Amine-to-Halogen Exchange Enables an Amine–Acid Etherification

TL;DR

A new method for creating ether compounds uses amine and acid reactions, enabling easier synthesis of valuable chemicals and medicines.

Contribution

A novel amine–acid etherification method is introduced, enabling direct C–O bond formation from readily available amines and acids.

Findings

The method allows diverse alkyl amines and acids to form valuable alkyl ethers efficiently.

The reaction enables late-stage diversification and synthesis of medicinally relevant α-deuterated ethers.

The approach includes a deamination strategy extendable to phenolic ethers and halide products.

Abstract

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.

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