Catalytic Formal Conjugate Addition: Direct Synthesis of δ-Hydroxynitriles from Nitriles and Allylic Alcohols

Abstract

Alcohols and nitrile functionalities have widespread applications in biochemical and chemical synthesis. Catalytic transformations involving C−C bond formation relying on unsaturated coupling partners create important pathways for processes in synthetic, material, and medicinal chemistry. The discovery of a simple and selective coupling of nitriles with allylic alcohols catalyzed by a ruthenium pincer complex is described, which tolerates reactive functional groups such as carbamate, sulfonate, olefin, cyano, and trifluoromethyl-substituted benzyl nitriles. Homo allylic alcohols also provided 1,4-addition products following the isomerization of double bonds. Mechanistic studies supported that the allylic alcohols initially undergo selective oxidation by the catalyst to α,β-unsaturated carbonyl compounds followed by 1,4-conjugate addition of benzyl nitriles catalyzed by a base and subsequent catalytic reduction of carbonyl functionality, leading to the formation of δ-hydroxynitrile products. The catalytic cycle of this tandem process is established by density functional theory studies. Remarkably, anipamil drug is successfully synthesized using this catalytic protocol. The utility of the δ-hydroxynitrile products in the synthesis of biologically active molecules and their further functionalization are also demonstrated.

Ruthenium-catalysed α-prenylation of ketones using prenol

“…The reaction of I with prenol involves amine-amide metal-ligand cooperation leading to O-H activation via intermediate II, which generates 3-methyl-2-butenal, and forms a ruthenium dihydride complex III. 20,25 In situ generated 3-methyl-2-butenal undergoes a base-and metal-mediated concomitant condensation reaction with the ketone and delivers an α,β-unsaturated chalcone in which the enone functionality is hydrogenated by ruthenium dihydride intermediate III involving a cyclic transition state IV. 20 This selective hydrogenation of electron-deficient conjugated alkene releases the prenylated product and regenerates the active catalyst I to complete the catalytic cycle.…”

“…19 Recently, a formal conjugate addition of nitriles with allyl alcohol was established, leading to the direct synthesis of δ-hydroxynitriles (Scheme 1c). 20 Herein, we report the alpha-prenylation of ketones directly from prenol (Scheme 1d). Notably, water is the only byproduct in the reaction.…”

Progressive study on ruthenium catalysis for de(hydrogenative) alkylation and alkenylation using alcohols as a sustainable source

“…The deuterium labelling experiments supported the proposed mechanism. In 2022, the same group 56 developed an efficient and convenient method for the conjugate addition of nitriles with allyl alcohols to form δ-hydroxynitriles using 1.0 mol% of Ru-MACHO pincer catalyst ( Ru-4 ) and 2.0 mol% of weak base K 2 CO 3 (Scheme 42). This new strategy explored the conjugate addition of diverse arylmethyl nitrile with a range of both primary and secondary alcohols.…”

Recent advances in C/N-alkylation with alcohols through hydride transfer strategies

“…Recently, Gunanathan's research group achieved the C-C coupling of aryl acetonitriles with allyl alcohols using [Ru-4] based on the borrowing hydrogen route (Scheme 13). 27 In this approach, oxidizing the allyl alcohol generates the α,β-unsaturated ketone/aldehyde, which is able to participate in Michael additions with aryl acetonitriles acting as the Michael donors. The unique feature of the protocol is the non-stoichiometric usage of the base.…”