xia, j.-b.; zhu, c.; chen, c. j. am. chem. soc. 2013, 135, 17494-17500. augusto césar...
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Xia, J.-B.; Zhu, C.; Chen, C. J. Am. Chem. Soc. 2013, 135, 17494-17500.
Augusto César Hernandez-PerezLiterature MeetingLiterature MeetingFebruary 19February 19thth, 2014, 2014
MALLORY REACTION.Visible Light-Promoted Metal-Free C-H Visible Light-Promoted Metal-Free C-H Activation: Diarylketone-Catalyzed Selective Activation: Diarylketone-Catalyzed Selective
Benzylic Mono- and DifluorinationBenzylic Mono- and Difluorination
CARBON RICH MATERIALS AND THE MALLORY REACTION.
Outline
2
Pr. Chuo Chen
Why fluorine?
Mono-fluorination
Reaction proposal
Difluorination
Mechanistic studies
Conclusion
http://pubs.rsc.org/en/content/articlehtml/2011/cc/c0cc90144jhttp://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)
Research Program
1. Chemical Biology: Synthesis of small-molecule inhibitors of the Hedgehog (Hh) and Wnt signal transduction
pathwaysMechanistic and medicinal chemical studies of a series of novel Hh and Wnt antagonists
4http://www4.utsouthwestern.edu/chuochen/group.htm
2. Natural product synthesis:
NHHN
NH
NHHN
NH
HNHN O
O HN
HN
Br Br
O
ClCl
OH
O
H
OH
Br
O
HO
OClCl
OH
O
H
OH
Br
O
O
HO O
NakiterpiosinoneNakiterpiosinAgeliferin
3. Synthetic methodology development: Palladium-Catalyzed Direct Fonctionalization of ImidazolinoneRegiocontrol in MnIII-Mediated Oxidative Heterobicyclizations
A Highly Selective Vanadium Catalyst for Benzylic C–H OxidationA Simple Method for the Electrophilic Cyanation of Secondary Amines
Why Fluorine? – Properties
5
•C-F bond: Strongest bond with carbonLenght similar C-O bond Trifluoromethyl (CF3) volume similiar to ethyl (CH3CH2)
van der Waals
radius / Å
Pauling
Electronegativity
Bond energy/
kcal mol-1
Bond length /
Å
Volume / Å3
C : 1.70 2.55 C-C : 83 (CH3)2CH : 56.2
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
•Special properties: High electronegativityRelatively 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.
Why Fluorine? – Utility in Different Fields
6
•Fluorine in nuclear medicine: PET : Positron emission tomographyNuclear medical imaging in vivo18F tracer has longer half life
Bohm, 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 11C 13N 15O 18F
Half live t1/2 / min 20 10 2 110
•Crop protection:28% of the halogenated products between 1940-2003 contained fluorineEnvironmental friendly compare to others halogens
•Material industryFluorinated 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 atomReduces basicity when close to a basic group (better membrane permeability)
Fluorine Incorporation
7Kirk, 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 nucleophileVarious nucleophilic reagents (F-, S-F reagents)
•Electrophilic fluorination: Not easily achieved because fluorine is the most electronegative elementUse of N-F reagents (even 5% F2 in N2)
•Radical fluorination:Use of N-F reagents
N
SF3
DAST
ON
SF3
O
Deoxo-fluor
NN
F
Cl
2 BF4
Selecfluor
NSS
F
O O O O
NFSI
NN
F 2 BF4
Selecfluor II
N
F BF4
N
F
Cl ClBF4
NHF
PPHFN
F
Mono-Fluorination – Literature Precedent
8
FG
Functional grouptransformation
F
•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.
S
FNOBF4 (2,2 equiv)PPHF (excess)
[0.5M] DCM, 0C, 1h
79%
NNHTs FK2CO3 (5.0 equiv) Et3N3HF (1.5 equiv)
[0.25M] PhMe, reflux, 2h
85%
BF3K FSelectfluor (1.0 equiv)[0.2M] MeCN, r.t., 24h
91%
FNFSI (5.0 equiv)
[0.1M] MeCN, 110C, 6min
45%
O
OO
Electrophilic / Radical fluorination
•Drawbacks:Narrow scope / few substratesMethodology not for large synthesis scale
Mono-Fluorination – Literature Precedent
9
H
Direct C-Hfluorination
F
•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.
FKB(C6F5)4 (0.10 equiv)
NHPI (0.10 equiv)Selectfluor (2.2 equiv)
[0.33M] MeCN, 25C, 24h
28%
NCu
N
Ph PhI(0.10 equiv)
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.
FFe(acac)2 (0.10 equiv)Selectfluor (2.2 equiv)
[0.33M] MeCN, 25C, o.n.
65%
•Features:Catalytic systemMild reaction conditions Decent scope
Reaction Proposal
10
Ar R
Visible light-promotedmetal-free catalysis
Ar R
H H H For
fluorine donorroom temperature
Ar R
F F
•Key steps: Formation of photoexcited arylketone
Benzylic hydrogen abstractionFluorine atom transferRegeneration 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.
Photoexcited Arylketone – Literature Precedent
11
O h O H OHOH
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.
•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
R
O
R
OHH R
RRR HO
RR
R
•Benzophenone: Acts like acetoneKnown 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
Reaction Conditions – Optimization
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O O
N
N
N
Ir
NN
F
Cl
2 BF4
Selecfluor (A)
NN
F 2 BF4
Selecfluor II (B)
NSS
F
O O O O
NFSI (C)
N
F BF4
D
N
F
Cl ClBF4
E
•Features:Use of visible light effective with compact fluorescent lamp (cheap!)9-fluorenone has suitable chromophore for visible lightIr(ppy)3 does not promote benzylic fluorinationNot water sensitive but oxygen sensitiveCheap electrophilic fluorine source
4,2$/g 5,7$/g 21,3$/g
76,1$/g 49,2$/g
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 compatibleMIDA boronate tolerated under reaction conditions
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 ringGood group toleranceSalt commercially available
Het HNaO
SCF2H
OTBHP (5.0 equiv)DCM/H2O (2.5:1)
TsOHH2O (1.0 equiv) ZnCl2 (1.5 equiv)
Het CF2Me
R
CuI (1.0 equivCsF (3.0 equiv)
TMSCF2H (5.0 equiv)NMP, 120C, 24h
RI CF2H
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.
5% F2
[0.01M] MeOH 0C, 7min
34%
F FNH2N
York, C.; Prakash, G. K. S.; Olah, G. A. Tetrahedron 1996, 52, 9-14.
NOBF4 (2.2 equiv)PPHF (excess)
[0.5M] DCM, 0C, 1h
92%
F FSS
•Other methods:Electrochemical difluorination (mixture of products)Few difluorination methods available
Benzylic Difluorination – Optimization
15
NN
F
Cl
2 BF4
Selecfluor
NN
F 2 BF4
Selecfluor II
NSS
F
O O O O
NFSI
O
A
O
MeO OMeB
O
OC
O
MeO OMeOD
•Features:Xanthone (C) is electron-rich enough to promote difluorinationSelectfluor II effective with xanthone (C)
Benzylic Difluorination – Scope
16
•Features:No or less than 5% of monofluorinated product in all casesAromatic halides tolerated (no UV light used)MIDA boronate tolerated under reaction conditions
Mechanistic Studies
17
•Features:Visible light and catalyst are requiredNo reaction in the darkNo thermal radical process9-fluorenone doesn’t act as an energy transfer photosensitizerReaction works in the presence of a 400 nm long-pass filter
•Kinetic isotope effect (KIE) :C-H abstraction in the rate-limiting step
Mechanistic Studies
18
•Site preference for reaction :2 1 3Electron rich substrates react faster than electron-poor substrates
•Gram scale reaction:20 mmol scaleNo flash chromatography!
Surprise Slide!
19
Happy birthday Mylène!
Conclusions
20
•Monofluorination:Mild reaction conditionsBroad scope•Difluorination:Mild reaction conditionsFirst catalytic C-H difluorination
•GeneralUse of visible lightApplication to gram scale reactionsNo transition-metal required
•Further improvements:Use of continuous-flow conditionsApplication to the synthesis of a drug
F
OMe
O
F-iburofen methyl esteranti-inflammatory
N
N
NN
S
NH
S
S
FF
O
O
Inhibitor of kidney urea transporter UT-B