Formation of synthetically relevant CF₃-substituted phenonium ions in superacid media

Abstract

Predestined to be transient theoretical species, phenonium ions can now be considered as cationic intermediates of choice in organic synthesis. Here, we demonstrate that under non-nucleophilic and superacidic conditions, CF₃-substituted phenonium ions can be generated to furnish original CF₃-substituted dihydrostilbenes of interest.

---

Since the pioneering studies of Cram¹ (Fig. 1a), considerable interest has been focused on phenonium ions. The first observations of the anthrylethyl bridged cation and p-anisonium ion respectively by Eberson, Winstein² and Olah³ (Fig. 1b) triggered numerous studies to understand the stability/reactivity of these original cations.⁴ These studies greatly participated in shifting the phenonium ion from a fundamental phenomenon to a synthetically useful cationic intermediate.⁵ The participation of an aryl neighbouring group to form a phenonium ion after leaving group activation can surprisingly favour processes that should not occur without such a stabilization. This is especially evident when electron-withdrawing groups adorn the phenonium cation (Fig. 1c).⁶ In this context, fluorinated phenonium ions have also recently been elegantly exploited (Fig. 1d).⁷ Among destabilized carbocations, CF₃-substituted carbocations⁸ are rarely considered as affordable intermediates for synthetic perspectives, despite an evident potential for modern applications to the design of fluorinated products.⁹ To the best of our knowledge, only one example of a CF₃-substituted phenonium ion has been postulated.^7e Herein, we describe the first evidence of this species and its selective exploitation to design trifluoromethylated dihydrostilbene derivatives (Fig. 1e).

Fig. 1 (a) First postulated phenonium ion; (b) first observed phenonium ions; (c) postulated destabilized phenonium ions; (d) postulated fluorinated phenonium ions; (e) this work.

In due course of our recent ongoing efforts to generate and exploit destabilized cations and polycations^10,11 in superacid HF/SbF₅,¹² we thus envisioned to generate trifluoromethylated phenonium ions from CF₃-substituted alcohols. To favour a substantial stabilization of the resonance-demanding phenonium ion by the lone pair of an amino group, 3-(4-(dimethylamino)phenyl)-1,1,1-trifluoropropan-2-ol 1 was chosen as a model substrate (Scheme 1a). Treatment of 1 with HF/SbF₅ furnished a clean ionic species whose NMR signals did not match with the ones of a phenonium ion. Nevertheless, the clean spectra allowed to identify dication A as the sole species generated in solution. In the ¹H NMR spectrum, the methyl groups of the amine function appear as a doublet at 1.84 ppm confirming the formation of the ammonium ion. The protonation of the OH group is also confirmed by the presence of a doublet at 9.72 ppm ¹³ and by the presence of a quadruplet in the ¹³C NMR spectrum at 119.2 ppm. This dicationic species was surprisingly stable up to 20 °C. Considering the difficulty to activate the C–OH bond geminal to the trifluoromethyl group, we turned our attention to the fluorinated analogue 2. This was especially motivated by previous results from Prakash and Olah: attempting to generate the p-anisonium ion from β-p-anisylethanol in superacid, only a dication coming from the protonation of alcohol and ether functions was observed.^3,14 Interestingly, the targeted phenonium ion could be generated from the corresponding p-anisyl-2-chloroethane suggesting that the carbon–halogen bond could be activated in these conditions. Capitalizing on our experience on fluoroalkylamino reagents (FAR) and their exploitation in synthesis,¹⁵ substrate 2 could be generated in two steps from perfluoropropene and ready to be tested under similar superacid conditions (see ESI†). Compound 2 reacted in superacid at −40 °C leading to a mixture of ionic species (Scheme 1b). The ¹H NMR spectrum resulting from this solution was difficult to interpret. However, in the ¹⁹F NMR spectrum, the signals at −83.8 ppm and −204.5 ppm confirmed the presence of ion B in solution. As for the alcohol derivative 1, the conditions were modified to tentatively favour the C–F bond activation by performing the reaction at higher temperature, but the reaction solution exhibited a complex mixture of different fluorinated species that were difficult to analyse. At −20 °C, after 10 min reaction, the reaction medium was hydrolysed and purified. The dihydrostilbene derivative 3 could be isolated from the reaction mixture in 14% yield. Although generated in a modest yield, the formation of this pseudodimeric compound could result from the reaction between the deactivated aromatic ring of the protonated ion B and the CF₃-substituted phenonium superelectrophilic ion C.¹⁰ To confirm the involvement of ion C in the process, a deuterium labelling experiment was conducted in the presence of cyclohexane-d₁₂ (Scheme 1c). With this nucleophilic source, any deuteration transfer reaction in superacid must occur through an ionic mechanism.^11a,16 Under these conditions, in addition to compound 3, the deuterated compounds 4 and 5 could be isolated after one hour reaction of substrate 2.¹⁷ The formation of the reduced/deuterated products which must respectively originate from the insertion of a cation into a C–H/C–D bond of the alkane confirms the involvement of a CF₃-substituted phenonium ion C. The regioselectivity of the reaction, identical for the formation of 3 and 4 is also in accordance with an ionic mechanism. Interestingly, the formation of compound 5 as a minor product confirms the highly destabilized character of the elusive α-CF₃ carbocation.

Scheme 1 (a) Exclusive formation of dication A after reaction of 3-(4-(dimethylamino)phenyl)-1,1,1-trifluoropropan-2-ol 1 in HF/SbF₅ at low temperature and characteristic NMR signals (δ in ppm); (b) reactivity of N,N-dimethyl-4-(2,3,3,3-tetrafluoropropyl)aniline 2 in HF/SbF₅ and characteristic NMR signals (δ in ppm); (c) deuterium labelling experiment supporting the involvement of dication C.

Considering that the trifluoromethylated 1,2-diarylethane motif could be considered as an interesting pharmacophore for further applications,¹⁸ we explored the ability to regioselectively trap the phenonium ion C with representative arenes. As a first instance, and encouraged by the formation of product 3 from intermolecular addition of the aniline, acetanilide 6a was chosen as a model nucleophilic partner and 2 as a source of phenonium ion to screen the reaction conditions (Table 1). Gratifyingly, a first attempt in HF/SbF₅ allowed to generate the targeted fluorinated product 7a, albeit in a modest 15% yield (Table 1, entry 1). Extending the reaction time and increasing the temperature throughout the reaction course was found ideal to favour a clean reaction (Table 1, entries 2–4) and product 7a could eventually be obtained in 97% yield. The necessity to use HF/SbF₅ superacid conditions to activate the C–F bond¹⁹ was demonstrated by the recovery of the starting material after exploring the reaction in trifluoromethanesulfonic superacid solutions, and thus whatever conditions used (Table 1, entries 5-6). Trying to activate the C–F bond²⁰ through a hydrogen bonding strategy in a hexafluoroisopropanol solution²¹ was unsuccessful (Table 1, entry 7). Lewis acid activation of the C–F bond²² was also explored with SbF₅, BF₃·OEt₂ or B(C₆F₅)₃ but remained inefficient (Table 1, entries 8–10). This seems to confirm that highly acidic conditions and the absence of any nucleophilic counter-anions in solution²³ are needed to activate the C–F bond that is geminal to the CF₃ group to form the targeted phenonium ion.

Table 1 Optimization of the reaction conditions between phenonium ion precursor 2 and acetanilide 6a

Entry	Acid^a (v/v)	Conditions	Yield^b [%]
a Used as solvent, unless stated otherwise.b 7a was isolated in each case as a 1/1 mixture of para/meta isomers.c Recovery of the starting material.d Complex mixture.e In CH2Cl2.f In MeNO2.
1	HF/SbF5 (1/1)	−20 °C, 0.5 h	15
2	HF/SbF5 (1/1)	−20 °C, 4 h	65
3	HF/SbF5 (1/1)	−20 to 0 °C, 0.5 h	71
4	HF/SbF5 (1/1)	−20 to 0 °C, 1 h	97
5	TfOH	20 °C, 1 h	0^c
6	TfOH/SbF5 (1/1)	−20 to 0 °C, 1 h	0^d
7	HFIP/CH2Cl2 (1/1)	20 °C, 16 h	0^c
8	SbF5	0 to 20 °C, 1 h	0^c
9	BF3·OEt2 (10 equiv.)^e	20 °C, 1 h	0^c
10	B(C6F5)3 (5 mol%)^f	20 °C, 16 h	0^c

---

With these optimized conditions in hand, to determine whether the external aromatic nucleophilic trapping of the CF₃-substituted phenonium ion can be extended to more elaborate substrates, compound 2 was submitted to superacid in the presence of different aromatic partners (Fig. 2).

Fig. 2 Formation of CF₃-containing diarylethanes 7 and 9 in superacid.

The reaction could be applied to the synthesis of halogen-substituted products 7b and 7c in good yields after reaction with 4-fluoro and 4-chloroacetanilide. Not limited to aromatic amides, the reaction was also found to be efficient with indoline and tetrahydroquinoline affording the trifluoromethylated dihydrostilbenes 7d and 7e.²⁴ The regioselectivity of the Friedel–Crafts type reaction is dictated by the orientating effect of the alkyl chain, the amine being protonated under its ammonium form under these conditions. The reaction was found not limited to the trapping of the phenonium ion C, as its oxygenated analogue that must be generated from substrate 8 could also be trapped by acetanilide to generate product 9a. At this stage it is also important to note that the reaction is highly regioselective, as the phenonium ion is selectively opened at the external position, in accordance with an ionic mechanism. No steric or electronic effect from the nucleophilic partner seems to affect this selectivity. To test this method on a more complex target, such as those that might be encountered in pharmaceutical research, vinburnine was tested as nucleophilic partner. Delightfully, the corresponding trifluoromethylated diarylethane analogue 7f could be generated in 67% yield as a mixture of regio- and diastereomers.

To conclude, the ability to generate CF₃-containing phenonium ions in superacid HF/SbF₅ was demonstrated. These cations can react with poor nucleophilic partners such as deactivated nitrogen-containing arenes, suggesting a superelectrophilic character for this family of cations. Following recent and excellent contributions demonstrating the synthetic utility of phenonium ions, this work opens perspectives to exploit their CF₃-substituted counterpart for synthetic purposes.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We gratefully acknowledge the Frontier Research in Chemistry Foundation (FRC), the Université de Strasbourg (grant FLE-FRC-0002-0035, SuperFlOx), the Université de Poitiers, and the CNRS for financial support. The authors also acknowledge financial support from the European Union (ERDF) and the Région Nouvelle Aquitaine (SUPERDIV project-HABISAN program). The authors thank the French fluorine network (GIS-FLUOR).

Notes and references

1. (a) D. J. Cram, J. Am. Chem. Soc., 1949, 71, 3863; (b) D. J. Cram and R. Davies, J. Am. Chem. Soc., 1949, 71, 3871.
2. L. Eberson and S. Winstein, J. Am. Chem. Soc., 1965, 87, 3506.
3. G. A. Olah, M. B. Comisarow, E. Namanworth and B. G. Ramsey, J. Am. Chem. Soc., 1967, 89, 5259.
4. For selected analytical and theoretical studies on phenonium ions, please see: (a) G. A. Olah, N. J. Head, G. Rasul and G. K. S. Prakash, J. Am. Chem. Soc., 1995, 117, 875; (b) G. A. Olah and R. Dudley Porter, J. Am. Chem. Soc., 1970, 92, 7627; (c) J. A. Manner, J. A. Cook Jr and B. G. Ramsey, J. Org. Chem., 1974, 39, 1199; (d) G. A. Olah, S. Hamanaka, J. A. Wilkinson and J. A. Olah, Proc. Natl. Acad. Sci. U. S. A., 1992, 89, 915; (e) E. del Rio, M. I. Menéndez, R. López and T. L. Sordo, J. Phys. Chem. A, 2000, 104, 5568; (f) E. del Rio, M. I. Menéndez, R. López and T. L. Sordo, J. Am. Chem. Soc., 2001, 123, 5064; (g) B. Guizzardi, M. Mella, M. Fagnoni and A. Albini, J. Org. Chem., 2003, 68, 1067; (h) I. Manet, S. Monti, G. Grabner, S. Protti, D. Dondi, V. Dichiarante, M. Fagnoni and A. Albini, Chem.–Eur. J., 2008, 14, 1029; (i) Y. Tsuji and J. P. Richard, J. Phys. Org. Chem., 2015, 29, 557.
5. For selected recent examples mentioning phenonium ions intermediates in key synthetic reactions, please see: (a) S. Xu, H. M. Holst, S. B. McGuire and N. J. Race, J. Am. Chem. Soc., 2020, 142, 8090; (b) X. Lei, Y. Li, Y. Lai, S. Hu, C. Qi, G. Wang and Y. Tang, Angew. Chem., Int. Ed., 2021, 60, 4221; (c) L. Min, W. Yang, Y. Weng, W. Zheng, X. Wang and Y. Hu, Org. Lett., 2019, 21, 2574; (d) Y. H. Jang and S. W. Youn, Org. Lett., 2014, 16, 3720; (e) O. E. Okoromoba, Z. Li, N. Robertson, M. S. Mashuta, U. R. Couto, C. F. Tormena, B. Xu and G. B. Hammond, Chem. Commun., 2016, 52, 13353. For a recent review, please see: (f) H. M. Holst, S. B. McGuire and N. J. Race, Synlett, 2021, 32, 1.
6. For selected examples mentioning phenonium ions substituted with electron withdrawing groups, please see: (a) A.-M. Dommröse and H.-F. Grützmacher, J. Mass Spectrom., 1987, 22, 437; (b) N. Jiang, Z. Qu and J. Wang, Org. Lett., 2001, 3, 2989; (c) S. Protti, M. Fagnoni and A. Albini, J. Am. Chem. Soc., 2006, 128, 10670; (d) A. Suneja and C. Schneider, Org. Lett., 2018, 20, 7576; (e) J. Li, A. Bauer, G. Di Mauro and N. Maulide, Angew. Chem., Int. Ed., 2019, 58, 9816.
7. For selected examples mentioning fluorinated phenonium ions, please see: (a) N. O. Ilchenko, B. O. A. Tasch and K. J. Szabó, Angew. Chem., Int. Ed., 2014, 53, 12897; (b) A. J. Durie, T. Fujiwara, N. Al-Maharik, A. M. Z. Slawin and D. O'Hagan, J. Org. Chem., 2014, 79, 8228; (c) S. M. Banik, J. W. Medley and E. N. Jacobsen, Science, 2016, 353, 51; (d) B. Zhou, M. K. Haj, E. N. Jacobsen, K. N. Houk and X.-S. Xue, J. Am. Chem. Soc., 2018, 140, 15206; (e) F. Scheidt, J. Neufeld, M. Schäfer, C. Thiehoff and R. Gilmour, Org. Lett., 2018, 20, 8073.
8. A. J. Fernandes, A. Panossian, B. Michelet, A. Martin-Mingot, F. R. Leroux and S. Thibaudeau, Beilstein J. Org. Chem., 2021, 17, 343.
9. (a) P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, 2nd edn, 2013, Wiley-VCH; (b) I. Ojima, Fluorine in Medicinal Chemistry and Chemical Biology, 2009, Wiley-Blackwell, Chichester; (c) H. Groult, F. Leroux and A. Tressaud, Modern Synthesis Processes and Reactivity of Fluorinated Compounds, 2017, Elsevier Science, London; (d) G. Haufe and F. Leroux, Fluorine in Life Sciences: Pharmaceuticals, Medicinal Diagnostics, and Agrochemicals, 2019, Academic press, London; (e) R. Littich and P. J. H. Scott, Angew. Chem., Int. Ed., 2012, 51, 1106; (f) S. Preshlock, M. Tredwell and V. Gouverneur, Chem. Rev., 2016, 116, 719; (g) R. Berger, G. Resnati, P. Metrangolo, E. Weber and J. Hulliger, Chem. Soc. Rev., 2011, 40, 3496; (h) D. O'Hagan, Chem. Soc. Rev., 2008, 37, 308; (i) J.-P. Bégué and D. Bonnet-Delpon, Bioorganic and Medicinal Chemistry of Fluorine, 2008, Wiley, New Jersey.
10. G. A. Olah and D. Klumpp, Superelectrohiles and Their Chemistry, 2008, John Wiley and Sons, New York.
11. (a) A. Martin, A. Arda, J. Désiré, A. Martin-Mingot, N. Probst, P. Sinaÿ, J. Jiménez-Barbero, S. Thibaudeau and Y. Blériot, Nat. Chem., 2016, 8, 186; (b) L. Lebedel, A. Ardá, A. Martin, J. Désiré, A. Mingot, M. Aufiero, N. A. Font, R. Gilmour, J. Jiménez-Barbero, Y. Blériot and S. Thibaudeau, Angew. Chem., Int. Ed., 2019, 58, 13758; (c) N. Bhuma, L. Lebedel, H. Yamashita, Y. Shimizu, Z. Abada, A. Ardá, J. Désiré, B. Michelet, A. Martin-Mingot, A. Abou-Hassan, M. Takumi, J. Marrot, J. Jiménez-Barbero, A. Nagaki, Y. Blériot and S. Thibaudeau, Angew. Chem., Int. Ed., 2021, 60, 2036; (d) G. Compain, A. Martin-Mingot, G. Frapper, C. Bachmann, M.-P. Jouannetaud and S. Thibaudeau, Chem. Commun., 2012, 48, 5877; (e) M. Artault, N. Mokhtari, T. Cantin, A. Martin-Mingot and S. Thibaudeau, Chem. Commun., 2020, 56, 5905.
12. Superacids, ed. G. A. Olah, G. K. S. Prakash, A. Molnar and J. Sommer, 2nd edn, 2009, Wiley Intersciences, New-York.
13. G. A. Olah and E. Namanworth, J. Am. Chem. Soc., 1966, 88, 5327.
14. (a) G. A. Olah and R. D. Porter, J. Am. Chem. Soc., 1971, 93, 6877; (b) G. A. Olah, N. J. Head, G. Rasul and G. K. S. Prakash, J. Am. Chem. Soc., 1995, 117, 875.
15. (a) S. Pazenok, F. Giornal, G. Landelle, N. Lui, J.-P. Vors and F. R. Leroux, Eur. J. Org. Chem., 2013, 4249; (b) F. Giornal, G. Landelle, N. Lui, J.-P. Vors, S. Pazenok and F. R. Leroux, Org. Process Res. Dev., 2014, 18, 1002; (c) E. Schmitt, G. Landelle, J.-P. Vors, N. Lui, S. Pazenok and F. R. Leroux, Eur. J. Org. Chem., 2015, 6052; (d) E. Schmitt, B. Rugeri, A. Panossian, J.-P. Vors, S. Pazenok and F. R. Leroux, Org. Lett., 2015, 17, 4510; (e) F. Aribi, E. Schmitt, A. Panossian, J.-P. Vors, S. Pazenok and F. R. Leroux, Org. Chem. Front., 2016, 3, 1392; (f) E. Schmitt, A. Panossian, J.-P. Vors, C. Funke, N. Lui, S. Pazenok and F. R. Leroux, Chem.–Eur. J., 2016, 22, 11239; (g) B. Commare, E. Schmitt, F. Aribi, A. Panossian, J.-P. Vors, S. Pazenok and F. R. Leroux, Molecules, 2017, 22, 977–981; (h) E. Schmitt, S. Bouvet, B. Pegot, A. Panossian, J.-P. Vors, S. Pazenok, E. Magnier and F. R. Leroux, Org. Lett., 2017, 19, 4960; (i) F. Aribi, A. Panossian, J.-P. Vors, S. Pazenok and F. R. Leroux, Eur. J. Org. Chem., 2018, 3792; (j) E. Schmitt, B. Commare, A. Panossian, J.-P. Vors, S. Pazenok and F. R. Leroux, Chem.–Eur. J., 2018, 24, 1311.
16. J. Sommer and J. Bukala, Acc. Chem. Res., 1993, 26, 370.
17. NMR analysis showed a 35% deuterium incorporation for compound 4; deuterium incorporation for compound 5 could not have been determined due to signal overlapping.
18. (a) For an example of 1,2-fluorinated diarylethane, please see: M. O'Duill, E. Dubost, L. Pfeifer and V. Gouverneur, Org. Lett., 2015, 17, 3466; For recent reports on bioactive natural dihydrostilbenes, please, see: (b) L. He, Q. Su, L. Bai, M. Li, J. Liu, X. Liu, C. Zhang, Z. Jiang, J. He, J. Shi, S. Huang and L. Guo, Eur. J. Med. Chem., 2020, 204, 112530; (c) L. W. K. Moodie, R. Trepos, G. Cervin, K. A. Bråthen, B. Lindgård, R. Reiersen, P. Cahill, H. Pavia, C. Hellio and J. Svenson, J. Nat. Prod., 2017, 80, 2001; (d) Y. Zhu, W.-H. Pan, C. F. Ku, H.-J. Zhang and S. W. Tsang, Eur. J. Med. Chem., 2018, 143, 1254.
19. For a seminal contribution on C–F bond activation in superacid, please see: G. A. Olah, Y. K. Mo and Y. Halpern, J. Org. Chem., 1972, 37, 1169.
20. For reviews on C–F bond activation, please see: (a) H. Amii and K. Uneyama, Chem. Rev., 2009, 109, 2119; (b) T. Ahrens, J. Kohlmann, M. Ahrens and T. Braun, Chem. Rev., 2015, 115, 931.
21. P. A. Champagne, Y. Benhassine, J. Desroches and J.-P. Paquin, Angew. Chem., Int. Ed., 2014, 53, 13835.
22. T. Stahl, H. F. T. Klare and M. Oestreich, ACS Catal., 2013, 3, 1578.
23. I. Krossing and I. Raabe, Angew. Chem., Int. Ed., 2004, 43, 2066.
24. For recent studies on bioactive properties of non-trifluoromethylated analogues of 7d and 7e, please see: (a) H. S. Sutherland, A. S. T. Tong, P. J. Choi, D. Conole, A. Blaser, S. G. Franzblau, C. B. Cooper, A. M. Upton, M. U. Lotlikar, W. A. Denny and B. D. Palmer, Bioorg. Med. Chem., 2018, 26, 1797; (b) T. D. Aicher, C. B. Taylor and C. A. Vanhuis, WO2015171610, A2, 2015.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/d1ra04901a

---