Mild Fluorination of Chloropyridines with in Situ Generated Anhydrous Tetrabutylammonium Fluoride

Abstract

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.

Nucleophilic Fluorination of Electron-Deficient Arenes

“…The anhydrous TBAF pre-prepared in this way is able to fluorinate a variety of chloro-and nitrobenzenes even at room temperature with high yields (Scheme 7) [31]. As reported by Sanford and coworkers, this reagent system is also applicable for the nucleophilic fluorination of quinoline derivatives as well as a number of 3-and 5substituted pyridines at room temperature, affording the corresponding (hetero)aryl fluorides in high yields (Scheme 8) [32]. Notably, anhydrous TBAF in situ generated from C 6 F 6 / TBACN also works well for the S N Ar fluorination, so it is not necessary to pre-form TBAF before the addition of the substrates.…”

“…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].…”

Diastereoselective Synthesis of Dialkylated Bis(phosphino)ferrocenes: Their Use in Promoting Silver‐Mediated Nucleophilic Fluorination of Chloroquinolines

“…2‐Fluoroquinoline (8): Analyses were similar to reported data. [19a] 1 H NMR (300 MHz, CDCl 3 ): δ = 7.09 (dd, J = 8.7 and 2.8 Hz, 1 H), 7.54 (m, 1 H), 7.74 (m, 1 H), 7.83 (m, 1 H), 7.94 (d, J = 8.4 Hz, 1 H), 8.25 (t, J = 8.4 Hz, 1 H) ppm. 19 F NMR (282 MHz, CDCl 3 ): δ = –61.7 ppm.…”

Synthesis of new fluorescent molecules having an aggregation-induced emission property derived from 4-fluoroisoxazoles

“…The importance of fluorinated heterocyclic derivatives in the pharmaceutical and agrochemical industries continues to grow, with several fluorinated 6-membered heteroaromatic derivatives finding applications in a wide variety of drugs and plantprotective agents [15][16][17][18][19][20][21][22][23][24][25][26][27]. However, there are only a few reports on the synthesis and properties of fluorinated 5-membered heteroaromatic systems, especially those comprising two heteroatoms such as pyrazoles [28,29], isoxazoles [30], and thiazoles [31,32].…”