Regioselective iridium-catalyzed C(7)-H borylation of 6-fluoroquinolones Eimear Courtney 1 , Aobha Hickey 1 , Dr Gerard P. McGlacken 1,2
1 School of Chemistry & Analytical and Biological Chemistry Research Facility, University College Cork, Ireland, 2 Synthesis and Solid State Pharmaceutical Centre, University College Cork, Ireland
C−H functionalisation of heteroarenes has emerged as an important synthetic methodology, considering the roles that heteroaromatics play in pharmaceuticals, agrochemicals, and material chemistry. 1 Iridium-catalysed C−H borylation has proven a useful means of heteroarene functionalisation due to its ability to produce highly versatile aryl organoboronate intermediates without the need for reactive groups, such as halides or sulfonates. 2 Given its role as a key scaffold in a plethora of synthetic and naturally occurring pharmacologically active compounds, the quinolone-nucleus is a strategic target. Previously, we have demonstrated the borylation of 6-fluoroquinolines with judicious choice of substituent at C-4 on the quinoline, facilitating the unmasking of a fluoroquinolone. 3 Herein, we have streamlined this process, enabling the direct borylation and transformation of the difficult to modulate C-7 position of 6-fluoroquinolones in excellent yields. Previous literature suggests the Bpin moiety may function as a traceless directing group for the C H borylation of nitrogen heterocycles. 4 However, recent collaborative efforts have revealed the quinolone – quinoline tautomerisation is a key process as, initially, O-borylation of the quinoline tautomer takes place. 5 In light of this, this work not only investigates the mechanistic aspects of how the C-7 borylation process occurs, but also showcases a robust one-pot protocol which enables rapid late-stage functionalisation of an important class of antibiotics and key pharmacophores. References 1. Welsch, M. E.; Snyder, S. A.; Stockwell, B. R., Curr. Opin. Chem. Biol. 2010 , 14 , 347-361. 2. (a) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E.; Smith, M. R., Science , 2002 , 295 , 305-308 (b) Hartwig, J. F., Chem. Soc. Rev. 2011 , 40 , 1992-2002 (c) Takagi, J.; Sato, K.; Hartwig, J. F.; Ishiyama, T.; Miyaura, N., Tetrahedron Lett. 2002, 43, 5649-5651. (d) Mkhalid, I. A. I.; Coventry, D. N.; Albesa-Jove, D.; Batsanov, A. S.; Howard, J. A. K.; Perutz, R. N.; Marder, T. B., Angew. Chem. Int. Ed. 2006 , 45 , 489-491 (d) Larsen, M. A.; Hartwig, J. F., J. Am. Chem. Soc. 2014 , 136 , 4287-4299. 3. Hickey, A., Merz, J., Al-Mamari, H. H., Friedrich, A., Marder, T. B., McGlacken, G. P., J. Org. Chem. 2022 , 87 , 9977–9987. 4. Smith, M. R., Maleczka Jr., R. E., Angew. Chem. Int. Ed. 2013 , 52 , 12915-12919. 5. Al-Mamari, H. H.; Borel, J.; Hickey, A.; Courtney, E.; Zhang, X.; Friedrich, A.; Marder, T. B.; McGlacken, G. P., manuscript under review.
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© The Author(s), 2023
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