Fluorination Seminar

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



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


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)


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


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



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


Electrophilic Trifluoromethylation• Electrophilic allylic trifluoromethylation


• Plausible mechanistic pathwaysAllylic radicals are unlikely based on

radical clock experiments


Nagib, D. A.; MacMillan, D. W. C. Nature 2011, 480, 224.

• Radical aryl trifluoromethylation

Fujiwara, Y. et al Nature 2012, 492, 95.


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


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



Selectfluor

Fluorination Seminar

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