Acetic Acid → Methyl 1-(4-bromo-3-fluorobenzyl)azetidine-3-carboxylate

Participants

Reaction Steps

Azetidine-3-carboxylic acid (43 g, 421 mmol), 4-bromo-3-fluorobenzaldehyde (81.4 g, 401 mmol), methyl orthoformate (219 mL, 2005 mmol), and AcOH (34 mL, 601 mmol), was added to DCM (700 mL) at rt under N2 atm. The mixture was stirred for 15 min, at which point sodium triacetoxyborohydride (127 g, 601 mmol) was added portionwise (exothermic). After 2 h, solvent swap with MeOH (257 g, 8019 mmol), and sulfuric acid (79 g, 802 mmol) was added slowly (exothermic). The mixture was heated at reflux for 18 h. Solvent was removed and the mixture was extracted using DCM and water. The organic layer was purified using Biotage column (isopropanol/heptane) affording methyl 1-(4-bromo-3-fluorobenzyl)azetidine-3-carboxylate as a clear oil. MS (ESI) m/z: Calculated: 301.0; Observed: 302.0 (M++1).

Provenance & Evidence