Condensation of Ortho-phenylenediamines and Phenylhydrazines with Ethyl 4-Chloro-3-oxobutanoate: A Facile Approach for the Synthesis of Substituted 1 H-Benzimidazoles, Pyrazolones, and Pyrazoles

Article abstract of DOI:10.1080/00397911.2015.1036884

Substituted 1H-benzimidazoles, pyrazolones, and pyrazoles have been synthesized by the condensation of ortho-phenylenediamines and phenylhydrazines, respectively, with ethyl 4-chloro-3-oxobutanoate in good yields. The present approach is novel, straightforward, and being reported for the first time with ethyl 4-chloro-3-oxobutanoate.

Full text of DOI:10.1080/00397911.2015.1036884

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Condensation of ortho-
Phenylenediamines and
Phenylhydrazines with Ethyl 4-Chloro-3-
oxobutanoate: A Facile Approach
for the Synthesis of Substituted 1H-
Benzimidazoles, Pyrazolones, and
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Pyrazoles
a
a
a
Cherupally Dayakar , Dondra Jyothi , Pathi Suman & Bhimapaka
a
China Raju
a
Natural Products Chemistry Division, CSIR Indian Institute of
Chemical Technology, Hyderabad, India
Published online: 08 May 2015.
To cite this article: Cherupally Dayakar, Dondra Jyothi, Pathi Suman & Bhimapaka China Raju (2015):
Condensation of ortho-Phenylenediamines and Phenylhydrazines with Ethyl 4-Chloro-3-oxobutanoate:
A Facile Approach for the Synthesis of Substituted 1H-Benzimidazoles, Pyrazolones, and Pyrazoles,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, DOI: 10.1080/00397911.2015.1036884
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1
Synthetic Communications , 0: 1–10, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2015.1036884
CONDENSATION OF ORTHO-PHENYLENEDIAMINES
AND PHENYLHYDRAZINES WITH ETHYL 4-CHLORO-3-
OXOBUTANOATE: A FACILE APPROACH FOR THE
SYNTHESIS OF SUBSTITUTED 1H-BENZIMIDAZOLES,
PYRAZOLONES, AND PYRAZOLES
Cherupally Dayakar, Dondra Jyothi, Pathi Suman, and
Bhimapaka China Raju
Natural Products Chemistry Division, CSIR Indian Institute of Chemical
Technology, Hyderabad, India
GRAPHICAL ABSTRACT
Abstract Substituted 1H-benzimidazoles, pyrazolones, and pyrazoles have been synthesized
by the condensation of ortho-phenylenediamines and phenylhydrazines, respectively, with
ethyl 4-chloro-3-oxobutanoate in good yields. The present approach is novel,
straightforward, and being reported for the first time with ethyl 4-chloro-3-oxobutanoate.
Keywords Ethyl 4-chloro-3-oxobutanoate; Lewis acids; pyrazoles; pyrazolones;
substituted 1H-benzimidazoles
INTRODUCTION
Benzimidazoles, pyrazolones, and pyrazoles are important heterocyclic compounds
and drug substances in the pharmaceutical industry because of their potential biologi-
[
1–6]
cal activities.
The benzimidazole ring is an important pharmacophore in modern
drug discovery and synthesis of benzimidazoles has led to potent drug molecules such
[
7]
as omeprazole, lansoprazole, rabeprazole, and pantoprazole. Phenazone, propy-
phenazone, ampyrone, edaravone, and metamizole sodium are useful pyrazolone
[
1–6]
drugs, whereas celecoxib and acomplia are potential pyrazole drugs.
The high-
profile applications of benzimidazoles, pyrazolones, and pyrazoles, and in continu-
ation of our previous research, prompted us to conduct further studies on these
Received January 7, 2015.
Address correspondence to Bhimapaka China, Natural Products Chemistry Division, CSIR Indian
Institute of Chemical Technology, Hyderabad 500 007, India. E-mail: chinaraju@iict.res.in
1

2
C. DAYAKAR ET AL.
[
8–11]
heterocyclic compounds.
Previously Chen et al. and Reddy Vaddula et al.
[
12,13]
reported pyrazolones by using ethyl 3-oxobutanoates and phenyl hydrazine.
Our studies focused on feasible reactions of carbonyl compounds=salicylaldehydes
with 3-oxobutanoates bearing chloro=trifluoro substituents. In this context, we studied
the reactivity of salicylaldehydes with ethyl 4-chloro-3-oxobutanoate to provide 2H-
[14]
chromenes, and these derivatives were successfully converted to useful heterocyclic
[15–17]
compounds.
We also studied the reactivity of various carbonyl compounds with
ethyl 4,4,4-trifluoro-3-oxobutanoate to provide a series of (E)-a,b-unsaturated esters
[18,19]
and ketones.
The present article describes a systematic study for the preparation
of 1H-benzimidazoles, pyrazolones, and pyrazoles by the condensation of ortho-
phenylenediamines and phenylhydrazines with ethyl 4-chloro-3-oxobutanoate.
RESULTS AND DISCUSSION
In a model reaction, ethyl 4-chloro-3-oxobutanoate 2 (1 mmol) was added to a
stirred solution of ortho-phenylenediamine 1a (1 mmol) in MeCN (2 mL) at room
temperature (38 h). This furnished a pale yellow product (40% yield; Scheme 1) that
was identified as 2-(chloromethyl)-1H-benzo[d]imidazole 3a based on spectral data.
However, ethyl 2-(quinoxalin-2-yl)acetate was obtained in a previous study with
[
20,21]
ortho-phenylenediamine and ethyl 4-chloro-3-oxobutanoate.
The present
reaction has been investigated with various solvents and catalysts, and the results
are summarized in Table 1 (entries 1–8). The compound 3a was obtained in 68%
yield with EtOH under reflux conditions (entry 6). To improve the yield of 3a, the
reaction was carried out with various catalysts such as AcOH (entry 9), p-TsOH
(
entry 10), and Lewis acids (entries 11–18). The yield of 3a was improved to 82%
[
22]
in the presence of SnCl in EtOH under reflux conditions.
2
To evaluate the scope of this methodology, substituted ortho-phenylenedia-
mines were reacted with 2 having electron-withdrawing and electron-donating
substituents, such as nitro (entry 2), chloro (entry 3), benzoyl (entry 4), and methyl
[22]
(entries 5 and 6), to give a series of 2-(chloromethyl)-1H-benzo[d]imidazoles 3b-f
in good yields (Table 2). Electron-withdrawing groups afforded better yields than
electron-donating groups.
A plausible mechanism is depicted in Scheme 2. Condensation of 1 with 2
provides A (Schiff base) and subsequent intramolecular nucleophilic addition to the
imine C-atom provides ethyl 2-(2-(chloromethyl)-2,3-dihydro-1H-benzoimidazolyl)
acetate B. Finally, B provides 3 via the elimination of AcOEt.
Having succeeded in the preparation of 2-chloromethyl-1H-benzimidazoles, next
we have studied the reaction of phenylhydrazines 4a–e with ethyl 4-chloro-3-oxobutano-
ate 2 (Scheme 3). In a model reaction, 2 (1mmol) was added to a stirred solution of
phenylhydrazine hydrochloride 4a (1 mmol) in THF (2 mL) at room temperature. This
reaction furnished two compounds, i.e., as 3-(chloromethyl)-1-phenyl-1H-pyrazol-5
Scheme 1. Preparation of substituted 2-chloromethyl 1H-benzimidazoles.

SUBSTITUTED 1H-BENZIMIDAZOLES, PYRAZOLONES, AND PYRAZOLES
3
a
Table 1. Synthesis of 2-(chloromethyl)-1H-benzo[d]imidazole 3a
d
Entry
Catalyst
Solvent
Reaction time (h)
Yield (%) 3
b
1
2
3
4
5
6
7
8
9
_
_
_
_
_
_
_
MeCN
38
20
18
12
32
12
24
18
10
12
8
8
10
9
6
10
8
40
40
48
62
56
68
52
63
70
72
65
70
65
60
82
66
69
72
c
MeCN
b
MeOH
MeOH
c
b
EtOH
c
EtOH
c
THF
c
2
_
CH
2
Cl
c
AcOH
p-TsOH
AlCl
CuI
CuCl
Cu(OAc)
SnCl
La(OTf)
Sc(OTf)
Bi(OTf)
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
c
c
c
c
c
c
c
c
10
11
12
13
14
15
16
17
18
3
2
2
2
3
3
c
3
8
a
Conditions: Ortho-phenylenediamine (1 mmol), ethyl 4-chloro-3-oxobutanoate (1 mmol), catalyst
(
0.1 mmol).
b
Rt.
Reflux.
c
d
Yields of isolated products.
(4H)-one (5a, 40%, Table 3, entry 5) and 3-(chloromethyl)-5-ethoxy-1-phenyl-1H-
pyrazole (6a, 18%). These compounds were separated by column chromatography
and characterized by spectral data.
Table 2. Synthesis of 2-(chloromethyl)-1H-benzo[d]imidazoles 3a–f
1
a
Entry
Reactant 1
R
R
Reaction time (h)
Product 3
Yield (%)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
H
NO
Cl
H
H
H
H
H
6
5
6
8
6
8
3a
3b
3c
3d
3e
3f
82
75
72
60
65
62
2
COPh
CH
CH
3
3
CH
3
a
Yields of isolated products.

4
C. DAYAKAR ET AL.
Scheme 2. Plausible mechanism.
Scheme 3. Preparation of pyrazolones 5a,b and pyrazoles 6a–e.
a
Table 3. Synthesis of 1H-pyrazolone 5 and pyrazole 6
c
c
Entry
Catalyst
Solvent
Reaction time (h)
Yield (%) 5
Yield (%) 6
b
1
2
3
4
5
6
7
8
9
—
—
CH
CH
2
Cl
Cl
2
24
24
48
14
18
16
18
20
24
20
18
20
18
18
12
12
—
—
—
30
40
42
35
28
32
30
20
25
46
50
62
56
—
—
—
15
18
15
14
10
13
14
08
11
14
11
05
08
2
2
—
Toluene
MeCN
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
MeCN
—
—
AcOH
p-TsOH
FeCl
AlCl
Cu(OAc)
CuCl
SnCl
La(OTf)
Sc(OTf)
3
3
1
1
1
1
1
1
1
0
1
2
3
4
5
6
2
2
2
3
3
Bi(OTf)
Bi(OTf)
3
3
a
Conditions: Phenylhydrazine hydrochloride (1 mmol), ethyl 4-chloro-3-oxobutanoate (1 mmol),
catalyst (0.1 mmol), under reflux.
b
Rt.
c
Yields of isolated products.

SUBSTITUTED 1H-BENZIMIDAZOLES, PYRAZOLONES, AND PYRAZOLES
5
To study the product selectivity, various catalysts and solvents were
investigated and summarized in Table 3. Tetrahydrofuran (THF) solvent provided
pyrazolone 5a in 62% yield when 4a (1 mmol) was reacted with 2 (1 mmol) in the
presence of Bi(OTf) (0.1 mmol) under reflux conditions (entry 15), and hence THF
3
was chosen as the solvent for further reactions. The catalysts such as protic acid
(entry 6), p-TsOH (entry 7), and Lewis acids (entries 8–16) were examined. In all
the reactions, pyrazolone 5a and pyrazole 6a have been obtained but in poor yields.
To evaluate the efficiency of this methodology, substituted phenylhydrazine
hydrochlorides having electron-withdrawing and electron-donating substituents
4
6
a–e were reacted with 2 to provide corresponding pyrazolones 5a,b and pyrazoles
a–e (Table 4, entries 2–5).
A plausible mechanism is depicted in Scheme 4. Condensation of 4 with 2
provides A (Schiff base). Then, the nucleophilic addition of amine to the ester
C=O group provides 3-(chloromethyl)-5-ethoxy-1-phenyl-4,5-dihydro-1H-pyrazolol
B. Finally, elimination of EtOH leads to pyrazolone 5 and the elimination of water
provides pyrazole 6.
Further, the condensation reaction has been carried out with 4a (1 mmol) and 2
(
(
(
1 mmol) in the presence of Bi(OTf) (0.1 mmol) in MeOH under reflux conditions
Scheme 5). This reaction furnished two pale yellow products identified as 3-
methoxymethyl)-1-phenyl-1H-pyrazol-5(4H)-one 7a (52% yield, Table 5, entry 1)
3
and 5-ethoxy-3-(methoxymethyl)-1-phenyl-1H-pyrazole 8a (15%).
This reaction provided an interesting result that the nucleophilic substitution
has been occurred in situ. The reaction prompted us to study in detail with various
alcoholic solvents and the results are summarized in Table 5. Under similar
conditions, the reaction of 4a with 2 in EtOH provided ethoxy 1H-pyrazolone 7b
and pyrazole 8b (entry 2). However, isopropyl alcohol, isobutanol, and n-butanol
provided selectively corresponding 1H-pyrazolones 7c-e (Table 5, entries 3–5). To
evaluate the efficiency of this methodology, phenylhydrazine hydrochlorides having
electron-withdrawing and electron-donating substituents 4b–g were reacted with 2 in
a
Table 4. Synthesis of 1H-pyrazolones 5a,b and pyrazoles 6a–e
b
b
Entry Reactant 4
R
Reaction time (h) Product 5 Yield (%) Product 6 Yield (%)
1
2
3
4
5
4a
4b
4c
4d
4e
H
m-NO
p-F
p-CH
p-NO
12
18
20
24
32
5a
5b
—
—
—
62
52
—
—
—
6a
6b
6c
6d
6e
05
10
18
20
22
2
3
2
a
Conditions: Phenylhydrazine hydrochloride (1 mmol), ethyl 4-chloro-3-oxobutanoate (1 mmol), Bi
3
OTf) (0.1 mmol), under reflux.
(
b
Yields of isolated products.

6
C. DAYAKAR ET AL.
Scheme 4. Plausible mechanism for pyrazolones and pyrazoles.
Scheme 5. Preparation of alkoxymethyl 1H-pyrazolone 7a and pyrazole 8a.
Table 5. Synthesis of alkoxymethyl 1H-pyrazolones 7a–o and pyrazoles 8a–j
a
1
b
b
Entry Reactant 4
R
R
Time (h) Product 7 Yield (%) Product 8 Yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
4a
4a
4a
4a
4a
4c
4e
4f
4d
4 g
4b
4d
4 g
4b
4 g
H
H
H
H
H
p-F
p-Br
p-OCH
p-CH
m-Cl
m-NO
p-CH
m-Cl
m-NO
m-Cl
CH
C H
2 5
(CH
(CH
n-C
CH
CH
CH
CH
CH
CH
3
16
20
18
20
20
16
20
16
18
18
14
20
18
20
22
7a
7b
7c
7d
7e
7f
7 g
7 h
7i
52
45
39
36
35
56
54
50
51
55
58
45
39
51
45
8a
8b
—
—
—
8c
8d
—
8e
8f
8 g
8 h
8i
8j
—
15
18
—
—
—
14
18
—
12
15
10
15
16
11
—
3
)
2
CH
CHCH
2
3
)
2
4
3
3
3
3
3
3
H
9
3
3
0
1
2
3
4
5
7j
2
7k
7 l
7 m
7n
7o
3
C
2
C
2
C
2
H
H
H
5
5
5
2
(CH
3
)
2
CH
a
Conditions: Phenylhydrazine hydrochloride (1 mmol), ethyl 4-chloro-3-oxobutanoate (1 mmol), Bi
3
OTf) (0.1 mmol), under reflux.
(
b
Yields of isolated products.

SUBSTITUTED 1H-BENZIMIDAZOLES, PYRAZOLONES, AND PYRAZOLES
7
a
Table 6. Preparation of methoxymethyl-1H-pyrazolone
b
Entry
Base
NaOH
KOH
Piperidine
Triethylamine
Reaction time (h)
Yield (%) 7a
1
2
3
4
3
3
5
6
91
90
82
75
a
b
Conditions: 3-(Chloromethyl)-1-phenyl-1H-pyrazol-5(4H)-one (1 mmol), base (1 mmol), rt.
Yields of isolated products.
the presence of Bi(OTf) in MeOH and EtOH (Table 5, entries 6–14) to give a series
3
of corresponding 1H-pyrazolones 7f–o and pyrazoles 8c, 8d, and 8e–j.
Further, to examine the nucleophilic substitution reaction on pyrazolones 5
and pyrazoles 6, the individual reaction of 5a and 6a have been carried out with
MeOH at room temperature (48 h) without catalyst. This provided corresponding
1
H-pyrazolone 7a and pyrazole 8a in poor yields. Next, the nucleophilic substitution
reaction of 5a has been studied with various bases such as NaOH, KOH, piperidine,
and Et N in MeOH at room temperature (Table 6). This provided 1H-pyrazolone 7a
3
in 91% yield with NaOH and 90% yield with KOH than did other bases.
Further, the nucleophilic substitution reaction of chloromethylpyrazolones 5a,
b and pyrazoles 6a–d have been carried out with NaOH and KOH in MeOH at room
temperature (Schemes 6 and 7) and provided corresponding alkoxy pyrazolones 7a
Scheme 6. Preparation of alkoxypyrazolones.
Scheme 7. Preparation of alkoxypyrazoles.

8
C. DAYAKAR ET AL.
and 7k and pyrazoles 8a, 8 g, 8c, and 8e in good yields. The compounds 7a, 7k, 8a,
8
g, 8c, and 8e were well characterized by spectral data.
In conclusion, we developed a method for the preparation of 1H-benzimida-
zoles, pyrazolones, and pyrazoles by the condensation of ortho-phenylenediamines
and phenylhydrazines with ethyl 4-chloro-3-oxobutanoate for the first time. In situ
nucleophilic substitution of pyrazolones and pyrazoles with protic solvents provided
corresponding alkoxy derivatives. All the products 3a–f, 5a,b, 6a–e, 7a–o, and 8a–j
1
13
were characterized by spectral data ( H NMR, C NMR, IR, and mass spectra).
EXPERIMENTAL
General Procedure for the Synthesis of 2-(Chloromethyl)-1H-benzo
[
d]imidazoles (3a–f)
The synthesis of 2-(chloromethyl)-1H-benzo[d]imidazoles (3a–f) is the same as
described for compound 3a.
SnCl (0.1 mmol) was added to a stirred solution of ortho-phenylenediamine (1,
2
1
mmol) and ethyl 4-chloro-3-oxobutanoate (2, 1 mmol) in EtOH (2 mL) at rt. The
mixture was stirred under reflux for 6 h. After completion of the reaction, monitored
by thin-layer chromatography (TLC), the solvent was removed under reduced press-
ure. The crude product was subjected to column chromatography (hexane=AcOEt
8
4:16) to give the pure benzimidazoles.
2
-(Chloromethyl)-1H-benzo[d]imidazole (3a)
1
Pale yellow solid; yield: 82%; mp 152–154 °C; H NMR (300 MHz, CDCl ): d
3
1
3
¼
4.85 (s, 2H, CH Cl), 7.19–7.28 (m, 2H, Ar-H), 7.55–7.62 (m, 2H, Ar-H); C NMR
75 MHz, CDCl ) d ¼ 37.4, 114.6, 121.7, 137.9, 148.7; MS (ESI ) m=z ¼ 167 (MþH) .
2
þ
þ
(
3
General Procedure for Synthesis of 3-(Chloromethyl)-1-phenyl-1H-
pyrazol-5(4H)-ones (5a,b, 6a–e)
The syntheses of 3-(chloromethyl)-1-phenyl-1H-pyrazol-5(4H)-ones (5a,b and
6
a–e) are the same as described for those of compound 6a.
Bi(OTf) (0.1 mmol) was added to a stirred solution of phenylhydrazine hydro-
3
chloride (1, 1 mmol) and ethyl 4-chloro-3-oxobutanoate (2, 1 mmol) in THF (3 mL).
The mixture was stirred under reflux for 12 h. After completion of the reaction
(TLC), the solvent was removed under reduced pressure. The crude product was
subjected to column chromatography (hexane=AcOEt 8:2) to give pure pyrazolones
and pyrazoles.
3
-(Chloromethyl)-5-ethoxy-1-phenyl-1H-pyrazole (6a)
Yellow liquid; yield: 5%; IR (KBr) 2928, 1561, 1262, 1140, 1044, 758,
ꢀ
1 1
6
90 cm ; H NMR (300 MHz, CDCl ): d ¼ 1.45 (t, J ¼ 7.0 Hz, 3H, CH ), 4.18 (q,
3
3
J ¼ 7.0 Hz, 2H, OCH ), 4.57 (s, 2H, CH ), 5.75 (s, 1H, CH), 7.27 (tt, J ¼ 1.1,
2
2
7
.5 Hz, 1H, Ar-H), 7.41 (t, J ¼ 7.5 Hz, 2H, Ar-H), 7.69 (dd, J ¼ 1.0, 8.5 Hz, 2H,
13
Ar-H); C NMR (75 MHz, CDCl ): d ¼ 4.5, 39.8, 68.0, 85.6, 122.1, 126.3, 128.7,
3

SUBSTITUTED 1H-BENZIMIDAZOLES, PYRAZOLONES, AND PYRAZOLES
9
þ
þ
þ
1
38.3, 148.5, 155.0.; MS (ESI ) m=z ¼ 236 (MþH) ; HRMS (ESI ) calcd. for
þ
C H ClN ONa (MþNa) 259.0608; found 259.0614.
1
2
13
2
General Procedure for the Synthesis of 3-(Chloromethyl)-1-phenyl-
H-pyrazol-5(4H)-ones (7a–o, 8a–j)
1
The syntheses of 3-(chloromethyl)-1-phenyl-1H-pyrazol-5(4H)-ones (7a–o and
a–j) are the same as described for those of compound 7a.
8
Bi(OTf) (0.1 mmol) was added to a stirred solution of phenylhydrazine hydro-
3
chloride (1, 1 mmol) and ethyl 4-chloro-3-oxobutanoate (2, 1 mmol) in alcohols such
as MeOH and EtOH (3 mL). The mixture was stirred under reflux for 16 h. After
completion of the reaction (TLC), the solvent was removed under reduced pressure.
The crude product was subjected to column chromatography (hexane=AcOEt 8:2) to
give pure pyrazolones and pyrazoles.
3
-(Methoxymethyl)-1-phenyl-1H-pyrazol-5(4H)-one (7a)
Pale yellow solid; yield: 52%; mp 122–124 °C; IR (KBr) 2925, 2821, 1737, 1553,
ꢀ
1
1
1
396, 1111, 1029, 755, 686 cm ; H NMR (300 MHz, CDCl ): d ¼ 3.42 (s, 3H,
3
OCH ), 3.54 (s, 2H, CH ), 4.28 (s, 2H, OCH ), 7.19 (t, J ¼ 7.4 Hz, 1H, Ar-H), 7.40
3
2
2
1
3
(
t, J ¼ 7.7 Hz, 2H, Ar-H), 7.85 (d, J ¼ 7.7 Hz, 2H, Ar-H); C NMR (75 MHz,
þ
CDCl ): d ¼ 40.3, 58.8, 69.6, 118.9, 125.2, 128.8, 137.8; MS (ESI ) m=z ¼ 205
3
þ
þ
þ
(
MþH) ; HRMS (ESI ) calcd. for C H N O (MþH) 205.0970; found 205.0971.
1
1
13
2
2
ACKNOWLEDGMENTS
The authors thank M. Lakshmi Kantam, Director, and S. Chandrasekhar,
Head, Natural Products Chemistry Division, Council of Scientific and Industrial
Relations–Indian Institute of Chemical Technology (CSIR-IICT), for their constant
encouragement.
FUNDING
C. D. and P. S. thank CSIR, New Delhi, for their research fellowships. B. C. R.
acknowledges CSIR, New Delhi, for financial support through the program ORI-
GIN of XII Five-Year Plan (CSC0108).
SUPPLEMENTARY MATERIAL
Spectral data for the synthesized compounds can be accessed on the publisher’s
website.
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