Mild, Additive-Free Thioetherification via Proton Transfer Dual Ionization Mechanism

29 June 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Thioethers represent prevalent motifs in highly sought after biologically active small molecules such as active pharma-ceutical ingredients (APIs) and natural products. While nucleophilic aromatic substitution (SNAr) has traditionally been used to synthesize aryl thioethers, modern approaches leverage transition metals to catalyze thermal or photochemical cross-coupling. During platform technology development for photochemical transformations, we uncovered an exceedingly mild thioetherification that does not require light, transition metal or exogenous base. An array of thiols and halogenated heterocycles were coupled to produce 40 diverse products including the penultimate precursor to the immunosuppressant azathioprine (1-step). Reaction progress kinetic analysis (RPKA) and computational studies support a unique mechanism, here termed proton transfer dual ionization (PTDI) SNAr. Rate-limiting proton transfer (RLPT) pre-equilibrium results in dual nucleophile and electrophile ionization prior to an asynchronous concerted SNAr. This transformation complements modern approaches to thioethers and motivates additional research evaluating PTDI as a general activation mode between coupling partners.

Keywords

Thioetherification
Proton Transfer Dual Ionization
SNAr
Total Synthesis

Supplementary materials

Title
Description
Actions
Title
Mild, Additive-Free Thioetherification via Proton Transfer Dual Ionization Mechanism
Description
Supporting information covering description of methods and results for this work.
Actions

Comments

Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.