2.3- disubstituted thiophenes, preparation

The stability of the bromothienyllithium reagents at —70°C have made them very useful for the preparation of isomer-free 2,3-, 2,4-, and 3,4-disubstituted thiophenes, since bromine atoms of the corre-... 

On the other hand, the thiaozonides 13 were unknown but could be prepared analogously via singlet oxygenation of 2,5-disubstituted thiophenes and subsequent diimide reduction at low temperature (Eq. 10)25). 

In another variation, a 2-alkanone can be reacted with a Grignard reagent, followed by acid-catalyzed dehydration to a mixture of alkenes, and catalytic reduction (Figure 8.2E) (Hwang et al., 1976 Suzuki, 1981 Lacey et al., 2008). Other methods have also been used. For example, in some of the pioneering work on insect cuticular hydrocarbons and their analyses, Pomonis and co-workers prepared a large number of monomethyl and dimethylalkanes from 2,5-disubstituted thiophenes (e.g., Pomonis et al., 1978). However, this route cannot be recommended because it requires as many as 12 steps per hydrocarbon. 

The highly substituted 3-aminofurans 240 can be conveniently prepared via a three-component reaction of thiazo-lium salts 239, aldehydes, and dimethyl acetylenedicarboxylate (Scheme 134) <2005JOC8919>, and 3,4-disubstituted thiophenes 242 are synthesized by an intermolecular cycloadditioncycloreversion procedure between substituted acetylenes and 4-substituted thiazoles 241 (Scheme 135) <1996CC339>. 

Solid phase synthesis of highly substituted thiophene derivatives 15 using a cyclic malonic acid ester resin 14 was also reported. Highly pure thiophene derivatives were reported to have been prepared by this solid phase synthesis <0314851>. While alkyl or aromatic substitutions on the P position to the carbonyl yielded the corresponding 5-alkyl/aryl substituted 2-acyl aminothiophene, acetaldehyde did not produce the corresponding 2,3- disubstituted thiophene. 

An alternative, less sophisticated approach to regioregular substituted polythiophenes is the use of asymmetric 3,4-disubstituted thiophene monomers as substrates, resulting in the selective activation of either the 2- or 5- positions on the thiophene ring. Using this method, poly(3-alkoxy-4-methylthiophenes) with > 95% HT couplings have been prepared via FeCl3 oxidation.48 59... 

The nitrene generated by thermolysis of 3-azidothiophene can also be captured by a suitably positioned divalent sulfur to form an S,N-ylide <86JCS(P1)483>. 2-Azathiabenzenes (519) fused to the thiophene ring have been prepared in this manner (Scheme 110). The 3,4-disubstituted thiophene (520) gave an unstable cyclic sulfimide (521). Cyclic suliimides in which the positions of the sulfur and nitrogen atoms are reversed with respect to the thiophene ring could also be made by this procedure. 

Oxidation of N-aromatic methanesulfonamides 321 with (diacetoxyiodo)benzene in the presence of thiophene in trifluoroethanol or hexafluoroisopropanol (HFIP) affords the respective coupling products 322 in good yield (Scheme 3.131) [380]. The head-to-tail thiophene dimers 324 can be selectively prepared by the hypervalent iodine oxidation of 3-substituted thiophenes 323 [381,382] and bipyrroles 326 can be regios-electively synthesized by oxidative dimerization of pyrroles 325 with [bis(trifluoroacetoxy)iodo]benzene in the presence of bromotrimethylsilane [383]. Likewise, bithiophenes 328 have been synthesized from 3,4-disubstituted thiophenes 327 using [hydroxy(tosyloxy)iodo]benzene in the presence of bromotrimethylsilane in hexafluoroisopropanol [384]. 

P-Halogenated thiophenes unsubstituted at a-positions are not directly accessible by substitution. However, exhaustive bromination, with regioselective dehalo-genation at a-positions is often used as a means to prepare p-halothiophenes. In the example in Scheme 68, the 3,4-disubstituted thiophene was obtained via reaction with -BuLi then water [106]. 

SCHEME 14.20 Preparation of naphthoquinones 63 starting from p-benzoquinone (61) and 3,4- disubstituted thiophene-1,1-dioxides (62) by Bailey and Williams. 

The bromination of 2-cyanothiophen with one equivalent of bromine in the presence of an excess of AICI3 gives 2-cyano-, 4-bromo-2-cyano-, 5-bromo-2-cyano-, and 4,5-dibromo-2-cyano-thiophen in the proportions 16 70 2 12, from which pure 4-bromo-2-cyanothiophen can easily be obtained. Nitration of 2-cyanothiophen in concentrated sulphuric acid led to mixtures of almost equal amounts of 4- and 5-nitrothiophen-2-carboxylic acid. The chloromethyl-ation of 2-acetylthiophen and 2-formylthiophen with ota -bis(chloromethyl) ether in 60—100% sulphuric acid has been studied. An increase in the acidity of the medium promoted the formation of 4-substituted products. From these products some otherwise difficultly obtainable 2,4-disubstituted thiophens were prepared. ... 

In a series of papers in late 1884 and early 1885, Paal and Knorr demonstrated that several 1,4-dicarbonyls could be transformed into furans, pyrroles, and thiophenes. Paal first discovered this transformation and used it to prepare di-, tri-, and tetrasubstituted furans. For example, dicarbonyl 3 yielded disubstituted furan 4 upon treatment with weak acid. 

It seems quite obvious that the thiophenes are related to the polyacetylenes which they accompany. This viewpoint has recently been illustrated by the formation of thiophenes from polyacetylenes and hydrogen sulfide under almost biological conditions. In a recent lecture summary, the preparation of terthienyl, junipal, and (241) from 1,4-disubstituted butadiynes and hydrogen sulfide is claimed. A large number of bithienyls have been prepared and their nemato-dicidal activity investigated. All the compounds with strong activity were found to be derivatives of 2,2 -bithienyl. ... 

Besides the domino Michael/SN processes, domino Michael/Knoevenagel reactions have also been used. Thus, Obrecht, Filippone and Santeusanio employed this type of process for the assembly of highly substituted thiophenes [102] and pyrroles [103]. Marinelli and colleagues have reported on the synthesis of various 2,4-disubstituted quinolines [104] and [l,8]naphthyridines [105] by means of a domino Michael addition/imine cyclization. Related di- and tetrahydroquinolines were prepared by a domino Michael addition/aldol condensation described by the Hamada group [106]. A recent example of a domino Michael/aldol condensation process has been reported by Brase and coworkers [107], by which substituted tetrahydroxan-thenes 2-186 were prepared from salicylic aldehydes 2-184 and cycloenones 2-185 (Scheme 2.43). 

The formyl group in orthoformylselenophenecarboxylic acids on reduction to an hydroxymethyl group undergoes ring closure to lactones.100 To obtain 2,4-disubstituted selenophenes, 4-bromo-2-formylselenophene was prepared by the swamping catalyst method.101 Selenopheno[2,3-b]thiophene derivatives may be prepared from compound 84.102 Another route to substituted... 

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