An efficient phosphine-free palladium coupling for the synthesis of new 2-arylbenzo[b]thiophenes

Straightforward and rapid access to 2-arylbenzo[b]thiophenes has been developed. It involved a catalytic coupling of 3-activated benzo[b]thiophenes with several aryl halides in the presence of a phosphine-free palladium system. In case of fragile functional groups such as aldehydes, a quaternary ammonium was used as an additive as with the other substrates, the coupling performed better and faster in the presence of a crown ether, the best one being DCH-18-C-6, with good yields and low reaction times. This method would provide a direct access to novel structures of biological interest.     

An efficient approach to construct 2-arylbenzo[b]furans from 2-methoxychalcone epoxides

An efficient and practical method for construction of 2-arylbenzo[b]furans from 2-methoxychalcone epoxides has been reported. Catalyzed by 2 mol % of BF₃·Et₂O, 2-methoxychalcone epoxides went through the Meerwein rearrangement, followed by deformylation in one-pot to successfully afforded 2-methoxydeoxybenzoins. Afterward, 2-arylbenzo[b]furans were obtained in high yields (87%–100%) via intermolecular cyclodehydration of 2-methoxydeoxybenzoins with 48% HBr. By utilization of this approach, the natural product stemofuran A and the key intermediate of eupomatenoid 6 have been synthesized conveniently.     

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 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.     

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.     

An efficient and novel approach to the synthesis of tetrahydrophenanthro[4,3-b]thiophenes

An elegant approach to the synthesis of 2,3,6,7-tetrahydrophenanthro[4,3-b]thiophenes has been described through base catalyzed ring transformation of 4-sec-amino-2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles with tetrahydrothiophen-3-one in very good yields.     

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.     

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.     

Insights into the reaction of trans-diarylethenes with thionyl chloride: a practical synthesis of chlorobenzo[b]thiophenes

The reactivity of a variety of trans-1,2-diarylethenes with thionyl chloride has been investigated. All the substrates could readily afford 3-chlorobenzo[b]thiophenes in moderate yields and a pair of threo- and erythro-1,2-dichloro-1,2-diarylethanes as the minor products under mild condition. The diastereoisomers of 1,2-dichloro-1,2-diarylethanes with a methoxy group on the benzene ring were found for the first time to be also converted into cholobenzo[b]thiophenes under treatment of thionyl chloride. The chemical transformations have been mechanistically rationalized and successfully applied to a one-pot synthesis of novel fluorescent liquid crystalline compounds containing benzo[b]thiophene and 1,3,4-oxadiazole units. Their spectroscopic and mesogenic behaviours are also described.     

Heck-like coupling and Pictet-Spengler reaction for the synthesis of benzothieno[3,2-c]quinolines

A series of 6-arylbenzothieno[3,2-c]quinolines were synthesised in three steps from benzo[b]thiophene. After a selective Heck-type coupling of benzo[b]thiophene with different o-nitroaryl bromides to obtain 2-(o-nitroaryl)benzo[b]thiophenes, corresponding 2-(benzo[b]thiophen-2-yl)anilines were involved in a Pictet-Spengler reaction to form the quinoline cycle.     

Regioselective synthesis of functionalized naphtho[b]thiophenes through a ‘lactone methodology’

Benzo[b]thiophene and its benzannulated derivatives are important classes of compounds due to their unique chemical properties and biosteric relationship with indole. In this letter, we report a convenient route for the synthesis of substituted naphtho[b]thiophenes through a ring transformation reaction of suitably functionalized 2H-pyran-2-ones with 6,7-dihydro-5H-benzothiophene-4-one, in good 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.     

Tandem palladium-catalyzed borylation and Suzuki coupling (BSC) to thienocarbazole precursors

Substituted 2-methyl-2′-nitro diaryl compounds in the benzo[b]thiophene series were prepared by palladium-catalyzed, two-step, one-pot borylation/Suzuki coupling (BSC) reaction in good to high yields. The borylation reaction was performed on methylated 6-bromobenzo[b]thiophenes using pinacolborane and was followed by in situ Suzuki coupling with substituted (CF₃, OMe) 2-bromonitrobenzenes. The compounds obtained were cyclized to the corresponding ring A substituted thienocarbazoles which can have biological activity or/and be used as biomarkers due to their fluorescence properties and possible DNA intercalation.     

The preparation of substituted bithiophenyl aldehydes via the ring opening of dithieno[2,3-b:3′,2′-d]thiophene in the presence of n-BuLi

In the presence of n-BuLi in THF at low temperature, the phenomena of ring opening of symmetric substituted dithieno[2,3-b:3′,2′-d]thiophenes were observed. After quenching the organolithium intermediates with dry DMF, a series of substituted novel bithiophenyl aldehydes were prepared in good to excellent yields. The mechanism shows the key step for the ring opening of dithieno[2,3-b:3′,2′-d]thiophene is the nucleophilic attack of butyl anion onto the sulfur atom of the central ring. Total ten samples of symmetric substituted dithieno[2,3-b:3′,2′-d]thiophenes and their ring-opened products, the substituted bithiophenyl aldehydes were characterized by ¹H NMR, ¹³C NMR, and HRMS. Two ring-opened products were confirmed by X-ray single crystal analysis.     

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.     

A novel efficient protocol for preparation of 3-formyl-2-arylbenzo[b]furan derivatives

An efficient method for preparation of 3-formyl-2-arylbenzo[b]furan derivatives 4 from 3-chloro-2-(2-methoxyaryl)-1-arylprop-2-en-1-one 2 was developed, and the desired product was obtained in good to excellent yields. By converting 2-(2-methoxyphenyl)-3-oxo-3-phenylpropanal 1 to 2, the regioselectivity problem occurring in the reaction when using 1 as the starting material was successfully avoided. Furthermore, a one-pot procedure for the successive demethylation, cyclization, and hydrolysis was evolved, although the intermediate 3-(dibromomethyl)-2-phenylbenzo[b]furan 3a could be isolated. A plausible mechanism was proposed based on some in situ investigations.     

A convenient approach towards 2- and 3-aminobenzo[b]thiophenes

Reaction of 1-(2-chloro-5-nitrophenyl)ethanone via Willgerodt-Kindler route with primary or secondary amines and sulfur allows a simple, efficient one-pot synthesis of 3-aminobenzo[b]thiophenes. Base-catalyzed transformation of 4-(2-chloro-5-nitrophenyl)-1,2,3-thiadiazole in the presence of primary and secondary amines offers a convenient approach towards 2-aminobenzo[b]thiophenes.     

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.     

A facile and convenient one-pot synthesis of polysubstituted thiophenes from 1,3-dicarbonyl compounds in water

A facile and convenient one-pot synthesis of polysubstituted thiophenes 2 and polysubstituted thieno[2,3-b]thiophenes 3 from 1,3-dicarbonyl compounds 1 has been achieved in high yields catalyzed by tetrabutylammonium bromide (TBAB) in the presence of K₂CO₃ in water. TBAB in the aqueous phase can be recycled after the separation of organic products.     

Synthese von basisch substituierten 2-Methyl-2,3-dihydro-benzo[b]thiophenen

N-substituted {2-methyl-benzo[b]thienyl-(3)}-acetamides were oxidized to the corresponding 1,1-dioxides, catalytic hydrogenation of which gave N-substituted {2-methyl-2,3-dihydro-benzo[b]thienyl-(3)}-acetamide-S,S-dioxides. The latter were reduced by LiAlH₄ to give N-substituted 2-methyl-3-(β-amino-ethyl)-2,3-dihydro-benzo[b]thiophenes.