Diels-Alder reactions benzynes

The discovery chemistry approach to benzazepine (8) appears in Scheme 1. Benzyne Diels-Alder reaction of 10 was used in the original Wittig/Grignard protocol with cyclopentadiene and magnesium turnings in THF (45-64% yield).31 Methodological... 

The original literature preparation of benzazepine 6 (Scheme 3.2) was reported in 1978 by Mazzocchi and Stahly" and began with benzonorbornadiene (3), a compound prepared by the benzyne Diels-Alder reaction of l-bromo-2-fluorobenzene (2) and cyclopentadiene. Mazzocchi and Stahly s preparation involved hydration of the olefin to generate 11 and sequential oxidations of 11 (Al(OtBu)3, Se02, and KO2) that ultimately led to intermediate diacid 13 (see Scheme 3.2). Conversion of 13 to the corresponding anhydride followed by treatment with ammonium hydroxide and thermal dehydration gave cyclic imide 14. Lithium aluminum hydride reduction provided 6 in 2% overall yield. 

SCHEME 3.3 Grignard-based benzyne Diels-Alder reaction with cyclopentadiene. 

The first report of a [4 + 2] cycloaddition of an oxazole with benzyne was the reaction of a trisubstituted oxazole with benzyne generated from anthranilic acid and isoamyl nitrite in refluxing dioxane. The product of this reaction was not the oxazole Diels-Alder adduct or a furan, but rather the bisfbenzyne) adduct 163 resulting from initial cycloaddition to give 161, subsequent retro-Diels-Alder reaction to give the isobenzofuran 162 and then a second benzyne Diels-Alder reaction to afford 163 (Fig. 3.49). 

Further mechanistic evidence comes from trapping experiments. When bromobenzene is treated with KNH2 in the presence of a diene such as furan, a Diels-Alder reaction (Section 14.5) occurs, implying that the symmetrical intermediate is a benzyne, formed by elimination of HBr from bromobenzene. Ben-zyne is too reactive to be isolated as a pure compound but, in the presence of water, addition occurs to give the phenol, in the presence of a diene, Diels-Alder cycloaddition takes place. 

Acid chloride 5 is readily available from the known benzylic alcohol 6,4e but intermediate 4 is still rather complex. It was recognized that compound 4 could conceivably be formed in one step from 2-methoxyfuran (9)10 and iodotriflate 10. The latter compound was designed with the expectation that it could be converted to benzyne 8," a highly reactive species that could be intercepted in an intermolecular Diels-Alder reaction with 2-methoxyfuran (9) to give 7. The intermediacy of 7 is expected to be brief, for it should undergo facile conversion to the aromatized isomer 4 either in situ or during workup. 

Kuzuya M., Noguchi A. The Nature of Substituent Effects on Tautomeric Equilibria of 2-Pyridones and Their Reactions Trends Org. Chem. 1991 2 73-92 Keywords chemo- and regiochemistry of Diels-Alder reactions with benzyne,... 

Species such as 5 and 6 are called benzynes (sometimes dehydrobenzenes), or more generally, arynes, and the mechanism is known as the benzyne mechanism. Benzynes are very reactive. Neither benzyne nor any other aryne has yet been isolated under ordinary conditions, but benzyne has been isolated in an argon matrix at 8 where its IR spectrum could be observed. In addition, benzynes can be trapped for example, they undergo the Diels-Alder reaction (see 15-58). It should be noted that the extra pair of electrons does not affect the aromaticity. The... 

Although benzobarrelene has been used in a number of recent studies, the best available published synthesis" starts with the Diels-Alder reaction of j8-naphthol and maleic anhydride, affording benzobarrelene in ca. 1% yield after five further steps. Minor improvements allow small quantities of benzobarrelene to be prepared in an overall yield of ca. 10%. The reaction of benzyne with benzene is relatively inefficient, giving benzobarrelene in ca. 2% yield. When benzyne is generated by decomposition of benzenediazonium-2-carboxylate at high dilution in benzene, the yield of benzobarrelene is raised to 14%. The reactions of benzyne with other aromatic substrates are equally inefficient. 

The reaction of benzyne with furan was the first example of a Diels-Alder reaction of benzyne to be studied b. No authenticated examples of arynes are known which fail to give cyclo-adducts with furan i38>. The tetrahalogenobenzynes all form the expected adducts 103, X = F 6), Cl 57>i39)j gr 59) or i 59)). d0 other highly fluorinated arynes i40,i4i>. The isomeric adducts (104) and (105) have been detected by 19F n.m.r. spectroscopy when the dilithio-compound (12) was allowed to decompose in the presence of furan 28 103). 

The reaction of benzyne with cyclohexadiene has been known for some time 4>, but although a number of steroidal cis-dienes are readily available no reactions with arynes had been reported prior to our beginning such investigations 145>. This was somewhat surprising in view of the number of reports concerning the modification of steroids by means of reactions with carbenes 146 i49) and the known Diels-Alder reactions of steroidal dienes and trienes iso.isi). 

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