A New Facile Sulfenylation of 2-Acetylbenzimidazoles

Article abstract of DOI:10.1080/10426507.2014.902833

A facile sulfenylation of 2-acetylbenzimidazoles has been achieved by using N-(phenylthio)phthalimide in the presence of potassium tert-butoxide in DMSO. The latter gave N-alkyl-β-phenylsulfenyl-2-acetylbenzimidazole on reaction with alkylating agents in the presence of potassium carbonate in N,N-dimethylformamide.

Full text of DOI:10.1080/10426507.2014.902833

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Phosphorus, Sulfur, and Silicon and the
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A New Facile Sulfenylation of 2-
Acetylbenzimidazoles
P. Praveen Kumara, Y. Dathu Reddya, Ch. Venkata Ramana Reddya, B.
Rama Devia & P. K. Dubeya
a Department of Chemistry, Jawaharlal Nehru Technological
University, Hyderabad College of Engineering, Kukatpally, Hyderabad
(A.P), India
Accepted author version posted online: 11 Jun 2014.Published
online: 13 Dec 2014.
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To cite this article: P. Praveen Kumar, Y. Dathu Reddy, Ch. Venkata Ramana Reddy, B. Rama Devi & P.
K. Dubey (2014) A New Facile Sulfenylation of 2-Acetylbenzimidazoles, Phosphorus, Sulfur, and Silicon
and the Related Elements, 189:12, 1775-1779, DOI: 10.1080/10426507.2014.902833
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Phosphorus, Sulfur and Silicon, 189:1775–1779, 2014
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2014.902833
A NEW FACILE SULFENYLATION OF
2-ACETYLBENZIMIDAZOLES
P. Praveen Kumar, Y. Dathu Reddy, Ch. Venkata Ramana
Reddy, B. Rama Devi, and P. K. Dubey
Department of Chemistry, Jawaharlal Nehru Technological University, Hyderabad
College of Engineering, Kukatpally, Hyderabad (A.P), India
GRAPHICAL ABSTRACT
Abstract A facile sulfenylation of 2-acetylbenzimidazoles has been achieved by using
N-(phenylthio)phthalimide in the presence of potassium tert-butoxide in DMSO. The latter
gave N-alkyl-β-phenylsulfenyl-2-acetylbenzimidazole on reaction with alkylating agents in
the presence of potassium carbonate in N,N-dimethylformamide.
Keywords N-(Phenylthio)phtalimide; 2-acetylbenzimidazole; sulfenylation; potassiumtert-
butoxide
INTRODUCTION
A large number of benzimidazole derivatives find use as pharmaceuticals,1–6 veteri-
nary anthelmentics,7,8 antiulcer agents,9,10 antihistaminic compounds,11,12 antiviral deriva-
tives, and analgesics.13,14 It was reported15 earlier from our laboratory that treatment of
N-methyl-2-acetylbenzimidazoles with bromine followed by reaction with sodium thio-
phenolate gave β-ketothiophenolate derivatives of benzimidazoles. Although, this is the
Received 9 December 2013; accepted 31 January 2014.
Address correspondence to P. Praveen Kumar, Department of Chemistry, Jawaharlal Nehru Technolog-
ical University, Hyderabad College of Engineering, Kukatpally, Hyderabad (A.P), 500 085, India. E-mail:
padampraveenku@gmail.com; info.ceh@jntuhceh.ac.in
1775

1776
P. P. KUMAR ET AL.
Table 1 Reaction time, yields for preparation of 4 and 5
S. No
Starting materials
2
Product
Time (h)
Yield∗(%)
1
2
3
4
5
6
7
8
9
1
4
4
4
4
3a
3b
3c
3d
4
5
1.5
2
2
2
62
78
75
70
75
74
72
68
70
Me2SO4
Et2SO4
C4H9Br
PhCH2Cl
5a
5b
5c
5d
5a
5b
5c
5d
2
2
2
2
3
4.5
4.5
5
∗Refers to yields of crude products only.
conventional method for making thiophenolates of α-arylacetyl compounds, it suffers
from the disadvantage, especially in the case of 1H-2-acetylbenzimidazole, that the lat-
ter is not amenable to direct bromination and subsequent reaction of the hypothetical
2-α-bromoacetyl-1H-benzimidazole with thiophenolate anion yielding 2-α-thiophenalato
acetylbenzimidazole.
Thus, it appeared to us that these is need for development of an alternative method
for sulfenylation of 2-acetylbenzimidazole. N-(Phenylthio)phthalimides are known to be
well-known suphenyltransfer reagents16,17 and were therefore, considered to be reagents of
choice for preparation of 2-α-thiophenolatoacetylbenzimidazole.
RESULTS AND DISCUSSION
As illustrated in Scheme 1, treatment of 2-acetylbenzimidazole
1 with
N-(phenylthio)phthalimide 2 in the presence of potassium t-butoxide as a base in DMSO
as a solvent at room temperature for 3 h yielded β-phenylsulfenyl-2-acetylbenzimidazole
4. The latter gave N-methyl-β-phenylsulfenyl-2-acetylbenzimidazole 5a (i.e., 5, R =
Me) on reaction with dimethyl sulfate in the presence of potassium carbonate in
N,N-dimethylformamide containing TBAB. The structure of this product was assigned
based on its spectral data. (For details, please see Experimental Section).
In an alternative sequence of reactions, 2-acetylbenzimidazole 1 was re-
acted with dimethyl sulfate in the presence of potassium carbonate as a base in
N,N-dimethylformamide containing TBAB as phase transfer catalyst to obtain
N-methyl-2-acetylbenzimidazole 3, which on reaction with N-(phenylthio)phthalimide
2 in the presence of potassium tert-butoxide in DMSO resulted in the formation of
N-methyl-β-ketosulfenyl-2-acetylbenzimidazole 5a.
The above reaction of conversion of 1 to 5a was extended to other alkylating agents
such as diethyl lsulfate, butyl bromide and benzyl chloride to give the corresponding
N-alkyl-β-ketosulfenyl-2-acetylbenzimidazole 5b–5d respectively (Scheme 1).
However, it should be kept in mind that in the reaction reported earlier15 from this lab,
the sulfenyl sulfur is introduced into the acetyl group of benzimidazole as a thiolate group
attacking the positively polarized carbon atom in α-position to the keto group whereas in
the reactions described using 2, the sulfenyl sulfur is introduced as positively charged sulfur
attacking the potential carbanion of the substrate 1.

A NEW FACILE SULFENYLATION OF 2-ACETYLBENZIMIDAZOLES
1777
Scheme 1
Mechanism
CONCLUSION
A new synthetic method for the sulfenylation of 2-acetylbenzimidazole and N-
alkylbenzimidazoles has been successfully achieved by using N-(phenylthio)phthalimide
as a sulfenyl transfer agent. Probably this appears to be the first ever case of
facile sulfenylation of 2-acetylbenzimidaazole and N-alkylbenzimidazoles. The use of N-
(phenylthio)phthalimide as a sulfenylating agent has been reported related reactions such as
sulfenylation of indoles and other active methyl groups. However, its use in the preparation
of 2-(α-sulfenylacetyl)benzimidaazole and N-alkyl-2-(α-sulfenylacetyl)benzimidazoles
from 2-acetylbenzimidaazole has probably not been reported so far.

1778
P. P. KUMAR ET AL.
EXPERIMENTAL SECTION
Melting points are uncorrected and were determined in open capillary tubes in a
sulfuric acid bath. TLC was run on silica gel G and visualization was done using iodine
vapor or UV light. IR spectra were recorded on a Perkin Elmer 1000 instrument in KBr
pellets. NMR spectra were recorded at 400 MHz (1H), and 100 MHz (13C) in DMSOd6 using
TMS as internal standard. Mass spectra were recorded on an Agilent-LCMS instrument.
1
1
The Supplemental Materials file contains selected H, 3C, and mass spectra for 4 and 5
(Figures S1–S6).
General Procedure for the Preparation of 4 from 1 and 2
To a solution of the 2-acetylbenzimidazole 1 (10 mmol) in DMSO (20 ml), t-BuOK
(10 mmol) was added at r.t. The mixture was stirred well for 30 min. To this mixture,
N-phenyl(thiophthalimide) 2 (10 mmol) was added and stirring was continued for 3 h. At
the end of the reaction, the reaction mixture was diluted with water and extracted with ethyl
acetate. The organic layer was separated, washed with satd. NaHCO3 solution followed by
brine and then dried. The solvent was evaporated to obtain a residue, which on purification
by silica gel column chromatography (hexane/ethyl acetate, 85:15) gave 4.
General Procedure for the Preparation of 5 from 3 and 2
To a solution of the N-alkyl-2-acetylbenzimidazole 3 (10 mmol) in DMSO (20 ml),
tBuOK (1 mmol) was added at r.t. The reaction mixture was stirred well for 30 min. To this
N-phenyl(thiophthalimide) 2 (10 mmol) was added and stirring was continued for about
2–3 h. The reaction mixture was monitored by TLC. At the end of the reaction, the mixture
was diluted with water and extracted with ethyl acetate. The organic layer (i.e., EtOAc)
was separated, washed with satd. NaHCO3 solution followed by brine and then dried. The
solvent (i.e., EtOAc) was evaporated to obtain a residue, which on purification by silica gel
column chromatography (hexane/ethyl acetate, 85:15) gave 5.
General Procedure for the Preparation of 5 from 4
A mixture of 4 (10 mmol), alkylating agent (11 mmol), K2CO3, TBAB and DMF
(20 ml) was stirred at r.t. for 1–2 h. The reaction mixture was monitored by TLC. At the
end of the reaction, the mixture was poured into cold water. The solid that separated out
from the mixture was filtered and then dried. The product was recrystallized from a suitable
solvent to obtain pure 5.
1-(1H-Benzo[d]imidazol-2-yl)-2-(phenylthio)ethanone (4). M.p. 126–128◦C. IR:
1
3418–2622 (m, NH), 1689.9 (s, C O) cm−1. H NMR: 5.08 (s, 2H, CH2), 7.12–8.08
(m, 9H, ArH), 10.28 (bs, 1H, NH, D2O-exchangeable). 13C NMR: 39.62, 113.7, 121.73,
128.39, 128.80, 133.69, 135.36, 138.75, 149.55, 193.26. HRMS calcd. for C15H12N2OS
[M+H]+: 269.0912, found: 269.0917.
1-(1-Methyl-1H-benzo[d]imidazol-2-yl)-2-(phenylthio)ethanone (5a). M.p. 94–
96◦C (ref15. 94–95◦C). HRMS calcd. for C16H14N2OS [M+H]+: 283.0988, found:
283.0984.
1-(1-Ethyl-1H-benzo[d]imidazol-2-yl)-2-(phenylthio)ethanone (5b). M.p. 110–
1
112◦C. IR: 1698.2 (s, C O) cm−1. H NMR: 1.21 (s, 3H, CH3), 4.24 (s, 2H, NCH2),

A NEW FACILE SULFENYLATION OF 2-ACETYLBENZIMIDAZOLES
1779
4.96 (s, 2H, SCH2), 7.15–7.86 (m, 9H, ArH). HRMS calcd. for C15H12N2OS [M+H]+:
297.1965, found: 297.1961.
1-(1-Butyl-1H-benzo[d]imidazol-2-yl)-2-(phenylthio)ethanone (5c). M.p. 153–
155◦C. IR: 1713 (s, C O) cm−1. 1H NMR: 0.84 (t, 3H, CH3), 1.2–1.4 (m, 4H, CH2CH2),
4.34 (s, 2H, SCH2), 4.9 (s, 2H, NCH2), 7.21–8.13 (m, 14H, ArH). HRMS calcd. for
C15H12N2OS [M+H]+: 325.2642, found: 325.2647.
1-(1-Benzyl-1H-benzo[d]imidazol-2-yl)-2-(phenylthio)ethanone (5d). M.p. 158–
1
160◦C. IR: 1710.8 cm−1 (s, C O). H NMR: 4.58 (s, 2H, SCH2), 5.22 (s, 2H, NCH2),
7.21–8.13 (m, 14H, ArH). HRMS calcd. for C15H12N2OS [M+H]+: 359.2952, found:
359.2957.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website, www.
tandfonline.com/gpss
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