Fluorination of 4-alkyl-substituted phenols and aromatic ethers with fluoroxy and N-F reagents: Cesium fluoroxysulfate and N-fluoro-1,4-diazonia-bicyclo[2.2.2]octane dication salts case

• Fluorination of 4-alkyl-substituted phenols or aromatic ethers with cesium fluoroxysulfate, Selectfluor F-TEDA-BF4 or Accufluor NFTh gave three types of products.
• Bulkiness of alkyl group on aromatic ring and at phenolic oxygen regulates the relative distribution of products.
• Reactions performed with NFTh are more selective than those with F-TEDA-BF4 and in MeOH more selective than in MeCN.

4-Alkyl-substituted phenols and aromatic ethers were comparatively fluorinated with electrophilic fluorinating reagents such as cesium fluoroxysulfate (CFS), Selectfluor™ F-TEDA-BF4, and Accufluor™ NFTh in MeCN or MeOH. Reactions resulted in the formation of three types of products: 2-fluoro-4-alkyl-substituted corresponding compounds (5) as a result of ortho fluorination process, 4-alkyl-4-fluoro-cyclohexa-2,5-dienone compounds (6), resulting after an addition–elimination process, and 4-fluorosubstituted corresponding compounds (7) derived from ipso attack and release of the 4-alkyl group. The distribution of products depends on the bulkiness of alkyl groups at both positions and reaction media. The reaction in methanol proved more selective toward the formation of 2-fluoro derivatives. Tyramin and l-tyrozine were transformed with NFTh reagent in methanol to their fluorophenyl-substituted derivatives in good yield.

Fluorination of 4-alkyl-substituted phenols or corresponding alkyl ethers with cesium fluoroxysulfate, Selectfluor F-TEDA-BF4 or Accufluor NFTh resulted in the formation of three types of products: 2-fluoro-substituted derivatives, 4-fluoro-dealkylated products, and 4-alkyl-4-fluoro-cyclohexa-2,5-dienone derivatives.Figure optionsDownload as PowerPoint slide