Synthesis of N-Fused Benzimidazole-4,7-diones via Sequential Copper-Catalyzed C–N Coupling/Cyclization and Oxidation

Abstract

2-(2-Bromovinyl)- and 2-(2-bromoaryl)-benzimidazoles, including their 4,7-dimethoxy analogs, react with primary amides by microwave irradiation (or usual heating) in dimethylformamide in the presence of a catalytic amount of CuI along with a base to give the corresponding benzo[4,5]imidazo[1,2- c ]-pyrimidines and -quinazolines in good yields. Treatment of benzo[4,5]imidazo[1,2- c ]-pyrimidines and -quinazolines having methoxy group on benzimidazole moiety with aqueous ceric ammonium nitrate affords unprecedented N-fused hybrid scaffolds, benzo[4,5]imidazo[1,2- c ]-pyrimidin-6,9-diones and -quinazoline-8,11-diones, respectively, in high yields.

Synthesis of Pyrimidine- and Quinazoline-Fused Benzimidazole-4,7-diones Using Combinatorial Cyclocondensation and Oxidation

“…First, we optimized the reaction conditions to produce precursors, dimethoxy-substituted benzo [4,5]imidazo [1,2-a]pyrimidines of N-fused hybrid scaffold A effectively. On the basis of recent reports on transition metal−free cyclocondensation of β-bromo-α,β-unsaturated aldehydes and 2halobenzaldehydes with 2-aminobenzimidazole, 7,9 Table 1 shows several attempted results for the cyclocondensation of 2-bromocyclohex-1-enecarbaldehyde (1a) with 4,7-dimethoxy-1H-benzo [d]imidazole-2-amine (2a) under various reaction conditions, leading to 8,11-dimethoxy-1,2,3,4-tetrahydrobenzo-[4,5]imidazo [1,2-a]quinazoline (3a).…”

“…With cyclic β-bromo-α,βunsaturated aldehydes 1d−f having various ring sizes, the corresponding N-fused scaffolds 3d−f were also formed in 72− 82% yields. The reaction of benzo-fused β-bromo-α,βunsaturated aldehydes 1g took place with 2a to give 8,11dimethoxy-13,14-dihydrobenzo [f ]benzo [4,5]imidazo [1,2-a]quinazoline (3g) in 21% yield along with its dehydrogenated product 3g′ (35% yield). Performing the reaction for prolonging reaction time (2 h) under the employed conditions solely afforded 3g′ in 61% yield.…”

“… We reported on the synthesis of N-fused hybrid scaffold B by step-by-step copper-catalyzed coupling and cyclization of 2-(2-bromovinyl)-4,7-dimethoxybenzimidazoles with primary amides to form pyrimidine-fused 4,7-dimethoxybenzimidazoles, and oxidation of such intermediates by aqueous ceric ammonium nitrate (CAN) (Scheme ). As part of our continuing studies directed toward transition metal–catalyzed and transition metal–free cyclization reactions for heterocycles, we have shown several new synthetic protocols for N-fused hybrid scaffolds . Among them, β-bromo-α,β-unsaturated aldehydes were found to be cyclocondensed with 2-aminobenzimidazole in the presence of a base under microwave irradiation to give pyrimidine-fused benzimidazoles, benzo­[4,5]­imidazo­[1,2- a ]­pyrimidines. , Under these circumstances, the present work started during the course of a combinatorial extension of such protocols to develop a new synthetic approach for N-fused hybrid scaffolds.…”

“…It is known that homonuclear pyrimidine-and benzimidazolequinone (1H-benzo [d]imidazole-4,7-dione)containing compounds show diverse biological activities, such as anticancer, antimalarial, antitumor, antiproliferative, and cytotoxic properties. 1,2 There are two N-fused modes of such homonuclear N-heterocycles, benzo [4,5]imidazo [1,2a]pyrimidine-6,9-diones (Scheme 1, A) and benzo [4,5]imidazo [1,2-c]pyrimidine-6,9-diones (Scheme 1, B). In contrast to many synthetic methods for other N-fused hybrid scaffolds, limited examples for the synthesis of such N-fused hybrid scaffolds A and B are known.…”

“…4 As part of our continuing studies directed toward transition metal−catalyzed and transition metal−free cyclization reactions for heterocycles, 5 we have shown several new synthetic protocols for N-fused hybrid scaffolds. 6 Among them, β-bromo-α,β-unsaturated aldehydes were found to be cyclocondensed with 2-aminobenzimidazole in the presence of a base under microwave irradiation to give pyrimidine-fused benzimidazoles, benzo [4,5]imidazo [1,2-a]pyrimidines. 7,8 Under these circumstances, the present work started during the course of a combinatorial extension of such protocols to develop a new synthetic approach for N-fused hybrid scaffolds.…”