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Pyrido[1,2-a]benzimidazole is one of the most important azaheterocyclic compounds consisting of three fused aromatic rings. Molecules containing this core have displayed a wide range of applications in the field of medicinal chemistry. The synthesis of pyrido[1,2-a]benzimidazole and its derivatives has attracted organic chemists because of its tremendous utility in interdisciplinary branches of chemistry. In this context, this review discusses the main advances in the synthesis of pyrido[1,2-a]benzimidazoles via metal-mediated and metal-free reactions from 2000 to 2016.1 Introduction2 Synthetic Approaches to Pyrido[1,2-a]benzimidazoles2.1 Type I: Transition-Metal-Catalyzed Methods2.2 Type II: Metal-Free Approaches3 Conclusion

A cobalt-catalyzed proton-coupled electron transfer (PCET) mediated regioselective ortho-specific nitration of aromatic C(sp2)-H bonds using chelation-assisted removable vicinal diamine directing groups was developed. The reaction proceeded under mild conditions in the presence of Co(OAc)2·4H2O as the catalyst with AgNO2 utilized as the nitro source as well as terminal oxidant in the presence of O2 as an external oxidant. No external base or additives were required for this process. Controlled experiments and mechanistic investigations with DFT calculations revealed that the reaction proceeds through a PCET promoted nitro functional group transfer pathway. Moreover, the produced compounds are valuable and pharmaceutically quite relevant.

A nickel-catalyzed cross-coupling reaction between methoxy-substituted carbazoles and MeMgBr has been developed. This protocol for the cleavage of the C(aryl)−OMe was used to efficiently assemble various methyl-substituted carbazoles and successfully applied to the total synthesis of the antitumor agent ellipticine.

A copper(II)-catalyzed selective CNH2 arylation of 2-aminobenzimidazoles and related C-amino-NH-azoles was achieved in presence of 2,2′-bipyridine and cesium carbonate at 60 °C under open air conditions and this is first method for the copper-catalyzed selective CNH2 arylation in the presence of other reactive nucleophilic sites. Previously unexplored heteroaromatics possessing multiple nucleophilic sites that are selectively arylated at the CNH2 position are obtained, providing an exceptional tool for rapid delivery of a diverse array of medicinally important CNH(aryl) derivatives of aminoazoles without any protection/deprotection of ring NH bonds. It is first example for the selective CNH2 arylation of 5-aminoindazole, 4-aminopyrazole, 5-aminopyrazole, 9H-purine-6-amine, and 1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives.

A novel method of transamidation of carboxamides with amines by using catalytic amounts of H2SO4–SiO2 has been developed under solvent free conditions. The transamidation is compatible with a wide range of aromatic, heteroaromatic, aliphatic, cyclic/acyclic primary or secondary amines. The metal/solvent-free conditions represent a significant improvement over other existing methods as the reaction can be performed in open air conditions and no column purification is required. The versatility of this methodology was further demonstrated by synthesizing the commercially available drug procainamide.

A cobalt-catalyzed proton-coupled electron transfer (PCET) mediated regioselective ortho-specific nitration of aromatic C(sp

An iodine(III) catalyzed C(sp2)–H functionalization–intramolecular amination reaction of N-aryl-2-amino-N-heterocycles has been developed in water and under ambient conditions. This metal-free open-flask chemistry is general and successfully applied in synthesizing the benzimidazole-fused heterocycles pyrido[1,2-a]benzimidazole, benzimidazo[1,2-a]quinoline and benzimidazo[2,1-a]isoquinoline derivatives.

Copper(II)-catalyzed boronic acid promoted C-N bond cross-coupling reactions have been successfully developed for sequential N-arylation of C-amino-NH-azoles. These general protocols are compatible with a variety of aryl/hetero-aryl boronic acids and provided rapid access to a diverse array of diarylaminoazole derivatives in a two-step sequence or in one-pot.

An unprecedented Pd/Ag synergistic catalysis in the direct carbonylation of C(sp(2))-H bonds utilizing DMF as the carbon source under oxygen is described and demonstrated in the synthesis of pyrido-fused quinazolinone and phenanthridinone scaffolds. Control experiments indicated that the "C" of the carbonyl group is derived from the methyl group of DMF and "O" originates from oxygen as in the case of Ge's recent work. This transformation offers an alternative avenue for "CO-free" carbonylations.

Pyrano[2,3-c]carbazoles which are biologically valuable and synthetically challenging frameworks are synthesized in high yields over five steps from commercially available resorcinol. Palladium-catalyzed arylation remains a key step in this novel strategy. The versatility of this protocol has been demonstrated by the synthesis of naturally occurring alkaloid clauraila C and 7-methoxyglycomaurin. The anti-proliferative activity of these designed compounds (5a, 5f, and 5l) has been evaluated in a cancer cell line (MOLT-4). The molecular docking study revealed that this pyrano[2,3-c]carbazole class of molecules selectively occupies the colchicine binding site of the tubulin-polymer.

The reaction cascade combines a Chan—Lam type coupling and a subsequent Ullmann type coupling.

A Cu (II)-catalyzed, inter/intramolecular C–N bond formation for the synthesis of various benzimidazole-fused heterocycles in a concise manner has been reported. The robustness of this reaction is demonstrated by the synthesis of a series of benzimidazole-fused heteroaromatics (e.g., pyrido[1,2-a] benzimidazole, benzimidazo[1,2-a]quinolines, benzimidazo [1,2-a]pyrazine, benzo[4,5] imidazo[2,1-b]thiazoles) directly from 2-aminoheteroarenens and 2-iodoarylboronic acids in one-pot. The novel cascade protocol for C–N bond formation operates via unique combination of Chan–Lam type coupling followed by Ullmann-type reaction.

Pyrano[2,3-c]carbazoles which are biologically valuable and synthetically challenging frameworks are synthesized in high yields over five steps from commercially available resorcinol. Palladium-catalyzed arylation remains a key step in this novel strategy. The versatility of this protocol has been demonstrated by the synthesis of naturally occurring alkaloid clauraila C and 7-methoxyglycomaurin. The anti-proliferative activity of these designed compounds (5a, 5f, and 5l) has been evaluated in a cancer cell line (MOLT-4). The molecular docking study revealed that this pyrano[2,3-c]carbazole class of molecules selectively occupies the colchicine binding site of the tubulin-polymer.

Transamidation of a series of N,N-dimethyl amides with a wide range of primary and secondary amines is accomplished environmentally friendly using sulfuric acid adsorbed on silica gel as recyclable catalytic system.

One of the rare examples in which water is used as a solvent in hypervalent iodine(III) catalyzed oxidative C—N bond formation is described.

Copper catalyzed N-arylation of iodoarenes with boronic acids followed by palladium catalyzed intramolecular C-H arylation provides carbazole-3-carboxylates including the naturally occurring alkaloids Clausine C (IVg), H (IVf) and L (IVe).

Copper promoted N-arylation of methyl 4-amino-3-iodobenzoate with boronic acids followed by Pd-catalyzed intramolecular C–H arylation provides an efficient route to methyl carbazole-3-carboxylate derivatives. This methodology was implemented in the synthesis of naturally occurring carbazole alkaloids clausine C, clausine H, clausine L, clausenalene, glycozoline, glycozolidine, glycozolidal and sansoakamine.

A wide range of N-arylated 2-amino-N-heterocycles were synthesized by a copper-catalyzed boronic acid cross coupling reaction at ambient temperature in air. This ligand and base free methodology is general and could provide rapid access to a diverse array of potential bioactive heterocyclic compounds.