JACS: Silver catalyzed deacidification and trifluoromethylation of aliphatic carboxylic acids

Trifluoromethyl (CF3) is a very important fluorine-containing group Its van der Waals radius (2.7 Å), van der Waals volume (42.6 Å), electronegativity (χ = 3.5) [Y1], is a strong lipophilic group (π = 0.88) The introduction of trifluoromethyl into organic molecules will change the physical, chemical properties and physiological activities of the compounds, mainly due to the electronic and spatial effects of trifluoromethyl Because of the special properties of trifluoromethyl, the introduction of one or more trifluoromethyl into organic molecules can change the size, acidity, even polar distance, lipophilicity, chemical and metabolic stability of parent molecules Trifluoromethyl compounds have been widely used in various fields, such as pharmaceutical chemistry, pesticide chemistry, material chemistry and so on In drug research and development, trifluoromethyl can be introduced to regulate pKa, lipophilicity, conformation, stability and binding ability with protein of drug molecules, so as to modify and modify drug molecules At present, several drugs on the market contain one or more trifluoromethyl, such as Prozac, Arava and Lariam Figure 1: several common molecular sources of trifluoromethyl containing drugs: 10.1021/jacs.7b07944 in nature, the fluorine element mainly exists in the form of inorganic substances, and the natural fluorine-containing organic compounds are especially rare At present, all trifluoromethyl compounds are obtained by artificial synthesis Therefore, the development of new reagents and methods for trifluoromethylation is of great significance Recently, Li Chaozhong, a researcher of Shanghai organic Research Institute, developed a new method of introducing trifluoromethyl The silver catalyzed decarboxylation and trifluoromethylation of aliphatic carboxylic acids (DOI: 10.1021 / JACS 7b07944) was realized with cheap and easily available carboxylic acids as the starting substrate Carboxylic acid, as a cheap and easily available industrial raw material, has been widely used in organic synthesis However, there are few studies on decarboxylation and trifluoromethylation One is indirect method: using SF 4, phsf 3, deoxo fluor, BRF 3 and other nucleophilic fluorination reagents to convert carboxyl group into trifluoromethyl group, but the reaction condition of this method is intense, the functional group compatibility is poor, and the substrate range is narrow; the other is direct method: using trifluoromethyl free radical to decarboxytrifluoromethylize sp2-c or SP-C carboxylic acid Figure 2: related research sources of decarboxylation and trifluoromethylation: the decarboxylation and release of alkyl radicals catalyzed by 10.1021/jacs.7b07944 silver has been quite mature (such as Minisci reaction) In the previous research work, the author used et 3 SIH / K 2S 2O 8 to trigger the release of alkyl radicals from bromoalkanes, (bpy) Cu (CF 3) 3 As a free radical receptor, trifluoromethylation (10.1021 / JACS 7b06044) was realized for the first time In continuation of the previous work, the decarboxylation of aliphatic carboxylic acids was carried out at 40 ℃ using (bpy) Cu (CF 3) 3 as trifluoromethyl source, znme 2 as reducing agent, AgNO 3 / K 2S 2O 8 as free radical initiator and CH 3CN / H 2O as mixed solvent, with high yield and wide substrate range In this paper, 1 - [(4-TOLYL) sulfonyl] - 4-piperidic acid was used as the template substrate The key of the reaction is the selection of the additive (reducing agent) No target product was obtained by adding NaBH 4, phsih 3 or et 3sih in the reaction system When znme 2 was used as the additive, the target product was obtained, the yield was 54%, and ZnEt 2 had similar effect After a series of reagent ratio and temperature adjustment, the optimal reaction conditions were determined At 40 ℃, bpy Cu (CF 3) 3 (4 equiv) / znme 2 (3 equiv) was used as the source of trifluoromethyl, AgNO 3 (30 mol%) / K 2S 2O 8 (4 equiv) was used as the initiator of free radical, and the yield of AgNO 3 and K 2S 2O 8 were 93% The control experiments showed that AgNO 3 and K 2S 2O 8 were necessary for the reaction Figure 3: source of condition optimization: 10.1021/jacs.7b07944 After determining the optimal reaction conditions, the author has expanded the substrate, which has a wide range of reaction substrates, good functional group compatibility, good yield for all kinds of aliphatic carboxylic acids containing alkyl or aryl group, all kinds of electron deficient or electron rich carboxylic acids, and can also be used for decarboxylation and trifluoromethylation of complex molecules, with good yield Figure 4: substrate expansion conditions: A-1 or A-2 (0.2 mmol), (bpy) Cu (CF 3) 3 (0.8 mmol), znme 2 (0.6 mmol), AgNO 3 (0.06 mmol), K 2S 2O 8 (0.8 mmol), MeCN (12 ml), H 2O (2 ml), 40 ° C, 10 h source: 10.1021/jacs.7b07944 the author determined the formation of alkyl radicals by ring closing experiment, separated and determined the single crystal structure of bu4ncu (CF3) 3me, and finally put forward the appropriate reaction mechanism Figure 5: possible reaction mechanism source: 10.1021/jacs.7b0794 4 Summary: the author has developed a method of decarboxylation and trifluoromethylation of aliphatic carboxylic acid, which uses carboxylic acid as free radical donor, (bpy) Cu (CF 3) 3 As a free radical receptor, the reaction conditions are mild, the yield is high, the functional group compatibility is good, and the raw materials are widely available, which provides a new way to introduce trifluoromethyl into organic molecules Paper link: http://pubs.acs.org/doi/abs/10.1021% 2fjacs.7b07944