A novel synthesis of theophylline derivatives

Treatment of 6-amino-5-arylazo-1,3-dimethyluracils with ethyl propiolate gave the corresponding Michael-type adducts, 5-arylazo-1,3-dimethyl-6-ethoxycarbonylvinylaminouracils, which on treatment with a mixture of hydrochloric acid and acetic acid caused the acid-catalyzed rearrangement accompanied with rearrangement to give rise to the corresponding 8-anilinomethyltheophylline derivatives. In the case that the arylazo group possesses an electron-releasing substituent such as methoxy, the reaction proceeded in a different way to afford 1,2-bis(theophyllin-8-yl)ethane. The presumable reaction mechanisms for the above purine syntheses were proposed.     

First examples of oxaphosphirane pentacarbonylchromium(0) and -molybdenum(0) complexes: synthesis, structures and reactions

Synthesis of the first oxaphosphirane chromium(0) and molybdenum(0) complexes of the type [{(R(1)PCH(R(2))-O}M(CO)(5)] (R(1) = C(5)Me(5)) (8a-e, 15a-e) and (R(1) = CH(SiMe(3))(2)) (9a-e, 16a-e) via reaction of dichloro(organo)- (1, 2, 10, 11) and chloro(organo)phosphane complexes (3,4,12) with lithium bases and aldehydes 7a-e is reported. Furthermore, bicyclic 1,3-oxaphospholane complexes 17 and 18 have been obtained via O-protonation of oxaphosphirane complexes 8a and 15a with HCl. All complexes were characterized by NMR, IR spectroscopic, mass spectrometric investigations and, in addition, single-crystal X-ray structures of complexes 8a-e, 9a,c, 15a,b,e, 16a-c, 17, 18 are presented and discussed.     

A new synthesis of pyrimido[5,4-e]-as-triazine 4-oxides and their ring transformation to pyrrolo[3,2-d]pyrimidines

A new synthesis of certain pyrimido[5,4-e]-as-triazine 4-oxides and their ring transformation to pyrrolo-[3,2-d]pyrimidines by the 1,3-dipolar cycloaddition reaction is described. Thus, reaction of 6-hydrazino-1,3-dimethyluracil ( 1 ) with triethyl orthoformate gave 6-ethoxymethylenehydrazino-1,3-dimethyluracil ( 2 ). Treatment of 2 with arylamines gave 6-arylaminomethylenehydrazino-1,3-dimethyluracils ( 3a-e ). Nitrosative cyclization of 3a-e with sodium nitrite afforded 3-arylaminofervenulin 4-oxides ( 6a-e ). Reaction of 6a-e with acetylenic esters yielded 7-alkoxycarbonyl-6-arylamino-1,3-dimethylpyrrolo[3,2-d]pyrimidine-2,4(1H,3H-diones ( 15a-e and 16 ).     

A highly enantioselective conjugate reduction of 3-arylinden-1-ones using bakers' yeast for the preparation of (S)-3-arylindan-1-ones

[formula: see text] The bakers' yeast reduction of 3-(1,3-benzodioxol-5-yl)-6-propoxy-1H-inden-1-one 4 has been shown to give (S)-3-(1,3-benzodioxol-5-yl)-2,3-dihydro-6-propoxy-1H-indan-1-one 6 in 65% yield with high enantioselectivity (> 99.0% ee), a key intermediate for the synthesis of the endothelin receptor antagonist SB 217242. In addition, the substituted 3-arylinden-1-ones 10a-e gave equally high enantioselectivity for the 3-arylindan-1-one products 13a-e. Mechanistic studies of the reaction indicate the operative pathway to be an asymmetric conjugate reduction, wherein the hydride transfer from NAD(P)H occurs from the Re-face of the indenone substrate.     

The regioselectivity in the formation of pyrazolines and pyrazoles from nitrile imines

The 1,3-cycloaddition of the nitrile imines 2a-e to the carbon-carbon double bond in benzalacetophenone leads to the formation of 4-phenyl-5-benzoylpyrazolines 3a-e which were converted into 4-phenyl-5-benzoylpyrazoles 5a-e upon treatment with chloranil in xylene. However, the cycloaddition of 2a-e to the carbon-carbon double bond in the enol tautomer of dibenzoylmethane gives the regioisomers 5-phenyl-5-hydroxy-4-benzoylpyrazolines which loose elements of water to yield 4-benzoyl-5-phenylpyrazoles 6a-e . The orientations in these reactions are interpretted in terms of the Frontier Molecular Orbital theory. The structures of the products 3 , 5 and 6 were substantiated by their chemical reactions and alternate synthesis wherever possible.     

Synthesis and reactions of halo-, nitro-, and arylazo-substituted 3-cinnamoyltropolones. Formation of styryl-substituted heterocycle-fused troponoid compounds

3-Cinnamoyltropolone ( 1 ) reacted with bromine to afford 7-bromo- ( 2 ), 5,7-dibromo-3-cinnamoyltropolone ( 3 ), and 6,8-dibromo-4,9-dihydrocyclohepta[b]pyrane-4,9-dione ( 4 ) according to amount of the reagent. Iodination and nitration of 1 gave respectively 7-iodo- ( 5 ) and 5-nitro-3-cinnamoyltropolone ( 6 ). Azo-coupling reactions gave 5-arylazo-3-cinnamoyltropolones 7a-f . Compounds 1, 2, 3 and 5 reacted with hydroxylamine to give 3-styryl-8H-cyclohept[d]isoxazol-8-ones 10-13 , while 6 and 7a gave 5-nitro-3-styryl-8H-cyclohept[d]-isoxazol-8-one oxime ( 14 ) and 2-cinnamoyl-7-methoxy-4-phenylazotropone ( 15 ), respectively. The reactions of 1,3 , and 5 with phenylhydrazine gave 3-styryl-1,8-dihydrocycloheptapyrazol-8-ones 16-19 .     

Bromination and diazo-coupling of pyridinethiones; microwave assisted synthesis of isothiazolopyridine, pyridothiazine and pyridothiazepines

Isothiazolopyridines, pyridothiazines and pyridothiazepines are important compounds that possess valuable biological activities. This paper reports on the synthesis of these compounds using both conventional chemical methods and modern microwave techniques. 3-Bromo-6-hydroxy-4-methyl-2-thioxo-2,3-dihydropyridine-3-carboxamide, 5-arylazo-6-hydroxy-4-methyl-2-thioxo-1,2-dihydropyridine-3-carboxamides, 3,5-bis-arylazo-6-hydroxy-4-methyl-2-thioxo-2,3-dihydropyridine-3-caboxamide, 4-methyl-2,3,6,7-tetra-hydroisothiazolo[5,4-b]-pyridine-3,6-dione, 2,2'-(methylene-bis-(sulfanediyl))bis(4-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide), 2-hydroxy-5-methyl-4H-pyrido[3,2-e][1,3]-thiazine-4,7(8H)-dione and 2-arylmethylene-8-hydroxy-6-methyl-2,3,4,5-tetrahydropyrido-[3,2-f][1,4]thiazepine-3,5-diones have been prepared from 6-hydroxy-4-methyl-2-thioxo-2,3-dihydropyridine-3-carboxamide. Some of these compounds were prepared using microwave-assisted reaction conditions, that provided higher yields in shorter times than the conventional methods.     

Synthese von (Methylthio)penam-Derivaten durch Keten-Addition an 4,5-Dihydro-5-(methylthio)-1,3-thiazole

Synthesis of (Methylthio)penam Derivatives via Keten Addition onto 4,5-Dihydro-5-(methylthio)-1,3-thiazoles The 4,5-dihydro-5-(methylthio)-2-phenyl-1,3-thiazoles 3a and 3b , easily prepared from the corresponding 1,3-thiazol-5(4H)-thiones and MeLi, react with dichloroacetyl chloride ( 5a ) and acidoacetyl chloride ( 5b ) in the presence of Et₃N to give (methylthio)penam derivatives 6 (Table 1). The reaction mechanism is either a [2 + 2] cycloaddition of in situ generated ketene or a two-step reaction (Scheme 2). The structure of 6f has been confirmed by X-ray crystallography (Fig. 2). The relative configuration of 6a-e follow from comparison of their ¹H-NMR spectra with those of 6f (Fig. 1). The 6-azidopenams 6d and 6f have been reduced to aminopenams 8a and 8b , respectively. Acylation of 8a with phenacetyl chloride yields 9 (Scheme 4).     

Imidazolin-2-iminato titanium complexes: synthesis, structure and use in ethylene polymerization catalysis

The Staudinger reaction of the imidazolin-2-ylidenes, 1,3-di-tert-butylimidazolin-2-ylidene (1a), 1,3-diisopropylimidazolin-2-ylidene (1b), 1,3-diisopropyl-4,5-dimethylimidazolin-2-ylidene (1c), 1,3-bis(2,4,6-trimethylphenyl)imidazolin-2-ylidene (1d) and 1,3-bis(2,6-diisopropylphenylimidazolin-2-ylidene (1e), with trimethylsilyl azide furnishes the corresponding N-silylated 2-iminoimidazolines 2a-e, which react with [(eta-C5H5)TiCl3] to afford half-sandwich cyclopentadienyl titanium complexes of the type [CpTi(L)Cl2] (3) (L = imidazolin-2-iminato ligand). Similarly, the reactions of 1,3-di-tert-butyl-2-(trimethylsilylimino)imidazoline (2a) with [(eta-tBuC5H4)TiCl3] results in the formation of [(eta-tBuC5H4)Ti(L)Cl2] (4) (L = 1,3-di-tert-butylimidazolin-2-imide). Bis(1,3-di-tert-butylimidazolin-2-iminato)titanium dichloride (5) is obtained from the reaction of two eq. of 2a with TiCl4. Treatment of 5 with methyllithium results in the formation of the corresponding dimethyl complex [L2Ti(CH3)2] (6), whereas [CpTi(L)(CH3)2] (7) is similarly obtained from 3a. The molecular structures of 3a, 3b, 3c, 3e x C7H8, 4 and 7 are reported revealing linearly coordinated imidazolin-2-iminato ligands together with very short Ti-N bond distances. All dichloro complexes (3a-e, 4 and 5) can be activated with methylaluminoxane (MAO) to give active catalysts for ethylene homopolymerization. In most cases, moderate to high activities are observed together with the formation of high (HMWPE) or even ultra high molecular weight polyethylene (UHMWPE).     

Synthesis of 6-aryl-1,3-dimethyl-6,7-dihydro-6-azalumazin-7-(6H)ones and their conversion into 2-aryl-1,2,4-triazine-3,5-(2H,4H)odiones. A new synthesis of 1-aryl-6-azauracils

Treatment of 6-amino-5-arylazo-1,3-dimethyluracils with urea or N,N′-carbonyldiimidazole gave the respective 6-aryl-1,3-dimethyl-6,7-dihydro-6-azalumazin-7-(6H)ones, which were hydrolyzed with alkali to afford 2-aryl-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carboxylic acids (1-aryl-6-azauracil-5-carboxylic acids). Thermal decomposition of these carboxylic acids gave the corresponding 2-aryl-1,2,4-triazine-3,5-(2H,4H)diones (1-aryl-6-azauracils). Methylation of the latter with methyl iodide gave the corresponding 2-aryl-4-methyl-1,2,4-triazine-3,5-(2H,4H)diones (1-aryl-3-methyl-6-azauracils).     

Synthesis of polycyclic pyridazinediones as chemiluminescent compounds

Reactions of 1,3-disubstituted 5-aminopyrazole-4-carbonitrile derivatives 3a-o with dimethyl acetylenedicarboxylate in the presence of potassium carbonate in dimethyl sulfoxide gave the corresponding dimethyl 1,3-disubstituted pyrazolo[3,4-b]pyridine-5,6-dicarboxylates 4a-o which were allowed to react with excess hydrazine hydrate under ethanol refluxing conditions followed by heating at 250-300° to give 1,3-disubstituted 4-amino-1H-pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyridazine-5,8(6H,7H)-diones 7a-s in good yields. Similarly, 1,3-disubstituted 4-hydroxy-1H-pyrazolo[4′3′:5,6]pyrido[2,3-d]pyridazine-5,8(6H,7H)-diones 10a-c were obtained from alkyl 1,3-disubstituted 5-aminopyrazole-4-carboxylates 8a-c . These tricyclic pyridazine derivatives were alternatively synthesized from 4-hydroxypyrrolo[3,4-e]pyrazolo[3,4-b]pyridine-5,7-diones 13a-c prepared by reactions of 5-aminopyrazoles (8e-g) with methyl 1-methyl-4-methylthio-2,5-dioxo-1H-pyrrole-3-carboxylate (11a) followed by the Gould/Jacobs reaction. 1-Methyl-4-methylthio-2,5-dioxo-1H-pyrrole-3-carbonitrile smoothly reacted with 2-aminobenzimidazoles to give the corresponding 5-amino-3-methyl-1H-pyrrolo[3′4′:4,5]pyrimido[1,2-a]benzimidazole-1,3(2H)-diones 16a-e , which were readily converted to the desired 12-aminopyridazino[4′,5′:4,5]pyrimido-[1,2-a]benzimidazole-1,4(2H,3H)-diones 17a-e in good yields. Other pyridazinopyrimidine derivatives were also obtained by the reaction of the corresponding 2-aminoheterocycles with the maleimide in good yields. Substituted anilines reacted 11b in refluxing methanol to give the corresponding methyl 4-phenylamino-1-methyl-2,5-dioxo-1H-pyrrole-3-carboxylates 25a-e which were converted in good yields to 2-methylpyrrolo[3,4-b]quinoline derivatives 26a-e by heating in diphenyl ether. Reaction of 26a-c with hydrazine hydrate gave 10-hydroxypyridazino[4,5-b]quinoline-1,4(2H,3H)-diones 27a-e in good yields. The desired 10-aminopyridazino[4,5-b]pyridazine-1,4(2H,3H)-diones 30a-e were obtained in good yields by the chlorination of 4a-e with phosphorus oxychloride followed by aminolysis with 28% ammonium hydroxide. Some pyridazino[4,5-a][2.2.3]cyclazine-1,4(2H,3H)-diones 37a,b as luminescent compounds were synthesized via several steps from indolizine derivatives. The key intermediates, dimethyl 6-dimethylamino[2.2.3]cyclazine-1,2-dicarboxylates 34, 36 , were synthesized by the [8 + 2] cycloaddition reaction of the corresponding 7-dimethylaminoindolizines 33, 35 with dimethyl acetylenedicarboxylate in the presence of Pd-C in refluxing toluene. Some were found to be more efficient than luminol in light production. 4-Amino-3-methylsufonyl-1-phenyl-1H-pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyridazine-5,8(6H,7H)-dione (7r) , 10-hydroxypyridazino[4,5-b]-quinoline-1,4(2H,3H)-diones 27a-e , and 10-aminopyridazino[4,5-b]quinoline-1,4(2H,3H)-diones 30a-e showed the greatest chemiluminescence intensity in the presence of hydrogen peroxide peroxidase in a solution of phosphate buffer at pH 8.0.     

Synthesis of multi ring-fused 2-pyridones via an acyl-ketene imine cyclocondensation

[STRUCTURE: SEE TEXT] Polycyclic ring-fused 2-pyridones (5a-e and 9a-e) have been prepared via a microwave-assisted acyl-ketene imine cyclocondensation. Starting from 3,4-dihydroisoquinolines (4a-b) or 3,4-dihydroharman (8), fused 2-pyridones could be prepared in a one-step procedure. By using either Meldrum's acid derivatives (1a-d) or 1,3-dioxine-4-ones (7a-b) as acyl-ketene sources, mono- or disubstitution of the fused 2-pyridone ring could be accomplished. As an application of the method, a formal synthesis of the indole alkaloid sempervilam was performed.     

Construction of pyrimido[5,4-e]-as-triazine,purine, v-triazolo-[4,5-d]pyrimidine and pyrazolo[3,4-d]pyrimidine ring systems from 5-arylazo-6-arylidenehydrazino-1,3-dimethyluracils

Reaction of 5-arylazo-6-arylidenehydrazino-1,3-dimethyluracils (II), prepared by the treatment of 6-aryl-idenehydrazino-1,3-dimethyluracils (I) with diazotized arylamines, with dimethylformamide dimethylacetal resulted in the formation of pyrimido[5,4-e]-as-triazine (V) system, while the thermolysis of II resulted in the formation of purine (X), v-triazolo[4,5-d]pyrimidine (XII), and pyrazolo[3,4-d]pyrimidine (XIV, XIX) systems in lieu of the expected V. Reasonable mechanisms have been proposed for the formation of the various ring systems in these reactions.     

Direct introduction of heterocyclic residues into 1,2,4-triazin-5(2H)ones

3-Aryl-1,2,4-triazin-5(2H)-ones 1a-c react with indoles 2a-c in trifluoroacetic acid/chloroform or in boiling butanol or acetic acid to give 3-aryl-6-(indolyl-3)-1,6-dihydro-1,2,4-triazin-5(2H)-ones 3a-g . Oxidation of the dihydro-1,2,4-triazin-5(2H)-ones 3a-e afforded 6-(indolyl-3)-1,2,4-triazin-5(2H)-ones 4a-e , products of nucleophilic substitution of hydrogen in 1a-c . Refluxing 1b with N-methylpyrrote 5b in butanol for an extended time resulted in the formation of 3-(4-chlorophenyl)-6-(1-meuiylpyrrolyl-2)-1,2,4-triazin-5(2H)-one 4h. The reaction of 1a-c with indoles 2a-c , pyrroles 5a,b , 1,3-dimethyl-2-phenylpyrazol-4-one (8) and aminothiazoles 9a,b in acetic anhydride affords the 1-acetyl-3-aryl-6-hetaryl-1,6-dihydro-1,2,4-triazin-5(2H)-ones 6a-s . Reaction of 1a-c with N-methyl-pyrrole 5b in acetic anhydride gives beside the 1:1 addition products 6h-k also the 2:1 addition products 7a-c .     

Photocyclization reactions. Part 4 . Synthesis of naphtho[1,8-bc]-furans and cyclohepta[cd]benzofurans using photocyclization of Ethyl 2-(8-Oxo-5,6,7,8-tetrahydro-1-naphthyloxy)acetates and ethyl 2-(5-Oxo-6,7,8,9-tetrahydro-5H-benzocyclohepten-4-yloxy)acetates

Photocyclization reactions were carried out on ethyl 2-(8-oxo-5,6,7,8-tetrahydro-1-naphthyloxy)acetates 1a-e and ethyl 2-(5-oxo-6,7,8,9-tetrahydro-5H-benzocyclohepten-4-yloxy)acetates 2a-e in acetonitrile. Irradiation of 1a-e gave naphtho[1,8-bc]furanols 3a-e and naphtho[1,8-bc]furans 4a-e in 33–83% yields and ethyl acrylates 5b-d were produced in 3–25% yields during irradiation of 1b-d . On the other hand, 2a-e afforded cyclohepta[ad|benzofuranols 6a-e and cyclohepta[ad]benzofurans 7a-e in 44–87% yields. Ethyl acrylates 8b-d were also produced in 7–43% yields from irradiation of 2b-d . Substituent effects on photocyclization and reaction pathways are discussed.     

Regiospecific synthesis of 6-alkyltropan-2-ones

A new synthetic approach for the regiospecific alkylation of the 6-position of the tropane ring system has been developed. Alkylation, desulfonylation and deprotection of tropanes 5 and 12 furnished a series of 6-endo-alkyltropan-2-one derivatives 8a-e, 15a-e and 16a-e (R = Me, Et, n-Pr, n-Bu, Bn) stereoselectively in good yields. The 6-endo isomers 15a-e and 6-exo isomers 16a-e were easily obtained as pure diastereoisomers.     

Haloacetylated enol ethers. 11. Synthesis of 1-methyl- and 1-phenyl pyrazole-3(5)-ethyl esters. A one-pot procedure

A one-pot synthesis of 1-methyl- and 1-phenylpyrazole-3(5)-ethyl esters 2,3a-e by the cyclocondensation of β-alkoxyvinyl trichloromethyl ketones 1a-e with methyl and phenyl hydrazine hydrochloride under mild conditions, is reported. A study using compounds 1a-e with different substituents proved that these are versatile building blocks for the synthesis of pyrazole derivatives, having a 3(5)-ethoxycarbonyl substituent in good yields (60–89%). The hydrazine and β-alkoxyvinyl trichloromethyl ketone substituent effects on the reaction regiochemistry on the formation of the 1,3- and 1,5-isomer were observed.     

Studies on Organophosphorus Compounds: Synthesis and Reactions of Some New 5′-Cyano-2′-(4-methoxyphenyl)spiro[cycloalkane-1,6′-[1,3,2]thiazaphosphixane]-2′,4′-disulfide Derivatives

2,4-Bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's Reagent, LR, 1 ) reacts with cycloalkylidenecyanothioacetamides ( 2 and 3 ) to give 5'-cyano-2'-(4-methoxyphenyl)spiro [cyclopentane(cyclohexane)-1,6'-perhydro-[1,3,2]thiazaphosphixane]-2',4'-disulfide ( 4 and 5 ). The reaction of compounds 4 and 5 with f -halo compounds led to the formation of the substituted thio-compounds 6a-e and 7a-e , respectively, these compounds, upon treatment with sodium ethoxide, produce the corresponding thienothiazaphosphixine derivatives 8a-e and 9a-e respectively. Compounds 8a-e and 9a-e react with LR under different reaction conditions to give polyfused heterocyclic compounds 10a-d and 11a-d respectively. Treatment of compounds 8b and 9b with CS 2 and (CH 3 ) 2 SO 4 gave the corresponding dithiocarbamate methyl ester derivatives 12 and 13 , respectively, which on treating with hydrazine hydrate yielded compounds 14 and 15 respectively. Compounds 14 and 15 reacted with LR to yield compounds 16a , b and 17a , b respectively.     

Fluoroalkyl-containing 2-arylhydrazono-1,3-dicarbonyl compounds in the reactions with ethylenediamine and polyethylenepolyamines

Acyclic N,N′-(poly)ethylene-bis(2-arylazo-1,3-aminovinylketones) are the main products in the reactions of fluoroalkyl-containing 2-arylhydrazono-1,3-diketones with ethylenediamine, diethylenetriamine and triethylenetetramine. Nickel(II) and copper(II) chelates were obtained from N,N′-ethylene-bis(2-arylazo-1,3-aminovinylketones). 2-Arylhydrazono-3-fluoroacyl esters formed N,N′-ethylenediamides of 2-arylhydrazono-3-fluoroacylpropionic acids with ethylenediamine. Interaction of 2-arylhydrazono-3-fluoroacyl esters with diethylenetriamine and triethylenetetramine resulted in and decomposition products.     

Acid-promoted reaction of trimethylsilylketene bis(ethylthio)acetal with imines. Synthesis of gamma,gamma-bis(ethylthio)allylamines

Acid-catalyzed reaction of silylketene dithioacetal 1 with iminium salts or imines 3b,d-h gave the corresponding gamma,gamma-bis(ethylthio)allylamines 2a-h or 5b,d-h in generally high yields. Similar reactions of 1 with (salicylidene)amines 6a-e afforded 4-amino-2,2-bis(ethylthio)chromans 8a-e in good to moderate yields.