Functionalized thiophenes

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... 

Some functionalized thiophenes have been investigated in order to assess the scope of ylide-derived chemistry. As already mentioned, 2-(hydroxymethyl)thiophene still gives the S-ylide upon Rh2(OAe)4-catalyzed reaction with dimethyl diazomalonate 146 but O/H insertion instead of ylide formation seems to have been observed by other workers (Footnote 4 in Ref. 2S4)). From the room temperature reaction of 2-(aminomethyl)thiophene and dimethyl diazomalonate, however, salt 271 was isolated quite unexpectedly 254). Rh2(OAc)4, perhaps deactivated by the substrate, is useless in terms of the anticipated earbenoid reactions. Formation of a diazo-malonic ester amide and amine-catalyzed cyclization to a 5-hydroxytriazole seem to take place instead. 

Fusion of a functionalized thiophene ring to a benzazepine can be achieved by a two-step procedure through the dinitrile intermediate 119 (Scheme 24 (2005IJC(B)1257)). 

Ortho-bi functional thiophenes provide the most convenient route to unsubstituted thieno[2,3-6]thiophene (1). 3-Bromothiophene yielded 3-thiophenealdehyde. The corresponding diethyl acetal, using the procedure for thienothiophene 2, led to thieno[2,3-6]thiophene (l) in about 40% yield based on 3-bromothiophene [Eq. (24)]. This method was also used by Gronowitz and Persson for the synthesis of thienothiophene 1. 

The overall yields are moderate at best (Table 10), since purification of 223 or 224 is tedious and detrimental due to unknown side products formed by CS2. Nevertheless several functionalized thiophenes are available by this unique route which might be optimized in singular cases and can possibly lead to other sulfur containing... 

Besides solution studies, a variety of thiophene derivatives have been studied in respect of their self-assembling behavior at the solid/liquid interface. Andostrene-based compounds arrange in lamellae <1999CEJ96>, urea-functionalized thiophenes assemble also in lamellae but the thiophene rings are tilted with respect to the surface due to some steric hindrance within the monolayer <2000L10385>. 

A range of copolymers involving functional thiophenes have also been formed electrochemically. For example, Sato and coworkers12 formed a copolymer containing 3-dodecylthiophene and 3-methylthiophene. The material had a solubility of 75 (w/w)% in chloroform and a conductivity of 220 S cm-1. 

Other workers have shown that polymerization of functional thiophenes from aqueous media is possible if surfactants are used to help solubilize the monomer.18 19 20 21 In the case of SDS being used as a solubilizing agent for bithiophene,18 it was also found to lower the oxidation potential and inhibit the dissolution of the... 

Because poly thiophene itself is prone to overoxidation during polymerization, most practical work has been carried out using alkylated thiophenes, which have higher overoxidation potentials. Synthesis of functionalized thiophenes (such as alkylated monomers) is much easier to achieve than that of its pyrrole counterpart. The decreased activity of the sulfur group compared to that of the -NH group means that the laborious steps involved in protecting the heteroatom during synthesis are not required for thiophene. 

Transition metal catalyzed processes are useful tools for the synthesis of functionalized thiophenes. Thus for instance, a phosphine-free, palladium catalyzed coupling protocol for the synthesis of 2-arylbenzo[d]thiophenes from various 3-substituted benzo[6]thiophenes and aryl bromides or iodides has been reported <04T3221>. Likewise, 2,2 -bithiophenes have been 5,5 -diarylated directly with aryl bromides in the presence of Pd(OAc)2, bulky phosphine ligands and CS2CO3 <04T6757>. A series of electron-deficient and relatively electron-rich benzo[6]thienyl bromides have been shown to participate in palladium catalyzed amination reactions, as exemplified by the interesting conversion of 63 to the tetracyclic system 64 upon reaction with 2-aminopyridine 65 <04EJO3679>. 

The major rate-limiting enzyme in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl Coenzyme A reductase (HMG-CoA reductase), has been a therapeutic target for many research groups. A synthesis of the functionalized thiophene 172, prepared for its biological activity, illustrates the utility of 162 for the introduction of one of the hydroxy chiral centers present in the molecule. This chiral center is then exploited for the introduction of the second chiral hydroxy center. Treatment of aldehyde 169 with the double anion of 162 at —95 °C in THF affords as the major product 170 (98.8 1.2). Treatment of the adduct with excess tert-butylacetate enolate at — 78 °C followed by acidic work-up furnishes the jS-hydroxyketone 171 in 86% isolated yield. Chelation-controlled reduction of the ketone, accomplished by initial complexation of the ketone and the hydroxy group with triethylborane followed by sodium borohydride addition, provides the desired dihydroxyester 172 (Scheme 39) [47]. 

Reports detailing the synthesis of highly functionalized thiophenes directed at the development of novel biologically-active compounds continue to appear with great frequency. A... 

It has been found that 3-lithiothiophene is stable even at room temperature in hexane <94TL36V3>. This makes it easy for the synthesis of 3-functionalized thiophenes, since even less reactive electrophiles can be used. A typical procedure involves reaction of 3-bromothiophene with Bu"Li at —40°C in hexane to which about 10% THE has been added. The solution is then warmed to room temperature and treated with electrophiles to give good yields of the products. C—C, C—S, C—hal and C—Si bonds have been created at position 3 by this method. 

At present, it is evident that diacetylene can be used for the creation of profitable pilot-scale facilities to produce simple and functionalized thiophenes, pyrroles, pyrazoles, pyrimidines, pyridines, and other heterocycles, as well as vitamins A and PP, geraniole, phytole derivatives, and many other high-priced specialty chemicals. 

Polythiophenes by Kumada Cross-Coupling 175 Table 7.1 Summary of reported poly(3-functionalized)thiophenes. 

Blanchard, P., B. Jousselme, P. Frere, and J. Roncali. 2002. 3- and 3,4-Bis(2-cyanoethylsulfanyl)thio-phenes as building blocks for functionalized thiophene-based tr-conjugated systems. J Org Chem... 

Chemical synthesis Poly condensation reaction of di-functional thiophene in presence of Ni catalysts Oxidative coupling reaction of bi-thiophene in presence of ferric chloride using AICI3, CUCI3 and organic solvents Plasma polymerization from 3-methyl thiophene or thiophene (1-6)... 

P. Vallat, J. P. Lamps, F. Schosseler, M. Rawiso and J. M. Catala. Quasi-controlled polymerization through a nickel catalyst process of a functionalized thiophene monomer kinetic studies and apphcation to the synthesis of regioregular poly(thiophene-3-acetic acid). Macromolecules 40(7), 2600-2602 (2007). 

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