Multiple Approaches to the In Situ Generation of Anhydrous Tetraalkylammonium Fluoride Salts for S_NAr Fluorination Reactions

This article focuses on the development of practical approaches to the in situ generation of anhydrous fluoride salts for applications in nucleophilic aromatic substitution (S_NAr) reactions. We report herein that a variety of combinations of inexpensive nucleophiles (e.g., tetraalkylammonium cyanide and phenoxide salts) and fluorine-containing electrophiles (e.g., acid fluoride, fluoroformate, benzenesulfonyl fluoride, and aryl fluorosulfonate derivatives) are effective for this transformation. Ultimately, we demonstrate that the combination of tetramethylammonium 2,6-dimethylphenoxide and sulfuryl fluoride (SO₂F₂) serves as a particularly practical route to anhydrous tetramethylammonium fluoride. This procedure is applied to the S_NAr fluorination of a range of electron-deficient aryl and heteroaryl chlorides as well as nitroarenes

Acyl Azolium Fluorides for Room Temperature Nucleophilic Aromatic Fluorination of Chloro- and Nitroarenes

The reaction of acid fluorides with <i>N</i>-heterocyclic carbenes (NHCs) produces anhydrous acyl azolium fluorides. With appropriate selection of acid fluoride and NHC, these salts can be used for the room temperature S_NAr fluorination of a variety of aryl chlorides and nitroarenes

Mild Fluorination of Chloropyridines with in Situ Generated Anhydrous Tetrabutylammonium Fluoride

This paper describes the fluorination of nitrogen heterocycles using anhydrous NBu₄F. Quinoline derivatives as well as a number of 3- and 5-substituted pyridines undergo high-yielding fluorination at room temperature using this reagent. These results with anhydrous NBu₄F compare favorably to traditional halex fluorinations using alkali metal fluorides, which generally require temperatures of ≥100 °C

Anhydrous Tetramethylammonium Fluoride for Room-Temperature S_NAr Fluorination

This paper describes the room-temperature S_NAr fluorination of aryl halides and nitroarenes using anhydrous tetramethylammonium fluoride (NMe₄F). This reagent effectively converts aryl-X (X = Cl, Br, I, NO₂, OTf) to aryl-F under mild conditions (often room temperature). Substrates for this reaction include electron-deficient heteroaromatics (22 examples) and arenes (5 examples). The relative rates of the reactions vary with X as well as with the structure of the substrate. However, in general, substrates bearing X = NO₂ or Br react fastest. In all cases examined, the yields of these reactions are comparable to or better than those obtained with CsF at elevated temperatures (i.e., more traditional halex fluorination conditions). The reactions also afford comparable yields on scales ranging from 100 mg to 10 g. A cost analysis is presented, which shows that fluorination with NMe₄F is generally more cost-effective than fluorination with CsF

Nucleophilic Deoxyfluorination of Phenols via Aryl Fluorosulfonate Intermediates

This report describes a method for the deoxyfluorination of phenols with sulfuryl fluoride (SO₂F₂) and tetramethylammonium fluoride (NMe₄F) via aryl fluorosulfonate (ArOFs) intermediates. We first demonstrate that the reaction of ArOFs with NMe₄F proceeds under mild conditions (often at room temperature) to afford a broad range of electronically diverse and functional group-rich aryl fluoride products. This transformation was then translated to a one-pot conversion of phenols to aryl fluorides using the combination of SO₂F₂ and NMe₄F. Ab initio calculations suggest that carbon–fluorine bond formation proceeds via a concerted transition state rather than a discrete Meisenheimer intermediate

Developing Efficient Nucleophilic Fluorination Methods and Application to Substituted Picolinate Esters

This report describes nucleophilic fluorination of 3 and 5-substituted picolinate ester substrates using potassium fluoride in combination with additive promoters. Agents such as tributylmethylammonium or tetraphenylphosphonium chloride were among the best additives investigated giving improved fluorination yields. Additionally, the choice of additive promoters could influence the potential formation of new impurities such as alkyl ester exchange. Other parameters explored in this study include additive stoichiometry, temperature influence on additive degradation, solvent selection, product isolation by solvent extraction, and demonstration of additive recycling