fluorination seminar
TRANSCRIPT
An Overviewof
Fluorination Strategies
Kiel Lazarski
Porco Research Group
Literature Presentation
February 13th, 2014
The Relevance of FluorocarbonsThe carbon–fluorine bond is the strongest carbon–heteroatom bond
• C–F ~125 kcal/mol; C–C ~88 kcal/mol .
Fluorine is significantly more electronegative than carbon (4.0 v. 2.5)
• Fluorine atoms are not polarizable
• Fluorocarbons have weak intermolecular forces and low surface energies
• highly volatile
• immiscible in both organic and aqueous phases
• significantly higher interstitial volume compared to hydrocarbons
• respiratory gases are highly soluble
• non-flammable and generally maintain low toxicity
Industrial uses:
Polytetrafluoroethylene
(Teflon)
Perfluorodecalin
(respiratory fluid, artificial blood)
Perfluorinated polyethers
(non-flammable coatings & foam)
Lemal, D. M.; J. Org. Chem. 2004, 69, 1.
Fluorine’s Importance as an Isotere
Isosterism is based on polarization, bond geometry, atomic radii, and the spatial arrangement of atoms
Isosteric with thiol
Isosteric with carbonyl
Isosteric with amide
Isosteric with carbonyl
Meanwell, N. J. Med. Chem. 2011, 54, 2529
Strategies for Introducing Fluorine
Fluorination
• Electrophilic fluorination
• Nucleophilic fluorination
Fluoromethylation
• Electrophilic fluoromethylation
• Nucleophilic fluoromethylation
Difluoromethylation
• Electrophilic difluoromethylation
• Nucleophilic difluoromethylation
Trifluoromethylation
• Electrophilic trifluoromethylation
• Nucleophilic trifluoromethylation
N-fluorobis(phenyl)sulfonamide(NFSI)
N-fluoropyridinium salts
Selectfluor
Electrophilic Fluorination
• Most electrophilic fluorinating reagents are derived from fluorine gas
• Traditional reagents (F2, XeF2, CsSO4F, CF3OF) are highly oxidizing
• N-fluoro reagents act formally as source of F+
• Reactions may progress via SN2 mechanism or single electron transfer
N-fluorobis(phenyl)sulfonamide(NFSI)
N-fluoropyridinium salts
Selectfluor
Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem. Int. Ed. 2013, 52, 8214.
DeYoung, J.; Kawa, H.; Lagow, R. J. J. Chem. Soc. Chem. Commun. 1992, 811.
Electrophilic Fluorination• C-H activation as a strategy to construct aromatic C-F bonds:
Hull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 7134.
Wang, X; Mei, T. –S; Yu, J. –Q. J. Am. Chem. Soc. 2009, 131, 7520.
Chan, K. S. L.; Wasa, M.; Wang, X; Yu, J. –Q, Angew. Chem. Int. Ed. 2011, 50, 9081.
Electrophilic Fluorination• Fluorination of activated methylene and methine groups:
Hinermann, L; Togni, A. Angew. Chem. Int. Ed. 2000, 39, 4359.
Ma, J. A.; Cahard, D. Tetrahedron: Asymmetry 2004, 15, 1007.
Hamashima, Y.; Suzuki, T.; Takano, H.; Shimura, Y.; Sodcoka, M.J. Am. Chem. Soc. 2005, 127, 10164.
Electrophilic Fluorination
Shibata, N.; Suzuki, E.; Takeuchi, Y. J. Am. Chem. Soc. 2000, 122, 10728.
Beeson, T. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 8826. Marigo, M.; Fielenbach, D. I.; Braunton, A.; Kjoersgaard, A.; Jorgensen, K. A. Angew. Chem. Int. Ed. 2005, 117, 3769.
Steiner, D. D.; Mase, N.; Barbas, C. F. Angew. Chem. Int. Ed. 2005, 44, 3706.
Electrophilic Fluorination• Alkene fluorination cascades
Dilman, A. D. et al. J. Org. Chem. 2010, 75, 5367.
Wu, T.; Yin, G.; Liu, G. J. Am. Chem. Soc. 2009, 131, 16354.
Lozano, O. et al. Angew. Chem. Int. Ed. 2011, 50, 8105.
Electrophilic Fluorination• Fluorination by radical mechanism
• N-F bond in electrophilic fluorinating reagents have
a relatively low bond-dissociation energy (2.84 eV
for N-fluorosultam)
Yin, F.; Wang, Z.; Li, Z.; Li, C. J. Am. Chem. Soc. 2012, 134, 10401.
Rueda-Becerrril, M. et al. J. Am. Chem. Soc. 2012, 134, 4026.
Leung, J. C. T. et al. Angew. Chem. Int. Ed. 2012, 51, 10804.
Nucleophilic Fluorination• High electronegativity of fluorine makes the kinetic barrier an obstacle in forming C-F bonds
• Alkali-metal fluoride salts are desirable reagents due to cost and toxicity
• Strong lattice energy and poor solubility diminish their nucleophilicity
• Crown ethers and polar aprotic solvents can improve reactivity
• Fluoride’s basicity makes elimination by-products problematic
Inorganic fluoride sources Organic soluble fluoride sources
Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem. Int. Ed. 2013, 52, 8214.
Nucleophilic Fluorination• Nucleophilic aromatic substitution
• These reactions are not general and show poor functional group tolerance
Nucleophilic Fluorination• Transition metal-catalyzed and –mediated nucleophilic fluorinations
• High electronegativity of fluoride makes reductive elimination of C-F bonds challenging
Watson, D. A.; Su, M. J.; Teverovskiy, G.; Zhang, Y.; Garcia-Fortanct, J.; Kinzel, T.; Buchwald, S. L. Science 2009, 325, 1661.
Nucleophilic Fluorination• Copper-mediated fluorination of electron-rich, electron-deficient, and sterically hindered aryl iodides
• Hydro-dehalogenated side products complicate purification of aryl fluorides
Fier, P. S.p Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 10795.
Nucleophilic Fluorination• Nucleophilic deoxyfluorination
• Nucleophilic deoxyfluorination may proceed via SN1 or SN2 mechanism depending on substrate and conditions
Beaulieu, F.; Beuregard, L. –P.; Courchesne, G.; Couturier, M.; LaFlamme, F.; L’Hereux, A. Org. Lett. 2009, 11, 5050.
Nucleophilic Fluorination• Nucleophilic deoxyfluorination reagents (prices from Sigma)
Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem. Int. Ed. 2013, 52, 8214.
Nucleophilic Fluorination• Nucleophilic deoxyfluorination
Yin, J. J.; Zarkowsky, D. S.; Thomas, D. W.; Zhao, M. M.; Huffman, M. A. Org. Lett. 2004, 6, 1465.
Tang, P.; Wang, W.; Ritter, T. J. Am. Chem. Soc. 2011, 133, 11482.
Electrophilic Mono-fluoromethylation• +CH2F reagent
• Fluoromethyl amines, ethers, and
thiols are unstable due to
hyperconjugation.
• Similar yields and substrate scope
observed using CH2ClF as
the alkylating reagent.
Prakash, G. K. S.; Ledneuiki, I.; Chacko, S.; Olah, G. A., Org. Lett. 2008, 10, 557.
Nucleophilic Mono-fluoromethylation• Di-sulfone moiety is removable under reducing conditions
Li. Y.; Ni, C. F.; Liu, J.; Zhang, L. J.; Zheng, J. Zhu, L. G.; Hu, J. B. Org. Lett. 2006, 8, 1693.
Liu, J.; Zhang, L.; Hu, J. Org. Lett. 2008, 10, 5377.
Fukuzumi, T.; Shibata, N,; Sugiura, M.; Yasui, H.; Nakamura, S.; Toru, T. Angew. Chem. Int. Ed. 2006, 45, 4973.
Moon, H. W.; Cho, M. J.; Kim, D. Y. Tet. Lett. 2009, 50, 4896.
Nucleophilic Mono-fluoromethylation• Di-sulfone moiety is removable under reducing conditions
Ni, C.; Hu, J. Tetrahedron Letters 2009, 50, 7252.
Electrophilic Difluoromethylation• Molecules with di-fluoro groups are important components of pesticides and pharmaceuticals
• Gem-di-fluoro groups may serve as hydrogen-bond donors and replace hydroxyl groups
or mimic tetrahedral intermediates derived from carbonyls
Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem. Int. Ed. 2013, 52, 8214.
Trifluoromethyl radicals are more stable than difluoromethyl radicals. Monofluoromethyl radicals are the least stable.
Why are there so many reactions using trifluoromethyl radicals and so few using monofluoromethyl radicals?
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Electrophilic Difluoromethylation• Electrophilic radical difluoromethylation
Fujiwara, Y. et al Nature 2012, 492, 95.
Iscki, K.; Asada, D.; Takahashi, M.; Nagai, T.; Kobayashi, Y. Chem. Pharm. Bull. 2009, 44, 1314.Cao, P.; Duan, J. X.; Chen, Q. Y. J. Chem. Soc. Chem. Commun. 1994, 737.
Electrophilic Difluoromethylation• Difluoromethylation via difluoromethyl carbene
• Not general to carbon nucleophiles
Nawrot, E.; Jonczyk, A. J. Fluorine Chem. 2009, 130, 466.
• Difluoromethylation via SN2 attack
• Straightforward concept, but poor reaction yields
Zafrani, Y.; Sod-Moriah, G.; Segall, Y. Tetrahedron 2009, 65, 5278.
Nucleophilic Difluoromethylation
Fier, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 5524.
Qui, W. M.; Burton, D. J. Tetrahedron Letters 1996, 37, 2745.
Ni, C.; Wang, F.; Hu, J. Beilstein J. Org. Chem. 2008, 4
Electrophilic Trifluoromethylation
• Trifluoromethyl groups are electron-withdrawing substituents that increase lipophilicity
• Fewer synthetic strategies available because 3 of the 4 substituents are pre-determined
Common electrophilic trifluoromethylating reagents
Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem. Int. Ed. 2013, 52, 8214.
Electrophilic Trifluoromethylation
Pham, P. V.; Nagib, D. A.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2011, 50, 6119.
Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 10875.
Deng, Q. –H.; Wadepohl, H.; Gade, L. H. J. Am. Chem. Soc. 2012, 134, 10769.
Electrophilic Trifluoromethylation• Electrophilic allylic trifluoromethylation
Parsons, A. T.; Buchwald, S. L. Angew. Chem. Int. Ed. 2011, 50, 9120.
Electrophilic Trifluoromethylation• Mechanistic probes
Parsons, A. T.; Buchwald, S. L. Angew. Chem. Int. Ed. 2011, 50, 9120.
Electrophilic Trifluoromethylation• Electrophilic allylic trifluoromethylation
Parsons, A. T.; Buchwald, S. L. Angew. Chem. Int. Ed. 2011, 50, 9120.
• Plausible mechanistic pathwaysAllylic radicals are unlikely based on
radical clock experiments
Electrophilic Trifluoromethylation
Nagib, D. A.; MacMillan, D. W. C. Nature 2011, 480, 224.
• Radical aryl trifluoromethylation
Fujiwara, Y. et al Nature 2012, 492, 95.
Electrophilic Trifluoromethylation
Liu, T.; Shen, Q. Org. Lett. 2011, 13, 5464.
• Trifluoromethylation of boronic acids
• Plausible reaction mechanisms
Chu, L; Qing, F. –L. Org. Lett. 2010, 12, 5060.
Nucleophilic Trifluoromethylation
• Originally accomplished by fluoride displacement of trihalomethyl substrates or fluorodeoxygenation of carboxylic acids
• Trifluoromethyl anion can be problematic due to competing difluoromethyl carbene formation
Common nucleophilic trifluoromethylating reagents
Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem. Int. Ed. 2013, 52, 8214.
Nucleophilic Trifluoromethylation
Prakash, G. K. S.; Mandal, M. J. Am. Chem. Soc. 2002, 124, 6538.
Furukawa, T. et al. Org. Lett. 2011, 13, 3972.Mizuta, S. et al. Org. Lett. 2007, 9, 3707.
Summary of Fluorination Strategies
Fluorination
• Electrophilic fluorination
• Nucleophilic fluorination
Fluoromethylation
• Electrophilic fluoromethylation
• Nucleophilic fluoromethylation
Difluoromethylation
• Electrophilic difluoromethylation
• Nucleophilic difluoromethylation
Trifluoromethylation
• Electrophilic trifluoromethylation
• Nucleophilic trifluoromethylation
N-fluorobis(phenyl)sulfonamide(NFSI)
N-fluoropyridinium salts
Selectfluor