The thesis is devoted to the development of photocatalytic methods for the (amino)alkyl functionalization of substituted pyrimidine-2(1H)-ones, the study of the photocyclization of 1-(2-(het)arylvinyl)-pyrimidine-2(1H)-ones to 4H-pyrimido[6,1-a]isoquinolin-4-ones and the study of the obtained heterocyclic compounds and their post-functionalization products as new inhibitors of poly(ADP-ribose)polymerases and fluorescent materials.
A novel regioselective direct hydroaminoalkylation of pyrimidine-2(1H)-ones at the C-6 position of the heterocycle was developed for accessing functional Biginelli-type pyrimidines. It was demonstrated that 10-(3,5-dimethoxyphenyl)-9-mesityl-1,3,6,8-tetramethoxyacridinium tetrafluoroborate is an effective organophotocatalyst for the redox-neutral hydroaminoalkylation by the aza-Giese reaction. This reaction, carried out with the corresponding aminoalkyltrifluoroborates under blue LED light irradiation, led to the formation of N-Boc-protected 4-aminoalkyl-3,4-dihydropyrimidin-2(1H)-one derivatives. The impact of substituents at the 4-, 5-, and 6-positions of the pyrimidine cycle, as well as the nature of the initial alkyl trifluoroborates, on the process of radical intermediate addition under photocatalytic conditions was examined.
A convenient general method for the selective alkyl derivatization of pyrimidine-2(1H)-ones via the Minisci organophotocatalytic reaction was proposed. This enables the synthesis of 4,6-disubstituted pyrimidone derivatives that were previously hardly accessible. The method is based on the interaction of starting 4-substituted pyrimidine-2(1H)-ones with secondary alkyl trifluoroborates under photoredox catalysis in the presence of a persulfuric acid salt as an oxidant and an acridinium organophotocatalyst. The optimal catalytic conditions were found which allowed the regiospecific radical CH-alkylation of the pyrimidone ring at position 6. The synthetic scope of the found transformation was investigated. The plausible mechanism of the Minisci photocatalytic reaction with pyrimidone substrates was proposed on the basis of the experimental data obtained.
An extension of the copper-catalytic approach to the N1-alkenylation of pyrimidine-2(1H)-ones and its optimization for the use of pinacol esters of styryl boronic acids instead of the corresponding boronic acids afforded previously not desribed N1-(2-(het)aryl)vinylpyrimidine-2(1H)-ones. They were employed as substrates for the investigation of photoinitiated cyclization in accordance with the Malory reaction scheme.
A novel approach to the synthesis of 2-trifluoromethyl substituted 4H-pyrimido[6,1-a]isoquinolin-4-one derivatives was proposed. This involves the photocyclization of N1-(2-(het)aryl)vinylpyrimidin-2(1H)-ones under blue light in the presence of air oxygen as an oxidant. In the model reaction, the optimal conditions for the isomerization of the starting trans-substrates into the corresponding cis-isomers with subsequent photocyclization were established. Furthermore, the impact of substituents in the styryl moiety on the reaction outcome was examined. It was demonstrated that N1-styryl substituted pyrimidones and their photocyclization products display fluorescent properties. The products obtained are promising for the further design of new fused heterocycles with valuable photophysical characteristics for material chemistry and novel organophotocatalysts design.
It was found that the endocyclic C=C bond of the obtained 6-aminomethyl-3,4-dihydropyrimidin-2(1H)-ones readily underwent catalytic stereoselective hydrogenation under hydrogen atmosphere, which gave rise to cis-4-trifluoromethyl-6-aminoalkyl-3,4,5,6-tetrahydropyrimidin-2(1H)-ones derivatively, valuable building blocks for medicinal chemistry.
The intramolecular cyclization of the aminomethylation products into promising N1-substituted 4-(fluoroalkyl)-3,6,7,7a-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-2,5-dions was studied. It was found that upon a week base treatment, aminomethyl-functionalized pyrimidines gave stable bicyclic aminals, ethyl-2,4,6-triazabicyclo[3.2.1]octane-8-carboxylates, whose structure was confirmed by X-ray diffraction study.
A novel approach to the synthesis of 3,6,7,7a-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-2,5-dione system was developed, which is based on readily available 2-(2-oxo-1,2,3,4-tetrahydropyrimidin-4-yl)acetic acid derivatives. The newly developed method proved effective for the preparation of both N1-alkyl- and N1-aryl-substituted 1H-pyrrolo[3,4-d]pyrimidin-2,5-diones.
The inhibitory activity of 3,6,7,7a-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-2,5-dione derivatives towards the poly(ADP-ribose)polymerase isoforms PARP-1 and PARP-2 was investigated using fluorometric and radiometric assays. The N1-aryl substituent was found to be crucial in achieving selectivity and high activity against PARP-2.
