Stable and easily available sulfide surrogates allow a stereoselective activation of alcohols.

Jérémy Merad,Martina Drescher,Alexandre Pinto,Ján Matyašovský,Nuno Maulide,Bogdan R. Brutiu,Tobias Stopka

doi:10.1039/d1sc01602d

Abstract

Isothiouronium salts are easily accessible and stable compounds. Herein, we report their use as versatile deoxasulfenylating agents enabling a stereoselective, thiol-free protocol for synthesis of thioethers from alcohols. The method is simple, scalable and tolerates a broad range of functional groups otherwise incompatible with other methods. Late-stage modification of several pharmaceuticals provides access to multiple analogues of biologically relevant molecules. Performed experiments give insight into the reaction mechanism.

Highlights

Sulfur is the 5th most abundant element in pharmaceuticals and agrochemicals
Require prior functional group interconversion (FGI) when alcohols and thiols are considered as the reaction substrates, effectively employing two linear steps to achieve this transformation (Scheme 1A)
Scheme 2 Thioetherification of optically active secondary alcohols: impact of the counteranion. aReactions were performed at rt for 2 h with alcohol (0.30 mmol, 1.0 equiv.), isothiouronium salt (0.30 mmol, 1.0 equiv.) and BTMG (0.33 mmol, 1.1 equiv.) in CHCl3 (0.14 M concentration). bReaction conditions: AgSbF6, H2O (0.35 M), rt, 30 min, 84% yield

Summary

Introduction

Sulfur is the 5th most abundant element (a er C, H, O and N) in pharmaceuticals and agrochemicals. Thio-Mitsunobu reaction efficiently converts alcohols into thioethers, while requiring a combination of two stoichiometric activating agents (Scheme 1A). Scheme 1 Synthetic strategies to access thioethers from alcohols.

Results

Conclusion