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

Abstract

Nucleophilic ionic sources of fluoride are essential reagents in the synthetic toolbox to access high added-value fluorinated building blocks unattainable by other means. In this review, we provide a concise description and rationale of the outstanding features of one of these reagents, tetramethylammonium fluoride (TMAF), as well as disclosing the different methods for its preparation, and how its physicochemical properties and solvation effects in different solvents are intimately associated with its reactivity. Furthermore, herein we also comprehensively describe its historic and recent utilization, up to December 2021, in C-F bond-forming reactions with special emphasis on nucleophilic aromatic substitution fluorinations with a potential sustainable application in industrial settings, as well as its use as a base capable of rendering unprecedented transformations.

Synthetic Utilization of 2H-Heptafluoropropane: Ionic 1,4-Addition to Electron-Deficient Carbon–Carbon Unsaturated Bonds

“…The use of tetrabutylammonium fluoride trihydrate (TBAF·3H 2 O) gave the desired product 2a in a 60% yield with a satisfactory material balance (entry 11). Although the conditions were favorable from the point of view of the raw material/product balance, a significant amount of tributylamine was found to be produced by the Hoffman elimination of TBAF . Therefore, the reactions were carried out using benzyltrimethylammonium fluoride and adamantyltrimethylammonium fluoride, which are less susceptible to Hoffman elimination.…”

“…Although the conditions were favorable from the point of view of the raw material/product balance, a significant amount of tributylamine was found to be produced by the Hoffman elimination of TBAF. 14 Therefore, the reactions were carried out using benzyltrimethylammonium fluoride and adamantyltrimethylammonium fluoride, which are less susceptible to Hoffman elimination. The results were comparable to those obtained using the TMAF (entries 2 vs 12 and 13).…”

Commercial Route Development Toward PF-07265807, an AXL-MER Inhibitor Oncology Candidate

“…After limited external process development work, 2,4-difluoro oxazoline 36 (HPLC purity 99.8% and chiral purity 99.7%) was prepared in four steps from commercially available 2,4-dichloronicontinic acid with 55% overall yield on greater than 500 g scale. 2,4-Dichloro oxazoline precursor 25 was converted to the difluoro analogue 36 using either (1) anhydrous tetramethylammonium fluoride or (2) cesium fluoride. Minimizing water content was the most important factor for this reaction, and on a larger scale, the cesium fluoride conditions were preferred due to the challenges faced with preparing anhydrous tetramethylammonium fluoride.…”

Retro-Favorskii Reaction Employing Fluoride Sources

“…It usually arises in systems where there is a weak interaction between the solvent/counterion and the fluoride anion, which drastically affect its reactivity. [13][14][15] While most of fluoride sources, such as inorganic salts or tetramethhylammonium fluoride (TMAF), are not soluble in common organic solvents, 13 higher tetralkylammonium cations are compatible with many solvents, including apolar ones. 16 They, however, suffer limited stability toward the Hoffmann degradation, especially at high temperatures.…”