Carbonylation reaction thiophenes

Pd(II) salts promote the carbonylation of organomercury compounds. Reaction of phenylmercury chloride and PdCh under CO pressure affords benzophenone (429)[387]. Both esters and ketones are obtained by the carbonylation of furylmercury(Il) chloride in alcohol[388]. Although the yields are not satisfactory, esters are obtained by the carbonylation of aryl- and alkylmercuryfll) chlorides[389,390]. One-pot catalytic carbonylation of thiophene, furan, and pyrrole (430) takes place at the 2-position via mercuration and transmetallation by the use of PdCb, Hg(N03), and CuCl2[391]. 

Fig. 7.11. Metabolism of S-(l- [(2,3,4,5-tetrahydro-2-oxothiophen-3-yl)amino]carbonyl ethyl) thiophene-2-carbothioate (MR 889, 7.71) in rats to the active thiol metabolite homocysteine thiolactone thiolactamide (7.72) and to thiophene-2-carboxylic acid (7.73) [154], Subsequent reactions of hydrolysis and conjugation are also shown.

The usefulness of the Gewald reaction for the synthesis of 2-amino-3-carbonyl-substituted thiophens has been amply demonstrated during the past two years (c/. ref. 6fl). These thiophens are very useful starting materials for complex condensed systems of pharmacological interest. I.r. and n.m.r. studies showed some anomalies which were interpreted in terms of electron delocalization in the enaminocarbonyl structure. From cyanoacetamide, benzylacetone, and sulphur, the thiophen (9) was obtained. 3-Aryl-substituted derivatives such as (10) were obtained from the appropriate aryl methyl ketone, ethyl cyanoacetate, and sulphur. It has been claimed that (11) is obtained from the reaction of acetoacetic acid anilide with malononitrile and sulphur. This hardly seems to be correct, as (12) is the product expected in the Gewald reaction. It was found that 2-amino-3-ethoxycarbonyl-thiophens (13) react with sodium ethoxide in ethanol, pre-... 

Pyrrole- and Furan-fused Thio diens and Related Compounds.— The interest in the chemistry of thienopyrroles is still increasing. Starting from 2-amino-3-carbonyl-substituted thiophens obtained by the Gewald reaction, the A -ethoxy-carbonylmethyl derivative (245) was prepared either by direct alkylation with ethyl bromoacetate, or by reductive alkylation with methyl glyoxalate. The compounds (245) were then ring-closed directly, or after acetylation, to the... 

Dieckmann-type reaction mechanism and not through a Stobbe-type reaction mechanism, as is the case in the Hinsberg reaction with oc-diketones. The usefulness of the Gewald reaction for the synthesis of 2-amino-3-carbonyl-substituted thiophens, important building-blocks for the synthesis of fused thiophens, has clearly been demonstrated. From the condensation products of cycloalkanones and nitriles (1), the thiophens (2) were obtained through the reaction with sulphur in the presence of diethylamine. Similarly, from the dithiacyclo-octane derivative (3), the thiophen (4) was prepared. In connection with the synthesis of psychophar-maca of the diazepine type, several substituted 2-amino-3-benzoylthiophens (5) were prepared through the reaction of phenacyl cyanides with aldehydes... 

In addition to benzene and naphthalene derivatives, heteroaromatic compounds such as ferrocene[232, furan, thiophene, selenophene[233,234], and cyclobutadiene iron carbonyl complexpSS] react with alkenes to give vinyl heterocydes. The ease of the reaction of styrene with sub.stituted benzenes to give stilbene derivatives 260 increases in the order benzene < naphthalene < ferrocene < furan. The effect of substituents in this reaction is similar to that in the electrophilic aromatic substitution reactions[236]. 

Benzoic acid and naphthoic acid are formed by the oxidative carbonylation by use of Pd(OAc)2 in AcOH. t-Bu02H and allyl chloride are used as reoxidants. Addition of phenanthroline gives a favorable effect[360], Furan and thiophene are also carbonylated selectively at the 2-position[361,362]. fndole-3-carboxylic acid is prepared by the carboxylation of 1-acetylindole using Pd(OAc)2 and peroxodisulfate (Na2S208)[362aj. Benzoic acid derivatives are obtained by the reaction of benzene derivatives with sodium palladium mal-onate in refluxing AcOH[363]. 

Endo adducts are usually favored by iateractions between the double bonds of the diene and the carbonyl groups of the dienophile. As was mentioned ia the section on alkylation, the reaction of pyrrole compounds and maleic anhydride results ia a substitution at the 2-position of the pyrrole ring (34,44). Thiophene [110-02-1] forms a cycloaddition adduct with maleic anhydride but only under severe pressures and around 100°C (45). Addition of electron-withdrawiag substituents about the double bond of maleic anhydride increases rates of cycloaddition. Both a-(carbomethoxy)maleic anhydride [69327-00-0] and a-(phenylsulfonyl) maleic anhydride [120789-76-6] react with 1,3-dienes, styrenes, and vinyl ethers much faster than tetracyanoethylene [670-54-2] (46). 

The carbonyl reactivity of pyrrole-, furan-, thiophene- and selenophene-2- and -3-carbaldehydes is very similar to that of benzaldehyde. A quantitative study of the reaction of iV-methylpyrrole-2-carbaldehyde, furan-2-carbaldehyde and thiophene-2-carbaldehyde with hydroxide ions showed that the difference in reactivity between furan- and thiophene-2-carbaldehydes was small but that both of these aldehydes were considerably more reactive... 

The direct combination of selenium and acetylene provides the most convenient source of selenophene (76JHC1319). Lesser amounts of many other compounds are formed concurrently and include 2- and 3-alkylselenophenes, benzo[6]selenophene and isomeric selenoloselenophenes (76CS(10)159). The commercial availability of thiophene makes comparable reactions of little interest for the obtention of the parent heterocycle in the laboratory. However, the reaction of substituted acetylenes with morpholinyl disulfide is of some synthetic value. The process, which appears to entail the initial formation of thionitroxyl radicals, converts phenylacetylene into a 3 1 mixture of 2,4- and 2,5-diphenylthiophene, methyl propiolate into dimethyl thiophene-2,5-dicarboxylate, and ethyl phenylpropiolate into diethyl 3,4-diphenylthiophene-2,5-dicarboxylate (Scheme 83a) (77TL3413). Dimethyl thiophene-2,4-dicarboxylate is obtained from methyl propiolate by treatment with dimethyl sulfoxide and thionyl chloride (Scheme 83b) (66CB1558). The rhodium carbonyl catalyzed carbonylation of alkynes in alcohols provides 5-alkoxy-2(5//)-furanones (Scheme 83c) (81CL993). The inclusion of ethylene provides 5-ethyl-2(5//)-furanones instead (82NKK242). The nickel acetate catalyzed addition of r-butyl isocyanide to alkynes provides access to 2-aminopyrroles (Scheme 83d) (70S593). 

Furans, thiophenes and pyrroles have all been obtained by addition of alkynic dienophiles to a variety of other five-membered heterocycles, as illustrated in Scheme 104. As the alkynic moiety provides carbons 3 and 4 of the resulting heterocycle, this synthetic approach provides an attractive way of introducing carbonyl containing substituents at these positions, especially as many of the heterocyclic substrates are readily generated. Such reactions do... 

With a,p-dihalo- or a-halo-a,p-unsaturated carbonyl derivatives A significant number of examples exist in which a,P-dihalogenated carbonyl derivatives undergo reactions with thioglycolates in the presence of base to produce thiophenes. " The reactions have been shown to occur through intermediate a-halo-a,P-unsaturated carbonyl derivatives produced by the elimination of HX. Thus the use of a-halo-a,P unsaturated carbonyl systems in place of the a,P-dihalocarbonyl compounds was found to efficiently provide thiophenes upon reaction with thioglycolates. In a modification of the work of Fiesselmann, readily accessible methyl-2-chloroacrylate 23 and 2-chloroacrylonitrile 24 have been used in this sense to provide 25 and 26, respectively. 

Mechanistically, the reaction of diketosulfides and glyoxal likely proceeds via an initial aldol reaction to provide 22. A second intramolecular aldol reaction and the elimination of two equivalents of water produce the thiophene 23. The timing of the elimination reactions and the ring-closing, carbonyl condensation reaction is not completely understood. However, 2,5-disubstituted thiophenes 23 are available in good yields via this process. 

The carbonyl group reactivities in thiophenes and benzenes are very similar, as shown by the similar rates of alkaline hydrolysis of esters and by the great similarity of the thiophenealdehydes to benzaldehyde in numerous carbonyl group reactions. This has been ascribed to the counteracting —I- -M effects of the thienyl group in this kind of reactions. ... 

Cases of the S-coordinated rhodium and iridium are quite scarce. To complete the picture, we next consider the possibilities of S-coordination using complicated derivatives of thiophene. 2,5-[Bis(2-diphenylphosphino)ethyl]thiophene is known to contain three potential donor sites, two phosphorus atoms and the sulfur heteroatom, the latter being a rather nucleophilic center (93IC5652). A more typical situation is coordination via the phosphorus sites. It is also observed in the product of the reaction of 2,5-bis[3-(diphenylphosphino)propyl]thiophene (L) with the species obtained after treatment of [(cod)Rh(acac)] with perchloric acid (95IC365). Carbonylation of [Rh(cod)L][C104]) thus prepared yields 237. Decarbonylation of 237 gives a mixture of 238 and the S-coordinated species 239. Complete decarbonylation gives 240, where the heterocycle is -coordinated. The cycle of carbonylation decarbonylation is reversible. 

Reaction of /3-carbonyl amides with the Lawesson s reagent under microwave irradiation gave thiazoles in acceptable yields [37]. The reaction was the same one previously reviewed for the synthesis of thiophenes and was also employed for the preparation of thiadiazoles (Scheme 10, X = NH, Y = CH). 

This gives tautomeric mixtures119 when the tert-butyl group is removed. The methyl ether has been used to obtain 3-hydroxy-2-carbonyl derivatives in the selenophene series.120 The unsubstituted 2-hydroxyselenophene system has been prepared by hydrogen peroxide oxidation of 2-selenophene-boronic acid.121 However, in the 5-methyl-substituted system deboronation became such an important side reaction that 5-methyl-2-hydroxyselenophene had to be prepared by acid-catalyzed dealkylation of 5-methyl-2-fert-butoxy-selenophene. Both 2-hydroxy- and 5-methyl-2-hydroxyselenophene exist mainly as 3-selenolene-2-ones (93) and for the 5-methyl derivative it was possible to isolate the / ,y-unsaturated form (92) and follow the tautomeric isomerization. The activation parameters thus obtained were compared with those for the corresponding furan and thiophene systems. 

Other aromatic heterocycles undergo Patemo-Btichi reaction with carbonyl compounds, although these reactions have seldom been applied to organic synthesis. For example, thiophene reacts cleanly with benzaldehyde to afford a single exo product in 63% yield87. Pyrroles also react with aldehydes and ketones however, as a result of the lability of the presumed initial cycloadducts, the only products isolated, even with the rigorous exclusion of acid, are the 3-hydroxyalkylpyrroles 200 (equation 7)89. 

The condensation of activated thiols onto adjacent nitriles is a common method for the preparation of amine-substituted thiophenes. A three component condensation was utilized to prepare a-aminothiophene 11 <00TL1597>. An alternate method for preparing amino-substituted thiophenes involved the treatment of ketene S,JV-acetal 12 with an activated carbonyl compound 13 which gave thiophene 14 <00JOC3690>. This type of reaction has also been utilized to prepare building blocks for the synthesis of fused thiophenes <00JHC363>. 

Novel C2-symmetric thiophene-containing ligands have recently been prepared and utilized in asymmetric synthesis. Dithiophene 158 was utilized as a ligand in the asymmetric reduction of p-ketoesters (prostereogenic carbonyl) and acrylic acids (carbon-carbon double bond) <00JOC2043>. Dibenzo[b]thiophene 159 was utilized as a ligand in enantioselective Heck reactions of 2-pyrrolines <00SL1470>. 

The tropone ring of cyclohepta[c]thiophen-6-one reacts preferentially at the C=C bond, instead of at the carbonyl group, with both dichloro- and dibromocarbene to give mono- and bis-adducts in relatively low yields (5-40%) [60]. Benzoquinones produce anfi-bis-insertion adducts in their reaction with chloroform (95%), or bromoform (57%), under basic conditions [29]. 

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