Radical C−H Alkylation with Ethers and Unactivated Cycloalkanes toward the Assembly of Tetrasubstituted Amino Acid Derivatives

Abstract

A radical α−C−H alkylation of a collection of N‐picolinamide amino acid derivatives with ethers and cycloalkanes as chemical feedstock is described. This cross‐dehydrogenative coupling is distinguished by its reliable scalability and removable auxiliary group, and enables the assembly of a variety of tri‐ and tetrasubstituted amino acid compounds.

Modular Synthesis of α-Aryl-α-Heteroaryl α-Amino Acid Derivatives via a Copper-Catalyzed Cross-Dehydrogenative-Coupling Reaction Using Air as the Sole Oxidant

“…Recently, we disclosed our pioneering findings on iron and nickel-catalyzed CDC reaction of α-tertiary α-AAs with different coupling partners for the preparation of diverse of α-(hetero)aryl-α-alkyl and α,α-dialkyl α-AA scaffolds with the assistance of 2-picolinamide as an efficient auxiliary . Inspired by our strategy, Correa’s group showed that ethers and cycloalkanes were suitable reaction partners and gained access to tri- and tetrasubstituted α-AA derivatives . More recently, Yazaki and Ohshima developed an efficient copper-catalyzed CDC process between α-AA Schiff bases and hydrocarbon feedstocks for the synthesis of sterically hindered α,β-tetrasubstituted α-AA precursors .…”

“…Based on the above observations and previous reports, ,, the plausible mechanism for this CDC process is proposed in Scheme c. Initially, the 2-picolinamide substrate acts as a ligand to coordinate with Cu(II) to generate intermediate IM1 .…”

“…9 Inspired by our strategy, Correa's group showed that ethers and cycloalkanes were suitable reaction partners and gained access to tri-and tetrasubstituted α-AA derivatives. 10 More recently, Yazaki and Ohshima developed an efficient copper-catalyzed CDC process between α-AA Schiff bases and hydrocarbon feedstocks for the synthesis of sterically hindered α,βtetrasubstituted α-AA precursors. 11 Following our continuous interest in synthesis of unnatural α-AA s, 9,12 herein we demonstrate a straightforward copper-catalyzed CDC protocol that allows for the modular assembly of α-aryl-α-heteroaryl α-AA derivatives between readily accessible arylglycine derivatives and commercially available N-heteroarenes by utilizing air as the sole oxidant (Scheme 1b).…”