Synthesis of 2,1-benzisoxazoles by nucleophilic substitution of hydrogen in nitroarenes activated by the azole ring

Article abstract of DOI:10.1055/s-0029-1216875

Reaction of 1-nitro-4-(1,2,3-triazolyl/tetrazolyl)benzenes with arylacetonitriles in an alcoholic medium in the presence of excess alkali gives novel 2,1-benzisoxazoles. These findings indicate a high reactivity of nitroarenes activated by the azole ring due to their electron-deficient character. Moreover, it was found that annulation of the isoxazole ring occurred regioselectively in disubstituted nitroarenes. In the case of 1-(4-nitrophenyl)-1H-tetrazole, the tetrazole ring cleaved faster than the sH-adduct was formed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216875

PAPER
2741
Synthesis of 2,1-Benzisoxazoles by Nucleophilic Substitution of Hydrogen in
Nitroarenes Activated by the Azole Ring
5
-(Tetrazol-1-yl/1,
a
2,3-triazol-
z
1-yl)-Subst
a
ituted3-Ar
r
yl-2,1-be
i
nzisox
y
a
zoles T. Pokhodylo,* Yuriy O. Teslenko, Vasyl S. Matiychuk, Mykola D. Obushak
Department of Organic Chemistry, Ivan Franko National University of Lviv, Kyryla i Mefodiya St. 6, Lviv 79005, Ukraine
Fax +38(32)2971668; E-mail: pokhodylo@gmail.com
Received 15 April 2009; revised 23 April 2009
O–
OH–
O
CN–
Abstract: Reaction of 1-nitro-4-(1,2,3-triazolyl/tetrazolyl)ben-
zenes with arylacetonitriles in an alcoholic medium in the presence
of excess alkali gives novel 2,1-benzisoxazoles. These findings in-
dicate a high reactivity of nitroarenes activated by the azole ring due
to their electron-deficient character. Moreover, it was found that an-
nulation of the isoxazole ring occurred regioselectively in disubsti-
tuted nitroarenes. In the case of 1-(4-nitrophenyl)-1H-tetrazole, the
tetrazole ring cleaved faster than the sH-adduct was formed.
N+
OH–
H2O
N
N
O–
Ar
N
O–
Ar
O
Ar
H
H
H
Ar
CN
CN
CN
Scheme 1 Mechanism of the isoxazole ring annulation in nitroaro-
matic substrates
Key words: 1H-1,2,3-triazole, tetrazole, nucleophilic substitution,
2,1-benzisoxazole, annulation
drawing substituents in the ring, such as the nitro group.
Electron-donor substituents do not generally allow the re-
action to proceed.4–7
Compounds containing an aromatic or heterocyclic ring in
the para-position to the nitro group have been insuffi-
ciently studied for 2,1-benzisoxazole synthesis. For
example, reaction of 2-(4-nitrophenyl)-5-phenyl-1,3,4-
oxadiazole with phenylacetonitrile gave 3-phenyl-5-(5-
phenyl-1,3,4-oxadiazol-2-yl)-2,1-benzisoxazole in 80%
yield. However, 4-nitrobiphenyl in such a reaction gave
3,5-diphenyl-2,1-benzisoxazole in only 44% yield.5,6
One of the most convenient methods for the synthesis of
2,1-benzisoxazoles (reagents for bioactive substances1), is
the reaction of nitroarenes with arylacetonitriles under
conditions found by Davis.2 The mechanism of the reac-
tion is a nucleophilic aromatic substitution (SNAr).3 It is
noteworthy, that SNAr reactions of hydrogen occur rarely
in contrast to SEAr reactions, because of the fact that the
hydride ion has a small electronegativity and is unfavor-
able in reactions as a nucleofuge. In addition, the hydride
ion, which does not form hydrogen bonds and solvates, is
not fixed as a kinetically independent particle in the reac-
tions of organic compounds.
Probably, the most general transformation of sH-adducts
into products of nucleophilic substitution of hydrogen oc-
curs when the reacting nucleophiles contain a leaving
group X at the nucleophilic center (b-elimination of HX
gives anionic products, which give products of hydrogen
replacement with the nucleophile moiety via protonation).
In contrast, anionic sH-adducts, formed by addition of nu-
cleophiles to the aromatic ring, undergo oxidation with
external or internal oxidants.3
In the current work, nitroarenes, activated by the azole
(tetrazole or triazole) ring, were selected for the synthesis
of 2,1-benzisoxazoles. The starting nitroarenes were syn-
thesized from commercially available 4-nitroanilines 1a–c
by several procedures (Scheme 2). Some new 1H-1,2,3-
triazol-4-yl ketones 4a,b and 1H-1,2,3-triazole-4-carbox-
ylic acids 4c–k were synthesized by base-catalyzed cyclo-
condensation of aryl azides 2a–c (prepared from sodium
azide and diazonium salts obtained from anilines 1a–c)
with b-diketones 3a,b and b-keto esters 3c–i according to
the procedure described in the literature.8 By decarboxy-
lation of acids 4c,k at temperatures 20 °C higher than their
melting points, 1H-1,2,3-triazoles 5a,b were obtained.8
The reaction required strict control of the temperature;
rapid decomposition of the triazole ring occurred when
the reaction was overheated.
Herein, we describe the reactions of arylacetonitriles with
para-substituted nitrobenzenes by elimination of water in
the sH-adducts to produce nitroso compounds, and subse-
quent cyclization with elimination of hydrogen cyanide to
form 2,1-benzisoxazoles (Scheme 1). It is known, that
such reactions are sensitive to electronic effects of substit-
uents in the aromatic ring. The addition of nucleophilic
agents to the aromatic ring occurs more effectively in the
case of electron-deficient character of the ring. It can be
possible due to the presence of strongly electron-with-
1-(4-Nitrophenyl)-1H-tetrazole (6) was synthesized by
the reaction of 4-nitroaniline (1a) with triethyl orthofor-
mate and sodium azide in acetic acid.9 1H-Tetrazoles 7a–c
were prepared by a two-step procedure: anilines 1a were
acylated by acid chlorides, the obtained acylanilides were
converted into imidoyl chlorides by phosphorus oxychlo-
ride and then one-pot reaction with sodium azide gave the
tetrazole ring. We have found that this reaction gave 5-
substituted tetrazoles 7a–c in 67–84% isolated yield.
SYNTHESIS 2009, No. 16, pp 2741–2748
x
x.
x
x
.
2
0
0
9
2-(4-Nitrophenyl)-2H-tetrazole-5-carboxylic acid (9), as
a type of 2,5-disubstituted tetrazole, was synthesized by
the Boulton–Katritzky rearrangement10 of 3-triazenoisox-
Advanced online publication: 26.06.2009
DOI: 10.1055/s-0029-1216875; Art ID: Z07409SS
© Georg Thieme Verlag Stuttgart · New York

2742
N. T. Pokhodylo et al.
PAPER
R1
R2
N
R1
H
N
COOH
N
NH2
N
N
N
N
d) for 6
N
f)
g)
h)
N
Me
N
NO2
N
N
O
e) for 7a–c
NO2
NO2
NO2
1a–c
8
9
6, 7a–c
6 R1 = R2 =H
7a R1 = H, R2 = Me
a)
7b R1 = H, R2 = (CH2)3Cl
7c R1 = OMe, R2 = Me
O
O
O
N
N
N
R1
N
R1
R3
R2
R3
R1
N3
1a, 2a R1 = H
1b, 2b R1 = Me
1c, 2c R1 = OMe
N
N
Δ
3
R2
R2
c)
NO2
b)
NO2
2a–c
NO2
4a–l
5a,b
4a R1 = H, R2 = R3 = Me
4b R1 = H, R2 = R3 = t-Bu
4c R1 = H, R2 = Me, R3 = OH
4d R1 = H, R2 = Et, R3 = OH
4e R1 = H, R2 = Pr, R3 = OH
4f R1 = H, R2 = i-Pr, R3 = OH
4g R1 = H, R2 = Bu, R3 = OH
5a R1 = H, R2 = Me
5b R1 = H, R2 = Ph
4j R1 = Me, R2 = Me, R3 = OH
4k R1 = OMe, R2 = Me, R3 = OH
4l R1 = H, R2 = Ph, R3 = OH
4i R1 = H, R2 = CH2OMe, R3 = OH
Scheme 2 Reagents and conditions: (a) NaNO2, HCl, then NaN3, 0 °C; (b) Na, MeOH, r.t., 1 d (for 4a), 61%; 65 °C, 1 h (for 4b–k), 54–94%;
(c) 20 °C above mp, 10 min, 85–91%; (d) CH(OEt)3, NaN3, AcOH, 100 °C, 4 h; (e) 1. R2COCl, dioxane, Et3N, r.t., 1 h; 2. POCl3, NaN3, MeCN,
100 °C, 4 h, 67–84%; (f) NaNO2, HCl, then 5-methylisoxazol-3-amine, NaOAc, H2O, r.t., 1 h; (g) NH3, acetone, 56 °C, 5 min; (h) KMnO4,
68% (from 1a).
Table 1 2,1-Benzisoxazoles 11a–n
N
R1
X
N
N
N
X
N
R2
NaOH
EtOH
N
N
+
R2
R1
O
NO2
N
10a–d
4a–k, 5a,b
11a–n
56–93%
10a R1 = H
10b R1 = F
10c R1 = Cl
10d R1 = Br
X = H, COOH, COt-Bu
Entry
1
Product
11a
11b
11c
X
H
H
H
R1
R2
Yielda (%)
H
Cl
H
H
H
H
F
Me
Me
Ph
70
84
88
2
3
b
4
11d
11e
COMe
COt-Bu
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
Me
t-Bu
Me
Me
Me
Me
Et
–
5
87
91
84
93
90
88
73
70
69
56
6
11f
7
11g
11h
11i
8
Cl
Br
H
H
H
H
H
9
10
11
12
13
14
11j
11k
11l
Pr
i-Pr
Bu
11m
11n
CH2OMe
a Isolated yields are based on a single experiment and yields were not optimized.
b Mixture of products.
Synthesis 2009, No. 16, 2741–2748 © Thieme Stuttgart · New York

PAPER
5-(Tetrazol-1-yl/1,2,3-triazol-1-yl)-Substituted 3-Aryl-2,1-benzisoxazoles
2743
Table 2 2,1-Benzisoxazoles 12a–d
azole 8 and oxidation of the acetone fragment to the cor-
responding acid by the action of potassium permanganate.
Entry
Product
12a
R1
H
R2
Yielda (%)
We found that the reaction of 4-nitroarenes 4, 5 with aryl-
acetonitriles 10a–d in ethanol in the presence of excess
sodium hydroxide formed compounds 11a–n in good
yield (Table 1). Formation of byproducts was not ob-
served. Moreover, the reaction occurred with sterically
shielded ketone 4b. However, the ketone 4a gave a mix-
ture of products.
1
2
3
4
Me
87
84
91
74
12b
Me
Cl
H
Me
12c
Me
12d
(CH2)3Cl
a Isolated yields.
In the reaction of 1,5-disubstituted 1H-tetrazoles 7a–c
with arylacetonitriles 10a,c,e, 2,1-benzisoxazoles 12a–d
were obtained as the main products. The reaction was car-
ried out using a methanolic potassium hydroxide solution
(Scheme 3); it exhibited an appreciable exothermal effect
and was complete within 5–10 min. In general, the prod-
uct of the reaction formed immediately after mixing the
reagents. The polycyclic compounds 12a–d were isolated
in good yields (74–91%) (Table 2). High yields were pos-
sible due to the presence of strongly electron-withdrawing
substituents in the arene ring, such as the electron-defi-
cient tetrazole ring. However, 1-(4-nitrophenyl)-1H-tetra-
zole (6) did not react with arylacetonitriles 10 to yield 2,1-
benzisoxazoles. It was found that under the reaction con-
ditions the tetrazole ring cleaved and lost a molecule of
nitrogen. The product of the reaction was (4-nitrophe-
nyl)cyanamide (13). Obviously, the cyanamide group was
formed faster than the nucleophile attacked the aryl ring
and formed the sH-adduct. In fact, the change of the char-
acter of substituents and the electronic configuration of
the ring made subsequent transformation impossible. We
were unsuccessful in our attempts to annulate the isox-
azole ring in the reaction of (4-nitrophenyl)cyanamide
(13) with phenylacetonitrile.
COOH
N
R1
N
N
N
COOH
N
N
N
N
N
NaOH
EtOH
+
O
N
R1
O2N
14a R1 = H 88%
14b R1 = Cl 90%
9
10a,c
Scheme 4
The structures of all new compounds were confirmed by
analytical and spectroscopic data. In the 1H NMR spectra
of 2,1-benzisoxazoles 11a–n, 12a–d, 14a,b there was a
large difference in chemical shift values for the H4, H6,
and H7 protons which is typical for the 2,1-benzisoxazole
system.11 Spin-spin coupling constant values between the
H6 and H7 protons were J = 9.2, 9.6 Hz. It is important to
emphasize that the chemical shift value for the H4 proton,
found in a low field, increased according to the I-effect of
the heterocycle in the position 3 of the aryl ring in order:
2H-tetrazole, 1H-tetrazole, and 1H-1,2,3-triazole deriva-
tives correspondingly.
N
N
In addition, it is necessary to point out that the reaction of
nucleophiles with asymmetric arenes occurred regioselec-
tively. It was found that in the reaction of 4-nitroarenes
4i,j, 7c with phenylacetonitrile only one of two possible
isomers (11o,p, 12e) was isolated (Table 3). The phenyl-
acetonitrile carbanion attacked the aryl ring in the para-
position to an electron-donor methyl or methoxy group. In
fact, electron-donor substituents had a negative influence
on the rate of the reaction. Thus, the less sterically hin-
dered position (with a low electron density) was prefera-
ble for the nucleophilic attack. Therefore, we have
presumed that regioselectivity can be achieved in similar
reactions of 2,1-benzisoxazole synthesis. The formation
of regioisomeric mixtures was excluded by the NMR
N
N
N
(when R2 = H)
R2
(when R2 = Me)
+
KOH
KOH
MeOH
MeOH
NO2
6, 7a,b
R1
74–91%
10a,c,e
R1
NHCN
N
N
N
N
O2N
R2
13
O
N
12a–d
1
spectral data. In H NMR spectroscopic data there were
two singlet signals at d = 7.2–7.8 and d = 8.1–8.6 of the
H7 and H4 protons of 2,1-benzisoxazoles.
Scheme 3
Furthermore, we have subsequently obtained 2,1-benz-
isoxazoles 14a,b in the highest yields (88–90%) from the
reaction of 2H-tetrazole 9 with arylacetonitriles 10a,c
(Scheme 4). It cannot be validly argued that the tetrazole
ring is suitable in such reactions due to a strong I-effect of
the ring, mostly exhibited in 2-substituted 2H-tetrazoles.
In conclusion, this method is very effective and allows the
preparation of 5-(tetrazolyl/1H-1,2,3-triazolyl)-2,1-benz-
isoxazoles under mild reaction conditions and with good
yields and regioselectivity. Moreover, the reaction dis-
plays an approach to the study of tetrazole and 1H-1,2,3-
triazole properties as substituents in the aromatic ring.
Synthesis 2009, No. 16, 2741–2748 © Thieme Stuttgart · New York

2744
N. T. Pokhodylo et al.
PAPER
1H NMR (DMSO-d6): d = 1.21 (s, 9 H, t-Bu), 1.38 (s, 9 H, t-Bu),
Table 3 2,1-Benzisoxazoles 11o,p, 12e
3
7.86 (d, J = 8.8 Hz, 2 H, H3Ar, H5Ar), 8.45 (d, J = 8.8 Hz, 2 H,
3
N
Y
H2Ar, H6Ar).
N
X
R1
MS (CI): m/z (%) = 331 (100) [M + H+].
N
N
+
Anal. Calcd for C17H22N4O3 (330.38): C, 61.80; H, 6.71; N, 16.96.
Found: C, 61.92; H, 6.67; N, 16.85.
10a
NO2
4j,k and 7c
5-Substituted 1-Aryl-1H-1,2,3-triazole-4-carboxylic Acids
4c–k; General Procedure
KOH
61–67%
MeOH
Na (0.23 g, 10 mmol) was added to abs MeOH (20 mL). b-Keto es-
ter 3 (10 mmol) and the appropriate azide 2 (10 mmol) were slowly
added (cooling with ice-water) to the obtained NaOMe soln. The
mixture was kept in an ice-water bath for 30 min and then slowly
heated under reflux for 1 h; the solid precipitated. Hot H2O was add-
ed to dissolve the precipitate (50 mL), if necessary the soln of
NaOH can be adjusted to pH 11–12 and heated under reflux for 1 h.
The hot soln was poured into concd HCl (10 mL) and left crystal-
lized. The obtained solid was filtered, washed with H2O (2 ×), and
crystallized (EtOH).
Y
N
X
N
R1
N
N
X
Y
N
+
N
O
N
O
R1
N
11p,r and 12e
Product
11o
not isolated
R1
Entry
X–Y
Yielda (%)
5-Methyl-1-(4-nitrophenyl)-1H-1,2,3-triazole-4-carboxylic
Acid (4c)
White crystals; yield: 1.66 g (67%); mp 190–191 °C (Lit.8 188–189
°C).
1
2
3
C–CO2H
C–CO2H
N
Me
67
61
65
11p
OMe
OMe
MS (CI): m/z (%) = 249 (100) [M + H+].
12e
a Isolated yields.
5-Ethyl-1-(4-nitrophenyl)-1H-1,2,3-triazole-4-carboxylic Acid
(4d)
White crystals; yield: 2.22 g (85%); mp 180–181 °C.
Further investigations on other azoles are in progress in
our laboratory.
3
1H NMR (DMSO-d6): d = 1.11 (t, J = 7.2 Hz, 3 H, Et), 3.02 (q,
3J = 7.2 Hz, 2 H, Et), 7.91 (d, 3J = 8.8 Hz, 2 H, H2Ar, H6Ar), 8.48 (d,
3J = 8.8 Hz, 2 H, H3Ar, H5Ar).
All melting points were determined in capillary tubes in a Thiele ap-
1
paratus and are uncorrected. H NMR spectra were recorded on a
MS (CI): m/z (%) = 263 (100) [M + H+].
1
Varian Mercury 400 instrument (400 MHz for H) with TMS or
Anal. Calcd for C11H10N4O4 (262.22): C, 50.38; H, 3.84; N, 21.37.
Found: C, 50.24; H, 3.72; N, 21.41.
deuterated solvent as an internal reference. Mass spectra were run
using Agilent 1100 series LC/MSD with an API-ES/APCI ioniza-
tion mode. The evolution of the reactions and purity of the synthe-
sized compounds were monitored chromatographically on Silufol
UV-254 plates. Aryl azides 2a–c were prepared from commercially
available 4-nitroanilines 1a–c according to the procedures de-
scribed in the literature.12 We used the following abbreviations in
NMR spectra presentation: Bis = 2,1-benzisoxazole, Tr = triazole.
1-(4-Nitrophenyl)-5-propyl-1H-1,2,3-triazole-4-carboxylicAcid
(4e)
White crystals; yield: 2.29 g (83%); mp 175–176 °C.
1H NMR (DMSO-d6): d = 0.82 (t, 3J = 7.2 Hz, 3 H, Pr), 1.43–1.51
(m, 2 H, Pr), 3.00 (t, 3J = 7.6 Hz, 2 H, Pr), 7.91 (d, 3J = 8.8 Hz, 2 H,
H2Ar, H6Ar), 8.48 (d, 3J = 8.8 Hz, 2 H, H3Ar, H5Ar).
MS (CI): m/z (%) = 277 (100) [M + H+].
1-[5-Methyl-1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl]ethanone
(4a)
Anal. Calcd for C12H12N4O4 (276.25): C, 52.17; H, 4.38; N, 20.28.
Found: C, 51.97; H, 4.54; N, 20.39.
To a soln of NaOMe (540 mg, 10.0 mmol) in anhyd MeOH (20 mL)
was added pentane-2,4-dione (3a, 1 mL, 10.0 mmol). To this soln
1-azido-4-nitrobenzene (2a, 1.6 g, 10.0 mmol) in anhyd MeOH
(2 mL) was added dropwise. The mixture was stirred at r.t. for 24 h.
The resulting suspension was filtered and the solid product was
washed with H2O and MeOH to give 4a as light yellow crystals;
yield: 1.50 g (61%); mp 132–133 °C (Lit.13 133–134 °C).
5-Isopropyl-1-(4-nitrophenyl)-1H-1,2,3-triazole-4-carboxylic
Acid (4f)
White crystals; yield: 1.49 g (54%); mp 164–165 °C;
1H NMR (DMSO-d6): d = 1.29 (d, 3J = 7.2 Hz, 6 H, i-Pr), 3.26 (m,
1 H, i-Pr), 7.92 (d, 3J = 8.8 Hz, 2 H, H2Ar, H6Ar), 8.48 (d, 3J = 8.8
Hz, 2 H, H3Ar, H5Ar).
MS (CI): m/z (%) = 247 (100) [M + H+].
MS (CI): m/z (%) = 277 (100) [M + H+].
1-[5-tert-Butyl-1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl]-2,2-
dimethylpropan-1-one (4b)
Anal. Calcd for C12H12N4O4 (276.25): C, 52.17; H, 4.38; N, 20.28.
Found: C, 52.02; H, 4.28; N, 20.17.
To the soln of NaOMe (540 mg, 10.0 mmol) in anhyd MeOH (20
mL) was added 2,2,6,6-tetramethylheptane-3,5-dione (2.1 mL, 10.0
mmol) and 1-azido-4-nitrobenzene (2a, 1.6 g, 10.0 mmol). The
mixture was kept in an ice-water bath for 30 min and then slowly
heated under reflux for 1 h. The mixture was cooled and the solid
started to precipitate. The solid product was filtered and washed
with H2O and MeOH to give 4b as white crystals; yield: 3.10 g
(94%), mp 135–136 °C.
5-Butyl-1-(4-nitrophenyl)-1H-1,2,3-triazole-4-carboxylic Acid
(4g)
White crystals; yield: 1.62 g (56%); mp 158–159 °C.
1H NMR (DMSO-d6): d = 0.81 (t, 3J = 7.6 Hz, 3 H, Me), 1.22 (m, 2
H, CH2), 1.43 (m, 2 H, CH2), 3.03 (t, 3J = 7.6 Hz, 2 H, CH2), 7.92
Synthesis 2009, No. 16, 2741–2748 © Thieme Stuttgart · New York

PAPER
5-(Tetrazol-1-yl/1,2,3-triazol-1-yl)-Substituted 3-Aryl-2,1-benzisoxazoles
2745
MS (CI): m/z (%) = 367 (100) [M + H+].
3
(d, J = 8.8 Hz, 2 H, H2Ar, H6Ar), 8.49 (d, J = 8.8 Hz, 2 H, H3Ar,
3
H5Ar).
Anal. Calcd for C14H10N4O2 (266.25): C, 63.15; H, 3.79; N, 21.04.
Found: C, 63.28; H, 3.62; N, 21.17.
MS (CI): m/z (%) = 291 (100) [M + H+].
Anal. Calcd for C13H14N4O4 (290.27): C, 53.79; H, 4.86; N, 19.30.
Found: C, 53.84; H, 4.93; N, 19.15.
1-(4-Nitrophenyl)-1H-tetrazole (6)
Prepared according to the procedure described previously in the lit-
erature.9
5-(Methoxymethyl)-1-(4-nitrophenyl)-1H-1,2,3-triazole-4-car-
boxylic Acid (4h)
White crystals; yield: 1.81 g (65%); mp 161–162 °C.
5-Substituted 1-(4-Nitrophenyl)-1H-tetrazoles 7a–c; General
Procedure
1H NMR (DMSO-d6): d = 3.31 (s, 3 H, Me), 4.85 (s, 2 H, CH2), 8.03
The 4-nitroaniline 1 (0.1 mol) was dissolved in dioxane and Et3N (7
mL, 0.1 mol) was added. The mixture was cooled to 0 °C and the
corresponding acyl chloride (0.025 mol) was added keeping the
temperature below 5 °C. The soln was left at r.t. for 1 h and H2O (50
mL) was then added. The obtained solid was filtered, washed with
H2O (2 ×), crystallized (EtOH), and dried in vacuo.
3
(d, J = 8.8 Hz, 2 H, H2Ar, H6Ar), 8.47 (d, J = 8.8 Hz, 2 H, H3Ar,
3
H5Ar).
MS (CI): m/z (%) = 279 (100) [M + H+].
Anal. Calcd for C11H10N4O5 (278.22): C, 47.49; H, 3.62; N, 20.14.
Found: C, 47.76; H, 3.44; N, 20.36.
A mixture of acylaniline (0.02 mol) with NaN3 (2.6 g, 0.04 mol) and
POCl3 (15.4 g, 0.1 mol) in MeCN (200 mL) was stirred under reflux
for 10 h. The solvent and excess POCl3 were removed under re-
duced pressure. The residue was cooled, neutralized with sat.
NaHCO3 soln, and evaporated to dryness. Compounds 7a–e were
crystallized (EtOH).
5-Methyl-1-(2-methyl-4-nitrophenyl)-1H-1,2,3-triazole-4-car-
boxylic Acid (4i)
White crystals; yield: 1.94 g (74%); mp 183–184 °C;
1H NMR (DMSO-d6): d = 2.07 (s, 3 H, Me), 2.46 (s, 3 H, Me), 7.93
(d, 3J = 8.8 Hz, 1 H, H6Ar), 8.23 (s, 1 H, H3Ar), 8.48 (d, 3J = 8.8 Hz,
1 H, H5Ar).
5-Methyl-1-(4-nitrophenyl)-1H-tetrazole (7a)
White crystals; yield: 3.46 g (84%); mp 107–108 °C.
MS (CI): m/z (%) = 263 (100) [M + H+].
1H NMR (DMSO-d6): d = 2.66 (s, 3 H, CH3), 8.01 (d, 3J = 8.8 Hz,
2 H, H2Ar, H6Ar), 8.47 (d, 3J = 8.8 Hz, 2 H, H3Ar, H5Ar).
Anal. Calcd for C11H10N4O4 (262.22): C, 50.38; H, 3.84; N, 21.37.
Found: C, 50.61; H, 3.67; N, 21.55.
MS (CI): m/z (%) = 206 (100) [M + H+].
1-(2-Methoxy-4-nitrophenyl)-5-methyl-1H-1,2,3-triazole-4-car-
boxylic Acid (4j)
White crystals; yield: 1.92 g (69%); mp 160–161 °C.
Anal. Calcd for C8H7N5O2 (205.17): C, 46.83; H, 3.44; N, 34.13.
Found: C, 46.66; H, 3.60; N, 34.04.
1H NMR (DMSO-d6): d = 2.43 (s, 3 H, Me), 3.91 (s, 3 H, OMe),
7.76 (d, 3J = 8.8 Hz, 1 H, H6Ar), 8.38 (s, 1 H, H3Ar), 8.48 (d, 3J = 8.8
Hz, 1 H, H5Ar).
5-(3-Chloropropyl)-1-(4-nitrophenyl)-1H-tetrazole (7b)
White crystals; yield: 3.58 g (67%); mp 80–81 °C.
1H NMR (DMSO-d6): d = 2.24 (m, 2 H, CH2), 3.10 (t, 3J = 7.2 Hz,
2 H, CH2), 3.69 (t, 3J = 7.2 Hz, 2 H, CH2), 7.98 (d, 3J = 8.8 Hz, 2 H,
H2Ar, H6Ar), 8.45 (d, 3J = 8.8 Hz, 2 H, H3Ar, H5Ar).
MS (CI): m/z (%) = 279 (100) [M + H+].
Anal. Calcd for C11H10N4O5 (278.22): C, 47.49; H, 3.62; N, 20.14.
Found: C, 47.56; H, 3.38; N, 20.06.
MS (CI): m/z (%) = 268 (100) [M + H+].
Anal. Calcd for C10H10ClN5O2 (267.67): C, 44.87; H, 3.77; N,
26.16. Found: C, 44.72; H, 3.49; N, 26.21.
1-(4-Nitrophenyl)-5-phenyl-1H-1,2,3-triazole-4-carboxylic
Acid (4k)
White crystals; yield: 2.82 g (91%); mp 182–183 °C.
1-(2-Methoxy-4-nitrophenyl)-5-methyl-1H-tetrazole (7c)
White crystals; yield: 3.52 g (75%); mp 138–139 °C;
1H NMR (DMSO-d6): 7.34–7.43 (m, 5 H, HPh), 7.89 (d, 3J = 8.8 Hz,
2 H, H2Ar, H6Ar), 8.49 (d, 3J = 8.8 Hz, 2 H, H3Ar, H5Ar).
1H NMR (DMSO-d6): d = 2.43 (s, 3 H, Me), 3.91 (s, 3 H, OMe),
7.76 (d, 3J = 8.8 Hz, 1 H, H6Ar), 8.38 (s, 1 H, H3Ar), 8.48 (d, 3J = 8.8
Hz, 1 H, H5Ar).
MS (CI): m/z (%) = 311 (100) [M + H+].
Anal. Calcd for C15H10N4O4 (310.26): C, 58.07; H, 3.25; N, 18.06.
Found: C, 57.73; H, 3.18; N, 17.97.
MS (CI): m/z (%) = 236 (100) [M + H+].
Anal. Calcd for C9H9N5O3 (235.20): C, 45.96; H, 3.86; N, 29.78.
Found: C, 46.07; H, 3.69; N, 29.64.
Decarboxylation of 1H-1,2,3-triazole-4-carboxylic Acids 4c,k;
General Procedure
Compound 4c or 4k (10 mmol) was heated at the temperature 20 °C
higher than its mp until evolution of CO2 ceased. The triazoles 5a,b
obtained were crystallized (EtOH).
2-(4-Nitrophenyl)-2H-tetrazole-5-carboxylic Acid (9)
NaNO2 (1.4 g, 20.3 mmol) was added to the soln of 4-nitroaniline
(1a, 2.8 g, 20.3 mmol) in 16% HCl (22 mL) keeping the temperature
below 5 °C. The resulting diazonium salt was added to a soln of 5-
methylisoxazol-3-amine (2 g, 20.4 mmol) and NaOAc (5.6 g, 68.3
mmol) in H2O (100 mL). The mixture was stirred at r.t. for 24 h. The
resulting suspension was filtered and the solid product was washed
with H2O to give the corresponding triazene 8 (mp 169–171 °C).
Compound 8 was heated in 5% NH3 in acetone soln for 5 min. The
mixture was diluted with H2O and 1-[2-(4-nitrophenyl)-2H-tetra-
zol-5-yl]propan-2-one started to precipitate (mp 132–134 °C). To
the soln [acetone (30 mL) and H2O (10 mL)] of 2H-tetrazole (10
mmol), KMnO4 (3.2 g, 20.3 mmol) was added in portions. The soln
was heated to discoloration. The hot soln was filtered, cooled and
5-Methyl-1-(4-nitrophenyl)-1H-1,2,3-triazole (5a)
White crystals; yield: 1.85 g (91%); mp 139–140 °C (Lit.8 140 °C).
MS (CI): m/z (%) = 205 (100) [M + H+].
1-(4-Nitrophenyl)-5-phenyl-1H-1,2,3-triazole (5b)
White crystals; yield: 2.26 g (85%); mp 103–104 °C.
1H NMR (DMSO-d6): 7.37–7.47 (m, 5 H, HPh), 7.89 (d, 3J = 8.8 Hz,
2 H, H2Ar, H6Ar), 8.02 (s, 1 H, HTr), 8.49 (d, 3J = 8.8 Hz, 2 H, H3Ar,
H5Ar).
Synthesis 2009, No. 16, 2741–2748 © Thieme Stuttgart · New York

2746
N. T. Pokhodylo et al.
PAPER
acidified with HCl. Acid 9 was filtered, washed with H2O, and
dried; yield: 1.60 g (68%); mp 184 °C (Lit.14 184 °C).14
MS (CI): m/z (%) = 321 (100) [M + H+].
Anal. Calcd for C17H12N4O3 (320.30): C, 63.75; H, 3.78; N, 17.49.
Found: C, 63.70; H, 3.81; N, 17.35.
MS (CI): m/z (%) = 236 (100) [M + H+].
3-Aryl-2,1-benzisoxazoles 11a–p; General Procedure
To a warm soln of NaOH (5.0 g, 0.125 mol) in EtOH (40 mL) was
added arylacetonitrile 10 (11.25 mmol) and a soln of nitroarene 4, 5
(10 mmol) in EtOH (25 mL). The mixture was stirred at 60 °C for 4
h and at r.t. for 1 d. The soln was diluted with H2O and acidified
with HCl. The precipitate was isolated by filtration, washed with
hot H2O, and dried.
1-[3-(4-Fluorophenyl)-2,1-benzisoxazol-5-yl]-5-methyl-1H-
1,2,3-triazole-4-carboxylic Acid (11g)
White crystals; yield: 2.3 g (84%); mp 235–236 °C (dec.) (EtOH).
1H NMR (DMSO-d6): d = 2.84 (s, 3 H, Me), 7.37 (t, 3J = 8.8 Hz, 2
3
H, H2Ar, H6Ar), 7.56 (d, J = 9.2 Hz, 1 H, H6Bis), 7.85 (d, J = 9.2
3
3
Hz, 1 H, H7Bis), 8.24 (dd, JHH = 8.8, JHF = 4.8 Hz, 2 H, H2Ar,
4
H6Ar), 8.42 (s, 1 H, H4Bis), 12.96 (s, 1 H, COOH).
MS (CI): m/z (%) = 339 (100) [M + H+].
5-(5-Methyl-1H-1,2,3-triazol-1-yl)-3-phenyl-2,1-benzisoxazole
(11a)
White crystals; yield: 1.93 g (70%); mp 148–149 °C (EtOH–H2O).
Anal. Calcd for C17H11FN4O3 (338.29): C, 60.36; H, 3.28; N, 16.56.
Found: C, 60.58; H, 3.37; N, 16.64.
1H NMR (DMSO-d6): d = 2.37 (s, 3 H, CH3), 7.57–7.66 (m, 3 H,
HPh), 7.72 (d, 3J = 9.2 Hz, 1 H, H7Bis), 7.92 (m, 2 H, H6Bis, HTr), 8.17
(m, 2 H, HPh), 8.36 (s, 1 H, H4Bis).
1-[3-(4-Chlorophenyl)-2,1-benzisoxazol-5-yl]-5-methyl-1H-
1,2,3-triazole-4-carboxylic Acid (11h)
White crystals; yield: 3.29 g (93%); mp 244–245 °C (dec.) (EtOH).
MS (CI): m/z (%) = 277 (100) [M + H+].
1H NMR (DMSO-d6): d = 2.61 (s, 3 H, Me), 7.58 (d, 3J = 9.6 Hz, 1
Anal. Calcd for C16H12N4O (276.29): C, 69.55; H, 4.38; N, 20.28.
Found: C, 69.39; H, 4.49; N, 20.19.
3
3
H, H6Bis), 7.61 (d, J = 8.8 Hz, 2 H, H2Ar, H6Ar), 7.87 (d, J = 9.6
Hz, 1 H, H7Bis), 8.19 (d, 3J = 8.8 Hz, 2 H, H2Ar, H6Ar), 8.44 (s, 1 H,
H4Bis), 12.99 (s, 1 H, COOH).
3-(4-Chlorophenyl)-5-(5-methyl-1H-1,2,3-triazol-1-yl)-2,1-
benzisoxazole (11b)
White crystals; yield: 2.61 g (84%); mp 189–190 °C (EtOH).
MS (CI): m/z (%) = 355 (100) [M + H+].
Anal. Calcd for C17H11ClN4O3 (354.75): C, 57.56; H, 3.13; N,
15.79. Found: C, 57.42; H, 3.01; N, 15.63.
1H NMR (DMSO-d6): d = 2.49 (s, 3 H, CH3), 7.61–7.70 (m, 3 H,
3
H6Bis, H3Ar, H5Ar), 7.73 (s, 1 H, HTr), 7.92 (d, J = 8.8 Hz, 1 H,
H7Bis), 8.19 (d, 3J = 8.8 Hz, 2 H, H2Ar, H6Ar), 8.34 (s, 1 H, H4Bis).
1-[3-(4-Bromophenyl)-2,1-benzisoxazol-5-yl]-5-methyl-1H-
1,2,3-triazole-4-carboxylic Acid (11i)
White crystals; yield: 3.59 g (90%); mp 230–231 °C (dec.) (EtOH).
MS (CI): m/z (%) = 311 (100) [M + H+].
Anal. Calcd for C16H11ClN4O (310.74): C, 61.84; H, 3.57; N, 18.03.
Found: C, 61.98; H, 3.38; N, 17.86.
1H NMR (DMSO-d6): d = 2.59 (s, 3 H, Me), 7.66 (d, 3J = 9.6 Hz, 1
3
3
H, H6Bis), 7.83 (d, J = 8.8 Hz, 2 H, H2Ar, H6Ar), 7.96 (d, J = 9.6
Hz, 1 H, H7Bis), 8.14 (d, 3J = 8.8 Hz, 2 H, H2Ar, H6Ar), 8.49 (s, 1 H,
H4Bis), 13.28 (s, 1 H, COOH).
3-Phenyl-5-(5-phenyl-1H-1,2,3-triazol-1-yl)-2,1-benzisoxazole
(11c)
White crystals; yield: 2.97 g (88%); mp 214–215 °C (EtOH).
MS (CI): m/z (%) = 399 (100) [M + H+], 401 (89) [M + H+].
3
1H NMR (DMSO-d6): d = 7.27 (d, J = 9.6 Hz, 1 H, H6Bis), 7.39–
Anal. Calcd for C17H11BrN4O3 (399.20): C, 51.15; H, 2.78; N,
14.03. Found: C, 51.24; H, 2.56; N, 14.19.
7.45 (m, 5 H, HPh), 7.52–7.61 (m, 3 H, HPh), 7.70 (d, 3J = 9.6 Hz, 1
H, H7Bis), 7.98 (d, 3J = 8.0 Hz, 2 H, H2Ph, H6Ph), 8.00 (s, 1 H, HTr),
8.18 (s, 1 H, H4Bis).
5-Ethyl-1-(3-phenyl-2,1-benzisoxazol-5-yl)-1H-1,2,3-triazole-4-
carboxylic Acid (11j)
White crystals; yield: 2.94 g (88%); mp 182–183 °C (dec.) (EtOH).
MS (CI): m/z (%) = 339 (100) [M + H+].
Anal. Calcd for C21H14N4O (338.36): C, 74.54; H, 4.17; N, 16.56.
Found: C, 74.40; H, 4.03; N, 16.39.
3
1H NMR (DMSO-d6): d = 1.12 (t, J = 7.2 Hz, 3 H, Et), 3.03 (q,
3J = 7.2 Hz, 2 H, Et), 7.50 (d, 3J = 9.2 Hz, 1 H, H6Bis), 7.56–7.64 (m,
3
3 H, H3Ph, H4Ph, H5Ph), 7.86 (d, J = 9.2 Hz, 1 H, H7Bis), 8.14 (d,
3J = 7.8 Hz, 2 H, H2Ph, H6Ph), 8.42 (s, 1 H, H4Bis), 12.95 (s, 1 H,
COOH).
1-[5-tert-Butyl-1-(3-phenyl-2,1-benzisoxazol-5-yl)-1H-1,2,3-tri-
azol-4-yl]-2,2-dimethyl-1-propanone (11e)
White crystals; yield: 3.5 g (87%); mp 178–179 °C (EtOH).
MS (CI): m/z (%) = 335 (100) [M + H+].
IR (KBr): 1650 cm–1 (s, C=O).
Anal. Calcd for C18H14N4O3 (334.33): C, 64.66; H, 4.22; N, 16.76.
Found: C, 64.46; H, 4.34; N, 16.42.
1H NMR (500 MHz, DMSO-d6): d = 1.25 (s, 9 H, t-Bu), 1.40 (s, 9
H, t-Bu), 7.59 (d, 3J = 9.3 Hz, 1 H, H6Bis), 7.60–7.65 (m, 3 H, H3Ph,
H4Ph, H5Ph), 7.89 (d, 3J = 9.3 Hz, 1 H, H7Bis), 8.21 (d, 3J = 7.8 Hz,
2 H, H2Ph, H6Ph), 8.60 (s, 1 H, H4Bis).
1-(3-Phenyl-2,1-benzisoxazol-5-yl)-5-propyl-1H-1,2,3-triazole-
4-carboxylic Acid (11k)
White crystals; yield: 2.54 g (73%); mp 193–194 °C (dec.) (EtOH).
MS: (CI) m/z (%) = 403 (100) [M + H+].
Anal. Calcd for C24H26N4O2 (402.49): C, 71.62; H, 6.51; N, 13.92.
Found: C, 74.40; H, 4.03; N, 16.39.
1H NMR (DMSO-d6): d = 0.82 (t, 3J = 7.2 Hz, 3 H, Pr), 1.50–1.55
(m, 2 H, Pr), 3.00 (t, 3J = 8.0 Hz, 2 H, Pr), 7.50 (d, 3J = 9.2 Hz, 1 H,
H6Bis), 7.56–7.64 (m, 3 H, H3Ph, H4Ph, H5Ph), 7.86 (d, 3J = 9.2 Hz, 1
H, H7Bis), 8.14 (d, 3J = 7.8 Hz, 2 H, H2Ph, H6Ph), 8.42 (s, 1 H, H4Bis),
12.95 (s, 1 H, COOH).
5-Methyl-1-(3-phenyl-2,1-benzisoxazol-5-yl)-1H-1,2,3-triazole-
4-carboxylic Acid (11f)
White crystals; yield: 2.91 g (91%); mp 210–211 °C (dec.) (EtOH).
MS (CI): m/z (%) = 349 (100) [M + H+].
1H NMR (DMSO-d6): d = 2.56 (s, 3 H, Me), 7.58–7.66 (m, 4 H,
H6Bis, H3Ph, H4Ph, H5Ph), 7.93 (d, 3J = 9.6 Hz, 1 H, H7Bis), 8.16 (d,
3J = 7.8 Hz, 2 H, H2Ph, H6Ph), 8.45 (s, 1 H, H4Bis).
Anal. Calcd for C19H16N4O3 (348.36): C, 65.51; H, 4.63; N, 16.08.
Found: C, 65.30; H, 4.78; N, 16.00.
Synthesis 2009, No. 16, 2741–2748 © Thieme Stuttgart · New York

PAPER
5-(Tetrazol-1-yl/1,2,3-triazol-1-yl)-Substituted 3-Aryl-2,1-benzisoxazoles
2747
5-Isopropyl-1-(3-phenyl-2,1-benzisoxazol-5-yl)-1H-1,2,3-tri-
azole-4-carboxylic Acid (11l)
White crystals; yield: 2.4 g (70%); mp 175–176 °C (dec.) (EtOH).
5-(5-Methyl-1H-tetrazol-1-yl)-3-phenyl-2,1-benzisoxazole (12a)
White crystals; yield: 2.41 g (87%); mp 154–155 °C (EtOH).
1H NMR (DMSO-d6): d = 2.64 (s, 3 H, Me), 7.56–7.64 (m, 4 H,
H6Bis, H3Ph, H4Ph, H5Ph), 7.86 (d, 3J = 9.6 Hz, 1 H, H7Bis), 8.14 (d,
3J = 7.2 Hz, 2 H, H2Ph, H6Ph), 8.51 (s, 1 H, H4Bis).
1H NMR (DMSO-d6): d = 1.35 (d, 3J = 7.2 Hz, 6 H, i-Pr), 3.30–3.35
(m, 1 H, i-Pr), 7.42 (d, 3J = 9.2 Hz, 1 H, H6Bis), 7.55–7.61 (m, 3 H,
H3Ph, H4Ph, H5Ph), 7.83 (d, 3J = 9.2 Hz, 1 H, H7Bis), 8.13 (d, 3J = 7.8
Hz, 2 H, H2Ph, H6Ph), 8.39 (s, 1 H, H4Bis), 12.95 (s, 1 H, COOH).
MS (CI): m/z (%) = 278 (100) [M + H+].
Anal. Calcd for C15H11N5O (277.28): C, 64.97; H, 4.00; N, 25.26.
Found: C, 64.81; H, 4.14; N, 25.03.
MS (CI): m/z (%) = 349 (100) [M + H+].
Anal. Calcd for C19H16N4O3 (348.36): C, 65.51; H, 4.63; N, 16.08.
Found: C, 65.44; H, 4.48; N, 16.21.
3-(4-Methylphenyl)-5-(5-methyl-1H-tetrazol-1-yl)-2,1-benz-
isoxazole (12b)
White crystals; yield: 2.44 g (84%); mp 171–172 °C (EtOH).
5-Butyl-1-(3-phenyl-2,1-benzisoxazol-5-yl)-1H-1,2,3-triazole-4-
carboxylic Acid (11m)
White crystals; yield: 2.5 g (69%); mp 246–247 °C (dec.) (EtOH).
1H NMR (DMSO-d6): d = 2.46 (s, 3 H, CH3), 2.63 (s, 3 H, CH3),
3
3
7.41 (d, J = 8.0 Hz, 2 H, H3Ar, H5Ar), 7.57 (d, J = 9.2 Hz, 1 H,
H6Bis), 7.83 (d, 3J = 9.2 Hz, 1 H, H7Bis), 8.03 (d, 3J = 8.0 Hz, 2 H,
H2Ar, H6Ar), 8.49 (s, 1 H, H4Bis).
1H NMR (DMSO-d6): d = 0.76 (t, 3J = 7.2 Hz, 3 H, Me), 1.34 (m, 2
H, CH2), 1.46 (m, 2 H, CH2), 3.15 (t, 3J = 8.0 Hz, 2 H, CH2), 7.47–
3
7.64 (m, 4 H, H6Bis, H3Ph, H4Ph, H5Ph), 7.83 (d, J = 9.2 Hz, 1 H,
H7Bis), 8.14 (d, 3J = 7.6 Hz, 2 H, H2Ph, H6Ph), 8.32 (s, 1 H, H4Bis),
12.95 (s, 1 H, COOH).
MS (CI): m/z (%) = 292 (100) [M + H+].
Anal. Calcd for C16H13N5O (291.31): C, 65.97; H, 4.50; N, 24.04.
Found: C, 65.64; H, 4.36; N, 23.92.
MS: (CI) m/z (%) = 363 (100) [M + H+].
Anal. Calcd for C20H18N4O3 (362.38): C, 66.29; H, 5.01; N, 15.46.
Found: C, 66.33; H, 4.89; N, 15.34.
3-(4-Chlorophenyl)-5-(5-methyl-1H-tetrazol-1-yl)-2,1-benz-
isoxazole (12c)
White crystals; yield: 2.84 g (91%); mp 163–164 °C (EtOH).
5-(Methoxymethyl)-1-(3-phenyl-2,1-benzisoxazol-5-yl)-1H-
1,2,3-triazole-4-carboxylic Acid (11n)
White crystals; yield: 1.96 g (56%); mp 201–202 °C (dec.) (EtOH).
1H NMR (DMSO-d6): d = 2.65 (s, 3 H, CH3), 7.57–7.64 (m, 3 H,
H6Bis, H3Ar, H5Ar), 7.87 (d, 3J = 9.2 Hz, 1 H, H7Bis), 8.18 (d, 3J = 8.4
Hz, 2 H, H2Ar, H6Ar), 8.53 (s, 1 H, H4Bis).
1H NMR (DMSO-d6): d = 3.34 (s, 3 H, Me), 4.85 (s, 2 H, CH2),
MS (CI): m/z (%) = 312 (100) [M + H+].
3
7.55–7.65 (m, 3 H, H3Ph, H4Ph, H5Ph), 7.68 (d, J = 9.6 Hz, 1 H,
3
H6Bis), 7.85 (d, J = 9.6 Hz, 1 H, H7Bis), 8.11 (d, 3J = 7.2 Hz, 2 H,
H2Ph, H6Ph), 8.47 (s, 1 H, H4Bis), 13.35 (s, 1 H, COOH).
Anal. Calcd for C15H10ClN5O (311.72): C, 57.79; H, 3.23; N, 22.47.
Found: C, 57.99; H, 3.07; N, 22.58.
MS (CI): m/z (%) = 351 (100) [M + H+].
5-[5-(3-Chloropropyl)-1H-tetrazol-1-yl]-3-phenyl-2,1-benzisox-
azole (12d)
White crystals; yield: 2.51 g (74%); mp 163–164 °C (EtOH).
Anal. Calcd for C18H14N4O4 (350.33): C, 61.71; H, 4.03; N, 15.99.
Found: C, 61.51; H, 4.17; N, 15.81.
1H NMR (DMSO-d6): d = 2.26 (m, 2 H, CH2), 3.10 (t, 3J = 7.2 Hz,
5-Methyl-1-(6-methyl-3-phenyl-2,1-benzisoxazol-5-yl)-1H-
1,2,3-triazole-4-carboxylic Acid (11o)
White crystals; yield: 2.24 g (67%); mp 209–210 °C (dec.) (EtOH);
2 H, CH2), 3.70 (t, 3J = 7.2 Hz, 2 H, CH2), 7.54–7.64 (m, 4 H, H6Bis
,
H3Ar, H4Ar, H5Ar), 7.86 (d, 3J = 9.6 Hz, 1 H, H7Bis), 8.15 (d, 3J = 8.4
Hz, 2 H, H2Ar, H6Ar), 8.52 (s, 1 H, H4Bis).
1H NMR (DMSO-d6): d = 2.04 (s, 3 H, Me), 2.46 (s, 3 H, Me), 7.54–
7.61 (m, 3 H, H3Ph, H4Ph, H5Ph), 7.68 (s, 1 H, H7Bis), 8.14 (d, 3J = 8.0
Hz, 2 H, H2Ph, H6Ph), 8.41 (s, 1 H, H4Bis), 12.99 (s, 1 H, COOH).
MS (CI): m/z (%) = 340 (100) [M + H+].
Anal. Calcd for C10H14ClN5O (339.79): C, 60.09; H, 4.15; N, 20.61.
Found: C, 59.89; H, 4.01; N, 20.70.
MS (CI): m/z (%) = 335 (100) [M + H+].
Anal. Calcd for C18H14N4O3 (334.33): C, 64.66; H, 4.22; N, 16.76.
Found: C, 64.49; H, 4.41; N, 16.52.
6-Methoxy-5-(5-methyl-1H-tetrazol-1-yl)-3-phenyl-2,1-benz-
isoxazole (12e)
White crystals; yield: 2.0 g (65%); mp 247–248 °C (EtOH).
1-(6-Methoxy-3-phenyl-2,1-benzisoxazol-5-yl)-5-methyl-1H-
1,2,3-triazole-4-carboxylic Acid (11p)
White crystals; yield: 2.13 g (61%); mp 205–206 °C (dec.) (EtOH).
1H NMR (DMSO-d6): d = 2.46 (s, 3 H, Me), 3.89 (s, 3 H, OMe),
7.29 (s, 1 H, H7Bis), 7.59–7.67 (m, 3 H, H3Ph, H4Ph, H5Ph), 8.15 (d,
3J = 8.0 Hz, 2 H, H2Ph, H6Ph), 8.62 (s, 1 H, H4Bis).
1H NMR (DMSO-d6): d = 2.42 (s, 3 H, Me), 3.91 (s, 3 H, OMe),
7.17 (s, 1 H, H7Bis), 7.52–7.62 (m, 3 H, H3Ph, H4Ph, H5Ph), 8.11 (d,
3J = 8.0 Hz, 2 H, H2Ph, H6Ph), 8.38 (s, 1 H, H4Bis), 12.97 (s, 1 H,
COOH).
MS (CI): m/z (%) = 308 (100) [M + H+].
Anal. Calcd for C16H13N5O2 (307.31): C, 62.53; H, 4.26; N, 22.79.
Found: C, 62.20; H, 4.04; N, 22.91.
MS (CI): m/z (%) = 351 (100) [M + H+].
2-(3-Phenyl-2,1-benzisoxazol-5-yl)-2H-tetrazole-5-carboxylic
Acid (14a)
White crystals; yield: 2.7 g (88%); mp 209–210 °C (dec.) (EtOH).
Anal. Calcd for C18H14N4O4 (350.33): C, 61.71; H, 4.03; N, 15.99.
Found: C, 61.59; H, 3.92; N, 15.82.
1H NMR (DMSO-d6): d = 7.59–7.71 (m, 3 H, H3Ph, H4Ph, H5Ph),
7.96 (d, J = 9.6 Hz, 1 H, H6Bis), 8.15 (d, J = 7.2 Hz, 2 H, H2Ph,
H6Ph), 8.20 (d, 3J = 9.6 Hz, 1 H, H7Bis), 8.75 (s, 1 H, H4Bis).
3-Aryl-2,1-benzisoxazoles 12a–e, 14a,b; General Procedure
To the soln of KOH (9.8 g, 0.17 mol) in MeOH (25 mL) was added
with stirring arylacetonitrile 10 (11 mmol) and a soln of nitroarene
6, 7 (10 mmol) in MeOH (15 mL). The mixture was stirred at r.t. for
1 h. The precipitate was isolated by filtration, washed with H2O, and
dried. Compounds 12a–e and 14a,b were crystallized (EtOH–
DMF).
3
3
MS (CI): m/z (%) = 308 (100) [M + H+].
Anal. Calcd for C15H9N5O3 (307.26): C, 58.63; H, 2.95; N, 22.79.
Found: C, 58.86; H, 2.75; N, 22.83.
Synthesis 2009, No. 16, 2741–2748 © Thieme Stuttgart · New York

2748
N. T. Pokhodylo et al.
PAPER
(3) Makosza, M.; Wojciechowski, K. Chem. Rev. 2004, 104,
2631.
(4) Orlov, V. Yu.; Kotov, A. D.; Rusakov, A. I.; Bystryakova,
E. B. Russ. J. Org. Chem. (Engl. Transl.) 1998, 34, 538.
(5) Orlov, V. Yu.; Sokovikov, Y. a. V.; Kotov, A. D.; Starikov,
A. A. Russ. J. Org. Chem. (Engl. Transl.) 2000, 36, 1735.
(6) Orlov, V. Yu.; Kotov, A. D.; Bystryakova, E. B.; Kopeykin,
V. V.; Mironov, G. S. Russ. J. Org. Chem. (Engl. Transl.)
1994, 30, 1481.
2-[3-(4-Chlorophenyl)-2,1-benzisoxazol-5-yl]-2H-tetrazole-5-
carboxylic Acid (14b)
White crystals; yield: 3.01 g (90%); mp 220–221 °C (dec.) (EtOH).
1H NMR (500 MHz, DMSO-d6): d = 7.76 (d, 3J = 8.0 Hz, 2 H, H3Ph,
3
H5Ph), 8.02 (d, J = 9.6 Hz, 1 H, H6Bis), 8.20–8.23 (m, 3 H, H2Ph,
H6Ph, H7Bis), 8.64 (s, 1 H, H4Bis), 13.28 (s, 1 H, COOH).
MS (CI): m/z (%) = 342 (100) [M + H+].
Anal. Calcd for C15H8ClN5O3 (341.71): C, 52.72; H, 2.36; N, 20.50.
Found: C, 52.44; H, 2.18; N, 20.41.
(7) Orlov, V. Yu.; Sokovikov, Y. a. V.; Kotov, A. D. Russ. J.
Org. Chem. (Engl. Transl.) 2002, 38, 100.
(8) Khadem, H.; Mansour, H. A. R.; Meshreki, M. H. J. Chem.
Soc. 1968, 1329.
References
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(12) Smith, P. A. S.; Boyer, J. H. Org. Synth. 1951, 31, 14.
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Synthesis 2009, No. 16, 2741–2748 © Thieme Stuttgart · New York