Salt-stabilized alkylzinc pivalates: versatile reagents for cobalt-catalyzed selective 1,2-dialkylation

The construction of Csp(3)-Csp(3) bonds through Negishi-type reactions using alkylzinc reagents as the pronucleophiles is of great importance for the synthesis of pharmaceuticals and agrochemicals. However, the use of air and moisture sensitive solutions of conventional alkylzinc halides, which show unsatisfying reactivity and limitation of generality in twofold Csp(3)-Csp(3) cross-couplings, still represents drawbacks. We herein report the first preparation of solid and salt-stabilized alkylzinc pivalates by OPiv-coordination, which exhibit enhanced stability and a distinct advantage of reacting well in cobalt-catalyzed difluoroalkylation-alkylation of dienoates, thus achieving the modular and site-selective installation of CF2- and Csp(3)-groups across double bonds in a stereoretentive manifold. This reaction proceeds under simple and mild conditions and features broad substrate scope and functional group compatibility. Kinetic experiments highlight that OPiv-tuning on the alkylzinc pivalates is the key for improving their reactivity in twofold Csp(3)-Csp(3) cross-couplings. Furthermore, facile modifications of bioactive molecules and fluorinated products demonstrate the synthetical utility of our salt-stabilized alkylzinc reagents and cobalt-catalyzed alkyldifluoroalkylation protocol.

Automated summary

The construction of Csp(3)-Csp(3) bonds using alkylzinc reagents through Negishi-type reactions is highly important for the synthesis of pharmaceuticals and agrochemicals. However, the conventional alkylzinc halides have limitations in terms of reactivity and generality. In this study, we successfully prepared solid and salt-stabilized alkylzinc pivalates by OPiv-coordination, which exhibited enhanced stability and excellent reactivity in a cobalt-catalyzed difluoroalkylation-alkylation of dienoates, allowing for the selective installation of CF2- and Csp(3)-groups across double bonds.