Synthesis of oxadiazoles, thiadiazoles and triazoles derived from benzo[b]thiophene

Article abstract of DOI:10.3390/10091161

In this work 3-chloro-2-chlorocarbonylbenzo[b]thiophene (1) was prepared from cinnamic acid and then converted into the acid hydrazide 2. The azomethines 3a-e were prepared from the corresponding aryl aldehydes and the acid hydrazide 2. Treatment of compo

Full text of DOI:10.3390/10091161

Molecules 2005, 10, 1161-1168
molecules
ISSN 1420-3049
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Synthesis of Oxadiazoles, Thiadiazoles and Triazoles Derived
from Benzo[b]thiophene.
A. Hussain K. Sharba *, R. H. Al-Bayati, M. Aouad and N. Rezki
Department of Chemistry, College of Science, Al-Mustansirya University, Baghdad, Iraq.
*Author to whom correspondence should be addressed; e- mail: hussainirk@yahoo.com
Received: 29 June 2005; in revised form: 29 August 2005 / Accepted: 30 August 2005 / Published: 30
September 2005
Abstract: In this work 3-chloro-2-chlorocarbonylbenzo[b]thiophene (1) was prepared from
cinnamic acid and then converted into the acid hydrazide 2. The azomethines 3a-e were
prepared from the corresponding aryl aldehydes and the acid hydrazide 2. Treatment of
compound 2 with formic acid gave the N-formyl acid hydrazide 4, which upon refluxing with
phosphorous pentoxide or phosphorous pentasulphide in xylene yielded the corresponding 2-
(3-chloro-1-benzothien-2-yl)-1,3,4-oxadiazole (5) and 2-(3-chloro-1-benzo-thien-2-yl)-1,3,4-
thiadiazole (6). Reaction of 1-thiosemicarbazide 7 with NaOH leads to ring closure giving 5-
(3-chloro-1-benzothien-2- yl)-4H–triazole-3-thiol (8) which is converted into a number of
derivatives 9-12 Reaction of 2 with phenyl isothiocyanate and NaOH afforded 5-(3-chloro-
1-benzothien-2-yl)-4-(phenyl)-4H-1,2,4-triazole-3-thiol (14).
Keywords: Benzo[b]thiophene, oxadiazole, thiadiazole, 4H-1,2,4-triazole-3-thiol,
azomethine, Mannich bases .
Introduction
Derivatives of 1,3,4–oxadiazole and 1,3,4 –thiadiazole have been found to possess a wide spectrum
of pharmacological ,medical,and biological activities [1]. Schiff bases have also been widely reported
to be biologically versatile compounds having antifungal, herbicidal and plant growth regulating
properties [2]. Moreover derivatives of 1,2,4-triazole are known to exhibit anti-inflammatory [3],
antiviral [4], analgesic [5], antimicrobial [6], anticonvulsant [7] and antidepressant activities [8]. A

Molecules 2005, 10
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series of 1,2,4-triazole derivatives have been patented and extensively employed in agriculture [9]. We
now report on the synthesis of compounds derived from benzo[b]thiophene containing oxadiazole,
thiadiazole and triazole moieties, with the purpose of investigating in the future their possible
antibacterial and antifungal activities.
Results and Discussion
The new oxadiazole and thiadiazole derivatives were prepared following the reaction sequences
depicted in Scheme 1. The starting material for the synthesis of the targeted compounds is 3-chloro-2-
chlorocarbonyl benzo[b]thiophene (1) which was prepared by the reaction of cinnamic acid with
thionyl chloride in DMF and dry pyridine according to the reported method [10]. Reaction between 1
and hydrazine hydrate afforded the acid hydrazide 2 in good yield. The IR spectra showed the N-H
stretching absorption near 3140 cm-1 and the C=O stretching one at 1640 cm-1. Condensation of the
acid hydrazide 2 with aryl aldehydes in absolute ethanol gave the Schiff bases 3a-e.
Scheme 1
COOH
SOCl2, pyridine
Cl
S
COCl
1
N2H4 · H2O
Cl
ArCHO
PhNCS
S
CONHNH2
Cl
Cl
2
S
HCOOH
Cl
S
CONHN=CHAr
S
CONHNHCNHPh
3a-e
13
NaOH
C6H5, p-Cl-C6H4,
p-NO2-C6H4, o-MeO-C6H4,
m-NO2-C6H4
Ar =
S
CONHNHCHO
4
Cl
P2S5
Cl
P2O5
N
Cl
O
S
N
N
N
Ph
14
N
SH
S
S
N
N
S
6
5

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1163
The formation of these Schiff bases was indicated by the presence in their IR spectra of the
azomethine (CH=N) stretching band at 1600 cm-1, combined with the disappearance of the NH2
stretching band. Further, 3-chloro-2-(N-formyl acid hydrazide)benzo[b]thiophene (4) was obtained in
70% yield when the acid hydrazide 2 was allowed to react with formic acid[11,12]. The structure of
compound 4 was confirmed by the presence of two amidic carbonyl stretching bands at 1720 cm-1 and
1660 cm-1 (CO-NH-NH-CHO).
Scheme 2
1
S
H2NHNCNH2
Cl
ClCH2C CH
S
CONHNHCNH2
S
7
NaOH (4%)
Cl
N
S
N
N
H
NHR2
8
SH
R'X
Cl
Cl
N
S
N
N
N
S
N
H
10
Am
N
H
9
SR'
R' = CH3, 2,4-diNO2-C6H4,
4-NO2-C6H4CH2
Am = morpholine, piperidine, piperazine
Cl
Cl
HNR'
HCHO
N
N
S
N
S
N
N
N
H
H
12
11
SCH2C CCH2Am
SCH2C CH
Refluxing compound 4 with phosphorous pentoxide in xylene for one hour afforded 2-(3-chloro-1-
benzothien-2-yl)-1,3,4- oxadiazole (5), which displayed two bands at 1245 cm-1 and 1080 cm-1 for the
C-O-C asymmetric and symmetric stretching, respectively [12,13], in addition to the band at 1620 cm-1
for the C=N stretch. Moreover, 2-(3-chloro-1-benzothien-2-yl)-1,3,4-thiadiazole (6) was obtained in
62-68% yield from the reaction of 4 with phosphorous pentasulphide under reflux in xylene solution.
The absorption band at 1610 cm-1 in the IR spectrum of 6 is due to C=N stetching. On the other hand

Molecules 2005, 10
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the reaction of 1 with powdered thiosemicarbazide in dry benzene afforded the acylthiosemicarbazide
7, which upon ring closure with NaOH gave 5-(3-chloro-1-benzothien-2-yl)-4H-1,2,4-triazole-3-thiol
(8) [14] which exists in a tautomeric thiol – thione equilibrium, as indicated by the C=S stretching
band at 1190 cm-1 and S-H stretch at 2600 cm-1 [15]. Alkylation of 8 gave compound 9, while
treatment with secondary amines resulted in compound 10 by nucleophilic displacement of the SH
group. Further, reaction of 8 with propargyl chloride led to the introduction of alkynyl functionality,
thus affording compound 11, as indicated by the strong band at 2100 cm-1 for the C≡C stretch and
3300 cm-1 for the ≡C-H stretching vibration, respectively. Treatment of 11 with secondary cyclic
amines, namely morpholine, piperidine or piperazine, under Mannich reaction conditions resulted into
the Mannich bases 12a-c, which was indicated by the disapperance of the ≡C-H vibration band.
In another triazole preparation, condensation of acid hydrazide 2 with phenyl isothiocyanate
afforded the corresponding thiosemicarbazide 13 in moderate yield. Ring closure of arylthiosemi-
carbazides in an alkaline medium is a well known method for the synthesis of 1,2,4-triazoles and thus
5–(3-chloro-1-benzothien-2-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol (14) was obtained from the
corresponding 13 by this method. The IR spectra of 1,4-substituted thiosemicarbazide derivative 13
display a C=O stretching band at 1680 cm-1 and C=S stretching band at 1240 cm-1. It is worth
mentioning that compounds 8 and 14 exist as thiol – thione tautomers, as indicated by their IR spectra
which showed a band due to SH and another band to N-C=S .
Experimental
General
Melting points were determined in open capillary tubes on a Gallenkamp mething point apparatus
and are uncorrected. The IR spectra (KBr discs) were recorded with a Pye–Unicam SP-300
spectrometer. UV spectra were recorded on Hitachi–2000 spectrophotometer using absolute ethanol as
solvent. 1H-NMR on a Hitachi–Perkin–Elmer 60 MHz NMR spectrometer in DMSO–d6 solutions and
with tetramethylsilane as an internal standard. Elemental analysis were done on a 1106 Carlo – Erba
instrument.
Preparation of 3-chloro-2-chloromethyl benzo[b]thiophene (1)
This compound was prepared according to the method reported in the literature [10]; mp 112-
114°C (lit. mp 110-112°C [10])
Preparation of 3- chloro benzo[b] thiophene-2-carboxylic acid hydrazide (2)
To a solution of compound 1 (0.001 mole) in dry chloroform (5 mL), hydrazine hydrate (0.0018
mole) was added dropwise. The mixture was refluxed for one hour. The solvent was removed in vacuo
and the solid product was collected and crystallized from ethanol, mp 164-166°C; 73% yield; IR (υ,
cm-1): 3280, 3140 (N-H), 1650(C =O), 1570 (C=C), 1070 (=C-Cl), 680 (C-S-C); UV (λmax): 297 nm.

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Preparation of compounds 3a-e.
A mixture of 2 (0.01 mole) and the corresponding aryl halide (0.01 mole) in ethanol (25 mL) was
refluxed for 3 hours and cooled. The precipitate was filtered and crystallized from ethanol. (3b) Yield
76%; mp 212-214; IR v (cm-1): 3180 (N-H), 3020 (C-H ar ), 1650 (C=O), 1600(C=N); UV: 295 nm;
(3c) Yield 82%; mp 240-242; IR v (cm-1): 3200 (N-H), 3050 (C-H ar), 1640 (C=O), 1610 (C=N); UV:
289 nm.
Preparation of compound 4.
A solution of 2 (0.01 mole) in formic acid (20 mL) was refluxed for 30 minutes. The solvent was
evaporated and the residue was crystallized from methanol; 73% yield; mp. 188-190°C; IR (υ, cm-1):
3200 (N-H), 1660, 1720 (C=O); UV (λmax): 306 nm; Calculated for C10H7N2O2SCl (%); C, 57.30; H,
3.09; N, 11.79; found (%): C, 56.95; H, 3.11; N, 11.65.
General Procedure for preparation of 2-(3-chloro-1-benzothien-2-yl)-1,3,4-oxadiazole (5) and 2-(3-
chloro-1-benzothien-2-yl)-1,3,4-thiadiazole (6).
To a solution of 4 (0.01 mole) in xylene (150 mL), phosphorous pentoxide or phosphorous
pentasulphide (0.01 mole) was added. The mixture was refluxed for one hour. The solvent was
evaporated, water (10 mL) was added and the mixture was extracted with chloroform. The solvent was
evaporated and the residue was recrystallized from benzene or ethylacetate. Compound 5: mp. 100-
102 °C; yield 53%; IR (υ, cm-1): 1620 (C=N), 1530 (C=C), 1245, 1080 (C-O-C); UV (λmax) 287 nm;
1H-NMR δ: 6.2 (s, 1H, oxadiazole), 7.0-7.5 (m, 4H, Ar-H); Compound 6: mp. 124-126°C; yield 63%;
1
IR (υ, cm-1) 1610 (C=N), 1550 (C=C); UV (λmax) 294 nm; H-NMR δ: 6.6 (s, 1H, thiadiazole), 7.7-8
(m, 4H, Ar-H); Calcd. for C10H5N2S2Cl (%): C, 47.62; H,1.98; N,11.11; found %: C, 47.29; H,2.07; N,
10.98.
Preparation of 3- chloro benzo[b]thiophene -2- carboxylic thiosemicarbazide (7).
To a solution of compound 1 (0.01 mole) in dry benzene (50 mL) was added thiosemicarbazide (0.01
mole). The mixture was refluxed for 2 hours and after cooling the precipitate was filtered and
crystallized from ethanol – water; mp 200-202°C; yield 78%; IR (υ, cm-1): 3170 (N-H); 1660 (C=O);
1
1220 (C=S); 1070 (C-Cl); 690 (C-S-C); UV (λmax): 298 nm; H-NMR δ (ppm): 10.4 (s, 1H, CONH);
9.7 (s, 1H, CSNH); 8-7.5 (m, 4H, Ar-H); 3.6 (s, 2H, CSNH2); Calcd. for C10H8N3OS2 Cl (%): C,
42.10; H, 2.80; N, 14.73; found (%): C,41.88; H,3.01; N,14.55.
Preparation of 5-(3-chloro-1-benzothien-2-yl)-4H-1,2,4-triazole-3-thiol (8).
A stirred mixture of compound 7 and aqueous sodim hydroxide (4%, 10 mL) was refluxed for 3
hours. The mixture was acidified with dil. HCl and the precipitate was collected and crystallized from
ethanol; yield 54%; mp. 231(dec)°C; IR υ (cm-1): 3130 (N-H), 3045 (C-Har), 2600 (SH), 1650 (C=N),

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1590 (C=C); 1190 (C=S); UV (λmax): 299.5 nm; Calcd. for C10H6N3S2Cl (%): C, 44.94; H, 2.28; N,
15.73; found (%): C, 44.59; H, 2.34; N, 15.48.
Preparation of compounds 9a-c.
To the stirred solution of compound 8 (0.001 mole) and sodium acetate (0.0024 mole) in ethanol
(20 mL), alkyl/aryl halide (0.001 mole) was added. The mixture was refluxed for 3 hours. After
cooling, the solution was poured onto crushed ice (30 g). The precipitate was filtered and recrystallized
from acetone – water.
5-(3-chloro-1-benzothien-2-yl)-4H-1,2,4-triazole-3 methyl thiol (9a): Yield 52%; mp. 150-152°C; IR
(υ, cm-1): 3330 (N-H), 3070 (C-Har), 1600 (C=N), 1550 (C=C), 1440 (S-CH3), 750 (C-S); UV (λmax):
252 nm; 1H-NMR (δ) ppm: 7.5-8.5 (m, 4H, Ar-H), 3.2 (s, 3H, SCH3).
5-(3-chloro-1-benzothien-2-yl)-4H-1,2,4-triazole-3-(4-nitrobenzyl) thiol (9b): Yield 40%; mp. 163-
165°C; IR (υ, cm-1): 3260 (N-H), 3070 (C-Har), 1600 (C=N), 1510 (C=C), 1510, 1340 (C–NO2); UV
(λmax): 381 nm; Calcd. for C17H11N4O2S2Cl (%): C, 52.57; H, 2.83; N, 10.82; found (%): C, 52.34; H,
2.95; N, 10.66.
5-(3-chloro-1-benzothien-2-yl)-4H-1,2,4-triazole-3-(2,4-dinitrophenyl) thiol (9 c): Yield 67%; mp 161
-163°C; IR (υ, cm-1): 3120 (N-H), 3050 (C-Har), 1620 (C=N), 1530 (C=C), 1540, 1350 (C-NO2), 760
(C-S); UV (λmax): 382 nm.
Preparation of compounds 10a-c.
To a stirred solution of compound 8 (0.003 mole) in dry dioxane (10 mL) was added a solution of
the appropriate secondary amine (0.003 mole) in dry dioxane (5 mL). The mixture was refluxed for
four hours. After cooling, the precipitate was filtered and crystallized from methanol.
5-(3-chloro-1-benzothien-2-yl)-4H-1,2,4-triazole-3-N-piperidine (10a): Yield 60%; mp 160-162°C; IR
(υ, cm-1): 3340 (N-H), 3030 (C-Har ), 2860, 2970 (C-Hal), 1640 (C=N), 1575 (C=C); UV (λmax): 300
1
nm; H-NMR (δ) ppm: 2.6-2.8 (m, piperidine ring protons), 6.5-6.8 (m, 4H, Ar-H). Calcd. for
C15H15N4SCl (%): C, 56.60; H, 4.71; N, 17.61; found (%): C, 56.33; H, 5.00; N, 17.44
General procedure for preparation of 5-(3-chloro-1-benzothien -2-yl)-4H-1,2,4-triazole-3-(prop-2-
ynyl) thiol (11)
To a stirred solution of compound 8 (0.01 mole) and triethylamine (0.01 mole) in ethanol (25 mL),
was added propargyl chloride (0.01 mole) dropwise. The mixture was refluxed for two hours in a water
bath. Excess ethanol was removed in vacuo. The product was collected and crystallized from ethanol –
water; Yield 75%; mp 108-110°C; IR (υ, cm-1): 3300 (≡ C-H), 3180 (N-H), 3060 (C-Har), 2970 (C-
Hal), 1650 (C=N), 1590 (C=C), 2100 (C≡C); UV (λmax): 298nm.

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General procedure for preparation of compounds 12a-c.
To a stirring solution of compound 11 (0.005 mole) in dioxane (25 mL) was added cuprous
chloride (0.0025 g) and the mixture was heated for a few minutes, then paraformaldehyde (0.005 mole)
and the appropriate secondary amine (0.005 mole) were added. The mixture was heated at 90°C for
two hours. After cooling, the mixture was filtered and the poured onto ice water (100 mL). The residue
was extracted with chloroform (3 x 25 mL) and purified on a column of silica gel using chloroform –
petroleum spirit as eluent. The product is oily. Yield of 12b 68% (from piperidine); IR (υ, cm-1): 3400
(N-H), 3050(C-Har), 2920, 2880 (C-Hal ), 1645 (C=N), 1560 (C=C), 1180 (C-N); UV (λmax): 305 nm.
General procedure for preparation of compound 14.
A mixture of the acid hydrazide 2 (0.01 mole) and phenyl isothiocyanate (0.01 mole) in dry C6H6
was refluxed for 6 hours. The solid material obtained on cooling was filtered off and recrystallized
from methanol to give compound 13. IR (υ, cm-1): 1680 (C=O), 1240 (C=S). A stirring mixture of
compound 13 (1 mmole) and sodium hydroxide (40 mg, 1 mmole) was refluxed for 4 hours. After
cooling, the solution was acidified with hydrochloric acid and the precipitate was filtered. The solid
5-(3-chloro-1-benzothien -2-yl-4-phenyl-4H-1,2,4-triazole-3-thiol (14) was recrystallized from ethyl
acetate. Yield: 73%; mp 240-242°C; IR (υ, cm-1): 3320 (N-H thione), 3060 (C-Har), 1635 (C=N),
1530 (C=C), 1310 (C=S thione); UV (λmax): 313 nm; 1H-NMR (δ) ppm: 3.8 (s, 1H, N-H thione), 8.3 –
8.9 (m, 9H, Ar-H); Calcd. for C16H10N3S2Cl (%): C, 55.97; H, 2.91; N, 12.44; found (%): C, 55.59; H,
3.08; N, 12.23.
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Sample availability: Available from the authors.
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