Selective and Non-selective Approach for Fluorination Reactions

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The trifluoromethylation of aldehydes and ketones is a potentially powerful method to introduce the CF3 moiety into organic molecules. In general, the trifluoromethylation reaction has been performed by treatment of Me3SiCF3 under initiation by TBAF, TBAT, TMAF as well as CsF. However, these commercially available fluorides are rather expensive and moisture sensitive. Potassium fluoride (KF) is an inexpensive and commonly used fluoride source and can be also used as an initiator for the trifluoromethylation, but the method suffers from the significant limitation that only DMF is available as a solvent. Therefore, novel methods are highly desirable for laboratory-scale as well as large-scale preparations. We wish to report a convenient procedure as follows.1.A KF/TBAB combination acts as a catalyst for trifluoromethylation of aldehydes, ketones, and imides in a variety of organic solvents to provide trimethylsilyl-protected a-trifluoromethyl alcohols in good to high yields.2.The first Lewis acid-catalyzed trifluoromethylation reactions of aldehydes with Me3SiCF3 under TiF4/DMF, Ti(OiPr)4/DMF and Cu(OAc)2/dppp/toluene conditions are described.We have successfully applied this methodology to the difluoromethylation of aldehydes using Me3SiCF2SePh, Me3SiCF2P(O)OEt2 and Me3SiCF2SPh.3.A truly catalytic nucleophilic trifluoromethylation reaction of carbonyl compounds with Ruppert's reagent, Me3SiCF3, has been shown to be efficiently promoted by a P(t-Bu)3-DMF system. Imines were also converted to the desired a-trifluoromethyl amines under similar reaction conditions.4.Selective introduction of fluorine : Monofluoromethylation with the fluoromethide equivalent fluorobis(phenylsulfonyl)methane was crucial in the syntheses of the pharmacologically important compounds (S)-methylfluorinated ibuprofen and 5-deoxy-5-fluoro-b-d-carbaribofuranose. The key step was a palladiumcatalyzed allylic monofluoromethylation reaction.