Synthesis, characterization and studies of new 3-benzyl-4H-1,2,4-triazole- 5-thiol and thiazolo[3,2-b][1,2,4]triazole-5(6H)-one heterocycles

Article abstract of DOI:10.1002/jhet.5570450339

(Chemical Equation Presented) 3-Benzyl-4-phenyl-1,2,4-triazole-5-thiol (1) was synthesized and used as starting material for preparation of 1,2,4-triazole bearing substituted thiosemicarbazides moiety (4a-d) in high yields. The thiosemicarbazides 4a-d were cyclized in basic medium to give two triazole rings linked by thiomethylene group (5a-d), while cyclization of thiosemicarbazides 4a-d with chloroacetyl chloride in the presence of CHCl₃ and K ₂CO₃ afforded the thiazolidinone derivatives 6a-d. The reaction of thiosemicarbazides 4a-c with phenacyl bromide in the presence of EtOH and fused CH₃COONa gave the corresponding thiazoline ring systems 7a-c. Condensation of the 3-benzyl-1,2,4-triazole-5(1H)-thiol (1) with chloroacetic acid and aromatic aldehydes (8a-g) in boiling acetic acid/acetic anhydride mixture in the presence of fused sodium acetate gave one single isomer only, which might be 9a-g or 10a-g. Upon application of Micheal addition reaction on compounds 9a-e with cyclic secondary amines such as piperidine or morpholine the 2-benzyl-6-(α-amino-aryl/methyl)-1,3-thiazolo[3,2-b][1,2,4] -triazol-5-ols (11a-j) were obtained in good yields The structure of all new compounds were determined using both spectral and elemental analyses.

Full text of DOI:10.1002/jhet.5570450339

May-Jun 2008
897
Synthesis, Characterization and Studies of New 3-Benzyl-4H-1,2,4-
triazole-5-thiol and Thiazolo[3,2-b][1,2,4]triazole-5(6H)-one
Heterocycles
Abdelwareth A. O. Sarhan*, Hassan. A. H. ElSherif, Abdalla M. Mahmoud
and Osama M. A. Habib
Chemistry Department, Faculty of Science, Assiut University
Assiut 71516, Egypt
E-mail: elwareth@acc.aun.edu.eg
Received November 6, 2006
N
N
N
N
N
X
H
N
R
Ph
Ph
Ph
N
S
N
SH
N
N
H
H
O
Ph
Ph
O
N
N
N
S
H
N
H
Ph
N
S
S
N
N
N
R
X
O
Ph
R
3-Benzyl-4-phenyl-1,2,4-triazole-5-thiol (1) was synthesized and used as starting material for
preparation of 1,2,4-triazole bearing substituted thiosemicarbazides moiety (4a-d) in high yields. The
thiosemicarbazides 4a-d were cyclized in basic medium to give two triazole rings linked by
thiomethylene group (5a-d), while cyclization of thiosemicarbazides 4a-d with chloroacetyl chloride
in the presence of CHCl3 and K2CO3 afforded the thiazolidinone derivatives 6a-d. The reaction of
thiosemicarbazides 4a-c with phenacyl bromide in the presence of EtOH and fused CH3COONa gave
the corresponding thiazoline ring systems 7a-c. Condensation of the 3-benzyl-1,2,4-triazole-5(1H)-
thiol (1) with chloroacetic acid and aromatic aldehydes (8a-g) in boiling acetic acid/acetic anhydride
mixture in the presence of fused sodium acetate gave one single isomer only, which might be 9a-g or
10a-g. Upon application of Micheal addition reaction on compounds 9a-e with cyclic secondary
amines such as piperidine or morpholine the 2-benzyl-6-(α-amino-aryl/methyl)-1,3-thiazolo[3,2-
b][1,2,4]-triazol-5-ols (11a-j) were obtained in good yields The structure of all new compounds were
determined using both spectral and elemental analyses.
J. Heterocyclic Chem., 45, 897 (2008).
Scheme 1
INTRODUCTION
N
N
N
N
N N
ClCH2COOH
SH
Ac2O/Py
SCH2COOH
Thiosemicarbazides are convenient intermediates for
synthesis of several heterocycles such as triazoles, thiazol-
ines and thiazolidinones. It has been reported that thiosemi-
carbazide derivatives have antitubercular [1,2], antifungal
[2-4] and hypoglycemic [5] activities. These findings
encouraged us to synthesize new s-triazole derivatives
incorporated thiosemicarbazide moiety, thiazoline, thiazoli-
dinone or triazole ring systems. Several thiazolo[3,2-b]-
[1,2,4]triazol-5(6H)-ones [6-12] have been prepared
directly in one step reaction using the mercaptotriazole,
chloroacetic acid and aromatic aldehydes.
Kendall et al. [13] have reported that the synthesis of
1,3-thiazolo-1,2,4-triazoles occurred by the reaction of 3-
mercapto-5-methyl-1,2,4-triazole with chloroacetic acid
to give the 1,2,4-triazolylthioglycolic acid derivative,
which on ring closure in the presence of acetic anhydride/
pyridine mixture afforded the thiazolo[2,3-c]-1,2,4-tri-
azol-5(6H)-one. No rigorous proof was given to exclude
the possible alternative structure 1,3-thiazolo[2,3-b]-
1,2,4-triazole, Scheme 1.
H3C
H3C
H3C
N
S
N
H
N
H
O
Gogoi [14] and Tozkoparan [15] and coworkers, have
studied also the cyclization of this type of reaction for the
preparation of the 2-substituted-6-arylidenylthiazolo[3,2-
b]-1,2,4-triazol-5-(6H)-one, either in two steps or in one
step reaction. Direct condenstation of 1,2,4-triazole-3-
thiol with chloroacetic acid and aromatic aldehydes under
the same reaction conditions gave the same result [10,16],
Scheme 2.
Scheme 2
O
O
N
N
N
N
N
NH
ClCH2COOH
AcONa/EtOH
N
ArCHO
N
R
R
SH
R
S
Ar
N
S
R = CH3, 2,3-Cl2C6H3

898
A. A. O. Sarhan, H.. A. H. ElSherif, A. M. Mahmoud and O. M. A. Habib
Vol 45
RESULTS AND DISCUSSION
N-(3-substituted-4-oxothiazolidine-2-ylidene)-N'-[(5'-
benzyl-4'phenyl-s-triazol-3'-yl)thioacetyl]hydrazines (6a-
d) [18,19]. While, reaction of the thiosemicarbazides 4a-c
with phenacyl bromide in boiling ethanol in the presence
of fused sodium acetate gave the N-(4-phenyl-3-
substituted-2,3-dihydrothiozol-2-ylidene-N'-[(5'-benzyl-
4'-phenyl-s-triazol-3'-yl)thioacetyl]hydrazines (7a-c)
respectively, Scheme 4.
The 3-benzyl-4-phenyl-1,2,4-triazole-5-thiol (1) was
prepared according to the reported method in good
yield [17]. Treatment of 1 with ethyl chloroacetate in
boiling ethanol containing fused sodium acetate gave
the corresponding ester 2 in 85% yields. The latter was
reacted with hydrazine hydrate in refluxing ethanol to
give the corresponding crystalline hydrazide 3 as
colorless needles in 90% yield. The hydrazide
derivative 3 was treated with the appropriate isothio-
cyanate derivatives in boiling ethanol to afford the
corresponding 1-[(5'-benzyl-4'-phenyl-1,2,4-triazol-3'-
yl)thioacetyl]-4-substituted-thiosemicarb-azides (4a-d)
in high yields as shown in Scheme 3.
The structures of the compounds 2, 3, 4a-d, 6a-d and
7a-c were confirmed on the basis of their spectral and
elemental analysis and are in satisfactory agreement with
the suggested structure. The IR spectra of compounds 4a-
d showed the appearance of three NH groups at ν 3300,
3200 and 3150 cm-1 respectively. Compounds 5a-d
revealed an absorption band at ν 3070 ~ 3090 cm-1
characterized to the NH besides the absorption band at ν
1070 cm-1 due to the presence of the (C=S) group. The
lowering of the NH absorption bands in compounds 5a-d
might be attributed to the tautomeric nature of the HN–
C=S ↔ N=C–SH group. While the IR spectra of
compounds 6a-d and 7a-c exhibited only one sharp
absorption band at ν 3150 ~ 3200 cm-1, characteristic of
the presence of the NH group, appeared in all compounds.
On the other hand, condensation of the 3-benzyl-1,2,4-
triazole-5(1H)-thiol (1) with chloroacetic acid [9] and
appropriate aromatic aldehydes 8a-g in boiling glacial
acetic acid/acetic anhydride mixture in the presence of
fused sodium acetate gave only one pure product, which
may be 9 or 10, Scheme 5.
Scheme 3
N
N
N
N
ClCH2COOEt
Ph
Ph
O
EtOH/AcONa, reflux
N
Ph
1
SH
N
Ph
2
S
C2H5
O
NH2NH2
EtOH, reflux
N
N
N
N
S
H
N
H
N
RNCS
EtOH, reflux
Ph
R
Ph
N
S
N
S
N
H
N
H
NH2
O
O
Ph
Ph
4a-d
3
4a; R = CH3, 4b; R = C2H5, 4c; R = C6H11, 4d; R = C6H5
On cyclization of the thiosemicarbazides 4a-d in basic
medium the 5-benzyl-4-phenyl-3-[(5'-mercapto-4'-substi-
tuted-s-triazol-3'-yl)methylthio]-s-triazoles 5a-d were
obtained in good yield. Further, the thiosemicarbazides
4a-d were reacted with chloroacetyl chloride in boiling
CHCl3 in the presence of anhydrous K2CO3 afforded the
Scheme 5
N
NH
ClCH2COOH
AcOH/Ac2O
R
CHO
Ph
N
SH
1
8a-g
AcONa, heat
Scheme 4
N
N
N
N
N
N
S
H
N
N
N
N
O
Ph
Ph
O
N
N
S
S
N
N
N
N
R
SH
N
R
Ph
S
Ph
O
Ph
Ph
N
S
6a-d
5a-d
a; R = CH3 b; R = C2H5
c; R = C6H11 d; R = C6H5
O
a; R = CH3 b; R = C2H5
c; R = C6H11 d; R = C6H5
l
C
%
O
C 2
5
H
H
C
O
a
l
R
N
C
10a-g
9a-g
R
N
N
S
H
N
a; R = H, b; R = Cl, c; R = NO2, d; R = OCH3
e; R = N(CH3)2, f; R = Br, g; R = OCOCH3
Ph
R
N
H
S
N
H
N
O
Ph
4a-c
The experimental 1H-NMR spectral analysis and
molecular modeling calculations of compounds 9 and 10
were found in satisfactory agreement with similar results
reported in literature [6]. The data obtained herein support
that formation of the derivatives 9a-g are favored over
compounds 10a-g. The 1H-NMR spectral data of the
products showed a singlet at δ 4.2-4.1 ppm which
PhCOCH2Br
EtOH,ACONa
reflux
N
N
S
H
N
N
Ph
Ph
S
N
N
O
Ph
R
7a-c
a; R = CH3 b; R = C2H5, c; R = C6H5

May-Jun 2008
Synthesis, Characterization and Studies of New 3-Benzyl-4H-1,2,4-triazole-5-thiol
899
attributed to the methylene protons (CH2) in addition to
the other expected protons, detailed of NMR spectra are
summarized in the experimental section. The IR spectra of
9a-g showed bands at 3030 (C-H aromatic), 2920 (C-H
aliphatic), 1730-1710 (C=O) and 1610-1580 (C=N), in
addition compound 9g exhibited an additional band at
1750 cm-1 for the second (C=O) due to the acetylation of
the hydroxyl group (OH). The mass spectra of compounds
9e and 9g showed the molecular ion peaks M+ at m/z 377
(75%) and 362 (100%) respectively.
On the other hand the molecular modeling study
revealed that the formation of compounds 9a-g is more
favorable than 10a-g, Table 1. Our studies based on the
MMX-M calculation, MOPAC force field calculation of
MM2+ type [20]. Further the stereochemistry of
compounds 9a-g has been achieved also by molecular
modeling calculations, which indicate that the (E)
configuration is more stable than the (Z) isomer, Table 1.
Moreover, when compounds 9a-e were reacted with
cyclic secondary amines such as piperidine or
morpholine, in tetrahydrofuran under the conditions of
Michael addition reaction gave the expected 2-benzyl-6-
(α-amino-aryl-methyl)-1,3-thiazolo[3,2-b]-1,2,4-triazole-
5-ols (11a-j) in relatively high yields, Scheme 6.
Scheme 6
O
OH
HN
N
N
X
N
N
Ph
Ph
H
C
N
S
CH
R
N
S
THF
N
X
X = CH2, O
11a-j
9a-e
No.
11a
11b
11c
11d
11e
R
R
H
Cl
NO2
OCH3
N(CH3)2
X
No
11f
11g
11h
11i
11j
X
O
O
O
O
O
CH2
CH2
CH2
CH2
CH2
Figure 1. Ball and stick model of the isomer 9a drawn from Chem3D 9.0.1.
Table 1
The structure of the addition products 11a-j was
confirmed by their elemental and spectral analysis. The IR
spectra of 11a-j showed an absorption band at 3200-3100
cm-1 (OH group) due to the enolic form instead of the
band at 1730-1710 cm-1 (C=O) of the ketonic form. The
1H-NMR spectral data of 11a-j in CDCl3 showed a set of
signals at δ 8.3-6.6 (m, aromatic protons) of the starting
9a-e, δ 7.0-6.8 (s, 1H, ArCHN), δ 4.2-4.1 (s, 2H, PhCH2-)
and at δ 3.7-1.3 (m, 10H, 5 CH2 of piperidine) or at δ 3.8-
3.3 ppm (m, 8H, 4CH2 of morpholine). The mass spectra
of 11a,b and 11g showed molecular ion peaks M+ with
weak intensity at m/z 404 (3%) (11a), 438 (1 %), 440
(2%) (11b) and 442 (1%) (11g) respectively, the base
The molecular mechanical calculations of compounds 9a-g (E-form
and Z-form) and 10a-g.
O
O
R
N
N
N
N
Ph
Ph
H
N
S
N
S
H
(E-form) 9a-g
(Z-form) 9a-g
R
Compd. No.
9 and 10
E (k.cal./mol.) E (k.cal./mol.) E (k.cal./mol.)
Comp. 9a-g
(E-form)
46.247
Comp. 9a-g Comp. 10a-g
(Z-form)
R
a
b
c
d
e
f
H
Cl
NO2
OCH3
N(CH3)2
Br
51.138
51.329
49.637
53.899
56.129
50.905
52.974
52.803
54.224
54.848
57.668
52.339
46.197
48.484
+
+
peak is (M - 85) or (M - 87) due to loss of a pipreidine
or morpholine molecule respectively.
53.419
50.544
45.679
The UV spectra of compounds 9a-f showed
a
g
OCOCH3
49.447
56.507
56.585
bathochromic shift (red shift) of about 204-103 nm as a

900
A. A. O. Sarhan, H.. A. H. ElSherif, A. M. Mahmoud and O. M. A. Habib
Vol 45
result of cyclization and the extended conjugation
occurring in the parent 1,2,4-triazole 1, which has λmax at
254, 210 nm. The effect of substituent on the absorption
wave length (λmax) was shown in the following order
N(CH3)2 > OCH3 > NO2 > Br > Cl > H. However, the
Micheal addition reaction products 11a-j showed a
hypsochromic shift (blue shift) of 38-99 nm due to the
shortening of conjugation.
Scheme 8
O
O
N
N
N
N
CH2(CN)2
Ph
Ph
CH(CN)2
CH
N
S
EtOH/Pyridine
N(CH3)2
N
N
S
HC
H
9e
HOH
N(CH3)2
OH
O
CN
C
NH
(H3C)2N
C
H
+
Ph
Finally, the reaction of 9e with malononitrile in ethanol
in the presence of pyridine as basic catalyst gave the 4-
N,N-dimethylaminobenzyledinemalononitrile (12) in 82%
yield instead of the targeted compound 13 besides the
formation of the starting 3-benzyl-4-phenyl-1,2,4-triazole-
5-thiol (1) in low yield [21]. The IR spectrum of
compound 12 showed a strong band at 2200 cm-1 due to
N
S
CN
12
HOH
NH
CH2(CN)2
N
O
(H3C)2N
C
Ph
N
SH
H
1
comparison to find out why the isomers 9a-g is formed
rather than 10a-g. We applied an unequivocal synthesis of
5-phenyl-3-benzyl-1,3-thiazolo[2,3-c][1,2,4]triazole (14). A
mixture of 1-phenylacetyl-3-thiosemicarbazide (15) and
phenyl bromomethyl ketone was refluxed in ethanol to give
2-(phenylacetyl-hydrazino)-4-phenylthiazole (16).
Refluxing of 16 in POCl3 afforded the isomeric 3-benzyl-5-
phenyl-1,3-thiazolo[2,3-c]-[1,2,4]triazole (14) as previously
reported for similar compounds, Scheme 9 [23].
the presence of two identical C≡N groups, while its H-
NMR spectrum in CDCl3 showed signals at δ 7.8 and 6.7
(d, 4H, aromatic-H), 7.4 (s, 1H, CH=C) and 3.15 ppm (s,
6H, 2 N(CH3)2). On the other hand, an authentic sample
of compound 12 was also prepared by the reaction of 4-
N,N-dimethylaminobenzaldehyde
and
malononitrile,
Scheme 7. The product 12 was found to be identical with
that obtained by the reaction explained in Scheme 7, in
terms of melting temperature and mixed melting
1
temperature [22]. Also the IR, H-NMR, mass spectral
Scheme 9
data and elemental analysis of both compounds were
found similar.
S
H
EtOH
heat
N
PhCOCH2Br
+
NH2
N
H
Scheme 7
O
15
O
NH2
N
N
N
N
N
Ph
POCl3
heat
N
Ph
Ph
N
S
H
N
CN
S
N
H
Ph
S
O
CH2(CN)2
EtOH
pyridine
reflux
N
N
H
Ph
O
Ph
16
14
13
N(CH3)2
CH
N
S
CN
The synthesized compound 14 were found to be
different on comparison with the isomeric compounds
17a-c, which synthesized using the procedures reported in
literature [24]. The direct reaction of 1 with acetophenone
derivatives in acetic acid catalyzed by concentrated
sulfuric acid lead to the formation of 17a-c rather than the
formation of 14. We found also the synthesized
compounds 17a-c using the literature method were
identical with those obtained by our method [24].
C
CN
+
C
N
NH
N(CH3)2
H
Ph
9e
N
SH
(H3C)2N
12
1
The mechanism of the formation of both compounds 12
and the starting material 1 is formulated to be as in
Scheme 8.
Unfortunately we tried to grow such crystal of any
compound of 9a-g enough for X-Ray analysis but we
could not succeed. This forced us to search how
compounds 9a-g are formed and how the reaction
proceeds. We concluded that in three ways: theoretically
how the cyclization took place, chemically and finally
N
N
R1
N
N
Ph
Ph
N
S
S
N
R
14, 17; R = H
R1
R
14a; R1 = C6H5, 14b; R1 = p-ClC6H4
14c; R1 = p-BrC6H4
17a; R1 = C6H5, 17b; R1 = p-ClC6H4
17c; R1 = p-BrC6H4
1
using the HNMR spectral data obtained experimentally
and compare it with the estimated one. To proof
chemically how the reaction and the cyclization occurs
another chemical reactions should be used in this
Another proof we used the estimation 1HNMR
(ACD/HNMR 1.0) for comparison purposes with the

May-Jun 2008
Synthesis, Characterization and Studies of New 3-Benzyl-4H-1,2,4-triazole-5-thiol
901
experimental 1HNMR data summarized in the
experimental section to proof which of the structures 9a-g
or 10a-g were obtained. We found that our suggested
structures 9a-g was in satisfactory agreement with the
estimated 9a-g. The experimental 1H NMR spectra of
compounds 9a-g showed a sharp singlet at δ 8.00 – 8.3
ppm typical for the CH=C proton linked to the aryl
group, which is in agreement with the estimated one
appearing at δ 8.14 for all derivatives indicating that the
isomers 9a-g were obtained rather than 10a-g (CH=C
appeared at δ 6.76 ppm). The comparison of these spectra
with theoretical predictions for both isomers is given in
Table 2.
EXPERIMENTAL
Melting points were recorded on a Gallencamp melting point
apparatus. Infrared spectra (IR) were measured on a Shimadzu
Table 2
Chemical shifts of the CH and CH2 in the Experimental and Estimated1HNMR Data of Compounds 9a-j (ppm).
Compd.
No.
1HNMR
Compd.
No.
1HNMR
Estimated
R
Experimental
Estimated
CH2
CH
CH2
CH
CH2
CH
9a
9b
9c
9d
9e
9f
H
Cl
NO2
OCH3
N(CH3)2
Br
4.20
4.20
4.15
4.20
4.20
4.10
4.15
8.20
8.10
8.30
8.20
8.05
8.00
8.20
4.78
4.79
4.79
4.79
4.79
4.79
4.79
8.14
8.14
8.14
8.14
8.14
8.14
8.14
10a
10b
10c
10d
10e
10f
10j
4.50
4.50
4.50
4.50
4.50
4.50
4.50
6.76
6.76
6.76
6.76
6.76
6.76
6.76
9j
OCOCH3
Figure 2. The experimental 1HNMR spectrum of 9b (R = Cl) in CDCl3, 500 MHz.

902
A. A. O. Sarhan, H.. A. H. ElSherif, A. M. Mahmoud and O. M. A. Habib
Vol 45
Figure 3. The experimental 13CNMR spectrum of 9b (R = Cl) in CDCl3, 125 MHz.
1
470 IR spectrometer (KBr, max in cm-1). HNMR Spectra were
recorded at room temperature on a Varian EM-390, 90 MHz
for 3 hours, then cooled at room temperature, filtered and
crystallized from ethanol to give white needles crystals of the
hydrazide derivative 3 in 90% yield, Mp. 151-152°C. IR (KBr) ν
= 3300s, 3200s, 3150m (NH-NH2), 3030w (C-H aromatic),
2960w (C-H aliphatic), 1580s (C=O), 3050w (C-H aromatic),
Spectrometer or on
a JEOL LA 400 MHz FT-NMR
spectrometer. Chemical shifts are denoted in δ ppm values,
relative to tetramethylsilane (TMS) as internal standard, J values
are given in Hz. CDCl3 is used as a deuterated solvent unless
otherwise stated. MS Spectra was obtained using a JEOL JMS-
600 mass spectrometer. Elemental analyses were recorded on a
Perkins Elmer 240C elemental analyzer (Assiut University unit).
The solvents were distilled before use. Compounds 1, 14 and
17a-c were prepared according to the method previously
described in literature [24].
1
1590s (C=N), 1400s, 1450s, 1500s cm-1 (C-H aromatic), H
NMR (CDCl3, 90 MHz) δ = 9.3 (s, 1H, NH), 7.6-6.8 (m, 10H,
aromatic-H), 3.8 (s, 2H, Ph-CH2-), 3.9 (s, 2H, SCH2CO), 4.0
ppm (s, 2H, NH2), and the (NH-NH2) protons are exchangeable
with D2O. Elemental analysis for C17H17N5OS (339.42). Calcd:
C, 60.16; H, 5.05; N, 20.63; S, 9.45%. Found: C, 59.78; H, 4.82;
N, 20.59; S, 9.10%.
Synthesis of ethyl (5-benzyl-4-phenyl-1,2,4-triazol-3-yl)-
mercaptoacetate (2). To a solution of 3-benzyl-4-phenyl-1,2,4-
triazol-5-thiol (1) [6] (0.01 mol) in ethanol (50 mL) and
anhydrous sodium acetate (1.0 g) ethyl chloroacetate (0.015
mole) was added, then the mixture was refluxed for 2 hours. The
reaction mixture was cooled, filtered and the crude product was
washed with water and crystallized from ethanol/benzene
mixture to give the corresponding ester derivative 2 as colorless
needles crystals in 85% yield, Mp. 75-76°C. IR (KBr) ν =
3050w (C-H aromatic), 2990m, 2910m (C-H aliphatic), 1700s
(C=O), 1590s (C=N), 1400s, 1530s, 1450s, 1500s (C-H
aromatic), 1280s, 1130s, 1010s (C-O, C-H, C-N), 700s, 730s,
750s cm-1 (aromatic). 1H NMR (CDCl3, 90 MHz) δ = 7.6-6.9 (m,
10H, aromatic-H), 4.0 (s, 2H, Ph-CH2-), 4.1 (s, 2H, SCH2CO),
4.2 (t, 3H, CH3), 1.2 ppm (t, 3H, CH3). Elemental analysis for
C19H19N3O2S (353.45); Calcd: C, 64.57; H, 5.42; N, 11.89; S,
9.07%. Found: C, 64.66; H, 5.30; N, 11.80; S, 8.71%.
Synthesis of 1-(2-(5-benzyl-4-phenyl-4H-1,2,4-triazol-3-
ylthio)acetyl)-4-substituted-thio-semicarbazides
(4a-d).
General procedure: A mixture of hydrazide 3 (0.01 mole) and
appropriate isothiocyanate derivatives (0.015 mole) in ethanol
(50 mL) was refluxed for 2 hours. The reaction mixture was then
cooled and the precipitate thus formed was collected by filtration
and crystallized from ethanol to give the thiosemi-carbazide
derivatives 4a-d as colorless needles in high yields.
1-(2-(5-Benzyl-4-phenyl-4H-1,2,4-triazol-3-ylthio)acetyl)-4-
methylthiosemicarbazide (4a). R = CH3. This compound was
obtained as needles crystals in 82% yield, Mp. 171-173 °C. IR
(KBr) ν = 3300s, 3200s, 3150m (three N-H), 3040w (C-H
aromatic) 2960w (C-H aliphatic), 1700s (C=O) and at 1140s
(C=S) 1250s, 1140s, 1000s (C-O, C-H, C-N), 700s, 760s, 800s
1
cm-1 (aromatic). H NMR (DMSO-d6, 90 MHz) δ ppm = 10.6,
9.3, 8.4 (s, 3H, 3 NH), 7.6-6.7 (m, 10H, aromatic-H), 3.8 (s, 2H,
Ph-CH2-), 4.0 (s, 2H, SCH2CO), 2.9 (d, 3H, CH3). Elemental
analysis for C19H20N6OS2 (412.54). Calcd: C, 55.32; H, 4.88; N,
20.37; S, 15.54%. Found: C, 54.91; H, 5.05; N, 20.22; S,
15.14%.
Synthesis of (5-benzyl-4-phenyl-1,2,4-triazol-3-yl)mercap-
toacetic hydrazide (3). A mixture of the ester 2 (0.01 mole) and
hydrazine hydrate (0.015 mole) was refluxed in ethanol (50 mL)

May-Jun 2008
Synthesis, Characterization and Studies of New 3-Benzyl-4H-1,2,4-triazole-5-thiol
903
10H, aromatic protons), 4.0 (s, 2H, PhCH2), 4.4 (s, 2H, SCH2),
4.1 (q, 2H, CH2), 1.3 (t, 3H, CH3). MS m/z (%) = 408 (15), 368
(5), 294 (2), 267 (100), 266 (50), 252 (7), 234 (18), 190 (2), 166
(2), 149 (20), 116 (16), 91 (70), 77 (25), 65 (21), 51 (17).
Elemental analysis for C20H20N6S2 (408.55). Calcd: C, 58.80; H,
4.93; N, 20.57; S, 15.70%. Found: C, 58.51; H, 5.15; N, 20.35;
S, 15.91%.
1-(2-(5-Benzyl-4-phenyl-4H-1,2,4-triazol-3-ylthio)acetyl)-4-
ethylthiosemicarbazide (4b). R = C2H5. This compound was
obtained as needles crystals in 89% yield, Mp. 159-161 °C. IR
(KBr) ν = 3300s, 3200s, 3150m (three N-H), 3040w (C-H
aromatic) 2960w, 2920w (C-H aliphatic), 1700s (C=O) and at
1140s (C=S) 1250s, 1140s, 1000s (C-O, C-H, C-N), 700s, 760s,
1
800s cm-1 (aromatic). H NMR (CDCl3, 90 MHz) δ ppm = 10.1,
8.6, 8.4 (s, 3H, 3 NH), 7.5-6.8 (m, 10H, aromatic-H), 3.8 (s, 2H,
Ph-CH2-), 4.0 (s, 2H, SCH2CO), 3.6 (m, 2H, CH2), 1.2 (t, 3H,
CH3). Elemental analysis for C20H22N6OS2 (426.57). Calcd: C,
56.32; H, 5.20; N, 19.70; S, 15.03%. Found: C, 56.37; H, 5.06;
N, 19.61; S, 14.70%.
[(5-Benzyl-4-phenyl-4H-1,2,4-triazol-3-ylthio)methyl]-4-
= C6H11. This
cyclohexyl-4H-1,2,4-triazole-3-thiol (5c). R
compound was obtained as needles crystals in 70% yield, Mp.
105-106 °C. IR (KBr) ν = 3070m (N-H), 3030m (C-H aromatic)
2960m, 2900m (C-H aliphatic), 1590s (C=N), 1070s (C=S),
1130m (C-H), 1020s (C-N), 690s, 730s, 760s cm-1 (aromatic).
1HNMR (CDCl3, 400 MHz) δ ppm = 12.9 (s, 1H, NH), 7.5-6.8
(m, 10H, aromatic protons), 4.0 (s, 2H, PhCH2), 4.5 (s, 2H,
SCH2-), 1.9-1.1 (m, 11H, C6H11). Elemental analysis for
C24H26N6S2 (462.64). Calcd: C, 62.31; H, 5.66; N, 18.17; S,
13.86%. Found: C, 62.26; H, 5.56; N, 17.82; S, 13.71%.
1-(2-(5-Benzyl-4-phenyl-4H-1,2,4-triazol-3-ylthio)acetyl)-4-
cyclohexylthiosemi-carbazide (4c). R = C6H11. This compound
was obtained as crystals in 86% yield, Mp. 173-174 °C. IR
(KBr) ν = 3300s, 3210s, 3160m (three N-H), 3050w (C-H
aromatic) 2970s, 2960m, 2920w (C-H aliphatic), 1710s (C=O),
1140s (C=S), 1250s, 1140s, 1000s (C-O, C-H, C-N), 710s, 760s,
1
800s cm-1 (aromatic). H NMR (CDCl3, 90 MHz) δ ppm = 9.8,
[(5-Benzyl-4-phenyl-4H-1,2,4-triazol-3-ylthio)methyl]-4-
phenyl-4H-1,2,4-triazole-3-thiol (5d). R = C6H5. This compound
was obtained as white needles crystals in 87% yield, Mp. 190-191
°C. IR (KBr) ν = 3070m (N-H), 3010m (C-H aromatic) 2890m (C-
H aliphatic), 1580s (C=N), 1070s (C=S), 1150m (C-H), 1000s (C-
8.4, 7.4 (s, 3H, 3 NH), 7.4-6.8 (m, 10H, aromatic-H), 3.8 (s, 2H,
Ph-CH2-), 3.9 (s, 2H, SCH2CO), 1.9-1.0 (m, 11H, C6H11).
Elemental analysis for C24H28N6OS2 (480.64). Calcd: C, 59.97;
H, 5.87; N, 17.48; S, 13.34%. Found: C, 59.57; H, 5.66; N,
17.30; S, 13.20%.
1
N), 680s, 730s, 750s cm-1 (aromatic). H NMR (CDCl3, 400 MHz)
δ ppm = 13.2 (s, 1H, NH), 7.5-6.9 (m, 15H, aromatic-H), 4.0 (s,
2H, PhCH2), 4.2 (s, 2H, SCH2-). Elemental analysis for C24H20N6S2
(456.60). Calcd: C, 63.13; H, 4.42; N, 18.41; S, 14.04%. Found: C,
63.20; H, 4.47; N, 18.27; S, 14.16%.
1-(2-(5-Benzyl-4-phenyl-4H-1,2,4-triazol-3-ylthio)acetyl)-4-
phenylthiosemicarbazide (4d). R = C6H5. This compound was
obtained as needles crystals in 82% yield, Mp. 184-185 °C. IR
(KBr) ν = 3300s, 3200s, 3150m (three N-H), 3050w (C-H
aromatic) 2960w (C-H aliphatic), 1720s (C=O), 1140s (C=S)
1260s, 1140s, 1020s (C-O, C-H, C-N), 700s, 760s, 800s cm-1
Synthesis of 2-(5-benzyl-4-phenyl-4H-1,2,4-triazol-3-ylthio)-
N' -(3 -substituted- 4-oxothia- zolidin-2-ylidene)acetohydra-
zide (6a-d). General procedure: A mixture of thiosemicarbazides
4a-d (2 mmol), chloroacetyl chloride (2 mmol) and potassium
carbonate (1 gm) in chloroform (30 mL) was refluxed on water-
1
(aromatic). H NMR (DMSO-d6, 90 MHz) δ ppm = 10.7, 9.8,
9.8 (s, 3H, 3 NH), 7.7-6.8 (m, 15H, aromatic-H), 3.8 (s, 2H, Ph-
CH2-), 3.9 (s, 2H, SCH2CO). Elemental analysis for
C24H22N6OS2 (474.61). Calcd: C, 60.74; H, 4.67; N, 17.70; S,
13.51%. Found: C, 60.78; H, 4.81; N, 17.66; S, 13.22%.
Synthesis of 5-[(5-benzyl-4-phenyl-4H-1,2,4-triazol-3-
ylthio)methyl]-4-substituted-4H-1,2,4-triazole-3-thioles (5a-d).
General procedure: A solution of thiosemicarbazides 4a-d (2
mmol) in sodium hydroxide (50 mL 5%) was refluxed gently for
3 hours. The reaction mixture was then cooled and acidified with
dilute HCl, the crude product thus obtained was crystallized
from ethanol to give 5a-d as white needles crystals in 70 ~ 87%
yield.
bath for
3 hours. The excess chloroform was removed
evaporated and the resulting solid products was washed with
cold water to remove the excess K2CO3 and dried followed by
crystallization from ethanol to give the corresponding
compounds 6a-d as needles crystals in 64 ~ 86% yields.
2-(5-Benzyl-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N'-(3-
methyl-4-oxothiazolidin-2-ylidene)-acetohydrazide (6a). R =
CH3. This compound was obtained as white crystals in 82%
yield, Mp. 204-205 °C. IR (KBr) ν = 3180m (N-H), 3030w (C-
H aromatic) 2960m, 2930m (C-H aliphatic), 1750s, 1700s (2
C=O), 1650s (C=N), 1130m (C-H), 1030m (C-N), 690s, 730s,
5-[(5-Benzyl-4-phenyl-4H-1,2,4-triazol-3-ylthio)methyl]-4-
CH3. This
1
methyl-4H-1,2,4-triazole-3-thiol (5a).
R
=
750s cm-1 (aromatic). HNMR (DMSO-d6, 400 MHz) δ ppm =
10.9 (s, 1H, NH), 7.5-6.9 (m, 10H, aromatic-H), 4.11, 4.09, 3.91
(s, 6H, 3 CH2), 3.02 (s, 3H, CH3). MS m/z (%) = 452 (9), 324
(5), 308 (18), 281 (63), 267 (100), 266 (65), 234 (85), 186 (1),
172 (32), 145 (25), 129 (19), 115 (2), 91 (88), 77 (23), 65 (16),
51 (10). Elemental analysis for C21H20N6O2S2 (452.56). Calcd:
C, 55.73; H, 4.45; N, 18.56; S, 14.17%. Found: C, 55.79; H,
4.40; N, 18.50; S, 13.86%.
2-(5-Benzyl-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N'-(3-ethyl-
4-oxothiazolidin-2-ylidene)acetohydrazide (6b). R = C2H5.
This compound was obtained as white crystals in 79% yield,
Mp. 174-175 °C. IR (KBr) ν = 3150m (N-H), 3050w (C-H
aromatic) 2980m, 2950m (C-H aliphatic), 1750s, 1700s two
(C=O), 1640s (C=N), 1130m (C-H), 1040m (C-N), 690s, 730s,
760s cm-1 (aromatic). 1HNMR (CDCl3, 400 MHz) δ ppm = 10.9
(s, 1H, NH), 7.5-6.9 (m, 10H, aromatic-H), 3.95, 3.90, 3.70 (s,
6H, 3 CH2), 3.20 (t, 2H, CH2), 1.05 (q, 3H, CH3). MS m/z (%) =
compound was obtained as white needles crystals in 81% yield,
Mp. 164-165 °C. IR (KBr) ν = 3090m (N-H), 3030m (C-H
aromatic) 2900m (C-H aliphatic), 1570s (C=N), 1070s (C=S),
1130m (C-H), 1000s (C-N), 690s, 730s, 750s cm-1 (aromatic). 1H
NMR (CDCl3, 400 MHz) δ ppm = 12.8 (s, 1H, NH), 7.6-6.9 (m,
10H, aromatic-H), 4.2 (s, 2H, Ph-CH2), 4.5 (s, 2H, SCH2-), 3.5
(s, 3H, CH3). Elemental analysis for C19H18N6S2 (394.52). Calcd:
C, 57.84; H, 4.60; N, 21.30; S, 16.25%. Found: C, 58.17; H,
4.42; N, 21.34; S, 15.90%.
5-[(5 -Benzyl-4 - phenyl -4H-1,2,4-triazol-3-ylthio)methyl]-
4-ethyl-4H-1,2,4-triazole-3-thiol (5b).
R
=
C2H5. This
compound was obtained as white needles crystals in 86% yield,
Mp. 194-195 °C. IR (KBr) ν = 3100m (N-H), 3030m (C-H
aromatic) 2900m (C-H aliphatic), 1590s (C=N), 1080s (C=S),
1130m (C-H), 1000s (C-N), 690s, 730s, 750s cm-1 (aromatic). 1H
NMR (CDCl3, 400 MHz) δ ppm = 13.8 (s, 1H, NH), 7.7-6.9 (m,

904
A. A. O. Sarhan, H.. A. H. ElSherif, A. M. Mahmoud and O. M. A. Habib
Vol 45
466 (5), 324 (6), 308 (12), 281 (86), 267 (77), 266 (50), 234
(38), 200 (10), 186 (16), 159 (6), 143 (9), 129 (5), 91 (100), 77
(23), 65 (17), 51 (11). Elemental analysis for C22H22N6O2S2
(466.59). Calcd: C, 56.63; H, 4.75; N, 18.01; S, 13.74%. Found:
C, 56.50; H, 4.88; N, 18.08; S, 13.39%.
(C=N), 1160m (C-H), 1060m (C-N), 690s, 730s, 750s cm-1
1
(aromatic). HNMR (CDCl3, 400 MHz) δ ppm = 10.5 (s, 1H,
NH), 7.5-6.9 (m, 15H, aromatic-H), 5.8 (s, 1H, CH=), 4.0, 3.9 (s,
4H, 2 CH2), 3.8 (q, 2H, CH2), 1.2 (t, 3H, CH3). Elemental
analysis for C28H26N6OS2 (526.69). Calcd: C, 63.85; H, 4.98; N,
15.96; S, 12.18%. Found: C, 63.61; H, 5.17; N, 15.66; S,
11.98%.
2-(5-Benzyl-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N'-(3-
cyclohexyl-4-oxothiazolidin-2-ylidene)acetohydrazide (6c). R
= C6H11. This compound was obtained as white crystals in 64%
yield, Mp. 170-171 °C. IR (KBr) ν = 3150m (N-H), 3050w (C-H
aromatic) 2980m, 2950m (C-H aliphatic), 1750s, 1700s two
(C=O), 1640s (C=N), 1130m (C-H), 1040m (C-N), 690s, 730s,
2-(5-Benzyl-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N'-(3-
phenyl-4-phenylthiazol-2(3H)-ylidene)acetohydrazide (7c). R
= C6H5. This compound was obtained as white crystals in 74%
yield, M.p. 213-214 °C. IR (KBr) ν = 3250m (N-H), 3030m (C-
H aromatic) 2960m, (C-H aliphatic), 1560s (C=O), 1580s
(C=N), 1160m (C-H), 1030m (C-N), 690s, 730s, 750s cm-1
1
760s cm-1 (aromatic). HNMR (CDCl3, 400 MHz) δ ppm = 7.5-
6.9 (m, 10H, aromatic-H and NH proton), 4.00, 3.95, 3.80 (s,
6H, 3 CH2-), 1.80-1.12 (m, 11H, C6H11). MS m/z (%) = 520 (1),
1
(aromatic). HNMR (DMSO-d6, 400 MHz) δ ppm = 10.8 (s, 1H,
324 (3), 308 (3), 281 (18), 267 (100), 266 (57), 254 (1),
240
NH), 7.7-6.9 (m, 20H, aromatic-H), 5.9 (s, 1H, CH=), 4.5, 3.9 (s,
4H, two-CH2-), 3.2 (s, 3H, CH3). Elemental analysis for
C32H26N6OS2 (574.73). Calcd: C, 66.88; H, 4.56; N, 14.62; S,
11.16%. Found: C, 66.48; H, 4.91; N, 14.44; S, 11.02%.
(4), 234 (46), 213 (3), 197 (4), 183 (1), 91 (46), 77 (16), 65 (11),
51 (8). Elemental analysis for C26H28N6O2S2 (520.68). Calcd: C,
59.98; H, 5.42; N, 16.14; S, 12.32%. Found: C, 59.72; H, 5.36;
N, 16.00; S, 12.02%.
Synthesis of (E)-2-benzyl-6-arylidenethiazolo[3,2-b][1,2,4]-
triazol-5(6H)-ones (9a-g). General procedure: A mixture of 3-
benzyl-1,2,4-triazole-5(1H)-thiol (1) (5 mmol), aromatic
aldehydes (8; 5 mmol), chloroacetic acid (5 mmol) and fused
sodium acetate (10 mmol) was refluxed in acetic acid/acetic
anhydride (25:5 mL) mixture for 3 hours. The reaction mixture
was then cooled, filtered and crystallized from acetic acid to
give the thiazolo[3,2-b][1,2,4]triazol-5(6H)-ones 9a-g in 66 ~
87% yields The Rf values were measured using benzene/ethyl
acetate mixture as an eluent in ratio (9:1) and the UV absorption
data of compounds 9a-f were measured in CHCl3 in
concentration (2 x 10-5 mol/Liter).
2-(5-Benzyl-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N'-(3-
phenyl-4-oxothiazolidin-2-ylidene)acetohydrazide (6d). R =
C6H5. This compound was obtained as pale yellow crystals in
86% yield, Mp. 166-167 °C. IR (KBr) ν = 3200m (N-H), 3050m
(C-H aromatic) 2980m (C-H aliphatic), 1740s, 1700s two
(C=O), 1640s (C=N), 1130m (C-H), 1040m (C-N), 690s, 730s,
760s cm-1 (aromatic). 1HNMR (CDCl3, 400 MHz) δ ppm = 7.60-
6.85 (m, 15H, aromatic-H and NH proton), 4.00, 3.95, 3.85 (s,
6H, 3 CH2). MS m/z (%) = 514 (11), 324 (10), 308 (20), 281
(50), 267 (15), 266 (31), 248 (35), 234 (47), 207 (18), 191 (24),
177 (7), 91 (72), 77 (100), 65 (47), 51 (70). Elemental analysis
for C26H22N6O2S2 (514.63). Calcd: C, 60.68; H, 4.31; N, 16.33;
S, 12.46%. Found: C, 59.92; H, 4.61; N, 16.40; S, 11.61%.
2-(5-Benzyl-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N'-(3-substi-
tuted-4-phenylthiazol-2(3H)-ylidene)acetohydrazides (7a-c).
General procedure: A mixture of thiosemicarbazides 4a,b and
4d (0.002 mole), phenacyl bromide (0.002 mole) and anhydrous
sodium acetate in ethanol (30 mL) was refluxed for 6 hours,
then, ethanol was evaporated and the product washed with water
several times, then crystallized from ethanol to give 7a-c,
respectively, as white needles in 62-74% yield.
(E) - 2 - Benzyl - 6 - benzylidenethiazolo[3,2 - b][1,2,4]triazol-
5(6H)-one (9a). R = H. This compound was obtained as
colorless crystals in 74% yield, Mp. 142-143 °C. Rf = 0.63. IR
(KBr) ν = 3030m (C-H aromatic) 2960m, (C-H aliphatic), 1730s
(C=O), 1590s (C=N), 1500s, 1460s, 1440s (aromatic skeleton),
690s, 730s, 750s cm-1 (C-H aromatic). 1HNMR (CDCl3, 90
MHz) δ = 7.70-7.30 (m, 10H, aromatic-H), 8.20 (s, 1H, CH),
4.20 (s, 2H, CH2). UV at λmax (ε) = 357.5 (21500), 302.5
(16950), 242.5 (9800) nm (L mol-1 cm-1), Abs. = 0.430, 0.339,
0.196 respectively.
Elemental analysis for C18H13N3OS
(319.39). Calcd: C, 67.69; H, 4.10; N, 13.15; S, 10.03%. Found:
C, 67.48; H, 3.82; N, 13.20; S, 9.78%.
2-(5-Benzyl-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N'-(3-
methyl-4-phenylthiazol-2(3H)-ylidene)acetohydrazide (7a). R
= CH3. This compound was obtained as white crystals in 66%
yield, M.p. 224-225 °C. IR (KBr) ν = 3150m (N-H), 3050w (C-
H aromatic) 2960m, 2910w (C-H aliphatic), 1660s (C=O), 1580s
(C=N), 1160m (C-H), 1070m (C-N), 690s, 730s, 750s cm-1
(E)-6-(4-Chlorobenzylidene)-2-benzylthiazolo[3,2-b][1,2,4]-
triazol-5(6H)-one (9b). R = Cl. This compound was obtained as
yellow crystals in 85% yield, Mp. 187-188 °C. Rf = 0.65. IR
(KBr) ν = 3030m (C-H aromatic) 2960m, (C-H aliphatic), 1730s
(C=O), 1590s (C=N), 1500s, 1480s, 1400s (aromatic skeleton),
1
(aromatic). HNMR (CDCl3, 400 MHz) δ ppm = 10.2 (s, 1H,
1
NH), 7.4-6.8 (m, 15H, aromatic-H), 5.8 (s, 1H, CH=), 3.8, 3.9 (s,
4H, 2 CH2), 3.2 (s, 3H, CH3). MS m/z (%) = 512 (7), 438 (8),
378 (20), 363 (1), 335 (2), 322 (15), 308 (11), 281 (20), 279
(37), 239 (36), 265 (95), 252 (20, 248 (11), 236 (38, 233 (96),
220 (85), 205 (60), 190 (45), 176 (10), 165 (10), 149 (35), 134
(30), 118 (47), 102 (45), 91 (100), 77 (67), 65 (40), 51 (35), 39
(30). Elemental analysis for C27H24N6OS2 (512.66). Calcd: C,
63.26; H, 4.72; N, 16.39; S, 12.51%. Found: C, 63.10; H, 4.99;
N, 16.48; S, 11.95%.
2-(5-Benzyl-4-phenyl-4H-1,2,4-triazol-3-ylthio)-N'-(3-
ethyl-4-phenylthiazol-2(3H)-ylidene)acetohydrazide (7b). R =
C2H5. This compound was obtained as white crystals in 62%
yield, Mp. 136-137 °C. IR (KBr) ν = 3200m (N-H), 3030w (C-H
aromatic) 2960m, 2910w (C-H aliphatic), 1650s (C=O), 1580s
690s, 730s, 760s cm-1 (C-H aromatic). HNMR (DMSO-d6, 90
MHz) δ ppm = 7.80-7.20 (m, 9H, aromatic-H), 8.15 (s, 1H, CH),
1
4.20 (s, 2H, CH2). HNMR (CDCl3, 500 MHz) δ ppm = 8.40-
8.37 (m, 2H, aromatic-H), 8.21 (s, 1H, arylidene-CH), 7.77-7.74
(m, 2H, aromatic-H), 7.40-7.33 (m, 3H, aromatic-H), 7.3-7.28
(m, 2H, aromatic-H), 4.17 (s, 2H, CH2Ph). 13CNMR (CDCl3, 135
MHz) δ ppm = 172.92 (C-2), 159.54 (C=O), 155.25 (C-8),
148.72 (CH=), 138.08, 137.09, 135.69 (aromatic-C), 131.05,
129.07, 128.81, 128.41, 127.22, 124.63 (aromatic-CH), 35.66
(CH2). UV at λmax (ε) = 362.0 (21500), 310.0 (16950), 246.5
(9800) nm (L mol-1 cm-1), Abs.
= 0.439, 0.319, 0.228
respectively. Elemental analysis for C18H12ClN3OS (353.83).
Calcd: C, 61.10; H, 3.41; N, 11.87; S, 9.06%. Found: C, 61.31;
H, 3.45; N, 11.64; S, 8.88%.

May-Jun 2008
Synthesis, Characterization and Studies of New 3-Benzyl-4H-1,2,4-triazole-5-thiol
905
ols (11a-j). General procedure: To a solution of 9a-e (2
mmol) in tetrahydrofurane (20 mL) a solution of
piperedine or morpholine (3 mmol) was added and the
mixture was stirred for 6 hours at room temperature. The
crude product thus formed was crystallized from
benzene/cyclohexane mixture to give the addition
products 11a-j in 65 ~ 75% yield. The UV absorption
spectra of compounds 11a-j were measured in CHCl3 in
concentration of 4x10-5 mol/liter.
2-Benzyl-6-[phenyl(piperidin-1-yl)methyl]thiazolo-
[3,2-b][1,2,4]triazol-5-ol (11a). R = H, X = CH2. This
compound was obtained as colorless crystals in 67% yield, Mp.
130-131 °C. IR (KBr) ν = 3100m (O-H), 3030m (C-H aromatic)
2960m, (C-H aliphatic), 1590s (C=N), 1520s, 1480s, 1440s
(aromatic skeleton), 680s, 750s, 700s cm-1 (C-H aromatic).
1HNMR (CDCl3, 90 MHz) δ = 7.70-7.30 (m, 10H, aromatic-H),
6.90 (s, 1H, CH), 4.20 (s, 2H, CH2), 3.7-3.2 (m, 4H, N(CH2)2 ),
1.7-1.4 (m, 6H, (CH2)3). UV at λmax (ε) = 274 (13800), 234
(9375) nm (L mol-1 cm-1), Abs. = 0.552, 0.375 respectively.
Elemental analysis for C23H24 N3OS (404.54). Calcd: C, 68.29;
H, 5.98; N, 13.85; S, 7.93%. Found: C, 68.40; H, 6.31; N, 13.88;
S, 7.58%.
(E)-6-(4-Nitrobenzylidene)-2-benzylthiazolo[3,2-b][1,2,4]-
triazol-5(6H)-one (9c). R = NO2. This compound was obtained
as yellow crystals in 79% yield, Mp. 201-202 °C, Rf = 0.53. IR
(KBr) ν = 3050m (C-H aromatic) 2960m, (C-H aliphatic), 1730s
(C=O), 1600s (C=N), 1500s, 1470s, 1410s (aromatic skeleton),
690s, 720s, 760s cm-1 (C-H aromatic). 1HNMR (DMSO-d6, 90
MHz) δ ppm = 8.20-7.30 (m, 9H, aromatic-H), 8.3 (s, 1H, CH),
4.15 (s, 2H, CH2). UV at λmax (ε) = 370.0 (21200), 302.5
(23800), 247.5 (10600) nm (L mol-1 cm-1), Abs. = 0.424, 0.476,
0.212 respectively. Elemental analysis for C18H12N4O3S
(364.37). Calcd: C, 59.33; H, 3.31; N, 15.36; S, 8.79%. Found:
C, 59.29; H, 3.42; N, 15.56; S, 8.61%.
(E)-6-(4-Methoxybenzylidene)-2-benzylthiazolo[3,2-b][1,2,4]-
triazol-5(6H)-one (9d). R = OCH3. This compound was
obtained as greenish yellow crystals in 81% yield, Mp. 183-184
°C, Rf = 0.48. IR (KBr) ν = 3030m (C-H aromatic) 2960m, (C-H
aliphatic), 1710s (C=O), 1590s (C=N), 1500s, 1460s,1440s
1
(aromatic skeleton), 690s, 750s cm-1 (C-H aromatic). HNMR
(CDCl3, 90 MHz) δ = 7.70-7.20 (m, 9H, aromatic-H), 8.20 (s,
1H, CH), 4.20 (s, 2H, CH2), 3.9 (s, 3H, OCH3). UV at λmax (ε) =
380.5 (30100), 314.5 (8000), 247.0 (12700) nm (L mol-1 cm-1),
Abs. = 0.602, 0.160, 0.255 respectively. Elemental analysis for
C19H15N3O2S (349.41). Calcd: C, 65.31; H, 4.32; N, 12.02; S,
9.17%. Found: C, 65.15; H, 4.16; N, 11.94; S, 8.84%.
2-Benzyl-6-[(4-chlorophenyl)(piperidin-1-yl)methyl]thia-
zolo[3,2-b][1,2,4]triazol-5-ol (11b). R = Cl, X = CH2 this
compound was obtained as colorless crystals in 70% yield, Mp.
171-172 °C. IR (KBr) ν cm-1 = 3180m (O-H), 3050m (C-H
aromatic) 2940m, (C-H aliphatic), 1600s (C=N), 1520s, 1480s,
1440s (aromatic skeleton), 680s, 750s, 700s (C-H aromatic).
1HNMR (CDCl3, 90 MHz) δ = 7.80-7.20 (m, 9H, aromatic-H),
6.80 (s, 1H, CH), 4.10 (s, 2H, CH2), 3.5-3.2 (m, 4H, N (CH2)2),
1.6-1.4 (m, 6H, (CH2)3 ), UV at λmax (ε) = 283 (18225), 236
(11575) nm (L mol-1 cm-1), Abs. = 0.729, 0.463 respectively.
Elemental analysis for C23H23 Cl N4OS (438.98). Calcd: C,
62.93; H, 5.28; N, 12.76; S, 7.30%. Found: C, 62.82; H, 5.63; N,
12.76; S, 6.86%.
(E)-6-(4-N,N-Dimethylaminobenzylidene)-2-benzylthia-
zolo[3,2-b][1,2,4]triazol-5(6H)-one (9e). R = N(CH3)2. This
compound was obtained as red crystals in 87% yield, Mp. 203-
204 °C. Rf = 0.37, IR (KBr) ν = 3030m (C-H aromatic) 2960m,
(C-H aliphatic), 1710s (C=O), 1580s (C=N), 1500s, 1460s,
1440s (aromatic skeleton), 690s, 720s, 760s cm-1 (C-H
aromatic). 1HNMR (CDCl3, 90 MHz) δ = 7.70-6.60 (m, 9H,
aromatic-H), 8.05 (s, 1H, CH), 4.20 (s, 2H, CH2), 3.1 (s, 6H,
N(CH3)2). UV at λmax (ε) = 458.5 (54150), 316.5 (5050), 268.5
(9350) nm (L mol-1 cm-1), Abs.
= 1.083, 0.101, 0.187
respectively. Elemental analysis for C20H18N4OS (362.46).
Calcd: C, 66.28; H, 5.01; N, 15.46; S, 8.84%. Found: C, 66.40;
H, 5.00; N, 15.49; S, 8.05%.
2-Benzyl-6-[(4-nitrophenyl)(piperidin-1-yl)methyl]thiazolo-
[3,2-b][1,2,4]triazol-5-ol (11c). R = NO2, X = CH2. This
compound was obtained as yellow crystals in 69% yield, Mp.
175-176 °C. IR (KBr) ν = 3120m (O-H), 3030m (C-H aromatic)
2900m, (C-H aliphatic), 1600s (C=N), 1500s, 1440s (aromatic
skeleton), 750s, 730s, 690s cm-1 (C-H aromatic). 1HNMR
(CDCl3, 400 MHz) δ = 7.80-7.20 (m, 9H, aromatic-H), 6.80 (s,
1H, CH), 4.10 (s, 2H, CH2), 3.45, 3.13 (m, 4H, N(CH2)2 ),
1.50 (m, 4H, (CH2)2 ), 1.33 (m, 2H, CH2) , UV at λmax (ε) = 332
(1575), 243 (14650) nm (L mol-1 cm-1), Abs. = 0.623, 0.586
respectively. Elemental analysis for C23H23 N3O3S (449.54).
Calcd: C, 61.45; H, 5.16; N, 15.68; S, 7.13%. Found: C, 61.31;
H, 4.89; N, 15.57; S, 7.00%.
(E)-6-(4-Bromobenzylidene)-2-benzylthiazolo[3,2-b][1,2,4]-
triazol-5(6H)-one (9f). R = Br. This compound was obtained as
yellow crystals in 91% yield, Mp. 194-195 °C, Rf = 0.66. IR
(KBr) ν = 3030m (C-H aromatic) 2960m, (C-H aliphatic), 1710s
(C=O), 1580s (C=N), 1500s, 1460s, 1440s (aromatic skeleton),
690s, 720s, 760s cm-1 (C-H aromatic). 1HNMR (CDCl3, 90
MHz) δ = 7.60-7.20 (m, 9H, aromatic-H), 8.00 (s, 1H, CH), 4.10
(s, 2H, CH2). UV at λmax (ε) = 363.5 (26100), 312.0 (18000),
246.5 (11550) nm (L mol-1 cm-1), Abs. = 0.522, 0.360, 0.231
respectively. Elemental analysis for C18H12 BrN3OS (398.28).
Calcd: C, 54.28; H, 3.03; N, 10.55; S, 8.05%. Found: C, 54.64;
H, 2.83; N, 10.60; S, 7.90%.
2-Benzyl-6-[(4-methoxyphenyl)(piperidin-1-yl)methyl]-
thiazolo[3,2-b][1,2,4]triazol-5-ol (11d). R = OCH3, X = CH2.
This compound was obtained as pale yellow crystals in 71%
yield, Mp. 128-129 °C. IR (KBr) ν = 3150m (O-H), 3030m (C-
H aromatic) 2920m, (C-H aliphatic), 1590s (C=N), 1500s, 1440s
(aromatic skeleton), 680s, 750s, 700s cm-1 (C-H aromatic).
1HNMR (CDCl3, 90 MHz) δ = 7.60-7.30 (m, 9H, aromatic-H),
6.90 (s, 1H, CH), 4.20 (s, 2H, CH2), 3.65 (s, 3H, OCH3) 3.6-3.2
(m, 4H, N (CH2)2 ), 1.6-1.4 (m, 6H, (CH2)3), UV at λmax (ε) =
313 (15800), nm (L mol-1 cm-1), Abs. = 0.632. Elemental
analysis for C24H26 N4O2S (434.56). Calcd: C, 66.33; H, 6.03; N,
12.88; S, 7.38%. Found: C, 66.41; H, 5.82; N, 12.80; S, 7.12%.
2-Benzyl-6-[(4-N,N-dimethylaminophenyl)(piperidin-1-yl)-
methyl]thiazolo[3,2-b][1,2,4]triazol-5-ol (11e). R = N (CH3)2,
(E)-6-(4-Acetyloxybenzylidene)-2-benzylthiazolo[3,2-b]-
[1,2,4]triazol-5(6H)-one (9g). R = OCOCH3. This compound
was obtained as colorless crystals in 66% yield, Mp. 123-124
°C, Rf = 0.39. IR (KBr) ν = 3030m (C-H aromatic) 2960m, (C-H
aliphatic), 1760s (OCO), 1730s (C=O), 1580s (C=N), 1500s,
1460s, 1440s (aromatic skeleton), 690s, 720s, 760s cm-1 (C-H
aromatic). 1HNMR (CDCl3, 90 MHz) δ = 7.60-7.20 (m, 9H,
aromatic-H), 8.00 (s, 1H, CH), 4.10 (s, 2H, CH2), 2.35 (s, 3H,
COCH3). Elemental analysis for C20H15 N3O3S (377.42). Calcd:
C, 63.64; H, 4.00; N, 11.13; S, 8.49%. Found: C, 63.58; H, 4.21;
N, 11.01; S, 8.37%.
Synthesis of 2-Benzyl-6-[phenyl(piperidin-1-yl/
morpholin-1-yl)methyl]thiazolo[3,2-b][1,2,4]triazol-5-

906
A. A. O. Sarhan, H.. A. H. ElSherif, A. M. Mahmoud and O. M. A. Habib
Vol 45
X = CH2. This compound was obtained as orange crystals in
75% yield, Mp. 182-183 °C. IR (KBr) ν = 3150m (O-H), 3030m
(C-H aromatic) 2920m, (C-H aliphatic), 1590s (C=N), 1500s,
1440s (aromatic skeleton), 680s, 720s, 780s cm-1 (C-H
aromatic). 1HNMR (CDCl3, 90 MHz) δ = 7.70-6.60 (m, 9H,
aromatic-H), 6.90 (s, 1H, CH), 4.10 (s, 2H, CH2), 3.65 (s, 3H,
OCH3), 3.5-3.3 (m, 4H, N (CH2)2), 1.6-1.3 (m, 6H, (CH2)3), 2.90
(s, 6H, N(CH3)2). UV at λmax (ε) = 359 (26150), 324 (12000) nm
(L mol-1 cm-1), Abs. = 1.046, 0.480 respectively. Elemental
analysis for C25H29 N5OS (447.61). Calcd: C, 67.08; H, 6.53; N,
15.64; S, 7.16%. Found: C, 67.21; H, 6.71; N, 15.74; S, 6.99%.
2-Benzyl-6-[morpholino(phenyl)methyl]thiazolo[3,2-b]-
[1,2,4]triazol-5-ol (11f). R = H, X = O. This compound was
obtained as colorless crystals in 65% yield, Mp. 174-175 °C.
IR (KBr) ν = 3150m (O-H), 3030m (C-H aromatic) 2920m, (C-
H aliphatic), 1590s (C=N), 1500s, 1440s (aromatic skeleton),
680s, 720s, 780s cm-1 (C-H aromatic). 1HNMR (CDCl3, 90
MHz) δ = 7.80-7.30 (m, 10H, aromatic-H), 6.90 (s, 1H, CH),
4.20 (s, 2H, CH2), 3.80-3.40 (m, 8H, 4CH2). UV at λmax (ε) =
281 (14375), 236 (11025) nm (L mol-1 cm-1), Abs. = 0.575,
0.441 respectively. Elemental analysis for C22H22N4O2S
(406.51). Calcd: C, 65.00; H, 5.46; N, 13.78; S, 7.88%. Found:
C, 64.77; H, 5.90; N, 13.79; S, 7.59%.
C23H24N4O3S (436.54). Calcd: C, 63.28; H, 5.54; N, 12.83; S,
7.34%. Found: C, 62.50; H, 6.01; N, 12.84; S, 7.39%.
2-Benzyl-6-[morpholino(4-N,N-dimethylaminophenyl)-
methyl]thiazolo[3,2-b][1,2,4]triazol-5-ol (11j). R = N(CH3)2, X
= O. This compound was obtained as orange crystals in 71%
yield, Mp. 165-166 °C. IR (KBr) ν = 3200m (O-H), 3050m (C-
H aromatic) 2960m, (C-H aliphatic), 1590s (C=N), 1430, 1480s,
1510s (aromatic skeleton), 690s, 700s, 750s cm-1 (C-H
aromatic). 1HNMR (CDCl3, 90 MHz) δ = 7.70-6.60 (m, 9H,
aromatic-H), 6.80 (s, 1H, CH), 4.10 (s, 2H, CH2), 3.60-3.40 (m,
8H, 4CH2), 3 (s, 6H, N (CH3)2). UV at λmax (ε) = 366 (21200),
326 (11200) nm (L mol-1 cm-1), Abs. = 0.848, 0.448 respectively.
Elemental analysis for C24H27N5O2S (449.58). Calcd: C, 64.12;
H, 6.04; N, 15.58; S, 7.12%. Found: C, 64.17; H, 5.81; N, 15.49;
S, 7.27%.
Synthesis of 4-(N,N-dimethylaminobenzylidene)malono-
nitrile (12). A mixture of 9e (3 mmol) with malononitrile and
few drops of pyridine in ethanol (30 mL) was refluxed on a
water bath for 3 hours. The reaction mixture was cooled and the
precipitate thus obtained was collected by filtration, dried and
crystallized from ethanol to give the unexpected benzylidene-
malononitrile 12 as orange needles in 82% yield, Mp. 180-
181°C (Lit. [21] 179-180°). In addition a minor amount of the
starting compound was isolated as colorless crystals and
identified by analysis as 3-benzyl-4-phenyl-1,2,4-triazol-5-thiol
(1) [6]. An authentic sample of 12 was prepared by the reaction
of p-N,N-dimethylaminobenzaldehyde (l0 mmol) and
malononitrile (12 mmol) in ethanol in the presence of pipreidine
for comparison purpose.
2-Benzyl-6-[morpholino(4-chlorophenyl)methyl]thiazolo-
[3,2-b][1,2,4]triazol-5-ol (11g). R = Cl, X = O. This compound
was obtained as colorless crystals in 72% yield, Mp. 141-142
°C. IR (KBr) ν = 3160m (O-H), 3050m (C-H aromatic) 2920m,
(C-H aliphatic), 1590s (C=N), 1420s, 1450s, 1480s (aromatic
skeleton), 680s, 710s, 750s cm-1 (C-H aromatic). 1HNMR
(CDCl3, 400 MHz) δ = 7.48-7.17 (m, 9H, aromatic-H), 6.77 (s,
1H, CH), 4.10 (s, 2H, CH2), 3.26 (m, 4H, O(CH2)2), 3.41 (m,
2H, NCH2), 3.28 (m, 2H, NCH2). UV at λmax (ε) = 288 (14500),
233 (10400) nm (L mol-1 cm-1), Abs. = 0.580, 0.416 respectively.
MS m/z (%) = 442 (7) [M+2], 440 (7) [M+], 354 (98), 352 (98),
325 (16), 323 (27), 289 (4), 243 (3), 220 (1), 208 (9), 190 (20),
169 (41), 167 (100), 135 (28), 117 (21), 116 (31), 103 (34), 91
(43), 87 (38), 77 (18), 57 (35). Elemental analysis for
C22H21ClN4O2S (440.96). Calcd: C, 59.93; H, 4.79; N, 12.71; S,
7.26%. Found: C, 60.11; H, 4.48; N, 12.60; S, 7.24%.
Acknowledgments. The authors wish to grateful thanks to
Assiut University (Egypt) for supporting this work.
REFERENCES
[1] Lang, J.; Tondys, H. Pol. Pharmacol.. Pharm. 1975, 27, 211.
[2] Bhat, A. K.; Bhamaria, R. P.; Bhllara, R. A.; Drliwala, A.
Indian J. Chem. 1967, 5, 397.
[3] Zsolnia, T. Bio. Chem. Pharmacol. 1962, 11, 271.
[4] Ram, J. V.; Dobe, V.; Pieters, A. C. L.; Vlltinek, A. J. J.
Heterocycl. Chem. 1989, 26, 625.
[5] Leane, E. L. Proc. 7th Brit. Weed Control Conf., Glasgow
1964, Chem.Abstr. 1960, 64, 1279.
[6] Tozkoparan, B.; Akgün, H.; Ertan, M.; Rübsemann, K. Arch.
Pharm. (Weinheim) 1995, 328, 169.
[7] Ilhan, E.; Ergenc, N.; Uzun, M.; Kaya, D. Arch. Pharm.
(Weinheim). 1994, 327, 825.
[8] Abd El-Samii, Z. K.; El. Feky, S. A. J. Chem. Technol.
Biotechnol. 1995, 63, 135; Chem.Abstr. 1995, 123, 256602k.
[9] Essawy, A.; El-Gendy, A. M., El-Safty, M. Said, S. A. Arab
Gulf J. Sci. Res. A 1988, 6, 181; Chem.Abstr. 1989, 110, 154233e.
[10] Pal, R.; Sharma, R.; Kumar, S.; Dahiya, R.; Pujari, K. Ind. J.
Chem. 1994, 33B, 634.
2-Benzyl-6-[morpholino(4-nitrophenyl)methyl]thiazolo-
= NO2, X = O. This
[3,2-b][1,2,4]triazol-5-ol (11h). R
compound was obtained as yellow crystals in 74% yield, Mp.
179-180 °C. IR (KBr) ν = 3120m (O-H), 3030m (C-H aromatic)
2920m, (C-H aliphatic), 1590s (C=N), 1500s, 1440s (aromatic
skeleton), 690s, 730s, 750s cm-1 (C-H aromatic). 1HNMR
(CDCl3, 90 MHz) δ = 8.30-7.30 (m, 9H, aromatic-H), 6.80 (s,
1H, CH), 4.20 (s, 2H, CH2), 3.70-3.30 (m, 8H, 4CH2). UV at
λmax (ε) = 239 (12800), 246 (11800) nm (L mol-1 cm-1), Abs. =
0.512, 0.472 respectively. Elemental analysis for C22H21N5O4S
(451.51). Calcd: C, 58.53; H, 4.69; N, 15.50; S, 7.10%. Found:
C, 58.54; H, 4.41; N, 15.56; S, 7.31%.
2-Benzyl-6-[morpholino(4-methoxyphenyl)methyl]thia-
zolo[3,2-b][1,2,4]triazol-5-ol (11i). R = OCH3, X = O. This
compound was obtained as pale yellow crystals in 68% yield,
Mp. 137-138 °C. IR (KBr) ν = 3150m (O-H), 3030m (C-H
aromatic) 2920m, (C-H aliphatic), 1590s (C=N), 1430, 1500s,
1520s (aromatic skeleton), 690s, 710s, 740s cm-1 (C-H
aromatic). 1HNMR (CDCl3, 90 MHz) δ = 7.70-7.20 (m, 9H,
aromatic-H), 6.80 (s, 1H, CH), 4.10 (s, 2H, CH2), 3.60-3.40 (m,
8H, 4CH2), 3.8 (s, 3H, OCH3). UV at λmax (ε) = 311 (20025) nm
[11] Mohan, J. Ind. J. Chem. 1998, 37B, 953.
[12] Mohan, J. Ind. J. Chem. 1999, 38B, 867.
[13] Kendall, J. D.; Duffin, G. F. and Hford Ltd., Brit. Pat. 634,
951 (1950); Chem.Abstr. 1950, 44, 9287b.
[14] Gogoi, P. C.; Kataky, J. C. S. Heterocycles, 1991, 32, 231.
[15] Tozkoparan, B. Akgün, H. Ertan M.; Rübsemann, K. Arch.
Pharm. (Weinheim) 1995, 328, 169.
[16] a) Gupta, R. P.; Sachedeva, M. L.; Pujari, H. K. Indian J.
Chem. 1977, 15B, 1143. b) Prasad, A. R.; Rao, A. N.; Ramalingam, T.;
Sattar, P. B. Indian J. Chem., 1986, 25B, 776. c) Mohan, J. Indian J. Chem.
1982, 21B, 243. d) Jain, K.; Handa, R. N. Indian J. Chem. 1982, 21B, 732.
(L mol-1 cm-1), Abs.
= 0.801. Elemental analysis for

May-Jun 2008
Synthesis, Characterization and Studies of New 3-Benzyl-4H-1,2,4-triazole-5-thiol
907
[17] Matei, I.; Comanita, E. Bul. Inst. Politeh. Iasi. 1966, 12, 175;
Chem. Abstr. 1969, 70, 47369n.
[18] Hassan, H.Y.; Ismaiel, A.A.; El-Sherief, H.A.H. Eur. J. Med.
Chem. 1991, 26, 1.
[19] Simiti, I.; Ghiran, D. Farmacia (Bucharest) 1971, 19, 199.
[20] a) Molecular mechanics calculations (MM2) were performed
using the computer program PCMODEL 486 version 4, available from
Serena Software. b) Schwartz M.H.; Rosenfeld S.M.; Lee C.I.; Jasinski
J.P.; Dardon E.H. Tetrahedron Lett, 1992 33, 6275. c) Okada K.; Kawai,
H.; Oda M. Tetrahedron Lett. 1992, 33, 257. d) Sakakibara K.; Allinger
N. L. J. Org. Chem. 1995, 60, 4044.
Prakt. Chem. 1990, 332.
[22] Legrand, R. Bull. Soc. Chim. Belg. 1944, 53, 166; Chem.
Abstr. 1946, 40, 4671.
[23] a) Mohan, J. and Kiran, Chim. Acta. Turc. 1988, 16, 91;
Chem. Abstr. 1989, 111, 232685r b) Mohan, J. and Verma, P.; J. Ind.
Chem. Soc., 1992, 268. c) Mohan, J.; Anjaneyulu, G. S. R.; Verma, P.;
Yamini, K.V. S. Ind. J. Chem. 1990, 29B, 88. d) Mohan, J.; Singh, V.;
Kumar, V. Ind. J. Heterocycl. Chem.; 1993, 3, 47.
[24] a) El-Sherif, H. A. H.; Mahmoud, A. M.; Sarhan, A. A. O.;
Hozien, Z. A.;. Habib, O. M. A J. Sulfur Chem. 2006, 27, 65. b) Mahmoud,
A. M.; El-Sherif, H. A. H.; Habib, O. M. A.; Sarhan, A. A. O. Phosphorus,
Sulfur, Silicon and their Related Elements. 2007, 182, 1757.
[21] Hennig, L.; Hofmann, J.; Alva-Astudillo, M.; Mann, G. J.