Lewis Acid‐Catalyzed Reductive Amination of Aldehydes and Ketones with N,N‐Dimethylformamide as Dimethylamino Source, Reductant and Solvent

Abstract

Ap ractical zinc acetate dihydrate-catalyzed reductive amination of various carbonyl compounds with N,N-dimethylformamide (DMF)a sd imethylamino (Me 2 N) source,r eductant and solvent has been developed. This reactions howsb road substrate scope,g oodf unctional group tolerance,a voids the need for ap ressure-proof reactor and column chromatographic isolation operationsa nd gives up to 98% yield,t om akei ta na ttractivem ethod for the preparation of tertiary N,N-dimethylamines.

Synthesis of tertiary amines by direct Brønsted acid catalyzed reductive amination

“…Two equivalents of water were found to be sufficient to mediate the reaction, whilst previous methods required excess amounts. [12] Lowering the catalyst loading led to longer reaction times but the overall product yield was not significantly affected by this parameter (see Table S2 in the ESI). [13] In order to aim for a broader substrate scope later on where the formamide is less readily available and cannot be used as solvent, we also explored the effect of solvents when using DMF only as a reactant.…”

“…To the best of our knowledge, however, no direct Brønsted acid catalyzed reductive amination method has been reported, except for some non-systematic examples with unsatisfactory outcomes in literature. [12] Herein we discuss the development of simple yet practical protocols using triflic acid as catalyst to efficiently promote reductive amination reactions of carbonyl compounds on a broad range of substrates (Scheme 1). Our procedure is not only applicable to DMF but also other formamides to form a diverse library of tertiary amine products.…”

Base‐Mediated Generation of Ketenimines from Ynamides: [3+2] Annulation with Azaallyl Anions

“…Considering all these results, a plausible mechanistic proposal was outlined and validated using DFT calculations (Scheme 5a). Under the strongly basic conditions, and possibly with the assistance of the zinc Lewis acid, [31] partial decomposition of the DMF to give lithium dimethylamide would be the trigger to initiate the cleavage of the Boc protecting group of ynamide 1 giving semi‐stabilized amide 10 that protonates to give ketenimine 2 . The generation of dimethylamine in the reaction mixture was confirmed by the isolation of amidines 15 , 15‐ D 6 (when DMF‐ D 7 was used) and 16 (Scheme 5b).…”

Synthesis of Tertiary Amines by Direct Brønsted Acid Catalyzed Reductive Amination

“…Bromobenzyl)pyrrolidine12 (compound number 4b): Prepared using the general procedure from 4-bromobenzaldehyde and 1-formylpyrrolidine to give the title compound as a yellow liquid (180 mg, 75% yield).1 H NMR (400 MHz, CDCl3) d 7.52 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 3.92 (s, 2H), 2.94 (m, 4H), 2.00 (m, 4H) ppm; 13 C NMR (100 MHz, CDCl3) d 132.…”