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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, 17494-17500. 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 http://pubs.rsc.org/en/content/articlehtml/2011/cc/c0cc90144j http://www4.utsouthwestern.edu/chuochen/group.htm 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 (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)

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 4 http://www4.utsouthwestern.edu/chuochen/group.htm 2. 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 : 1.702.55C-C : 83(CH 3 ) 2 CH : 56.2 H : 1.202.20C-H : 98C-H : 1.09 CH 3 : 21.26 F : 1.473.98C-F : 116C-F : 1.41CF 3 : 39.8 O : 1.523.44C-O : 91C-O : 1.43CH 3 CH 2 : 38.9 Special properties:  High electronegativity  Relatively small size Bondi, A. J. Phys. Chem. 1964, 68, 441-451. Jeschke, P. ChemBioChem 2004, 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. Science 2007, 317, 1881-1886.

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, 9226-9233. Jeschke, P. ChemBioChem 2004, 5, 570-589. Okazoe, T. Proc. Jpn. Acad., Ser. B 2009, 85, 276-289. Radionuclide 11 C 13 N 15 O 18 F Half live t 1/2 / min20102110 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) 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, 305-321. 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, 2154-2156. York, C.; Prakash, G. K. S.; Olah, G. A. Tetrahedron 1996, 52, 9-14. 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. Cazorla, C.; Métay, E.; Andrioletti, B.; Lemaire, M. Tetrahedron Lett. 2009, 50, 3936-3938.  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, 1722-1724. 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. 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, 5322-5363. Tucker, J. W.; Stephenson, C. R. J. J. Org. Chem. 2012, 77, 1617-1622.

11 Photoexcited Arylketone – Literature Precedent 11 Yang, N. C.; Yang, D.-D. H. J. Am. Chem. Soc. 1958, 80, 2913-2914. http://goldbook.iupac.org/N04218.htmlhttp://goldbook.iupac.org/N04218.html. Walling, C.; Gibian, M. J. J. Am. Chem. Soc. 1965. 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, 3949-3952. 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, 5524-5527. Patrick, T. B.; Flory, P. A. J. Fluorine. Chem. 1984, 25, 157-164. York, C.; Prakash, G. K. S.; Olah, G. A. Tetrahedron 1996, 52, 9-14. 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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