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

Abstract

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.

Anhydrous N,N-Dimethyl-N,N-Dineopentylammonium Fluoride Electrolyte for Fluoride Ion Batteries

“…Tetraalkylammonium fluorides, including Np 1 F and Np 2 F, are typically prepared by first reacting a tetraalkylammonium iodide starting material with silver oxide to give the tetraalkylammonium hydroxide intermediates, followed by neutralization with aqueous hydrofluoric acid. ,, Ammonium fluorides are extremely hygroscopic, however, so obtaining anhydrous products under this reaction scheme is difficult. ,− To remove the residual water content, a harsh drying processlong periods under high vacuum at high temperature combined with azeotropic distillationis required. ,,− The use of strongly corrosive reagents such as hydrofluoric acid also poses inherent safety risks, particularly if the process is to be carried out at an industrial scale. − Therefore, milder and safer synthetic methods are highly desirable.…”

Tetramethylammonium Fluoride: Fundamental Properties and Applications in C-F Bond-Forming Reactions and as a Base

“…In this manner, the authors devised that fluoride anions could be rapidly generated, which would be stabilized with the free tetramethylammonium cation, and thus promote the S N Ar fluorination of the model substrate in situ (Scheme 10c). In practice, tetramethylammonium acetate proved to be ineffective to yield any fluorinated end-product (92). However, the tetramethylammonium salt of 2,6-dimethylphenoxide (97) exhibited superior performance compared to tetrabutylammonium cyanide or tetramethylammonium phenoxide to afford 92 in an excellent 92% of yield after 24h of reaction in DMF at room temperature.…”

“…The remaining solid was nearly anhydrous, yet next it was azeotropically distilled from isopropanol (i-PrOH) and then also recrystallized from dry i-PrOH. Finally, a very recent report by chemists at Eli Lilly describes the preparation of anhydrous TMAF at a bulk scale (with just <0.2 wt% H2O and 60 ppm of i-PrOH) directly from the readily available TMAF tetrahydrate salt [92]. This process involves azeotropic distillation with i-PrOH, and then DMF at an elevated temperature.…”

“…This process involves azeotropic distillation with i-PrOH, and then DMF at an elevated temperature. Subsequently, the authors prepared 36.8 kg of 4-fluorothiazole via SNAr fluorination of 4-chlorothiazole using Finally, a very recent report by chemists at Eli Lilly describes the preparation of anhydrous TMAF at a bulk scale (with just <0.2 wt% H 2 O and 60 ppm of i-PrOH) directly from the readily available TMAF tetrahydrate salt [92]. This process involves azeotropic distillation with i-PrOH, and then DMF at an elevated temperature.…”

“…TMAF encompasses a unique series of features in the realm of nucleophilic fluorination. Firstly, it holds larger potential applicability in multi-gram-scale industrial processes than most other covalent and ionic fluorinating nucleophilic reagents due to its simplicity, relatively low cost, and the recent development of optimized methodologies to prepare it anhydrously-in large amounts [55,92] or in situ [97,98]-with minimal impurities (Section 2.3). Secondly, TMAF outcompetes almost all the remaining fluorinating nucleophilic reagents in terms of the atom economy and the potential environmental impact inherent to its use.…”