Nickel-Catalyzed Reductive Alkenylation of Enol Derivatives: A Versatile Tool for Alkene Construction.

ConspectusKetone-to-alkene transformations are essential in organic synthesis, and transition-metal-catalyzed cross-coupling reactions involving enol derivatives have become powerful tools to achieve this goal. While substantial progress has been made in nucleophile-electrophile reactions, recent developments in nickel-catalyzed reductive alkenylation reactions have garnered increasing attention. These methods accommodate a broad range of functional groups such as aldehyde, ketone, amide, alcohol, alkyne, heterocycles, and organotin compounds, providing an efficient strategy to access structurally diverse alkenes. This Account primarily highlights the contributions from our laboratory to this growing field while also acknowledging key contributions from other researchers.Our early efforts in this area focused on coupling radical-active substrates, such as α-chloroboronates. This method follows the conventional radical chain mechanism, resulting in facile access to valuable allylboronates. Encouraged by these promising results, we subsequently expanded the substrate scope to encompass radical-inactive compounds. By developing new strategies for controlling cross-selectivity, we enabled the coupling of Csp electrophiles (e.g., alcohols and sulfonates), Csp electrophiles (e.g., bromoalkenylboronates and acyl fluorides), and heavier group-14 electrophiles like chlorosilanes and chlorogermanes with alkenyl triflates. These advances have provided efficient synthetic routes to a wide range of valuable products, including aliphatic alkenes, enones, dienylboronates, and silicon- and germanium-containing alkenes. Notably, these methods are particularly effective for synthesizing functionalized cycloalkenes, which are traditionally challenging to obtain through conventional methods involving alkenyl halide or organometallic couplings. We have also extended the scope of enol derivatives from triflates to acetates. These compounds are among the most accessible, stable, cost-effective, and environmentally friendly reagents, while their application in cross-coupling has been hampered by low reactivity and selectivity challenges. We showcased that by the use of a Ni(I) catalyst, alkenyl acetates could undergo reductive alkylation with a broad range of alkyl bromides, yielding diverse cyclic and acyclic aliphatic alkenes.Furthermore, our work has demonstrated that reductive coupling of enol derivatives with alkenes provides a highly appealing alternative for alkene synthesis. Particularly, this approach offers opportunity to address the regioselectivity challenges encountered in conventional alkene transformations. For instance, achieving regioselective hydrocarbonation of aliphatic 1,3-dienes has been a longstanding challenge in synthetic chemistry. By using a phosphine-nitrile ligand, we developed a nickel-catalyzed reductive alkenylation of 1,3-dienes with alkenyl triflates, delivering a diverse array of 1,4-dienes with high 1,2-branch selectivity (>20:1) while preserving the geometry of the C-C double bond. Additionally, our investigations laid the foundation for enantioselective reductive alkenylation methodologies, offering new pathways for constructing enantioenriched diketones as well as complex carbo- and heterocyclic compounds. The introduced alkenyl functionality can be further diversified, enhancing molecular diversity and complexity.