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Redox-neutral organocatalytic Mitsunobu reactions

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Science  30 Aug 2019:
Vol. 365, Issue 6456, pp. 910-914
DOI: 10.1126/science.aax3353

Displacing OH groups catalytically

The Mitsunobu reaction is widely used to invert the configuration of alcohols. However, its major drawback is the need to activate the alcohol with a full equivalent of phosphine, thereby generating a phosphine oxide co-product. Beddoe et al. report a phosphine oxide compound that achieves the same result catalytically (see the Perspective by Longwitz and Werner). The key is a phenol substituent that can reversibly bond through its oxygen to phosphorus, forming a ring that the alcohol opens. The phosphorus thus remains in the +5 oxidation state throughout the reaction, and water is the only by-product.

Science, this issue p. 910; see also p. 866

Abstract

Nucleophilic substitution reactions of alcohols are among the most fundamental and strategically important transformations in organic chemistry. For over half a century, these reactions have been achieved by using stoichiometric, and often hazardous, reagents to activate the otherwise unreactive alcohols. Here, we demonstrate that a specially designed phosphine oxide promotes nucleophilic substitution reactions of primary and secondary alcohols in a redox-neutral catalysis manifold that produces water as the sole by-product. The scope of the catalytic coupling process encompasses a range of acidic pronucleophiles that allow stereospecific construction of carbon-oxygen and carbon-nitrogen bonds.

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