Synthesis and alkylation of 5-(3-chlorobenzo[b]thien-2-yl) -4H-1,2,4-triazole-3-thiol under classical and microwave conditions. AM1 semiemperical calculations for investigating the regioselectivity of alkylation

Article abstract of DOI:10.1002/jhet.5570430602

Under microwave irradiation (MWI), 5-(3-chlorobenzo[b]thien-2-yl)-4H-1,2,4- triazole-3-thiol (3) was synthesized in a good yield by intramolecular cyclization of the carbonyl thiosemicarbazide 2. A regioselective S-alkylation of 3 with benzyl chloride or

Full text of DOI:10.1002/jhet.5570430602

Nov-Dec 2006
1421
Synthesis and Alkylation of 5-(3-Chlorobenzo[b]thien-2-yl)
-4H-1,2,4-triazole-3-thiol Under Classical and Microwave Conditions.
AM1 Semiemperical Calculations for
Investigating the Regioselectivity of Alkylation
E. S. H. El Ashry*, A. A. Kassem, H. Abdel-Hamid, F. F. Louis, Sh. A. N. Khattab,
and M. R. Aouad.
Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt.
E-mail: eelashry60@hotmail.com, Phone: +2034246601. Fax: +2034271360
Received July 5, 2005
Received Revised June 22, 2006
H
H
N
Cl
Cl
Cl
N
N
N
N
N
N
RX
base
SR
SH
S
N
H
N
S
S
S
RX
base
RX
base
R1
Cl
Cl
N
N
N N
+
SR
SR
N
N
S
S
R1
Under microwave irradiation (MWI), 5-(3-chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole-3-thiol (3) was
synthesized in a good yield by intramolecular cyclization of the carbonyl thiosemicarbazide 2. A
regioselective S-alkylation of 3 with benzyl chloride or allyl bromide has been achieved by using
triethylamine as a base, while other different basic conditions led to a mixture of bis(alkylated) derivatives
N4, S- and S, N2-, under both of classical and MWI conditions. The relative stabilities, charge densities,
dipole moments and electronic energies of reactants, transition states and intermediates were calculated by
the AM1 method and used for investigating the regioselectivity.
J. Heterocyclic Chem., 43, 1421 (2006).
Introduction.
program package [24], to explain the regioselectivity of
the alkylation reactions.
Literature is enriched with progressive advances for the
synthesis and pharmacological action of fused
heterocycles. Those containing the benzo[b]thiophene
nucleus are associated with diverse biological activities
against inflammatory, analgesic [1,2], microbial [3], and
herbicidal [4] effects. Substituted-1,2,4-triazoles also have
pharmacological properties including sedative, nicotine
antagonistic, anticonvulsant [5-7] and antitumor [8]
activities; the 3-thio analogs act as angiotensin II
antagonists [9], anticonvulsant [10] and dopamine D3
antagonists [11,12].
Results and Discussion.
3-Chloro-2-chlorocarbonylbenzo[b]thiophene (1) was
obtained in 82% yield by MW irradiation for 2 min of
cinnamic acid with SOCl2 in presence of catalytic amount
of pyridine in a closed Teflon vessel; conventional
heating required 1 h to give 69% yield [25]. When
compound 1 was reacted with thiosemicarbazide in dry
acetone under MWI for 2 min, it gave the corresponding
acyl thiosemicarbazide 2 in high yield (90%), compared
to the 78 % yield resulted from conventional heating for 2
h [26]. Under basic conditions, the thiosemicarbazide 2
was converted to 5-(3-chlorobenzo[b]thien-2-yl)-4H-
1,2,4-triazole-3-thiol (3) in 54% yield upon reflux for 4 h
[26], while under MWI the reaction time was dramatically
reduced to 3 min with an improvement in the isolated
yield (85%) (Scheme 1).
The recent role of microwave (MW) irradiation in
performing organic reactions [13-16], attracted our
attention to develop its use in our laboratory [17-22] and
in the present work both of the conventional and MW
irradiation conditions were performed to explore the
optimum conditions for the synthesis of new
benzo[b]thienyl-1,2,4-triazoles and investigating the
selectivity encountered on their alkylation. The AM1
calculations [23] were performed, using MOPAC7
Alkylation of the 1,2,4-triazole-3-thione may afford
four possible mono alkylated derivatives depending on the
alkylating agent and the applied conditions. However,

1422
E. S. H. El Ashry*, A. A. Kassem, H. Abdel-Hamid, F. F. Louis,
Sh. A. N. Khattab, and M. R. Aouad
Vol 43
alkylation of 3 with one or two equivalents of benzyl
chloride in presence of triethylamine gave only the S-
alkylated product 4 in 89 and 94% yield, after 1 h heating
under reflux and after 1.5 min irradiation under MW,
respectively (Table 1).
respectively. Compound 5 showed instead of the NH
signal, a singlet for the NCH2-benzyl protons at ꢀ =
5.30 ppm which appeared at a higher field than that at
ꢀ = 5.43 ppm of its isomeric structure 6. The
differentiation between the two isomers with N-4 and
1
N-2 substituents could be concluded from their H nmr
On the other hand, benzylation of 3 with one
equivalent of benzyl chloride using different bases,
powdered KOH, NaH or K2CO3 in DMF as a solvent,
afforded a mixture of the bis(benzylated) products N4,
S- 5 and S, N2- 6 in addition to the recovery of the
starting material 3. When two equivalents of benzyl
chloride were used under the last various reaction
conditions, the products 5 and 6 were obtained in
comparable total yields (84-89%) within 3-5 h (Scheme
1). Improvement of the isolated total yields to 90-94%
and significant reductions in reaction times have been
achieved under the irradiation with MW (Table 1).
The reactions were monitored on TLC, where the
bis(benzylated) products could always be identified by
their Rf values (RfN-4> RfN-2 ). The structures of
spectra based on literature [27-30] for chemical shift
data of the N-methyl derivatives of substituted 1,2,4-
triazoles; the benzyl -CH2- protons on N-2 should be
deshielded than that on the N-4 atom. Accordingly, the
isomeric ratio in the crude mixture could be estimated
before the purification, whereby the ratio of the N-4-
benzyl isomer was much higher than that of N-2-
benzyl one (96: 4). This regioselective alkylation
may presumably be due to the steric effects of the
benzo[b]thiophene ring on position 1 of the triazole
ring which prohibited the substitution on N-1.
Allylation of compound 4 by allyl bromide in
presence of K2CO3 in DMF gave also a mixture of the
bis(alkylated) products 7 and 8 in 88 and 92% total
yield with ratio 86:14, respectively, after 4 h stirring
1
products were assigned based on ir and H nmr spectra
1
1
and 2 min of MW irradiation. The H nmr spectrum of
as well as elemental analyses. The H nmr spectrum of
4 showed two singlets at ꢀ = 14.49 and 4.45 ppm due
to the NH proton of the triazole ring and SCH2 protons,
compound 7 showed the NCH2-allyl protons as a
doublet of doublet of doublet at ꢀ = 4.67 ppm with
Scheme 1
Cl
Cl
N
N
COOH
a
c
COR
SH
N
H
S
S
1
2
R= Cl
R= NHNHCSNH2
3
b
f, g, h, i, j or k
d or e
R1
Cl
Cl
Cl
N
N
N
N
N
N
l or m
n or o
+
SCH2Ph
SCH2Ph
SCH2Ph
N
N
N
H
S
S
S
R1
5 R1= CH2Ph
7 R1= CH2CH=CH2
6 R1= CH2Ph
8 R1= CH2CH=CH2
4
a) SOCl2, Pyridine, DMF, MWI 2 min; b) NH2NHCSNH2, Acetone, MWI 3 min; c) NaOH (4%), MWI 3 min;
d) ClCH2Ph, NEt3, EtOH, reflux 1 h; e) ClCH2Ph, NEt3, EtOH, MWI 1.5 min; f) ClCH2Ph, KOH, DMF, reflux 4 h;
g) ClCH2Ph, KOH, DMF, MWI 3 min; h) ClCH2Ph, NaH, DMF, st. 4 h; i) ClCH2Ph, NaH, DMF, MWI 3 min;
j) ClCH2Ph, K2CO3, DMF, st. 5 h; k) ClCH2Ph, K2CO3, DMF, MWI 3.5 min; l) ClCH2Ph, KOH, DMF, reflux 3 h;
m) ClCH2Ph, KOH, DMF, MWI 2.5 min; n) CH2=CHCH2Br, K2CO3, DMF, st. 4 h; o) CH2=CHCH2Br, K2CO3,
DMF, MWI 2 min

Nov-Dec 2006
Synthesis and Alkylation of 5-(3-Chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole-3-thiol
1423
coupling constants J = 1.60, 3.00 and 5.40 Hz.
Conversely, compound 8 showed these protons as a
doublet at a lower field at ꢀ = 4.78 ppm with coupling
constant J = 5.30 Hz. Accordingly, it can be deduced
that compound 7 has a suitable geometry for the
coupling between NCH2 and =CH2 protons, which is
not present in compound 8.
(Table 1). The ir spectrum of 9 showed bands at 1644
and 3193 cm-1 for the C=N and NH groups,
1
respectively. Its
H nmr spectrum showed two
doublets at ꢀ = 5.09 and 5.28 ppm due to =CH2, a
doublet at ꢀ = 3.85 ppm due to SCH2, a multiplet at ꢀ
= 5.88-5.96 ppm due to =CH and a singlet at ꢀ = 14.50
ppm for the NH group.
Formation of the bis(alkylated) products 5 and 6 may
be due to the tautomerism exhibited in triazole ring in 3,
resulting from the mobility of the NH proton [31], where
the thione [32,33] and the thiol tautomers [34] may exist.
Similarly, compounds 7 and 8 were formed due to the
mobility of NH proton in compound 4.
In a similar manner to that used for the benzylation of
3, the allylation of 3 and 9 by two and one equivalents of
allyl bromide, respectively, in presence of K2CO3 or NaH
in DMF, produced also a mixture of the bis(allylated)
compounds 10 and 11, under both classical and MW
conditions in 89-90% yield after 3-4 h and 94-96% yield
after 1.5-2.0 min, respectively (Table 1).
1H nmr analysis of the crude mixture showed that
compounds 10 and 11 exist as 97:3 mixture of isomers,
respectively. Compound 10 showed NCH2-allyl protons at
ꢀ = 4.80 ppm which appeared at a higher field than that at
ꢀ = 4.94 ppm of its isomeric structure 11.
Allylation of compound 3 with allyl bromide was
also studied by using the same previous procedures
under both conventional and MWI conditions. Thus,
compound 3 was reacted with one equivalent of allyl
bromide in the presence of triethylamine to give the S-
alkylated product 3-allylthio-5-(3-chlorobenzo[b]-
thien-2-yl)-4H-1,2,4-triazole (9) in 91% yield after
reflux for 0.5 h (Scheme 2), while under MWI the
yield was 98% and the time was reduced to 1 min
The apparent regioselectivity in the alkylation of 3 has
been investigated by studying the possible equilibrium of
the tautomers of 3 founded by the mobility of two protons
Scheme 2
Cl
N
N
Cl
N
N
p or q
SH
N
H
SCH2CH=CH2
N
H
S
S
9
3
v or w
r, s, t or u
R1
Cl
S
N
N
Cl
N
N
SCH2CH=CH2
+
N
SCH2CH=CH2
N
S
R1
10 R1= CH2CH=CH2
11 R1= CH2CH=CH2
p) CH2=CHCH2Br, NEt3, EtOH, reflux 0.5 h; q) CH2=CHCH2Br, NEt3, EtOH, MWI 1 min;
r) CH2=CHCH2Br, K2CO3, DMF, st. 4 h; s) CH2=CHCH2Br, K2CO3, DMF, MWI 2 min;
t) CH2=CHCH2Br, NaH, DMF, st. 3 h; u) CH2=CHCH2Br, NaH, DMF, MWI 2 min;
v) CH2=CHCH2Br, K2CO3, DMF, st. 4 h; w) CH2=CHCH2Br, K2CO3, DMF, MWI 2 min

1424
E. S. H. El Ashry*, A. A. Kassem, H. Abdel-Hamid, F. F. Louis,
Sh. A. N. Khattab, and M. R. Aouad
Vol 43
Table 1
Comparison between reaction times and yields obtained from conventional and MWI conditions.
Compound
No
Conditions
Base
Conventional method
Time (hour)
Yield (%)+
Microwave method
Reagent*
Solvent
DMF
(Me)2CO
H2O
Time (min)
Yiled (%)
1
2
a
b
C5H5N
-
1.0
69 [25]
2.0
2.0
3.0
1.5
3.0
3.0
3.5
2.0
2.0
1.0
2.0
2.0
1.5
82
90
85
94
93
90
91
94
92
98
96
96
94
2.0
4.0
1.0
4.0
3.0
5.0
3.0
4.0
0.5
4.0
3.0
3.0
78 [26]
54 [26]
89
87
84
3
c
NaOH
NEt3
KOH
NaH
4
d, e
f, g
h, i
j, k
l, m
n, o
p, q
r, s
t, u
v, w
EtOH
DMF
DMF
DMF
DMF
DMF
EtOH
DMF
DMF
DMF
5, 6
5, 6
5, 6
5, 6
7, 8
9
10, 11
10, 11
10, 11
K2CO3
KOH
K2CO3
NEt3
K2CO3
NaH
86
89
88
91
90
89
K2CO3
89
*
See schemes; + % yield of the crude mixture.
which led to five possible tautomeric forms 3a-e (Scheme
3). Existence of the thione-thiol equilibrium in 5-
substituted-3-thione-4H-1,2,4-triazole has been reported
[31,35]. Compound 3 readily dissolves in alkaline
solution to generate the anions of the tautomeric forms
3b-d due to the acidity of the triazole ring protons
resulting from its aromatic character [36].
method in the MOPAC 7.0 program [24]. All the structures
were optimized to a gradient norm of 0.1 in the gas phase.
The results of the calculations of heat of formation, relative
stability, dipole moments, the highest occupied molecular
orbital energies and the lowest unoccupied molecular orbital
energies as well as the charge density on triazole
heteroatoms are given in Table's 2, 3 and 4.
Scheme 3
2
NH
1
N
Cl
Cl
Cl
N
N
N
NH
4
S
SH
SH
N
N
H
N
S
S
S
H
3a
3c
3b
Cl
Cl
HN NH
N
HN
N
S
SH
N
S
S
3e
3d
To interprete the regioselectivity of alkylation of the
triazole, semiemperical gas phase AM1 calculations [23] for
reactants, transition states and intermediates have been used.
Theoretical calculations were carried out at the Hartree-
Fock level (RHF) using AM1 semiemperical SCF-MO
The atomic charge density localized on the sulfur atom
in each tautomer 3b-d (Table 2) was found to be greater
than that on nitrogen atoms in the triazole ring, which
explained the higher reactivity of the sulfur than nitrogen
atoms in the triazole ring, which explained the higher

Nov-Dec 2006
Synthesis and Alkylation of 5-(3-Chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole-3-thiol
1425
reactivity of the sulfur than nitrogen atoms towards the
electrophilic attack presumably due to the higher
nucleophilic properties and the lower electronegativity of
the sulfur atom [37].
in equilibrated tautomeric forms that upon reaction with
alkyl halides gave the corresponding bis(alkylated)
derivatives (Scheme 4).
Charge density measurements localized on triazole
nitrogen atoms of tautomers of both S-alkylated
derivatives 4b-d and 9b-d as intermediates and their
anionic transition states showed that the N-4 atom has the
highest negative charge density followed by N-2 and then
N-1. This explains the isomeric ratio obtained
experimentally, where N-4 substituted products were
obtained in much higher yield than the N-2 substituted
products, whereas no products from substitution on N-1
were isolated. Moreover, the relative stability energy
calculations for possible substitution on N-4, N-2 and N-1
also coincide with the experimental results (Table 3 and
4). Furthermore, a steric hindrance factor may also
contribute to prohibiting substitution on N-1.
Comparison of the calculated relative stability (RS) of
the possible thione-thiol tautomers led to the conclusion
that the equilibrated tautomers have favored the thiol form
3b to be the more predominant one. The relative stability
of thiols 3b, 3c and 3d compared to 3a were -6.061, -
1.692 and -3.754 kcal, respectively. Moreover, 3a has
been found to have more relative stability than 3e (RS -
12.867 kcal). Consequently, the stability of thiols can be
stated in the order 3b > 3d > 3c > 3a > 3e. Furthermore,
charge density measurements for the anionic forms of
compounds 3a-e, generated by proton-abstraction from
thiol groups, showed that the negative charge density was
more localized on the sulfur atom than that on the
nitrogen atoms. The above relative stability energy
calculations and electron density measurements could
explain the preference formation of the mono S-alkylated
products 4b, and 9b.
Conclusion.
A regioselective alkylation of 5-benzothiophene-
1,2,4-triazole-3-thiol has been achieved to give the
Table 2
Calculated (AM1) Heat of Formation (kcal), Relative Stability (kcal), Dipole Moments, (μ, Debye), HOMO Orbital
Energies (EHOMO, eV) and Charge Density on triazole heteroatoms for the reactant tautomers.
Tautomer Heat of Formation (ꢀHf)
μ
EHOMO ELUMO
eV eV
Charge Density
Relative stability (RS)
Kcal
No
Kcal
Debye
5.547
on triazole heteroatoms
3a
121.577
-8.570 -1.277
-0.200 (S)
-6.061 (3b – 3a)
-1.692 (3c – 3a)
-3.754 (3d – 3a)
-0.277 (N-4)
-0.238 (N-2)
-0.028 (N-1)
0.210 (S)
-0.193 (N-4)
-0.093 (N-2)
3b
115.516
4.436
-8.507 -0.994
-4.369 (3b – 3c)
-2.307 (3b – 3d)
-0.039 (N-1)
0.209 (S)
-0.166 (N-4)
-0.166 (N-2)
-0.049 (N-1)
0.239 (S)
-0.170 (N-4)
-0.063 (N-2)
-0.157 (N-1)
-0.006 (S)
3c
3d
3e
119.885
117.823
134.144
1.545
3.870
5.962
-8.358 0.6654
-8.567 -1.163
-8.754 -1.174
-12.867 (3a – 3e)
-16.221 (3d – 3e)
-0.171 (N-4)
-0.220 (N-2)
-0.193 (N-1)
iRS = The difference in the heat of formation between each two possible tautomers.
In the present work, formation of the bis(alkylated)
products 5-8 and 10, 11 can be presumed to pass through
the S-alkylated derivatives 4 and 9 which could generate
one or more of the anionic transition states that may exist
mono S-alkylated derivatives which upon further
alkylation gave the N4, S- bis(alkylated) products
selectively; the S, N2- bis(alkylated) products were
obtained as minor ones.

1426
E. S. H. El Ashry*, A. A. Kassem, H. Abdel-Hamid, F. F. Louis,
Sh. A. N. Khattab, and M. R. Aouad
Vol 43
Scheme 4
H
Cl
Cl
N
N
N
N
S
SR
N
N
S
S
Transition states
Transition states
R1
H
N
H
Cl
Cl
Cl
N
N
N
N
N
N
SR
SR
SH
N
N
S
S
S
4b-d 4 R= CH2Ph
9 R= CH2CH=CH2
5, 6 R = R1= CH2Ph
7, 8 R = CH2Ph, R1 = CH2CH=CH2
10, 11 R = R1 = CH2CH=CH2
3b-d
9b-d
Reactant
Intermediates
Products
Flex silica gel 1B-F plates using ethyl-acetate-hexane as
developing solvent and the spots were detected by UV light
absorption. Irradiation was done in a domestic microwave
oven EM-230M (800 Watt output power under defrost
temperature). The ir spectra were recorded with Perkin-
The AM1 calculations data are in agreement with the
resulting isomeric ratio distribution in experimental data
where the electrophilic attack occurs predominately at the
N-4 atom and to less extent at N-2 atom. MW irradiation
has accelerated the reaction rates.
1
Elmer 1430 spectrometer. H nmr spectra were recorded on
Jeol spectrometer (500 MHz). Chemical shifts (ꢀ) are given
in ppm relative to the signal for TMS as internal standard.
Isomer ratios were obtained on the basis of H nmr analysis
of the product mixture. Elemental analyses were performed
in the unit of Microanalyses at Faculty of Science, Cairo
University.
EXPERIMENTAL
Chemistry.
1
Melting points were determined with
apparatus and are uncorrected. TLC performed on Baker-
a Melt-temp
Table 3
Calculated (AM1) Heat of Formation (kcal), Relative Stability (kcal), Dipole Moments, (μ, debye), HOMO Orbital Energies (EHOMO, eV)
and Charge Density on triazole heteroatoms for the intermediate tautomers.
Tautomer Heat of Formation (ꢀHf)
μ
EHOMO ELUMO
Charge Density
Relative stability (RS)
No
4b
Kcal
138.077
Debye
6.536
eV eV
on triazole heteroatoms
-0.180 (N-4)
-0.029 (N-2)
-0.059 (N-1)
-0.166 (N-4)
-0.172 (N-2)
-0.051 (N-1)
-0.131 (N-4)
-0.046 (N-2)
-0.157 (N-1)
-0.197 (N-4)
-0.102 (N-2)
-0.039 (N-1)
- 0.173 (N-4)
-0.170 (N-2)
-0.052 (N-1)
-0.164 (N-4)
-0.070 (N-2)
-0.156 (N-1)
Kcal
-3.097 (4b – 4c)
-4.610 (4b – 4d)
-8.568 -1.059
-8.294 -0.590
-8.469 -1.097
-8.228 -0.967
-8.298 -0.619
-8.266 -1.098
4c
4d
9b
9c
9d
141.174
142.687
127.801
131.828
130.933
2.332
3.435
3.935
2.602
3.591
-1.513 (4c – 4d)
-4.027 (9b – 9c)
-3.132 (9b – 9d)
1.095 (9c – 9d)
iRS = The difference in the heat of formation between each two possible tautomers.

Nov-Dec 2006
Synthesis and Alkylation of 5-(3-Chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole-3-thiol
1427
Table 4
Calculated (AM1) Heat of Formation (kcal), Relative Stability (kcal), Dipole Moments, (μ, debye), HOMO Orbital Energies (EHOMO
,
eV) and Charge Density on triazole heteroatoms for the transition state tautomers.
Tautomer Heat of Formation (ꢀHf)
μ
EHOMO ELUMO
eV eV
-4.499 2.439
Charge Density
on triazole heteroatoms
-0.132 (N-4)
-0.116 (N-2)
-0.096 (N-1)
-0.144 (N-4)
-0.119 (N-2)
-0.094 (N-1)
-0.167 (N-4)
-0.109 (N-2)
-0.121 (N-1)
-0.117 (N-4)
-0.089 (N-2)
-0.083 (N-1)
-0.141 (N-4)
-0.110 (N-2)
-0.095 (N-1)
-0.155 (N-4)
-0.170 (N-2)
-0.081 (N-1)
Relative stability (RS)
Kcal
No
4b
Kcal
90.083
Debye
6.790
-0.521 (4b – 4c)
-4.408 (4b – 4d)
4c
4d
9b
9c
9d
90.604
94.491
82.466
82.562
82.698
5.903
8.318
6.294
6.986
3.580
-4.347
2.439
-3.887 (4c – 4d)
-4.211 2.499
-4.262
-4.260
2.505
2.608
-0.090 (9b – 9c)
-0.232 (9b – 9d)
-0.136 (9c – 9d)
-3.889 -1.098
iRS = The difference in the heat of formation between each two possible tautomers.
3-Chloro-2-chlorocarbonylbenzo[b]thiophene (1).
mmol) was added with stirring. The conditions of the reaction
are shown in Table 1. The solvents were removed by
evaporation under reduced pressure in case of ethanol, when
DMF was used as solvent; the reaction mixture was poured on
crushed ice. The obtained products were washed with water,
dried and recrystallized from ethanol and in case of mixtures;
the products were separated by column chromatography.
A mixture of cinnamic acid (0.304 g, 2.3 mmol), pyridine
(0.05 ml), dry DMF (0.1 ml) and (0.6 ml) thionyl chloride was
irradiated by MW for 2 min in a closed Teflon vessel. The
mixture was taken up in 10 ml of dry hexane, heated and
decanted from the gummy residue. The yellow decanted solution
solidified to give yellow crystals, mp 111-113 °C, Lit. mp 110-
112 °C [25].
Microwave method (MW)
3-Chlorobenzo[b]thiophene-2-carbonyl thiosemicarbazide (2).
A mixture of compound (1 mmol), base (1 or 2 mmol) and
appropriate alkyl halide (1 or 2 mmol) in solvent (5 ml) was
irradiated by MW in a closed Teflon vessel. The obtained
reaction mixture was treated as described above (Table 1).
A mixture of compound 1 (0.230 g, 1 mmol), dry acetone (5
ml) and thiosemicarbazide (0.091 g, 1 mmol) was irradiated by
MW for 2 min in a closed Teflon vessel. The product was
recrystallized from ethanol as yellow crystals, mp 201-202 ºC,
Lit. mp 200-202 °C [26].
3-Benzylthio-5-(3-Chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole
(4).
5-(3-Chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole-3-thiol (3).
This compound was obtained as yellow crystals, mp 175-177
ºC; ir (potassium bromide): 3286 (NH), 1652 (C=N), 1597
A mixture of compound 2 (0.285 g, 1 mmol) and aqueous
sodium hydroxide (4%, 10 ml) was irradiated by MW for 3 min.
The mixture was cooled, filtered and acidified with dilute
hydrochloric acid. The precipitate was collected by filtration,
washed with water and recrystallized from ethanol to give
yellow crystals, mp 283-284 ºC, Lit. mp 281-282 °C [26]; ir
(potassium bromide): 3232-3355 (NH), 1638 (C=N), 1591
(C=C) cm1ꢀ; 1H nmr (dimethyl sulfoxide-d6): ꢀ 7.52-7.56 (m, 2H,
5-H, 6-H benzothiophene), 7.82-7.85 (m, 1H, 4-H benzothio-
phene), 8.07-8.10 (m, 1H, 7-H benzothiophene), 14.00 (s, 2H,
deuterium oxide-exchangeable, NH, SH).
1
(C=C), 2956 (C-H al.) cm-1; H nmr (dimethyl sulfoxide-d6): ꢀ
4.45 (s, 2H, SCH2), 7.21-7.43 (m, 5H, Ar-H), 7.51-7.55 (m, 2H,
5-H and 6-H benzothiophene), 7.85 (d, 1H, 4-H benzothiophene,
J = 7.70 Hz), 8.07 (d, 1H, 7-H benzothiophene, J = 6.90 Hz),
14.49 (s, 1H, deuterium oxide-exchangeable, NH).
Anal. Calcd. for C17H12ClN3S2: C, 57.05; H, 3.38; N, 11.74.
Found: C, 57.17; H, 3.63; N, 11.41.
4-Benzyl-3-benzylthio-5-(3-chlorobenzo[b]thien-2-yl)-1,2,4-
triazole (5).
This compound was separated by column chromatography
(eluent EtOAc: Hexane, 1:35) as white plates, (78%, CM) yield,
mp 131-132 ºC; ir (potassium bromide): 1629 (C=N), 1570
Anal. Calcd. for C10H6ClN3S2: C, 44.86; H, 2.26; N, 15.69.
Found: C, 44.91; H, 2.69; N, 15.64.
1
(C=C), 2920 (C-H al.) cm-1; H nmr (dimethyl sulfoxide-d6): ꢀ
General Method for the Alkylation.
Conventional Method (CM).
4.49 (s, 2H, SCH2), 5.30 (s, 2H, NCH2), 7.11-7.42 (m, 10H,
phenyl protons), 7.50-7.55 (m, 2H, 5-H and 6-H benzothio-
phene), 7.85 (dd, 1H, 4-H benzothiophene, J = 1.50, 7.70 Hz),
8.06 (dd, 1H, 7-H benzothiophene, J = 1.50, 7.70 Hz).
To a solution of compound (10 mmol) in a solvent (50 ml)
and base (10 or 20 mmol), the appropriate alkyl halide (10 or 20

1428
E. S. H. El Ashry*, A. A. Kassem, H. Abdel-Hamid, F. F. Louis,
Sh. A. N. Khattab, and M. R. Aouad
Vol 43
Anal. Calcd. for C24H18ClN3S2: C, 64.34; H, 4.05; N, 9.38.
Found: C, 64.72; H, 4.41; N, 8.97.
mp 56-57 ºC; ir (potassium bromide): 1639 (C=N), 1566 (C=C),
1
2985 (C-H al.) cm-1; H nmr (dimethylsulfoxide-d6): ꢀ 3.90 (d,
2H, SCH2, J = 6.90 Hz), 4.80 (d, 2H, NCH2, J = 5.30 Hz), 5.10 (2d,
2H, =CH2, J = 10.70, 16.80 Hz), 5.30 (2d, 2H, =CH2, J = 10.70,
16.80 Hz), 5.90-5.96 (m, 2H, =CH), 7.48-7.53 (m, 2H, 5-H and 6-
H benzothiophene), 7.83 (d, 1H, 4-H benzothiophene, J = 7.70 Hz),
8.04 (d, 1H, 7-H benzothiophene, J = 7.70 Hz).
2-Benzyl-3-benzylthio-5-(3-chlorobenzo[b]thien-2-yl)-1,2,4-
triazole (6).
This compound was separated by column chromatography
(eluent EtOAc: Hexane, 1:35) as white plates, (3%, CM) yield, mp
139-140 ºC; ir (potassium bromide): 1600 (C=N), 1570 (C=C),
2967 (C-H al.) cm-1; 1H nmr (dimethyl sulfoxide-d6): ꢀ 4.73 (s, 2H,
SCH2), 5.43 (s, 2H, NCH2), 7.23-7.48 (m, 12H, phenyl protons, 5-H
and 6-H benzothiophene), 7.82 (d, 1H, 4-H benzothiophene, J =
7.70 Hz), 7.92 (d, 1H, 7-H benzothiophene, J = 7.70 Hz).
Anal. Calcd. for C16H14ClN3S2: C, 55.24; H, 4.06; N, 12.08.
Found: C, 54.94; H, 4.24; N, 11.95.
2-Allyl-3-allythio-5-(3-chlorobenzo[b]thien-2-yl)-1,2,4-triazole (11).
This compound was separated by column chromatography
(eluent EtOAc: Hexane, 1:25) as white crystals (2%, CM), mp
63-65 ºC; ir (potassium bromide): 1639 (C=N), 1565 (C=C),
2932 (C-H al.) cm-1; 1H nmr (dimethyl sulfoxide-d6): ꢀ 3.76 (d,
2H, SCH2, J = 6.70 Hz), 4.94 (d, 2H, NCH2, J = 5.30 Hz), 5.02,
5.08, 5.16, 5.26 (4dd, 4H, =CH2, J = 1.50, 16.80, 1.50, 11.40
Hz), 5.88-5.97 (m, 2H, =CH), 7.57-7.62 (m, 2H, 5-H and 6-H
benzothiophene), 7.88-7.92 (m, 1H, 4-H benzothiophene), 8.13-
8.16 (m, 1H, 7-H benzothiophene).
Anal. Calcd. for C24H18ClN3S2: C, 64.34; H, 4.05; N, 9.38.
Found: C, 64.51; H, 3.71; N, 8.94.
4-Allyl-3-benzylthio-5-(3-chlorobenzo[b]thien-2-yl)-1,2,4-
triazole (7).
This compound was separated by column chromatography
(eluent EtOAc: Hexane, 1:27) as yellow crystals, (80%, CM)
yield, mp 118-119 ºC; ir (potassium bromide): 1637 (C=N), 1572
1
(C=C), 2921 (C-H al.) cm-1; H nmr (dimethyl sulfoxide-d6): ꢀ
Anal. Calcd. for C16H14ClN3S2: C, 55.24; H, 4.06; N, 12.08.
Found: C, 54.89; H, 4.10; N, 12.01.
4.50 (s, 2H, SCH2), 4.67 (ddd, 2H, NCH2, J = 1.60, 3.00, 5.40 Hz),
5.17, 5.25 (2dd, 2H, =CH2, J = 0.80, 16.80, 1.50, 11.50 Hz), 5.91
(ddd, 1H, =CH, J = 4.60, 11.50, 16.80), 7.25-7.32 (m, 3H, phenyl
protons), 7.40-7.47 (m, 4H, phenyl protons, 5-H and 6-H
benzothiophene), 7.83 (dd, 1H, 4-H benzothiophene, J = 1.50,
7.70 Hz), 7.92 (dd, 1H, 7-H benzothiophene, J = 1.50, 7.70 Hz).
Anal. Calcd. for C20H16ClN3S2: C, 60.36; H, 4.05; N, 10.56.
Found: C, 60.60; H, 4.34; N, 10.35.
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1
(C=C), 2979 (C-H al.) cm-1; H nmr (dimethyl sulfoxide-d6): ꢀ
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Synthesis and Alkylation of 5-(3-Chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole-3-thiol
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