tert-Butanol → tert-Butyl (4-bromothiophen-2-yl)carbamate

Participants

Reaction Conditions

Reaction Steps

As shown in Scheme 5, a mixture of 4-bromothiophene-2-carboxylic acid (53 g, 255 mmol), diphenylphosphoryl azide (70 mL, 323 mmol), and triethylamine (45 mmol) in tertiary butanol (675 mL) was heated at 100° C. for 5 hours. After cooling to room temperature, the volatiles were removed in vacuo to give a brown gum, which was dissolved in ethyl acetate (500 mL). The organics were washed with saturated NaHCO3 and water, followed by drying over Na2SO3 and concentration in vacuo. The residue was dissolved in a minimum amount of CH2Cl2 and purified by chromatography on silica gel (10-15% EtOAc/hexanes) to produce tert-butyl 4-bromothiophen-2-ylcarbamate as a white solid (compound 1010, 47 g, ESMS: M+H+=2781). Compound 1010 (96.7 mg, 0.35 mmol) was treated with 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (compound 1011, obtained from 2-chloro-4-bromopyridine by lithiation and subsequent reaction with 2-chloro-4,4,5,5-tetramethyl-1,3,2-dioxaborolane), a catalytic amount of tetrakis(triphenylphosphine)palladium(0), and potassium carbonate (2.06 mmol, 284 mg) in dioxane/water (2.4 mL/0.8 mL) to produce tert-butyl 4-(2-chloropyridin-4-yl)thiazol-2-ylcarbamate (compound 1012, ESMS: M+H+=311.5). The reaction mixture was dissolved in ethyl acetate, (10 mL) and washed with NaHCO3 and H2O. After drying, the solvent was removed in vacuo and the mixture carried forward without further purification. Compound 1012 was treated with 4M HCl/dioxane (3 mL) at room temperature for 2 hours. The resulting precipitate was filtered to produce 4-(2-chloropyridin-4-yl)thiazol-2-amine HCl salt (compound 1013, ESMS: M+H+=211.5, 85% yield). Compound 1013 (30 mg, 0.14 mmol) was combined with 2-(3-methoxyphenyl)acetic acid (28 mg, 0.17 mmol), N-(1-methanesulfonyl)benzotriazole (55 mg, 0.28 mmol) and triethylamine (41 μL, 0.30 mmol) in 2 mL THF and the mixture irradiated with microwave radiation for 10 minutes at 160° C. After removal of the solvent, the reaction mixture was taken into ethyl acetate, washed with 2N NaOH, and water. After removal of the solvent, the reaction mixture was purified by reversed-phase HPLC to produced N-(4-(2-chloropyridin-4-yl)thiazol-2-yl)-2-(3-methoxyphenyl)acetamide (compound 62, ESMS: M+H+=359, 33% yield).

Provenance & Evidence