methyl (2R)-4,4-difluoropyrrolidine-2-carboxylate

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To solution of (R)-methyl 4,4-difluoropyrrolidine-2-carboxylate (2.00 g, 12.11 mmol) in THF (40 mL) was added manganese dioxide (8.42 g, 97 mmol) and the resulting mixture was heated at reflux (oil bath temp ˜70° C.) for 3 h. After cooling to rt, the reaction mixture was filtered through a pad of Celite, rinsed with additional THF (20 mL×4), and DCM (40 mL×4) and the resulting filtrate was concentrated under vacuum to afford a dark brown oil as the crude product which was purified via flash silica gel chromatography (eluent: CH2Cl2/MeOH, 0-10%) to afford 0.98 g (56%) of the title compound as a white solid. HPLC (condition B): retention time=1.71 min. LCMS (condition B): m/z 144 +ve. 1H NMR (400 MHz, MeOD) δ ppm 6.81 (1 H, dd, J=3.63, 1.87 Hz), 6.59 (1 H, d, J=1.32 Hz), 3.86 (3 H, s). the resulting mixture was heated After cooling to rt the reaction mixture was filtered through a pad of Celite rinsed with additional THF (20 mL×4), and DCM (40 mL×4) the resulting filtrate was concentrated under vacuum to afford a dark brown oil as the crude product which was purified via flash silica gel chromatography (eluent: CH2Cl2/MeOH, 0-10%)

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

Procedure: To solution of (R)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate (4.33 g, 16.32 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (12.58 mL, 163 mmol) and the resulting mixture was stirred at rt for 5 h, then concentrated and sat. aqueous sodium bicarbonate (50 mL) was added followed by stirring for 20 min before extracting with diethyl ether (40 mL×3). The combined extracts were washed with brine and dried over sodium sulfate, filtered, and concentrated at rt (note: product is volatile) to afford 2.0 g (74%) of the title compound as a light tan oil that was used directly in the next transformation without any further purification. 1H NMR (400 MHz, MeOD) δ ppm 4.03 (1 H, dd, J=8.80, 6.82 Hz), 3.77 (3 H, s), 3.22-3.32 (1 H, m), 3.07-3.23 (1 H, m), 2.51-2.69 (1 H, m), 2.30-2.50 (1 H, m). concentrated sat. aqueous sodium bicarbonate (50 mL) was added by stirring for 20 min before extracting with diethyl ether (40 mL×3) The combined extracts were washed with brine dried over sodium sulfate filtered concentrated at rt (note: product is volatile)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To solution of (R)-methyl 4,4-difluoropyrrolidine-2-carboxylate (2.00 g, 12.11 mmol) in THF (40 mL) was added manganese dioxide (8.42 g, 97 mmol) and the resulting mixture was heated at reflux (oil bath temp ˜70° C.) for 3 h. After cooling to rt, the reaction mixture was filtered through a pad of Celite, rinsed with additional THF (20 mL×4), and DCM (40 mL×4) and the resulting filtrate was concentrated under vacuum to afford a dark brown oil as the crude product which was purified via flash silica gel chromatography (eluent: CH2Cl2/MeOH, O-10%) to afford 0.98 g (56%) of the title compound as a white solid. HPLC (condition B): retention time=1.71 min. LCMS (condition B): m/z 144+ve. 1H NMR (400 MHz, MeOD) δ ppm 6.81 (1 H, dd, J=3.63, 1.87 Hz), 6.59 (1 H, d, J=1.32 Hz), 3.86 (3 H, s). the resulting mixture was heated After cooling to rt the reaction mixture was filtered through a pad of Celite rinsed with additional THF (20 mL×4), and DCM (40 mL×4) the resulting filtrate was concentrated under vacuum to afford a dark brown oil as the crude product which was purified via flash silica gel chromatography (eluent

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

Procedure: To solution of (R)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate (4.33 g, 16.32 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (12.58 mL, 163 mmol) and the resulting mixture was stirred at rt for 5 h, then concentrated and sat. aqueous sodium bicarbonate (50 mL) was added followed by stirring for 20 min before extracting with diethyl ether (40 mL×3). The combined extracts were washed with brine and dried over sodium sulfate, filtered, and concentrated at rt (note: product is volatile) to afford 2.0 g (74%) of the title compound as a light tan oil that was used directly in the next transformation without any further purification. 1H NMR (400 MHz, MeOD) δ ppm 4.03 (1 H, dd, J=8.80, 6.82 Hz), 3.77 (3 H, s), 3.22-3.32 (1 H, m), 3.07-3.23 (1 H, m), 2.51-2.69 (1 H, m), 2.30-2.50 (1 H, m). concentrated sat. aqueous sodium bicarbonate (50 mL) was added by stirring for 20 min before extracting with diethyl ether (40 mL×3) The combined extracts were washed with brine dried over sodium sulfate filtered concentrated at rt (note: product is volatile)