Nucleophilic Fluorination

Souvik Rakshit

Burke group Literature Seminar

July 13, 2013

20% of pharmaceuticals contain fluorine

Relevance

C. Heidelberger et al. Nature 1957, 179, 663.

K. Müller et al. Science 2007, 317, 1881.

5-fluorouracil Antineoplastic agent, 1957

Lipitor (Atorvastatin) Statin, 1985

Advair (Fluticasone)

Corticosteroid Lexapro (Escitalopram)

Antidepressant

Fluconazole

Triazole antifungal drug

Levaquin (Levofloxacin) Fluoroquinolone, antibiotic

• more bioavailable, lipophilic and metabolically stable

• increase the strength of a compound’s interactions with a target protein

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Polymer polytetrafluoroethylene (Teflon) is perfluorinated: low coefficient of friction and

hydrophobicity.

Perfluorinated solvents: Immiscible ‘fluorous phase’ that can be useful for recovering

catalysts or in purification procedures.

18F positron-emitting isotope ([18F]FDG): molecular positron emission tomography (PET)

imaging in oncology.

19F NMR technique: In the study of protein structure and dynamics.

Teflon, -(CF2CF2)-

D. P. Curran Angew. Chem. Int. Ed. 1998, 37, 1174.

J. C. Patterson et al. Mol. Imaging Biol. 2005, 7, 197.

T. Ritter et al. Nature 2011, 473, 470. 3

Properties of Fluorine and its effect

T. Hiyama Organofluorine Compounds, Springer, 2000.

Element EN

(Pauling)

IP

(kcal/mol)

Rv(Ǻ)

(Pauling)

CH3-X (Ǻ) BE CH3-X

(kcal/mol)

H 2.1 313.6 1.20 1.09 99

F 4.0 401.8 1.35 1.39 116

Cl 3.0 299.0 1.80 1.77 81

Br 2.8 272.2 1.95 1.93 68

O(OH) 3.5 310.4 1.40 1.43 86

S(SH) 2.5 238.9 1.85 1.82 65

EN: Electronegativity; IP: Ionization potential; BE: Bond energy.

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http://www.manchesterorganics.com/article.php/24/fluorination-chemistry

Basic Strategy for Fluorination

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V. Gouverneur et al. Chem. Commun. 2012, 48, 2929.

Nucleophilic Fluorination

A selection of nucleophilic fluorinating reagents.

Challenge to the use of F- for fluorination: poor solubility

dual reactivity as a nucleophile and a base.

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Fluorination using Aminosulfertrifluoride

Deoxyfluorination using DAST:

DAST decomposes at 90 C within 3h

J. Shreeve et al.Synthesis 2002, 17, 2561.

T. Ritter et al. J. Am. Chem. Soc. 2013, 135, 2470.

..

Mild fluorinating reagent Oligomycin A

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Halex process via Meisenheimer complex

Classical approach

Balz–Schiemann Reaction

Efficient nucleophilic aromatic substitution

with anhydrous TBAF

The presence of water in TBAF reduces the nucleophilicity of fluoride by hydrogen bonding.

Preparation of anhydrous TBAF

S. G. DiMagno et al. J. Am. Chem. Soc. 2005, 127, 2050. 8

Transition Metal catalyzed Nucleophilic Fluorination

C(sp2)-F bond construction

Ar-F bond formation

• SNAr nucleophilic substitution: harsh reaction conditions & substrate bearing electron-withdrawing group.

• Challenge in TM catalyzed: 1) high barrier to Ar-F bond formation

2) fluoride-bridged dimer formation ({PdArL( -F)}2) and formation of P–F

containing side products

V. V. Grushin Acc. Chem. Res. 2010, 43, 160.

S. L. Buchwald et al. Science 2009, 325, 1661.

..

Tricordinated 14e-

arylpalladium fluoride complex

Ligand promote reductive elemination and prevent

dimeric complex formation 9

• Cu-catalyzed aryl C-F bond formation:

Oxidative addition Cu(I) to Cu(III) into an aryl halide, exchange of halide by F and reductive elemination

X. Ribas et al. J. Am. Chem. Soc. 2011, 133, 19386.

J. F. Hartwig et al. J. Am. Chem. Soc. 2012, 134, 10795.

• Copper-Mediated Fluorination of Aryl Iodides

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Alkenyl fluoride

• Pd(0) catalyzed alkenyl-F bond forming cross-coupling reactions are NOT known!!*

• In 2005, Sadighi et al. first isolated gold(I) fluoride complex.

* V. Gouverneur et al. Chem. Commun. 2012, 48, 2929.

J. P. Sadighi, et al. J. Am. Chem. Soc. 2007, 29, 7736.

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C(sp3)–F bond construction

Allylic fluorides

• Most common synthesis of allylic fluorides is the DAST-mediated fluorination of allylic alcohols

• 16e- Rutheniumfluoride complex mediated halide metathesis

W. J. Middleton, J. Org. Chem. 1975, 40, 574; Togni et al. Helv. Chim. Acta 1999, 82, 2448.

A. G. Doyle et al. J. Am. Chem. Soc. 2010, 132, 17402; G. Liu et al. Angew. Chem. Int. Ed. 2013, 125, 7697.

• Pd(0)-catalyzed allylic fluorination

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Benzyl and alkyl fluoride

• Bergman et al. 1995: Synthesis of Ir(III)-F complex

• Ru(II)-catalyzed SN1 type fluorination using thallium fluoride

R. G. Bergman et al. J. Am. Chem. Soc. 1995, 117, 12478.

A. Togni et al. Organometallics 2001, 20, 3472.

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• Mn(III) catalyzed oxidative C-H fluorination

J. T. Groves et al. Science 2012, 337, 1322.

..

..

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G. Liu et al. J. Am. Chem. Soc. 2009, 131, 16354.

M. S. Sanford et al. Org. Lett. 2012, 14, 4094.

• Pd-Catalyzed Intramolecular Aminofluorination of Unactivated Alkenes

• Pd-Catalyzed C-H Fluorination

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G. Haufe et al. J. Fluorine Chem. 2000, 104, 247.

Fluorohydrins

• Hydrofluorinaton of epoxides: HF-containing reagents suitable for ring opening of epoxide

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A. G. Doyle et al. J. Am. Chem. Soc. 2010, 132, 3268

• Enantioselective Ring Opening of Epoxides by a Cooperative Dual-Catalyst System

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Summary and Outlook

F+ sources are commercially available, more expensive than fluoride reagents.

Significant advances in transition-metal-mediated nucleophilic fluorination of poorly

activated substrates.

Important breakthroughs: Site-selective Late-Stage Deoxyfluorination

Pd(0)/Pd(II)-catalyzed nucleophilic fluorination.

Selective fluorination of simple hydrocarbons

Tsuji-Trost type allylic fluorination

Electrophilic fluorinating reagents are much less desirable than fluoride for PET imaging

applications, because 18F- has significantly higher specific activity than 18F+ precursors.

Electrophilic F-sources

Nucleophilic F-sources

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