Diels-Alder reactions benzyne-furan

When the dichloro diaryl ether 112 was treated with x-BuIi, a dibenzyne was generated and subsequently trapped by 2-methoxyfuran, affording dinaphthyl ethers 113 and 114 after aromatization (Scheme 12.34) [64]. The monocycloadducts 115 and 116 were also present in the reaction mixture. With carefijl control of the stoichiometry of the butyl lithium, an iterative double benzyne-furan Diels-Alder reaction was achieved between benzyne precursor l,4-difluoro-2,5-dime-thoxybenzene and two different furans. 

Let us now explore the reactivity of these compounds as dienes (furan, pyrrole, thiophene) with a dienophile (benzyne) in Diels-Alder reactions. One approach that, for a long time, has been widely employed by chemists, is the use of Frontier Molecular Orbital (FMO) [19] energy gap between two of the reactants. According to this theory, the most reactive reactant pair will be the one that has a lower FMO energy gap. The reaction is predicted to be HOMO diene-controlled. If... 

Arynes with their reactive triple bond would be expected to participate readily in cycloaddition reactions. However, as demonstrated in the previous section, the addition of nucleophiles is extremely facile, and therefore reactions with non-nucleophilic reagents cannot usually be observed unless the aryne is generated in the absence of nucleophiles. In practice this usually means that routes involving the treatment of aryl halides with nucleophilic bases cannot be used. The first cycloaddition reaction of ortho-benzyne, the Diels-Alder reaction with furan was observed in 1955 by Wittig and used 2-fluorobromobenzene as the precursor. The cycloadduct was obtained in almost 90% yield, and the reaction has formed the basis for numerous synthetically useful Diels-Alder cycloadditions involving arynes. Tetrabromobenzene reacts with butyllithium to give the diaryne intermediate with furan to form a tetrahydroanthracene. The mixture of syn and anti conformers can be separated based on differences in methanol solubility (Scheme 7.26). 

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. 

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). 

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). 

A neat intramolecular trap for benzyne works in this way. A standard benzyne-generating reaction—the diazotization of an ortho-amino benzoic acid (Chapter 23) gives a zwitterion that loses nitrogen and CO2 to release the benzyne. A furan tethered to the next ortho position traps the benzyne in an intramolecular Diels-Alder reaction. The yield is impressive and the trap is very efficient. 

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)... 

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 ... 

Evidence for the benzyne intermediate is extensive. The most compelling is its capture in a Diels-Alder reaction by a diene such as furan, illustrated by the reaction of l-bromo-2-fluorobenzene with lithium amalgam in the presence of furan (Scheme 9.9). 

Although benzyne is too unstable to be isolated, evidence that it is formed can be obtained by a trapping experiment. When furan is added to a reaction that forms a benzyne intermediate, furan traps the benzyne intermediate by reacting with it in a Diels-Alder reaction (Section 8.8). The product of the Diels-Alder reaction can be isolated. 

Diels-Alder reactions with benzyne. Shepard has recently demonstrated that benzyne generated from chlorobenzene and LiTMP undergoes expected T)iels-Alder cycloadditions with reactive dienes. The reaction with furane itself fails because of a base-promoted side reaction. 

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. ... 

In contrast, acetylenic dienophiles including benzynes participate in a well-defined [4 + 2] cycloaddition with oxazoles to provide substituted furans IS which arise from the retro-Diels-Alder reaction with loss of... 

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... 

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). 

Interestingly, when the number of equivalents of t-butyllithium was reduced from 4.0 to 1.1, all three benzyne-furan cycloadducts (i.e., 97a, 102, and 103) resulting from the three possible dibromoindole starting materials (lOOa-c) were isolated in excellent yields (Scheme 28). It is noteworthy that while the ortho dichlOTO- and dibromo-substituted indoles (94, lOOa-c) resulted in clean formation of the aryne species, the ortho difluoro derivatives lOOd-f did not behave in the same way. The attempted Diels-Alder reactions with 4,5 and 6,7-difluoroindoles lOOe and lOOf resulted only in the recovery of starting material. However, in the case of 5,6-difluoroindole lOOd, the cycloaddition resulted in the formation of 103,... 

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