Benzo thiophenes, formation

Sulfur. Thiophene and benzo[ >] thiophene are both aromatic heterocycles, as discussed earlier in this review. Isothiazole is a planar molecule with an aromaticity comparable with those of thiazole and pyrazole, and higher than those of isoxazole and oxazole,122 140 as evaluated on the basis of Bird s aromaticity index A, based upon the statistical degree of uniformity of the bond orders of the ring periphery. Theoretical calculations and experimental data in connection with the aromaticity of isothiazole have been reviewed.141 Thiazole is also viewed as an aromatic molecule, similar to thiophene. It lacks an experimental aromaticity value, but the heat of formation together with bond lengths and angles have been calculated by various computational meth-... 

The first proton to be removed from N-methylpyrrole by n-butyllithium is from an a-position a second deprotonation occurs to give a mixture of 2,4- and 2,5-dilithiated derivatives. The formation of a 2,4-dilithio derivative is noteworthy since in the case of both furan and thiophene initial abstraction of a proton at C-2 is followed by proton abstraction from C-5 (77JCS(P1)887). Af-Methylindole, benzo[ >]furan and benzo[ >]thiophene are also deprotonated at C-2. Selenophene and benzo[ >]selenophene and tellurophene and benzo[6]tellurophene similarly yield 2-lithio derivatives (77AHC(2l)ll9). 

Ylide formation. Thiophenium bis(alkoxycarbonyl)methylides 51 are obtained in high yield by rhodium(II) carboxylate-catalyzed reaction of diazomalonate esters with thiophenes. Likewise, ylides (e.g., 52) from benzo[ ] thiophene and dibenzothiophene are obtained by tmns-ylidation using phenyliodonium bis(phenylsulfonyl) methylide. 

Pyrroles, indoles, and benzo[ ]thiophene act as good dienophiles in inverse electron demand DielsAlder reactions with 1,2-diazines, 1,2,4-triazines, and jy/w-tetrazines. This is exemplified by the formation of compounds 230 in excellent yields on interaction of indoles or benzo[r]thiophene with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate. There are also many examples in which the azadiene is tethered, i.e., the processes are intramolecular for example, 231 heated in triisopropylbenzene gives 232 <1995TL6591 >. 

Benzo[ ]thiophene normally undergoes electrophilic substitution at the 3-position more rapidly than at the 2-position <1971AHC(13)284>, so both this and formation of the thioester group favor ketonization of 2-hydro-xybenzo[ ]thiophene which occurs 40 times faster than ketonization of 3-hydroxybenzo[ ]thiophene. The rapid rate of ketonization of the thio-ester enol 2-hydroxybenzo[ ]thiophene is also indicated by its 4.4-fold greater rate of ketonization compared to 2-hydroxyindene, which contrasts with what is found with 3-hydroxybenzo[. ]thiophene and 1-hydroxyindene <1986TL3275>. 

Pd-catalyzed C-P bond formation (Equation 44) has been used to synthesise several highly active thiophene- and benzo[ ]thiophene-based phosphine ligands, for example, 99 and 100, for use in asymmetric allylation reactions <2004SL1113, 2002SL2083>. The catalyst used was 101. 

Benzo[/ ]thiophene behaves similarly. If the 2,5-positions in 255 are blocked by methyl groups, deprotonation followed by metal migration leads to the formation of a Re-C bond at C-3 of the thiophene. 

Michael addition of appropriate nucleophiles to benzo [ ] thiophene 1,1-dioxides followed by intramolecular condensation leads to the formation of heterocycle-annelated benzothiophene 1,1-dioxides. Thus, a wide variety of heterocycle-annelated compounds such as 138-142 were synthesized by addition of nucleophiles to 2-benzoyl-3-chlorobenzo[b] thiophene 1,1-dioxide 121 (Scheme 75) [195,203,204]. 

Formation of benzo thiophenes (70) by catalytic dehydrogenation of (69) probably involves thiyi radicals as an intermediate <83JCR(S)276>. Similarly, formation of tetrahydrothiophenes (72) by cyclization of (71) on treatment with PrjB/Oj in methanol may also involve a thiyi radical intermediate <89IZV2115>. 

Direct benzo[b]thiophene formation via S jAr Scheme 4.2 The proposed mechanism. 

Benzo[Z)]furans and indoles do not take part in Diels-Alder reactions but 2-vinyl-benzo[Z)]furan and 2- and 3-vinylindoles give adducts involving the exocyclic double bond. In contrast, the benzo[c]-fused heterocycles function as highly reactive dienes in [4 + 2] cycloaddition reactions. Thus benzo[c]furan, isoindole (benzo[c]pyrrole) and benzo[c]thiophene all yield Diels-Alder adducts (137) with maleic anhydride. Adducts of this type are used to characterize these unstable molecules and in a similar way benzo[c]selenophene, which polymerizes on attempted isolation, was characterized by formation of an adduct with tetracyanoethylene (76JA867). 

The use of free-radical reactions for this mode of ring formation has received rather more attention. The preparation of benzo[Z)]thiophenes by pyrolysis of styryl sulfoxides or styryl sulfides undoubtedly proceeds via formation of styrylthiyl radicals and their subsequent intramolecular substitution (Scheme 18a) (75CC704). An analogous example involving an amino radical is provided by the conversion of iV-chloro-iV-methylphenylethylamine to iV-methylindoline on treatment with iron(II) sulfate in concentrated sulfuric acid (Scheme 18b)(66TL2531). 

The direct combination of selenium and acetylene provides the most convenient source of selenophene (76JHC1319). Lesser amounts of many other compounds are formed concurrently and include 2- and 3-alkylselenophenes, benzo[6]selenophene and isomeric selenoloselenophenes (76CS(10)159). The commercial availability of thiophene makes comparable reactions of little interest for the obtention of the parent heterocycle in the laboratory. However, the reaction of substituted acetylenes with morpholinyl disulfide is of some synthetic value. The process, which appears to entail the initial formation of thionitroxyl radicals, converts phenylacetylene into a 3 1 mixture of 2,4- and 2,5-diphenylthiophene, methyl propiolate into dimethyl thiophene-2,5-dicarboxylate, and ethyl phenylpropiolate into diethyl 3,4-diphenylthiophene-2,5-dicarboxylate (Scheme 83a) (77TL3413). Dimethyl thiophene-2,4-dicarboxylate is obtained from methyl propiolate by treatment with dimethyl sulfoxide and thionyl chloride (Scheme 83b) (66CB1558). The rhodium carbonyl catalyzed carbonylation of alkynes in alcohols provides 5-alkoxy-2(5//)-furanones (Scheme 83c) (81CL993). The inclusion of ethylene provides 5-ethyl-2(5//)-furanones instead (82NKK242). The nickel acetate catalyzed addition of r-butyl isocyanide to alkynes provides access to 2-aminopyrroles (Scheme 83d) (70S593). 

Kropp KG, JA Goncalves, JT Anderson, PM Fedorak (1994) Microbially mediated formation of benzonaph-thothiophenes from benzo[b]thiophenes. Appl Environ Microbiol 60 3624-3631. 

In addition, the formation of terminal metabolites may be adverse either for the organism itself, or for other organisms in the ecosystem. Microbial metabolites may also undergo purely chemical reactions to compounds that are terminal products. Examples include the formation of 5-hydroxyquinoline-2-carboxylate from 5-aminonaphthalene-2-sulfonate (Nortemann et al. 1993) or benzo[fc]naphtho[l,2- /]thiophene from benzothiophene (Kropp et al. 1994). Microbial metabolites may be toxic to both the bacteria producing them and to higher organisms. Illustrative examples of toxicity include the following ... 

The [2 + 2] photodimerization of a, j8-unsaturated sulfones is correctly viewed as a photoreaction of alkenes, rather than the sulfone group, and this aspect has been reviewed recently by Reid, as part of a wider survey of the photoreaction of O- and S-heterocycles. The topic continues to attract considerable interest and a few recent examples, as well as some synthetic applications, will be discussed here. Much of the photodimerization work has been carried out on the benzo[fc]thiophene (thianaphthene) 1,1-dioxide system. For example. Porter and coworkers have shown that both 3-carboxybenzo[i]thiophene 1,1-dioxide (65) and its methyl ester give only the head-to-head (hth), anti dimer (66) on irradiation in ethanol. In a rather unusual finding for such systems, the same dimer was obtained on thermal dimerization of 65. Similar findings for a much wider variety of 3-substituted benzo[fi]thiophene 1,1-dioxides have been reported more recently by Geneste and coworkers . In the 2-substituted analogs, the hth dimer is accompanied by some of the head-to-tail (htt), anti dimer. The formation of the major dimer appears to proceed by way of an excited triplet and the regiochemistry observed is in accord with frontier MO theory. 

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