Thiophenes carbonylation

In order to investigate the antitubercular activity of thiophene analogs, thiosemicarbazones were synthesized 12). It was found that the addition of a small amount of acetic acid facilitated the reaction between thiosemicarbazide and the thiophene carbonyl compound and that the reaction was essentially completed in one half to one hour. The activities of these semicarbazones, however, were not recorded. 

The reaction of various thiophene carbonyl compounds with ethyl bromocrotonates was carried out smoothly in the presence of zinc in... 

The thiophene carbonyl compounds could be readily converted to the secondary ethynylcarbinols (78), while the tertiary ethynylcarbinols were obtained in low yields (80). 

For nonsymmetrical bicyclic imidazoles, direct TV-alkylation (arylation or acylation) is problematic since site-selectivity is influenced by many subtle electronic effects. Thus, Curtius rearrangement-based syntheses have been used widely for the synthesis of differentiated TV-substituted thienoimidazoles (104), (106) from (acylamido)thiophene carbonyl azides (103), (105) (Equations (30) and (31)) <79JCR(S)96>. These intermediates are useful for the synthesis of angiotensin II antagonists (Equation (32)) <91EUP483683,92EUP520423>. 

Eqn. (a) shows the interaction between thiophene-2-carboxylic acid chloride and 2, 3-dichloro-anisole in the presence of CS2, anhydrous aluminium chloride and subsequent hydrolysis yields [2, 3-dichloro-4-(2-thiophen carbonyl) phenoxy]-methyl (I). The methoxy function present in the latter reactant, being an ortho- and para-director, helps to hook on the thiophene-2-carbonyl moiety at the para-position of the 2, 3-dichloro anisole to give (I). Obviously, the ori/io-position is pre-occupied by a chloro group. 

Eqn. (6) depicts the hydrolysis of compound (I) in the presence of aluminium chloride and benzene followed by refluxing for two hours and subsequently carrying out the hydrolysis with sodium hydroxide solution to give a corresponding phenol (II) i.e., 2, 3-dichloro-4-(2-thiophen carbonyl)-phenol plus one mole of methanol gets eliminated. 

Step I. Preparation of [2, 3-Dichloro-4-(2-thiophen carbonyl)-phenoxy]-methyl (I) ... 

The low-frequency CO band (1637 cm ) of benzoylazulenothiophene 133a is evidence for a strong thiophene-carbonyl mesomeric interaction (71JA2196), comparable with 2-benzoylthiophene (1636 cm ), but different from usual diarylketones (1670-1660 cm ). Compared with five-membered cyclic imides (for instance, N-methylphthalimide, 1780 and 1705 cm ), pyridinedione 216 (a six-membered imide) also exhibits low IR absorption (1695 and 1665 cm ) (69ISJ435), similar to that of naphthalene-1,8-dicarboxylic N-methylimide (1705 and 1665 cm ). 

Ab initio studies of the conformational equihbria of 2-substituted furan and thiophene carbonyl derivatives (Scheme 33) revealed that electron-withdrawing substituents favor the cis conformer in furan carbonyls but the trans form in thiophene derivatives. These effects in the cis forms are ascribed to a decrease in electrostatic repulsive interaction between two oxygen atoms in furan systems and attractive interactions between oxygen and sulfur atoms in thiophene carbonyls (1996TCA(93)199). Solvent effects only slightly influence the absolute value of the energy differences between conformers but can lead to the reverse order of the stability. The cis conformer with higher dipole moment is more stable in solution than the trans conformer. 

A third concept, utilizing thiophene carboxylic acid esters instead of EDOT derivatives for the construction of PEG-EEXDT block copolymers was disclosed Esterification of 2-thiophene carbonyl chloride with PEG or PEG monoethers yields reactive, thiophene-functionalized PEG blocks, which also can be copolymerized with EEXDT. ... 

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]. 

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]. 

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). 

A comparison of the relative basicities of pyrrole, furan and thiophene may be made by comparing the pK values of their 2,5-di-t-butyl derivatives, which were found to be -1.01, —10.01 and —10.16, respectively. In each case protonation was shown by NMR to occur at position 2. The base-strengthening effect of alkyl substitution is clearly apparent by comparison of pyrrole and its alkyl derivatives, e.g. A-methylpyrrole has a pKa. for a-protonation of -2.9 and 2,3,4,5-tetramethylpyrrole has a pK of 4-3.7. In general, protonation of a-alkylpyrroles occurs at the a -position whereas /3-alkylpyrroles are protonated at the adjacent a-position. As expected, electron-withdrawing groups are base-weakening thus A-phenylpyrrole is reported to have a p/sTa of -5.8. The IR spectrum of the hydrochloride of 2-formylpyrrole indicates that protonation occurs mainly at the carbonyl oxygen atom and only to a limited extent at C-5. 

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... 

The 4- and 5-hydroxy-imidazoles, -oxazoles and -thiazoles (499, 501) and 4-hydroxy-pyrazoles, -isoxazoles and -isothiazoles (503) cannot tautomerize to an aromatic carbonyl form. However, tautomerism similar to that which occurs in hydroxy-furans, -thiophenes and -pyrroles is possible (499 500 503 504 501 502), as well as a zwitterionic... 

Benzisothiazoles also suffer N—S bond cleavage, following attack at sulfur, but 1,2-benzisothiazole 1,1-dioxides are cleaved at the C—N bond. Saccharin derivatives are attacked at the carbonyl function. In cases where N—S bond cleavage occurs, recyclization can sometimes occur, often producing thiophene compounds. 

Benzo[b]thiophene-2-carbonyl chloride, 3-chloro-synthesis, 4, 870, 889... 

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. 

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