摘要：William S. Bechara, Irina K. Sagamanova, LéaThai-Savard, Maxime Dauphinais, Sophie Régnier, Charlotte Noël, Scott B. D.Jarvis, and

转自：康龙化成

Universal Reagent for Mild andStereospecific Nucleophilic Substitution of Alcohols with Amines

William S. Bechara, Irina K. Sagamanova, LéaThai-Savard, Maxime Dauphinais, Sophie Régnier, Charlotte Noël, Scott B. D.Jarvis, and André B. Charette*

Université de Montréal,FRQNT Centre inGreen Chemistry and Catalysis, Centre for Continuous Flow Synthesis, Departmentof Chemistry, 1375 av. Thérèse Lavoie-Roux, Montréal, QC, H2V 0B3 Canada

—Angew. Chem. Int. Ed. 2025, e202420312

Recommended by Shi Li_MOC & Murong Xu_ MC3

KEYWORDS:Nucleophilic substitution,Mitsunobu reaction(反应类型), C(sp3)–N, C(sp3)–C, C(sp3)–O, C(sp3)–S, C(sp3)–X (成键类型), alcohols, amines (原料), amine (产物), BEHT triflate (其他)

ABSTRACT: Auser-friendly reagent for mild and general activation of alcohols towardsbimolecular nucleophilic substitution (SN2) leveraging diverse nucleophiles,including primary and secondary amines is reported herein. The new ion-pairedreagent discovery was based upon the putative zwitterionic betaine intermediateof the Mitsunobu reaction and enabled the one-step conversion ofenantioenriched alcohols to valuable chiral C–X bonds (where X = N, C, S, O orhalide). The described activating reagent has also been applied to a one-stepmethylation reaction using methanol and to an intermolecularamination/intramolecular cyclization sequence that generates heterocycles, suchas tetrahydroisoquinolines.This work provides the first evidence by X-ray crystallography of a protonatedbetaine as intermediate in the Mitsunobu reaction.

Background and this work

First steps of the Mitsunobureaction

Synthesis of BEHT triflate fromPh3P, diethyl azodicarboxylate (DEAD), and triflicacid (TfOH)

Synthetic scope (selected)

AndréB. Charette et al developed a synthetically usefulMitsunobu-based activating reagent for the direct, mild and stereospecific SN2of alcohols, while harnessing the potential embedded in a wide range ofnucleophiles. Readily generated from Ph3P, DEAD and TfOHin hundred gram-scale, BEHT triflate is bench-stable and safe to handle. Inessence, BEHT triflate exhibited a broader reactivity profile than traditionalMitsunobu manifolds. The outstanding reactivity of the reagent allows not onlythe substitution of structurally diverse alcohols, but also of various hindered primaryand secondary amines containing a range of functionalities as coupling partners for the synthesis ofa-chiral amines. In addition to the formation of C–N bonds from alcohols, thesubstitution reaction allows the direct formation of C–C,C–S, C–O, and C–X (X = Cl, Br, I) bonds from alcohols. We anticipate thisnovel Mitsunobu reagent will significantly enhance the synthetic toolbox andcontribute to the advancement of drug discovery efforts.

来源：新浪财经