- Tetramethylammonium Fluoride Alcohol Adducts for SNAr Fluorination
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Nucleophilic aromatic fluorination (SNAr) is among the most common methods for the formation of C(sp2)-F bonds. Despite many recent advances, a long-standing limitation of these transformations is the requirement for rigorously dry, aprotic conditions to maintain the nucleophilicity of fluoride and suppress the generation of side products. This report addresses this challenge by leveraging tetramethylammonium fluoride alcohol adducts (Me4NF·ROH) as fluoride sources for SNAr fluorination. Through systematic tuning of the alcohol substituent (R), tetramethylammonium fluoride tert-amyl alcohol (Me4NF·t-AmylOH) was identified as an inexpensive, practical, and bench-stable reagent for SNAr fluorination under mild and convenient conditions (80 °C in DMSO, without the requirement for drying of reagents or solvent). A substrate scope of more than 50 (hetero) aryl halides and nitroarene electrophiles is demonstrated.
- Bland, Douglas C.,Lee, So Jeong,Morales-Colón, Mariá T.,Sanford, Melanie S.,Scott, Peter J. H.,See, Yi Yang
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supporting information
p. 4493 - 4498
(2021/06/28)
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- Nucleophilic fluorination facilitated by a CsF-CaF2 packed bed reactor in continuous flow
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A simple to prepare, dry and handle packed bed reactor carrying CsF on CaF2, towards nucleophilic fluorinations in continuous flow, is reported. The reactor also proved adaptable for silyl-ether deprotection and trifluoromethylations with Ruppert's reagent. The study includes reactor stability and scale-up investigations.
- Johansen,Lindhardt
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supporting information
p. 825 - 828
(2018/02/06)
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- PROCESS FOR FLUORINATING COMPOUNDS
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Disclosed are mild temperature (e.g., from 0 to 80°C) SNAr fluorinations of a variety of halide and sulfonate substituted aryl and heteroaryl substrates using NMe4F.
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Page/Page column 29; 33; 34
(2017/02/28)
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- Anhydrous Tetramethylammonium Fluoride for Room-Temperature SNAr Fluorination
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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 cost-effective than fluorination with CsF.
- Schimler, Sydonie D.,Ryan, Sarah J.,Bland, Douglas C.,Anderson, John E.,Sanford, Melanie S.
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p. 12137 - 12145
(2016/01/09)
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