New tetramethylthiepinium (TMTI) for copper-free click chemistry

Abstract

A new derivative of the strained 3,3,6,6-tetramethylthiacycloheptyne (TMTH) bearing a functional handle is reported. Following an optimized synthesis, the handle was introduced by mild alkylation of the sulphur atom. The resulting functionalized strained 4,5-didehydro-3,3,6,6-tetramethyl-2,3,6,7-tetrahydrothiepinium (TMTI) proved to be stable and underwent extremely fast [3+2] cycloaddition reaction with benzyl azide in both organic and aqueous solvents. The reaction was equally efficient in cell lysate and serum and therefore opens interesting prospects for chemical-biology applications.

TMTHSI, a superior 7-membered ring alkyne containing reagent for strain-promoted azide–alkyne cycloaddition reactions

“…Attempts in this direction by Wagner et al underlined this requirement. 18 Thus we set out to develop a practical synthesis of a new and stable TMTH click reagent, in which unwanted side reactions can be mitigated by optimal reaction conditions and which above all contains a functional group for convenient introduction of a variety of linkers for ligand attachment.…”

Isomeric triazines exhibit unique profiles of bioorthogonal reactivity

“…This rate is on par with many commonly used distortion-accelerated azide-alkyne cycloadditions. 2,[44][45][46][47] Under similar conditions, no reactivity was observed between 6substituted triazine (1) and TMTH (9) (Fig. S12 †).…”

CuFeO2/tetrabutylammonium bromide catalyzes selective synthesis of 1,4‐disubstituted 1,2,3‐triazoles in neat water at room temperature

“…But this process gave a mixture of 1,4‐ and 1,5‐disubstituted 1,2,3‐triazole isomers. Meldal et al and King et al found that copper(Ι) catalyzes azide–alkyne cycloaddition (CuAAC) and only one regioisomer (1,4‐disubstituted 1,2,3‐triazole) can be obtained using this procedure. Also they concluded that copper(Ι) can increase the reaction rate.…”

“…Also they concluded that copper(Ι) can increase the reaction rate. There are some other methods for producing these compounds including copper‐free cycloaddition (CFC) strategies, but their regioselectivity and/or rate of the reaction is low. In some cases, CFCs need organic solvents and longer reaction times .…”