Thiophenes with benzyne

A DFT study of the 2 + 2/4 + 2-cycloaddition of benzyne with thiophene to produce 1-naphthyl- and 2-naphthyl phenyl sulfides led to a modification of the originally proposed reaction pathway.1 The reaction of an E-Z mixture of 7-benzylidenecycloocta-1,3,5-triene (1) with TCNE yields a mixture of 2 + 2- [(2) and (3)], 4 + 2- [(4) and (5)], and 8 + 2- (6) cycloadducts. The presence of pentadienyl and homotropylium zwitterions accounts for the products isolated (Scheme l).2... 

As benzothiophene was a product of both the reaction of benzyne with thiophene and the pyrolysis of thiophene alone (Fields and Meyerson, 1966d), we investigated the reaction of benzyne with benzothiophene. Pyrolysis of a mixture of phthalic anhydride and benzothiophene gave the products shown in Table 11. Anthracene and dibenzothiophene probably arose via 1,2-, and phenanthrene via 1,4-addition to the thiophene ring ... 

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). 

Incidentally, a 1,3-cycloaddition of benzyne to thiophene has been postulated (81CC124) to account for the small, but reproducible amount of benzo[ >]thiophene formed in this reaction (Scheme 79). Reactive alkynes have been successfully used as dienophiles to cycloadd with thiophenes benzene derivatives are obtained after extrusion of sulfur from the adduct (Scheme 80) (72TL605, 72TL1909, 73CB674). 

A report of 2 + 2- and 4 + 2-cycloadditions of benzyne and thiophene provides several reaction paths to account for the 1-naphthyl and 2-naphthyl phenyl sulfide products. A DFT study of these paths shows that some presumed reaction intermediates are not stable entities. A new reaction path adapting a portion of the literature paths but with a lower activation free energy, is described.2 The 4 + 2 path crosses over from (5) and joins the 2 + 2 path with structure (6). The paths appear to proceed by both 2 + 2 and 2 + 4-additions with equal facility. 

Benzyne in solution reacts as a dienophile Wittig (1957) first demonstrated this in the reaction of benzyne with furan. Corbett and Porter (1965) obtained further supporting evidence by isolating 1,4-addition products from benzyne with 1-vinylnaphthalene and 3-vinylbenzo[b]-thiophene Dilling (1966) did the same with styrene. 

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. 

We propose rather that thiophyne is formed by intramolecular dehydrogenation, and that the minor pyrolysis products of thiophene arise from the reaction of thiophyne with thiophene (Scheme 22). Phenylthiophene is a major product from benzyne and thiophene, and therefore suggests the intervention of benzyne in thiophene pyrolysis. A likely source of benzyne in this system is the 1,4-addition of thiophyne to thiophene followed by loss of acetylene and sulfur (Scheme 23). Such a scheme parallels the behavior of benzene, which at 690° gives a small amount of naphthalene, arising presumably from intramolecular... 

In the same way, benzyne reacts with thiophene 1-oxides to give aromatic products (Equation 49). Ar, Ar... 

Photoaddition of 3-acetylbenzoxazole-2(3H)-thione with thiophenes was reported to give 106, which was unstable at room temperature and thus underwent an elimination to yield 107 <03HCA3255>. Benzyne intermediates produced by heating diphenyliodonium-2-carboxylate... 

Benzyne (from pyrolysis of phthalic anhydride) reacts with thiophen at 690°C to give mainly naphthalene, benzo [b] thiophen (54), 2- and 3-phenyl-thiophens, and bithienyl.57 The bithienyl (probably the 2,2 -isomer) is also formed from thiophen alone under the same conditions. The phenylthiophens arise by insertion of benzyne into C—H bonds of thiophen. The source of naphthalene is most likely to be via a Diels-Alder reaction (Scheme 7, X = H), and Fields and Meyerson assume a mechanism involving initially 1,2-cyclo-addition of benzyne to a C—S bond of thiophen to account for the formation of 54 (Scheme 8).2,57,58 However, there is no evidence to support such a route, which seems unconvincing, not least because benzo [b]thiepin (53)... 

The same authors have also reported the reactions of other arynes with thiophen and the reactions of benzyne with 54.57,58 They present speculative reaction mechanisms to account for the formation of products, which in many cases are imperfectly identified from mass spectra alone. For example, although they acknowledge an inability to distinguish between anthracene and phenanthrene,58 they claim, in the same article, both of these as products of distinct reactions of benzyne with 54. Two minor products are claimed to be 59 and 60, respectively, and to provide evidence for the intervention of 2,3-dehydrobenzo[h] thiophen (58). 

Useful reviews on redox transformations of thiophen derivatives (179 references), on the stereochemistry of carbonyl derivatives of five-membered heterocycles (257 references), on synthetic approaches to dihydrothiophens (135 references), and on biosteric thiophens" have been published. Aspects of thiophen chemistry have been treated in reviews on the synthesis of heterocycles by thermal [2 + 2] cycloaddition reactions of acetylenes and on aspects and perspectives of organic heterocyclic chemistry. A review comparing the chemistry of thieno[2,3-h]- and thieno [3,2-i ]-thiophen with that of benzo[ft] thiophen and quinoline has been published. In Advances in Heterocyclic Chemistry, the development of benzo[6] thiophen from 1968 to 1980 and of selenophen from 1970 to 1980 was presented. Other aspects of thiophen chemistry are treated in chapters on Dewar Heterocycles," on Cyclizations under Vilsmeier Conditions, on Polyfluoroheteroaromatic Compounds, and on Reactions of Benzyne with Heterocyclic Compounds. " Several dissertations treating various aspects of thiophen chemistry have appeared. " ... 

Although the reaction of arynes with thiophenes as a route to naphthalenes leaves much to be desired, the reaction with thiophene-1,1 -dioxides is synthetically useful. An excess of benzyne precursor (benzenediazonium carboxylate) is used, and the solvent was refluxing 1,2-dichloroethane. Yields of naphthalenes are moderate and conversions are good. Thus 3-methylbenzyne and tetrachlorothiophene dioxide 296 gives naphthalene 297 in 65% yield (96% conversion). The thiophene dioxides may be prepared by m-CPBA oxidation of the corresponding thiophenes. 

The importance of choosing the proper benzyne precursor for a successful cycloaddition with thiophene was mentioned in CHEC-I. The most suitable precursor was found to be diphenyl-iodonium-2-carboxylate. This reaction has been critically reexamined <88JOC5799,89JOC2i42>. Several mono- and di-substituted thiophenes have been used as substrates in this study, and minor products identified. The major pathway appears to be the [4 + 2] cycloaddition, leading to naphthalene after sulfur elimination. The [2 + 2] pathway is also operative, especially with 3-halothiophenes. A [3 + 2] cycloaddition, followed by elimination of acetylene, leads to the observed small amounts of benzo[6]thiophene. 

The 4-hydroxy-THISs react with electron-deficient alkynes to give cycloadducts (3) that spontaneously eliminate sulfur, producing 2-pyridones (3). Bulky 5-substituents lead to a decrease in the addition rate, and elimination of isocyanate with formation of thiophenes becomes favored (3, 12, 13). Benzyne yields an isolable adduct that exclusively extrudes isocyanate on thermolysis, but sulfur on irradiation (Scheme 7)... 

Benzyne, generated from diphenyliodonium 2-carboxyIate, reacts with various thiophenes by addition to the sulfur and /3-carbon to give, after loss of an acetylene moiety, benzo[Z)]thiophenes in low (<4%) yield (Scheme 52) (81CC124). 

Dehydrobenzene or benzyne 158 can be trapped by all manner of species. 1,2-Dehydro-o-carborane 159 has been shown to undergo many of the same reactions as its two-dimensional relative, 1,2-dehydrobenzene. Although dehydroaromatic molecules can be formed in a variety of ways, synthetic pathways to 1,2-dehydro-o-carborane are quite limited. An effective procedure reported so far78 first forms the dianion by deprotonation of o-carborane with 2 equiv. of butyllithium. Precipitated dilithium carborane is then treated with 1 equiv. of bromine at 0°C to form the soluble bromo anion 160. Thermolysis of 160 with anthracene, furan, and thiophene as substrates leads to the adducts 161-164.79 80 1,2-Dehydro-o-carborane reacts with norbomadiene to give both homo 2+4 and 2+2 addition, leading to three products 165-167, in a 7 1 ratio79. An acyclic diene, 2,3-dimethyl-... 

Despite the fact that the history of hetarynes is older than that of the benzynes (cf. 2), physical data on these compounds are scarce. Numerous trapping experiments furnished evidence for the formation of brradicaloid intermediates in the field of five-membered heterocycles (didehydrofurans, -thiophenes, and -pyrroles)." Direct spectroscopic data on these species, however, do not exist, which may be attributable to the increased ring strain in the five-membered o-arynes, associated with a strong tendency to undergo ring-opening reactions. 

Vinylbenzo[6]thiophene is reported to form a Diels-Alder adduct with 1,4-naphthoquinone (70AHC(ll)i77>. The 3-vinyl isomer is known to be a reactive diene its cycloaddition products with maleic anhydride, p-benzoquinone, benzyne, etc. have been described. 

Vinylbenzo[6]thiophene undergoes Diels-Alder reactions with benzyne,468 maleic anhydride,469 benzo[6]thiophene-1,1-dioxide,469 p-benzoquinone, and various 1,4-naphthaquinones.469,470 With quinones, the product depends on the reaction conditions. For... 

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