康 · 学术 | Reaction of the Day No. 1714

Reinventing the Mitsunobu Reaction with Iminophosphorane Reagents

Maud T. H. Tregear1, Shisato Yamamura2, Darren J. Dixon1

1Department of Chemistry, University of Oxford, Oxford, OX1 3TA, United Kingdom; 2Department of Applied Chemistry, Graduate School of Engineering, The University of Osaka, Suita, Osaka 565-0871, Japan;

—https://chemrxiv.org/doi/10.26434/chemrxiv.15006188

Recommended by Xuemei Yao _ MC3

KEY WORDS: Mitsunobu Reaction (反应类型), alcohols (原料), ester, thioether, ether (产物), Csp3-N, Csp3-S, Csp3-Csp3(成键类型), PBu3, PMe3, 1-azido-4-methoxybenzene, Iminophosphorane (其他) 

ABSTRACT: The Mitsunobu reaction is one of the most celebrated reactions in organic synthesis, enabling stereospecific C–O, C–N, and C–S bond formation from abundant alcohol feedstocks. However, its widespread use is constrained by explosive reagents, laborious product purification and a pronucleophile pKa window that precludes C–C bond formation. Herein, we disclose iminophosphoranes as a new class of reagents for the Mitsunobu reaction that readily overcome these limitations. The key iminophosphorane reagent is rapidly and quantitively formed in situ from commercially-available 1-azido-4-methoxybenzene and a trialkylphosphine, allowing the construction of C–O, C–N, C–S and, notably, C–C bonds from primary and secondary alcohol substrates with vastly simplified product purification. Furthermore, we demonstrate that the direct use of a solution of pre-formed iminophosphorane eliminates end-user azide handling altogether. The utility of the reaction was demonstrated through reaction scale-up and late-stage functionalisation of pharmaceutically-relevant compounds.

Background and this work:

(A) The classical Mitsunobu reaction; (B) Tsunoda reagents (CMBP and CMMP) enabled C–C bond formation with stabilised carbon nucleophiles; 

(C) Phase-tagging strategies for simplified purification; (D) Catalytic Mitsunobu protocol developed by Denton et al; (E) Structural analogy between the Morrison-Brunn-Huisgen betaine and iminophosphorane intermediates provided the basis for reagent design; 

(F) Reagent design and proposed mechanism; (G) This work: an iminophosphorane-enabled Mitsunobu strategy.

Scope for C–O, C–N and C–C bond formation (selected examples)

Scope of the disulfide pronucleophile

Summary and Comments

Prof. Darren J. Dixon and colleagues reported iminophosphorane reagents derived from commercially available 1-azido-4-methoxybenzene and trimethyl- or tributylphosphineoffer a practical and broadly applicable alternative to the standard diazodicarboxylate / triarylphosphine Mitsunobu reagents. Generated in-situ or pre-formed, these reagents demonstrated the stereospecific substitution of alcohols across a wide range of oxygen, nitrogen, carbon and disulfide pronucleophiles, including complex and medicinally-relevant substrates. The new protocol greatly simplified purification due to easy removal of the by-products and enabled gram-scale reactions and late-stage functionalisation. Collectively, this strategy preserves and extends the synthetic utility of the classical Mitsunobu reaction while addressing its major safety and purification limitations, rendering the methodology well positioned for widespread adoption across diverse synthetic contexts.