Expedient Method for Direct Mono-amidation of Phosphonic and Phosphoric Acids

06 April 2020, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Mono-amidated P(V) pro-drugs predominately contribute to the vastly improved delivery of phosphate and phosphonate-containing anti-viral/cancer nucleotide analogues. However, synthetic approaches towards their formation are often harsh and unreliable, which may hamper the identification of novel, more effective amine pro-drugs. Here, we show that direct mono-amidation of structurally complex phosphonic and phosphoric acids may be accomplished in as quickly as seconds by re-purposing the PPh3/DIAD redox pair. Where the triphenylphosphine oxide byproduct is often cited as a vulnerability, we use its formation as an asset. Juxtaposing the anionic nature of the generated mono-amidated product, the desired product may be isolated with a single water extraction. Compared to state-of-the-art strategies towards phosphoramidates, our approach is mild, reliable, and enables access to a variety of aliphatic and benzylic amines for pro-drug attachment.


Mitsunobu reaction
amidation methods

Supplementary materials

SI ChemRxiv


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