Synthesis and spatial structure of 1-(cytisin-1-ylmethyl)benzimidazole-2- thione

Article abstract of DOI:10.1134/S1070363213060169

New derivatives of cytisine and anabasine alkaloids containing benzothiazole and benzimidazole fragments were discussed. Physicochemical characteristics of the new compounds were determined. The structure of 1-(cytisin-1-yl-methyl)benzimidazole-2-thione w

Full text of DOI:10.1134/S1070363213060169

ISSN 1070-3632, Russian Journal of General Chemistry, 2013, Vol. 83, No. 6, pp. 1098–1102. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © A.M. Gazaliev, M.K. Ibraev, M.B. Isabaeva, Zh.A. Ibataev, 2013, published in Zhurnal Obshchei Khimii, 2013, Vol. 83, No. 6,
pp. 967–971.
Synthesis and Spatial Structure
of 1-(Cytisin-1-ylmethyl)benzimidazole-2-thione
A. M. Gazaliev, M. K. Ibraev, M. B. Isabaeva, and Zh. A. Ibataev
Karaganda State Technical University, ul. Mira 56, Karaganda, 100000 Kazakhstan
e-mail: mkibr@mail.ru
Received September 27, 2012
Abstract—New derivatives of cytisine and anabasine alkaloids containing benzothiazole and benzimidazole
fragments were discussed. Physicochemical characteristics of the new compounds were determined. The
structure of 1-(cytisin-1-yl-methyl)benzimidazole-2-thione was studied by X-ray diffraction analysis.
DOI: 10.1134/S1070363213060169
Benzimidazole derivatives attract attention by their
high biological activity, they are used to produce a
variety of drugs [1–3] and as tuberculocidal, anti-
microbial, antineoplastic, anti-inflammatory, antiulcer
agent [4]. Depending on the substitution in the scaffold
they can be assigned to different classes of drugs. The
presence of small substituents in the positions 2 and 5
of the benzimidazole moiety is typical for anthelmintic
drugs. On the contrary, benzimidazole derivatives with
bulky substituents in the 2 position are used for
treating gastric ulcer and duodenal ulcer. The presence
Synthesis of new Mannich compounds based on 2-
mercaptobenzimidasole (I) and 2-mercaptobenzo-
thiazole (II), the study of their structure, physico-
chemical properties, reactivity, and mechanisms of
formation are the object of this work.
Cytisine, anabasine, and morpholine were used as
the amines. Anabasine and cytisine are alkaloids,
natural nitrogen-containing organic compounds of the
basic nature with strong physiological and
pharmacological action. Anabasine is used as
insecticide, as well as for the treatment of head lice
and ringworm in animals [6]. Cytisine acts as an
exciter of the respiratory and cardiac function, as well
as exhibits insecticidal, anti-smoking and other
activities [4]. Morpholine derivatives also are part of
the drugs and are used as narcotic analgesics, i.e.,
belong to the neurotrophic substances of central action,
the main feature of which is the selective control of
pain sensitivity without loss of consciousness [1]. In
this regard, the use of biogenic amines in modifying
benzimidazole and benzothiazole would make possible
not only to expand the spectrum of biological activity,
but also the new synthetic possibility of compounds
obtained.
1
2
of bulky substituents at the atoms N and C is
characteristic of H1-antihistamines [5]. Benzimidazole
system is also present in a number of natural
substances [4].
This defines the high importance of further
development of research in the field of chemistry of
benzimidazole and its derivatives. It is promising to
look for new pharmacologically active compounds,
particularly promising is the polyfunctional targeted
synthesis of benzimidazole derivatives which exhibit
selective activity. An important area in benzimidazole
chemistry is chemical modification with various
functions, leading to a variety of compounds with a
broad spectrum of biological activities.
It is known that 2-mercaptobenzimidazole I and 2-
mercaptobenzothiazole II can react both in the thiol
and thione forms.
It is known that the compound having at least one
reactive hydrogen atom react with formaldehyde and
amines to form a Mannich base. Recently, the range of
compounds entering into the Mannich reaction is
greatly expanded.
N
NH
SH
S
NH(S)
NH(S)
1
098

SYNTHESIS AND SPATIAL STRUCTURE OF 1-(CYTISIN-1-YLMETHYL)...
1099
According to the UV spectral data, in solutions the
compounds are mainly in the thione form irrespective
of the nature of the solvent; and only the alkalis shift
the equilibrium toward the thiol form. The reaction
giving the Mannich bases can be represented as
follows.
NH
O
H
N
CH2
S
N
S + HC
+ H
N
_
H O
2
NH(S)
NH(S)
I (II)
III (II)
N
N
(c).
O
N
=
(а),
(b),
N
N
N
O
The reaction of the starting compound with
formaldehyde and amine was performed in an alcohol
solution at cooling. The synthesized Mannich bases
containing cytisine or anabasine fragment are
crystalline or oily substances, respectively. These
compounds are insoluble in water and readily soluble
in most organic solvents. They are unstable at high
temperatures and easily decompose by the action of
aqueous alkaline and acid solutions: a 10% hydro-
chloric acid even at room temperature decomposes
them into the original substances. The decomposition
occurs significantly faster and more completely when
heated. Diluted aqueous solutions of sodium hydroxide
and ammonia act similarly.
The structures of compounds III, IV was confirmed
by the IR and H NMR spectroscopy and X-ray
1
diffraction data. Thus, continuing the study of
stereochemistry of cytisine derivatives we carried out
the XRD analysis of 1-(cytisin-1-ylmethyl)benzimidazol-
2-thione IIIb. General view of its molecule is shown in
the figure.
The bond lengths and angles in cytisine scaffold are
close to the standard values [7]. The exception is the
12
bond angles at the atom N : here the plane trigonal
coordination is observed (sum of bond angles is 341°).
In the previously investigated N-methylcytisine [8] and
12
N-cyanomethylcytisine [9] the coordination of the N
atom is pyramidal (sum of the bond angles equals
3
35.7° and 334.0°, respectively). The difference in the
The resulting compounds III, IV may be of interest
for a comprehensive study of their biological activity.
Physicochemical constants, elemental analysis data of
the Mannich bases of 2-mercaptobenzimidazole and 2-
mercaptobenzothiazole are shown in Table 1.
coordination of the nitrogen atom in the above-
mentioned molecules is due to the mesomeric effect.
The dihydropyridine ring is planar to within 0.005 Å.
1
The carbonyl atom O is almost in this plane (deviation
Table 1. Physicochemical constants, elemental analysis of compounds III, IV
Found, %
Calculated, %
Comp.
no.
Yield, %
mp, °С
R
f
Formula
C
H
N
C
H
N
а
Iа
77.71
84.79
86.78
68.66
89.94
68.29
155–156
296–297
211–212
57–58
0.68
66.67
6.18
17.30
C
C
C
C
C
C
18
19
12
18
19
12
H
20
H
20
H
15
H
19
H
19
H
14
N
4
N
4
N
3
N
3
N
3
N
2
S
66.63
6.21
17.27
b
b
а
Ib
0.88
0.93
64.67
57.68
63.34
61.79
54.02
5.78
6.07
5.65
5.22
5.26
15.93
16.87
12.36
11.38
10.58
OS
OS
64.75
57.81
63.31
61.76
54.11
5.72
6.06
5.61
5.18
5.30
15.90
16.85
12.30
11.37
10.52
Ic
IIа
IIb
IIc
0.85
0.75
0.80
S
2
а
а
140–141
144–145
OS
2
2
OS
a
b
Acetone–benzene, 1:1. Isopropanol–ammonia–water, 7:2:1.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 6 2013

1
100
GAZALIEV et al.
EXPERIMENTAL
The melting points were determined on a Boetius
instrument. The reaction progress and purity of the
products were monitored by thin layer chromatography
using Silufol UV-254 plates.
XRD analysis. The unit cell parameters and the
intensities of the 1827 independent reflections were
measured on a Bruker P4 automatic diffractometer at
room temperature (MoK -irradiation, graphite mono-
α
chromator, θ/2θ-scanning, 2θ ≤ 52°). The transparent
crystals are monoclinic (0.8×0.4×0.15), C H N OS;
1
9
20
4
cell parameters: a 8.2961(7), b 12.4753(9), c 8.9381(7) Å,
3
–3
β 106.362(7)°, V 887.60(12) Å , d 1.319 g cm , Z 2,
calc
space group P21. The structure was solved by the
direct method and refined by full-matrix least-square
method in anisotropic approximation for non-hydrogen
atoms. The positions of H atoms were geometrically
calculated and refined in the rider model. In the
calculations 1735 reflections with I > 2σ(I) were used.
The final divergence factors are R 0.0314 and wR2
0
2
.0846. The structure was solved by the program SIR-
002 [10] and refined by the program SHELXL-97
Crystal structure of 1-(cytisine-1-ylmethyl)benzimidazol-2-
thione IIIb molecule.
[11]. The geometrical parameters of compound Ib
were deposited in the Cambridge Structural Database
(
CCDC 773770).
-(Anabasin-1-ylmethyl)benzimidazole-2-thione
IIIa). To a solution of 0.5 g (0.003 mol) of 2-mer-
1
(
is 0.06 Å). The tetrahydropyridine ring is in a semi-
captobenzimidazole I in 50 ml of alcohol was added
with stirring 0.25 g (0.003 mol) of formalin solution.
Then to the mixture was added 0.52 ml (0.003 mol) of
anabasine dissolved in alcohol. After evaporation of
the solvent, the thick orange oil was triturated with
diethyl ether. The product is a white amorphous
substance, mp 155–156°C (ethyl alcohol, water). Yield
8
8
chair conformation (ΔС 10.5°). The bridging atom C
s
deviates from the mean plane of the remaining ring
atoms by 0.76 Å. The piperidine ring adopts an almost
9
s
perfect chair conformation (ΔС 0.73°).
Atoms of benzimidazole fragment are coplanar
within ±0.006 Å, the sulfur atom lies in the plane of
the remaining atoms. We believe that the flattening of
the substituent is due to the coupling of the electron
clouds of free electron pair of the nitrogen atom and of
the double bond of the sulfur atom in imidazolethione.
The bulky substituent is equatorially oriented relative
77.71%, R 0.68.
f
1
-(Cytisin-1-ylmethyl)benzimidazole-2-thione
(IIIb) was synthesized similarly from 0.5 g (0.003 mol)
of 2-mercaptobenzimidazole I, 0.25 g (0.003 mol) of
formalin, and 0.63 g (0.003 mol) of cytisine. Upon
standing the reaction mixture for 4 h the precipitate
forms. Yield 1 g (84.8%), colorless crystals, mp 296–
7
13 12 14
to the piperidine ring (torsion angle С С N C is
165.4°), while the average plane through the
–
benzimidazole-2-thione is virtually parallel to the
mean plane of cytisine (interplanar distance is 4.26 Å).
The molecules in the crystal are bound by a strong
2
97°C (alcohol), R 0.88.
f
1-(Morpholin-4-ylmethyl)benzimidazole-2-thione
3
intermolecular hydrogen bond N –H(x, y, z)···
(IIIc) was synthesized similarly from 0.5 g (0.003 mol)
of 2-mercaptobenzimidazole I, 0.25 g (0.0033 mol) of
formalin, and 0.29 g (0.0033 mol) of morpholine.
Upon standing the reaction mixture for 4 h the pre-
cipitate forms, which was recrystallized from alcohol.
1
3
1
3
1
O (1 – x, 0.5 + y, 2 – z) (N –H···O 1.87 Å, <N –HO =
62.79°), which stabilizes the molecule and builds
1
endless spiral along the axis b. Main characteristics of
the crystal lattice parameters are shown in Tables 2, 3.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 6 2013

SYNTHESIS AND SPATIAL STRUCTURE OF 1-(CYTISIN-1-YLMETHYL)...
Table 2. Bond lengths (d, Å) and bond angles (ω, deg) in the molecule of IIIb
1101
Bond, angle
d, ω
1.673(3)
1.368(3)
1.398(3)
1.482(3)
1.363(3)
1.395(3)
1.463(3)
1.355(3)
1.379(4)
1.442(3)
1.457(3)
1.459(3)
1.248(4)
1.410(4)
1.339(5)
1.404(5)
1.360(4)
1.512(3)
Bond
ω
Bond, angle
d, ω
Bond
ω
1
15
14 12 13
7
8
8
9
11
9
S –C
C N C
113.64(18)
115.47(18)
112.10(18)
118.2(3)
125.6(3)
116.2(3)
121.6(3)
120.7(3)
119.2(3)
120.1(2)
120.9(2)
118.8(2)
111.8(2)
107.42(18)
109.3(2)
106.83(18)
108.6(2)
112.69(19)
C –C
1.525(4)
1.531(3)
1.521(4)
1.515(4)
1.524(3)
1.385(3)
1.395(4)
1.371(6)
1.392(5)
1.378(4)
1.387(4)
122.2(2)
123.0(2)
114.8(2)
110.16(18)
126.07(19)
123.7(2)
110.3(2)
C C C
111.0(2)
114.9(2)
109.37(18)
108.57(18)
109.05(15)
106.4(2)
126.68(19)
126.95(17)
107.2(2)
131.9(3)
120.9(3)
117.0(3)
121.7(3)
121.9(3)
116.3(3)
122.2(2)
105.9(2)
131.8(2)
1
6
14 12 11
7
13
1
10
N –C
C N C
C –C
N C C
1
2
13 12 11
8
9
12 11
9
7
2
N –C
C N C
C –C
N C C
1
10
15
21
14
15
16
1
2
1
9
10
12 13
N –C
O C N
C –C
N C C
2
1
2
3
9
11
12 14
N –C
O C C
C –C
N C N
2
1
2
3
16
21
17
18
19
20
21
2
3
15
2
N –C
N C C
C –C
N C N
2
4
3
2
5
4
1
16
3
15 1
N –C
C C C
C –C
N C S
3
3
4
17
2
15 1
N –C
C C C
C –C
N C S
3
6
5
18
3
16 21
N –C
C C C
C –C
N C C
1
2
14
13
11
5
6
19
3
16 17
N –C
C C N
C –C
N C C
1
2
5
6
7
20
21 16 17
N –C
C C C
C –C
C C C
1
2
1
6
7
6
1
18 17 16
N –C
N C C
C N C
C C C
1
2
6
7
8
6
1
10
17 18 19
O –C
C C C
C N C
C C C
2
3
4
5
6
7
6
7
13
13
7
2
1
10
20 19 18
C –C
C C C
C N C
C C C
3
8
7
15
2
21
14
14
16
19 20 21
C –C
C C C
C N C
C C C
4
9
8
15
2
16 21 20
C –C
C C C
C N C
C C C
5
10
9
8
21
2
16 21
2
C –C
C C C
C N C
C C N
6
10
9
11
15
3
20 21
2
C –C
C C C
C N C
C C N
Table 3. Torsion angles in the molecule of IIIb
Angle
τ, deg
177.2(2)
–2.2(3)
Angle
τ, deg
83.4(3)
Angle
τ, deg
–61.8(2)
79.0(2)
Angle
τ, deg
–1.3(6)
6
1
2
1
5
6
7
13
8
7
13 12
17 18 19 20
C N C O
C C C C
C C C N
C C C C
1
0
1
2
1
1
6
7
13
13 12 14
2
2
18 19 20 21
C N C O
N C C C
–91.3(3)
–58.6(3)
60.2(2)
C N C N
C C C C
0.5(5)
6
1
2
3
6
7
8
9
11 12 14
3
16 21 20
C N C C
–3.1(3)
C C C C
C N C N
–149.40(19)
–111.5(2)
66.7(3)
N C C C
178.3(2)
–1.1(4)
1
0
1
2
3
13
7
8
9
15
2
14 12
17 16 21 20
C N C C
177.6(2)
–177.5(3)
2.8(5)
C C C C
C N C N
C C C C
1
2
3
4
7
8
9
10
11
9
21
2
14 12
3
16 21
2
O C C C
C C C C
65.8(2)
C N C N
N C C N
0.4(3)
1
2
3
4
7
8
9
16
3
15
2
17 16 21
2
N C C C
C C C C
–58.6(2)
12.9(3)
C N C N
0.1(3)
C C C N
–179.0(2)
0.7(4)
2
3
4
5
6
1
6
1
10
16
3
15
1
19 20 21 16
C C C C
–0.3(6)
C N C C
C N C S
–178.64(17)
0.1(2)
C C C C
3
4
5
2
1
10
9
21
2
15
3
3
19 20 21
2
C C C C
–2.0(5)
C N C C
–167.8(2)
–43.4(3)
80.0(3)
C N C N
C C C N
178.0(3)
–0.4(2)
4
5
6
8
9
10
1
14
2
15
15
2
21 16
C C C N
1.8(4)
C C C N
C N C N
178.48(19)
178.91(16)
–2.8(3)
C N C C
4
5
6
7
11
9
10
1
21
2
15
1
14
2
21 16
C C C C
–172.9(3)
0.9(3)
C C C N
C N C S
C N C C
–178.74(18)
–178.0(2)
3.6(4)
2
1
6
5
14 12 11
9
9
14
2
15
1
15
2
21 20
C N C C
C N C C
168.49(19)
–59.2(2)
–64.1(3)
–165.40(18)
61.4(2)
C N C S
C N C C
1
0
1
6
5
7
13 12 11
15
3
16 21
14
2
21 20
C N C C
–179.9(2)
175.67(19)
–5.1(3)
C N C C
C N C C
–0.4(3)
C N C C
2
1
6
7
10
9
11 12
15
3
16 17
C N C C
C C C N
C N C C
179.0(3)
–179.0(3)
0.3(4)
1
0
1
6
14 12 13
7
3
16 17 18
C N C C
C N C C
N C C C
5
6
7
8
11 12 13
7
21 16 17 18
C C C C
–156.7(2)
28.6(3)
C N C C
C C C C
1
6
7
8
6
7
13 12
16 17 18 19
N C C C
C C C N
59.6(2)
C C C C
0.9(6)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 6 2013

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102
GAZALIEV et al.
Yield 0.82 g (84.8%), colorless amorphous solid, mp
11–212°C, R 0.93.
REFERENCES
2
f
1
2
. Mashkovskii, M.D., Lekarstvennye sredstva (Drugs),
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Buxeraud, J., and Raby, C., Arzneimit., 1995, vol. 45,
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1
-(Anabasin-1-ylmethyl)benzothiazole-2-thione
IVa) was obtained analogously from 0.97 g (0.006 mol)
of anabasine, 0.45 g of 40% formalin solution and 1 g
0.006 mol) of 2-mercaptobenzothiazole II. After
(
(
3. Garaliene, V., Labanauskas, L., Brukstus, A., and
evaporation of the solvent, a thick brown oily sub-
stance was obtained, which crystallizes after boiling in
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4
5
hexane. Yield 68.66%, mp 57–58°C, R 0.85.
f
1
-(Cytisin-1-ylmethyl)benzothiazole-2-thione (IVb)
was synthesized analogously from 1 g (0.006 mol) of
-mercaptobenzothiazole II, 0.45 g (0.006 mol) of
6
2
formalin solution, and 1.14 g (0.006 mol) of cytisine.
After evaporation of the solvent, the resulting oil was
triturated with ether and recrystallized from a mixture
of ethanol and ether (1:1) to give 2 g (89.94%) of pale
7
. Allen, F.H., Kennard, O., Watson, D.G., Brammer, L.,
Orpen, A.G., and Taylor, R., J. Chem. Soc., Perkin
Trans. 2, 1987, no. 3, p. 1356.
8. Freer, A.A., Robins, D.J., and Sheldrake, G.N., Acta
Cryst. (C), 1987, vol. 43, p. 1119.
yellow powder, mp 140–141°C, R 0.75.
f
9
. Nurkenov, O.A., Gazaliev, A.M., Shalbaeva, A.B.,
Turdybekov, K.M., Zhurinov, M.J., Aubakirova, A., Zh.
Obshch. Khim., 1999, vol. 69, no. 4, p. 675.
1
-(Morpholin-1-ylmethyl)benzothiazole-2-thione
(
IVc) was synthesized analogously from 1 g (0.006 mol)
1
1
0. Burla, M.C., Camalli, M., Carrozzini, B., Cascarano, G.L.,
Giacovazzo, C., Polidori, G., and Spagna, R., J. Appl.
Cryst., 2003, vol. 36, no. 4, p. 1103.
1. Sheldrick, G.M., SHELXL-97. Program for the
Refinement of Crystal Structures, University of
Göttingen, Germany, 1997.
of 2-mercaptobenzothiazole II, 0.45 g (0.006 mol) of
formalin solution, and 0.52 ml (0.006 mol) of mor-
pholine. After recrystallization from alcohol 1.1 g
(
89.94%) of light yellow crystalline substance was
obtained, mp 144–145°C, R 0.80.
f
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 6 2013