Thiophene from 1,4-dicarbonyl compounds

Pyrroles, furans, thiophenes and pyrazolones from dicarbonyl compounds. 

Ketyls from dicarbonyl compounds in the thiophene series have also been examined. The Bologna group has studied the conformational equilibria in the anion-radical of thiophene-2,5-dicarbaldehyde. They have also investigated the intramolecular cation exchange process within ion-pairs of this ketyl, and of analogous ketyls from the isomeric thienothiophenes, and the consequence for this process of variation in the size of the cation and its complexation by macrocyclic polyethers. The anion-radicals of the isomeric l,2-dithienylethane-l,2-diones (thenils) were recorded several years ago. " ... 

Tetrasubstituted thiophenes obtained by the Gewald reaction serve as templates for structural diversification and semi-automated library synthesis. Thiophene 31, prepared from 3-ketoester 29 and t-butylcyanoacetate 30, could be selectively derivatized at three of the four substituents to maximize library diversity. This procedure represents an improvement over previously published methods for utilizing 1,3-dicarbonyl compounds in the Gewald reaction. 

The reaction of diketosulfides with 1,2-dicarbonyl compounds other than glyoxal is often not efficient for the direct preparation of thiophenes. For example, the reaction of diketothiophene 24 and benzil or biacetyl reportedly gave only glycols as products. The elimination of water from the P-hydroxy ketones was not as efficient as in the case of the glyoxal series. Fortunately, the mixture of diastereomers of compounds 25 and 26 could be converted to their corresponding thiophenes by an additional dehydration step with thionyl chloride and pyridine. 

The Paal thiophene synthesis involves the addition of a sulfur atom, typically from phosphorus pentasulfide, to 1,4-dicarbonyl compounds and subsequent dehydration. 

Benzothiepins 2 can be synthesized by a double Knoevenagel condensation starting from phthalaldehydes I and diesters of thiodiglycolic acid, or diphenacyl sulfide.33-63 " 66 In principle, this is an extension of Hinsberg s synthesis of thiophenes (see Houben-Weyl, Vol. E6a, p 282) which employs 1,4-dialdehydes rather than 1,2-dicarbonyl compounds. 

Whereas it was reported in CHEC-II(1996) <1996CHEC-II(7)229> that examples of this system were rare, the increase in synthetic activity since then has been significant. Such compounds can be obtained using either a thiophene or a pyrazine precursor. Virtually all of the molecules prepared from thiophene precursors follow the pathway shown in Equation (185). The appropriate diaminothiophenes 491, usually obtained by reduction of the corresponding nitro groups, are condensed with the desired 1,2-dicarbonyl compound under generally mild conditions to yield 492. 

Dioxins behave as masked cis y-hydroxy enones and as such are an excellent source of y-lactones, notably in an enantio-enriched form <02JOC5307>. Treatment of the dioxin with an amine base results in rearrangement to 1,4-dicarbonyl compounds from which pyrroles and thiophenes are available in a one-pot synthesis <02TL3199>. Stabilised phosphonates add to 1,2-dioxins to yield diastereo-pure substituted cyclopropanes <02JOC3142>. 

Pyrroles, thiophenes, andfurans from 1,4-dicarbonyl compounds... 

Condensation of, J,iV-acetals 77 with 1,3-dicatbonyl compounds in the presence of mercury acetate leads to thiophenes 80. Mercury complexes 78 derived from 77 react with 1,3-dicarbonyl compounds to generate intermediates 79, which undergo cyclization and subsequent hydrolysis-deacylation to afford 80 <1998JOC6086, 2000JOC3690, 2000JHC363>. Thiophenes 82 <20020L873, 2004JOC4867> are also prepared by reaction of 77 with 2-diazo-3-trimethylsilyloxy-3-butenoate 81 (Scheme 18). 

Treatment of 1,4-dicarbonyl compounds 565 with P2SS leads to mercaptothienoindoles 566 <1998JOC2909>. The role of red phosphorus in the synthesis of 3-aryl thiophene 568 from disodium 2-arylsuccinate 567 using P4S10 has been discussed (Scheme 89) <1995SC235>. 

The electronic absorption spectrum of the cation-radical of thiophene itself has been observed following low-temperature y-radiolysis of the heterocycle in a Freon matrix.The radical has also been implicated in the oxidation of thiophene by dibenzoyl peroxide it is believed to be formed at the contact of certain transition metal layer-silicates with thiophene.The anodic oxidation of 2,5-dimethylthiophene has been studied by Japanese workers who found strong evidence for the formation of the cation-radical as the primary oxidation product.In the presence of strong nucleophiles such as cyanide ion, the cation-radical undergoes nucleophilic attack before further oxidation. In the presence of more basic species such as acetate ion, the cation-radical is deprotonated to give a thienylmethyl radical which undergoes further reaction. The results were compared with similar observations for the oxidation of 2,5-dimethylfuran. Czech workers have also studied the anodic oxidation of substituted thiophenes. This work has focused on the preparative value of anodic oxidations in acidified methanol. Cation-radical formation is implied for the primary step, but the value of the method lies in the fact that sulfur is ultimately eliminated from the substrate and functionalized y-dicarbonyl compounds result. 

Anodic oxidation in methanol of thiophene and substituted thiophenes at low temperatures (—20 to — 30°C) results in methoxylation and ring opening with loss of sulfur as SO2 [190]. From thiophene is isolated butenedialdehyde tetramethylacetal, some methoxysuc-cinic dialdehyde tetramethylacetal, and a small amount of methyl y6-formylpropionate. In general, oxidation of thiophenes results in the formation of derivatives of a, -unsaturated y-dicarbonyl compounds or y-keto esters. Cyanomethoxylation of 2,5-dimethyl thiophene yields mainly cis- and rm/i5-2-cyano-5-methoxy-2,5-dimethyldihydrothiophene and 3-cyano-2,5-dimethylthiophene [191]. 

The ring synthesis of five-membered heterocycles has been extensively investigated, and many and subtle methods have been devised. Each of these three heterocyclic systems can be prepared from 1,4-dicarbonyl-compounds, for furans by acid-catalysed cyclising dehydration, and for pyrroles and thiophenes by interaction with ammonia or a primary amine, or a source of sulfur, respectively. 

As illustrations of the variety of methods available, the three processes below show (i) the addition of isonitrile anions to a,P-unsaturated nitro-compounds, with loss of nitrous acid to bring about aromatisation, (ii) the interaction of thioglycolates with 1,3-dicarbonyl-compounds, for the synthesis of thiophene 2-esters, and (iii) the cycloaddition/cycloreversion preparation of furans from oxazoles. 

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