Facile one-pot preparation of 5-aryltetrazoles and 3-arylisoxazoles from aryl bromides

Article abstract of DOI:10.1016/j.tet.2018.06.044

The successive treatment of aryl bromides with n-BuLi, DMF, hydroxylamine hydrochloride, and finally diphenylphosphoryl azide provided efficiently the corresponding 5-aryltetrazoles in good to moderate yields. Similarly, the successive treatment of aryl bromides with n-BuLi, DMF, hydroxylamine hydrochloride, and finally diethyl acetylenedicarboxylate and Oxone provided efficiently the corresponding diethyl 3-arylisoxazole-4,5-dicarboxylates in good to moderate yields. Aromatic aldoximes are the key intermediates in both reactions, and 5-aryltetrazoles and 3-arylisoxazoles could be obtained from aryl bromides in one pot under transition-metal-free conditions.

Full text of DOI:10.1016/j.tet.2018.06.044

Accepted Manuscript
Facile one-pot preparation of 5-aryltetrazoles and 3-arylisoxazoles from aryl bromides
Eiji Kobayashi, Hideo Togo
PII:
S0040-4020(18)30744-0
10.1016/j.tet.2018.06.044
TET 29640
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 9 May 2018
Revised Date: 15 June 2018
Accepted Date: 16 June 2018
Please cite this article as: Kobayashi E, Togo H, Facile one-pot preparation of 5-aryltetrazoles and 3-
arylisoxazoles from aryl bromides, Tetrahedron (2018), doi: 10.1016/j.tet.2018.06.044.
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Facile One-pot Preparation of 5-Aryltetrazoles and
3-Arylisoxazoles from Aryl Bromides
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Eiji Kobayashi and Hideo Togo
Graduate School of Science, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522 Japan

ACCEPTED MANUSCRIPT
Tetrahedron
1
TETRAHEDRON
Pergamon
Facile One-pot Preparation of 5-Aryltetrazoles and 3-Arylisoxazoles
from Aryl Bromides
Eiji Kobayashi and Hideo Togo*
Graduate School of Science, Chiba University, Yayoi-cho 1-33,
Inage-ku, Chiba 263-8522 Japan
Abstract—The successive treatment of aryl bromides with n-BuLi, DMF, hydroxylamine hydrochloride, and finally diphenylphosphoryl
azide provided efficiently the corresponding 5-aryltetrazoles in good to moderate yields. Similarly, the successive treatment of aryl
bromides with n-BuLi, DMF, hydroxylamine hydrochloride, and finally diethyl acetylenedicarboxylate and Oxone® provided efficiently
the corresponding diethyl 3-arylisoxazole-4,5-dicarboxylates in good to moderate yields. Aromatic aldoximes are the key intermediates in
both reactions, and 5-aryltetrazoles and 3-arylisoxazoles could be obtained from aryl bromides in one pot under transition-metal-free
conditions.
© 2018 Elsevier Science. All rights reserved
1. Introduction
As recent studies of the preparation of 5-aryltetrazoles,
the reaction of aromatic nitriles and sodium azide in
DMF,4a the reaction of aromatic nitriles, sodium azide,
and Amberlyst-15 in DMSO,4b and other related reactions
The Ugi
reaction with aldehydes or ketones, amines, isonitriles,
and TMSN3 in CH3OH was also reported.5a~5d
For the
Nitrogen-containing heterocyclic compounds are very
attractive due to their potent biological activities.1
Tetrazoles2a and isoxazoles,3a in particular, are one of the
most important nitrogen-containing five-membered
heterocyclic compounds and serve as units or cores of some
with aromatic nitriles4c~4f were reported.
pharmaceuticals and agrochemicals.
For example,
Losartan, 5-(2’-biphenyl)tetrazole derivative, is an
a
angiotensin II receptor blocker bearing antihypertensive
activity,2b and Valdecoxib, a 3-phenylisoxazole derivative,
is a COX-2 inhibitor bearing anti-inflammatory activity,3d,3e
as shown in Fig. 1. Extensive synthetic studies of
5-substituted tetrazoles and 3-substituted isoxazoles have
been carried out.2,3 The conventional methods for the
preparation of 5-aryltetrazoles and 3-arylisoxazoles include
the reactions of aromatic nitriles with metal azides [N1 +
N3]2 and the reactions of aromatic nitrile oxides derived
from aromatic aldoximes with alkynes,3 respectively.
preparation of 5-substituted tetrazoles using transition
metals, the reaction of aldehyde hydrazones with
PhI(OAc)2 (DIB), TMSN3, and Cu(OAc)2,6a the reaction
of arylboronic acids with NaN3 and Pd(II) complex,6b the
reaction of allyl carbonates with t-butyl isonitrile, TMSN3,
and Pd(OAc)2,6c and the reaction of aldoximes with NaN3
6d
and InCl3 were reported. For the construction of
5-substituted tetrazoles via [N2 + N2], the reaction of
aromatic
aldehydes,
hydrazine,
(DBAD), and
di-t-butylazodicarboxylate
[bis(trifluoroacetoxy)iodo]benzene (PIFA),7a the reaction
of aryldiazonium salts, amidine, and I2•KI,7b and the
N
NH
N
reaction
of
aryldiazonium
salts,
N
2,2,2-trifluorodiazomethane, and AcOAg7c were reported.
N
O
As recent studies of the preparation of 3-substituted
isoxazoles, the reaction of benzylic chlorides with
N-methylmorpholine N-oxide (NMO), NH2OH•HCl, and
then Oxone® in the presence of alkynes,8a the reaction of
α,α difluoromethyl aldoxime with N-chlorosuccinimide
(NCS) in the presence of alkynes,8b the reaction of
aldoximes and DIB in the presence of alkynes,8c and
other related reactions8d~8k under transition-metal-free
N
SO2NH2
N
HO
Cl
Valdecoxib
(COX-2 Inhibitor Drug)
Losartan
(Angiotensin II Receptor Blocker)
Fig. 1 Typical Pharmaceuticals Bearing 5-Aryltetrazole or 3-
Arylisoxazole Unit
conditions were reported.
For the preparation of
3-substituted isoxazoles using transition metals, the

ACCEPTED MANUSCRIPT
2
Tetrahedron
(1.5 equiv.) and Et3N (1.5 equiv.) at room temperature for 2
h, gave the corresponding aldoxime 2A in over 90% yield.
Based on this result, the same successive treatment of
4-methylphenyl bromide 1A with n-BuLi, DMF, and
NH2OH•HCl, followed by solvent evaporation and
treatment of the residue with DPPA (2.0 equiv.) and DBU
(4.0 equiv.) in toluene for 15 h at refluxing conditions,10
was carried out to give 5-(4’-methylphenyl)tetrazole 3A in
reaction of terminal alkynes, primary amines, t-BuONO,
ZnCl2, and CuI,9a the reaction of α-hydroxyimino acids
with alkenes, Oxone®, and Ru(bpy)3Cl2 under irradiation
with blue LED,9b and other related reactions9c~9e were
reported.
Among the above mentioned reactions, the reaction of
aromatic aldoximes with diphenylphosphoryl azide (DPPA)
[N1 + N3] for the preparation of 5-aryltetrazoles10 and the
reaction of aromatic nitrile oxides derived from aromatic
aldoximes with alkynes for the preparation of
3-arylisoxazoles are very attractive due to the simple
operation and the ease of handling of the reagents. On the
other hand, aryl bromides are either commercially available
or can be easily obtained from the reactions of arenes with
brominating reagents, such as Br2, Br2 with Fe, NBS,
1,3-dibromo-5,5-dimethylhydantoin (DBH), etc. In this
28% yield, as shown in Table 1 (entry 1).
To improve
the yield of 3A, K2CO3 (0.75 equiv. and 1.5 equiv.) instead
of Et3N was used in the 3rd step, the amount of DPPA (2.5
equiv. and 3.0 equiv.) was increased, and the amount of
DBU was reduced in the 5th step under the same procedure
and conditions except that the reaction temperature was
-50 °C in the 1st step (entries 2~5). Consequently, it was
found that the treatment of 4-methylphenyl bromide 1A
with n-BuLi (1.2 equiv.) at -50 °C for 0.5 h in the 1st step,
DMF (1.2 equiv.) at room temperature for 1 h in the 2nd
step, and NH2OH•HCl (1.5 equiv.) and K2CO3 (1.5 equiv.)
at room temperature for 2 h in the 3rd step, followed by
solvent evaporation and final treatment of the residue with
DPPA (2.5 equiv.) and DBU (3.5 equiv.) in toluene for 15
report, we would like to present
a one-pot and
transition-metal-free preparation of 5-aryltetrazoles and
3-arylisoxazole-4,5-dicarboxylates through the reaction of
aryl bromides with n-BuLi, DMF, and then NH2OH•HCl,
followed by the reactions with DPPA and Oxone® in the
presence of diethyl acetylenedicarboxylate, respectively.
h
under
refluxing
conditions
gave
5-(4’-methylphenyl)tetrazole 3A in 70% yield (entry 4). As
a gram-scale experiment, the treatment of 4-methylphenyl
bromide 1A (6 mmol) with n-BuLi, DMF, NH2OH•HCl
and K2CO3, solvent removal, and then treatment with
DPPA and DBU under the same procedure and conditions
gave 3A in 64% yield, as shown in Scheme 1.
2. Results and Discussion
Table 1. Transformation of 4-Methylphenyl Bromide 1A to
5-(4´-Methylphenyl)tetrazole 3A
1) nꢀBuLi (1.2 equiv.)
THF (6.0 mL), temp., 0.5 h
H
Br
OH
C
N
DMF
r.t., 1 h
—HCl (1.5 equiv.)
r.t., 2 h
2)
3)
(1.2 equiv.),
Me
Me
NH OH
2
1A
(3.0 mmol)
2A
Based on those results, the treatment of 3-methylphenyl
base,
bromide
1B,
3,4-dimethylphenyl
bromide
1C,
4-isopropylphenyl bromide 1D, phenyl bromide 1G,
4-biphenyl bromide 1H, and 4-methoxyphenyl bromide 1I
with n-BuLi, DMF, and then NH2OH•HCl with K2CO3,
followed by solvent evaporation and the reaction of the
residue with DPPA and DBU in toluene under the same
procedure and conditions, gave the corresponding
5-aryltetrazoles 3B~3D and 3G~3I in good to moderate
yields, respectively, as shown in Scheme 1. The same
treatment of aryl bromides 1J and 1K bearing an
O-methoxymethyl (O-MOM) group and aryl bromide 1L
bearing a cyclic acetal group gave 5-aryltetrazoles 3J and
3K, both of which were deprotected by extraction of the
reaction mixture after acidification with aq. HCl, and 3L in
good to moderate yields, respectively. As examples of
aryl bromides bearing electron-withdrawing groups, such
as chloro and trifluoromethyl groups, 4-chlorophenyl
bromide 1M, 3-chlorophenyl bromide 1N, and
4-trifluoromethylphenyl bromide 1O were also treated with
n-BuLi, DMF, and NH2OH•HCl with K2CO3. Then, the
solvent was evaporated and the reaction with DPPA and
DBU under the same procedure and conditions was carried
out to give the corresponding 5-aryltetrazoles 3M~3O in
70%, 73%, and 54% yields, respectively, as shown in
N
N
C
4) evaporation
DPPA
N
5)
, DBU
N
H
toluene (3.0 mL),
110 °C, 15 h
Me
3A
entry
Temp.
base
DPPA
(equiv.)
DBU
(equiv.)
Yield
(%)
(°C)
-70
-50
Et3N (1.5
equiv.)
K2CO3 (0.75
equiv.)
K2CO3 (0.75
equiv.)
K2CO3 (1.5
equiv.)
1a
2
2.0
2.5
2.5
2.5
3.0
4.0
28
67
46
70
59
3.5
3b
4
-50
-50
-50
3.5
3.5
3.5
K2CO3 (1.5
equiv.)
5
a The mixture was warmed at 0 °C for 5 min before addition of DMF at
2nd step reaction.
b Reaction was carried out without evaporation, before addition of DPPA.
First, the one-pot preparation of 5-aryltetrazoles from aryl
bromides via aromatic aldoximes was studied. The
reaction of 4-methylphenyl bromide 1A with n-BuLi (1.55
M in hexane, 1.2 equiv.) in THF at -70 °C for 0.5 h,
followed by the reaction with DMF (1.2 equiv.) at room
temperature for 1 h and then the reaction with NH2OH•HCl
Scheme 1.
Applying the same treatment to
2-bromonaphthalene 1Q and 1-bromonaphthalene 1R gave
3Q and 3R in good to moderate yields, respectively. On
the other hand, the treatment of 4-(ethoxycarbonyl)phenyl

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Tetrahedron
3
those heteroaromatics were directly treated with n-BuLi,
DMF, and then NH2OH•HCl and K2CO3. Solvent removal
followed by the reaction with DPPA and DBU gave
5-heteroaryltetrazoles 3S~3V in good to moderate yields,
respectively, as shown in Scheme 1. When aryl iodides 1’,
such as phenyl iodide 1G’, 4-methoxyphenyl iodide 1I’,
and 4-chlorophenyl iodide 1M’, instead of aryl bromides 1
were subjected to the same procedure and conditions, the
yields of 5-aryltetrazoles 3 became moderate, as shown in
Scheme 1. 2-Methylphenyl bromide 1E and 2-biphenyl
bromide 1F were also used in the present one-pot
preparation of 5-aryltetrazoles 3, but the yields of
5-(2’-methylphenyl)tetrazole
3E
and
5-(biphenyl-2’-yl)tetrazole 3F were less than 10% because
of steric hindrance in the reaction of the corresponding
aromatic aldoximes and DPPA.
Table 2. Transformation of 4-Methylphenyl Bromide 1A to
3-(4
´-Methylphenyl)isoxazole 4A
entry
Solvent (mL)
Yield
(%)
1a
2b
3c
4b,d
5b
6b
7b
CH3CN : H2O = 1 : 1 (6 mL)
44
42
68
44
53
75
77
CH3CN : 1M HCl aq. = 1 : 1 (6 mL)
CH3CN : H2O = 1 : 1 (30 mL)
CH3CN : H2O : 1M HCl aq. = 3 : 1 : 2 (6 mL)
CH3CN : H2O : 1M HCl aq. = 3 : 1 : 2 (6 mL)
CH3CN : H2O : 1M HCl aq. = 5 : 2 : 3 (20 mL)
CH3CN : H2O : 1M HCl aq. = 15 : 4 : 11 (30 mL
a K2CO3 (0.75 equiv.) was used.
b The mixture was cooled at 0 °C for 5 min before addition of 1M HCl.
c The mixture was cooled at 0 °C for 5 min before addition of Oxone®.
d NH2OHꢀHCl (0.5 equiv.) was added after the solvent was removed.
Then, the one-pot preparation of 3-arylisoxazoles from aryl
bromides via aromatic aldoximes was studied.
4-Methylphenyl bromide 1A was treated with n-BuLi,
DMF, and then NH2OH•HCl and K2CO3 to form aldoxime
2A. After solvent removal, the residue was treated with
diethyl acetylenedicarboxylate (1.5 equiv.) and Oxone®
(1.5 equiv.) at room temperature for 1 h in a mixture of
CH3CN and H2O (1:1, 6 mL, entry 1),8a CH3CN and 1M
HCl aq. (1:1, 6 mL, entry 2), CH3CN and H2O (1:1, 30 mL,
bromide 1P bearing an ester group with i-PrMgCl•LiCl,11
DMF, and then NH2OH•HCl with K2CO3, followed by
solvent removal and the reaction with DPPA and DBU,
provided 3P in 96% yield.
As regards heteroaromatics, such as benzothiophene 1S,
benzofuran 1T, 2-ethylthiophene 1U, and 2-ethylfuran 1V,

ACCEPTED MANUSCRIPT
4
Tetrahedron
entry 3), CH3CN, H2O, and 1M HCl aq. (3:1:2, 6 mL,
entries 4,5), CH3CN, H2O, and 1M HCl aq. (5:2:3, 20 mL,
entry 6), and CH3CN, H2O, and 1M HCl aq. (15:4:11, 30
mL,
entry
7)
to
provide
diethyl
3-(4’-methylphenyl)isoxazole-4,5-dicarboxylate 4A in
moderate to good yields, respectively, as shown in Table 2.
Among them, compound 4A was obtained in 77% yield
when the oxidative cycloaddition of formed aldoxime 2A to
diethyl acetylenedicarboxylate was carried out in a diluted
mixture of CH3CN, H2O, and 1M HCl aq. (30 mL) (entry
7). The addition of H2O and 1M HCl aq. increased the
solubility and the oxidizing ability of Oxone®. As a
gram-scale experiment, 4-methylphenyl bromide 1A (6
mmol) was treated with n-BuLi, DMF, and NH2OH•HCl
with K2CO3, subjected to solvent removal, and finally
reacted with diethyl acetylenedicarboxylate and Oxone®
under the same procedure and conditions to give 4A in 80%
yield, as shown in Scheme 2.
Based on those results, aryl bromides 1B~1I were treated
with n-BuLi, DMF, and then NH2OH•HCl with K2CO3, and
this was followed by solvent evaporation and reaction of
the residue with diethyl acetylenedicarboxylate and
Oxone® under the same procedure and conditions to give
the
corresponding
diethyl
3-arylisoxazole-4,5-
dicarboxylates 4B~4I in good to moderate yields,
respectively, as shown in Scheme 2. Aryl bromide 1L
bearing a cyclic acetal group, aryl bromides 1M, 1N, and
1O bearing electron-withdrawing groups, such as chloro
and trifluoromethyl groups, and naphthyl bromides 1Q and
1R were also treated with n-BuLi, DMF, and then
NH2OH•HCl with K2CO3. Solvent evaporation, followed
by the reaction with diethyl acetylenedicarboxylate and
Oxone® under the same procedure and conditions provided
the
dicarboxylates 4L~4O, 4Q, and 4R in good to moderate
yields, respectively. Diethyl
corresponding
diethyl
3-arylisoxazole-4,5-
3-(4’-ethoxycarbonylphenyl)isoxazole-4,5-dicarboxylate
4P was also prepared in 52% yield from
4-(ethoxycarbonyl)phenyl bromide 1P by the successive
treatment with i-PrMgCl•LiCl, DMF, NH2OH•HCl with
K2CO3, and then diethyl acetylenedicarboxylate and
Oxone®. On the other hand, benzothiophene 1S and
benzofuran 1T were directly treated with n-BuLi, DMF,
NH2OH•HCl and K2CO3, and finally with diethyl
acetylenedicarboxylate and Oxone® to form the
corresponding 3-heteroarylisoxazoles 4S and 4T in
moderate yields, respectively, as shown in Scheme 2.
Then, dimethyl acetylenedicarboxylate, ethyl propiolate,
and
phenylacetylene
instead
of
diethyl
acetylenedicarboxylate were used. Thus, the successive
treatment of 4-methylphenyl bromide 1A with n-BuLi,
DMF, NH2OH•HCl and K2CO3, and finally with those
alkynes and Oxone® under the same procedure and
conditions gave 3-(4’-methylphenyl)isoxazoles 4W, 4X,
and 4Y in good to moderate yields, respectively. In the
above successive treatment of aryl bromides to yield
3-arylisoxazoles, chloride ion derived from NH2OH•HCl

ACCEPTED MANUSCRIPT
Tetrahedron
5
and 1M HCl aq. plays an important role in the formation of
3-arylisoxazoles via nitrile oxides from aromatic aldoximes.
Thus, the successive treatment of 4-methylphenyl bromide
1A with n-BuLi, DMF, and NH2OH•H2O (1.5 equiv.),
solvent removal, and finally the reaction with diethyl
acetylenedicarboxylate and Oxone® in a mixture of CH3CN
and H2O (1:1, 30 mL) under the same procedure and
conditions did not generate 4A at all and instead,
4-methylphenylaldoxime and 4-methylbenzonitrile were
obtained in 31% and 45% yields, respectively. Today, the
oxidation of aromatic aldoximes to the corresponding
nitrile oxides with Oxone® in the presence of chloride ion is
known.12
Treatment of aromatic aldoxime 2 with DPPA under
warming conditions gave 5-aryltetrazole 3, as shown in
Scheme
3.
The treatment of 4-methylbenzonitrile with sodium azide in
toluene at 110 °C for 15 h did not generate 3A at all.
Therefore, aromatic nitrile is not an intermediate for the
present reaction. Similarly, treatment of formed aromatic
aldoxime
Oxone® in the presence of chloride ion at room temperature
generates diethyl 3-arylisoxazole-4,5-dicarboxylate
2 with diethyl acetylenedicarboxylate and
4
through the 1,3-dipolar cycloaddition of the formed nitrile
oxide to diethyl acetylenedicarboxylate, as shown in
Scheme 4. Here, the chloride ion plays an important role
as a catalyst for the oxidation of aromatic aldoxime 2 to
nitrile oxide in the presence of Oxone®.8a,12
3) NH2OH·HCl
-
+
O Li
K2CO3
1) n-BuLi
OH
3. Conclusion
Ar Br
Ar
N
N
2) DMF
Ar
4) evaporation
1
2
5-Aryltetrazoles and 3-arylisoxazoles were efficiently
obtained from aryl bromides in one pot without using any
transition metals by the successive treatment with n-BuLi,
DMF, NH2OH•HCl and K2CO3, and finally with
diphenylphosphoryl azide, and with n-BuLi, DMF,
NH2OH•HCl and K2CO3, and finally with diethyl
acetylenedicarboxylate and Oxone®, respectively. We
believe that the present methods for the preparation of
5-aryltetrazoles and 3-arylisoxazoles from aryl bromides
would be useful because aryl bromides are easily available
or can be easily prepared from arenes.
-
O
N
+
-
N
5) PhO
P
OPh
N3
N
OPh
OPh
N3
O
O
-
N
P
O
P
O
N
Ar
N
Ar
DBU
H
OPh
OPh
-
N
+
N
+
N
N
-
HN
N
N
N
N
Ar
- (PhO)2PO2
NH
NH
Ar
Ar
3
Scheme 3. Reaction Pathway for 5-Aryltetrazole
4. Experimental Section
+
-
3) NH2OH·HCl
O Li
1) n-BuLi
K2CO3
OH
4.1 General: 1H NMR spectra were measured on 400 MHz
spectrometers. Chemical shifts were recorded as follows:
chemical shift in ppm from internal tetramethylsilane on the
δ scale, multiplicity (s = 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 number, cm-1.
High-resolution mass spectra were recorded with 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).
Ar Br
Ar
N
N
2) DMF
Ar
4) evaporation
1
2
-
+
K
Cl
5)
R1
R2
O
N
Oxone®
HCl aq.
R1
Oxone®
Ar
R2
+
Cl
4
Oxone®
1,3-Dipolar Cycloaddition
-
Cl
-
-
R1
R2
O
N
O
Cl
+
+
N
O
H
Ar
N
(- H )
Ar
Ar
4.2A Typical Experimental Procedure for Preparation of
5-Aryltetrazoles 3 from Aryl Bromides 1:ꢀ n-BuLi (1.55 M
solution in hexane, 2.32 mL, 3.6 mmol) was added dropwise to a
solution of 4-methylphenyl bromide (513 mg, 3.0 mmol) in THF
(6.0 mL) at −50 °C under Ar atmosphere. After 30 min, DMF
(278 ꢀL, 3.6 mmol) was added and the obtained mixture was
gradually warmed to r.t. After one hour at the same temperature,
NH2OH•HCl (313 mg, 4.5 mmol) and K2CO3 (622 mg, 4.5 mmol)
were added and the obtained mixture was stirred for 2 h at r.t.
Then, after removal of the solvent under reduced pressure, toluene
(3.0 mL), DPPA (1.61 mL, 7.5 mmol), and DBU (1.57 mL, 10.5
mmol) were added to the obtained residue under Ar atmosphere.
Scheme 4. Reaction Pathway for 3-Arylisoxazole
The possible reaction pathways for the present one-pot
preparation of 5-aryltetrazoles 3 and 3-arylisoxazoles 4
from aryl bromides 1 are shown in Schemes 3 and 4,
respectively. Treatment of aryl bromide 1 with n-BuLi
generates the corresponding aryllithium that reacts with
DMF to form the adduct in the 2nd step. Then, the adduct
reacts with NH2OH•HCl to form aromatic aldoxime 2.

ACCEPTED MANUSCRIPT
6
Tetrahedron
After being stirred for 16 h under refluxing conditions, the
mixture was cooled to r.t. and then, saturated NaHCO3 aq. (15.0
mL) was added. After being stirred for 5 min, the mixture was
diluted with water (5.0 mL). The aqueous layer was then washed
with AcOEt (25.0 mL) and acidified with 1.0 M HCl aq. to pH 2.
The aqueous layer was extracted with AcOEt (2 × 25.0 mL).
Removal of the solvent, followed by purification of the residue by
short column chromatography on neutral silica gel (AcOEt :
hexane = 1:3-1:1) gave 5-(4’-methylphenyl)tetrazole 3A (336.1
mg, 70%).
4.2.1 5-(4’-Methylphenyl)-1H-tetrazole (3A): Yield: 336.1 mg
(70%); white solid; Mp: 248-249 °C (250-251 °C)[13]; IR (neat)
2359 (br), 1504, 990, 822, 741 cm-1; 1H NMR (400 MHz,
DMSO-d6): δ = 2.38 (s, 3H), 7.41 (d, 2H, J =7.2 Hz), 7.92 (d, 2H,
J = 7.2 Hz); 13C{1H}NMR (100 MHz, DMSO-d6): δ = 21.1, 121.3,
126.9 (2C), 130.0 (2C), 141.3, 155.1; HRMS (ESI) Calcd for
C8H9N4 [M+H]+ = 161.0822, Found =161.0822.
4.2.2 5-(3’-Methylphenyl)-1H-tetrazole (3B): Yield: 384.4 mg
(80%); white solid; Mp: 150-152 °C; IR (neat) 2609 (br), 801, 687,
1
505 cm-1; H NMR (400 MHz, DMSO-d6): δ = 2.40 (s, 3H), 7.40
(d, 1H, J = 7.7 Hz), 7.48 (t, 1H, J = 7.7 Hz), 7.82 (d, 1H, J = 7.7
Hz), 7.86 (s, 1H); 13C{1H}NMR (100 MHz, DMSO-d6): δ = 21.0,
124.0, 124.1, 127.4, 129.4, 131.9, 138.9, 155.2; HRMS (ESI)
Calcd for C8H9N4 [M+H]+ = 161.0822, Found = 161.0821.
4.2B Typical Experimental Procedure from Arenes 1S~1V to
5-Aryltetrazoles 3S~3V: n-BuLi (1.55 M solution in hexane, 2.32
mL, 3.6 mmol) was added dropwise to
a solution of
benzothiophene (403 mg, 3.0 mmol) in THF (6.0 mL) at −50 °C
under Ar atmosphere. After one hour, the resulting mixture was
stirred for 5 min at 0 °C and then DMF (278 ꢀL, 3.6 mmol) was
added. The obtained mixture was gradually warmed to r.t. After
one hour at the same temperature, NH2OHꢁHCl (313 mg, 4.5
mmol) and K2CO3 (622 mg, 4.5 mmol) were added and the
obtained mixture was stirred for 2 h at r.t. Then, after removal of
the solvent under reduced pressure, toluene (3.0 mL), DPPA (1.61
mL, 7.5 mmol), and DBU (1.57 mL, 10.5 mmol) were added to
the obtained residue under Ar atmosphere. After being stirred for
16 h under refluxing conditions, the mixture was cooled to r.t. and
then, saturated NaHCO3 aq. (15.0 mL) was added. After being
stirred for 5 min, the mixture was diluted with water (5.0 mL).
The aqueous layer was washed with AcOEt (25.0 mL) and
acidified with 1.0 M HCl aq. to pH 2. The aqueous layer was
extracted with AcOEt (2 × 25.0 mL). Removal of the solvent,
followed by purification of the residue by short column
chromatography on neutral silica gel (AcOEt : hexane = 1:3-1:1)
gave 5-(benzothiophen-2’-yl)tetrazole 3S (497.4 mg 82%).
4.2.3 5-(3’,4’-Dimethylphenyl)-1H-tetrazole (3C): Yield: 292.7
mg (56%); white solid; Mp: 194-196 °C; IR (neat) 2745 (br),
1039, 825, 742 cm-1; 1H NMR (400 MHz, DMSO-d6): δ = 2.29 (s,
3H), 2.31 (s, 3H), 7.36 (d, 1H, J = 7.6 Hz), 7.74 (d, 1H, J = 7.6
Hz), 7.82 (s, 1H); 13C{1H}NMR (100 MHz, DMSO-d6): δ = 19.4,
19.5, 124.4 (2C), 127.8, 130.4, 137.6, 140.1; HRMS (ESI) Calcd
for C9H11N4 [M+H]+ =175.0978, Found = 175.0979.
4.2.4 5-(4’-Isopropylphenyl)-1H-tetrazole (3D): Yield: 412.2
mg (73%); white solid; Mp: 186-189 °C (lit.[10] Mp: 189 °C); IR
1
(neat) 2617 (br), 840, 545 cm-1; H NMR (400 MHz, DMSO-d6):
δ = 1.23 (d, 6H, J = 6.8 Hz) , 2.96 (sep, 1H, J = 6.8 Hz) , 7.47 (d,
2H, J = 8.2 Hz), 7.95 (d, 2H, J = 8.2 Hz); 13C{1H}NMR (100
MHz, DMSO-d6): δ = 23.6 (2C), 33.5, 121.7, 127.1 (2C), 127.4
(2C), 152.0, 155.1; HRMS (ESI) Calcd for C10H11N4 [M-H]-
=187.0978, Found =187.0980.
4.2.5 5-Phenyl-1H-tetrazole (3G): Yield: 280.6 mg (64%); white
solid; Mp: 204-208 °C (213-214 °C) [13]; IR (neat) 2479 (br), 725
4.2C Experimental Procedure for Preparation of
1
cm-1; H NMR (400 MHz, DMSO-d6): δ = 7.59~7.62 (m, 3H),
5-(4’-Ethoxycarbonylphenyl)tetrazole
3P
from
Ethyl
8.02~8.04 (m, 2H); 13C{1H}NMR (100 MHz, DMSO-d6): δ =
124.1, 127.0 (2C), 129.5 (2C), 131.3; HRMS (ESI) Calcd for
C7H7N4 [M+H]+ =147.0665, Found =147.0664.
4-Bromobenzoate 1P: ꢀi-PrMgCl·LiCl (1.24 M solution in THF,
2.66 mL, 3.3 mmol) was added dropwise to a solution of ethyl
4-bromobenzoate (0.83 mg, 3.9 mmol) in dry THF (3.5 mL) at
-15 °C under Ar atmosphere. After one hour, the resulting mixture
was stirred for 5 min at 0 °C and then DMF (278 ꢀL, 3.6 mmol)
was added. The obtained mixture was gradually warmed to r.t.
After 3 h at the same temperature, NH2OHꢁHCl (313 mg, 4.5
mmol) and K2CO3 (622 mg, 4.5 mmol) were added and the
obtained mixture was stirred for 20 h at r.t. Then, after removal of
the solvent under reduced pressure, toluene (3.0 mL), DPPA (1.61
mL, 7.5 mmol), and DBU (1.57 mL, 10.5 mmol) were added to
the residue under Ar atmosphere. After being stirred for 22 h
under refluxing conditions, the mixture was cooled to r.t. and then,
saturated NaHCO3 aq. (15.0 mL) was added. After being stirred
for 5 min, the mixture was diluted with water (5.0 mL). The
aqueous layer was washed with AcOEt (25.0 mL) and acidified
with 1.0 M HCl aq. to pH 2. The aqueous layer was extracted with
AcOEt (2 × 25.0 mL). Removal of the solvent, followed by
purification of the residue by short column chromatography on
4.2.6 5-([Biphenyl]-4’-yl)-1H-tetrazole (3H): Yield: 433.4 mg
(65%); yellow solid; Mp: 232-235 °C; IR (neat) 2958 (br), 743
cm-1; 1H NMR (400 MHz, DMSO-d6): δ = 7.42 (t, 1H, J = 7.4 Hz),
7.51 (t, 2H, J = 7.4 Hz), 7.78 (d, 2H, J = 7.4 Hz), 7.92 (d, 2H, J =
8.3 Hz), 8.12 (d, 2H, J = 8.3 Hz); 13C{1H}NMR (100 MHz,
DMSO-d6): δ = 123.1, 126.9 (2C), 127.7 (2C), 127.7 (2C), 128.4,
129.2 (2C), 139.0, 142.8, 155.2; HRMS (ESI) Calcd for C13H11N4
[M+H]+ = 223.0978, Found = 223.0979.
4.2.7 5-(4’-Methoxyphenyl)-1H-tetrazole (3I): Yield: 375.3 mg
(71%); white solid; Mp: 232-234 °C (lit.[13] Mp: 231-233 °C); IR
1
(neat) 2359(br), 1262, 1034, 749, 505 cm-1; H NMR (400 MHz,
DMSO-d6): δ = 3.83(s, 3H), 7.15 (d, 2H, J = 8.8 Hz), 8.00 (d, 2H,
J = 8.8 Hz); 13C{1H}NMR (100 MHz, DMSO-d6): δ = 55.5, 114.9
(2C), 116.3, 128.7 (2C), 154.8, 161.5; HRMS (ESI) Calcd for
C8H9ON4 [M+H]+ = 177.0771, Found = 177.0770.
silica
gel
(AcOEt
:
hexane
=
1:3-1:1)
gave
5-(4’-ethoxycarbonyl)phenyltetrazole 3P (625.8 mg, 96%).
4.2.8 5-(2’-Hydroxyphenyl)-1H-tetrazole (3J): Yield: 311.3 mg
(64%); white solid; Mp: 220-222 °C; IR (neat) 3200~2500 (br),
For isolation of each 5-aryltetrazole, a mixture of AcOEt and
hexane (3:1) was initially used as an eluent for short column
chromatography to remove diphenyl phosphate species. After
that, a mixture of AcOEt and hexane (1:1) was used as an eluent
to isolate 5-aryltetrazole.
1
1068, 745 cm-1; H NMR (400 MHz, DMSO-d6): δ = 7.00 (t, 1H,
J = 7.6 Hz), 7.06 (d, 1H, J = 8.3 Hz), 7.39 (td, 1H, J = 7.6, 1.4
Hz) , 7.98 (dd, 1H, J = 7.6, 1.4 Hz); 13C{1H}NMR (100 MHz,
DMSO-d6): δ = 110.5, 116.4, 119.7, 129.1, 132.7, 151.7, 155.4;

ACCEPTED MANUSCRIPT
Tetrahedron
7
HRMS (ESI) Calcd for C7H7ON4 [M+H]+ = 163.0614, Found =
163.0614.
990, 822, 741 cm-1; 1H NMR (400 MHz, DMSO-d6): δ =
7.63~7.72 (m, 3H), 7.98 (d, 1H, J =8.3 Hz), 8.07~8.10 (m, 1H),
8.19 (d, 1H, J = 8.3 Hz) , 8.53~8.55 (m, 1H); 13C{1H}NMR (100
MHz, DMSO-d6): δ =121.4, 125.1, 125.4, 126.8, 127.8, 128.5,
128.7, 130.0, 131.5, 133.4; HRMS (ESI) Calcd for C11H9N4
[M+H]+ =197.0822, Found =197.0823.
4.2.9 5-(4’-Hydroxyphenyl)-1H-tetrazole (3K): Yield: 262.5 mg
(54%); white solid; Mp: 229-234 °C (lit.[10] Mp: 234-235 °C); IR
(neat) 3200~2500 (br), 1612, 1504, 842 cm-1; 1H NMR (400 MHz,
DMSO-d6): δ = 6.94 (d, 2H, J = 8.8 Hz), 7.85 (d, 2H, J =8.8 Hz),
10.18 (br, 1H); 13C{1H}NMR (100 MHz, DMSO-d6): δ = 114.6,
116.2 (2C), 128.8 (2C), 154.8, 160.1 (2C); HRMS (ESI) Calcd for
C7H5ON4 [M-H]- = 161.0458, Found = 161.0460.
4.2.17 5-(Benzo[b]thiophen-2’-yl)-1H-tetrazole (3S): Yield:
497.4 mg (82%); white solid; Mp: 221-223 °C; IR (neat) 2619
(br), 1594, 945, 753, 722, 555 cm-1; 1H NMR (400 MHz,
DMSO-d6): δ = 7.45~7.52 (m, 2H), 8.01~8.04 (m, 1H), 8.10~8.12
(m, 1H), 8.14 (s, 1H); 13C{1H}NMR (100 MHz, DMSO-d6): δ =
122.9, 125.0, 125.3, 125.7, 125.9, 126.4, 139.1, 139.7; HRMS
(ESI) Calcd for C9H5N4S [M-H]- = 201.0229, Found = 201.0234.
4.2.10
5-[3’,4’-(Methylenedioxy)benzen-1’-yl]-1H-tetrazole
(3L): Yield: 353.7 mg (62%); white solid; Mp: 236-238 °C (lit.[13]
Mp: 250-252 °C); IR (neat) 2613 (br), 1488, 1250, 1086, 926
1
cm-1; H NMR (400 MHz, DMSO-d6): δ = 6.14 (s, 2H), 7.14 (d,
1H, J = 8.1 Hz), 7.51 (d, 2H, J = 1.8 Hz) , 7.57 (dd, 1H, J = 8.1,
1.8 Hz); 13C{1H}NMR (100 MHz, DMSO-d6): δ = 102.0, 106.8,
109.2, 117.7, 121.8, 148.1, 149.7; HRMS (ESI) Calcd for
C8H7O2N4 [M+H]+ = 191.0564, Found = 191.0564.
4.2.18 5-(Benzofuran-2’-yl)-1H-tetrazole (3T): Yield: 307.2 mg
(55%); white solid; Mp: 203-206 °C; IR (neat) 2717 (br), 1634,
990, 1028, 767 cm-1; 1H NMR (400 MHz, DMSO-d6): δ = 7.37 (t,
1H, J = 7.5 Hz), 7.48 (t, 1H, J =7.5 Hz), 7.73 (s, 1H), 7.75 (d, 1H,
J = 9.3 Hz), 7.82 (d, 1H, J = 9.3 Hz); 13C{1H}NMR (100 MHz,
DMSO-d6): δ = 108.8, 111.7, 122.5, 124.1, 126.7, 127.4, 142.0,
4.2.11 5-(4’-Chlorophenyl)-1H-tetrazole (3M): Yield: 379.2 mg
(70%); yellow solid; Mp: 244-245 °C (lit.[13] Mp: 250-252 °C); IR
149.1, 154.8; HRMS (ESI) Calcd for C9H7ON4 [M+H]+
187.0614, Found = 187.0615.
=
1
(neat) 2636 (br), 1434, 828, 742, 504 cm-1; H NMR (400 MHz,
DMSO-d6): δ = 7.69 (d, 2H, J =8.5 Hz), 8.04 (d, 2H, J = 8.5 Hz);
13C{1H}NMR (100 MHz, DMSO-d6): δ = 123.2, 128.8 (2C),
129.6 (2C), 136.0, 154.7; HRMS (ESI) Calcd for C7H6N4Cl
[M+H]+ = 181.0276, Found = 181.0276.
4.2.19 5-(5’-Ethylthiophen-2’-yl)-1H-tetrazole (3U): Yield:
475.8 mg (88%); white solid; Mp: 209-213 °C; IR (neat) 2629
1
(br), 1594, 1519, 812, 739 cm-1; H NMR (400 MHz, DMSO-d6):
δ = 1.27 (t, 3H, J =7.5 Hz), 2.88 (q, 2H, J = 7.5 Hz), 7.01 (d, 1H,
J = 3.9 Hz) , 7.60 (d, 1H, J = 3.9 Hz); 13C{1H}NMR (100 MHz,
DMSO-d6): δ = 15.7, 22.9, 122.5, 125.4, 129.2, 151.1, 151.7;
HRMS (ESI) Calcd for C7H7N4S [M-H]- = 179.0386, Found =
179.0388.
4.2.12 5-(3’-Chlorophenyl)-1H-tetrazole (3N): Yield: 395.5 mg
(73%); white solid; Mp: 141-142 °C (lit.[13] Mp: 138-139 °C); IR
1
(neat) 2656 (br), 1080, 773, 740, 674 cm-1; H NMR (400 MHz,
DMSO-d6): δ = 7.61~7.68 (m, 2H), 7.99 (dt, 1H, J = 6.8, 2.0 Hz) ,
8.05 (d, 1H, J = 2.0 Hz); 13C{1H}NMR (100 MHz, DMSO-d6): δ
=125.8, 126.4, 126.7, 131.2, 131.6, 134.2, 154.9 ; HRMS (ESI)
Calcd for C7H6N4Cl [M+H]+ = 181.0276, Found = 181.0274.
4.2.20 5-(5’-Ethylfuran-2’-yl)-1H-tetrazole (3V): Yield: 330.0
mg (67%); white solid; Mp: 157-158 °C; IR (neat) 2359 (br),
1640, 1568, 1020, 805 cm-1; 1H NMR (400 MHz, DMSO-d6): δ =
1.23 (t, 3H, J =7.5 Hz), 2.74 (q, 2H, J =7.5 Hz), 6.40 (d, 1H, J =
3.4 Hz) , 7.15 (d, 1H, J = 3.4 Hz); 13C{1H}NMR (100 MHz,
DMSO-d6): δ = 11.8, 20.9, 107.3, 114.0, 138.1, 148.0, 160.6;
HRMS (ESI) Calcd for C7H7ON4 [M-H]- = 163.0614, Found =
163.0615.
4.2.13 5-(4’-trifluoromethylphenyl)-1H-tetrazole (3O): Yield:
346.9 mg (54%); white solid; Mp: 211-216 °C (220-222 °C) [13]
;
1
IR (neat) 2473 (br), 1323, 1122, 847 cm-1; H NMR (400 MHz,
DMSO-d6): δ = 7.98 (d, 2H, J = 7.9 Hz), 8.24 (d, 2H, J = 7.9 Hz);
13C{1H}NMR (100 MHz, DMSO-d6): δ =124.0 (d, JC-F = 272.8
Hz), 126.4 (2C), 127.7 (2C, d, JC-F = 3.8 Hz), 128.4, 131.1 (d, JC-F
= 31.5 Hz), 155.2; HRMS (ESI) Calcd for C8H4N4F3 [M-H]-
=213.0383, Found =213.0387.
4.3A Typical Experimental Procedure for Preparation of
Diethyl 3-Arylisoxazole-4,5-dicarboxylates
4
from Aryl
Bromides 1: n-BuLi (1.55 M solution in hexane, 2.32 mL, 3.6
mmol) was added dropwise to a solution of 4-methylphenyl
bromide (513 mg, 3.0 mmol) in THF (6.0 mL) at −50 °C under Ar
atmosphere. After 30 min., DMF (278.0 ꢀL, 3.6 mmol) was added,
and the mixture was gradually warmed to r.t. under Ar atmosphere.
After one hour at the same temperature, NH2OHꢁHCl (312.7 mg,
4.5 mmol) and K2CO3 (621.9 mg, 4.5 mmol) were added and the
obtained mixture was stirred for 2 h at r.t. Then, after removal of
the solvent under reduced pressure, CH3CN (15.0 mL), 1.0 M HCl
aq. (4.0 mL), H2O (11.0 mL), diethyl acetylenedicarboxylate (716
ꢀL, 4.5 mmol), and Oxone® (2.766 g, 4.5 mmol) were added to
the residue at 0 °C. After 3 min, the reaction mixture was stirred
at r.t. for one hour under Ar atmosphere. The resulting mixture
was quenched with sat. aq. Na2S2O3 and then extracted with
AcOEt (3 × 25.0 mL). The organic layer was washed with brine
and dried over Na2SO4. Removal of the solvent, followed by
purification of the residue by short column chromatography on
4.2.14 5-(4’-Ethoxycarbonylphenyl)-1H-tetrazole (3P): Yield:
625.8 mg (96%); white solid; Mp: 158-160 °C; IR (neat) 3157
1
(br), 2800~2200 (br), 1716, 1274, 865, 732 cm-1; H NMR (400
MHz, DMSO-d6): δ = 1.33 (t, 3H, J =7.3 Hz), 4.34 (q, 2H, J =7.3
Hz), 8.13~8.19 (m, 4H); 13C{1H}NMR (100 MHz, DMSO-d6): δ =
14.1, 61.2, 127.2 (2C), 128.5, 130.1 (2C), 131.9, 155.4, 165.0;
HRMS (ESI) Calcd for C10H9O2N4 [M-H]- = 217.0720, Found
=217.0726.
4.2.15 5-(Naphthalen-2’-yl)-1H-tetrazole (3Q): Yield: 365.0 mg
(62%); white solid; Mp: 201-204 °C (lit.[13] Mp: 204-206 °C); IR
1
(neat) 2670 (br), 821, 758 cm-1; H NMR (400 MHz, DMSO-d6):
δ = 7.62 (d, 1H, J = 8.3 Hz), 7.64 (d, 1H, J = 8.3 Hz), 8.01~8.15
(m, 4H), 8.65 (s, 1H); 13C{1H}NMR (100 MHz, DMSO-d6): δ
=121.6, 123.7, 127.0, 127.3, 127.9 (2C), 128.7, 129.2, 132.6,
133.9, 155.6; HRMS (ESI) Calcd for C11H9N4 [M+H]+ =197.0822,
Found =197.0823.
silica gel (hexane
:
AcOEt
=
10:1) gave diethyl
3-(4’-methylphenyl)isoxazole-4,5-dicarboxylate 4a (700.1 mg,
77%).
4.2.16 5-(Naphthalen-1’-yl)-1H-tetrazole (3R): Yield: 241.4 mg
(41%); white solid; Mp: 208-212 °C; IR (neat) 2496 (br), 1504,

ACCEPTED MANUSCRIPT
8
Tetrahedron
4.3.1 Diethyl 3-(4’-methylphenyl)isoxazole-4,5-dicarboxylate
(4A): Yield: 700.1 mg (77%); white solid; Mp: 45-46 °C
4.3.7 Diethyl 3-phenylisoxazole-4,5-dicarboxylate (4G): Yield:
1
(44~46 °C) [8]; IR (neat) 2923, 1737, 1447, 1274, 826 cm-1; H
538.1 mg (62%); colorless oil; IR (neat) 2985, 1733, 1443, 1302,
1
NMR (400 MHz, CDCl3): δ = 1.33 (t, 3H, J = 7.0 Hz), 1.43 (t, 3H,
J = 7.0 Hz), 2.41 (s, 3H), 4.38 (q, 2H, J = 7.0 Hz), 4.47 (q, 2H,
J = 7.0 Hz), 7.27 (d, 2H, J = 8.2 Hz), 7.60 (d, 2H, J = 8.2 Hz);
13C{1H}NMR (100 MHz, CDCl3): δ = 13.6, 13.7, 21.1, 62.1, 62.6,
115.9, 123.9, 127.7 (2C), 129.3 (2C), 140.7, 155.9, 159.1, 160.1,
161.3; HRMS (APCI) Calcd for C16H18O5N (M+H)+ 304.1179,
Found 304.1176.
1273, 1066, 694 cm-1; H NMR (400 MHz, CDCl3): δ = 1.31 (t,
3H, J = 7.3 Hz), 1.43 (t, 3H, J = 7.3 Hz), 4.37 (q, 2H, J = 7.3 Hz),
4.48 (q, 2H, J = 7.3 Hz), 7.45~7.53 (m, 3H), 7.70 (dd, 2H, J = 7.9,
1.4 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 13.8, 14.0, 62.4,
62.8, 116.1, 127.0, 128.1 (2C), 128.8 (2C), 130.6, 156.0, 159.4,
161.1, 161.4; HRMS (APCI) Calcd for C15H16O5N (M+H)+
290.1023, Found 290.1019.
4.3.2 Diethyl 3-(3’-methylphenyl)isoxazole-4,5-dicarboxylate
4.3.8 Diethyl 3-(biphenyl-4’-yl)isoxazole-4,5-dicarboxylate
(4H): Yield: 822.1mg (75%); white solid; Mp: 79-80 °C (lit.[8a]
Mp: 78~79 °C); IR (neat) 2965, 1727, 1283, 1070, 733, 510 cm-1;
1H NMR (400 MHz, CDCl3): δ = 1.35 (t, 3H, J = 7.0 Hz), 1.44 (t,
3H, J = 7.0 Hz), 4.41 (q, 2H, J = 7.0 Hz), 4.49 (q, 2H, J = 7.0
Hz), 7.40 (t, 1H, J = 7.3 Hz), 7.46~7.50 (m, 2H), 7.63 (d, 2H, J =
7.3 Hz), 7.70 (d, 2H, J = 8.6 Hz) , 7.80 (d, 2H, J = 8.6 Hz);
13C{1H}NMR (100 MHz, CDCl3): δ =13.9, 14.0, 62.5, 62.9, 125.8,
127.1 (2C), 127.5 (2C), 127.9, 128.6 (2C), 128.9 (2C), 140.0,
143.4, 156.1, 159.5, 160.9, 161.5; HRMS (APCI) Calcd for
C21H20O5N (M+H)+ 366.1336, Found 366.1335.
(4B): Yield: 564.2 mg (62%); colorless oil; IR (neat) 2984, 1734,
1
1445, 1304, 1069 cm-1; H NMR (400 MHz, CDCl3): δ = 1.32 (t,
3H, J = 7.2 Hz), 1.43 (t, 3H, J = 7.2 Hz), 2.41 (s, 3H), 4.38 (q, 2H,
J = 7.0 Hz), 4.47 (q, 2H, J = 7.0 Hz), 7.31 (d, 1H, J = 7.4 Hz),
7.36 (t, 1H, J = 7.4 Hz) , 7.48 (d, 1H, J = 7.4 Hz) , 7.53 (s, 1H);
13C{1H}NMR (100 MHz, CDCl3): δ = 13.9, 14.0, 21.3, 62.3, 62.8,
116.2, 125.2, 126.9, 128.7, 128.7, 131.4, 138.6, 156.1, 159.3,
161.2, 161.4; HRMS (APCI) Calcd for C16H18O5N (M+H)+
304.1179, Found 304.1177.
4.3.3
Diethyl
3-(3’,4’-dimethylphenyl)isoxazole-
4,5-dicarboxylate (4C): Yield: 742.6 mg (78%); white solid; Mp:
4.3.9 Diethyl 3-(4’-methoxyphenyl)isoxazole-4,5-dicarboxylate
(4I): Yield: 555.6 mg (58%); yellow oil; IR (neat) 2985, 1733,
1610, 1455, 1254, 1066, 753 cm-1; 1H NMR (400 MHz, CDCl3): δ
= 1.33 (t, J = 7.3 Hz, 3H), 1.43 (t, J = 7.3 Hz, 3H), 3.86 (s, 3H),
4.38 (q, J = 7.3 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{1H}NMR (100 MHz,
CDCl3) δ = 13.9, 14.0, 55.3, 62.4, 62.8, 114.2 (2C), 115.9, 119.2,
129.6 (2C), 156.1, 159.2, 160.7, 161.4, 161.6; HRMS (APCI)
Calcd for C16H18O6N (M+H)+ 320.1129, Found 320.1127.
1
43-46 °C; IR (neat) 2991, 1725, 1444, 1290, 1071 cm-1; H NMR
(400 MHz, CDCl3): δ = 1.33 (t, 3H, J = 7.2 Hz), 1.43 (t, 3H, J =
7.2 Hz), 2.31 (s, 3H), 2.31 (s, 3H), 4.38 (q, 2H, J = 7.2 Hz), 4.47
(q, 2H, J = 7.2 Hz), 7.22 (d, 1H, J = 7.9 Hz), 7.41 (d, 1H, J = 7.9
Hz), 7.49 (s, 1H); 13C{1H}NMR (100 MHz, CDCl3): δ = 13.9,
14.0, 19.7, 19.7, 62.3, 62.8, 116.2, 124.3, 125.4, 129.0, 130.0,
137.2, 139.6, 156.1, 159.0, 161.1, 161.6; HRMS (APCI) Calcd for
C17H20O5N (M+H)+ 318.1336, Found 318.1335.
4.3.4
Diethyl
3-(4’-isopropylphenyl)isoxazole-4,5-
4.3.10
Diethyl
3-[3’,4’-(methylenedioxy)benzen-1’-yl]-
dicarboxylate (4D): Yield: 735.6 mg (74%); yellow oil; IR (neat)
isoxazole-4,5-dicarboxylate (4L): Yield: 699.9 mg (70%);
1
2964, 1737, 1450, 1275, 1068, 754 cm-1; H NMR (400 MHz,
yellow solid; Mp: 76-77 °C; IR (neat) 2901, 1741, 1731, 1457,
1
CDCl3): δ = 1.28 (d, 6H, J = 7.0 Hz), 1.33 (t, 3H, J = 7.0 Hz),
1.43 (t, 3H, J = 7.0 Hz), 2.96 (sep, 1H, J = 7.0 Hz), 4.38 (q, 2H, J
= 7.0 Hz), 4.47 (q, 2H, J = 7.0 Hz), 7.32 (d, 2H, J = 8.2 Hz), 7.64
(d, 2H, J = 8.2 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 13.8,
14.0, 23.7 (2C), 34.0, 62.4, 62.8, 116.1, 124.4, 126.9 (2C), 128.1,
151.7, 156.1, 159.2, 161.1, 161.6; HRMS (APCI) Calcd for
C18H22O5N (M+H)+ 332.1492, Found 332.1490.
1288, 1196, 1030, 818 cm-1; H NMR (400 MHz, CDCl3): δ =
1.34 (t, 3H, J = 7.0 Hz), 1.42 (t, 3H, J = 7.0 Hz), 4.39 (q, 2H, J =
7.0 Hz), 4.47 (q, 2H, J = 7.0 Hz), 6.04 (s, 2H), 6.89 (d, 1H, J =
8.6 Hz), 7.19~7.22 (m, 2H); 13C{1H}NMR (100 MHz, CDCl3): δ
= 13.9, 14.0, 62.4, 62.8, 101.6, 108.3, 108.6, 116.0, 120.5, 122.6,
148.1, 149.6, 156.0, 159.3, 160.6, 161.5; HRMS (APCI) Calcd for
C16H16O7N (M+H)+ 334.0921, Found 334.0918.
4.3.5 Diethyl 3-(2’-methylphenyl)isoxazole-4,5-dicarboxylate
4.3.11 Diethyl 3-(4’-chlorophenyl)isoxazole-4,5-dicarboxylate
(4E): Yield: 555.1 mg (61%); colorless oil; IR (neat) 2984, 1733,
(4M): Yield: 485.6 mg (50%); colorless oil; IR (neat) 2985, 1732,
1
1
1463, 1304, 1065, 756 cm-1; H NMR (400 MHz, CDCl3): δ =
1272, 1065, 731 cm-1; H NMR (400 MHz, CDCl3): δ = 1.33 (t,
1.14 (t, 3H, J = 7.2 Hz), 1.44 (t, 3H, J = 7.2 Hz), 2.28 (s, 3H), 4.2
(q, 2H, J = 7.2 Hz), 4.50 (q, 2H, J = 7.2 Hz), 7.24~7.31 (m, 3H),
7.38 (td, 1H, J = 8.2, 1.8 Hz); 13C{1H}NMR (100 MHz, CDCl3):
δ = 13.6, 14.0, 19.9, 61.8, 62.9, 116.4, 125.6, 126.6, 129.6, 130.0,
130.3, 137.3, 156.3, 160.0, 160.3, 162.2; HRMS (APCI) Calcd for
C16H18O5N (M+H)+ 304.1179, Found 304.1178.
3H, J = 7.2 Hz), 1.43 (t, 3H, J = 7.2 Hz), 4.38 (q, 2H, J = 7.2 Hz),
4.48 (q, 2H, J = 7.2 Hz), 7.66 (d, 2H, J = 8.5 Hz), 7.46 (d, 2H, J =
8.5 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 13.8, 14.0, 62.5,
62.9, 115.7, 125.4, 129.1 (2C), 129.5 (2C), 136.9, 156.0, 159.9,
160.2, 161.1; HRMS (APCI) Calcd for C15H15O5NCl(M+H)+
324.0633, Found 324.0628.
4.3.6 Diethyl 3-(biphenyl-2’-yl)isoxazole-4,5-dicarboxylate
4.3.12 Diethyl 3-(3’-chlorophenyl)isoxazole-4,5-dicarboxylate
(4F): Yield: 855.0 mg (78%); yellow oil; IR (neat) 2985, 1731,
(4N): Yield: 466.0 mg (47%); colorless oil; IR (neat) 2984, 1733,
1
1
1456, 1268, 1072, 742, 700 cm-1; H NMR (400 MHz, CDCl3): δ
1300, 1067, 755 cm-1; H NMR (400 MHz, CDCl3): δ = 1.33 (t,
= 1.04 (t, 3H, J = 7.3 Hz), 1.37 (t, 3H, J = 7.3 Hz), 3.93 (q, 2H, J
= 7.3 Hz), 4.40 (q, 2H, J = 7.3 Hz), 7.17~7.21 (m, 2H), 7.27~7.31
(m, 3H), 7.44~7.48 (m, 2H), 7.54 (d, 1H, J = 7.7 Hz), 7.57 (t, 1H,
J = 7.4 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 13.5, 13.9,
61.6, 62.8, 116.5, 125.6, 127.4 (2C), 128.4 (2C), 129.3 (2C),
130.2, 130.5, 130.6, 139.4, 141.6, 156.1, 159.3, 159.7, 163.3;
HRMS (APCI) Calcd for C21H20O5N (M+H)+ 336.1336, Found
366.1333.
3H, J = 7.0 Hz), 1.44 (t, 3H, J = 7.0 Hz), 4.39 (q, 2H, J = 7.2 Hz),
4.48 (q, 2H, J = 7.0 Hz), 7.41 (t, 1H, J = 7.5 Hz), 7.49 (dt, 1H, J =
7.5, 1.6 Hz) , 7.60 (dt, 1H, J = 7.5, 1.6 Hz) , 7.72 (t, 1H, J = 1.6
Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 13.9, 14.0, 62.6, 63.0,
115.9, 126.4, 128.4, 128.7, 130.1, 130.7, 134.8, 156.0, 160.0,
160.1, 161.0; HRMS (APCI) Calcd for C15H15O5NCl(M+H)+
324.0633, Found 324.0632.

ACCEPTED MANUSCRIPT
Tetrahedron
9
4.3.13
Diethyl
3-(4’-trifluoromethylphenyl)isoxazole-4,5-
dicarboxylate (4O): Yield: 509.9 mg (48%); yellow oil; IR (neat)
2987, 1734, 1324, 1306, 1128, 1061, 848 cm-1; 1H NMR (400
MHz, CDCl3): δ = 1.32 (t, 3H, J = 7.0 Hz), 1.44 (t, 3H, J = 7.0
Hz), 4.38 (q, 2H, J = 7.0 Hz), 4.49 (q, 2H, J = 7.0 Hz), 7.75 (d,
2H, J = 8.2 Hz), 7.85 (d, 2H, J = 8.2 Hz); 13C{1H}NMR (100
MHz, CDCl3): δ = 13.9, 14.0, 62.6, 63.1, 115.7, 123.7 (2C, d, JC-F
= 272.8 Hz), 125.7 (d, JC-F = 3.8 Hz), 128.8 (2C), 130.5, 132.5 (d,
JC-F = 32.4 Hz), 156.0, 160.2, 160.3, 160.9; HRMS (APCI) Calcd
for C16H15F3NO5 (M+H)+ 358.0897, Found 358.0893.
4.3.19
Dimethyl
3-(4’-methylphenyl)isoxazole-4,5-
dicarboxylate (4W): Yield: 578.0 mg (70%); white solid; Mp:
66-68 °C; IR (neat) 2959, 1731, 1448, 1280, 1218, 1068, 820, 806
cm-1; 1H NMR (400 MHz, CDCl3): δ = 3.02 (s, 3H), 3.91 (s, 3H),
4.02 (s, 3H), 7.28 (d, 2H, J = 8.2 Hz), 7.58 (d, 2H, J = 8.2 Hz);
13C{1H}NMR (100 MHz, CDCl3): δ = 21.4, 53.1, 53.3, 116.0,
123.9, 127.9 (2C), 129.6 (2C), 141.0, 156.5, 159.1, 161.2, 161.9;
HRMS (APCI) Calcd for C14H14O5N (M+H)+ 276.0866 Found
276.0863.
4.3.14 Diethyl 3-(4’-(ethoxycarbonyl)phenyl)isoxazole-4,5-
4.3.20 Ethyl 3-(4’-methylphenyl)isoxazole-5-carboxylate (4X):
Yield: 353.8 mg (51%); white solid; Mp: 46-48 °C; IR (neat)
2980, 1729, 1445, 1278, 821, 509 cm-1; 1H NMR (400 MHz,
CDCl3): δ = 1.44 (t, 3H, J = 7.0 Hz), 2.41 (s, 3H), 4.46 (q, 2H, J
= 7.0 Hz), 7.23 (s, 1H), 7.29 (d, 2H, J = 8.2 Hz), 7.73 (d, 2H, J =
8.2 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 14.1, 21.4, 62.2,
107.3, 125.1, 126.7 (2C), 129.7 (2C), 140.8, 156.8, 160.7, 162.8;
HRMS (APCI) Calcd for C13H14O5(M+H)+ 232.0968, Found
232.0969.
dicarboxylate (4P): Yield: 563.7 mg (52%); colorless oil; IR
1
(neat) 2983, 1718, 1270, 1106, 1065 cm-1; H NMR (400 MHz,
CDCl3): δ = 1.32 (t, 3H, J = 7.0 Hz), 1.42 (t, 3H, J = 7.3 Hz),
1.44 (t, 3H, J = 7.3 Hz), 4.38 (q, 2H, J = 7.3 Hz), 4.41 (q, 2H, J =
7.3 Hz), 4.49 (q, 2H, J = 7.0 Hz), 7.78 (d, 2H, J = 8.6 Hz), 8.15
(d, 2H, J = 8.6 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 13.9,
14.0, 14.3, 61.4, 62.6, 63.0, 116.0, 128.3 (2C), 129.9 (2C), 131.1,
132.3, 156.0, 160.0, 160.5, 161.1, 165.8; HRMS (APCI) Calcd for
C18H20O7N (M+H)+ 362.1234, Found 362.1235.
4.3.21 3-(4’-Methylphenyl)-5-phenylisoxazole (4Y): Yield:
4.3.15 Diethyl 3-(naphthalen-2’-yl)isoxazole-4,5-dicarboxylate
310.6 mg (44%); white solid; Mp: 125-128 °C; IR (neat) 2915,
(4Q): Yield: 753.4 mg (74%); yellow oil; IR (neat) 2984, 1733,
1
1445, 813, 761, 688, 528 cm-1; H NMR (400 MHz, CDCl3): δ =
1
1300, 1272, 748 cm-1; H NMR (400 MHz, CDCl3): δ = 1.33 (t,
2.42 (s, 3H), 6.82 (s, 1H), 7.29 (d, 2H, J = 8.1 Hz), 7.43~7.52 (m,
3H), 7.77 (d, 2H, J = 8.1 Hz), 7.84 (d, 2H, J = 7.0 Hz);
13C{1H}NMR (100 MHz, CDCl3): δ = 21.4, 97.4, 125.8 (2C),
126.2, 126.7 (2C), 127.5, 129.0 (2C), 129.6 (2C), 130.1, 140.1,
162.9, 170.2; HRMS (APCI) Calcd for C16H14ON (M+H)+
236.1070, Found 236.1070.
3H, J = 7.0 Hz), 1.45 (t, 3H, J = 7.0 Hz), 4.40 (q, 2H, J = 7.0 Hz),
4.50 (q, 2H, J = 7.0 Hz), 7.52~7.59 (m, 2H), 7.80 (dd, 1H, J = 8.6,
1.8 Hz), 7.88~7.92 (m, 2H), 7.94 (d, 1H, J = 8.6 Hz), 8.2 (s, 1H);
13C{1H}NMR (100 MHz, CDCl3): δ = 13.9, 14.0, 62.5, 62.9,
116.3, 124.3, 124.8, 126.8, 127.5, 127.8, 128.4, 128.6, 128.7,
132.9, 134.1, 156.1, 159.5, 161.2, 161.5; HRMS (APCI) Calcd for
C19H18O5N (M+H)+ 340.1179, Found 340.1177.
Supporting Information: Copies of 1H NMR and 13C NMR
spectra of all 5-aryltetrazoles 3 and 3-arylisoxazoles 4.
4.3.16 Diethyl 3-(naphthalen-1’-yl)isoxazole-4,5-dicarboxylate
(4R): Yield: 855.2 mg (84%); colorless oil; IR (neat) 2983, 1732,
1
1300, 1095, 776 cm-1; H NMR (400 MHz, CDCl3): δ = 0.85 (t,
Acknowledgements
Financial support in the form of a Grant-in–Aid for Scientific
Research (No. 18K05118) from the Ministry of Education,
Culture, Sports, Science, and Technology in Japan is gratefully
acknowledged.
3H, J = 7.3 Hz), 1.46 (t, 3H, J = 7.3 Hz), 4.04 (q, 2H, J = 7.3 Hz),
4.53 (q, 2H, J = 7.3 Hz), 7.48-7.61 (m, 4H), 7.79 (d, 1H, J = 7.7
Hz), 7.92 (d, 1H, J = 7.7 Hz), 7.99 (d, 1H, J = 8.2 Hz);
13C{1H}NMR (100 MHz, CDCl3): δ = 13.3, 14.0, 61.8, 63.0,
117.2, 124.5, 124.8, 124.9, 126.3, 127.0, 128.2, 128.4, 130.6,
133.4, 133.3, 156.3, 160.1, 160.2, 161.5; HRMS (APCI) Calcd for
C19H18O5N (M+H)+ 340.1179, Found 340.1177.
References and notes
4.3.17
Diethyl
3-(benzo[b]thiophen-2’-yl)isoxazole-4,5-
1
Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor,
R. J. K. “Comprehensive Heterocyclic Chemistry III”,
Elsevier, 2008.
dicarboxylate (4S): Yield: 424.8 mg (41%); red solid; Mp:
115-120 °C; IR (neat) 2953, 1731, 1286, 1198, 749 cm-1; 1H NMR
(400 MHz, CDCl3): δ = 1.41 (t, 3H, J = 7.3 Hz), 1.44 (t, 3H, J =
7.3 Hz), 4.48 (q, 2H, J = 7.3 Hz), 4.49 (q, 2H, J = 7.3 Hz),
7.38~7.45 (m, 2H), 7.84~7.89 (m, 2H), 7.93 (s, 1H);
13C{1H}NMR (100 MHz, CDCl3): δ = 13.9, 14.0, 62.7, 63.1,
115.2, 122.3, 124.7, 124.9, 126.2, 127.0, 127.7, 139.2, 140.4,
156.0, 156.1, 160.2, 161.2; HRMS (APCI) Calcd for C17H16O5NS
(M+H)+ 346.0744, Found 346.0741.
2
Tetrazoles: (a) Ostrovskii, V. A.; Koldobskii, G. I.; Trifonov,
R. E. “Other Five-membered Rings with Three or more
Heteroatoms, and their Fused Carbocyclic Derivatives”,
p.257-p.423, Chap. 6.07, Vol. 6, Eds. Katritzky, A. R.;
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(4T): Yield: 444.6 mg (45%); yellow solid; Mp: 67-70 °C; IR
(neat) 2985, 1734, 1288, 1191, 720 cm-1; H NMR (400 MHz,
1
CDCl3): δ = 1.42 (t, 3H, J = 7.3 Hz), 1.45 (t, 3H, J = 7.3 Hz),
4.49 (q, 2H, J = 7.3 Hz), 4.49 (q, 2H, J = 7.3 Hz), 7.31 (t, 1H, J =
7.0 Hz), 7.41 (t, 1H, J = 7.0 Hz), 7.51 (s, 1H), 7.56 (d, 1H, J = 7.9
Hz), 7.67 (d, 1H, J = 7.9 Hz); 13C{1H}NMR (100 MHz, CDCl3):
δ = 14.0 (2C), 62.6, 63.1, 109.9, 111.8, 115.1, 122.1, 123.7, 126.5,
127.5, 143.0, 153.0, 155.2, 155.8, 159.8, 160.7; HRMS (APCI)
Calcd for C17H16O6N (M+H)+ 330.0972, Found 330.0970.

ACCEPTED MANUSCRIPT
10
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Tetrahedron
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