Anhydrous Tetramethylammonium Fluoride for Room-Temperature SNAr Fluorination

Anhydrous Tetramethylammonium Fluoride for Room-Temperature SNAr Fluorination

Sydonie D. Schimler,† Sarah J. Ryan,† Douglas C. Bland,‡ John E. Anderson,‡ and Melanie S. Sanford*,†

† Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States ‡ Process Science, Dow Chemical Company, 1710 Building, Midland, Michigan 48674, United States

J. Org. Chem. DOI: 10.1021/acs.joc.5b02075
http://pubs.acs.org/doi/pdf/10.1021/acs.joc.5b02075

Abstract:

This paper describes the room-temperature SNAr 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 costeffective than fluorination with CsF.

TOC: