Accessing Aryldifluoromethyl Derivatives through Alkene Insertion into Benzylic C–F Bonds

Abstract

We report our formal insertion of alkenes into benzylic C–F bonds of electron-deficient perfluoroalkylarenes under organophotocatalytic conditions with Et₃N·3HF as an external fluoride source. The absence of a fluoride scavenger or other external reductant permits the formation of a carbocation and its trapping by other nucleophiles. This three-component reaction represents one of the most efficient methods for preparing a variety of complex partially fluorinated organic molecules. This redox-neutral transformation features mild conditions, a broad substrate scope, and extraordinary functional-group tolerance. Moreover, several examples of modifications of complex drug molecules further demonstrated its utility.

Key words

photocatalysis - organocatalysis - aryldifluoromethyl compounds - late-stage functionalization - C–F bond cleavage - radical–polar crossover reaction

Publication History

Received: 13 March 2023

Accepted after revision: 04 April 2023

Accepted Manuscript online:
04 April 2023

Article published online:
09 May 2023

• References

• 1a Müller K, Faeh C, Diederich F. Science 2007; 317: 1881
• 1b Hagmann WK. J. Med. Chem. 2008; 51: 4359
• 1c Gillis EP, Eastman KJ, Hill MD, Donnelly DJ, Meanwell NA. J. Med. Chem. 2015; 58: 8315
• 2 Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications. Kirsch P. Wiley-VCH; Weinheim: 2004
• 3 Meanwell NA. J. Med. Chem. 2011; 54: 2529
• 4a Yoshida S, Shimomori K, Kim Y, Hosoya T. Angew. Chem. Int. Ed. 2016; 55: 10406
• 4b Munoz SB, Ni C, Zhang Z, Wang F, Shao N, Mathew T, Olah GA, Prakash GK. S. Eur. J. Org. Chem. 2017; 2322
• 4c Feng Z, Xiao Y.-L, Zhang X. Acc. Chem. Res. 2018; 51: 2264
• 4d Yoshida S. Chem. Rec. 2023; in press
• 5 Wang C, Berg N, Gschwind R, König B. J. Am. Chem. Soc. 2017; 139: 18444
• 6a Wang H, Jui N. J. Am. Chem. Soc. 2018; 140: 163
• 6b Vogt D, Seath C, Wang H, Jui N. J. Am. Chem. Soc. 2019; 141: 13203
• 7 Sap JB. I, Straathof NJ. W, Knauber T, Meyer C, Médebielle M, Bugiloni L, Genicot C, Trabanco AA, Noël T, am Ende CW, Gouverneur V. J. Am. Chem. Soc. 2020; 142: 9181
• 8 Luo Y.-C, Tong F.-F, Zhang Y.-X, He C.-Y, Zhang X.-G. J. Am. Chem. Soc. 2021; 143: 13971

For selected examples, see:
• 9a Heinrich MR. Chem. Eur. J. 2009; 15: 820
• 9b Jiang H, Studer A. Chem. Soc. Rev. 2020; 49: 1790
• 9c Wang P.-Z, Xiao W.-J, Chen J.-R. Chin. J. Catal. 2022; 43: 548
• 9d Gao P, Niu Y.-J, Yang F, Guo L.-N, Duan X.-H. Chem. Commun. 2022; 58: 730
• 9e Campbell MW, Compton JS, Kelly CB, Molander GA. J. Am. Chem. Soc. 2019; 141: 20069
• 9f Huang H.-M, Bellotti P, Pflüger PM, Schwarz JL, Heidrich B, Glorius F. J. Am. Chem. Soc. 2020; 142: 10173
• 9g Guo L, Yuan M, Zhang Y, Wang F, Zhu S, Gutierrez O, Chu L. J. Am. Chem. Soc. 2020; 142: 20390
• 9h Wang P.-Z, Gao Y, Chen J, Huan X.-D, Xiao W.-J, Chen J.-R. Nat. Commun. 2021; 12: 1815
• 9i Lu F.-D, Lu L.-Q, He G.-F, Bai J.-C, Xiao W.-J. J. Am. Chem. Soc. 2021; 143: 4168
• 9j Yan D.-M, Xu S.-H, Qian H, Gao P.-P, Bi M.-H, Xiao W.-J, Cheng J.-R. ACS Catal. 2022; 12: 3279
• 9k Wei S, Zhang G, Wang Y, You M, Wang Y, Zhou L, Zhang Z. i-Science 2023; 26: 106137
• 10a Mattay J, Runsink J, Rumbach T, Ly C, Gersdorf J. J. Am. Chem. Soc. 1985; 107: 2557
• 10b Mattay J, Runsink J, Gersdorf J, Rumbaeh T, Ly C. Helv. Chim. Acta 1986; 69: 442
• 10c Mezhenkova TV, Karpov VM, Zonov YV. J. Fluorine Chem. 2018; 207: 59
• 11 Wang F, Nishimoto Y, Yasuda M. J. Am. Chem. Soc. 2021; 143: 20616

For recent examples of fluorinations through radical-polar crossovers, see:
• 12a Deng W.-L, Feng W.-W, Li Y.-J, Bao H.-L. Org. Lett. 2018; 20: 4245
• 12b Xiong P, Long H, Xu H.-C. Asian J. Org. Chem. 2019; 8: 658
• 12c Webb EW, Park JB, Cole EL, Donnelly DJ, Bonacorsi SJ, Ewing WR, Doyle AG. J. Am. Chem. Soc. 2020; 142: 9493
• 12d Tang H.-J, Zhang B, Xue F, Feng C. Org. Lett. 2021; 23: 4040
• 12e Qian H, Chen J, Zhang B, Cheng Y, Xiao W.-J, Chen J.-R. Org. Lett. 2021; 23: 6987