, V.; Kaushik, M. P. Tetrahedron Lett 2006, 47, 1457.
[11] (a) Just, G.; Dahl, K. Tetrahedron 1968, 24, 5251; (b) Kiegiel,
J.; Poplawska, M.; Józwik, J.; Kosior, M.; Jurczak, J. Tetrahedron Lett
1999, 40, 5605.
[19] (a) De, S. K.; Mallik, A. K. Tetrahedron Lett 1998, 39, 2389;
(b) Chaudhari, S. S.; Akamanchi, K. G. Tetrahedron Lett 1998, 39,
3209; (c) Corsaro, A.; Chiacchio, U.; Librando, V.; Pistara, V.; Rescifina,
A. Synthesis, 2000, 10, 1469; (d) Bose, D. S.; Narsaiah, A. V. Synth
Commun 1999, 29, 937.
[20] Raihan, M. J.; Kavala, V.; Kuo, C.; Raju, B. R.; Yao, C. Green
Chem 2010, 12, 1090.
[21] (a) Rebrovic, L.; Koser, G. F. J Org Chem 1984, 49, 4700; (b)
Margida, A. J.; Koser, G. F. J Org Chem 1984, 49, 4703; (c) Lodaya, J. S.;
Koser, G. F. J Org Chem 1990, 55, 1513.
[22] Aicher, T. D.; Balkan, B.; Bell, P. A.; Brand, L. J.; Cheon,
S. H.; Deems, R. O.; Fell, J. B.; Fillers, W. S.; Fraser, J. D.; Gao, J.;
Knorr, D. C.; Kahle, G. G.; Leone, C. L.; Nadelson, J.; Simpson, R.;
Smith, H. C. J Med Chem 1998, 41, 4556.
[12] (a) Das, B.; Holla, H.; Mahender, G.; Banerjee, J.; Reddy, M.
R. Tetrahedron Lett 2004, 45, 7347; (b) Prakash, O.; Pannu, K. Arkivoc
2007, 13, 28.
[13] Amstrong, S. K.; Collington, E. W.; Knight, J. G.; Naylor, A.;
Warren, S. J Chem Soc Perkin Trans 1 1993, 13, 1433.
[14] Gi, H.; Xiang, Y.; Schinazi, R. F.; Zhao, K. J Org Chem 1997,
62, 88.
[23] Srivastava, S.; Bajpa, L. K.; Batra, S.; Bhaduri, A. P.;
Maikhuri, J. P.; Gupta, G.; Dhar, J. D. Biorg Med Chem 1999, 7, 2607.
[24] Kurangi, R. F.; Kawthankar, R.; Sawal, S.; Desai, V. G.; Tilve,
S. G. Synth Commun 2007, 37, 585.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet