Benzo thiophenes addition reactions

Pathway III of Fig. 26 has been demonstrated for thiophene and benzo-thiophene with Ir complexes (4) and for all thiophenes, including dibenzo-thiophene, with Rh complexes (94, 95). These oxidative additions appear to be influenced by substituents present on the carbon atoms adjacent to the sulfur atom. Insertion between sulfur and the unsubstituted carbon is highly preferred. For 2-methylthiophene the exclusive product is the 1-5 bond insertion product, whereas for 3-methylthiophene, no preference for insertion was observed (1-2 and 1-5 bond insertion products were equal). In competitive studies, thiophene was found to be about twice as reactive as 2,5-dimethylthiophene. This behavior is similar to that observed for relative reaction rates of substituted thiophenes observed with conventional HDS catalysts. Thus steric limitations can occur, even with monomeric, homogeneous catalysts. 

The 2,3-double bond in benzo[6]thiophene-1,1-dioxides undergoes addition reactions with nucleophiles in a manner comparable to that of other a,/9-unsaturated sulfones no aromatic properties are detectable in this way for the thiophene ring.718-723 For example, thiophenol and p-thiocresol give the adducts (340 R = H or Me) in the presence of base.723 However, if the aryl mercaptan and the sulfone are heated together, a radical reaction occurs to give the corresponding 2-substituted compound.723 In contrast to the behavior of aryl mercap-... 

The reaction of thiophenes and benzo[3]thiophenes with alkylidenecyclopropanes in the presence of catalytic amounts of Pd(PPh3>4 and tributylphosphine oxide has been reported (Scheme 14) <2002JOC3445>. Yields are around 60%. The role of tributylphosphine oxide in the detailed mechanism is not clear, but it certainly served to accelerate the addition reaction. 

Several excellent reviews are available on the reactivity of organotransition metal complexes of thiophenes <20010M1259, 2000CCR63, 1998ACR109>. In addition, Sadimenko has provided a compendium of all the known syntheses and reactions of the organometallic derivatives of thiophene and benzo[ ] thiophene <2001AHC(78)1>. 

The 77 -bound benzo[/ ]thiophene and dibenzothiophene complexes of iridium undergo reduction to the corresponding 77-complexes by hydride reaction with 2 mol of Red-Al results in addition of two H to give the cyclohexadiene complexes (Scheme 78) <2000CCR63>. 

A similar mercaptoacetate addition reaction to 5-acyl-4,7-dioxo-4,7-dihydrobenzo[i]thiophene-2-carboxylates followed by cyclization and oxidation to give benzo[ 1,2-6 5,4-ft ]dithiophene-4,8-dione derivatives 29 has been shown <03H1689>. Nitrogen bridged heterocycles, 3-(benzylthio)thieno[3,4-6]indolizine derivatives 30 have been synthesized and intramolecular arene-arene interactions within these compounds were reported <03CPB75>. The arene-arene interaction leads to significant shifts in the proton NMR signals and red shifts in the absorption maxima. 

If the 2-position is blocked, cyanation occurs at the 3-position. Similarly, cyanation of 1-methylpyrazole gives a mixture of the 4- and 5-carbonitrile [228]. The efficient substitution observed for many pyrroles, imidazoles [229], and indoles contrasts markedly the addition reactions observed for furans (cf. Chapter 16) and thiophenes [230]. However, this difference may only be apparent. At least for two of the cases already cited [226], it has been demonstrated [231] that the cyanosubstituted pyrroles arise as a result of elimination during workup of the 2,5-addition product originally formed. For benzo[b]thiophenes, cyanation leads predominantly to substitution products [232] ... 

Examples of the former two reaction types are illustrated. An early Heck cyclization of 2-carboxy-2 -iododiphenylamine to 1-carbazolecarboxylic acid (73% yield) [346] has been generally overlooked by subsequent investigators. A microwave method is useful for the synthesis of azaindoles from aminopyridines and ketones [347], and a variety of cyclopent[/ ]indolones and carbazolones are available using this Heck chemistry [348, 349]. The requisite enamines can also be generated in situ by the addition of 2-haloani-lines to alkynes with TiC [350]. The aryl Heck variation affords carbazoles [351-353] including novel indolo[3,2-/ ]benzo[/ ]thiophenes [353]. 

Benzo[h]thiophenes, photochemical addition reactions of 84MI38. 

Benzo[b]thiophenes and Benzo[b]furans Reactions and Synthesis 437 Rhodium-catalysed carbenoid addition to benzofuran using a chiral catalyst proceeds with high ee. ... 

Oxidation of benzo[b] thiophene 1,1-dioxide with KMn04 affords the sulfonic acid 172 [189], while oxidation with alkaline H202 yields the ketone 173 (Scheme 97) [244]. Oxidation of 3-substituted benzo[ ]thiophene 1,1-dioxides 174 with alkaline H202 affords the alcohols 175 as the principal product (Scheme 98) [244]. Compounds 173 and 175 are presumably formed through Michael addition of HOO to the 3-position of the substrates. Indeed, the reaction of 3,4-di-ferf-butylthiophene 1,1-dioxide 83 with H202 under alkaline conditions at room temperature afforded the Michael adduct 177 in 91 % yield, while the reaction carried out at 50-60 °C gave the ring-opened product 178 in 15% yield in addi-... 

The detailed structure of the clathrate compound formed between 2,5,5-trimethylhex-3-yn-2-ol and 4-p hydroxyphenyl-2,2,4-trimethylthio> chroman has been determined by A -ray crystallography. tra/i5 -3,4-Dibromothiochroman and analogous dibromo-naphthothio-pyrans, prepared by addition of bromine to the appropriate A -thio-chromenes, may exist in sofa conformations. The dibromo-compounds undergo ring-contraction reactions with alkalis, yielding benzo[ ]thiophen derivatives. ... 

Benzo[Z)]thiophene reacts with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate in a cyclo-addition-fragmentation reaction to yield (143), whereas benzo[A]furan and N- methylindole yield products (144) arising from ring opening and recyclization (76AP679). 

There are reports of an increasing number of palladium-assisted reactions, in some of which the palladium has a catalytic function. Thus furan and thiophene undergo facile palladium-assisted alkenylation giving 2-substituted products. Benzo[6 Jfuran and TV- acetyl-indole yield cyclization products, dibenzofurans and carbazoles respectively, in addition to alkenylated products (8UOC851). The arylation of pyrroles can be effected by treatment with palladium acetate and an arene (Scheme 86) (81CC254). 

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). 

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 ... 

In the reaction of ketones with thionyl chloride the intermediate sulfinyl (or sulfenyl) chloride can cyclize on to an aromatic ring located two carbon atoms away giving benzo[b]thiophenes (48) (Scheme 7).54 Additional... 

Gold catalyzed reactions are currently enjoying considerable interest, and have also found applications in thiophene ring synthesis. A series of (a-alkoxyalkyl)(o-alkynylphenyl) sulfides 14 was subjected to treatment with catalytic amounts of AuCl, giving the benzo[fe]thiophenes 15 in excellent yields. Some additional, more complex examples were also provided <06AG(E)4473>. 

The first successful Diels-Alder addition of thiophene appears to have been with tetrafluorobenzyne (66CC143). The adduct apparently loses sulfur, resulting in the isolation of the tetrafluoronaphthalene in 40% yield (Scheme 78). Other thiophene derivatives (69T25) and fluorinated benzynes <71JCS(C)604) have been similarly reacted. Subsequently it was found (80H 14)647) that unsubstituted benzyne, generated from diphenyliodonium-2-carboxylate, could be trapped with thiophene to form naphthalene in 33% yield. The earlier failure to add thiophene to benzyne generated by other methods must have been due to intervention of side reactions. Thiophyne also has been similarly trapped to yield benzo[A]thiophene (see Section 3.14.2.2). 

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