Benzyne Diels Alder addition

When benzyne is generated in the presence of potential dienes, additions at the highly strained triple bond occur. Among the types of compounds that give Diels-Alder addition products are furans, cyclopentadienones, and anthracene. 

In the case of 1,3-diphenylisoindole (29), Diels-Alder addition with maleic anhydride is readily reversible, and the position of equilibrium is found to be markedly dependent on the solvent. In ether, for example, the expected adduet (117) is formed in 72% yield, whereas in aeetonitrile solution the adduet is almost completely dissociated to its components. Similarly, the addition product (118) of maleic anhydride and l,3-diphenyl-2-methjdi.soindole is found to be completely dissociated on warming in methanol. The Diels-Alder products (119 and 120) formed by the addition of dimethyl acetylene-dicarboxylate and benzyne respectively to 1,3-diphcnylisoindole, show no tendency to revert to starting materials. An attempt to extrude carbethoxynitrene by thermal and photochemical methods from (121), prepared from the adduct (120) by treatment with butyl-lithium followed by ethyl chloroform ate, was unsuccessful. 

Aromatic compounds can also behave as dienes.858 Benzene is very unreactive toward dienophiles very few dienophiles (one of them is benzyne) have been reported to give Diels-Alder adducts with it.859 Naphthalene and phenanthrene are also quite resistant, though naphthalene has given Diels-Alder addition at high pressures.860 However, anthracene and other compounds with at least three linear benzene rings give Diels-Alder reactions readily. The interesting compound triptycene can be prepared by a Diels-Alder reaction between benzyne and anthracene 861... 

The intramolecular Diels-Alder addition of a benzyne to a furan has been exploited in a synthesis of mansonone E (81TL4877). The benzyne (211), generated from the anthranilic acid (210), yields the adduct (212 86%) which is easily converted into the naphthalene (213 Scheme 79). A similar addition was achieved by generating the benzyne by treating an o -dibromobenzene with butyllithium. 

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). 

The outstanding dienophilicity of benzynes is highlighted by their Diels-Alder additions to benzenes. Tetrachlorobenzyne (520), easily generated by lithiation of hexachlorobenzene (519), smoothly reacted with benzene to afford tetrachlorobenzobarrelene (521) in -60% yield (Scheme 122). The parent benzyne (478) underwent similar addition to benzene, although not so efficiently. ... 

The tetrakis(methylidene)-7-oxabicyclo[2.2.1]heptane (527) offers an interesting route to linear poly-annulated ring systems, e.g. 4Klemethoxydaunomycinone (641), via a sequence of two Diels-Alder reactions (Scheme 124). Monoadduct (528) could be isolated and subjected to the [4 + 2] cycloaddition of benzyne. An alternative synthesis of anthracyclinone analogs starts with the Diels-Alder addition of 3-methoxybenzyne to a derivative of the bis-cisoid tetraene (527). ... 

Structurally related is biflorin (351), isolated from Capraria biflora, and the first naphtho[l,8-hc]pyranquinone found in nature. It has antibiotic properties. Its structure was determined by Prelog and co-workers (58HCA1386 63HCA409, 63HCA415) and it was synthesized by an intramolecular Diels-Alder addition between a benzyne and furan (86AJC647). 

D. Zhu et at., Heterocycles, 1982, T7> 345. The structure (125, Ri=R2=oMe) for pontevedrine has been confirmed by synthesis of the alkaloid by photo-catalysed cyclisation and oxidation of the lactam (128) in alkaline solution, followed by y-methy-lation (Castedo et al.. Tetrahedron Letters, 1978, 2179) and norcepharadione-B has been synthesised by a Diels-Alder addition of benzyne to the masked diene 1,6,7-trimethoxy-l-methyl-tetrahydroisoquinol ine-3,4-dione (Castedo et al.. Tetrahedron Letters, 1982, 23, 451). 

Benzyne is reactive as a dienophile and provides many examples of Diels-Alder addition. It is efficiently trapped by anthracene to give triptycene and by tetracyclone to give 1,2,3,4-tetraphenylnaphthalene via decarbonylation of adduct 23, reactions which are commonly used to quantify the formation of benzyne under given conditions. 

Cycloaddition of benzyne occurs in two cases of homo-Diels-Alder additions (e.g., to norbomadiene) reported in Ref. 1. 

Carpino and Barr5 used the carbo-t-butoxy group for protection of the nitrogen atom of pyrrole during Diels-Alder addition to benzyne for the preparation of... 

Oxazole cycloadditions have been reported with alkyne dienophiles (tandem Diels-Alder addition and retro Diels-Alder loss of a nitrile leads on to furans), benzyne (the primary adduct can be isolated), and with typical alkene dienophiles and the adducts can be transformed into pyridines (8.14.1.4). 

Three rotameric forms of (26) have been isolated at room temperature. In fact Diels Alder addition of dimethylacetylene dicarboxylate to 2,3-dichloro-9-(l,l-dimethyl-2-phenylethyl)anthracene produces only the ap-rotamer (26). The other rotamers can be isolated by thermal equilibrium at 150 °C and subsequent chromatographic separation. Reaction of benzyne with the above anthracene yields only the d,/-triptycene derivative, and 4,5-dichlorobenzyne addition to 9-(l,l-dimethyl-2-phenylethyl)-... 

Phenylpyrrole is formed from pyrrole and benzyne , a reaction which again shows the reluctance of pyrrole to undergo Diels-Alder addition (pp. 70 and 82). 

In contrast to pyrrole itself (p. 71), 1-methyl- and 1-benzyl-pyrrole undergo Diels-Alder addition with benzyne giving (53) and substances derived from these, 308. pyrryl magnesium iodide gives a-naphthylamine formed by aromatization of the Diels-Alder intermediate os. 

Tb 3 z-r] Pyrroles undergo Diels-Alder additions with benzyne derivatives of 2-naphthylamine result from rearrangement of the initial products . ... 

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