In Science this week Beddoe et al. report on a catalytic Mitsunobu reaction (DOI). The classic Mitsunobu is a seemingly simple reaction of an alcohol with an acid to form an ester but with two improbable stoichiometric additives triphenyl phoshine and DEAD. The reaction mechanism is bewildering but the reaction has key advantages: inversion of stereochemistry and friendly to secondary alcohols.
In previous efforts towards a catalytic version only one of the two additives was catalytic and even then with use of sacrificial catalysts. The new effort promises true catalysis. With substrates an unactivated alcohol and an organic acid the catalyst with 10% loading is organocatalyst (2-hydroxybenzyl)diphenylphosphine oxide. The experimental setup is refluxing xylenes in a Dean-Stark apparatus as the only byproduct is water that needs to be removed from the reaction. In terms of mechanism: the nucleophilic acid (ROOH) dehydrates the catalyst forming a ROO- Ar-O-P+(Ph)2-R oxyphosphonium salt. The alcohol then brings about ring-opening to a alkoxyphosphonium-nucleophile ion pair with a classic substition in the final step. A related reaction (also with stereoinversion) would be the Tsuji-Trost reaction. The nucleophiles have a specific acidity window 3.4 to 1.5. Optimal results with lower catalyst concentration and longer reaction times. Patience pays of.