The Development of Catalytic Nucleophilic Additions of Terminal Alkynes in Water

摘要

One of the major research endeavors in synthetic chemistry over thenpast two decades is the exploration of synthetic methods thatnwork under ambient atmosphere with benign solvents, that maximizenatom utilization, and that directly transform natural resources, such asnrenewable biomass, from their native states into useful chemical products, thus avoiding the need for protecting groups.nThe nucleophilic addition of terminal alkynes to various unsaturated electrophiles is a classical (textbook) reaction innorganic chemistry, allowing the formation of a C C bond while simultaneously introducing the alkyne functionality.nA prerequisite of this classical reaction is the stoichiometric generation of highly reactive metal acetylides.nOver the past decade, our laboratory and others have been exploring an alternative, the catalytic and direct nucleo-nphilic addition of terminal alkynes to unsaturated electrophiles in water. We found that various terminal alkynes cannreact efficiently with a wide range of such electrophiles in water (or organic solvent) in the presence of simple andnreadily available catalysts, such as copper, silver, gold, iron, palladium, and others. In this Account, we describe thendevelopment of these synthetic methods, focusing primarily on results from our laboratory.nOur studies include the following: (i) catalytic reaction of terminal alkynes with acid chloride, (ii) catalytic addi-ntion of terminal alkynes to aldehydes and ketones, (iii) catalytic addition of alkynes to CdN bonds, and (iv) catalyticnconjugate additions. Most importantly, these reactions can tolerate various functional groups and, in many cases, per-nform better in water than in organic solvents, clearly defying classical reactivities predicated on the relative aciditiesnof water, alcohols, and terminal alkynes. We further discuss multicomponent and enantioselective reactions that werendeveloped.nThese methods provide an alternative to the traditional requirement of separate steps in classical alkyne reac-ntions, including the pregeneration of metal acetylides with stoichiometric, highly basic reagents and the preprotec-ntion of sensitive functional groups. Accordingly, these techniques have greatly enhanced overall synthetic efficienciesnand furthered our long-term objective of developing Grignard-type reactions in water.