Nat. Chem.: α - fluorination of carbonyl compounds by nucleophilic fluorinators

In recent years, the application of organic fluoride in medicine and pesticide is more and more extensive, and more and more chemists pay attention to the research of organic fluoride Fluorine is the most electronegative element in nature, and its atomic radius is closest to that of hydrogen atom Therefore, the substitution of C-F bond for C-H bond will not significantly distort or change the geometry of the molecule, but will have a great impact on the electronic density distribution of the molecule In drug discovery, drug chemists often use the unique properties of fluorine to design and modify drugs It has been found that the introduction of fluorine atoms into drug molecules can often improve the metabolic stability and change the physical and chemical properties of drugs, so as to improve the bioavailability of drugs At present, α - fluorination of carbonyl compounds is mainly carried out by nucleophilic fluorination reagents (enols or amines) and electrophilic fluorination reagents (NFSI reagents and selectfluor reagents, etc.) However, the electrophilic fluorination reagent has some disadvantages, such as poor solubility, strong oxidation, high cost, and good for industrial application It is not suitable for fluorination of amide compounds (Figure 1b) Although lectka, rovis and others have developed simple methods for the synthesis of α - fluoroamide (Figure 1c), these methods still rely on electrophilic fluorination reagents and cannot obtain the required products from the amide raw materials in one step Therefore, organic chemists hope to realize α - fluorination of carbonyl compounds by simple nucleophilic fluorination reagents Recently, the research team of Professor Nuno maulide at the University of Vienna, Austria, proposed a new strategy to reverse the polarity of enols, so that nucleophilic fluorinators can be directly used for chemically selective α - C-H fluorination Relevant research results were published on NAT Chem (DOI: 10.1038/s41557-019-0215-z) It is suggested that trifluoromethylsulfonic anhydride is used to selectively activate the amide, and then an oxidant is added to form the 'enol' type species in situ Then fluoride is used to attack the α position of the compound to form the α - fluoroamide product, so as to realize the direct fluorination of the α - C-H bond (Figure 1D) (source: Nat Chem.) firstly, we used 1A as the reaction substrate and TBAF as the nucleophilic fluorine source to carry out the pre experiment (Table 1) α - fluoroamide 2a was obtained in 54% NMR yield Based on this, the author screened the fluorine source, alkali and oxidant, and finally determined that when tetrabutyl ammonium difluoro triphenylsilicate (tbat) was used as the fluorine source, the product 2A could be obtained in the highest yield (84%) (source: Nat Chem.) next, the author studied the substrate range of the reaction (Table 2), including the change of carbon chain and the substitution mode of amide nitrogen atom First of all, the reaction showed good functional group tolerance to C-chain amides, and olefinamide, alkynamide, ester amide, ketamide and so on could react smoothly and get corresponding products in good yield Then, the tertiary amides and unsymmetrical amides derived from pyrrolidine, azacyclobutane, piperidine, azazhuo, morpholine, diallylamine, all of which can react smoothly and get the corresponding products in 42% - 80% yield In order to prove the practicability of carboxyamide group of fluorinated products (Table 2), the author first carried out electrophilic activation and esterification of 2a to obtain α - fluorinated ester, and then selectively reduced the amide 2a to β - fluorinated alcohol 4 using lithium aluminum hydride and sodium borohydride Finally, n-heterocyclobutanamide 2K can be converted into α - fluorone 5 in good yield under the action of Meli and THF (source: Nat Chem.) in order to prove the effectiveness and practicability of the synthesis strategy, the author carried out nucleophilic fluorination of the antidepressant citalopram and the bactericide fluralin, and obtained fluorinated analogues of figure 2a, fluralin and fentanyl The biological activity of fluoro citalopram and its chiral isomers was tested The results show that f-citalopram retains SERT activity as a clinical target of citalopram with little difference in biological activity (Figure 2b), and its isomer (s, s) - 9 has the strongest activity (Figure 2C) due to the additional hydrogen bond interaction between the fluorine atom and the enzyme pocket Therefore, the introduction of fluorine atoms into drug molecules changes its metabolic stability and physical and chemical properties, but does not affect its biological activity (source: Nat Chem.) conclusion: the author developed a new synthesis strategy which depends on polarity reversal In this method, the nucleophilic enols are converted into electrophilic enols, and the nucleophilic fluorination reagents which are easy to obtain and commonly used are used for carbonyl α - fluorination This strategy has greatly expanded the scope of α - fluorination reaction, thus promoting the rapid development of nucleophilic fluorination reagents.