Thiophenes base-catalyzed

Addition reactions with tetracyanoethane have provided access to 2,5-diamino-3,4-dicyano-thiophene and -selenophene (58JA2775,81ZOR1958). Base catalyzed rearrangement gives the isomeric pyrrolethiol (Scheme 53). 

The mechanism of the Fiesselmann reaction between methylthioglycolate and a,P-acetylenic esters proceeds via consecutive base-catalyzed 1,4-conjugate addition reactions to form thioacetal Enolate formation, as a result of treatment with a stronger base, causes a Dieckmann condensation to occur providing ketone 8. Elimination of methylthioglycolate and tautomerization driven by aromaticity provides the 3-hydroxy thiophene dicarboxylate 9. 

Replacement of a benzene ring by its isostere, thiophene, is one of the more venerable practices in medicinal chemistry. Application of this stratagem to the NSAID piroxicam, gives tenoxicam, 136, a drug with substantially the same activity, nie synthesis of this compound starts by a multi-step conversion of hydroxy thiophene carboxylic ester 130, to the sulfonyl chloride 133. Reaction of that with N-methylglycinc ethyl ester, gives the sulfonamide 134. Base-catalyzed Claisen type condensation serves to cyclize that intermediate to the p-keto ester 135 (shown as the enol tautomer). The final product tenoxicam (136) is obtained by heating the ester with 2-aminopyridine [22]. 

There have been a number of different synthetic approaches to substituted PTV derivatives proposed in the last decade. Almost all focus on the aromatic ring as the site for substitution. Some effort has been made to apply the traditional base-catalyzed dehydrohalogenation route to PTV and its substituted analogs. The methodology, however, is not as successful for PTV as it is for PPV and its derivatives because of the great tendency for the poly(u-chloro thiophene) precursor spontaneously to eliminate at room temperature. Swager and co-workers attempted this route to synthesize a PTV derivative substituted with a crown ether with potential applications as a sensory material (Scheme 1-26) [123]. The synthesis employs a Fager condensation [124] in its initial step to yield diol 78. Treatment with a ditosylate yields a crown ether-functionalized thiophene diester 79. This may be elaborated to dichloride 81, but pure material could not be isolated and the dichloride monomer had to be polymerized in situ. The polymer isolated... 

The same group of authors has recently reported a combination of various palladium- and copper-catalyzed Suzuki, cyanation, and Ullmann condensation reactions for the synthesis of thiophene-based selective angiotensin II AT2 receptor antagonists (Scheme 6.24) [55],... 

Thiophenols undergo base-catalyzed, Michael addition to acetylenic acids and esters to give trans addition products. These vinyl thioethers have been used in the synthesis of thiochromones. " Recently, Undheim and Lie have shown that thiophenol adds to DMAD with concomitant cyclization to give benzo[6]thiophenes. 

The known dibromide 464 was converted in good yield to the dinitrile 465 by reaction with buffered potassium or sodium cyanide. Reaction of 2,5-dimethoxycarbonyl-3,4-dicyanomethylthiophene 465 with thionyl chloride and selenium oxychloride gave thieno[3,4-f]thiophene 466 and selenolo[3,4-f]thiophene 467, respectively (Scheme 57) <2002JOC2453>. In the case of thionyl chloride as the sulfur transfer reagent, an intermediate sulfoxide 468 must be involved, which then suffers a spontaneous base-catalyzed Pummerer reaction to give 466 in high yield. 

Iron(iii) chloride has been used as an oxidant to catalyze the cyclization of acyclic precursors to highly derivatized benzodithiophenes <2006TL1551>. Thus, thiophene-based polycyclic aromatics have been produced in high yield (Equation 75). 

Thiophene-2-carbaldehyde condenses easily with ethyl acetoacetate or ethyl nitroacetate in the presence of TiCU and a tertiary organic base (pyridine or N- methylmorpholine) at 0-22 °C, giving (361) (72T663). Base-catalyzed condensation of thiophene-2-carbaldehyde with methyl (methylthio)methyl sulfoxide followed by treatment with HC1 in alcohols gives (2-thienyl)acetic esters (Scheme 114) (79BCJ2013). 

The kinetics of base-catalyzed deuterium exchange of deuterioselenophenes in DMSO in the presence of lithium or potassium butoxide has been studied. Deuterium exchange occurs approximately 50 000 times faster at the a-positions than at the /8-positions. In furans the ratio of a to /3 exchange rates is 500 and in thiophene 250 000. Relative rate data are given in Figure 3. It can be seen that /3-deuterium exchange occurs approximately 8 times faster in selenophene than in thiophene (70AHC(i2)i). 

The base-catalyzed intramolecular condensation of the aldehyde-ester (171) led to the isomeric thieno[3,2-6]thiophene acid (172), which upon decarboxylation led to thieno[3,2-6]thiophene (3 Scheme 58) (76AHC(19)123). 

The 3-substituted thieno[3,2-6]thiophenes were prepared via the same sequence of reactions using the appropriately substituted acetic acid. For example, methyl 2-acetyl-3-thienylthioacetate (173) underwent base-catalyzed condensation to yield, after decarboxylation, 3-methylthieno[3,2-6]thiophene (174 Scheme 59) (76AHC(19)123). 

Base-catalyzed hydrogen isotope exchange in inactivated selenophenes occurs only in highly basic media. The relative rates of exchange of deuterium at the a-position in furan, thiophene, and selenophene in 0.4 M t-BuOK/DMSO... 

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