無水氟化試劑可以通過SNAr氟化交換掉芳環的鹵素，這在很多文獻上已經有報道。
OPRD在2021年4月份的最新報道中提到，通過小試篩選，他們發現無水的四甲基氟化銨(TMAF, anh)可以通過氟氯交換成功實現噻唑環的氟化。
但是市場上可商業獲得的TMAF都是四水合物（TMAF-4H2O），很難買到無水的TMAF，而且作者期望他們的工藝是能用於放大生產的，因此能夠穩定可靠的獲得這種無水TMAF試劑就顯得非常重要。但是，TMAF-4H2O中的水分子是以氫鍵的方式與氟結合的。普通的處理方法很難除去其中的水份，隻有用醇類才能破壞原有的氫鍵，將原來的水合物結構替換為溶劑絡合物結構。
於是，他們對不同含水量或經不同處理方式處理過的TMAF水合物進行了測試。
實驗結果顯示，采用異丙醇共沸除水，再用DMF溶劑置換異丙醇的處理方式，可以把TMAF含水量降低到0.16%，滿足反應需要。
具體實施辦法如下：
TMAF·4H2O (32.5 g, 200 mmol, 10.5 equiv) was charged into a three-neck round-bottom flask followed by IPA (200 mL, 6.1 mL/g relative to TMAF·4H2O). The reaction mixture was concentrated and azeotropically distilled with IPA 10 times until the water content was measured to be <0.2% (by KF analysis). DMF (200 mL, 6.1 mL/g) was next added to the reaction mixture. The mixture was concentrated with DMF added back 10 times until the IPA concentration was measured to be <60 ppm. The TMAF/ DMF solution was adjusted to provide a final concentration of 20 mL/g DMF relative to compound 2a (100 mL). Compound 2a (5.0 g, 19.0 mmol) was charged into the flask. The reaction mixture was heated to 100 °C for 2 h and then cooled to 25 °C. 2-MeTHF (100 mL, 20 mL/g) was added, followed by addition of saturated NH4Cl (150 mL, 30 mL/g). The mixture was stirred for 17 h, and then, the layers were separated. The organic layer was concentrated to dryness, and the residue was purified via flash column chromatography (2:1 petroleum ether/EtOAc). Fractions containing the desired product were combined and concentrated to provide fluorothiazole 1a (1.4 g) as a yellow solid in 30% isolated yield (96.2% purity). 1 H NMR (400 MHz, CDCl3, ppm): δ 9.933 (1H, s, CHO), 1.567 (9H, s, CCH3); 13C NMR (400 MHz, CDCl3, ppm): δ 179.2, 164.9, 164.7, 164.1, 161.4, 151.7, 107.2, 107.1, 84.7. ESI-MS m/z: C9H11FN2O3S [M + 1]+ , 247.05.
從下圖可以看出，除水效果非常顯著，經五次異丙醇共沸以後，含水量可以從8.5%降低到0.2%：
Org.Process Res. Dev; https://doi.org/10.1021/acs.oprd.1c00042
來自網絡
