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

Abstract

This article focuses on the development of practical approaches to the in situ generation of anhydrous fluoride salts for applications in nucleophilic aromatic substitution (SAr) 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 (SOF) serves as a particularly practical route to anhydrous tetramethylammonium fluoride. This procedure is applied to the SAr fluorination of a range of electron-deficient aryl and heteroaryl chlorides as well as nitroarenes.

Ex Situ Generation of Sulfuryl Fluoride for the Synthesis of Aryl Fluorosulfates

“…We hypothesize that fluorosulfation is the rate-limiting step instead of the SO 2 F 2 generation from SDI. 13 C NMR confirmed that SDI completely decomposed in less than 30 s under the optimized reaction conditions (see SI). It was also shown that under these circumstances, the actual pressure inside the vessel remained well under the maximally allowed internal pressure (see SI).…”

“…Furthermore, aryl fluorosulfates are also versatile intermediates as they can be converted into aryl fluorides, 10 aryl sulfamate esters, 11 and others 12 or can even be used for the synthesis of anhydrous tetraalkylammonium fluoride salts. 13 Historically, aryl fluorosulfates are mainly synthesized via four different approaches. 14 The first method relies on the pyrolysis of arenediazonium fluorosulfate salts.…”

Nucleophilic Fluorination of Electron-Deficient Arenes

“…However, the preparation of quaternary ammonium fluorides is always accompanied with hydration of the fluoride ions, which would decrease the nucleophilicity of fluoride ions as well as cause further transformation and side reactions [28]. To avoid the impact of water on the S N Ar fluorination reactions, either predried [29] or in situ prepared [30][31][32] anhydrous quaternary ammonium fluorides have been used to achieve high yields of the (hetero)aryl fluorides. The results with these anhydrous quaternary ammonium fluoride salts compare favorably to traditional S N Ar fluorination using alkali metal fluorides, which generally require temperatures at higher than 100 C [7].…”

“…The formation of the side products is nearly completely suppressed at this low reaction temperature. In addition, anhydrous TMAF in situ generated from inexpensive nucleophiles (such as tetramethylammonium cyanide and phenoxide salts) and fluorine-containing electrophiles (such as acid fluoride, fluoroformate, benzenesulfonyl fluoride, and aryl fluorosulfonate derivatives) can be used for the same purpose with excellent results [30].…”

Synthesis and Chemical Transformations of Fluorosulfates

“…Sanford and co‐workers reported that 4‐methoxyphenyl sulfurofluoridate ( 2 ) reacted with tetramethylammonium 2,6‐dimethylphenoxide in DMF for 15 min at room temperature to afford 2,6‐dimethyl phenyl(4‐methoxyphenyl)sulfate ( 113 ; Scheme ) …”