methyl 4-fluoro-1H-pyrrole-2-carboxylate

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 93.7 mg (0.655 mmol) 4-fluoro-1H-pyrrole-2-carboxylic acid methyl ester (synthesis described in J. Leroy et al. Tetrahedron 58, p. 6713, 2002) and 640 mg (1.96 mmol) cesium carbonate in 1.3 ml DMF is heated to 50° C. under stirring. 167 mg (0.655 mmol) 2-bromo-1-(4-tert-butyl-phenyl)ethanone is added and the reaction mixture is stirred for 18 hours at 50° C. The reaction mixture is filtered with suction and the filtrate is evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 1-[2-(4-tert-butyl-phenyl)-2-oxo-ethyl]-4-fluoro-1H-pyrrole-2-carboxylic acid methyl ester as brown amorphous solid; HPLC/MS 3.26 min (B), [M+H] 318. the reaction mixture is stirred for 18 hours at 50° C The reaction mixture is filtered with suction the filtrate is evaporated The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 93.7 mg (0.655 mmol) 4-fluoro-1H-pyrrole-2-carboxylic acid methyl ester (synthesis described in J. Leroy et al. Tetrahedron 58, p. 6713, 2002) and 640 mg (1.96 mmol) cesium carbonate in 1.3 ml DMF is heated to 50° C. under stirring. 167 mg (0.655 mmol) 2-bromo-1-(4-tert-butyl-phenyl)ethanone is added and the reaction mixture is stirred for 18 hours at 50° C. The reaction mixture is filtered with suction and the filtrate is evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 1-[2-(4-tert-butyl-phenyl)-2-oxo-ethyl]-4-fluoro-1H-pyrrole-2-carboxylic acid methyl ester as brown amorphous solid; HPLC/MS 3.26 min (B), [M+H] 318. the reaction mixture is stirred for 18 hours at 50° C The reaction mixture is filtered with suction the filtrate is evaporated The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of ammonium chloride (6.0 g, 112 mmol) in diethyl ether (220 mL) was cooled to −5° C., and concentrated aq. ammonium hydroxide (9.4 mL) was added dropwise with vigorous stirring. After the addition was complete, commercial grade aq. sodium hypochlorite solution (145 mL) was added via addition funnel at a rate such that the internal temperature was maintained below 0° C. The mixture was then stirred for 15 min, then the layers were separated, and the organic layer was washed with brine and dried over anhyd. calcium chloride. The resulting solution of chloramine was used directly as follows: In a separate flask, containing a solution of methyl 4-fluoro-1H-pyrrole-2-carboxylate (0.98 g, 6.85 mmol) in DMF (15 mL) at 0° C. was added 60% sodium hydride dispersion (0.329 g, 8.22 mmol) and the resulting mixture was allowed to warm to rt and stir for 45 minutes. At this time, a portion of the previously prepared chloramine solution (55 mL) was added via syringe over ˜1 minute. After stirring for an additional 1.5 h at rt, the reaction mixture was quenched by adding sat. aq. Na2S2O3 followed by diluting with water and extracting with diethyl ether (100 mL×2). The combined extracts were dried over anhyd. sodium sulfate, filtered and concentrated under vacuum to afford 0.98 g (91%) of the title compound as a light tan oil. HPLC (condition B): retention time=1.57 min. LCMS (condition B): m/z 159 +ve. 1H NMR (400 MHz, MeOD) δ ppm 6.86 (1 H, d), 6.51 (1 H, d, J=2.42 Hz), 3.85 (3 H, s). After the addition was maintained below 0° C the layers were separated the organic layer was washed with brine dried over anhyd to warm to rt stir for 45 minutes After stirring for an additional 1.5 h at rt the reaction mixture was quenched by adding sat. aq. Na2S2O3 by diluting with water extracting with diethyl ether (100 mL×2) The combined extracts were dried over anhyd sodium sulfate, filtered concentrated under vacuum

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:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of ammonium chloride (6.0 g, 112 mmol) in diethyl ether (220 mL) was cooled to −5° C., and concentrated aq. ammonium hydroxide (9.4 mL) was added dropwise with vigorous stirring. After the addition was complete, commercial grade aq. sodium hypochlorite solution (145 mL) was added via addition funnel at a rate such that the internal temperature was maintained below 0° C. The mixture was then stirred for 15 min, then the layers were separated, and the organic layer was washed with brine and dried over anhyd. calcium chloride. The resulting solution of chloramine was used directly as follows: In a separate flask, containing a solution of methyl 4-fluoro-1H-pyrrole-2-carboxylate (0.98 g, 6.85 mmol) in DMF (15 mL) at 0° C. was added 60% sodium hydride dispersion (0.329 g, 8.22 mmol) and the resulting mixture was allowed to warm to rt and stir for 45 minutes. At this time, a portion of the previously prepared chloramine solution (55 mL) was added via syringe over ˜1 minute. After stirring for an additional 1.5 h at rt, the reaction mixture was quenched by adding sat. aq. Na2S2O3 followed by diluting with water and extracting with diethyl ether (100 mL×2). The combined extracts were dried over anhyd. sodium sulfate, filtered and concentrated under vacuum to afford 0.98 g (91%) of the title compound as a light tan oil. HPLC (condition B): retention time=1.57 min. LCMS (condition B): m/z 159+ve. 1H NMR (400 MHz, MeOD) δ ppm 6.86 (1 H, d), 6.51 (1 H, d, J=2.42 Hz), 3.85 (3 H, s). After the addition was maintained below 0° C the layers were separated the organic layer was washed with brine dried over anhyd to warm to rt stir for 45 minutes After stirring for an additional 1.5 h at rt the reaction mixture was quenched by adding sat. aq. Na2S2O3 by diluting with water extracting with diethyl ether (100 mL×2) The combined extracts were dried over anhyd sodium sulfate, filtered concentrated under vacuum

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