Vol. 16 No. 1(61) (2018)
Published:
2018-03-14
Original Researches
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Domino-reactions of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide, hetarenecarbaldehydes and active methylene nitriles in the construction of new 2-amino-4H-pyrans and the study of their antimicrobial properties
Multicomponent domino reactions are an effective modern approach in the synthesis of different types of organic compounds, including biologically active pyrans.
Aim. To study the three-component interaction of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide with different hetarenecarbaldehydes and active methylene nitriles in order to synthesize new 2-amino-4H-pyran derivatives, as well as the antimicrobial activity of the compounds obtained.
Results and discussion. 2-Amino-4-heteryl-4,6-dihydropyrano[3,2-c][2,1]benzoxathiin-3-carbonitrile 5,5-dioxides were obtained by stepwise and multicomponent reactions of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide with hetarenecarbaldehydes and malononitrile. For the same interaction with ethyl cyanoacetate the reaction selectivity decreased and not only target ethyl 2-amino-4H-pyran-3-carboxylates were obtained, but also triethylammonium salts of bis(1,2-benzoxathiin-2,2-dioxo-4-ol-3-yl)(heteryl)methane. The latter were also purposefully synthesized by the two-component reaction of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide with hetarenecarbaldehydes in the presence of triethylamine. The compounds obtained revealed a higher antimicrobial activity against gram-positive bacteria and fungi compared to the reference drugs.
Experimental part. 3-Amino-4-heteryl-4,6-dihydropyrano[3,2-c][2,1]benzoxathiin-3-carbonitrile 5,5-dioxides and triethylammonium 3-[1-(4-hydroxy-2,2-dioxido-1,2-benzoxathiin-3-yl)heteryl]-1,2-benzoxathiin-4-olate 2,2-dioxides were synthesized. The antimicrobial activity of the compounds synthesized was studied by the agar diffusion method.
Conclusions. It has been proven that the multicomponent format for the three-component interaction of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide with hetarenecarbaldehydes and active methylene nitriles is more favorable and convenient than the stepwise approach to obtain new derivatives of 2-amino-4H-pyrans. Triethylammonium 3-[(4-hydroxy-2,2-dioxido-2,1-benzoxathiin-3-yl)heteryl]-2,1-benzoxathiin-5-olate 2,2-dioxides have been also synthesized. The antimicrobial properties of the compounds obtained are higher than in the reference drugs, especially against gram-positive bacteria and fungi. -
The proton-initiated cyclization of N-alkylamides of styrylacetic acids. The synthesis of 5-arylpirrolidine-2-ones
Aim. To study the effect of the structural parameters of styrylacetic acid amides on the course of the reaction of the electrophilic intramolecular cyclization under the action of polyphosphoric acid and search the rational approaches to obtain N-unsubstituted 5-arylpyrrolidine-2-ones.
Results and discussion. The literature sources related to the main methods of synthesis, as well as the biological activity of 5-arylpyrrolidine-2-ones, have been analyzed and systematized. The regiochemistry of the cyclization of N-unsubstituted and N-alkyl amides of styrylacetic acids has been studied using polyphosphoric acid (PPA).
Experimental part. It has been found that N-unsubstituted styrylacetic acid amides when heating at 100 °C in PPA are cyclized to 5-arylpyrrolidine-2-ones with the yields of 44-58 %. For N-tert-butylamides with donor substituents in the styrenic moiety of the molecule the cyclization under similar conditions is accompanied with elimination of the N-alkyl fragment resulting in N-unsubstituted 5-arylpyrrolidine-2-ones with the yields of 50-95 %. Lactamization of N-benzylamide and N-isopropylamides under the action of PPA proceeds with formation of 1-alkyl-5-arylpyrrolidine-2-ones.
Conclusions. It has been found that the proton-initiated cyclization of N-unsubstituted and N-tert-butylamides of styrylacetic acid with donor substituents in the styrene fragment in polyphosphoric acid when heating at 100 °C is a preparative convenient method for the synthesis of 1-unsubstituted 5-arylpyrrolidine-2-ones. A similar reaction of N-benzyl (isopropyl) amides leads to the preferential formation of 1-alkyl-5-arylpyrrolidine-2-ones. -
The synthesis of isoxazole-containing arylcyclopentenyl sulfones by the ring-closing metathesis reaction
The synthesis of new isoxazole-containing arylcyclopentenyl sulfones is presented by the ring-closing metathesis reaction (RCM).
Aim. To develop the preparative methods for the synthesis of new potential biologically active 3-aryl-5-[1-(aryl-4-sulfonyl)-cyclopent-3-enyl]isoxazoles obtained by RCM.
Results and discussion. A number of new sulfones with an active methylene group was obtained by the interaction of bromo derivatives of isoxazoles with sodium salts of sulfinic acids. By alkylation of the active methylene group with allyl bromide a number of new diallyl derivatives was synthesized. The target isoxazolecontaining arylcyclopentenyl sulfones were synthesized from the diallyl derivatives obtained using the ruthenium-carbene catalyst.
Experimental part. The synthesis of the starting and target compounds was performed under classical preparative conditions; the methods of column chromatography; elemental analysis; LCMS; 1H and 13C NMRspectroscopy were used.
Conclusions. The synthetic sequence for preparation of new isooxazole-containing aryl cyclopentenyl sulfones has been developed using RCM at the final stage. -
The synthesis of a tricyclic system with the 7-deazaadenine nucleus
Aim. To develop new convenient approaches to the synthesis of new tricyclic compounds with the 7-deazaadenine nucleus as promising synthons for the search of biologically active compounds.
Results and discussion. A new simple approach to the synthesis of 4-amino substituted pyrrolo[2,3-d]pyrimidine-6-carboxylic acids was found. A tricyclic derivative of 7-deazadenine was obtained by the intramolecular cyclization of methyl 7-oxiranylmethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate.
Experimental part. Treatment of 4-methoxypyrrolo[2,3-d]pyrimidine with ammonium acetate while heating leads to 4-aminopyrolo[2,3-d]pyrimidine-6-carboxylic acid. This acid reacts with iodine in acetic acid producing 8-iodomethylpyrimido[5’,4’:4,5]pyrrolo[2,1-c][1,4]oxazine with a high yield. Treatment of oxazine with sodium methylate gives 7-(oxiran-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate; when it is heated with triethylamine hydrochloride in acetonitrile, 10-amino-5,6-dihydro-4H-1-deazapyrimido[1,2,3-cd]purine-2-carboxylate previously unknown is obtained. The structure and composition of the substances obtained were confirmed by NMR-spectroscopy, chromatography mass-spectrometry and elemental analysis.
Conclusions. A new convenient approach to the synthesis of 10-amino-5,6-dihydro-4H-1-deazapyrimido[1,2,3-cd]purine-2-carboxylate has been developed. This compound is a tricyclic system with the 7-deazaadenine nucleus. Its further modification may produce potential biologically active substances. -
The study of the three-component interaction between isatin, α-amino acids and N,N’-di(3-carboxypropenoyl)-1,2-ethylenediamine and determination of the structure of the compounds obtained
Aim. To develop the preparative methods for obtaining new series of biologically active substances by the three-component interaction between isatin, α-amino acids and N,N’-di(3-carboxypropenoyl)-1,2-ethylenediamine and determine the structure of the compounds obtained.
Results and discussion. Using the three-component cascade transformation of isatin with α-amino acids and N,N’-di(3-carboxypropenoyl)-1,2-ethylenediamine a series of new derivatives of ethylene-N,N’-bis(spiroindole- 3,3’-pyrrolo[3,4-c]pyrrole-2a’,5a’-dihydro-2,2’,6’(1H,1’H,5’H)-trione) was synthesized. It was found that as a result of N,N’-di(3-carboxypropenoyl)-1,2-ethylenediamine cyclization in the course of the reaction the derivatives of N,N’-ethan-1,2-diyl-bis-spiro-2-oxidol[3,2’]-3’H,4’H,5’H-pyrrolo-4’-carboxy-3’-carboxamide were not formed. Instead of the expected hypothetical structures the derivatives of ethylene-N,N’-bis(spiroindole-3,3’-pyrrolo[3,4- c]pyrrole-2a’,5a’-dihydro-2,2’,6’(1H,1’H,5’H)-trione) were selected. The structure of the compounds synthesized was reliably proven by the instrumental methods (1H NMR, IR-spectroscopy), as well as counter synthesis.
Experimental part. The synthesis of compounds was performed using the three-component condensation in the alcoholic-aqueous medium and instrumental methods for determining the structure of organic compounds.
Conclusions. The reaction of the three-component interaction between isatin, α-amino acids and N,N’- di(3-carboxypropenoyl)-1,2-ethylenediamine has been studied. It has been proven that the preparatory method for the three-component cascade transformation of isatin with α-amino acids and ethylenebismaleinimide is an effective method for the synthesis of ethylene-N,N’-bis(spiroindole-3,3’-pyrrolo[3,4-c]pyrrole-2a’,5a’-dihydro-2,2’,6’(1H,1’H,5’H)-triones). The structure of the compounds obtained has been proven. -
The study of the interaction of 4,6-dichloropyrimidine-5-carbaldehyde with glycine esters
Aim. To study the interaction of 4,6-dichloropyrimidine-5-carbaldehyde with methyl- and with tert-butylglycinate depending on the reaction conditions.
Results and discussion. It has been found that the reaction of 4,6-dichloro-5-formylpyrimidine with hydrochlorides of glycine esters in the presence of triethylamine leads to obtaining derivatives of N-(5-formylpyrimidin-4-yl)glycinate and cyclization products: pyrrolo[2,3-d]pyrimidine and pyrido[2,3-d]pyrimidine.
Experimental part. The interaction of 4,6-dichloropyrimidine-5-carbaldehyde with methyl or tert-butyl glycinate in methanol in the presence of triethylamine depending on the molar ratio gives the mixture of 5-hydroxy-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine and 6-amino-4-chloro-7-oxopyrido[2,3-d]pyrimidine-8(7H)-yl)acetate.
The composition and structure of the compounds synthesized have been confirmed by NMR-spectroscopy, chromatography mass-spectrometry and elemental analysis.
Conclusions. The previously unknown derivatives of pyrrolo[2,3-d]pyrimidine and pyrido[2,3-d]pyrimidine have been obtained as a result of the interaction of 4,6-dichloro-5-formylpyrimidine with methyl and tert-butylglycinate.
The reaction features depending on the reactants ratio have been studied. The prospects for the synthesis of potential biologically active compounds from 6-amino-4-chloro-7-oxopyrido[2,3-d]pyrimidine-8(7H)-yl)acetate have been described. -
The molecular design of biologically active derivatives of N-phenylanthranilic acid
Most QSAR methods are based on determination of dependence of different types of biological activity of compounds on their physicochemical parameters, which determination is experimentally quite difficult, while those compounds that are calculated theoretically often have systematic deviations.
Aim. To determine the increments of substituents in isostructural series of hydrazides and thiosemicarbazides of substituted N-phenylanthranilic acids for their anti-inflammatory activity by the empirical method on the de nova model.
Results and discussion. The study was conducted for 18 thiosemicarbazide (batch 1) and 15 hydrazides (batch 2) of substituted N-phenylanthranilic acid. The increments calculated show that introduction of substituents in the anthranilic moiety of the thiosemicarbazide molecule increases the anti-inflammatory activity. The increments of substituents in the non-anthranilic fragment of the molecule have different signs and values, depending on the nature and position of the radical. Introduction of substituents (Cl-, NO2-) into the para-position of the anthranilic fragment of the molecule of N-phenylantranilic acid hydrazide increases the anti-inflammatory activity, while introduction of various substituents into the non-anthranilic fragment of the molecule causes both an increase and a decrease in lg P.
Experimental part. The study of the anti-inflammatory activity was performed on the “formalin edema” model in rats using the oncometric method. The substances were administered orally in the form of a fine suspension stabilized by the emulsifier Tween-80 in the doses of 50 mg/kg of the animal body weight. The reference drug indomethacin was administered in the dose of 50 mg/kg.
Conclusions. The increments of substituents in isostructural series of hydrazides and thiosemicarbazides of substituted N-phenylanthranilic acids have been determined by the empirical method. The dependence of the increments on the nature and position of substituents in molecules has been analyzed.
