The thesis is devoted to the study of regio- and stereoselective transformations of acyclic trifluoromethylketimines and their heterocyclic analogues in reactions with a wide range of functional C-nucleophiles. As a result, original approaches have been developed, including asymmetric, for synthesizing chiral derivatives of α-trifluoromethyl α tertiary amines, e.g. β-aminoketones, β-amino acids and partially unsaturated pyrimidine systems, which are promising synthetic blocks and molecular scaffolds for application in medicinal chemistry. For the first time, an effective asymmetric organocatalytic method for obtaining enantiomerically enriched 4-amino-4-aryl-5,5,5-trifluoropentan-2-ones has been developed starting from N-unsubstituted aryltrifluoromethylketimines. Semi-empirical and ab initio calculations were carried out to explain the observed experimental enantioselectivity. Application of the obtained products in preparation of various optically active trifluoromethyl-containing heterocyclic systems was demonstrated.
A decarboxylation addition of malonic acid derivatives, cyanoacetic acid and β-keto acids to aryltrifluoromethylketimines and 4-trifluoromethylpyrimidin-2(1H)-ones has been investigated. Based on this approach, efficient methods for preparation of β fluoroalkyl-β-amino acids and their derivatives, as well as functionally substituted 4 trifluoromethyl-1,2-dihydropyrimidin-2-ones with a stereogenic carbon atom were developed. Synthetic application of β-aryl-β-trifluoromethyl-β-amino acids as multifunctional building blocks for the construction of promising heterocyclic derivatives such as 4-aryl-4-(trifluoromethyl)-1,3-oxazin-2-ones, 8-aryl-8-(trifluoromethyl)-5-oxa-9-azaspiro[3.5]nonanes, 2-aryl-2-(trifluoromethyl)azetidines and 3-(aryl)-3-(trifluoromethyl)-2,3-dihydro-1H-pyrrolizine-1-ones was shown.
A new cyclocondensation of readily available benzyl N-(1-chloro-2,2,2-trifluoroethylidene)carbamates with β-aminocrotonates gave rise to previously unknown esters of 4-trifluoromethyl-1,2-dihydropyrimidine-5-carboxylic acid. It was shown that the prepared products represent a convenient synthetic platform for preparation of trifluoromethyl-substituted 2-aminopyrimidine-5-carboxylates, 2-oxo-6- (dialkylamino)methyl-1,2-dihydropyrimidine-5-carboxylates, 1,2-dihydropyrimidine-5- carboxylic acids and 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates. As found, the Chan-Evans-Lam reaction of 1-unsubstituted 4-fluoroalkylpyrimidine-2(1H)-ones with boronic acids is a preparative method for the synthesis of previously unavailable N1-(het) aryl- and N1-alkenyl-4-fluoroalkylpyrimidine-2(1H)-ones.
It was shown that addition of C-nucleophilic reagents to the π-conjugated system of 4-trifluoromethylpyrimidin-2(1H)-one’s endocyclic C=N and C=C bonds occurs in accordance to the principles of classic kinetic and thermodynamic control and leads to regioisomeric tetrahydropyrimidines – adducts derived from 3,4-addition and adducts of conjugated 3,6-addition. The asymmetric organocatalytic reaction of 4 trifluoromethylpyrimidin-2(1H)-ones with acetone is an example of equilibrium system in which Michael products are reversibly formed under kinetic control conditions and are prone to intermolecular rearrangement to isomeric thermodynamically stable Mannich products. The latter were isolated in enantioenriched form (40-69% ee) using (S)-1-(2-pyrrolidinylmethyl)pyrrolidine as a chiral organocatalyst. In a further study, a stereoselective asymmetric synthesis of analogous regioisomeric nitromethyl-substituted 4 trifluoromethyl-3,4-dihydropyrimidin-2(1H)-ones has been developed by asymmetric bifunctional thiourea-catalyzed nitro-Mannich reaction with nitromethane. Nitromethane adducts were used for synthesis of isomeric pyrrolo[3,4-d]pyrimidine-2,5-dione derivatives by zinc reduction of the nitro group and subsequent cyclization of amine intermediates to the target products.
Regioselective hydrocyanation of 5,6-unsubstituted 4-trifluoromethylpyrimidin-2 (1H)-ones with trimethylsilylcyanide in organocatalytic conditions and subsequent conversion of isolated unstable carbonitriles into the corresponding stable methyl esters was proposed as a preparatively convenient approach for synthesizing previously unknown trifluoromethyl derivatives of 4,5-dihydroorotic acid analogues in racemic and enantiomerically pure forms. A new example of a rare dipolar orthogonal intramolecular C–F…C=O interaction between fluorine atom of the CF3 group and carbon atom of the ester group of methyl 2-oxo-6- (trifluoromethyl) hexahydropyrimidine-4-carboxylate was found in crystal state.
