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Contemporary synthetic strategies in organofluorine chemistry

Abstract

Fluorinated molecules have a wide range of applications and are used as medicines, agrochemicals and refrigerants and in smartphone liquid crystal displays, photovoltaic solar cells, Teflon tapes and the coatings of textiles and buildings. Fluorination and fluoroalkylation — incorporation of a trifluoromethyl, difluoromethyl or monofluoromethyl group — are the major strategies used for the construction of carbon–fluorine bonds and fluorinated carbon–carbon bonds, respectively. The past two decades have witnessed a rapid growth in fluorination and fluoroalkylation methods thanks to the development of new reagents and catalysts. This Primer aims to provide an overview of state-of-the-art strategies in fluorination, trifluoromethylation, difluoromethylation and monofluoromethylation, with an emphasis on using C–H functionalization, although other strategies for fluorination and fluoroalkylation are also discussed. Further landmark achievements are expected in the fields of fluorination and fluoroalkylation as organofluorine compounds are used increasingly in everyday applications.

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Fig. 1: Outline of synthetic organofluorine chemistry.
Fig. 2: Incorporation of fluorine via C–H activation.
Fig. 3: Main palladium-catalysed and copper-catalysed C–H fluorination protocols.
Fig. 4: Main C–H fluorination protocols via carbon-centred radical intermediates.
Fig. 5: General overview of trifluoromethylation methods.
Fig. 6: Example trifluoromethylation protocols.
Fig. 7: Main protocols of introducing CF2H at sp3 carbon centres.
Fig. 8: Main protocols of introducing CF2H at (hetero)aromatic carbons and heteroatoms.
Fig. 9: Monofluoromethylating reagents and their use in C–H monofluoromethylation reactions.
Fig. 10: Applications of synthetic organofluorine chemistry in life sciences.

References

  1. Cottet, F., Marull, M., Lefebvre, O. & Schlosser, M. Recommendable routes to trifluoromethyl-substituted pyridine- and quinolinecarboxylic acids. Eur. J. Org. Chem. 2003, 1559–1568 (2003).

    Google Scholar 

  2. Caron, S. Where does the fluorine come from? A review on the challenges associated with the synthesis of organofluorine compound. Org. Process. Res. Dev. 24, 470–480 (2020).

    Google Scholar 

  3. Zhou, Y. et al. Next generation of fluorine-containing pharmaceuticals, compounds currently in phase II–III clinical trials of major pharmaceutical companies: new structural trends and therapeutic areas. Chem. Rev. 116, 422–518 (2016).

    Google Scholar 

  4. Wang, J. et al. Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001–2011). Chem. Rev. 114, 2432–2506 (2014).

    Google Scholar 

  5. Gillis, E. P., Eastman, K. J., Hill, M. D., Donnelly, D. J. & Meanwell, N. A. Applications of fluorine in medicinal chemistry. J. Med. Chem. 58, 8315–8359 (2015).

    Google Scholar 

  6. Swallow, S. Fluorine in medicinal chemistry. Prog. Med. Chem. 54, 65–133 (2015).

    Google Scholar 

  7. Ogawa, Y., Tokunaga, E., Kobayashi, O., Hirai, K. & Shibata, N. Current contributions of organofluorine compounds to the agrochemical industry. iScience 23, 101467 (2020). This article comprehensively summarizes the fluorinated agrochemicals on the market.

    ADS  Google Scholar 

  8. Bégué, J.-P. & Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine (Wiley-Hoboken, 2008).

  9. Ojima, I. (ed.) Fluorine in Medicinal Chemistry and Chemical Biology (Wiley-Blackwell, 2009).

  10. Gouverneur, D. & Müller, K. (eds) Fluorine in Pharmaceutical and Medicinal Chemistry: From Biophysical Aspects to Clinical Applications (Imperial College Press, 2012).

  11. Deng, X. et al. Chemistry for positron emission tomography: recent advances in 11C-, 18F-, 13N-, and 15O-labeling reactions. Angew. Chem. Int. Ed. 58, 2580–2605 (2019).

    Google Scholar 

  12. O’Hagan, D., Schaffrath, C., Cobb, S. L., Hamilton, J. T. G. & Murphy, C. D. Biosynthesis of an organofluorine molecule. Nature 416, 279–279 (2002).

    ADS  Google Scholar 

  13. Kirk, K. L. Fluorination in medicinal chemistry: methods, strategies, and recent developments. Org. Process. Res. Dev. 12, 305–321 (2008).

    Google Scholar 

  14. Dumas, J. & Peligot, E. Ueber den Holzgeist und die verschiedenen ätherartigen Verbindungen, welche er bildet [German]. Ann. Pharm. 15, 1–60 (1835).

    Google Scholar 

  15. Prakash, G. K. S. & Wang, F. in Organic Chemistry: Breakthroughs and Perspectives (eds Ding, K. & Dai, L.-X.) 413–476 (Wiley-VCH, 2012).

  16. Banks, R. E., Sharp, D. W. A. & Tatlow, J. C. (eds) Fluorine: The First Hundred Years (1886−1986) (Elsevier, 1986).

  17. Banks, R. E. (ed.) Fluorine Chemistry at the Millennium. Fascinated by Fluorine (Elsevier, 2000).

  18. Hiyama, T. Organofluorine Compounds: Chemistry and Applications (Springer, 2000).

  19. Chambers, R. D. Fluorine in Organic Chemistry (Blackwell, 2004).

  20. Uneyama, K. Organofluorine Chemistry (Blackwell, 2006).

  21. Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications 2nd ed. (Wiley-VCH, 2013).

  22. Ni, C., Hu, M. & Hu, J. Good partnership between sulfur and fluorine: sulfur-based fluorination and fluoroalkylation reagents for organic synthesis. Chem. Rev. 115, 765–825 (2015). This article includes important references on fluorination and fluoroalkylation.

    Google Scholar 

  23. Liu, Q., Ni, C. & Hu, J. China’s flourishing synthetic organofluorine chemistry: innovations in the new millennium. Nat. Sci. Rev. 4, 303–325 (2017).

    Google Scholar 

  24. Szpera, R., Moseley, D. F. J., Smith, L. B., Sterling, A. J. & Gouverneur, V. The fluorination of C−H bonds: developments and perspectives. Angew. Chem. Int. Ed. 58, 14824–14848 (2019). This article is a concise review on fluorination of C−H bonds.

    Google Scholar 

  25. Yerien, D. E., Bonesi, S. & Postigo, A. Fluorination methods in drug discovery. Org. Biomol. Chem. 14, 8398–8427 (2016).

    Google Scholar 

  26. Ni, C. & Hu, J. The unique fluorine effects in organic reactions: recent facts and insights into fluoroalkylations. Chem. Soc. Rev. 45, 5441–5454 (2016).

    Google Scholar 

  27. Sather, A. C. & Buchwald, S. L. The evolution of Pd0/PdII-catalyzed aromatic fluorination. Acc. Chem. Res. 49, 2146–2157 (2016).

    Google Scholar 

  28. Champagne, P. A., Desroches, J., Hamel, J. D., Vandamme, M. & Paquin, J. F. Monofluorination of organic compounds: 10 years of innovation. Chem. Rev. 115, 9073–9174 (2015).

    Google Scholar 

  29. Ma J.-A. & Cahard, D. (ed.) Emerging Fluorinated Motifs: Synthesis, Properties, and Applications Vol. 2 (Wiley-VCH, 2020).

  30. Olah, G. A. et al. Synthetic methods and reactions. 63.1 Pyridinium poly(hydrogen fluoride) (30% pyridine–70% hydrogen fluoride): a convenient reagent for organic fluorination reactions. J. Org. Chem. 44, 3872–3881 (1979).

    Google Scholar 

  31. Haufe, G. Triethylamine trishydrofluoride in synthesis. J. Prakt. Chem./Chem.-Ztg. 338, 99–113 (1996).

    Google Scholar 

  32. Okoromoba, O. E., Han, J., Hammond, G. B. & Xu, B. Designer HF-based fluorination reagent: highly regioselective synthesis of fluoroalkenes and gem-difluoromethylene compounds from alkynes. J. Am. Chem. Soc. 136, 14381–14384 (2014).

    Google Scholar 

  33. Hu, W. L., Hu, X. G. & Hunter, L. Recent developments in the deoxyfluorination of alcohols and phenols: new reagents, mechanistic insights, and applications. Synthesis 49, 4917–4930 (2017).

    Google Scholar 

  34. Liang, S., Hammond, G. B. & Xu, B. Hydrogen bonding: regulator for nucleophilic fluorination. Chem. Eur. J. 23, 17850–17861 (2017).

    Google Scholar 

  35. Baudoux, J. & Cahard, D. in Organic Reactions 1–326 (Wiley, 2008).

  36. Watson, D. A. et al. Formation of ArF from LPdAr(F): catalytic conversion of aryl triflates to aryl fluorides. Science 325, 1661–1664 (2009).

    ADS  Google Scholar 

  37. Hull, K. L., Anani, W. Q. & Sanford, M. S. Palladium-catalyzed fluorination of carbon–hydrogen bonds. J. Am. Chem. Soc. 128, 7134–7135 (2006).

    Google Scholar 

  38. Casitas, A., Canta, M., Solà, M., Costas, M. & Ribas, X. Nucleophilic aryl fluorination and aryl halide exchange mediated by a CuI/CuIII catalytic cycle. J. Am. Chem. Soc. 133, 19386–19392 (2011). This article is a seminal work on copper-catalysed aromatic fluorination.

    Google Scholar 

  39. Truong, T., Klimovica, K. & Daugulis, O. Copper-catalyzed, directing group-assisted fluorination of arene and heteroarene C–H bonds. J. Am. Chem. Soc. 135, 9342–9345 (2013).

    Google Scholar 

  40. Rueda-Becerril, M. et al. Direct C–F bond formation using photoredox catalysis. J. Am. Chem. Soc. 136, 2637–2641 (2014).

    Google Scholar 

  41. Ventre, S., Petronijevic, F. R. & Macmillan, D. W. C. Decarboxylative fluorination of aliphatic carboxylic acids via photoredox catalysis. J. Am. Chem. Soc. 137, 5654–5657 (2015).

    Google Scholar 

  42. Beeson, T. D. & MacMillan, D. W. C. Enantioselective organocatalytic α-fluorination of aldehydes. J. Am. Chem. Soc. 127, 8826–8828 (2005).

    Google Scholar 

  43. Wang, X., Lan, Q., Shirakawa, S. & Maruoka, K. Chiral bifunctional phase transfer catalysts for asymmetric fluorination of β-keto esters. Chem. Commun. 46, 321–323 (2010).

    Google Scholar 

  44. Rauniyar, V., Lackner, A. D., Hamilton, G. L. & Dean Toste, F. Asymmetric electrophilic fluorination using an anionic chiral phase-transfer catalyst. Science 334, 1681–1684 (2011).

    ADS  Google Scholar 

  45. Yang, X., Wu, T., Phipps, R. J. & Toste, F. D. Advances in catalytic enantioselective fluorination, mono-, di-, and trifluoromethylation, and trifluoromethylthiolation reactions. Chem. Rev. 115, 826–870 (2015).

    Google Scholar 

  46. Pupo, G. et al. Asymmetric nucleophilic fluorination under hydrogen bonding phase-transfer catalysis. Science 360, 638–642 (2018). This article provides a conceptually novel method for asymmetric nucleophilic fluorination.

    ADS  Google Scholar 

  47. Pupo, G. et al. Hydrogen bonding phase-transfer catalysis with potassium fluoride: enantioselective synthesis of β-fluoroamines. J. Am. Chem. Soc. 141, 2878–2883 (2019).

    Google Scholar 

  48. Roagna, G. et al. Hydrogen bonding phase-transfer catalysis with ionic reactants: enantioselective synthesis of γ-fluoroamines. J. Am. Chem. Soc. 142, 14045–14051 (2020).

    Google Scholar 

  49. Neumann, C. N. & Ritter, T. Late-stage fluorination: fancy novelty or useful tool? Angew. Chem. Int. Ed. 54, 3216–3221 (2015).

    Google Scholar 

  50. Furuya, T. et al. Mechanism of C–F reductive elimination from palladium(IV) fluorides. J. Am. Chem. Soc. 132, 3793–3807 (2010).

    Google Scholar 

  51. Chan, K. S. L., Wasa, M., Wang, X. & Yu, J. Q. Palladium(II)-catalyzed selective monofluorination of benzoic acids using a practical auxiliary: a weak-coordination approach. Angew. Chem. Int. Ed. 50, 9081–9084 (2011).

    Google Scholar 

  52. Lou, S. J., Xu, D. Q. & Xu, Z. Y. Mild and versatile nitrate-promoted C–H bond fluorination. Angew. Chem. Int. Ed. 53, 10330–10335 (2014).

    Google Scholar 

  53. Lee, S. J., Makaravage, K. J., Brooks, A. F., Scott, P. J. H. & Sanford, M. S. Copper-mediated aminoquinoline-directed radiofluorination of aromatic C–H bonds with K18F. Angew. Chem. Int. Ed. 131, 3151–3154 (2019).

    Google Scholar 

  54. Zhao, S.-B., Becker, J. J. & Gagné, M. R. Steric crowding makes challenging Csp3–F reductive eliminations feasible. Organometallics 30, 3926–3929 (2011).

    Google Scholar 

  55. Racowski, J. M., Gary, J. B. & Sanford, M. S. Carbon(sp3)–fluorine bond-forming reductive elimination from palladium(IV) complexes. Angew. Chem. Int. Ed. 51, 3414–3417 (2012).

    Google Scholar 

  56. Zhang, Q., Yin, X. S., Chen, K., Zhang, S. Q. & Shi, B. F. Stereoselective synthesis of chiral β-fluoro α-amino acids via Pd(II)-catalyzed fluorination of unactivated methylene C(sp3)–H bonds: scope and mechanistic studies. J. Am. Chem. Soc. 137, 8219–8226 (2015).

    Google Scholar 

  57. Zhu, R. Y. et al. Ligand-enabled stereoselective β-C(sp3)–H fluorination: synthesis of unnatural enantiopure anti-β-fluoro-α-amino acids. J. Am. Chem. Soc. 137, 7067–7070 (2015).

    Google Scholar 

  58. Liao, G., Zhang, T., Lin, Z.-K. & Shi, B.-F. Transition metal-catalyzed enantioselective C–H functionalization via chiral transient directing group strategies. Angew. Chem. Int. Ed. 59, 19773–19786 (2020).

    Google Scholar 

  59. Park, H., Verma, P., Hong, K. & Yu, J. Q. Controlling Pd(IV) reductive elimination pathways enables Pd(II)-catalyzed enantioselective C(sp3)–H fluorination. Nat. Chem. 10, 755–762 (2018).

    Google Scholar 

  60. Braun, M. G. & Doyle, A. G. Palladium-catalyzed allylic C–H fluorination. J. Am. Chem. Soc. 135, 12990–12993 (2013).

    Google Scholar 

  61. Rueda-Becerril, M. et al. Fluorine transfer to alkyl radicals. J. Am. Chem. Soc. 134, 4026–4029 (2012).

    Google Scholar 

  62. Bloom, S. et al. A polycomponent metal-catalyzed aliphatic, allylic, and benzylic fluorination. Angew. Chem. Int. Ed. 51, 10580–10583 (2012).

    Google Scholar 

  63. Danahy, K. E., Cooper, J. C. & Van Humbeck, J. F. Benzylic fluorination of aza-heterocycles induced by single-electron transfer to selectfluor. Angew. Chem. Int. Ed. 130, 5228–5232 (2018).

    Google Scholar 

  64. Meanwell, M., Nodwell, M. B., Martin, R. E. & Britton, R. A convenient late-stage fluorination of pyridylic C–H bonds with N-fluorobenzenesulfonimide. Angew. Chem. Int. Ed. 55, 13244–13248 (2016).

    Google Scholar 

  65. Bower, J. K., Cypcar, A. D., Henriquez, B., Stieber, S. C. E. & Zhang, S. C(sp3)–H fluorination with a copper(II)/(III) redox couple. J. Am. Chem. Soc. 142, 8514–8521 (2020).

    Google Scholar 

  66. Liu, W. et al. Oxidative aliphatic C–H fluorination with fluoride ion catalyzed by a manganese porphyrin. Science 337, 1322–1325 (2012).

    ADS  Google Scholar 

  67. Liu, W. & Groves, J. T. Manganese-catalyzed oxidative benzylic C–H fluorination by fluoride ions. Angew. Chem. Int. Ed. 52, 6024–6027 (2013).

    Google Scholar 

  68. Huang, X. et al. Late stage benzylic C–H fluorination with [18F]fluoride for PET imaging. J. Am. Chem. Soc. 136, 6842–6845 (2014).

    Google Scholar 

  69. Groendyke, B. J., Abusalim, D. I. & Cook, S. P. Iron-catalyzed, fluoroamide-directed C–H fluorination. J. Am. Chem. Soc. 138, 12771–12774 (2016).

    Google Scholar 

  70. Xia, J. B., Zhu, C. & Chen, C. Visible light-promoted metal-free C–H activation: diarylketone-catalyzed selective benzylic mono- and difluorination. J. Am. Chem. Soc. 135, 17494–17500 (2013).

    Google Scholar 

  71. Nodwell, M. B. et al. 18F-Fluorination of unactivated C–H bonds in branched aliphatic amino acids: direct synthesis of oncological positron emission tomography imaging agents. J. Am. Chem. Soc. 139, 3595–3598 (2017).

    Google Scholar 

  72. Yuan, Z. et al. Site-selective, late-stage C–H 18F-fluorination on unprotected peptides for positron emission tomography imaging. Angew. Chem. Int. Ed. 130, 12915–12918 (2018).

    Google Scholar 

  73. Fier, P. S. & Hartwig, J. F. Selective C–H fluorination of pyridines and diazines inspired by a classic amination reaction. Science 342, 956–960 (2013).

    ADS  Google Scholar 

  74. Yamamoto, K. et al. Palladium-catalyzed electrophilic aromatic C–H fluorination. Nature 554, 511–514 (2018).

    ADS  Google Scholar 

  75. Alonso, C., Martinez de Marigorta, E., Rubiales, G. & Palacios, F. Carbon trifluoromethylation reactions of hydrocarbon derivatives and heteroarenes. Chem. Rev. 115, 1847–1935 (2015).

    Google Scholar 

  76. Hu, W.-Q., Pan, S., Xu, X.-H., Vicic, D. A. & Qing, F.-L. Nickel-mediated trifluoromethylation of phenol derivatives by aryl C–O bond activation. Angew. Chem. Int. Ed. 59, 16076–16082 (2020).

    Google Scholar 

  77. Meucci, E. A. et al. Nickel(IV)-catalyzed C–H trifluoromethylation of (hetero)arenes. J. Am. Chem. Soc. 141, 12872–12879 (2019).

    Google Scholar 

  78. Cho, E. J. et al. The palladium-catalyzed trifluoromethylation of aryl chlorides. Science 328, 1679–1681 (2010). This article describes the trifluoromethylation of aryl chlorides via a Pd0/PdII catalytic cycle.

    ADS  Google Scholar 

  79. Li, G.-B., Zhang, C., Song, C. & Ma, Y.-D. Progress in copper-catalyzed trifluoromethylation. Beilstein J. Org. Chem. 14, 155–181 (2018).

    Google Scholar 

  80. Zeng, Y. et al. Silver-mediated trifluoromethylation-iodination of arynes. J. Am. Chem. Soc. 135, 2955–2958 (2013).

    Google Scholar 

  81. Gonda, Z. et al. Efficient copper-catalyzed trifluoromethylation of aromatic and heteroaromatic iodides: the beneficial anchoring effect of borates. Org. Lett. 16, 4268–4271 (2014).

    Google Scholar 

  82. Hu, M., Ni, C. & Hu, J. Copper-mediated trifluoromethylation of α-diazo esters with TMSCF3: the important role of water as a promoter. J. Am. Chem. Soc. 134, 15257–15260 (2012).

    Google Scholar 

  83. Chu, L. & Qing, F.-L. Copper-mediated oxidative trifluoromethylation of boronic acids. Org. Lett. 12, 5060–5063 (2010).

    Google Scholar 

  84. Chen, Q.-Y. & Wu, S.-W. Methyl fluorosulphonyldifluoroacetate; a new trifluoromethylating agent. J. Chem. Soc. Chem. Commun. https://doi.org/10.1039/C39890000705 (1989). This article is the first description of methyl fluorosulphonyldifluoroacetate, which has proved to be an efficient trifluoromethylation reagent; copper-mediated trifluoromethylation using this reagent can be scaled up to kilograms.

  85. Clarke, S. L. & McGlacken, G. P. Methyl fluorosulfonyldifluoroacetate (MFSDA): an underutilised reagent for trifluoromethylation. Chem. Eur. J. 23, 1219–1230 (2017).

    Google Scholar 

  86. Xie, Q. & Hu, J. Chen’s reagent: a versatile reagent for trifluoromethylation, difluoromethylenation, and difluoroalkylation in organic synthesis. Chin. J. Chem. 38, 202–212 (2020).

    Google Scholar 

  87. Knauber, T., Arikan, F., Roeschenthaler, G.-V. & Gooβen, L. J. Copper-catalyzed trifluoromethylation of aryl iodides with potassium (trifluoromethyl)trimethoxyborate. Chem. Eur. J. 17, 2689–2697 (2011).

    Google Scholar 

  88. Zanardi, A., Novikov, M. A., Martin, E., Benet-Buchholz, J. & Grushin, V. V. Direct cupration of fluoroform. J. Am. Chem. Soc. 133, 20901–20913 (2011).

    Google Scholar 

  89. Novák, P., Lishchynskyi, A. & Grushin, V. V. Fluoroform-derived CuCF3 for low-cost, simple, efficient, and safe trifluoromethylation of aryl boronic acids in air. Angew. Chem. Int. Ed. 51, 7767–7770 (2012).

    Google Scholar 

  90. Zhang, C.-P. et al. Copper-mediated trifluoromethylation of heteroaromatic compounds by trifluoromethyl sulfonium salts. Angew. Chem. Int. Ed. 50, 1896–1900 (2011). This study describes a trifluoromethylation method that has found valuable applications in drug development.

    Google Scholar 

  91. Dai, J.-J. et al. Copper-promoted Sandmeyer trifluoromethylation reaction. J. Am. Chem. Soc. 135, 8436–8439 (2013).

    Google Scholar 

  92. Morimoto, H., Tsubogo, T., Litvinas, N. D. & Hartwig, J. F. A broadly applicable copper reagent for trifluoromethylations and perfluoroalkylations of aryl iodides and bromides. Angew. Chem. Int. Ed. 50, 3793–3798 (2011).

    Google Scholar 

  93. Morstein, J., Hou, H., Cheng, C. & Hartwig, J. F. Trifluoromethylation of arylsilanes with [(phen)CuCF3]. Angew. Chem. Int. Ed. 55, 8054–8057 (2016).

    Google Scholar 

  94. Tomashenko, O. A., Escudero-Adan, E. C., Belmonte, M. M. & Grushin, V. V. Simple, stable, and easily accessible well-defined CuCF3 aromatic trifluoromethylating agents. Angew. Chem. Int. Ed. 50, 7655–7659 (2011).

    Google Scholar 

  95. Paeth, M. et al. Csp3–Csp3 bond-forming reductive elimination from well-defined copper(III) complexes. J. Am. Chem. Soc. 141, 3153–3159 (2019).

    Google Scholar 

  96. Lu, Z. et al. A key intermediate in copper-mediated arene trifluoromethylation, [nBu4 N][Cu(Ar)(CF3)3]: synthesis, characterization, and C(sp2)–CF3 reductive elimination. Angew. Chem. Int. Ed. 58, 8510–8514 (2019).

    Google Scholar 

  97. Liu, S. et al. C(sp3)–CF3 reductive elimination from a five-coordinate neutral copper(III) complex. J. Am. Chem. Soc. 142, 9785–9791 (2020).

    Google Scholar 

  98. Zhang, C. Application of Langlois’ reagent in trifluoromethylation reactions. Adv. Synth. Catal. 356, 2895–2906 (2014).

    Google Scholar 

  99. Wu, X., Chu, L. & Qing, F. L. Silver-catalyzed hydrotrifluoromethylation of unactivated alkenes with CF3SiMe3. Angew. Chem. Int. Ed. 52, 2198–2202 (2013).

    Google Scholar 

  100. Wang, S.-M., Han, J.-B., Zhang, C.-P., Qin, H.-L. & Xiao, J.-C. An overview of reductive trifluoromethylation reactions using electrophilic ‘+CF3’ reagents. Tetrahedron 71, 7949–7976 (2015).

    Google Scholar 

  101. Charpentier, J., Früh, N. & Togni, A. Electrophilic trifluoromethylation by use of hypervalent iodine reagents. Chem. Rev. 115, 650–668 (2015).

    Google Scholar 

  102. Iqbal, N., Jung, J., Park, S. & Cho, E. J. Controlled trifluoromethylation reactions of alkynes through visible-light photoredox catalysis. Angew. Chem. Int. Ed. 53, 539–542 (2014).

    Google Scholar 

  103. Merino, E. & Nevado, C. Addition of CF3 across unsaturated moieties: a powerful functionalization tool. Chem. Soc. Rev. 43, 6598–6608 (2014).

    Google Scholar 

  104. Egami, H. & Sodeoka, M. Trifluoromethylation of alkenes with concomitant introduction of additional functional groups. Angew. Chem. Int. Ed. 53, 8294–8308 (2014).

    Google Scholar 

  105. Zhu, L., Fang, Y. & Li, C. Trifluoromethylation of alkyl radicals: breakthrough and challenges. Chin. J. Chem. 38, 787–789 (2020).

    ADS  Google Scholar 

  106. Prakash, G. K. S. & Mandal, M. Nucleophilic trifluoromethylation tamed. J. Fluor. Chem. 112, 123–131 (2001). This article details the synthetic utilities of a commonly used nucleophilic trifluoromethylation reagent, TMSCF3.

    Google Scholar 

  107. Prakash, G. K. S. & Yudin, A. K. Perfluoroalkylation with organosilicon reagents. Chem. Rev. 97, 757–786 (1997).

    Google Scholar 

  108. Umemoto, T. & Ishihara, S. Power-variable electrophilic trifluoromethylating agents. S-, Se-, and Te-(trifluoromethyl)dibenzothio-, -seleno-, and -tellurophenium salt system. J. Am. Chem. Soc. 115, 2156–2164 (1993).

    Google Scholar 

  109. Matsnev, A. et al. Efficient access to extended Yagupolskii–Umemoto-type reagents: triflic acid catalyzed intramolecular cyclization of ortho-ethynylaryltrifluoromethylsulfanes. Angew. Chem. Int. Ed. 49, 572–576 (2010).

    Google Scholar 

  110. Wang, X., Truesdale, L. & Yu, J.-Q. Pd(II)-catalyzed ortho-trifluoromethylation of arenes using TFA as a promoter. J. Am. Chem. Soc. 132, 3648–3649 (2010).

    Google Scholar 

  111. Zhang, X.-G., Dai, H.-X., Wasa, M. & Yu, J.-Q. Pd(II)-catalyzed ortho trifluoromethylation of arenes and insights into the coordination mode of acidic amide directing groups. J. Am. Chem. Soc. 134, 11948–11951 (2012).

    Google Scholar 

  112. Miura, M., Feng, C.-G., Ma, S. & Yu, J.-Q. Pd(II)-catalyzed ortho-trifluoromethylation of benzylamines. Org. Lett. 15, 5258–5261 (2013).

    Google Scholar 

  113. Chu, L. & Qing, F.-L. Copper-catalyzed direct C–H oxidative trifluoromethylation of heteroarenes. J. Am. Chem. Soc. 134, 1298–1304 (2012).

    Google Scholar 

  114. Shang, M. et al. Exceedingly fast copper(II)-promoted ortho C–H trifluoromethylation of arenes using TMSCF3. Angew. Chem. Int. Ed. 53, 10439–10442 (2014).

    Google Scholar 

  115. Liu, Z. et al. Copper-catalyzed remote C(sp3)–H trifluoromethylation of carboxamides and sulfonamides. Angew. Chem. Int. Ed. 58, 2510–2513 (2019).

    Google Scholar 

  116. Xiao, H. et al. Copper-catalyzed late-stage benzylic C(sp3)–H trifluoromethylation. Chem 5, 940–949 (2019).

    Google Scholar 

  117. Sarver, P. J. et al. The merger of decatungstate and copper catalysis to enable aliphatic C(sp3)–H trifluoromethylation. Nat. Chem. 12, 459–467 (2020).

    Google Scholar 

  118. Zheng, Y. & Ma, J.-A. Combination catalysis in enantioselective trifluoromethylation. Adv. Synth. Catal. 352, 2745–2750 (2010).

    Google Scholar 

  119. Bizet, V., Besset, T., Ma, J.-A. & Cahard, D. Recent progress in asymmetric fluorination and trifluoromethylation reactions. Curr. Top. Med. Chem. 14, 901–940 (2014).

    Google Scholar 

  120. Calvo, R., Comas-Vives, A., Togni, A. & Katayev, D. Taming radical intermediates for the construction of enantioenriched trifluoromethylated quaternary carbon centers. Angew. Chem. Int. Ed. 58, 1447–1452 (2019).

    Google Scholar 

  121. Banik, S. M., Medley, J. W. & Jacobsen, E. N. Catalytic, asymmetric difluorination of alkenes to generate difluoromethylated stereocenters. Science 353, 51–54 (2016).

    ADS  Google Scholar 

  122. Hu, J., Zhang, W. & Wang, F. Selective difluoromethylation and monofluoromethylation reactions. Chem. Commun. https://doi.org/10.1039/B916463D (2009). This article is the first comprehensive review on difluoromethylation and monofluoromethylation.

  123. Motherwell, W. B., Tozer, M. J. & Ross, B. C. A convenient method for replacement of the anomeric hydroxy group in carbohydrates by difluoromethyl functionality. J. Chem. Soc. Chem. Commun. https://doi.org/10.1039/C39890001437 (1989).

    Article  Google Scholar 

  124. Sap, J. B. I. et al. Organophotoredox hydrodefluorination of trifluoromethylarenes with translational applicability to drug discovery. J. Am. Chem. Soc. 142, 9181–9187 (2020).

    Google Scholar 

  125. Belhomme, M.-C., Besset, T., Poisson, T. & Pannecoucke, X. Recent progress toward the introduction of functionalized difluoromethylated building blocks onto C(sp2) and C(sp) centers. Chem. Eur. J. 21, 12836–12865 (2015).

    Google Scholar 

  126. Rong, J., Ni, C. & Hu, J. Metal-catalyzed direct difluoromethylation reactions. Asian J. Org. Chem. 6, 139–152 (2017).

    Google Scholar 

  127. Yerien, D. E., Barata-Vallejo, S. & Postigo, A. Difluoromethylation reactions of organic compounds. Chem. Eur. J. 23, 14676–14701 (2017).

    Google Scholar 

  128. Levi, N., Amir, D., Gershonov, E. & Zafrani, Y. Recent progress on the synthesis of CF2H-containing derivatives. Synthesis 51, 4549–4567 (2019).

    Google Scholar 

  129. Zhao, Y., Huang, W., Zheng, J. & Hu, J. Efficient and direct nucleophilic difluoromethylation of carbonyl compounds and imines with Me3SiCF2H at ambient or low temperature. Org. Lett. 13, 5342–5345 (2011). This article introduces Me3SiCF2H (TMSCF2H) as a general and mild direct difluoromethylation reagent.

    Google Scholar 

  130. Endo, Y., Ishii, K. & Mikami, K. Chiral copper-catalyzed enantioselective Michael difluoromethylation of arylidene meldrum’s acids with (difluoromethyl)zinc reagents. Tetrahedron 75, 4099–4103 (2019).

    Google Scholar 

  131. Zeng, X. et al. Copper-catalyzed decarboxylative difluoromethylation. J. Am. Chem. Soc. 141, 11398–11403 (2019).

    Google Scholar 

  132. Zeng, X. et al. Copper-catalyzed, chloroamide-directed benzylic C–H difluoromethylation. J. Am. Chem. Soc. 141, 19941–19949 (2019).

    Google Scholar 

  133. Gu, Y., Lu, C., Gu, Y. & Shen, Q. Ligand-controlled copper-catalyzed highly regioselective difluoromethylation of allylic chlorides/bromides and propargyl bromides. Chin. J. Chem. 36, 55–58 (2018).

    Google Scholar 

  134. Song, H., Cheng, R., Min, Q.-Q. & Zhang, X. Decarboxylative and deaminative alkylation of difluoroenoxysilanes via photoredox catalysis: a general method for site-selective synthesis of difluoroalkylated alkanes. Org. Lett. 22, 7747–7751 (2020).

    Google Scholar 

  135. Lemos, A., Lemaire, C. & Luxen, A. Progress in difluoroalkylation of organic substrates by visible light photoredox catalysis. Adv. Synth. Catal. 361, 1500–1537 (2019).

    Google Scholar 

  136. He, Z., Tan, P., Ni, C. & Hu, J. Fluoroalkylative aryl migration of conjugated N‑arylsulfonylated amides using easily accessible sodium di- and monofluoroalkanesulfinates. Org. Lett. 17, 1838–1841 (2015). This article introduces HCF2SO2Na as a practical radical difluoromethylation reagent.

    Google Scholar 

  137. Lin, Q.-Y., Ran, Y., Xu, X.-H. & Qing, F.-L. Photoredox-catalyzed bromodifluoromethylation of alkenes with (difluoromethyl)triphenylphosphonium bromide. Org. Lett. 18, 2419–2422 (2016).

    Google Scholar 

  138. Zhang, W. et al. Leaving group assisted strategy for photoinduced fluoroalkylations using N-hydroxybenzimidoyl chloride esters. Angew. Chem. Int. Ed. 58, 624–627 (2019).

    Google Scholar 

  139. Meyer, C. F., Hell, S. M., Misale, A., Trabanco, A. A. & Gouverneur, V. Hydrodifluoromethylationof alkenes with difluoroacetic acid. Angew. Chem. Int. Ed. 58, 8829–8833 (2019).

    Google Scholar 

  140. Xie, Q., Zhu, Z., Li, L., Ni, C. & Hu, J. A general protocol for C–H difluoromethylation of carbon acids with TMSCF2Br. Angew. Chem. Int. Ed. 58, 6405–6410 (2019).

    Google Scholar 

  141. Zhu, J. et al. Carbon-selective difluoromethylation of soft carbon nucleophiles with difluoromethylated sulfonium ylide. Chin. J. Chem. 36, 1069–1074 (2018).

    Google Scholar 

  142. Lu, S.-L. et al. Air- and light-stable S-(difluoromethyl)sulfonium salts: C-selective electrophilic difluoromethylation of β-ketoesters and malonates. Org. Lett. 20, 6925–6929 (2018).

    Google Scholar 

  143. Duchemin, N., Buccafusca, R., Daumas, M., Ferey, V. & Arseniyadis, S. A unified strategy for the synthesis of difluoromethyl- and vinylfluoride-containing scaffolds. Org. Lett. 21, 8205–8210 (2019).

    Google Scholar 

  144. Zeng, X. et al. Copper-catalyzed deaminative difluoromethylation. Angew. Chem. Int. Ed. 59, 16398–16403 (2020).

    Google Scholar 

  145. Fier, P. S. & Hartwig, J. F. Copper-mediated difluoromethylation of aryl and vinyl iodides. J. Am. Chem. Soc. 134, 5524–5527 (2012).

    Google Scholar 

  146. Ferguson, D. M., Malapit, C. A., Bour, J. R. & Sanford, M. S. Palladium-catalyzed difluoromethylation of aryl chlorides and bromides with TMSCF2H. J. Org. Chem. 84, 3735–3740 (2019).

    Google Scholar 

  147. Gu, Y., Leng, X. & Shen, Q. Cooperative dual palladium/silver catalyst for direct difluoromethylation of aryl bromides and iodides. Nat. Commun. 5, 5405 (2014).

    ADS  Google Scholar 

  148. Lu, C. et al. Palladium-catalyzed difluoromethylation of aryl chlorides and triflates and its applications in the preparation of difluoromethylated derivatives of drug/agrochemical molecules. J. Org. Chem. 83, 1077–1083 (2018).

    Google Scholar 

  149. Lu, C., Gu, Y., Wu, J., Gu, Y. & Shen, Q. Palladium-catalyzed difluoromethylation of heteroaryl chlorides, bromides and iodides. Chem. Sci. 8, 4848–4852 (2017).

    Google Scholar 

  150. Pan, F., Boursalian, G. B. & Ritter, T. Palladium-catalyzed decarbonylative difluoromethylation of acid chlorides at room temperature. Angew. Chem. Int. Ed. 57, 16871–16876 (2018).

    Google Scholar 

  151. Xu, L. & Vicic, D. A. Direct difluoromethylation of aryl halides via base metal catalysis at room temperature. J. Am. Chem. Soc. 138, 2536–2539 (2016).

    Google Scholar 

  152. Xu, C. et al. Difluoromethylation of (hetero)aryl chlorides with chlorodifluoromethane catalyzed by nickel. Nat. Commun. 9, 1170 (2018).

    ADS  Google Scholar 

  153. Bacauanu, V. et al. Metallaphotoredox difluoromethylation of aryl bromides. Angew. Chem. Int. Ed. 57, 12543–12548 (2018).

    Google Scholar 

  154. Miao, W. et al. Iron-catalyzed difluoromethylation of arylzincs with difluoromethyl 2‑pyridyl sulfone. J. Am. Chem. Soc. 140, 880–883 (2018).

    Google Scholar 

  155. Fu, X.-P., Xiao, Y.-L. & Zhang, X. Nickel-catalyzed difluoromethylation of arylboronic acids with bromodifluoromethane. Chin. J. Chem. 36, 143–146 (2018).

    Google Scholar 

  156. Motohashi, H., Kato, M. & Mikami, K. Ligand-less iron-catalyzed aromatic cross-coupling difluoromethylation of Grignard reagents with difluoroiodomethane. J. Org. Chem. 84, 6483–6490 (2019).

    Google Scholar 

  157. Hori, K., Motohashi, H., Saito, D. & Mikami, K. Precatalyst effects on Pd-catalyzed cross-coupling difluoromethylation of aryl boronic acids. ACS Catal. 9, 417–421 (2019).

    Google Scholar 

  158. Feng, Z., Min, Q.-Q. & Zhang, X. Access to difluoromethylated arenes by Pd-catalyzed reaction of arylboronic acids with bromodifluoroacetate. Org. Lett. 18, 44–47 (2016). This article represents a mechanically novel method for metal-catalysed difluoromethylation.

    Google Scholar 

  159. Deng, X.-Y., Lin, J.-H. & Xiao, J.-C. Pd-catalyzed transfer of difluorocarbene. Org. Lett. 18, 4384–4387 (2016).

    Google Scholar 

  160. Feng, Z., Min, Q.-Q., Fu, X.-P., An, L. & Zhang, X. Chlorodifluoromethane-triggered formation of difluoromethylated arenes catalyzed by palladium. Nat. Chem. 9, 918–923 (2017).

    Google Scholar 

  161. Fu, X.-P. et al. Controllable catalytic difluorocarbene transfer enables access to diversified fluoroalkylated arenes. Nat. Chem. 11, 948–956 (2019).

    Google Scholar 

  162. Zhu, S.-Q., Liu, Y.-L., Li, H., Xu, X.-H. & Qing, F.-L. Direct and regioselective C–H oxidative difluoromethylation of heteroarenes. J. Am. Chem. Soc. 140, 11613–11617 (2018).

    Google Scholar 

  163. Zhu, S.-Q., Xua, X.-H. & Qing, F.-L. Silver-mediated oxidative C–H difluoromethylation of phenanthridines and 1,10-phenanthrolines. Chem. Commun. 53, 11484–11487 (2017).

    Google Scholar 

  164. Fujiwara, Y. et al. A new reagent for direct difluoromethylation. J. Am. Chem. Soc. 134, 1494–1497 (2012). This article develops a practical method for the direct introduction of a difluoromethyl group into organic molecules.

    Google Scholar 

  165. Dai, P., Yu, X., Teng, P., Zhang, W.-H. & Deng, C. Visible-light- and oxygen-promoted direct Csp2–H radical difluoromethylation of coumarins and antifungal activities. Org. Lett. 20, 6901–6905 (2018).

    Google Scholar 

  166. Zhang, W. et al. Direct C–H difluoromethylation of heterocycles via organic photoredox catalysis. Nat. Commun. 11, 638 (2020).

    ADS  Google Scholar 

  167. Sakamoto, R., Kashiwagi, H. & Maruoka, K. The direct C–H difluoromethylation of heteroarenes based on the photolysis of hypervalent iodine(III) reagents that contain difluoroacetoxy ligands. Org. Lett. 19, 5126–5129 (2017).

    Google Scholar 

  168. Tung, T. T., Christensen, S. B. & Nielsen, J. Difluoroacetic acid as a new reagent for direct C–H difluoromethylation of heteroaromatic compounds. Chem. Eur. J. 23, 18125–18128 (2017).

    Google Scholar 

  169. Rubinski, M. A., Lopez, S. E. & Dolbier, W. R. Jr. Direct access to 2-difluoromethyl indoles via photoredox catalysis. J. Fluor. Chem. 224, 80–88 (2019).

    Google Scholar 

  170. Su, Y.-M. et al. Visible light-mediated C–H difluoromethylation of electron-rich heteroarenes. Org. Lett. 16, 2958–2961 (2014).

    Google Scholar 

  171. McAtee, R. C., Beatty, J. W., McAtee, C. C. & Stephenson, C. R. J. Radical chlorodifluoromethylation: providing a motif for (hetero)arene diversification. Org. Lett. 20, 3491–3495 (2018).

    Google Scholar 

  172. Ye, F. et al. Aryl sulfonium salts for site-selective late-stage trifluoromethylation. Angew. Chem. Int. Ed. 58, 14615–14619 (2019).

    Google Scholar 

  173. Zhao, H., Herbert, S., Kinzel, T., Zhang, W. & Shen, Q. Two ligands transfer from Ag to Pd: en route to (SIPr)Pd(CF2H)(X) and its application in one-pot C–H borylation/difluoromethylation. J. Org. Chem. 85, 3596–3604 (2020).

    Google Scholar 

  174. Ni, C. & Hu, J. Recent advances in the synthetic application of difluorocarbene. Synthesis 46, 842–863 (2014).

    Google Scholar 

  175. Levchenko, K. et al. Copper-catalyzed O-difluoromethylation of functionalized aliphatic alcohols: access to complex organic molecules with an OCF2H group. J. Org. Chem. 81, 5803–5813 (2016).

    Google Scholar 

  176. Xie, Q. et al. Efficient difluoromethylation of alcohols using TMSCF2Br as a unique and practical difluorocarbene reagent under mild conditions. Angew. Chem. Int. Ed. 56, 3206–3210 (2017).

    Google Scholar 

  177. Xiao, X. et al. Recent advances in difluoromethylthiolation. Synthesis 52, 197–207 (2020). This article includes important references on difluoromethylthiolation.

    Google Scholar 

  178. Reichel, M. & Karaghiosoff, K. Reagents for selective fluoromethylation-A challenge in organofluorine chemistry. Angew. Chem. Int. Ed. 59, 12268–12281 (2020). This article is the most comprehensive review on monofluoromethylation.

    Google Scholar 

  179. Harry Szmant, H. & Dudek, J. Relative chloromethylation rates of some aromatic compounds. J. Am. Chem. Soc. 71, 3763–3765 (1949).

    Google Scholar 

  180. Meanwell, M. & Britton, R. Synthesis of heterobenzylic fluorides. Synthesis 50, 1228–1236 (2018).

    Google Scholar 

  181. Parisi, G. et al. Exploiting a “beast” in carbenoid chemistry: development of a straightforward direct nucleophilic fluoromethylation strategy. J. Am. Chem. Soc. 139, 13648–13651 (2017).

    Google Scholar 

  182. Shen, X., Ni, C. & Hu, J. Highly stereoselective and one-pot synthesis of tetra-substituted monofluoroalkenes with aldehydes and fluorobis(phenylsulfonyl)methane. Chin. J. Chem. 31, 878–884 (2013).

    Google Scholar 

  183. Koizumi, T., Hagi, T., Horie, Y. & Takeuchi, Y. Diethyl 1-fluoro-1-phenylsulfonylmethanephosphonate, a versatile agent for the preparation of monofluorinated building blocks. Chem. Pharm. Bull. 35, 3959–3962 (1987).

    Google Scholar 

  184. Zhu, L., Ni, C., Zhao, Y. & Hu, J. 1-tert-Butyl-1H-tetrazol-5-yl fluoromethyl sulfone (TBTSO2CH2F): a versatile fluoromethylidene synthon and its use in the synthesis of monofluorinated alkenes via JuliaKocienski olefination. Tetrahedron 66, 5089–5100 (2010).

    Google Scholar 

  185. Shen, X., Zhou, M., Ni, C., Zhang, W. & Hu, J. Direct monofluoromethylation of O-, S-, N-, and P-nucleophiles with PhSO(NTs)CH2F: the accelerating effect of α-fluorine substitution. Chem. Sci. 5, 117–122 (2014).

    Google Scholar 

  186. Rong, J. et al. Radical fluoroalkylation of isocyanides with fluorinated sulfones by visible-light photoredox catalysis. Angew. Chem. Int. Ed. 55, 2743–2747 (2016).

    Google Scholar 

  187. Tang, X. J. & Dolbier, W. R. Efficient Cu-catalyzed atom transfer radical addition reactions of fluoroalkylsulfonyl chlorides with electron-deficient alkenes induced by visible light. Angew. Chem. Int. Ed. 54, 4246–4249 (2015).

    Google Scholar 

  188. Cao, J. J., Wang, X., Wang, S. Y. & Ji, S. J. Mn(III)-mediated reactions of 2-isocyanobiaryl with 1,3-dicarbonyl compounds: efficient synthesis of 6-alkylated and 6-monofluoro-alkylated phenanthridines. Chem. Commun. 50, 12892–12895 (2014).

    Google Scholar 

  189. Olah, G. A. & Pavlath, A. The investigation of fluoromethylation. Acta Chim. Acad. Sci. Hung. 3, 425 (1953).

    Google Scholar 

  190. Olah, G. A. & Pavlath, A. The preparation of fluoromethanol. Acta Chim. Acad. Sci. Hung. 3, 203–207 (1953).

    Google Scholar 

  191. Orr, J. C., Edwards, J. & Bowers, A. (Syntex Corp.) 2-Halo methyl derivatives of the androstane series. US Patent 3,080,395 (1963).

  192. Ding, T. et al. Highly carbon-selective monofluoromethylation of β-ketoesters with fluoromethyl Iodide. Org. Lett. 21, 6025–6028 (2019).

    Google Scholar 

  193. Prakash, G. K. S., Ledneczki, I., Chacko, S. & Olah, G. A. Direct electrophilic monofluoromethylation. Org. Lett. 10, 557–560 (2008).

    Google Scholar 

  194. Liu, Y., Lu, L. & Shen, Q. Monofluoromethyl-substituted sulfonium ylides: electrophilic monofluoromethylating reagents with broad substrate scopes. Angew. Chem. Int. Ed. 56, 9930–9934 (2017).

    Google Scholar 

  195. Nomura, Y., Tokunaga, E. & Shibata, N. Inherent oxygen preference in enolate monofluoromethylation and a synthetic entry to monofluoromethyl ethers. Angew. Chem. Int. Ed. 50, 1885–1889 (2011).

    Google Scholar 

  196. Yang, Y.-D. et al. Cation versus radical: studies on the C/O regioselectivity in electrophilic tri-, di- and monofluoromethylations of β-ketoesters. ChemistryOpen 1, 221–226 (2012).

    Google Scholar 

  197. Yang, Y. D., Wang, X., Tsuzuki, S., Tokunaga, E. & Shibata, N. Studies on the C/O-regioselectivity in electrophilic fluoromethylations of β-ketoesters based on thermodynamics by ab initio calculations. Bull. Kor. Chem. Soc. 35, 1851–1854 (2014).

    Google Scholar 

  198. Raymond, J. I. & Andrews, L. Matrix reactions of fluorohalomethanes with alkali metals: infrared spectrum and bonding in the monofluoromethyl radical. J. Phys. Chem. 75, 3235–3242 (1971).

    Google Scholar 

  199. Fujiwara, Y. et al. Practical and innate carbon–hydrogen functionalization of heterocycles. Nature 492, 95–99 (2012).

    ADS  Google Scholar 

  200. Huang, Q. & Zard, S. Z. Inexpensive radical methylation and related alkylations of heteroarenes. Org. Lett. 20, 1413–1416 (2018).

    Google Scholar 

  201. Ruan, Z. et al. Ruthenium(II)-catalyzed meta C–H mono- and difluoromethylations by phosphine/carboxylate cooperation. Angew. Chem. Int. Ed. 56, 2045–2049 (2017).

    Google Scholar 

  202. Li, Z. Y. et al. Ruthenium-catalyzed meta-selective C–H mono- and difluoromethylation of arenes through ortho-metalation strategy. Chem. Eur. J. 23, 3285–3290 (2017).

    Google Scholar 

  203. Reutrakul, V. & Rukachaisirikul, V. Fluoromethyl phenyl sulfoxide: highly convenient syntheses of vinyl fluorides and fluoromethylketones. Tetrahedron Lett. 24, 725–728 (1983).

    Google Scholar 

  204. Zhao, Y. et al. Copper-catalyzed debenzoylative monofluoromethylation of aryl iodides assisted by the removable (2-pyridyl)sulfonyl group. ACS Catal. 3, 631–634 (2013).

    Google Scholar 

  205. Peters, D. & Miethchen, R. Symptoms and treatment of hydrogen fluoride injuries. J. Fluor. Chem. 79, 161–165 (1996).

    Google Scholar 

  206. Inoue, M., Sumii, Y. & Shibata, N. Contribution of organofluorine compounds to pharmaceuticals. ACS Omega 5, 10633–10640 (2020). This article comprehensively summarizes the fluorinated pharmaceuticals on the market.

    Google Scholar 

  207. Halperin, S. D., Fan, H., Chang, S., Martin, R. E. & Britton, R. A convenient photocatalytic fluorination of unactivated C–H bonds. Angew. Chem. Int. Ed. 53, 4690–4693 (2014).

    Google Scholar 

  208. Yale, H. L. The trifluoromethyl group in medical chemistry. J. Med. Chem. 1, 121–133 (1958).

    Google Scholar 

  209. Meanwell, N. A. Fluorine and fluorinated motifs in the design and application of bioisosteres for drug design. J. Med. Chem. 61, 5822–5880 (2018).

    Google Scholar 

  210. Estrada, A. A. et al. Discovery of highly potent, selective, and brain-penetrable leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors. J. Med. Chem. 55, 9416–9433 (2012).

    Google Scholar 

  211. Jurica, E. A. et al. Discovery of pyrrolidine-containing GPR40 agonists: stereochemistry effects a change in binding mode. J. Med. Chem. 60, 1417–1431 (2017).

    Google Scholar 

  212. Trump, L. et al. Late-stage 18F-difluoromethyl labeling of N-heteroaromatics with high molar activity for PET imaging. Angew. Chem. Int. Ed. 58, 13149–13154 (2019).

    Google Scholar 

  213. Kuttruff, C. A., Haile, M., Kraml, J. & Tautermann, C. S. Late-stage functionalization of drug-like molecules using Diversinates. ChemMedChem 13, 983–987 (2018).

    Google Scholar 

  214. Noisier, A. F. M. et al. Late-stage functionalization of histidine in unprotected peptides. Angew. Chem. Int. Ed. 58, 19096–19102 (2019).

    Google Scholar 

  215. Jiang, J. et al. Late-stage difluoromethylation leading to a self-immobilizing fluorogenic probe for the visualization of enzyme activities in live cells. Chem. Commun. 55, 15000–15003 (2019).

    Google Scholar 

  216. Smith, J. M., Dixon, J. A., deGruyter, J. N. & Baran, P. S. Alkyl sulfinates: radical precursors enabling drug discovery. J. Med. Chem. 62, 2256–2264 (2019).

    Google Scholar 

  217. Campbell, M. G. et al. Bridging the gaps in 18F PET tracer development. Nat. Chem. 9, 1–3 (2017).

    Google Scholar 

  218. Yuan, Z. et al. Electrostatic effects accelerate decatungstate-catalyzed C–H fluorination using [18F]- and [19F]NFSI in small molecules and peptide mimics. ACS Catal. 9, 8276–8284 (2019).

    Google Scholar 

  219. Huiban, M. et al. A broadly applicable [18F]trifluoromethylation of aryl and heteroaryl iodides for PET imaging. Nat. Chem. 5, 941–944 (2013).

    Google Scholar 

  220. Ivashkin, P. et al. CuCF3: a [18F]trifluoromethylating agent for arylboronic acids and aryl iodides. Chem. Eur. J. 20, 9514–9518 (2014).

    Google Scholar 

  221. Vanderborn, D. et al. A universal procedure for the [18F]trifluoromethylation of aryl iodides and aryl boronic acids with highly improved specific activity. Angew. Chem. Int. Ed. 53, 11046–11050 (2014).

    Google Scholar 

  222. Yang, B. Y., Telu, S., Haskali, M. B., Morse, C. L. & Pike, V. W. A gas phase route to [18F]fluoroform with limited molar activity dilution. Sci. Rep. 9, 14835 (2019).

    ADS  Google Scholar 

  223. Ashworth, S. et al. 18F-Trifluoromethanesulfinate enables direct C–H 18F-trifluoromethylation of native aromatic residues in peptides. J. Am. Chem. Soc. 142, 1180–1185 (2020).

    Google Scholar 

  224. Zheng, L. & Berridge, M. S. Synthesis of [18F]fluoromethyl iodide, a synthetic precursor for fluoromethylation of radiopharmaceuticals. Appl. Radiat. Isot. 52, 55–61 (2000).

    Google Scholar 

  225. Iwata, R. et al. [18F]Fluoromethyl triflate, a novel and reactive [18F]fluoromethylating agent: preparation and application to the on-column preparation of [18F]fluorocholine. Appl. Radiat. Isot. 57, 347–352 (2002).

    Google Scholar 

  226. Degrado, T. R. et al. Synthesis and evaluation of 18F-labeled choline as an oncologic tracer for positron emission tomography: initial findings in prostate cancer. Cancer Res. 61, 110–117 (2001).

    Google Scholar 

  227. Doi, H., Goto, M. & Suzuki, M. Pd0-mediated rapid C-[18F]fluoromethylation by the cross-coupling reaction of a [18F]fluoromethyl halide with an arylboronic acid ester: novel method for the synthesis of a 18F-labeled molecular probe for positron emission tomography. Bull. Chem. Soc. Jpn. 85, 1233–1238 (2012).

    Google Scholar 

  228. Vitaku, E., Smith, D. T. & Njardarson, J. T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among US FDA approved pharmaceuticals. J. Med. Chem. 57, 10257–10274 (2014).

    Google Scholar 

  229. Ichiishi, N. et al. Protecting group free radical C–H trifluoromethylation of peptides. Chem. Sci. 9, 4168–4175 (2018).

    Google Scholar 

  230. Imiołek, M. et al. Selective radical trifluoromethylation of native residues in proteins. J.Am. Chem. Soc. 140, 1568–1571 (2018).

    Google Scholar 

  231. O’Neill, B. T. et al. Design and synthesis of clinical candidate PF-06751979: a potent, brain penetrant, β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor lacking hypopigmentation. J. Med. Chem. 61, 4476–4504 (2018).

    Google Scholar 

  232. Greszler, S. N., Shelat, B. & Voight, E. A. Enabling synthesis of ABBV-2222, a CFTR corrector for the treatment of cystic fibrosis. Org. Lett. 21, 5725–5727 (2019).

    Google Scholar 

  233. Kubota, S. Manufacturing method of pyrazole derivative and intermediate products thereof. Patent JP2017/206453A (2017).

  234. Fujiwara, T. & O’Hagan, D. Successful fluorine-containing herbicide agrochemicals. J. Fluor. Chem. 167, 16–29 (2014).

    Google Scholar 

  235. Okui, S. et al. Pyrazol derivatives, pest control agent comprising the same as active ingredient, and process for producing the same. US Patent 7371768 B2 (2008).

  236. Sharma, R. & Aboagye, E. Development of radiotracers for oncology — the interface with pharmacology. Br. J. Pharmacol. 163, 1565–1585 (2011).

    Google Scholar 

  237. Everaert, H. et al. Optimal dose of 18F-FDG required for whole-body PET using an LSO PET camera. Eur. J. Nucl. Med. Mol. Imaging 30, 1615–1619 (2003).

    Google Scholar 

  238. World Health Organization. Essential medicines and health products. World Health Organization https://www.who.int/medicines/areas/quality_safety/quality_assurance/production/en/ (2021).

  239. Dolbier, W. R. Jr. Guide to Fluorine NMR for Organic Chemists 2nd ed. (Wiley, 2016)

  240. Halperin, S. D. et al. Development of a direct photocatalytic C–H fluorination for the preparative synthesis of odanacatib. Org. Lett. 17, 5200–5203 (2015).

    Google Scholar 

  241. Nobile, E., Castanheiro, T. & Besset, T. Radical-promoted distal C–H functionalization of C(sp3) centers with fluorinated moieties. Angew. Chem. Int. Ed. https://doi.org/10.1002/anie.202009995 (2021).

    Article  Google Scholar 

  242. Zhang, F.-G. et al. Remote fluorination and fluoroalkyl(thiol)ation reactions. Chem. Eur. J. 26, 15378–15396 (2021).

    Google Scholar 

  243. Josephson, B. et al. Light-driven post-translational installation of reactive protein side chains. Nature 585, 530–537 (2020).

    ADS  Google Scholar 

Download references

Acknowledgements

This work is partially supported by the National Key Research and Development Program of China (2016YFB0101200), the National Natural Science Foundation of China (21632009, 21421002, 21672242, 21971252 and 21991122), Key Programs of the Chinese Academy of Sciences (KGZD-EW-T08), the Key Research Program of Frontier Sciences of CAS (QYZDJ-SSW-SLH049), Shanghai Science and Technology Program (18JC1410601) and the Youth Innovation Promotion Association CAS (2019256). R.B. acknowledges support from a Natural Sciences and Engineering Research Council (NSERC) of Canada Discovery Grant (2019-06368) and M.M. was supported by a NSERC CGSM award. The authors also thank the European Research Council (grant agreements 832994 and 789553) for financial support.

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Contributions

Introduction (J.H.); Experimentation, Applications, Reproducibility and data deposition, Limitations and optimizations: Fluorination (G.P. and V.G.), Trifluoromethylation (J.-H.L. and J.-C.X.), Difluoromethylation (C.N. and J.H.), Monofluoromethylation (M.M. and R.B.); Outlook (J.H.); Overview of Primer (all authors).

Corresponding author

Correspondence to Jinbo Hu.

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Nature Reviews Methods Primers thanks L. Hunter, N. Shibata and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Heteroelement

Any element in the periodic table that is not carbon or hydrogen.

Positron emission tomography

(PET). A functional imaging technique that uses radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities.

Swarts reaction

A fluorination method used to prepare alkyl fluorides from alkyl chlorides or bromides. The typical fluorination reagent is antimony(III) trifluoride in the presence of a catalytic amount of antimony(V) salts.

Balz–Schiemann reaction

A method for the production of aryl fluorides from primary aromatic amine via a diazonium tetrafluoroborate intermediate.

Halex reaction

The nucleophilic substitution reaction between an aryl or alkyl halide and the other halide ions.

Phase transfer catalysis

A process in which the rate of a reaction in a heterogeneous two-phase system is enhanced by the addition of a substance that transfers one of the reactants across the interface between the two phases.

C–H bond dissociation energies

Measures of the strength of C–H bonds, which can be defined as the standard enthalpy change when C–H is cleaved by homolysis to give a carbon radical and a hydrogen atom.

Density functional theory

A computational quantum mechanical modelling method to investigate the electronic structure or nuclear structure of atoms, molecules and the condensed phases.

Heteroatom

Any atom that is not a carbon atom or a hydrogen atom, similar to heteroelement.

Bioisosteres

Chemical substituents or groups with similar physical or chemical properties.

Minisci reaction

A nucleophilic radical substitution to an electron-deficient aromatic compound, most commonly involving the introduction of an alkyl group to a nitrogen-containing aromatic heterocycle.

Cryptand

A family of synthetic bicyclic and polycyclic multidentate ligands for a range of cations.

Atom economy

The conversion efficiency of a chemical process in terms of all atoms involved and the desired products produced.

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Britton, R., Gouverneur, V., Lin, JH. et al. Contemporary synthetic strategies in organofluorine chemistry. Nat Rev Methods Primers 1, 47 (2021). https://doi.org/10.1038/s43586-021-00042-1

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