Synthesis and crystal structures of benzimidazole-2-thione derivatives by alkylation reactions

Article abstract of DOI:10.3390/molecules21010012

Alkylated, benzylated and bromoalkylated benzimidazole-thione that intramolecularly heterocyclized to 3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazole were synthesized. The chemical structure of the synthesized product was characterized by Infra Red, ¹H-NMR, ¹³C-NMR, and Mass spectroscopy. Furthermore, the molecular structures of 8 and 9 were confirmed by X-ray single crystallography in different space groups, Pbca and P2₁/c, respectively.

Full text of DOI:10.3390/molecules21010012

Article
Synthesis and Crystal Structures of
Benzimidazole-2-thione Derivatives by
Alkylation Reactions
El Sayed H. El Ashry * , Yeldez El Kilany 1,2,†, Nariman M. Nahas 2,†, Assem Barakat 1,3,†
1
, ,†
,
Nadia Al-Qurashi 2 , Hazem A. Ghabbour
,†
4,†
and Hoong-Kun Fun
4,†
Received: 9 November 2015 ; Accepted: 1 December 2015 ; Published: 22 December 2015
Academic Editor: Derek J. McPhee
1
Chemistry Department, Faculty of Science, Alexandria University, P. O. Box 426, Alexandria 21321, Egypt;
yeldez244@hotmail.com (Y.E.K.); ambarakat@ksu.edu.sa (A.B.)
2
3
4
Chemistry Department, Faculty of Applied Science, Umm Al-Qura University, Makkah 21955, Saudi Arabia;
narinahas@hotmail.com (N.M.N.); maam10@hotmail.com (N.A.-Q.)
Department of Chemistry, College of Science, King Saud University, P. O. Box 2455, Riyadh 11451,
Saudi Arabia
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P. O. Box 2457,
Riyadh 11451, Saudi Arabia; ghabbourh@yahoo.com (H.A.G.); hfun.c@ksu.edu.sa (H.-K.F.)
Correspondence: eelashry60@hotmail.com; Tel.: +20-122-743-0924
*
†
These authors contributed equally to this work.
Abstract: Alkylated, benzylated and bromoalkylated benzimidazole-thione that intramolecularly
heterocyclized to 3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazole were synthesized. The chemical
1
13
structure of the synthesized product was characterized by Infra Red, H-NMR, C-NMR, and Mass
spectroscopy. Furthermore, the molecular structures of and were confirmed by X-ray single
8
9
crystallography in different space groups, Pbca and P2 /c, respectively.
1
Keywords: benzimidazole-thione; thiazino[3,2-a]benzimidazole; X-ray
1
. Introduction
Benzimidazole is a biologically important scaffold and it is a useful structural motif
for the development of molecules of pharmaceutical or biological interest. Appropriately
substituted benzimidazole derivatives have found diverse therapeutic applications. It has earned
an important place as a pharmacophore in chemotherapeutic agents of pharmacological activities.
The biological significance of benzimidazoles can be correlated with its close relationship with
the structure of purines that have vital role in the biological system. Moreover, 5,6-dimethyl-1-
(
α
-D-ribofuranosyl)benzimidazole is an integral part of the structure of Vitamin B12. Different
pharmacological effects, including antifungal [ ], anthelmintic [ ], anti-HIV [ ], antihistaminic [ ],
antiulcer [ ], cardiotonic [ ], antihypertensive [10 11], and neuroleptic [12], have been reported.
1
2
3
4–6
7,
8
9
,
The optimization of benzimidazole-based structures has resulted in various drugs that are currently
on the market, such as omeprazole (proton pump inhibitor), pimobendan (ionodilator), and
mebendazole (anthelmintic).
Having the above aspects in mind, our attention has been attracted to synthesizing
benzimidazolethione ring and its N-acetyl derivative to study their alkylation, aralkylation and
bromoalkylation, which subsequently underwent intramolecular cyclisation to give the fused tricyclic
ring 3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazole. The X-ray crystallographic analysis of the
alkylated derivatives was also investigated.
Molecules 2016, 21, 12; doi:10.3390/molecules21010012
www.mdpi.com/journal/molecules

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2
. Results
2
.1. Chemistry
Diversified methods for the preparation of 1H-benzo[d]imidazole-2(3H)-thione
1
have been
1
reported [13
–
15], which can exhibit tautomerism of the type thione-thiol. Its H-NMR spectrum
12.20 ppm, which disappeared upon addition of D O.
showed the presence of 2NH as a singlet at
δ
2
The protons of the phenyl ring showed two sets of signals at
δ
7.19 and 7.10 ppm. Thus, it existed
in the thione form. Its reported [16] X-ray also agreed with the thione tautomer. The minimized
energy structure agreed with that of the X-ray, which has been repeated and found to be similar to that
reported earlier.
The reaction of 1H-benzo[d]imidazole-2(3H)-thione
-(2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethanone
1
with boiling acetic anhydride gave
1
2 (Scheme 1). The product was similar to
that prepared in literature [17]. The structure was confirmed from the spectral characteristics. Its IR
´
1
1
spectrum showed the presence of broad signal at 1716 (C=O) and 3450 cm (NH). Its H-NMR
spectrum showed the presence of CH as a singlet at 1.92 ppm, the signal of NH disappeared because
δ
3
13
the sample was measured in a solvent mixture including D O. Its C-NMR spectrum showed the
2
presence of CH as a singlet at
δ 27.1 ppm, the C=O as a singlet at δ 171.1 ppm and C=S as a singlet at
3
δ 168.9 ppm.
Scheme 1. Synthesis of 1-(2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethanone 2.
Attempted alkylation of
indicating the loss of the acetyl group during the alkylation. Thus, reaction of 1-(2-thioxo-
,3-dihydro-1H-benzo[d]imidazol-1-yl)ethanone with different bases in acetone as a solvent gave
H-benzo[d]imidazole-2(3H)-thione whose rate of formation depend on the base and time. Piperidine
1 and 2 in presence of base gave the same alkylated products,
2
2
1
1
was found to be the most efficient base for the deacetylation. This was followed by potassium
hydroxide, triethylamine and then potassium carbonate. Hydrazine hydrate led to hydrolysis of the
acetyl group without further reaction. These results confirmed that our conclusion of losing the acetyl
group during the alkylation was due to the base present in the reaction medium.
Similarly, reaction of 5,6-Dimethyl-1H-benzo[d]imidazole-2(3H)-thione
gave a product that was identified as 1-(5,6-dimethyl-2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-
-yl)ethanone (Scheme 2). The chemical structure was deduced from the spectral analysis. IR spectrum
showed the presence carbonyl amide at 1685 cm . Its H-NMR spectrum showed the presence of two
CH as a singlet at 2.22 ppm and NH as a singlet at
13.14 ppm. Its 13C-NMR spectrum showed the
presence of two CH as two signals at 18.6 and 18.9 ppm. The C=S appeared as a signal at 168.4 ppm,
3 with acetic anhydride
1
4
´
1
1
δ
δ
3
δ
3
and the C=O as a signal at 171.1 ppm.
Scheme 2. 1-(5,6-Dimethyl-2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethanone 4.

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Reaction of 1-(5,6-dimethyl-2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethanone
4
in ethanol
with hydrazine hydrate gave a crystalline product that was identified as 5,6-dimethyl-1H-
benzo[d]imidazole-2(3H)-thione but 1-(2-hydrazono-5,6-dimethyl-2,3- dihydro-1H-benzo[d]imidazol-
-yl)ethanone did not form.
Reaction of 1H-benzo[d]imidazole-2(3H)-thione
bases in dry acetone gave ethyl 2-(1H-benzo[d]imidazol-2-ylthio)acetate
3
1
1
with ethyl bromoacetate, in presence of different
(Scheme 3). When using
5
triethylamine as base, the product was obtained in high yield, but low yield was obtained when
potassium carbonate was used [18]. The structure of the compound is consistent with the expected
´
1
product. The IR data showed bands at
Its H-NMR spectrum showed the presence of one NH as a singlet at
group show one singlet at
ν
3457 (NH), 1739 (C=O), 1269, and 1167 cm (C-O).
12.60 ppm, the methylene
δ
4.18 ppm connected with sulfur but not nitrogen. Its 13C-NMR spectrum
1
δ
showed the presence of one CH as a signal at
δ 13.2, two CH as a signal at δ 32.0 and 60.4 ppm, and
2
3
the presence of C=O at 167.8 ppm.
Scheme 3. Synthesis of 5 and 6.
It was found that reaction of
triethylamine in dry acetone gave diethyl 2,2 -(2-thioxo-1H-benzo[d]imidazole-1,3(2H)-diyl)diacetate
From spectral analysis, IR data showed bands at
spectrum showed the presence of two methylene groups as one singlet at
1 with two equivalents of ethylbromoacetate, in the presence of
1
6
.
´
δ
1
1
ν
: 1739 (C=O) and 1055 cm (C=S). Its H-NMR
5.16 ppm connected
with two nitrogens and indicated the absence of NH signals. This confirmed that the two methylene
groups were attached to the two nitrogen atoms but not attached to sulfur and nitrogen. Its 13C-NMR
showed the presence of two CH as signal at
δ
13.10, and two CH as signals at
δ
44.00 and 60.40 ppm.
The 13C-NMR showed the presence of C=S as signal at δ 166.20 and C=O as signal at δ 169.20 ppm
Reaction of 1-(2-mercapto-1H-benzo[d]imidazol-1-yl)ethanone with 1-bromobutane in acetone
as a solvent in the presence of triethylamine gave a product that was identified as 2-(butylthio)-1H-
3
2
2
´
δ 3450 cm
1
benzo[d]imidazole
8
(Scheme 4) [15]. Its IR spectrum showed the presence of a band at
12.47 ppm and did
1
(
NH). Its H-NMR spectrum showed the presence of NH as a singlet at
δ
not show the presence of a methyl group. Its 13C-NMR spectrum showed the presence of CH3
at 12.5, and three sets of signals belong to CH at 20.3, 29.9 and 30.4 ppm. The compound
-(2-(butylthio)-1H-benzo[d]imidazol-1-yl)ethanone cannot be formed because the acetyl group was
removed by base. The structure of was confirmed by X-ray crystallography. The butyl group was
δ
δ
2
1
7
8
found to exist in a zigzag conformation, as shown in Figure 1 which shows the Oak Ridge Thermal
Ellipsoid Plot Program (ORTEP) for Crystal Structure.

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Scheme 4. Synthesis of the 2-(butylthio)-1H-benzo[d]imidazole 8.
Figure 1. ORTEP diagram of the titled compound 8 drawn at 50% ellipsoids for non-hydrogen atom.
Reaction of 1H-benzo[d]imidazole-2(3H)-thione
1 with dibromopropane, in ethanol as solvent
and in the presence of triethylamine gave 3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazole
9 and
1
not the 1,3-bis(1H-benzo[d]imidazol-2-ylthio)propane 10
the synthesized compound showed the presence of a methylene group at
sulfur, another methylene group at 4.18 ppm connected with nitrogen and the disappearance of
signal belongs to NH. This confirmed that the alkylation occurred on the ring-sulfur that followed
intramolecular cyclisation with the nitrogen atom of the same ring to give and not with another
ring to give 10. The structure of was confirmed by the X-ray crystallography (Figure 2). It showed
[17] (Scheme 5). The H-NMR spectrum of
δ
3.25 ppm connected with
δ
9
9
that one of the CH is out of the plane of the ring system. Thus, the envelope conformation is the one
2
having the minimized energy structure.
Reaction of 1-(2-mercapto-1H-benzo[d]imidazol-1-yl)ethanone
as a solvent in the presence of triethylamine gave afford 2-(benzylthio)-1H-benzo[d]imidazole 13
Scheme 6). The structure was confirmed from the spectral analysis [19]. Its IR spectrum showed
2 with benzyl chloride in acetone
(
´
1
1
the presence at 3400 cm (NH), and did not show C=O band. The H-NMR spectrum showed the
presence of NH as a singlet at 12.56 ppm, and the CH as a singlet at
4.50 ppm. Its 13C-NMR
spectrum showed the presence of CH as a signal at 30.5, and the C=N at 149.1 ppm.
δ
δ
2
δ
δ
2
The 1-(2-(benzylthio)-1H-benzo[d]imidazol-1-yl)ethanone 12 was not obtained because the acetyl
group was removed by the base.

Molecules 2016, 21, 12
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H
N
H
N
SH BrCH CH CH CH
2
2
2
3
S
N
NEt3
N
1
8
Br
H
N
H
N
N
N
BrCH CH CH Br
2
2
2
S
S
S
NEt3
N
H
N
1
'
9
NEt3
Br
COCH3
N
COCH3
N
BrCH CH CH Br
2
2
2
S
S
NEt3
N
N
H
1
0
2
COCH3
N
N
S
S
BrCH CH CH Br
2
2
2
NCOCH3
N
NEt3
1
1
Scheme 5. Synthesis of 3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazole 9.
Figure 2. ORTEP diagram of the titled compound
9 drawn at 50% ellipsoids for non-hydrogen atoms.
Scheme 6. Synthesis of 2-(benzylthio)-1H-benzo[d]imidazole 13.

Molecules 2016, 21, 12
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2
.2. X-ray Single Crystal of 8 and 9
The structures of compounds
8
and
9
were unambiguously deduced by single-crystal X-ray
diffraction (Figures 1–4) technique. CCDC-1433060 and CCDC-1433059 contain the supplementary
crystallographic data for this paper. These data can be obtained free of charge via http://www.ccdc.
cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK;
Fax: +44-1223-336033; E-mail: deposit@ccdc.cam.ac.uk. The structures were resolved by direct methods
using the SHELXS97 program in the SHELXTL-plus package, and refined by a full-matrix least-squares
2
procedure on F using SHELXS97 [20]. Diffraction data were collected on a Bruker SMART APEXII
CCD diffractometer (Bruker AXS Advanced X-ray Solutions GmbH, Karlsruhe, Germany). The crystal
structure and refinement data of compounds
and angles are presented in Tables 2–4. ORTEP drawings of final X-ray model of compounds
8
and
9
are listed in Table 1. The selected bond distances
and
8
9
with the atomic numbering scheme are presented in Figures 1 and 2 while crystal packing presentation
of compounds 8 and 9 are shown in Figures 3 and 4 respectively.
Figure 3. Crystal packing of compound
along the c-axis.
8 showing intermolecular hydrogen bonds as dashed lines
Figure 4. Crystal packing of compound 9, dotted lines are short S¨ ¨ ¨ S interactions.

Molecules 2016, 21, 12
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Table 1. The crystal and experimental data of compounds 8 and 9.
Crystal Data
Compound 8
Compound 9
Empirical formula
Formula weight
C11H14N2S
206.30
C10H10N2S
190.27
Temperature
293 K
293 K
Wavelength
Crystal system
Space group
0.71073 Å
Orthorhombic
Pbca
0.71073 Å
Monoclinic
P2 /c
1
a
b
c
β
8.9060 (4)
9.6531 (4)
24.8720 (13)
90.00
6.0874 (3)
12.3309 (6)
12.4511 (6)
110.087 (3)
877.77 (8)
4
Volume
2138.26 (17)
8
Z
´
3
´3
Calculated density
Absorption coefficient
F(000)
1.282 Mg¨ m
1.440 Mg¨ m
0.26
0.32
400
880
Crystal size
θ range
0.38 ˆ 0.25 ˆ 0.22 mm
0.68 ˆ 0.53 ˆ 0.40 mm
˝
˝
˝
˝
2.8 to 30.5
2.4 to 30.6
Reflections Collected
3278
0.087
0.056
0.142
1.20
2691
0.066
0.035
0.091
1.06
(
Rint
)
R with I > 2σ (I)
1
R with I > 2σ (I)
2
Goodness of fit
´3
max/min ρeÅ
CCDC number
0.77 and ´0.29
0.42 and ´0.33
1433060
1433059
˝
Table 2. Selected geometric parameters (Å, ) of 8.
˝
˝
Bond Length or Angle
(Å, )
Bond Length or Angle
(Å, )
S1—C7
S1—C8
N1—C1
1.7350 (18)
1.8070 (19)
1.385 (2)
N1—C7
N2—C6
N2—C7
1.365 (2)
1.393 (2)
1.325 (2)
C7—S1—C8
C1—N1—C7
C6—N2—C7
N1—C1—C2
N1—C1—C6
N2—C6—C5
104.03 (9)
106.36 (15)
104.41 (15)
132.08 (16)
105.54 (15)
130.10 (16)
N2—C6—C1
S1—C7—N2
N1—C7—N2
S1—C7—N1
S1—C8—C9
109.87 (15)
120.67 (13)
113.81 (16)
125.46 (13)
105.48 (13)
˝
Table 3. Hydrogen-bond geometry (Å, ) of 8.
D—H¨ ¨ ¨ A
D—H
H¨ ¨ ¨ A
D¨ ¨ ¨ A
D—H¨ ¨ ¨ A
N1—H1N1¨ ¨ ¨ N2 i
0.86 (3)
2.07 (3)
2.886 (2) 159 (3)
Symmetry code: (i) – x + 1/2, y + 1/2, z.
˝
Table 4. Selected geometric parameters (Å, ) of 9.
˝
˝
Bond Length or Angle
(Å, )
Bond Length or Angle
(Å, )
S1—C1
S1—C10
N1—C1
N1—C2
C1—N1—C2
C1—N2—C7
C1—N2—C8
C7—N2—C8
S1—C1—N1
S1—C1—N2
1.7402 (11)
1.8174 (12)
1.3226 (15)
1.3925 (15)
104.02 (10)
105.90 (9)
128.83 (9)
125.04 (10)
122.49 (9)
123.29 (8)
N2—C1
N2—C7
N2—C8
1.3700 (16)
1.3850 (14)
1.4654 (15)
N1—C2—C3
N1—C2—C7
N2—C7—C2
N2—C7—C6
N2—C8—C9
S1—C10—C9
130.19 (11)
110.22 (10)
105.67 (10)
131.10 (11)
111.91 (10)
111.49 (8)

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3
. Materials and Methods
General Methods
The stated melting points are uncorrected and were performed on Gallenkamp melting
point apparatus (Toledo, OH, USA). The purities of the compounds were checked by TLC using
Merk Kieselgel 60-F254 plates (Darmstadt, Germany), and visually detected in an iodine chamber.
The structures of the synthesized compounds were elucidated by using IR spectra on FT-IR
(
Shizmadu-series, Kyoto, Japan) using KBr disc technique at spectral laboratories in King Saud
1
University. H-NMR spectra were determined with Jeol spectrometer (Tokyo, Japan) at 500 MHz and
expressed in
at Alexandria University. 13C-NMR spectra were recorded with Jeol spectrometer at 125.7 MHz.
The chemical shifts are expressed in (ppm) relative to the reference tetramethylsilane. The DMSO-d6
δ units (ppm) relative to an internal standard of tetramethylsilane in solvent DMSO-d
6
δ
was used as a solvent. Elemental analyses were performed at the micro-analytical laboratory at Cairo
University, Egypt.
1
-(2-Thioxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethanone 2
Acetic anhydride (30 mL, 0.033 mol) was added to 1H-benzo[d]imidazole-2(3H)-thione
.033 mol) and the stirred mixture was heated to 110–115 C for 30 min. The solution was cooled
1 (5 g,
˝
0
then water (150 mL) was added, and finally kept for 30 min at room temperature. Colorless crystals
were filtered off (6.21 g, 97% Yield); TLC, R = 0.773 (1:1, n-hexane:ethyl acetate). The product was
f
˝
˝
recrystallized from benzene to give white crystals. m.p. 201–202 C, (lit. [21] m.p., 195 C); IR (KBr)
´
1716 (C=O), 1368 (CH ), 2996 (CH aliphatic), and 3146 (CH aromatic), 1591 cm (C=C). H-NMR
3
CDCl /D O) δ: 1.92 (s, 3H, CH ), 7.19 (m, 2H, Ar-H), and 7.26 ppm (m, 2H, Ar-H). C-NMR
3 2 3
1
1
ν
13
(
(
(
DMSO-d6)
C=S), and 171.1 ppm (C=O).
δ: 27.1 (CH ), 108.5 (CH), 114.3 (CH), 122.3 (CH), 124.3 (CH), 129.8 (C), 130.1 (C), 168.9
3
1
-(5,6-Dimethyl-2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethanone 4
Acetic anhydride (0.002 mol, 4 mL) was added to (0.002 mol, 0356 g) of 5,6-dimethyl-1H-
benzo[d]imidazole-2(3H)-thione
3 and the mixture was heated for 0.5 h. The solution was cooled,
stirred and poured onto water, and finally kept for 30 min at room temperature. Colorless sparkling
crystals were filtered off (0.39 g, 89% yield), TLC, R = 0.966 (1:1, n-hexane:ethyl acetate). The product
f
˝
was recrystallized from ethanol, m.p. 258–259 C; IR (KBr)
ν 1685 (N-C=O), 1627 (C=N), 1506 (C=C),
´
1
1
3
192 cm (C-H aromatic). H-NMR (DMSO-d )
δ: 2.22 (s, 6H, 2CH ), 2.94 (s, 3H, CH ), 6.88 (s, 1H,
6
3
3
13
Ar-H), 7.76 (s, 1H, Ar-H), and 13.14 ppm (s, 1H, NH). C-NMR (DMSO-d6)
δ
: 18.6 (CH ), 18.9 (CH ),
3
3
2
7.1 (CH ), 109.0 (CH), 115.0 (CH), 128.2 (C), 130.7 (C), 132.9 (C), 168.4 (C=S), and 171.1 ppm (C=O).
3
Calc. for C H N OS (220.29); C, 59.97; H, 5.49; N, 12.72%, Found C, 59.66; H, 5.23; N, 12.43%
11
12
2
Ethyl 2-(1H-benzo[d]imidazol-2-ylthio)acetate 5
A mixture of 1H-benzo[d]imidazole-2(3H)-thione
1
(0.01 mol, 1.5 g), in dry acetone 25 mL and
potassium carbonate (0.01 mol, 1.62 g) was stirred and heated under reflux for 1 h. Ethyl bromoacetate
0.01 mol, 1.67 g, 1.1 mL) was added to the reaction mixture and continuing stirring and heating for
(
another 15 h until completion of the reaction. The reaction mixture was cooled then filtered off. Water
was added to the filtrate and left at room temperature for 24 h. The precipitate was filtered off and
washed with water to give product, yield 77%. It was recrystallized from ethanol to give white crystal,
˝
˝
˝
m.p. 97–98 C (Lit. [18] m.p. 60–62 C, Lit. [15] m.p. 117 C), TLC, R = 0.554 (1:1, n-hexane:ethyl
f
acetate) IR (KBr)
ν 3457 (NH), 1507 (NH) IP, 1739 (C=O), 1269, 1167 (C-O), 3150 (CH aromatic), and
´
1
1
1591 cm (C=C). H-NMR (DMSO-d )
δ
: 1.13 (t, 3H, CH ), 4.09 (q, 2H, CH ), 4.18 (s, 2H, CH ), 7.1
6
3
2
2
13
(s, 2H, Ar-H), and 7.40 (d, 2H, Ar-H), 12.60 ppm (s, 1H, NH). C-NMR (DMSO-d6)
δ: 13.2 (CH3),
3
2.0 (CH ), 60.4 (CH ), 120.7 (Ar-C), 148.3 (C=N), and 167.8 ppm (C=O).
2
2

Molecules 2016, 21, 12
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Diethyl 1,3-(2-thioxo-1H-benzo[d]imidazole-1,3(2H)-diyl)diacetate 6
A mixture of 1H-benzo[d]imidazole-2(3H)-thione
triethylamine (0.01 mol, 1.7 mL) was stirred and heated under reflux for 1 h. Ethylbromoacetate
0.02 mol, 2.2 mL) was added to the reaction mixture and continuing stirring and heating for another
9 h until completion of the reaction. The reaction mixture was cooled then filtered off. Water was
added to the filtrate and left at room temperature for 24 h till precipitate was filtered off with water.
1 (0.01 mol, 1.5 g), in dry acetone (25 mL) and
(
1
˝
The product was white powder, yield 76%. It was recrystallized from ethanol. m.p. 199–201 C,
TLC, R = 0.722 (1:1, n-hexane:ethyl acetate), IR (KBr) 3457 (NH), 1507 (NH) IP, 1739 (C=O), 1220,
ν
f
´
093 (C-O), 1055 (C=S), 3058 (CH aromatic), and 1617 cm (C=C); H-NMR (DMSO-d ) δ: 1.18 (t,
6
1
1
1
6
H, 2CH ), 4.14 (q, 4H, 2CH ), 5.16 (s, 4H, 2CH ), 7.25 (m, 2H, Ar-H), and 7.47 ppm (m, 2H, Ar-H).
C-NMR (DMSO-d6) δ: 13.1 (2CH ), 44 (2CH ), 60.4 (2CH ), 108.9 (2CH), 122.3 (2CH), 130.7 (2C), 166.2
3 2 2
3
2
2
1
3
(
2C=O), and 169.2 ppm (C=S). Calc. for C H N O S (322.38): C, 55.88; H, 5.63; N, 8.69%. Found;
15 18 2 4
C, 55.88; H, 5.63; N, 8.69%.
2
-(Butylthio)-1H-benzo[d]imidazole 8
To a stirred solution of 1-bromobutane (0.005 mol, 0.54 mL) in 10 mL of acetone was added
a solution of 1-(2-mercapto-1H-benzo[d]imidazol-1-yl)ethanone (0.005 mol, 0.96 g) in 40 mL acetone
2
containing triethylamine (0.01 mol, 1.4 mL). The reaction mixture was stirred for 28 h at room
temperature, then evaporated under vacuum, water was added to the precipitate, filtered off and the
product (0.64 g, 52% yield); TLC, R = 0.601 (1;1, n-hexane:ethyl acetate) and was crystallized from
f
˝ ˝ ˝
8, m.p. 135 C (135 C lit. [19], 134–135 C lit. [22]);
ethanol to give 2-(butylthio)-1H-benzo[d]imidazole
IR (KBr) 3400 (NH), 1671 (C=N), 1619 (NH-IP), 1588 (C=C), 3047 (CH-aromatic), 2955 (CH aliphatic),
and 1498, 1465, 1432.7 cm (CH ). H-NMR (DMSO-d )
ν
´
1
1
δ
: 0.85 (t, 3H, CH ), 1.37 (sextet, 2H, CH ),
2
6
3 2
1
.63 (quint, 2H, CH ), 3.23 (t, 2H, CH ), 7.06 (m, 2H, Ar-H), 7.50 (s, 2H, Ar-H), and 12.50 ppm (s,
2
2
IH, NH). 13C-NMR (DMSO-d6)
δ
: 12.52 (CH ), 20.3 (CH ), 29.9 (CH ), 30.4 (CH ), 120.4 (Ar), and
3
2
2
2
1
49.3 ppm (C=N). Calc. for: C H N S (206.31); C, 64.04; H, 6.84; N, 13.58%, Found C, 64.32; H, 6.34;
11 14 2
N, 13.26%.
3
,4-Dihydro-2H-[1,3]thiazino[3,2-a]benzimidazole 9
A mixture of 1H-benzo[d]imidazole-2(3H)-thione
1
(0.026 mole, 5 gm) in 60 mL ethanol and in
presence of triethylamine (0.01 mol, 1.39 mL) was refluxed for 1 h, then 1,3-dibromopropane (0.013 mol,
.6 g) was added. The reaction mixture was further heated under reflux for 5 h. Then, ethanol was
2
removed under vacuum, and water (20 mL) was added to the product, and kept for 24 h at room
temperature to give white crystals. The product (4.68 g, 83% yield), was recrystallized from ethanol,
˝
1
TLC, R = 0.382 (1:1, n-hexane:ethyl acetate), m.p. 201–202 C. H-NMR (DMSO-d ) δ: 2.29 (m, 2H,
f
6
13
CH ), 3.26 (t, 2H, CH ), 4.17 (t, 2H, CH ), 7.11 (m, 2H, Ar-H), and 7.39 ppm (m, 2H, Ar-H). C-NMR
2
2
2
(
DMSO-d6) δ: 21.9 (CH ), 24.3 (CH ), 41.7 (CH ), 107.9 (CH), 116.1 (CH), 120.02 (CH), 120.94 (CH),
2 2 2
1
34.69 (C), 134.81 (C), 141.4; 145.75 ppm (C=N). Calc. for C H N S (190.26): C, 63.13; H, 5.30;
10 10 2
N, 14.72%. Found: C, 63.42; H, 5.11; N, 14.41%.
2
-(Benzylthio)-1H-benzo[d]imidazole 13
To a stirred solution of benzyl chloride (0.005 mol, 0.57 mL) in 10 mL of acetone was added
a solution of 1-(2-mercapto-1H-benzo[d]imidazol-1-yl)ethanone (0.005 mol, 0.96 g) in 40 mL acetone
containing triethylamine (0.01 mol, 1.39 mL). The reaction mixture was stirred for 30 h at room
temperature, then evaporated under vacuum, water was added to the precipitate, filtered off and
the product (0.4 g, 74% yield), TLC, R = 0.644 (1:1, n-hexane: ethyl acetate) was recrystallized from
f
˝
˝
ethanol to give 2-(benzylthio)-1H-benzo[d]imidazole, m.p. 185–186 C (lit. [19] m.p. 184 C, lit. [23].
ν 3400 (NH), 1585 (NH-IP), 1453 (CH ), 2963 (CH aliphatic), 3070 (CH
2
aromatic), and 1610, 1515 cm (C=C). H-NMR (DMSO-d ); δ: 4.50 (s, 2H, CH ), 7.08 (m, 2H. Ar-H),
2
˝
m.p. 184–185 C); IR (KBr)
´
1
1
6

Molecules 2016, 21, 12
10 of 11
7
(
.21 (t, 1H, Ar-H), 7.30 (t, 2H, Ar-H), and 7.41–7.51 ppm (bd, 4H, Ar-H). 13C-NMR (DMSO-d6);
CH ), 120.8 (CH), 126.7 (CH), 127.9 (CH), 128.2 (CH), 137.0 (C), and 149.1 ppm (C=N).
δ: 30.5
2
4
. Conclusions
The benzimidazole ring has been considered a pharmacophore ring. It has active centers
that can be modified by some chemical reactions such as alkylation and acetylation to provide
compounds of potential biological activity. The alkylation of 1H-benzo[d]imidazole-2(3H)-thione
with dibromopropane did not give the respective alkylated derivatives 2-(3-bromopropylthio)-1H-
benzo[d]imidazole or 1,3-bis(1H-benzo[d]imidazol-2-ylthio)propane, but gave 3,4-dihydro-2H-
[
1,3]thiazino[3,2-a]benzimidazole. The formation of the last tricyclic ring indicated that the alkylation
that occurred on the ring-sulfur atom was followed by intramolecular cyclisation with the nitrogen
atom of the benzimidazole ring. This was confirmed by the X-ray crystallography. Alkylation of
benzimidazole thione and its acetyl derivative gave the corresponding S-alkylated products, and
in some cases a deacetylation process has been occurred. In the case of using ethyl bromacetate,
it gave S-mono- or S-, N-dialkylated derivatives depending on the ratio of the molar equivalents
of the reactants. Deacetylation of acetyl benzimidazolethione derivative by different bases gave
the imidazole thione, together with the starting acetyl-benzimidazolethione. However, increasing
time caused a gradual change in their ratio till complete conversion to the deacetylated derivative.
Both 1H-benzo[d]imidazole-2(3H)-thione and 5,6-dimethyl-1H-benzo[d]imidazole-2(3H)-thione can
exhibit tautomerism, and it has also been proven that the compounds in the solid state and in solution
1
exist in the thione form, as confirmed by H-NMR spectra.
Acknowledgments: The authors would like to extend their sincere appreciation to the Deanship of Scientific
Research at King Saud University for funding this Research group NO (RGP-1436-038).
Author Contributions: E.S.H.E.A. and Y.E.K. conceived and designed the experiments; N.A.-Q. performed
the experiments; E-S.H.E.-A., Y.E.K. and N.M.N. analyzed the data; A.B., H.A.G. and H.-K.F. contributed
reagents/materials/analysis tools; and E.-S.H.E.-A. wrote the paper.
Conflicts of Interest: The authors declare no conflict of interest.
References
1
.
Berg, D.; Büchel, K.H.; Plempel, M.; Zywietz, A. Action mechanisms of cell-division-arresting benzimidazoles
and of sterol biosynthesis-inhibiting imidazoles, 1,2,4-triazoles, and pyrimidines. Mycoses 1986, 29, 221–229.
[CrossRef]
2.
3.
4.
5.
Saimot, A.; Cremieux, A.; Hay, J.; Meulemans, A.; Giovanangeli, M.; Delaitre, B.; Coulaud, J. Albendazole as
a potential treatment for human hydatidosis. Lancet 1983, 322, 652–656. [CrossRef]
Chimirri, A.; Grasso, S.; Monforte, A.; Monforte, P.; Zappala, M. Anti-HIV agents. I: Synthesis and in vitro
anti-HIV evaluation of novel 1H,3H-thiazolo [3,4-a] benzimidazoles. Farmaco 1991, 46, 817–823. [PubMed]
Niemegeers, C.; Awouters, F.; Janssen, P. The pharmacological profile of a specific, safe, effective and
non-sedative anti-allergic, astemizole. Agents Actions 1986, 18, 141–144. [CrossRef] [PubMed]
Iemura, R.; Hori, M.; Ohtaka, H. Syntheses of the metabolites of 1-(2-ethoxyethyl)-2-(hexahydro-
4-methyl-1H-1,4-diazepin-1-yl)-1H-benzimidazole difumarate (KG-2413) and related compounds.
Chem. Pharm. Bull. 1989, 37, 962–966. [CrossRef] [PubMed]
6.
7.
8.
Benavides, J.; Schoemaker, H.; Dana, C.; Claustre, Y.; Delahaye, M.; Prouteau, M.; Manoury, P.; Allen, J.;
Scatton, B.; Langer, S. In vivo and in vitro interaction of the novel selective histamine H1 receptor antagonist
mizolastine with H1 receptors in the rodent. Arzneim. Forsch. 1995, 45, 551–558.
Ishihara, K.; Ichikawa, T.; Komuro, Y.; Ohara, S.; Hotta, K. Effect on gastric mucus of the proton
pump inhibitor leminoprazole and its cytoprotective action against ethanol-induced gastric injury in rats.
Arzneim. Forsch. 1994, 44, 827–830.
Graham, D.Y.; McCullough, A.; Sklar, M.; Sontag, S.J.; Roufail, W.M.; Stone, R.C.; Bishop, R.H.; Gitlin, N.;
Cagliola, A.J.; Berman, R.S. Omeprazole versus placebo in duodenal ulcer healing. Dig. Dis. Sci. 1990, 35,
6
6–72. [CrossRef] [PubMed]

Molecules 2016, 21, 12
11 of 11
9
1
1
.
Piazzesi, G.; Morano, I.; Rüegg, J. Effect of sulmazole and pimobendan on contractility of skinned fibres
from frog skeletal muscle. Arzneim. Forsch. 1987, 37, 1141–1143.
0. Wiedemann, I.; Peil, H.; Justus, H.; Adamus, S.; Brantl, V.; Lohmann, H. Pharmacokinetics of adimolol after
single and multiple dose administration in healthy volunteers. Arzneim. Forsch. 1984, 35, 964–969.
1. Kubo, K.; Kohara, Y.; Imamiya, E.; Sugiura, Y.; Inada, Y.; Furukawa, Y.; Nishikawa, K.; Naka, T. Nonpeptide
angiotensin II receptor antagonists. Synthesis and biological activity of benzimidazolecarboxylic acids.
J. Med. Chem. 1993, 36, 2182–2195. [CrossRef] [PubMed]
1
2. Janssen, P.; Niemegeers, C.; Schellekens, K.; Dresse, A.; Lenaerts, F.; Pinchard, A.; Schaper, W.; van Nueten, J.;
Verbruggen, F. Pimozide, a chemically novel, highly potent and orally long-acting neuroleptic drug. I.
The comparative pharmacology of pimozide, haloperidol, and chlorpromazine. Arzneim. Forsch. 1968, 18,
2
61–279.
1
3. El Ashry, E.S.; Aly, A.A.; Aouad, M.R.; Amer, M.R. Revisit to the reaction of o-phenylene diamine with
thiosemicarbazide to give benzimidazole-2-thione rather than benzotriazine-2-thione and its glycosylation.
Nucleosides Nucleotides Nucleic Acids 2010, 29, 698–706. [CrossRef] [PubMed]
1
1
1
1
1
4. Bakavoli, M.; Seresht, E.R.; Rahimizadeh, M. Reinvestigation of o-phenylenediamine thermal
cyclocondensation with thiosemicarbazide. Heterocycl. Commun. 2006, 12, 273–274. [CrossRef]
5. Elrayess, R.A.; Ghareb, N.; Azab, M.M.; Said, M.M. Synthesis and antimicrobial activities of some novel
benzimidazole and benzotriazole derivatives containing β-lactam moiety. Life Sci. J. 2013, 10, 1784–1793.
6. Form, G.; Raper, E.; Downie, T. The crystal and molecular structure of 2-mercaptobenzimidazole. Acta Cryst.
1
976, B32, 345–348. [CrossRef]
7. Lubenets, V.; Stadnitskaya, N.; Novikov, V. Synthesis of thiosulfonates belonging to quinoline derivatives.
Russ. J. Electrochem. 2000, 36, 851–853. [CrossRef]
8. Shingalapur, R.V.; Hosamani, K.M.; Keri, R.S.; Hugar, M.H. Derivatives of benzimidazole pharmacophore:
Synthesis, anticonvulsant, antidiabetic and DNA cleavage studies. Eur. J. Med. Chem. 2010, 45, 1753–1759.
[CrossRef] [PubMed]
1
2
2
9. Narkhede, H.; More, U.; Dalal, D.; Mahulikar, P. Solid supported synthesis of 2-mercaptobenzimidazole
derivatives using microwaves. J. Sci. Ind. Res. 2008, 67, 374–376.
0. Sheldrick, G.M. Shelxs 97, Program for the Solution of Crystal Structure; University of Göttingen: Göttingen,
Germany, 1997.
1. Parras, F.; Guerrero, M.D.C.; Bouza, E.; Blázquez, M.J.; Moreno, S.; Menarguez, M.C.; Cercenado, E.
Comparative study of mupirocin and oral co-trimoxazole plus topical fusidic acid in eradication of nasal
carriage of methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 1995, 39, 175–179.
[CrossRef] [PubMed]
2
2
2. Saxena, D.; Khajuria, R.; Suri, O. Synthesis and spectral studies of 2-mercaptobenzimidazole derivatives 1.
J. Heterocycl. Chem. 1982, 19, 681–683. [CrossRef]
3. Suri, O.; Khajuria, R.; Saxena, D.; Rawat, N.; Atal, C. Synthesis and spectral studies of
-mercaptobenzimidazole derivatives 2. J. Heterocycl. Chem. 1983, 20, 813–814. [CrossRef]
2
Sample Availability: Samples of the compounds 2–13 are available from the authors.
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2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons by Attribution
CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
(