Difluoromethylthiolator: A Toolbox Of Reagents For Difluoromethylthiolation
ACCOUNTS OF CHEMICAL RESEARCH(2021)
Abstract
Recently, the strategic installation of a fluorine atom or a fluoroalkyl group site-selectively at the specific position of the target molecule has become a routine approach and daily practice for medicinal chemists in their endeavor to fine tune the structure of the lead compound to improve its physicochemical properties such as the cell membrane permeability and metabolic stability. Among many fluoroalkyl groups, the difluoromethylthio group (-SCF2H) has attracted recent intense attention. Largely due to the weak acidity of the proton in the difluoromethylthio group, the difluoromethylthio group is generally considered to be a lipophilic hydrogen-bonding donor and a bioisostere of the hydroxy/thio group that might interact with the heteroatom of the enzyme via a hydrogen bond to improve the binding selectivity of the drug molecule. Besides, the difluoromethylthio group is less lipophilic, less electron-withdrawing, and less stable to the acidic or basic environment than its analogue trifluoromethylthio group (-SCF3), making it easier to regulate the metabolic stability of drug molecules. These beneficial effects render the difluoromethylthio group one of the most favorable functional groups in drug design; consequently, there is an urgent need to develop new strategies for the efficient introduction of the difluoromethylthio group into small molecules under mild conditions. Over the last few decades, several different approaches to the preparation of difluoromethylthiolated compounds have been developed, including the difluoromethylation of thiolated substrates with an electrophilic/nucleophilic difluoromethylating reagent or the insertion of a difluoromethyl carbene into the S-H bond of the thiols. In contrast, we adopt an alternative approach to the preparation of difluoromethylthiolated compounds by late-stage direct difluoromethylthiolation of the specific substrates with a difluoromethylthiolating reagent. With this aim in mind, in the last 6 years we have successfully developed a toolbox of reagents that are capable of the direct introduction of the difluoromethylthio group into the target molecules, including nucleophilic difluoromethylthiolating reagent [(SIPr)AgSCF2H] I, electrophilic difluoromethylthiolating reagent PhthSCF(2)H II, three optically pure difluoromethylthiolating reagents camphorsultam-SCF2H III, radical difluoromethylthiolating reagent PhSO2SCF2H IV, and reagent PhSO2SCFClH V that could be used for the preparation of F-18-labeled [F-18]ArSCF2H. These reagents reacted with a broad range of substrates to get access to difluoromethylthiolated compounds efficiently, thus providing medicinal chemists a powerful weapon for the direct introduction of the difluoromethylthio group into promising molecules during the search for new drugs.
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