Synthesis of diarylmethylamines via palladium-catalyzed regioselective arylation of 1,1,3-triaryl-2-azaallyl anions

Abstract

Diarylmethylamines are of great interest due to their prevalence in pharmaceutical chemistry. As a result, new methods for their synthesis are in demand. Herein, we report a versatile protocol for the synthesis of diarylmethylamine derivatives involving palladium-catalyzed arylation of in situ generated 2-azaallyl anion intermediates. The 2-azaallyl anions are generated by reversible deprotonation of readily available aldimine and ketimine precursors. Importantly, the arylated aldimine and ketimine products do not undergo isomerization under the reaction conditions. Scale-up of the arylation and hydrolysis of the resulting products to furnish diarylmethylamines were also successfully performed.

Fig. 1

Important diarylmethylamine containing molecules.

Fig. 2

Structures of relevant phosphines used in screening reactions.

Scheme 1

Umpolung retrosynthesis of diarylmethylamines.

Scheme 2

Arylation by Oshima and co-workers (X = Cl, Br).

Scheme 3

Use of benzylation to identify the base and solvent.

Scheme 4

Reaction pathway for arylation of the 1,1,3-triaryl-2-azaallyl anion.

Scheme 5

Arylation of 1f with 2h.

Scheme 6

Coupling of aryl bromides with (a) a free N–H, (b) ortho-substitution, and (c) to give a bis-heterocyclic diarylmethylamine derivative.

Scheme 7

Scale-up of the imine arylation.

Scheme 8

Functionalization of diarylmethylamines.