Phase-transfer catalytic synthesis and hypocholesterolemic activity of thiazino[3,2-a]benzimidazole and its silicon analog

Article abstract of DOI:10.1007/s10593-007-0034-9

The reaction of 2-mercaptobenzimidazole with 1,3-dichloropropane or bis(chloromethyl)dimethylsilane in the two-phase catalytic system of solid K₂CO₃-18-crown-6-toluene at 111°C leads to a selective formation of tricyclic benzimidazole sulfides in 56 and 92% yields. The synthesized compounds were tested as hypocholesterolemic agents.

Full text of DOI:10.1007/s10593-007-0034-9

Chemistry of Heterocyclic Compounds, Vol. 43, No. 2, 2007
PHASE-TRANSFER CATALYTIC SYNTHESIS AND HYPOCHOLESTEROLEMIC
ACTIVITY OF THIAZINO[3,2-a]BENZIMIDAZOLE AND ITS SILICON ANALOG
E. Abele, R. Abele, P. Arsenyan, S. Belyakov, M. Veveris, and E. Lukevics
The reaction of 2-mercaptobenzimidazole with 1,3-dichloropropane or bis(chloromethyl)dimethylsilane
in the two-phase catalytic system of solid K2CO3 – 18-crown-6 – toluene at 111oC leads to a selective
formation of tricyclic benzimidazole sulfides in 56 and 92% yields. The synthesized compounds were
tested as hypocholesterolemic agents.
Keywords: thiazino[3,2-a]benzimidazole, hypocholesterolemic activity, phase-transfer catalysis.
Thiazolobenzimidazoles and similar tricyclic benzimidazole sulfides show high biological effectiveness
[1]; in fact showing vasodilator [2], antihypertensive [3-5], anti-inflammatory [6, 7], antiulcer [8-10], and
antimicrobial [11-13] activity. The high cholesterol-lowering activity of aromatic silicon-containing sulfides of
the types HetS(CH2)nSiR3 (n = 1,3) and HetSCH2Si(Me2)CH2SHet has been shown in some patents and articles
[14-19].
The synthesis of thiazolobenzimidazoles and related heterocyclic systems has been presented in detail in
the review [1]. A first method is based on the synthesis of thiazolo[3,2-a]benzimidazoles and
thiazino(3,2-a]benzimidazoles via the reaction of 2-mercaptobenzimidazoles with α-halocarbonyl compounds
[20]. A second method is the reaction of 2-mercaptobenzimidazole (or 2,3-dihydrobenzimidazole-2-thione) with
α,ω-dihaloalkanes in the systems NaHCO3 – KI – 2-PrOH [21], EtOH – DMF – NaHCO3 [22], Na – ether [23], or
NaOH – H2O – PhH – cetyltributylammonium bromide [24]. However, in many examples the product yields and
reaction selectivity were quite low.
Cl(CH2)3Cl–K2CO3–KI–
–18-crown-6 –PhMe
N
N
N
SH
S
N
H
1
2
N
ClCH2Si(Me2)CH2Cl–KI–
–K2CO3–18-crown-6–PhMe
S
N
Si
Me
3
Me
__________________________________________________________________________________________
Lativian Institute of Organic Synthesis, Riga LV-1006; e-mail: abele@osi.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 2, pp. 274-279, February, 2007. Original article submitted October 4, 2006.
220
0009-3122/07/4302-0220©2007 Springer Science+Business Media, Inc.

TABLE 1. Basic Bond Lengths (l) and Valence Angles (ω) in the
Structure of Molecule 3
Bond
l, (Å)
Valence angle
ω, deg.
S(1)–C(2)
S(1)–C(6)
Si(3)–C(2)
Si(3)–C(4)
N(5)–C(4)
N(5)–C(6)
N(5)–C(13)
N(7)–C(6)
N(7)–C(8)
1.804(4)
1.740(3)
1.863(3)
1.875(3)
1.471(3)
1.372(3)
1.382(4)
1.322(4)
1.375(4)
C(2)–S(1)–C(6)
S(1)–C(2)–Si(3)
C(2)–Si(3)–C(4)
Si(3)–C(4)–N(5)
C(4)–N(5)–C(6)
C(4)–N(5)–C(13)
N(5)–C(6)–S(1)
N(5)–C(6)–N(7)
C(6)–N(7)–C(8)
105.6(2)
112.2(2)
103.2(2)
114.3(2)
130.0(2)
124.2(2)
128.0(2)
113.2(3)
104.8(2)
We have developed a phase-transfer catalytic method for the synthesis of thiazino[3,2-a]benzimidazole
(2) and its sila analog 3 in the system 1,3-dichloropropane or bis(chloromethyl)dimethylsilane – solid K2CO3 –
solid KI – 18-crown-6 – toluene at high dilution. Under these conditions the products 2 and 3 were separated in
56 and 92% yields respectively.
With the aim of objective establishing the structure of compound 3 we carried out an X-ray
crystallographic study of the crystals. Figure 1 shows the spatial model and atomic numbering for the molecule
3. The basic bond length and valence angle values in the molecule are given in Table 1.
Fig. 1. Structure of the 3,3-dimethyl-3,4-dihydro-2H-1-thia-4a,9-diaza-
3-silafluorene (3) with atomic numbering and thermal vibrational ellipsoids.
The molecule consists of three condensed rings, of which the benzene and imidazole rings are planar but
the 1-thia-5-aza-3-sila-cylcohexane system has a near to twist conformation. The values of the torsional angles
which characterize this ring conformation are given in Table 2.
The projection of the crystal structure on the crystal plane yz is given in Fig. 2. The molecules are
associated in the crystal as centrosymmetric dimers via weak π-π interaction. The distance between the mean
planes of the interacting molecules is 3.815(5) Å. The comparatively loose packing of the 3 molecule is due to
relatively low density of the substance (1.217 g/cm3).
221

TABLE 2. Some Torsional Angles Values (δ) in the Molecule 3
Torsional angle
δ, deg
S(1)–C(2)–Si(3)–C(4)
C(2)–Si(3)–C(4)–N(5)
Si(3)–C(4)–N(5)–C(6)
C(4)–N(5)–C(6)–S(1)
N(5)–C(6)–S(1)–C(2)
C(6)–S(1)–C(2)–Si(3)
56.4(2)
-44.2(2)
21.9(2)
-6.8(2)
17.5(2)
-43.7(2)
Fig. 2. Projection of the crystal structure of compound 3
along the [1 0 0] direction.
TABLE 3. Cholesterolemic Activity of Compounds 2 and 3 in the Dietary
Hypercholsterolemia Model (M±m)
Cholesterol, mg/dl*
Compound
Overall
HDL
LDL
К
Cholesterol control
143.2 ± 12.9**
121.2 ± 16.8
124.0 ± 17.9
98.5 ± 2.3
99.8 ± 5.4
106.8 ± 14.2
101.9 ± 13.4
96.2 ± 2.6
43.4 ± 13.4
14.4 ± 4.5
22.1 ± 6.3
2.3 ± 0.8
0.448 ± 0.155***
0.135 ± 0.033***
0.213 ± 0.051***
0.024 ± 0.007
2
3
Control (standard diet)
_______
* HDL is high density lipoprotein, LDL low density lipoprotein, and K the
atherosclerosis index (K = HDL/LDL).
** Differences relative to statistical confidence control at P < 0.05.
*** Differences relative to statistical confidence control at P < 0.01.
222

TABLE 4. Crystallographic Data for Compound 3
Empirical formula
C10H14N2SSi
222.386
Mr
Crystal symmetry
Monoclinic
P 21/c
Space group
Unit cell parameters
a, Å
6.7001(2)
12.4130(4)
15.2739(6)
107.132(1)
1213.94(7)
4
b, Å
c, Å
β,deg
V, Å3
Z
Crystal density, d, g/cm3
µ, mm-1
1.217
0.33
Number of independent reflections
Number of reflections with I > 3σ(I)
Number of refinement parameters
Final difference factor R
2946
1927
192
0.046
Program used
SIR97 [27], maXus [28]
The compounds synthesized were tested as hypocholesterolemic agents. Compound 2 and its silicon analog
3 were introduced into mice diet orally. It was found that both compounds 2 and 3 have weak activity. The
thiazino[3,2-a]benzimidazole (2) (LD50 > 2000 mg/kg) has a better atherosclerosis index (K = 0.135±0.033). The
3,3-dimethyl-3,4-dihydro-2H-1-thia-4a,9-diaza-3-silafluorene (3) (LD50 = 1055 mg/kg) shows an atherosclerosis
index of K = 0.213±0.051.
EXPERIMENTAL
Thiazino[3,2-a]benzimidazole (2). 2-Mercaptobenzimidazole (1) (2.25 g, 15 mmol), solid K2CO3 (8.28
g, 60 mmol), and solid KI (9.96 g, 60 mmol) were added to a solution of 1,3-dichloropropane (1.42 ml , 15
mmol) and 18-crown-6 (0.39 g, 1.5 mmol) in toluene (250 ml). The mixture was refluxed with vigorous stirring
for 10 h, filtered through a thin layer of silica gel, and the toluene was evaporated on a rotary evaporator. The
product 2 was separated by column chromatography using toluene–ethyl acetate (1 : 1) as eluent. The spectroscopic
properties of compound 2 agreed with those given in the study [25]. Yield 1.59 g (56%), mp 137-138°C.
The synthesis and spectroscopic properties of 3,3-dimethyl-3,4-dihydro-2H-1-thia-4a,9-diaza-3-silafluorene
(3) are given in the study [26].
A monocrystal of compound 3 of size 0.23×0.25×0.32 mm was obtained by crystallization from a
mixture of petroleum ether and ethyl acetate. The X-ray analysis was performed on a Nonius KappaCCD
automatic diffractometer to 2θmax = 55° (λMo = 0.71073 Å). The basic crystallographic parameters for compound
3 and also the refinement parameters for the structure are given in Table 4.
Cholesterol-lowering activity and toxicity were determined by the methods given in the article [16].
All of the animal experiments were carried out according to the Animal Ethical Committee of BaltLASA
(Riga, Latvia).
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