Cu Single-Atom Sites for Electrochemical Cross-Coupling Epoxidation of Alkenes

Abstract The construction of the tetrahydrofuran (THF) ring is one of the central challenges in the synthesis of nucleoside analogues, which play a vital role in advancing the treatment of viral infectious diseases and tumor chemotherapy. Thus, mild and straightforward construction of the THF ring can effectively shorten the total number of synthetic steps for many related products. Herein, we report a heterogeneous electrocatalytic cross-coupling epoxidation route for the one-step synthesis of 2,5-differentially substituted THF derivatives. By tuning the ratio of functional groups within the covalent polymer-supported Cu single-atom-site catalysts, we observed significant changes in the electronic environment of the Cu sites using EXAFS and XPS, and these changes were reflected in distinct catalytic activities. Among them, the optimal catalyst, Cu-0.5BPh0.5BPy, exhibits excellent performance with >95% conversion under mild conditions using H2O as the oxygen source at room temperature. Combined with a selective cross-coupling strategy that leverages the potential difference between substrates, using 4-chlorostyrene and 1,1-diphenylethylene as examples, excellent cross-coupling yields of ∼90% were achieved. Furthermore, this strategy was extended to the synthesis of a broad range of THF derivatives and a uracil nucleoside analogue. Moreover, we demonstrate durable electrolysis operation for 48 h in a flow reactor and gram-level production of the cross-coupled product with an overall yield of approximately 73%.