Synthesis and antimicrobial evaluation of some 1,3-thiazole, 1,3,4-thiadiazole, 1,2,4-triazole, and 1,2,4-triazolo[3,4-b][1,3,4]-thiadiazine derivatives including a 5-(benzofuran-2-yl)-1-phenylpyrazole moiety

Article abstract of DOI:10.1007/s00706-008-0099-x

Potassium hydrazinecarbodithioate were prepared by treatment of acid hydrazides with carbon disulfide in the presence of potassium hydroxide. Reaction of this potassium salt with hydrazine hydrate, phenacyl bromide, or hydrazonoyl chlorides afforded 1,2,4

Full text of DOI:10.1007/s00706-008-0099-x

Monatsh Chem (2009) 140:601–605
DOI 10.1007/s00706-008-0099-x
ORIGINAL PAPER
Synthesis and antimicrobial evaluation of some 1,3-thiazole,
1,3,4-thiadiazole, 1,2,4-triazole, and 1,2,4-triazolo[3,4-b]
[1,3,4]-thiadiazine derivatives including
a 5-(benzofuran-2-yl)-1-phenylpyrazole moiety
Bakr F. Abdel-Wahab Æ Hatem A. Abdel-Aziz Æ
Essam M. Ahmed
Received: 7 July 2008 / Accepted: 29 October 2008 / Published online: 2 December 2008
Ó Springer-Verlag 2008
Abstract Potassium hydrazinecarbodithioate were pre-
pared by treatment of acid hydrazides with carbon disulfide
in the presence of potassium hydroxide. Reaction of this
potassium salt with hydrazine hydrate, phenacyl bromide,
or hydrazonoyl chlorides afforded 1,2,4-triazole, 1,3-thia-
zole, and 1,3,4-thiadiazoles. Reaction of 1,2,4-triazole with
phenacyl bromide or hydrazonoyl chlorides afforded the
corresponding 1,2,4-triazolo[3,4-b][1, 3, 4]-thiadiazines.
All these new compounds were screened for antibacterial
and antifungal activity. Some had promising activity.
bimolecular targets which are sensitive to molecules con-
taining benzofurans. Benzofuran-containing molecules also
have in-vitro antibacterial activity. Examples include bac-
terial enzymes involved in the methionine cycle, for
example methionine aminopeptidase [7] and deformylase
[8], enzymes involved in peptidoglycan synthesis, for
example UDP-N-acetylmuramyl-L-alanine ligase [9], and
chorismate synthase, an enzyme in the shikimate pathway,
essential for bacterial viability [10]. Compounds containing
a pyrazole nucleus are known to have analgesic, anti-
inflammatory, antipyretic, antiarrhythmic, tranquillizing,
muscle relaxant, psychoanaleptic, anticonvulsant, hypo-
tensive, monoamine oxidase inhibitor, antidiabetic, and
antibacterial activity [11–18]. These facts coupled with our
desire to develop efficacious antimicrobial agents, and in
continuation of our work in heterocycles of biological
interest [19–25], prompted us to devise an efficient and
convenient method of synthesis of hitherto unknown
and novel 1,3-thiazole, 1,3,4-thiadiazole, 1,2,4-triazole,
and 1,2,4-triazolo[3,4-b][1,3,4]-thiadiazine derivatives with
a 5-(benzofuran-2-yl)-1-phenylpyrazole nucleus. Results
from assessment of the antimicrobial activity of these newly
synthesized compounds are reported in this study.
Keywords 2-Acetylbenzofuran ꢀ Hydrazonoyl chlorides ꢀ
Antimicrobial activity
Introduction
Benzofurans have attracted much attention over the last
few years because of their profound physiological and
chemotherapeutic properties and their widespread occur-
rence in nature [1, 2]. The antimicrobial activity of
benzofuran derivatives seems to be more dependent on
substitution on the heterocyclic furan ring than on substi-
tution on the benzene moiety [3, 4]. Use of benzofurans as
fungal N-myristoyltransferase (Nmt) inhibitors against
human pathogenic Candida albicans has led to a novel
group of fungicides [5, 6]. There are a few other
Results and discussion
Chemistry
B. F. Abdel-Wahab (&) ꢀ H. A. Abdel-Aziz
Department of Applied Organic Chemistry,
National Research Center, Dokki, Giza, Egypt
e-mail: Bakrfatehy@yahoo.com
Recently, we prepared the acid hydrazide 4 [25] by reac-
tion of 2-acetylbenzofuran (1) with diethyl oxalate in
sodium methoxide to afford ethyl 4-(benzofuran-2-yl)-2,4-
dioxobutanoate (2) which, on reaction with phenylhydr-
azine heated under reflux in glacial acetic acid, furnished
the pyrazole derivative 3. Reaction of this ester with
E. M. Ahmed
Department of Natural and Microbial Products Chemistry,
National Research Center, Dokki, Giza, Egypt
123

602
B. F. Abdel-Wahab et al.
O
N
hydrazine hydrate in absolute ethanol afforded the target
hydrazide 4 [25] (Scheme 1).
NH2
N
H
N
Generally, acid hydrazides can be regarded as useful
intermediates leading to the formation of several heterocy-
cles, for example 1,2,4-triazoles and 1,2,4-triazolo[3,4-
b][1,3,4]-thiadiazines [26, 27]. Treatment of acid hydrazide
4 with carbon disulfide in ethanol, in the presence of potas-
sium hydroxide, resulted in the formation of the potassium
salt of hydrazinecarbodithioate 5. Treatment of the salt 5
with hydrazine hydrate in aqueous ethanol afforded the
corresponding 4-amino-1,2,4-triazole-5-thione 6. In con-
trast, treatment of 5 with phenacyl bromide in ethanol gave
the 1,3-thiazole derivative 7, whereas its reaction with hyd-
razonoyl chlorides 8a–8d, namely 1-(2-phenylhydrazono)
-1-chloropropan-2-one (8a), 1-(2-(4-bromophenyl)hydraz-
ono)-1-chloropropan-2-one (8b), 1-(2-(4-chlorophenyl)
hydrazono)-1-chloropropan-2-one (8c), or 1-(2-(4-fluoro-
phenyl)hydrazono)-1-chloropropan-2-one (8d), under the
same conditions, produced 1,3,4-thiadiazole derivatives 9a–
9d (Scheme 2). The structures of compounds 6, 7, and 9a–9d
was in agreement with spectral and analytical data. For
example, the 1H NMR spectrum of compound 7 contained a
new singlet, not present in the spectrum of the starting
material, at d = 8.08 ppm, attributed to CH of the 2-thi-
oxothiazole ring, and the mass spectra of 6, 7, and 9a
contained molecular ion peaks at m/z = 374, 494, and 520,
respectively, which was in agreement with their calculated
masses.
O
Ph
4
H
CS2/KOH
O
N
S
N
H
N
SK
N
NH2
N
NH2NH2.H2O
S
H
N
N
O
N
N
Ph
O
Ph
6
5
O
O
Br
Ph
N
Ar
Me
N
H
Cl
S
S
Ar
8a-8d
O
N
S
N
N
O
N
N
N
Ph
Me
N
H
H
N
O
N
O
N
O
Ph
9
Ar
Ph
b 4-BrC6H4
4-ClC6H4
Ph
9a-9d
7
a
c
d 4-FC6H4
Scheme 2
H
CHO
Cl
N
S
N
N
H
N
S
N
N
N
N
NO2
NH2
N
O
Cl
N
N
Ph
O
NO2
10
Ph
O
6
Br
Ph
O
N
Ar
Me
N
H
Cl
8
Furthermore, the Schiff base 10 was produced by reac-
tion of 4-amino-1,2,4-triazole-5-thione derivative 6 with
2-chloro-4-nitrobenzaldehyde heated under reflux in ethanol
containing a few drops of glacial acetic acid as a catalyst. The
reaction of 6 with phenacyl bromide or hydrazonoyl chlo-
rides 8 in ethanol containing a catalytic amount of
triethylamine furnished 1,2,4-triazolo[3,4-b][1,3,4]-thiadi-
azine derivatives 11 and 12a–12c (Scheme 3).
N
S
N
N
N
N
S
N
N
N
N
Ph
Ar
N
N
N
H
O
N
Me
Ph
N
Ph
O
11
12 Ar
a
b
c
Ph
12a-12c
4-ClC6H4
2,4-Cl2C6H3
Scheme 3
The structures of compounds 10, 11, and 12a–12c were
established on the basis of both microanalytical and spec-
tral data. For example, the 1H NMR spectrum of compound
10 contained a new singlet, not present in the spectrum of
the starting material, at d = 9.01 ppm attributed to
–N=CH–, whereas the 1H NMR spectrum of compound 11
contained a singlet signal at d = 4.35 ppm corresponding
to the two protons of –S–CH2 in the thiadiazine ring. The
mass spectrum of 12a contained the molecular ion peak at
m/z = 516, this was in exact agreement with the calculated
mass.
COOEt
Me
O
(COOEt)2
MeONa
O
O
O
O
1
2
PhNHNH2
O
N
NH2
Biology
COOEt
N
H
NH2NH2.H2O
N
N
Ph
The new compounds were tested for their antimicrobial
activity, at a concentration of 100 lg/cm3, against five
strains of microorganism, namely Aspergillus niger, E. coli,
Bacillus subitilis, Pseudomonas aeruginosa, and Candida
O
N
O
Scheme 1
123
3
Ph
4

Synthesis and antimicrobial evaluation of some derivatives
603
Potassium 2-(5-(benzofuran-2-yl)-1-phenyl-1H-pyrazole-3-
carbonyl)hydrazinecarbodithioate (5)
Table 1 Antimicrobial activities of the newly synthesized compounds
Compound Inhibition zone (mm)
To a solution of 3.18 g hydrazide 4 (10 mmol) in
100 cm3ethanol, a solution of 0.84 g potassium hydroxide
(15 mmol) in 10 cm3 water and 1.5 g carbon disulfide
(20 mmol) were added. The reaction mixture was heated
under reflux for 3 h then the solvent was evaporated under
reduced pressure until dryness. The residue was then
treated with 30 cm3 dry benzene and the precipitate which
formed was collected by filtration, washed with ether, and
A. niger E. coli B. subitilis P. aeruginosa C. albicans
5
20
20
–
12
20
12
–
20
15
20
–
20
15
20
–
30
30
25
–
6
7
9a
9b
9c
9d
10
11
12a
12b
12c
–
–
–
–
–
–
–
–
–
–
–
dried to afford the potassium salt 5 in 76% yield. IR (KBr):
-1
15
20
–
15
20
20
–
–
–
30
40
20
–
ꢀ
m = 3,368, 3,128 (2NH), 1,648 (C=O) cm
.
–
20
–
–
4-Amino-3-(5-(benzofuran-2-yl)-1-phenyl-1H-pyrazol-3-
yl)-1H-1,2,4-triazole-5(4H)-thione (6, C19H14N6OS)
–
–
–
To a solution of 4.32 g 5 (10 mmol) in 20 cm3 ethanol and
10 cm3 water, 1 g hydrazine hydrate (20 mmol) was
added. The reaction mixture was heated under reflux for
3 h, left to cool, and then poured on to crushed ice. The
resulting solution was acidified with dilute hydrochloric
acid to pH 7 and the resulting solid was collected by
filtration, washed with water, and crystallized from ethanol
to give 1,2,4-triazole-5-thione derivative 6 in 73% yield
–
–
–
20
30
–
15
–
–
– indicates the compound has no activity
albicans. From the results in Table 1, we can conclude that
compounds 6, 10, and 11 have equal activity against E. coli
compared with the control, but 5, 6, 9d, 10, and 12c resulted
in the highest inhibition zones in plates seeded with
C. albicans. The activity of the other compounds was low
compared with that of flucanazol or amoxicillin. The
growth inhibition zones are shown in Table 1.
ꢀ
with m.p. 264–265 °C. IR (KBr): m = 1,296 (C=S), 1,629
(C=N), 3,321, 3,108, 3,058 (NH2 and NH) cm-1; 1H NMR
(DMSO-d6): d = 6.70 (s, 1H, pyrazole–H), 7.23 (s, 1H,
benzofuran–H), 7.24–7.64 (m, 9H, Ar–H), 9.64 (s, 2H,
NH2, D2O exchangeable), 12.52 (s, 1H, NH, D2O
exchangeable) ppm; MS: m/z (%) = 374 (M?, 0.59), 77
(100).
We recently reported that some 3-substituted 5-(benzo-
furan-2-yl)pyrazole and 3-(benzofuran-2-yl)-4,5-dihydro-
5-aryl-1-[4-(aryl)-1,3-thiazol-2-yl]-1H-pyrazole derivatives
had significant antimicrobial activity against a variety of
microorganisms [24, 25]. From structure–activity rela-
tionships it can be concluded that benzofuran, pyrazole,
and thiazole moieties are essential for the antimicrobial
activity. Also, increasing the number of nitrogen atoms
sharply increases the antimicrobial activity.
5-(Benzofuran-2-yl)-1-phenyl-N-(4-phenyl-2-thioxothiazol-
3(2H)-yl)-1H-pyrazole-3-carboxamide
(7, C27H18N4O2S2)
A mixture of 0.86 g 5 (2 mmol) and 0.4 g phenacyl
bromide (2 mmol) in 20 cm3 ethanol was heated under
reflux for 3 h. The solid formed was collected by filtration,
washed with ethanol, dried, and recrystallized from EtOH–
Experimental
DMF to afford 7 in 81% yield with m.p. 194–195 °C; IR
-1
ꢀ
(KBr): m = 1,642 (C=N), 1,667 (C=O), 3,230 (NH) cm
;
Chemistry
1H NMR (DMSO-d6): d = 6.66 (s, 1H, pyrazole–H), 7.25
(s, 1H, benzofuran–H), 7.28–7.72 (m, 14H, Ar–H), 8.08 (s,
1H, CH), 9.31 (s, 1H, NH, D2O exchangeable) ppm; MS:
m/z (%) = 494 (M?, 0.11), 478 (100).
All melting points were taken on an Electrothermal IA
9000 series digital melting-point apparatus. Elemental
analytical data were obtained by the microanalytical unit,
Cairo University, Giza, Egypt, and results agreed favorably
with calculated values. The IR spectra (KBr) were recorded
N0-(5-Acetyl-3-aryl-1,3,4-thiadiazol-2(3H)-ylidene)-5-
(benzofuran-2-yl)-1-phenyl-1H-pyrazole-3-
1
carbohydrazides 9a–9d
by use of a Shimadzu CVT-04 spectrophotometer. The H
To a solution of 0.86 g 5 (2 mmol) in 20 cm3 ethanol,
2 mmol of the appropriate hydrazonyl chloride 8a–8d was
added. The reaction mixture was heated under reflux for
3 h. The solid formed was collected by filtration, washed
with ethanol, dried, and recrystallized from EtOH–DMF to
afford 9a–9d.
NMR spectra were recorded at 270 MHz on a Varian EM-
360 spectrometer using TMS as internal standard. Mass
spectra were recorded by use of a Varian MAT CH-5
spectrometer (70 eV). All reactions were monitored
by TLC (aluminium foil-backed, 0.25 mm silica gel 60
F254; Merck).
123

604
B. F. Abdel-Wahab et al.
N0-(5-Acetyl-3-phenyl-1,3,4-thiadiazol-2(3H)-ylidene)-5-
(benzofuran-2-yl)-1-phenyl-1H-pyrazole-3-carbohydrazide
(9a, C28H20N6O3S)
3-(5-(Benzofuran-2-yl)-1-phenyl-1H-pyrazol-3-yl)-6-
phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine
(11, C27H18N6OS)
Yield 84%, m.p. 249–250 °C; IR (KBr): ꢀm = 1,611 (C=N),
A mixture of 0.75 g 6 (2 mmol) and 0.4 g phenacyl
bromide (2 mmol) in 30 cm3 absolute ethanol containing
0.2 g triethylamine (2 mmol) was heated under reflux for
3 h. The precipitate formed was isolated by filtration,
washed with ethanol, dried, and recrystallized from EtOH–
1,658, 1,685 (2 C=O), 3,113 (NH) cm-1 1H NMR
;
(DMSO-d6): d = 2.58 (s, 3H, CH3), 6.54 (s, 1H, pyra-
zole–H), 7.25 (s, 1H, benzofuran–H), 7.27–8.06 (m, 14H,
Ar–H), 11.38 (s, 1H, NH, D2O exchangeable) ppm; MS: m/
z (%) = 520 (M?, 67.89), 287 (100).
DMF to give 11 in 78% yield, m.p. 178–80 °C. IR (KBr):
1
m = 1,599 (C=N) cm-1; H NMR (DMSO-d6): d = 4.35
ꢀ
N0-(5-Acetyl-3-(4-bromophenyl)-1,3,4-thiadiazol-2(3H)-
ylidene)-5-(benzofuran-2-yl)-1-phenyl-1H-pyrazole-3-
carbohydrazide (9b, C28H19BrN6O3S)
(s, 2H, CH2), 6.61 (s, 1H, pyrazole–H), 7.03 (s, 1H,
benzofuran–H), 7.22–7.57 (m, 14H, Ar–H) ppm; MS: m/z
(%) = 474 (M?, 9.03), 77 (100).
ꢀ
Yield 86%, m.p. 254–255 °C; IR (KBr): m = 1,608 (C=N),
1,665, 1,687 (2 C=O), 3,180 (NH) cm-1 1H NMR
;
3-(5-(Benzofuran-2-yl)-1-phenyl-1H-pyrazol-3-yl)-7-
(2-arylhydrazono)-6-methyl-7H-1,2,4-triazolo[3,4-b]-
1,3,4-thiadiazines 12a–12c
(DMSO-d6): d = 2.57 (s, 3H, CH3), 6.56 (s, 1H, pyra-
zole–H), 7.24 (s, 1H, benzofuran–H), 7.27–8.06 (m, 13H,
Ar–H), 11.29 (s, 1H, NH, D2O exchangeable) ppm; MS:
m/z (%) = 99 (M?, 66.20), 287 (100).
A mixture of 0.75 g 6 (2 mmol) and 2 mmol of the
appropriate hydrazonyl chloride in 30 cm3 absolute ethanol
containing 0.2 g triethylamine (2 mmol) was heated under
reflux for 3 h. The precipitated solid was collected by
filtration, washed with ethanol, dried, and then crystallized
from EtOH–DMF to afford 12a–12c.
N0-(5-Acetyl-3-(4-chlorophenyl)-1,3,4-thiadiazol-2(3H)-
ylidene)-5-(benzofuran-2-yl)-1-phenyl-1H-pyrazole-3-
carbohydrazide (9c, C28H19ClN6O3S)
ꢀ
Yield 83%, m.p. 238–239 °C; IR(KBr): m = 1614 (C=N),
3-(5-(Benzofuran-2-yl)-1-phenyl-1H-pyrazol-3-yl)-6-
methyl-7-(2-phenylhydrazono)-7H-1,2,4-triazolo[3,4-b]-
1,3,4-thiadiazine (12a, C28H20N8OS)
1,648, 1,685 (2 C=O), 3,180 (NH) cm-1 1H NMR
;
(DMSO-d6): d = 2.53 (s, 3H, CH3), 6.62 (s, 1H, pyra-
zole–H), 7.21 (s, 1H, benzofuran–H), 7.25–8.03 (m, 13H,
Ar–H), 11.54 (s, 1H, NH, D2O exchangeable) ppm; MS:
m/z (%) = 555 (M?, 49.52), 287 (100).
ꢀ
Yield 62%, m.p. 268–9 °C; IR (KBr): m = 1,608 (C=N)
1
cm-1; H NMR (DMSO-d6): d = 2.57 (s, 3H, CH3), 6.60
(s, 1H, pyrazole–H), 7.08 (s, 1H, benzofuran–H), 7.38–8.06
(m, 14H, Ar–H), 11.62 (s, 1H, NH, D2O exchangeable)
ppm; MS: m/z (%) = 516 (M?, 9.03), 77 (100).
N0-(5-Acetyl-3-(4-fluorophenyl)-1,3,4-thiadiazol-2(3H)-yli-
dene)-5-(benzofuran-2-yl)-1-phenyl-1H-pyrazole-3-carbo-
hydrazide (9d, C28H19FN6O3S)
3-(5-(Benzofuran-2-yl)-1-phenyl-1H-pyrazol-3-yl)-7-(2-(4-
chlorophenyl)hydrazono)-6-methyl-7H-1,2,4-triazolo[3,4-
b]-1,3,4-thiadiazine (12b, C28H19ClN8OS)
ꢀ
Yield 75%, m.p. 258–260 °C; IR (KBr): m = 1,618 (C=N),
1,652, 1,690 (2 C=O), 3,198 (NH) cm-1 1H NMR
;
(DMSO-d6): d = 2.49 (s, 3H, CH3), 6.53 (s, 1H, pyra-
zole–H), 7.19 (s, 1H, benzofuran–H), 7.18–7.78 (m, 13H,
Ar–H), 11.38 (s, 1H, NH, D2O exchangeable) ppm; MS: m/
z (%) = 538 (M?, 68.08), 287 (100).
ꢀ
Yield 69%, m.p. 240–241 °C; IR (KBr): m = 1,619 (C=N)
1
cm-1; H NMR (DMSO-d6): d = 2.54 (s, 3H, CH3), 6.59
(s, 1H, pyrazole–H), 7.19 (s, 1H, benzofuran–H), 7.38–8.03
(m, 13H, Ar–H), 11.70 (s, 1H, NH, D2O exchangeable)
ppm; MS: m/z (%) = 551(M?, 11.03), 77 (100).
3-(5-(Benzofuran-2-yl)-1-phenyl-1H-pyrazol-3-yl)-4-
(2-chloro-4-nitrobenzylideneamino)-1H-1,2,4-triazole-
5(4H)-thione (10, C26H16ClN7O3S)
3-(5-(Benzofuran-2-yl)-1-phenyl-1H-pyrazol-3-yl)-7-
(2-(2,4-dichlorophenyl)hydrazono)-6-methyl-7H-1,2,4-
triazolo[3,4-b]-1,3,4-thiadiazine (12c, C28H18Cl2N8OS)
A
mixture of 0.37 g 2-chloro-4-nitrobenzaldehyde
(2 mmol) and 0.75 g 6 (2 mmol) in 20 cm3 ethanol
and 0.2 cm3 glacial acetic acid was heated under reflux
for 4 h. The solid product was collected by filtration,
washed with ethanol, and crystallized from EtOH–DMF
ꢀ
Yield 65%, m.p. [ 300 °C; IR (KBr): m = 1,612 (C=N)
1
cm-1; H NMR (DMSO-d6): d = 2.55 (s, 3H, CH3), 6.61
(s, 1H, pyrazole–H), 7.14 (s, 1H, benzofuran–H), 7.31–7.99
(m, 12H, Ar–H), 11.56 (s, 1H, NH, D2O exchangeable)
ppm; MS: m/z (%) = 585 (M?, 8.09), 77 (100).
ꢀ
to afford 78% 10, m.p. [ 300 °C. IR (KBr): m = 1616
(C=N), 3,100 (NH) cm-1 1H NMR (DMSO-d6):
;
d = 6.60 (s, 1H, pyrazole–H), 7.20 (s, 1H, benzofuran–
H), 7.24–7.64 (m, 12H, Ar–H), 9.01 (s, 1H, CH), 12.43
(s, H, NH, D2O exchangeable) ppm; MS: m/z (%) = 541
(M?, 58.02), 77 (100).
Biology
The antimicrobial activity was determined applying the cup–
plate agar-diffusion method [28]. Results were obtained in
123

Synthesis and antimicrobial evaluation of some derivatives
605
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