Intramolecular 4+2 cycloaddition of thieno[2,3-e][1,2,4]triazines: routes towards condensed thieno[2,3-b]pyridines

Synthetic approaches towards new condensed thienopyridine ring systems including furo[2,3-b]thieno[3,2-e]pyridines, bisthieno[2,3-b:3′,2′-e]pyridines, 5H-chromeno[2,3-b]thieno[3,2-e]pyridines, 5H-benzo(f)chromeno[2,3-b]thieno[3,2-e]pyridines have been achieved by application of intramolecular 4+2 cycloaddition reactions of suitably designed thieno[2,3-e][1,2,4]triazines tethered with alkene or alkyne terminals.     

A new route to pyrazolo[3,4-c] and [4,3-c]pyridinones via heterocyclization of vic-substituted hydroxamic acids of acetylenylpyrazoles

We report in this paper the synthesis of 6-substituted pyrazolo[4,3-c]pyridin-4-ones, 6-substituted 5-hydroxypyrazolo[4,3-c]pyridin-6-ones, 5-substituted pyrazolo[3,4-c]pyridin-7-ones and 5-substituted 6-hydroxypyrazolo[3,4-c]pyridin-7-ones by heterocyclization of vic-acetylenylpyrazol-hydroxamic acids under the influence of copper(I) salt in dimethylformamide or with organic bases in butanol or methanol.     

Novel fluoro-substituted benzo- and benzothieno fused pyrano[2,3-c]pyrazol-4(1H)-ones

A straightforward, two-step synthesis of fluoro substituted chromeno[2,3-c]pyrazol- and [1]benzothieno[2′,3′:5,6]pyrano[2,3-c]pyrazol-4(1H)-ones, respectively, is presented. Hence, treatment of 1-substituted or 1,3-disubstituted 2-pyrazolin-5-ones with fluoro substituted 2-fluorobenzoyl chlorides or 3-chloro-6-fluoro-1-benzothiophene-2-carbonyl chloride using calcium hydroxide in refluxing 1,4-dioxane gave the corresponding 4-aroylpyrazol-5-ols, which were cyclized into the fused ring systems. 5-Fluorochromeno[2,3-c]pyrazol-4(1H)-one was obtained upon treatment of the 1-(4-methoxybenzyl) protected congener with trifluoroacetic acid. Treatment of 5-fluorochromeno[2,3-c]pyrazol-4(1H)-ones with methylhydrazine afforded novel tetracyclic ring systems such as 2-methyl-7-phenyl-2,7-dihydropyrazolo[4′,3′:5,6]pyrano[4,3,2-cd]indazole. Detailed NMR spectroscopic investigations (¹H, ¹³C, ¹⁵N, ¹⁹F) with the obtained compounds were undertaken.     

Microwave assisted synthesis of 2,3-dihydro-4H-benzo[4,5]thiazolo[3,2-a]furo[2,3-d]pyrimidin-4-ones and 6,7-dihydro-5H-furo[2,3-d]thiazolo[3,2-a]pyrimidin-5-ones using Mn(OAc)3

2-Hydroxy-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-one 2a and 7-hydroxy-5H-thiazolo[3,2-a]pyrimidin-5-one 2b, were obtained in high yields under mild conditions from the cyclization reactions of bis-(2,4,6-trichlorophenyl) malonate and 2-aminobenzothiazole or 2-aminothiazole, respectively. A new class of compounds, 2,3-dihydro-4H-benzo[4,5]thiazolo[3,2-a]furo[2,3-d]pyrimidin-4-ones and 6,7-dihydro-5H-furo[2,3-d]thiazolo[3,2-a]pyrimidin-5-ones, were synthesized via the microwave assisted radical addition of compounds 2a and 2b to various alkenes using manganese(III) acetate. A preliminary acetylcholine esterase (AchE) inhibition test of compound 4e showed excellent (92%) inhibitory potential, comparable with the standard drug Donapezil®.     

Construction of new heteroacenes based on benzo[b]thieno[2,3-d]thiophene / quinoline or 1,8-naphthyridine systems using the Friedländer reaction

Two new classes of heteroacenes, namely benzo[4′,5′]thieno[2′,3′:4,5]thieno[3,2-b]quinolines and benzo[4′,5′]thieno[2′,3′:4,5]thieno[3,2-b][1,8]naphthyridines, have been formed using the Friedländer reaction to annulate the benzo[b]thieno[2,3-d]thiophene scaffold to quinoline or 1,8-naphthyridine fragments. In accordance with this synthetic strategy, benzo[b]thieno[2,3-d]thiophen-3(2H)-ones were treated with 2-aminobenzaldehydes or 2-aminonicotinaldehyde in the presence of pyrrolidine in glacial acetic acid at reflux to give the desired quinoline- or 1,8-naphthyridine-fused compounds, respectively. The optical and electrochemical properties of selected heteroacenes were determined.     

A convenient synthesis of furo[3,2-c]pyran-3-carboxylates from 3-bromo-3-nitroacrylates

Novel 4-oxo-4H-furo[3,2-c]pyran-3-carboxylates and 4-oxo- 4H-furo[3,2-c]chromene-3-carboxylates were prepared from available alkyl 3-bromo-3-nitroacrylates and 4-hydroxy-6- methyl-2H-pyran-2-one or 4-hydroxycoumarin, respectively. Their structures were confirmed by NMR and X-ray data.     

Microwave-assisted synthesis of novel N-(4-phenylthiazol-2-yl)-benzo[d]thiazole-, thiazolo[4,5-b]pyridine-, thiazolo[5,4-b]pyridine- and benzo[d]oxazole-2-carboximidamides inspired by marine topsentines and nortopsentines

We report the synthesis of novel N-(4-phenylthiazol-2-yl)-substituted benzo[d]thiazole-, thiazolo[4,5-b]pyridine-, thiazolo[5,4-b]pyridine- and benzo[d]oxazole-2-carboximidamides, which were inspired by marine topsentines and nortopsentines. Condensation of 4,5-dichloro-1,2,3-dithiazolium chloride (Appel salt) with various ortho-halogenated anilines, aminopyridines and aminophenols gave the corresponding aryliminodithiazoles in good to excellent yields. Copper(I)-mediated or nucleophilic-assisted cyclization of aryliminodithiazoles furnished cyano-functionalized benzo[d]thiazoles, thiazolo[4,5-b]- and thiazolo[5,4-b]-pyridines and benzo[d]oxazoles. The latter were condensed with substituted 4-phenylthiazol-2-amines to furnish twenty seven new polyaromatic carboximidamides in moderate to good yields.     

Oxidation products of 2-arylphenanthro-[9,10-d]imidazoles—II : Structure and photochromism of oxidation products of 2-(4-methoxyphenyl)-phenanthro-[9,10-d]imidazole

By ferricyanide oxidation of 2-(4-methoxyphenyl)phenanthro[9,10-d]imidazole, three new photochromic compounds were obtained. These were 4-ethoxy-4H-, 4-methoxy-4H- and 2-methoxy-2H-phenanthro[9,10-d]imidazoles. These compounds gave the 2-(4-methoxyphenyl)-phenanthro[9,10-d]imidazolyl radical and acetaldehyde or formaldehyde by light irradiation. The imidazolyl radical dimerized gradually in the dark and the dimer dissociated to the imidazolyl radical on heating.     

Synthesis and electrochemical evaluation of substituted imidazo[4,5-d]pyrrolo[3,2-f][1,3] diazepine scaffolds

Substituted 4-(2,5-dihydro-1H-pyrrol-3-yl)-1H-imidazoles were prepared from 5-amino-1-aryl-4-cyanoformimidoylimidazoles and cyanoacetamide, under mild experimental conditions. The pyrrolyl-imidazoles were cyclized to the corresponding 7,8-dihydroimidazo[4,5-b]pyrrolo[3,4-d]pyridines by reflux in ethanol, with catalysis by DBU. The same pyrrolyl-imidazoles were reacted with orthoesters, at room temperature and in the presence of sulfuric acid, to generate 3,7-dihydro-8H-imidazo[4,5-d]pyrrolo[3,2-f]diazepines in very good yield. Electrochemical studies of the imidazo[4,5-d]pyrrolo[3,2-f][1,3] diazepine derivatives were carried out. The reduction potential of 7-ethyl-3-(4-methoxyphenyl)-8-oxo-7,8-dihydro-3H-imidazo[4,5-d]pyrrolo[3,2-f][1,3] diazepine-9-carbonitrile was in the adequate range for presenting bioreduction properties.     

Imidazo- und Diazino-Anellierungen an das [1]Benzothieno[2,3—d]pyrimidin-System

Derivatives of the following six ring systems were synthesized:

1. 3,10-Dihydro-[1]benzothieno[2,3-d]imidazo[1,5-a]-pyrimidine (I)
2. 6H-[1]Benzothieno[2,3-d]pyrazino[1,2-a]pyrimidine (II)
3. 1,5-Dihydro-[1]benzothieno[2,3-d]imidazo[1,2-a]-pyrimidine (III)
4. 6H-[1]Benzothieno[2,3-d]pyrimido[1,2-a]pyrimidine (IV)
5. 1,5-Dihydro-imidazo[1,2-a]thieno[2,3-d]pyrimidine (V)
6. 4H-Pyrimido[1,2-a]thieno[2,3-d]pyrimidine (VI)

The first four types are new heterocyclic systems. 2-Aminomethyl-5,6,7,8-tetrahydro-[1]benzothieno[2,3-d]pyrimidin-4(3H)-one (5), which was used as intermediate for typesI andII, was synthesized by various methods. TypesIII andIV were prepared from 2-methylthio-5,6,7,8-tetrahydro-[1]-benzothieno[2,3-d]pyrimidin-4(3H)-one via the corresponding 2-benzylamino derivatives, followed by ring closure.     

Microwave-assisted synthesis of pyrazolo[3,4-b]pyridine-spirocycloalkanediones by three-component reaction of 5-aminopyrazole derivatives, paraformaldehyde and cyclic β-diketones

New pyrazolo[3,4-b]pyridine-5-spirocycloalkanedione derivatives were prepared via three-component reaction between 5-(4-R-benzylamino)pyrazoles, cyclic β-diketones and paraformaldehyde. The use of indandione as β-diketone resulted in the formation of two products, the pyrazolo[3,4-b]pyridine-5-spiroindanediones and 3-tert-butyl-1-phenylindeno[2,3-e]pyrazolo[3,4-b]pyridine. The structures of the pyrazolo[3,4-b]pyridine-5-spirocycloalkanedione were confirmed by single-crystal X-ray diffraction. This protocol provides a simple one-step synthetic methodology with the advantages of easy work-up, mild reaction conditions and environmentally benign.     

Synthesis of furo[2,3-c]-2,7-naphthyridine derivatives via domino heterocyclization reaction

2-Amino-4-cyanomethyl-6-dialkylamino-3,5-pyridinedicarbonitriles were found to react with substituted oxiranes yielding 5,6-diamino-8-dialkylamino-1,2-dihydrofuro[2,3-c]-2,7-naphthyridine-9-carbonitriles. The oxirane ring was shown to be opened selectively from the unsubstituted side and further cyclization occurred with participation of 3-CN, but not 5-CN of the starting pyridines. The furonaphthyridines obtained were converted into 2-dialkylamino-5-methyl-9,10-dihydro-4H-furo[2,3-c]pyrimido[4,5,6-ij]-2,7-naphthyridine-1-carbonitriles and 2-dialkylamino-5,6,9,10-tetrahydro-4H-spiro{furo[2,3-c]pyrimido[4,5,6-ij]-2,7-naphthyridine-5,1′-cyclohexane}-1-carbonitriles by treatment with acetic anhydride and cyclohexanone, respectively. The structure of prepared compounds was confirmed unambiguously by X-ray crystallographic study.     

Heterocycles [h]-fused onto 4-oxoquinoline-3-carboxylic acid, Part VI [1]. Synthesis and X-ray structure of model indolo[3,2-b]- and [2,3-b]pyrido[2,3-f]quinoxaline-3-carboxylic esters

Cyclocondensation reaction of ethyl 7,8-diamino-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate with 1-methylisatin produced a separable mixture of the corresponding indolo[3,2-b]- and [2,3-b]pyrido[2,3-f]quinoxaline-3-carboxylates, of which the latter isomer predominates. On the other hand, interaction with 1H-isatin or 5-chloroisatin gave the respective indolo[2,3-b]pyrido[2,3-f]quinoxaline-3-carboxylates as the sole regiospecific products. The structures of these new pentacyclic derivatives are based on microanalytical, spectral (IR, MS, and NMR) and X-ray crystal structure data.     

Preparation of novel pyridine-fused tris-heterocycles; pyrido[4,3-e]pyrrolo-/pyrido[4,3-e]furano[2,3-c]pyridazines and pyrido[3,4-b]pyrrolo[3,2-d]pyrrole

Three novel pyrido-fused tris-heterocycles have been prepared based on a Suzuki coupling and subsequent cyclisation approach. Pyrido[4,3-e]pyrrolo[2,3-c]pyridazine (3b, 77%) and pyrido[4,3-e]furano[2,3-c]pyridazine (5b, 76%) were obtained by intramolecular diazocoupling. Successful diazocoupling of furan (5b) is thus reported for the first time by NOBF₄ generation of the diazonium intermediate. N-TIPS-pyrido[3,4-b]pyrrolo[3,2-d]pyrrole (TIPS-4b) was synthesised by thermal cyclisation of pyridyl nitrene in considerably higher yield (71%) than previously experienced from similar cyclisations, due to TIPS-activation.     

New pyrrolo[3,2-b]pyrrole derivatives with multiple-acceptor substitution: Efficient fluorescent emission and near-infrared two-photon absorption

Two new D-π-A organic chromophores, 1,2,4,5-tetra(4-cyanophenyl)pyrrolo[3,2-b]pyrrole (4CNPP) and 1,2,3,4,5,6-hexa(4-cyanophenyl)pyrrolo[3,2-b]pyrrole (6CNPP), were developed by modifying the electron-rich pyrrolo[3,2-b]pyrrole (PP) unit with four and six 4-cyanophenyls respectively. The compounds exhibited bright blue emissions in low- to high-polarity solvents, with high Ф_fs of 88–90% in toluene, as well as impressive two-photon absorption cross-sections at the near-infrared (NIR) 700?nm.     

Synthesis of benzothieno[2,3-b]thiophenes, [2,3-b:3′,2′-d]-dithienothiophenes and their selenium derivatives via electrophilic cyclization and McMurry cyclization

Benzothieno[2,3-b]thiophenes, [2,3-b:3′,2′-d]-dithienothiophenes, and their selenium derivatives were synthesized in good yields from readily available 3-ethynyllithio-benzo[b]thiophenyllithio compounds, sulfur or selenium, and 2 equiv of acid chlorides. Two heteroarene rings were constructed by a twofold cyclization via an acid chloride-induced electrophilic ring closing and the McMurry cyclization using Zn/TiCl₄ reagents.     

One-pot synthesis of polycyclic heterocyclic compounds by condensation of 1-carbamoylmethyl-2,3,3-trimethyl-3H-indolium salts with pyridine-2, 3, and 4- and quinoline-4-carboxaldehydes

A one-pot synthesis of new polycyclic heterocyclic compounds was carried out via the condensation of 1-carbamoylmethyl-2,3,3-trimethyl-3H-indolium chloride with pyridine- and quinolinecarboxaldehydes. The heating of the aforementioned 3H-indolium salts with 1 eq. of pyridine-2, 3, and 4- or quinoline-4-carboxaldehyde in ethanol in the presence of piperidine as a catalyst provided 9a-[2-(pyridyl)ethenyl]- or 9a-[2-(quinolyl)ethenyl]-9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)-one derivatives as the main products. However, reaction outcome was dramatically different for the analogous reactions in acetic acid. In this case, the heating of the chloride with 2 eq. of pyridine-2-carboxaldehyde afforded derivatives of 9a-[3-(pyridin-2-yl)indolizin-2-yl]-9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)-one as the major product, while the use of 2 eq. of pyridine-3 and 4- or quinoline-4-carboxaldehyde led to the formation 2-heteroaryl-1-heteroarylmethyl-9H-pyrrolo[1,2-a]indole-3-carboxamides. Plausible pathways for the cyclization reactions are discussed. The structural assignments were based on ¹H, ¹³C and ¹⁵N NMR spectroscopy, HRMS and single-crystal X-ray diffraction data.     

Efficient synthesis of novel dipyridoimidazoles and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives

Novel dipyrido[1,2-a;3′,4′-d]imidazoles 7a-d, dipyrido[1,2-a;4′,3′-d]imidazoles 8a,c and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives 9a-d were synthesized by two pathways: thermal electrocyclic reaction of 3-alkenylimidazopyridine-2-oximes 10 and direct condensation of ethyl glycinate (or hydrazine) with 2,3-dicarbonylimidazo[1,2-a]pyridines 11.     

Palladium-catalyzed amination and cyclization to heteroannellated indoles and carbazoles

New ortho-bromodiarylamines in the benzo[b]thiophene series were prepared by palladium-catalyzed amination, either in the benzene or in the thiophene ring. These were submitted to palladium-catalyzed cyclization, under different required conditions, to give several differently substituted thieno[3,2-c] or [2,3-b]carbazoles and indolo[3,2-b]benzo[b]thiophenes. This constitutes a novel synthetic route to both tetracyclic systems.     

Facile synthesis of regio-isomeric naphthofurans and benzodifurans

Naphtho[1,2-b]furans 1a-f, naphtho[2,1-b]furans 2a-f, benzo[1,2-b:5,4-b′]difurans 3a-b, benzo[1,2-b:4,5-b′]difurans 4a-b, and benzo[1,2-b:4,3-b′]difurans 5a-b were synthesized by base-catalyzed cyclization reaction of the corresponding o-alkoxybenzoylarene derivatives. The o-alkoxybenzoylarenes were obtained from the etherification reaction of the o-hydroxybenzoylarenes, which were prepared either by the reaction of methoxyarenes with benzoyl chloride in the presence of aluminum chloride or by photo-Fries rearrangement of aryl benzoates.