Nucleophilic Fluorination. Souvik Rakshit Burke group Literature Seminar July 13, 2013

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1 Nucleophilic Fluorination Souvik Rakshit Burke group Literature Seminar July 13, 2013

2 Relevance 20% of pharmaceuticals contain fluorine 5-fluorouracil Antineoplastic agent, 1957 Lipitor (Atorvastatin) Statin, 1985 Fluconazole Triazole antifungal drug Advair (Fluticasone) Corticosteroid Levaquin (Levofloxacin) Fluoroquinolone, antibiotic Lexapro (Escitalopram) Antidepressant more bioavailable, lipophilic and metabolically stable increase the strength of a compound s interactions with a target protein C. Heidelberger et al. Nature 1957, 179, 663. K. Müller et al. Science 2007, 317,

3 Polymer polytetrafluoroethylene (Teflon) is perfluorinated: low coefficient of friction and hydrophobicity. Teflon, -(CF 2 CF 2 )- Perfluorinated solvents: Immiscible fluorous phase that can be useful for recovering catalysts or in purification procedures. 18 F positron-emitting isotope ([ 18 F]FDG): molecular positron emission tomography (PET) imaging in oncology. 19 F NMR technique: In the study of protein structure and dynamics. D. P. Curran Angew. Chem. Int. Ed. 1998, 37, J. C. Patterson et al. Mol. Imaging Biol. 2005, 7, 197. T. Ritter et al. Nature 2011, 473,

4 Element EN (Pauling) Properties of Fluorine and its effect IP (kcal/mol) R v (Ǻ) (Pauling) CH 3 -X (Ǻ) BE CH 3 -X (kcal/mol) H F Cl Br O(OH) S(SH) EN: Electronegativity; IP: Ionization potential; BE: Bond energy. T. Hiyama Organofluorine Compounds, Springer,

5 Basic Strategy for Fluorination 5

6 Nucleophilic Fluorination Challenge to the use of F - for fluorination: poor solubility dual reactivity as a nucleophile and a base. A selection of nucleophilic fluorinating reagents. V. Gouverneur et al. Chem. Commun. 2012, 48,

7 Fluorination using Aminosulfertrifluoride Deoxyfluorination using DAST: DAST decomposes at 90 C within 3h.. Oligomycin A Mild fluorinating reagent J. Shreeve et al.synthesis 2002, 17, T. Ritter et al. J. Am. Chem. Soc. 2013, 135,

8 Classical approach Halex process via Meisenheimer complex The presence of water in TBAF reduces the nucleophilicity of fluoride by hydrogen bonding. Preparation of anhydrous TBAF Efficient nucleophilic aromatic substitution with anhydrous TBAF Balz Schiemann Reaction S. G. DiMagno et al. J. Am. Chem. Soc. 2005, 127,

9 Transition Metal catalyzed Nucleophilic Fluorination C(sp 2 )-F bond construction Ar-F bond formation S N Ar 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 Tricordinated 14e - arylpalladium fluoride complex.. V. V. Grushin Acc. Chem. Res. 2010, 43, 160. S. L. Buchwald et al. Science 2009, 325, Ligand promote reductive elemination and prevent 9 dimeric complex formation

10 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 Copper-Mediated Fluorination of Aryl Iodides X. Ribas et al. J. Am. Chem. Soc. 2011, 133, J. F. Hartwig et al. J. Am. Chem. Soc. 2012, 134,

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

12 C(sp 3 ) 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 Pd(0)-catalyzed allylic fluorination W. J. Middleton, J. Org. Chem. 1975, 40, 574; Togni et al. Helv. Chim. Acta 1999, 82, A. G. Doyle et al. J. Am. Chem. Soc. 2010, 132, 17402; G. Liu et al. Angew. Chem. Int. Ed. 2013, 125,

13 Benzyl and alkyl fluoride Bergman et al. 1995: Synthesis of Ir(III)-F complex Ru(II)-catalyzed S N 1 type fluorination using thallium fluoride R. G. Bergman et al. J. Am. Chem. Soc. 1995, 117, A. Togni et al. Organometallics 2001, 20,

14 Mn(III) catalyzed oxidative C-H fluorination.... J. T. Groves et al. Science 2012, 337,

15 Pd-Catalyzed Intramolecular Aminofluorination of Unactivated Alkenes Pd-Catalyzed C-H Fluorination G. Liu et al. J. Am. Chem. Soc. 2009, 131, M. S. Sanford et al. Org. Lett. 2012, 14,

16 Fluorohydrins Hydrofluorinaton of epoxides: HF-containing reagents suitable for ring opening of epoxide G. Haufe et al. J. Fluorine Chem. 2000, 104,

17 Enantioselective Ring Opening of Epoxides by a Cooperative Dual-Catalyst System A. G. Doyle et al. J. Am. Chem. Soc. 2010, 132,

18 Summary and Outlook 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 F + sources are commercially available, more expensive than fluoride reagents. Nucleophilic F-sources Electrophilic F-sources Electrophilic fluorinating reagents are much less desirable than fluoride for PET imaging applications, because 18F - has significantly higher specific activity than 18F + precursors. 18