Synthesis of Quinone Derivatives of Benzannelated Heterocycles with Bridgehead Nitrogen
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hesis of Quinone Derivatives of Benzannelated Heterocycles with Bridgehead Nitrogen R. S. Begunova,*, A. A. Sokolova, and S. I. Filimonovb a
Demidov Yaroslavl State University, Yaroslavl, 150003 Russia Yaroslavl State Technical University, Yaroslavl, 150023 Russia *e-mail: [email protected]
b
Received March 5, 2020; revised March 18, 2020; accepted March 22, 2020
Abstract—A facile synthesis of para-quinones derived from fused benzimidazoles with a bridgehead nitrogen atom was developed. The heterocyclic quinone core formed as a result of reductive cyclization of ortho-nitroarenes containing alicyclic and aromatic azaheterocycles. Functionalization of 1,2,3,4-tetrahydro- and pyrido[1,2-a]benzimidazoles via SEAr, condensation, and reduction reactions allowed synthesis of amino derivatives which were oxidized with KNO3 in H2SO4 to obtain novel heterocyclic quinones. Keywords: reductive heterocyclization, 1-(2-nitroaryl)pyridinium salts, 2-nitro-1-tert-anilines, 8-bromo-7-chloropyrido[1,2-a]benzimidazole-6,9-dione, 8-bromo-7-chloro-1,2,3,4-tetrahydropyrido[1,2-a]benzimidazole-6,9dione, pyrido[1,2-a]imidazo[4,5-f]benzimidazole-6,10-dione, 1,2,3,4-tetrahydropyrido[1,2-a]imidazo[4,5-f]benzimidazole-6,10-dione
DOI: 10.1134/S1070428020080084 Quinones derived from benzimidazole and its fused derivatives are important biologically active compounds (Fig. 1). They exhibit antiprotozoal [1], antifungal [2], and vascular cell proliferation [3] and Photosystem II inhibitory activities [4]. O
N
Ph Ph
O
antiprotozoal
Br
N
O Angiogenic inhibitor
O N
N
anticancer
N H
Cl
O
N
Br
O
H N
N
They are of particular interest as potential anticancer drugs [5–7]. As known, some fused benzimidazole derivatives are far superior in activity than the well-known anticancer drug Mitomycin C [5]. These compounds are bioreductive prodrugs which induce DNA cross-linking
O
O X = Cl or Br anticancer
N
O
N
CH3 O
Photosystem II inhibitor
O
X X
N
Ph
N
N N
O
anticancer
Fig. 1. Structure and biological activity of quinones derived from benzimidazole and its fused derivatives.
1383
1384
BEGUNOV et al. Scheme 1.
R
_ Cl + N
2.1 equiv SnCl2, 4% HCl, i-PrOH 40°C, 0.1 h
N R
NO2 1a, 1b
N 3a, 98% 3b, 91%
1, 3, R = Cl (ɚ), NO2 (b).
activated by the reduction of the imidazolequinone fragment [8, 9]. The cellular reduction of heterocyclic quinones is effected by DT-diaphorase enzyme, the level of expression of which in tumors, especially lung, colon, and breast tumors, is increased with respect to the surrounding normal tissues [10–12]. Therefore, drugs activated by DT-diaphorase can be expected to highly selectively and specifically destroy tumor cells. Heterocyclic quinones can be used for annelation of various heterocycles, which will allow preparation of novel polyfused heterocyclic systems [13–16]. These compounds can also exhibit promising biological activity. A few examples of the synthesis of quinones derived from fused benzimidazole derivatives have been reported. Depending on the structure the latter, the
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