O‐Trifluoromethylation of N,N‐Disubstituted Hydroxylamines with Hypervalent Iodine Reagents

• DOI: 10.1002/ejoc.201402225
• Publication Date: 2014-03-27T08:37:57Z
• Authors: Václav Matoušek; Ewa Pietrasiak; Lukas Sigrist; Barbara Czarniecki; Antonio Togni
• Keywords: 01 natural sciences; 0104 chemical sciences

AbstractA mild trifluoromethylation reaction of N,N‐disubstituted hydroxylamines that is tolerant towards a variety of functional groups, including nitriles, alcohols, ketones, esters, amides, imides, and nitrogen heterocycles, is reported. The key feature of this reaction is the activation of the CF3 reagent with either trimethylsilyl triflate or LiClO4 and partial or full deprotonation of the substrate with tetramethylguanidine or lithium diisopropylamide. Products were obtained in up to 80 % yield. Preliminary mechanistic studies suggested that the reaction follows a radical pathway in which the deprotonated hydroxylamine and a Lewis or Brønsted acid activated CF3 reagent engages in a single‐electron‐transfer step to generate a pair of radicals that recombine to afford the desired product. The trifluoromethylation procedure was successfully used in the modification of secondary nitrogen groups of pharmaceutically relevant targets (Fluoxetine and Mefloquine), which afforded new derivatives containing a novel N‐trifluoromethoxy moiety.