Amide/Ester Cross-Coupling via C–N/C–H Bond Cleavage: Synthesis of β-Ketoesters

Abstract

Activated primary, secondary, and tertiary amides were coupled with enolizable esters in the presence of LiHMDS to obtain good yields of β-ketoesters at room temperature. Notably, this protocol provides an efficient, mild, and high chemoselectivity method to synthesis of β-alkylketoesters using the cross-coupling between aliphatic amides and esters. Meanwhile, gram-scale secondary and primary amides reacted via in situ generated activated tertiary amides and exhibited good reactivity when coupled with esters.

Classes of Amides that Undergo Selective N–C Amide Bond Activation: The Emergence of Ground-State Destabilization

“…Recently, methods on transition-metal-free N–C bond cleavage of activated amides have been reported. − …”

Transition-metal-catalyst-free reaction of amides and acetonitriles: synthesis of β-ketonitriles

“…32 Subsequently, we established that the condensation of amides and enolizable carbonyl compounds, such as ketones, esters, and amides, afforded the corresponding β-keto carbonyl compounds in the absence of transition metal catalysts when activated amides were employed (Scheme 1B-c). 33 However, the unactivated amides were not applicable in the reaction. During our studies on C–N bond activation for the reactions of amides with carbon nucleophiles, we envisioned that β-ketonitriles would be obtainable from the reaction of amides and acetonitrile.…”

Palladium and Copper‐Catalyzed Friedel–Crafts Acylation with Activated Amides

“…[6] In 2018, our group reported the nickel-catalyzed transamidation of secondary amides, producing transamidated secondary and tertiary amides. [7] Since then, both transition metal-catalyzed and metal-free conditions have been applied to facilitate the synthesis of a diverse array of compounds, including primary amides, [8] β-keto amides, [9] β-keto esters, [10] β-keto nitriles, [11] 1,3-diketones, [12] acyl fluorides, [13] and acyl azides. [14] The use of activated amides in transformation reactions has received significant attention in recent years.…”