Angew.Chem.Int.Ed.http://doi.org/f2bdvd(2013)

First reported in 1967, the Mitsunobu reaction is a methodology widely used to activate alcohols towards reaction with nucleophiles. In its original incarnation, it is used to form esters from the reaction of alcohols and carboxylic acids, but similar conditions can be used to react alcohols with a variety of nucleophiles including azides, imides, phenols and sulfonamides. Activation of the alcohol is achieved through reaction with a stoichiometric combination of an azodicarboxylate and a phosphine, which, at the end of the reaction, produce waste in the form of a hydrazine dicarboxylate and a phosphine oxide. Even putting aside the environmental issue posed by such waste, these by-products can be difficult to separate from the desired reaction products.

Now, Tsuyoshi Taniguchi and co-workers from Kanazawa University, Japan, have developed conditions under which the hydrazine component of this waste can be recycled so that it may be used catalytically. The research team had previously reported the use of an iron(ii) phthalocyanine catalyst for aerobic oxidation of a hydrazine monocarboxylate, and wondered if this reaction might be applied in the context of a Mitsunobu reaction. Hydrazine dicarboxylate had to be replaced with arylhydrazine carboxylate for an effective aerobic oxidation, and the team then showed that this could be applied in a modified Mitsunobu setting. Recent work from other research groups has described phosphine oxides that can be recycled for application in the Wittig reaction — it remains to be seen whether the two procedures could be combined to effect a Mitsunobu reaction that is catalytic in all the necessary components.

An inversion of stereochemistry in the reaction of chiral alcohols is a key piece of evidence that the reaction occurs by a Mitsunobu-type mechanism. Taniguchi and co-workers have also previously described alcohol–acid condensations catalysed by an iron(ii) phthalocyanine alone. These reactions, however, occurred with retention of configuration, and this raises the intriguing possibility that the hydrazine somehow inhibits that reaction while promoting the Mitsunobu pathway.