Regioselectivity of heterocyclization of 2-substituted 3,3- bis(methylsulfanyl)acrylo-nitriles with 2-benzimidazoleacetonitrile

Article abstract of DOI:10.1007/s10593-010-0605-z

Functionalized pyrido[1,2-a]benzimidazoles have been synthesized by the interaction of 2-substituted 2-cyano-3,3-bis(methylsulfanyl)acrylonitriles with 2-benzimidazoleacetonitrile under S _N Vin reaction conditions.

Full text of DOI:10.1007/s10593-010-0605-z

Chemistry of Heterocyclic Compounds, Vol. 46, No. 8, 2010
REGIOSELECTIVITY OF HETEROCYCLIZATION OF
2-SUBSTITUTED 3,3-BIS(METHYLSULFANYL)ACRYLO-
NITRILES WITH 2-BENZIMIDAZOLEACETONITRILE
V. D. Dyachenko1*, O. S. Bityukova1, and A. D. Dyachenko1
Functionalized pyrido[1,2-a]benzimidazoles have been synthesized by the interaction of 2-substituted
2-cyano-3,3-bis(methylsulfanyl)acrylonitriles with 2-benzimidazoleacetonitrile under SNVin reaction
conditions.
Keywords: 2-benzimidazoleacetonitrile, 2-cyano-3,3-bis(methylsulfanyl)acrylonitriles, pyrido[1,2-a]benz-
imidazole, regioselective heterocyclization.
It has been shown for the first time that the condensation of 2-(benzimidazol-2-yl)acetonitrile (1) with
an activated alkene under SNVin reaction conditions [1] proceeds regioselectively through the corresponding
transition state A with the formation of pyrido[1,2-a]benzimidazole 3. Regioselectivity was also observed in the
case of the interaction of compound 1 with 2-cyano-3,3-bis(methylsulfanyl)acrylic acid ethyl ester 4, leading to
the formation of pyrido[1,2-a]benzimidazole 5.
At the same time the unexpected formation of the heterocyclic system 5 occurs on condensing
compound 1 with 2-cyano-3,3-bis(methylsulfanyl)acrylamide 6.
It has therefore been established that the anilide fragment of 2-cyano-N-(2-methoxyphenyl)-
3,3-bis(methylsulfanyl)acrylamide (2) is transferred into compound 3, and the amide fragment of alkene 6
undergoes an intramolecular rearrangement forming pyrido[1,2-a]benzimidazole 5.
The synthesized compounds 3, 5 fluoresce on UV irradiation.
The biological activity of the obtained compounds has been predicted with the aid of the PASS
programs [2]. The probability that the obtained compounds 3, 5 may display antiasthmatic activity was
67.3-92.9%, antiallergic 65.3-91.2%, and as antagonists of chemoxin receptors CXCRI 53.5-64.8%
EXPERIMENTAL
1
The IR spectra were recorded on a Perkin-Elmer FIR Spectrum One instrument in KBr. The H NMR
spectra were recorded on Bruker Avance II 400 (400 MHz) (compound 3) and Varian Mercury-500 (500 MHz)
_______
* To whom correspondence should be addressed, e-mail: dvd_lug@online.lg.ua.
1Taras Shevchenko Lugansk National Pedagogical University, Lugansk 91001, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, 1162-1164, August, 2010. Original
article submitted December 1, 2009.
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0009-3122/10/4608-0938©2010 Springer Science+Business Media, Inc.

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(compound 5) instruments in DMSO-d6, internal standard was TMS. The EI mass spectra were obtained on a
MX-1321 (70 eV) (compound 3) with direct insertion of substance into the ion source (70 eV) and on a
Chrommas GC/MS Hewlett-Packard 5890/5972 with HP-5MS column (compound 5).
The melting points of compounds were determined on a Kofler block. A check on the progress of
reactions and the homogeneity of compounds was carried out by TLC on Silufol UV 254 plates in the system
acetone–hexane, 3:5, visualization was with iodine vapor and in UV light.
2-cyano-N-(2-methoxyphenyl)-3,3-bis(methylsulfanyl)acrylamide (2) was obtained by the procedure
of [3].
1-Amino-4-cyano-3-methylthio-N-(2-methoxyphenyl)pyrido[1,2-a]benzimidazole-2-carboxamide (3).
2-(Benzimidazol-2-yl)acetonitrile (1) (1.57 g, 10 mmol) was added to a suspension of KOH (0.56 g, 10 mmol)
in DMSO (10 ml) and the mixture stirred for 15 min. 2-cyano-N-(2-methoxyphenyl)-3,3-bis(methylsulfanyl)-
acrylamide (2) (2.94 g, 10 mmol) was then added to the reaction mixture, which was stirred for 1 h, and heated
at 80oC for 15 min. The mixture was then left for 2 h, poured into cold water, the mixture was acidified with an
equimolar quantity of 30% HCl solution, the resulting solid was filtered off, and washed with water. Yield 2.41
g (60%); mp 126-130oC (butanol). IR spectrum, , cm-1: 1556 (NH2, NH), 1643 (C=O), 2216 (C≡N), 3234,
3334. 1H NMR spectrum, δ, ppm (J, Hz): 9.63 (1H, br. s, NH); 8.45 (1H, d, J = 8.1, H benzimidazole); 8.20 (1H,
d, J = 8.1, H arom); 7.89 (2H, br. s, NH2); 7.80 (1H, d, J = 8.1, H benzimidazole); 7.53 (1H, t, J = 7.7,
H benzimidazole); 7.34 (1H, t, J = 7.7, H benzimidazole); 7.11 (1H, t, J = 7.7, H arom); 7.02 (1H, d, J = 8.1,
H arom); 6.96 (1H, t, J = 7.7, H arom); 3.88 (3H, s, OCH3); 2.63 (3H, s, SCH3). Mass spectrum, m/z (Irel, %):
108 [M]+ (24), 206 (9), 281 (7), 403 (13). Found, %: C 62.52; H 4.25; N 17.36. C21H17N5O2S. Calculated, %:
C 62.59; H 4.09; N 17.36.
1-Hydroxy-3-methylsulfanylpyrido[1,2-a]benzimidazole-2,4-dicarbonitrile (5) was obtained
analogously to compound 3 using as ketenedithioacetal the diethyl ester of 2-cyano-3,3-bis(methylsulfanyl)-
acrylic acid (4) or 2-cyano-3,3-bis(methylsulfanyl)acrylamide (6). Yield 2.02 g (72%) and 2.24 g (80%)
respectively, mp 290-297oC (butanol). IR spectrum, , cm-1: 2215 (C≡N), 3450 (OH). 1H NMR spectrum, δ,
ppm, (J, Hz): 8.45 (1H, d, J = 8.0, H arom); 7.64 (1H, d, J = 7.8, H arom.); 7.45 (1H, t, J = 7.6, H arom); 7.30
(1H, t, J = 7.6, H arom.); 2.74 (3H, s, SCH3). The signal of the OH group proton was not displayed, probably as
a result of rapid deuterium exchange. Mass spectrum, m/z (Irel, %): 279 [M-1]+ (100). Found, %: C 59.99;
H 2.88; N 19.99. C14H8N4OS. Calculated, %: C 60.05; H 2.97; N 19.86.
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