Direct synthesis of ethers from alcohols & aldehydes enabled by an oxocarbenium ion interception strategy

Abstract

A new method has been established for formation of ethers from aldehydes and alcohols – a net reductive etherification. Reactions of these entities with phosphines in the presence of acid enable formation of α-(alkoxyalkyl)phosphonium salts, which, upon hydrolysis, result in formation of ether products in isolated yields of 63–92%. Formation and hydrolysis of the α-(alkoxyalkyl)phosphonium salts were done in an efficient telescoped two-step, one-pot process that does not require inert atmosphere conditions. Formation of the key phosphonium salt intermediates was found to occur in preference to acetal formation and is proposed based on both experimental and computational evidence to involve interception of oxocarbenium ions formed by reaction of the aldehyde, alcohol and acid by phosphine. This method represents the first instance in which net reductive etherifications have been achieved without the requirement for use of hydrides or hydrogen as reductants, and exhibits excellent functional group tolerance, thus enabling facile hydride-free synthesis of ethers. These are amongst the most important functional groups in organic synthesis. The new etherification method also enables deuteride-free synthesis of deuterated ethers.