Azaindole derivatives

1-Benzyl-6-hydroxy-7-cyano-5-azaindoline, which was converted to 6-chloro-5-azaindoline through 6-hydroxy-5-azaindoline, was synthesized from O-methylbutyrolactim through 1-benzyl-2-pyrrolidone, 1-benzyl-2-cyano (carbamoylmethylene)-pyrrolidine, and the product of its condensation with dimethylformamide diethylacetal.See [1] for communication LII.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 355–358, March, 1978.     

Synthesis of optically active 2-benzyldihydrobenzopyrans for the hypoglycemic agent englitazone

Two syntheses of some optically active 2-benzyl-2,3-dihydro-4H-benzopyrans and benzopyran-4-ones are presented. An asymmetric synthesis starting from D- and L-phenylalanine was used to provide both enantiomers of 2-benzyl-6-(methoxycarbonyl)-2,3-dihydro-4H-benzopyran-4-one 19. Phenylalanine was diazotized in aqueous sulfuric acid to 2-hydroxy-3-phenylpropionic acid 6 which was converted in four steps to 1-bromo-2-(4-methoxycarbonylphenoxy)-3-phenylpropane 11. (4R,S)-Benzamido-2-benzyl-2,3-dihydro-6-(methoxycarbonyl)-4H-1-benzopyran-4-carboxylic acid 16 was prepared from 11 by amidoalkylation with α-hydroxyhippuric acid in methanesulfonic acid solution followed by spiroalkylation to (4R,S)-2-benzyl-2,3-dihydro-6-(methoxycarbonyl)spiro[4H-benzopyran-4,4′-2′-phenyloxazolidin]-5′-one 15. After the phenyloxazolidin-5-one 15 was hydrolyzed to the spirobenzamido carboxylic acid 16 , oxidative decarboxylation with sodium hypochlorite yielded optically active 2-benzyl-6-(methoxycarbonyl)-2,3-dihydro-4H-benzopyran-4-one 19. The ketone in 19 was reduced by hydrogenation over palladium on carbon to a methylene group and the ester was converted to the aldehyde to give both isomers of the desired intermediate 2-benzyl-6-(formyl)-2,3-dihydro-4H-benzopyran 25. The second synthesis relied on an enzymatic hydrolysis of ethyl 2,3-dihydrobenzopyran-2-carboxylate 27 with the lipase from P. fluorescens to provide the desired 2R-ester. The ester group in (R)- 27 was converted to the triflate (R)- 29. Displacement of the triflate group with phenylmagnesium bromide and cuprous bromide as catalyst gave 2R-benzyl-2,3-dihydro-4H-benzopyran (R)- 30. Formylation of (R)- 30 provided 2R-benzyl-6-(formyl)-2,3-dihydro-4H-benzopyran (R)- 25 identical with that from the first synthesis. These optically active intermediates are used in the preparation of the hypoglycemic agent englitazone.     

Configuration and isomerization of 2,4,5-substituted 1,3,2-dioxaborinanes

Reaction of esters of isobutylboronic acid with 2-methyl-1-phenyl-1,3 propanediol and 2-benzyl-1,3-butanediol gave 2-isobutyl-5-methyl-4-phenyl- and 4-methyl-5-benzyl-1, 3, 2-dioxaborinanes respectively, with a preponderance of the cis-isomers in the mixtures. Cis-2-isobutyl-5-methyl-4-phenyl-1, 3, 2-dioxaborinane was converted to thetrans isomer on heating to 150°C with a catalytic amount of ZnCl₂.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1291–1294, September, 1995.     

Synthesis of substituted benzo[g]isoquinolines and 8-azabenzo[a]fluoranthenes

The conversion of l,3-dimethyl-2,6-diphenyl-4-benzyl-4-piperidol and its N-unsubstituted analog by means of pyridine N-oxide to 3-methyl-2,6-diphenyl-4-benzylpyridine (I) is accompanied by the formation of l,2-diphenyl-l,2-bis(3'-methyl-2',6'-diphenyl-4'-pyridyl)ethane, which was obtained under the same conditions directly from y-benzyl-substituted pyridine I. The initial product in the catalytic dehydrocyclization of pyridine baseI is l,3-diphenylbenzo[g]isoquinoline, which is subsequently partially converted to 7-phenyl-8-azabenzo[a]fluoranthene. Spectral data for these heterocyclic compounds and the characteristics of the substances obtained by oxidation of them are presented.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 648–651, May, 1979.     

Preparation,structural characterization,and acid-catalyzed isomerization of 3-, 7-, and 9-benzyl-6-benzylthiopurines

Benzylation of 6-benzylthiopurine was examined. Structural assignments of the products were determined by 1-D and 2-D nmr spectroscopy (HMQC, HMBC, and nOe). In the presence of base, the isomeric N3-, N7-, and N9-benzylated products 4, 3 , and 2 were isolated; however, only 9-benzyl-6-benzylthio-purine ( 2 ) was obtained in the absence of base. In the latter case, the initially formed N3- and N7-isomers were, in the presence of acid, converted to 9-benzyl-6-benzylthiopurine ( 2 ) via a 6-benzylthiopurine intermediate as evidenced by analysis of the reaction over time using reversed-phase hplc.     

An efficient synthetic methodology of chiral isoquinuclidines by the enantioselective Diels-Alder reaction of 1,2-dihydropyridines using chiral cationic palladium-phosphinooxazolidine catalyst

High purity chiral isoquinuclidines (97% ee) were obtained from the enantioselective Diels-Alder reaction of 1-phenoxycarbonyl-1,2-dihydropyridine with 1-benzyl-2-acryloylpyrazolidin-3-one using chiral cationic palladium-phosphinooxazolidine (Pd-POZ) catalyst. The obtained DA adduct was easily converted to the chiral piperidine derivative bearing three stereogenetic centers in the structure.     

Synthesis of New Heterocyclic Systems on the Basis of 7-Benzyl-3-chloro-1-(morpholin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthiridine-4-carbonitrile

Methods have been developed for the synthesis of new 8-amino-3-benzyl-5-(morpholin-4-yl)-1,2,3,4-tetrahydropyrimido[4′,5′: 4,5]thieno[2,3-c][2,7]naphthyridine starting from 7-benzyl-3-chloro-1-(morpholin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile. 8-Hydrazinyl-3-benzyl-5-(morpholin-4-yl)-1,2,3,4-tetrahydropyrimido[4′,5′: 4,5]thieno[2,3-c][2,7]naphthyridine has been converted to isomeric pentacyclic structures with a triazole ring fused through the [c] side of the pyrimidine ring, and their Dimroth rearrangement has been accomplished in both acidic and basic media. New heterocyclic systems containing pyrrolo[1,2-a]pyrimidinone and pyrimido[1,2-a]azepinone fragments were obtained on the basis of the thieno-[2,3-c][2,7]naphthyridine derivative.     

Substituted pyridines 5-methyl-4-benzyl-2-styryl(phenylethynyl)pyridines

5-Methyl-4-benzyl-2-styrylpyridine (II), its p-dimethylaminostyryl analog IV, and 5-methyl-4-benzyl-2-(1,3-dioxo-2-hydrindenyl)pyridine (V) have been prepared. II has been converted into 5-methyl-4-benzyl-2-phenylethynylpyridine (VII), 5-methyl-4-benzylpyridine-2-carboxylic acid (VIII), and 3-styryl-6, 7-benzoisoquinoline (X).Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1228–1231, September, 1970.     

Reaction of 2 -methyl-2-cinnamoyloxiranes with benzylamine and thioacetic acid

Reaction of 2-methyl-2-cinnamoyloxiranes with benzylamine gave stereoisomeric 3-hydroxy-3-methyl-1-benzyl-6-aryl-4-piperidones, which were converted to 3-hydroxy-1,3-dimethyl-6-aryl-4-piperidones by debenzylation and subsequent methylation. 3-Hydroxy-3-methyl-6-phenyltetrahydro-4-thiopyrone acetate was obtained by reaction of 2-methyl-2-cinnamoyloxirane with thioacetic acid. The three-dimensional configurations of the synthesized compounds were established by means of their IR and PMR spectra.     

Reactions of aromatic and heteroaromatic compounds containing electron-acceptor substituents

Synthetic methods based on accessible furan compounds of 5-benzyl(3-furyl)carbinol, a necessary component for the preparation of modified pyrethrins, were studied. The carbinol was obtained in 24% overall yield by a five-step synthesis starting from 4-bromofuran-2-carboxylic acid, for the preparation of which an improved method is proposed. Acylation of benzene with the chloride of the latter acid gave 4-bromo-2-benzoylfuran (in 77% yield), the reduction of which by the action of AlCl₃ + LiAlH₄ gave 4-bromo-2-benzylfuran (in 74% yield). The latter was treated with butyllithium and dimethylformamide to give 5-benzyl-3-formylfuran, which was converted to the carbinol in quantitative yield by the action of LiAlH₄.See [1] for communication XXI.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 306–310, March, 1978.     

The synthesis and hydrolysis of N-benzyl-S-methylisothiazolidinium salts

A series of N-benzyl-S-methylisothiazolidinium salts were obtained by iodinic oxidation of the corresponding N-benzyl-3-methylthiopropylamines at neutral pH followed by their isolation as the chloride salts. The parent N-benzyl-3-methylthiopropylamines were prepared by reacting substituted benzaldehydes with 3-methylthiopropylamine and sodium cyanoborohydride. Acid hydrolysis of the isothiazolidinium salts resulted in their quantitative conversion to the corresponding N-benzyl-3-methylsulfenylpropylamines. Although methylsulfenylpropylamine formation also predominated in alkaline solution, a significant fraction was converted to the parent benzaldehyde and presumably, 3-methylthiopropylamine. The latter conversion is believed to involve opening of the isothiazolidine ring via an elimination reaction followed by hydrolysis of the resulting Schiff's base.     

Studies on the syntheses of heterocylic compounds—762: Synthesis of 3-benzyl-6-methyl-2-oxo-3,6-diazabicyclo[3.1.0]hexane as a synthetic intermediate of mitomycins

(±)-1-Benzyl-3α-hydroxy-4β-methylamino-2-oxopyrrolidine (15) and its cis-isomer (16) were synthesised from 1-benzyl-4-ethoxycarbonyl-2,3-dioxopyrrolidine (2) in several steps. The former (15) was converted to 3-benzyl-6-methyl-2-oxo-3,6-diazabicyclo[3.1.0]hexane (17) with a mixture of triphenylphosphine, carbon tetrachloride and triethylamine.     

Reaction of 2-dimethylaminomethylene-1,3-diones with dinucleophiles. VI. Synthesis of ethyl or methyl 1,5-disubstituted 1H-pyrazole-4-carboxylates

Reaction of ethyl or methyl 3-oxoalkanoates with N,N-dimethylformamide dimethyl acetal gave, generally in excellent yields, a series of ethyl or methyl 2-dimethylaminomethylene-3-oxoalkanoates II which reacted with phenylhydrazine to afford the esters of 5-substituted 1-phenyl-1H-pyrazole-4-carboxylic acids III in high yields. Esters III were hydrolyzed to the relative 5-substituted 1-phenyl-1H-pyrazole-4-carboxylic acids which were converted by heating to 5-substituted 1-phenyl-1H-pyrazoles in excellent yields. Reaction of II with methylhydrazine afforded in general a mixture of 3- and 5-substituted ethyl 1-methyl-1H-pyrazole-4-carboxylates with the exception of IIg , which gave in high yield methyl 5-benzyl-1-methyl-1H-pyrazole-4-carboxylate, which was hydrolyzed to the relative pyrazolecarboxylic acid. This afforded by heating 5-benzyl-1-methyl-1H-pyrazole in quantitative yield.     

A novel approach to substituted 2H-azirines

2-(Benzotriazol-1-yl)-2H-azirines 4a-c, obtained by treatment of oximes 2a-c with tosyl chloride and aqueous KOH, were reacted with benzylmagnesium bromide or 4-methylbenzylmagnesium bromide in the presence of zinc chloride to give 2-benzyl-2H-azirines 5a-f. Potassium phthalimide and sodium salt of benzenethiol converted 2-(benzotriazol-1-yl)-2H-azirines 4a-c into novel 2H-azirines 6a-c and 7 in good yields.     

Condensed Isoquinolines. 10. Borohydride Reduction in the 5H-Isoquino[2,3-a]quinazolin-5-one Series

Borohydride reduction in a series of 7-benzyl- and newly synthesized 7-arylmethylene-7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-ones leads stereoselectively to erythro-7-benzyl-6,6a,7,12-tetrahydro-5H-isoquino[2,3-a]quinazolin-5-ones. 7,7-Disubstituted 7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-ones are inert to the action of sodium borohydride, but spiro[5H-isoquino[2,3-a]quinazolin-7(12H),2'-indane]-5-one is reduced under rigid conditions to 6,6a-dihydrospiro[5H-isoquino[2,3-a]quinazolin-7(12H),2'-indan]-5-one. 7-Acetyl- and 7-benzoyl-6,11-dihydro-5H-isoquino[2,3-a]quinazolin-5-ones are converted in an aqueous alcoholic solution of sodium borohydride to the previously described 6,6a,7,12-tetrahydro-5H-isoquino[2,3-a]quinazolin-5-one. The structure and special features of the conformational behavior of the reduction products obtained were demonstrated by ¹H NMR spectroscopy.!     

Studies on the syntheses of analgesics. Part XXXII. An alternative synthesis of 1,2,3,4,5,6-Hexahydro-8-hydroxy-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazoeine [Studies on the syntheses of heterocyclic compounds. Part CDLXXX]

Bischler-Napieralski reaction of the amides (VIII and IX), derived from the 3-methyl-3-pentenylamine (III) with the phenylacetic acid derivatives (V ～ VII), gave the 5,6-dihydropyridines (XII and XIII), which were reduced, followed by N-benzylation, to afford the 1,2,5,6-tetrahydropyridines (XIX ～ XXI). Grewe-type cyclization of these compounds gave 3-benzyl-3-benzazocine (II), which was already converted into pentazocine (Ic). Moreover, the 1,2,5,6-tetrahydropyridines (XIX ～ XXI) were also obtained from the 2-benzylidene-1,2,5,6-tetrahydropyridine (XVII ～ XVIII) from the N-benzylamine (IV) of III via the amides (X and XI).     

2-Phenylphthalimidine derivatives. A probable formation mechanism of adducts from 3-benzylidenephthalide and aniline

3-Benzyl-3-hydroxy-2-phenylphthalimidine ( 1 ) and 3-anilino-3-benzyl-2-phenylphthalimidine ( 2 ), the unusual adduct, are obtained from the title compounds. 3-Alkoxy-3-benzyl-2-phenylphthalimidines 3 are synthesized. The behaviour of 1 , 3-benzylidene-2-phenylphthalimidines ( 4 and 5 ), 3-(α-bromobenzylidene)-2-phenylphthalimidines ( 6 and 7 ) with respect to bases and the preparation of the open tautomer 13 of 1 and its hydrochloride are described. A hypothetical mechanism about the formation of 1 and 2 is suggested.     

双咪唑啉酮衍生物的有效合成

用烯基膦亚胺与二硫化碳、苄胺的串联aza—Wittig反应制取2-硫代-3-苄基-5-芳基亚甲基4-咪唑啉二酮（5）,5经S-烷基化反应合成了双2-烷硫基-3-苄基-5-芳基亚甲基-4H-咪唑啉-4-酮衍生物（6a-6d）。提出了可能的反应机理,探讨了5和6a-6d的反应条件和波谱性质。经^1H NMR,IR,MS和元素分析确证6a-6d均为新化合物。     

Synthesis and cytotoxic activity of some 3-benzyl-5-arylidenefuran-2(5H)-ones

3-Benzyl-furan-2(5H)-one (2a) and 3-(4-bromobenzyl)-furan-2(5H)-one (2b) were treated with TBDMSOTf and converted into the corresponding tert-butyldimethyl-silylfuran ethers. These furans were further condensed with several aromatic aldehydes affording compounds 5-14 with general 3-benzyl-5-arylidene-furan-2(5H)-one structures in 31% to 98% yields. Such compounds are analogues of the naturally occurring nostoclide lactones, reported to present moderate cytotoxic activity. Compounds 5-14 were submitted to an in vitro bioassay against the HL-60, HCT-8, SF295 and MDA-MB-435 cancer cell lines using the MTT cytotoxicity assay.     

Reaction of aromatic and heteroaromatic compounds bearing electron-accepting substituents 25. Synthesis of (5-benzyl-3-thienyl)methanol from 2-benzoylthiophene

Under the action of paraformaldehyde and AlCl₃, 2-benzoylthiophene has been converted into 2-benzoyl-4-chloromethylthiophene, which on treatment with anhydrous sodium acetate has given 4-acetoxymethyl-2-benzoylthiophene. The reduction and simultaneous saponification of the latter under the conditions of the Kizhner reaction has yielded (5-benzyl-3-thienyl)methanol.For Communication 24, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 472–474, April, 1980.