Difluorocarbene‐Derived Trifluoromethylthiolation and [¹⁸F]Trifluoromethylthiolation of Aliphatic Electrophiles

Abstract

The first trifluoromethylthiolation and [18F]trifluoromethylthiolation of alkyl electrophiles with in situ generated difluorocarbene in the presence of elemental sulfur and external (radioactive) fluoride ion is described. This transition metal-free approach is high yielding, compatible with variety of functional groups and operated under mild conditions. The conceptual advantage of this exogenous fluoride mediated transformation enables unprecedented syntheses of [18F]CF3S-labeled molecules from most commonly used [18F]fluoride ion. The rapid radiochemical reaction time (≤ 1 min) and highly functional group tolerance allow this method to access a variety of aliphatic [18F]CF3S compounds in high yields.

Synthesis of 18F‐Difluoromethylarenes from Aryl (Pseudo) Halides

“…2 Development of modern 18 F-multi-fluoromethylation reactions, for example to incorporate 18 F into trifluoromethyl groups, are now also addressed, due to the prospects of having more labeled chemotypes available for imaging. 3 A challenge in the preparation of 18 F-labeled compounds that contain more than one fluorine atom, especially when located on the same carbon atom, is the probability of isotope exchange that can substantially lower the specific activity. Here we describe a general method for difluoromethyl [ 18 F]CHF 2 –arenes from [ 18 F]fluoride.…”

“…The most extensive work to date on multi-fluorinated 18 F-labeled molecules has been directed at the synthesis of 18 F-trifluoromethyl groups: 3 Gouverneur and co-workers have established a practical method based on [ 18 F]CuCF 3 species, with large substrate scope. 3f A year later, three other groups independently reported different methods to prepare [ 18 F]CuCF 3 , which was also explored for [ 18 F]trifluoromethylation of aryl boronic acids.…”

“…3f A year later, three other groups independently reported different methods to prepare [ 18 F]CuCF 3 , which was also explored for [ 18 F]trifluoromethylation of aryl boronic acids. 3g-3i Groves and co-workers have reported a direct C–H to C– 18 F transformation based on Mn–salen-catalyzed benzylic fluorination with [ 18 F]fluoride, 2j which was also extended to 18 F-trifluoromethylarenes.…”

“…3f A year later, three other groups independently reported different methods to prepare [ 18 F]CuCF 3 , which was also explored for [ 18 F]trifluoromethylation of aryl boronic acids. 3g-3i Groves and co-workers have reported a direct C–H to C– 18 F transformation based on Mn–salen-catalyzed benzylic fluorination with [ 18 F]fluoride, 2j which was also extended to 18 F-trifluoromethylarenes. 3j [ 18 F]CHF 2 arenes such as [ 18 F]4-(difluoromethyl)-1,1'-biphenyl, can be synthesized through decarboxylative 18 F-fluorination with [ 18 F]Selectfluor generated from [ 18 F]F 2 or Ag I -mediated halogen-exchange with [ 18 F]fluoride ion.…”

“…3g-3i Groves and co-workers have reported a direct C–H to C– 18 F transformation based on Mn–salen-catalyzed benzylic fluorination with [ 18 F]fluoride, 2j which was also extended to 18 F-trifluoromethylarenes. 3j [ 18 F]CHF 2 arenes such as [ 18 F]4-(difluoromethyl)-1,1'-biphenyl, can be synthesized through decarboxylative 18 F-fluorination with [ 18 F]Selectfluor generated from [ 18 F]F 2 or Ag I -mediated halogen-exchange with [ 18 F]fluoride ion. 3e,k Gouverneur's group improved the substrate scope of Ag I -mediated halogen-exchange; but the CHFCl–arene starting materials still require several synthetic steps for preparation.…”