Amine to Halogen Exchange Enables an Amine-Acid Etherification

Reactions that form ethers are used broadly for pharmaceutical, fragrance, materials, and agrichemical applications. We report here an amine-acid etherification reaction that proceeds via a facile amine-halogen exchange and an ester-selective reduction. The method employs free aliphatic amines and carboxylic acids to form C(sp3)–O ether bonds directly. This method allows a diverse range of readily available alkyl amines and acids to be transformed into synthetically valuable alkyl ethers, which are challenging to access by conventional methods. The etherification reaction proves to be suitable for late-stage diversification and repurposing of building blocks to expand chemical space. Additionally, this methodology provides a straightforward approach for accessing medicinally relevant α-deuterated ethers. Reaction development was facilitated by high-throughput experimentation and computational and experimental mechanistic studies. Furthermore, the deamination strategy can be extended to other nucleo-philes, enabling the synthesis of phenolic ethers and a range of halide products. Our reaction protocol exhibited selective reduction of esters in the presence of amides, supported by both experimental and computational studies. Overall, this work establishes a versatile amine-halogen exchange as a platform for constructing structurally diverse ethers from abundant feedstocks.