Electrochemical Benzylic C(sp³)–H Isothiocyanation

Abstract

Selective C­(sp3)–H isothiocyanation represents a significant strategy for the synthesis of isothiocyanate derivatives. We report herein an electrochemical benzylic isothiocyanation in a highly chemo- and site-selective manner under external oxidant-free conditions. The high chemoselectivity is attributed to the facile in situ isomerization of benzylic thiocyanates to isothiocyanates. Notably, the method exhibits high functional group compatibility and is suitable for late-stage functionalization of bioactive molecules.

Site-selective electrochemical thiocyanation of benzylic C–H bonds

“…The corresponding isothiocyanates were obtained using DCE/HFIP as the co-solvent and nBu 4 NClO 4 as the electrolyte. 15 In contrast, the thiocyanates were selectively generated under conditions A or C. Although the exact reason for the observed chemoselectivity was unclear, the fact that electron-deficient thiocyanates could not be converted to isothiocyanates can be probably attributed to the high oxidative potential based on the cyclic voltammetry experiments (Fig. S4 †).…”

“…On the basis of previous reports, 6,15 a radical-polar crossover reaction mechanism was proposed as shown in Scheme 5. Initially, anodic oxidation of substrate 37 generates a radical cation A.…”

“…Benzylic isothiocyanates were obtained with substrates bearing electron-donating groups on the aromatic ring (OMe, OPh, OBn), in which the optimal solvent was DCE/HFIP. 15 However, for electron-deficient substrates (compounds 8–10 , 12 , and 24 ), condition B was the best and benzylic thiocyanates were selectively afforded, and replacing of DCE/HFIP with DCE completely shut down these reactions. Furthermore, when substrates bearing halogen or electron-neutral groups were used, the chemoselectivity relied on the reaction conditions (compounds 3–6 , 14–18 ).…”

“…14 Very recently, our group reported an electrochemical benzylic isothiocyanation (Scheme 1c). 15 On the basis of this result, we envisioned that the chemoselective thiocyanation could be realized through the regulation of substrates and reaction parameters. As part of our continuing interest in electrochemical synthesis, 16 herein we report an efficient site-selective benzylic C(sp 3 )–H thiocyanation under mild electrochemical conditions (Scheme 1d).…”

Electrochemical Benzylic C(sp3)–H Acyloxylation

“…Recently, amines, alcohols, isothiocyanates, and electron-rich aromatic rings have been reported as appropriate nucleophilic partners for electrochemically generated benzylic cations ( Figure 1 A). 8 − 14 …”