Taming the Imidazole Core: Entry to Enantiopure 6,7-Dihydrobenzimidazoles via Organocatalytic [4+2] Cycloadditions

Benzimidazole derivatives are privileged nitrogen-containing heterocyclic scaffolds with high potential in drug discovery, due to their isostructural pharmacophore of naturally occurring bioactive molecules. Synthetic methodologies for accessing three-dimensional and chiral dihydrobenzimidazoles remain still elusive, the majority of methods pertaining to the domain of bidimensional and achiral aromatic benzimidazole relatives.1 Documented herein is an unprecedented example of organocatalytic eliminative [4+2] formal cycloaddition reaction between novel imidazole-based alkylidene malononitriles 1, functioning as γ-activatable o-quinodimethane (oQDM) diene precursors, and diverse enals 2 functioning as organocatalytically activatable dienophiles.2 A series of N-protected dihydrobenzimidazoles of type 3 was efficiently obtained in one step with excellent enantioselectivities, which could be further elaborated into valuable imidazole-containing products without losing the chiral integrity. Different challenging issues had to be faced in this endeavour, including the non-facile, remote γ-deprotonation/temporary dearomatization3 of the highly stable 5-methyl-imidazole-4-carbaldehyde precursors, and cohabitation of the basic/nucleophilic imidazole ring with the amine organocatalyst. Finely merging the traceless-malononitrile activation strategy4 with the chiral iminium ion LUMO-lowering activation modality5 turned out to be a good option, successfully consigning the designed products upon careful optimization of the experimental conditions.