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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 MALLORY REACTION.

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Presentation on theme: "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 MALLORY REACTION."— Presentation transcript:

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

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

3 CARBON RICH MATERIALS AND THE MALLORY REACTION. Pr. Cho Chen 3 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 ( ) 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)

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 Natural product synthesis: NakiterpiosinoneNakiterpiosinAgeliferin 3. Synthetic methodology development: Palladium-Catalyzed Direct Fonctionalization of Imidazolinone Regiocontrol in Mn III -Mediated Oxidative Heterobicyclizations A Highly Selective Vanadium Catalyst for Benzylic C–H Oxidation A Simple Method for the Electrophilic Cyanation of Secondary Amines

5 Why Fluorine? – Properties 5 C-F bond:  Strongest bond with carbon  Lenght similar C-O bond  Trifluoromethyl (CF 3 ) volume similiar to ethyl (CH 3 CH 2 ) van der Waals radius / Å Pauling Electronegativity Bond energy/ kcal mol -1 Bond length / Å Volume / Å 3 C : C-C : 83(CH 3 ) 2 CH : 56.2 H : C-H : 98C-H : 1.09 CH 3 : F : C-F : 116C-F : 1.41CF 3 : 39.8 O : C-O : 91C-O : 1.43CH 3 CH 2 : 38.9 Special properties:  High electronegativity  Relatively small size Bondi, A. J. Phys. Chem. 1964, 68, Jeschke, P. ChemBioChem 2004, 5, Smart, B. E. J. Fluorine Chem. 2001, 109, Banks, R. E. J. Fluorine Chem. 1998, 87, Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317,

6 Why Fluorine? – Utility in Different Fields 6 Fluorine in nuclear medicine:  PET : Positron emission tomography  Nuclear medical imaging in vivo  18 F tracer has longer half life Böhm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637−643. Phelps, M. E. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, Jeschke, P. ChemBioChem 2004, 5, Okazoe, T. Proc. Jpn. Acad., Ser. B 2009, 85, Radionuclide 11 C 13 N 15 O 18 F Half live t 1/2 / min Crop protection:  28% of the halogenated products between contained fluorine  Environmental friendly compare to others halogens Material industry  Fluorinated polymers exhibit interesting properties (high thermal stability, chemical inertness) 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)

7 Fluorine Incorporation 7 Kirk, K. L. Org. Process Res. Dev. 2008, 12, 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% F 2 in N 2 ) Radical fluorination:  Use of N-F reagents

8 Mono-Fluorination – Literature Precedent 8 Functional group transformation:  Nucleophilic fluorination Yadav, A. K.; Srivastava, V. P.; Yadav, L. D. S. Chem. Commun. 2013, 49, York, C.; Prakash, G. K. S.; Olah, G. A. Tetrahedron 1996, 52, 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, Cazorla, C.; Métay, E.; Andrioletti, B.; Lemaire, M. Tetrahedron Lett. 2009, 50,  Electrophilic / Radical fluorination Drawbacks:  Narrow scope / few substrates  Methodology not for large synthesis scale

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

10 Reaction Proposal 10 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, Tucker, J. W.; Stephenson, C. R. J. J. Org. Chem. 2012, 77,

11 Photoexcited Arylketone – Literature Precedent 11 Yang, N. C.; Yang, D.-D. H. J. Am. Chem. Soc. 1958, 80, Walling, C.; Gibian, M. J. J. Am. Chem. Soc 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

12 Reaction Conditions – Optimization 12 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 4,2$/g5,7$/g21,3$/g 76,1$/g49,2$/g

13 Benzylic Monofluorination – Scope 13 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 14 Zhou, Q.; Ruffoni, A.; Gianatassio, R.; Fujiwara, Y.; Sella, E.; Shabat, D.; Baran, P. S. Angew. Chem., Int. Ed. 2013, 52, Baran’s zinc sulfinate salt:  Broad scope of nitrogen-rich heterocycle / not possible on benzene ring  Good group tolerance  Salt commercially available Fier, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, Patrick, T. B.; Flory, P. A. J. Fluorine. Chem. 1984, 25, York, C.; Prakash, G. K. S.; Olah, G. A. Tetrahedron 1996, 52, Other methods :  Electrochemical difluorination (mixture of products)  Few difluorination methods available

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

16 Benzylic Difluorination – Scope 16 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 17 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 18 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! 19 Happy birthday Mylène!

20 Conclusions 20 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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