Mitsunobu reaction

In a typical protocol, one dissolves the alcohol, the carboxylic acid, and triphenylphosphine in tetrahydrofuran or other suitable solvent (e.g. diethyl ether), cool to 0 °C using an ice-bath, slowly add the DEAD dissolved in THF, then stir at room temperature for several hours.

[2] The alcohol reacts with the phosphine to create a good leaving group then undergoes an inversion of stereochemistry in classic SN2 fashion as the nucleophile displaces it.

A common side-product is produced when the azodicarboxylate displaces the leaving group instead of the desired nucleophile.

Initially, the triphenyl phosphine (2) makes a nucleophilic attack upon diethyl azodicarboxylate (1) producing a betaine intermediate 3, which deprotonates the carboxylic acid (4) to form the ion pair 5.

To preform the betaine, add DEAD to triphenylphosphine in tetrahydrofuran at 0 °C, followed by the addition of the alcohol and finally the acid.

[20] Denton and co-workers have reported a redox-neutral variant of the Mitsunobu reaction which employs a phosphorus(III) catalyst to activate the substrate, ensuring inversion in the nucleophilic attack, and uses a Dean-Stark trap to remove the water by-product.

[21] Tsunoda et al. have shown that one can combine the triphenylphosphine and the diethyl azodicarboxylate into one reagent: a phosphorane ylide.

The reaction has been used to synthesize quinine, colchicine, sarain, morphine, stigmatellin, eudistomin, oseltamivir, strychnine, and nupharamine.