tert-butyl N-(2-chloroanilino)carbamate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Triethylamine (1.7 mL, 12.1 mmol) was added dropwise to a cooled (0° C.) solution of (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 25; 1.00 g, 4.66 mmol) in dichloromethane (10 mL), yielding a thick slurry. Dichloromethane (5 mL) was added to facilitate stirring. The reaction mixture was stirred at 0° C. for 5 min and then N′-(2-chloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (Intermediate 30; 936 mg, 3.85 mmol) was added in small portions over 2-3 min. The reaction mixture was allowed to warm to room temperature and stir overnight, then it was cooled again to 0° C. and triethylamine (0.5 mL, 3.6 mmol) and a solution of N′-(2-chloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (Intermediate 30; 241 mg, 1.12 mmol) in dichloromethane (1 mL) were added. The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 6 h. Again triethylamine (0.8 mL, 5.7 mmol) and a solution of N′-(2-chloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (Intermediate 30; 431 mg, 2.0 mmol) in dichloromethane (1 mL) were added at 0° C. and the reaction mixture was allowed to warm to room temperature and stir over the weekend. The solvent was evaporated and the residue was taken up in ethyl acetate and washed with water (25 mL), 1 M HCl (50 mL), and brine (2×50 mL). The organic layer was dried (sodium sulfate), filtered, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc. Burlington, Wis.) with a RediSep-40 g silica gel column, eluting with 5-50% ethyl acetate/hexanes, to give N′-(2-chloro-phenyl)-N′-((1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (1.275 g, 79%) as a pale yellow foam. yielding a thick slurry The reaction mixture was stirred at 0° C. for 5 min stir overnight it was cooled again to 0° C. The reaction mixture was stirred at 0° C. for 30 min to warm to room temperature stir over the weekend The solvent was evaporated washed with water (25 mL), 1 M HCl (50 mL), and brine (2×50 mL) The organic layer was dried (sodium sulfate) filtered evaporated purified eluting with 5-50% ethyl acetate/hexanes

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Triethylamine (43 mL, 309 mmol) was added over 2-3 min to a cooled (0° C.) solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 23.2 g, 103.8 mmol) in dry dichloromethane (260 mL), yielding a heavy precipitate. Dichloromethane (25 mL) was added, followed by N′-(2-chloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (Intermediate 30; 19.36 g, 79.8 mmol) in one portion. Dichloromethane (35 mL) was added and the mixture was stirred at 0° C. for 5 min and then heated in an oil bath at 50° C. for 4 h. The mixture was poured into cold water (500 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2×300 mL) and the combined organic layers were washed with brine (200 mL), dried (magnesium sulfate), filtered, evaporated, and purified by silica gel chromatography, eluting with 20-100% ethyl acetate/petroleum ether. Fractions homogeneous for the product were evaporated and dried under high vacuum to give N′-(2-chloro-phenyl)-N′-((1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (23.4 g, 70%) as a pale foam. yielding a heavy precipitate heated in an oil bath at 50° C. for 4 h the layers were separated The aqueous layer was extracted with dichloromethane (2×300 mL) the combined organic layers were washed with brine (200 mL) dried (magnesium sulfate) filtered evaporated purified by silica gel chromatography eluting with 20-100% ethyl acetate/petroleum ether Fractions homogeneous for the product were evaporated dried under high vacuum