Pivalic acid → 4-methyl-6-(1,3-thiazol-5-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine

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Reaction Steps

In a dry flask, allylpalladium(II) chloride dimer (1.333 g, 3.64 mmol) and butyldiadamantylphosphine (5.23 g, 14.57 mmol) were taken-up in degassed dimethylacetamide (50 mL). The vessel was evacuated and backfilled with argon (3 times), and then stirred at rt for 10 minutes. Additional degassed dimethylacetamide (50 mL), 6-bromo-4-methyl-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine (12.1 g, 36.4 mmol), thiazole (10.36 mL, 146 mmol), potassium carbonate (15.11 g, 109 mmol), and pivalic acid (6.34 mL, 54.6 mmol) were added. The vessel was evacuated and backfilled with argon (3 times) and stirred under argon at 130° C. overnight. The reaction mixture was then diluted with EtOAc (500 mL), cooled to rt, filtered through Celite®, and concentrated. Water was added to the crude product mixture and the resulting precipitate was collected via filtration and subjected to silica gel flash chromatography (ethyl acetate-hexanes). Purification yielded 4-methyl-6-(1,3-thiazol-5-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine (5.29 g, 15.72 mmol, 43% yield) as a yellow solid. MS ESI calcd for C15H11F3N4S [M+H]+ 337, found 337. 1H NMR (600 MHz, DMSO) δ 10.21 (s, 1H), 9.14 (s, 1H), 8.59 (s, 1H), 8.52 (s, 1H), 8.47 (d, J=5.1 Hz, 1H), 7.43 (s, 1H), 7.20 (d, J=5.1 Hz, 1H), 7.11 (s, 1H), 2.30 (s, 3H) ppm.

Provenance & Evidence