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
Outline
CARBON RICH MATERIALS
AND THE MALLORY REACTION.
Pr. Chuo Chen
Why fluorine?
Mono-fluorination
Reaction proposal
Difluorination
Mechanistic studies
Conclusion
2
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
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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
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Why Fluorine? – Properties
•Special properties:
High electronegativity
Relatively small size
Bond energy/ Bond length /
Volume / Å3
van der Waals
Pauling
radius / Å
Electronegativity
kcal mol-1
C : 1.70
2.55
C-C : 83
H : 1.20
2.20
C-H : 98
C-H : 1.09
CH3 : 21.26
F : 1.47
3.98
C-F : 116
C-F : 1.41
CF3 : 39.8
O : 1.52
3.44
C-O : 91
C-O : 1.43
CH3CH2 : 38.9
Å
(CH3)2CH : 56.2
•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. 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.
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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
Radionuclide
11C
13N
15O
18F
Half live t1/2 / min
20
10
2
110
•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. 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.
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Okazoe, T. Proc. Jpn. Acad., Ser. B 2009, 85, 276-289.
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.
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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. Tetrahedron 1996,
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
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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
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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.
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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.
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Reaction Conditions – Optimization
4,2$/g
76,1$/g
5,7$/g
21,3$/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
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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
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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. Tetrahedron 1996,
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
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Benzylic Difluorination – Optimization
•Features:
Xanthone (C) is electron-rich enough to promote difluorination
Selectfluor II effective with xanthone (C)
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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
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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
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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!
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Surprise Slide!
Happy birthday
Mylène!
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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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