Palladium and Nickel Catalyzed Hydroxycarbonylation of a Steroidal Bromodiene in the Synthesis of Episteride, a Potent 5α-Reductase Inhibitor

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• Palladium Catalyzed Synthesis of 3: A 3-necked 250 mL round bottom flask was fitted with a vacuum adapter, rubber septa, stir bar. The flask was charged with 6N NaOH (20 mL), N-amyl alcohol (10.0 mL), cetyltrimethylammonium bromide (20 mg, 0.054 mmol) and triphenylphosphine (40.0 mg, 0.153 mmol). The reaction mixture was degassed under aspirator vacuum (12 mm) and charged with carbon monoxide (1.0 atm). This was repeated three times. Palladium acetate (20.0 mg, 0.089 mmol) was added and the mixture was heated to 50°C for 0.5 h under 1.0 atm CO. The steroid 2 (2.0 g, 4.6 mmol) was dissolved in warm amyl alcohol (35°C, 10.0 mL) and degassed and flushed with carbon monoxide. The steroid mixture was added to the catalyst mixture over a 5 min. period at 50°C. The reaction mixture was then heated at 80°C for 18 h. The mixture was filtered hot and the amyl alcohol was removed by vacuum distillation. The reaction mixture was brought to pH 1.0 with HCl (12.0 N). The acid mixture was extracted with methylene chloride (2 x 40 mL), and the organic layer was dried over MgSO4 and filtered. The solvent was removed by vacuum distillation. This yielded crude 3, which was recrystallized from boiling acetonitrile (50 mL) to yield SK&F 105657 (1.41 g, 77%) as a white crystalline solid. The product was identical to previously reported 3.13
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• Nickel Catalyzed Synthesis of 3: A 250 mL 3-necked flask was fitted with a gas adapter and mechanical stirrer. The reactor was charged with n-butanol (20 mL), 20 % NaOH (20 mL), and Ni(CN)2·4 H2O (131 mg, 0.72 mmol). The reaction was degassed under vacuum (12 mm) (3×) and flushed with carbon monoxide (1.0 atm). The mixture was heated with vigorous stirring to 80°C for 0.5 h under 1.0 atm of carbon monoxide Cetyltrimethylammonium bromide (100 mg, 0.266 mmol) was added and the mixture was stirred for 5 min. The steroid 2 (2.0 g, 4.6 mmol) was added all at once, and the mixture was heated at 87°C under 1.0 atm. carbon monoxide for 18 h. The mixture was filtered and the organic solvent was removed by vacuum distillation. The basic solution was brought to pH 2 with 1.0 N HCl and was extracted with methylene chloride (2 x 20 mL). The methylene chloride layer was dried over MgSO4 and filtered. The solvent was removed under vacuum. The crude product was recrystallized from boiling acetonitrile (50 mL) to yield SK&F 105657 (1.10 g, 60%) as a white crystalline solid. The product was identical to previously reported 3.13
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• Baine , N. H. , Owings , F. , Klein , D. N. , Resnick , T. , Ping , L. J. , Mewshaw , R. E. , Fox , M. , Tickner , A. M. and Kowalski , C. J. 1994 . J. Org. Chem. , 59 : 5987
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