Recent Advances in the Synthesis of Isoquinoline-Fused Benzimidazoles

Abstract

This review includes recent developments in the synthesis of benzo[4,5]imidazo[2,1-a]isoquinolines with particular attention given to categorizing protocols based on the structural features of the ring architecture and crystallographically characterized reaction products.

Keywords: benzimidazo[2,1-a]isoquinoline; benzimidazole; benzo[4,5]imidazo[2,1-a]isoquinoline; isoquinoline; nitrogen heterocycles.

Figure 1

Isoquinoline, benzimidazole, and benzimidazo[2,1-a]isoquinoline 1.

Figure 2

Copper(I)-catalyzed coupling protocols with o-bromophenyl benzimidazoles 2 and 1,3-diketones 3 [5,6].

Figure 3

Copper(I)-catalyzed coupling protocol using o-bromophenyl benzimidazoles 2 and calcium carbide as reactants.

Figure 4

Hydroamination of bromoacetylene 5 by benzimidazole 4a.

Figure 5

Annulation of benzimidazole 4b with sulfoxonium ylides 6.

Figure 6

Synthesis of functionalized benzimidazo[2,1-a]isoquinolines 1a,d,e via rhodium(III)-catalyzed annulation of α-diazoketoesters 7 and 2-arylbenzimidazoles 4a.

Figure 7

Oxidative annulation of 2-phenylbenzimidazoles 4a and their fused homologs with internal alkynes 8 by different protocols [12,13,14,15,16,17,18,19].

Figure 8

Application of vinylene carbonate 9 in rhodium-catalyzed oxidative annulation of 2-arylbenzimidazoles 1g.

Figure 9

Synthesis of diversely functionalized benzimidazo[2,1-a]isoquinoline 1h with the use of bromoacetaldehyde derivative 10.

Figure 10

Palladium- and rhodium-catalyzed intramolecular cross-coupling of N-styrylbenzimidazoles 11 [22,23].

Figure 11

C–H cycloamination of N-phenyl-2-aminoisoquinoline 12 catalyzed by an in situ-generated hypervalent iodine reagent or copper/iron bimetallic system [24,25].

Figure 12

Nickel-catalyzed annulation of chlorohalobenzimidamides 13 with terminal alkynes 14a.

Figure 13

Copper-catalyzed annulation between o-alkynylbenzonitrile 15 and o-iodoanilines 16.

Figure 14

Rhodium-catalyzed annulation (and amination, bottom) of amidines 17 with alkynes 8b.

Figure 15

Synthesis of benzimidazo[2,1-a]isoquinoline 1a by reaction of 2-ethynylbenzaldehyde 18 and o-phenylenediamine 19a (top) and by a one-pot reaction of bromobenzaldehydes 21, terminal acetylenes 14b, and o-phenylenediamines 19a (bottom) [1,30,32,33,34,35].

Figure 16

Synthesis of 5-iodobenzimidazo[2,1-a]isoquinolines 1m.

Figure 17

One-pot tandem cyclization leading to 5-amino- and 6-carbonyl functionalized benzimi-dazo[2,1-a]isoquinolines 1n.

Figure 18

Reaction of acetyliminoisocoumarin 23 and o-phenylenediamine 19b.

Figure 19

Mechanistic outline illustrating one of the amino groups of o-phenylenediamine reacting with the alkyne first.

Figure 20

Mechanistic outline for the formation of benzimidazo[2,1-a]isoquinolines 1m with carbonyl group reacting first, illustrating regioselectivity of a reaction using EDG- and EWG-substituted phenylenediamine.

Figure 21

Isolation of mechanistically relevant imine intermediates 31a,b.

Figure 22

Structures and CSD reference codes of crystallographically characterized derivatives of benzimidazo[2,1-a]isoquinolines 1 [10,11,12,13,20,21,27,28,29,33,34,36,37].