A three step one-pot regioselective synthesis of highly substituted pyrazolo[1,5-a]pyrimidines assisted by KHSO4 in aqueous media under ultrasound irradiation

Abstract

A simple and efficient synthesis of substituted pyrazolo[1,5-a]pyrimidine derivatives has been developed by the use of ultrasound. 5-Methyl-4-phenyl-1H-pyrazol-3-amine required for the synthesis of pyrazolo[1,5-a]pyrimidine derivatives has been easily obtained by the reaction of 3-(dimethylamino)-2-phenylacrylonitrile (formed from readily available 2-phenylacetonitrile) with hydrazine hydrate in refluxing ethanol. The 5-aminopyrazole was then reacted with various formylated active proton compounds in presence of KHSO₄ in aqueous medium under ultrasound irradiation to give the desired products. The chemical structures of the newly synthesized compounds were confirmed by IR, ¹H NMR, ¹³C NMR and Mass spectral data. X-ray crystallographic study of a selected compound 6-(4-chlorophenyl)-2-methyl-3-phenylpyrazolo[1,5-a]pyrimidin-7-amine (7c) was performed to ascertain the regioselectivity of the reaction. Crystal data for compound 7c: Triclinic, space group P-1 (no. 2), a = 8.0198(3) Å, b = 14.0341(6) Å, c = 14.2099(6) Å, α = 87.672(2)°, β = 83.902(2)°, γ = 89.120(2)°, V = 1588.87(11) ų, Z = 4, T = 293(2) K, μ(MoKα) = 0.248 mm^-1, D_calc = 1.400 g/cm³, 12918 reflections measured (4.012° ≤ 2Θ ≤ 49°), 5152 unique (R_int = 0.0411, R_sigma = 0.0429) which were used in all calculations. The final R₁ was 0.0486 (I > 2σ(I)) and wR₂ was 0.1320 (all data).