4-Fluoro-2-methylaniline 6.258g (50 mmol) was dissolved in anhydrous acetic acid 20mL and acetic anhydride 5.00mL (53 mmol) was added without cooling (exothermic reaction). After 10 minutes, the mixture was heated to 90 C on oil bath and a solution of tBuOCl 9.0mL (81.8mmol) in acetic acid 60mL was slowly added (using an addition funnel) over a 3 hour period and the reaction was then continued for additional 1 hour at 90C. The mixture was cooled and evaporated to dryness. The solid residue was re-crystallized from a mixture of ethanol 20mL and water 20mL (5 hours at ambient temperature). The precipitated product (6.305g) was collected by filtration, dried on highvac and re-crystallized from benzene (100mL, overnight), to obtain 5.484g of the chloroacetanilide intermediate as a white crystalline solid (96% pure by HPLC). 1H(d6-DMSO, 400MHz): 9.476 (br s, 1H), 7.316(dd, 8.4Hz, 2.9Hz, 1H), 7.158(dd, 9.3Hz, 2.8Hz, 1H), 2.174(s, 3H), 2.042(s, 3H).
The chloroacetanilide 5.484g was dissolved in conc. HCl 120mL. Water 120mL was added and the resulting slurry was refluxed for 3 hours (oil bath 130-140C). The resulting homogenous mixture was evaporated to dryness, the residue was dissolved in water 100mL, the solution was made basic with concentrated ammonia (pH approx 9.5 to 10) and the mixture was extracted with dichloromethane (2x100mL). The combined extracts were dried (MgSO4) and evaporated. The residue was dried on higvac with cooling on ice bath. Y=4.259g (53.5% overall) of a light-tan liquid that solidifies upon cooling to 0C.
1H(d6-DMSO, 400MHz): 7.022(dd, 8.5Hz, 2.9Hz, 1H), 6.866(dd, 9.3Hz, 2.8Hz, 1H), 4.880(br s, 2H), 2.139(s, 3H); 19F(d6-DMSO, 376.5MHz): -128.10(m, 1F)