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

• Published in: Journal of organic chemistry Vol. 87; no. 2; pp. 920 - 943
• Main Authors: Popov, Kirill K, Campbell, Joanna L. P, Kysilka, Ondřej, Hošek, Jan, Davies, Christopher D, Pour, Milan, Kočovský, Pavel
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 21-01-2022
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.1c01561

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 CH2Cl2 at room temperature. The reduction tolerates ketone carbonyls, esters, amides, nitriles, sulfones, sulfonamides, NO2, SF5, and CF3 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 N3 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 NaHCO3 (i.e., NaCl and silica) are environmentally benign. As a greener alternative, DMA can be employed as a catalyst instead of DMF.