Insights into Recent Nickel-Catalyzed Reductive and Redox C–C Coupling of Electrophiles, C(sp 3 )–H Bonds and Alkenes

Conspectus Transition metal-catalyzed reductive cross-coupling of two carbon electrophiles, also known as cross-electrophile coupling (XEC), has transformed the landscape of C–C coupling chemistry. Nickel catalysts, in particular, have demonstrated exceptional performance in facilitating XEC reactions, allowing for diverse elegant transformations by employing various electrophiles to forge C–C bonds. Nevertheless, several crucial challenges remain to be addressed. First, the intrinsic chemoselectivity between two structurally similar electrophiles in Ni-catalyzed C(sp 3 )–C(sp 3 ) and C(sp 2 )–C(sp 2 ) cross-coupling has not been well understood; this necessitates an excess of one of the coupling partners to achieve synthetically useful outcomes. Second, the substitution of economically and environmentally benign nonmetal reductants for Zn/Mn can help scale up XEC reactions and avoid trace metals in pharmaceutical products, but research in this direction has progressed slowly. Finally, it is highly warranted to leverage mechanistic insights from Ni-catalyzed XEC to develop innovative thermoredox coupling protocols, specifically designed to tackle challenges associated with difficult substrates such as C(sp 3 )–H bonds and unactivated alkenes. In this Account, we address the aforementioned issues by reviewing our recent work on the reductive coupling of C–X and C–O electrophiles, the thermoredox strategy for coupling associated with C(sp 3 )–H bonds and unactivated alkenes, and the use of diboron esters as nonmetal reductants to achieve reductive coupling. We focus on the mechanistic perspectives of the transformations, particularly how the key C–Ni III –C intermediates are generated, in order to explain the chemoselective and regioselective coupling results. The Account consists of four sections. First, we discuss the Zn/Mn-mediated chemoselective C(sp 2 )–C(sp 2 ) and C(sp 3 )–C(sp 3 ) bond formations based on the coupling of selected alkyl/aryl, allyl/benzyl, and other electrophiles. Second, we describe the use of diboron esters as versatile reductants to achieve C(sp 3 )–C(sp 3 ) and C(sp 3 )–C(sp 2 ) couplings, with an emphasis on the mechanistic consideration for the construction of C(sp 3 )–C(sp 2 ) bonds. Third, we discuss leveraging C(sp 3 )–O bonds for effective C(sp 3 )–C bond formation via in situ halogenation of alcohols as well as the reductive preparation of α-vinylated and -arylated unusual amino esters. In the final section, we illustrate the thermoredox functionalization of challenging C(sp 3 )–H bonds with aryl and alkyl halides to afford C(sp 3 )–C bonds by taking advantage of the compatibility of Zn with the oxidant di- tert -butylperoxide (DTBP). Furthermore, we discuss a Ni-catalyzed and SiH/DTBP-mediated hydrodimerization of terminal alkenes to selectively forge head-to-head and methyl branched C(sp 3 )–C(sp 3 ) bonds. This process, conducted in the presence or absence of catalytic CuBr 2, provides a solution to a long-standing challenge: site-selective hydrocoupling of unactivated alkenes to produce challenging C(sp 3 )–C(sp 3 ) bonds.