Indian Journal of Chemistry

Vol. 44B, June 2005, pp. 1239-1242

Synthesis of 1-(n-hexyl-5-one)-2-chlorobenzimidazole
P K Dubey*, A Naidu, V Anandam & G Hemasunder
Dept of Chemistry, College of Engg, J N T University, Kukatpally, Hyderabad, 500 072, India
E-mail: pkdubeyjntu@tatanova.com
Received 29 December 2003; accepted (revised) 27 December 2004

o-Phenylenediamine on condensation with urea gives the known benzimidazolin-2-one, which on reaction with
phosphoryl chloride in the presence of catalytic amount of phenol yields the already reported 2-chlorobenzimidazole. The
latter on alkylation with 6-chloro-2-hexanone in the presence of K2CO3 in DMF medium, gives the title compound.

IPC: Int.Cl.7 C 07 D 233/54

Pentoxyfyllin is a well-known vasodilator1 used in the
treatment of several cardiac disorders. Its molecule is
made up of two crucial structural entities, namely
chlorohexanone and theobromine (3,7-dimethylxan-
thine), both of which are believed to be responsible for
its biological activity. A structural variant of this drug
may be conceived of as possessing a chlorohexanone
moiety and a heterocyclic ring (in place of theobromine).
Thus, a potentially useful molecule and a substitute of
pentoxyfyllin may be prepared by hooking a chloro-
hexanone on to a new/other heterocyclic ring. Several
derivatives of benzimidazoles are also known2 to posses
diverse types of biological activities. In continuation of
our earlier work3,4 on benzimidazoles, it was considered
worthwhile to prepare new benzimidazoles derived from
chlorohexanones and benzimidazoles substituted in 1, 2,
3 positions. The results of these studies are presented in
this paper.
o-Phenylenediamine 1 was heated with urea in
DMF at 135-40oC for 12 hr, followed by simple
processing to obtain the known benzimidazolin-2-one
2 in 94% yield. The reported procedure5 for the
preparation of 2 involves dry fusion of 1 with urea at
150oC followed by simple processing to obtain the
product 2 in 88% yield. The later method of
condensation gave a lower yield of the product and
the product was found to be inferior in quality in m.p.
and TLC. In the present work, compound 2 was
prepared by using first method only. The product 2 is
known in literature. However, in the present work, 2
was characterized by spectral methods also.
Thus, its IR showed peaks at ~3000 (very broad,
strongly bonded-NH-stretching vibration) and at 1747
cm-1 (very strong, sharp,-C=O stretching vibration) as
diagnostic absorptions. Its 1H NMR spectrum in DMSO-
d6 showed peaks at δ 6.92 (s, 4H, aryl protons) and at
10.60 (s, 2H, -NH-protons). Its mass spectrum showed
the molecular ion peak at m/z 135 in Q+1 mode.
N-Alkylation of 2 with 6-chloro-2-hexanone 3 in 1:1
molar ratio in the presence of K2CO3 in DMF at 135-
40oC for 9 hr followed by simple processing and column
chromatographic separation gave mixture of two
products as seen in TLC. The two products were 1:1 (4)
and 1:2 (5) derivatives, respectively. Their structures
were determined by spectral methods as follows: The
compound 4 showed in its IR spectrum peaks at 3200 (-
NH-stretching) and at 1710 cm-1 (-CO-stretching). Its 1H
NMR showed peaks at δ 1.55-1.90 (m, 4H (-CH2-CH2-
CH2-CHO), 2.10 (sharp, s, 3H, -CH3), 2.30 (t, 3H,-N-
CH2), 6.90-7.20 (m, 4H, aryl protons). Its mass spectrum
showed the molecular ion peak at m/z 233 in Q+1 mode.
Similarly, 5 was also characterized by its spectral data.
Thus, its IR showed the peaks at 1715 and 1695 cm-1
(strong, sharp doublet due to -NHCO, and -C=O
stretching). 1H NMR spectra in CDCl3 showed peaks at
δ 1.50-1.85 (m, 8H, (CH2-CH2-CH2-CO) × 2), 2.10
(sharp s, 6H, CH3 × 2), 2.50 (t, 4H, -CH2CO × 2), 3.85
(t, 4H, -NCH2 × 2), 6.85-7.15 (m, 4H, aryl protons). Its
mass spectrum showed the molecular ion peak at m/z
331 when recorded in Q+1 mode.
When the reaction was carried out by using 1:2
molar ratio of 2 and 3 under similar conditions, 5 was
obtained exclusively as the product in the reaction.
Attempted chlorination of compound 4 with
phosphoryl chloride (POCl3) in the presence of
catalytic amount of phenol at 110oC for 12 hr, did not
1240
give the expected compound 7. But it gave only tarry
material. In view of the above, an alternative
approach, involving conversion of benzimidazolin-2-
one 2 to the corresponding chloro compound with
POCl3 followed by its alkylation to obtain the title
compound was adopted. Thus, compound 2 was
reacted with phosphoryl chloride in the presence of
catalytic amount of phenol at 110oC for 12 hr, to
obtain 2-chlorobenzimidazole 6 in 90% yield. The
compound 6 is also known in literature6, however it
was characterized by spectral data. IR showed peaks
at 3061 (very broad, strong-NH-bonded stretching)
and other absorptions at 1525, 1436,1270,1232 cm-
1
etc as series of sharp absorptions.1H NMR spectrum
in CDCl3 showed peaks at δ 6.50-7.90 (m,4H, aryl
protons),and at 12.25 (s,1H,-NH-).
N-Alkylation of compound 6 with 6-chloro-2-
hexanone 3 in 1:1 molar ratio in the presence of an
acid scavenger like K2CO3 in DMF medium at 140-
45oC for 14 hr followed by simple processing gave
the title compound 7 as crude syrupy residue. This
residue was further purified by column chromato-
graphy (ethyl acetate:n-hexane 1:3) to obtain white
colourless crystals of 7 in 54% yield. The compound
7 was characterized by spectral data. Thus, its IR
spectrum showed the peak at 1715 (very strong, -C=O
stretching vibration) and other peaks at 1470, 1378,
1280 cm-1 etc as series of sharp absorptions. Its
1
POCl3
H
N
Cl
N
6 O
3 O
O 4
N CH3
Cl
N
7 POCl3
INDIAN J. CHEM., SEC B, JUNE 2005
1
H NMR spectrum in CDCl3 showed peaks at δ 1.50-
1.90 (m, 4H, -CH2-CH2, -CH2-CO), 2.15 (s, 3H, -CO-
CH3), 2.30-2.60 (t, 2H, -CH3-CO), 4.10-4.30 (t, 2H,
-N-CH2), 7.10-7.80 (m, 4H, aryl protons). Its mass
spectrum showed the molecular ion peak at m/z 250
(22.5%) and 252 (2%) corresponding to the twin
peaks of 35Cl and 37Cl, respectively.
The reagent which is used as alkylating agent
namely, 6-chloro-2-hexanone 3 was prepared by
simple method as follows: Condensation of the active
methylene compound, methyl acetoacetate 8, with 3-
chloro-1-bromopropane in the presence of K2CO3 gave
a cyclic pyran ester 9 in 90% yield. The reaction of 9
with conc HCl at 50oC followed by treatment with 5%
aq NaHCO3 solution gave the compound 3 in yield of
93%. The compound 3, although known in literature
was further characterized in the present work. Thus, its
IR spectrum showed peaks at 1720 cm-1 as the only
diagnostic absorption. Its 1H NMR spectrum in CDCl3
showed peaks at δ 1.60-1.80 (m, 4H, -CH2-CH2-CH2-
CO), 2.10 (sharp s, 3H, -CH3), 2.40-2.0 (t, 2H, -CH2-
10), 3.45-3.60 (t, 2H, 4-CH2). Its mass spectrum
showed the molecular ion peak at m/z 137 and 135
when recorded in Q+1 mode corresponding to
chlorines of masses 37 and 35 respectively.
All the above reactions are briefly summarized in
Schemes I and II. Characterization data for some of
the compounds have been given in Table I.
NH2 H2N
O
NH2 H2N
DMF/K2CO3
135 -400C
H
N
O
N
H 3
2 CH3-CO-(CH2)3-CH2-Cl
(1:1) Moles of 2 & 3 (1:2) Moles of 2 & 3
O
5
N CH3 CH3
N
O
N N
H CH3
5 O
x
Scheme I
 DUBEY et al.: SYNTHESIS OF 1-(N-HEXYL-5-ONE)-2-CHLOROBENZIMIDAZOLE 1241

H3C C CH COOCH3
CH3-CO-CH2-COOCH3 Br IPA/K2CO3
O CH2
Cl
800C / 10 hr
8 Br CH2
C
H2

COOCH3
H3COOC
H3C C C COOCH3 H3C
-HBr
OH CH2
Br CH2 O
C H3C O
H2
9

HCl (g) / 500C

H3C-CO-(CH2)3-CH2-Cl
Conc.HCl / 4 hr 3
Scheme II
Table I ⎯ Characterization data of compounds 2-7

Compd m.p. Yield Mol. formula Mol. Found (%) (Calcd)

°C (%) Wt C H N O
2 312-14 94 C7H6N2O 134 62.14 4.20 21.0 11.83
(62.68 4.47 20.89 11.94)
4 46-48 46 C13H17N2O2 233 66.42 7.10 11.93 13.03
(66.95 7.29 12.01 13.73)
5 58-60 65 C19H26N2O3 330 68.98 7.78 8.34 14.33
(69.09 7.87 8.48 14.54)
6 181-83 97 C7H5N2Cl 152 55.03 3.08 18.13 ⎯
(55.26 3.28 18.42 ⎯)
7 54-56 54 C13H16N2OCl 251 61.05 6.17 11.09 6.14
(62.15 6.37 11.15 6.37)
Experimental Section with aq HCl (35%). The separated product was
filtered, washed and dried to obtain pure 2, yield 5.8 g
All melting points are uncorrected and were
(94%).
obtained by using open capillary tubes in sulphuric
Preparation of (5-oxo-hexyl)-1,3-dihydrobenzimi-
acid-bath. TLC checking was done on glass plates
dazol-2-one 4 and 1,3-bis-(5-oxo-hexyl)-1,3-dihydro-
coated with silica gel G and spotting was done using
benzimidazolin-2-one 5. To a solution of 2 (1.0 g,
Iodine/UV lamp. IR spectra were recorded using
0.007 mole) in DMF was added 3 (1.0 g, 0.007 mole)
Perkin-Elmer model 446 instrument in KBr phase. 1H
and K2CO3 (1.53 g, 0.011 mole). The reaction mixture
NMR were recorded on a Brukner instrument
was heated in an oil-bath at 135- 40oC for 9 hr. At end of
operating at 250 MHz. Mass spectra have been
this period, DMF was removed in vacuo, the residue
recorded on a CEC-21-110 under electron impact or
was cooled and diluted with water. The reaction mixture
under chemical ionization conditions.
was then extracted with ethyl acetate and evaporated to
Preparation of 1,3-dihydro-benzimidazol-2-one obtain a crude residue. Purification of the latter by
2. To a solution of o-phenylenediamine 1 (5 g, 0.046 column chromatography on silica gel (n-hexane:ethyl
mole) in DMF was added urea (5.52 g, 0.092 mole) acetate 3:1) gave two compounds as colourless crystals
and the mixture heated to 135-40oC for 12 hr. When which on recrystallization with (ether : hexane) gave 4
the reaction was complete, DMF was removed (1:1) and 5 (1:2) as pure products in the yields 0.8 g
in vacuo, the separated solid was washed with water, (46%) and 0.69 g (30%), respectively.
and then dissolved in 10% NaOH solution. The Preparation of 1,3-bis-(5-oxo-hexyl)-1,3-dihydro-
aqueous alkaline solution was filtered and neutralised benzimidazolin-2-one 5. To a solution of 2 (0.5 g,
1242 INDIAN J. CHEM., SEC B, JUNE 2005
0.0037 mole) in DMF was added 3 (1 g, 0.007 mole)
and K2CO3 (1.02 g, 0.007 mole). The reaction mixture
was heated in oil-bath at 135-40oC for 9 hr. At the end
of this period, DMF was removed in vacuo, the
mixture was diluted with water and extracted with
ethyl acetate, dried over Na2SO4 and concentrated to
yield a crude residue. The latter was purified by
column chromatography on silica gel (n-hexane:ethyl
acetate 2:1) to obtain a colourless syrup, which was
recrystallized (ether:n-hexane 1:3) to obtain pure 5,
yield 0.8 g (65%).
Preparation of 6-(2-chloro-2-benzimidazol-1-yl)-
hexane-2-one 7. A mixture of 4 (10 g, 0.043 mole),
phosphoryl chloride (22.88 g, 0.149 mole) and
catalytic amount of phenol was added and heated to
100-10oC for 12 hr. After completion of the reaction,
the mixture was treated with xylene and then distilled
under reduced pressure (to remove excess POCl3).
The hot reaction mixture was filtered. To the filterate
was added crushed ice, neutralized with 40% NaOH
solution to pH 10.0 leading to separation of black
tarry material.
Preparation of 2-chloro-1H-benzimidazole 6: A
mixture of 2 (10.0 g, 0.07 mole), POCl3 (22.88 g, 0.14
mole) and catalytic amount of phenol was heated to
103-07oC for 12 hr. After completion of reaction the
mixture was treated with xylene to remove excess
POCl3. Then the reaction mixture was cooled in ice,
and neutralized with 40% NaOH to pH~10.0, the
separated crude 4 was recrystallized to obtain 6, yield
11.0 g (97%).
Preparation of 2-methyl-5,6-dihydro-4H-pyran-
3-carboxylic acid methyl ester 9. To a solution of
methyl acetoacetate 8 (10.0 g, 0.086 mole) in iso-
propyl alcohol (100 mL) was added chlorobromo-
propane (13.5 g, 0.08 mole) and K2CO3 (14.24 g,
0.103 mole) and the reaction mixture heated on a
steam-bath at 80oC for 9 hr. The reaction was
monitored by TLC. When the reaction was complete,
isopropyl alcohol was removed in vacuo, the residue
was cooled to rt, diluted with water and extracted with
methylene chloride (2×50=100mL). The methylene
chloride extract was washed with water (150 mL)
dried over Na2SO4 filtered, and concentrated to obtain
a liquid which on fractional distillation gave 9, yield
12.1 g (90%).
Preparation of 6-chloro-2-hexanone 3. A solution
of pyran ester 9 (5 g, 0.03 mole) in concentrated HCl
(20 mL) at 60oC was simultaneously saturated with
HCl gas. The reaction mixture was heated to 50oC for
3 hr. When the reaction was complete, the mixture
was cooled to rt, diluted with water, extracted with
methylene chloride (3×30=90 mL) and the combined
layer distilled to obtain a residue. Purification of the
crude residue by fractional distillation gave a pure
compound 3, yield 4 g (93%).
Preparation of 2-chloro-1H-benzimidazole 6: A
mixture of 2 (10.0 g, 0.07 mole), POCl3 (22.88 g, 0.14
mole) and catalytic amount of phenol was heated for
103-07oC for 12 hr. After completion of the reaction,
the mixture was cooled in ice, and neutralized with
40% NaOH to pH ~10.0, the crude material was
recrystallized to obtain pure product 6, yield 11.0 g
(97%).
Preparation of 6-(2-chloro-2-benzimidazol-1-yl)-
hexan-2-one 7. To a solution of 6 (10 g, 0.065 mole)
in DMF (10 mL) was added 3 (0.92 g, 0.0068 mole)
and K2CO3 (1.81 g, 0.0131 mole), and the mixture
heated in oil-bath at 140-45oC. After completion of
the reaction, DMF was removed in vacuo, the residue
was cooled to rt and diluted with water. The mixture
was then extracted with ethyl acetate, the organic
extract dried over Na2SO4 and then evaporated to
obtain a crude residue. The latter on separation by
column chromatography (n-hexane-ethyl acetate 2:1)
gave pure compound 7, yield 9 g (54%).
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