Abstract: 4-(tris(4-methyl-1H-pyrazol-1-yl)methyl)aniline was prepared in a 63% yield utilizing a C–F activation strategy from a mixture of 4-(trifluoromethyl)aniline, 4-methylpyrazole, and KOH in dimethylsulfoxide (DMSO). The identity of the product was confirmed by nuclear magnetic resonance spectroscopy, infrared spectroscopy, mass spectrometry, and single-crystal analysis. An analysis of crystals grown from the layering method (CH2Cl2/acetone/pentane) indicated two distinct polymorphs of the title compound. Moreover, density functional theory calculations utilizing the MN15L density functional and the def2-TZVP basis set indicated that 4-(tris(4-methyl-1H-pyrazol-1-yl)methyl)aniline forms with similar energetics to the previously reported unmethylated analog.
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The reaction was performed under argon. Substituted azole (excess) and potassium tert-butoxide were dissolved at RT in dry and degassed DMSO. An exothermic reaction occurred. The mixture was stirred for 10 min to allow the reaction to finish and cool. Then, a substituted halopyridine was added. The reaction mixture was stirred for 24 h at 140C to give a suspension. It was cooled to RT. Water (50mL) was added: the product precipitated on stirring/sonication. The solid was filtered, washed with water, and extracted with dichloromethane and water. The organic layer was washed with water to extract DMSO. Purification by chromatography on silica (20g) removed the starting materials and by-products on elution with 0-0.4% CH3OH in CH2Cl2, and provided the pure product on elution with 0.4-1.0% CH3OH in CH2Cl2. Anal. Calc. for C14H12N4 (MW 236.27): C, 71.17; H, 5.12; N, 23.71. Found: C, 71.44; H, 5.10; N, 24.05%.
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