The efficient construction of C–C bonds constitutes the quintessence of organic synthesis chemistry, with the unveiling of updated strategies for such bond construction significantly expanding the conceptual sphere of synthetic design and substantially elevating the liberty of synthetic exploration. As a result, the development of C–C bond-forming methodologies has attracted considerable interest. Among these, transition-metal-catalyzed coupling reactions stand out as particularly potent, exemplified by the ubiquity of Suzuki and Negishi cross-couplings in the assembly of functional molecules relevant to pharmaceuticals and materials. Nevertheless, the construction of quaternary carbon centers via C–C coupling remains challenging. These centers are prevalent in a vast array of natural and therapeutic compounds, yet their synthesis is impeded by the significant steric bulk associated with tertiary C(sp3) atoms, leading to a multitude of side reactions such as elimination and isomerization. To date, only a few successful couplings involving tertiary C(sp3) with C(sp2) and primary C(sp3) have been reported. Moreover, the coupling of tertiary C(sp3) with secondary C(sp3) has been rarely recorded with two special examples, and both used Grignard reagents as nucleophiles. Addressing this challenge is not only a key fundamental issue for synthetic chemistry but also provides a foundation toward a paradigm shift in the synthetic approach to the construction of quaternary carbons.
Recently, Shou-Fei Zhu’s group have successfully developed a type of bisphosphine ligand iron complex-catalyzed coupling reactions of tertiary alkyl halides with secondary alkyl zinc reagents and efficiently realized the coupling reaction between tertiary C(sp3) and secondary C(sp3) with high selectivity for the initial instance, which provided an efficient method for the construction of quaternary carbon centers with high steric hindrance. The combination of an iron catalyst and directing group of the substrate makes the great challenging transformation possible. J. Am. Chem. Soc., 2024, DOI: 10.1021/jacs.3c14032
