2,6-Lutidine → tert-butyl 3-(5-chloro-2-fluorophenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

Palladium(II) acetate (106 mg, 0.473 mmol, 0.020 equiv) was added to a vigorously stirred, deoxygenated mixture of tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate (4.00 g, 23.6 mmol, 1 equiv) and 5-chloro-2-fluorobenzenediazonium tetrafluoroborate (10.4 g, 42.5 mmol, 1.80 equiv) in water and carbon tetrachloride (1:1, 150 mL) at 23° C., and the resulting mixture was stirred for 20 hours. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (200 ml) and dichloromethane (2×200 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was dissolved in toluene (200 mL), and the resulting solution concentrated in vacuo to facilitate azeotropic removal of residual water. 2,6-Lutidine (5.51 mL, 47.3 mmol, 2.00 equiv) and trifluoroacetic anhydride (1.67 mL, 11.8 mmol, 0.500 equiv) were then sequentially added to a solution of the residue in toluene (150 mL) at −20° C. The resulting mixture was kept at −20° C. for 5 hours, then allowed to slowly warm to 23° C. After 16 hours at 23° C., the reaction mixture was heated at reflux for 30 minutes. The reaction mixture was allowed to cool to 23° C., then partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (hexanes initially, grading to 30% EtOAc in hexanes) to give tert-butyl 3-(5-chloro-2-fluorophenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate (17-1) as an orange oil. LRMS m/z (M+H CH3) 283.0 found, 283.1 required.

Provenance & Evidence