Mechanochemical Mitsunobu Reactions

A Mitsunobu process performed under neat grinding conditions, using a mixer mill, is reported. It proceeds in the absence of reaction solvent and in short reactions times (10-20 min). A broad substrate scope encompassing primary and secondary alcohols, as well as oxygen, nitrogen, sulfur, and carbon-centered nucleophiles is demonstrated. Application to the functionalization of a selection of APIs is shown, also. The developed process is amenable to scale up on a planetary ball-mill, yielding over 2 grams of product. Finally, a representative alcohol is inverted with excellent stereoselectivity. + image