Engaging α-Oxy Radicals in Nickel-Catalyzed Cross Coupling Reactions

Abstract

Transition metal-catalyzed cross coupling reactions have transformed the way in which chemists construct the C–C framework of organic molecules. This strategy has seen broad use in a variety of chemical industries including pharmaceuticals, agrochemicals, materials science, and academic total syntheses. The success of this approach stems in large part due to the robust and functional group tolerant conditions by which these reactions proceed, making cross coupling a quite modular way to stitch together C(sp2)–C(sp2) bonds. In contrast the use of alkyl electrophiles in cross coupling to form C(sp3) bonds remains a challenge, due in part to the lack of catalyst systems that are capable of engaging these reaction partners.

We have developed a nickel-catalyzed cross coupling approach for the synthesis of alkyl ethers utilizing acetals as unconventional electrophiles. The combination of a Lewis acid and a reductant generates α-oxy radicals in situ that are capable of undergoing cross coupling with aryl halides. This C–C bond-forming approach allows for the synthesis of alkyl ethers under quite mild conditions and without the need for base.

The strategy of using α-oxy radicals as viable cross coupling partners has been extended to create a broad reactivity platform. Acyl, vinyl, and even alkyl electrophiles can be utilized in conjunction with these radicals to generate a variety of α-substituted ethers. Excellent chemoselectivity is observed even when using coupling partners that have functionality that is typically considered to be incompatible with radical reactions.

Detailed studies of a nickel-containing catalytic intermediate have shed light on the origin of chemoselectivity and have revealed an important parameter that should be considered when selecting a ligand for catalysis.