Study On The Electrophilic Fluorination Of Imidazolyl Six-membered Aromatic Heterocycles By SelectFluo

The introduction of fluorine-containing groups into drug molecules can improve the metabolic stability of drug molecules,enhance the lipid solubility and promote the interaction with target proteins,and then it can improve their physiological activity to enhance the efficacy.The introduction of fluorine-containing groups by highly selective and low-cost ways has become one of the research directions for new pharmaceutical design,especially,the research of fluorine-containing heterocyclic compounds has become a hot spot.Due to high activity and strong electronegativity of fluorine element,it seems very hard to introduce fluorine on C-3 of six-membered imidazole-containing heterocycles by normal method.In this study,six-membered imidazole-containing heterocycles compounds were designed and synthesized,then it was regarded as substrates.Using 1-chloromethyl-4-fluoro-1,4-diazodiacyclic[2.2.2]octane di-（tetrafluoroboric acid）salt（Select Fluor）as the fluorine source,the C-H bond at C-3 position of six-membered imidazole-containing heterocycles was broken down and carried out by electrophilic fluorination in one step.Then the isolated yield of electrophilic fluorination for synthesized fluorine-containing compound 6-bromo-3-fluoro-7-methylimidazolium[1,2-a]pyridine-2-carboxylate（A1）was used as the investigation index.The effects of fluorination yield for target compound with reaction time,reaction temperature and Select Fluor reagent dosage were studied by single factor experiment.Subsquently,the process conditions was optimized by using response surface method.The best condition was confirmed that the amount of Select Fluor reagent was 2 equivalent,the reaction temperature was 30℃,the reaction time was 2 h,and the isolated yield reached 88.58%.20 compounds of fluorsubstituted six-membered imidazole-containing heterocycles（A1～A10,B1～B5 and C1～C5）were successfully prepared by using the process condition,of which 14 compounds（A1,A3,A4～A6,A9,A10,B2,B4 and C1～C5）was new fluorides.The structures of these compounds were identified by ¹H NMR,¹³C NMR,and HRMS（high resolution mass spectrometry）,IR（infrared spectroscopy）and ¹⁹F NMR.In order to study the effect of the electrophilic fluorination yield with different substituents on six-membered imidazole-containing heterocycles,firstly,the fluorides（A1～A10,B1 and C1）of different substituents on six-membered ring were compared,and then fluoro-substituted imidazolypyridine（B1～B5）and imidazolypyrazine（C1～C5）with five different groups of amide,ester,aldehyde,cyanide and trifluoromethyl at C-2 position were synthesized and their isolated yield was compared.The research results showed that the change of substituents on the six-membered aromatic heterocyclic ring had very small effect on the electrophilic fluorination yield.However,while the change of substituents on C-2 site of the five-membered imidazole ring has a great effect on the electrophilic fluorination yield.Specifically,the weaker electron withdrawing group,the more favorable electrophilic fluorination reaction and the higher the yield are.On the contrary,the stronger electron withdrawing group and the weaker the electrophilicity,the lower the yield are.