Efficient transformation of electron-rich arenes into diethyl 3-arylisoxazole-4,5-dicarboxylates

Article abstract of DOI:10.1016/j.tet.2020.131255

Treatment of electron-rich arenes with Tf₂O and DMF, followed by the reaction with NH₂OH·HCl and then with Oxone in the presence of diethyl acetylenedicarboxylate generated diethyl 3-arylisoxazole-4,5-dicarboxylates in good to modera

Full text of DOI:10.1016/j.tet.2020.131255

Tetrahedron xxx (xxxx) xxx
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Tetrahedron
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Efficient transformation of electron-rich arenes into diethyl
3-arylisoxazole-4,5-dicarboxylates
Ryuhta Nakano, Hideo Togo*
Graduate School of Science, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba, 263-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of electron-rich arenes with Tf2O and DMF, followed by the reaction with NH2OH$HCl and
then with Oxone® in the presence of diethyl acetylenedicarboxylate generated diethyl 3-arylisoxazole-
4,5-dicarboxylates in good to moderate yields. Other alkynes could be also used for the present one-pot
transformation of arenes into 3-arylisoxazole derivatives. Click here and insert your abstract text. © 2020
Elsevier Science. All rights reserved.
Received 25 March 2020
Received in revised form
28 April 2020
Accepted 30 April 2020
Available online xxx
© 2020 Published by Elsevier Ltd.
Keywords:
Arene, Isoxazole
Cycloaddition
Oxone
Alkyne
1. Introduction
with aromatic aldoximes, 1-alkynes, and isoamyl nitrite [3f]; the
preparation of 3-arylisoxazoles with aromatic aldoximes, acetyle-
Isoxazoles are one of the most important nitrogen-containing
heteroaromatics, because there are many biologically active com-
pounds and natural products containing isoxazole unit [1]. For
example, Valdecoxib and Oxacillin, both of which are 3-
arylisoxazole derivatives, are anti-inflammatory and antibiotic
drugs, respectively, as shown in Fig. 1 [1]. Therefore, extensive
synthetic studies have been carried out [2].
nedicarboxylate esters, and (diacetoxyiodo)benzene (DIB) [3 g]; the
preparation of 4,5-disubstituted 3-arylisoxazoles with hydroximoyl
chloride and
b-ketoamides in the presence of 1,1,3,3-
tetramethylguanidin (TMG) [3 h]; the preparation of 5-
substituted 3-phenylisoxazoles with N-hydroxybenzimidonyl
chloride and 1-alkynes in the presence of CuSO4 [3i]; and the
preparation of 5-substituted 3-arylisoxazoles with arylnitrile oxide,
and allenyl-MgBr in the presence of organo-NHC catalyst [3j].
Other methods for synthesis of isoxazoles have been also
developed. Recent reports include the preparation of 3-(qunoline-
20-yl)isoxazoles with 2-methylquinoline, ethynylarenes, and HNO3
[4a], the preparation of 4-substituted 3,5-diarylisoxazoles with
alkynone O-methyloximes, ethynylarenes, and [C2O2mim]Cl in the
presence of Pd(TFA)2 [4b], the preparation of 3-difluoromethyl- and
The most common method for the preparation of isoxazoles is
the 1,3-dipolar cycloaddition of nitrile oxides onto alkynes [2].
Recent reports for the preparation of isoxazoles with nitrile oxides
are as follows:3 the preparation of 3,5-disubstituted isoxazoles with
O-silylated hydroxamic acids, Tf2O, Et3N, and 1-alkynes [3a]; the
t
preparation of 3,5-disubstituted isoxazoles with alkynes, BuONO,
a
-diazo esters, and Cu(OAc)2 [3b]; the preparation of 3,5-
disubstituted isoxazoles with hydroximoyl fluorides, 1-alkynes,
and Ag2CO3 [3c]; the preparation of 3-arylisoxazoles with N-
hydroxybenzimidoyl chloride and enamino carbonyl compounds
under ball milling conditions [3d]; the preparation of 5-
3-trifluoromethyl-5-arylisoxazoles
with
ethynylarenes,
t
XCF2CH2NH2 (X ¼ H, F), and BuONO in the presence of ZnBr2 and
CuI [4c], the preparation of 5-acyl-3-cyanoisoxazoles with nitro-
isoxazolone and a-chloro-a,b-unsaturated ketones [4d], the prep-
arylisoxazole-4,5-dicarboxylates with
a-(aroyl)acetates, ethyl a-
aration of 3,5-diaryl(alkyl)isoxazoles with ynones and
trimethylsilylazide [4e], the preparation of 3,5-diarylisoxazoles
with enone oximes in the presence of Cu(OAc)2 under O2 atmo-
sphere [4f], the preparation of 4-borylated 3-arylisoxazoles with
ynone oximes and HBcat in the presence of IPrAuTFA [4 g], and the
diazoacetate, and tBuONO in the presence of Cu(OAc)2 and
Mg(OTf)2 [3e]; the preparation of 5-substituted 3-arylisoxazoles
preparation of 3-thiomethyl-5-arylisoxazoles with
thioesters and NH2OH [4 h].
b-oxodi-
* Corresponding author.
E-mail address: togo@faculty.chiba-u.jp (H. Togo).
https://doi.org/10.1016/j.tet.2020.131255
0040-4020/© 2020 Published by Elsevier Ltd.
Please cite this article as: R. Nakano, H. Togo, Efficient transformation of electron-rich arenes into diethyl 3-arylisoxazole-4,5-dicarboxylates,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131255

2
R. Nakano, H. Togo / Tetrahedron xxx (xxxx) xxx
arenes into 3-arylisoxazoles through the intermolecular CeC bond
formation has scarcely been studied. We would like to report herein
the preparation of diethyl 3-arylisoxazole-4,5-dicarboxylates by
the reaction of electron-rich arenes with DMF and Tf2O using the
Vilsmeier-Haack reaction, followed by the reaction with
NH2OH$HCl, and then diethyl acetylenedicarboxylate and Oxone®
in one-pot under transition-metal-free conditions.
2. Results and discussion
First, treatment of 1,3-dimethoxybenzene 1A (3.0 mmol) with
trifluoromethanesulfonic anhydride (Tf2O, 1.4 equiv.) and DMF (1.4
equiv.) at room temperature for 4 h under stirring and solvent-free
conditions (1st step), followed by reaction with NH2OH$HCl (1.2
equiv.) and K2CO3 (0.6 equiv.) in a mixture of acetonitrile and water
(5:1, 6.0 mL) (2nd step) gave 2,5-dimethoxybenzaldoxime 2A in
93% yield. Based on this result, after treatment of compound 1A
with Tf2O and DMF (1st step), and then with NH2OH$HCl and K2CO3
under the same procedure and conditions (2nd step), the mixture
was treated with diethyl acetylenedicarboxylate (1.5 equiv.) and
Oxone® (1.5 equiv.) in the presence of 1-hexene (0.5 equiv.) [5b] in
a mixture of acetonitrile and water (1:1, 30.0 mL) at room tem-
perature for 1.5 h (3rd step) to give diethyl 3-(20,40-dimethox-
yphenyl)isoxazole-4,5-dicarboxylate 3A in 58% yield, together with
3-(50-chloro-20,40-dimethoxyphenyl)isoxazole-1,4-dicarboxylate
3B, the chlorinated compound of 3A, in 18% yield, as shown in
Table 1 (entry 1). Under the same procedure and conditions,
treatment of formed compound 2A in the presence of 1-hexene (1.0
Fig. 1. Typical pharmaceuticals bearing 3-Arylisoxazole unit.
Among the above mentioned methods, the preparation of 3-
arylisoxazoles with nitrile oxides and alkynes via the 1,3-dipolar
cycloaddition reaction is rather useful due to the availability of
the starting materials, although it is a common and classic method.
Previously, we reported the preparation of 3,5-diarylisoxazoles
from the reactions of ethynylarenes with n-BuLi, followed by the
reaction with aromatic aldehydes, and then molecular iodine and
hydroxylamine [5a], and the preparation of diethyl 3-arylisoxazole-
4,5-dicarboxylates from the reactions of aryl bromides with n-BuLi,
followed by the reaction with DMF, hydroxylamine, and then
diethyl acetylenedicarboxylate and Oxone® (2KHSO5$KH-
SO4$K2SO4) [5b].
To the best of our knowledge, the one-pot transformation of
Table 1
Transformation of 1,3-dimethoxybenzene 1A to diethyl 3-(20,40-dimethoxyphenyl)isoxazole-4,5-dicarboxylate 3A.
3rd
En try
Solvent
Conditions
Oxone® (equiv.)
1-Hexene (equiv.)
Yield (%)
Time (h)
1
2
3
4
5
6
e
4 h, r.t.
4 h, r.t.
4 h, r.t.
4 h, r.t.
4 h, r.t.
4 h, r.t.
4 h, r.t.
4 h, 40 ꢀC
4 h, 40 ꢀC
1.5
1.5
1.0
1.0
1.5
3.0
1.5
2.0
2.0
0.5
1.0
e
1.5
1.5
1.5
1.5
4
4
1.5
5
58 (18)a
87
80
-
e
e
1.0
e
82
e
16 (60)a
(74)a
0
e
e
7b
8c
9c
e
1.0
e
DMF (0.6 mL)
DMF (0.6 mL)
40 (27)a
67 (10)a
0.5
4
a
Yeild of 3B.
b
c
NH2OH$H2O (1.2 equiv.) was used instead of NH2OH$HCl.
POCl3 (1.5 equiv.) was used instead of Tf2O. CH3CN (3.0 mL) was used in the 2nd reaction step. A mixtue of CH3CN and H2O (1:1, 10.0 mL) was used in the 3rd reaction
step.
Please cite this article as: R. Nakano, H. Togo, Efficient transformation of electron-rich arenes into diethyl 3-arylisoxazole-4,5-dicarboxylates,
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R. Nakano, H. Togo / Tetrahedron xxx (xxxx) xxx
3
equiv.) in the 3rd step reaction gave isoxazole 3A in 87% yield
without the formation of chlorinated isoxazole 3B (entry 2). When
reactions of the formed compound 2A with Oxone® (1.0 equiv.) was
carried out in the absence and presence of 1-hexene (1.0 equiv.) in
the 3rd step under the same procedure and conditions, isoxazole
3A was obtained in 80% and 82% yields without the formation of
chlorinated isoxazole 3B, respectively (entries 3, 4). Thus, when 1.5
equiv. of Oxone® was used in the presence of 1-hexene (1.0 equiv.)
in the 3rd step reaction, only isoxazole 3A was obtained in the best
yield (entries 2, 4). However, when the 3rd reaction step was car-
ried out for 4 h under the same conditions, chlorinated oxazole 3B
was obtained in 60% yield, together with oxazole 3A in 16% yield
(entry 5). Moreover, when 3.0 equiv. of Oxone® was used in the 3rd
reaction step for 4 h under the same conditions, chlorinated oxa-
zole 3B was obtained in 74% yield as a single product (entry 6). In
contrast, the same treatment of 1,3-dimethoxybenzene 1A with
Tf2O and DMF, and then with K2CO3 and NH2OH$H2O, instead of
NH2OH$HCl, followed by the reaction with diethyl acetylenedi-
carboxylate and Oxone® under the same procedure and condition
as those of entry 2 did not generate isoxazole 3A at all (entry 7).
Thus, chloride ion derived from NH2OH$HCl plays an important
role for the formation of isoxazole 3A in the 3rd reaction step.
Moreover, when 1,3-dimethoxybenzene 1A was treated with POCl3
(1.5 equiv.) and DMF (0.6 mL), a standard Vilsmeier-Haack reaction,
instead of Tf2O and DMF, a slight excess of DMF (0.6 mL) and
warming at 40 ꢀC for 4 h (1st step) were required to maintain
smooth stirring and effective electrophilic CeC bond formation (1st
step). Further treatment of the reaction mixture with NH2OH$HCl
(1.2 equiv.) and K2CO3 (0.6 equiv.), and then with diethyl acetyle-
nedicarboxylate (1.5 equiv.) and Oxone® (2.0 equiv.) in the absence
and presence of 1-hexene (0.5 equiv.) generated isoxazole 3A in
40% and 67% yields, together with chlorinated isoxazole 3B in 27%
and 10% yields, respectively (entries 8, 9). Thus, a Tf2O and DMF
system is better than a POCl3 and DMF system, because chlorine
atom may come from both POCl3 and NH2OH$HCl in the presence of
Oxone® (3rd step) in the latter system, and the electrophilic
introducing ability of the iminium group onto 1,3-
dimethoxybenzene 1A in the former system is slightly higher
than that in the latter system. As a gram-scale experiment, treat-
ment of compound 1A (9.0 mmol) under the same procedure and
conditions as those of entry 2 gave isoxazole 3A in 94% yield, as
shown in Scheme 1.
the absence of 1-hexene in the 3rd reaction step under the same
conditions, diethyl 3-(50-chloro-20,30,40-trimethoxyphenyl)iso-
xazole-4,5- dicarboxylate 3L, a chlorinated compound, was ob-
tained in 54% yield. In those reactions, DCE (1.5 mL) was used in the
1st step because stirring could not be carried out effectively
without DCE. Mesitylene 1M was not so reactive toward Tf2O and
DMF, and therefore it was treated with Tf2O (2.2 equiv.) and DMF
(2.2 equiv.) at 110 ꢀC for 40 h in the 1st reaction step. After the same
treatment in the 2nd and 3rd reaction steps, diethyl 3-(20,40,60-
trimethylphenyl)isoxazole-4,5-dicarboxylate 3M was obtained in
48% yield. On the other hand, same treatment of mesitylene 1M
with POCl3 (2.2 equiv.) and DMF (2.2 equiv.) under the same pro-
cedure and conditions, did not give isoxazole 3M at all. Treatment
of 1-methoxynaphthalene 1N, 2-methoxynaphthalene 1O, and 1,6-
dimethoxynaphthalene 1P with Tf2O and DMF in DCE for 4 h, fol-
lowed by the removal of DCE, the reaction with NH2OH$HCl and
K2CO3, and then reaction with diethyl acetylenedicarboxylate and
Oxone® in the presence of 1-hexene gave the corresponding
diethyl 3-arylisoxazoles-4,5-dicarboxylates 3N~3P in good yields,
respectively. When heteroaromatics, such as benzothiophene,
benzofuran, and N-methylindole, were treated under the same
procedure and conditions, the corresponding 3-arylisoxazoles were
not obtained at all, because the former two substrates did not react
with Tf2O and DMF in the 1st step, and multi chlorination of the
indole ring occurred in the 3rd step in the latter substrate.
When diethyl acetylenedicarboxylate was changed to dimethyl
acetylenedicarboxylate, ethyl propiolate, 3-butyn-1-ol, ethy-
nylbenzene, and 1-octyne in the present reaction with 1,3-
dimethoxybenzene 1A in the 3rd step under the same conditions,
the corresponding 3-arylisoxazoles 3Q~3V were obtained in good
to moderate yields, respectively, although the amounts of alkynes
in the 3rd reaction step were different, and mixtures of 3Ra and
3Rb, 3Sa and 3Sb, 3Ua and 3Ub, and 3Va and 3Vb were obtained
from the reaction with ethyl propiolate, ethynylbenzene, and 1-
octyne, respectively.
Once diethyl 3-arylisoxazole-4,5-dicarboxylates 3 were ob-
tained, they could be transformed into various 3-arylisoxazole de-
rivatives. Thus, treatment of diethyl 3-(20,40-dimethoxyphenyl)
isoxazole-4,5-dicarboxylate 3A with NH2NH2$H2O (12.0 equiv.) in
ethanol at 90 ꢀC for 6 h gave pyridazine derivative 4A bearing an
isoxazole core in 91% yield, as shown in Scheme 2. Treatment of
isoxazole derivative 3A with DIBAL (4.0 equiv.) in THF at 20 ꢀC for
19 h gave 3-(20,40-dimethoxyphenyl)-4,5- di(hydroxymethyl)iso-
xazle 5A in 67% yield. Reaction of isoxazole 3A with BBr3 (4.0 equiv.)
in CH2Cl2 at ꢁ78 ꢀC to room temperature gave 3-(20,40-dihydrox-
yphenyl)isoxazole-4,5-dicarboxylic acid 6A in 74% yield.
Based on those results, treatment of arenes 1 (3.0 mmol), such as
1-bromo-2,4-dimethoxybenzene 1C, m-methylanisole 1D, m-tert-
butylamisole 1E, 1,3-diethoxybenzene 1F, o-methylanisole 1G, 2,3-
dihydrobenzofurane
1H,
p-methylanisole
1I,
1,3,5-
trimethoxybenzene 1J, 1,2,3-trimethoxybenzene 1K, and 4-
methyl-1,2-dimethoxybenzene 1L with Tf 2O (1.4 equiv.) and DMF
(1.4 equiv.) in DCE (1.5 mL) at room temperature or warming
temperature for 3 h, 4 h, or 6 h depending on the electrophilicity of
the aromatics (1st step), followed by removal of DCE, the reaction
with NH2OH$HCl (1.2 equiv.) and K2CO3 (0.6 equiv.) in a mixture of
acetonitrile and water (5:1, 6.0 mL) at room temperature for 19 h
(2nd step), and then reaction with diethyl acetylenedicarboxylate
(1.5 equiv.) and Oxone® (1.5 equiv.) in the presence of 1-hexene (1.0
equiv.) in a mixture of acetonitrile and water (1:1, 30 mL) (3rd step)
gave the corresponding 3-arylisoxazole-4,5-dicarboxylates 3C~3L
in good to moderate yields, although a mixture of 3Da and 3Db was
obtained from m-methylanisole 1D, and diethyl 3-(30-chloro-
20,40,60-trimethoxyphenyl)- isoxazole-4,5-dicarboxylate 3J, a chlo-
rinated compound, was formed as a single product from 1,3,5-
trimethoxybenzene 1J, as shown in Scheme 1. When 1,2,3-
trimethoxybenzene 1K was treated with Oxone® (3.0 equiv.) in
A possible reaction pathway of the present method is shown in
Scheme 3. Electron-rich arenes 1 react with Tf2O and DMF to form
N,N-dimethyliminium triflates I. Iminium triflates I react with
NH2OH$HCl to form aromatic aldoximes 2. Treatment of aromatic
aldoximes 1 with Oxone® in the presence of chloride ion generates
nitrile oxides II, which further react with alkynes to form 3-
arylisoxazoles 3 via the 1,3-dipolar cycloaddition reaction. Here,
the chloride ion plays an important role in the formation of aro-
matic nitrile oxides from aromatic aldoximes in the presence of
Oxine® [5b].
3. Conclusion
Electron-rich arenes could be smoothly transformed into diethyl
3-arylisoxazole-4,5-dicarboxylates in good to moderate yields by
the successive treatment with Tf2O and DMF, with NH2OH$HCl and
K2CO3, and with diethyl acetylenedicarboxylate and Oxone® in the
Please cite this article as: R. Nakano, H. Togo, Efficient transformation of electron-rich arenes into diethyl 3-arylisoxazole-4,5-dicarboxylates,
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R. Nakano, H. Togo / Tetrahedron xxx (xxxx) xxx
Scheme 1. Transformation of arenes 1 to 3-Arylisoxazoles 3.
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R. Nakano, H. Togo / Tetrahedron xxx (xxxx) xxx
5
4. Experimental section
4.1. General
1H NMR and 13C NMR spectra were obtained with JEOL-JNM-
ECX400 and JEOL-JNM-ECS400 spectrometers. Chemical shifts
were recorded as follows: chemical shift in ppm from internal
tetramethylsilane (TMS) on the
d
scale, multiplicity (s ¼ singlet;
d ¼ doublet; t ¼ triplet; q ¼ quartet; m ¼ multiplet; br ¼ broad),
coupling constant (Hz), integration, and assignment. High-
resolution mass spectra (HRMS) were recorded by a Thermo
Fisher Scientific Exactive Orbitrap mass spectrometer. IR spectra
were measured with a JASCO FT/IR-4100 spectrometer. Melting
points were determined with a Yamato Melting Point Apparatus
Model MP-21. Silica gel 60F254 (Merck) was used for TLC and Silica
gel 60 N (63e210 mesh, Kanto Kagaku Co.) was used for short
column chromatography.
4.2. Transformation of 1,3-dimethoxybenzene 1A into 1,3-
dimethoxybenzaldoxime 2A
Tf2O (690.2
mL, 4.2 mmol) was added to a solution of 1,3-
dimethoxybenzene 1A (414.5 mg, 3.0 mmol) in DMF (323.5
mL,
4.2 mmol) at 0 ꢀC. The obtained mixture was stirred at room
temperature for 4 h under Ar atomosphere. Then, CH3CN (5.0 mL),
H2O (1.0 mL), NH2OH・HCl (257.9 mg, 3.6 mmol) and K2CO3
(248.8 mg, 1.8 mmol) were added, and the obtained mixture was
stirred for 19 h at room temperature. The mixture was quenched
with sat. aq. Na2CO3 and extracted with Et2O (3 ꢂ 10.0 mL). The
organic layer was washed with brine and dried over Na2SO4. After
removal of the solvent, purification by short column chromatog-
Scheme 2. Derivatization of Isoxazole 3A.
raphy on silica gel (hexane:AcOEt
dimethoxybenzaldoxime 2A (508.0 mg, 93%).
¼
4:1) gave 1,3-
4.2.1. 1,3-dimethoxybenzaldoxime (2A)
Colorless Solid (1134 mg, 93% yield) : mp 98e100 ꢀC; IR (neat)
3276, 1607, 1216, 1158, 1120 cmꢁ1 1H-NMR (400 MHz, CDCl3)
;
d
¼ 3.84 (s, 3H), 3.85 (s, 3H), 6.46 (d, J ¼ 2.3 Hz, 1H), 6.51 (dd, J ¼ 8.6,
2.3 Hz, 1H), 7.61 (d, J ¼ 8.6 Hz, 1H), 8.40 (s, 1H); 13C NMR (100 MHz,
CDCl3)
d
¼ 55.4, 55.5, 98.4, 105.2, 113.6, 128.4, 146.6, 158.9, 162.3;
HRMS (ESI) Calcd for C9H12O3N (M þ H)þ 182.1965, Found 182.1967.
4.3. Typical procedure for Transformation of arenes 1 into 3-
arylisoxazoles 3
Tf2O (690.2
mL, 4.2 mmol) was added to a solution of 1,3-
dimethoxybenzene 1A (414.5 mg, 3.0 mmol) in DMF (323.5
m
L,
Scheme 3. Reaction Pathway.
4.2 mmol) at 0 ꢀC. The obtained mixture was stirred at room
temperature for 4 h under Ar atomosphere. Then, CH3CN (5.0 mL),
H2O (1.0 mL), NH2OH・HCl (257.9 mg, 3.6 mmol) and K2CO3
(248.8 mg, 1.8 mmol) were added, and the obtained mixture was
stirred for 19 h at room temperature. After that, CH3CN (10.0 mL),
presence of 1-hexene. Other alkynes, such as dimethyl acetylene-
dicarboxylate, ethyl propiolate, 3-buten-1-ol, ethynylbenzene, and
1-octyne, could also be used instead of diethyl acetylenedicarbox-
ylate to form the corresponding 3-arylisoxazole derivatives under
the same procedure and conditions. Those reactions could be car-
ried out in one pot under transition-metal-free conditions.
Although the arenes used in the present method were limited to
rather electron-rich aromatics, we believe the present method
would be useful because 3-arylisoxazoles could be obtained in one
pot with easily available substrates and reagents.
H2O (14.0 mL), diethyl acetylenedicarboxylate (745.2
mL, 4.5 mmol),
1-hexene (375.8 L, 3.0 mmol) and Oxone® (2766.4 mg, 4.5 mmol)
m
were added to the mixture, and the obtained mixture was stirred at
room temperature for 1.5 h. The mixture was quenched with sat. aq.
Na2SO3 and extracted with Et2O (3 ꢂ 10.0 mL). The organic layer
was washed with brine and dried over Na2SO4. After removal of the
solvent, purification by short column chromatography on silica gel
(hexane:AcOEt ¼ 4:1) gave diethyl 3-(20,40-dimethoxyphenyl)iso-
xazole-4,5-dicarboxylate 3A (914.9 mg, 87%).
Please cite this article as: R. Nakano, H. Togo, Efficient transformation of electron-rich arenes into diethyl 3-arylisoxazole-4,5-dicarboxylates,
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6
R. Nakano, H. Togo / Tetrahedron xxx (xxxx) xxx
4.3.1. Diethyl 3-(20,40-dimethoxyphenyl)isoxazole-4,5-
dicarboxylate (3A)
4.3.7. Diethyl 3-(20,40-diethoxyphenyl)isoxazole-4,5- dicarboxylate
(3F)
Colorless Oil (876.3 mg, 77% yield); IR (neat) 1734, 1612, 1444,
1308, 1280, 1187, 1120, 1065 cmꢁ1 1H-NMR (400 MHz, CDCl3)
Colorless Oil (914.9 mg, 87% yield); IR (neat) 1732, 1611, 1282,
1209, 1162, 1123, 1066 cmꢁ1; 1H-NMR (400 MHz, CDCl3)
d
¼ 1.25 (t,
;
J ¼ 7.2 Hz, 3H), 1.42 (t, J ¼ 7.2 Hz, 3H), 3.74 (s, 3H), 3.86 (s, 3H), 4.27
(q, J ¼ 7.2 Hz, 2H), 4.46 (q, J ¼ 7.2 Hz, 2H), 6.49 (d, J ¼ 2.3 Hz, 1H),
6.59 (dd, J ¼ 8.5, 2.3 Hz, 1H), 7.53 (d, J ¼ 8.4 Hz, 1H); 13C NMR
d
¼ 1.20 (t, J ¼ 7.2 Hz, 3H), 1.31 (t, J ¼ 7.2 Hz, 3H), 1.43 (t, J ¼ 7.0 Hz,
3H),1.44 (t, J ¼ 7.0 Hz, 3H), 3.98 (q, J ¼ 7.0 Hz, 2H), 4.07 (q, J ¼ 7.0 Hz,
2H), 4.23 (q, J ¼ 7.2 Hz, 2H), 4.46 (q, J ¼ 7.2 Hz, 2H), 6.48 (d, J ¼
(100 MHz, CDCl3)
d
¼ 13.8, 13.9, 55.0, 55.4, 61.5, 62.6, 98.4, 105.0,
2.3 Hz, 1H), 6.55 (dd, J ¼ 8.4, 2.3 Hz, 1H), 7.46 (d, J ¼ 8.4 Hz, 1H), 13
C
108.8, 117.3, 131.2, 156.2, 157.9, 158.5, 159.7, 161.2, 163.0; HRMS (ESI)
NMR (100 MHz, CDCl3)
d
¼ 13.8, 14.0, 14.3, 14.7, 61.4, 62.6; 63.6,
Calcd for C17H20O7N (M þ H)þ 350.1234, Found 350.1229.
64.0, 99.7, 105.2, 109.1, 117.3, 131.2, 156.3, 157.5, 158.8, 160.2, 160.9,
162.2, HRMS (ESI) Calcd for C19H24O7N (M þ H)þ 378.1547, Found
378.1542.
4.3.2. Diethyl 3-(50-chloro-20,40-dimethoxyphenyl)isoxazole- 4,5-
dicarboxylate (3B)
4.3.8. Diethyl 3-(40-methoxy-30-methylphenyl)isoxazole-4,5-
dicarboxylate (3G)
Colorless Solid (854.8 mg, 74% yield) : mp 90e92 ꢀC; IR (neat)
1739, 1727, 1604, 1318, 1290, 1215, 1191, 1135 cmꢁ1 1H-NMR
;
Colorless Oil (806.4 mg, 81% yield); IR (neat) 1733, 1610, 1381,
(400 MHz, CDCl3)
3.79 (s, 3H), 3.97 (s, 3H), 4.29 (q, J ¼ 7.2 Hz, 2H), 4.47 (q, J ¼ 7.2 Hz,
2H), 6.53 (s, 1H), 7.61 (s, 1H); 13C NMR (100 MHz, CDCl3)
d
¼ 1.27 (t, J ¼ 7.2 Hz, 3H), 1.43 (t, J ¼ 7.2 Hz, 3H),
1189, 1125, 1071 cmꢁ1
;
1H-NMR (400 MHz, CDCl3)
d
¼ 1.34 (t, J ¼
7.2 Hz, 3H), 1.42 (t, J ¼ 7.2 Hz, 3H), 2.25 (s, 3H), 3.88 (s, 3H), 4.39 (q,
d
¼ 13.9,
J ¼ 7.2 Hz, 2H), 4.46 (q, J ¼ 7.2 Hz, 2H), 6.88 (d, J ¼ 8.8 Hz,1H), 7.51 (s,
14.0, 55.5, 56.3, 61.7, 62.8, 96.1, 109.0, 114.4, 117.2, 131.2, 156.1, 156.7,
157.7, 158.8, 158.9, 161.0; HRMS (APCl) Calcd for C17H19O7N35Cl
(M þ H)þ 384.0845, Found 384.0843.
1H), 7.52 (d, J ¼ 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
¼ 13.9,
14.0, 16.2, 55.4, 62.3, 62.8, 109.9, 116.1, 118.7, 127.0, 127.3, 130.2,
156.1, 159.0, 159.6, 160.8, 161.7, HRMS (ESI) Calcd for C17H20O6N
(M þ H)þ 334.1285, Found 334.1279.
4.3.3. Diethyl 3-(50-bromo-20,40-dimethoxyphenyl)isoxazole- 4,5-
dicarboxylate (3C)
4.3.9. Diethyl 3-(20,30-dihydrobenzofuran-50-yl)isoxazole-4,5-
dicarboxylate (3H)
Colorless Solid (1075.9 mg, 84% yield): mp 91e93 ꢀC; IR (neat)
1716, 1599, 1447, 1289, 1194, 1142 cmꢁ1; 1H-NMR (400 MHz, CDCl3)
Colorless Oil (657.2 mg, 66% yield); IR (neat) 1731, 1613, 1441,
d
¼ 1.27 (t, J ¼ 7.2 Hz, 3H), 1.43 (t, J ¼ 7.2 Hz, 3H), 3.79 (s, 3H), 3.96 (s,
3H), 4.29 (q, J ¼ 7.2 Hz, 2H), 4.47 (q, J ¼ 7.2 Hz, 2H), 6.50 (s, 1H), 7.77
(s, 1H); 13C NMR (100 MHz, CDCl3)
1298, 1197, 1102, 1061 cmꢁ1; 1H-NMR (400 MHz, CDCl3)
d
¼ 1.34 (t,
J ¼ 7.2 Hz, 3H), 1.42 (t, J ¼ 7.2 Hz, 3H), 3.26 (t, J ¼ 8.9 Hz, 2H), 4.38 (q,
J ¼ 7.2 Hz, 2H), 4.46 (q, J ¼ 7.2 Hz, 2H), 4.64 (t, J ¼ 8.9 Hz, 2H), 6.85
(d, J ¼ 8.4 Hz, 1H), 7.45 (dd, J ¼ 8.4, 2.0 Hz, 1H), 7.58 (d, J ¼ 2.0 Hz,
d
¼ 13.9, 14.0, 55.5, 56.4, 61.7,
62.8, 95.9, 102.5, 109.7, 117.1, 134.1, 156.1, 157.4, 158.7 (2C), 158.9,
161.0; HRMS (ESI) Calcd for C17H19O7N79Br (M þ H)þ 428.0339,
Found 428.0336.
1H); 13C NMR (100 MHz, CDCl3)
109.5, 115.9, 119.0, 124.9, 127.9, 128.6, 156.1, 159.1, 160.9, 161.7, 162.2;
HRMS (ESI) Calcd for C17H18O6N (M þ H)þ 332.1119, Found
332.1129.
d
¼ 13.8, 13.9, 29.3, 62.3, 62.7, 71.7,
4.3.4. Diethyl 3-(20-methoxy-40-methylphenyl)isoxazole- 4,5-
dicarbsecxylate (3Da)
Colorless Oil (537.8 mg, 54% yield); IR (neat) 1733, 1608, 1296,
4.3.10. Diethyl 3-(20-methoxy-50-methylphenyl)isoxazole-4,5-
dicarboxylate (3I)
1244, 1199, 1065 cmꢁ1
;
1H-NMR (400 MHz, CDCl3)
d
¼ 1.19 (t, J ¼
7.2 Hz, 3H), 1.44 (t, J ¼ 7.2 Hz, 3H), 2.28 (s, 3H), 3.83 (s, 3H), 4.24 (q,
J ¼ 7.2 Hz, 2H), 4.49 (q, J ¼ 7.2 Hz, 2H), 6.79 (dd, J ¼ 8.4, 2.7 Hz, 1H),
6.83 (d, J ¼ 2.7 Hz, 1H), 7.24 (d, J ¼ 8.4 Hz, 1H); 13C NMR (100 MHz,
Yellow Oil (791.6 mg, 79% yield); IR (neat) 1732, 1615, 1273, 1251,
1191, 1120, 1068 cmꢁ1
;
1H-NMR (400 MHz, CDCl3)
d
¼ 1.23 (t, J ¼
7.2 Hz, 3H), 1.43 (t, J ¼ 7.2 Hz, 3H), 2.34 (s, 3H), 3.74 (s, 3H), 4.27 (q,
J ¼ 7.2 Hz, 2H), 4.47 (q, J ¼ 7.2 Hz, 2H), 8.84 (d, J ¼ 8.4 Hz, 1H), 7.26
(dd, J ¼ 8.4, 2.0 Hz, 1H), 7.41 (d, J ¼ 2.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3)
d
¼ 13.7, 13.9, 20.2, 55.1, 61.8, 62.8, 111.0, 115.9, 116.5, 118.7,
131.0, 139.0, 156.3, 169.7, 160.5, 160.7, 161.9; HRMS (ESI) Calcd for
C
17H20O6N (M þ H)þ 334.1285, Found 334.1276.
CDCl3)
d
¼ 13.8, 13.9, 20.2, 55.0, 61.5, 62.6, 110.6, 115.7, 117.4, 130.2,
130.8, 132.3, 154.6, 156.1, 158.6, 160.0, 160.9; HRMS (ESI) Calcd for
4.3.5. Diethyl 3-(40-methoxy-20-methylphenyl)isoxazole- 4,5-
dicarboxylate (3Db)
C
17H20O6N (M þ H)þ 334.1285, Found 334.1281.
4.3.11. Diethyl 3-(30-chloro-20,40,60-trimethoxyphenyl)- isoxazole-
4,5-dicarboxylate (3J)
Colorless Oil (419.5 mg, 42% yield); IR (neat) 1732, 1613, 1282,
1196, 1122, 1064 cmꢁ1
;
1H-NMR (400 MHz, CDCl3)
d
¼ 1.24 (t, J ¼
Colorless Solid (1152.8 mg, 93% yield): mp 92e94 ꢀC; IR (neat)
7.2 Hz, 3H), 1.42 (t, J ¼ 7.2 Hz, 3H), 2.41 (s, 3H), 3.75 (s, 3H), 4.27 (q,
1732, 1600, 1433, 1283, 1219, 1183, 1138, 1094 cmꢁ1 1H-NMR
;
J ¼ 7.2 Hz, 2H), 4.46 (q, J ¼ 7.2 Hz, 2H), 6.76 (s,1H), 6.88 (d, J ¼ 7.7 Hz,
1H), 7.48 (d, J ¼ 7.7 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
¼ 13.9,
(400 MHz, CDCl3)
d
¼ 1.61 (t, J ¼ 7.2 Hz, 3H), 1.44 (t, J ¼ 7.2 Hz, 3H),
14.0, 21.9, 54.9, 61.5, 62.6, 111.5, 113.3, 117.4, 130.1, 142.6, HRMS (ESI)
3.74 (s, 3H), 3.77 (s, 3H), 3.96 (s, 3H), 4.21 (q, J ¼ 7.2 Hz, 2H), 4.48 (q,
Calcd for C17H20O6N (M þ H)þ 334.1285, Found 334.1285.
J ¼ 7.2 Hz, 2H), 6.37 (s, 1H); 13C NMR (100 MHz, CDCl3)
¼ 13.9,14.1,
d
56.1, 56.5, 61.6, 62.0, 62.9, 92.2, 104.4, 109.0, 117.3, 156.3, 156.5,
156.7, 157.3, 158.2, 159.8, 160.3; HRMS (APCI) Calcd for
4.3.6. Diethyl 3-(40-tert-butyl-20-methoxyphenyl)isoxazole- 4,5-
dicarboxylate (3E)
C
18H21O8N35Cl (M þ H)þ 414.0950, Found 414.0948.
Yellow Oil (752.6 mg, 67% yield); IR (neat) 1734,1614,1367,1268,
1203, 1105, 1063 cmꢁ1
;
1H-NMR (400 MHz, CDCl3)
d
¼ 1.23 (t, J ¼
4.3.12. Diethyl 3-(20,30,40-trimethoxyphenyl)isoxazole-4,5-
dicarboxylate (3K)
7.2 Hz, 3H), 1.35 (s, 9H), 1.43 (t, J ¼ 7.2 Hz, 3H), 3.78 (s, 3H), 4.28 (q,
J ¼ 7.2 Hz, 2H), 4.47 (q, J ¼ 7.2 Hz, 2H), 6.95 (d, J ¼ 1.6 Hz, 1H), 7.09
(dd, J ¼ 7.9, 1.6 Hz, 1H), 7.52 (d, J ¼ 7.9 Hz, 1H); 13C NMR (100 MHz,
Colorless Solid (574.6 mg, 50% yield): mp 48e50 ꢀC; IR (neat)
1733, 1603, 1311, 1270, 1227, 1184, 1149, 1100, 1082 cmꢁ1 1H-NMR
;
CDCl3)
d
¼ 13.8, 14.0, 31.2 (3C), 35.2, 54.9, 61.5; 62.6, 108.0, 113.3,
(400 MHz, CDCl3)
d
¼ 1.26 (t, J ¼ 7.2 Hz, 3H), 1.43 (t, J ¼ 7.2 Hz, 3H),
117.5, 118.1, 129.9, 156.9, 156.2, 156.5, 158.6, 160.0, 161.2, HRMS (ESI)
3.74 (s, 3H), 3.88 (s, 3H), 3.92 (s, 3H), 4.29 (q, J ¼ 7.2 Hz, 2H), 4.47 (q,
Calcd for C20H26O6N (M þ H)þ 376.1755, Found 376.1750.
J ¼ 7.2 Hz, 2H), 6.76 (d, J ¼ 8.6 Hz, 1H), 7.33 (d, J ¼ 8.6 Hz, 1H); 13
C
Please cite this article as: R. Nakano, H. Togo, Efficient transformation of electron-rich arenes into diethyl 3-arylisoxazole-4,5-dicarboxylates,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131255

R. Nakano, H. Togo / Tetrahedron xxx (xxxx) xxx
7
NMR (100 MHz, CDCl3)
d
¼ 13.8, 13.9, 56.0, 60.9, 61.1, 61.7, 62.7,
CDCl3)
d
¼ 0.65 (t, J ¼ 7.2 Hz, 3H), 1.45 (t, J ¼ 7.2 Hz, 3H), 3.64 (s, 3H),
107.4, 113.8, 117.2, 124.8, 141.9, 151.7, 155.8, 156.2, 158.7, 159.6, 160.9;
HRMS (ESI) Calcd for C18H22O8N (M þ H)þ 380.1340, Found
380.1334.
3.87e3.94 (m, 2H), 4.04 (s, 3H), 4.51 (q, J ¼ 7.2 Hz, 2H), 6.83 (dd, J ¼
7.9, 1.1 Hz, 1H), 6.88 (d, J ¼ 8.1 Hz, 1H), 7.39 (d, J ¼ 8.1 Hz, 1H), 7.41
(dd, J ¼ 8.4, 7.9 Hz, 1H), 7.94 (dd, J ¼ 8.4, 1.1 Hz, 1H); 13C NMR
(100 MHz, CDCl3)
d
¼ 13.1, 13.9, 55.0, 55.6, 60.9, 62.7, 103.4, 106.3,
4.3.13. Diethyl 3-(50-chloro-20,30,40-trimethoxyphenyl)isoxazole-
4,5-dicarboxylate (3L)
114.8, 114.8, 117.4, 124.3, 125.6, 127.0, 129.8, 155.1, 156.8, 157.0, 158.4,
160.2, 165.9; HRMS (APCI) Calcd for C21H22O7N (M þ H)þ 400.1391,
Found 400.1383.
Colorless oil (665.9 mg, 54% yield); IR (neat) 1734, 1606, 1316,
1267, 1220, 1191, 1103, 1067 cmꢁ1 1H-NMR (400 MHz, CDCl3)
;
d
¼ 1.26 (t, J ¼ 7.2 Hz, 3H),1.44 (t, J ¼ 7.2 Hz, 3H), 3.72 (s, 3H), 3.93 (s,
3H), 3.97 (s, 3H), 4.29 (q, J ¼ 7.2 Hz, 2H), 4.48 (q, J ¼ 7.2 Hz, 2H), 7.39
(s, 1H); 13C NMR (100 MHz, CDCl3)
4.3.19. Dimethyl 3-(20,40-dimethoxyphenyl)isoxazole-4,5-
dicarboxylate (3R)
d
¼ 13.8, 13.9, 61.2 (2C), 61.3,
Colorless Solid (844.9 mg, 88% yield); mp 83e85 ꢀC; IR (neat)
61.8, 62.8, 117.0, 117.2, 123.3, 124.9, 147.3, 150.8, 152.3, 156.0, 158.6,
159.2, 160.6; HRMS (ESI) Calcd for C18H21O8N35Cl (M þ H)þ
414.0956, Found 414.0958.
1730, 1617, 1313, 1275, 1208, 1125, 1073 cmꢁ1 1H-NMR (400 MHz,
;
CDCl3)
J ¼ 2.2 Hz, 1H), 6.60 (dd, J ¼ 8.5, 2.2 Hz, 1H), 7.56 (d, J ¼ 8.5 Hz, 1H);
13C NMR (100 MHz, CDCl3)
d
¼ 3.75 (s, 3H), 3.82 (s, 3H), 3.86 (s, 3H), 4.00 (s, 3H), 6.50 (d,
d
¼ 52.4, 53.2, 55.1, 55.5, 98.5, 105.1,
4.3.14. Diethyl 3-(40,50-dimethoxy-20-methylphenyl)isoxazole- 4,5-
dicarboxylate (3 M)
108.7, 117.4, 131.2, 156.6, 157.9, 158.3, 159.7, 161.7, 163.1; HRMS (ESI)
Calcd for C15H16O7N (M þ H)þ 322.0921, Found 322.0920.
Colorless Oil (868.4 mg, 80% yield); IR (neat) 1731, 1608, 1293,
1218, 1169, 1106, 1058 cmꢁ1; 1H-NMR (400 MHz, CDCl3)
d
¼ 1.20 (t,
4.3.20. Ethyl 3-(20,40-dimethoxyphenyl)isoxazole-5-carboxylate
(3Sa)
J ¼ 7.2 Hz, 3H), 1.44 (t, J ¼ 7.2 Hz, 3H), 2.24 (s, 3H), 3.85 (s, 3H), 3.92
(s, 3H), 4.25 (q, J ¼ 7.2 Hz, 2H), 4.49 (q, J ¼ 7.2 Hz, 2H), 6.78 (s, 1H),
ꢀ
Colorless Solid (495.6 mg, 60% yield): mp 93e95 C; IR (neat)
6.85 (s, 1H); 13C NMR (100 MHz, CDCl3)
d
¼ 13.4, 13.6, 19.1, 55.4,
1721, 1611, 1424, 1281, 1209, 1157, 1116, 828 cmꢁ1 1H-NMR
;
55.6, 61.6, 62.5, 112.3, 113.0, 116.3, 117.6, 129.8, 146.4, 149.7, 155.9,
159.3, 160.3, 161.5; HRMS (ESI) Calcd for C18H22O7N (M þ H)þ
364.1391, Found 364.1385.
(400 MHz, CDCl3)
d
¼ 1.43 (t, J ¼ 7.2 Hz, 3H), 3.87 (s, 3H), 3.90 (s,
3H), 4.45 (q, J ¼ 7.2 Hz, 2H), 6.55 (d, J ¼ 2.2 Hz, 1H), 6.59 (dd, J ¼ 8.5,
2.2 Hz, 1H), 7.42 (s, 1H), 7.89 (d, J ¼ 8.5 Hz, 1H); 13C NMR (100 MHz,
CDCl3)
d
¼ 14.2, 55.5, 55.5, 62.1, 98.8, 105.3, 109.7, 110.7, 130.2, 157.2,
4.3.15. Diethyl 3-mesitylisoxazole-4,5-dicarboxylate (3 N)
158.5, 159.6, 160.3, 162.7; HRMS (ESI) Calcd for C14H16O5N (M þ H)þ
Colorless Oil (474.1 mg, 48% yield); IR (neat) 1734, 1612, 1295,
278.1023, Found 278.1022.
1203, 1123, 1063 cmꢁ1
;
1H-NMR (400 MHz, CDCl3)
d
¼ 1.09 (t, J ¼
7.2 Hz, 3H), 1.45 (t, J ¼ 7.2 Hz, 3H), 2.07 (s, 6H), 2.32 (s, 3H), 4.16 (q,
4.3.21. Ethyl 3-(20,40-dimethoxyphenyl)isoxazole-4-carboxylate
(3Sb)
J ¼ 7.2 Hz, 2H), 4.50 (q, J ¼ 7.2 Hz, 2H), 6.92 (s, 2H); 13C NMR
(100 MHz, CDCl3)
d
¼ 13.5, 13.9, 19.9, 21.1, 61.6, 62.9, 116.4, 123.4,
Colorless Oil (223.8 mg, 27% yield); IR (neat) 1731, 1614, 1437,
128.1 (2C), 137.1, 139.4, 156.4, 160.1, 160.2, 162.0; HRMS (ESI) Calcd
1297, 1209, 1161, 1119, 834 cmꢁ1 1H-NMR (400 MHz, CDCl3)
;
for C18H22O5N (M þ H)þ 332.1492, Found 332.1490.
d
¼ 1.23 (t, J ¼ 7.2 Hz, 3H), 3.75 (s, 3H), 3.86 (s, 3H), 4.21 (q, J ¼
7.2 Hz, 2H), 6.53 (d, J ¼ 2.2 Hz, 1H), 6.57 (dd, J ¼ 8.4, 2.5 Hz, 1H), 7.36
4.3.16. Diethyl 3-(40-methoxynaphthalen-10-yl)isoxazole-4,5-
dicarboxylate (3O)
(d, J ¼ 8.4 Hz, 1H), 8.91 (s, 1H); 13C NMR (100 MHz, CDCl3)
¼ 14.1,
d
55.4, 55.4, 60.7, 98.6, 104.4, 109.5, 114.8, 131.1, 158.7, 158.9, 161.1,
162.1, 162.6; HRMS (ESI) Calcd for C14H16O5N (M þ H)þ 278.1023,
Found 278.1026.
ꢀ
Colorless Solid (1001.8 mg, 90% yield): mp 82e84 C; IR (neat)
1758, 1730, 1584, 1301, 1240, 1220, 1098, 1081 cmꢁ1
;
1H-NMR
(400 MHz, CDCl3)
d
¼ 0.92 (t, J ¼ 7.2 Hz, 3H), 1.46 (t, J ¼ 7.2 Hz, 3H),
4.06 (s, 3H), 4.07 (q, J ¼ 7.2 Hz, 2H), 4.51 (q, J ¼ 7.2 Hz, 2H), 6.88 (d,
J ¼ 8.2 Hz, 1H), 7.49e7.53 (m, 2H), 7.55 (d, J ¼ 8.2 Hz, 1H), 7.76e7.80
4.3.22. Ethyl 3-(50-chloro-20,40-dimethoxyphenyl)isoxazole-5-
carboxylate (3Ta)
(m, 1H), 8.31e8.36 (m, 1H); 13C NMR (100 MHz, CDCl3)
d
¼ 13.5,
[1e3] Colorless Solid (411.9 mg, 44% yield): mp 187e189 ꢀC; IR
14.0, 55.7, 61.8, 62.9, 103.0, 116.5, 117.4, 122.4, 124.6, 125.5, 125.6,
127.4, 128.9, 132.3, 156.4, 157.3, 159.8,160.6,161.5; HRMS (ESI) Calcd
for C20H20O6N (M þ H)þ 370.1285, Found 370.1283.
(neat) 1729, 1589, 1442, 1291, 1214, 1124, 1070, 830 cmꢁ1; 1H-NMR
(400 MHz, CDCl3)
d
¼ 1.44 (t, J ¼ 7.2 Hz, 3H), 3.95 (s, 3H), 3.98 (s,
3H), 4.46 (q, J ¼ 7.2 Hz, 2H), 6.57 (s, 1H), 7.41 (s, 1H), 7.99 (s, 1H); 13
C
NMR (100 MHz, CDCl3)
d
¼ 14.2, 56.0, 56.3, 62.2, 96.4, 109.8, 110.5,
4.3.17. Diethyl 3-(20-methoxynaphthalen-10-yl)isoxazole-4,5-
dicarboxylate (3P)
114.7, 130.0, 157.19, 157.12, 157.4, 159.3, 159.9; HRMS (ESI) Calcd for
C
14H15O5N35Cl (M þ H)þ 312.0633, Found 312.0629.
Colorless Solid (1.0691 mg, 96% yield): mp 95e97 ꢀC; IR (neat)
1729, 1623, 1269, 1205, 1103 cmꢁ1
;
1H-NMR (400 MHz, CDCl3)
4.3.23. Ethyl 3-(50-chloro-20,40-dimethoxyphenyl)isoxazole-4-
carboxylate (3 Tb)
d
¼ 0.95 (t, J ¼ 7.2 Hz, 3H), 1.46 (t, J ¼ 7.2 Hz, 3H), 3.87 (s, 3H), 4.08
(q, J ¼ 7.2 Hz, 2H), 4.52 (q, J ¼ 7.2 Hz, 2H), 7.32 (d, J ¼ 9.0 Hz, 1H),
7.28 (ddd, J ¼ 8.1, 6.8, 1.4 Hz, 1H), 7.45 (ddd, J ¼ 8.1, 6.8, 1.4 Hz, 1H),
7.69 (dd, J ¼ 8.1, 1.4 Hz, 1H), 7.83 (dd, J ¼ 8.1, 1.4 Hz, 1H), 7.99 (d, J ¼
Colorless Oil (282.5 mg, 30% yield); IR (neat) 1728, 1608, 1436,
1282, 1209, 1126, 1069, 819 cmꢁ1 1H-NMR (400 MHz, CDCl3)
;
d
¼ 1.25 (t, J ¼ 7.2 Hz, 3H), 3.79 (s, 3H), 3.97 (s, 3H), 4.23 (q, J ¼
7.2 Hz, 2H), 6.56 (s,1H), 7.44 (s,1H), 8.92 (s,1H); 13C NMR (100 MHz,
CDCl3)
9.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
¼ 13.1, 13.5, 55.6, 60.9,
62.4, 108.9, 111.9, 117.6, 123.4, 123.5, 127.1, 127.7, 128.2, 131.9, 132.3,
154.9, 156.0, 158.4, 159.5, 159.8; HRMS (ESI) Calcd for C20H20O6N
(M þ H)þ 370.1285, Found 370.1284.
d
¼ 14.1, 55.9, 56.3, 60.8, 96.3, 109.7, 113.8, 114.7, 131.3, 157.3,
157.5, 158.0, 160.8, 162.3; HRMS (ESI) Calcd for C14H15O5NCl
(M þ H)þ 312.0633, Found 312.0632.
4.3.18. Diethyl 3-(40,80-dimethoxynaphthalen-10-yl)isoxazole- 4,5-
dicarboxylate (3Q)
Colorless Solid (818.3 mg, 68% yield); mp 112e114 ꢀC; IR (neat)
1730, 1593, 1363, 1327, 1254, 1082, 1061 cmꢁ1; 1H-NMR (400 MHz,
4.3.24. 3-(50-Chloro-20,40-dimethoxyphenyl)-5-(200- hydroxyethyl)
isoxazole (3U)
Colorless Solid (468.9 mg, 55% yield): mp 107e109 ꢀC; IR (neat)
3418, 1597, 1435, 1306, 1213, 1049, 823 cmꢁ1 1H-NMR (400 MHz,
;
Please cite this article as: R. Nakano, H. Togo, Efficient transformation of electron-rich arenes into diethyl 3-arylisoxazole-4,5-dicarboxylates,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131255

8
R. Nakano, H. Togo / Tetrahedron xxx (xxxx) xxx
CDCl3)
d
¼ 1.66 (t, J ¼ 5.9 Hz,1H), 3.07 (t, J ¼ 6.1 Hz, 2H), 3.92 (s, 3H),
organic layer was washed brine and dried over Na2SO4. After
removal of the solvent, purification by short column chromatog-
3.96 (s, 3H), 4.01 (q, J ¼ 6.1 Hz, 2H), 6.56 (s, 1H), 6.57 (s, 1H), 7.90 (s,
1H); 13C NMR (100 MHz, CDCl3)
d
¼ 30.4, 56.0, 56.2, 60.3, 96.5,103.1,
raphy on silica gel (hexane:AcOEt
¼
1:2) gave 4,5-
di(hydroxymethyl)-3-(20,40-dimethoxyphenyl)isoxazole
(88.3 mg, 67%).
5A
111.1, 114.4, 130.1, 156.8, 157.0, 158.9, 169.7; HRMS (ESI) Calcd for
C
13H15O4N35Cl (M þ H)þ 284.0684, Found 284.0683.
4.5.1. 4,5-di(hydroxymethyl)-3-(20,40-dimethoxyphenyl)- isoxazole
(5A)
4.3.25. 3-(20,40-dimethoxyphenyl)-5-phenylisoxazole (3Va)
Colorless Solid (556.6 mg, 66% yield): mp 108e110 ꢀC; IR (neat)
1607, 1319, 1280, 1207, 1119, 817 cmꢁ1 1H-NMR (400 MHz, CDCl3)
;
Colorless Solid (88.3 mg, 67% yield): mp 79e81 ꢀC; IR (neat)
3272, 1617, 1418, 1307, 1286, 1209, 1162 cmꢁ1 1H-NMR (400 MHz,
;
d
¼ 3.87 (s, 3H), 3.92 (s, 3H), 6.57 (d, J ¼ 2.5 Hz, 1H), 6.61 (dd, J ¼ 8.5,
CDCl3)
d
¼ 2.52 (t, J ¼ 5.8 Hz,1H), 3.09 (t, J ¼ 6.3 Hz,1H), 3.82 (s, 3H),
2.5 Hz, 1H), 7.00 (s, 1H), 7.40e7.50 (m, 3H), 7.83e7.86 (m, 2H), 7.89
(d, J ¼ 8.5 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
¼ 55.5, 55.6, 98.9,
3.86 (s, 3H), 4.49 (d, J ¼ 5.8 Hz, 2H), 4.87 (d, J ¼ 6.3 Hz, 2H), 6.56 (d,
J ¼ 2.2 Hz, 1H), 6.60 (dd, J ¼ 8.5, 2.2 Hz, 1H), 7.37 (d, J ¼ 8.5 Hz, 1H);
100.7, 105.1, 110.9, 125.7 (2C), 127.9, 128.9 (2C), 129.8, 130.2, 158.5,
160.4, 162.2, 169.0; HRMS (ESI) Calcd for C17H16O3N (M þ H)þ
282.1125, Found 282.1122.
13C NMR (100 MHz, CDCl3)
d
¼ 54.4, 55.4, 55.5, 55.6, 98.8, 105.0,
109.8, 116.4, 131.8, 158.0, 160.1, 162.4, 168.4; HRMS (ESI) Calcd for
C
13H16O5N (M þ H)þ 266.1023, Found 266.1024.
4.3.26. 3-(50-Chloro-20,40-dimethoxyphenyl)-5-phenylisoxazole
(3Vb)
4.6. Preparation of 3-(20,40-dihydroxyphenyl)isoxazole-4,5-
dicarboxylic acid 6A
Colorless Solid (98.0 mg, 10% yield): mp 179e181 ꢀC; IR (neat)
1605, 1320, 1279, 1210, 1095, 818 cmꢁ1 1H-NMR (400 MHz, CDCl3)
To a solution of 3A (174.7 mg, 0.5 mmol) in CH2CH2 (1.0 mL) was
added boron tribromide (2.3 mL, 17% in dichloromethane, ca.
1.0 mol/L) at ꢁ78 ꢀC. Resulting mixture was stirred at room tem-
perature for 24 h. The mixture was quenched with ice and extracted
with AcOEt (3 ꢂ 10.0 mL). The organic layer was washed with brine
and dried over Na2SO4. Then, removal of the solvent gave 3-(20,40-
dihydroxyphenyl)isoxazole-4,5-dicarboxylic acid 6A (101 mg, 76%).
d
¼ 3.96 (s, 3H), 3.98 (s, 3H), 6.58 (s, 1H), 6.99 (s, 1H), 7.41e7.50 (m,
3H), 7.82e7.85 (m, 2H), 7.98 (s, 1H); 13C NMR (100 MHz, CDCl3)
¼ 56.0, 56.2, 96.6, 100.5, 111.1, 114.5, 125.7 (2C), 127.7, 128.9 (2C),
d
129.9, 130.1, 156.9, 157.1, 159.4, 169.4; HRMS (ESI) Calcd for
C
17H15O3N35Cl (M þ H)þ 316.7586, Found 316.7581.
4.3.27. 3-(2,4-dimethoxyphenyl)-5-hexylisoxazole (3Wa)
Colorless Solid (470.5 mg, 54% yield): mp 39e41 ꢀC; IR (neat)
4.6.1. 3-(20,40-dihydroxyphenyl)isoxazole-4,5-dicarboxylic acid (6A)
1596, 1428, 1287, 1211, 1164, 1135, 833 cmꢁ1 1H-NMR (400 MHz,
;
CDCl3)
Yellow Solid (101 mg, 76% yield): mp 192e194 ꢀC (dec); IR (neat)
d
¼ 0.90 (t, J ¼ 7.0 Hz, 3H), 1.30e1.44 (m, 6H), 1.70e1.77 (m,
3327, 1752, 1697, 1617, 1173, 1078 cmꢁ1 1H-NMR (400 MHz,
;
2H), 2.77 (t, J ¼ 7.5 Hz, 2H), 3.85 (s, 3H), 3.88 (s, 3H), 6.42 (s, 1H),
6.53 (d, J ¼ 2.5 Hz, 1H), 6.57 (dd, J ¼ 8.5, 2.5 Hz, 1H), 7.81 (d, J ¼
DMSO‑d6)
d
¼ 6.76 (d, J ¼ 2.3 Hz, 1H), 6.85 (dd, J ¼ 8.6, 2.3 Hz, 1H),
7.88 (d, J ¼ 8.6 Hz, 1H); 13C NMR (100 MHz, DMSO‑d6)
d
¼ 101.3,
8.5 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
¼ 14.0, 22.5, 26.7, 27.5,
103.3, 106.2, 113.6, 125.2, 153.2, 154.5, 156.5, 156.9, 162.2, 163.5;
HRMS (APPI) Calcd for C11H8O7N (M þ H)þ 266.0295, Found
266.0295.
28.8, 31.4, 55.4, 55.5, 98.8, 101.7, 105.0, 111.2, 130.2, 158.4, 159.7,
162.0, 172.7; HRMS (ESI) Calcd for C17H24O3N (M þ H)þ 290.1751,
Found 290.1750.
4.4. Preparation of 3-(20,40-dimethoxyphenyl)isoxazolo[4,5- d]
Acknowledgments
pyridazine-4,7-diol 4A
This research was funded by JSPS (KAKENHI) Grant Number JP
No. 18K05118 in Japan.
Hydrazine monohydrate (182
mL, 3.5 mmol) was added to a
solution of 3A (174.7 mg, 0.5 mmol) in EtOH (0.75 mL). The mixture
was stirred for 6 h at 90 ꢀC. Then, filtration of the reaction mixture
gave
Appendix A. Supplementary data
3-(20,40-dimethoxyphenyl)isoxazolo[4,5-d]pyridazine-4,7-
diol 4A (131.7 mg, 91%).
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2020.131255.
4.4.1. 3-(20,40-dimethoxyphenyl)isoxazolo[4,5-d]pyridazine- 4,7-
diol (4A)
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Colorless Solid (131.7 mg, 91% yield): mp 181e185 ꢀC; IR (neat)
3341, 3300, 1583, 1436, 1271, 1209, 1150, 1101 cmꢁ1 1H-NMR
;
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Please cite this article as: R. Nakano, H. Togo, Efficient transformation of electron-rich arenes into diethyl 3-arylisoxazole-4,5-dicarboxylates,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131255