Radical Trifluoromethyl- and Perfluoroalkylation via Reductive and Oxidative Processes
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.
Publications
- Iodinated (Perfluoro)alkyl Quinoxalines via Atom Transfer Radical Addition using ortho- Diisocyanoarenes as Radical Acceptors, Angew. Chem. Int. Ed. 2016, 55, 11660-11663
D. Leifert, A. Studer
(See online at https://doi.org/10.1002/anie.201606023) - Radical Perfluoroalkylation – Easy Access to 2 Perfluoroalkylindol-3-imines via Electron Catalysis, Chem. Commun. 2016, 52, 5997-6000
D. Leifert, D. G. Artiukhin, J. Neugebauer, A. Galstyan, C. A. Strassert, A. Studer
(See online at https://doi.org/10.1039/c6cc02284g) - Sodium-Ketyl Radical Anions by Reverse Pinacol Reaction and their Coupling with Iodoarenes, Org. Lett. 2016, 18, 4448-4450
X. Tang, A. Studer
(See online at https://doi.org/10.1021/acs.orglett.6b02184) - 1-Trifluoromethylisoquinolines from α-Benzylated Tosylmethyl Isocyanide Derivatives in a Modular Approach, Org. Lett. 2017, 19, 5701-5704
L. Wang, A. Studer
(See online at https://doi.org/10.1021/acs.orglett.7b02882) - Remote Site-Specific Radical Alkynylation of Unactivated C-H Bonds, Org. Lett. 2018, 20, 5817-5820
L. Wang, Y. Xia, K. Bergander, A. Studer
(See online at https://doi.org/10.1021/acs.orglett.8b02514) - Site-selective Radical Remote C‒H Functionalization of Unactivated C‒H Bonds in Amides with Sulfone Reagents, Angew. Chem. Int. Ed. 2018, 57, 12940-12944
Y. Xia, L. Wang, A. Studer
(See online at https://doi.org/10.1002/anie.201807455) - Cooperative NHC and Photoredox Catalysis for the Synthesis of β-Trifluoromethylated Alkyl Aryl Ketones, Angew. Chem. Int. Ed. 2020, 59, 19956-19960
Q.-Y. Meng, N. Döben, A. Studer
(See online at https://doi.org/10.1002/anie.202008040)
