Preparation of new nitrogen-bridged heterocycles. 54.increased arene-arene interactions of 3-(bicyclic and tricyclic arylmethylthio)thieno[3,4-b]indolizine derivatives

Some thieno[3,4-b]indolizine derivatives having a 1-naphthylmethylthio, 2-methyl-1-naphthylmethylthio, 2-naphthylmethylthio, or 9-anthrylmethylthio group at the 3-position were prepared and their intramolecular arene-arene interactions were investigated. In comparison with 3-(methylthio)thieno[3,4-b]indolizines which have no such interactions, the (1)H-NMR spectra of title compounds showed large high-field shifts (delta 0.06-0.89 ppm) for the protons of the pyridine ring in the thieno[3,4-b]indolizine, and these values were considerably larger than those (delta <0.3 ppm) in 3-(benzylthio)thieno[3,4-b]indolizines. The UV spectra also exhibited a characteristic absorption band near 425 nm attributable to the arene-arene interaction. In the X-ray analyses of some compounds, however, the presence of both the gauche and the anti conformers at the sulfide spacer were confirmed.     

Preparation of new nitrogen-bridged heterocycles. 59. Syntheses and intramolecular interactions of 3-(acylmethylthio)- and 3-[(3-ethoxycarbonyl-2-propenyl)thio]thieno[3,4-b]indolizine derivatives

Various thieno[3,4-b]indolizine derivatives having an acylmethylthio or (3-ethoxycarbonyl-2-propenyl)thio group at the 3-position which could not be obtained by a conventional method were prepared by a new procedure using cyanoethyl group as a protecting group and their intramolecular arene-pi interactions were investigated. In the (1)H-NMR spectra of these thieno[3,4-b]indolizines, the low-field shifts (delta 0.10-0.33 ppm) for the 5-protons were observed in comparison with those of 3-(methylthio)thieno[3,4-b]indolizines as a standard. The UV spectra also exhibited a characteristic absorption band at 425-445 nm attributable to the arene-pi interaction but their intensities were generally lower than those of 3-(arylmethylthio)thieno[3,4-b]indolizines. In their X-ray analyses, the anti conformation for 3-(acylmethylthio)thieno[3,4-b]indolizines and the gauche one for the 3-(3-ethoxycarbonyl-2-propenyl)thio derivatives were exhibited.     

Preparation of new nitrogen-bridged heterocycles. 55. Reinvestigation of the bromination/dehydrobromination of ethyl 3-[2-(methylthio)indolizin-3-yl]acrylate derivatives

The bromination/dehydrobromination reactions of ethyl 3-[1-alkoxycarbonyl-2-(methylthio)indolizin-3-yl]acrylates were reinvestigated. Reactions of the title compounds with two equivalents of bromine, followed by heating of the resulting reaction mixture and then treatment with a base gave the unexpected dialkyl 7-bromothieno[2,3-b]indolizine-2,9-dicarboxylates, while similar reactions using benzyltrimethylammonium tribromide as a brominating agent afforded only non-brominated thieno[2,3-b]indolizine derivatives, which were converted to the corresponding 7-bromo derivatives upon further treatment with bromine.     

Synthesis and Reactions of Some New Heterocyclic Compounds Containing Cycloalka[e]thieno[2,3‐b]pyridine Moiety

Hydrolysis of ethyl 3-amino-4-aryl-cycloalka[e]thieno[2,3-b]pyridine-2-carboxylates ( 3a-d) gave the corresponding o-aminocarboxylic acids 4a-d . Heating the latter compounds ( 4a-d) with acetic anhydride furnished the oxazinone derivatives 5a-d which, in turn, underwent recyclization reaction to give the corresponding pyrimidinones 6a-d upon treatment with ammonium acetate in acetic acid. Reaction of 3-amino-4-aryl-cycloalka[e]thieno[2,3-b]pyridine-2-carboxamides ( 3f,h ) with triethyl orthoformate gave pyrimidinone derivatives 7a,b . Reaction of 3-amino-4-phenyl-cycloalka[e]thieno[2,3-b]pyridine-2-carboxamides 3e,h with aromatic aldehydes furnished tetrahydropyridothienopyrimidinones 8a-d . Chlorination of 7a,b and 6a-d by using phosphorous oxychloride produced 4-chlorocycloalka[5′,6′]pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine derivatives 9a-f which were used as key intermediates in the synthesis of several new cycloalkapyrido-thienopyrimidines 10a-f ˜ 14a-f . Moreover, some cycloalkapyridothienotriazinones 15a,b-17a,b were synthesized.     

Studies on disease-modifying antirheumatic drugs. IV. Synthesis of novel thieno[2,3-b:5,4-c']dipyridine derivatives and their anti-inflammatory effect.

The syntheses and anti-inflammatory activities of novel thieno[2,3-b]pyridine and thieno[2,3-b:5,4-c']-dipyridine derivatives are described. These compounds were designed by modification of the quinoline template of a new type of disease-modifying antirheumatic drug (DMARD), TAK-603, and prepared by the Friedl?nder reaction as a key reaction. Their anti-inflammatory effects were evaluated using an adjuvant arthritis rat model. Most of the compounds which included a diethylamino moiety in the side chain had potent anti-inflammatory effect. In particular, ethyl 2-(diethylaminomethyl)-4-(3,4-dimethoxyphenyl)thieno[2,3-b:5,4-c'] dipyridine-3-carboxylate (21) exhibited more potent activity than TAK-603.     

Reactions of some new thienothiophene derivatives

Facile and convenient syntheses of bisdimethylthieno[2,3-b]thiophen-2,5-diyl bis(oxazole-2-amine), bis(1H-imidazol-2-amine), bis((3a)-H-indole),[1,2-a]pyrimidine), bis(1H-imidazo[1,2-b][1,2,4]triazole) and bis(9H-benzo[d]imidazo[1,2-a]imidazole) derivatives incorporating a thieno[2,3-b]thiophene moiety from the versatile and readily accessible 1,1'(3,4-dimethylthieno[2,3-b]thiophene-2,5-diyl)-bis(2-bromo-ethanone) (1) are described.     

Structural effects on the electronic properties of extended fused-ring thieno[3,4-b]pyrazine analogues

The synthesis and characterization of the extended thieno[3,4-b]pyrazine analogues acenaphtho[1,2-b]thieno[3,4-e]pyrazine (3a), 3,4-dibromoacenaphtho[1,2-b]thieno[3,4-e]pyrazine (3b), 3-octylacenaphtho[1,2-b]thieno[3,4-e]pyrazine (3c), dibenzo[f,h]thieno[3,4-b]quinoxaline (4), and thieno[3',4':5,6]pyrazino[2,3-f][1,10]phenanthroline (5) are reported. Comparison of structural, electrochemical, and photophysical properties to those of simple thieno[3,4-b]pyrazines are provided in order to provide structure-function relationships within this series of compounds.     

Preparation of new nitrogen-bridged heterocycles. 58. Syntheses and intramolecular arene-pi interactions of 3-(allylthio)- and 3-(propargylthio)thieno[3,4-b]indolizine derivatives

Various thieno indolizine derivatives having an allylthio or propargylthio group at the 3-position were prepared and their intramolecular arene-pi interactions were investigated. Their 1H-NMR spectra showed significant low-field shifts (delta 0.10-0.34 ppm) to the 5-proton on the thieno indolizine ring, and this effect was the reverse to that observed in 3-(arylmethylthio)thieno indolizines. However, their UV spectra exhibited a characteristic absorption band due to the arene-pi interaction near 430 nm and these values were almost similar to those for arene-arene interaction of 3-arylmethylthio derivatives though their molar extinction coefficients were largely varied by the 3-substituents. Furthermore, both types of gauche conformations in which the intramolecular arene-pi interactions are possible in one form and impossible in the other were confirmed by X-ray analyses of some compounds.     

1,3-Disubstitutedpyrazole-4-caboxaldehyde in Heterocyclic Synthesis: A Novel Synthesis of Pyridine-2(1H)-thione and Fused Nitrogen and/or Sulfur Heterocyclic Derivatives

Pyridine-2(1H)-thione 5 was synthesized from the reaction of 3-[3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl]-1-phenylpropenone (3) and cynothioacetamide (4). Compound 5 reacted with halogented compounds 6a–e to give 2-S-alkylpyridine derivatives 7a–e, which could be in turn cyclized into the corresponding thieno[2,3-b]-pyridine derivatives 8a–e. Compound 8a reacted with hydrazine hydrate to give 9. The latter compound reacted with acetic anhydride (10a), formic acid (10b), acetic acid, ethyl acetoacetate, and pentane-2,4-dione to give the corresponding pyrido[3′,2′:4,5]thieno-[3,2-d]pyrimidine 13a,b, pyrazolo[3′,4′:4,5]thieno[3,2-d]pyridine 14 and thieno[2,3-b]-pyridine derivatives 18 and 20, respectively. Alternatively, 8c reacted with 10a,b and nitrous acid to afford the corresponding pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 24a,b and pyrido[3′,2′:4,5]thieno[3,2-d][1,2,3]triazine 26 derivatives, respectively. Finally compound 5 reacted with methyl iodide to give 2-methylthiopyridine derivative 27, which could be reacted with hydrazine hydrate to yield the corresponding pyrazolo[3,4-b]-pyridine derivative 29.     

Potential antitumor agents. III. Synthesis of pyrazolo[3,4-e]pyrrolo[3,4-g]indolizine and 1H-pyrazolo[3,4-e]indolizine derivatives

The preparation of 5-dimethylaminoethyl-4,6-dioxo-1-phenyl-1,4,5,6-tetrahydropyrazolo[3,4-e]pyrrolo-[3,4-g]indolizine, a derivative of the still unknown tetracyclic parent ring pyrazolo[3,4-e]pyrrolo[3,4-g]indolizine, is reported starting from 1-phenyl-5-(1-pyrryl)pyrazole-4-acetonitrile by PPA catalyzed double cyclization of the related oxalylcyanomethyl derivative and subsequent alkylation. The synthesis of 4,5-bis(isopro-pylaminocarbonyloxymethyl) and 4,5-bis-(cyclohexylaminocarbonyloxymethyl) derivatives of 1-phenyl-1H-pyrazolo[3,4-e]indolizine is also described. The new tricyclic and tetracyclic derivatives were tested as potential antitumor agents.     

Preparation of new nitrogen-bridged heterocycles. 49. A new access to thieno[3,4-b]indolizine derivatives

The title compounds, together with 3-vinylindolizine-1-carbonitriles (4-56%), were prepared in 1-18% yields from the S-alkylation of pyridinium 1-[3-ethoxycarbonyl-1-[cyanomethylthio(thiocarbonyl)]]all ylides with alkyl halides, followed by treatment of the resulting pyridinium salts with a base and then a dehydrogenating agent. In several reactions of pyridinium salts obtained from reaction of the allylides with benzylic halides, trace amounts of bis[1-cyano-9-(ethoxycarbonyl)thieno[3,4-b]indolizin-3-yl] disulfides with an interesting superimposed structure were also isolated. The structures of these compounds were confirmed by X-ray analyses.     

Synthesis of New Polyfused Thienopyrimidine,Thienopyridine, Thienothiazine,Thienoxazine, and Thienodiazepine Derivatives

3,4-Diamino-2-carbethoxy-5-cyanothieno(2,3-b)thiophene (1) was treated with ethylenediamine to afford 3,4-diamino-2,5-bi[2-(4,5-dihydro-1H-imidazole-2-yl]-thieno(2,3-b)thiophene 2 , which in turn was treated with chloroacety chloride to give bis[imidazolothieno diazepine] derivative 3 and with each of p-chlorobenzaldehyde, triethyl orthoformate, and Lawesson's reagent (LR) to yield bis[imidazolothienopyrimidine] derivatives 4-6 . Compound 1 was subjected to Mannich reaction to afford Mannich bases 7 and 8a , b . The later products ( 8a , b ) were treated with malononitrile yielding 9a and 9b . Treatment of compound 1 with CS 2 , NaOH and CH 3 I produced compounds 10 and 11 . The reaction of compound 10 with each of o-aminothiphenal, o-phenylenediamen, hydrazine hydrate, and phenylhydrazine afforded compounds 12a , b , 13a , b . Compound 1 was allowed to react with CS 2 , phenyl (benzoyl)isothiocyanate and phenylisocyanate to get the described products 14-19 , respectively. On reacting compound 1 with ethylcyanoacetate thieno(2,3-b)pyridine derivative 21 was obtained through the intermediate 20 . Finally, compound 1 was treated with malononitrile to yield compound 22 .     

Condensed thienopyrimidines. II. Synthesis and gastric antisecretory activity of thiazole and polymethylene condensed thienopyrimidine derivatives

Thiazolo[3,2-a]thieno[3,2-d]-, [3,4-d]- and [2,3-d]pyrimidin-5-one derivatives (6, 11 and 16), and polymethylene condensed thieno[3,2-d]-, [3,4-d]- and [2,3-d]pyrimidin-5-one derivatives (19-21), in which the oxygen atom of the oxazolidine moiety in 3 was replaced by a sulfur atom or methylene groups, were synthesized and evaluated for gastric antisecretory activity in pylorus-ligated rats. The structure-activity relationships of these compounds are discussed.     

Facile synthesis of some novel pyrido[3',2':4,5]thieno[2,3-b][1,4]thiazine-8-carboxylic acids

Model tetrahydropyrido[3',2':4,5]thieno[2,3-b][1,4]thiazines 9a-c were synthesized via reductive lactamization, using sodium dithionite, of the respective 2-[(carboxyalkyl)thio]-3-nitro-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acids 7a-c. The latter derivatives were made via interaction of 2-chloro-7-cyclopropyl-3-nitro-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid (6) with each of alpha-mercaptoacetic, alpha-mercaptopropionic, and alpha-mercaptosuccinic acids and triethylamine in aqueous acetone at room temperature. The structures of 7a-7c and 9a-9c are supported by microanalytical and spectral (IR, MS, NMR) data. Compounds 9a and 9c showed potent inhibitory activity against the IGROV1 (Ovarian Cancer) cell line.     

Fused pyrazolopyrimidines II. Thieno[3″,2″:5′,6′]pyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrimidines

The reaction of 3-amino-1H-pyrazolo[3,4-d]thieno[2,3-b]pyridine with 1,3-dicarbonyl compounds and with ethoxy-methylene reagents gives the title ring system and its derivatives. The electrophilic substitutions occur in the thiophene ring of the system.     

Thieno[3,4-b]pyrazines and their applications to low band gap organic materials

The application of fused-ring thieno[3,4-b]pyrazines in conjugated organic polymers has been found to be a powerful approach to the production of low band gap materials. While thieno[3,4-b]pyrazine-based materials date back to the early 1990s, significant advances in the preparation and scope of thieno[3,4-b]pyrazine-based materials have been reported in recent years, primarily in response to the increasing demand for reduced band gap materials in photovoltaic devices. In this review, we provide an overview of thieno[3,4-b]pyrazines and their application to conjugated materials, highlighting in particular the recent advances in the breadth of thieno[3,4-b]pyrazine building blocks and the promise of tuning materials to achieve optimal properties for specific applications.     

1,1-Disubstituted-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolecarboxylic acid esters and ketones. The base catalyzed transformation of 1-(2′,3′,4′,9′-tetrahydrospiro[cyclohexane-1,1′-[1H]pyrido[3,4-b]indol]-2-yl)alkanones into 2-(4,9-dihydro-3H-pyrido[3,4-b]indol-1-yl)-1 -alkylcyclohexanols

Condensation of 1H-indole-3-ethanamines 1 with cyclic β-keto esters 2 under azeotropic conditions followed by acid-catalyzed ring closure of the resulting enamines 3 gave 2′,3′,4′,9′-tetrahydrospiro[piperidine-3,1′,-[1H]pyrido[3,4-b]indole] -4-carboxylic acid alkyl esters 4 . Condensation of 1 with 2-acylcycloalkanones 8 gave two types of enamines, 10 and 11 , respectively. Enamines 10 on treatment with acid gave 1-(2′,3′,4′,9′-tetrahydro-3H-pyrido[3,4-b]indol-1-yl)-1-alkylcyclohexanols 17 . Compounds 17 were further dehydrated to give cycloalkane derivatives 19.     

Synthesis of cycl[3.2.2]azine and benzo[g]cycl[3.2.2]azine derivatives by use of the [2 + 8] cycloaddition reaction of indolizines and dimethyl acetylenedicarboxylate

The reaction of 1-ethoxycarbonylmethylpyridinium bromides 5a-k with nitro ketene dithioacetal, 1,1-bis-(methylthio)-2-nitroethylene ( 2 ), in the presence of triethylamine in ethanol gave the desired ethyl 2-methyl-thioindolizine-3-carboxylates 3a-k in good yields, along with ethyl 2-methylthio-1-nitroindolizine-3-carboxyl-ates 4a-d . Deesterification of 3 using sodium hydroxide in methanol followed by treatment with polyphosphoric acid gave the corresponding 2-methylthioindolizines 5a-d in good yields. The desulfurization of 5 with Raney-nickel in ethanol occurs smoothly to give the 1,2,3-unsubstituted indolizines 6a-c (a , parent indolizine; b , 8-methylindolzine; c , 6,8-dimethylindolizine). Similarly, pyrrolo[2,1-a]isoquinoline ( 19 ) was also synthesized. These indolizine and pyrrolo[1,2-a]isoquinoline derivatives were allowed to react with dimethyl acetylene to give the corresponding cycl[3.2.2]azine and benzo[g]cycl[3.2.2]azine derivatives in good results.     

A highly selective fluorescence chemosensor for Pb(II) in neutral buffer aqueous solution

A 3,4-dimethylthieno[2,3-b]thiophene-based fluorogenic probe bearing benzo[d]-thiazole-2-thio unit (sodium 3,4-bis ((benzo[d]thiazol-2-ylthio)methyl) thieno [2, 3-b]thio-phene-2, 5-dicarboxylate) was developed as a novel fluorescent chemosensor with high selectivity towards Pb(II) over other cations tested. The new probe exhibited good water solubility and only sensed Pb(II) among metal ions examined in neutral 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffer solution. The selectivity and sensitivity of fluorogenic probe to Pb(II) were discussed on the basis of experimental results.     

Synthesis of dihydrodiol metabolites implicated in the mechanism of carcinogenesis of phenanthro[4,3-b][1]benzothiophene and phenanthro[3,4-b][1]benzothiophene,the polycyclic sulfur heterocycles with a "Fjord" structure

Dihydrodiols, which are potential proximate carcinogens of phenanthro[4,3-b][1]benzothiophene (3) and phenanthro[3,4-b][1]benzothiophene (4) and possess a "fjord" structure, were synthesized. The dihydrodiols synthesized were trans-3,4-dihydroxy-3,4-dihydrophenanthro[4,3-b][1]benzothiophene (5) and trans-3,4-dihydroxy-3,4-dihydrophenanthro[3,4-b][1]benzothiophene (6). The precursors to the dihydrodiols 5 and 6 were 3-methoxyphenanthro[4,3-b][1]benzothiophene (11) and 3-methoxyphenanthro[3,4-b][1]benzothiophene (16). Compound 11 was obtained via Suzuki cross-coupling reaction of easily accessible starting materials. However, this synthetic strategy utilizing Suzuki reaction for the preparation of 16 was comparatively less productive than that described previously due to time-consuming synthesis of the starting material(s), and extremely poor yield associated with cyclization of the epoxide 15 to 16. The methoxy derivatives 11 and 16 were converted to the corresponding dihydrodiols 5 and 6 by a sequence involving demethylation, oxidation, and reduction. The trans-stereochemistry of the dihydrodiols was established by (1)H NMR, which indicated a large coupling constant between vicinal carbinol protons. The UV spectra of the dihydrodiols 5 and 6 are presented.