Regioselective Rapid Analogue Syntheses of 1-Methyl-3,5-diarylpyrazoles via Palladium-catalysed Coupling to 3(5)-Pyrazolyl Nonaflates

Abstract

Regioselective rapid analogue syntheses of 1-methyl-3,5-diarylpyrazoles were developed, based on Pd-catalysed couplings to 1-methyl-3(5)-arylpyrazole nonaflates, which offered an advantage in hydrolytic stability over the corresponding triflates. The new bifunctional reagent 1-methyl-3-bromo-pyrazol-5-yl nonaflate underwent highly chemoselective Pd-catalysed couplings to the nonaflate, followed by Suzuki couplings to the bromide, allowing sequential, regioselective introduction of the two aryl substituents.

Key words

regioselectivity - chemoselectivity - palladium - cross-coupling - heterocycles

References

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  A solution of MeNHNH₂ (26 mL) in (EtO)₂CO (60 mL) was refluxed under N₂ for 46 h. The solution was distilled at 1 atm to remove EtOH, then at 10 mmHg through a vigreux column, collecting the fraction boiling at 60-80 °C. Chromatography, eluting with MeOH-CH₂Cl₂ (3:97 then 5:95) gave ethyl 2-methyl-hydrazinecarboxylate (13.5 g, 85% pure by NMR) then ethyl 3-methylhydrazine-carboxylate (21.3 g, 93% pure by NMR).

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New address: I. Collins, CRUK Centre for Cancer Therapeutics, The Institute for Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, U.K.