Synthesis of novel purinyl-1'-homocarbanucleosides based on a cyclopenta[b]pyrazine system

cis-2,3-Diphenyl-6,7-dihydro-5H-cyclopenta[b]pyrazine-5,7-dimethanol, prepared by Diels-Alder reaction from cyclopentadiene and appropriately protected 2-imidazolone--followed by dihydroxylation, glycol protection, diamine deprotection, condensation with benzyl, glycol deprotection, oxidative cleavage and reduction--, was used to synthesize (+/-)-cis-([7-(6-chloro-9H-purin-9-yl)methyl]-2,3-diphenyl-6,7-dihydro-5H-cyclopenta[b]pyrazin-5-yl)methanol, a key intermediate for novel 1'-homocarbanucleosides based on a cyclopenta[b]pyrazine scaffold as shown by its conversion into several 6-substituted purinyl derivatives.     

Polycyclic N-hetero compounds. XXXV. Syntheses and anti-platelet aggregation activity of 5,6-Dihydro-4H-benzo[3,4]cyclohept[1,2-e]imidazo[1,2-c]pyrimidines with an oxygen function at the 1-position

Various 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d][pyrimidines bearing amino acid group at the 4-position of the skeleton were synthesized by the reaction of 4-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]-pyrimidine with some amino acid, which were cyclized to 5,6-dihydro-4H-benzo[3,4]cyclohept[1,2-e]imidazo-[1,2-c]pyrimidines, corresponding to B-homo-11,13,15-triazasteroids. Their inhibitory activities against platelet aggregation induced by collagen were also investigated.     

Synthesis and properties of substituted 2-methylene-hydrazono-2,3-dihydro-3-benzo[<Emphasis Type="Italic">b</Emphasis>]furanones

The reaction of 2,3-dihydro-2,3-benzo[b]furandione with the triphenylphosphazines of diazo compounds leads to substituted 2-methylenehydrazono-2,3-dihydro-3-benzo[b]furanones, which are hydrolyzed in an acidic medium to the substituted methylenehydrazides of o-hydroxyphenylglyoxalic acid and react with amines to form the products of addition at the activated CH=N bond of the side chain or 2-hydrazono-2,3-dihydro-3-benzo[b]furanone respectively. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 817–822, June, 2007.     

Synthesis and some heterocyclization reactions of new diethyl (1,1-difluoro-3,3-dicyano-2-trifluoromethylallyl)phosphonate and ethyl 3,3-dicyano-2-[(diethoxyphosphoryl)difluoromethyl]acrylate

A new CF₂X-analogue of 1,1-bis(trifluoromethyl)-2,2-dicyanoethylene (X = P(O)(OEt)₂), diethyl (1,1-difluoro-3,3-dicyano-2-trifluoromethylallyl)phosphonate, has been synthesized from diethoxyphosphoryl pentafluoroacetone 1. A similar phosphoryl analogue of ethyl 3,3-dicyano-2-trifluoromethylacrylate, ethyl 3,3-dicyano-2-[(diethoxyphosphoryl)difluoromethyl]acrylate, has been obtained from ethyl 3-(diethoxyphosphoryl)-3,3-difluoro-2-oxopropionate 2. By heterocyclization of these new ethylenes with 3-methyl-2-pyrazoline-5-ones, 3(5)-aminopyrazoles, dimedone, 2-aminopyridines, 1-aryl-3-methyl-5-aminopyrazoles, 1,3,3-trimethylisoquinolines, as well as by condensation with anilines and ketones, the difluoromethylphosphonate-substituted derivatives of 1,4-dihydropyrano[2,3-c]pyrazole, 4,5-dihydropyrazolo[1,5-a]pyrimidine, 5,6,7,8-tetrahydro-4H-chromene, 2H-pyrido[1,2-a]pyrimidine, 4,7-dihydro-1H-pyrazolo[3,4-b]pyridine, 1,4-dihydropyridine, 4,5,6,7-tetrahydro-1H-[1]pyrindine, 1,4,5,6,7,8-hexahydroquinoline, and 6,7-dihydro-2H-pyrido[2,1-a]isoquinoline have been obtained in one stage.     

Condensed isoquinolines 23. Reaction of <Emphasis Type="Italic">o</Emphasis>-bromomethylphenyl-acetonitrile with anthranilic acids: Synthesis of 6H, 12H,17H-dibenzo[3,4:6,7][1,8]-naphthyridino[1,8-<Emphasis Type="Italic">ab</Emphasis>]quinazoline-6,17-diones

The direction of the reaction of anthranilic acids with o-bromomethylphenylacetonitrile upon fusion depends on the temperature and nature of the substituent in the anthranilic acid. The reaction may lead to three types of products: Derivatives of 7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-ones below 150°C and to 6,11-dihydro-13H-isoquino[3,2-b]quinazolin-13-one or derivatives of 6H,12H,17H-dibenzo[3,4:6,7][1,8]naphthyridino[1,8-ab]quinazoline-6,17-diones above 150°C depending on the nature of the substituent in the anthranilic acid. A study was carried out on the mechanism for the formation of 6H,12H,17H-dibenzo[3,4:6,7][1,8]naphthyridino[1,8-ab]quinazoline-6,17-diones, which permitted the preparation of 6-(4-methylphenyl)-6,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-one. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1059–1067, July, 2007.     

Polycyclic N-hetero compounds. XXXIII. Syntheses of 4-substituted 6,7-dihydro-5H-benzo[6,7]-cyclohepta[1,2-d]pyrimidines and their inhibitory activities on platelet aggregation and on reserpine-induced hypothermia

Various 4-substituted 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidines were synthesized by the reaction of 4-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine with amines. Their inhibitory activities against collagen-induced platelet aggregation and also against reserpine-induced hypothermia in mice were investigated.     

Derivatives of benzo[b]furan. Part II. Structural studies of derivatives of 2- and 3-benzo[b]furancarboxylic acids

Structural Chemistry - The selected derivatives of the 2- and 3-benzo[b]furancarboxylic acids were synthesized and their structures were studied using the X-ray crystallography and the...     

Synthesis of 5-[2-(Phenoxy)ethyl] Derivatives of 6-Methyluracil, 6-Methyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one,and 2-Imino-6-methyl-2,3-dihydro-1H-pyrimidin-4-one

A synthesis of novel derivatives of 6-methyluracil, 6-methyl-2-thioxo-, and 2-imino-6-methyl-2,3-dihydro-1H-pyrimidin-4-one containing a 2-(phenoxy)ethyl substituent at position 5 of the pyrimidine ring has been carried out. It was found that 5-[2-(phenoxy)ethyl] derivatives of 6-methyl-2-thioxo- and 2-imino-6-methyl-2,3-dihydro-1H-pyrimidin-4-one are obtained by the condensation of the corresponding ethyl 3-oxo-2-(2-phenoxyethyl)butanoates with thiourea or guanidine. 6-Methyl-5-[2-(phenoxy)ethyl]uracils can be prepared by treating 6-methyl-5-[2-(phenoxy)ethyl]-2-thioxo-2,3-dihydro-1H-pyrimidin-4-ones with an excess of aqueous monochloroacetic acid solution. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1213–1217, August, 2005.     

Synthesis of 3-amino derivatives of benzo[b]furo[2,3-c]pyridines

The reaction of 1,7-dimethyl-3(2H)-benzo[b]furo[2,3-c]pyridone with phosphoric acid amides gave 1,7-dimethyl-3-dimethylamino (morpholino)benzo[b]furo[2,3-c]pyridines. A method for the synthesis of 3-amino derivatives of 4-nitrobenzo[b]furo[2,3-c]pyridines, which consists in heating 1,7-dimethyl-4-nitro-3(2H)-benzo[b]furo[2,3-c]pyridone with hexamethyldisilazane and secondary or primary amines in pyridine, was developed.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1552–1555, November, 1991.     

Polycyclic N-hetero compounds. XXXII Synthesis and antidepressive evaluation of B-homo-11,13,15-triazasteroids and their precursors

Synthesis of 4-(2-hydroxyethylamino)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine derivatives V and their cyclized products, B-homo-11,13,15-triazasteroidal compounds VI and VII , are described. These products were screened to evaluate the antidepressive activity.     

Synthesis and Biological Evaluation of Some Novel N,N ′-Bis-(1,2,4-Triazin-4-Yl)Dicarboxylic Acid Amides and Some Fused Rings with 1,2,4-Triazine Ring

Some of novel N , N '-bis-(1,2,4-triazin-4-yl)dicarboxylic acid amides ( 2-5 ) and thiadiazolo[2,3- b ][1,2,4]triazin-7-yl carboxylic acid derivatives ( 6 , 7 ) were prepared by heating 4-amino-6-methyl-5-oxo-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazine ( 1 ) with different dicarboxylic acids (oxalic, malonic, fumaric, maleic, succinic, and phthalic acids respectively) in POCl 3 . Refluxing 1 with 1-chloro-2,4-dinitrobenzene in DMF yielded 3-methyl-6-nitro-10 H -benzo[1,2,4]thiadiazino[2,3- c ][1,2,4]triazin-4-one ( 8 ). Condensation of 1 with 2,4-pentandione in refluxing acetic acid furnished 6-methyl-4-(1-methyl-3-oxobut-1-enylamino)-3-thioxo-3,4-dihydro-2 H -[1,2,4]triazin-5-one ( 9 ). 3,8-D imethyl[1,2,4] triazino[3,4- b ][1,3,4]thiadiazine-4,7-dione ( 11 ) was prepared by refluxing 1 with 2-bromopropionyl bromide in anhydrous benzene to afford the corresponding N -acetylated derivative 10 , which was cyclized by using triethylamine. Also, some triazinylquinazolinones 13a , b were obtained by fusion of 1 with 6-bromo(and/or 6,8-dibromo)-2-methyl-3,1-benzoxazin-4 H -ones.     

Synthesis of pyrroloazepines. Facile synthesis of 2-substituted pyrrole derivatives by the phosgene method

A highly convenient method for the synthesis of 2-substituted pyrrole derivatives 7a-c from pyrrole using phosgene was developed. Successively, 7-methyl-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione 1a and 6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione 1b (aldisin) were synthesized by phosphorus pentoxide/methanesulfonate and polyphosphoric acid cyclization.     

Synthesis of thiopyrano[2,3-d] pyrimidines and thieno[2,3-d]pyrimidines

The reaction of 4-chloro-5-cyano-2-methylthiopyrimidine (I) with ethyl mercaptosuccinate (II) in refluxing ethanol containing sodium carbonate has afforded diethyl 3-amino-2-(methyl-thio)-7H-thiopyrano[2,3-d]pyrimidine-6,7-dicarboxylate (IV). Displacement of the methylthio group in IV with hydrazine gave the corresponding hydrazino derivative which underwent Schiff base formation with benzaldehyde or 2,6-dichlorobenzaldehyde. Treatment of IV in refluxing acetic anhydride afforded the corresponding diacetylated amino derivative. Partial saponification of IV with sodium hydroxide gave 5-amino-2-(methylthio)-7H-thiopyrano-[2,3-d]pyrimidine 6,7-dicarboxylic acid 6 ethyl ester (VIII). The reaction of 4-amino-6-chloro-5-cyano-2-phenylpyrirnidine (XI) with II resulted in the formation of ethyl 4-amino-6-(ethoxy-carbonyl)-5,6-dihydro-5-amino-2-phenylthieno[2,3-d]pyrimidine-6-acetate (XIII) which when subjected to hydrolysis gave ethyl 4,5-diamino-2-phenylthieno[2,3-d]pyrimidine-6-acetate isolated as the hydrochloride (XIV). Diazotization of IV with sodium nitrite in acetic acid unexpectedly afforded diethyl 5-(acetyloxy)-6,7-dihydro-6-hydroxy-2-(methylthio)-5H-thio-pyrano[2,3-d]pyrimidine-6,7-diearboxylate (XV). Several structural ambiguities were resolved by ir and pmr spectra.     

Synthesis and antimicrobial agents of thiazolidinone derivatives from benzocyclohepetenone

A series of benzosuberone coupled piperazin-1-yl thiazolidin-4-one derivatives 6a-j were synthesized from 3-(2-[9-chloro-2,3-dimethyl-6,7-dihydro-5H-benzo[7]annulen-8-yl]-4-oxothiazolidin-3-yl)propanoic acid ( 4 ) and substituted piperazines/secondary amines 5a-j using 1-hydroxy benzotriazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and triethyl amine in good yields and their structures were characterized by ¹H NMR, ¹³C NMR, IR, and Mass spectra. The newly synthesized compounds were evaluated for their antimicrobial activity against bacterial strains and a fungal strain. Compounds 6f and 6g were indicated promising and broad spectrum antibacterial activity.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. XX. Synthesis of 2H-pyrano[2,3-f]quinazoline derivatives

The polar 1,4-cycloaddition of dichloroketene to N,N-disubstituted (E)-6-aminomethylene-7,8-dihydro-(2-methyl)(2-phenyl)quinazolin-5(6H)-ones III , prepared in good yields from 7,8-dihydro-(2-methyl)-(2-phenyl)quinazolin-5(6H)-ones via their 6-hydroxymethylene derivatives I and II , gave in satisfactory to excellent yields N-N-disubstituted 4-amino-3,3-dichloro-3,4,5,6-tetrahydro-(8-methyl)(8-phenyl)-2H-pyrano- [2,3,-f]quinazolin-2-ones IV , which are derivatives of the new heterocyclic system pyrano[2,3-f]quinazoline. This cycloaddition occurred both in the case of aliphatic and aromatic N-substitution only with 2-phenyl-enaminones III , whereas with 2-methyl derivatives III the reaction took place only in the case of aromatic N-monosubstitution. Dehydrochlorination of IV with DBN afforded, generally in excellent yields, N,N-disubstituted 4-amino-3-chloro-5,6-dihydro-(8-methyl)(8-phenyl)-2H-pyrano[2,3-y]quinazolin-2-ones, which were dehydrogenated with DDQ to give N,N-disubstituted 4-amino-3-chloro-(8-methyl)(8-phenyl)-2H-pyrano[2,3-f]quinazolin-2-ones in excellent yields.     

A new course of the Perkin cyclization of 2-(2-formyl-6-methoxyphenoxy)alkanoic acids. Synthesis of 2-alkyl-7-methoxy-5-nitrobenzo[b]furans

2-Alkyl-7-methoxy-5-nitrobenzo[b]furan, 2-alkyl-9-methoxy-7-nitro-3-oxo-2,3-dihydro-5H-benzo[e][1,4]-dioxepin-5-yl acetate and 2-alkyl-5-hydroxy-9-methoxy-7-nitro-5H-benzo[e][1,4]-dioxepin-3-one were formed as a result of the cyclization of 2-(2-formyl-6-methoxy-4-nitrophenoxy)alkanoic acids under classical Perkin reaction conditions. The products were characterized by spectroscopic methods and the mechanism of the cyclization is discussed.     

The synthesis of β-carboline derivatives-II A synthesis of some benz-indolo[2,3-a]pyridocolinium salts, including sempervirine

A novel synthetic method for β-carboline derivatives, described in the preceding paper, is now applied to the syntheses of 6,7-dihydro-12H-benz[f]indolo[2,3-a]pyridocolinium salt, 8,9-dihydro-14H-benz[h]indolo-[2,3-a]pyridocolinium salt and sempervirine. In the course of synthesis of sempervirine, 2-[2-(3-indolyl)ethyl]-3-chloro-5,6,7,8-tetrahydro-isoquinolinium bromide is obtained as an intermediate, lending strong support for the mechanism previously proposed.     

Reaction of 2-aminothiophenol with acrylic acid and conversion of the resultant adducts

The reaction of acrylic acid with 2-aminothiophenol gives 5-carboxyethyl-2,3-dihydro-5H-benzo[b][1,4]-thiazepin-4-one and N-[2-(carboxyethylthio)phenyl]-α-alanine, while the reaction of acrylic acid with bis(2-aminophenyl) disulfide gives bis[2-(carboxyethylamino)phenyl] disulfide. The action of potassium thiocyanate in acid medium on the carboxyethylamino derivatives yields 1-[2-carboxyethylthio)phenyl]dihydro-4(1H,3H)-pyrimidinone-2-thione, bis-{2-[dihydro-4(1H, 3H)-pyrimidinone-2-thion-1-yl]phenyl} disulfide, and 3-(2-mercaptobenzothiazol-3-yl)propanoic acid. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 256–261, February, 2006.     

Oligomerization of indole derivatives with incorporation of thiols

Two molecules of indole derivative, e.g. indole-5-carboxylic acid, reacted with one molecule of thiol, e.g. 1,2-ethanedithiol, in the presence of trifluoroacetic acid to yield adducts such as 3-[2-(2-amino-5-carboxyphenyl)-1-(2-mercaptoethylthio)ethyl]-1Hindole-5-carboxylic acid. Parallel formation of dimers, such as 2,3-dihydro-1H,1'H-2,3'-biindole-5,5'-dicarboxylic acid and trimers, such as 3,3'-[2-(2-amino-5-carboxyphenyl) ethane-1,1-diyl]bis(1H-indole-5-carboxylic acid) of the indole derivatives was also observed. Reaction of a mixture of indole and indole-5-carboxylic acid with 2-phenylethanethiol proceeded in a regioselective way, affording 3-[2-(2-aminophenyl)-1-(phenethylthio)ethyl]-1H-indole-5-carboxylic acid. An additional product of this reaction was 3-[2-(2-aminophenyl)-1-(phenethylthio)ethyl]-2,3-dihydro-1H,1'H-2,3'-biindole-5'-carboxylic acid, which upon standing in DMSO-d6 solution gave 3-[2-(2-aminophenyl)-1-(phenethylthio)ethyl]-1H,1'H-2,3'-biindole-5'-carboxylic acid. Structures of all compounds were elucidated by NMR, and a mechanism for their formation was suggested.     

Heterocyclization of 1,1-dicyano-2-(trifluoromethyl)ethylenes with 1,3,3-trimethyl-3,4-dihydroisoquinoline and its derivatives

1,3,3-Trimethyl-3,4-dihydroisoquinolines react with 1,1-dicyano-2,2-bis(trifluoromethyl)ethylene to give 4-amino-6,6-dimethyl-2,2-bis(trifluoromethyl)-3-cyano-6,7-dihydro-2H-benzo[a]quinolizines. The reaction of 3,3-dimethyl-1-cyanomethylidene-1,2,3,4-tetrahydroisoquinoline and the methyl ester of 3,3-dicyano-2-(trifluoromethyl)acrylic acid leads to 5,5-dimethyl-3-oxo-2-(trifluoromethyl)-2-(dicyanomethyl)-2,3,5,6-tetrahydropyrrolo[2,1-a]isoquinoline.A. N. Nesmeyanov Institute of Heteroorganic Compounds, Russian Academy of Sciences, 117813 Moscow. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 8, pp. 1888–1892, August, 1992.