The cooperative effect of Lewis pairs in the Friedel–Crafts hydroxyalkylation reaction: a simple and effective route for the synthesis of (±)-carbinoxamine

Abstract

An efficient C–C bond formation strategy between aromatic/heteroaromatic π-nucleophiles and Lewis acid activated aldehydes is described. This aromatic electrophilic substitution reaction of arenes or heteroarenes is facilitated by Lewis acid AlBr₃. Aromatic rings with electron donating substituents are excellent nucleophilic counterparts in this reaction, generating carbinols in excellent yields (61–94%). The formation of triarylmethanes is also witnessed in the case of certain reactive aldehydes and aromatic π-nucleophiles through reactive carbocation formation. The formation of triarylmethane is reduced to a greater extent via retardation of the second π-nucleophile addition through a Lewis base, for example, pyridine, coordination with an aluminium alkoxide intermediate. Various aliphatic aldehydes also underwent Friedel–Crafts type hydroxyalkylation and generated the expected carbinols in moderate yields (41–53%) in the presence of AlBr₃. This protocol has been successfully applied to the synthesize of the (±)-carbinoxamine, a therapeutically important histamine H₁ antagonist, in a one-pot manner.