O. S. Ermakova

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.

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.

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.

Reaction of 5-Nitroso-6-Aminouracils with Glyoxylic Acid – A Simple Synthetic Pathway to Uric Acid Derivatives

Purines are commonly synthesized by the method proposed by Traube that is based on cyclization of 4,5-aminopyrimidines with urea, formamide, or formic acid [1]. The reaction of 4,5-aminopyrimidines with C2 cyclizing agents (glyoxal, glyoxylic acid derivatives, etc.) synthesized pteridine derivatives [1, 2]. Heating 5-nitroso-6-aminouracils with aldehydes formed 7-hydroxyxanthine derivatives [3]. Uric acid is the final product from oxidation (metabolism) of purines in living organisms. Its level characterizes the metabolic condition. Serious diseases can manifest if its in vivo content increases. Therefore, monitoring of the secretion level of uric-acid and its derivatives is especially significant [4]. Practically the whole set of natural purine bases or the nucleic acids incorporated into the structure or resulting from purine metabolism can be synthesized from uric acid [1]. The reactions of uracil amine derivatives with C2 cyclizing agents were investigated in order to develop simple and convenient synthetic pathways to purine and pteridine derivatives. An unusual transformation of 5-nitroso-6-aminouracils 1a and 1b during the reaction with glyoxylic acid was discovered during the work. Thus, brief heating of 1a and 1b and glyoxylic acid in formic acid formed smoothly and in high yield uric-acid derivatives 2a and 2b (Scheme 1).

Transformations of 6,7-difluoroquinoxaline with Indoles: Synthesis of Indole-Substituted 6,7-difluoroquinoxalines and Tris(indol-3-yl)methane Derivatives

6,7-Difluoroquinoxaline (1) reacted with 1- and 2-methylindoles (2a and 2b) with heating in AcOH to give products from substitution of H in the heterocyclic fragment (3a and 3b) and tris(indol-3-yl)methane derivatives (4a and 4b).

New reactions of benzocaine

Reaction of benzocaine with indane-1,3-dione-2-carbaldehyde afforded the corresponding azomethine. Ethoxymethylenemalonate reacted with benzocaine to form ethyl 4-{[2-(ethoxycarbonyl)-4-methoxy-3-oxobuten-1-yl]amino}benzoate, which was converted to the corresponding quinolone when heated to 185–190°C. Reactions of benzocaine with aliphatic aldehydes furnished 2,3-alkyl-substituted quinolines.

Features of quinoxaline reactions with C-nucleophiles: Examples of dimerization of heterocycle in course of hydrogen substitution

Reaction of quinoxaline or its 6,7-difluoroderivative with C-nucleophiles in nitrogen atmosphere afforded along with the products of hydrogen substitution in the heterocyclic ring the corresponding bisquinoxalines. An ESR signal of the cation-radical of the diprotic salt of quinoxaline was detected in the DMSO solution of quinoxaline and dimedone.