Alkyl Nitrites: Novel Reagents for One-Pot Synthesis of 3,5-Disubstituted Isoxazoles from Aldoximes and Alkynes

Article abstract of DOI:10.1055/s-0035-1561464

An efficient, one-pot approach has been described for the synthesis of 3,5-disubstituted isoxazoles from substituted aldoximes (mixture of E and Z) and alkynes, using alkyl nitrites under conventional heating conditions. The key nitrile oxide intermediates that are required for the synthesis of isoxazoles are formed by treatment of substituted aldoxime with either tert-butyl nitrite or isoamyl nitrite. The generated nitrile oxides underwent in situ [3+2] dipolar cycloaddition to the substituted alkynes to give 3,5-disubstituted isoxazoles regioselectively in high to excellent yields. The developed synthetic methodology was applied for the synthesis of a previously reported potent hDGAT1 inhibitor.

Full text of DOI:10.1055/s-0035-1561464

SYNTHESIS
0
0
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9
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1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–M
paper
A
K. S. Kadam et al.
Paper
Synthesis
Alkyl Nitrites: Novel Reagents for One-Pot Synthesis of 3,5-Disub-
stituted Isoxazoles from Aldoximes and Alkynes
Kishorkumar S. Kadama
Thirumanavelan Gandhi*b
Amol Guptea
A. K. Gangopadhyaya
Rajiv Sharmaa
OH
O–
N
O
+
N
N
O
O
H
R2
R1
N
R2
H
ethyl methyl ketone
65 °C
ethyl methyl ketone
65 °C
R
R
R
37 examples
74–96% yield
a Department of Medicinal Chemistry, Piramal Enterprises
Limited, Goregaon (E), Mumbai 400063, Maharashtra, India
b Department of Chemistry, School of Advanced Sciences,
VIT University, Vellore 632014, Tamil Nadu, India
velan.g@vit.ac.in
Received: 18.03.2016
Accepted after revision: 29.04.2016
Published online: 22.06.2016
chlorite,14 and tert-butyl hypochlorite,15 or by using direct
oxidizing agents such as magtrieve (CrO2),16 potassium fer-
ricyanide (K3Fe(CN)6),17 manganese dioxide (MnO2),18 ceri-
um(IV) ammonium nitrate (CAN),19 or lead acetate
(Pb(OAC)4),20 or by using hypervalent iodine reagents such
as (diacetoxyiodo)benzene (DIB),21 hydroxyl(tosyloxy)iodo-
benzene (HTIB),22 or phenyliodine bis(trifluoroacetate) (PI-
FA).23 However, these reagents suffer from certain draw-
backs such as the requirement for excess reagents, toxic
transition metals, harsh reaction conditions, poor regiose-
lectivity, formation of aldehydes as side product and low
synthetic yields. Therefore, the development of a regiose-
lective and metal-free synthetic methodology for 3,5-
disubstituted isoxazoles is highly desirable.
DOI: 10.1055/s-0035-1561464; Art ID: ss-2016-z0198-op
Abstract An efficient, one-pot approach has been described for the
synthesis of 3,5-disubstituted isoxazoles from substituted aldoximes
(mixture of E and Z) and alkynes, using alkyl nitrites under conventional
heating conditions. The key nitrile oxide intermediates that are required
for the synthesis of isoxazoles are formed by treatment of substituted
aldoxime with either tert-butyl nitrite or isoamyl nitrite. The generated
nitrile oxides underwent in situ [3+2] dipolar cycloaddition to the substi-
tuted alkynes to give 3,5-disubstituted isoxazoles regioselectively in
high to excellent yields. The developed synthetic methodology was ap-
plied for the synthesis of a previously reported potent hDGAT1 inhibi-
tor.
Key words isoxazoles, nitrile oxides, aldoximes, tert-butyl nitrite, iso-
We recently reported the synthesis of hDGAT1 inhibitor
3-phenylisoxazole-5-carboxamide derivative 1 with 16%
overall yield (Figure 1) by using ethyl 3-(4-nitrophe-
nyl)isoxazole-5-carboxylate (7) as the key precursor.24
However, compound 7 was synthesized in low yield (51%) in
two steps. Our main objective was to improve the overall
yield of 1 by enhancing the yield of 7. Alkyl nitrites are
commonly utilized for the oxidation of amines to their di-
azonium salts.25 Therefore, we envisaged the oxidation of
aldoximes by alkyl nitrites to their corresponding nitrile ox-
ides and their subsequent [3+2] cycloaddition to the termi-
nal alkynes, resulting in the formation of 3,5-disubstituted
isoxazole derivatives. Herein, we report the exploitation of
tert-butyl nitrite (3) and isoamyl nitrite (4) towards the
synthesis of 3,5-disubstituted isoxazoles.
amyl nitrite
Isoxazole and its derivatives are privileged heterocyclic
intermediates that exist in various natural products,1 bio-
logically active compounds,2 and functional materials.3 The
isoxazole core exhibits anti-inflammatory (Valdecoxib),4
antibiotic (Oxacillin),5 antirheumatic (leflunomide),6 anti-
depressant (isocarboxazid),7 anticancer,8 and antifungal
(micafungin)9 properties. Traditionally, 3,5-disubstituted
isoxazoles have been synthesized by the [3+2] dipolar cy-
cloaddition of alkynes to nitrile oxides generated from
oximes or dehydrohalogenation of hydroxymoyl halides.
Dang and co-workers synthesized 3,5-disubstituted isoxaz-
oles by the treatment of an aldoxime with n-butyl lithium
and diethyl oxalate followed by dehydration with an acid.10
Perumal and co-workers reported AuCl3-catalyzed
cycloisomerization of various α,β-acetylenic oximes, lead-
ing to the formation of isoxazoles.11 Thus, aldoximes were
established as precursors for the generation of nitrile oxides
in situ either by utilizing halogenating reagents such as N-
bromosuccinimide,12 N-chlorosuccinimide,13 sodium hypo-
At the outset, we initiated the investigation by using
commercially available alkyl nitrites, tert-butyl nitrite (3)
and isoamyl nitrite (4) as oxidizing agent (due to their ac-
ceptable boiling points of 63 and 99 °C, respectively) to
generate 5, which was expected to take part in [3+2] cy-
cloaddition with the terminal alkyne 6 resulting in the for-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

B
K. S. Kadam et al.
Paper
Synthesis
Replacing the conventional heating conditions with mi-
crowave irradiation at 300 MW did not improve the product
yield (Table 1, entry 4). The lower yield of 7 was observed
along with formation of deoximated product 8, when sol-
vents such as acetonitrile, toluene, and ethylene dichloride
were used (entries 5, 6, and 7, respectively). Use of ethyl
methyl ketone in the reaction resulted in improved yield of
7 along with small amounts of deoximated product 8 (entry
8). The above experimental data suggests formation of isox-
azole 7 along with deoximated product 8, thus limiting the
scope of reaction with tert-butyl nitrite 3.
O
O
N
H
N
O
OH
O
O
N
N
H
H
1
in vitro (hDGAT1 IC50 = 63 nM)
in vivo (TG reduction at 3 mpk = 90%)
Figure 1 3-Phenylisoxazole-5-carboxamide derivative 1 as hDGAT1 in-
hibitor
We then investigated the use of isoamyl nitrite 4, which
is another commercially available oxidant, because its high-
er boiling point (99 °C) compared with 3 would allow high-
er reaction temperature conditions. To optimize and identi-
fy the best set of conditions, we scouted six distinct experi-
ments for isoxazole synthesis from aldoxime 2 (1.0 mol
equiv) and alkyne 6 (1.1 mol equiv) in the presence of 4 (1.1
mol equiv) at 65 °C for 2 hours in different solvents (Table 1,
entries 9–14). The improvement in the yield (83%) of 7
along with reduced amounts of deoximated product 8 was
observed in THF (entry 9), whereas when the reaction was
run in acetonitrile, toluene or ethylene dichloride, 7 was
furnished in comparable yields (77–79%; entries 10–12). Fi-
nally, best yield of 7 (90%) was obtained when the reaction
was carried out with ethyl methyl ketone as solvent (entry
13). However, microwave irradiation at 300 MW for 0.5
hour at 65 °C in ethyl methyl ketone did not improve the
yield of 7 (entry 14). Therefore, isoamyl nitrite 4 (1.1 equiv)
found to be the best reagent in combination with 2 (1.0
equiv) and 6 (1.1 equiv) in ethyl methyl ketone as solvent
for the synthesis of 7 (Scheme 1). Our study was restricted
to the applicability of commercially available alkyl nitrites
3 and 4 because the other commercial alkyl nitrites are ei-
ther low-boiling liquids or gases.
mation of 3,5-disubstituted isoxazole derivatives (Scheme
1). The starting materials, i.e., aldoximes required for the
synthesis of isoxazoles, were synthesized from aldehydes
by using reported procedures.26 First, we attempted the re-
action of aldoxime 2 (1.0 mol equiv) and alkyne 6 (1.1 mol
equiv) in the presence of alkyl nitrite 3 (1.1 mol equiv) in
tetrahydrofuran (THF) at 50 °C for 4 hours. To our surprise,
the reaction resulted in the formation of the desired isoxaz-
ole 7 in 75% yield along with 10% 4-nitrobenzaldehyde 8 as
deoximated product (Table 1, entry 1). As shown in Table 1,
different reaction conditions were probed to improve the
yield of compound 7. The use of alkyne 6 (1.5 mol equiv)
and alkyl nitrite 3 (1.5 mol equiv) afforded isoxazole 7 in a
73% yield along with 11% of deoximated product 8 (entry
2). The formation of nitrile oxide intermediate 5 was con-
firmed by isolation of dimerized product 3,4-di-4-nitro-
phenylfuroxan 9 (81% yield) along with 9% of aldehyde 8,
when the reaction was carried out in the absence of alkyne
6 (entry 3). Hence, subsequent experiments were carried
out by using an equimolar amount of aldoxime 2, with alkyl
nitrite 3 (1.1 equiv) and alkyne 6 (1.1 mol equiv.; entries 4–
14).
OH
t-Bu
NO
O
O
O–
N
N
O
COOEt
+
N
O
O
6
H
H
3
+
O
O2N
O2N
O2N
O2N
50–65 °C
0.5–4 h
NO
2
5
8 (5–14%)
7 (67–90%)
4
in absence
of 6
O
O
N
N
O
H
+
O2N
O2N
NO2
9 (81%)
8 (9%)
Scheme 1 Synthesis of ethyl 3-(4-nitrophenyl)isoxazole-5-carboxylate (7) and 3,4-di-4-nitrophenylfuroxan 9
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

C
K. S. Kadam et al.
Paper
Synthesis
With the optimized reaction conditions in hand (Table
1, entry 13), we explored the application of 4 for the syn-
thesis of isoxazole derivatives 10a–x (Scheme 2). To under-
stand the steric and electronic effects of substituents on the
aromatic aldoximes, we selected substituted phenyl aldox-
imes having an electron-withdrawing (2b–l) or electron-
donating (2m–x) group at either the ortho-, meta-, or para-
position. The para-substituted phenyl aldoximes gave the
desired isoxazoles 10f, 10i, 10l, 10o, 10r, 10u, and 10x (Ta-
ble 2, entries 6, 9, 12, 15, 18, 21, 24, respectively) in high
yields (88–96%).
The presence of a meta-substituent on the phenyl ald-
oxime also resulted in the formation of the desired prod-
ucts 10c, 10e, 10h, 10k, 10n, 10q, 10t, and 10w in good
yields ranging from 83 to 89% (Table 2, entries 3, 5, 8, 11, 14,
17, 20, 23, respectively). On the other hand, ortho-substitu-
ents on the phenyl aldoxime afforded the corresponding
isoxazole compounds 10b, 10d, 10g, 10j, 10m, 10p, 10s,
and 10v in slightly lower yields ranging from 74 to 81% (en-
tries 2, 4, 7, 10, 13, 16, 19, 22, respectively). In case of the
ortho-substituted aldoximes, around 4–9% corresponding
deoximated products were obtained along with the desired
product. However, formation of deoximated side-products
was not observed in the case of meta- or para-substituted
aldoximes. Electron-withdrawing as well as electron-
donating aldoximes gave similar results. As a result, the ste-
ric effects, with regards to the proximity of the substituents
to the reaction site, appear to play a far greater role in de-
termining product yields compared with the electronic ef-
fects of the phenyl substituents on aldoximes 2a–x.
Table 1 Optimization Studies
Entry Alkyl Solvent
nitrite
Temp Time Yield
Yield of
(°C)
(h)
(%)e
8 (%)e
1
2
3
3
3
3
3
3
3
3
4
4
4
4
4
4
THFa
50
50
50
50
50
50
50
50
65
65
65
65
65
65
4.0
75 (7)
10
11
9
THFb
4.0
4.0
0.5
4.0
4.0
4.0
4.0
2.0
2.0
2.0
2.0
2.0
0.5
73 (7)
81 (9)
67 (7)
69 (7)
71 (7)
67 (7)
81 (7)
83 (7)
78 (7)
79 (7)
77 (7)
90 (7)
80 (7)
3
THFc
4
THFd
13
11
10
14
7
Table 2 One-Pot Synthesis of 3,5-Disubstituted Isoxazoles 10a–xa
5
acetonitrilea
toluenea
6
Entry
2
R
Time (h)
Yield of 10 (%)b
7
ethylene dichloridea
ethyl methyl ketonea
THFa
1
2
2a
2b
2c
2d
2e
2f
H
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
3
3
87 (10a)
76 (10b)
86 (10c)
74 (10d)
85 (10e)
94 (10f)
75 (10g)
86 (10h)
94 (10i)
74 (10j)
87 (10k)
93 (10l)
75 (10m)
84 (10n)
90 (10o)
77 (10p)
83 (10q)
88 (10r)
81 (10s)
89 (10t)
96 (10u)
77 (10v)
85 (10w)
90 (10x)
8
2-NO2
3-NO2
2-F
9
5
3
10
11
12
13
14
acetonitrilea
toluenea
8
4
6
5
3-F
ethylene dichloridea
ethyl methyl ketonea
ethyl methyl ketoned
8
6
4-F
–
7
2g
2h
2i
2-Br
7
8
3-Br
a Reaction conditions: 2 (1.0 equiv), 3 or 4 (1.1 equiv), 6 (1.1 equiv).
b Reaction conditions: 2 (1.0 equiv), 3 (1.5 equiv), 6 (1.5 equiv).
c Reaction conditions: 2 (1.0 equiv), 3 (1.1 equiv).
d Reaction carried out in microwave.
9
4-Br
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
2j
2-CF3
3-CF3
4-CF3
2-Me
3-Me
4-Me
2-OMe
3-OMe
4-OMe
2-Ph
e Isolated yield after purification.
2k
2l
2m
2n
2o
2p
2q
2r
OH
O–
NO
+
N
N
O
4 (1.1 equiv)
H
ethyl methyl ketone
65 °C
R
R
5a–x
2a–x (1.0 equiv)
2s
2t
3-Ph
N
O
COOEt
2u
2v
2w
2x
4-Ph
O
4 (1.1 equiv)
2-OPh
3-OPh
4-OPh
O
ethyl methyl ketone
65 °C
R
10a–x (74–96%)
a Reaction conditions: 2a–x (1.0 equiv), 4 (1.1 equiv), 6 (1.1 equiv).
b Isolated yield after purification.
Scheme 2 One-pot synthesis of 3,5-disubstituted isoxazoles 10a–x
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

D
K. S. Kadam et al.
Paper
Synthesis
We then studied the substrate scope of the reaction by
using heterocyclic and aliphatic aldoximes for the synthesis
of isoxazole derivatives 13a–e (Scheme 3). On treatment of
2-pyridyl aldoxime 11a with 4 and 6, the desired isoxazole
13a was afforded in 86% yield (Table 3, entry 1). However,
the 3-pyridyl analogue 13b (entry 2) and 4-pyridyl ana-
logue 13c (entry 3) were obtained from the corresponding
aldoximes in 80 and 79% yields, respectively. Replacing the
pyridine aldoxime with five-membered thiophene aldox-
ime 11d furnished the desired isoxazole 13d in 82% yield
(entry 4). Isobutyraldehyde oxime (11e) afforded the corre-
sponding isoxazole 13e in 81% yield (entry 5). Our current
methodology, which is extended to heterocyclic and ali-
phatic aldoximes, readily afforded the corresponding isox-
azoles in excellent yields.
butylacetylene (14d) and cyclohexylacetylene (14e) to fur-
nish 15d and 15e with 88 and 87% yields, respectively (en-
tries 4 and 5). Cycloaddition of polar alkyne such as 1-hy-
droxyprop-2-yne (14f) with aldoxime 2 yielded 15f in 85%
yield (entry 6), whereas but-3-yn-2-one (14g) afforded 15g
in 90% yield (entry 7). Thus, aliphatic acetylenes as well as
aromatic acetylenes were well tolerated under the present
reaction conditions.
NO
OH
H
O
N
+
N
O–
4 (1.1 equiv)
ethyl methyl ketone
65 °C
O2N
O2N
2 (1.0 equiv)
5
NO
H
R2
N
O
O
OH
N
O–
+
N
R2
4 (1.1 equiv)
14a–g (1.1 equiv)
R1
H
R1
O2N
ethyl methyl ketone
65 °C
ethyl methyl ketone
65 °C
11a–e (1.0 equiv)
12a–e
15a–g (80–90%)
Scheme 4 One-pot synthesis of 3,5-disubstituted isoxazoles 15a–g
from aldoxime 2 and substituted terminal alkynes 14a–g
COOEt
6 (1.1 equiv)
N
O
O
Table 4 One-Pot Synthesis of 3,5-Disubstituted Isoxazoles 15a–ga
R1
ethyl methyl ketone
65 °C
O
Entry
14
14a
R2
Ph
Time (h)
Yield of 13 (%)b
13a–e (79–86%)
1
2
3
4
5
6
7
4
4
5
4
5
3
3
81 (15a)
82 (15b)
80 (15c)
88 (15d)
87 (15e)
85 (15f)
90 (15g)
Scheme 3 One-pot synthesis of 3,5-disubstituted isoxazoles 13a–e
Table 3 One-Pot Synthesis of 3,5-Disubstituted Isoxazoles 13a–ea
14b
14c
14d
14e
14f
4-FC6H4
4-MeOC6H4
tert-butyl
cyclohexyl
CH2OH
Entry
11
11a
R1
2-pyridyl
Time (h)
Yield of 13 (%)b
1
2
3
4
5
3
3
3
3
3
86 (13a)
80 (13b)
79 (13c)
82 (13d)
81 (13e)
11b
11c
11d
11e
3-pyridyl
14g
COMe
a Reaction conditions: 2 (1.0 equiv), 4 (1.1 equiv), 6 (1.1 equiv).
4-pyridyl
b Isolated yield after purification.
thiophen-3-yl
3-isopropyl
The developed synthetic methodology was implement-
ed for the synthesis of hDGAT1 inhibitor 1 (Scheme 5), and
we were pleased to find that the overall yield of 1 was im-
proved from 16 to 28% by using this novel transformation.24
The regioselectivity of all the 3,5-disubstituted isoxaz-
oles 10a–x, 13a–e, and 15a–g synthesized by using the syn-
thetic protocol described above was established on the ba-
sis of available precedence.27 1H NMR analysis of synthe-
sized analogues 10a–y, 13a–e, and 15a–g each showed a
singlet signal in the region of 6.2–7.8 ppm, characteristic of
isoxazole proton (C4-H) and the corresponding isoxazole
a Reaction conditions: 11a–e (1.0 equiv), 4 (1.1 equiv), 6 (1.1 equiv).
b Isolated yield after purification.
Finally, to explore the scope of the reaction with respect
to alkynes, we selected aldoxime 2, having an electron-
withdrawing nitro group, and altered the nature of the
alkyne (Scheme 4). The reaction of aldoxime 2 with phenyl-
acetylene (14a) under the optimized conditions resulted in
the formation of the desired isoxazole 15a in 81% yield (Ta-
ble 4, entry 1). Similarly, 4-fluorophenylacetylene (14b)
and 4-methoxyphenylacetylene (14c) afforded 15b and 15c
with 82 and 80% yields, respectively (entries 2 and 3). The
scope of this reaction was further extended by using tert-
carbon (C4) appeared in the range of 96–111 ppm in the 13
C
NMR spectrum, confirming the formation of 3,5-disubsti-
tuted isoxazoles with complete regioselectivity.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

E
K. S. Kadam et al.
Paper
Synthesis
NO
COOEt
O
OH
H
O
N
N
6
4
CHO
O
H2NOHHCl, Na2CO3
EtOH, H2O, r.t., 1 h
ethyl methyl ketone
65 °C , 3 h
O
O2N
O2N
O2N
96%
90%
7
16
2
O
O
N
H
N
O
OH
O
O
N
N
H
H
1
overall yield of compound 1
was improved from 16% to 28%
Scheme 5 Synthesis of 3-phenylisoxazole-5-carboxamide derivative 1 from isoxazole 7 with overall improved yield
We propose a probable mechanism for the synthesis of
isoxazole 7 by oxidation of aldoxime 2 using alkyl nitrite 4
to nitrile oxide 5 following cycloaddition to alkyne 6 in situ
(Scheme 6). Support for the alkyl nitrite 4 mediated oxida-
tion of aldoxime 2 proceeding through a seven-membered
transition state to nitrile oxide 5 came from the formation
of isoamyl alcohol 17, which was confirmed by the ob-
served mass fragment at m/z 88 by GCMS analysis of the re-
action mass. The formed nitrile oxide 5, on further [3+2]
cycloaddition to alkyne 6 in situ, furnished isoxazole 7 (m/z
262), which was confirmed by GCMS analysis, with the 3,5-
imes over meta- or para-substituted aldoximes. A variety of
functional groups on the aromatic ring of the aldoxime as
well as aldoximes derived from heterocyclic rings were well
tolerated under the present reaction conditions. Therefore,
the present mild and metal-free reaction methodology of-
fers an attractive alternative to the existing methodologies.
The biological activity of all synthesized isoxazole ana-
logues will be evaluated in due course.
Reagents and starting materials, including compounds 2r, 11a, 11b,
11c, and 11e, were obtained commercially and used without prior
purification.
1
disubstituted regioselectivity supported by H NMR analy-
sis of isolated isoxazole 7.
Unless mentioned otherwise all reactions were performed under
open air. 1H, 13C NMR spectra were recorded with a Bruker spectrom-
eter (300 or 400 MHz) using CDCl3 or DMSO-d6 as the solvent. Chemi-
cal shifts, δ, are reported in ppm relative to the solvent peak. Multi-
plicities are indicated by s (singlet), d (doublet), t (triplet), q (quartet),
and m (multiplet). Coupling constants, J, are reported in hertz. High-
resolution mass spectra (HRMS) were obtained with a Bruker Dalton-
ics ESI-QTOF instrument equipped with an ESI interface. Melting
points were determined with a manually operated Veego (VMP-1)
In conclusion, we have developed a novel methodology
for the synthesis of 3,5-disubstituted isoxazoles with com-
plete regioselectivity by using commercially available alkyl
nitrites by the reaction of aldoximes and terminal alkynes.
In general, it was observed that the steric effects govern the
desired product formation over the electronic effects. The
formation of the deoximated product as a side-product was
observed to be restricted to the ortho-substituted aldox-
O
H
O
N
O
N
O
N
H
O
O
O2N
H
O2N
2
4
5
6
1
2
O
O
N
5
3
+
HO
O
4
O2N
Scheme 6 Plausible reaction mechanism for the synthesis of isoxazole 7
7
17
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

F
K. S. Kadam et al.
Paper
Synthesis
melting-point apparatus and are reported uncorrected. Flash chroma-
tography was conducted with a Teledyne Isco advances CombiFlash®
Rf automated flash chromatography system (Lincoln, USA) equipped
with a UV variable dual-wavelength, software selectable (200–360
nm), using prefabricated RediSep Flash Column silica columns. The al-
doximes used for synthesis were prepared in-house by using a report-
ed procedure and characterized completely based on 1H NMR spec-
troscopy and mass spectrometry.
3-Fluorobenzaldehyde Oxime (2e)33
Yield: 3.6 g (80%); white solid; mp 102–104 °C.
1H NMR (300 MHz, DMSO-d6): δ = 11.45 (s, 1 H, OH), 8.16 (s, 1 H,
N=CH), 7.49–7.37 (m, 3 H, Ar-H), 7.25–7.18 (m, 1 H, Ar-H).
MS (ESI+): m/z = 140 [M + H]+.
4-Fluorobenzaldehyde Oxime (2f)34
Yield: 4.12 g (92%); white solid; mp 82–84 °C.
Synthesis of Aldoximes; General Procedure
1H NMR (300 MHz, DMSO-d6): δ = 11.67 (s, 1 H, OH), 8.05 (t, J =
8.7 Hz, 2 H, Ar-H), 7.43 (s, 1 H, N=CH), 7.27 (t, J = 8.7 Hz, 2 H, Ar-H).
MS (ESI+): m/z = 140 [M + H]+.
To a mixture of hydroxylamine hydrochloride (15.88 mmol, 1.2 equiv)
in EtOH (4 mL) and water (20 mL) was added sodium carbonate
(15.88 mmol, 1.2 equiv) and the mixture was stirred for 5 min to ob-
tain a clear solution. To this, the appropriate aldehyde (13.23 mmol,
1.0 equiv) was added and the solution was stirred at r.t. for 0.5–1 h;
the progress of the reaction was monitored by TLC. After addition of
water (30 mL), the resulting solids were filtered and dried to obtain
the corresponding aldoximes. When the solid did not precipitate out
of the reaction, the reaction mixture was extracted with EtOAc
(2 × 50 mL). The combined organic layers were dried over anhydrous
sodium sulfate, filtered and evaporated under reduced pressure to ob-
tain the corresponding aldoximes, which were used without further
purification.
2-Bromobenzaldehyde Oxime (2g)35
Yield: 3.8 g (88%); off-white solid; mp 101–103 °C.
1H NMR (300 MHz, DMSO-d6): δ = 11.70 (s, 1 H, OH), 8.31 (s, 1 H,
N=CH), 7.81–7.78 (m, 1 H, Ar-H), 7.69–7.65 (m, 1 H, Ar-H), 7.44–7.39
(m, 2 H, Ar-H).
MS (ESI+): m/z = 200 [M + H]+.
3-Bromobenzaldehyde Oxime (2h)33
Yield: 3.18 g (84%); off-white solid; mp 74–76 °C.
1H NMR (300 MHz, DMSO-d6): δ = 11.46 (s, 1 H, OH), 8.14 (s, 1 H,
N=CH), 7.77–7.76 (m, 1 H, Ar-H), 7.62–7.55 (m, 2 H, Ar-H), 7.45–7.33
(m, 1 H, Ar-H).
Benzaldehyde Oxime (2a)28
Yield: 1.0 g (88%); colorless liquid.
1H NMR (300 MHz, DMSO-d6): δ = 11.24 (s, 1 H, OH), 8.14 (s, 1 H,
N=CH), 7.60–7.57 (m, 2 H, Ar-H), 7.44–7.37 (m, 3 H, Ar-H).
MS (ESI+): m/z = 199.9 [M + H]+.
MS (ESI+): m/z = 122.1 [M + H]+.
4-Bromobenzaldehyde Oxime (2i)31
Yield: 3.9 g (90%); pale-brown liquid.
1H NMR (300 MHz, DMSO-d6): δ = 11.38 (s, 1 H, OH), 8.13 (s, 1 H,
N=CH), 7.63–7.55 (m, 4 H, Ar-H).
MS (ESI+): m/z = 199.9 [M + H]+.
2-Nitrobenzaldehyde Oxime (2b)29
Yield: 0.98 g (86%); off-white solid; mp 127–129 °C.
1H NMR (300 MHz, DMSO-d6): δ = 11.78 (s, 1 H, OH), 8.40 (s, 1 H,
N=CH), 8.04 (d, J = 7.8 Hz, 1 H, Ar-H), 7.88 (d, J = 7.8 Hz, 1 H, Ar-H),
7.76 (d, J = 7.8 Hz, 1 H, Ar-H), 7.67–7.62 (m, 1 H, Ar-H).
2-(Trifluoromethyl)benzaldehyde Oxime (2j)36
MS (ESI+): m/z = 167 [M + H]+.
Yield: 3.7 g (85%); off-white solid; mp 51–53 °C.
1H NMR (300 MHz, DMSO-d6): δ = 11.87 (s, 1 H, OH), 8.30 (s, 1 H,
N=CH), 8.01 (d, J = 7.5 Hz, 1 H, Ar-H), 7.79 (d, J = 7.5 Hz, 1 H, Ar-H),
7.71 (t, J = 7.5 Hz, 1 H, Ar-H), 7.63 (t, J = 7.5 Hz, 1 H, Ar-H).
3-Nitrobenzaldehyde Oxime (2c)30
Yield: 1.0 g (91%); off-white solid; mp 122–124 °C.
1H NMR (300 MHz, DMSO-d6): δ = 11.64 (s, 1 H, OH), 8.40 (t, J =
1.8 Hz, 1 H, Ar-H), 8.31 (s, 1 H, N=CH), 8.20 (dd, J = 1.8 Hz, 1 H, Ar-H),
8.03 (d, J = 7.8 Hz, 1 H, Ar-H), 7.68–7.65 (m, 1 H, Ar-H).
MS (ESI+): m/z = 190.1 [M + H]+.
3-(Trifluoromethyl)benzaldehyde Oxime (2k)33
MS (ESI+): m/z = 165 [M – H]–.
Yield: 4 g (92%); off-white solid; mp 84–86 °C.
1H NMR (300 MHz, DMSO-d6): δ = 11.54 (s, 1 H, OH), 8.27 (s, 1 H,
N=CH), 7.92–7.90 (m, 2 H, Ar-H), 7.74 (d, J = 8.1 Hz, 1 H, Ar-H), 7.67 (t,
J = 8.1 Hz, 1 H, Ar-H).
4-Nitrobenzaldehyde Oxime (2)31
Yield: 21 g (96%); off-white solid; mp 127–129 °C.
1H NMR (300 MHz, DMSO-d6): δ = 11.85 (s, 1 H, OH), 8.31 (s, 1 H,
N=CH), 8.26 (d, J = 9.0 Hz, 2 H, Ar-H), 7.85 (d, J = 9.0 Hz, 2 H, Ar-H).
MS (ESI+): m/z = 189.9 [M + H]+.
MS (ESI+): m/z = 376.1 [M + H]+.
4-(Trifluoromethyl)benzaldehyde Oxime (2l)36
Yield: 3.8 g (87%); colorless liquid.
1H NMR (300 MHz, DMSO-d6): δ = 11.65 (s, 1 H, OH), 8.25 (s, 1 H,
N=CH), 7.78 (dd, J = 8.4 Hz, 4 H, Ar-H).
2-Fluorobenzaldehyde Oxime (2d)32
Yield: 2 g (89%); white solid; mp 64–66 °C.
1H NMR (300 MHz, DMSO-d6): δ = 11.59 (s, 1 H, OH), 8.22 (s, 1 H,
N=CH), 7.74 (t, J = 7.5 Hz, 1 H, Ar-H), 7.47–7.41 (m, 1 H, Ar-H), 7.29–
7.21 (m, 2 H, Ar-H).
MS (ESI+): m/z = 189.9 [M + H]+.
2-Methylbenzaldehyde Oxime (2m)36
MS (ESI+): m/z = 140.1 [M + H]+.
Yield: 4.2 g (93%); pale-brown liquid.
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1H NMR (300 MHz, DMSO-d6): δ = 11.28 (s, 1 H, OH), 8.32 (s, 1 H,
N=CH), 7.62 (d, J = 7.2 Hz, 1 H, Ar-H), 7.29–7.18 (m, 3 H, Ar-H), 2.37 (s,
3 H, Ar-CH3).
2-Phenoxybenzaldehyde Oxime (2v)38
Yield: 3.76 g (87%); colorless liquid.
1H NMR (300 MHz, DMSO-d6): δ = 11.45 (s, 1 H, OH), 8.21 (s, 1 H,
N=CH), 7.84 (d, J = 7.5 Hz, 1 H, Ar-H), 7.44–7.36 (m, 3 H, Ar-H), 7.22 (t,
J = 7.5 Hz, 1 H, Ar-H), 7.12 (t, J = 7.2 Hz, 1 H, Ar-H), 6.98–6.94 (m, 3 H,
Ar-H).
MS (ESI+): m/z = 136 [M + H]+.
3-Methylbenzaldehyde Oxime (2n)30
MS (ESI+): m/z = 214 [M + H]+.
Yield: 3.9 g (87%); off-white solid; mp 59–61 °C.
1H NMR (300 MHz, DMSO-d6): δ = 11.18 (s, 1 H, OH), 8.09 (s, 1 H,
N=CH), 7.38 (d, J = 8.4 Hz, 2 H, Ar-H), 7.30 (t, J = 7.5 Hz, 1 H, Ar-H),
7.18 (d, J = 7.5 Hz, 1 H, Ar-H), 2.31 (s, 3 H, Ar-CH3).
3-Phenoxybenzaldehyde Oxime (2w)39
Yield: 3.6 g (84%); colorless liquid.
MS (ESI+): m/z = 136 [M + H]+.
1H NMR (300 MHz, DMSO-d6): δ = 11.31 (s, 1 H, OH), 8.12 (s, 1 H,
N=CH), 7.48–7.31 (m, 4 H, Ar-H), 7.20–7.15 (m, 2 H, Ar-H), 7.07–7.01
(m, 3 H, Ar-H).
4-Methylbenzaldehyde Oxime (2o)30
MS (ESI+): m/z = 214 [M + H]+.
Yield: 5.3 g (94%); off-white solid; mp 75–77 °C.
1H NMR (300 MHz, DMSO-d6): δ = 11.11 (s, 1 H, OH), 8.09 (s, 1 H,
N=CH), 7.48 (d, J = 8.1 Hz, 2 H, Ar-H), 7.20 (d, J = 8.1 Hz, 2 H, Ar-H),
2.30 (s, 3 H, Ar-CH3).
4-Phenoxybenzaldehyde Oxime (2x)39
Yield: 3.9 g (91%); colorless liquid.
MS (ESI+): m/z = 136 [M + H]+.
1H NMR (300 MHz, DMSO-d6): δ = 11.14 (s, 1 H, OH), 8.12 (s, 1 H,
N=CH), 7.60 (d, J = 8.4 Hz, 2 H, Ar-H), 7.40 (t, J = 8.1 Hz, 2 H, Ar-H),
7.18 (t, J = 7.5 Hz, 1 H, Ar-H), 7.03 (dd, J = 8.1 Hz, 4 H, Ar-H).
2-Methoxybenzaldehyde Oxime (2p)36
MS (ESI+): m/z = 214 [M + H]+.
Yield: 3.6 g (81%); colorless liquid.
1H NMR (300 MHz, DMSO-d6): δ = 11.22 (s, 1 H, OH), 8.29 (s, 1 H,
N=CH), 7.65 (dd, J = 1.8 Hz, 1 H, Ar-H), 7.37 (t, J = 8.7 Hz, 1 H, Ar-H),
7.06 (d, J = 8.1 Hz, 1 H, Ar-H), 6.95 (t, J = 7.5 Hz, 1 H, Ar-H), 3.81 (s,
3 H, OCH3).
Thiophene-3-carbaldehyde Oxime (11d)30
Yield: 3.1 g (91%); pale-brown solid; mp 120–122 °C.
1H NMR (300 MHz, DMSO-d6): δ = 11.53 (s, 1 H, OH), 8.23 (s, 1 H,
N=CH), 7.58–7.53 (m, 2 H, Ar-H), 7.49 (s, 1 H, Ar-H).
MS (ESI+): m/z = 152 [M + H]+.
MS (ESI+): m/z = 127.9 [M + H]+.
3-Methoxybenzaldehyde Oxime (2q)30
Yield: 4 g (90%); colorless liquid.
3,4-Di-4-nitrophenylfuroxan (9)40
1H NMR (300 MHz, DMSO-d6): δ = 11.24 (s, 1 H, OH), 8.10 (s, 1 H,
N=CH), 7.33 (t, J = 8.1 Hz, 1 H, Ar-H), 7.16 (d, J = 7.5 Hz, 2 H, Ar-H),
6.94 (dd, J = 2.1, 7.2 Hz, 1 H, Ar-H), 3.76 (s, 3 H, OCH3).
To a solution of aldoxime 2 (200 mg, 1.65 mmol, 1.0 equiv) in ethyl
methyl ketone (10 mL) was added alkyl nitrite 4 (155 mg, 1.32 mmol,
1.1 equiv) and the reaction mixture was stirred at 65 °C for 4 h. The
solvent was removed under reduced pressure and the residue was pu-
rified by flash chromatography (EtOAc–n-hexane, 2:8 v/v) to afford 9.
MS (ESI+): m/z = 152 [M + H]+.
[1,1′-Biphenyl]-2-carbaldehyde Oxime (2s)37
Yield: 160 mg (81%); pale-yellow solid; mp 198–200 °C.
1H NMR (400 MHz, CDCl3): δ = 8.21 (t, J = 8.0 Hz, 4 H, Ar-H), 7.61 (t, J =
Yield: 2.8 g (86%); colorless liquid.
1H NMR (300 MHz, DMSO-d6): δ = 11.30 (s, 1 H, OH), 7.89–7.83 (m,
8.0 Hz, 4 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 176.7 (Ar-CNO2), 169.8 (Ar-CNO2),
153.8 (C=N), 148.33 (C=N), 131.60, 129.31 (2C), 129.19 (2C), 128.17,
124.16 (2C), 123.98 (2C).
2 H, N=CH, Ar-H), 7.57–7.39 (m, 5 H, Ar-H), 7.35–7.30 (m, 3 H, Ar-H).
MS (ESI+): m/z = 198 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C14H9N4O6+: 329.0522; found:
[1,1′-Biphenyl]-3-carbaldehyde Oxime (2t)36
329.0530.
Yield: 3.7 g (85%); colorless liquid.
1H NMR (300 MHz, DMSO-d6): δ = 11.30 (s, 1 H, OH), 8.22 (s, 1 H,
N=CH), 7.85 (s, 1 H, Ar-H), 7.68 (d, J = 7.5 Hz, 3 H, Ar-H), 7.62 (d, J =
7.5 Hz, 1 H, Ar-H), 7.52–7.46 (m, 3 H, Ar-H), 7.41–7.36 (m, 1 H, Ar-H).
Synthesis of 3,5-Disubstituted Isoxazoles 10a–x, 13a–e, and 15a–g;
General Procedure
To a solution of the appropriate aldoxime (1.2 mmol, 1.0 equiv) in
ethyl methyl ketone (10 mL) was added appropriately substituted
alkyne (1.32 mmol, 1.1 equiv) followed by alkyl nitrite 4 (1.32 mmol,
1.1 equiv). After 5 min stirring at r.t., the turbid reaction mixture be-
came a clear solution and the reaction mixture was stirred at 65 °C
until the aldoxime had been consumed. The solvent was removed un-
der reduced pressure and the residue was purified by flash chroma-
tography (EtOAc–n-hexane, 1:9 v/v) to afford the desired compound.
MS (ESI+): m/z = 198 [M + H]+.
[1,1′-Biphenyl]-4-carbaldehyde Oxime (2u)36
Yield: 3.8 g (88%); colorless liquid.
1H NMR (300 MHz, DMSO-d6): δ = 11.29 (s, 1 H, OH), 8.19 (s, 1 H,
N=CH), 7.77–7.66 (m, 6 H, Ar-H), 7.48 (t, J = 7.8 Hz, 2 H, Ar-H), 7.38 (t,
J = 7.2 Hz, 1 H, Ar-H).
MS (ESI+): m/z = 198 [M + H]+.
Ethyl 3-Phenylisoxazole-5-carboxylate (10a)39
Yield: 311 mg (87%); off-white solid; mp 47–49 °C.
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K. S. Kadam et al.
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1H NMR (300 MHz, CDCl3): δ = 7.87–7.84 (m, 2 H, Ar-H), 7.51–7.49
(m, 3 H, Ar-H), 7.27 (s, 1 H, isoxazole-H), 4.48 (q, J = 7.2 Hz, 2 H,
OCH2), 1.44 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 162.96 (C=O), 160.95 (C=N), 156.82
(isoxazole-CO), 130.56, 129.09 (2C), 128.00, 126.86 (2C), 107.35 (isox-
azole-CH), 62.34 (OCH2), 14.16 (CH3).
Ethyl 3-(3-Fluorophenyl)isoxazole-5-carboxylate (10e)
Yield: 287 mg (85%); white solid; mp 80–82 °C.
1H NMR (300 MHz, CDCl3): δ = 7.64–7.56 (m, 2 H, Ar-H), 7.51–7.44
(m, 1 H, Ar-H), 7.25–7.17 (m, 2 H, Ar-H, isoxazole-H), 4.48 (q, J =
7.2 Hz, 2 H, OCH2), 1.46 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 164.66 (C=O), 162.03 (Ar-CF), 161.27
(C=N), 156.65 (isoxazole-CO), 130.86, 129.95, 122.65, 117.69, 114.05,
107.26 (isoxazole-CH), 62.46 (OCH2), 14.15 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C12H12NO3+: 218.0817; found:
218.0830.
HRMS (ESI): m/z [M + H]+ calcd for C12H11FNO3+: 236.0723; found:
236.0729.
Ethyl 3-(2-Nitrophenyl)isoxazole-5-carboxylate (10b)
Yield: 240 mg (76%); pale-brown oil.
1H NMR (300 MHz, CDCl3): δ = 8.10 (d, J = 7.8 Hz, 1 H, Ar-H), 7.79–
7.67 (m, 3 H, Ar-H), 7.06 (s, 1 H, isoxazole-H), 4.48 (q, J = 7.2 Hz, 2 H,
OCH2), 1.45 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 160.66 (C=O), 160.61 (C=N), 156.50
(isoxazole-CO), 148.27 (Ar-CNO2), 133.38, 132.39, 131.86, 124.88,
123.42, 109.69 (isoxazole-CH), 62.50 (OCH2), 14.14 (CH3).
Ethyl 3-(4-Fluorophenyl)isoxazole-5-carboxylate (10f)23
Yield: 317 mg (94%); white solid; mp 140–142 °C.
1H NMR (300 MHz, CDCl3): δ = 7.87–7.82 (m, 2 H, Ar-H), 7.23–7.16
(m, 3 H, isoxazole-H, Ar-H), 4.48 (q, J = 7.2 Hz, 2 H, OCH2), 1.45 (t, J =
7.2 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 165.77 (C=O), 162.03 (Ar-CF), 161.10
(C=N), 156.72 (isoxazole-CO), 128.92, 128.81, 124.25, 116.41, 116.12,
107.15 (isoxazole-CH), 62.39 (OCH2), 14.14 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C12H11N2O5+: 263.0668; found:
263.0683.
HRMS (ESI): m/z [M + H]+ calcd for C12H11FNO3+: 236.0723; found:
236.0731.
Ethyl 3-(3-Nitrophenyl)isoxazole-5-carboxylate (10c)23
Yield: 271 mg (86%); white solid; mp 126–128 °C.
1H NMR (300 MHz, CDCl3): δ = 8.68 (d, J = 1.5 Hz, 1 H, Ar-H), 8.36 (dd,
J = 1.5, 8.1 Hz, 1 H, Ar-H), 8.24 (d, J = 7.8 Hz, 1 H, Ar-H), 7.72 (t, J =
7.8 Hz, 1 H, Ar-H), 7.36 (s, 1 H, isoxazole-H), 4.50 (q, J = 7.2 Hz, 2 H,
OCH2), 1.46 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 161.81 (C=O), 161.15 (C=N), 156.42
(isoxazole-CO), 148.69 (Ar-CNO2), 132.53, 130.33, 129.76, 125.15,
121.87, 107.08 (isoxazole-CH), 62.63 (OCH2), 14.15 (CH3).
Ethyl 3-(2-Bromophenyl)isoxazole-5-carboxylate (10g)
Yield: 223 mg (75%); light-brown oil.
1H NMR (300 MHz, CDCl3): δ = 7.71 (t, J = 1.2 Hz, 2 H, Ar-H), 7.47–7.45
(m, 1 H, Ar-H), 7.42 (s, 1 H, isoxazole-H), 7.39–7.34 (m, 1 H, Ar-H),
4.49 (q, J = 7.2 Hz, 2 H, OCH2), 1.46 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 163.00 (C=O), 160.12 (C=N), 156.80
(isoxazole-CO), 133.71, 131.55, 131.38, 128.48, 127.80, 122.24 (Ar-
CBr), 110.67 (isoxazole-CH), 62.41 (OCH2), 14.19 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C12H11N2O5+: 263.0668; found:
263.0676.
HRMS (ESI): m/z [M + H]+ calcd for C12H11BrNO3+: 295.9922; found:
295.9928.
Ethyl 3-(4-Nitrophenyl)isoxazole-5-carboxylate (7)24
Yield: 285 mg (90%); white solid; mp 151–153 °C.
Ethyl 3-(3-Bromophenyl)isoxazole-5-carboxylate (10h)41
1H NMR (300 MHz, CDCl3): δ = 8.37 (d, J = 8.7 Hz, 2 H, Ar-H), 8.05 (d,
J = 8.7 Hz, 2 H, Ar-H), 7.34 (s, 1 H, isoxazole-H), 4.50 (q, J = 6.9 Hz, 2 H,
OCH2), 1.46 (t, J = 6.9 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 161.86 (C=O), 161.18 (C=N), 156.40
(isoxazole-CO), 149.02 (Ar-CNO2), 133.96, 127.81 (2C), 124.38 (2C),
107.28 (isoxazole-CH), 62.66 (OCH2), 14.15 (CH3).
Yield: 256 mg (86%); white solid; mp 90–92 °C.
1H NMR (300 MHz, CDCl3): δ = 8.02 (t, J = 1.8 Hz, 1 H, Ar-H), 7.79 (d,
J = 7.8 Hz, 1 H, Ar-H), 7.63 (dd, J = 7.8, 0.9 Hz, 1 H, Ar-H), 7.38 (t, J =
7.8 Hz, 1 H, Ar-H), 7.26 (s, 1 H, isoxazole-H), 4.49 (q, J = 7.2 Hz, 2 H,
OCH2), 1.46 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 161.76 (C=O), 161.29 (C=N), 156.61
(isoxazole-CO), 133.54, 130.64, 129.94, 129.86, 125.43, 123.19 (Ar-
CBr), 107.19 (isoxazole-CH), 62.46 (OCH2), 14.16 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C12H11N2O5+: 263.0668; found:
263.0678.
HRMS (ESI): m/z [M + H]+ calcd for C12H11BrNO3+: 295.9922; found:
295.9931.
Ethyl 3-(2-Fluorophenyl)isoxazole-5-carboxylate (10d)
Yield: 251 mg (74%); white solid; mp 37–39 °C.
1H NMR (300 MHz, CDCl3): δ = 8.08–8.02 (m, 1 H, Ar-H), 7.53–7.45
(m, 1 H, Ar-H), 7.40 (d, J = 3.6 Hz, 1 H, Ar-H), 7.31–7.19 (m, 2 H, Ar-H,
isoxazole-H), 4.49 (q, J = 7.2 Hz, 2 H, OCH2), 1.46 (t, J = 7.2 Hz, 3 H,
CH3).
13C NMR (75 MHz, CDCl3): δ = 161.94 (C=O), 160.80 (C=N), 158.34 (Ar-
CF), 156.78 (isoxazole-CO), 132.34, 129.08, 124.79, 116.60, 116.20,
109.87 (isoxazole-CH), 62.35 (OCH2), 14.16 (CH3).
Ethyl 3-(4-Bromophenyl)isoxazole-5-carboxylate (10i)12,17
Yield: 277 mg (94%); white solid; mp 128–130 °C.
1H NMR (300 MHz, CDCl3): δ = 7.72 (d, J = 8.4 Hz, 2 H, Ar-H), 7.63 (d,
J = 8.4 Hz, 2 H, Ar-H), 7.25 (s, 1 H, isoxazole-H), 4.48 (q, J = 7.2 Hz, 2 H,
OCH2), 1.45 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 162.07 (C=O), 161.23 (C=N), 156.65
(isoxazole-CO), 132.36 (2C), 128.34 (2C), 126.93, 125.00 (Ar-CBr),
107.11 (isoxazole-CH), 62.44 (OCH2), 14.15 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C12H11FNO3+: 236.0723; found:
236.0733.
HRMS (ESI): m/z [M + H]+ calcd for C12H11BrNO3+: 295.9922; found:
295.9927.
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Ethyl 3-[2-(Trifluoromethyl)phenyl]isoxazole-5-carboxylate
(10j)39
13C NMR (75 MHz, CDCl3): δ = 163.07 (C=O), 160.83 (C=N), 156.85
(isoxazole-CO), 138.91, 131.33, 128.98, 127.86, 127.44, 124.00, 107.43
(isoxazole-CH), 62.32 (OCH2), 21.37 (Ar-CH3), 14.17 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C13H14NO3+: 232.0974; found:
232.0981.
Yield: 224 mg (74%); colorless oil.
1H NMR (300 MHz, CDCl3): δ = 7.84 (d, J = 6.6 Hz, 1 H, Ar-H), 7.67 (s,
3 H, Ar-H), 7.16 (s, 1 H, isoxazole-H), 4.49 (q, J = 7.2 Hz, 2 H, OCH2),
1.46 (t, J = 7.2 Hz, 3 H, CH3).
Ethyl 3-(4-Tolyl)isoxazole-5-carboxylate (10o)10
13C NMR (75 MHz, CDCl3): δ = 161.96 (C=O), 160.45 (C=N), 156.69
2
Yield: 309 mg (90%); white solid; mp 51–53 °C.
(isoxazole-CO), 132.10, 131.83 (q, JC–F = 33.2 Hz), 130.25, 129.08,
126.56, 126.05 (q, 3JC–F = 3.03 Hz), 121.75 (q, 1JCF3 = 272.5 Hz), 110.52
1H NMR (300 MHz, CDCl3): δ = 7.75 (d, J = 7.5 Hz, 2 H, Ar-H), 7.31 (d,
J = 7.5 Hz, 2 H, Ar-H), 7.25 (s, 1 H, isoxazole-H), 4.48 (q, J = 6.6 Hz, 2 H,
OCH2), 2.43 (s, 3 H, Ar-CH3), 1.46 (t, J = 6.6 Hz, 3 H, CH3).
(isoxazole-CH), 62.46 (OCH2), 14.15 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C13H11F3NO3+: 286.0691; found:
13C NMR (75 MHz, CDCl3): δ = 162.91 (C=O), 160.76 (C=N), 156.88
(isoxazole-CO), 140.82, 129.78 (2C), 126.75 (2C), 125.14, 107.32 (isox-
azole-CH), 62.30 (OCH2), 21.46 (Ar-CH3), 14.17 (CH3).
286.0698.
Ethyl 3-[3-(Trifluoromethyl)phenyl]isoxazole-5-carboxylate
(10k)39
HRMS (ESI): m/z [M + H]+ calcd for C13H14NO3+: 232.0974; found:
Yield: 262 mg (87%); white solid; mp 52–54 °C.
232.0979.
1H NMR (300 MHz, CDCl3): δ = 8.11 (s, 1 H, Ar-H), 8.06 (d, J = 7.5 Hz,
1 H, Ar-H), 7.77 (d, J = 7.5 Hz, 1 H, Ar-H), 7.65 (t, J = 7.5 Hz, 1 H, Ar-H),
7.31 (s, 1 H, isoxazole-H), 4.49 (q, J = 7.2 Hz, 2 H, OCH2), 1.46 (t, J =
7.2 Hz, 3 H, CH3).
Ethyl 3-(2-Methoxyphenyl)isoxazole-5-carboxylate (10p)
Yield: 252 mg (77%); white solid; mp 57–59 °C.
1H NMR (300 MHz, CDCl3): δ = 7.96 (d, J = 7.5 Hz, 1 H, Ar-H), 7.44 (m,
2 H, Ar-H), 7.10–7.02 (m, 2 H, Ar-H, isoxazole-H), 4.48 (q, J = 7.2 Hz,
2 H, OCH2), 3.94 (s, 3 H, OCH3), 1.45 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 160.56 (C=O), 159.78 (C=N), 157.19 (2C,
Ar-C-OCH3, isoxazole-CO), 131.81, 129.41, 121.01, 116.85, 111.42,
111.06 (isoxazole-CH), 62.16 (OCH2), 55.57 (OCH3), 14.21 (CH3).
13C NMR (75 MHz, CDCl3): δ = 161.83 (C=O), 161.50 (C=N), 156.56
2
(isoxazole-CO), 131.90, 130.05 (q, JC–F = 33.1 Hz), 129.73, 128.89 (q,
1
3JC–F = 3.5 Hz), 127.21, 123.77, 123.72 (q, JCF3 = 272.9 Hz), 107.12
(isoxazole-CH), 62.52 (OCH2), 14.15 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C13H11F3NO3+: 286.0691; found:
286.0700.
HRMS (ESI): m/z [M + H]+ calcd for C13H14NO4+: 248.0923; found;
248.0932.
Ethyl 3-[4-(Trifluoromethyl)phenyl]isoxazole-5-carboxylate
(10l)21,23
Ethyl 3-(3-Methoxyphenyl)isoxazole-5-carboxylate (10q)10
Yield: 281 mg (93%); white solid; mp 125–127 °C.
Yield: 271 mg (83%); white solid; mp 102–104 °C.
1H NMR (300 MHz, CDCl3): δ = 7.98 (d, J = 8.1 Hz, 2 H, Ar-H), 7.76 (d,
J = 8.1 Hz, 2 H, Ar-H), 7.31 (s, 1 H, isoxazole-H), 4.49 (q, J = 7.2 Hz, 2 H,
OCH2), 1.46 (t, J = 7.2 Hz, 3 H, CH3).
1H NMR (300 MHz, CDCl3): δ = 7.40 (d, J = 7.5 Hz, 3 H, Ar-H), 7.25 (s,
1 H, isoxazole-H), 7.05–7.02 (m, 1 H, Ar-H), 4.48 (q, J = 7.2 Hz, 2 H,
OCH2), 3.88 (s, 3 H, OCH3), 1.45 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 162.89 (C=O), 160.92 (C=N), 160.07 (Ar-
C-OCH3), 156.80 (isoxazole-CO), 130.16, 129.19, 119.34, 116.68,
111.75, 107.46 (isoxazole-CH), 62.35 (OCH2), 55.43 (OCH3), 14.16
(CH3).
13C NMR (75 MHz, CDCl3): δ = 161.83 (C=O), 161.51 (C=N), 156.56
2
3
(isoxazole-CO), 132.62 (q, JC–F = 33.4 Hz), 131.42 (q, JC–F = 3.6 Hz),
127.23 (4C), 126.13 (q, 1JCF3 = 272.4 Hz), 107.24 (isoxazole-CH), 62.53
(OCH2), 14.15 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C13H11F3NO3+: 286.0691; found:
286.0702.
HRMS (ESI): m/z [M + H]+ calcd for C13H14NO4+: 248.0923; found:
248.0927.
Ethyl 3-(2-Tolyl)isoxazole-5-carboxylate (10m)10
Ethyl 3-(4-Methoxyphenyl)isoxazole-5-carboxylate (10r)10
Yield: 257 mg (75%); white solid; mp 45–47 °C.
Yield: 288 mg (88%); white solid; mp 83–85 °C.
1H NMR (300 MHz, CDCl3): δ = 7.54 (d, J = 7.5 Hz, 1 H, Ar-H), 7.42–
7.32 (m, 3 H, Ar-H), 7.15 (s, 1 H, isoxazole-H), 4.49 (q, J = 7.2 Hz, 2 H,
OCH2), 2.50 (s, 3 H, Ar-CH3), 1.46 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 163.56 (C=O), 160.18 (C=N), 156.92
(isoxazole-CO), 136.95, 131.23, 130.01, 129.47, 127.65, 126.18, 109.96
(isoxazole-CH), 62.32 (OCH2), 21.06 (Ar-CH3), 14.17 (CH3).
1H NMR (300 MHz, CDCl3): δ = 7.78 (d, J = 8.4 Hz, 2 H, Ar-H), 7.21 (s,
1 H, isoxazole-H), 7.00 (d, J = 8.4 Hz, 2 H, Ar-H), 4.47 (q, J = 6.9 Hz, 2 H,
OCH2), 3.88 (s, 3 H, OCH3), 1.45 (t, J = 6.9 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 162.56 (C=O), 161.40 (C=N), 160.67 (Ar-
C-OCH3), 156.90 (isoxazole-CO), 128.31 (2C), 120.44, 114.47 (2C),
107.16 (isoxazole-CH), 62.29 (OCH2), 55.40 (OCH3), 14.17 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C13H14NO3+: 232.0974; found:
232.0977.
HRMS (ESI): m/z [M + H]+ calcd for C13H14NO4+: 248.0923; found:
248.0934.
Ethyl 3-(3-Tolyl)isoxazole-5-carboxylate (10n)10
Ethyl 3-[(1,1′-biphenyl)-2-yl]isoxazole-5-carboxylate (10s)
Yield: 289 mg (84%); white solid; mp 58–60 °C.
Yield: 242 mg (81%); white solid; mp 64–66 °C.
1H NMR (300 MHz, CDCl3): δ = 7.69 (s, 1 H, Ar-H), 7.63 (d, J = 7.5 Hz,
1 H, Ar-H), 7.38 (t, J = 7.5 Hz, 1 H, Ar-H), 7.30 (m, 1 H, Ar-H), 7.26 (s,
1 H, isoxazole-H), 4.48 (q, J = 7.2 Hz, 2 H, OCH2), 2.44 (s, 3 H, Ar-CH3),
1.45 (t, J = 7.2 Hz, 3 H, CH3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

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K. S. Kadam et al.
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Synthesis
1H NMR (300 MHz, CDCl3): δ = 7.81 (d, J = 6.9 Hz, 1 H, Ar-H), 7.59–
7.46 (m, 3 H, Ar-H), 7.38–7.36 (m, 3 H, Ar-H), 7.27–7.26 (m, 2 H, isox-
azole-H, Ar-H), 6.20 (s, 1 H, Ar-H), 4.37 (q, J = 7.2 Hz, 2 H, OCH2), 1.37
(t, J = 7.2 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 162.51 (C=O), 161.04 (C=N), 158.06 (Ar-
C-OAr), 156.74, 156.58 (isoxazole-CO), 130.53, 129.97 (2C), 129.63,
123.86, 121.56, 120.71, 119.22 (2C), 116.94, 107.42 (isoxazole-CH),
62.40 (OCH2), 14.16 (CH3).
13C NMR (75 MHz, CDCl3): δ = 163.74 (C=O), 159.46 (C=N), 156.78
(isoxazole-CO), 141.59 (Ar-C-OCH3), 140.00, 130.63, 130.21, 129.93,
129.36 (2C), 128.47 (2C), 127.81, 127.77, 126.93, 110.46 (isoxazole-
CH), 62.12 (OCH2), 14.07 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C18H16NO4+: 310.1079; found:
310.1092.
Ethyl 3-(4-Phenoxyphenyl)isoxazole-5-carboxylate (10x)
HRMS (ESI): m/z [M + H]+ calcd for C18H16NO3+: 294.1130; found:
Yield: 261 mg (90%); white solid; mp 55–57 °C.
294.1135.
1H NMR (300 MHz, CDCl3): δ = 8.81 (d, J = 8.7 Hz, 2 H, Ar-H), 7.41 (t,
J = 8.1 Hz, 2 H, Ar-H), 7.23–7.17 (m, 2 H, isoxazole-H, Ar-H), 7.11–7.08
(m, 4 H, Ar-H), 4.48 (q, J = 7.2 Hz, 2 H, OCH2), 1.46 (t, J = 7.2 Hz, 3 H,
CH3).
Ethyl 3-[(1,1′-biphenyl)-3-yl]isoxazole-5-carboxylate (10t)
Yield: 266 mg (89%); white solid; mp 63–65 °C.
1H NMR (300 MHz, CDCl3): δ = 8.09 (br. s, 1 H, Ar-H), 7.83 (d, J =
7.5 Hz, 1 H, Ar-H), 7.74 (d, J = 7.5 Hz, 1 H, Ar-H), 7.66 (d, J = 7.5 Hz,
2 H, Ar-H), 7.58 (t, J = 7.5 Hz, 1 H, Ar-H), 7.50 (t, J = 7.2 Hz, 2 H, Ar-H),
7.42 (d, J = 7.2 Hz, 1 H, Ar-H), 7.33 (s, 1 H, isoxazole-H), 4.48 (q, J =
7.2 Hz, 2 H, OCH2), 1.45 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 162.38 (C=O), 160.88 (C=N), 159.65 (Ar-
C-OAr), 156.84 (isoxazole-CO), 156.11, 129.99 (2C), 128.51 (2C),
124.18, 122.58, 119.69 (2C), 118.64 (2C), 107.21 (isoxazole-CH), 62.36
(OCH2), 14.18 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C18H16NO4+: 310.1079; found:
13C NMR (75 MHz, CDCl3): δ = 162.95 (C=O), 161.02 (C=N), 156.81
(isoxazole-CO), 142.23, 140.21, 129.56, 129.31, 128.92 (2C), 128.50,
127.83, 127.21 (2C), 125.68, 125.61, 107.44 (isoxazole-CH), 62.38
(OCH2), 14.18 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C18H16NO3+: 294.1130; found:
294.1137.
310.1088.
Ethyl 3-(Pyridin-2-yl)isoxazole-5-carboxylate (13a)23
Yield: 306 mg (86%); white solid; mp 59–61 °C.
1H NMR (300 MHz, CDCl3): δ = 8.72 (d, J = 3.6 Hz, 1 H, Py-H), 8.14 (d,
J = 7.5 Hz, 1 H, Py-H), 7.84 (t, J = 7.5 Hz, 1 H, Py-H), 7.60 (s, 1 H, isox-
azole-H), 7.40 (t, J = 6.3 Hz, 1 H, Py-H), 4.48 (q, J = 7.2 Hz, 2 H, OCH2),
1.45 (t, J = 7.2 Hz, 3 H, CH3).
Ethyl 3-[(1,1′-biphenyl)-4-yl]isoxazole-5-carboxylate (10u)
Yield: 286 mg (96%); white solid; mp 112–114 °C.
13C NMR (75 MHz, CDCl3): δ = 163.82 (C=O), 160.98 (C=N), 156.76
(isoxazole-CO), 149.91, 147.48, 137.02, 124.95, 121.75, 108.30 (isox-
azole-CH), 62.32 (OCH2), 14.14 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C11H11N2O3+: 219.0770; found:
219.0776.
1H NMR (300 MHz, CDCl3): δ = 7.94 (d, J = 8.4 Hz, 2 H, Ar-H), 7.70 (dd,
J = 8.4, 7.2 Hz, 4 H, Ar-H), 7.50 (t, J = 7.2 Hz, 2 H, Ar-H), 7.41 (dd, J =
7.2 Hz, 2 H, Ar-H), 7.31 (s, 1 H, isoxazole-H), 4.50 (q, J = 7.2 Hz, 2 H,
OCH2), 1.47 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 162.67 (C=O), 160.99 (C=N), 156.83
(isoxazole-CO), 143.38, 140.05, 128.94 (2C), 127.94, 127.75 (2C),
127.29 (2C), 127.11 (2C), 126.82, 107.35 (isoxazole-CH), 62.36 (OCH2),
14.18 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C18H16NO3+: 294.1130; found:
294.1141.
Ethyl 3-(Pyridin-3-yl)isoxazole-5-carboxylate (13b)42
Yield: 285 mg (80%); pale-brown solid; mp72–74 °C.
1H NMR (300 MHz, CDCl3): δ = 9.06 (d, J = 1.5 Hz, 1 H, Py-H), 8.75 (d,
J = 1.5 Hz, 1 H, Py-H), 8.21 (d, J = 7.5 Hz, 1 H, Py-H), 7.46 (dd, J =
4.8 Hz, 1 H, Py-H), 7.32 (s, 1 H, isoxazole-H), 4.50 (q, J = 7.2 Hz, 2 H,
OCH2), 1.46 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 161.50 (C=O), 160.51 (C=N), 156.53
(isoxazole-CO), 151.54, 147.88, 134.16, 124.29, 123.95, 106.96 (isox-
azole-CH), 62.56 (OCH2), 14.14 (CH3).
Ethyl 3-(2-Phenoxyphenyl)isoxazole-5-carboxylate (10v)
Yield: 223 mg (77%); white solid; mp 97–99 °C.
1H NMR (300 MHz, CDCl3): δ = 8.08 (dd, J = 1.5 Hz, 1 H, Ar-H), 7.46–
7.36 (m, 4 H, Ar-H), 7.26–7.15 (m, 2 H, isoxazole-H, Ar-H), 7.04 (d, J =
8.1 Hz, 2 H, Ar-H), 6.96 (d, J = 8.1 Hz, 1 H, Ar-H), 4.45 (q, J = 7.2 Hz,
2 H, OCH2), 1.42 (t, J = 7.2 Hz, 3 H, CH3).
HRMS (ESI): m/z [M + H]+ calcd for C11H11N2O3+: 219.0770; found:
219.0775.
13C NMR (75 MHz, CDCl3): δ = 160.29 (C=O), 160.08 (C=N), 157.00 (Ar-
C-OAr), 156.25 (isoxazole-CO), 155.12, 131.79, 130.05 (2C), 129.65,
124.04, 123.74, 119.49, 119.17 (2C), 118.93, 110.60 (isoxazole-CH),
62.21 (OCH2), 14.17 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C18H16NO4+: 310.1079; found:
310.1083.
Ethyl 3-(Pyridin-4-yl)isoxazole-5-carboxylate (13c)42
Yield: 282 mg (79%); pale-brown solid; mp 120–122 °C.
1H NMR (300 MHz, CDCl3): δ = 8.87 (d, J = 5.7 Hz, 2 H, Py-H), 7.74 (d,
J = 5.7 Hz, 2 H, Py-H), 7.32 (s, 1 H, isoxazole-H), 4.50 (q, J = 7.2 Hz, 2 H,
OCH2), 1.47 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 161.82 (C=O), 161.13 (C=N), 156.41
(isoxazole-CO), 150.78 (2C), 135.45, 120.92 (2C), 107.11 (isoxazole-
CH), 62.61 (OCH2), 14.14 (CH3).
Ethyl 3-(3-Phenoxyphenyl)isoxazole-5-carboxylate (10w)
Yield: 246 mg (85%); white solid; mp 62–64 °C.
HRMS (ESI): m/z [M + H]+ calcd for C11H11N2O3+: 219.0770; found:
219.0774.
1H NMR (300 MHz, CDCl3): δ = 7.58 (d, J = 10.2 Hz, 1 H, Ar-H), 7.49–
7.43 (m, 2 H, Ar-H), 7.39–7.37 (m, 2 H, Ar-H), 7.22 (s, 1 H, isoxazole-
H), 7.17–7.08 (m, 2 H, Ar-H), 6.92 (d, J = 8.1 Hz, 2 H, Ar-H), 4.47 (q, J =
7.2 Hz, 2 H, OCH2), 1.45 (t, J = 7.2 Hz, 3 H, CH3).
Ethyl 3-(Thiophen-3-yl)isoxazole-5-carboxylate (13d)
Yield: 288 mg (82%); off-white solid; mp 56–58 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

K
K. S. Kadam et al.
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Synthesis
1H NMR (300 MHz, CDCl3): δ = 7.80 (s, 1 H, thiophene-H), 7.56 (d, J =
4.8 Hz, 1 H, thiophene-H), 7.47 (d, J = 2.7 Hz, 1 H, thiophene-H), 7.17
(s, 1 H, isoxazole-H), 4.47 (q, J = 7.2 Hz, 2 H, OCH2), 1.45 (t, J = 7.2 Hz,
3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 160.67 (C=O), 158.79 (C=N), 156.76
(isoxazole-CO), 129.27, 127.22, 125.85, 125.42, 107.64 (isoxazole-CH),
62.35 (OCH2), 14.16 (CH3).
13C NMR (100 MHz, CDCl3): δ = 182.95 (C=N), 160.30 (isoxazole-CO),
148.53 (Ar-C-NO2), 135.67, 127.56 (2C), 124.14 (2C), 96.65 (isoxazole-
CH), 32.97 ((CH3)3C), 28.83 (3C, (CH3)3).
HRMS (ESI): m/z [M + H]+ calcd for C13H15N2O3+: 247.1083; found:
247.1087.
5-Cyclohexyl-3-(4-nitrophenyl)isoxazole (15e)
HRMS (ESI): m/z [M + H]+ calcd for C10H10NO3S+: 224.0376; found:
Yield: 286 mg (87%); white solid; mp125–127 °C.
224.0380.
1H NMR (400 MHz, DMSO-d6): δ = 8.34 (d, J = 8.8 Hz, 2 H, Ar-H), 8.13
(d, J = 8.8 Hz, 2 H, Ar-H), 6.99 (s, 1 H, isoxazole-H), 2.92–2.87 (m, 1 H,
cyclohexyl), 2.04–2.01 (m, 2 H, cyclohexyl), 1.78–1.74 (m, 2 H, cyclo-
hexyl), 1.69–1.66 (m, 1 H, cyclohexyl), 1.52–1.34 (m, 4 H, cyclohexyl),
1.30–1.21 (m, 1 H, cyclohexyl).
13C NMR (100 MHz, CDCl3): δ = 179.54 (C=N), 160.33 (isoxazole-CO),
148.52 (Ar-C-NO2), 135.68, 127.56 (2C), 124.14 (2C), 97.28 (isoxazole-
CH), 36.42, 31.15 (2C), 25.74, 25.63 (2C).
Ethyl 3-Isopropylisoxazole-5-carboxylate (13e)
Yield: 341 mg (81%); pale-yellow oil.
1H NMR (400 MHz, CDCl3): δ = 6.82 (s, 1 H, isoxazole-H), 4.42 (q, J =
7.2 Hz, 2 H, OCH2), 3.16–3.11 (m, 1 H, (CH3)2CH), 1.40 (t, J = 7.2 Hz,
3 H, CH3), 1.31 (d, J = 7.2 Hz, 6 H, (CH3)2CH).
13C NMR (100 MHz, CDCl3): δ = 163.13 (C=O), 160.08 (C=N), 156.97
(isoxazole-CO), 107.56 (isoxazole-CH), 62.08 (OCH2), 26.48 (CH),
21.62 (2C, (CH3)2CH), 14.10 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C15H17N2O3+: 273.1239; found:
273.1241.
HRMS (ESI): m/z [M + H]+ calcd for C9H14NO3+: 184.0974; found:
184.0979.
[3-(4-Nitrophenyl)isoxazol-5-yl]methanol (15f)45
Yield: 226 mg (85%); pale-yellow solid; mp 118–120 °C.
3-(4-Nitrophenyl)-5-phenylisoxazole (15a)43
1H NMR (400 MHz, DMSO-d6): δ = 8.35 (d, J = 8.8 Hz, 2 H, Ar-H), 8.16
(d, J = 8.8 Hz, 2 H, Ar-H), 7.11 (s, 1 H, isoxazole-H), 5.78 (t, J = 6.0 Hz,
1 H, OH), 4.65 (d, J = 6.0 Hz, 2 H, CH2).
13C NMR (100 MHz, DMSO-d6): δ = 174.51 (C=N), 160.10 (isoxazole-
CO), 148.15 (Ar-C-NO2), 134.80, 127.70 (2C), 124.03 (2C), 100.12
(isoxazole-CH), 54.90 (CH2).
Yield: 261 mg (81%); white solid; mp 221–223 °C.
1H NMR (400 MHz, DMSO-d6): δ = 8.41 (d, J = 8.8 Hz, 2 H, Ar-H), 8.21
(d, J = 8.8 Hz, 2 H, Ar-H), 7.94 (d, J = 2.0 Hz, 2 H, Ar-H), 7.80 (s, 1 H,
isoxazole-H), 7.62–7.56 (m, 3 H, Ar-H).
13C NMR (100 MHz, DMSO-d6): δ = 170.49 (isoxazole-CO), 161.10
(C=N), 148.34 (Ar-C-NO2), 134.65, 130.63, 129.23 (2C), 127.80 (2C),
126.54, 125.58 (2C), 124.26 (2C), 98.94 (isoxazole-CH).
HRMS (ESI): m/z [M + H]+ calcd for C10H9N2O4+: 221.0562; found:
221.0566.
HRMS (ESI): m/z [M + H]+ calcd for C15H11N2O3+: 267.0770; found:
267.0772.
1-[3-(4-Nitrophenyl)isoxazol-5-yl]ethanone (15g)46
Yield: 253 mg (90%); white solid; mp 158–160 °C.
1H NMR (400 MHz, DMSO-d6): δ = 8.40 (d, J = 8.8 Hz, 2 H, Ar-H), 8.24
(d, J = 8.8 Hz, 2 H, Ar-H), 8.12 (s, 1 H, isoxazole-H), 2.63 (s, 3 H, CH3).
5-(4-Fluorophenyl)-3-(4-nitrophenyl)isoxazole (15b)23
Yield: 281 mg (82%); white solid; mp 207–209 °C.
1H NMR (400 MHz, DMSO-d6): δ = 8.38 (d, J = 8.8 Hz, 2 H, Ar-H), 8.15
(d, J = 8.8 Hz, 2 H, Ar-H), 7.97 (dd, J = 5.6 Hz, 2 H, Ar-H), 7.74 (s, 1 H,
isoxazole-H), 7.43 (t, J = 8.8 Hz, 2 H, Ar-H).
13C NMR (100 MHz, DMSO-d6): δ = 185.97 (C=O), 166.80 (C=N),
161.20 (isoxazole-CO), 148.50 (Ar-C-NO2), 133.70, 127.91 (2C), 124.11
(2C), 107.12 (isoxazole-CH), 27.26 (CH3).
13C NMR (100 MHz, DMSO-d6): δ = 169.79 (isoxazole-CO), 162.64 (Ar-
C-F), 161.41 (C=N), 148.59 (Ar-C-NO2), 134.69, 128.34 (2C), 128.03
(2C), 124.61 (2C), 123.43, 116.86, 116.64, 99.18 (isoxazole-CH).
HRMS (ESI): m/z [M + H]+ calcd for C11H9N2O4+: 233.0562; found:
233.0566.
HRMS (ESI): m/z [M + H]+ calcd for C15H10FN2O3+: 285.0675; found:
285.0687.
(S)-2-(3-{4-[3-(4-Methoxyphenyl)ureido]phenyl}isoxazole-5-car-
boxamido)-3-methylbutanoic Acid (1)24
To a solution of (S)-methyl-2-[3-(4-aminophenyl)isoxazole-5-carbox-
amido]-3-methylbutanoate (4 g, 12.62 mmol, 1.0 equiv) in THF (20
mL) was added 4-methoxyphenylisocyanate (1.98 g, 13.25 mmol, 1.1
equiv) and the reaction mixture was stirred at r.t. for 5 h. The precipi-
tated solid was filtered and dried to obtain the ester compound (5.3 g)
as a white solid. To a solution of the ester (5.3 g, 11.37 mmol, 1. 0
equiv) in THF (25 mL) was added 1 M LiOH solution (5.68 mL, 56.86
mmol, 5.0 equiv) and the mixture was stirred at r.t. for 12 h. The sol-
vent was evaporated under reduced pressure to obtain a residue,
which was diluted with water and acidified with concd HCl to pH 2.
The precipitated solid was filtered and dried to afford the desired
compound 1.
5-(4-Methoxyphenyl)-3-(4-nitrophenyl)isoxazole (15c)23
Yield: 286 mg (80%); white solid; mp 173–175 °C.
1H NMR (400 MHz, DMSO-d6): δ = 8.40 (d, J = 8.8 Hz, 2 H, Ar-H), 8.18
(d, J = 8.8 Hz, 2 H, Ar-H), 7.87 (d, J = 8.8 Hz, 2 H, Ar-H), 7.64 (s, 1 H,
isoxazole-H), 7.14 (d, J = 8.8 Hz, 2 H, Ar-H), 3.84 (s, 3 H, OCH3).
HRMS (ESI): m/z [M + H]+ calcd for C16H13N2O4+: 297.0875; found:
297.0884.
5-(tert-Butyl)-3-(4-nitrophenyl)isoxazole (15d)44
Yield: 262 mg (88%); white solid; mp 155–157 °C.
Yield: 4.63 g (81%); off-white solid; mp 220–222 °C.
1H NMR (400 MHz, DMSO-d6): δ = 8.35 (d, J = 8.8 Hz, 2 H, Ar-H), 8.14
(d, J = 8.8 Hz, 2 H, Ar-H), 7.02 (s, 1 H, isoxazole-H), 1.36 (s, 9 H,
(CH3)3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

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1H NMR (300 MHz, DMSO-d6): δ = 12.61 (br. s, 1 H, OH), 9.00 (s, 1 H,
NH), 8.91 (d, J = 8.1 Hz, 1 H,CONH), 8.68 (s, 1 H, NH), 7.81 (d, J =
8.7 Hz, 2 H, Ar-H), 7.67 (s, 1 H, isoxazole-H), 7.60 (d, J = 8.7 Hz, 2 H,
Ar-H), 7.36 (d, J = 8.7 Hz, 2 H, Ar-H), 6.85 (d, J = 8.7 Hz, 2 H, Ar-H),
4.28–4.23 (t, J = 7.2 Hz, 1 H, NHCH), 3.70 (s, 3 H, OCH3), 2.23–2.16 (m,
1 H, CH(CH3)2), 0.95 (dd, J = 4.2 Hz, 6 H, (CH3)2).
13C NMR (75 MHz, DMSO-d6): δ = 172.95 (C=O), 163.90 (C=N), 162.74
(NHC=O), 156.65 (isoxazole-CO), 155.18 (Ar-C-OCH3), 153.13
(NHCONH), 142.82, 133.08, 128.03 (2C), 121.28, 120.75 (2C), 118.70
(2C), 114.58 (2C), 105.19 (isoxazole-CH), 58.67 (CHNH), 55.75 (OCH3),
30.05 (CH(CH3)2), 19.78 (CH3), 19.21 (CH3).
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Brahma, M. K.; Deshmukh, N. J.; Dixit, A.; Doshi, L.; Potdar, N.;
Enose, A. A.; Vishwakarma, R. A.; Sivaramakrishnan, H.;
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Acknowledgment
The authors want to thank the analytical facility at Piramal Enterpris-
es Ltd, Mumbai, India, for their support. The authors also would like
to thank Dr. D. R. Garud, S.P. College, Pune, for his help.
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Supporting Information
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Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561464.
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