Synthesis of new heterocyclic compounds having 1,2,3-triazole and isoxazole rings in a single molecule

Article abstract of DOI:10.1002/jhet.5570450104

(Chemical Equation Presented) Five series of new heterocyclic compounds of 1,2,4-triazole Mannich bases, 1,3,4-oxadiazole Mannich bases, 1,3,4-oxadiazolines, 1,2,4-triazolo[3,4-b]1,3,4-thiadiazines and 1,2,4-triazolo[3,4-b]1,3,4-thiadiazoles, in which 1,2

Full text of DOI:10.1002/jhet.5570450104

Jan-Feb 2008
77
Synthesis of New Heterocyclic Compounds Having 1,2,3-Triazole
and Isoxazole Rings in a Single Molecule
Qiu Chen, Fangming Liu*, Feng Xu, Chun Yang
Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education
Hangzhou Normal University, Hangzhou, 310012, China
Received October 13, 2006
NCH2NR1R2
S
NCH2NR1R2
S
O
N
N
N
N
N
N
N
N
O
C
Ph
N
Ph
Ph
N
N
Ph N
NHNH2
N
N
N
N
N
Ph
CH3
O
O
O
N
CH3
CH3
O
C
N
N
N
N
N
N
N
N
N
N
N
N
CH3
R1
Ph
N
Ph N
S
N
R2
N
S
O
N
N
N
O
O
CH3
O
CH3
CH3
R
R
Five series of new heterocyclic compounds of 1,2,4-triazole Mannich bases, 1,3,4-oxadiazole Mannich
bases, 1,3,4-oxadiazolines, 1,2,4-triazolo[3,4-b]1,3,4-thiadiazines and 1,2,4-triazolo[3,4-b]1,3,4-thia-
diazoles, in which 1,2,3-triazolyl and isoxazolyl have been united, were synthesized from the intermediate
of 5-methyl-3-(2-phenyl-2H-1,2,3-triazol-4-yl)isoxazole-4-carbohydrazide, Their structures were
established by spectroscopy.
J. Heterocyclic Chem., 45, 77 (2008).
designed 5-methyl-3-(2-phenyl-2H-1,2,3-triazol-4-yl)is-
oxazole-4-carbohydrazide as an intermediate (5), and
synthesized five new series of heterocyclic derivatives of
1,2,4-triazole Mannich bases, 1,3,4-oxadiazole Mannich
bases, 1,3,4-oxadiazolines, 1,2,4-triazolo[3,4-b]1,3,4-thia-
diazines and 1,2,4-triazolo[3,4-b]1,3,4-thiadizoles, in
which 1,2,3-triazolyl and isoxazolyl have been united.
The synthetic route is shown in Scheme 1.
INTRODUCTION
Recent studies show that many sorts of heterocyclic
compounds containing the rings system of triazole,
isoxazole, oxadiazole, thiadiazole and thiadiazine, have a
wide range of biological activities. Generally, triazole
derivatives have been synthesized as possible
antidepressants and plant growth regulators [1-3]. Some
of the 1,2,4-triazole derivatives have anti-inflammatory
activities and some are antifungal agents or herbicides
[4-6]. Isoxazole derivatives form a part of many drugs
used for antidepressant therapy and the treatment of
osteoarthritis or rheumatoid arthritis [7,8]. On the other
hand, 1,3,4-oxadiazoline-5-thiones, 1,2,4-triazolo[3,4-b]-
1,3,4-thiadiazines and 1,2,4-triazolo[3,4-b]1,3,4-thiadiaz-
oles have anticancer, antibacterial , antiseptic, anthel-
mintic and antimicrobial physiological activities [9-12].
Thus, it seemed of interest to combine various hetero-
cyclic rings into a single molecule with the hope of
finding activities and improving the function of some
drugs.
RESULTS AND DISCUSSION
For preparation of the intermediate of 4, the ꢀ-chloro-2-
phenyl-1,2,3-triazole-4-formaldehyde oxime (3) can
easily undergo auto-polymerization easily, if sodioaceto-
acetic ester was added into the solution of 3. Therefore,
3 was added drop by drop into a stirring solution of sodio-
acetoacetic ester at low temperature to avoid polymerizing
and obtain excellent yields of 4.
The concentration of hydrazine affects the yield of 5
greatly. Higher yield of 5 was obtained, as volume
proportion of ethanol/hydrazine is 1:0.4-0.5.
Although the present literature revealed that a lot of
compounds with 1,3,4-oxadiazoles, 1,3,4-oxadiazolines
1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines and 1,2,4-triazolo-
[3,4-b]-1,3,4-thiadizoles, containing a 1,2,3-triazole ring
or isoxazole ring, have been synthesized [13-15], to our
knowledge, not much have been mentioned in the
synthesis of compounds containing the 1,2,3-triazole ring
and isoxazole ring together in a single molecule. We
To avoid more subsidiary reactions, the synthesis of
1,3,4-oxadiazole Mannich bases 9a-9d should be operated
at room temperature.
If the reaction time is not long enough during the
preparation of the derivatives of 1,2,4-triazolo[3,4-b]-
1,3,4-thiadiazines 13a-13c, a mixture of product and
intermediate is obtained, and must be purified through a
difficult recrystallization. Prolonging the reaction time

78
Q. Chen , F. M. Liu, F. Xu, C. Yang
Vol 45
Scheme 1: Synthetic Route
N
N
O
COEt
N
Ph
N
N
N
N
N
2
CH3COCH2COOEt
NaOEt
.
(CH3)3COCl
Cl
C
NH2OH
HCl
Ph
N
Ph N
Ph N
NOH
CH2ClCH2Cl
(CH3)3COH
CHO
CH
NOH
NCS
CH3COONa
N
N
O
CH3
4
3
1
N
N
N
R1
R2
N
N
N
NCH2NR1R2
S
O
NH
N
Ph N
N
.
N NH
H2NNH2 H2O
HCHO
Ph
Ph
N
,
CNHNH2
N
CH3CH2OH
S
N
NaOH
N
N
Ph
CH3
O
CH3
N
O
Ph
CH3
O
7a-7d
6
5
KOH
,
R1R2NH
p-ClC6H4NH2
p-CH3C6H4NH2
Piperidine
C6H5NH2
,
=
,
,
CS2
c
a
d
b
N
N
NH
N
N
N
N
N
O
N
NCH2NR1R2
R1
R2
Ph N
Ph
NH
HCHO
S
O
,
S
O
N
O
O
CH3
CH3
R1 C R2
9a-9d
8
KOH
,
,
CS2
p-ClC6H4NH2
Piperidine
p-CH3C6H4NH2
R1R2NH
C6H5NH2
,
=
,
,
d
c
H2O
a
NH2NH2
b
O
N
C CH3
R1
R2
N
N
O
C
N
N
Ph
N
NHN
CR1R2
Ac2O
Ph N
N
O
N
N
O
CH3
CH3
O
10a-10f
11a-11f
O
C6H5CHO
p-CH3OC6H4CHO
p-ClC6H4CHO
,
,
,
,
R1
R2
=
C
a
b
c
O
p-O2NC6H4CHO
C6H5COCH3
,
d
e
N
N
f
N
N
SH
Ph
N
N
ArCOCH2Br
ab. EtOH
N
N
N
NH2
CH3
N
Ph N
S
O
N
N
N
12
N
O
CH3
C6H5
,
p-CH3OC6H4
p-ClC6H4
Ar
,
=
,
RCOOH
POCl3
Ar
a
b
c
13a-13c
N
N
N
N
Ph N
p-CH3OC6H4
,
R
C6H5
p-O2NC6H4
p-ClC6H4
=
,
,
,
S
N
a
b
c
d
N
N
O
R
CH3
CH3
C2H5
C3H7
C4H9
,
,
,
14a-14h
g
e
f
h
and recrystallization with ethyl acetate/ethanol were the
key of synthesis.
were used in the reaction of aliphatic acids than in the
reaction of aromatic acid.
At higher temperature partial charring occurred during
the synthesis of the derivatives of 1,2,4-triazolo[3,4-b]-
1,3,4-thiadiazoles 14a-14h, therefore, lower temperature
All compounds IR spectra showed absorption bands at 1520-
1650cm-1, 2900-2940cm-1, which coincided with the vibration
of C=N, C=C and the extension vibration of CH3 or CH2.

Jan-Feb 2008
New Heterocyclic Compounds of 1,2,3-Triazole and Isoxazole
79
Scheme 3: Proposal Fragmentation Processes of 9a
The compounds of 7a-7c's and 9a-9c's IR spectra
displayed absorption bands of NH at 3300-3400 cm-1
except 7d and 9d, where the absorption bands of C=S at
1042cm-1 were observed. The compounds of 11a-11f's IR
spectra showed characteristic absorption bands at 1660
cm-1 for carbonyl C=O. The compounds of 13a-13c's and
14a-14h's spectra displayed characteristic absorption
bands at 1480 cm-1, which coincided with the vibration of
N=C–S [16].
a
N
N
CH2NH
N
N
Ph
N
H2C
N
a
S
O
N
d
m/z 105
M-326
CH3
O
m/z 431
a
b
N
NH
e
c
1
N
N
N
N
f
The H NMR spectra of N=C–H of 1,2,3-triazoles was
C
b
NH
Ph
N
Ph
N
S
O
ꢀ 7.8-8.5, singlet. The chemical shift of Ar-H displayed
multiplet at ꢀ 6.5-8.0. The signal of CH3 on isoxazole
rings exhibited at ꢀ 2.6-2.8, shifting to downfield, because
of magnetic anisotropy of the ring. Inductive effect of N
atom resulted in the shift of H of NCH2N at ꢀ 5.0-5.5, The
weak broad peak at ꢀ 5.0-5.7 corresponds to NH.
N
N
CH3
d
O
O
m/z
237
m/z 326
f
c
e
N
Ph
N
N
Total target molecules' MS Spectra displayed strong
peaks at m/z 77, m/z 91, m/z 170 or 171, m/z 251 or 252.
Those were characteristic peaks of the molecular ion
fragment of 1,2,3-triazole containing phenyl and
isoxazole ring.
Because of poor molecular stability of 1,2,4-triazole
Mannich bases of 7a-7d, molecular ion peaks were not
observed in their electron impact mass spectra, but
showed characteristic peaks of m/z 401, m/z
corresponding to [M-401], m/z 135, m/z 149, m/z 216.
The fragmentation pattern of 7b was shown in Scheme 2.
N
NH
HN
N
N
O
m/z 69
m/z 211
m/z 91
m/z 77
Molecular ion peaks are observed in all oxadiazolines
(11a-11f) spectra, and showed characteristic peaks at m/z
[M-42] or m/z [M-41]. The fragmentation pattern of 11c
is shown in Scheme 4.
Scheme 4: Proposal Fragmentation Processes of 11c
b
O
a
N
N C CH3
N
N
c
H
Scheme 2: Proposal Fragmentation Processes of 7b
Ph
N
O
N
a
CH3
450
O
Cl
N
N
CH2NH
b
m/z
448 m/z
N
N
isotopic peak
CH3
Ph
a
N
S
N
a
c
b
Ph
CH3
N
O
N
NH2
e
N
N
g
N
N
f
N
d
b
c
H
Ph
N
Ph
N
Ph
N
N
a
C
O
O
C
NH
N
N
N
S
CH3
M-41
e
CH3
N
NH
O
O
CH3
O
N
N
Cl
d
e
m/z
d
407
Ph
N
m/z
253
S
m/z
f
252
N
N
Ph
H2C
N
CH3
g
N
Ph
N
O
O
CH3
e
m/z 216
m/z 119
M-401
m/z 401
c
N
N
Ph
N
c
NH
Ph
N N
d
N
O
S
g
N
N
f
m/z 91
N
m/z
211
m/z
105
m/z 77
C
NH
Ph
N
Ph
N
C
S
Ph
N
Ph
N
N
C
N
N
N
O
m/z 135
m/z 170
m/z 149
CH3
Molecular ion peak are observed for all 1,2,4-triazolo-
g
m/z
252
f
[3,4-b]-1,3,4-thiadiazines (13a-13c), and showed
characteristic peaks at m/z [M-337] or m/z [M-336] and
m/z [M-323]. The fragmentation pattern of 13b is shown
in Scheme 5.
NH
91
m/z
m/z
77
Molecular ion peaks are obsesrved for all 1,2,4-
triazolo[3,4-b]-1,3,4-thiadiazoles (14a-14h), and showed
characteristic peaks at m/z [M-42], m/z [M-305] or m/z
[M-336] . The fragmentation pattern of 14f was shown in
Scheme 6.
The molecular stability of 1,3,4-oxadiazole Mannich bases
of 9a-9d was poor as well, and only some of the compounds
showed molecular ion peaks, but there were characteristic
peaks at m/z 326, m/z corresponding to [M-326]. The
fragmentation pattern of 9a is shown in Scheme 3.

80
Q. Chen , F. M. Liu, F. Xu, C. Yang
Vol 45
Scheme 5: Proposal Fragmentation Processes of 13b
Synthesis of 3-(2-phenyl-1,2,3-triazol-4-yl)-5-methylisoxaz-
ole-4-ethyl formate (4). To a solution of ethanol of 0.08 mol
sodio-acetoacetic ester, 0.08 mol of chloroformaldehyde oxime
(3), dissolved in 100 ml of absolute ethanol, was added
gradually at –5~0 °C under stirring condition. The solution was
stirred at low temperature for 1 h again, then stirred at room
temperature for 2 h. Cold water was added into the solution. The
resulting solid was filtered, washed with water, and finally
recrystallized from ethanol to give white crystal of 4, yield 78%,
mp 83-84 °C.
a
+
.
N
N
N
N
Ph
N
S
N
c
+
.
N
N
H2
C
O
CH3
b
c
m/z 470
a
N
H3CO
m/z 147
C
M-323
b
OCH3
d
h
g
N
N
f
+
.
C
NH
+
d
5-Methyl-3-(2-phenyl-2H-1,2,3-triazol-4-yl)isoxazole-4-car-
bohydrazide (5). A solution of 0.04 mol of isoxazole ethyl
formate (4), dissolved in 30 ml of ethanol, was treated to 15 ml
85% of hydrazine and refluxed for 5 h. A white solid separated
out after the mixture had cooled. The solid was collected by
filtration, washed and recrystallized from ethanol to get white
crystal of 5, yield 77%, mp 176-178 °C.ꢀ
Ph
N
N
N
C
C
CH2O
e
N
132
m/z 103
m/z
O
CH3
h
m/z 252
g
f
e
+
+
m/z
77
.
.
+
N
NH
CN
H
N
.
Ph
N
Synthesis of 1-substituted-aminomethyl-3-(3-(2-phenyl-
1,2,3-triazol-4-yl)-5-methylisoxazol-4-yl)-4-phenyl-1,2,4-tria-
zole-5-thiones (Mannich bases 7a-7d). A mixture of 8 mmol of
carbohydrazide (5) and 8.8 mmol of phenylisosulfocyanate was
dissolved in ethanol, and heated under reflux for 4 h to give a
white solid. The resulting solid was treated to 160 ml 5% of
NaOH, and refluxed for 1.5 h. The pH of the mixture was
brought to 5 by adding 1:1 of hydrochloric acid to give white
solid. A white crystal of 6 was obtained after recrystallization
from ethanol. Yield 80%, mp 247-248°C.
Ph
N
N
CN
N
m/z
91
N
170
m/z
m/z 209
Scheme 6: Proposal Fragmentation Processes of 14f
+
.
b
+
.
N N
h
N
N
b
N
N
N
N
Ph
N
c
S
N
Ph
N
S
N
i
N
N
C2H5
a
N
N
C2H5
O
CH3
c
Compound 6 (1 mmol) and 0.5 ml 36% of formaldehyde were
refluxed in 20 ml of ethanol for 1 h, and 1.1 mmol substituted
amine was added at room temperature under stirring condition,
then refluxed for 2 h, and stirred again at room temperature until
M-42
m/z
336
m/z 378
a
i
h
+
H2
N
N
e
.
g
f
N
N
+
.
+
CN
+
Ph
N
a
white solid was separated. The resulting solid was
C2H5
C
N
S
C
C2H5
d
recrystallized from ethanol/benzene to give Mannich bases 7a-
7d.
N
N
m/z 73
M-305
O
CH3
m/z 55
O
251
m/z
1
m/z 110
7a, Yield 62%, mp 154-155 °C, white crystal. H NMR ꢀH:
g
d
f
e
7.81 (s, 1H, triazole-H), 7.82-6.96 (m, 15H, ArH), 5.75 (d, 2H,
NCH2N), 5.47 (t, 1H, NH), 2.41 (s, 3H, isoxazole-CH3).IR.
ꢁmax: 3405 (NH), 3061 (PhH), 2941 (CH3 or CH2), 1651, 1603,
1557, 1498 (Ar, C=N), 1252 (N-N=C), 1170, 1075, 1042 (C=S).
MS. m/z: 401, 216, 149, 135, 105, 91, 77. Anal. Calcd. for
C27H22N8OS: C, 64.02; H, 4.38; N, 22.12, Found: C, 63.89; H,
4.27; N, 22.06.
+
.
N
N
CN
H
+
.
+
Ph
N
N
.
N
NH
m/z 91
Ph
N
CN
N
m/z 77
m/z 209
m/z 170
1
7b, Yield 69%, mp 145-146 °C, white crystal. H NMR ꢀH:
7.83(s, 1H, triazole-H), 7.88-6.88 (m, 14H, ArH), 5.73(s, 2H,
NCH2N), 5.44 (s, 1H, NH), 2.42 (s, 3H, isoxazole-CH3), 2.18 (s,
3H, PhCH3). IR. ꢁmax: 3406 (NH), 3015 (PhH), 2920 (CH3 or
CH2), 1619, 1589, 1551, 1498 (Ar, C=N), 1256 (N-N=C), 1168,
1075, 1040 (C=S). MS. m/z: 401, 252, 216, 149, 135, 119, 91,
77. Anal. Calcd. for C28H24N8OS: C, 64.60; H, 4.65; N, 21.52,
Found: C, 64.49; H, 4.57; N, 21.46.
EXPERIMENTAL
Melting points were taken in an X-5 micro melting point
apparatus and were uncorrected. IR spectra were recorded on a
Bruker Tensor 27 spectrometer (KBr pellets). Mass spectra were
1
recorded on an Agilent 5975 spectrometer (EI, 70ev). HNMR
Spectra were obtained on a Bruker AV 400MHz instrument in
CDCl3 using TMS as an internal standard. Elemental analyses
were performed on a Perkin-Elmer 2400 CHN analyzer.
Synthesis of 2-phenyl-1,2,3-triazole-4-formaldehyde (1).
Compound of 1 was prepared according to literature [17], mp
67-68 °C.
1
7c, Yield 79%, mp 236-238 °C, pale yellow crystal. H NMR
ꢀH: 7.88 (s, 1H, triazole-H), 7.82-6.88 (m, 14H, ArH), 6.40 (s,
2H, NCH2N), 5.71 (s, 1H, NH ), 2.42 (s, 3H, isoxazole-CH3). IR.
ꢁmax: 3428 (NH), 3132 (PhH), 2963 (CH3 or CH2), 1666, 1596,
1542, 1500 (Ar, C=N), 1264 (N-N=C), 1202, 1155, 1042 (C=S).
MS. m/z: 401, 252, 171, 149, 139, 135, 91, 77. Anal. Calcd. for
C27H21N8OSCl: C, 59.99; H, 3.92; N, 20.74, Found: C, 59.78; H,
3.87; N, 20.67.
Synthesis of 2-phenyl-1,2,3-triazole-4-formaldehyde oxime
(2). Compound of 2 was prepared according to literature [18],
mp 135-137 °C.
1
7d, Yield 80%, mp 199-201 °C, white crystal. H NMR ꢀH:
Synthesis of ꢀ-chloro-2-phenyl-1,2,3-triazole-4-formalde-
hyde oxime (3). Compound of 3 was prepared according to
literature [19], mp 143-145 °C.
7.98 (s, 1H, triazole-H), 7.99-7.08 (m, 10H, ArH), 5.30 (s, 2H,
NCH2N), 2.50 (s, 3H, isoxazole -CH3), 2.82, 1.52, 1.23 (m, 10H,
piperidine-H). IR. ꢁmax: 3100 (PhH), 2938 (CH3 ), 2853(CH2),

Jan-Feb 2008
New Heterocyclic Compounds of 1,2,3-Triazole and Isoxazole
81
1648, 1585, 1556, 1499 (Ar, C=N), 1225 (N-N=C), 1156, 1118,
1041 (C=S). MS. m/z: 401, 252, 216, 170, 149, 135, 91, 77.
Anal. Calcd. for C26H26N8OS: C, 62.63; H, 5.26; N, 22.49,
Found : C, 62.59; H, 5.27; N, 22.31.
separated after the mixture had cooled, which was collected by
filtration and washed with ethanol to give 10a-10f. The crude
products were used without further purification. 10a, Yield 88%,
mp 145-146 °C, pale yellow crystal. 10b, Yield 89%, mp 177-
178 °C, pale yellow crystal. 10c, Yield 81%, mp 225-226 °C,
pale yellow crystal. 10d, Yield 91%, mp 253-255 °C, white
crystal. 10e, Yield 74%, mp 132-134 °C, white crystal. 10f,
Yield 82%, mp 170-171 °C, white crystal.
Synthesis of 2-(3-(2-phenyl-1,2,3-triazol-4-yl)-5-methyl-
isoxazol-4-yl)-4-substituted-amino methyl-1,3,4-oxadiazoline-
5-thiones (Mannich bases 9a-9d). 10 mmol of carbohydrazide
(5) was dissolved in 100 ml of ethanol containing 15 mmol of
KOH, and 50 ml of ethanol solution of 15 mmol CS2 was added
gradually at room temperature. The reaction mixture was heated
on water-bath for 6 h then the solvent was removed by
distillation. The residue was stirred with 200 ml of water, and
the solution was brought to a pH of 7-5 to give a large amount of
white solid. The precipitated product was collected by filtration,
washed thoroughly with water, dried and recrystallized from
ethanol/DMF to give white needle crystal of 8. Yield 75%, mp
229-231 °C.
A mixture of 6 and 5 ml of acetic anhydride was refluxed for
1.5 h. The product was poured into cold water, and allowed to
stand overnight to turn the oily matter into solid. The separated
solid was washed, dried and recrystallized from ethanol to give
crystals of 11a-11f.
1
11a, Yield 76%, mp 159-160 °C, white crystal. H NMR ꢀH:
8.38 (s, 1H, triazole-H), 7.90-7.41 (m, 10H, ArH), 7.26 (s, 1H,
oxadiazoline-H), 2.86 (s, 3H, COCH3), 2.15 (s, 3H, isoxazole-
CH3). IR. ꢁmax: 3170, 3061 (PhH), 2922 (CH3), 1660 (C=O),
1249 (N-N=C), 1075 (C-O-C ). MS. m/z: 414 (M+), 253, 252,
211, 172, 105, 91, 77. Anal. Calcd. for C22H18N6O3: C, 63.75; H,
4.38; N, 20.29, Found: C, 63.69; H, 4.29; N, 20.19.
A solution of 1 mmol of 8 in 10 ml of ethanol containing 0.5
ml 36% of formaldehyde was refluxed for 1 h, and 1 mmol of
substituted amine in 5 ml of ethanol was added at room
temperature under stirring condition. After a moment, a white
solid was separated, and continued to stir for 2 h. The mixture
allowed to stand overnight, filtered and recrystallized from
ethanol to give white or pale yellow crystals of 9a-9d.
1
11b, Yield 71%, mp 189-191 °C, white crystal. H NMR ꢀH:
8.39 (s, 1H, triazole-H), 8.23-7.00 (m, 9H, ArH), 7.01 (s, 1H,
oxadiazoline-H), 3.90 (s, 3H, OCH3), 2.86 (s, 3H, COCH3), 2.15
(s, 3H, isoxazole-CH3). IR. ꢁmax: 3159, 3078 (PhH), 2929
(CH3), 1672(C=O), 1250 (N-N=C). 1081 (C-O-C). MS. m/z: 444
(M+), 403, 252, 211, 171, 105, 91, 77. Anal. Calcd. for
C23H20N6O4: C, 62.14; H, 4.54; N, 18.92, Found: C, 61.98; H,
4.47; N, 18.89.
1
9a, Yield 77%, mp 154-156 °C, pale yellow crystal. H NMR
ꢀH: 8.29 (s,1H, triazole-H ), 8.14-6.88 (m, 10H, ArH ), 5.56 (s,
2H, NCH2N ), 5.13 (s, 1H, NH ), 2.69 (s, 3H, isoxazole-CH3).
IR. ꢁmax: 3338 (NH), 3034 (PhH), 2968 (CH3 or CH2), 1662,
1603, 1527, 1499 (Ar, C=N), 1260 (N-N=C), 1089, 1044 (C=S).
MS. m/z: 431 (M+), 326, 237, 211, 105, 91, 77, 69. Anal. Calcd.
for C21H17N7O2S: C, 58.45; H, 3.97; N, 22.74, Found: C, 58.21;
H, 3.90; N, 22.69.
1
11c, Yield 71%, mp 134-136 °C, white crystal. H NMR ꢀH:
8.32 (s, 1H, triazole-H), 8.23-7.36 (m, 9H, ArH), 7.01 (s, 1H,
oxadiazoline-H), 2.85 (s, 3H, COCH3), 2.15 (s, 3H, isoxazole-
CH3). IR. ꢁmax: 3172, 3083 (PhH), 2921(CH3), 1681 (C=O),
1248 (N-N=C), 1072 (C-O-C ). MS. m/z: 448 (M+), 450 (M++2),
407, 253, 252, 211, 171, 105, 91, 77. Anal. Calcd. for
C22H17N6O3Cl: C, 58.91; H, 3.82; N, 18.75, Found: C, 58.70; H,
3.78; N, 18.61.
9b, Yield 74%, mp 143-145 °C, pale yellow crystal. 1H NMR
ꢀH: 8.27 (s, 1H, triazole-H), 8.15-6.77 (m, 9H, ArH), 5.52 (s,
2H, NCH2N), 5.04 (s, 1H, NH), 2.70 (s, 3H, isoxazole-CH3),
2.21 (s, 3H, PhCH3). IR. ꢁmax: 3366 (NH), 3049 (PhH), 2921
(CH3 or CH2), 1616, 1597, 1519, 1497 (Ar, C=N), 1250 (N-
N=C), 1095, 1042 (C=S). MS. m/z: 326, 237, 251, 211, 170,
119, 91, 77. Anal. Calcd. for C22H19N7O2S: C, 59.31; H, 4.30; N,
22.02, Found: C, 59.15; H, 4.24; N, 22.00.
11d, Yield 90%, mp 140-142 °C, yellow crystal. 1H NMR ꢀH:
8.31(s, 1H, triazole-H), 8.22-7.27 (m, 9H, ArH), 7.11 (s, 1H,
oxadiazoline-H), 2.77 (s, 3H, COCH3), 2.33 (s, 3H, isoxazole-
CH3). IR. ꢁmax: 3117, 3059 (PhH), 2927 (CH3), 1663 (C=O),
1249 (N-N=C ), 1081 (C-O-C). MS. m/z: 459 (M+), 418, 253,
252, 211, 105, 91, 77. Anal. Calcd. for C22H17N7O5: C, 57.50; H,
3.73; N, 21.35, Found: C, 57.38; H, 3.66; N, 21.20.
1
9c, Yield 76%, mp 139-141 °C, pale yellow crystal. H NMR
ꢀH: 8.26 (s, 1H, triazole-H), 8.13-6.79 (m, 9H, ArH), 5.50 (d,
2H, NCH2N), 5.14 (t, 1H, NH), 2.73 (s, 3H, isoxazole-CH3). IR.
ꢁmax: 3398 (NH), 3118, 3060 (PhH), 2940 (CH3 or CH2), 1621,
1601, 1520, 1494 (Ar, C=N), 1248 (N-N=C), 1089, 1042 (C=S).
MS. m/z: 326, 237, 251, 211, 170, 91, 77, 69. Anal. Calcd. for
C21H16N7O2SCl: C, 54.18; H, 3.47; N, 21.08, Found: C, 54.01;
H, 3.39; N, 20.95.
1
11e, Yield 70%, mp 103-105 °C, white crystal. H NMR ꢀH:
8.33 (s, 1H, triazole-H), 8.23-7.26 (m, 10H, ArH), 2.73 (s, 3H,
COCH3), 2.28 (s, 3H, oxadiazoline-CH3), 2.28 (s, 3H, isoxazole-
CH3). IR. ꢁmax: 3178, 3070 (PhH), 2949 (CH3), 1658 (C=O),
1253 (N-N=C), 1084 (C-O-C ). MS. m/z: 428 (M+), 371, 253,
252, 211, 105, 91, 77. Anal. Calcd. for C23H20N6O3: C, 64.46; H,
4.71; N, 19.62, Found: C, 64.39; H, 4.67; N, 19.57.
1
9d, Yield 79%, mp 132-134 °C, white crystal. H NMR ꢀH:
8.35 (s, 1H, triazole-H), 8.15-7.26 (m, 5H, ArH ), 5.07 (s, 2H,
NCH2N), 2.79 (s, 3H, isoxazole-CH3), 1.31-2.78 (m, 10H,
piperidine-H). IR. ꢁmax: 3154 (PhH), 2936 (CH3 or CH2),
1596, 1494 (Ar, C=N), 1248 (N-N=C), 1087, 1042 (C=S).
MS.m/z: 326, 251, 211, 171, 91, 77, 69. Anal. Calcd. for
C20H21N7O2S: C, 56.72; H, 5.00; N, 23.16, Found: C, 57.64; H,
4.87; N, 23.08.
Synthesis of 2-substituted-3-acetyl-5-(3-(2-phenyl-1,2,3-
triazol-4-yl)-5-methylisoxazol-4-yl)-1,3,4-oxadiazolines (11a-
11f). 1 mmol of carbohydrazide (5) was dissolved in 15 ml of
ethanol with 2-3 D glacial acetic acid, and 1.1 mmol of
substituted aldehydes or ketones was added. The mixture was
heated under reflux for 3 h, and a yellow or white crystal
1
11f, Yield 70%, mp 134-135 °C, white crystal. H NMR ꢀH:
8.38(s, 1H, triazole-H), 8.15-7.26 (m, 5H, ArH), 2.76(s, 3H,
COCH3), 2.65-1.36 (m, 10H, cyclohexanyl-H), 2.24(s, 3H,
isoxazole-CH3). IR. ꢁmax: 3024 (PhH), 2946, 2854 (CH3, CH2 ),
1661 (C=O), 1246 (N-N=C), 1078(C-O-C). MS. m/z: 406 (M+),
364, 321, 253, 211, 171, 105, 91, 77. Anal. Calcd. for
C21H22N6O3: C, 62.04; H, 5.46; N, 20.69, Found: C, 61.97; H,
5.40; N, 20.51.
Synthesis of 3-(3-(2-phenyl-1,2,3-triazol-4-yl)-5-methylis-
oxazol-4-yl)-6-substituted-7H-1,2,4-triazolo[3,4-b]1,3,4-thia-
diazines (13a-13c). 10 mmol of carbohydrazide (5) and 15 mmol of
KOH were dissolved in 25 ml of ethanol. 5 ml of ethanol solution of

82
Q. Chen , F. M. Liu, F. Xu, C. Yang
Vol 45
15 mmol of CS2 was added slowly at room temperature under
stirring condition, stirred for 15 h then the mixture was diluted with
10 ml of dry ether, and kept stirring for 0.5 h. The solid was
collected by filtration, washed with ether to give the white
potassium salt, and was employed without further purification.
The salt, prepared as described above, was refluxed for 6 h in
4 ml of water containing 4 ml 85% of hydrazine. Dilution with
100 ml of cold water and acidification with 1:1 of hydrochloric
acid resulting in a large amount of pale yellow solid. This
product was collected by filtration, recrystallized from
ethanol/DMF to give crystal of 12. Yield 73%, mp 243-246 °C.
A mixture of 12 and ꢀ-substitued-bromoacetophenone was
dissolved in 25 ml of absolute ethanol, and refluxed for 6-10 h.
The 1:1 of aqueous ammonia brought pH of the solution to 9
after the mixture had cooled. Having stood overnight, the
product was collected by filtration and recrystallized from
ethanol/ethyl acetate to give the crystals of 13a-13c.
14c, Yield 75%, mp 195-197 °C, pale yellow crystal. 1H NMR
ꢀH: 8.14 (s, 1H, triazole-H), 7.75-7.24 (m, 9H, ArH), 2.74 (s,
3H, isoxazole-CH3). IR. ꢁmax: 3143, 3049 (PhH), 1670, 1595,
1461 (Ar, C=N, C=N-S), 1245 (N-N=C), 693 (C-S-C). MS. m/z:
460 (M+), 462 (M++2), 418, 251, 209, 170, 155, 137, 110, 91,
77. Anal. Calcd. for C21H13N8OSCl: C, 54.78; H, 2.85; N, 24.35,
Found: C, 54.61; H, 2.79; N, 24.21.
1
14d, Yield 65%, mp 208-209 °C, pale yellow crystal. H
NMR ꢀH: 8.30 (s, 1H, triazole-H), 7.74-6.87 (m, 9H, ArH), 3.83
(s, 3H, OCH3), 2.73 (s, 3H, isoxazole-CH3). IR. ꢁmax: 3152,
3049 (PhH), 2933 (CH3), 1686, 1608, 1459 (Ar, C=N, C=N-S),
1265(N-N=C), 702 (C-S-C). MS. m/z: 456 (M+), 251, 209, 171,
151, 136, 110, 108, 91, 77. Anal. Calcd. for C22H16N8O2S: C,
57.89; H, 3.53; N, 24.55, Found: C, 57.71; H, 3.47; N, 24.43.
14e, Yield 60%, mp 191-192 °C, brown crystal. 1H NMR ꢀH:
8.29 (s, 1H, triazole-H), 7.74-7.26 (m, 5H, ArH), 2.68 (s, 3H,
isoxazole-CH3), 2.50 (s, 3H, thiadiazole-CH3). IR. ꢁmax: 3132
(PhH), 2922 (CH3), 1651, 1596, 1455 (Ar, C=N, C=N-S), 1244
(N-N=C), 700 (C-S-C). MS. m/z: 364 (M+), 322, 252, 209, 170,
110, 91, 77, 59. Anal. Calcd. for C16H12N8OS: C, 52.74; H, 3.32;
N, 30.75, Found: C, 52.57; H, 3.27; N, 30.69.
13a, Yield 56%, mp 202-204 °C, yellow crystal. 1H NMR ꢀH:
8.16 (s, 1H, triazole-H), 7.76-7.27 (m, 10H, ArH), 3.68 (s, 2H,
thiadiazine-H), 2.73 (s, 3H, isoxazole-CH3). IR. ꢁmax: 3110,
3073 (PhH), 2902 (CH3), 1646, 1592, 1562, 1492 (Ar, C=N,
C=N-S), 1226 (N-N=C), 685 (C-S-C ). MS. m/z: 440 (M+), 252,
170, 117, 103, 91, 77. Anal. Calcd. for C22H16N8OS: C, 59.98; H,
3.66; N, 25.45, Found: C, 59.79; H, 3.59; N, 25.33.
1
14f, Yield 65%, mp 137-138 °C, brown crystal. H NMR ꢀH:
8.29 (s, 1H, triazole-H), 7.73-7.27 (m, 5H, ArH), 2.70 (s, 3H,
isoxazole-CH3), 2.79 (q, 2H, thiadiazole-CH2R), 1.11 (t, 3H,
RCH3). IR. ꢁmax: 3134(PhH), 2981, 2925 (CH3, CH2), 1650,
1596, 1454 (Ar, C=N, C=N-S), 1243 (N-N=C), 700 (C-S-C).
MS. m/z: 378 (M+), 336, 251, 209, 170, 110, 91, 77, 73, 55.
Anal. Calcd. for C17H14N8OS: C, 53.96; H, 3.73; N, 29.61,
Found: C, 53.73; H, 3.67; N, 29.50.
14g, Yield 63%, mp 125-127 °C, brown crystal. 1H NMR ꢀH:
8.28 (s, 1H, triazole-H), 7.73-7.28 (m, 5H, ArH), 2.71 (t, 3H,
isoxazole-CH3), 2.71 (s, 2H, thiadiazole-CH2R), 1.54 (m, 2H,
R1CH2R2), 0.84 (t, 3H, RCH3). IR. ꢁmax: 3132 (PhH), 2965,
2928 (CH3, CH2), 1643, 1599, 1455 (Ar, C=N, C=N-S), 1245
(N-N=C), 686 (C-S-C). MS. m/z: 392 (M+), 350, 251, 209, 172,
110, 91, 77. Anal. Calcd. for C18H16N8OS: C, 55.09; H, 4.11; N,
28.55, Found: C, 54.89; H, 4.07; N, 28.48.
14h, Yield 67%, mp 118-119°C, brown crystal.1H NMR ꢀH:
8.28 (s, 1H, triazole-H), 7.73-7.28 (m, 10H, ArH), 2.70 (s, 3H,
isoxazole-CH3), 2.71 (s, 2H, thiadiazole -CH2R), 1.49-1.13 (m,
4H, R1(CH2)2R2), 0.74 (t, 3H, CH3R). IR. ꢁmax: 3052 (PhH),
2963, 2934 (CH3, CH2), 1637, 1599, 1456 (Ar, C=N, C=N-S),
1244 (N-N=C), 687 (C-S-C ). MS. m/z: 406 (M+), 364, 251, 209,
170, 110, 105, 89, 91, 77, 57. Anal. Calcd. for C19H18N8OS: C,
56.14; H, 4.46; N, 27.57, Found: C, 55.92; H, 4.37; N, 27.42.
1
13b, Yield 73%, mp 170-171 °C, white crystal. H NMR ꢀH:
8.15 (s, 1H, triazole-H), 7.74-6.79 (m, 9H, ArH), 3.81 (s, 3H,
OCH3), 3.62 (s, 2H, thiadiazine-H), 2.74 (s, 3H, isoxazole-CH3).
IR. ꢁmax: 3101 (PhH), 2903 (CH3), 1608, 1551, 1519, 1457 (Ar,
C=N, C=N-S), 1261 (N-N=C), 688 (C-S-C). MS. m/z: 470, 252,
209, 170, 147, 132, 103, 91, 77. Anal. Calcd. for C23H18N8O2S:
C, 58.71; H, 3.86; N, 23.83, Found: C, 58.68; H, 3.79; N, 23.74.
1
13c, Yield 56%, mp 182-183 °C, white crystal. H NMR ꢀH:
8.14 (s, 1H,triazole-H), 7.75-7.24 (m, 9H, ArH), 3.63 (s, 2H,
thiadiazine-H), 2.74 (s, 3H, isoxazole-CH3). IR. ꢁmax: 3112
(PhH), 2911 (CH3), 1633, 1593, 1522, 1493 (Ar, C=N , C=N-S),
1229 (N-N=C), 698 (C-S-C). MS. m/z: 474 (M+), 476 (M++2),
251, 209, 170, 151, 137, 103, 91, 77. Anal. Calcd. for
C22H15N8OSCl: C, 55.69; H, 3.19; N, 23.63, Found: C, 55.47; H,
3.13; N, 23.51.
Synthesis of 3-(3-(2-phenyl-1,2,3-triazol-4-yl)-5-methylis-
oxazol-4-yl)-6-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiaz-
oles (14a-14c). A mixture of 1.47 mmol of 12 and 1.62 mmol of
carboxylic acid in 5.0 ml of POCl3, was heated under reflux at
90-115 °C for 5 h. After removed of the excess of POCl3 under
reduced pressure, 50 ml of cold water was added into the
residue. The resulting solid was filtered, washed with 10%
NaOH and water, then dried, recrystallized from ethanol/DMF
to give products of 14a-14h.
REFERENCES
14a, Yield 77%, mp 183-184 °C, pale yellow crystal. 1H
NMR ꢀH: 8.25 (s, 1H, triazole-H), 7.80-7.24 (m, 10H, ArH),
2.75 (s, 3H, isoxazole-CH3). IR. ꢁmax: 3138, 3074 (PhH), 1648,
1596, 1457 (Ar, C=N ,C=N-S), 1234 (N-N=C), 682 (C-S-C).
MS. m/z: 426 (M+), 384, 252, 209, 170, 121, 110, 91, 77. Anal.
Calcd. for C21H14N8OS: C, 59.14; H, 3.31; N, 26.29, Found: C,
59.01; H, 3.27; N, 26.15.
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1
14b, Yield 80%, mp 256-257 °C, pale yellow crystal. H
NMR ꢀH: 8.32 (s, 1H, triazole-H), 8.26-7.25 (m, 9H, ArH), 2.76
(s, 3H, isoxazole-CH3). IR. ꢁmax: 3110, 3034 (PhH), 1638,
1603, 1455 (Ar, C=N, C=N-S), 1244 (N-N=C), 687 (C-S-C).
MS. m/z: 471 (M+), 429, 251, 209, 166, 136, 120, 110, 91, 77.
Anal. Calcd. for C21H13N9O3S: C, 53.49; H, 2.78; N, 26.75,
Found: C, 53.30; H, 2.70; N, 26.67.

Jan-Feb 2008
New Heterocyclic Compounds of 1,2,3-Triazole and Isoxazole
83
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