Alkenylation of thiophenes and furans at the 2-position and a synthesis of allenes conjugated with α,β-unsaturated ester with magnesium alkylidene carbenoids

The reaction of 1-chlorovinyl p-tolyl sulfoxides, derived from ketones and chloromethyl p-tolyl sulfoxide, with i-PrMgCl at −78 °C gave magnesium alkylidene carbenoids. Treatment of the magnesium carbenoids with 2-lithiothiophenes and 2-lithiofurans resulted in the formation of 2-alkenylated thiophenes and furans, respectively, in good to high yields. The intermediates of these reactions were found to be alkenylmagnesium, which could be trapped with several electrophiles to afford thiophenes and furans bearing a fully substituted alkene at the 2-position. Treatment of the magnesium alkylidene carbenoids with 2-lithio-5-methoxyfuran afforded allenes conjugated with α,β-unsaturated methyl ester in moderate yields. These procedures offer a new and versatile one-pot synthesis of 2-alkenylthiophenes, 2-alkenylfurans, and allenes conjugated with α,β-unsaturated methyl ester from 1-chlorovinyl p-tolyl sulfoxides.     

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.     

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.     

General synthesis of polysubstituted thiophenes from diketo sulfides

Treatment of diketo sulfides with a low-valent titanium reagent at 0 °C (in two cases at room temperature) affords 3,4-dihydroxythiolanes in good yields. The acid-catalyzed (p-toluenesulfonic acid) dehydration of the latter compounds leads to the corresponding thiophenes in excellent yields.     

Halocyclization of 2-alkynylthioanisoles by cupric halides: synthesis of 2-substituted 3-halobenzo[b]thiophenes

Reaction of 2-alkynylthioanisoles 3 with 2 equiv of CuX₂ (X=Br or Cl) in refluxing CH₃CN for 2.5 h gave the 2-substituted 3-halobenzo[b]thiophenes 4 in good yields.     

A versatile one-pot multicomponent synthesis of novel quinazolinon-2-yl-tetrasubstituted thiophenes

Here, we report a versatile multicomponent synthesis of novel quinazolinon-2-yl-tetrasubstituted thiophenes by a one-pot reaction using different alkyl-3-aminobutenoates, isothiocyanates and 2-halomethyl quinazolinones in good to excellent yields. The reaction probably proceeds by an intramolecular 5-exo-trig cyclisation.     

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.     

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.     

Efficient coupling of heteroaryl halides with arylboronic acids in the presence of a palladium-tetraphosphine catalyst

Cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane:·1/2[PdCl(C₃H₅)]₂ system catalyses the Suzuki cross-coupling of heteroaryl halides with a range of arylboronic acids with very high ratio substrate/catalyst in good yields. Substrates such as pyridines, quinolines, thiophenes, an indole, pyrimidines or a furane have been used successfully.     

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.     

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.     

Site-specific preparation of 4-substituted-6-fluoro(carboalkoxyl)benzo[b]furans and benzo[b]thiophenes via base-catalyzed cyclization of enyne derivatives

A site-specific synthesis of 4-substituted-6-fluoro(carboalkoxyl)benzo[b]furans and benzo[b]thiophenes is described. The reactions of heterocyclic aromatic aldehydes with a Wittig reagent, followed by Sonogashira reaction with terminal alkynes, and subsequent base-catalyzed cyclization site-specifically provide 4-substituted-6-fluoro(carboalkoxyl)benzo[b]furans and benzo[b]thiophenes in good yields.     

Palladium-catalyzed alkenation of thiophenes and furans by regioselective C-H bond functionalization

A palladium-catalyzed direct alkenation of thiophenes and furans has been developed in the presence of AgOAc and pyridine. A variety of olefinic substrates such as acrylates, acrylamides, and acrylonitrile can perform the direct oxidative coupling reactions with various thiophenes and furans to give the mono-alkenylated products in good yields. In most cases, the (E)-isomers were isolated as the major products.     

Regioselective synthesis of poly-substituted thiophenes from Baylis-Hillman adducts

The reaction of Baylis-Hillman acetates and ethyl mercaptoacetate in the presence of DBU in DMF produced 2,3,4-trisubstituted tetrahydrothiophenes at room temperature as a diastereomeric mixture via the sequential S_N2′ and Michael addition. Aromatization of tetrahydrothiophenes by DDQ oxidation produced 2,3,4-trisubstituted thiophenes in good yields.     

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 estradiol backbone mimics via the Stille reaction using copper(II) oxide as co-reagent

Sterically hindered biaryls and 2-phenylbenzo[b]thiophenes that can serve as templates for mimics of the estradiol backbone were prepared in modest to good yields by the Stille reaction using CuO as a co-reagent. Due to the neutral conditions applied in the Stille reaction, protection strategies were unnecessary for hydroxy containing coupling partners. Ligandless coupling conditions were also evaluated.     

Facile synthesis of dihaloheterocycles via electrophilic iodocyclization

An efficient and facile electrophilic iodocyclization for the synthesis of various O-, N-, and S-containing dihaloheterocycles has been developed. A wide range of the substituted propargyl alcohols having -OH, -NTs, and -SAc functional groups reacted with molecular iodine or bromoiodine at ambient temperature to produce the corresponding dihalogenated O-, N-, and S-containing five- and six-membered heterocycles in good to high yields; Under optimized solvent conditions, the reactions of various substituted but-2-yn-1-ones bearing -OH, -NTs, and -SAc functional groups at C4-position, with iodine or bromoiodine at ambient temperature afforded the corresponding 3,4-diiodo- and 3-bromo-4-iodo-substituted furans, pyrroles, and thiophenes in good to high yields. Further transformation of the resulting iodine- or bromine-containing products to polyaromatics potentially of useful as organo-material intermediates has been investigated.     

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.     

Synthesis of regioselectively functionalized benzo[b]thiophenes by combined ortho-lithiation-halocyclization strategies

An efficient synthesis of 3-halo-7-oxygen-functionalized benzo[b]thiophenes bearing different substituents at C-2 has been developed from N,N-diethyl O-3-halophenylcarbamates. The key steps are an ortho-lithiation reaction, which gives rise to 3-halo-2-sulfanylphenol derivatives, and a electrophilic cyclization. The subsequent functionalization of the prepared halobenzothiophenes allows the access of a wide variety of 2,3,7-regioselectively functionalized benzo[b]thiophenes in good overall yields.     

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.