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 can be challenging to access by conventional methods. Our etherification reaction is suitable for late-stage diversification and building block repurposing to expand chemical space access. Additionally, this methodology provides straightforward access to 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 nucleophiles, enabling the synthesis of phenolic ethers and a range of halide products from amines. Critically, the distinct recipe of etherification reagents we identified enables selective reduction of esters in the presence of secondary amides and distinctly promotes the one-pot amine-acid etherification, whereas related conditions for ester reduction cannot. Overall, this work establishes a versatile amine-halogen exchange as a platform for constructing structurally diverse ethers from abundant feedstocks.