Science | Prof. Yifeng Wang's team at CUHK develops a new way to prepare fluorinated organic compounds

Research background

Fluorine, known as "asmall atom with a bigego", is the most electronegative element in the periodic table, and at the same time, fluorine atoms have a small atomic radius, so fluorine-containing organic compounds have many special properties. A large amount of literature shows that the introduction of fluorine atoms or fluorine-substituted molecular blocks in organic molecules often causes changes in their physical and chemical properties as well as their pharmacological and physiological activities. For example, the introduction of fluorine atoms into active small molecules can improve the cell membrane permeability, metabolic stability and bioavailability of the molecules, which makes the roles of fluorine-containing compounds in the fields of pharmaceuticals, pesticides, and functional materials of great concern. However, despite the abundance of fluorine in the earth's crust (also the most abundant halogen), there are few naturally occurring organic fluorides, so how to efficiently introduce fluorine into organic compounds has become one of the current hotspots of research in organic synthesis.

So far, a large number of synthetic methods have been reported for organic fluorides, mainly including direct fluorination and fluorinated block method, of which, the direct fluorination method using fluorinated reagents has been widely used in the synthesis of fluorinated blocks and fluorinated pharmaceutical molecules, while the development of the fluorinated block method is more limited due to the narrow source of fluorinated raw materials. Trifluoromethyl compounds are simple to prepare and have many synthetic methods, as early as 2017, König et al. reported the preparation of difluorinated organic compounds by selectively breaking the C(sp3)-F bond with trifluoromethyl compounds as feedstock (Fig. 2), and then the preparation of mono- and difluorinated compounds with trifluoromethyl compounds as feedstock has been reported one after another, however, the selective breakage of one or both of the C-F bonds in trifluoromethyls activation and the use of cheaper and more readily available trifluoroacetic acid derivatives as feedstock, thus developing more efficient and economical synthetic methods for organofluorides, is obviously of greater importance.

Research

Since the bond energy of the C-F bond decreases with the progress of the defluorination reaction, when the first C-F bond is broken, the second and the third C-F bonds are more easily activated, thus making the chemoselectivity of the defluorination process difficult to control. Inspired by the SCS (spin-centershift) pathway in DNA biosynthesis (Figure 3-B), Prof. Yifeng Wang's team applied it to the C-F bond breaking of trifluoroacetic acid derivatives, and took advantage of the difference in the reactivity of 4-dimethylaminopyridinyl-boron radical with trifluoro, difluoro and monofluoroacyl compounds to successfully develop stepwise controllable defluorination functionalization reaction (Figure 3)

Based on the designed reaction strategy, the researchers examined the substrates for mono- and difluorination reactions, respectively (Figure 4). Substitution of either electron-donating or electron-absorbing groups on the aromatic ring of the aromatic amine portion of the reaction substrate could efficiently obtain mono- and difluorinated products, respectively, under the corresponding reaction conditions, and fluorine or trifluoromethyl groups on the aromatic ring were well compatible with the reaction (Fig. 4,2d-2e,3d-3e), and other functionalized substituents, such as acetals, amines, double bonds, and ester groups, could also successfully obtain the target products; when the amine portion of the substrate was aliphatic amine, a product with one C-F bond broken could be obtained successfully, but a product with both C-F bonds broken could not be detected (Figs. 4,2s and 3s); moreover, similar results were obtained when the reaction substrate was an ester substituted with a steroid (Figs. 4,2u and 3u).

Subsequently, according to the designed reaction pathway, the researchers added olefins as another substrate in the reaction system, which was used to capture the radical intermediates generated by the substrate after breaking one C-F bond, and finally successfully realized the coupling reaction between the difluorinated intermediates and olefins, obtaining a series of chained difluorinated organic compounds (Figure 5). In general, when the fluorine-containing substrate is an amide derivative, the olefin can be an aromatic olefin with different substitutions on the aromatic ring, such as mono- or di-substituted (Figure 5-5h,5i); some alkenyl ethers, aliphatic olefins and extra-cyclic double bonding, etc., can be reacted to obtain the corresponding coupling products successfully (Figure 5-5j-5p). When the fluorine-containing substrate is an ester, some heteroaromatic ring-substituted olefins, methoxystyrene and aminostyrene can be compatible with the reaction (Figure 5-C). In addition, when the substrates were some long-chained olefins, or the olefinic substrates contained natural product structures such as steroids, or the fluorinated substrates contained long-chained structures, terpenes, or steroids, the reactions were able to take place smoothly (Fig. 5-D), which reflects the great value of this method in the synthesis of fluorinated active molecules.

The authors also performed simple derivatization of the product, such as complete reduction of the C=O bond on the amide in the product (Figure 6-A), or reduction and conversion of the ester bond in the substrate to a ketone or an amine, etc. (Figure 6-B).

Course of a reaction

The spin-center transfer reaction process shears one C-F bond in trifluoromethyl for the first time, allowing the carbon atom and the functional group (represented by a square) to bond, producing difluoride; the spin-center transfer reaction process shears one C-F bond in the product difluoride for the second time, allowing the other functional group (represented by a triangle) to bond with the carbon atom, producing monofluoride.