Citric Acid → (S)-8-Fluoro-6-methyl-5,6-dihydrophenanthridine

Participants

Reaction Conditions

Reaction Steps

To a stirred suspension of sodium borohydride (9.28 g, 0.245 mole) in anhydrous tetrahydrofuran (372 mL) kept under nitrogen at 0° C. was added dropwise a solution of (S)-N-isobutyloxycarbonylproline (160 g, 0.743 mole; prepared according to S. Atarashi et al., J. Heterocyclic Chem. 28, 329 (1991)) in anhydrous tetrahydrofuran (372 mL). After stimring the reaction mixture overnight at room temperature the solvent was removed to provide a solid foam (168 g). This material was dissolved in dichloromethane (272 mL), the solution was cooled to 0° C. and treated dropwise under nitrogen with a solution of 8-fluoro-6methylphenanthridine (17.3 g, 0.082 mole) in dichloromethane (100 mL). The progress of the reaction was monitored by NMR. After 4 days at room temperature conversion reached 50% . Additional solution of S-hydridotris[1-(2-methylpropyl) 1,2-pyrrolidinedicarboxylato-O2]borate(1-) (freshly prepared from 4.7 g of sodium borohydride and 81.6 g of (S)-N-isobutyloxycarbonylproline as described above) in dichloromethane (150 mL) was added dropwise at 0° C. After 7 days at room temperature the conversion reached 100% . The reaction mixture was cooled to 0° C. and 10% aqueous citric acid was added dropwise (200 mL). The mixture was allowed to reach room temperature (over 80 minutes) and then it was diluted with ethyl acetate (1.2 L). The organic layer was washed with 10% aqueous citric acid, followed by saturated aqueous potassium dihydrogenphosphate (2×200 mL). The organic layer was divided in 3 portions and each portion was washed sequentially with 1:1 (v/v) saturated aqueous sodium bicarbonate/ water (2×400 mL), water (1×400 mL), 1:1 (v/v) saturated aqueous sodium bicarbonate/ water (2×400 mL), water (1×400 mL), and brine (1×400 mL) to remove the (S)-N-isobutyloxycarbonyl proline. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated to dryness to give 26.57 g of a brown oil which was immediately used in the next step without further purification.

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