Methanamine, N-methoxy-, hydrochloride (1:1) → 4-chloro-2-(2-chloro-phenylamino)-N-methoxy-N-methyl-benzamide

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Reaction Steps

In a 500 mL round bottom flask, 4-chloro-2-(2-chloro-phenylamino)-benzoic acid (1.15 g, 4.08 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP, 2.28 g, 4.89 mmol), N,O-dimethylhydroxylamine hydrochloride (0.80 g, 8.2 mmol) and N,N-diisopropylethylamine (7.5 mL, 42.9 mmol) were added to dichloromethane (60.0 mL). The mixture was stirred at room temperature overnight. LCMS the next day indicated a mixture of starting material and product. The reaction was further charged with N,O-dimethylhydroxylamine hydrochloride (1.61 g, 16.5 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 1.86 g, 4.89 mmol) and the mixture was stirred overnight at room temperature. LCMS the next day showed complete consumption of starting material. The reaction mixture was poured into ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, water and brine. The organic layer was dried, filtered and concentrated. The crude was purified by flash chromatography using 0-15% ethyl acetate-hexanes to give 4-chloro-2-(2-chloro-phenylamino)-N-methoxy-N-methyl-benzamide as an orange oil. 1H NMR (DMSO-d6) δ ppm 8.03 (s, 1H) 7.39-7.58 (m, 2H) 7.20-7.37 (m, 2H) 6.92-7.17 (m, 3H) 3.52 (s, 3H) 3.24 (s, 3H). MS calcd. for C15H14Cl2N2O2 [(M+H)+] 326.0, obsd. 324.9, [(M-C2H6NO2)+] 265.0, obsd. 264.0.

Provenance & Evidence