Reductive Amination Revisited: Reduction of Aldimines with Trichlorosilane Catalyzed by Dimethylformamide─Functional Group Tolerance, Scope, and Limitations

Aldimines, generated in situ from aliphatic, aromatic, and heteroaromatic aldehydes and aliphatic, aromatic, and heteroaromatic primary or secondary amines, can be reduced with trichlorosilane in the presence of dimethylformamide (DMF) as an organocatalyst (≤10 mol %) in toluene or CH 2 Cl 2 at room temperature. The reduction tolerates ketone carbonyls, esters, amides, nitriles, sulfones, sulfonamides, NO 2, SF 5, and CF 3 groups, boronic esters, azides, phosphine oxides, C═C and C≡C bonds, and ferrocenyl nucleus, but sulfoxides and N -oxides are reduced. α,β-Unsaturated aldimines undergo 1,2-reduction only, leaving the C═C bond intact. N -Monoalkylation of primary amines is attained with a 1:1 aldehyde to amine ratio, whereas excess of the aldehyde (≥2:1) allows second alkylation, giving rise to tertiary amines. Reductive N -alkylation of α-amino acids proceeds without racemization; the resulting products, containing a C≡C bond or N 3 group, are suitable for click chemistry. This reaction thus offers advantages over the traditional methods (borohydride reduction or catalytic hydrogenation) in terms of efficiency and chemoselectivity. Solubility of some of the reacting partners appears to be the only limitation. The byproducts generated by the workup with aqueous NaHCO 3 (i.e., NaCl and silica) are environmentally benign. As a greener alternative, DMA can be employed as a catalyst instead of DMF.