Synthesis and Structure of 4-Indolyl-5-(thieno[3,2-<Emphasis Type="Italic">b</Emphasis>]pyrrol-6-yl)imidazoles

A procedure was proposed for regioselective acylation of methyl 2-methyl-4H-thieno[3,2-b]-pyrrole-5-carboxylate with 2-(3-indolyl)-2-oxoacetyl chloride. Reactions of the resulting methyl 6-[2-(3-indolyl)-1,2-dioxoethyl]-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate with aromatic aldehydes and ammonium acetate in acetic acid afforded the corresponding methyl 6-[2-aryl-4-(3-indolyl)imidazol-5-yl]-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylates. The structure of methyl 6-[2-(4-chlorophenyl)-4-(3-indolyl)imidazol-5-yl]-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate was studied by X-ray analysis.     

Effect of the β-substituent with respect to the azido group on the reactivity of methyl (2E)-3-[5-(azidomethyl)-2,2-diethyl-1,3-dioxolan-4-yl]-2-methylprop-2-enoate

Unlike methyl (2E)-3-[5-(azidomethyl)-2,2-diethyl-1,3-dioxolan-4-yl]-2—methylprop-2-enoate which is stable on storage, its acyclic derivative, methyl (2E,4S,5S)-6-azido-5-hydroxy-2-methyl-4-(pent-3-yloxy) hex-2-enoate at 20°C undergoes unusual decomposition with formation of exo-methylidenepyrrolidine. Analogous transformation was also observed in the epoxide ring opening in methyl (2E)-2-methyl-4-[(S)-oxiran-2-yl]-4-(pent-3-yloxy)but-2-enoate and in the substitution reaction of ethyl 5,6-bis(methanesulfonyloxy)-2-methyl-4-(pent-3-yloxy)hex-2-enoate with azide ion. Opening of the oxirane ring in the former by the action of azide ion was accompanied by formation of oxazetidine derivative as a minor product. The major intramolecular cyclization products, 4-hydroxy- and 4-mehtanesulfonyloxypyrrolidines were converted into stable pyrrole derivatives via elimination of the leaving groups. The hydrogenation of methyl and ethyl (2E)-3-[5-(azidomethyl)-2,2-diethyl-1,3-dioxolan-4-yl]-2-methylprop-2-enoates over palladium catalyst afforded the expected reduction products.     

1,3- versus 1,4-[π4+π2] Cycloadditions between methyl glyoxylate oxime and cyclopentadiene or cyclopentene

The acid catalyzed cycloaddition reaction of methyl glyoxylate oxime with cyclopentadiene (CPD) afforded the corresponding aza-Diels–Alder adducts, the endo and exo isomers of (±)-methyl 2-hydroxy-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylates, and as the major product a 1,3-cycloadduct, methyl (1RS,4RS,5RS)-(2-oxa-3-azabicyclo[3.3.0]oct-7-ene)-4-carboxylate. The similar reaction using cyclopentene (CP) provided only the 1,3-cycloadduct methyl (1SR,4RS,5SR)-(2-oxa-3-azabicyclo[3.3.0]octane)-4-carboxylate. The influence of various parameters on the reaction outcome was studied and, based on the results obtained, a mechanism for the formation of both 1,3- and 1,4-cycloadducts is proposed. The structure of all adducts was confirmed by NMR spectroscopic data and/or by X-ray crystallography.     

Three-Component Spiro Heterocyclization of Pyrrolediones with Indan-1,3-dione and Acyclic Enamines

Ethyl 4,5-dioxo-2-phenyl-4,5-dihydro-1H-pynole-3-carboxylates reacted with indan-1,3-dione and 3-amino-1-phenylbut-2-en-1-one or 3-aminobut-2-enenitrile to give 3-benzoyl-2-methyl-2′,5-dioxo-5′-prienyl-1,1′,2′,5-tetrahydrospiro[indeno[1,2-b]pyridine-4,3′-pyrroles] and 2-methyl-2′,5-dioxo-5′-phenyl-1,1′,2′,5-tetrahydrospiro[indeno[1,2-b]pyridine-4,3′-pyrrole]-3-carbonitriles, respectively.

     

Photochemical Synthesis and Some Reactions of 7-Oxa-and 7-Thiatricyclo[3.2.1.03,6]octan-2-ones

Irradiation (λ = 350 nm) of newly synthesized 2-acetyl- or 2-methyl-2-(alk-2-enyl)furan-3(2H)-ones 1 and 2-acetyl- or 2-methyl-2-(prop-2-enyl)thiophen-3(2H)-ones 2 affords the corresponding 1-acetyl- or 1-methyl-substituted 7-oxa- and 7-thiatricyclo[3.2.1.0^3,6]octan-2-ones 10 and 11 , respectively, via regioselective intramolecular [2 + 2] photocycloaddition in 65–95% yield (Scheme 2). The 1-acetyl-substituted O-derivatives 10b and 10c undergo ring opening on treatment with MeONa in MeOH at–78° to afford stereoselectively methyl 3-exo-acetyl-2-oxabicyclo[3.2.0]heptane-7-endo-carboxylates 12b and 12c , respectively, while a 2:1 diastereoisomeric mixture of methyl 3-acetyl-2-thiabicyclo[3.2.0]heptane-7-endo-carboxylates 13 and 14 is obtained from the corresponding S-derivative 11b . The outcome of the Huang-Minlon reduction of the 1-methyl-substituted ketones 10a and 11a is again influenced by the heteroatom in the tricycle. While 1-methyl-7-oxatricyclo[3.2.1.0^3,6]-octane ( 15 ) is the only product from the corresponding oxatricyclooctanone 10a , a 1:2 mixture of 1-methyl-7-thiatricyclo[3.2.1.0^3,6]-octane ( 16 ) and 3-methylbicyclo[3.1.1]hept-2-ene-6-endo-thiol ( 17 ) is obtained from the analogous S-compound 11a , both products stemming from a common carbanion precursor.     

Recyclization of ethyl 1-alkyl-5-benzoyl-6-methylsulfanyl-2-oxo-1,2-dihydropyridine-3-carboxylates into Bicyclic <Emphasis Type="Italic">N</Emphasis>-alkyl-5-benzoyl-2-oxo-1,2-dihydropyridine-3-carboxamide derivatives by the action of nitrogen-containing 1,4- and 1,5-binucleophiles

Reactions of ethyl 1-alkyl-5-benzoyl-6-methylsulfanyl-2-oxo-1,2-dihydropyridine-3-carboxylates with nitrogen-containing 1,4- and 1,5-binucleophiles (o-phenylenediamine, o-aminobenzenethiol, ethane-1,2-diamine, and propane-1,3-diamine) involved recyclization, leading to the formation of fused N-alkyl-5-benzoyl- 2-oxo-1,2-dihydropyridine-3-carboxamides, diethyl 6,6′-oxybis(1-alkyl-5-benzoyl-2-oxo-1,2-dihydropyridine-3-carboxylates), and diethyl 6,6′-[ethane-1,2-diyl(or propane-1,3-diyl)diimino]bis(1-alkyl-5-benzoyl-2-oxo-1,2-dihydropyridine-3-carboxylates), depending on the reactant ratio. The sequence of formation of intermediate recyclization products was determined.     

Synthesis of substituted 2,3,5,6,7,8-hexahydropyrazolo[4,3-d][1,2]diazepine-8-carboxylates

Substituted 2,3,5,6,7,8-hexahydropyrazolo[4,3-d][1,2]diazepine-8-carboxylates were prepared in good to excellent yields from ethyl (2E)-3-(dimethylamino)-2-{(4Z)-4-[(dimethylamino)methylidene]-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl}propenoate with 1,2-disubstituted hydrazines by heating in an alcohol.     

Acid-Catalyzed Rearrangements of 5,6-exo-Epoxy-7-oxabicyclo[2.2.1]hept-2-yl Derivatives. Migratory Aptitudes of Acyl vs. Alkyl Groups in Wagner-Meerwein Transpositions

In the presence of HSO₃F/Ac₂O in CH₂CL₂, 2-exo- and 2-endo-cyano-5,6-exo-epoxy-7-oxabicyclo[2.2.1]hept-2-yl acetates ( 6a , b ) gave products derived from the epoxide-ring opening and a 1,2-shift of the unsubstituted alkyl group (σ bond C(3)–C(4)). In contrast, under similar conditions, the 5,6-exo-epoxy-7-oxabicyclo[2.2.1]heptan-2-one ( 6c ) gave 5-oxo-2-oxabicyclo[2.2.1]heptane-3,7-diyl diacetates 20 and 21 arising from the 1,2-shift of the acyl group. Acid treatment of 5,6-exo-epoxy-2,2-dimethoxy-7-oxabicyclo[2.2.1]heptane ( 6d ) and of 5,6-exo-epoxy-2,2-bis(benzyloxy)-7-oxabicyclo[2.2.1]heptane ( 6e ) gave minor products arising from epoxide-ring opening and the 1,2-shift of σ bond C(3)–C(4) and major products ( 25 , 29 ) arising from the 1,3-shift of a methoxy and benzyloxy group, respectively. Under similar conditions, 5,6-exo-epoxy-2,2-ethylenedioxy-7-oxabicyclo[2.2.1]heptane ( 6f ) gave 1,1-(ethylenedioxy)-2-(2-furyl)ethyl acetate ( 32 , major) and a minor product 33 , arising from the 1,2-shift of σ bond C(3)–C(4). The following order of migratory aptitudes for 1,2-shifts toward electron-deficient centers has been established: acyl > alkyl > alkyl α-substituted with inductive electron-withdrawing groups. This order is valid for competitive Wagner-Meerwein rearrangements involving equilibria between carbocation intermediates with similar exothermicities.     

Intramolecular heterocyclization of N-(pyrimidin-2-yl)imines of methyl trifluoropyruvate

The reactions of N-(pyrimidin-2-yl)imines of methyl trifluoropyruvate with trimethyl phosphite afforded methyl 3-fluoroimidazo[1,2-a]pyrimidin-2-carboxylates, which were transformed into N-substituted methyl 3-aminoimidazo[1,2-a]pyrimidine-2-carboxylates by the reactions with amines.     

Access to new 2-oxofuro[2,3-b]pyrroles and 2-methylenepyrroles through the reaction of 1,2-diaza-1,3-butadienes and gamma-ketoesters

New and interesting 2-oxofuro[2,3-b]pyrroles and 19-methyl-15-oxa-20-azatricyclo[12.3.3.0(1,14)]icos-18-en-18-carboxylates have been obtained in good yields by the one-pot reaction, in basic medium, of 1,2-diaza-1,3-butadienes with diethyl or dimethyl acetylsuccinate or methyl 2-(1,3-dioxo-2-cyclotetradecyl)acetate, respectively, under mild conditions. Treatment of the same starting materials with diethyl 2-acetylglutarate, in acidic medium, afforded unknown 2-methylenepyrrole derivatives in high yields. Novel 4-(3-oxopropyl)-2,5-dimethyl-1H-pyrrole-3-carboxylates also have been achieved by reacting 1,2-diaza-1,3-butadienes with ethyl or methyl 4-acetyl-5-oxo-hexanoate.     

Efficient preparation of 9-Z-11-methylretinal and 11-Z-11-methylretinal

[2-(β-Ionylidene)propyl]triphenylphosphonium bromide is reacted with 3-methyl-4-oxobut-2-enenitrile in refluxing 1,2-epoxybutane to give a mixture of 11-Z- and all-E-11-methylretinal via DIBAL-H reduction. In an analogous fashion, β-ionyl triphenylphosphonium bromide is reacted with 3,5-dimethyl-6-oxohexa-2,4-dienenitrile in 1,2-epoxybutane followed by subsequent DIBAL-H reduction to afford a mixture of new products consisting of 9-Z-11-methylretinal, its all-E isomer and 1-(2′,6′,6′-trimethylcyclohex-2′-en-1′-yl)-6-(buten-2″-al-3″-yl)-3,5-dimethylcyclohexa-1,3-diene. These molecules were obtained in pure form by HPLC.     

Three-Component Spiro Heterocyclization of Pyrrolediones with Malononitrile and Cyclic Enols

Ethyl 4,5-dioxo-2-phenyl-4,5-dihydro-1H-pyrrole-3-carboxylates reacted with malononitrile and five-membered cyclic enols, indan-1,3-dione and cyclopentane-1,3-dione to give 1-substituted ethyl 2-amino-3- cyano-2′,5-dioxo-5′-phenyl-1′,2′-dihydro-5H-spiro[indeno[1,2-b]pyran-4,3′-pyrrole]-4′-carboxylates and ethyl 2-amino-3-cyano-2′,5-dioxo-5′-phenyl-1′,2′,6,7-tetrahydro-5H-spiro[cyclopenta[b]pyran-4,3′-pyrrole]-4′-carboxylates, respectively.     

Annulation reaction of methyl 2-(benzo[b][1,4]thiazin-3-ylidene)acetate with β-nitrostyrenes and 3-nitrochromenes

The acid catalyzed domino reaction of β-nitrostyrenes with methyl 2-(benzo[b][1,4]thiazin-3-ylidene)acetate, which were previously prepared from the cyclization of 2-aminobenzenethiol and methyl 4-chloroacetoacetate, resulted in 2-arylbenzo[b]pyrrolo[1,2-d][1,4]thiazine-3-carboxylates in high yields. Under same reaction conditions, the similar reaction with 3-nitrochromenes afforded corresponding benzo[b]chromeno[4′,3':4,5]pyrrolo[1,2-d][1,4]thiazine derivatives in good yields.     

Five-membered 2,3-dioxo heterocycles: LXXX. Recyclization of 1H-pyrrole-2,3-diones into pyrazolo[1,5-a]pyrimidines by the action of pyrazolamine. Crystalline and molecular structure of substituted pyrazolo[1,5-a]pyrimidine

Methyl 1-aryl-3-aroyl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates reacted with 3-methyl-4-phenyl-1H-pyrazol-5-amine to give methyl 7-arylcarbamoyl-6-aroyl-2-methyl-3-phenylpyrazolo[1,5-a]-pyrimidine-5-carboxylates. The molecular and crystalline structures of methyl 6-benzoyl-7-(4-chlorophenylcarbamoyl)-2-methyl-3-phenylpyrazolo[1,5-a]pyrimidine-5-carboxylate were studied by X-ray analysis.     

Synthesis of 3-pyrrol-3′-yloxindoles with a carbamate function

By the reaction of methyl {4(3)-[2-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetyl]phenyl} carbamates with ethyl 3-aminocrotonate at boiling in the mixture toluene-anhydrous ethanol, 2: 1, ethyl 5-{3(4)-[(methoxycarbonyl)amino]phenyl}-2-methyl-4-(2-oxo-2,3-dihydro-1H-indol-3-yl)-1H-pyrrole-3-carboxylates were obtained. The condensation of methyl {3(4)-[2-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetyl] phenyl}carbamates with ethyl acetoacetate in the presence of ammonium acetate and 20 mol% of 1-methyl-3-butylimidazolium chloride or 1-methyl-3-octylimidazolium tetrafluoroborate at boiling in anhydrous ethanol led to the formation of the corresponding 3-pyrrol-3′-yloxindoles with a carbamate function.     

Synthesis of diarylazolo[<Emphasis Type="Italic">a</Emphasis>]pyridines from [(<Emphasis Type="Italic">Z</Emphasis>)-2,4-diaryl-4-oxo-2-butenyl]azolium salts

A method for the synthesis of derivatives of [1, 3]thiazolo[3,2-a]pyridines, pyrido[2,1-b][1, 3]benzo-thiazole, [1, 3, 4]thiadiazolo[3,2-a]pyridine, and [1, 2, 4]triazolo[4,3-a]pyridine, which includes base initiated cyclization of quaternary azolium salts, formed by the interaction of (Z)-1,3-diaryl-4-bromo-2-buten-1-ones with 1-alkyl-1H-1,2,4-triazoles, 4-methyl-1,3-thiazole, 1,3-benzothiazole, and N-phenyl-1,3,4-thiadiazole-2-amine. Derivatives of 2-chloroimidazo[1,2-a]pyridine were obtained when 5-chloro-1-methyl-1H-imidazole was used.     

Heterocyclizations of 5-methylpyrazol-3-amine with unsaturated arylaliphatic carboxylic acid derivatives

Cyclocondensation of 5-methylpyrazol-3-amine with methyl cinnamate and arylmethylidenemalonic acids in DMF and methanol leads to the formation of 7-aryl-2-methyl-6,7-dihydropyrazolo[1,5-a]-pyrimidin-5(4H)-ones. Arylmethylidenemalonic acids react with the title amine at a ratio of 1:2 in nitrobenzene to give 4-aryl-3,5-dimethyl-1,7-dihydrodipyrazolo[3,4-b:4′,3′-e]pyridines. Heterocyclizations of 5-methylpyrazol-3-amine with 5-arylmethylidene-2,2-dimethyl-1,3-dioxane-4,6-diones or their precursors, para-substituted benzaldehydes and 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum’s acid) in all solvents (methanol, DMF, and nitrobenzene) give the corresponding 4-aryl-3-methyl-2,4,5,7-tetrahydropyrazolo[3,4-b]pyridin-6-ones. The structure of 3-methyl-4-(4-nitrophenyl)-2,4,5,7-tetrahydropyrazolo[3,4-b]pyridin-6-one was proved by X-ray analysis.     

Synthesis of 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide

The reaction of methyl 2-bromo-6-(trifluoromethyl)-3-pyridinecarboxylate ( 1 ) with methanesulfonamide gave methyl 2-[(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridine-carboxylate ( 2 ). Alkylation of compound 2 with methyl iodide followed by cyclization of the resulting methyl 2-[methyl(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridinecarboxylate ( 3 ) yielded 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 4 ). The reaction of compound 4 with α,2,4-trichlorotoluene, methyl bromopropionate, methyl iodide, 3-trifluoromethylphenyl isocyanate, phenyl isocyanate and 2,4-dichloro-5-(2-propynyloxy)phenyl isothiocyanate gave, respectively, 4-[(2,4-dichlorophenyl)methoxy]-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazine 2,2-dioxide ( 5 ), methyl 2-[[1-methyl-2,2-dioxido-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4-yl]oxy]propanoate ( 6 ), 1,3,3-trimethyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 7 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-[3-(trifluoromethyl)phenyl]-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 8 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-phenyl-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 9 ) and N-[2,4-dichloro-5-(2-propynyloxy)phenyl]-4-hydroxy-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2] thiazine-3-carboxamide 2,2-dioxide ( 10 ).     

Reaction of chloroacetylenephosphonates with 5-thiotetrazoles

1-Chloroacetylene-2-phosphonates react with 1-substituted 5-thio-1H-1,2,3,4-tetrazoles in anhydrous acetonitrile to form new fused heterocycles, 6-(dialkoxyphosphoryl)-3H-[1,3]thiazolo[3,2-d][1,2,3,4]tetrazol-7-ium chlorides, with a small quantity of Z-dialkyl (1,2-bis{[1-amino(methyl/phenyl)-1H-tetrazol-5-yl]sulfanyl}ethenyl)phosphonates.     

Synthesis of new functionally substituted hetarylcarbamates from methyl {4-[(2<Emphasis Type="Italic">E</Emphasis>)-3-(4-methoxyphenyl)-prop-2-enoyl]phenyl}carbamate

Three-component condensation of methyl {4-[(2E)-3-(4-methoxyphenyl)prop-2-enoyl]phenyl}- carbamate with ninhydrin and L-proline in methanol–water (10: 1) afforded methyl {4-[1,3-dioxo-1′- (4-methoxyphenyl)-1,1′,2′,3,5′,6′,7′,7a′-octahydrospiro[indene-2,3′-pyrrolizin]-2′-ylcarbonyl]phenyl}carbamate. Heating of methyl {4-[(2E)-3-(4-methoxyphenyl)prop-2-enoyl]phenyl}carbamate with isatin and benzylamine in methanol gave methyl {4-[4′-(4-methoxyphenyl)-2-oxo-5′-phenyl-1,2-dihydrospiro[indole-3,2′-pyrrolidin]-3′-ylcarbonyl]phenyl}carbamate. The condensation of methyl {4-[(2E)-3-(4-methoxyphenyl)prop-2- enoyl]phenyl}carbamate with sarcosine and 11H-indeno[1,2-b]quinoxalin-11-one generated in situ from ninhydrin and o-phenylenediamine in boiling ethanol led to the formation of methyl {4-[4′-(4-methoxyphenyl)-1′-methyl-11,11a-dihydro-5aH-spiro[benzo[b]phenazine-6,2′-pyrrolidin]-3′-ylcarbonyl]phenyl}carbamate.