Synlett 2015; 26(01): 51-54
DOI: 10.1055/s-0034-1378915
cluster
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 4,4-Difluoro-1H-pyrazole Derivatives

Jessica R. Breen
a  Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, UK   Fax: +44(191)3830347   Email: Graham.Sandford@Durham.ac.uk
,
Graham Sandford*
a  Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, UK   Fax: +44(191)3830347   Email: Graham.Sandford@Durham.ac.uk
,
Bhairavi Patel
b  Pfizer Global Research & Development, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK
,
Jonathan Fray
b  Pfizer Global Research & Development, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK
› Author Affiliations
Further Information

Publication History

Received: 22 September 2014

Accepted after revision: 10 October 2014

Publication Date:
05 November 2014 (online)


Abstract

Fluorination of 3,5-diarylpyrazole substrates by SelectfluorTM in acetonitrile gave 4,4-difluoro-1H-pyrazoles in addition to 4-fluoropyrazole derivatives. The structure of this new class of fluorinated heterocycle was established by X-ray crystallography.

Supporting Information

 
  • References and Notes

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  • 21 Typical Procedure (Conditions A); 4-Fluoro-3,5-diphenyl-1H-pyrazole (2d) and 4,4-Difluoro-3,5-diphenyl-4H-pyrazole (3a): 3,5-Diphenyl-1H-pyrazole (0.30 g, 1.36 mmol) and SelectfluorTM (0.482 g, 1.36 mmol) were dissolved in MeCN (5 mL) and the mixture was heated by microwave irradiation for 15 min at 90 °C. The mixture was then extracted with CH2Cl2 (3 × 50 mL) and washed with NaHCO3 (30 mL) and H2O (30 mL). The combined extracts were dried (MgSO4) and evaporated. Column chromatography on silica gel using hexane and EtOAc (1:1) as the eluent, gave 4-fluoro-3,5-diphenyl-1H-pyrazole (0.135 g, 45%) as pale yellow crystals; mp 185–188 °C. 1H NMR (400 MHz, CDCl3): δ = 7.41–7.47 (m, 2 H, 4-H), 7.48–7.51 (m, 4 H, 3-H), 7.77–7.80 (m, 4 H, 2-H), 10.3 (br s, 1 H, NH). 13C NMR (126 MHz, CDCl3): δ = 128.2 (Ar), 129.0 (Ar), 129.3 (Ar), 131.1 (d, 2 J CF = 15.0 Hz, C-3), 140.0 (d, 1 J CF = 226.6 Hz, C-4), 148.7 (Ar). 19F NMR (376 MHz, CDCl3): δ = –174.3 (s). MS: m/z (%, EI+) = 237.9 (100) [M]+, 107.8 (43), 76.9 (40). HRMS: m/z [M + H]+ calcd for C15H12FN2: 239.0983; found: 239.0972. 4,4-Difluoro-3,5-diphenyl-4H-pyrazole (3a): obtained as yellow crystals (0.122 g, 21%); mp 105–107 °C. 1H NMR (400 MHz, CDCl3): δ = 7.44–7.67 (m, 6 H, ArH), 8.06–8.15 (m, 4 H, ArH). 13C NMR (126 MHz, CDCl3): δ = 125.4 (Ar), 125.6 (t, 1 J CF = 267.5 Hz, CF2), 128.3 (Ar), 129.5 (Ar), 133.1 (Ar), 162.1 (t, 2 J CF = 23.1 Hz, C-2). 19F NMR (376 MHz, CDCl3): δ = –116.3 (s). MS: m/z (%, EI+) = 256.1 (100) [M]+, 153.0 (45), 103.1 (99), 77.1 (36). HRMS: m/z [M + H]+ calcd for C15H11F2N2: 257.0890; found: 257.0894.