Mechanistic Study on Copper-Catalyzed C(sp ³ )–H Alkylation of Amino Acid Schiff Bases for Synthesis of Highly Congested Unnatural α-Amino Acids

Unnatural α-amino acids with sterically congested centers are valuable in pharmaceuticals and materials science, yet their synthesis mechanism remains unclear. This study uses DFT calculations to clarify the mechanism of Cu-catalyzed C(sp³)-H alkylation of amino acid Schiff bases with tertiary alkyl bromides for constructing such compounds. Key findings include the following: the reaction proceeds via a Cu(II)-Cu(I)-Cu(II) redox cycle without Cu(III) intermediates; Cu(II)-acetate promotes aza-allyl radical (<b>R</b>_<b>1</b><b>·</b>) formation through single-electron transfer (SET); the tertiary alkyl radical (<b>R</b>_<b>2</b><b>·</b>) is generated via halogen-atom transfer (XAT) by the Cu(I)-deprotonated Schiff base complex rather than the previously proposed Cu(I)-acetate complex; and <b>R</b>_<b>1</b><b>·</b> preferentially undergoes heterocoupling with <b>R</b>_<b>2</b><b>·</b> over homocoupling to form the desired product. These findings clarify experimentally ambiguous mechanistic issues, explain why the expected heterocoupled product rather than self-coupled byproducts is obtained, and provide important theoretical insights for developing efficient synthetic methods for unnatural α-amino acids.