Nickel‐Catalysis Enabling α‐Alkylation of Ketones by Secondary Alcohols

Abstract

The α-alkylation of ketones utilizing a secondary alcohol has been accomplished by an isolable, bench-stable, inexpensive nickel catalyst affording high yields of β,β-disubstituted products. This report contributes a nickel catalyst in the pool of a few scarce examples of base metal discovered for this purpose. The substrate scope can span a wide range including aliphatic, alicyclic, and cyclic secondary alcohols. Functionalization of a cholesterol molecule is also possible following this methodology. The catalyst can interconvert between azo and hydrazo form in a reversible fashion to enable this chemical transformation.

Mechanistic Elucidation of a Radical‐Promoted Hydrogenation Relevant to Borrowing Hydrogen Catalysis

“…To endeavor C-alkylation of a ketone by utilizing secondary alcohol as the source of alkyl group, we recently forged β, βdisubstituted ketone products utilizing nickel catalyst 1. [14] The starting ketone in this reaction is ortho-di-substituted phenyl acetophenone, and the steric protection of the aryl ketone is very much required to stop detrimental condensation and Cannizaro-type reactions. [15] The major design principle behind our catalyst 1 is the redox-responsive azo arm in the azo-phenolate ligand, which is easy to reduce given its low-lying π* orbital.…”

“…At the end of such dehydrogenation reaction the catalyst remains in the form of 1 H,H that will be used to hydrogenate an in situ‐ generated enone. We previously disclosed that both 1‐phenyl ethanol and cyclohexanol were appropriate secondary alcohol substrates that afforded β , β ‐dialkylated products in 69 % and 82 % yields [14] . To mechanistically interrogate the hydrogenation of enone further, we chose cyclohexanol as the model substrate.…”

“…In stark contrast, a hydrogenation via radical pathway, adopting one‐electron HAT without the involvement of metal hydride is very much rare in BH catalysis [12] . Our current interest is focused to base metal‐catalysis where ligand‐based redox plays a preeminent role [13] Along the mechanistic probation of an α‐alkylation reaction, [14] we present in this report a complementary radical mechanism of hydrogenation to an olefinic bond, which completely bypasses the traditional metal‐hydride pathway (Figure 2). Interestingly, such radical‐based hydrogenation is chemoselective and reduces only the double bond of an enone substrate sparing the carbonyl functionality.…”

Phosphine‐Free Pincer Ruthenium‐Catalyzed α‐Alkylation of Ketones with Secondary Alcohols to form β‐Branched Ketones

“…It has been mostly addressed by employing a sterically bulkier aryl ketone as the carbonyl substrate. Inspired by this seminal work, Sundararaju, [7b] Renaud, [7c] Maji, [7d] and Adhikari [7e] have demonstrated the synthesis of β ‐branched carbonyl compounds with pentamethyl phenyl (Ph*) ketone or trisubstituted aryl ketones as the coupling partner. However, this methodology was found to be less‐successful in the case of unsubstituted and non‐hindered aryl ketones and thus, suffers from a limited substrate scope.…”

Fe3O4@CS‐Ni: An efficient and recyclable magnetic nanocatalyst for α‐alkylation of ketones with benzyl alcohols by borrowing hydrogen methodology

“…[18,22] Moreover, although some nickel-catalyzed α-alkylation of ketones with primary alcohols has been reported, they involve a homogeneous catalytic system and need specific ligands. [23,24] Nevertheless, in spite of the impressive developments achieved in these reactions, recovery and reutilization of homogeneous catalysts are still a big challenge. [25] A promising alternative is heterogeneous supports due to their simple separation from the reaction mixture and reutilization.…”