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α-Fluorination of carbonyls with nucleophilic fluorine

Abstract

Given the unique properties of fluorine, and the ability of fluorination to change the properties of organic molecules, there is significant interest from medicinal chemists in innovative methodologies that enable the synthesis of new fluorinated motifs. State-of-the-art syntheses of α-fluorinated carbonyl compounds invariably rely on electrophilic fluorinating agents, which can be strongly oxidizing and difficult to handle. Here we show that reversing the polarity of the enolate partner to that of an enolonium enables nucleophilic fluorinating agents to be used for direct chemoselective α-C–H-fluorination of amides. Reduction of these products enables facile access to β-fluorinated amines and the value of this methodology is shown by the easy preparation of a number of fluorinated analogues of drugs and agrochemicals. A fluorinated analogue of citalopram, a marketed antidepressant drug, is presented as an example of the preserved biological activity after fluorination.

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Fig. 1: Importance of fluorination in medicinal chemistry and approaches to α-fluorinated amides.
Fig. 2: Preparation of fluorinated analogues of pharmaceutical and agrochemical compounds.

Data availability

The data that support the findings of this study are available from the corresponding author upon request.

References

  1. 1.

    Bondi, A. van der Waals volumes and radii. J. Phys. Chem. 68, 441–451 (1964).

    CAS  Article  Google Scholar 

  2. 2.

    O’Hagan, D. Understanding organofluorine chemistry. An introduction to the C–F bond. Chem. Soc. Rev. 37, 308–319 (2008).

    Article  Google Scholar 

  3. 3.

    DeBernardis, J. F. et al. Conformationally defined adrenergic agents. 1. Design and synthesis of novel α2 selective adrenergic agents: electrostatic repulsion based conformational prototypes. J. Med. Chem. 28, 1398–1404 (1985).

    CAS  Article  Google Scholar 

  4. 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).

    CAS  Article  Google Scholar 

  5. 5.

    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).

    CAS  Article  Google Scholar 

  6. 6.

    Purser, S., Moore, P. R., Swallow, S. & Gouverneur, V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 37, 320–330 (2008).

    CAS  Article  Google Scholar 

  7. 7.

    Lankin, D. C., Chandrakumar, N. S., Rao, S. N., Spangler, D. P. & Snyder, J. P. Protonated 3-fluoropiperidines: an unusual fluoro directing effect and a test for quantitative theories of solvation. J. Am. Chem. Soc. 115, 3356–3357 (1993).

    CAS  Article  Google Scholar 

  8. 8.

    van Niel, M. B. et al. Fluorination of 3-(3-(piperidin-1-yl)propyl)indoles and 3-(3-(piperazin-1-yl)propyl)indoles gives selective human 5-HT1D receptor ligands with improved pharmacokinetic profiles. J. Med. Chem. 42, 2087–2104 (1999).

    Article  Google Scholar 

  9. 9.

    Park, B. K., Kitteringham, N. R. & O’Neill, P. M. Metabolism of fluorine-containing drugs. Annu. Rev. Pharmacol. Toxicol. 41, 443–470 (2001).

    CAS  Article  Google Scholar 

  10. 10.

    Banks, R. E., & Mohialdin-Khaffaf, S. N. & Lal, G. S. & Sharif, I. & Syvret, R. G. 1-Alkyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane salts: a novel family of electrophilic fluorinating agents. J. Chem. Soc. Chem. Commun. 0, 595–596 (1992).

    CAS  Article  Google Scholar 

  11. 11.

    Differding, E. & Ofner H. N-Fluorobenzenesulfonimide: a practical reagent for electrophilic fluorinations. Synlett.187–18 9 (1991)..

  12. 12.

    Nyffeler, P. T., Durón, S. G., Burkart, M. D., Vincent, S. P. & Wong, C.-H. Selectfluor: mechanistic insight and applications. Angew. Chem. Int. Ed. 44, 192–212 (2005).

    CAS  Article  Google Scholar 

  13. 13.

    Guo, S., Cong, F., Guo, R., Wang, L. & Tang, P. Asymmetric silver-catalysed intermolecular bromotrifluoromethoxylation of alkenes with a new trifluoromethoxylation reagent. Nat. Chem. 9, 546–551 (2017).

    CAS  Article  Google Scholar 

  14. 14.

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

    CAS  Article  Google Scholar 

  15. 15.

    Saadi, J. & Wennemers, H. Enantioselective aldol reactions with masked fluoroacetates. Nat. Chem. 8, 276–280 (2016).

    CAS  Article  Google Scholar 

  16. 16.

    Liang, T., Neumann, C. N. & Ritter, T. Introduction of fluorine and fluorine-containing functional groups. Angew. Chem. Int. Ed. 52, 8214–8264 (2013).

    CAS  Article  Google Scholar 

  17. 17.

    Peng, J. & Du, D.-M. Efficient enantioselective fluorination of β-keto esters/amides catalysed by diphenylamine-linked bis(thiazoline)–Cu(OTf)2 complexes. RSC Adv. 4, 2061–2067 (2013).

    Article  Google Scholar 

  18. 18.

    Li, F., Wu, Z. & Wang, J. Oxidative enantioselective α-fluorination of aliphatic aldehydes enabled by N-heterocyclic carbene catalysis. Angew. Chem. Int. Ed. 54, 656–659 (2015).

    CAS  Google Scholar 

  19. 19.

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

    CAS  Article  Google Scholar 

  20. 20.

    Paull, D. H., Scerba, M. T., Alden-Danforth, E., Widger, L. R. & Lectka, T. Catalytic, asymmetric α-fluorination of acid chlorides: dual metal−ketene enolate activation. J. Am. Chem. Soc. 130, 17260–17261 (2008).

    CAS  Article  Google Scholar 

  21. 21.

    Wheeler, P., Vora, H. U. & Rovis, T. Asymmetric NHC-catalyzed synthesis of α-fluoroamides from readily accessible α-fluoroenals. Chem. Sci. 4, 1674–1679 (2013).

    CAS  Article  Google Scholar 

  22. 22.

    Dong, X., Yang, W., Hu, W. & Sun, J. N-Heterocyclic carbene catalyzed enantioselective α-fluorination of aliphatic aldehydes and α-chloro aldehydes: synthesis of α-fluoro esters, amides, and thioesters. Angew. Chem. Int. Ed. 54, 660–663 (2015).

    CAS  Google Scholar 

  23. 23.

    Wu, J. Review of recent advances in nucleophilic C–F bond-forming reactions at sp 3 centers. Tetrahedron Lett. 55, 4289–4294 (2014).

    CAS  Article  Google Scholar 

  24. 24.

    Hollingworth, C. & Gouverneur, V. Transition metal catalysis and nucleophilic fluorination. Chem. Commun. 48, 2929–2942 (2012).

    CAS  Article  Google Scholar 

  25. 25.

    Neumann, C. N., Hooker, J. M. & Ritter, T. Concerted nucleophilic aromatic substitution with 19F and 18F. Nature 534, 369–373 (2016).

    CAS  Article  Google Scholar 

  26. 26.

    Liu, Z. et al. An organotrifluoroborate for broadly applicable one-step 18F-labeling. Angew. Chem. Int. Ed. 53, 11876–11880 (2014).

    CAS  Article  Google Scholar 

  27. 27.

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

    CAS  Article  Google Scholar 

  28. 28.

    Jacobson, O., Kiesewetter, D. O. & Chen, X. Fluorine-18 Radiochemistry, Labeling Strategies and Synthetic Routes. Bioconjug. Chem. 26, 1–18 (2015).

    CAS  Article  Google Scholar 

  29. 29.

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

    CAS  Article  Google Scholar 

  30. 30.

    Falmagne, J.-B., Escudero, J., Taleb-Sahraoui, S. & Ghosez, L. Cyclobutanone and cyclobutenone derivatives by reaction of tertiary amides with alkenes or alkynes. Angew. Chem. Int. Ed. Engl. 20, 879–880 (1981).

    Article  Google Scholar 

  31. 31.

    Charette, A. B. & Grenon, M. Spectroscopic studies of the electrophilic activation of amides with triflic anhydride and pyridine. Can. J. Chem. 79, 1694–1703 (2001).

    CAS  Article  Google Scholar 

  32. 32.

    Movassaghi, M. & Hill, M. D. Synthesis of substituted pyridine derivatives via the ruthenium-catalyzed cycloisomerization of 3-azadienynes. J. Am. Chem. Soc. 128, 4592–4593 (2006).

    CAS  Article  Google Scholar 

  33. 33.

    Da Costa, R., Gillard, M., Falmagne, J. B. & Ghosez, L. α,β Dehydrogenation of carboxamides. J. Am. Chem. Soc. 101, 4381–4383 (1979).

    Article  Google Scholar 

  34. 34.

    Kaiser, D., de la Torre, A., Shaaban, S. & Maulide, N. Metal-free formal oxidative C−C coupling by in situ generation of an enolonium species. Angew. Chem. Int. Ed. 56, 5921–5925 (2017).

    CAS  Article  Google Scholar 

  35. 35.

    Kaiser, D., Teskey, C. J., Adler, P. & Maulide, N. Chemoselective intermolecular cross-enolate-type coupling of amides. J. Am. Chem. Soc. 139, 16040–16043 (2017).

    CAS  Article  Google Scholar 

  36. 36.

    Charette, A. B. & Chua, P. A new mild method for the cleavage of the amide bond: conversion of secondary and tertiary amides to esters. Synlett 1998, 163–165 (1998).

    Article  Google Scholar 

  37. 37.

    Gyoung, Y. S., Ko, S. H. & Yoon, N. M. A convenient procedure for the conversion of tertiary amides to the corresponding alcohols with lithium aluminum hydride. J. Korean Chem. Soc. 35, 296–298 (1991).

    CAS  Google Scholar 

  38. 38.

    Liu, C., Achtenhagen, M. & Szostak, M. Chemoselective ketone synthesis by the addition of organometallics to N-acylazetidines. Org. Lett. 18, 2375–2378 (2016).

    CAS  Article  Google Scholar 

  39. 39.

    Otte, C. et al. Major depressive disorder. Nat. Rev. Dis. Primers 2, 16065 (2016).

    Article  Google Scholar 

  40. 40.

    Ionescu, D. F. & Papakostas, G. I. Experimental medication treatment approaches for depression. Transl. Psychiatry 7, e1068 (2017).

    CAS  Article  Google Scholar 

  41. 41.

    Alarcón, R. D. et al. Antidepressants: Past, Present, and Future (Springer, New York, NY, 2004).

  42. 42.

    Cipriani, A. et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet 391, 1357–1366 (2018).

    CAS  Article  Google Scholar 

  43. 43.

    Dahlmann, H. A. Spotlight. Chem. Res. Toxicol. 26, 1776–1777 (2013).

    CAS  Article  Google Scholar 

  44. 44.

    Fallahi-Sichani, M., Honarnejad, S., Heiser, L. M., Gray, J. W. & Sorger, P. K. Metrics other than potency reveal systematic variation in responses to cancer drugs. Nat. Chem. Biol. 9, 708–714 (2013).

    CAS  Article  Google Scholar 

  45. 45.

    Coleman, J. A., Green, E. M. & Gouaux, E. X-ray structures and mechanism of the human serotonin transporter. Nature 532, 334–339 (2016).

    CAS  Article  Google Scholar 

  46. 46.

    Jeschke, P. The unique role of fluorine in the design of active ingredients for modern crop protection. Chembiochem 5, 570–589 (2004).

    CAS  Article  Google Scholar 

  47. 47.

    Brown, J. K. M. & Evans, N. Selection on responses of barley powdery mildew to morpholine and piperidine fungicides. Crop. Prot. 11, 449–457 (1992).

    CAS  Article  Google Scholar 

  48. 48.

    Volpe, D. A. et al. Uniform assessment and ranking of opioid Mu receptor binding constants for selected opioid drugs. Regul. Toxicol. Pharmacol. 59, 385–390 (2011).

    CAS  Article  Google Scholar 

  49. 49.

    Higashikawa, Y. & Suzuki, S. Studies on 1-(2-phenethyl)-4-(N-propionylanilino)piperidine (fentanyl) and its related compounds. VI. Structure–analgesic activity relationship for fentanyl, methyl-substituted fentanyls and other analogues. Forensic Toxicol. 26, 1–5 (2008).

    CAS  Article  Google Scholar 

  50. 50.

    Frank, R. G. & Pollack, H. A. Addressing the fentanyl threat to public health. N. Engl. J. Med. 376, 605–607 (2017).

    Article  Google Scholar 

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Acknowledgements

A. Roller (University of Vienna) is thanked for X-ray crystallographic determination, E. Macoratti (University of Vienna) for preparative HPLC and G. Di Mauro for assistance with LigandScout. The authors thank the University of Vienna for continued support of their research programmes. Financial support by the Austrian Research Fund/FWF (grant F3506 to H.S.S.; grant M2274 to C.J.T.; grant P30226 to N.M.) and the Austrian Academy of Sciences (DOC-fellowship to D.K.) is acknowledged.

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P.A., C.J.T and D.K. performed and analysed the chemical experiments. P.A., C.J.T and N.M. co-wrote the manuscript. M.H and H.H.S. performed the biological testing. N.M. directed the project.

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Correspondence to Nuno Maulide.

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Supplementary information

Supplementary Information

Supplementary optimization data, experimental details and compound characterization data

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Crystallographic data

CIF for compound (S,S)−9-L-DBTA; CCDC reference: 1866533

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Adler, P., Teskey, C.J., Kaiser, D. et al. α-Fluorination of carbonyls with nucleophilic fluorine. Nat. Chem. 11, 329–334 (2019). https://doi.org/10.1038/s41557-019-0215-z

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