Novel Mitsunobu Reagent Enables Stereospecific Substitution of Alcohols with Amines

Significance

The Mitsunobu reaction is a crucial tool in drug synthesis because of its mild conditions, broad monomer sets, and stereospecific nature. Traditionally, C–N bond formation via the Mitsunobu reaction is limited to acidic pronucleophiles with a pK _a ≤ 11. Nitrogen nucleophiles that meet this requirement include azides, sulfonamides, and phthalimides. This limitation necessitates further transformations to access the desired free amine. Alternative approaches to the direct conversion of alcohols into amines (e. g., hydrogen borrowing), often lack the stereospecific qualities of the Mitsunobu reaction. Although advances in Mitsunobu chemistry have been reported, none allow for the use of primary or secondary amines as nucleophiles in the preparation of chiral amines from chiral alcohols. This report describes a novel Mitsunobu reagent capable of overcoming these challenges.

Comment

The authors designed an azaphosphonium salt with a non-nucleophilic counterion, BEHT triflate, and synthesized it on > 100 g scale. This reagent is bench-stable for several years. The shock sensitivity and thermal instability were de-risked. The authors hypothesized that the use of an acid with a non-nucleophilic conjugate base would enable an exogenous nucleophile, with a pK _a outside of the traditional requirements, to participate in the substitution. A large substrate scope with good functional group tolerance was demonstrated. Minor amounts of double alkylation were observed when using primary alcohols in some cases. Moderate to excellent stereospecificity was achieved. Alternative nucleophiles were also tested. BEHT triflate has expanded the scope of the traditional Mitsunobu reaction.

Publication History

Article published online:
23 June 2025

© 2025. Thieme. All rights reserved.

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany