Synthesis and physical chemical properties of CF3O-containg secondary amines—Perspective building blocks for drug discovery

• Published in: Journal of fluorine chemistry Vol. 257-258; pp. 109990 - 110005
• Main Authors: Logvinenko, Ivan G., Kondratov, Ivan S., Pridma, Stanislav O., Tolmachova, Nataliya A., Morev, Roman N., Dolovanyuk, Violetta G., Boretskyi, Andrii L., Stepaniuk, Roman O., Trofymchuk, Serhii A., Mück-Lichtenfeld, Christian, Daniliuc, Constantin G., Haufe, Günter
• Format: Journal Article
• Language: English
• Published: LAUSANNE Elsevier B.V 01.05.2022; Elsevier; Elsevier BV
• Subjects: Alcohols; Amines; Building blocks; Chemical properties; Chemical synthesis; Chemistry; Chemistry, Inorganic & Nuclear; Chemistry, Organic; Conformation; Fluorination; Gauche-conformation; Physical Sciences; Piperidine; Science & Technology; Trifluoromethoxy group; Amines; Gauche-conformation; Fluorination; Trifluoromethoxy group; Building blocks; DESIGN; PHARMACEUTICALS; SULFONAMIDES; DEPROTECTION; TRENDS; ALCOHOLS; TRIFLUOROMETHYL ETHERS; CHEMISTRY; ALPHA-FLUORINATED ETHERS; THIOETHERS
• ISSN: 0022-1139; 1873-3328
• DOI: 10.1016/j.jfluchem.2022.109990

•Ten CF3O-containing cyclic aliphatic secondary amines were prepared using different approaches.•Effect of CF3O group on physico-chemical properties of several aliphatic secondary amines was evaluated. The effect of CF3O-group on the acid/base properties and lipophilicity is rather complex and depends on the substitution position and the conformation of the molecules.•DFT calculations and X-ray data for one of the compounds (trifluoromethoxymethyl)piperidine) show a favored gauche-arrangement with regard to the amino group. Conformational and electronic effects of the trifluoromethoxy group make it attractive to be introduced in biorelevant structures. A mini-library of CF3O-substituted piperidines, pyrrolidines and azetidines was synthesized in 4-5 steps from commercial amino alcohols. Comparison of the measured pKa- and log D7.4 values of selected regioisomeric CF3O piperidines with the corresponding CF3- and MeO analogues shows that the effect on the acid/base properties and lipophilicity is rather complex and depends of the substitution position and the conformation of the molecules. For the most stable conformers of β-OCF3 compounds 2-(trifluoromethoxymethyl)piperidine (1c) and 3-trifloromethoxypiperidine (1e), DFT calculations and X-ray data (for 1c) show a favored gauche-arrangement with regard to the amino group. [Display omitted]