Azines and Azoles: CXXI. Alkylation of 5,7-Dihydro-4H-pyrano[2,3-d:6,5-d']- dipyrimidine-4,6(3H)-dione and Its 5-Phenyl Derivative

Methylation of 5,7-dihydro-4H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(3H)-dione and its 5-phenyl analog with dimethyl sulfate in the presence of LiOH in aqueous solution gives rise to the corresponding 3,7-dimethyl derivatives. The same isomers are formed by methylation of 5-phenyl-5,7-dihydro-4H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(3H)-dione with methyl iodide in the presence of K2CO3 in N,N-dimethylacetamide. However, with ethyl bromide, propyl iodide, or butyl bromide instead of methyl iodide, mixtures of 3,7- and 1,7-dialkyl-5-phenyl-5,7-dihydro-4H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6-diones were obtained.     

Azines and azoles: CXXVII. Glycosylation of 5,7-dihydro-4 H -pyrano-[2,3- d :6,5- d′ ]dipyrimidine-4,6(3 H )-dione and its 5-phenyl-substituted analog

Glycosylation of 5-phenylpyrano[2,3-d:6,5-d′]dipyrimidine-4,6-diones through the corresponding di-O-trimethylsilyl derivative with excess 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose gives a mixture of 3-mono-and 3,7-bis(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-5-phenylpyrano[2,3-d:6,5-d′]dipyrimidines; in the reaction with equimolar amounts of the reactants, only the monoriboside is formed. Isomeric N,N′-disubstituted pyranodipyrimidines, as well as mixtures of their mono-and disubstituted derivatives can be separated by fractional crystallization. The alkylation of pyrano[2,3-d:6,5-d′]dipyrimidine-4,6-dione and its 5-phenyl-substituted derivative with 2-oxabutane-1,4-diyl diacetate provides an efficient procedure for the synthesis of acyclic analogs of glycosides based on pyrano[2,3-d:6,5-d′]dipyrimidines. Original Russian Text ? E.V. Fedorova, V.V. Kvasha, E.P. Studentsov, A.V. Moskvin, B.A. Ivin, 2007, published in Zhurnal Obshchei Khimii, 2007, Vol. 77, No. 4, pp. 630–636. For communication CXXVI, see [1].     

Synthesis of some 3-alkenyl-4-oxo-6,7-dihydro-4H-pyrano[3,4-d]isoxazoles

A series of 3-alkenyl-4-oxo-6,7-dihydro-4H-pyrano[3,4-d]isoxazole derivatives was prepared by reaction of hydroxylamine with 4,5-dioxo-2,3,7,8-tetrahydro-4H,5H-pyrano[4,3-b]pyran derivatives.     

Condensed Pyridazines. Part I. Synthesis of 2-Oxo-2H-pyrano[2,3-D]-pyridazine and 2-Oxo-2H-pyrano[2,3-c] pyridazine

The reaction of 4,7-diehlorofuro[2,3-d]pyridazine (1) with potassium cyanide in DMSO gave two products, (E)-3,6-diehloro-5-(2-cyanovinyl)-4-hydroxypyridazine (II) and 5,8-dichloro-2-oxo-2H-pyrano[2,3-d]pyridazine (III) as a result of ring opening or ring expansion. A new ring system, 2-oxo-2H-pyrano[2,3-c]pyridazines (IX, XII, XIII) was obtained from 5,8-dichloro-3-methyl-2-oxo-2H-pyrano[2,3-d]pyridazine (VI).     

Synthesis of 8-methylpyrido[2,3-d:6,5-d'x]dipyrimidine-2,4,6(3H,10H,7H)-triones and their use in the oxidation of alcohols

A new-type pyridodipyrimide, 8-methylpyrido[2,3-d:6,5-d']dipyrimidine-2,4,6(3H,10H,7H)-triones were prepared by the condensation of 6-alkyl- or 6-aryl-amino-2-methylpyrimidin-4(3H)-ones with 2,4,6-trichloropyrimidine-5-carbaldehyde or 3-alkyl-6-chloro-5-formyluracils. The pyridodipyrimidines thus obtained oxidized alcohols under neutral conditions to yield the corresponding carbonyl compounds and a significant autorecycling in the oxidation was observed.     

One-step synthesis of substituted 2-amino-5,6,7,8-tetrahydro-4H-benzo[b]pyrans. Molecular and crystal structure of 2-amino-3-(2-methoxyethoxycarbonyl)-4-(2-nitrophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-benzo[b]pyran

Substituted 2-aminobenzo[b]pyrans were synthesized by three-component condensation of aromatic aldehydes, cyanoacetic acid derivatives, and cyclic 1,3-diketones. The molecular and crystal structure of 2-amino-3-(2-methoxyethoxycarbonyl)-4-(2-nitrophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-benzo[b]pyran was established by X-ray diffraction analysis.     

4-(3-Cyanopyridin-2-ylthio)acetoacetates in synthesis of heterocycles

Substituted 2-amino-4-aryl-3-cyano-5-oxo-5,6-dihydro-4H-pyrano[2,3-d]pyrido[3",2":4,5]thieno[3,2-b]pyridines were synthesized by the reactions of 4-hydroxy-1H-thieno[2,3-b;4,5-b]dipyridin-2-ones with arylidenemalononitriles or by the three-component reactions of hydroxythienodipyridinones with aldehydes and malononitrile in DMF in the presence of triethylamine. Methods for syntheses of substituted 3-alkoxycarbonyl-6-amino-4-aryl-2-(3-cyanopyridin-2-ylthiomethyl)-4H-pyrans were developed on the basis of the reactions of 4-(3-cyanopyridin-2-ylthio)acetoacetates and arylidenemalononitriles or aldehydes and malononitrile. Ethyl 4-(3-cyanopyridin-2-ylthio)acetoacetate and 4-methoxybenzylidenecyanothioacetamide were used for the synthesis of 6-(pyridin-2-ylthiomethyl)-3-cyanopyridine-2(1H)-thione.     

Synthesis of 5,8-dihydro-5-oxo-2-(3- or 4-pyridinyl)-pyrido[2,3-d]pyrimidine-6-carboxylic acids and the reinvestigation of the thermal cyclization of diethyl (2-hydroxy-4-pyrimidinyl)amino-methylenemalonate

Diethyl [2-(3- or 4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonates 5 prepared by the reaction between 2-(3- or 4-pyridinyl)-4-pyrimidinamines 3 and diethyl ethoxymethylenemalonate ( 4 ) were thermally cyclized to afford ethyl 5,8-dihydro-5-oxo-2-(3- or 4-pyridinyl)pyrido[2,3-d]pyrimidine-6-carboxylates 6 . The later were alkylated with ethyl iodide and then saponified to give 5,8-dihydro-8-ethyl-5-oxo-2-(3- or 4-pyridinyl)pyrido-[2,3-d]pyrimidine-6-carboxylic acids 2 . Thermal cyclization of diethyl (2-hydroxy-4-pyrimidinyl)amino-methylenemalonate ( 8 ) gave ethyl 1,6-dihydro-4,6-dioxo-4H-pyrimido[1,6-a]pyrimidine-3-carboxylate ( 10 ) instead of ethyl 5,8-dihydro-2-hydroxy-5-oxopyrido[2,3-d]pyrimidine-6-carboxylate ( 9 ) as previously claimed.     

One-step synthesis of 5-acetyl-2-amino-4-aryl-3-cyano-4H-pyrano[3,2-b]indoles. Molecular and crystal structure of 5-acetyl-2-amino-4-(4"-chloro-3"-nitrophenyl)-3-cyano-4H-pyrano[3,2-b]indole

A one-step procedure was developed for the synthesis of 5-acetyl-2-amino-4-aryl-3-cyano-4H-pyrano[3,2-b]indoles involving the three-component reaction of 1-acetylindol-3(2H)-one with aromatic aldehydes and malononitrile in ethanol in the presence of triethylamine as the catalyst. The structure of 5-acetyl-2-amino-4-(4"-chloro-3"-nitrophenyl)-3-cyano-4H-pyrano[3,2-b]indole was established by X-ray diffraction analysis.     

Synthesis and Spectral Characterization of Some New 4-(2,6-Diarylpyridin-4-yl)-2H-chromen-2-ones

Some new 4-(2,6-diarylpyridin-4-yl)-2H-chromen-2-one derivatives 5a–l have been synthesized by reacting 4-(3-oxo-3-arylprop-1-enyl)-2H-chromen-2-ones 3a–c with appropriate 1-(2-oxo-2-arylethyl)pyridinium bromide salt 4a–d in the presence of ammonium acetate in refluxing glacial acetic acid. The newly synthesized compounds have been characterized by elemental and spectral analysis.     

Isopropylidenemalononitrile in the synthesis of 2-amino-4,6,6-trimethylcyclohexa-2,4-diene-1,1,3-tricarbonitrile, 6-amino-2-(4-methoxybenzoylmethylsulfanyl)-4,4-dimethyl-1,4-dihydropyridine-3,5-dicarbonitrile, and fused 2-aminopyrans according to Michael

Michael reactions of isopropylidenemalononitrile with cyanothioacetamide (in the presence of 4-methoxyphenacyl bromide), cyclohexane-1,3-dione, and 4-hydroxycoumarin, gave 6-amino-2-(4-methoxy-benzoylmethylsulfanyl)-4,4-dimethyl-1,4-dihydropyridine-3,5-dicarbonitrile, 2-amino-4,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile, and 2-amino-4,4-dimethyl-5-oxo-4H,5H-pyrano[3,2-c]-chromene-3-carbonitrile, respectively. In the reaction of isopropylidenemalononitrile with cyanoacetamide, only dimerization product of the former, 2-amino-4,6,6-trimethylcyclohexa-2,4-diene-1,1,3-tricarbonitrile, was isolated. Its structure was proved by X-ray analysis.     

Condensed pyridazines. Part IV. Reductive cyclization of (Z)-methyl 3-(6-azido-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazin-5-yl)-2-rnethylacrylatc (I) to pyrido[2,3-c] pyridazines and the acid-catalysed cyclization of I to a pyrano[2,3-d] pyridazine

Reduction followed by cyclization of (Z)-methyl 3-(6-azido-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazin-5-yl)-2-methylacrylate (I) to pyrido[2,3-c]pyridazines by treatment with triethyl phosphite or hydrazine hydrate as the reducing agents is described. Compound I was also reductively cyclized with sodium borohydride. Treatment of I with concentrated sulfuric acid gave 8-chloro-3,6-dimethyl-2,5-dioxo-5,6-dihydro-2H-pyrano[2,3-d] pyridazine (VII) which also could be synthesized by another independent route. A mechanism for the cyclization is proposed.     

Synthesis of some 4-carboxy-3- and 5-(2-hydroxyalkyl)pyrazole lactone derivatives

The synthesis and biological activities of some 4-oxo-1-or-2-substituted 1H-or-2H-pyrano[4,3-c]pyrazole derivatives are described.     

Reaction of sulfene and dichloroketene with N,N-disubstituted 5-aminomethylene-1,5,6,7-tetrahydro-2-methyl-1-phenylindol-4-ones. Synthesis of 1,2-oxathiino[6,5-E] indole and of pyrano[2,3-e] indole derivatives

The 1,4-cycloaddition of sulfene to N,N-disubstituted 5-aminomethylene-1,5,6,7-tetrahydro-2-methyl-1-phenylindol-4-ones afforded N,N-disubstituted 3,4,5,6-tetrahydro-8-methyl-7-phenyl-7H-1,2-oxathiino[6,5-e]indol-4-amine 2,2-dioxides only in the case of aliphatic N-substitution. The 1,4-cycloaddition of dichloroketene occurred normally only in the case of 1,5,6,7-tetrahydro-2-methyl-1-phenyl-5-piperidinomethyleneindol-4-one to give 3,3-dichloro-3,4,5,6-tetrahydro-8-methyl-7-phenyl-4-piperidino-7H-pyrano[2,3-e]indol-4-one. Attempted recrystallisation, dehydro-chlorination or treatment with palladium on carbon of this adduct, as well as reaction of similar enaminoketones with dichloroketene, gave instead the same product, namely 3-chloro-8-methyl-7-phenyl-7H-pyrano[2,3-e]indol-4-one, as a result of dehydrochlorination, dehydrogenation and subsequent hydrogenolysis of the C-NR₂ bond in the primary adduct.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. XIII. Synthesis of 2H-pyrano[3,2-d]-1-benzoxepin derivatives

Cycloaddition of dichloroketone to N,N-disubstituted (E)-4-aminomethylene-3,4-dihydro-1-benzoxepin-5(2H)-ones gave N,N-disubstituted 4-amino-3,3-dichloro-3,4,5,6-tetrahydro-2H-pyrano[3,2-d]-1-benzoxepin-2-ones II, which are derivatives of the new heterocyclic system 2H-pyrano[3,2-d]-1-benzoxepin. Dehydrochlorination with triethylamine of II afforded N,N-disubstituted 4-amino-3-chloro-5,6-dihydro-2H-pyrano-[3,2-d]-1-benzoxepin-2-ones III in good to moderate yields. In the triethylamine treatment of IIh (NR₂ = diphenylamino), 3-chloro-5,6-dihydro-2H-pyrano[3,2-d]-1-benzoxepin-2-one was isolated in low yield near to IIIh, whereas IIc (NR² = diisopropylamino) gave in low yield 4-diisopropylamino-5,6-dihydro-2H-pyrano(3,2-d)-1-benzoxepin-2-one.     

Synthesis of Substituted 1,3-Cyclohexadienes,Pyridine-2(1H)-thiones,and Thieno[2,3-d]pyrimidine- 4(3H)-thiones by the Michael Reaction

Cyclopentylidene- and cyclohexylidene(cyano)acetamides reacted with malononitrile and cyano-(thioacetamide) according to the Michael pattern with exchange of the methylene components to give substituted 1-amino-2,6,6-tricyano-1,3-cyclohexadienes and thieno[2,3-d]pyrimidine-4(3H)-thiones. Condensation of cyclopentylidene- and cyclohexylidene(cyano)acetamide with 1,3-dicarbonyl compounds afforded 4,6-di-methyl-3-cyanopyridine-2(1H)-thione and morpholinium 4-methyl-6-oxo-3-cyano-1,6-dihydropyridine-2-thiolate which were converted into substituted 2-alkylsulfanylpyridines, thieno[2,3-b]pyridines, thiazolo[3,2-a]pyridine, and 2H-[1,3]thiazino[3,2-a]pyridine.     

The base-promoted dehydration of rac.-trans-tetrahydro-6-hydroxy-4-[(2-(dimethylamino)ethyl]-7-(4-methoxyphenyl)-1,4-thiazepin-5(2H)-one

The base-catalyzed alkylation of rac.-trans-tetrahydro-6-hydroxy-7-(4-methoxyphenyl)-1,4-thiazepin-5(2H)-one ( 1 ) with dimethylaminoethyl chloride in dimethyl sulfoxide provided predominantly rac.-trans-tetrahydro-6-hydroxy-4-[(2-dimethylamino)ethyl]-7-(4-methoxyphenyl)-1,4-thiazepin-5(2H)-one ( 2 ) and in addition, 2,3-dihydro-4-[2-(dimethylamino)-ethyl]-7-(4-methoxyphenyl)-1,4-thiazepin-5(4H)-one ( 3 ). A plausible mechanism is postulated for the dehydration of the rac.-trans-amide 2 .     

The synthesis of methyl 2-(benzyloxycarbonyl)amino-3-dimethylaminopropenoate. The synthesis of trisubstituted pyrroles, 3-amino-2H-pyran-2-ones,fused 2H-pyran-2-ones and 4H-pyridin-4-ones

Methyl 2-(benzyloxycarbonyl)aimno-3-dimemylaminopropenoate ( 2 ) was prepared from methyl N-(benzyloxycarbonyl)glycinate ( 1 ) and t-butoxybis(dimethylamino)methane, and used as a reagent for preparation of substituted 3-(benzyloxycarbonyl)amino-4H-quinolizin-4-ones 5 and 6 , ?2H-pyran-2-ones 17–19 , ?2H-1-benzopyran-2-ones 28–31 , and -naphthopyrans 32–35 , ?2H-pyrano[3,2-c]pyridine-2,5-dione 46 , -pyrano-[4,3-b]pyran-2,5-dione 47 , -pyrano[3,2-c]benzopyran-2,5-dione 48 , -pyrano[2,3-c]pyrazol-6-ones 49 and 50 , -pyrano[2,3-d]pyrirnidin-7-ones 51 and 52 derivatives. In the reaction of 2 with 1,3-diketones trisubsti tuted pyrroles 14–16 were formed. Selective removal of benzyloxycarbonyl group was achieved by cat alytic transfer hydrogenation with Pd/C in the presence of cyclohexene to afford free 3-amino compounds 7 , 8 , 20 , 36–38 and 53–57 in yields better than 80%.     

Synthesis and antimicrobial testing of 2-amino-6-hydroxymethyl-4-(3H)pyrido[3,2-d]pyrimidinone

Synthesis of 2-amino-6-hydroxymethyl-4-(3H)pyrido[3,2-d]pyrimidinone ( 5 ) from 2-amino-6-methyl-4-(3H)-pyrido[3,2-d]pyrimidinone ( 2 ) was accomplished by selenium dioxide oxidation of 2 to the aldehyde 4 followed by sodium borohydride reduction. Compound 2 was available in four steps from 5-aminouracil or in two steps from 5-nitroisocytosine ( 3a ). Catalytic reduction of 4 or 5 gave a mixture of 2-amino-6-methyl-5,6,7,8-tetrahydro-4-(3H)pyrido[3,2-d]pyrimidinone ( 6a ) and the 6-hydroxymethyl compound 6b . These compounds showed only weak inhibitory activity in the coupled reactions catalyzed by 7,8-dihydro-6-hydroxymethylpterin pyrophosphokinase and 7,8-dihydropteroate synthetase from E. Coli. No significant antibacterial activity was observed.     

Synthesis, reactions and antineoplastic activity of 3-(2-oxo-2H-chromen-3-yl)-2-oxo-2H,5H-pyrano[3,2-c]chromene derivatives

The key 3-(2-oxo-2H-chromen-3-yl)-2-oxo-2H,5H-pyrano[3,2-c]chromen-5-yl acetates 3 were synthesized in high yields by cyclocondensation of 4-oxo-4H-chromen-3-carbaldehydes 1 with coumarin-3-acetic acids 2 under mild conditions. The reaction pathway involves aldol condensation and subsequent intramolecular lactonization to afford 2-oxo-2H,5H-pyrano[3,2-c]chromene skeleton 3. Further treatment of acetates 3 with alcohols, water or nitrogen containing compounds led to 5-alkoxy-, 5-hydroxy- or 5-acylamino-2H,5H-pyrano[3,2-c]chromen-2-ones 4-6 via nucleophilic substitution of acetyloxy group at C-5. Acetates and hydroxyl derivatives 3 and 5 undergo facile rearrangement in an acid medium yielding 5-hydroxypyrano[2,3-b]chromen-2(10aH)-ones 7. Twelve prepared compounds were evaluated on their antineoplastic activities on 60 human tumour cell line panels in NCI USA. The obtained biological results confirmed that 3-(2-oxo-2H-chromen-3-yl)-2H,5H-pyrano[3,2-c]chromen-2-one represents a new leading skeleton suitable for further antitumour activity study.