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O ‐Trifluoromethylation of N , N ‐Disubstituted Hydroxylamines with Hypervalent Iodine Reagents
Author(s) -
Matoušek Václav,
Pietrasiak Ewa,
Sigrist Lukas,
Czarniecki Barbara,
Togni Antonio
Publication year - 2014
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201402225
Subject(s) - chemistry , trifluoromethylation , hypervalent molecule , reagent , deprotonation , lithium diisopropylamide , organic chemistry , medicinal chemistry , lewis acids and bases , trifluoromethyl , catalysis , ion , alkyl
A 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 CF 3 reagent with either trimethylsilyl triflate or LiClO 4 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 CF 3 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.