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Synlett 2006(9): 1404-1406  
DOI: 10.1055/s-2006-939703
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Concise Synthesis of Trifluoromethyl-Substituted 4-Aryloxy Pyrazoles

Lyn H. Jones*, Charles Mowbray
Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
Fax: +44(1304)651821; e-Mail: Lyn.Jones@pfizer.com;
Further Information

Publication History

Received 6 February 2006
Publication Date:
22 May 2006 (online)

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Abstract

An efficient route to 4-aryloxy pyrazoles bearing a tri­fluoromethyl group has been developed. A facile removal of the N-hydroxyethyl group has also been developed.

Key words

pyrazoles - heterocycles - medicinal chemistry - hydrazones - dealkylation

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7

Preparation of 10.
Hydroxy pyrazole 8 (0.3 mmol, 105 mg) was dissolved in DMF (0.5 mL), K2CO3 (0.3 mmol, 42 mg) then aryl fluoride 9 (0.3 mmol, 44 mg) were added and the mixture was heated to 90 °C for 5 h. The mixture was cooled to r.t., brine was added, extracted with EtOAc, dried (MgSO4), filtered and concentrated under reduced pressure. The colourless oil was purified by FCC (silica gel, 5% MeOH-CH2Cl2) to provide 10 as a white foam (92 mg, 85% yield). 1H NMR (400 MHz, CDCl3): δ = 0.72-0.76 (2 H, m), 0.92-0.97 (2 H, m), 1.40-1.90 (2 H, m), 4.18 (2 H, t), 4.40 (2 H, t), 7.38 (2 H, s), 7.63 (1 H, s). 19F NMR (376 MHz, CDCl3): δ = -62.5 (s). IR (solid): 3400, 1588, 1298 cm-1. LRMS (CI+): 363 [M + H]. LCMS (CI+): >95%(363)[M + H].
Preparation of 14.
Pyrazole 10 (0.64 mmol, 230 mg) was dissolved in CH2Cl2 (5 mL), methane sulfonyl chloride (0.7 mmol, 54 µL) then Et3N (0.7 mmol, 98 µL) were added and the mixture stirred at r.t. for 10 min. Then, H2O was added and the mixture was extracted with CH2Cl2, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was dissolved in DMF (5 mL), NaCN (2.2 mmol, 110 mg) was added and the mixture heated to 75 °C. After 3 h, H2O was added and the mixture extracted with CH2Cl2, dried (MgSO4), filtered and concentrated under reduced pressure. The colourless oil was purified by FCC (silica gel, 4% MeOH-CH2Cl2) to provide 13 as a white solid (132 mg, 65% yield). Pyrazole 13 (0.21 mmol, 66 mg) was dissolved in DMF (4 mL), 2-(2-bromoethoxy)tetrahydro-2H-pyran (0.21 mmol, 31 µL) then NaH (0.21 mmol, 8.4 mg of 60% in mineral oil) were added and after 4 h brine was added, extracted with EtOAc, dried (MgSO4), filtered, concentrated under reduced pressure and purified by FCC (silica gel, 10% EtOAc-toluene) to yield a more polar compound (22 mg) and a less polar compound (36 mg). The less polar com-pound was dissolved in MeOH (0.5 mL), TSA monohydrate (0.008 mmol, 1.5 mg) was added and after 3 h the solvent was removed under reduced pressure and the residue purified by FCC (silica gel, 2% MeOH-CH2Cl2) to yield 14 as a colourless oil (29 mg, 38% yield over 2 steps). 1H NMR (400 MHz, CD3OD): δ = 0.78-0.95 (4 H, m), 1.55-1.65 (1 H, m), 3.92 (2 H, t), 4.25 (2 H, t), 7.73 (2 H, s), 7.90 (1 H, s). 19F NMR (376 MHz, CD3OD): δ = -60.1 (s). LRMS: (CI+): 363 [M + H]. LCMS (CI+): >95%(363)[M + H].
Data for 15.
1H NMR (400 MHz, CDCl3): δ = 2.19 (3 H, s), 2.45 (1 H, t), 4.10 (2 H, m), 4.20 (2 H, m), 6.87 (1 H, d), 6.96 (1 H, s), 7.05 (1 H, d). 19F NMR (376 MHz, CDCl3): δ = -62.5 (s), -107.5 (s). LRMS (CI+): 330 [M + H]. LCMS (CI+): >95% (330) [M + H].
Data for 16.
1H NMR (400 MHz, CDCl3): δ = 2.20 (3 H, s), 2.35 (1 H, br s), 4.13 (2 H, m), 4.25 (2 H, m), 7.40 (2 H, s), 7.62 (1 H, s). 19F NMR (376 MHz, CDCl3): δ = -62.3 (s). LRMS (ES-): 335 [M - H]. LCMS (ES-): >95% (335) [M - H].
Data for 17.
1H NMR (400 MHz, CD3OD): δ = 2.19 (3 H, s), 7.60 (2 H, s), 7.87 (1 H, s). 19F NMR (376 MHz, CD3OD): -64.3 (s). LRMS (ES-): 291 [M - H]. LCMS (ES-): >95% (291)
[M - H].