C(sp3)-H (N-Phenyltetrazole)thiolation as an Enabling Tool for Molecular Diversification

Angew Chem Int Ed Engl. 2024 Apr 24:e202404879. doi: 10.1002/anie.202404879. Online ahead of print.ABSTRACTMethods enabling the broad diversification of C(sp3)-H bonds from a common intermediate are especially valuable in chemical synthesis. Herein, we report a site-selective (N-phenyltetrazole)thiolation of aliphatic and (hetero)benzylic C(sp3)-H bonds using a commercially available disulfide to access N-phenyltetrazole thioethers. The thioether products are readily elaborated in diverse fragment couplings for C-C, C-O, or C-N construction. The C-H functionalization proceeds via a radical-chain pathway involving hydrogen atom transfer by the electron-poor N-phenyltetrazolethiyl radical. Hexafluoroisopropanol was found to be essential to reactions involving aliphatic C(sp3)-H thiolation, with computational analysis consistent with dual hydrogen bonding of the N-phenyltetrazolethiyl radical imparting increased radical electrophilicity to facilitate the hydrogen atom transfer. Substrate is limiting reagent in all cases, and the reaction displays an exceptional functional group tolerance well suited to applications in late-stage diversification.PMID:38657161 | DOI:10.1002/anie.202404879

Source: Angewandte Chemie - April 24, 2024 Category: Chemistry Authors: Ashley Zachmann Justine Drappeau Shubin Liu Erik John Alexanian Source Type: research