One-pot synthesis of substituted 2-aminobenzo[b]thiophenes

Reaction of 1-(2-chloro-5-nitrophenyl)ethanone 1, via Willgerodt-Kindler routes, using the primary and secondary amines 2a-k resulted in a simple, efficient three-component one-pot synthesis of 2-aminobenzo[b]thiophenes 3a-k.     

Synthesis of 1,1-dialkylindolium-2-thiolates via base-induced transformation of 4-(2-chloro-5-nitrophenyl)-1,2,3-thiadiazole in the presence of secondary amines

4-(2-Chloro-5-nitrophenyl)-1,2,3-thiadiazole undergoes ring-opening to produce a thioketene intermediate that reacts with secondary amines forming 2-(2-chloro-5-nitrophenyl)-N,N-dialkylthioacetamides. Intramolecular cyclization of these thioamides via nucleophilic substitution of the halogen on the aromatic ring affords nonaromatic 1,1-dialkylindolium-2-thiolates instead of the expected aromatic N,N-dialkylaminobenzo[b]thiophenes.     

An efficient synthesis of 3-aryl-2-aryl(or methyl)sulfanylbenzo[b]thiophenes via cyclization of aryl 2-aryl(or methyl)sulfanylmethylsulfanylphenyl ketones

A convenient method for the preparation of 2-aryl(or methyl)sulfanylbenzo[b]thiophenes has been developed. Thus, aryl 2-aryl(or methyl)sulfanylmethylsulfanylphenyl ketones, easily prepared from readily available aryl 2-sulfanylphenyl ketones or 2-chloro-5-nitrophenyl phenyl ketone, are treated with LDA in 1,2-dimethoxyethane (DME) to give 3-aryl-2-aryl(or methyl)sulfanylmethylsulfanyl-2,3-dihydrobenzo[b]thiophen-3-ols, which in turn were dehydrated with thionyl chloride to afford 3-aryl-2-aryl(or methyl)sulfanylbenzo[b]thiophenes in reasonable overall yields.     

A metal-free,one-pot route to substituted benzo[b]thiophenes and their hetero-fused analogs via iodine mediated intramolecular arylthiolation of in situ generated β-(het)aryl-β-cyanoenethiolates

A metal-free one-pot route to substituted 3-cyanobenzo[b]thiophenes has been developed via iodine mediated intramolecular arylthiolation of 2-(het)aryl-2-cyanoenethiolates generated in situ by base mediated condensation of arylacetonitriles and (het)aryl dithioesters. The methodology has been further extended to the synthesis of 2-aminobenzo[b]thiophenes as well as hetero-fused thiophenes such as thieno[2,3-b]thiophenes, thieno[2,3-b]indoles and thieno[3,2-c]pyrazoles. An electrophilic cyclization mechanism has been proposed based on experimental observations.     

A Convenient Approach to 2-Aminobenzo[<Emphasis Type="Italic">b</Emphasis>]chalcogenophenes Based on Copper-Catalyzed Transformation of 4-(2-Bromophenyl)-1,2,3-chalcogenodiazoles in the Presence of a Base and Amines

The reactions of 4-(2-bromophenyl)-1,2,3-thia-and -selenadiazoles with amines in the presence of potassium carbonate and copper(I) iodide afforded 2-aminobenzo[b]chalcogenophenes. The corresponding thiaand selenamides, prepared by interaction of 4-(2-bromophenyl)-1,2,3-thia- and -selenadiazoles with amines in the absence of copper salt, were transformed into 2-aminobenzo[b]chalcogenophenes by the action of potassium carbonate and copper(I) iodide in DMF in different yields.     

One-step synthesis of substituted 2-amino-5,6,7,8-tetrahydro-4H-benzo[b]pyrans. Molecular and crystal structure of 2-amino-3-(2-methoxyethoxycarbonyl)-4-(2-nitrophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-benzo[b]pyran

Substituted 2-aminobenzo[b]pyrans were synthesized by three-component condensation of aromatic aldehydes, cyanoacetic acid derivatives, and cyclic 1,3-diketones. The molecular and crystal structure of 2-amino-3-(2-methoxyethoxycarbonyl)-4-(2-nitrophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-benzo[b]pyran was established by X-ray diffraction analysis.     

Synthesis and Transformations of 3-Ethoxycarbonyl-2-(N-R-thioureido)thiophenes

3-Ethoxycarbonyl-2-(N-R-thioureido)-4,5,6,7-tetrahydrobenzo[b]thiophenes were obtained by the reaction of 2-amino-3-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene with isothiocyanates and of 3-ethoxycarbonyl-2-isothiocyanato-4,5,6,7-tetrahydrobenzo[b]thiophene with primary and secondary amines. The cyclization paths of the products leading to derivatives of thieno[2,3-d]pyrimidine and thieno[2,3-d]-1,3-thiazine were studied. The corresponding S-substituted derivatives were obtained by the alkylation of 3-R-2-thioxo-3,4,5,6,7,8-hexahydrobenzo[b]thieno[2,3-d]pyrimidin-4-ones.     

Intramolecular Heck reaction: A facile sequential one-pot synthesis of 1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridines

A simple and convenient sequential one-pot synthesis of 1,2,3,4-tetrahydrobenzo[b][1,6] naphthyridines has been developed. The reductive amination of 2-chloro-3-formylquinolines with various amines in the presence of sodium borohydride provided the corresponding secondary amines in high yields. Further, a sequential one-pot reaction involving N-allylation and intramolecular Heck type 6-exo-trig cyclization was performed on the secondary amines to afford a range of desired 1,2,3,4-tetrahydrobenzo[b][1,6]-naphthyridine derivatives in good to high yields.     

Synthesis of 6-Amino-5-R2-7-(6-R1-4-oxo-3,4-dihydro-2-quinazolyl)-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles

It has been found that malonodinitrile and 2-(6-R¹-oxo-3,4-dihydro-2-quinazolyl)acetonitrile in the presence of triethylamine undergo hetarylation by 5,6-dichloro-2,3-pyrazinedicarbonitrile at the active methylene group to give the triethylammonium salt of 2-(3-chloro-5,6-dicyano-2-pyrazinyl)malononitrile or 5-chloro-6-cyano(6-R¹-4-oxo-1,2,3,4-tetrahydro-2-quinazolylidene)methyl-2,3-pyrazinedicarbonitriles. Reaction of these with primary amines leads to annelation of the pyrrole ring at the pyrazine [b] edge to give 6-amino-5-R-5H-pyrrolo[2,3-b]pyrazine-2,3,7-tricarbonitriles and 6-amino-5-R²-7-(6-R¹-4-oxo-3,4-dihydro-2-quinazolyl)-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles respectively.     

Dipyridyl/pyridinium thieno[2,3-b]thiophenes as new atropisomeric systems. Synthesis, conformational analysis and energy minimization

Synthesis of a new class of cofacially oriented dipyridyl(pyridinium)lthieno[2,3-b]thiophenes with or without -CO₂Et and -COMe substituents at C2, and C5 positions of thieno[2,3-b]thiophene ring was readily accomplished using a double Dieckman cyclization protocol as the key step. While C2/C5 substituted dipyridylthieno[2,3-b]thiophenes exhibited syn/anti atropisomerism at least up to 70 °C with Arrhenius energy of activation (ΔG^≠) in the range of 17-18 kcal/mol, on the other hand unsubstituted dipyridylthieno[2,3-b]thiophene and its bis-N-quaternized salt were found to show free conformational rotation with an estimated ΔG^≠ of lower than 10 kcal/mol. Conformational energy minimization using AM1 protocol revealed a slight preference for the anti over syn isomers. Compared to the unsubstituted dipyridylthieno[2,3-b]thiophenes, higher energy barriers to rotation (3.7-5.1 kcal/mol) in substituted dipyridylthieno[2,3-b]thiophenes can be attributed to steric encumbrance resulting from -CO₂Et and -COMe substituents located on the non-rotating thienothiophene platform.     

A new synthesis of benzo[b]thiophenes utilizing an interrupted Pummerer reaction

A convenient synthesis of 3-arylbenzo[b]thiophenes utilizing an interrupted Pummerer reaction of 2-(1-arylvinyl)phenyl ethyl sulfoxides is described. Thus, treatment of these sulfoxides, which were readily prepared from 2-sulfanylphenyl ketones or 2-fluoro-5-methoxybenzaldehyde, with acetic anhydride at 100 °C afforded 3-arylbenzo[b]thiophenes in reasonable yields.     

Synthesis of diarylamines in the benzo[b]thiophene series bearing electron donating or withdrawing groups by Buchwald-Hartwig C-N coupling

Diarylamines in the benzo[b]thiophene series bearing electron donating or withdrawing groups, were prepared by Buchwald-Hartwig C-N coupling in moderate to high yields. The conditions used were Pd(OAc)₂ (3 mol%), BINAP as ligand (4 mol%) and Cs₂CO₃ as base (1.4 equiv.), in toluene at 100°C, being 6-bromo or amino benzo[b]thiophenes coupled, respectively, with substituted anilines or phenylbromides. The 6-aminobenzo[b]thiophene derivatives were also prepared by palladium catalyzed C-N coupling of the corresponding 6-bromo compounds with benzophenone imine, followed by acidic hydrolysis of the imino derivatives. When 4-nitrobromobenzene and 4-bromobenzonitrile were used as coupling components, triarylamines were also isolated in small amounts. The presence of a fluorine atom on the phenylbromide highly increases the diarylamine yields.     

Efficient route to benzo[4,5]imidazo[2,1-a]phthalazines

Benzo[4,5]imidazo[2,1-a]phthalazines have been obtained from various o-nitrophenylhydrazines through different 2-(2-nitrophenyl)-1,2-dihydro-1-phthalazinones as intermediates using an elaborated advanced procedure. An activated chlorine atom in 2-nitrophenyl moiety of the latter is able to undergo nucleophilic substitution for secondary alicyclic amines yielding novel substituted phthalazinones. Their one-pot reduction and cyclodehydration yield a series of novel substituted benzo[4,5]imidazo[2,1-a]phthalazines.     

Synthesis of 4H-furo[3,2-b]indole derivatives. III. Preparation of 4H-furo[3,2-b]indole-2-carboxylic acid derivatives

Methyl or ethyl 4H-furo[3,2-b]indole-2-carboxylates (Va,b) were prepared from deoxygenation of methyl or ethyl 5-(2-nitrophenyl)-2-furoates (IIIa,b) and thermolysis of methyl or ethyl 5-(2-azidophenyl)-2-furoates (VIIIa,b). 4H-Furo[3,2-b]indole-2-carboxylic acid amides (XIa-h) were obtained by the reaction of 4H-furo[3,2-b]indole-2-carboxyl chloride (X) with the appropriate amines.     

A facile domino protocol for the regioselective synthesis and discovery of novel 2-amino-5-arylthieno-[2,3-b]thiophenes as antimycobacterial agents

A series of novel 2-amino-5-arylthieno[2,3-b]thiophenes has been synthesized regioselectively from the reaction of 5-aryldihydro-3(2H)-thiophenones with ethyl cyanoacetate/malononitrile and sulfur powder in the presence of morpholine under thermal as well as microwave irradiation conditions. This transformation presumably occurs via domino Gewald reaction-dehydrogenation sequence. The 2-amino-5-arylthieno[2,3-b]thiophenes were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB). Among 12 compounds screened, ethyl 2-amino-5-(1-naphthyl)thieno[2,3-b]thiophene-3-carboxylate was found to be the most active compound with MIC of 1.1 μM against MTB and MDR-TB.     

Amidine derivatives of α-arylglycines from N-(1-aryl-2,2,2-trichloroethyl)amides of arenesulfonic acids and secondary amines

The interaction of N-(1-aryl-2,2,2-trichloroethyl)amides of arenesulfonic acids with secondary amines or their salts in the presence of inorganic bases involves the formation of chloroaziridine intermediates. Depending upon the solvent and reagent ratio, the reaction results in N-[1-dialkylamino-2-chloro-2-arylethylidene]-, N-[2-dialkylamino-1-chloro-2-arylethylidene]-, N-[1,2-bis(dialkylamino)-2-arylethylidene]-, and N-(1,2-dioxo-2-arylethene)amides of arenesulfonic acids.     

New synthesis of 4-(1-adamantyl)-2-aryl-1,3-thiazoles from 4-(1-adamantyl)-1,2,3-thiadiazole

Treatment of 4-(1-adamantyl)-1,2,3-thiadiazole with potassium tert-butoxide generated potassium 2-(1-adamantyl)ethynethiolate which reacted with aromatic carboxylic acid chlorides to give unstable S-[2-(1-adamantyl)ethynyl] arenecarbothioates whose acid hydrolysis afforded S-[2-(1-adamantyl)-2-oxoethyl] arenecarbothioates. The latter reacted with ammonium acetate in acetic acid yielding 4-(1-adamantyl)-2-aryl-1,3-thiadiazoles. Reactions of 4-(1-adamantyl)-2-(4-chloro-3-nitrophenyl)-1,3-thiadiazole with cyclic secondary amines gave the corresponding products of nucleophilic replacement of the chlorine atom in the aromatic ring.     

Synthesis and biological evaluation of 5-substituted benzo[b]thiophene derivatives as anti-inflammatory agents

Abstract  5-Aminobenzo[b]thiophene-2-carboxylic acid was converted to the corresponding 5-(2-chloroacetamido)benzo[b]thiophene-2-carboxylic acid by reaction with chloroacetyl chloride. This acetamido product was treated with different alkyl, cycloalkyl, aryl, and heterocyclic amines to afford a series of C5-substituted benzo[b]thiophenes. These compounds were found to possess potent anti-inflammatory activity. Graphical abstract        

Photoreactivite de systemes hexatrieniques heterocycliques. Aryl-2 et 3 benzo[b]thiophene

The photochemical behavior of several benzo[b]thiophenes 1–4 in neutral solutions or in the presence of primary and tertiary amines has been examined. In most cases, the photoformation of adducts or dimers, rather than cyclisation, has been observed. An unusual photocyclisation of a saturated compound 12 obtained by photolysis of 3 in a primary amine was observed     

One-step synthesis of 5-acetyl-2-amino-4-aryl-3-cyano-4H-pyrano[3,2-b]indoles. Molecular and crystal structure of 5-acetyl-2-amino-4-(4"-chloro-3"-nitrophenyl)-3-cyano-4H-pyrano[3,2-b]indole

A one-step procedure was developed for the synthesis of 5-acetyl-2-amino-4-aryl-3-cyano-4H-pyrano[3,2-b]indoles involving the three-component reaction of 1-acetylindol-3(2H)-one with aromatic aldehydes and malononitrile in ethanol in the presence of triethylamine as the catalyst. The structure of 5-acetyl-2-amino-4-(4"-chloro-3"-nitrophenyl)-3-cyano-4H-pyrano[3,2-b]indole was established by X-ray diffraction analysis.