Yu. A. Azev

New Opportunities for the Synthesis of Quinoxaline-Substituted Heterocyclic and Aryl Moieties

6.7-Difluoroquinoxaline (I) reacted with dimedone, indandione, and 3-methyl-1-phenylpyrazol-5-one in DMSO solution in the presence of acid to form mono-substituted products IIa – c. Heating I with resorcinol in EtOH in the presence of acid gave resorcinol derivative IId. 6.7-Difluoroquinoxaline in the presence of base reacted with 3-methyl-1-phenylmethylpyrazol-5-one to form dipyrazolylmethane III and tetrapyrazolylethane derivative IV. Heating products IIa – c with N-methylpiperazine produced 7-methylpiperazine derivatives Va – c of 2-substituted quinoxalines.

Nucleophilic substitution in 2-nitro-3-halopyridines

Nucleophilic substitution occurs in the 2 or 3 position in 2-nitro-3-halopyridines depending on the nature of the halogen and the substituting agent. A series of new 2,3-substituted pyridines were obtained as a result of the reactions.

A simple means of preparing quinoxaline derivatives: direct introduction of C-nucleophiles into the quinoxaline nucleus by substituting a hydrogen atom

Unsubstituted quinoxaline (I) reacts with dimedone, indanedione, and 1-phenyl-3-methylpyrazol-5-one in dimethylsulfoxide in the presence of acid to form monosubstitution products II – IV. Quinoxaline reacts with 1,3-dimethylbarbituric acid in dimethylsulfoxide solution at room temperature to form monosubstitution product V without external catalysis. Heating of I with resorcinol in ethanol in the presence of acid produced resorcinol derivative VI. In the presence of base, quinoxaline reacts with 1-phenyl-3-methylpyrazol-5-one to form dipyrazolylmethane VII and tetrapyrazolylethane derivative VIII. Compound VIII undergoes cleavage to form dipyrazolylmethane VII in dimethylformamide solution with boiling or in the presence of iodine at room temperature.

Products of Interaction of Fervenulin-3-one-4-oxide with o-Phenylenediamines

Pyrimidotriazine antibiotics were reported to exhibit a broad spectrum of pharmacological activity [1 – 3]. For example, reumycin – a representative of this series of compounds – is used as an antitumor drug [4]. As is known, fervenul-3-one smoothly reacts with various C-nucleophilic compounds with the formation of addition products with respect to the C4a node atom of the pyrimidotriazine nucleus [5]. At the same time, the synthesis of new analogs of these compounds is hindered because of low availability of fervenul-3-one. Recently, one of the authors described fervenul-3-one-4-N-oxide and proposed a simple method for the synthesis of this compound from more available fervenulin-4-oxide [6]. Below we will demonstrate that fervenul-3-one-4-oxide (I) interacts with o-phenylenediamines (IIa, IIb) with the formation of known diaminophenyl derivatives IIIa and IIIb [5]. It is interesting to note that 4-chloro-, 4,5-dimethyl-, and 3,6-dimethoxyphenylenediamines (IIc – IIe) do not attach to the pyrimidotriazine nucleus and the reaction terminates by the formation of a colorless adduct with ethanol (IV). Heating compound IV may lead to detachment of the ethanol fragment with the formation of fervenulone V. Recrystallization of compound V from ethanol again leads to the formation of adduct IV. The H and C NMR spectra of compounds IIIa and IIIb were described in [5]. The H NMR spectra indicate that protons of the 2-NH and 4-NH groups exhibit a spin – spin coupling characterized by J2,4 = 1.9 Hz. The chemical shift and the character of splitting of the signals corresponding to these protons were affected neither by increasing temperature of the solution nor by adding deuterated solvents. An important diagnostic feature of the 4a-substituted fervenulone derivatives is the presence of a tetrahedral node occupied by a carbon atom, the signal of which is observed at ~ 60 ppm in the C NMR spectrum. IIa: R = R = R = R = H; IIb: R = CH3, R 2 = R = R = H; IIc: R = R = R = H, R = Cl; IId: R = R = H, R = R = CH3; IIe: R = R = OCH3, R 2 = R = H.

Synthesis and antiinflammatory activity of derivatives of pyrimido [1,2,4]triazine and of the methylamide of 5-methylamino-1,2,4-triazine-6-carboxylic acid

Among the 3-subst i tuted pyrimido[4, 5-e] [1,2,4]triaz ine-6, 8-diones that we have synthesized, compounds have been detected which possess an ant i inf lammatory activity [1]. Inv iewof this, to elucidate the link between s t ruc ture and ant i inf lammatory activity it appeared desi rable to obtain new derivat ives of this class. At the same time, to asce r ta in the role of the annellated pyridine ring it was of in teres t to study the biological p rope r t ies of 3-subst i tuted der ivat ives of the methylamide of 5 -methy laminol ,2 ,4 t r i az ine -6 -ca rboxy l i c acid, all the more since some compounds of this se r i e s are readi ly obtained by the hydrolyt ic cleavage of the corresponding pyrimido[4,5-e] [1,2,4]triazines [2].

Synthesis and study of the covalent solvation of 6-nitroazalopyrimidines

The corresponding 6-nitroazolo[1,5-a]pyrimidines were obtained by the reaction of the sodium salt of nitromalondialdehyde with 3(5)-aminotriazoles and 3(5)-aminopyrazoles. The covalent solvation of the synthesized compounds was investigated by PMR spectroscopy.

Synthesis and some pharmacological properties of isofervenulin derivatives

Previously, derivatives of isofervenulin were obtained by nucleophilic substitution of a 3-alkylthio group in 5,6,7,8-tetrahydropyrimido[4,5-e]l,2,4-triazine-6,8-diones (Ia-c) by amine residues on extended heating of the reagents [3]. However, the possibilities of this method are limited as a result of the low reactivity of the alkylthio group. Furthermore, as a result of the use of drastic conditions destruction of the pyrimidine ring 6ccurs in certain cases in addition to replacement of the alkylthio group [3].

Synthesis of fluoroquinoxalin-2(1H)-one derivatives containing substituents in the pyrazine and benzene fragments

Abstract6,7-Difluoroquinoxalin-2-one reacted with indoles, 5,5-dimethylcyclohexane-1,3-dione, 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one, resorcinol, and pyrogallol on heating in acetic acid to give products of hydrogen substitution in the heterocyclic fragment. Heating of 6,7-difluoro-3-(1H-indol-3-yl)quinoxalin-2(1H)-ones with N-methylpiperazine gave the corresponding 7-(4-methylpiperazin-1-yl) derivatives.

New Synthetic Potential of Pteridine Derivatives: Direct Substitution of H in 1,3-Dimethyllumazine During Reaction with C-Nucleophiles

The pteridine core is a heterocyclic scaffold for a large series of significant natural and synthetic biologically active compounds. Many natural pteridines are involved in cellular metabolism. Therefore, the regioselective synthesis of new pteridine derivatives with potential biological activity is exceedingly crucial [1]. Use of SN H-functionalization of C–H bonds via direct substitution of H by C-nucleophiles and production of products with C–C bonds was promising during development of effective synthetic methods for natural and synthetic biologically active heterocyclic compounds [2, 3]. Chichibabin substitution of H in unsubstituted 1,3-dimethyllumazine was reported for the reaction with alkylamines in the presence of oxidizers to give 7-substituted 1,3-dimethyl-2,4-dioxopyrimido-[4,5-b]pyrazine derivatives [4]. The C-6 atom of 1,3-dimethyllumazine was alkoxylated regioselectively during the reaction with N-bromosuccinimide in alcohols [5]. Examples of direct functionalization of C–H bonds using C-nucleophiles are unknown for 1,3-dimethyllumazine. The goals of the present work were to investigate the specifics and features of direct H substitution in reactions of 1,3-dimethyllumazine with C-nucleophiles, to study ways of activating the substrate and reagents, and to determine the points of nucleophilic attack.

Reactions of quinazoline and its 4-oxo- and 4-chloro-substituted derivatives with nucleophiles

Reaction of quinazoline (I) with 2-methylindole, pyrogallol, and 1-phenyl-3-methylpyrazol-5-one in the presence of acid led to the formation of C-4 adducts II, III, and V. Adduct IV was obtained by heating I with 1,3-dimethylbarbituric acid without acid catalysis. 1-Phenyl-3-methylpyrazol-5-one reacts with I without acid catalysis with the formation of dipyrazolylmethane VI. 4-Chloroquinazoline VIII reacts with 1-phenyl-3-methylpyrazol-5-one to yield 4-(1-phenyl-3-methyl-5-oxopyrazol-4-yl)quinazoline IX and dipyrazolylmethane VI. Heating VIII with 2-methylindole leads to formation of 4-(2-methylindol-3-yl)quinazoline X and tris(2-methylindol-3-yl)methane XI. The proposed structures were confirmed by NMR spectral data.