Hydrofluoromethylation of alkenes with fluoroiodomethane and beyond Sebastiano Ortalli, Sandrine M. Hell, Claudio F. Meyer, Jeroen B. I. Sap, Xuanxiao Chen,
Véronique Gouverneur University of Oxford, UK
The incorporation of fluorine in medicinally active compounds can serve as a powerful tool for the modulation of multiple biological and physio-chemical properties, hence reactions enabling the selective introduction of fluorinated alkyl groups have gained significant interest in the context of drug discovery. 1-2 In particular, the fluoromethyl group features prominently in pharmaceuticals and is often incorporated to improve metabolic stability by serving as bio-isosteric replacement of functional groups responsible for poor performance. 3-4 Nevertheless, whilst the fields of radical trifluoromethylation and difluoromethylation have been extensively explored, the fluoromethyl radical has been the subject of much less attention. This may be partly attributed to the challenges associated with the generation of the fluoromethyl radical. 5-7 In fact, whilst several reagents serving as fluoromethyl radical precursors have been previously employed, these often require harsh reaction conditions for their activation, are toxic, expensive, hard to handle or necessitate laborious synthesis. A process for the first direct hydrofluoromethylation of alkenes is herein reported. 8 This operationally simple and mild procedure relies on a silyl radical-mediated activation of fluoroiodomethane, a commercially available, easy to handle and non-ozone depleting reagent, traditionally used in electrophilic, nucleophilic and carbene-type chemistry, but never investigated as CH 2 F radical source prior to the disclosure of this work. By circumventing the challenges associated with the high reduction potential of CH 2 FI and harnessing instead the favourable bond dissociation energy of the C–I bond, a variety of electron-deficient alkenes could be successfully hydrofluoromethylated under blue LED activation. This minimalist yet powerful methodology was extended to additional fluoroiodoalkanes enabling facile product homologation as well as a range of (halo)methyl radical precursors including ICH 2 I, ICH 2 Br, ICH 2 Cl, CHBr 2 F, and CH 3 I itself, allowing direct hydromethylation. In addition, 18 F-, 13 C-, and D-labelled reagents as well as complex biologically relevant alkenes could be versatilely accessed, resulting in a large variety of products for applications in medicinal chemistry and positron emission tomography.
Scheme 1) Direct silyl radical-mediated hydrofluoromethylation of electron-deficient alkenes with fluoroiodomethane and extension to numerous other halomethyl radicals and isotopologues thereof. References 1. S. Purser, P. R. Moore, S. Swallow and V. Gouverneur, Chem. Soc. Rev., 2008, 37, 320–330. 2. A. Meanwell, J. Med. Chem., 2018, 61, 5822–5880. 3. Inoue, Y. Sumii and N. Shibata, ACS Omega., 2020, 5 , 10633−10640. 4. M. Johnson, Y. Z. Shu, X. Zhuo and N. A. Meanwell, J. Med. Chem., 2020, 63,6315–6386. 5. Reichel and K. Karaghiosoff, Angew. Chem. Int. Ed. , 2020, 59, 12268–12281. 6. Koike and M. Akita, Org. Biomol. Chem ., 2019, 17, 5413–5419. 7. Hu, W. Zhang and F. Wang, Chem. Cmmun ., 2009, 7465–7478. 8. M. Hell, C. F. Meyer, S. Ortalli, J. B. I. Sap, X. Chen and V. Gouverneur, Chem. Sci. , 2021, 12, 12149–12155.
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© The Author(s), 2022
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