Heteroaromatic oxidation thiophene

Extrusion of sulfur dioxide from oxidized thiophene derivatives is an exceptional method to prepare cis-dienes as components for Diels-Alder reactions. An example of this approach utilizes the Diels-Alder reactivity of the furan ring in substituted 4//,6ff-thieno[3,4-c]furan-3,S-dioxides to react with a variety of dienophiles such as DMAD, dimethyl maleate and dimethyl fumarate which then lose SO2 to form another reactive diene (Eq. 17) <94H961>. A review of the preparation and use of 4i/,6f/-thieno[3,4-c]furan-S,5-dioxides as well as other heteroaromatic-fused 3-suIfolenes is report <94H1417>. The preparation of dihydrothienooxazole 80 requires the careful control of the reaction time and temperature as well as the reactants molar ratio <94JOC2241>. Specific control of the alkylation conditions for 81 (X = COCH3) allows for the preparation of either 1,4-disubstituted or 1,6-disubstituted 4, 6//-thieno[3,4-c]furan-S,S-dioxides. These molecules could be used as intermediates for the preparation of novel pentacyclic compounds <94JCS(P1)1371>. 

Pyrroles, furans and thiophenes undergo photoinduced alkylation with diarylalkenes provided that the alkene and the heteroaromatic compound have similar oxidation potentials, indicating that alkylation can occur by a non-ionic mechanism (Scheme 20) (81JA5570). 

The site of dihydroxylation in heterocycles depends on the nature of the heteroaromatic system (Scheme 9.31) usually, electron-rich heterocycles like thiophene are readily biooxidized but give conformationally labile products, vhich may undergo concomitant sulfoxidation [241]. Electron deficient systems are not accepted only pyridone derivatives give corresponding cis-diols [242]. Such a differentiated behavior is also observed for benzo-fused compounds biotransformation of benzo[b] thiophene gives dihydroxylation at the heterocyclic core as major product, while quinoline and other electron-poor systems are oxidized at the homoaromatic core, predominantly [243,244]. 

It has been known that aromatic heterocycles such as furan, thiophene, and pyrrole undergo Diels-Alder reactions despite their aromaticity and hence expected inertness. Furans have been especially used efficiently as dienes due to their electron-rich properties. Thiophenes and pyrroles are less reactive as dienes than furans. But pyrroles with A-elecIron-withdrawing substituents are efficient dienes. There exists a limited number of examples of five-membered, aromatic heterocycles acting as dienophiles in Diels-Alder reactions. Some nitro heteroaromatics serve as dienophiles in the Diels-Alder reactions. Heating a mixture of l-(phenylsulfonyl)-3-nitropyrrole and isoprene at 175 °C followed by oxidation results in the formation of indoles (see Eq. 8.22).35a A-Tosyl-3-nitroindole undergoes high-yielding Diels-Alder reactions with... 

V. P. Litvinov, T. V. Shchedrinskaya, P. A. Konstantinov, and Ya. L. Gol dfarb, Condensed heteroaromatic sytems including the thiophene ring. 33. Catalytic liquid-phase oxidation of 3-methyl-substituted thieno[2,3-h]thiophene and thieno[3,2-h]thiophene. Khim. Geterotsikl. Soedin., 492 (1975). 

Fortunately, there is now a comprehensive body of knowledge on the metabolic reactions that produce reactive (toxic) intermediates, so the drug designer can be aware of what might occur, and take steps to circumvent the possibility. Nelson (1982) has reviewed the classes and structures of drugs whose toxicities have been linked to metabolic activation. Problem classes include aromatic and some heteroaromatic nitro compounds (which may be reduced to a reactive toxin), and aromatic amines and their N-acylated derivatives (which may be oxidized, before or after hydrolysis, to a toxic hydroxylamine or iminoquinone). These are the most common classes, but others are hydrazines and acyl-hydrazines, haloalkanes, thiols and thioureas, quinones, many alkenes and alkynes, benzenoid aromatics, fused polycyclic aromatic compounds, and electron-rich heteroaromatics such as furans, thiophenes and pyrroles. 

Oxidative cross-coupling with alkenes is possible with Pd(OAc)2 [109], The reaction proceeds by the palladation of benzene to form phenylpalladium acetate (164), followed by alkene insertion and elimination of /1-hydrogen. Heteroaromatics such as furan and thiophene react more easily than benzene [109]. Stilbene (177) is formed by the reaction of benzene and styrene. The complex skeleton of paraberquamide 179 was obtained in 80% yield by the Pd(II)-promoted coupling of the indole ring with the double bond in 178, followed by reduction of the intermediate with NaBELt [110]. 

Preparative oxidation of EtjAs and PhjAs or PhjSb in the presence of aromatic or heteroaromatic compounds leads to formation of quaternary arsonium or stibonium salts . The oxidations were carried out in nominally dry MeCN in the presence of an excess of the aromatic compound which, in the case of the arsines, were naphthalene, thiophene, pyridine and furan , and in the case of Ph3Sb were thiophene and toluene . ... 

Extensive experimental and DFT studies on the influence of substituents on /cc couplings in heteroaromatic compounds have been performed by Ka-mienska-Trela and co-workers this included data for variously 2- and 3-substituted thiophenes and for a large set of variously substituted pyr-idines and their A-oxides. " Particularly interesting results have been obtained for 2-lithiothiophenes where very small Jqc coupling values of ca. 30 Hz only have been measured. The experimental values have been very well reproduced by the DFT calculations. Similarly low coupling values are predicted for 2-lithiopryridines and their A-oxides. " ... 

The electrochemical oxidation of thiophene and its derivatives forms part of a recent exhaustive review of such oxidations of several heteroaromatic compounds <86CJC76>. The mechanism has been explained. The initially formed radical cation is sufficiently stable to dimerize, but not so stable as to diffuse away from the electrode surface. Chain propagation takes place by coupling of the monomer radical cation with the dimer radical cation and so on. Cyclic voltammetric data for thiophene and its derivatives have been provided. 

Bromide or stoichiometric Silver(I) Oxide, respectively. In many cases, one or both of the aromatic species can be heteroaromatic such as pyridine, furan, thiophene, quinoline, oxazole, thia-zole, or indole. Symmetrical biaryls have been prepared in excellent yields by the Pd(Ph3P)4-catalyzed homocoupling of ArBr/I under phase transfer conditions. ... 

Different heteroaromatic rings (e.g., pyridine, furan and thiophene) and carbon-carbon double bonds are well tolerated under the reaction conditions. Moreover, reagent 130 can be easily recycled from the reaction mixture and reused. The mechanism of this reaction includes initial homolytic cleavage of the I—Cl bond providing a chlorine atom and the iodanyl radical 132, which is in equilibrium with the benzoyloxy radical 133. TEMPO (134) is oxidized by the chlorine atom to oxoammonium salt 135, which then oxidizes the alcohol 129 to the corresponding carbonyl compound 131 and is itself reduced to hydroxylamine 136. The benzoyloxy radical 133 accomplishes the regeneration of TEMPO 134 from hydroxylamine 136, giving rise to 2-iodobenzoic acid and the catalytic cycle is complete (Scheme 3.55) [158]. 

Recyclable [bis(trifluoroacetoxy)iodo]arenes 66 and 70 are excellent reagents for oxidative coupling of thiophenes or pyrroles [79] and for direct oxidative cyanation of heteroaromatic compounds using Me3SiCN as source of cyanide anion [80,81]. 

Dixneuf s group developed an interesting synthesis of heteroaromatic esters by a palladium-promoted oxidative carbonylation of thiophene, furan, benzofuran. 

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