Stereoselective α-alkylation of methyl 6-deoxy-3,4-di-O-(tert-butyldimethylsilyl)-2-O-(2-methyl-3-oxobutanoyl)-α-d-glucopyranoside

Allylation and benzylation at the α-carbon of α-methylated acetoacetyl (2-methyl-3-oxobutanoyl) group incorporated into the 2-OH of methyl 6-deoxy-3,4-O-(tert-butyldimethylsilyl)-α-d-glucopyranoside provided the respective α,α-differentially alkylated acetoacetyl derivatives, both with high diastereoselectivity. Thus-obtained doubly alkylated products possess an all-carbon quaternary stereogenic center with an absolute stereochemistry opposite to that introduced by using the 4-O-acetoacetyl regioisomer as the alkylation substrate.     

Feasible selective synthesis of 3-Acetylindoles and 3-Acetoacetylindoles from β-ethylthio-β-indoly α, β-unsaturated ketones

An efficient and selective synthesis of 3-acetyl free(N-H)/N-substituded indoles and 3-acetoacetyl free(N-H)/N-substituded indoles has been developed via the hydrolysis reaction of β-ethylthio-β-indoly α, β-unsaturated ketones in the presence of 3 equivalent of NaOH and 5?mol% of H₂SO₄, respectively. The procedure features easy operation, excellent yields, and high selectivity, compatibility and practicability.     

Cu(I)-mediated lactone formation in subcritical water: a benign synthesis of benzopyranones and urolithins A–C

Benzopyranones were successfully synthesized using Cu(I)-mediated C–O bond formation in subcritical water. A number of benzopyranone derivatives including polymethoxy benzopyranones, benzopyranopyridones, chromenoindolones, and furochromenones were synthesized in satisfactory yield. This methodology was further applied to synthesize the intestinal microbial metabolites, urolithins A, B, and C, which were found to exhibit potent antioxidant activity.     

3-Hydrazino-1,2,4-triazin-5(2H)-ones in Reactions with Compounds Containing Carbonyl and Active Methylene Groups

Boiling of ethyl cyanoacetate with 6-tert-butyl-3-hydrazino-1'2'4-triazin-5(2H)-one in alkalinemedium yielded 6-tert-butyl-3-(5-hydroxy-3-oxo-2'3-dihydro-1H-pyrazol-1-yl)-1'2'4-triazin-5(2H)-one.Acylation of 6-tert-butyl-3-hydrazino-1'2'4-triazin-5(2H)-one with benzoyl chloride furnished 3-benzoyl-hydrazido-1'2'4-triazine that cyclized when treated with POCl₃ providing a derivative of[1'2'4]triazolo[4'3-b][1'2'4]triazine. Boiling of 6-tert-butyl-3-hydrazino-1'2'4-triazin-5(2H)-one in glacialacetic acid gave rise to diacetylated derivative whereas the boiling with acetic anhydride in an inert solventafforded monoacetylated product.     

Chemistry of 5(2H)-isoxazolones: Novel conversion of positional isomers

Reactions of 4-arylidene-3-methyl-5(4H)-isoxazolones with nucleophiles lead to 4-substituted-benzyl-3-methyl-5(2H)-isoxazolones. Formation of 5(4H)- and 5(2H)-isoxazolone derivatives have been observed when 4-substituted-arylidene-3-rriethyl-5(4H)-isoxazolones are reacted with methyl magnesium iodide. Oxidation of 4-substituted-benzyl-3-methyl-5(2H)-isoxazolones with manganic acetate and pyridinium chlorochromate, gives 4,4′-bis[4-substituted-benzyl-3-methyl-5(4H)-isoxazolone]. Oxidation of 4-substituted-benzyl-3-methyl-5(2H)-isoxazolones with metachloroperbenzoic acid gives 4-hydroxy-4-substituted-benzyl-3-methyl-5(4H)-isoxazolones and reactions of the same substrates with N-bromosuccinimide furnish 4-bromo-4-substitutedbenzyl-3-methyl-5(4H)isoxazolones.     

Ringerweiterungen und Ringverengungen bei der Umsetzung von 1, 3-Oxazolidin-2, 4-dionen und 1, 3-Thiazoiidin-2, 4-dion mit 3-Amino-2H-azirinen

Ring Enlargements and Ring Contractions in the Reaction of 1, 3-Oxazolidine-2, 4-diones and l, 3-Thiazolidine-2, 4-dione with 3-Amino-2H-azirines The reaction of 3-amino-2H-azirines 1 and 1, 3-oxazolidine-2, 4-diones 2 in MeCN at room temperature leads to 3, 4-dihydro-3-(2-hydroxyacetyl)-2H-imidazol-2-ones 3 in good yield (Scheme 2, Table 1). A reaction mechanism proceeding via ring enlargement of the bicyclic zwitterion A to give B, followed by transannular ring contraction to C, is proposed for the formation of 3 . This mechanism is in accordance with the result of the reaction of 2a and the ¹⁵N-labelled 1a *: in the isolated product 3a *, only N(3) is labelled (Scheme 1). The analogous reaction of 1 and 1, 3-thiazolidine-2, 4-dione ( 5 ) is more complex (Schemes 4 and 5, Table 2). Besides the expected 3, 4-dihydro-3-(2-mercaptoacetyl)-2H-imidazol-2-ones 7, 5-amino-3, 4-dihydro-2H-imidazol-2-ones of type 8 and/or N-(1, 4-thiazin-2-ylidene)ureas 9 are formed. In the case of 2-(dimethylamino)-1-azaspiro[2. 3]hex-1-ene ( 1d ), the postulated eight-membered intermediate 6d could be isolated. Its structure as well as that of 9f has been determined by X-ray structure analysis. A reaction mechanism for the formation of the 1, 4-thiazine derivatives of type 9 is proposed in Scheme 6.     

A study on ester formylhydrazones

A series of ester formylhydrazones 2 were synthesized from the reaction of alkyl imidate hydrochlorides 1 with formylhydrazine. Treatment of 2 with hydrazine hydrate, ethyl carbazate and tert-butyl carbazate led to the formation of 3-alkyl-4-amino-, 3-alkyl-4-ethoxycarbonylamino- and 3-alkyl-4-tert-butoxycar-bonylamino-4H-1,2,4-triazoles 3–5 , respectively. Reaction of compounds 2 with formylhydrazine gave N,N'-diformylhydrazine 6 . Compounds 2 were reacted with 2,5-dimethoxytetrahydrofuran to afford 3-alkyl-4-(1H-pyrrol-1-yl)-4H-1,2,4-triazoles 8 .     

Synthesis of 6-amino-2-aryl-1,2-dihydro-3H-pyrido[2,3-d]pyrimidin-4-one derivatives

This paper reports the synthesis of new pyrido[2,3-d]pyrimidin-4-one derivatives as diuretic agents. Starting with 1,2-dihydro-5-nitro-2-oxo-3-pyridinecarboxylic acid 1 , ethyl 2-ethoxy-5-nitro-3-pyridincarboxylate 4 was obtained. Compound 4 reacts with ammonia, methylamine or S-methylpseudothiourea to give the respective 2-amino-5-nitro-3-pyridinecarboxamide derivatives 5 and 6 or 2-methylthio-6-nitro-3H-pyrido[2,3-d]pyrimidin-4-one 8. Treating carboxamide 5 with arylaldehydes and zinc dichloride, new 2-aryl-1,2-dihydro-6-nitro-3H-pyrido[2,3-d]pyrimidin-4-ones 9 were synthetised. These compounds reduced with iron(II) hydroxide gave 6-amino-2-aryl-1,2-dihydro-3H-pyrido[2,3-d]pyrimidin-4-ones 10 as expected.     

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.     

The synthesis of 3-deazapyrimidine nucleosides related to uridine and cytidine and their derivatives

Condensation of 2,4-bis(trimethylsilyloxy)pyridine ( 1 ) with 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide ( 2 ) gave 4-hydroxy-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2-pyridone ( 3 ). Deblocking of 3 gave 4-hydroxy-1-β-D-ribofuranosyl-2-pyridone (3′-deazauridine) ( 4 ). Treatment of 4 with acetone and acid gave 2′,3′-O-isopropylidene-3-deazauridine ( 6 ). Reaction of 4 with diphenylcarbonate gave 2-hydroxy-1-β-D-arabinofuranosyl-4-pyridone-O₂←2′-cyclonucleoside ( 7 ) which established the point of gylcosidation and configuration of 4 . Base-catalyzed hydrolysis of 7 gave 4-hydroxy-1-β-D-arabinofuranosyl-2-pyridone (3-deazauracil arabinoside) ( 12 ). Fusion of 1 with 3,5-di-O-p-toluyl-2-deoxy-D-erythro-pentofuranosyl chloride ( 5 ) gave the blocked anomeric deoxynucleosides 8 and 10 which were saponified to give 4-hydroxy-1-(2-deoxy-β-D-erythro-pentofuranosyl)-2-pyridone (2′-deoxy-3-deazauridine) ( 11 ) and its α anomer ( 9 ). Condensation of 4-acetamido-2-methoxypridine ( 13 ) with 2 gave 4-acetamido-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2-pyridone ( 14 ) which was treated with alcoholic ammonia to yield 4-acetamido-1-β-D-ribofuranosyl-2-pyridone ( 15 ) or with methanolic sodium methoxide to yield 4-amino-1-β-D-ribofuranosyl-2-pyridone (3-deazacytidine) ( 16 ). Condensation of 13 and 2,3,5-tri-O-benzyl-D-arabinofuranosyl chloride ( 17 ) gave the blocked nucleoside 22 which was treated with base and then hydrogenolyzed to give 4-amino-1-β-D-arabinofuranosyl-2-pyridone (3-deazacytosine arabinoside) ( 23 ). Fusion of 13 with 5 gave the blocked anomeric deoxynucleosides 18 and 20 which were deblocked with methanolic sodium methoxide to yield 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-2-pyridone (2′-deoxy-3-deazacytidine) ( 21 ) and its a anomer 19 . The 2′-deoxy-erythro-pentofuranosides of both 3-deazauracil and 3-deazacytosine failed to obey Hudson's isorotation rule but did follow the “quartet”-“triplet” anomeric proton splitting pattern in the ¹H nmr spectra.     

Reaktion von 3-Amino-2H-azirinen mit Diphenylcyclopropenthion. Vorläufige Mitteilung

Reaction of 3-Amino-2H-azirines with Diphenylcyclopropenethione 3-Dimethylamino-2H-azirines ( 4a , 4b ) react with diphenylcyclopropenethione ( 8 ) to give 4(3 H)-pyridinethione derivatives of type 10 (Scheme 3). The reaction mechanism for the formation of 10 is given in Scheme 3 by analogy with a previous reported one [4] [5]. Hydrolysis of the 4(3 H)-pyridinethione 10a yields 2-oxo-2, 3-dihydro-4(1 H)-pyridinethione ( 11 ) and reduction of 10a with sodium borohydride leads to the 2, 3-dihydro-4 (1 H)-pyridinethione 12 (Scheme 4). The results of the reaction of 4a , 4b and the thione 8 demonstrate the similarity to the reaction of 4a , 4b and 2 [5] (cf. Scheme 1). In contrast, the reactions of imines of type 7a with 2 and 8 , respectively, lead to different products (cf. [1] [6]).     

New Quinoline Derivatives on the Basis of (4-Hydroxy-2-methylquinolin-3-yl)acetic Acid

A procedure was developed for the synthesis of (4-hydroxy-2-methylquinolin-3-yl)acetic acid and the corresponding acyl chloride. Reactions of the latter with o-aminobenzenethiol, o-phenylenediamine, o-aminophenol, anthranilic acid, and thiosemicarbazide gave, respectively, 2-(4-hydroxy-2-methylquinolin-3-ylmethyl)-1,3-benzothiazole, -benzoxazole, -benzimidazole, 2-(4-hydroxy-2-methylquinolin-3-ylmethyl)-4H-3,1-benzoxazin-4-one, and 4-hydroxy-2-methyl-3-(5-sulfanyl-1H-1,2,4-triazol-3-ylmethyl)quinoline.     

Stereochemistry of [4 + 2] Cycloadditions of Perfluorinated Selenocarbonyls to 1, 3‐Dienes

In completely stereospecific [4+2] cycloadditions, the perfluorinated selenocarbonyls 1 and 2 react both with trans‐trans‐2, 4‐hexadiene and cis‐trans‐2, 4‐hexadiene to yield 3, 6‐dihydro‐cis‐3, 6‐dimethyl‐2H‐selenapyrans 3 , 4a and 4b . The observed stereoselectivity leads to the conclusion, that the [4+2] cycloaddition of perfluorinated selenocarbonyls follows a concerted pathway. An identical mixture of isomers was isolated when using the precursor for 2 , trimethylstannyl (pentafluoroethyl)selane, which reacts with both 1, 3‐dienes over several weeks to form a mixture of syn‐2‐fluoro‐3, 6‐dihydro‐cis‐3, 6‐dimethyl‐2‐trifluoromethyl‐2H‐selenapyran ( 4a ) and anti‐2‐fluoro‐3, 6‐dihydro‐cis‐3, 6‐dimethyl‐2‐trifluoromethyl‐2H‐selenapyran ( 4b ) in the same ratio as found for 2 , thus proving the intermediate formation of Se=C(F)CF₃ ( 2 ). Complex 2D NMR experiments were used to distinguish the isomers 4a and 4b and to assign the ¹H, ¹³C and ¹⁹F NMR data of the selenaheterocycles.     

Synthesis and cytotoxic activity of derivatives of the <Emphasis Type="Italic">tert</Emphasis>-butyl ester of 7<Emphasis Type="Italic">Z</Emphasis>-acetylmethylene-3-methyl-3-cephem-4-carboxylic acid

The condensation of the acetylmethylene group in the tert-butyl esters of 7Z-acetylmethylene-3-methyl-3-cephem-4-carboxylic acid and 7Z-acetylmethylene-3-methyl-1,1-dioxo-3-cephem-4-carboxylic acid and in 7Z-acetylmethylene-3-methylene-1,1-dioxo-3-cephem with arylmethoxyamines and O-alkylation of the tert-butyl ester of 7Z-(2-hydroxyimino)propylidene-3-methyl-1,1-dioxo-3-cephem-4-carboxylic acid using substituted benzyl bromides as well as pyridylmethyl chlorides gave arylmethoxyimino and pyridylmethoxyimino derivatives of these compounds in the syn and anti isomeric forms. The Vilsmaier reagent was used to introduce the N,N-dimethylaminomethylene group at C-2 of the cephem system in the tert-butyl esters of 7Z-[2-(arylmethoxyimino)propylidene]-3-methyl-1,1-dioxo-3-cephem-4-carboxylic acid. Subsequent transformation of the N,N-dimethylaminomethylene cephems using hydroxylamine led to 3Z-[2-(anti-arylmethoxyimino)propylidene]-tert-butoxycarbonylmethyl-4-(5-methyl-4-isoxazolylsulfonyl)- azetidin-2-ones. Condensation of the acetyl group in the tert-butyl ester of 7Z-acetylmethylene- 3-methyl-1,1-dioxo-3-cephem-4-carboxylic acid with 4-bromophenylhydrazine gave a cephem with a 2-(4-bromophenylhydrazono)propylidene group at C-7. Acylation of the tert-butyl ester of 7Z-(2-hydroxyimino)propylidene-3-methyl-1,1-dioxo-3-cephem-4-carboxylic acid by 2-bromobenzoyl chloride gave a cephem with a 2-(2-bromo-benzoyloxyimino)propylidene group at C-7. Biological screening of these products towards to malignant and normal cells in vitro showed that their antitumor activity and cytotoxic selectivity towards to malignant and normal cells depend on the structure and configuration of the arylmethoxyimino and pyridylmethoxyimino groups in the 7-alkylidene substituent as well as on the presence or absence of N,N-dimethylaminomethylene and carboxyl groups, respectively, at C-2 and C-4 of the cephem system.     

Pyridine-substituted hydroxythiophenes. V. Preparation of 5-(2-, 3-and 4-pyridyl)-2-hydroxythiophenes

5-(2-, 3- and 4-Pyridyl)-2-t-butoxythiophenes have been prepared in very good yields by Pd(0) catalyzed cross-coupling of the three isomeric bromopyridines with 5-trimethylstannyl-2-t-butoxythiophene derived from 2-bromothiophene via 2-t-butoxythiophene. Dealkylation of 5-(2-, 3- and 4-pyridyl)-2-t-but-oxythiophenes with boron trifluoride etherate in dichloromethane at room temperature led to predominant formation of rearranged products, 5-(2- and 3-pyridyl)-3-t-butyl-3-thiolene-2-ones, together with a small amount of 5-(2- and 3-pyridyl)-2-hydroxythiophenes as a mixture of two tautomeric keto forms in the case of the 2-pyridyl and the 3-pyridyl isomers, and exclusive formation of rearranged product in the case of the 4-pyridyl isomer. However, dealkylation of 2-methoxy-5-(2-, 3- and 4-pyridyl)thiophenes, prepared similarly to the 5-(2-, 3- and 4-pyridyl)-2-t-butoxythiophenes, with boron tribromide under the same reaction conditions as above resulted exclusively in the tautomeric mixture of 5-(2- and 3-pyridyl)-3-thiolene-2-ones and 5-(2- and 3-pyridyl)-4-thiolene-2-ones in the case of the 2-pyridyl and 3-pyridyl isomers. In the case of the 4-pyridyl isomer polymerization took place.     

Reaction of 2,6-dibutylaminohepta-2,5-dien-4-one with malononitrile

Malononitrile reacted with the title compound to give 6-amino-5-cyano-2-(3,3-dicyano-2-methylallylidene-4-methyl-2H-pyran (3). Treatment of 3 with hot 80% sulfuric acid yielded 4,7-dimethyl-56-hydroxy-2(1H)quinolone. With concentrated aqueous sodium hydroxide, 3 gave 5-amino-3,6-dicyano-4,7-dimethyl-2(1H)quinolone and 5-amino-6-carbamoyl-3-cyano-4,7-dimethyl-2(1H)quinolone. The reaction of 3 with hydrochloric in acetic acid gave a mixture of 6-amino-3,7-dicyano-2,8-dimethyl-4-quinolizone and 3-cyano-4-methyl-6-(3,3-dicyano-2-methylallyl)-2-pyrone. Compound 3 also reacted with methylamine, butylamine and piperidine to give 8-amino-5-cyano-4-methyl-2-pyridone, 6-bulylamino-5-cyano-4-methyl-2-pyridone and 5-eyano-4-methyl-6-piperidino-2-pyridone respectively.     

Studies on ketene and its derivatives. Part 119. Reactions of haloketenes with 2-arylideneaminopyridines

Reactions of haloketenes with 2-arylideneaminopyridines were examined. Reaction of dichloroketene with 2-benzylideneaminopyridines gave 2,2-dichloro-3-phenyl-3-(2-pyridylamino)propanoic acids and 3-chloro-2-phenylpyrido[1,2-a]pyrimidin-4(4H)-ones. Similar reaction of dichloroketene with 2-(2-furfurylideneamino)-pyridines gave 3-chloro-2-(2-furyl)pyrido[1,2-a]pyrimidin-4-(4H)-ones. Chloroketene and chlorophenylketene also reacted with 2-arylideneaminopyridines to give pyrido[1,2-a]pyrimidin-4(4H)-ones. Ring transformations of pyrido[1,2-a]pyrimidin-4-(4H)-ones were carried out to give 1,8-naphthyridin-4(1H)-ones and imidazo[1,2-a]-pyridines.     

A new approach to the synthesis of pyridazino[4,5-c]pyridazinones

The reaction of 5-hydrazinopyridazin-3(2H)-ones 1 with α-keto diester 2 in acetic acid afforded the corresponding 4,6-dihydropyridazino[4,5-c]pyridazin-5(1H)-ones 3 and pyrrolo[2,3-d)pyridazin-4(5H)-ones 4 . Compounds 3 were also obtained from 4-bromo-5-hydrazinopyridazin-3(2H)-ones 8 and 2 under milder conditions. 5-Bromo-4-hydrazinopyridazin-3(2H)-one 9 , the regioisomer of 8b , also reacted readily with 2a to give 4,7-dihydropyridazino[4,5-c]pyridazin-8(1H)-one 10b , the regioisomer of 3b .     

Synthesis of 1-[3-methyl-2(3H)-benzazolon-5- or 6-yl]-4-{4-[cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-yl]methyleneoxyphenyl}piperazines

Reactions of 3-methyl-6-[4-(4-hydroxyphenyl)-1-piperazinyl]-2(3H)-benzoxazolone, 3-methyl-6-[4-(4-hydroxy-phenyl)-1-piperazinyl]-2(3H)-benzothiazolone and 1,3-dimethyl-5-[4-(4-hydroxyphenyl)-1-piperazinyl]-2(3H)-benzimidazolone with cis-{[2-(2,4-dichlorophenyl) -2-(1H-imidazol-1-ylmethyl)]-1,3-dioxolan-4-yl}methyl meth-anesulfonate in the presence of sodium hydride furnish the title compounds.     

Base- and acid-catalyzed condensation reactions of reissert compounds with vinylpyridines

The hydrochloric acid-catalyzed condensation of 2-p-anisoyl-1,2-dihydroisoquinaldonitrile ( 3 ) with 2-vinylpyridine gave 2-(1-isoquinolyl)-3-(2-pyridyl)-5-p-anisylpyrrole ( 4 ), and the corresponding reaction of 3 with 4-vinylpyridine afforded 2-(1-isoquinolyl)-3-(4-pyridyl)-5-p-anisylpyrrole (5). The condensation of the lithium salt of 3 with 4-vinylpyridine gave α-(4-pyridyl)-β-(1-iso-quinolyl)-p-methoxypropiophenone ( 10 ), which was cyclized to 2-(4-pyridyl)-3-p-anisylpyrrolo-[2,1-a]isoquinoline (7) by the action of concentrated hydrochloric acid. 2-(4-Pyridyl)-3-phenyl-pyrrolo[2,1-a]isoquinoline ( 6 ) and 2-(2-pyridyl)-3-p-anisylpyrrolo[2,1-a]isoquinoline ( 8 ) were prepared by analogous sequences of reactions.