Synthesis of novel substituted 3-(4-((1H-benzo[d]imidazol-2-ylthio)methyl)-1-phenyl-1H-pyrazol-3-yl)-2H-chromen-2-ones: various approaches

Article abstract of DOI:10.1007/s11164-018-3397-x

Abstract: Considering benzimidazole as a privileged structure for developing probes of impressive pharmacological potentials, some new coumarin and pyrazole conjugates of benzimidazoles were synthesized with a sulphur linkage. Thus, 3-(2-oxo-2H-chromen-3-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde (3) was prepared starting from simple salicylaldehyde which has been?used as an important synthon and incorporated in a series of structural manipulations to obtain various of pharmacophoric motif conjugates 9(a–b) and 13(a–f), in fair yields. We have developed facile and stepwise methods for the synthesis of all these compounds in various approaches, which also involves sub-sequences. All synthesized compounds were well characterized by IR, ¹HNMR, ¹³CNMR and mass spectra data.

Full text of DOI:10.1007/s11164-018-3397-x

Res Chem Intermed
https://doi.org/10.1007/s11164-018-3397-x
Synthesis of novel substituted 3-(4-((1H-
benzo[d]imidazol-2-ylthio)methyl)-1-phenyl-1H-
pyrazol-3-yl)-2H-chromen-2-ones: various approaches
1
1
Devulapally Srikrishna
•
Pramod Kumar Dubey
Received: 26 January 2018 / Accepted: 16 March 2018
Ó Springer Science+Business Media B.V., part of Springer Nature 2018
Abstract Considering benzimidazole as a privileged structure for developing probes of
impressive pharmacological potentials, some new coumarin and pyrazole conjugates of
benzimidazoles were synthesized with a sulphur linkage. Thus, 3-(2-oxo-2H-chromen-3-
yl)-1-phenyl-1H-pyrazole-4-carbaldehyde (3) was prepared starting from simple salicy-
laldehyde which has been used as an important synthon and incorporated in a series of
structural manipulations to obtain various of pharmacophoric motif conjugates 9(a–b) and
1
all these compounds in various approaches, which also involves sub-sequences. All syn-
3(a–f), in fair yields. We have developed facile and stepwise methods for the synthesis of
1
13
thesized compounds were well characterized by IR, HNMR, CNMR and mass spectra
data.
Graphical Abstract
O
O
N
R
N
O
O
N
S
CHO
OH
N
N
N
X
CHO
13 (a-f )
(3)
1
3a:X=H, R=CH ,
3
1
3b: X=H, R=C
3c: X=H, R=CH
3d:X=OCH , R=CH
3e:X=OCH , R=C
2
3f:X=OCH , R=CH Ph
2 5
H ,
1
2
Ph,
1
3
3
3
,
1
2 5
H ,
1
3
&
Devulapally Srikrishna
devulapallisrikrishna@gmail.com
1
Department of Chemistry, Jawaharlal Nehru Technological University Hyderabad College of
Engineering, Kukatpally, Hyderabad, Telangana 500 085, India
123

D. Srikrishna, P. K. Dubey
Keywords Coumarins Á Pyrazoles Á Benzimidazoles Á Prazoles Á Various
approaches
Introduction
The class of coumarin compounds exhibit diversified biological activity, which have
been recently reviewed by us [1]. Apart from these, other therapeutic properties of
coumarin include histone deacetylase inhibition activity [2], free-radical scavenging
activity [3] and immunomodulatory activity [4]. Beside these properties coumarin
and its derivatives were found to show a variety of photophysical properties [5, 6].
Nitrogen-containing heterocycles are significant and play vital role in chemistry
and biology. Pyrazoles are five-membered heterocyclic compounds with 1,2 diaza
groups present in natural and synthetic heterocyclic compounds. Generally,
pyrazoles are rarely found in nature due to difficulty in the formation of N–N
bonds by living organisms [7]. Some drugs with a pyrazole nucleus include
rimonabant, which is used in the treatment of obesity, fomepizole, which acts as an
alcohol dehydrogenase, celecoxib, which exhibits anti-inflammatory activity.
Various other pharmacological activities of pyrazole includes analgesic [8],
antioxidant [9], anti-inflammatory [10], antimicrobial [11], anti-cancer [12],
anticonvulsant [13], fungistatic [14]. Also, pyrazoles have exhibited diverse
properties such as insecticidal [15], dyes [16], and fluorescence [17].
Benzimidazoles are also very important therapeutic agents in pharmaceutical
chemistry where they exhibit various biological properties such as antihypertensive
[18] (candesartan, talemisartan), antihelmentics [19, 20] (albendazole, mebendazole),
antiviral [21], and anticancer [22]. Other applications of benzimidazoles include their
use as organic ligands [23], fluorescent whitening dyes [24], functional materials [25],
various photophysical properties [26], and photoelectric properties [27]. The most
prominent activity of benzimidazoles is as proton pump inhibitors when linked with a
sulphur atom, which is generally known as a prazole class [28] (Fig. 1).
Proton pump inhibitors are mainly used to treat symptoms of gastro-esophageal
reflux disease and gastritis. They are also used to treat peptic ulcers (duodenal and
gastric) and drug-induced ulcers, such as those associated with non-steroidal anti-
inflammatory drugs, and to promote healing of erosive esophagitis, which can lead
to scarring and narrowing of the esophagus (stricture), or to Barrett’s esophagus,
which is a risk factor for esophageal cancer [29].
In the design of new drugs, the concept of molecular hybridization is an attractive
strategy [30]. The literature reports showed enhanced therapeutic activity when two
pharmacophoric moieties of different bioactive substances produce a new hybrid
compound compared to the individual components. Liu et al. [31] reported the
anthelmintic activity of coumarin-benzimidazole hybrid derivatives. Arora et al. [32]
reported the combined effect of hybrid scaffolds of coumarin-benzimidazoles with
antioxidant and anti-inflammatory activities. The combined pharmacological effect of
coumarin with a pyrazole ring as a potent antioxidant and antihyperglycemic agents has
been described by Kenchappa et al. [33]. Synthesis, as well as antioxidant and
anticancer activity of some new coumarin derivatives linked with pyrazole moiety has
1
23

Synthesis of novel substituted 3-(4-((1H-benzo[d]imidazol…
O
F
O
O O
O
N
O
S
O
N
S
F
N
H
N
H
N
N
Pantaprazole
Rabeprazole
F
F
F
O
O
S
O
N
O
S
O
N
N
H
N
H
N
N
Lansaprazole
Omeprazole
Fig. 1 Commercially available proton pump inhibitors
been reported by Khaled et al. [34]. Galal et al. [35] reported the synthesis and
biological activity evaluation of novel pyrazole-benzimidazole conjugates as check-
point kinase 2 (Chk2) inhibitors. Mahesh et al. [36] described the synthesis and
antioxidant activity of some new N-alkylated pyrazole-containing benzimidazoles.
So, based on the mentioned literature precedence and in continuation of earlier
work [37–40], it was considered worthwhile to prepare compounds bearing
coumarin, pyrazole and benzimidazoles in a single framework with a sulphur
linkage, which may act as potential anti-ulcer agents.
Experimental
General
All chemicals, unless otherwise specified, were purchased from commercial sources
and were used without further purification. All the solvents were freshly dried and
distilled before use. Melting points were measured in a hot sulphuric acid bath and
1
13
are uncorrected. HNMR and CNMR spectra were acquired with a Bruker Avance
DRX-400 instrument at 400 MHz in DMSO-d6 at room temperature. FT-IR spectra
were recorded on a Perkin Elmer spectrometer. The development of the reactions
and purity of the products were monitored by thin layer chromatography (TLC)
analysis on Merck pre-coated silica gel aluminium sheets, visualized by UV light or
iodine. All the synthesized compounds were dried under hot air oven.
General procedure for the preparation of 2 from 1 A mixture of 1 (5 mmol) and
phenylhydrazine (5 mmol) and acetic acid (10 mL) was stirred at room temperature
123

D. Srikrishna, P. K. Dubey
for 10 min. Then, the mixture was poured into ice-cold water (30 mL). The
separated solid was filtered, washed with aqueous acetic acid (1:1, 2 9 5 mL) and
dried. The crude product was recrystallized from a suitable solvent to obtain pure 2.
-
1
Yield = 1.29 g (93%); mp 186-188 °C; IR (KBr): 1717 cm (strong, sharp, –CO
-
1
1
(broad, medium, –NH group); H-NMR
of coumarin ring), 3380–3430 cm
(
400 MHz, DMSO-d /TMS): d 2.22 (s, 3H, –CH ), 6.77–7.85 (m, 8H, Ar–H), 8.20
s, 1H, Ar–H), 9.42 (s, 1H, –NH); HRMS calculated for C H N O [M?H] :
17 14 2 2
6
3
?
(
2
79.1133, Found: 279.1131.
General procedure for synthesis of 3 from 2 Sample 2 (5 mM) was added to a
cold solution of DMF (25 mL) and POCl (5 mL) at 0–5 °C. The reaction mixture
3
was stirred at RT for 2–3 h. After the completion of reaction, as indicated by the
disappearance of starting materials on TLC, the mixture was poured into ice-cold
water (30 mL). The separated solid was filtered, washed with water (2 9 15 mL)
and dried to obtain crude 3. Recrystallization from a suitable solvent gave pure 3.
-
1
-1
IR (KBr): 1716 cm
strong, sharp, –CO of coumarin ring); H NMR (400 MHz, DMSO-d /TMS): d
(strong, sharp, –CO of aldehyde group), 1731 cm
1
(
6
7
CHO); C NMR (100 MHz, DMSO-d /TMS): 114.8, 119.3, 119.9, 120.1, 123.4,
.36–8.10 (m, 8H, Ar–H), 8.46 (s, 1H, Ar–H), 9.27 (s, 1H, Ar–H), 9.97 (s, 1H, –
1
3
6
1
Calculated for C H N O [M?H] : 317.0926, Found: 317.0933.
24.8, 127.8, 129.7, 132.6, 138.5, 142.8, 143.3, 146.4, 147.3, 159.0, 185.4; HRMS
?
1
9 12 2 3
General procedure for the synthesis of 4 from 2 A mixture of 2 (5 mM), DMF-
DMA (5 mM) and dioxane (20 mL) was heated at 100 °C for about 4 h. The
reaction was monitored by TLC analysis. After the completion of reaction, the
mixture was cooled to RT and poured into ice-cold water (30 mL). The separated
solid was filtered, washed with water (2 9 10 mL) and dried. The crude product
was recrystallized from a suitable solvent to yield pure 4.
-
1
1
IR (KBr): 1736 cm
(strong, sharp, –CO of coumarin ring); H-NMR
(
Ar–H), 7.86 (d, 1H, Ar–H), 8.20 (s, 1H, Ar–H); C-NMR (100 MHz, DMSO-d6/
400 MHz, DMSO-d /TMS): d 6.76 (d, J = 8 Hz, 1H, Ar–H), 7.28–7.72 (m, 9H,
6
1
3
TMS): 114.8, 119.3, 119.9, 120.1, 123.4, 124.8, 127.8, 129.7, 132.6, 138.5, 142.8,
?
43.3, 146.4, 147.3, 159.0; HRMS calculated for C H N O [M?H] : 289.0977,
1
Found: 289.0966.
General method for the synthesis of 3 from 4 Sample 4 (5 mM) to a cold mixture
1
8 12 2 2
of DMF (25 mL) and POCl (5 mL) in an ice-bath at 0–5 °C. Then the reaction
3
mixture temperature was allowed to rise to RT and further to 55–60 °C in an oil-
bath and maintained for 4–6 h. The completion of the reaction was checked by TLC
for the disappearance of starting material. After completion of the reaction, the
mixture was poured into ice-cold water (30 mL). The separated solid was filtered,
washed with water (2 9 20 mL) and dried to obtain a crude product. The latter was
recrystallized from a suitable solvent to obtain pure 3.
Preparation of 5 from 3 A mixture of 3 (5 mM), NaBH (5 mM) and THF
4
(
25 mL) was stirred at RT for a period of 2 h. After the completion of reaction as
indicated by disappearance of 3 on TLC, the mixture was poured into ice-cold water
40 mL). The separated solid was filtered, washed with water (2 9 20 mL) and
dried to obtain crude product, which was recrystallized from methanol to get pure 5.
(
1
23

Synthesis of novel substituted 3-(4-((1H-benzo[d]imidazol…
-
IR (KBr): 1725 cm (strong, sharp, –CO of coumarin ring), 3310–3335 (broad,
1
1
medium, –OH group); H NMR (400 MHz, DMSO-d /TMS): d 4.51 (d, J = 5.6 Hz,
6
2
H), 8.47 (s, 1H, Ar–H); Ms: m/z 319 [M. ?1].
H, –CH ), 4.95 (t, J = 8.2 Hz, 1H, OH), 7.31–7.89 (m, 9H, Ar–H), 8.33 (s, 1H, Ar–
2
?
Preparation of 6 from 5 A mixture of 5 (5 mM), SOCl (5 mL) in benzene was
2
refluxed on a water bath for about 1 h. Progress of the reaction was monitored on
TLC. After completion of reaction as indicated by TLC, the mixture was cooled to
RT and was distilled off, washed with hexane (2 9 20 mL) and dried to obtain
crude 6. The latter was recrystallized from chloroform to obtain pure 6.
-
1
1
IR (KBr): 1718 cm
(strong, sharp, –CO of coumarin ring); H NMR
(
400 MHz, DMSO-d /TMS): d 4.50 (s, 2H, –CH ), 7.31–7.85 (m, 9H, Ar–H),
6
2
?
.29 (s, 1H, Ar–H), 8.41 (s, 1H, Ar–H); Ms: m/z 337 [M. ? 1].
Preparation of 7 from 6 O-ethyl carbonodithioate (5 mM) was added to a
8
solution of 6 (5 mM) in ethanol (20 mL), and the resulting mixture was refluxed in a
water bath for about 2 h. The reaction was monitored by TLC analysis. After the
completion of reaction, the mixture was cooled to RT and poured into ice-cold water
(
30 mL). The separated solid was filtered, washed with water (2 9 10 mL) and
dried. The crude product was recrystallized from ethanol to yield pure 7.
-
IR (KBr): 1238 cm (strong, sharp, –C=S of thiocarbonyl ring), 1726 cm
1
-1
1
(
strong, sharp, –CO of coumarin ring); H NMR (400 MHz, DMSO-d /TMS): d
6
1
.18 (t, J = 7.6 Hz, 3H, –CH ), 4.0 (s, 2H, –CH ), 4.60 (q, 2H, OCH ), 6.75–7.81
3 2 2
?
(
m, 10H, Ar–H), 8.19 (s, 1H, Ar–H), 8.41 (s, 1H, Ar–H); Ms: m/z 423 [M. ?1].
General method for the preparation of 9 from 7 by reaction with 8 A mixture of 7
5 mM), 8 (5 mM) in ethanol was refluxed for a period of 3–4 h. After the
(
completion of reaction, the mixture was cooled to RT and poured into ice-cold
water. The separated solid was filtered and washed with water (2 9 30 mL) to
obtain crude 9. The crude product was recrystallized from suitable solvent to give
pure 9.
3-(4-(((1H-benzo[d]imidazol-2-yl)thio)methyl)-1-phenyl-1H-pyrazol-3-yl)-2H-
chromen-2-one 9a
-
IR (KBr): 1723 cm (strong, sharp, –COof coumarin ring), 3405–3430 (broad,
1
1
medium, –NH group); H NMR (400 MHz, DMSO-d /TMS): d 4.58 (s, 2H, –CH ),
6
2
6
NH); C NMR (100 MHz, DMSO-d /TMS): 24.8, 109.4, 115.3, 116.8, 117.5,
.96–7.83 (m, 13H, Ar–H), 8.26 (s, 1H, Ar–H), 8.61 (s, 1H, Ar–H), 12.50 (s, 1H, –
1
3
6
1
1
20.8, 123.1, 127.0, 127.2, 128.0, 128.8, 129.1, 129.4, 129.5, 130.7, 135.2, 136.7,
39.2, 142.5, 144.4, 146.9, 155.0, 160.4; HRMS Calculated for C H N O S
2
6 18 4 2
?
[
M?H] : 451.12587, Found: 451.12556.
3-(4-(((6-Methoxy-1H-benzo[d]imidazol-2-yl)thio)methyl)-1-phenyl-1H-pyrazol-3-
yl)-2H-chromen-2-one 9b
-
1
IR (KBr): 1714 cm (strong, sharp, –COof coumarin ring), 3400–3434 (broad,
1
medium, –NH group); H NMR (400 MHz, DMSO-d /TMS): d 3.66 (s, 2H, –CH ),
6
2
4
.52 (s, 3H, OCH ), 6.57–7.84 (m, 12H, Ar–H), 8.21 (s, 1H, Ar–H), 8.60 (s, 1H, Ar–
3
123

D. Srikrishna, P. K. Dubey
1
H); C NMR (100 MHz, DMSO-d /TMS): 26.1, 55.0, 109.8, 115.2, 116.3, 117.4,
3
6
1
1
21.2, 123.4, 127.2, 127.5, 128.1, 129.1, 129.6, 129.9, 130.1, 130.9, 135.3, 137.1,
?
39.4, 141.9, 144.2, 146.8, 155.1, 158.4; Ms: m/z 481 [M. ?1].
General method for the preparation of 10 from 6 A mixture of 6 (5 mM),
thiourea (5 mM) in ethanol was refluxed for 3 h in a water bath. After completion of
the reaction as indicated by the disappearance of starting materials on TLC, the
mixture was cooled to RT and poured into ice-cold water, and the separated solid
was filtered to get crude 10. The crude product was then recrystallized from
acetonitrile to obtain pure 10.
-
1
IR (KBr): 1724 cm (strong, sharp, –COof coumarin ring), 2880–2930 (broad,
1
medium, –SH group); H NMR (400 MHz, DMSO-d /TMS): d 4.52 (s, 2H, –CH ),
6
2
7
.32–7.96 (m, 9H, Ar–H), 8.34 (s, 1H, Ar–H), 8.46 (s, 1H, Ar–H); Ms: m/z 335
?
M. ?1].
[
General method for the preparation of 9 from 10 by reaction with 11 A mixture
of 10 (5 mM), 11 (5 mM) in DMF (20 mL) containing K CO (2 mM) and TBAB
2
3
(
2 mM) was stirred at RT for a period of 3–5 h. The reaction was monitored by TLC
analysis. After the completion of reaction, the mixture was poured into ice-cold
water (30 mL). The separated solid was filtered, washed with water (2 9 10 mL)
and dried. The crude product was recrystallized from a suitable solvent to yield pure
9
.
General method for the preparation of 9 from 6 by reaction with 12 Sample 11
5 mM) was added to a mixture of 6 (5 mM) in DMF (20 mL) containing K CO
2 mM) and TBAB (2 mM), and the mixture stirred at RT for 3–5 h. The reaction
(
(
2
3
was monitored by checking TLC. After completion of reaction, the mixture was
poured into ice-cold water (30 mL). The separated solid was filtered, washed with
water (2 9 10 mL) and dried. The crude product was recrystallized from
a suitable solvent to yield pure 9.
General method for the preparation of 13 from 9 A mixture of 9 (5 mM) in DMF
20 mL) containing K CO (2 mM) and TBAB (2 mM), alkylating agent (DMS or
2 3
(
DES or benzyl chloride) (5 mM) was added and stirred at RT for 3–5 h. The
reaction was monitored by checking TLC. After completion of reaction, the mixture
was cooled to RT and poured into ice-cold water (30 mL). The separated solid was
filtered, washed with water (2 9 10 mL) and dried. The crude product was
recrystallized from a suitable solvent to yield pure 13.
3-(4-(((1-Methyl-1H-benzo[d]imidazol-2-yl)thio)methyl)-1-phenyl-1H-pyrazol-3-
yl)-2H-chromen-2-one (13a)
-
1
1
IR (KBr): 1718 cm (strong, sharp, –COof coumarin ring); H NMR (400 MHz,
DMSO-d /TMS): d 3.58 (s, 3H, –CH ), 4.64 (s, 2H, –CH ), 6.95–7.89 (m, 13H, Ar–
6
3
2
1
H), 8.27 (s, 1H, Ar–H), 8.65 (s, 1H, Ar–H); C NMR (100 MHz, DMSO-d /TMS):
3
6
2
1
6.9, 30.3, 109.8, 116.5, 117.9, 118.9, 119.4, 119.8, 121.2, 121.8, 122.1, 125.2,
27.2, 129.3, 129.5, 130.1, 132.7, 137.0, 139.5, 143.0, 146.7, 151.2, 153.8, 159.8;
?
Ms: m/z 465 [M. ?1].
1
23

Synthesis of novel substituted 3-(4-((1H-benzo[d]imidazol…
3
2
-(4-(((1-Ethyl-1H-benzo[d]imidazol-2-yl)thio)methyl)-1-phenyl-1H-pyrazol-3-yl)-
H-chromen-2-one (13b)
-
IR (KBr): 1718 cm (strong, sharp, –COof coumarin ring); H NMR (400 MHz,
1
1
DMSO-d /TMS): d 1.08 (t, J = 7.6 Hz, 3H, –CH ), 3.94 (q, 3H, –CH ), 4.62 (s, 2H,
6
3
2
1
3
–CH ), 6.90–7.87 (m, 13H, Ar–H), 8.22 (s, 1H, Ar–H), 8.60 (s, 1H, Ar–H);
NMR (100 MHz, DMSO-d /TMS): 14.2, 27.2, 30.8, 108.7, 116.7, 117.3, 117.9,
C
2
6
1
1
20.1, 121.2, 121.7, 121.9, 122.3, 125.6, 128.0, 129.7, 130.1, 130.5, 133.0, 137.2,
?
40.1, 142.9, 146.6, 150.9, 153.9, 160.4; Ms: m/z 478 [M. ?1].
3-(4-(((1-Benzyl-1H-benzo[d]imidazol-2-yl)thio)methyl)-1-phenyl-1H-pyrazol-3-
yl)-2H-chromen-2-one (13c)
-
IR (KBr): 1727 cm (strong, sharp, –COof coumarin ring); H NMR (400 MHz,
1
1
DMSO-d /TMS): d 3.13 (s, 2H, –CH ), 4.61 (s, 2H, –CH ), 6.85–7.89 (m, 19H, Ar–
6
2
2
1
H), 8.29 (s, 1H, Ar–H), 8.68 (s, 1H, Ar–H); C NMR (100 MHz, DMSO-d /TMS):
3
6
2
1
1
5.9, 49.0, 110.0, 115.2, 116.1, 118.0, 119.9, 120.9, 121.9, 123.0, 125.4, 125.7,
26.2, 127.6, 127.9, 128.3, 128.6, 129.3, 129.5, 134.2, 137.3, 138.9, 139.7, 140.0,
?
46.1, 152.6, 153.0, 161.9; Ms: m/z 541 [M. ?1].
3-(4-(((6-Methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)thio)methyl)-1-phenyl-1H-
pyrazol-3-yl)-2H-chromen-2-one (13d)
-
IR (KBr): 1723 cm (strong, sharp, –COof coumarin ring); H NMR (400 MHz,
1
1
DMSO-d /TMS): d 3.13 (s, 2H, –CH ), 4.49 (s, 2H, –CH ), 4.73 (s, 3H, –OCH ),
6
2
2
3
1
.98–7.83 (m, 12H, Ar–H), 8.32 (s, 1H, Ar–H), 8.65 (s, 1H, Ar–H); C NMR
3
6
(
100 MHz, DMSO-d /TMS): 27.2, 31.0, 55.8, 110.1, 115.8, 117.7, 119.1, 119.5,
6
1
1
19.9, 121.3, 121.9, 122.3, 124.9, 127.1, 129.0, 129.7, 130.3, 131.9, 137.3, 139.6,
?
43.2, 146.8, 151.5, 153.8, 158.2; Ms: m/z 495 [M. ?1].
3-(4-(((1-Ethyl-6-methoxy-1H-benzo[d]imidazol-2-yl)thio)methyl)-1-phenyl-1H-
pyrazol-3-yl)-2H-chromen-2-one (13e)
-
IR (KBr): 1726 cm (strong, sharp, –COof coumarin ring); H NMR (400 MHz,
1
1
DMSO-d /TMS): d 1.08 (t, J = 6.4 Hz, 3H, –CH ), 3.94 (q, 3H, –CH ), 4.46 (s, 2H,
6
3
2
–
CH ), 4.71 (s, 2H, –OCH ), 6.92–7.96 (m, 12H, Ar–H), 8.23 (s, 1H, Ar–H), 8.48
2 3
1
3
(
s, 1H, Ar–H); C NMR (100 MHz, DMSO-d /TMS): 14.5, 27.7, 30.9, 55.4, 109.1,
6
1
1
16.4, 117.6, 117.9, 120.2, 121.4, 121.8, 122.9, 123.2, 125.8, 128.1, 129.6, 130.2,
?
30.8, 133.2, 137.3, 141.5, 143.7, 146.5, 151.2, 154.4, 158.4; Ms: m/z 509 [M. ?1].
3-(4-(((1-Benzyl-6-methoxy-1H-benzo[d]imidazol-2-yl)thio)methyl)-1-phenyl-1H-
pyrazol-3-yl)-2H-chromen-2-one (13f)
-
1
IR (KBr): 1718 cm (strong, sharp, –COof coumarin ring); H NMR (400 MHz,
1
DMSO-d /TMS): d 3.13 (s, 2H, –CH ), 4.43 (s, 2H, –CH ), 4.69 (s, 3H, OCH ),
6
2
2
3
1
.81–7.93 (m, 18H, Ar–H), 8.31 (s, 1H, Ar–H), 8.64 (s, 1H, Ar–H); C NMR
3
6
123

D. Srikrishna, P. K. Dubey
O
O
O
DMF / POCl3
OH
O
+
60 0C / 4 h
N
CHO
N
O
(
4)
Triethanolamine /
L-proline /
DMF - DMA /
Dioxane /
RT / 30 min
1
00 0C / 4 h
O
O
O
O
DMF / POCl3
RT / 2 h
O
O
O
Ph-NH-NH2
CHO
RT / Acetic acid /
0-15 min.
N
N
N
1
NH
(
1)
(2)
(3)
Scheme 1 Synthesis of 3-(2-oxo-2H-chromen-3-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde (3) in two
different routes
O
O
N
O
O
N
Cl
O
O
N
OH
CHO
NaBH4 / THF
RT / 2 h
SOCl2 / Benzene
Ref lux / 1 h
N
N
N
(
3)
(5)
(6)
Scheme 2 Synthesis of 3-(4-(chloromethyl)-1-phenyl-1H-pyrazol-3-yl)-2H-chromen-2-one (6)
(
100 MHz, DMSO-d /TMS): 27.1, 49.1, 56.3, 109.6, 114.9, 115.8, 118.1, 120.2,
6
1
1
20.8, 122.0, 123.1, 124.9, 125.2, 126.4, 127.5, 128.0, 128.4, 128.8, 129.4, 129.8,
?
33.8, 137.1, 137.8, 139.6, 140.2, 145.6, 151.7, 153.2, 159.8; Ms: m/z 571 [M. ?1].
General method for the preparation of 13 from 10 by reaction with 14 A mixture
of 10 (5 mM), 14 (5 mM) in DMF (20 mL) containing K CO (2 mM) and TBAB
2
3
(2 mM) was stirred at RT for a period of 3–5 h. The reaction was monitored by TLC
analysis. After the completion of reaction, the mixture was poured into ice-cold
S
2 5
OC H
O
O
S
H
2
N
X
O
O
S
O
O
N
Cl
S
C
2
H
5
NH
KS
O
H
2
N
N
Ethanol /
Reflux /
(8)
N
N
N
N
N
X
2
h
Ethnaol /3-4 h
Reflux
(
6)
(7)
(9)
X = H, OCH
3
Scheme 3 Synthesis of substituted 3-(4-((1H-benzo[d]imidazol-2-ylthio)methyl)-1-phenyl-1H-pyrazol-
-yl)-2H-chromen-2-ones (9)
3
1
23

Synthesis of novel substituted 3-(4-((1H-benzo[d]imidazol…
O
O
O
O
O
O
S
S
S
S
S
S
H
NH2
2 5
-C H OH
NH
2
N
HN
N
N
N
C
2
H
5
O
H N
2
C
2
H
5
O
N
N
N
H
H
2
N
(
7A)
(
8)
(
7)
O
O
O
S
HS
H
N
O
NH
O
O
S
H
S
S
HN
N
N
N
H
N
N
N
H
N
N
N
(
9)
Scheme 4 Plausible mechanism for the formation of 9 from 7
H
N
X
O
O
O
O
O
O
Cl
Cl
SH
S
Thiourea /
N
NH
(
11)
N
Ethanol /
N
N
N
N
N
Ref lux / 3 h
DMF / K CO / RT /
N
2
3
TBAB / 3-5 h
X
(6)
(10)
(9)
X = H, OCH3
Scheme 5 Alternative synthesis of compounds 9 from 6
O
O
N
O
O
N
S
Cl
H
N
NH
X
DMF / K
2 3
CO /
N
+
HS
TBAB / RT / 3-4 h
N
N
X
N
(6)
(12)
(9)
X = H, OCH
3
Scheme 6 Another alternative approach or the synthesis of 9 from 6
water (30 mL). The separated solid was filtered, washed with water (2 9 10 mL)
and dried. The crude product was recrystallized from ethanol to yield pure 13.
123

D. Srikrishna, P. K. Dubey
Table 1 Reaction conditions, yield and physical data of compounds 5, 6, 7, 9 (a–b) and 10
S. no.
Substrate-I
Substrate-II
Reaction
condition
Product
obtained
Yield
(%)
Melting
point (°C)
1
2
3
4
5
6
7
8
9
3
NaBH
4
RT/2 h
5
76
66
61
54
50
63
78
72
77
70
143–145
202–204
88–90
5
SOCl
2
Reflux/1 h
Reflux/2 h
Reflux/3 h
Reflux/4 h
Reflux/3 h
RT/3 h
6
6
KSC(S)OC
2
H
5
7
7
8a: X=H
9a: X=H
9b: X=OCH
10
215–217
234–236
108–110
215–217
234–236
215–217
234–236
7
8b: X=OCH
3
3
6
Thiourea
10
10
6
11a: X=H
9a: X=H
9b: X=OCH
9a: X=H
9b: X=OCH
11b: X=OCH
3
3
RT/5 h
3
3
12a: X=H
RT/3 h
10
6
12b: X=OCH
RT/4 h
R
N
O
O
N
O
O
N
S
S
Alkylating agent /
NH
N
N
DMF /K CO /
2 3
TBAB / RT / 3-5 h
X
N
N
X
(
13)
(
9)
X = H, OCH ,
3
R= CH , C H , CH Ph
3
2
5
2
Scheme 7 Alkylation of 9 to obtain the corresponding compounds 13
O
O
N
O
O
R
N
R
N
SH
S
DMF /K CO3
/
X
2
+
Cl
N
TBAB / RT / 3-5 h
N
N
X
N
N
(
14)
(
10)
(13)
X = H, OCH ,
3
R= CH , C H , CH Ph
3
2
5
2
Scheme 8 Alternative synthesis of 13 from 10
Results and discussion
Commercially available salicylaldehyde was treated with ethyl acetoacetate in
triethanolamine containing a catalytic amount of L-proline at room temperature for
3
0 min to yield 3-acetyl-2H-chromen-2-one (1). This on reaction with phenylhy-
drazine in acetic acid at RT for 10-15 min resulted in the formation of (3-(1-(2-
phenylhydrazono)ethyl)-2H-chromen-2-ones (2). Vilsmeier–Haack reaction of 2 at
room temperature for 2 h gave the compound 3-(2-oxo-2H-chromen-3-yl)-1-
1
23

Synthesis of novel substituted 3-(4-((1H-benzo[d]imidazol…
phenyl-1H-pyrazole-4-carbaldehydes (3). In another approach, 2 in treatment with
DMF-DMA in dioxane at 100 °C for 4 h, resulted in the formation of 3-(1-phenyl-
1
H-pyrazol-3-yl)-2H-chromen-2-one (4), which on Vilsmeier–Haack reaction gave
. This product was compared with the products prepared in earlier routes and were
3
found to be identical in all respects with mp, mmp and co-TLC (Scheme 1).
Reduction of 3 with sodium borohydride in tetrahydrofuran (THF) at RT for 2 h
resulted in the formation of 3-(4-(hydroxymethyl)-1-phenyl-1H-pyrazol-3-yl)-2H-
chromen-2-one (5). The latter was chlorinated with thionyl chloride in refluxing
benzene for 1 h to afford 3-(4-(chloromethyl)-1-phenyl-1H-pyrazol-3-yl)-2H-chro-
men-2-one (6) (Scheme 2).
6
was treated with potassium O-ethyl carbonodithioate in ethanol under refluxing
conditions for 2 h resulting in the formation of O-ethyl S-((3-(2-oxo-2H-chromen-3-
yl)-1-phenyl-1H-pyrazol-4-yl)methyl) carbonodithioate (7). O-ethyl car-
bonodithioate itself was obtained by the reaction of freshly prepared ethanolic
KOH solution with CS at 5–10 °C for 2 h. 7 when refluxed with o-phenylene-
2
diamine (8) in ethanol for 3–4 h gave 3-(4-(((1H-benzo[d]imidazol-2-yl)thio)-
methyl)-1-phenyl-1H-pyrazol-3-yl)-2H-chromen-2-ones (9), which were identified
based on their spectral data (Scheme 3). (Please see the ‘‘Experimental’’ section.)
A plausible mechanism has been proposed for the formation of 9 from 7, and it
seems to be as follows. The nucleophilic addition reaction of o-phenylenediamine
(
8) with the thiocarbonyl group of 7 initiates the process, followed by concomitant
loss of ethanol to form 7A. 7A with another amine group again undergoes
nucleophilic addition reaction with the thiocarbonyl group, subsequent cyclization
to give 9 (Scheme 4).
Alternatively, 9 could also be prepared by the reaction of 6 with thiourea under
refluxing ethanol for 3 h to yield 3-(4-(mercaptomethyl)-1-phenyl-1H-pyrazol-3-
Table 2 Reaction conditions, yield and physical data of compounds 13(a–f) prepared from 9(a–b) and
10
S. no. Substrate-I
Substrate-II
Reaction Product obtained
condition
Yield Melting
(%)
point
°C)
(
1
2
3
4
5
6
7
8
9
1
1
1
9a: X=H
DMS
DES
RT/3 h
RT/4 h
13a: X=H, R=CH
13b: X=H, R=C
3
76
69
71
74
70
184–186
153–155
210–212
194–196
205–207
233–235
184–186
153–155
210–212
194–196
205–207
233–235
9a: X=H
2
H
5
9a: X=H
PhCH
DMS
DES
2
Cl
Cl
RT/3‘ h 13c: X=H, R=CH
2
Ph
9b: X=OCH
3
3
3
RT/4 h
13d: X=OCH
3
, R=CH
, R=C
, R=CH
RT/3‘ h 13a: X=H, R=CH
RT/4 h 13b: X=H, R=C
RT/4‘ h 13c: X=H, R=CH
RT/5 h 13d: X=OCH
RT/3‘ h 13e: X=OCH
Ph RT/4 h 13f: X=OCH
3
9b: X=OCH
RT/5 h
13e: X=OCH
3
2 5
H
9b: X=OCH
PhCH
2
RT/4‘ h 13f: X=OCH
3
2
Ph 75
10
10
10
10
10
10
14a: X=H, R=CH
14b: X=H, R=C
14c: X=H, R=CH
14d: X=OCH
14e: X=OCH
14f: X=OCH
3
3
71
2
H
5
2
H
5
73
2
Ph
2
Ph
76
0
1
2
3
, R=CH
, R=C
, R=CH
3
3
, R=CH
, R=C
, R=CH
3
69
72
3
2
H
5
3
2
H
5
3
2
3
2
Ph 73
123

D. Srikrishna, P. K. Dubey
O
O
N
O
O
N
OH
CHO
NaBH4 / THF
RT / 2 h
N
N
(3)
(5)
SOCl2 / Benzene
Reflux / 1 h
S
2 5
OC H
O
O
N
O
O
N
SH
S
Cl
O
O
N
S
Thiourea /
C H
2 5
KS
O
Ethanol / Reflux
/ 3 h
N
N
Ethanol / Reflux /
N
2
h
(6)
(7)
(
10)
H
X
N
HS
H N
X
2
N
(
12)
H
N
H N
2
X
DMF / K CO / RT /
(8)
2
3
Cl
TBAB / 3-5 h
Ethnaol / Ref lux /
-4 h
N
3
(
11)
O
O
N
S
NH
DMF / K CO3 / RT /
2
N
N
TBAB / 3-5 h
X
(9)
R
N
Alkylation /
DMF /K CO / RT /
X
2
3
Cl
TBAB / 3-5 h
N
(
14)
R
N
O
O
S
DMF / K CO3 / RT /
2
N
TBAB / 3-5 h
N
X
N
X = H, OCH3
3 2 3 2
R = CH , CH CH , CH Ph
(
13)
Scheme 9 Synthesis of title compounds (13) in various approaches
yl)-2H-chromen-2-one (10) followed by its reaction with 2-chlorobenzimidazoles
(
(
11) in DMF containing K CO as base and tetra-n-butylammonium bromide
2 3
TBAB) as a phase transfer catalyst at RT for a period of 3–5 h (Scheme 5).
Also, the reaction of 6 with 2-thiobenzimidazole (12) in DMF containing K CO
2
3
and TBAB at RT for 3–4 h gave a product which was found to be identical with 9 in
all respects, such as mp, mmp & co-TLC (Scheme 6). Here, the alkylation
preferably occurs on SH group rather than NH, because the nucleophilicity of
sulphur is more than that of nitrogen atom (Table 1).
9
on further alkylation with alkylating agents independently, with each of
dimethyl sulphate (DMS), diethyl sulphate (DES) and benzyl chloride in DMF using
K CO as a base and TBAB as phase transfer catalyst at RT for 3–5 h gave the
2
3
1
23

Synthesis of novel substituted 3-(4-((1H-benzo[d]imidazol…
corresponding N-alkylated products (13) (Scheme 7). The structures of all these
products have been established on the basis of their spectral data. (Please see the
experimental Section).
Alternatively, 13 could also be prepared by the reaction of 10 with N-alkylated-2-
chloro-1H-benzo[d]imidazoles (14) in DMF containing TBAB, K CO at RT for
2
3
3
–5 h (Scheme 8). 13 were itself prepared by the alkylation of 2-chlorobenzim-
idazole (11) with each of the alkylating agent independently. Thus, the products
obtained in this method were found to be identical with the ones obtained in the
earlier sequence i.e., 9?13 (Table 2).
All the mentioned reactions are very nicely depicted in the summarizing
Scheme 9.
Conclusion
In the present work, 3-(2-oxo-2H-chromen-3-yl)-1-phenyl-1H-pyrazole-4-carbalde-
hyde (3) was prepared as a precursor in good yield in two different approaches. The
reactivity of this compound was exploited in a series of synthetic transformations
encompassing various condensation approaches for the synthesis of new coumarin-
pyrazole-benzimidazole–pharmacophoric–motif probes with a sulphur linker. We
have developed simple, stepwise and efficient protocols for the synthesis of title
compounds in various approaches with sub-sequences. All these compounds were
1
13
characterized by IR, HNMR, CNMR and mass spectral data.
Acknowledgements The authors are thankful to the authorities of Jawaharlal Nehru Technological
University Hyderabad for providing laboratory facilities. They are grateful to Department of Science and
Technology, Govt. of India, New Delhi, for financial support to DS in the form of INSPIRE Fellowship.
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3
3
3
4
1
23