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Radical Trifluoromethyl- and Perfluoroalkylation via Reductive and Oxidative Processes

Subject Area Organic Molecular Chemistry - Synthesis and Characterisation
Term from 2012 to 2021
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 223531595
 
Final Report Year 2021

Final Report Abstract

Tifluoromethylated heterocycles are important compounds that can be found in various pharmaceuticals, agrochemicals and organic materials. Within this project, several processes to access such fluorinated heteroarenes were developed. The isoquinoline scaffold is a prominent chemical core structure that also appears in natural products. We found that readily prepared alpha-alkylated alpha-benzyl tosylmethyl isocyanides serve as efficient CF3-radical acceptors that provide trifluoromethylated isoquinolines in a cascade reaction. Starting with aryl isonitriles, we also developed a method for the preparation of 2-perfluoroalkylindol-3-imines. In these cascades, the CF3-radical and perfluoroalkyl radicals were generated via reductive processes. We further showed that ortho-diisocyanoarenes react with perfluoroalkyl iodides in a redox neutral radical I-atom transfer process to afford 2-iodo-3-perfluoroalkyl quinoxalines and the synthesis of alpha-perfluoroalkylated indoles was also achieved via the aryl isonitrile radical route. In a subproject, we used the reversibility of the pinacol coupling in pinacolates as a route to generate ketyl radical anions, that were reacted with aryl iodides to provide tertiary alcoholates in a formal reductive coupling. Attempted oxidative trifluoromethyl radical generation starting with CF3-B-ate complexes failed. Considering oxidative CF3-radical generation, we therefore switched to the Langlois reagent (CF3SO2Na) as the C-radical precursor and developed cooperative NHC/photoredox catalysis for the preparation of ß-trifluoromethylated-alpha-arylated ketones starting from styrenes and aroyl fluorides. Reaction worked well with a standard carbene as the organocatalyst and an Ir-based photoredox catalyst. Finally, trifluoromethyl radical addition reactions were applied to the generation of amidyl radicals. Applying this approach, we were able to develop a method for the remote C-H functionalization at unactivated positions using readily available triflone-type reagents. Thus, using CF3SO2CCAryl, CF3SO2N3, CF3SO2Cl and CF3SO2Br, remote radical C-H alkynylation, azidation and halogenation was accomplished, convincingly documenting the generality of that strategy. Unlike the other reactions developed in this project, the CF3-group does not appear in the final product and hence the trifluoromethyl radical acts exclusively as a mediator for the N-radical generation.

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