Direct Synthesis of <i>Gem</i>-β,β′-Bis(alkyl) Alcohols Using Nickel Catalysis via Sequential DCR Approach
Lalit Mohan Kabadwal, Atanu Bera, Debasis Banerjee
Abstract
Chemoselective synthesis of functionalized gem-β,β′-bis(alkyl)alcohols by coupling of a β-alkylated secondary alcohol with a primary alcohol is reported using nickel via sequential DCR (dehydrogenation–condensation–rehydrogenation) approach. Using our method, 1-arylethanol and benzyl alcohols undergo a one-pot successive double alkylation reaction to form functionalized alcohols. Methanol, C2–C12 alcohols, citronellol, and fatty acid-derived oleic alcohols are tolerated, including late-stage functionalization of steroid hormones (cholesterol and testosterone) and 5-pregnen-3β-ol-20-one. The catalytic transformations enabled the synthesis of donepezil drug (used for Alzheimer’s disease), N -heteroarenes (quinoline and acridine), including chromane and intermediate flavan derivatives. Hammett kinetic plot analysis of differently p -substituted benzyl alcohols with 1-phenyl propanol indicated that the oxidation of benzyl alcohol might be the rate-determining step and expected a strong influence of substitution on the reaction kinetics. A negative ρ value (−0.60) strongly signify the formation of the positive charge on benzyl alcohol. Preliminary mechanistic investigation revealed that the dehydrogenation of alcohol to aldehyde is the rate-determining step as it involves the C–H/D bond breaking of the alcohol, and a P H / P D value of 6.0 was calculated. Reaction profile studies, EPR experiments, Hammett-plot studies, cyclic voltammetry, and UV–visible experiments, including XPS analysis, indicated the structural and electronic changes at the Ni-center as well as the behavior of the catalysts and alcohols during the progress of the reactions.