Synthesis of [1,2,3]triazolo-[4′,5′:4,5]pyrimido[1,6-a] benzimidazole, a new heterocyclic system

Full text of DOI:10.1007/s10593-009-0255-1

Chemistry of Heterocyclic Compounds, Vol. 45, No. 2, 2009
LETTERS TO THE EDITOR
SYNTHESIS OF [1,2,3]TRIAZOLO-
[4',5':4,5]PYRIMIDO[1,6-a]BENZIMIDAZOLE,
A NEW HETEROCYCLIC SYSTEM
N. T. Pokhodylo1, V. S. Matiychuk1, and M. D. Obushak1*
Keywords: azides, benzimidazole, [1,2,3]triazolo[4',5':4,5]pyrimido[1,6-a]benzimidazole, heterocycli-
zation, cycloaddition.
Benzimidazole derivatives are used in medicine as antiulcer, antihypertonic, antivirus, antifungal,
antineoplastic, antihistaminic, and anthelmintic agents [1-3]. Biological activity is also found for
imidazo[1,2-a]pyrimidine [4-9] and triazolo[4,5-d]pyrimidine [10-16]. In the present work, we propose a
convenient method for the synthesis of a new polynuclear system, namely, [1,2,3]triazolo[4',5':4,5]pyrimido-
[1,6-a]benzimidazole, in which the above-mentioned fragments are combined.
Derivatives of 1H-1,2,3-triazole are formed upon the cycloaddition of aryl azides to CH-acids [17].
However, the reactions of azides with nitriles possessing an active methylene group have not been studied
sufficiently.
N
N3
N
NaOMe
+
MeOH
N
R
H
1
2a,b
N
N
N
N
N
H
N
N
N
CH(OEt)3
N
N
N
NH2
AcOH
TsOH
R
4a, b
R
3a,b
a R = Br, b R = NO2
_______
* To whom correspondence should be addressed, e-mail: obushak@in.lviv.ua.
1Ivan Franko Lvov National University, Lvov 79005, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 304-306, February, 2009. Original
article submitted December 21, 2008.
0009-3122/09/4502-0245©2009 Springer Science+Business Media, Inc.
245

We assumed that 1H-benzimidazol-2-ylacetonitrile 1 would react as readily as the analog,
1,3-benzotriazol-2-ylacetonitrile, for which the reaction time is 1-2 min and the yield of triazoles is more than 80%.
However, our experiments showed that the yields of 3a and 3b in the reaction of nitrile 1 with aryl azides
are lower (52 and 68%). The reaction time was longer and an additional equivalent of base was required. This
discrepancy may be a result of stabilization of the carbanion of 1 due to possible charge delocalization involving
the nitrogen atom in the 1H-benzimidazole system and competing reactions.
The existence of two nucleophilic sites in amines 3 (NH2 and NH) may be exploited to form a new ring.
We have found that closure to form a pyrimidine ring proceeds rather readily upon the reaction of
aminotriazoles 3a and 3b with ethyl orthoformate. Benzimidazoles 4a and 4b are obtained in good yields despite
the low reactivity of the amino group deactivated by the electron-withdrawing effect of the triazole ring.
Analogous 1-aryl-4-(thiazolyl)- and 1-aryl-4-(benzthiazolyl)-1H-1,2,3-triazol-5-ylamines and methyl 5-amino-
1-aryl-1H-1,2,3-triazole-4-carboxylates do not react with ethyl orthoformate in acetic acid. In the case of
formation of benzimidazoles 4a and 4b, the reaction probably starts with attack of ethyl orthoformate at the
nitrogen atom in the benzimidazole fragment. Subsequent reaction of the resultant adduct with the amino group
in the thiazole ring leads to the formation of an aromatic system.
Thus, our approach permits the synthesis of representatives of a new heterocyclic system, namely,
[1,2,3]triazolo[4',5':4,5]pyrimido[1,6-a]benzimidazoles by variation of the substituents in azides 2,
1H-benzimidazole, and the orthoester.
1
The H NMR spectra were taken on a Varian Unity +400 spectrometer at 400 MHz in DMSO-d6 with
TMS as the internal standard. The mass spectra were taken on an Agilent 1100LC/MSD unit with chemical
ionization.
4-(1H-Benzimidazol-2-yl)-1-(4-bromophenyl)-1H-1,2,3-triazol-5-ylamine (3a). 1H-Benzimidazol-
2-ylacetonitrile 1 (1.57 g, 0.01 mol) and aryl azide 2a (0.01 mol) were added with vigorous stirring to a solution
of sodium methylate prepared from sodium (0.5 g) and methanol (20 ml). The mixture was stirred at room
temperature until a precipitate formed. The precipitate was filtered off and recrystallized from ethanol–DMF to
1
give 3a in 52% yield; mp 237-238°C. H NMR spectrum, δ, ppm (J, Hz): 6.71 (2H, s, NH2); 7.10-7.13 (2H, m,
H
Bim-6,5); 7.44-7.47 (1H, m, HBim-4); 7.54-7.56 (1H, m, HBim-7); 7.67 (2H, d, J = 8.8, HAr-3,5); 7.77 (2H, d,
J = 8.8, HAr-2,6); 12.83 (1H, s, HBim-1). Mass spectrum, m/z: 356 [M+H]+. Found, %: C 50.64; H 3.22; N 23.48.
C15H11BrN6. Calculated, %: C 50.72; H 3.12; N 23.65.
4-(1H-Benzimidazol-2-yl)-1-(4-nitrophenyl)-1H-1,2,3-triazol-5-ylamine (3b) was synthesized
1
analogously in 68% yield using 4-nitrophenyl azide 2b; mp >300°C. H NMR spectrum, δ, ppm (J, Hz): 6.99
(2H, s, NH2); 7.10-7.17 (2H, m, HBim-6,5); 7.50-7.55 (2H, m, HBim-4,7); 8.05 (2H, d, J = 8.8, HAr-2,6); 8.46 (2H,
d, J = 8.8, HAr-3,5). Mass spectrum: 322 [M+H]+. Found, %: C 55.89; H 3.56; N 30.47. C15H11N7O2. Calculated,
%: C 56.07; H 3.45; N 30.52.
3-(4-Bromophenyl)-3H-[1,2,3]triazolo[4',5':4,5]pyrimido[1,6-a]benzimidazole (4a). Acetic acid
(40 ml) and toluenesulfonic acid (0.2 g) were added with stirring to a suspension of compound 3 (50 mmol) in
ethyl orthoformate (25 ml) and heated for 4 h at 95-100°C. A precipitate formed. The mixture was cooled to
room temperature. The precipitate and recrystallized from ethanol–DMF to give 4a in 80% yield; mp >300°C.
1H NMR spectrum, δ, ppm (J, Hz): 7.54 (1H, t, J = 8.0, HBim-9); 7.62 (1H, t, J = 8.0, HBim-8); 7.89 (2H, d,
J = 8.8, HAr-3,5); 7.95 (1H, d, J = 8.0, HBim-7); 8.17 (2H, d, J = 8.8, HAr-2,6); 8.45 (1H, d, J = 8.0, HBim-10);
10.03 (1H, s, HPy-5), Mass spectrum, m/z: 366 [M+H]+. Found, %: C 52.47; H 2.40; N 23.13. C16H9BrN6.
Calculated, %: C 52.62; H 2.48; N 23.01.
3-(4-Nitrophenyl)-3H-[1,2,3]triazolo[4',5':4,5]pyrimido[1,6-a]benzimidazole (4b) was synthesized
1
analogously in 88% yield; mp >300°C. H NMR spectrum, δ, ppm (J, Hz): 7.58 (1H, t, J = 8.0, HBim-9); 7.65
(1H, t, J = 8.0, HBim-8); 7.99 (1H, d, J = 8.0, HBim-7); 8.49 (1H, d, J = 8.0, HBim-10); 8.58 (4H, br. s, C6H4), 10.07
(1H, s, HPy-5). Mass spectrum: 332 [M+H]+. Found, %: C 57.90; H 2.53; N 29.47. C16H9N7O2. Calculated, %:
C 58.01; H 2.74; N 29.60.
246

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