Furan reaction with benzyne

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

Chemical modiflcation of cahx[6]furan 41 by Diels-Alder reactions with benzyne and dimethyl acetylenedicarboxylate (DMAD) was studied by Kohnke et al. (Scheme 13) [53]. The reaction of 41 with benzyne afforded the adduct 95, which was converted to caUx[5]furan[l]naphthalene 96 by hydrogenation and subsequent dehydration. Two isomeric calix[4]furan[2]-naphthalenes 97 and 98 were obtained by similar chemical transformation starting from the corresponding bis-benzyne-adducts. Preparation of the tris-benzyne-adduct 99 was also reported. 

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). 

Strong base treatment of the spiro salt 49 gives a benzyne (107) from which the isolated products were produced by further reaction. For example, with n-butyllithium and furan in tetrahydrofuran, 108 is produced after hydrogenation and acid treatment via 109. Reaction with phenyllithium gives 110 (R == Ph and Me) by subsequent addition of phenyl or methyl anion to the benzyne, respectively, and 110 (R = I) by subsequent reaction with iodine anion. Similarly the 9,9-diphenyl salt 111 gives 112 with phenyllithium. Pyrolysis of the spiro salt 49 gives 50. 

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. 

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. 

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)... 

The high efficiency of the present precursor 2 is demonstrated by comparison with a similar precursor, 2-(trimethylsilyl)phenyl triflat (4), which generates benzyne under mild conditions (room temperature and neutral).7 Benzyne precursor 2 gives the adduct, 1,4-epoxy-1,4-dihydronaphthalene 3, quantitatively in the reaction with furan, while the reaction of benzyne precursor 4 under the same conditions leads to a lower yield of adduct 3 and needs longer reaction time. 

Benzynes are readily formed when we have a leaving group ortho to a lithium atom. Thus when ortho-bromo(1 uorobenzene 143 is reacted with butyl lithium, the intermediate formed is ortho-lithiofluorobenzene 144. Lithium fluoride can eliminate from this to yield benzyne 145. Benzynes are reactive species and do not hang about. Here, ort/to-bromofluorobenzene is treated with butyl lithium in the presence of furan. When the benzyne forms it rapidly reacts with furan in a cycloaddition reaction to form the adduct 146 in a 68% yield. 

The very efficient reaction of furan with benzyne, discovered by Wittig and Pohmer was the earliest example of benzyne behaving as a dienophile.39 Formation of the oxygen-bridged adduct 39 and its acid-catalyzed isomerization into 1-naphthol are often used diagnostically for the detection of benzyne generated by new pathways. 

Furan also undergoes cycloadditions with allenes," " with benzyne" and with simpler dienophiles, like acrylonitrile and acrylate various Lewis acidic catalysts can assist" in some cases, zinc iodide is one such, hafnium tetrachloride another, and improved endo exo ratios are obtained in an ionic liquid as reaction solvent. Maleate and fumarate esters react if the addition is conducted under high pressure. This device can also be used to increase markedly the reactivity of 2-methoxyfuran and 2-acetoxyfuran towards dienophiles. At higher reaction temperatures alkynes and even electron-rich alkenes will add to furan. 3- or 5-Halo-furans react faster in these cycloadditions. ... 

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. 

A new cathodic cyclodimerisation of 4-pyrones yields either (90) or (91) depending on conditions,88 2-Benzopyran-3-one has been isolated at low temperature and intercepted by NPM as the adduct (92) 88 high-pressure cycloaddition reactions of 2H-pyran-3-ones with a variety of dienophiles have been recorded.88 Cycloaddition reactions of furans and isobenzofurans continue to dominate this section. Dienophiles whose reactions with furan have been studied recently include phenylsulphonylpropadiene (giving predominantly the endo-adduct (93) 8b. benzynes (derived from aryloxazoli nesJ.8 and... 

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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