Thiophenes preparation from dicarbonyl compounds

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. 

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. 

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). 

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. 

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. 

Other interesting methods can generate furans. One method treats an allylic diol such as 125 with pyridinium chlorochromate (PCC see Chapter 17, Section 17.2.3), in an oxidative-cyclization process, to give 3-ethylfuran, 126. Thiophene derivatives can also be prepared from 1,4-dicarbonyl compounds. A Paal-Knorr thiophene synthesis reacts 2,4-hexanedione (115) with phosphorus pentasulfide (P4S10) to give 2,5-dimethylthiophene, 127. 

Thiophenes are generally obtained by sulfuration of 1,4-dicarbonyl compounds (Paal s)mthesis). The preparation of the highly substituted 2-(4-bromophenyl)-5-(3,4-dimethoxyphenyl)-3,4-dimethylthiophene from the respective 1,4-diketone represents a recent example. This type of reaction can be performed as a solid-phase synthesis with polymer-bound diketones (132) and LR (eq 44). Trifluoroacetic acid releases the thiophene (133) from the solid support. Bismuth triflate in 1,3-dialkylimida-zolium fluoroborate has been utilized as a catalytic ionic liquid system for the synthesis of thiophenes from 1,4-diketones and LR with significantly improved yields. 

Pyrroles furans and thiophenes are prepared from y-dicarbonyl compounds... 

---