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Xia, J.-B.; Zhu, C.; Chen, C. J. Am. Chem. Soc. 2013, 135 , 17494-17500.

MALLORY REACTION. Visible Light-Promoted Metal-Free C-H Activation: Diarylketone-Catalyzed Selective Benzylic Mono- and Difluorination. Xia, J.-B.; Zhu, C.; Chen, C. J. Am. Chem. Soc. 2013, 135 , 17494-17500. Augusto César Hernandez-Perez Literature Meeting February 19 th , 2014.

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Xia, J.-B.; Zhu, C.; Chen, C. J. Am. Chem. Soc. 2013, 135 , 17494-17500.

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  1. MALLORY REACTION. Visible Light-Promoted Metal-Free C-H Activation: Diarylketone-Catalyzed Selective Benzylic Mono- and Difluorination Xia, J.-B.; Zhu, C.; Chen, C. J. Am. Chem. Soc. 2013, 135, 17494-17500. Augusto César Hernandez-Perez Literature Meeting February 19th, 2014

  2. Outline CARBON RICH MATERIALS AND THE MALLORY REACTION. • Pr. Chuo Chen • Why fluorine? • Mono-fluorination • Reaction proposal • Difluorination • Mechanistic studies • Conclusion

  3. Pr. Cho Chen CARBON RICH MATERIALS AND THE MALLORY REACTION. Birth: Taipei, Taiwan B.S. degree: National Taiwan University (1995) Ph.D.: Harvard University under the direction of Prof. Matthew D. Shair (2001) Post-doc: Harvard University under the guidance of Prof. Stuart L. Schreiber (2001-2004) Joined the Biochemistry Department at the University of Texas Southwestern Medical Center (2004) Promoted Associated Professor (2010) Award: Southwestern Medical foundation Scholar in Biomedical Research (2004) http://pubs.rsc.org/en/content/articlehtml/2011/cc/c0cc90144j http://www4.utsouthwestern.edu/chuochen/group.htm

  4. Research Program 1. Chemical Biology: Synthesis of small-molecule inhibitors of the Hedgehog (Hh) and Wnt signal transduction pathways Mechanistic and medicinal chemical studies of a series of novel Hh and Wnt antagonists 2. Natural product synthesis: Ageliferin Nakiterpiosin Nakiterpiosinone 3. Synthetic methodology development: Palladium-Catalyzed Direct Fonctionalization of Imidazolinone Regiocontrol in MnIII-Mediated Oxidative Heterobicyclizations A Highly Selective Vanadium Catalyst for Benzylic C–H Oxidation A Simple Method for the Electrophilic Cyanation of Secondary Amines http://www4.utsouthwestern.edu/chuochen/group.htm

  5. Why Fluorine? – Properties • Special properties: • High electronegativity • Relatively small size • C-F bond: • Strongest bond with carbon • Lenght similar C-O bond • Trifluoromethyl (CF3) volume similiar to ethyl (CH3CH2) Bondi, A. J. Phys. Chem.1964, 68, 441-451. Jeschke, P. ChemBioChem2004, 5, 570-589. Smart, B. E. J. Fluorine Chem. 2001, 109, 3-11. Banks, R. E. J. Fluorine Chem.1998, 87, 1-17. Müller, K.; Faeh, C.; Diederich, F. Science2007, 317, 1881-1886.

  6. Why Fluorine? – Utility in Different Fields • Useful in medical chemistry: • Increase metabolic stability: oxidation by liver enzymes (P450 cytochromes) : block reactive site by the introduction of a fluorine atom • Reduces basicity when close to a basic group (better membrane permeability) • Fluorine in nuclear medicine: • PET : Positron emission tomography • Nuclear medical imaging in vivo • 18F tracer has longer half life • Crop protection: • 28% of the halogenated products between 1940-2003 contained fluorine • Environmental friendly compare to others halogens • Material industry • Fluorinated polymers exhibit interesting properties (high thermal stability, chemical inertness) Böhm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem2004, 5, 637−643. Phelps, M. E. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 9226-9233. Jeschke, P. ChemBioChem2004, 5, 570-589. Okazoe, T. Proc. Jpn. Acad., Ser. B2009, 85, 276-289.

  7. Fluorine Incorporation • Nucleophilic fluorination: • Small size of the atom and low polarisability encourages F- to act more like a base rather than a nucleophile • Various nucleophilic reagents (F-, S-F reagents) • Electrophilic fluorination: • Not easily achieved because fluorine is the most electronegative element • Use of N-F reagents (even 5% F2 in N2) • Radical fluorination: • Use of N-F reagents Kirk, K. L. Org. Process Res. Dev.2008, 12, 305-321.

  8. Mono-Fluorination – Literature Precedent • Functional group transformation: • Nucleophilic fluorination Yadav, A. K.; Srivastava, V. P.; Yadav, L. D. S. Chem. Commun. 2013, 49, 2154-2156. York, C.; Prakash, G. K. S.; Olah, G. A. Tetrahedron1996, 52, 9-14. • Electrophilic / Radical fluorination Cazorla, C.; Métay, E.; Andrioletti, B.; Lemaire, M. Tetrahedron Lett.2009, 50, 3936-3938. Rueda-Becerril, M.; Sazepin, Chatalova Sezapin, C.; Leung, J. C. T.l Okbinoglu, T.; Kennepohl, P.; Paquin, J.-F.; Sammis, G.M..dav, L. D. S. J. Am. Chem. Soc.2012, 134, 4026-4029. • Drawbacks: • Narrow scope / few substrates • Methodology not for large synthesis scale

  9. Mono-Fluorination – Literature Precedent • Direct C-H fluorination: • Electrophilic / Radical fluorination Bloom, S.; Ross Pitts, C.; Curtin Miller, D.; Haselton, N.; Gargiulo Holl, M.; Urheim, E.; Lectka, T. Angew. Chem., Int. Ed.2012, 51, 10580-10583. Bloom, S.; Ross Pitts, C.; Woltornist, R.; Griswold, A.; Gargiulo Holl, M.; Urheim, E.; Lectka, T. Org. Lett.2013, 15, 1722-1724. • Features: • Catalytic system • Mild reaction conditions • Decent scope

  10. Reaction Proposal • Key steps: • Formation of photoexcited arylketone • Benzylic hydrogen abstraction • Fluorine atom transfer • Regeneration of catalyst • Use of visible light • No transition-metal used • Photoredox chemistry: • Use of visible light • Use of transition-metal (Ru, Ir) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev.2013, 113, 5322-5363. Tucker, J. W.; Stephenson, C. R. J. J. Org. Chem.2012, 77, 1617-1622.

  11. Photoexcited Arylketone – Literature Precedent • Yang’s report: • Acetone in cyclohexane gives cyclohexylpropan-2-ol under UV light • Intramolecular reaction: Norrish-Yang cyclization • Intramolecular H abstraction at  position and cyclization • Benzophenone: • Acts like acetone • Known to abstract hydrogen from the triplet state (photo-excited state) • Abstracts hydrogen from cylohexane or ethylbenzene (benzylic position) • Drawbacks: • Use of UV light (mercury lamp) • High dilution conditions Yang, N. C.; Yang, D.-D. H. J. Am. Chem. Soc. 1958, 80, 2913-2914. http://goldbook.iupac.org/N04218.html. Walling, C.; Gibian, M. J. J. Am. Chem. Soc.1965.

  12. Reaction Conditions – Optimization 4,2$/g 5,7$/g 21,3$/g 76,1$/g 49,2$/g • Features: • Use of visible light effective with compact fluorescent lamp (cheap!) • 9-fluorenone has suitable chromophore for visible light • Ir(ppy)3 does not promote benzylic fluorination • Not water sensitive but oxygen sensitive • Cheap electrophilic fluorine source

  13. Benzylic Monofluorination – Scope • Features: • Fast reaction with EDG (if too electron rich, side reaction with Selectfluor) • Aromatic halides tolerated (no UV light used) • 1 and 2 alcohols not compatible • MIDA boronate tolerated under reaction conditions

  14. Difluorination – Literature Precedent • Baran’s zinc sulfinate salt: • Broad scope of nitrogen-rich heterocycle / not possible on benzene ring • Good group tolerance • Salt commercially available Zhou, Q.; Ruffoni, A.; Gianatassio, R.; Fujiwara, Y.; Sella, E.; Shabat, D.; Baran, P. S. Angew. Chem., Int. Ed.2013, 52, 3949-3952. Patrick, T. B.; Flory, P. A. J. Fluorine. Chem. 1984, 25, 157-164. York, C.; Prakash, G. K. S.; Olah, G. A. Tetrahedron1996, 52, 9-14. Fier, P. S.; Hartwig, J. F. J. Am. Chem. Soc.2012, 134, 5524-5527. • Other methods: • Electrochemical difluorination (mixture of products) • Few difluorination methods available

  15. Benzylic Difluorination – Optimization • Features: • Xanthone (C) is electron-rich enough to promote difluorination • Selectfluor II effective with xanthone (C)

  16. Benzylic Difluorination – Scope • Features: • No or less than 5% of monofluorinated product in all cases • Aromatic halides tolerated (no UV light used) • MIDA boronate tolerated under reaction conditions

  17. Mechanistic Studies • Features: • Visible light and catalyst are required • No reaction in the dark • No thermal radical process • 9-fluorenone doesn’t act as an energy transfer photosensitizer • Reaction works in the presence of a 400 nm long-pass filter • Kinetic isotope effect (KIE) : • C-H abstraction in the rate-limiting step

  18. Mechanistic Studies • Site preference for reaction : • 2  1  3 • Electron rich substrates react faster than electron-poor substrates • Gram scale reaction: • 20 mmol scale • No flash chromatography!

  19. Surprise Slide! Happy birthday Mylène!

  20. Conclusions • Monofluorination: • Mild reaction conditions • Broad scope • Difluorination: • Mild reaction conditions • First catalytic C-H difluorination • General • Use of visible light • Application to gram scale reactions • No transition-metal required • Further improvements: • Use of continuous-flow conditions • Application to the synthesis of a drug

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