A Concise Synthesis of Trifluoromethyl-Substituted 4-Aryloxy Pyrazoles

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.

pyrazoles - heterocycles - medicinal chemistry - hydrazones - dealkylation

References and Notes

For example, see:

1a Dalinger IL. Vatsadse IA. Shevelev SA. Ivachtchenko AV. J. Comb. Chem.  2005,  7:  236 

1b Donohue BA. Michelotti EL. Reader JC. Reader V. Stirling M. Tice CM. J. Comb. Chem.  2002,  4:  23 

1c Pinto DJP. Orwat MJ. Wang S. Fevig JM. Quan ML. Amparo E. Cacciola J. Rossi KA. Alexander RS. Smallwood AM. Luettgen JM. Liang L. Aungst BJ. Wright MR. Knabb RM. Wong PC. Wexler RR. Lam PYS. J. Med. Chem.  2001,  44:  566 

2a Iwata S. Namekata J. Tanaka K. Mitsuhashi K. J. Heterocycl. Chem.  1991,  28:  1971 

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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].