Catalytic Mitsunobu Reaction

Significance

An interesting variant of the Mitsunobu reaction is described. Diethyl azodicarboxylate (DEAD, 1), which is normally required stoichiometrically, is used catalytically (10 mol%) in the presence of PhI(OAc)₂ as the stoichiometric re-oxidant. In general, aromatic and aliphatic carboxylic acids as well as Boc-protected amino acids could be employed as pronucleophiles 2. Several primary alcohols 3 served as electrophiles giving moderate to good yields (54-88%) of esters 4. Compared to non-catalytic versions, the yields were slightly lower. If secondary alcohols were used, triphenylphosphine addition had to be very slow (0.25 equiv/h) to achieve reasonable yields of Mitsunobu products 4. Surprisingly, in all cases a background reaction took place, yielding up to 50% of the desired product.