Isobenzofurans Diels—Alder reactions

Benzo[c]furans (isobenzofurans) are reactive molecules usually employed as reactive dienes in the synthesis of more complex molecules. In the synthesis of spiro compounds related to fredericamycin A, Kumar generated the trimethylsiloxytrimethylsilylbenzo[c]furan 125 from phthalide via two consecutive deprotonations and silylations of the resulting anions. Diels-Alder reaction of the isobenzofuran as shown below with a spiroenedione leads to the formation of an endo-exo mixtures that can be smoothly converted to the dihydroxydione <00IJC(B)738>. 

An even more pronounced retro-Diels-Alder reaction occurs by using 1,3-di-phenylisobenzofuran (DPIF), 9-methylanthracene or 9,10-dimethylanthracene as dienes [8, 10-12]. The monoadduct of DPIF cannot be isolated from the reaction mixture, while the monoadduct of the 9-methyl- or 9,10-dimethyl- derivatives of anthracene can be isolated at temperatures lower than room temperature [10]. Both anthracene derivatives decompose at room temperature, the adduct with one methyl group within hours, the adduct with two methyl groups within minutes. For DPIF and the anthracene compounds the retro-Diels-Alder reaction seems to be facilitated by steric repulsion due to the bulky groups. However, as shown by Wudl and coworkers [13], the cycloadduct of with isobenzofuran (Scheme 4.2), which was generated in situ from l,4-dihydro-l,4-epoxy-3-phenylisoquinoline, is stable in the solid state as well as in solution and shows no tendency to undergo cycloreversion. 

The Diels-Alder reaction of cyclopentadiene or isobenzofuran derivatives withlV-acetyl-2-azetine gives cycloadducts (e.g., 1) in high yield by endo addition <99TL443>. 

Arylnaphthalide lignans. A novel synthesis of these lignans involves in situ generation of an isobenzofurane (a) from a substrate such as I, which is trapped by a Diels-Alder reaction with methyl acetylenedicarboxylate. The adduct aromatizes lo u naphthol 2 in the presence of an acid. Selective reduction of the 3-... 

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. 

In the synthesis of the bisdienophilic phthalocyanine 102, a Diels-Alder reaction of a reactive isobenzofuran (generated by the tetracyclone route) is involved (97CB801). For further work see [95JCS(CC)2449 98ZN(B)1069],... 

Wege and Moursounidis found that a linear Herndon relationship (log k vs log SC 82JCE371) is obeyed. Extrapolation to naphtho[2,3-c]furan gives ki = 3.15 x 104 mol-1 s-1, which is 415 times greater than the reactivity of isobenzofuran 2. The effects of substituents in isobenzofuran on a Diels-Alder reaction (with A-methylmaleimide, which gives nearly exclusively endo-adducts) was quantified by Rickborn and co-workers (Table III ... 

A further conclusion which can be drawn when the corresponding data of butadiene are taken into consideration [80AG773,80AG(E)779] is that the relative reactivity is nearly the same in both series. For more detailed discussion of this aspect see Rickborn (89MI1). Ethyl (diethoxyphos-phinyl)propynoate is less reactive by a factor of 5 than dimethyl acetylen-dicarboxylate (82TL2603). Isobenzofuran retro-Diels-Alder reactions have... 

Novel polymers have been prepared by the Diels-Alder reaction of two bis(isobenzofuran)s and a series of bis(acetylene) imides. Bis(isobenzofuran) 317 was prepared from phenylphthalide precursors. Two varieties of bis(acetylene)s 318 and 319 were prepared by the reaction of various aromatic anhydrides with amine 320 (Equation 7) or by the reactions of various diamines 321 with 4-phenylethynylphthalic anhydride 322 (Equation 8). One example of the polymers formed is 323 (Equation 9) <2000MI299>. 

Coupling of a cyanocarbene complex with an alkyne-aldehyde yielded isoquinolines. This occurs through an isobenzofuran intermediate followed by an intramolecular Diels-Alder reaction. Yields are poor to moderate and the reactions with good yields are plagued by product mixtures <03OL4261>. Preparations of benzo analogues were more successful. 

Azirine 91 has also heen shown to undergo a Diels-Alder reaction with diphenyl isobenzofuran to provide 94. The exo-isomct was reported to isomerize to the endo-isorac,i 95 upon heating, although no yields for this transformation were reported <2001J(P1)2969>. 

The pyridyl azirine 97 was prepared from mesitylsulfonyloxy oxime 96. This is one of the first examples of heteroaromatic substituted azirines reported. This azirine undergoes a Diels-Alder reaction with isobenzofuran to provide the rwn-cycloadduct 98 in 54% yield <2005S555>. In addition to isobenzofuran, this azirine undergoes cycloaddition with a number of different dienes, including cyclopentadiene (82%), 1-methoxy-butadiene (58%), and Danishefsky s diene (67%). 

The unparalleled employ of five Diels Alder reactions (3 normal, 2 retro) in the Kende "isobenzofuran" route (Eq.3) provides a fitting conclusion to the discussion of Diels Alder sequences. Although a 1 1 mixture of regiolsomers is produced, the yield of 8c is 17% based on 75a. 

Oxazoles ate another 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 isobenzofuran (517), which can be trapped by [4 + 2] cycloaddition to a variety of dienophiles, e.g. by A(-methylmaleimide (Scheme 121). 

The IR, UV, H NMR, C NMR, and mass spectra of several benzo[c]furan derivatives, (272-273). <83CJC1987>, (274) <86JOC3973>, (275-279) <82JOC409> and (280-281) <84JCS(Pl)859> have been used to elucidate structural features concerning the Diels-Alder reaction of isobenzofurans with dienophiles the endo exo ratios were readily estimated by H NMR since the differences between the isomers are typical of all Diels-Alder adducts. 

Reactions where 1,3-diarylisobenzofuran derivatives act as the diene component in Diels-Alder reactions are well known and new routes have been developed, especially to isobenzofurans that are oxygenated in the benzenoid ring <8773681, 89BSF44i>. Diels-Alder reactions of isobenzofurans... 

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). 

The Elbs persulfate oxidation procedure was used by Bach and cowoikers at an early stage of their synthesis of model compounds related to ftedericamycin A. Thus the phenol (59) gave 2,S-dihydroxy-4-methoxybenzoic acid (60) in modest yield (30%). This was then transformed in several steps to the isobenzofutanone (61). Gmeration of the isobenzofuran (62) in situ and Diels-Alder reaction of this with the enedione (63) gave, after loss of die trimethylsilyl group, the desired compound (64 Schone 23) in 62% yield from the isobenzofiiranone (61). 

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