Direct C–H functionalization can quickly increase useful structural and functional molecular complexity1,2,3. Site selectivity can sometimes be achieved through appropriate directing groups or substitution patterns1,2,3,4—in the absence of such functionality, most aromatic C–H functionalization reactions provide more than one product isomer for most substrates1,4,5. Development of a C–H functionalization reaction that proceeds with high positional selectivity and installs a functional group that can serve as a synthetic linchpin for further functionalization would provide access to a large variety of well-defined arene derivatives. Here we report a highly selective aromatic C–H functionalization reaction that does not require a particular directing group or substitution pattern to achieve selectivity, and provides functionalized arenes that can participate in various transformations. We introduce a persistent sulfur-based radical to functionalize complex arenes with high selectivity and obtain thianthrenium salts that are ready to engage in different transformations, via both transition-metal and photoredox catalysis. This transformation differs fundamentally from all previous aromatic C–H functionalization reactions in that it provides direct access to a large number of derivatives of complex small molecules, quickly generating functional diversity with selectivity that is not achievable by other methods.
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Mkhalid, I. A. I., Barnard, J. H., Marder, T. B., Murphy, J. M. & Hartwig, J. F. C–H activation for the construction of C–B bonds. Chem. Rev. 110, 890–931 (2010).
Lyons, T. W. & Sanford, M. S. Palladium-catalyzed ligand-directed C–H functionalization reactions. Chem. Rev. 110, 1147–1169 (2010).
Leow, D., Li, G., Mei, T.-S. & Yu, J.-Q. Activation of remote meta-C–H bonds assisted by an end-on template. Nature 486, 518–522 (2012).
Cheng, C. & Hartwig, J. F. Rhodium-catalyzed intermolecular C–H silylation of arenes with high steric regiocontrol. Science 343, 853–857 (2014).
Olah, G. A. Aromatic substitution. XXVIII. Mechanism of electrophilic aromatic substitutions. Acc. Chem. Res. 4, 240–248 (1971).
Tang, R.-J., Milcent, T. & Crousse, B. Regioselective halogenation of arenes and heterocycles in hexafluoroisopropanol. J. Org. Chem. 83, 930–938 (2018).
Saito, Y., Segawa, Y. & Itami, K. para-C–H borylation of benzene derivatives by a bulky iridium catalyst. J. Am. Chem. Soc. 137, 5193–5198 (2015).
Mo, F. et al. Gold-catalyzed halogenation of aromatics by N-halosuccinimides. Angew. Chem. Int. Ed. 49, 2028–2032 (2010).
Samanta, R. C. & Yamamoto, H. Selective halogenation using an aniline catalyst. Chem. Eur. J. 21, 11976–11979 (2015).
Maddox, S. M., Nalbandian, C. J., Smith, D. E. & Gustafson, J. L. A practical Lewis base catalyzed electrophilic chlorination of arenes and heterocycles. Org. Lett. 17, 1042–1045 (2015).
Xiong, X., Tan, F. & Yeung, Y.-Y. Zwitterionic-salt-catalyzed site-selective monobromination of arenes. Org. Lett. 19, 4243–4246 (2017).
Boursalian, G. B., Ham, W. S., Mazzotti, A. R. & Ritter, T. Charge-transfer-directed radical substitution enables para-selective C–H functionalization. Nat. Chem. 8, 810–815 (2016).
Ham, W.-S., Hillenbrand, J., Jacq, J., Genicot, C. & Ritter, T. Divergent late-stage (hetero)aryl C–H amination by the pyridinium radical cation. Angew. Chem. Int. Ed. 58, 532–536 (2019).
Shine, H. J. & Silber, J. J. Ion radical. XXII. Reaction of thianthrenium perchlorate (C12H8S2 •+ ClO4 −) with aromatics. J. Org. Chem. 36, 2923–2926 (1971).
Kim, K., Hull, V. J. & Shine, H. J. Ion radicals. XXIX. Reaction of thianthrene cation radical perchlorate with some benzene derivatives. J. Org. Chem. 39, 2534–2537 (1974).
Shin, S.-R. & Shine, H. J. Reactions of phenols with thianthrene cation radical. J. Org. Chem. 57, 2706–2710 (1992).
Shine, H. J., Silber, J. J., Bussey, R. J. & Okuyama, T. Ion radicals. XXV. The reactions of thianthrene and phenothiazine perchlorates with nitrite ion, pyridine, and other nucleophiles. J. Org. Chem. 37, 2691–2697 (1972).
Kim, K. & Shine, H. J. Ion radicals. XXX. Reactions of thianthrene cation radical perchlorate with amino compounds. J. Org. Chem. 39, 2537–2539 (1974).
Shine, H. J. & Yueh, W. Reaction of thianthrene cation radical with alcohols: cyclohexanols. Tetrahedron Lett. 33, 6583–6586 (1992).
Hirano, M., Monobe, H., Yakabe, S. & Morimoto, T. Kaolin-assisted aromatic chlorination and bromination. J. Chem. Res. (S), 662–663 (1998).
Windscheif, P.-M. & Vögtle, F. Substituted dipyridylethenes and -ethynes and key pyridine building blocks. Synthesis 1994, 87–92 (1994).
Srogl, J., Allred, G. D. & Liebeskind, L. S. Sulfonium salts. Participation par excellence in metal-catalyzed carbon–carbon bond-forming reactions. J. Am. Chem. Soc. 119, 12376–12377 (1997).
Minami, H., Otsuka, S., Nogi, K. & Yorimitsu, H. Palladium-catalyzed borylation of aryl sulfoniums with diborons. ACS Catal. 8, 579–583 (2018).
Kim, K. S., Ha, S. M., Kim, J. Y. & Kim, K. 5-arylthianthreniumyl perchlorates as benzyne precursor. J. Org. Chem. 64, 6483–6486 (1999).
Yoon, K. & Ha, S. M. Kim, K. A convenient route to diverse heterocycles through an addition of β-amino carbonyl compounds to 3-halo-4-methoxybenzenes. J. Org. Chem. 70, 5741–5744 (2005).
Heck, R. F. Palladium-catalyzed reactions of organic halides with olefins. Acc. Chem. Res. 12, 146–151 (1979).
Sonogashira, K. Development of Pd–Cu catalyzed cross-coupling of terminal acetylenes with sp 2-carbon halides. J. Org. Chem. 653, 46–49 (2002).
Negishi, E.-I. Palladium- or nickel-catalyzed cross coupling. A new selective method for carbon-carbon bond formation. Acc. Chem. Res. 15, 340–348 (1982).
Suzuki, A. Recent advances in the cross-coupling reactions of organoboron derivatives with organic electrophiles, 1995–1998. J. Organomet. Chem. 576, 147–168 (1999).
Brennführer, A., Neumann, H. & Beller, M. Palladium-catalyzed carbonylation reactions of aryl halides and related compounds. Angew. Chem. Int. Ed. 48, 4114–4133 (2009).
Prier, C. K., Rankic, D. A. & MacMillan, D. W. C. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis. Chem. Rev. 113, 5322–5363 (2013).
Brown, H. C. & Okamoto, Y. Electrophilic substituent constants. J. Am. Chem. Soc. 80, 4979–4987 (1958).
We thank M. van Gastel (Max Planck Institute for Chemical Energy Conversion) for the acquisition of electron paramagnetic resonance spectra, as well as S. Marcus and D. Kampen (Max-Planck-Institut für Kohlenforschung) for mass spectrometry analysis. We thank G. Berger for assistance with the construction of a photoreactor. We thank UCB Biopharma and the Max-Planck-Institut für Kohlenforschung for funding.
Nature thanks Kuangbiao Liao and the other anonymous reviewer(s) for their contribution to the peer review of this work.
A patent application (number EP18204755.5, Germany), dealing with the use of thianthrene and its derivatives for C–H functionalization and with reagent 1, has been filed and F.B. and T.R. may benefit from royalty payments.
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Berger, F., Plutschack, M.B., Riegger, J. et al. Site-selective and versatile aromatic C−H functionalization by thianthrenation. Nature 567, 223–228 (2019) doi:10.1038/s41586-019-0982-0
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