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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.