Diels-Alder Reactions of Benzyne

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). 

I highly reactive triple bond of benzyne is a powerful dienophile. Predict the product of the Diels-Alder reaction of benzyne (from chlorobenzene and NaOH, heated) with cyclopentadiene. 

Benzyne undergoes [4+2]-cycloaddition reactions in which it acts as a dienophile. The Diels-Alder reaction of benzynes give fused- or bridged-ring systems. 

One of the early examples of an intramolecular Diels-Alder reaction of benzynes involved cycloaddition to a furan that was tethered to the benzyne moiety . Diazoti-zation of anthranilic acid 669 gave in 86% yield the cycloadduct 670, which was subsequently converted to the o-naphthoquinone 671 (mansonone E 7 steps) as well as to the structurally related mansonones F and I and biflorin. ... 

The Diels-Alder reaction of benzynes offers a route to the synthesis of fused azepine derivatives. Thus it is possible to convert the furan (15) into the fused system (16) in approximately 50% yield by reaction with LiTMP in THF at -78 °C... 

Racemic epoxytetrahydronaphthalenediol and syn-naphthalene 1,2 3,4-dioxide are available by a novel synthesis which starts with a Diels-Alder reaction of benzyne (Scheme 18), ... 

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,... 

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 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). 

Figure 7.3.4. Diels-Alder reaction of encapsulated o-benzyne 67 with host cage 259.

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... 

Diels-Alder reactions of oxazoles afford useful syntheses of pyridines (Scheme 53) (74AHC( 17)99). A study of the effect of substituents on the Diels-Alder reactivity of oxazoles has indicated that rates decrease with the following substituents alkoxy > alkyl > acyl >> phenyl. The failure of 2- and 5-phenyl-substituted oxazoles to react with heterodienophiles is probably due to steric crowding. In certain cases, bicyclic adducts of type (359) have been isolated and even studied by an X-ray method (87BCJ432) they can also decompose to yield furans (Scheme 54). With benzyne, generated at 0°C from 1-aminobenzotriazole and lead tetraacetate under dilute conditions, oxazoles form cycloadducts (e.g. 360) in essentially quantitative yield (90JOC929). They can be handled at room temperature and are decomposed at elevated temperatures to isobenzofuran. 

Synthesis of benzo[c]furans and isoindoles (181) is also possible by the addition of benzyne to the respective monocycles (178), followed by reduction (179 — 180) and pyrolysis. In an alternative procedure, (179) is reacted with 3,6-bis(2-pyridyl)-l,2,4,5-tetrazine, which affords (181) under far less vigorous conditions via a retro Diels-Alder reaction of the intermediate (182). 4-Phenyl-1,2,4-triazoles pyrolyze to form isoindoles (Section 3.4.3.12.2). 

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... 

Naphthalene oxides. The Diels-Alder reaction of 1,4-diacetoxybutadiene (1) with benzyne (generated from o-benzenediazonium carboxylate, 1, 46) gives the diacetate of l,4-dihydronaphthalene-cis-l,4-diol (2) in 53% yield. The product is converted into 3 by reaction with hydrogen peroxide and catalytic amounts of osmium tetroxide. The monotosylate of 3 is converted into 4 by treatment with base. This epoxy diol has the stereochemistry found in the carcinogenic epoxy diols formed as metabolites of aromatic hydrocarbons. The dimesylate of 3 is converted into the syft-diepoxide 5. 

Diels-Alder reactions of furans were the subject of a recent review (1986). Their intermolecular versions profit notably from high-pressure conditions (Section 4.1.4.2.1) or the use of benzynes as dienophiles (Section 4.1.7). 

A route to partially hydrogenated phenanthrenes relies on the Diels-Alder reaction of a benzyne to an annulated furan, e.g. (501) - (503) (Scheme 117). However, regiochemistry raises its ugly head when both the furan and the benzyne are nonsymmetrically substituted (Scheme 118). Hence, the [4 + 2] cycloaddition of 3-methylbenzyne with 2>substituted furans (504) gave the anti and syn adducts (506)... 

Oxazoles are anodier class of heteroaromatic dienes which readily undergo Diels-Alder reactions with benzynes. For example, slow, simultaneous injection of solutions of triazole (483) and lead tetraacetate to a solution of oxazole (515) in CH2CI2 at 0 C afforded cycloadduct (516) in essentially quantitative yield. The latter is a convenient source for the unstable isobenzofiiran (517), which can be trapped by [4 + 2] cycloaddition to a variety of dienophiles, e.g. by -methylmaleimide (Scheme 121). 

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