Full text of DOI:10.1002/ejoc.201701726

A Journal of
Accepted Article
Title: One-pot Preparation of 3-Arylisoxazole-4,5-dicarboxylates from
Benzylic Chlorides via Aldehydes, Oximes, and Nitrile N-Oxides
with Acetylenedicarboxylates
Authors: Hideo Togo and Taro Imai
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701726
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10.1002/ejoc.201701726
European Journal of Organic Chemistry
FULL PAPER
DOI: 10.1002/ejoc.200((will be filled in by the editorial staff))
One-pot Preparation of 3-Arylisoxazole-4,5-dicarboxylates from Benzylic
Chlorides via Aldehydes, Oximes, and Nitrile N-Oxides with
Acetylenedicarboxylates
Taro Imai[a] and Hideo Togo*[1]
Keywords: Benzylic halide / Isoxazole / NMO / Oxone® / Acetylene
Various diethyl 3-arylisoxazole-4,5-dicarboxylates were efficiently, with NMO, hydroxylamine•hydrochloride, and then Oxone® in
smoothly, and quickly prepared in good to moderate yields by the the presence of diethyl acetylenedicarboxylates under mild and
successive treatment of benzylic chlorides and alkyl p-tosylates
transition-metal-free conditions.
chlorides, terminal alkynes, and Cu(Phen)(Ph3P)2NO3 (cat.),3n and
____________
[a]
Graduate School of Science, Chiba University, Yayoi-cho 1-33,
the
preparation
of
3,5-disubstituted
isoxazoles
with
Inage-ku, Chiba 263-8522 Japan
Fax: 81-43-290-2792
E-mail: togo@faculty.chiba-u.jp
homopropargylic alcohols, t-BuONO, and Fe(OTf)3 (cat.)3o were
reported.
Homepage: http://reaction-2.chem.chiba-u.jp/index.html
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.xxxxxxxxx.
OH
[ O ]
O
R'
R'
N
N
R
N O
R'
R
R
Nitrile N-oxide
R'
Introduction
Scheme 1. Conventional Mehtod for Preparation of Isoxazoles
Some nitrogen-containing heteroaromatics are very important
because of their potent biological activities.1 Isoxazoles, in
particular, are one of the most important nitrogen-containing
heteroaromatics.2 Isoxazole derivatives possessing anti-
inflammatory,2b antimicrobial,2c anticancer,2d and antinociceptive2e
activities are known. Therefore, extensive synthetic studies of
isoxazoles have been carried out, and the most typical preparation
method is the 1,3-dipolar cycloaddition of nitrile N-oxides to
alkynes, as shown in Scheme 1. Recent reports for the preparation
of isoxazoles via nitrile N-oxides with alkynes are as follows:3 the
preparation of 3-(difluoromethyl)isoxazoles with difluoromethyl
nitrile N-oxide and alkynes,3b the preparation of 3-arylisoxazoles
with aldoximes, alkynes, and alkyl nitrites,3c the preparation of 3,4-
disubstituted and 3,4,5-trisubstituted isoxazoles with aldoximes,
alkynes, and (diacetoxyiodo)benzene,3d the preparation of 3-
(trifluoromethyl)isoxazoles with (trifluoromethyl)hydroximoyl
bromide and alkynes,3e the preparation of 3,4,5-trisubstituted
isoxazoles with nitrile N-oxides and ketones in the presence of
1,1,3,3-tetramethylquanidine,3f the preparation of 3,5-disubstituted
We also reported the preparation of 3,5-disubstituted isoxazoles
with high regioselectivity in one pot by the treatment of terminal
alkynes with n-BuLi, aromatic aldehydes, molecular iodine, and
then hydroxylamine through the formation of propargyl alkoxides
and -alkynyl ketones.4 On the other hand, we reported the one-pot
conversion of methylarenes into aromatic aldehydes via benzylic
bromides through the Wohl-Ziegler bromination of methylarenes,
and the subsequent SN2 and E2 reactions with N-methylmorpholine
N-oxide (NMO).5a Based on the results for oxidation of benzylic
bromides with NMO5a and benzylic chlorides with NMO5b, here
we would like to report one-pot preparation of 3-arylisoxazoles and
3-alkylisoxazoles from benzylic chlorides and alkyl p-tosylates by
the treatment with NMO, hydroxylamine•hydrochloride, and
Oxone® in the presence of acetylene derivatives. To the best of our
knowledge, the transformation of benzylic halides into 3-
arylisoxazoles and related reactions have never been reported.
Results and Discussion
isoxazoles
with
aldoximes,
alkynes,
and
Oxone®(2KHSO5•KHSO4•K2SO4) in the presence of 3,5-Me2C6H3I
(cat.),3g and the preparation of 3,5-disubstituted isoxazoles with
aldoximes, alkynes, and [bis(trifluoroacetoxy)iodo]benzene.3h As
other preparation methods for isoxazoles, the preparation of 3,5-
disubstituted isoxazoles with ynones and trimethylsilylazide3i and
the preparation of 3,5-diarylisoxazoles with 1,3-diaryl-1-thioketo-
3-ketopropanes or 1,3-diaryl-3-thiomethyl-2-propen-1-ones and
hydroxylamine3j were reported. On the other hand, as examples of
transition-metal-catalyzed methods, the preparation of 3,5-
disubstituted isoxazoles with ethynylarenes, t-BuONO, and
Sc(OTf)3 (cat.),3k the preparation of 3,5-disubstituted isoxazoles
with hydroxyimino acids, alkenes, Oxone®, and Ru(bpy)3Cl2
(cat.),3l the preparation of 4-borylated 3,5-disubstituted isoxazoles
with oximes of ynones, HBcat, and IPrAuTFA (cat.),3m the
preparation of 3,5-disubstituted isoxazoles with N-hydroxyimidoyl
At first, p-chlorobenzyl chloride 1a (1.0 mmol) was treated with
NMO (4.0 mmol) in acetonitrile at 80 °C for 4 h to form p-
chlorobenzaldehyde (1st step).5a Then, NH2OH•HCl (2.0 mmol)
and K2CO3 (1.0 mmol) were added and the mixture was stirred at
room temperature for 30 min to form the corresponding oxime
quantitatively (2nd step). Once the oxime was formed, Oxone® (1.1
mmol), diethyl acetylenedicarboxylate (I) (1.5 mmol), and water (5
mL) were added and the obtained mixture was stirred at room
temperature for
1
h
(3rd step) to give diethyl 3-(4’-
chlorophenyl)isoxazole-4,5-dicarboxylare 2a-I in 54% yield, as
shown in Table 1 (entry 1). When the reaction with 1a was carried
out under the same procedure and conditions without the addition
of water at the 3rd step, the yield of isoxazole 2a-I was dramatically
decreased to 6% (entry 2) due to the insolubility of Oxone®. After
Submitted to the European Journal of Organic Chemistry
1
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701726
European Journal of Organic Chemistry
the same oxidation of 1a with NMO, treatment of the formed
aldehyde with reduced amounts of NH2OH•HCl (1.2 mmol) and
K2CO3 (0.6 mmol) at room temperature for 30 min and the
subsequent treatment with Oxone® (1.1 mmol) and I (1.5 mmol)
without water and with water (5 mL) at room temperature for 1 h
gave isoxazole 2a-I in 0% and 88% yields, respectively (entries 3,
4). Thus, the addition of water at the 3rd step is quite important to
form isoxazole 2a-I. The same treatment of 1a with NH2OH•H2O
(1.2 equiv.) alone instead of NH2OH•HCl and K2CO3 under the
same procedure and conditions at the 2nd step slightly reduced the
yield of isoxazole 2a-I to 81% (entry 5). On the other hand, the
same treatment of 1a under the same procedure and conditions
using reduced amounts of Oxone® (1.2 mmol) and I (1.2 mmol)
(diacetoxyiodo)benzene (DIB) were used instead of Oxone® under
the same procedure and conditions, isoxazole 2a-I was not
obtained at all (entries 7~12). Thus, Oxone® plays an important
role in the present one-pot preparation of isoxazole 2a-I from the
oxime. On the other hand, when p-chlorobenzyl bromide and p-
chlorobenzyl iodide instead of p-chlorobenzyl chloride 1a were
treated under the same procedure and conditions, isoxazole 2a-I
was obtained in 56% and 0% yields, respectively (entries 13, 14).
Thus, benzyl bromide showed moderate reactivity, whereas benzyl
iodide was not effective in the present reaction at all.
Table 2. One-pot Transformation of Benzylic Chlorides or Alkyl
p-Tosylates 1 into Isoxazoles 2
Table 1. Optimization for One-pot Transformation of p-
Chlorobenzyl Chloride 1a to Isoxazole 2a-I
NH2OH•HCl (1.2 equiv.)
K2CO3 (0.6 euivq.)
R1
NMO (4.0 equiv.)
NH2OH•HCl
X
CH3CN (5 mL), 80 °C, 4 h
r.t., 30 min.
K2CO3
NMO (4.0 equiv.)
1 (1 mmol)
Oxone (1.5 equiv.)
EtO2C CO Et
Cl
O
N
A: X = Cl,
B: X = OTs
(I) (1.5 equiv.)
H2O (5 mL), r.t., 1 h
CH3CN (5 mL), 80 °C, 4 h
r.t., 30 min.
(2nd step)
2
CO2Et
Cl
R1
Cl
(1st step)
1a (1 mmol)
CO2Et
2
Oxidant
EtO2C
O
N
Product, Yield (A: X = Cl, B: X = OTs)
(I)
CO2Et
CO2Et
O
O
O
N
N
N
H2O, r.t., 1 h
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
Cl
CO2Et
(3rd step)
Cl
2a-I
H2O
CO2Et
Cl
2a-I A: 88%, 86%a
B: 72%b
2b-I A :82%
2c-I A: 88%
Entr
NH2OH▪
HCl
K2CO3
(equiv.)
Oxidant
(equiv.)
I
Yiel
d
y
(equiv.)
(mL)
(equiv.)
(%)
54
O
N
O
N
O
N
Oxone®
(1.1)
1.5
1.5
1.5
1.5
1.5
1.2
1.5
1.5
H2O
(5)
-
CO2Et
CO2Et
CO2Et
1
2.0
2.0
1.2
1.2
1.2
1.2
1.2
1.0
1.0
0.6
0.6
-
Oxone®
(1.1)
6
0
CO2Et
CO2Et
CO2Et
Br
MeO2C
F
2
2d-I A: 69%
2e-I A :79%
2f-I A: 67%
Oxone®
(1.1)
-
O
N
O
N
O
N
3
CO2Et
CO2Et
CO2Et
Oxone®
(1.5)
H2O
(5)
H2O
(5)
H2O
(5)
H2O
(5)
88
81
68
0
4
CO2Et
CO2Et
CO2Et
NC
Ph
O2N
Oxone®
(1.5)
5a,b
6
2g-I A: 51%
2i-I A: 82%
2h-I A: 57%
O
N
O
N
Oxone®
(1.2)
O
N
CO2Et
0.6
CO2Et
CO2Et
30% H2O2
(1.5)
70%
TBHP
(1.5)
CO2Et
CO2Et
CO2Et
Ph(O=)C
7
8
0.6
0.6
Me
2j-I B: 97%
2k-I A: 69%
2l-I A: 77%
H2O
(5)
0
O
N
O
N
1.2
O
N
CO2Et
CO2Et
CO2Et
9
0.6
0.6
0.6
0.6
0.6
0.6
DTBP
(1.5)
Na2S2O8
(1.5)
BPO
(1.5)
1.5
1.5
1.5
1.5
1.5
1.5
-
0
0
1.2
1.2
1.2
1.2
1.2
1.2
CO2Et
CO2Et
CO2Et
tBu
MeO
10
11
12
13c
14d
H2O
(5)
-
2m-I A: 61%
2n-I A: 77%
2o-I A :91%
O
N
O
N
O
N
0
CO2Et
CO2Et
CO2Et
S
CO2Et
DIB
-
-
-
0
CO2Et
CO2Et
O
S
(1.5)
2q-I A: 52%
2r-I A: 58%(6%)c
2p-I A: 60%
Oxone®
(1.5)
56
0
O
N
O
N
O
N
CO2Et
Oxone®
(1.5)
CO2Et
CO2Et
CO2Et
2t-I B: 37%b
CO2Et
N
CO2Et
Ts
2s-I A : 57%d
N
2u-I A: 6%e
B: 72%b
a NH2OH (50% in water) was used instead of NH2O▪HCl. b 3rd step reaction was
carried out for 2 h. c p-Chlorobenzyl bromide was used instead of p-chlorobenzyl
chloride 1a. d p-Chlorobenzyl iodide was used instead of p-chlorobenzyl chloride 1a.
O
O
N
N
CO2Et
CO2Et
CO2Et
2w-I B: 57%b
CO2Et
with water at the 3rd step reduced the yield of isoxazole 2a-I to
68% (entry 6). Thus, the treatment of 1a (1 mmol) with NMO (4.0
equiv.) in acetonitrile under refluxing conditions for 4 h, and the
subsequent treatment with NH2OH•HCl (1.2 equiv.) and K2CO3
(0.6 equiv.) at room temperature for 30 min, followed by the
treatment with Oxone® (1.5 equiv.), I (1.5 equiv.), and water (5
mL) at room temperature for 1 h gave the best yield of isoxazole
2a-I (entry 4). When other oxidants, such as 30% hydrogen
peroxide, 70% t-butyl hydrogen peroxide (TBHP), di-t-butyl
peroxide (DTBT), Na2S2O8, benzoyl peroxide (BPO), and
2v-I A: 12%f
B : 64%b
a 1a (10 mmol) was used. b 1st step reaction was carried out for 2 h. c Yield of
isoxazole 2r-I'. d 2nd step reacion conditions : NH2OH (2.4 equiv.) and K2CO3 (1.2
equiv.) were used, and the mixture was stirred at r.t. for 60 h. e 1st step reaction was
carried out for 5 h. f 1st step reaction was carried out for 4 h.
O
N
Cl
CO2Et
Isoxazole 2r-I' :
CO2Et
S
Submitted to the European Journal of Organic Chemistry
2
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701726
European Journal of Organic Chemistry
As
a
gram-scale experiment, successive treatment of p-
Table 3. One-pot Transformation of p-Chlorobenzyl Chloride 1a
into Isoxazoles 2a
chlorobenzyl chloride 1a (10 mmol) with NMO (1st step),
NH2OH•HCl and K2CO3 (2nd step), and then Oxone® (15 mmol), I
(15 mmol), and water (3rd step) under the same procedure and
conditions provided isoxazole 2a-I in 86% yield, as shown in Table
2.
NH2OH•HCl (1.2 equiv.)
K2CO3 (0.6 equiv.)
NMO (4.0 equiv.)
Cl
CH3CN (5 mL), 80 °C, 4 h r.t., 30 min.
Cl
1a (1 mmol)
O
Oxone (1.5 equiv.)
N
R1
R1
R2 II~X (1.5 equiv.)
Based on those results, various benzylic chlorides, such as m-
chlorobenzyl chloride 1b, o-chlorobenzyl chloride 1c, p-
fluorobenzyl chloride 1d, p-bromobenzyl chloride 1e, p-
(methoxycarbonyl)benzyl chloride 1f, p-nitrobenzyl chloride 1g, p-
cyanobenzyl chloride 1h, p-phenylbenzyl chloride 1i, benzyl
chloride 1k, p-methylbenzyl chloride 1l, p-t-butylbenzyl chloride
1m, p-methoxybenzyl chloride 1n, and (naphthalen-1-yl)methyl
chloride 1o, were treated with NMO, NH2OH•HCl and K2CO3, and
then Oxone®, I, and water under the same procedure and
conditions to form the corresponding isoxazoles 2b-I~2i-I and 2k-
I~2o-I in good to moderate yields, respectively, as shown in Table
2. As regards heteroaromatic groups, when (benzothiophen-3-
yl)methyl chloride 1p, (benzofuran-3-yl)methyl chloride 1q,
(thiophene-2-yl)methyl chloride 1r, and (1-tosylindole-3-yl)methyl
chloride 1s, were also treated with NMO, NH2OH•HCl and K2CO3,
and then Oxone®, I, and water under the same procedure and
conditions, the corresponding isoxazoles 2p-I~2s-I were obtained
in moderate yields, respectively, as shown in Table 2. On the
other hand, when aliphatic chlorides, such as 3-(phenyl)propyl
chloride 1u and 1-octyl chloride 1v, were treated with NMO,
NH2OH•HCl and K2CO3, and then Oxone®, I, and water under the
same procedure and conditions, the corresponding isoxazoles 2u-I
and 2v-I were obtained in only 6% and 12% yields, respectively, as
shown in Table 2. The reason why the yields of isoxazoles 2u-I
and 2v-I were low is that the first transformation of alkyl chlorides
into the corresponding aldehydes with NMO did not proceed
effectively due to the low reactivity of the alkyl chlorides toward
NMO. Therefore, for alkyl groups, (3-phenyl)propyl p-tosylate
1u’, 1-octyl p-tosylate 1v’, and (cyclohexyl)methyl p-tosylate 1w’
were treated with NMO, NH2OH•HCl and K2CO3, and then
Oxone®, I, and water under the same procedure and conditions to
form the corresponding isoxazoles 2u-I~2w-I in good to moderate
yields, respectively, as shown in Table 2, although the same
treatment of neopentyl p-tosylate did not generate the
corresponding isoxazole at all. Similarly, for aromatic groups,
when p-chlorobenzyl p-tosylate 1a’, (p-benzoyl)benzyl p-tosylate
1j’, and (2-methylquinoline-4-yl)methyl p-tosylate 1t’ were treated
with NMO, NH2OH•HCl and K2CO3, and then Oxone®, I, and
water under the same procedure and conditions, the corresponding
isoxazoles 2a-I, 2j-I, and 2t-I were obtained in good to moderate
yields, respectively. Then, other acetylene derivatives, such as
dimethyl acetylenedicarboxylate (II), ethyl propiolate (III),
phenylacetylene (IV), (m-chlorophenyl)acetylene (V), (p-
methylphenyl)acetylene (VI), (p-methoxyphenyl)acetylene (VII),
4-phenyl-3-butyn-2-one (VIII), (naphthalene-1-yl)acetylene (IX),
and (thiophen-3-yl)acetylene (X), were used instead of diethyl
H2O (5 mL), r.t., 3rd time
R2
Cl
2a
Product, Yield, 3rd time
O
N
O
N
O
N
CO2Et
CO2Me
CO2Me
Cl
Cl
Cl
2a-II 76%, 1 h
2a-III 60%(14%)a, 1 h
2a-IV 64%, 3 h
Cl
O
N
O
N
O
N
Me
OMe
Cl
Cl
Cl
Cl
2a-VI 46%, 1.5 h
2a-V 42%, 2.5 h
2a-VII 24%, 1.5h
O
N
O
N
O
N
S
Cl
O
Cl
2a-X 48%b, 5 h
2a-VIII 42%, 1.5 h
2a-IX 42%, 3 h
a Yield of isoxazole 2a-III'. b Oxone (2.0 equiv.) was used at 3rd step.
isoxazole 2a-III':
To understand the role of chloride ion derived from benzylic
chloride and/or NH2OH•HCl in the present one-pot preparation of
3-arylisoxazoles 2 from benzylic chlorides 1, p-chlorobenzyl p-
tosylate 1a’ instead of p-chlorobenzyl chloride 1a was used. Thus,
when p-chlorobenzyl p-tosylate 1a’ was treated with NMO,
NH2OH•HCl and K2CO3, and then Oxone®, I, and water under the
same procedure and conditions, isoxazole 2a-I was obtained in
72% yield, as shown in Scheme 2 (eq. 1). However, when p-
chlorobenzyl p-tosylate 1a’ was treated with NMO, NH2OH•H2O,
and then Oxone®, I, and water under the same procedure and
conditions, isoxazole 2a-I was not obtained at all (eq. 2). Thus,
chloride ion plays an important role in the oxidation of the oxime
to nitrile N-oxide in the presence of Oxone®, where the formed
nitrile N-oxide reacts with diethyl acetylenedicarboxylate (I) to
give isoxazole 2a-I.7
NH2OH•HCl (1.2 equiv.)
K2CO3 (0.6 equiv.)
NMO (4.0 equiv.)
OTs
CH3CN (5 mL)
r.t., 30 min.
Cl
80 °C, 2 h
O
N
1a' (1 mmol)
Oxone (1.5 equiv.)
CO2Et
1)
EtO2C
CO Et
(I) (1.5 equiv.)
2
CO2Et
2a-I 72%
acetylenedicarboxylate (I).
p-Chlorobenzyl chloride 1a was
H2O (5 mL), r.t., 1 h
Cl
treated with NMO in acetonitrile under refluxing conditions for 4
h, and then with NH2OH•HCl and K2CO3 at room temperature for
30 min. This was followed by the reaction with Oxone®, acetylene
derivatives (II~X), and water at room temperature for 1 h~5 h to
give isoxazoles 2a-II~2a-X in good to moderate yields, except 2a-
VII, as shown in Table 3. This is because electron-rich alkynes,
such as (p-methoxyphenyl)acetylene (VII), reacted with active
species, the chloro cation formed by the reaction of chloride ion
and Oxone® at the 3rd reaction step and the formation of nitrile N-
oxide from oxime was disturbed.6
NMO (4.0 equiv.)
NH2OH•H2O (1.2 equiv.)
OTs
CH3CN (5 mL)
r.t., 30 min.
Cl
80 °C, 2 h
O
N
1a' (1 mmol)
Oxone (1.5 equiv.)
EtO2C CO Et
CO2Et
2)
2a-I 0% (56%)a
(I) (1.5 equiv.)
H2O (5 mL), r.t., 1 h
2
CO2Et
Cl
a Yield of recovered oxime
Scheme 2. Reaction with p-Chlorobenzyl p-Tosylate 1a’
Submitted to the European Journal of Organic Chemistry
3
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10.1002/ejoc.201701726
European Journal of Organic Chemistry
A possible reaction pathway is shown in Scheme 3. Benzylic
chlorides react with NMO through an SN2 reaction and a
subsequent E2 reaction to form aromatic aldehydes (1st step).5 The
formed aromatic aldehydes react smoothly with NH2OH•HCl in the
presence of K2CO3 to form oximes (2nd step). Then, the oximes are
oxidized to nitrile N-oxides by a chloro cation that is formed by the
reaction of chloride ion and Oxone®,7 and the formed nitrile N-
oxides react with acetylene derivatives to form isoxazoles. Here,
chloride ion derived from benzylic chlorides and/or NH2OH•HCl
probably works as a catalyst for the formation of nitrile N-oxides
from oxime in the presence of Oxone®.
General Procedure for Preparation of Isoxazoles 2 from
Benzylic Chlorides or Alkyl p-Tosylates
1 with NMO,
NH2OH•HCl, and Oxone® in the presence of Acetylene
Derivatives:
To a solution of 4-chlorobenzyl chloride 1a (161.03 mg, 1.0 mmol)
in CH3CN (5.0 mL) in a 50 mL screw-capped flask was added N-
methylmorpholine N-oxide (468.6 mg, 4.0 mmol) at room
temperature. The mixture was stirred at 80 °C for 4 h. Then,
hydroxylamine hydrochloride (83.4 mg, 1.2 mmol) and K2CO3
(82.9 mg, 0.6 mmol) were added, and the obtained mixture was
stirred at room temperature for 0.5 h. After that, H2O (5.0 mL),
diethyl acetylenedicarboxylate (239.0 µL, 1.5 mmol), and Oxone®
(922.1 mg, 1.5 mmol) were added to the mixture at room
temperature. The obtained mixture was stirred at room temperature
for one hour. The resulting mixture was quenched with sat. aq.
Na2S2O3 and extracted with AcOEt (3 × 10 mL). The organic layer
was washed with brine and dried over Na2SO4. Purification of the
residue by short column chromatography on neutral silica gel
(hexane/AcOEt = 10:1) gave diethyl 3-(4’-chlorophenyl)isoxazole-
4,5-dicarboxylate 2a (284.9 mg, 88%).
O
X
SN2
N
O
E2
O
2 NMO
H
R
X
R
(- NMO)
R
O
1
N
-
N
O
(X = Cl or OTs)
O
H
X
Diethyl 3-(4’-chlorophenyl)isoxazole-4,5-dicarboxylate (2a-I).8
Colorless Oil (284.9 mg, 88% yield): IR (neat) 2985, 1732, 1272,
(X = Cl)
O
N
1
1065, 731 cm-1; H-NMR (CDCl3 : 400 MHz) δ = 1.33 (t, J = 7.2
R1
NH2OH•HCl
K2CO3
R
Hz, 3H), 1.43 (t, J = 7.2 Hz, 3H), 4.38 (q, J = 7.2 Hz, 2H), 4.48 (q,
J = 7.2 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ = 13.8, 14.0, 62.5, 62.9, 115.7,
125.4, 129.1, 129.5, 136.9, 156.0, 159.9, 160.2, 161.1; HRMS
(APCI) Calcd for C15H15O5NCl(M+H)+ 324.0633, Found 324.0628.
Diethyl 3-(3’-chlorophenyl)isoxazole-4,5-dicarboxylate (2b-I).
Colorless Oil (266.4 mg, 82% yield): IR (neat) 2985, 1733, 1300,
Cl
R2
Isoxazole
2
1,3-Dipolar
Cycloaddition
(- K Cl )
R1
R2
Cl
®
Oxone
H
Cl
(- H
1
1067, 755 cm-1; H-NMR (CDCl3 : 400 MHz) δ = 1.33 (t, J = 7.0
OH
O
O
N
N
N
Hz, 3H), 1.44 (t, J = 7.3 Hz, 3H), 4.39 (q, J = 7.0 Hz, 2H), 4.48 (q,
J = 7.3 Hz, 2H), 7.41 (dd, J = 8.2, 7.7 Hz, 1H), 7.49 (dt, J = 8.2,
1.4 Hz, 1H), 7.60 (dt, J = 7.7, 1.4 Hz,1H), 7.72 (t, J = 1.6 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ = 13.8, 13.9, 62.5, 62.9, 115.8,
126.4, 128.3, 128.6, 130.0, 130.6, 134.7, 155.9, 159.9, 160.0,
160.9; HRMS (APCI) Calcd for C15H15O5NCl (M+H)+ 324.0633,
Found 324.0634.
(- H
)
)
R
Cl
R
R
Scheme 3. Possible Reaction Pathway
Diethyl 3-(2’-chlorophenyl)isoxazole-4,5-dicarboxylate (2c-I).8
Colorless Oil (285.6 mg, 88 % yield): IR (neat) 2985, 1732, 1304,
Conclusions
1
1081, 758 cm-1; H-NMR (CDCl3 : 400 MHz) δ = 1.14 (t, J = 7.0
A variety of benzylic chlorides and alkyl p-tosylates were treated
with NMO, and then hydroxylamine•hydrochloride and potassium
carbonate, followed by the reaction with Oxone® in the presence of
acetylene derivatives to give 3-arylisoxazoles and 3-
alkylisoxazoles in one pot under mild and transition-metal-free
conditions. The key step of the present reaction is the oxidation of
benzylic chlorides and alkyl p-tosylates by NMO to the
corresponding aldehydes and the chloride-catalyzed oxidation of
oximes to nitrile N-oxides by Oxone®. We believe the present
method would be useful for the preparation of various 3-aryl- and
3-alkylisoxazole derivatives due to its simple operation using
easily available substrates and reagents in one pot.
Hz, 3H), 1.45 (t, J = 7.3 Hz, 3H), 4.23 (q, J = 7.0 Hz, 2H), 4.51 (q,
J = 7.3 Hz, 2H), 7.39 (td, J = 7.4, 1.6 Hz, 1 H), 7.43-7.50 (m, 3H);
13C NMR (100 MHz, CDCl3) δ = 13.5, 13.9, 61.7, 63.0, 116.0,
126.7, 126.8, 129.5, 131.2, 131.4, 133.5, 156.1, 159.7, 160.5,
160.9; HRMS (APCI) Calcd for C15H15O5NCl(M+H)+ 324.0633,
Found 324.0629.
Diethyl 3-(4’-fluorophenyl)isoxazole-4,5-dicarboxylate (2d-I).
Colorless Oil (211.1 mg, 69% yield): IR (neat) 2998, 1736, 1448,
1
1276, 844 cm-1; H-NMR (CDCl3 : 400 MHz) δ = 1.32 (t, J = 7.2
Hz, 3H), 1.43 (t, J = 7.2 Hz, 3H), 4.38 (q, J = 7.2 Hz, 2H), 4.48 (q,
J = 7.2 Hz, 2H), 7.17 (t, J = 8.8 Hz, 2H), 7.72 (dd, J = 8.8, 5.2 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ = 13.7, 13.8, 62.3, 62.8, 115.6,
115.9 (d, JC-F = 21.9 Hz), 123.1 (d, JC-F = 3.8 Hz), 130.3 (d, JC-F
=
9.5 Hz), 155.9, 159.7, 160.2, 161.1, 164.0 (d, JC-F = 251.8 Hz);
HRMS (APCI) Calcd for C15H15O5NF (M+H)+ 308.0929, Found
308.0925.
Experimental Section
1H NMR spectra were measured on 400 MHz spectrometers.
Chemical shifts were recorded as follows: chemical shift in ppm
Diethyl 3-(4’-bromophenyl)isoxazole-4,5-dicarboxylate (2e-I).
Colorless Oil (289.8 mg, 79% yield): IR (neat) 2984, 1732, 1272,
singlet; d = doublet; t = triplet; q = quartet; m = multiplet; br =
broad), coupling constant (Hz), integration, and assignment. 13C
NMR spectra were measured on 100 MHz spectrometers. Chemical
shifts were recorded in ppm from the solvent resonance employed
as the internal standard (deuterochloroform at 77.0 ppm).
Characteristic peaks in the infrared (IR) spectra were recorded in
wave numbers, cm-1. High-resolution mass spectra were recorded
by Thermo Fisher Scientific Exactive Orbitrap mass spectrometers.
Melting points were uncorrected. Thin-layer chromatography
(TLC) was performed using 0.25 mm silica gel plates (60F-254).
The products were purified by column chromatography on neutral
silica gel 60N (63–210 mesh).
1
1063, 831 cm-1; H-NMR (CDCl3 : 400 MHz) δ = 1.33 (t, J = 7.2
Hz, 3H), 1.43 (t, J = 7.2 Hz, 3H), 4.37 (q, J = 7.2 Hz, 2H), 4.48 (q,
J = 7.2 Hz, 2H), 7.58~7.63 (m, 4H); 13C NMR (100 MHz, CDCl3)
δ = 13.7, 13.8, 62.4, 62.8, 115.5, 125.1, 125.8, 129.6, 131.9, 155.8,
159.8, 160.2, 161.0; HRMS (APCI) Calcd for C15H15O5NBr
(M+H)+ 368.0128, Found 368.0128.
Diethyl
3-[4’-(methoxycarbonyl)phenyl]isoxazole-4,5-
dicarboxylate (2f-I). Colorless Oil (232.1 mg, 67% yield): IR
1
(neat) 2986, 1723, 1273, 1065, 756 cm-1; H-NMR (CDCl3 : 400
MHz) δ = 1.31 (t, J = 7.2 Hz, 3H), 1.44 (t, J = 7.2 Hz, 3H), 3.96 (s,
3H), 4.38 (q, J = 7.2 Hz, 2H), 4.49 (q, J = 7.2 Hz, 2H), 7.79 (d, J
Submitted to the European Journal of Organic Chemistry
4
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701726
European Journal of Organic Chemistry
1
= 8.5 Hz, 2H), 8.14 (d, J = 8.5 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ = 13.7, 13.8, 52.2, 62.4, 62.8, 115.7, 128.1, 129.7, 131.0,
131.8, 155.7, 159.8, 160.2, 160.8, 166.0; HRMS (APCI) Calcd for
C17H18O7N (M+H)+ 348.1078, Found 324.1077.
Diethyl 3-(4’-nitrophenyl)isoxazole-4,5-dicarboxylate (2g-I).
Colorless Solid (170.1 mg, 51% yield): mp 74-75 °C; IR (neat)
2916, 1729, 1524, 1289, 855 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ
= 1.33 (t, J = 7.0 Hz, 3H), 1.45 (t, J = 7.3 Hz, 3H), 4.39 (q, J = 7.0
1254, 750 cm-1; H-NMR (CDCl3 : 400 MHz) δ = 1.33 (t, J = 7.0
Hz, 3H), 1.43 (t, J = 7.3 Hz, 3H), 3.86 (s, 3H), 4.38 (q, J = 7.0 Hz,
2H), 4.47 (q, J = 7.3 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 7.66 (d, J
= 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ = 13.8, 13.9, 55.2,
62.3, 62.7, 114.1, 115.8, 119.1, 129.5, 156.0, 159.2, 160.6, 161.3,
161.5; HRMS (APCI) Calcd for C16H18O6N (M+H)+ 320.1129,
Found 320.1129.
Diethyl 3-(naphthalen-1’-yl)isoxazole-4,5-dicarboxylate (2o-I).8
Hz, 2H), 4.50 (q, J = 7.3 Hz, 2H), 7.93 (d, J = 8.8 Hz, 2H), 8.34 (d, Colorless Oil (307.5 mg, 91% yield): IR (neat) 2983, 1732, 1300,
1
J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ = 13.9, 14.0, 62.7,
63.2, 115.5, 123.9, 129.6, 133.2, 149.1, 155.9, 159.7, 160.7, 160.8;
HRMS (APCI) Calcd for C15H15 O7N2 (M+H)+ 335.0874, Found
335.0871.
1095, 776 cm-1; H-NMR (CDCl3 : 400 MHz) δ = 0.85 (t, J = 7.3
Hz, 3H), 1.46 (t, J = 7.3 Hz, 3H), 4.04 (q, J = 7.3 Hz, 2H), 4.53 (q,
J = 7.3 Hz, 2H), 7.48-7.62 (m, 4H), 7.79 (d, J = 8.4 Hz, 1H), 7.92
(d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ = 13.0, 13.6, 61.5, 62.7, 117.0, 124.2, 124.5, 124.6, 126.1,
126.7, 127.9, 128.1, 130.4, 131.1, 133.1, 156.0, 159.8, 159.9,
161.2; HRMS (APCI) Calcd for C19H18O5N (M+H)+ 340.1179,
Diethyl 3-(4’-cyanophenyl)isoxazole-4,5-dicarboxylate (2h-
I):Colorless Solid (187.1 mg, 60% yield); mp 91-93 °C; IR (neat)
1
2993, 2230, 1735, 1449, 1276, 844 cm-1; H-NMR (CDCl3 : 400
MHz) δ = 1.33 (t, J = 7.2 Hz, 3H), 1.44 (t, J = 7.2 Hz, 3H), 4.38 (q, Found 340.1179.
J = 7.2 Hz, 2H), 4.50 (q, J = 7.2 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H),
7.86 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ = 13.8,
14.0, 62.6, 63.2, 114.4, 115.4, 118.0, 129.1, 131.4, 132.5, 155.8,
159.9, 160.6, 160.7; HRMS (APCI) Calcd for C16H15O5N2 (M+H)+
315.0975, Found 315.0974.
Diethyl 3-(biphenyl-4’-yl)isoxazole-4,5-dicarboxylate (2i-I).
Colorless Solid (299.6 mg, 82% yield): mp 78-79 °C; IR (neat)
2981, 1727, 1283, 1071, 734 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ
= 1.35 (t, J = 7.2 Hz, 3H), 1.44 (t, J = 7.2 Hz, 3H), 4.41 (q, J = 7.2
Hz, 2H), 4.49 (q, J = 7.2 Hz, 2H), 7.39 (t, J = 7.2 Hz, 1H), 8.34
(dd, J = 7.2, 7.0 Hz, 2H), 7.63 (d, J = 7.0 Hz, 2H), 7.70 (d, J = 8.5
Hz, 2H), 7.79 (d, J = 8.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
= 13.8, 13.9, 62.3, 62.8, 116.0, 125.7, 127.0, 127.3, 127.8, 128.4,
128.8, 139.8, 143.3, 155.9, 159.4, 160.7, 161.4; HRMS (APCI)
Calcd for C21H20O5N (M+H)+ 366.1336, Found 366.1335.
Diethyl 3-(benzo[b]thiophen-3’-yl)isoxazole-4,5-dicarboxylate
(2p-I). Yellow Solid (206.2 mg, 60% yield): mp 105-107 °C; IR
1
(neat) 2984, 1731, 1277, 1105, 756 cm-1; H-NMR (CDCl3 : 400
MHz) δ = 1.41 (t, J = 7.3 Hz, 3H), 1.44 (t, J = 7.3 Hz, 3H), 4.48 (q,
J = 7.3 Hz, 2H), 4.49 (q, J = 7.3 Hz, 2H),7.38-7.45 (m, 2H),7.84-
7.89 (m, 2H), 7.93 (s, 1H); 13C NMR (100 MHz, CDCl3) δ = 13.8,
13.9, 62.6, 63.0, 115.1, 122.2, 124.6, 124.8, 126.1, 126.9, 127.6,
139.1, 140.3, 155.9, 156.0, 160.1, 161.1; HRMS (APCI) Calcd for
C17H16O5NS (M+H)+ 346.0744, Found 346.0745.
Diethyl 3-(benzofuran-3’-yl)isoxazole-4,5-dicarboxylate (2q-I).
Pale Yellow Solid (181.1 mg, 55% yield): mp 63-65 °C; IR (neat)
3648, 1735, 1289, 1191, 755 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ
= 1.42 (t, J = 7.3 Hz, 3H), 1.44 (t, J = 7.3 Hz, 3H), 4.49 (q, J = 7.3
Hz, 2H), 4.49 (q, J = 7.3 Hz, 2H), 7.30 (t, J = 7.7 Hz, 1H), 7.41 (t,
J = 7.7 Hz, 1H), 7.51 (s, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.67 (d, J =
7.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ = 13.9, 14.0, 62.5,
63.0, 109.8, 111.6, 114.9, 122.0, 123.5, 126.4, 127.4, 142.9, 152.9,
155.1, 155.7, 159.7, 160.6; HRMS (APCI) Calcd for C17H16O6N
(M+H)+ 330.0972, Found 330.0971.
Diethyl 3-(4’-benzoylphenyl)isoxazole-4,5-dicarboxylate (2j-I).
Colorless Oil (381.4 mg, 97% yield): IR (neat) 2984, 1731, 1660,
1272, 699 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ = 1.34 (t, J = 7.2
Hz, 3H), 1.45 (t, J = 7.2 Hz, 3H), 4.40 (q, J = 7.2 Hz, 2H), 4.50 (q,
J = 7.2 Hz, 2H), 7.51 (t, J = 7.6 Hz, 2H), 7.63 (t, J = 7.6 Hz, 1H),
7.82-7.85 (m, 4H), 7.91 (d, J = 8.3 Hz, 2H); 13C NMR (100 MHz,
Diethyl 3-(thiophen-2’-yl)isoxazole-4,5-dicarboxylate (2r-I).
Pale Yellow Oil (170.9 mg, 58% yield): IR (neat) 2983, 1731, 1273,
CDCl3) δ = 13.8, 14.0, 62.5, 63.0, 115.9, 128.2, 128.4, 130.0, 130.2, 1193, 714 cm-1; H-NMR (CDCl3 : 400 MHz) δ = 1.39 (t, J = 7.3
1
130.6, 132.8, 136.9, 139.2, 155.9, 160.0, 160.4, 161.0, 195.8;
HRMS (APCI) Calcd for C22H20O6N (M+H)+ 394.1285, Found
394.1285.
Hz, 3H), 1.43 (t, J = 7.3 Hz, 3H), 4.43 (q, J = 7.3 Hz, 2H), 4.47 (q,
J = 7.3 Hz, 2H), 7.14 (dd, J = 5.2, 3.9 Hz, 1H), 7.50 (d, J = 5.2,
1.1 Hz, 1H), 7.64 (dd, J = 3.9, 1.1 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ = 13.8, 13.8, 62.4, 62.8, 114.9, 127.2, 127.7, 128.9, 129.6,
155.7, 155.8, 159.7, 161.0; HRMS (APCI) Calcd for C13H14O5NS
(M+H)+ 296.0587, Found 296.0583.
Diethyl 3-phenylisoxazole-4,5-dicarboxylate (2k-I).8 Colorless
Oil (198.7 mg, 69% yield): IR (neat) 2984, 1733, 1302, 1138 1066
1
cm-1; H-NMR (CDCl3 : 400 MHz) δ = 1.31 (t, J = 7.2 Hz, 3H),
1.43 (t, J = 7.2 Hz, 3H), 4,38 (q, J = 7.2 Hz, 2H), 4.48 (q, J = 7.2
Hz, 2H), 7.45-7.51 (m, 3H), 7.70 (d, J = 8.0 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ = 13.7, 13.9, 62.3, 62.8, 116.0, 126.9, 128.1,
128.7, 130.5, 156.0, 159.4, 161.1, 161.3; HRMS (APCI) Calcd for
C15H16O5N (M+H)+ 290.1023, Found 290.1018.
Diethyl 3-(1-tosylindol-3’-yl)isoxazole-4,5-dicarboxylate (2s-I).
Colorless Solid (277.0 mg, 57% yield): mp 83-85 °C; IR (neat)
2920, 1748, 1364, 1176, 752 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ
= 1.39 (t, J = 7.3 Hz, 3H), 1.44 (t, J = 7.3 Hz, 3H), 2.35 (s, 3H),
4.45 (q, J = 7.3 Hz, 2H), 4.49 (q, J = 7.3 Hz, 2H), 7.25 (d, J = 8.4
Hz, 2H), 7.32-7.42 (m, 2H), 7.82 (d, J = 8.4 Hz, 2H), 8.02 (d, J =
8.2 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 8.28 (s, 1H); 13C NMR (100
MHz, CDCl3) δ = 13.9, 14.0, 21.5, 62.6, 63.0, 109.3, 113.3, 115.1,
122.5, 124.3, 125.6, 127.0, 127.9, 128.1, 130.0, 134.6, 134.7, 145.5,
155.1, 156.3, 160.0, 161.2; HRMS (APCI) Calcd for C24H23O7N2S
(M+H)+ 483.1220, Found 483.1220.
Diethyl 3-(4’-methylphenyl)isoxazole-4,5-dicarboxylate (2l-I).8
Colorless Solid (233.4 mg, 77% yield); mp 44-46 °C: IR (neat)
2923, 1737, 1447, 1274, 826 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ
= 1.33 (t, J = 7.2 Hz, 3H), 1.43 (t, J = 7.2 Hz, 3H), 2.41 (s, 3H),
4.38 (q, J = 7.2 Hz, 2H), 4.47 (q, J = 7.2 Hz, 2H), 7.27 (d, J = 8.0
Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
= 13.6, 13.7, 21.1, 62.1, 62.6, 115.9, 123.9, 127.7, 129.3, 140.7,
155.9, 159.1, 160.1, 161.3; HRMS (APCI) Calcd for C16H18O5N
(M+H)+ 304.1179, Found 304.1175.
Diethyl 3-(2’-methylquinolin-4’-yl)isoxazole-4,5-dicarboxylate
(2t-I). Colorless Oil (131.1 mg, 37% yield): IR (neat) 2985, 2939,
1736, 1281, 1098 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ = 0.88 (t, J
= 7.0 Hz, 3H), 1.47 (t, J = 7.0 Hz, 3H), 2.81 (s, 3H), 4.06 (q, J =
7.0 Hz, 2H), 4.54 (q, J = 7.0 Hz, 2H), 7.42 (s, 1H), 7.50 (dd, J =
7.7, 7.5 Hz, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.74 (dd, J = 8.4, 7.5 Hz,
1H), 8.11 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ =
13.3, 14.0, 25.3, 62.0, 63.3, 116.6, 123.0, 124.2, 124.5, 126.7,
129.2, 130.0, 133.4, 147.9, 156.0, 158.3, 159.7(2C), 160.9; HRMS
(APCI) Calcd for C19H19O5N2 (M+H)+ 355.1288, Found 355.1284.
Diethyl 3-phenethylisoxazole-4,5-dicarboxylate (2u-I). Colorless
Oil (229.2 mg, 72% yield): IR (neat) 2983, 2359, 1726, 1268, 1098
Diethyl
3-[4’-(tert-butyl)phenyl]isoxazole-4,5-dicarboxylate
(2m-I). Yellow Oil (211.8 mg, 61% yield): IR (neat) 2965, 1734,
1302, 1270, 1065 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ = 1.33 (t, J
= 7.2 Hz, 3H), 1.35 (s, 9H), 1.43 (t, J = 7.2 Hz, 3H), 4.39 (q, J =
7.2 Hz, 2H), 4.47 (q, J = 7.2 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H),
7.65 (d, J = 8.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ = 13.8,
13.9, 31.1, 34.8, 62.3, 62.8, 116.0, 124.0, 125.8, 127.7, 153.9,
156.1, 159.2, 160.9, 161.5; HRMS (APCI) Calcd for C19H24O5N
(M+H)+ 346.1649, Found 346.1649.
1
cm-1; H-NMR (CDCl3 : 400 MHz) δ = 1.36 (t, J = 7.3 Hz, 3H),
Diethyl 3-(4’-methoxyphenyl)isoxazole-4,5-dicarboxylate (2n-
I).8 Yellow Oil (246.6 mg, 77% yield): IR (neat) 2985, 1733, 1611,
1.42 (t, J = 7.3 Hz, 3H), 3.00-3.04 (m, 2H), 3.16-3.20 (m, 2H),
Submitted to the European Journal of Organic Chemistry
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701726
European Journal of Organic Chemistry
4.35 (q, J = 7.3 Hz, 2H), 4.46 (q, J = 7.3 Hz, 2H), 7.20-7.24 (m,
4-Acetyl-3-(4’-chlorophenyl)-5-phenylisoxazol
(2a-VIII).
3H), 7.28-7.32 (m, 2H); 13C NMR (100 MHz, CDCl3) δ = 13.9(2C), Colorless Solid (125.5 mg, 42% yield): mp 107-108 °C; IR (neat)
27.4, 33.8, 61.7, 62.9, 113.8, 126.3, 128.3, 128.4, 140.2, 156.8,
160.5, 161.2, 162.6; HRMS (APCI) Calcd for C17H20O5N (M+H)+
318.1336, Found 318.1335.
Diethyl 3-heptylisoxazole-4,5-dicarboxylate (2v-I). Colorless Oil
(199.3 mg, 64% yield): IR (neat) 2929, 2857, 2362, 1729, 1098 cm-
1; 1H-NMR (CDCl3 : 400 MHz) δ = 0.88 (t, J = 6.7 Hz, 3H), 1.28-
1691, 1419, 1090, 944, 838 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ =
2.22 (s, 3H), 7.48 (d, J = 8.4 Hz, 2H), 7.52-7.58 (m, 3H), 7.61 (d, J
= 8.4 Hz, 2H), 7.80 (dd, J = 8.0, 1.6 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ = 31.5, 117.0, 126.7, 126.8, 128.5, 128.9, 129.0, 130.2,
131.5, 136.5, 161.1, 170.9, 195.0; HRMS (APCI) Calcd for
C17H13O2NCl (M+H)+ 298.0629, Found 298.0627.
1.43 (m, 14H), 1.69 (quin, J = 7.6 Hz, 2H), 2.85 (t, J = 7.6 Hz, 2H), 3-(4’-Chlorophenyl)-5-(naphthalen-1”-yl)isoxazole
(2a-IX).
Yellow Solid (128.4 mg, 42% yield): mp 98-100 °C; IR (neat)
4.36 (q, J = 7.2 Hz, 2H), 4.45 (q, J = 7.2 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ = 14.0(3C), 22.6, 25.4, 27.7, 28.8, 29.1, 31.6, 61.7,
62.9, 114.0 156.9, 160.7, 160.9, 163.4; HRMS (APCI) Calcd for
C16H26O5N (M+H)+ 312.1805, Found 312.1802.
1559, 1426, 1080, 819, 795cm-1; 1H-NMR (CDCl3 : 400 MHz) δ =
6.91 (s, 1H), 7.50 (d, J = 8.6 Hz, 2H), 7.57-7.64 (m, 3H), 7.86-7.90
(m, 3H), 7.65 (d, J = 7.7 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 8.35 (d,
J = 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ = 101.5, 125.0,
125.1, 125.3, 126.6, 127.6, 127.7, 127.8, 128.3, 128.8, 129.4, 130.4,
131.2, 133.9, 136.2, 161.9, 170.9; HRMS (APCI) Calcd for
C19H13ONCl (M+H)+ 306.0680, Found 306.0679.
Diethyl
3-cyclohexylisoxazole-4,5-dicarboxylate
(2w-I).
Colorless Oil (156.5 mg, 53% yield): IR (neat) 2932, 2855, 1730,
1
1266, 1100 cm-1; H-NMR (CDCl3 : 400 MHz) δ = 1.21-1.42 (m,
3H), 1.37 (t, J = 7.3 Hz, 3H), 1.41 (t, J = 7.0 Hz, 3H), 1.52-1.62
(m, 2H), 1.72-1.76 (m, 1H), 1.83-1.87 (m, 2H), 1.98-2.01 (m, 2H),
3.00 (tt, J = 11.8, 3.4 Hz, 1H), 4.37 (q, J = 7.3 Hz, 2H), 4.44 (q, J
= 7.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ = 13.7(2C), 25.5,
25.9, 31.0, 35.6, 61.5, 62.6, 113.7, 156.7, 160.3, 160.7, 166.7;
HRMS (APCI) Calcd for C15H22O5N (M+H)+ 296.1492, Found
296.1492.
3-(4’-Chlorophenyl)-5-(thiophen-3”-yl)isoxazole
(2a-X).
Colorless Solid (125.6 mg, 48% yield): mp 167-169 °C; IR
1
(neat)1615, 1415, 1091, 787, 695 cm-1; H-NMR (CDCl3 : 400
MHz) δ = 6.66 (s, 1H), 7.43-7.47 (m, 4H), 7.79 (d, J = 8.6 Hz, 2H),
7.84 (dd, J = 2.5, 1.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ =
97.3, 125.8, 127.2, 127.6, 128.0, 129.0, 129.2, 130.4, 136.0, 162.0,
170.7; HRMS (APCI) Calcd for C13H9ONClS (M+H )+ 262.0088,
Found 262.0086.
Dimethyl 3-(4’-chlorophenyl)isoxazole-4,5-dicarboxylate (2a-
II).8,9 Colorless Solid (223.5 mg, 76% yield): mp 80-81 °C (lit.,9
1
mp 84-85 °C); IR (neat) 2962, 1726, 1445, 1268, 831 cm-1; H-
NMR (CDCl3 : 400 MHz) δ = 3.91 (s, 3H), 4.02 (s, 3H), 7.46 (d, J
= 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ = 53.1, 53.4, 115.6, 125.3, 129.1, 129.5, 136.9, 156.3,
159.7, 160.3, 161.5; HRMS (APCI) Calcd for C13H11O5NCl
(M+H)+ 296.0320, Found 296.03180.
Supporting Information: (see footnote on the first page of this
article): Copies of the 1H NMR and 13C NMR spectra of all
isoxazoles 2.
Acknowledgements
Ethyl 3-(4’-chlorophenyl)isoxazole-5-carboxylate (2a-III).10
Colorless Solid (186.5 mg, 60% yield): mp 129-130 °C; IR (neat)
1725, 1592, 1282, 827, 763 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ =
1.44 (t, J = 7.3 Hz, 3H), 4.47 (q, J = 7.3 Hz, 2H), 7.23 (s, 1H),
7.63 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ = 14.1, 62.4, 107.1, 125.0, 126.9, 128.3, 132.3,
156.6, 161.2, 162.0; HRMS (APCI) Calcd for C12H11O3NCl
(M+H)+ 252.0422, Found 252.0421.
Financial support in the form of a Grant-in–Aid for Scientific
Research (No. 15K05418) from the Ministry of Education, Culture,
Sports, Science, and Technology in Japan is gratefully
acknowledged.
Keywords: Benzylic halide / Isoxazole / NMO / Oxone® /
Acetylene
____________
3-(4’-Chlorophenyl)-5-phenylisoxazole (2a-IV).11,12 Colorless
Solid (163.6 mg, 64% yield): mp 173-174 °C (lit.,12 mp 177-
[1] (A. R. Katritzky, C. A. Ramsden, E. F. V. Scriven, R. J. K.
Taylor, “Comprehensive Heterocyclic Chemistry III”, Elsevier,
2008.
1
179 °C); IR (neat) 1592, 1445, 1422, 1091, 766 cm-1; H-NMR
(CDCl3 : 400 MHz) δ = 6.81 (s, 1H), 7.44-7.52 (m, 5H), 7.79-7.85
(m, 4H); 13C NMR (100 MHz, CDCl3) δ = 97.3, 125.8, 127.2,
127.6, 128.0, 129.0, 129.2, 130.4, 136.0, 162.0, 170.7; HRMS
(APCI) Calcd for C15H11ONCl (M+H)+ 256.0524, Found 256.0522.
5-(3’-Chlorophenyl)-3-(4”-chlorophenyl)isoxazole (2a-V). Pale
Yellow Solid (121.9 mg, 42% yield): mp 135-137 °C; IR (neat)
1559, 1426, 1103, 819, 795 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ =
6.84 (s, 1H), 7.44-7.45 (m, 2H), 7.47 (d, J = 8.5 Hz, 2H), 7.70-7.75
(m, 1H), 7.81 (d, J = 8.5 Hz, 2H), 7.82-7.83 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ = 98.1, 123.9, 125.9, 127.3, 128.0, 128.8,
129.2, 130.3, 130.4, 135.1, 136.2, 162.1, 169.2; HRMS (APCI)
Calcd for C15H10ONCl2 (M+H)+ 290.0134, Found 290.0131.
[2] Isoxazoles: (a) D. Giomi, F. M. Cordero, F. Machetti, “Five-
membered Rings with Two Heteroatoms, each with their Fused
Carbocyclic Derivatives”, p.365-p.485, Chap. 4.03, Vol. 4, Eds.
by A. R. Katritzky, C. A. Ramsden, E. F. V. Scriven, R. J. K.
Taylor, “Comprehensive Heterocyclic Chemistry III”, Elsevier,
2008. (b) G. Daidone, D. Raffa, B. Maggio, F. Plescia, V. M.
C. Cutuli, N. G. Mangano, A. Caruso, A. Arch. Pharm. Pharm.
Med. Chem., 1999, 332, 50-54. (c) T. H. Al-Tel, R. A. Al-
Qawasmeh, R. Zaarour, Eur. J. Med. Chem., 2011, 46, 1874-
1881. (d) W. Li, D. Hwang, D. Chen, C. Shen, C. Huang, T.
Chen, C. Lin, Y. Chang, Y. Lo. H. Tseng, C. Lin, J. Song, H.
Chen, S. Chen, S. Wu, C. Chen, J. Med. Chem., 2003, 46,
1706-1715. (e) P. Ratcliffe, J. Maclean, L. Abernnethy, T.
Clatkson, M. Dempster, A. M. Easson, D. Edwards, K. Everett,
H. Feilden, P. Littlewood, D. McArthur, D. McGregor, H.
MeLuskey, O. Nimz, L. A. Nisbet, R. Palin, H. Tracey, G.
Walker, Bioorg. Med. Chem. Lett., 2011, 21, 2559-2563.
[3] Recent review: (a) A. Sysak, B. Obminska-Mrukowicz, Eur. J.
Med. Chem., 2017, 137, 292-309. Recent reports: for 1,3-
dipolar cycloaddition of nitrile oxides (b) A. Khutorianskyi, B.
Chalyk, P. Borysko, A. Kondratiuk, P. K. Mykhailiuk, Eur. J.
Org. Chem., 2017, 3935-3940. (c) K. S. Kadam, T. Gandhi, A.
Gupte, A. K. Gangopadhyay, R. Sharma, Synthesis, 2016, 48,
3996-4008. (d) A. Singhal, S. K. R. Parumala, A. Sharma, R. K.
Peddinti, Tetrahedron Lett., 2016, 57, 719-722. (e) J. Poh, C.
Garcia-Ruiz, A. Zuniga, F. Meroni, D. C. Blakemore, D. L.
Browne, S. V. Ley, Org. Biomol. Chem., 2016, 14, 5983-5991.
3-(4’-Chlorophenyl)-5-(4”-methylphenyl)isoxazole
(2a-VI).
Colorless Solid (124.1 mg, 46% yield): mp 194-196 °C; IR (neat)
2919, 1491, 1428, 1092, 807 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ
= 2.42 (s, 3H), 6.75 (s, 1H), 7.30 (d, J = 8.2 Hz, 2H), 7.46 (d, J =
8.6 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H), 7.80 (d, J = 8.6 Hz, 2H); 13
C
NMR (100 MHz, CDCl3) δ = 21.5, 96.7, 124.5, 125.8, 127.7,
128.0, 129.2, 129.7, 135.9, 140.7, 161.9, 170.9; HRMS (APCI)
Calcd for C16H13ONCl (M+H)+ 270.0680, Found 270.0790.
3-(4’-Chlorophenyl)-5-(4”-methoxyphenyl)isoxazole (2a-VII).
Colorless Solid (68.6 mg, 24% yield): mp 173-175 °C; IR (neat)
2934, 1611, 1496, 1251, 836 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ
= 3.88 (s, 3H), 6.69 (s, 1H), 7.00 (d, J = 8.8 Hz, 2H), 7.46 (d, J =
8.5 Hz, 2H), 7.78 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 8.8 Hz, 2H); 13
C
NMR (100 MHz, CDCl3) δ = 55.4, 95.9, 114.4, 120.1, 127.4, 127.7,
128.0, 129.1, 135.9, 161.2, 161.9, 170.7; HRMS (APCI) Calcd for
C16H13O2NCl (M+H)+ 286.0629, Found 286.0627.
Submitted to the European Journal of Organic Chemistry
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10.1002/ejoc.201701726
European Journal of Organic Chemistry
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Received: ((will be filled in by the editorial staff))
Published online: ((will be filled in by the editorial staff))
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Entry for the Table of Contents ((Please choose one layout.))
Layout 1:
((Key Topic))
Benzylic chlorides were treated with
NMO, and then NH2OH•HCl, followed
by the reaction with Oxone® in the
presence of acetylenedicarboxylates to
give the corresponding 3-arylisoxazole-
4,5-dicarboxylates in good to moderate
yields in one pot under transition-metal-
free conditions.
Taro Imai and Hideo Togo…….. Page
No. – Page No.
One-pot Preparation of 3-
Arylisoxazole-4,5-dicarboxylates from
Benzylic Chlorides via Aldehydes,
Oximes, and Nitrile N-Oxides with
Acetylenedicarboxylates
Keywords: Benzylic halide / Isoxazole
/ NMO / Oxone® / Acetylene
Supporting Information
((Please insert the Supporting Information here))
Submitted to the European Journal of Organic Chemistry
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