Tetramethylammonium Fluoride Tetrahydrate for SNAr Fluorination of 4-Chlorothiazoles at a Production Scale

This article describes the use of tetramethylammonium fluoride tetrahydrate (TMAF·4H2O) for the large-scale preparation of a challenging 4-fluorothiazole. Commercially available TMAF·4H2O was procured on a large scale and rigorously dried by distillation with isopropyl alcohol and then dimethylformamide at elevated temperature. This method of drying provided anhydrous TMAF [TMAF (anh)] containing <0.2 wt % water and <60 ppm isopropanol. The use of TMAF (anh) was essential for production of the 4-fluorothiazole. When the chlorothiazole starting material was treated with other anhydrous fluoride sources, poor conversion of the starting material or potential safety issues were observed. SNAr fluorination using dried TMAF·4H2O was carried out at a 45.1 kg scale at 95–100 °C to produce 36.8 kg of 4-fluorothiazole 1b.