Enamines as Surrogates of Alkyl Carbanions for the Direct Conversion of Secondary Amides to α‐Branched Ketones

Abstract

A direct transformation of secondary amides into a-branched ketones with enamines as soft alkylation reagents was developed. In this reaction, enamines serve as surrogates of alkyl carbanions, rather than the conventional enolates equivalents in the Stork's reactions, which allowed for the easy introduction of alkyl groups with electrophilic functional groups. In the presence of 4 Å molecular sieves, the method can be extended to the one-pot coupling of secondary amides with aldehydes to yield ketones.

Cross‐Coupling of Secondary Amides with Tertiary Amides: The Use of Tertiary Amides as Surrogates of Alkyl Carbanions for Ketone Synthesis

“…Very recently, our group have developed two organometallic reagent‐free syntheses of ketones from secondary amides . The method relies on the nucleophilic addition of enamines[14a] or alkenes[14b] to nitrilium ion intermediates, generated in situ from secondary amides, and on the subsequent in situ deformylation. In view of the possibility of catalytic partial reduction of tertiary amides to enamines, the use of the former as precursor of the latter for C—C bond formation was envisaged.…”

“…In 2015, our group reported the first versatile direct transformation of common tertiary amides to ketones [7e]. Very recently, our group have developed two organometallic reagent‐free syntheses of ketones from secondary amides . The method relies on the nucleophilic addition of enamines[14a] or alkenes[14b] to nitrilium ion intermediates, generated in situ from secondary amides, and on the subsequent in situ deformylation.…”

Ti-Catalyzed Modular Ketone Synthesis from Carboxylic Derivatives and gem-Dihaloalkanes

“…In this context, traditional methods mainly involve nucleophilic additions of organometallic reagents to carbonyl compounds, such as Weinreb ketone synthesis (Figure a), and aromatic substitutions, including Friedel–Crafts acylations . Notably, Huang’s group and Charette’s group independently reported the versatile transformation of unactivated secondary amides into ketones by adding organometallic reagents to in situ generated electrophilic imidoyl triflate intermediates. Recently, remarkable progress has been made in the transition-metal (e.g., Pd, Ni, etc.)…”

Chemoselective Reactions of Isocyanates with Secondary Amides: One-Pot Construction of 2,3-Dialkyl-Substituted Quinazolinones

“…Normal nucleophiles include highly reactive organometallic reagents, such as Grignard reagents, organolithium reagents, and organocerium reagents . Recently, a series of metal-free intermolecular coupling reactions of secondary amides with weak nucleophiles, such as alkenes, alkynes, isocyanoacetates, isocyanides, enamines, and imines, have been reported. Organic isocyanates are broadly used reagents in academia and industry, particularly in the synthesis of agrochemicals, pharmaceuticals, and polymers .…”