Advances in Regiocontrol and Bench Stability in Nickel Catalyzed Reductive Couplings of Aldehydes and Alkynes.

Abstract

Advances in nickel catalyzed reactions have been achieved that allow for alteration and control of the rate- and regioselectivity determining step in nickel-catalyzed aldehyde-alkyne reductive couplings for the synthesis of allylic alcohols. Combinations of ligand, reducing agent, and reaction conditions have been identified that allow access to highly regioselective outcomes that were not possible using previously developed protocols. Previous mechanistic studies have shown the rate determining step to be metallacycle-forming oxidative cyclization, however this study shows that reaction conditions can be changed so that the rate determining step can be altered for one of the two product pathways. These modified conditions render metallacycle formation reversible for one of the product pathways and sigma bond metathesis becomes rate determining. This improved mechanistic understanding has allowed access to highly regioselective outcomes for a variety of substrates that were not previously possible. The selectivity for a variety of biased alkynes has been increased to >98:2 in many cases that had previously only been ~4:1. Methodology has been developed to allow bench stable and inexpensive nickel sources to be used in reductive couplings, eliminating the need for a glove box or air sensitive reducing agents. Previous protocols have typically employed air sensitive Ni0 sources or air-sensitive reducing agents, and this methodology eliminates the need for either of these. Two different protocols have been developed to efficiently couple a variety of aldehydes and alkynes using inexpensive and bench stable NiII pre-catalysts as well as bench-stable trialkylsilane reducing agents.