Acetaldehyde → (4S,7R)-7,8,8-trimethyl-2-naphthalen-1-yl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one

Participants

Reaction Conditions

Reaction Steps

Naphthylhydrazine was prepared by treating a mixture of 1-naphthylhydrazine hydrochloride with 10% methanol/dichloromethane and saturated aqueous sodium carbonate). A solution of 1-naphthylhydrazine (501 mg, 3.2 mmol) in toluene (45 mL) was cooled to 0° C. under nitrogen, and a solution of acetaldehyde (440 μL, 7.9 mmol) in cole toluene (5 mL) was added dropwise over 15 min. The mixture was allowed to stir at 0° C. for 5 min and then at room temperature for 1 h. The solvent was decanted off and the remaining material was evaporated to give a dark oil which was dissolved in 1,2-dichloroethane (5 mL). The solution was added to a solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; ˜1 equivalent) and pyridine (˜1.5 equivalents) in 1,2-dichloroethane (10 mL) at 0° C. to give an immediate precipitate. The reaction mixture was stirred at room temperature for 15 min, then at 50° C. for 40 min. The reaction mixture was cooled to room temperature and HCl in dioxane (4 M; 3 mL, 12 mmol) was added. The mixture was stirred at room temperature for 5 min, then glacial acetic acid (10 mL) was added and the mixture was stirred at 100° C. for 25 min. The reaction mixture was cooled, and solvents were evaporated. Dichloromethane (200 mL) was added and the solution was washed with 1:1 water/brine (2×50 mL). The combined aqueous layers were back-extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (100 mL), dried (magnesium sulfate), filtered, evaporated and purified by elution through silica gel with 30% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated and dried under high vacuum for 20 min to give (4S,7R)-7,8,8-trimethyl-2-naphthalen-1-yl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (459 mg, 46%) as an orange gummy solid.

Provenance & Evidence