The dissertation is devoted to study of β-alkoxyvinyl α-ketoesters (glyoxylates) as CCC bis-electrophiles in condensation reactions with classical binucleophiles, i.e. substituted aminoheterocycles (5-aminopyrazoles, 5-aminoisoxazoles, 5-amino[1,2,4]-triazoles and 6-aminouracils) as asymmetric NCN and NCC components, as well as amidines and guanidines as symmetric NCN binucleophiles. The heterocycization reactions of the simplest β-alkoxyvinyl α-ketoesters were studied, in particular, acyclic ethyl 4-ethoxt-2-oxobut-3-enoate and the corresponding α- or β-methylated analogues, as well as cyclic ethyl 2- (4,5-dihydrofuran-3-yl) -2-oxoacetate and ethyl 2- (3,4-dihydro-2H-pyran-5-yl) -2-oxoacetate.
Two optimized protocols for synthesis of series of pyrimidin-4-carboxylates were disclosed, which relied on a base-mediated condensation of amidines, S-methylthiuronium salt or guanidines in the presence of K2CO3 in MeCN or Et3N in 1,4-dioxane. It was found that the first method was efficient for the most reactive substrates – amidines as NCN components and methoxy-2-oxopent-3-enoate as CCC bis-electrophile (the highest reactivity towards this type of binucleophiles). Instead, the second approach was more expedient and provided improved synthesis of 2-substituted and 2,5-disubstituted pyrimidine-4-carboxylates as compared to using K2CO3.Moreover, synthetic transformations of pyrimidine-4-carboxylates were applied for the synthesis of building blocks, i.e. carboxylic acids, alcohols, aldehydes, chlorides and primary amines.
A regioselective approach towards the synthesis of functionalized pyrazolo
[1,5-a]pyrimidines and [1,2,4]triazolo[1,5-a]pyrimidines by reactions of acyclic β-alkoxyvinyl glyoxylates with N-unsubstituted 5-aminopyrazoles and triazoles was also developed. In all cases, heterocylization proceeded in chemo- and regioselective manner and provided exclusively azolopyrimidine-7-carboxylates. Regioselective condensation of a five-membered enone with NCN binucleophiles was found to be an efficient method for the synthesis of tricyclic fused pyrimidines with δ-lactone moiety. The formation of the six-membered lactone occurred due to the subsequent lactonization of ester and hydroxyethyl fragments of condensed pyrimidine, which was primarily formed upon condensation.
It was shown that the six-membered β-alkoxyvinyl α-ketoester reacted with NCN binucleophiles also regioselectively upon similar conditions, but lead to the corresponding bicyclic pyrimidinylpropyl alcohols. In contrast to the five-membered homologue, the formation of a seven-membered lactone after condensation was not observed an all cases.
Synthesis of fused pyridine α- and γ-carboxylates via heterocyclizations with heterocyclic NCC binucleophiles was demonstrated. It was found that regioselectivity of the condensation was very sensitive to even minimal changes in the structure of the starting materials. Reactions of β-alkoxyvinyl glyoxylates bearing no substituent in the β-position provided the corresponding α-isomers, or were either non-regioselective under non-optimized conditions. Ethyl 4-ethoxy-3-methyl-2-oxobut-3-enoate as a CCC bis-electrophile was less selective compared to the parent homologue in cases of performaing condensations in acetic acid. Optimization of reaction conditions included changing solvents and acidic additives. It was found that the condensation of aminopyrazoles and amino¬isoxazole proceeded regioselectively in refluxing HOAc or in the presence of HCl – 1,4-dioxane in EtOH. On the contrary, β-methyl-substituted derivative demonstrated an opposite regioselectivity, and the isomeric γ-isomers were isolated exclusively.
