Thiophenes and benzothiophenes

A limited number of hypervalent iodine-mediated synthesis of thiophenes and benzothiophenes have been reported. An indirect approach for the synthesis of thiophenes involves formation of 1,4-butanediones [85JC-S(CC)420 87JCS(P1)559 88TL3703 89JOC2605], followed by treatment with phosphorus pentasulfide. This approach is especially useful for the synthesis of 3,2 5, 3 -terthiophene (134) starting from 1,4-diketone 65 (85SC789). 

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Thiophenes continue to play a major role in commercial applications as well as basic research. In addition to its aromatic properties that make it a useful replacement for benzene in small molecule syntheses, thiophene is a key element in superconductors, photochemical switches and polymers. The presence of sulfur-containing components (especially thiophene and benzothiophene) in crude petroleum requires development of new catalysts to promote their removal (hydrodesulfurization, HDS) at refineries. Interspersed with these commercial applications, basic research on thiophene has continued to study its role in electrocyclic reactions, newer routes for its formation and substitution and new derivatives of therapeutic potential. New reports of selenophenes and tellurophenes continue to be modest in number. 

Scheme 1.55 Test reaction with thiophene- and benzothiophene-oxazoline/ phosphine-containing ligands.

Ohta s group investigated the heteroaryl Heck reaction of thiophenes and benzothiophenes with aryl halides [127] and chloropyrazines [128]. Addition of the electrophiles invariably took place at C(2) as exemplified by the formation of arylbenzothiophene 156 from the reaction of benzothiophene and p-bromobenzaldehyde [127]. As expected, the heteroaryl Heck reaction of 2-thienylnitrile, an activated thiophene, with iodobenzene afforded the arylation product 157 [129],... 

In describing catalytic activities and selectivities and the inhibition phenomenon, we will use a common format, where possible, which is based on a common reaction pathway scheme as outlined in Scheme 1. In contrast to the simple one- and two-ring sulfur species from which direct sulfur extrusion is rather facile, in the HDS of multiring aromatic sulfur compounds such as dibenzothiophene derivatives, the observed products are often produced via more than one reaction pathway. We will not discuss the pathways that are specific for thiophene and benzothiophene as this is well represented in the literature (7, 5, 8, 9) and, in any event, they are not pertinent to the reaction pathways involved in deep HDS processes whereby all of the highly reactive sulfur compounds have already been completely converted. 

As discussed in Section III, when the sulfur content is lowered from 0.20 to 0.05%, the chemistry of HDS of gas oils is essentially the chemistry of alkyl-substituted dibenzothiophenes. Though gas oils initially contain mostly alkyl-substituted benzothiophenes, these are completely removed by the time 0.20% S is achieved. Thus, this review will deal predominantly with the reaction pathways involved in the HDS of alkyl-substituted dibenzothiophenes. There are many excellent reviews on reaction pathways of the more reactive sulfur species such as thiophenes and benzothiophenes (2, 5, 8, 23, 24), and the reader is referred to those reviews for information on the reaction pathways and mechanisms of HDS for the more reactive... 

Equilibrium and rate constants for the keto-enol tautomerization of 3-hydroxy-indoles and -pyrroles are collected in Table 32 (86TL3275). The pyrroles ketonize substantially (103-104 times) faster than their sulfur or oxygen analogues, and faster still than the benzo-fused systems, indole, benzofuran, and benzothiophene. The rate of ketonization of the hydroxy-thiophenes and -benzothiophenes in acetonitrile-water (9 1) is as follows 2-hydroxybenzo[b]thiophene > 2,5-dihydroxythiophene > 2-hydroxythiophene > 3-hydroxybenzo[/ Jthiophene > 3-hydroxythiophene. 3-Hydroxythiophene does not ketonize readily in the above solvent system, but in 1 1 acetonitrile-water, it ketonizes 6.5 times slower than 2-hydroxythiophene (87PAC1577). 

The metabolism of thiophene (100) was first studied in 1886 by Heffter (1886MI10900), who administered it orally to dogs and noted the increased output of ethereal sulfates in urine. This is typical of aromatic hydrocarbons conversion to phenolic products which are excreted in urine as sulfate conjugates. When fed to rabbits, there was no increase in the ethereal sulfate output, but there was some indirect evidence of the presence in urine of dihydrodiols and thienylmercapturic acids (45MI10900). This was confirmed by Bray and coworkers (71MI10906,68BJ(109)11P>, who studied thiophene and benzothiophene metabolism in rabbits and rats. The only identifiable metabolites in urine were the thienylmercapturic acids (101) and (102), which are probably formed via conjugation of the intermediate... 

SUMMARY OF PRACTICAL SYNTHESES OF THIOPHENE AND BENZOTHIOPHENE DERIVATIVES... 

The purpose of this section is to call attention to the best laboratory synthetic methods of producing thiophene and benzothiophene derivatives in yields satisfactory for utility. Since methods of constructing the parent ring systems have been surveyed earlier in the chapter, and the introduction of substituents on the parent ring systems has been discussed in Chapter 3.14, specific examples of the synthetic reactions have been discussed earlier. Industrial processes for the parent ring systems, thiophene and benzothiophene, have been adequately covered <52HC(3)i, 54HC(7)l). 

Carbon and Proton NMR Spectra of Thiophenes. Some examples are given in Scheme 5.62 that provide proton and carbon data for thiophenes and benzothiophenes that bear a trifluoromethyl group. 

Diels-Alder reactivity of thiophene and benzothiophene remains poorly understood. AMI semiempirical studies examining the activation of thiophene for this thermally allowed [4+2] cycloaddition process have shown that the usual synthesis approaches (use of highly reactive dienophiles, substitution on thiophene, increased reaction pressures) have only small effects on rate enhancement. However, use of the corresponding S-methylthiophenium salts, which have little aromaticity, should provide excellent activation for Diels-Alder reactions of thiophenes even with poor dienophiles such as ethylene <95JHC483>. This AMI approach has been applied to examine Diels-Alder reactions of benzo[6] and benzo[c]thiophenes the theoretical data agree with experimental results <95JCS(P1)1217>. 

The reactions of a series of arynes from aromatic anhydrides with thiophene and benzothiophene at 690° revealed some processes not as clearly evident with other reagents. 

The major products from the reaction of arynes with thiophene and benzothiophene by addition and insertion are shown in Table 11. Benzyne from phthalic anhydride reacted with thiophene at 690° to give naphthalene and benzothiophene by 1,4-addition and loss of sulfur, and by 1,2-addition and loss of acetylene, respectively, as well as phenyl-thiophene by insertion (Fields and Meyerson, 1966d, 1967e) (Scheme 19). The ratio of naphthalene to benzothiophene was about 9 1, nearly the same preference for 1,4-over 1,2-addition as was inferred from the reaction of benzyne with dichlorobenzenes and pyridine at the same temperature, and again reflects the strong tendency of benzyne to act as a dienophile. 

Insertion and Addition Products of Arynes with Thiophene and Benzothiophene... 

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