Synthesis of some new benzofuran-based thiophene, 1,3-oxathiole and 1,3,4-oxa(thia)diazole derivatives

Article abstract of DOI:10.1002/hc.20298

Treatment of 3-(3-methylbenzofuran-2-yl)-3-oxopropanenitrile (1) with phenyl isothiocyanate afforded the thioacetanilide derivative 3, which when reacted with α-haloketones, α-halodiketones, and hydrazonoyl chlorides gives thiophene, 1,3-oxathiole, and 1,

Full text of DOI:10.1002/hc.20298

Heteroatom Chemistry
Volume 18, Number 3, 2007
Synthesis of Some New Benzofuran-Based
Thiophene, 1,3-Oxathiole and
1,3,4-Oxa(Thia)diazole Derivatives
Kamal M. Dawood,1 Ahmad M. Farag,1 and Hatem A. Abdel-Aziz2
1Department of Chemistry, Faculty of Science, University of Cairo, Giza 12613, Egypt
2Department of Applied Organic Chemistry, National Research Centre, Dokki, Giza, Egypt
Received 9 January 2006; revised 26 April 2006
having antimicrobial [10,11], anticonvulsant, and
ABSTRACT: Treatment of 3-(3-methylbenzofuran-2-
anti-inflammatory activities [12,13]. In this context,
yl)-3-oxopropanenitrile (1) with phenyl isothiocyanate
we continue our research on the utility of 3-(3-
afforded the thioacetanilide derivative 3, which
methylbenzofuran-2-yl)-3-oxopropanenitrile (1) in
when reacted with α-haloketones, α-halodiketones,
the synthesis of some new heteroaromatic deriva-
and hydrazonoyl chlorides gives thiophene, 1,3-
tives incorporating benzofuran nucleus.
oxathiole, and 1,3,4-thiadiazole derivatives 6a,b,
10a,b and 14a–g, respectively. Treatment of 3-methyl-
2-benzofurancarboxylic acid hydrazide (15) with ben-
RESULTS AND DISCUSSION
zaldehyde followed by bromine afforded the 1,3,4-
oxadiazole derivative 18. Treatment of the acid
hydrazide 15 with phenyl isothiocyanate gave
the thiosemicarbazide 20. Compound 20 could
be converted into 1,3,4-oxadiazole, 1,2,4-triazole-3-
thione, and 1,3,4-thiadiazole derivatives 21, 22, and
When 3-(3-methylbenzofuran-2-yl)-3-oxopropaneni-
trile (1) [10] was treated with phenyl isoth-
iocyanate, in dimethylformamide, in the pres-
ence of potassium hydroxide, it afforded the
corresponding potassium salt 2, which was
converted into 2-cyano-2-(3-methylbenzofuran-2-
yl)thioacetanilide (3) upon treatment with di-
lute hydrochloric acid (Scheme 1). Reaction of
compound 3 with 1-aryl-2-bromoethanones 4a,b
in ethanol and in the presence of catalytic
amount of triethylamine resulted in the forma-
tion of 2-aroyl-4-cyano-3-(3-methylbenzofuran-2-
carbonyl)-5-(N-phenylamino)thiophenes 6a,b. The
IR spectrum of compound 6a, for example, exhib-
ited three absorption bands at 3233, 2222, and 1650
cm−1 characteristic of imine, nitrile, and carbonyl
groups, respectively. The appearance of the nitrile
function in the IR spectra of the reaction products
supports structures 6a,b and rules out the possibility
of other structures 7a,b (Scheme 1).
ꢀ
C
23, respectively.
2007 Wiley Periodicals, Inc. Het-
eroatom Chem 18:294–300, 2007; Published online in
Wiley InterScience (www.interscience.wiley.com). DOI
10.1002/hc.20298
INTRODUCTION
Benzofuran derivatives have been associated with
diverse pharmacological activities, such as insecti-
cidal [1], anti-inflammatory [2], antihistaminic [3],
antiallergic [4], and antitumor agents [5], in ad-
dition to their natural occurrence [6–9]. Recently,
we reported several benzofuran-based heterocycles
Correspondence to: Kamal M. Dawood; e-mail: dr_dawood@
In addition, compound
α-chloroacetylacetone (8a) and with ethyl
3
reacted with
yahoo.com.
c
ꢀ
2007 Wiley Periodicals, Inc.
294

Synthesis of Some New Benzofuran-Based Thiophene, 1,3-Oxathiole and 1,3,4-Oxa(Thia)diazole Derivatives 295
Me
Me
O
O
PhNCS
- +
HCl
S K
KOH/DMF
O
O
CN
NC
HN Ph
1
2
O
S
Me
Me
Ar
ArCOCH2Br
O
O
4
SH
O
EtOH/TEA
O
NC
Ph
HN
Ph
NC HN
5
3
−H2O
O
O
EtOH
TEA
Me
R
Me
Cl
O
8
Ar
CH3
O
H
R
N
S
Ph
O
Me
O
Me
O
O
Ph
H2N
S
N
NC
S
H
O
O
O
6
Ar
7
NC HN Ph
4–7 Ar
9
a
b
C6H5
−PhNH2
−H2O
4-MeOC6H4
Me
O
Me
O
O
O
8–11
R
S
S
R
R
O
O
a
b
Me
OEt
NC
O
NC
N
Me
Me
Ph
11
10
SCHEME 1
α-chloroacetoacetate (8b) to give the corresponding
1,3-oxathiole derivatives 10a,b, respectively and
not the other possible thiazole structures 11a,b,
according to the spectral data of the isolated prod-
ucts (Scheme 1). The elemental analyses and mass
spectra of the reaction products were completely
consistent with the loss of aniline molecule instead
of water from the reaction intermediates 9a,b.
Treatment of 2-cyano-2-(3-methylbenzofuran-2-
yl)thioacetanilide (3) with the hydrazonoyl chlorides
12a–g in refluxing ethanol and in the presence of
a catalytic amount of triethylamine afforded the
corresponding 1,3,4-thiadiazole derivatives 14a–g
(Scheme 2). The IR spectra of the isolated com-
pounds revealed, in each case, a strong absorp-
tion band corresponding to a nitrile function near
2200 cm−1 and an absorption band(s) corresponding
to carbonyl group(s) in the region 1620–1751 cm−1.
Their mass spectra revealed, in each case, a peak
corresponding to the molecular ion.
16 (Scheme 3). The structure of the latter product
was established on the basis of its elemental anal-
ysis and spectral data. For example, its 1H NMR
spectrum revealed a signal at δ 9.65 (D2O exchange-
able) due to NH proton and a signal at δ 7.87 due to
CH N proton. Its mass spectrum showed a peak
at m/z 278, corresponding to its molecular ion.
Next, treatment of the hydrazone 16 with
bromine in glacial acetic acid, in the presence
of anhydrous sodium acetate, afforded a product
identified as 2-(3-methylbenzofuran-2-yl)-5-phenyl-
1,3,4-oxadiazole (18) (Scheme 3). The 1H NMR
spectrum of compound 18 revealed a singlet at δ
2.49 due to CH3 protons and a multiplet in the
region δ 7.15–7.76 due to aromatic protons. Its
mass spectrum showed a peak at m/z 276 corre-
sponding to the molecular ion. Moreover, the struc-
ture of compound 18 was further supported by an
independent synthesis from Nꢁ-benzoyl-3-methyl-2-
benzofurancarbohydrazide (17) via cyclization of
the latter with phosphorus oxychloride to afford
a product identical in all respect with compound
18. Compound 17 was prepared by the reaction of
Treatment of 3-methyl-2-benzofurancarboxylic
acid hydrazide (15) [14] with benzaldehyde in reflux-
ing ethanol afforded the corresponding hydrazone
Heteroatom Chemistry DOI 10.1002/hc

296 Dawood, Farag, and Abdel-Aziz
Me
Cl
O
Et3N
R
R
S
+
3
H
N
N
Ar
O
N
12
NC
13
NH
HN Ar
Ph
Me
O
−PhNH2
R
12–14
R
Ar
S
a
b
c
d
e
f
C6H5
CH3CO
C6H5
O
N
N
4-CH3C6H4
C6H5
NC
14
C2H5OCO
C2H5OCO
C2H5OCO
C6H5NHCO
C6H5NHCO
Ar
4-CH3C6H4
4-ClC6H4
4-CH3C6H4
4-ClC6H4
g
SCHEME 2
3-methyl-2-benzofurancarbohydrazide (15) with
benzoyl chloride in pyridine (Scheme 3).
refluxing benzene, it gave the thiosemicarbazide
derivative 20 (Scheme 3). The structure of the latter
product was established on the basis of its elemental
analyses and spectral data. However, when com-
pound 15 was treated with phenyl isothiocyanate in
refluxing DMF, it gave a different product compared
with compound 20 obtained above. Under this
condition, the single isolated product was identified
as 2-(3-methylbenzofuran-2-yl)-5-phenylamino-1,3,-
4-oxadiazole (21) (Scheme 3). The structure of the
isolated product 21 was established on the basis
of its elemental analysis and spectral data. For
example, its IR spectrum was free of any band due
Treatment of compound 16 with thioglycolic
acid afforded the corresponding thiazolidine deriva-
tive 19 (Scheme 3). The IR spectrum of compound
19 revealed absorption bands at 3263, 1713, and
1659 cm−1 due to one NH and two C O functions,
respectively. Its 1H NMR spectrum revealed four sin-
glets at δ 2.56, 4.23, 5.23, and 9.35 due to CH3, CH2,
CH, and NH protons, respectively, in addition to the
aromatic multiplet in the region δ 7.28–7.89.
When
3-methyl-2-benzofurancarbohydrazide
(15) was treated with phenyl isothiocyanate in
CH3
CH3
CH3
O S
NaOH
KI / I2
N
S
POCl3
N
N
N
NH
NH
O
HN NH Ph
Ph
O
O
N
S
20
H
Ph
23
PhNCS
PhH
22
NaOH
CH3
CH3
CH3
O
O O
N
PhCOCl
pyridine
PhNCS
DMF
N
Ph
O
HN NH2
Ph
O
HN NH
O
O
N
H
21
15
17
POCl3
CH3
PhCHO
CH3
CH3
N
N
O
AcOH / Br2
AcONa
Ph
O
HSCH2CO2H
PhH
Ph
O
O
O
N
HN
S
O
HN N
18
Ph
16
19
O
SCHEME 3
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Some New Benzofuran-Based Thiophene, 1,3-Oxathiole and 1,3,4-Oxa(Thia)diazole Derivatives 297
to C O absorption, and its mass spectrum showed a
yield; mp 170–172◦C; IR (KBr) ν 3240 (NH), 2206
(C≡N), 1682 (C O), 1589 (C N) cm−1; 1H NMR
(DMSO-d6) δ 2.05 (s, 3H, CH3), 7.03–7.51 (m, 9H,
ArH), 10.85 (s, 1H, NH, D2O exchangeable), 11.30 (s,
1H, SH, D2O exchangeable); MS m/z (%) 334 (M+,
100), 159 (46.2), 135 (29.9), 131 (33,1), 77 (40.8). For
C19H14N2O2S: Calcd. C, 68.25%; H, 4.22%; N, 8.38%.
Found C, 68.56%; H, 4.03%; N, 8.46%.
peak at m/z 291 corresponding to the molecular ion.
Furthermore, treatment of the thiosemicarbazide
derivative 20 with potassium iodide and iodine,
in the presence of sodium hydroxide, afforded a
product identical in all respect with compound 21.
Heating of the thiosemicarbazide derivative
20 in aqueous sodium hydroxide solution led to
the formation of a single product that was iden-
tified as 5-(3-methylbenzofuran-2-yl)-4-phenyl-2,4-
dihydro-3H-1,2,4-triazole-3-thione (22) (Scheme 3).
However, heating of the thiosemicarbazide deriva-
tive 20 with phosphorus oxychloride resulted in
the formation of 2-(3-methylbenzofuran-2-yl)-5-
phenylamino-1,3,4-thiadiazole (23) (Scheme 3). The
structures of the isolated products 22 and 23 were
confirmed by their elemental and spectral analyses
(see Experimental section).
Reaction of 2-Cyano-2-(3-methylbenzofuran-2-
carbonyl)thioacetanilide (3) With 1-Aryl-2-bromo-
ethanone 4a,b
General Procedure. To a solution of 3 (0.33 g, 1
mmol) in ethanol (20 mL), the appropriate 1-aryl-
2-bromoethanone 4a,b (1 mmol) and triethylamine
(0.5 mL) were added. The mixture was refluxed for
2 h, and then allowed to cool. The formed solid was
filtered off, washed with ethanol, and finally recrys-
tallized from EtOH/DMF to afford the corresponding
thiophene derivatives 6a,b.
EXPERIMENTAL
6a: Yield (78%); mp 211–213◦C; IR (KBr) ν
3233 (NH), 2222 (C N), 1650 (C O) cm−1; 1H NMR
(DMSO-d6) δ 2.05 (s, 3H, CH3), 7.02–7.08 (m, 4H,
ArH), 7.18–7.27 (m, 5H, ArH), 7.40–7.47 (m, 5H,
ArH), 9.50 (s, 1H, NH, D2O exchangeable); MS m/z
(%) 435 (M+ + 1, 23.8), 434 (M+, 74.6), 417 (100),
357 (55.9), 193 (10.6), 105 (51.9), 77 (81.1). For
C27H18N2O2S: Calcd. C, 74.63%; H, 4.18%; N, 6.45%;
S, 7.38%. Found C, 74.44%; H, 4.32%; N, 6.19%; S,
7.56%.
Melting points were measured with a Gallenkamp
apparatus and are uncorrected. The IR spec-
tra were recorded on Shimadzu FT-IR 8101 PC
infrared spectrophotometer. The 1H NMR spec-
tra were determined in CDCl3 or DMSO-d6 at
300 MHz on a Varian Mercury VX-300 NMR
spectrometer using TMS as an internal stan-
dard. Mass spectra were recorded on a GCMS-
QP1000 EX spectrometer at 70 eV. Elemental anal-
yses were carried out at the Microanalytical Cen-
ter of Cairo University. 3-(3-Methylbenzofuran-2-
yl)-3-oxopropanenitrile (1) [10], 3-methyl-2-benzo-
funcarbohydrazide (15) [14], l-aryl-2-bromoetha-
nones 4a,b [15], α-chloroacetylacetone (8a) [16],
ethyl α-chloroacetoacetate (8b) [17], hydrazonoyl
chlorides 12a [18], 12b [16], 12c–e [17], and 12f,g
[19] were prepared from the following procedures
reported in the literature.
6b: Yield (86%); mp 180–182◦C; IR (KBr) ν
3279 (NH), 2214 (C N), 1657 (C O) cm−1; 1H NMR
(DMSO-d6) δ 2.05 (s, 3H, CH3), 3.68 (s, 3H, OCH3),
6.96–7.09 (m, 5H, ArH), 7.11–7.60 (m, 8H, ArH),
7.40–7.47 (m, 5H, ArH), 9.32 (s, 1H, NH); MS m/z
(%) 464 (M+ + 1, 32.6), 434 (M+, 100), 330 (82.1), 302
(31.4), 105 (75.1), 77 (64.2). For C28H20N2O3S: Calcd.
C, 72.39%; H, 4.34%; N, 6.03%; S, 6.90%. Found C,
72.64%; H, 4.52%; N, 5.98%; S, 6.76%.
2-Cyano-2-(3-methylbenzofuran-2-carbonyl)thio-
acetanilide (3)
Reaction of 2-Cyano-2-(3-methylbenzofuran-2-
carbonyl)thioacetanilide (3) With α-Halodiketo-
nes 8a,b
To a stirred solution of potassium hydroxide (0.56 g,
10 mmol) in dimethylformamide (20 mL), 3-
(3-methylbenzofuran-2-yl)-3-oxopropanenitrile (1)
(1.99 g, 10 mmol) was added. After stirring
for 30 min, phenyl isothiocyanate (1.35 g,
10 mmol) was added to the resulting mixture.
Stirring was continued for 6 h, and then poured
onto crushed ice containing hydrochloric acid.
The solid product that formed was filtered off,
washed with water, dried, and finally recrys-
tallized from EtOH/DMF to afford 2-cyano-2-(3-
methylbenzofuran-2-yl)thioacetanilide (3) in 88%
General Procedure. To a solution of 3 (0.33 g,
1 mmol) in ethanol (20 mL) and the appropriate α-
halodiketones 8a,b (1 mmol), triethylamine (0.5 mL)
was added. The mixture was refluxed for 2 h, and
then allowed to cool. The formed solid was filtered
off, washed with ethanol, and finally recrystallized
from EtOH/DMF to afford the corresponding 1,3-
oxathiole derivatives 10a,b.
10a: Yield (85%); mp 242–244◦C; IR (KBr) ν
2199 (C N), 1666 (C O), 1574 (C N) cm−1; 1H NMR
(DMSO-d6) δ 1.92 (s, 3H, CH3), 2.60 (s, 3H, CH3), 2.68
Heteroatom Chemistry DOI 10.1002/hc

298 Dawood, Farag, and Abdel-Aziz
(s, 3H, CH3), 7.36–7.84 (m, 4H, ArH); MS m/z (%)
339 (M+, 46.2), 280 (100), 159 (49.0), 77 (33.6). For
C18H13NO4S: Calcd. C, 63.71%; H, 3.86%; N, 4.13%;
S, 9.45%. Found C, 63.48%; H, 3.98%; N, 4.32%; S,
9.62%.
NMR (DMSO-d6) δ 1.34 (t, 3H, CH3, J = 7.26 Hz),
2.54 (s, 3H, CH3), 2.67 (s, 3H, CH3) 4.31 (q, 2H, CH2,
J = 7.26 Hz), 7.30–7.50 (m, 3H, ArH), 7.58–7.89 (m,
5H, ArH); MS m/z (%) 445 (M+, 100), 346 (67.2), 314
(34.8), 159 (73.4), 77 (61.2). For C24H19N3O4S: Calcd.
C, 64.71%; H, 4.30%; N, 9.43%; S, 7.20%. Found C,
64.52%; H, 4.15%; N, 9.21%; S, 7.38%.
10b: Yield (5%); mp 192–194◦C; IR (KBr) ν 2214
(C N), 1728, 1651 (2C O), 1566 (C N) cm−1; 1H
NMR (DMSO-d6) δ 1.32 (t, 3H, CH3, J = 7.26 Hz),
2.60 (s, 3H, CH3), 2.68 (s, 3H, CH3) 4.32 (q, 2H, CH2,
J = 7.26 Hz), 7.36–7.84 (m, 4H, ArH); MS m/z (%)
369 (M+, 58.7), 323 (15.5), 281 (100), 159 (88.5), 77
(46.7). For C19H15NO5S: Calcd. C, 61.78%; H, 4.09%;
N, 3.79%; S, 8.68%. Found C, 61.55%; H, 4.21%; N,
3.59%; S, 8.49%.
14e: Yield (90%); mp 260–262◦C; IR (KBr) ν 2214
(C N), 1736, 1620 (2C O), 1558 (C N) cm−1; 1H
NMR (DMSO-d6) δ 1.35 (t, 3H, CH3, J = 7.26 Hz),
2.53 (s, 3H, CH3), 4.32 (q, 2H, CH2, J = 7.26 Hz),
7.30–7.51 (m, 4H, ArH), 7.60–7.89 (m, 4H, ArH);
MS m/z (%) 465 (M+, 96.9), 334 (17.0), 298 (14.3),
159 (100), 125 (57.1), 77 (88.1). For C23H16ClN3O4S:
Calcd. C, 59.29%; H, 3.46%; N, 9.02%; S, 6.88%.
Found C, 59.11%; H, 3.35%; N, 8.85%; S, 6.95%.
14f: Yield (82%); mp 258–260◦C; IR (KBr) ν 3395
(NH), 2206 (C N), 1682, 1627 (2C O), 1543 (C N)
Reaction of 2-Cyano-2-(3-methylbenzofuran-2-
carbonyl)thioacetanilide (3) With Hydrazonoyl
chlorides 12a–g
1
cm−1; H NMR (DMSO-d6) δ 2.51 (s, 3H, CH3), 2.57
General Procedure. To a solution of 3 (0.33 g, 1
mmol) in ethanol (20 mL) and the appropriate hy-
drazonyl chlorides 12a–g (1 mmol), triethylamine
(0.5 mL) was added. The mixture was refluxed for 2
h, and then allowed to cool. The formed solid was
filtered off, washed with ethanol, and finally recrys-
tallized from EtOH/DMF to afford the corresponding
1,3,4-thiadiazole derivatives 14a–g.
(s, 3H, CH3), 7.21–7.44 (m, 5H, ArH), 7.47–7.89 (m,
8H, ArH), 12.34 (s, 1H, NH, D2O exchangeable); MS
m/z (%) 492 (M+, 100), 346 (23.3), 314 (26.5), 159
(66.7), 119 (33.7), 77 (91.1). For C28H20N4O3S: Calcd.
C, 68.28%; H, 4.09%; N, 11.37%; S, 6.51%. Found C,
68.44%; H, 4.00%; N, 11.59%; S, 6.24%.
14g: Yield (88%); mp 255–257◦C; IR (KBr) ν 3395
(NH), 2206 (C N), 1682, 1627 (2C O), 1543 (C N)
cm−1; 1H NMR (DMSO-d6) δ 2.57 (s, 3H, CH3), 7.23–
7.50 (m, 6H, ArH), 7.756–7.86 (m, 7H, ArH), 12.37 (s,
1H, NH, D2O exchangeable); MS m/z (%) 512 (M+,
100), 338 (43.7), 306 (72.4), 159 (29.4), 77 (34.6).
For C27H17ClN4O3S: Calcd. C, 63.22%; H, 3.34%; N,
10.92%; S, 6.25%. Found C, 63.41%; H, 3.10%; N,
10.79%; S, 6.14%.
14a: Yield (86%); mp 237–239◦C; IR (KBr) ν
2199 (C≡N), 1620 (C O), 1558 (C N) cm−1; 1H NMR
(DMSO-d6) δ 2.54 (s, 3H, CH3), 7.28–7.44 (m, 5H,
ArH), 7.51–7.65 (m, 4H, ArH), 7.69–7.85 (m, 5H,
ArH); MS m/z (%) 435 (M+, 100), 159 (31.4), 119
(22.7), 77 (16.3). For C26H17N3O2S: Calcd. C, 71.71%;
H, 3.93%; N, 9.65%; S, 7.36%. Found C, 71.46%; H,
3.78%; N, 9.75%; S, 7.52%.
14b: Yield (84%); mp 266–268◦C; IR (KBr) ν
2206 (C N), 1697, 1620 (2C O), 1566 (C N) cm−1;
1H NMR (DMSO-d6) δ 2.13 (s, 3H, CH3), 2.51 (s,
3H, CH3), 2.58(s, 3H, CH3), 7.23–7.46 (m, 4H, ArH),
7.55–7.89 (m, 4H, ArH); MS m/z (%) 415 (M+, 100),
346 (15.8), 314 (31.1), 159 (43.0), 77 (18.5). For
C23H17N3O3S: Calcd. C, 66.49%; H, 4.12%; N, 10.11%;
S, 7.72%. Found C, 66.25%; H, 4.00%; N, 10.26%; S,
7.50%.
Reaction of 3-Methyl-2-benzofurancarbohydra-
zide (15) With Benzaldehyde
A mixture of 3-methyl-2-benzofurancarbohydrazide
(15) (1.9 g, 10 mmol) and benzaldehyde (1.1 g,
10 mmol) in ethanol (20 mL) was refluxed for
2 h, and then left to cool. The solid product
was collected by filtration, washed with water,
and dried. Recrystallization from EtOH/DMF af-
forded 3-methyl-Nꢁ-(phenylmethylene)benzofuran-
2-carbohydrazide (16) in 82% yield; mp 236–238◦C;
IR (KBr) ν 2209 (NH), 1651 (C O), 1605 (C N) cm−1;
1H NMR (DMSO-d6) δ 2.53 (s, 3H, CH3), 7.28–7.50
(m, 5H, ArH), 7.56–7.83 (m, 4H, ArH), 7.87 (s, 1H,
CH N , 9.65 (s, 1H, NH, D2O exchangeable); MS
m/z (%) 278 (M+, 25.2), 237 (45.1), 175 (31.7), 159
(100), 130 (36.9), 103 (49.0), 77 (76.0), 51 (41.5). For
C17H14N2O2: Calcd. C, 73.37%; H, 5.07%; N, 10.07%.
Found C, 73.23%; H, 4.86%; N, 9.84%.
14c: Yield (88%); mp 220–222◦C; IR (KBr) ν 2206
(C N), 1751, 1620 (2C O), 1551 (C N) cm−1; 1H
NMR (DMSO-d6) δ 1.35 (t, 3H, CH3, J = 7.26 Hz),
2.54 (s, 3H, CH3), 4.33 (q, 2H, CH2, J = 7.26 Hz),
7.30–7.51 (m, 4H, ArH), 7.60–7.89 (m, 5H, ArH); MS
m/z (%) 431 (M+, 100), 332 (53.6), 300 (26.9), 159
(49.7), 77 (41.0). For C23H17N3O4S: Calcd. C, 64.03%;
H, 3.97%; N, 9.74%; S, 7.43%. Found C, 64.21%; H,
4.12%; N, 9.61%; S, 7.22%.
14d: Yield (85%); mp 241–243◦C; IR (KBr) ν 2206
1
(C≡N), 1744, 1622 (C = O), 1551 (C = N) cm−1; H
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Some New Benzofuran-Based Thiophene, 1,3-Oxathiole and 1,3,4-Oxa(Thia)diazole Derivatives 299
Nꢁ-Benzoyl-3-methyl-1-benzofuran-2-carbohydra-
zide (17)
3-Methyl-N-(4-oxo-2-phenyl-1,3-thiazolidin-3-yl)-
benzofuran-2-carboxamide (19)
To stirred cold solution of 3-methyl-2-
a
A mixture of compound 16 (1.4 g, 5 mmol) and thio-
glycolic acid (0.5 g, 5 mmol) was refluxed in dry
benzene (50 mL) for 6 h. The solvent was evapo-
rated, and then the reaction mixture was neutral-
ized with cold dilute sodium bicarbonate solution.
The formed product was filtered off and recrystal-
lized from ethanol to give compound 19 in 80% yield;
mp 185–1878◦C; IR (KBr) ν 3263 (NH), 1713, 1659
benzofurancarbohydrazide (15) (1.9 g, 10 mmol) in
pyridine (20 mL), benzoyl chloride (1.4 g, 10 mmol)
was added drop wise over a period of 30 min. After
complete addition, the reaction mixture was stirred
for further 1 h at room temperature, after which it
was poured onto an ice–water mixture with stirring.
The precipitated solid was collected by filtration,
washed with dilute hydrochloric acid followed by
cold water, then dried, and finally recrystallized
from EtOH/DMF to afford compound 17 in 93%
yield; mp 180–182◦C; IR (KBr) ν 3387, 3238 (2NH),
1698, 1682 (2C O) cm−1; 1H NMR (DMSO-d6) δ
2.50 (s, 3H, CH3), 7.24–7.65 (m, 9H, ArH), 11.47
(s, 2H, 2NH, D2O exchangeable); MS m/z (%) 294
(M+, 11.6), 174 (13.7), 159 (100), 130 (22.5). For
C17H14N2O3 Calcd. C, 69.38%; H, 4.79%; N, 9.52%.
Found C, 69.15%; H, 4.56%; N, 9.63%.
1
(2C O), 1605 (C N) cm−1; H NMR (DMSO-d6) δ
2.56 (s, 3H, CH3), 4.23 (s, 2H, CH2), 5.23 (s, 1H, CH),
7.28–7.63 (m, 5H, ArH), 7.70–7.89 (m, 4H, ArH),
9.35 (s, 1H, NH, D2O exchangeable); MS m/z (%)
352 (M+, 34.1), 174 (83.4), 159 (100), 131 (31.5). For
C19H16N2O3S: Calcd. C, 64.76%; H, 4.58%; N, 7.95%;
S, 9.10%. Found C, 64.52%; H, 4.43%; N, 8.03%; S,
8.92%.
1-[(3-Methylbenzofuran-2-yl)carbonyl]-4-phen-
ylthiosemicarbazide (20)
2-(3-Methylbenzofuran-2-yl)-5-phenyl-1,3,4-oxa-
diazole (18)
Phenyl isothiocyanate (1.4 g, 10 mmol) was added
to a mixture of 3-methyl-2-benzofurancarbohydra-
zide (15) (1.9 g, 10 mmol) in dry benzene (20 mL),
and the reaction mixture was heated under reflux for
2 h, and then left to cool. The solid that separated
was collected by filtration, washed with ethanol,
and finally recrystallized from ethanol to afford the
thiosemicarbazide derivative 20 in 87% yield; mp
168–170◦C; IR (KBr) ν 3287, 3186, 3101 (3NH), 1643
(C O), 1605 (C N) cm−1; 1H NMR (DMSO-d6) δ 2.56
(s, 3H, CH3), 7.25–7.49 (m, 4H, ArH), 7.53–7.85 (m,
5H, ArH), 9.89 (s, 1H, NH, D2O exchangeable), 11.55
(s, 1H, NH, D2O exchangeable), 12.75 (s, 1H, NH,
D2O exchangeable); MS m/z (%) 325 (M+, 100), 159
(65.1), 135 (82.0), 77 (51.8). For C17H15N3O2S: Calcd.
C, 62.75%; H, 4.65%; N, 12.91%; S, 9.85%. Found C,
62.48%; H, 4.46%; N, 12.80%; S, 9.72%.
Method A. A solution of 3-methyl-Nꢁ-(phenyl-
methylene)benzofuran-2-carbohydrazide (16) (2.8 g,
10 mmol) and anhydrous sodium acetate (3.3 g,
40 mmol) in glacial acetic acid (30 mL) was refluxed
while stirring. To the hot mixture, a bromine solu-
tion (1.6 g, 10 mmol) in glacial acetic acid (20 mL)
was added drop wise over a period of 30 min with
stirring and reflux. After the addition was complete,
the mixture was refluxed and stirred vigorously for
further 1 h. The mixture was treated with a solu-
tion of sodium acetate trihydrate till complete pre-
cipitation of the product. The solid that formed was
filtered off, washed with water, and dried. Recrystal-
lization from EtOH/DMF afforded compound 18 in
73% yield.
Method B. A solution of Nꢁ-benzoyl-3-methyl-
benzofuran-2-carbohydrazide (17) (2.9 g, 10 mmol)
in phosphorus oxychloride (30 mL) was refluxed for
1 h, and then left to cool and poured onto crushed
ice. The precipitated product was collected by fil-
tration, washed with water, and dried. Recrystalliza-
tion from EtOH/DMF afforded compound 18 in 77%
yield; mp 168–170◦C; IR (KBr) ν 1630 (C N) cm−1;
1H NMR (DMSO-d6) δ 2.49 (s, 3H, CH3), 7.15–7.76
(m, 9H, ArH); MS m/z (%) 276 (M+, 54.6), 219 (41.5),
159 (25.1), 115 (10.8), 77 (100). For C17H12N2O2:
Calcd. C, 73.90%; H, 4.38%; N, 10.14%. Found C,
73.68%; H, 4.50%; N, 10.00%.
2-(3-Methylbenzofuran-2-yl)-5-phenylamino-1,3,-
4-oxadiazole (21)
Method A. Phenyl isothiocyanate (1.4 g,
10 mmol) was added to a mixture of 3-methyl-2-
benzofurancarbohydrazide (15) (1.9 g, 10 mmol) in
DMF (20 mL). The reaction mixture was heated un-
der reflux for 15 h, and then left to cool and poured
onto crushed ice. The solid that separated was col-
lected by filtration, washed with ethanol, and finally
recrystallized from EtOH/DMF to afford compound
21 in 71% yield.
Heteroatom Chemistry DOI 10.1002/hc

300 Dawood, Farag, and Abdel-Aziz
1
(NH), 1605 (C N) cm−1; H NMR (DMSO-d6) δ 2.52
Method B. To a solution of the thiosemicar-
bazide derivative 20 (1.6 g, 5 mmol) in ethanol
(50 mL), sodium hydroxide solution (4N, 5 mL) was
added with cooling and shaking. A solution of io-
dine in potassium iodide was added dropwise with
stirring till the color of iodine persisted. The mix-
ture was refluxed over a water bath for 4 h, and
then left to cool. The separated solid was filtered off,
washed with water, and finally recrystallized from
EtOH/DMF to give compound 21 in 65% yield; mp
270–272◦C; IR (KBr) ν 3171 (NH), 1589 (C N) cm−1;
1H NMR (DMSO-d6) δ 2.56 (s, 3H, CH3), 7.26–7.49
(m, 4H, ArH), 7.54–7.78 (m, 5H, ArH), 10.37 (s, 1H,
NH, D2O exchangeable); MS m/z (%) 291 (M+, 77.5),
172 (100), 115 (37.6), 77 (73.4). For C17H13N3O2:
Calcd. C, 70.09%; H, 4.50%; N, 14.42%. Found C,
69.88%; H, 4.36%; N, 14.34%.
(s, 3H, CH3), 7.18–7.30 (m, 4H, ArH), 7.36–7.78 (m,
5H, ArH), 10.56 (s, 1H, NH, D2O exchangeable); MS
m/z (%) 307 (M+, 100), 189 (14.2), 156 (37.8), 118
(17.2), 77 (45.3). For C17H13N3OS: Calcd. C, 66.43%;
H, 4.26%; N, 13.67%; S, 10.43%. Found C, 66.17%;
H, 4.12%; N, 13.58%, S, 10.28%.
REFERENCES
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dro-3H-1,2,4-triazole-3-thione (22)
A mixture of thiosemicarbazide 20 (0.7 g, 2 mmol)
and sodium hydroxide (2N, 20 mL) was refluxed for
3 h, and then allowed to cool, filtered, and finally the
filtrate was acidified with dilute hydrochloric acid.
The precipitated solid was filtered off, washed with
water, and recrystallized from EtOH/DMF to afford
the 1,2,4-triazole derivative 22 in 76% yield; mp 240–
242◦C; IR (KBr) ν 3425 (NH), 1605 (C N) cm−1; H
1
NMR (DMSO-d6) δ 2.49 (s, 3H, CH3), 7.19–7.33 (m,
3H, ArH), 7.38–7.76 (m, 6H, ArH), 10.13 (s, 1H, NH,
D2O exchangeable); MS m/z (%) 307 (M+, 100), 234
(14.0), 156 (17.5), 77 (57.1). For C17H13N3OS: Calcd.
C, 66.43%; H, 4.26%; N, 13.67%; S, 10.43%. Found
C, 66.54%; H, 4.10%; N, 13.49%; S, 10.51%.
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2-(3-Methylbenzofuran-2-yl)-5-phenylamino-1,3,-
4-thiadiazole (23)
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A solution of 1-(3-methylbenzofuran-2-yl)carbonyl-
4-phenylthiosemicarbazide (20) (3.25 g, 10 mmol)
in phosphorus oxychloride (30 mL) was refluxed
for 1 h, then left to cool, and finally poured onto
crushed ice. The precipitated solid was collected by
filtration, washed with water, and then dried. Re-
crystallization from EtOH/DMF afforded compound
23 in 73% yield; mp 253–255◦C; IR (KBr) ν 3186
Heteroatom Chemistry DOI 10.1002/hc