Recent Advances in the Mitsunobu Reaction: Modified Reagents and the Quest for Chromatography‐Free Separation

Abstract

Recent progress in synthetic approaches to the Mitsunobu reaction are reviewed. Efforts that have focused on the phase-switching modifications of phosphane, azodicarboxylate, and nucleophilic components are emphasized. An approach to product separation with fluorous compounds is

Enantioselective Allylation of Thiophene‐2‐carbaldehyde: Formal Total Synthesis of Duloxetine

“…Under classical conditions, the reaction was carried out in the presence of DIAD/ PPh 3 in THF, the desired ether 7 was isolated in the range of 10-13% yield. Attempts to change the reaction conditions and carry out the reaction by using other reagent combinations [21] did not, unfortunately, improve the overall outcome. The use of DIAD/PMe 3 did not provide ether 7 at all, changing the phosphine for PBu 3 [22] using otherwise the same conditions furnished ether 7 in 15% isolated yield.…”

Purification of Fluorous Mitsunobu Reactions by Liquid‐Liquid Extraction

“…Indeed, the Mitsunobu reaction has become somewhat of a proving ground for the introduction and trial of new separation methods and reagents. [2] Despite the large amount of work devoted towards separation-friendly Mitsunobu reactions, [2] we are not aware of any procedure in which the reagents and reagent by-products of a Mitsunobu reaction can be directly removed by a liquid-liquid extraction. To date, procedures that rely on liquid-liquid extraction are indirect in that they require a separate reaction after the Mitsunobu reaction to convert the reagents into extractable form.…”

“…To date, procedures that rely on liquid-liquid extraction are indirect in that they require a separate reaction after the Mitsunobu reaction to convert the reagents into extractable form. [2,3] Conducting the second reaction requires additional effort and imposes its own set of constraints on the kinds of Mitsunobu products that can be formed.…”

Redox‐Switchable Phase Tags – Facile Mitsunobu Reactions using Ferrocenyl‐Tagged Triphenylphosphine

“…[1] However, there are a number of chemical transformations that are highly useful from a synthetic point of view, but are often plagued by purification problems. Infamous in this respect are reactions in which triphenylphosphine is used as a stoichiometric reagent [2] such as the Mitsunobu [3] and the Staudinger reactions [4] or the reduction of primary ozonides. [5] Nonetheless, the Mitsunobu reaction is a powerful synthetic tool for the condensation of an acidic pronucleophile (RXH) and an alcohol (R'OH), due to its wide applicability, stereospecificity and mild reaction conditions.…”