Geometry-Constrained N,N,O-Nickel Catalyzed α-Alkylation of Unactivated Amides via a Borrowing Hydrogen Strategy

Abstract

Reported herein is a well-defined geometry-constrained tridentate N,N,O-nickel complex for selective α-alkylation of unactivated amides using readily available alcohols as the alkylating reagents. The newly developed transformation could accommodate a broad substrate scope including various substituted benzylic or aliphatic alcohols and tertiary/secondary acyclic amides or lactams. The tolerance of methanol and ethanol in this protocol provided a novel possibility of carbon chain homologation of amides. Mechanistic studies suggested that the reaction proceeds through a borrowing hydrogen pathway.

Nickel-Catalyzed Alkylation of Oxindoles with Secondary Alcohols

“…Over the past couple of years, we have established that the Ni–H species is the active catalytic intermediate and alcohol serves as a generic hydride source for such alkylation reactions . Therefore, the olefin intermediate 3′ was independently synthesized and allowed to undergo a reaction in the absence and presence of 2a , respectively.…”

“…Therefore, to gain more insight for the alkylation process, catalytic reaction 1a with phenylethan-1-ol 2a was carried out using the defined Ni-catalyst A and the desired product 3 was obtained in 87% yield (Scheme A and Scheme S1). Next, catalyst B and catalyst C were independently synthesized ([Ni­(PCy 3 ) 2 (H)­Br] and [Ni­(PCy 3 ) 2 Br 2 ]) and used for the model reaction. Notably, up to 90% yield of the desired product 3 was obtained (Scheme A).…”

“…Notably, Ni-catalyzed alkylation of amides and esters was reported using primary alcohols. However, application of a nickel catalyst for C-alkylation using secondary alcohol remains elusive (Scheme A). , …”

“…Recently, our group started a program to explore the applications of non-precious-metal-based catalysts using renewable alcohols or diols and a couple of novel protocols were demonstrated for the alkylation of amines and amides, synthesis of indoles, N -heterocycles, and olefins, etc …”

Copper-Catalyzed Borrowing Hydrogen Reaction for α-Alkylation of Amides with Alcohols

“…Catalysts have played a key role in α-alkylation of amides, which achieved the dehydrogenation of alcohols to aldehydes and the hydrogenation of intermediate α,β-unsaturated amides. Previously, efficient catalysts for these transformations of alcohols and amides were mainly based on transition-metal complexes, including ruthenium, iridium, cobalt, manganese, and nickel . However, these systems suffered from some drawbacks, such as the need for expensive, air-sensitive metal precursors and ligands to prepare metal complexes as catalysts and a limited range of substrates.…”