Heteroaromatic oxidation furan

Anodic oxidations of heteroaromatic cycles (furans, pyrroles, benzofurans) in the presence of methanol have been extensively studied [148-165]. The electromethoxyla-tion of differently substituted furans gives 2,5-dimethoxy-2,5-dihydrofurans in moderate to good yields (Scheme 96) [148-159, 166-170]. 

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). 

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... 

Heterocycles Both non-aromatic unsaturated heterocycles and heteroaromatic compounds are able to play the role of ethene dipolarophiles in reactions with nitrile oxides. 1,3-Dipolar cycloadditions of various unsaturated oxygen heterocycles are well documented. Thus, 2-furonitrile oxide and its 5-substituted derivatives give isoxazoline adducts, for example, 90, with 2,3- and 2,5-dihydro-furan, 2,3-dihydropyran, l,3-dioxep-5-ene, its 2-methyl- and 2-phenyl-substituted derivatives, 5,6-bis(methoxycarbonyl)-7-oxabicyclo[2.2.1]hept-2-ene, and 1,4-epoxy-l,4-dihydronaphthalene. Regio- and endo-exo stereoselectivities have also been determined (259). 

Among heteroaromatic compounds able to react with nitrile oxides as dipo-larophiles, furan, probably, is the best known. Recently, a novel nitrile oxide was generated from a sulfoximine and converted in situ to a cycloadduct with furan (Scheme 1.25) (287). The starting racemic N-methyl-S-nitromethyl-S-phenylsul-foximine 124 was prepared in 87% yield via nitration of N,S-dimethyl-S-phenyl-sulfoximine. Reaction of 124 with p-chlorophenyl isocyanate and a catalytic quantity of triethylamine, in the presence of furan, afforded dihydrofuroisoxazole 125, the product of nitrile oxide cycloaddition, in 42% yield (65 35 diastereomer ratio). The reaction of 125 with phenyllithium and methyllithium afforded compounds 126, which are products formed by replacement of the sulfoximine group by Ph and Me, respectively. 

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. 

Anodic addition to an electron-rich heteroaromatic compound is used to transform furan to 2,5-dimethoxy-2,5-dihydrofuran, a valuable synthetic intermediate. Again, an indirect electrochemical process occurs. The bromide ion as redox catalyst is electrochemically oxidized to give bromine, which then acts as chemical oxidant for furan [7] ... 

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]. 

For fiirther reactions of this type see <95CC2025>. The synthesis of l,4-dihydrofurano[3,4-d]-3,2-oxathiine-2-oxides, precursors for nonclassical heteroaromatic o-quinodimethanes, and their application in the Diels-Alder reaction were reported <95CC2537>. The intramolecular Diels-Alder reaction with furans (e. g., 47) offers a rapid access to highly functionalized isoquinolines <95 JCS(P 1)2393>. 

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 . ... 

Ruthenium-based catalysts display some utility for electrophilic amination of heteroaromatic substrates. Che and coworkers have found that [Ru(TTP)(CO)J in combination with PhI=NTs will oxidize arenes such as furan, indole, and pyrrole (Fig. 13) [68]. Reactions occur optimally under the action of ultrasound, a rather unusual addendum to the standard protocol for C-H amination. More intriguingly still, iV,A-ditosylated products are isolated in most instances, a finding that is not easily resolved mechanistically. As the substrate profile for this amination process involves only electron-rich heteroaromatics, aziridination of the arene nucleus would seem a likely step along the reaction coordinate. Interestingly, no amination product is observed when stoichiometric [Ru(TMP)(NTs)2] (TMP = tetra(2,4,-6-trimethylphenyl)porphyrin) is mixed with either furan or /V-phenylpyrrole. though a reduction of the starting Ru(VI) complex to a Ru(IV) species is noted... 

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>. 

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]. 

Since its discovery, the Songashira reaction has been a valuable tool for the functionalization of aromatic and heteroaromatic halides with the versatile alkyne function [9]. Among the many possible alkyne transformations, these derivatives can undergo cyclization reactions to prepare indoles, benzo- and heteroaryl- furans, and other useful pharmacophores. One of the difficulties of the reaction is the propensity of acetylenes to oxidatively dimerize under the reaction conditions, particularly when the cross-coupling reaction is slow as in the case of aromatic... 

Natural product synthesis as a test of newly developed methodologies, for example, partial reduction of furans and pyrroles, nucleophilic addition to pyridinium salts. Os-catalyzed oxidative cyclization for the synthesis of tet-rahydrofurans and pyrrolidines, tethered aminohydroxylation of aUcenes, and ring-closing- and cross-metathesis for the constmction of heteroaromatics 12CC11924. 

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

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