Diels-Alder-type furan

As a result of its reduced aromaticity, relative to pyrrole, furan undergoes [4 + 2] cycloaddition reactions much more readily. It combines as a diene with electron-poor dienophiles to yield Diels-Alder-type adducts. Maleic [(Z)-butenedioic acid] anhydride, for example, reacts at room temperature, and the only isolated adduct is the exo isomer (the more thermodynamically favoured adduct) (Scheme 6.27a). 

By far the most important property of benzo[c] furans is their capacity to act as 471-components in cycloaddition reactions. Whereas the reactions described before 1969 were almost always of the Diels-Alder type, more recent investigations have shown that they can also participate in [7 4 + 714]-and [714 + TCgj-addition (Section IV,C). In this chapter Diels-Alder reactions will be discussed. Benzo[c]furans have been used for two main purposes. First, Diels-Alder adducts with olefinic compounds can conveniently be dehydrated to naphthalene derivatives or higher condensed hydrocarbons not easily accessible by other methods second, benzo[c]furans are excellent... 

Furans and unsaturated ketones undergo a condensation similar to the Diels-Alder type (cf. method 34) to give furyl-substituted ketones for example, a-methylfuran and methyl vinyl ketone react under mild acidic conditions to yield 5-methylfurfurylacetone (65%). ... 

As previously mentioned, short-life cycloalkynes add to reactive dienes such as l,3-diphenylbenzo[c]furan (16) and tetracyclone to give Diels-Alder-type adducts, and the reaction has frequently been used to establish the intermediacy of short-life cyclic acetylenes. The addition reactions have found synthetic applications - > > . The addition of 1-diethylaminobutadienc to cycloalkynes provides an interesting synthetic route for benzo annelation . Intervention of dehydrobullvalene was also confirmed by the formation of DicIs-Alder-type adducts - . At present only azides are used as 1,3 dipoles in the addition reaction with short-life cycloalkynes - - . ... 

Of the three five-membered systems with one heteroatom considered in this book, furan is the least aromatic and as such has the greatest tendency to react in such a way as to give addition products - this is true in the context of its interaction with the usual electrophilic substitution reagents, considered in this section, as well as in Diels-Alder-type processes (see 18.7). 

Oxazoles readily undergo Diels-Alder type cycloaddition across the 2,5-positions, in parallel with the behaviour of furans (18.7). Thiazole and imidazole do not show this mode of reactivity, however they do react with highly electrophilic alkynes via initial electrophilic addition to the nitrogen, then nucleophilic intramolecular cyclising addition (cf the comparable reactivity of quinohnes, 9.13). ... 

Georg Wittig et al. pioneered the trapping of dehydroarenes with cyclic dienes, in particular cyclopentadiene, " furan, 1-methylpyrroIe, " 2-methylisoindole, and anthracene. In this way, the synthetically attractive Diels-Alder-type cycloadducts 1,4-dihydro-1,4-methanonaphthalene (300, 65%), 1,4-epoxy-1,4-dihydro-naphthalene (289, 76%), l,4-dihydro-9-methylnaphthalene-l,4-imine (301, 50%), 9,10-dihydro-11-methylanthracene-9,10-imine (302, 54%), and triptycene (9,10[1, 2 ]-benzenoanthracene 303, 28%) were made readily available (Scheme 1-236). 

The balance between aromatic and aUphatic reactivity is affected by the type of substituents on the ring. Furan functions as a diene in the Diels-Alder reaction. With maleic anhydride, furan readily forms 7-oxabicyclo [2.2.1]hept-5-ene-2,3-dicarboxyhc anhydride in excellent yield [5426-09-5] (4). 

Benzo[Z)]furans and indoles do not take part in Diels-Alder reactions but 2-vinyl-benzo[Z)]furan and 2- and 3-vinylindoles give adducts involving the exocyclic double bond. In contrast, the benzo[c]-fused heterocycles function as highly reactive dienes in [4 + 2] cycloaddition reactions. Thus benzo[c]furan, isoindole (benzo[c]pyrrole) and benzo[c]thiophene all yield Diels-Alder adducts (137) with maleic anhydride. Adducts of this type are used to characterize these unstable molecules and in a similar way benzo[c]selenophene, which polymerizes on attempted isolation, was characterized by formation of an adduct with tetracyanoethylene (76JA867). 

When benzyne is generated in the presence of potential dienes, additions at the highly strained triple bond occur. Among the types of compounds that give Diels-Alder addition products are furans, cyclopentadienones, and anthracene. 

An example of the second type of modification is the application of the Diels-Alder cycloaddition reaction to polders and copol ers containing pendant or backbone furan moieties. The use of bis-dienophiles such as propiolic acid and its esters or bis-maleimides provides a means of crosslinking based on multiple bridging by the double interchain lycloadditions. The thermal reversibility of these reactions allows the return to the original linear structure (thermoplastic material) by simply heating the gel. 

Other 2-substituted cyclopropylideneacetates of type 3-X also entered this cycloaddition (Scheme 15) [19]. The endolexo selectivity is low but usually still higher than that of simple acrylic acid esters. The relative Diels-Alder reactivities of dienophiles 1-Me and 3-X as determined by competition experiments (Scheme 15) suggest a mechanism involving either diradicals or zwitterions as intermediates [19]. Surprisingly, the 2-fluoro derivative 3-F is less reactive than the parent compound 3-H. The 2-chloro and 2-bromo derivatives 1-Me and 3-Br have similar reactivities and cycloadd to furan (57) about 16 times faster than methyl acrylate. 

The Diels-Alder reaction between l,3-diarylbenzo[c]furans and simple alkenes and alkynes has been much investigated kinetically. Glass and Smith found a remarkable enhancement of dienophilicity by the trifluoromethane sulfonyl group in a series of substituted phenylacetylenes of type 205 with 205 (R = SiMcj) no reaction occurred. 

Whereas compounds of type 345 are not known, the transient existence of tetraphenylthieno[3,4- ]furan (348) has been demonstrated. Sulfoxide 347 refluxed in acetic anhydride under nitrogen gave a pale violet color which was attributed to 348 in the presence of dimethyl acetylenedicar-boxylate a Diels-Alder adduct (349) was formed in 70% yield. 76-479 dehydration of 347 can also be effected by base treatment with hydroxide ion in benzene/water with a phase-transfer catalyst affords a deep-blue... 

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. 

An important variation of the theme is found in furans with a 3-substituent adjacent to the 2-substituent, for then elimination can give heteroquinone methides , possibly by cyclic mechanisms (71CCC4082). A common type is found in the breakdown of furodysin as illustrated in Scheme 8b (78TL4951), and which is probably reversed Diels-Alder in mechanism it often fails if the carbocyclic ring is seven-membered (75TL1421). 

In the fused compounds (241) and (242) the furan ring fails to react as a diene and Diels-Alder reaction with dienophiles occurs on the terminal carbocyclic rings. However, (243) and (244) afford monoadducts with dimethyl fumarate by addition to the furan rings (70JA972). The rates of reaction (Table 2) of a number of dehydroannuleno[c]furans with maleic anhydride, which yield fully conjugated dehydroannulenes of the exo type (247), have been correlated with the aromaticity or antiaromaticity of the products (76JA6052). It was assumed that the transition state for the reactions resembled products to some extent, and the relative rates therefore are a measure of the resonance energy of the products. The reaction of the open-chain compound (250), which yields the adduct (251), was taken as a model. Hence the dehydro[4 + 2]annulenes from (246) and (249) are stabilized compared to (251), and the dehydro[4 ]annulenes from (245) and (248) are destabilized (Scheme 84). 

Furans are able to undergo photocycloaddition of the [W2S+ 2S] and the [W4S+ 4S] type to suitable substrates. With benzene (80JCS(P1)2174) five 1 1 products are obtained. The relative proportions of these products are highly variable and depend on the relative concentration of the reactants, the irradiation time, the light intensity and the temperature of the solution. For the shortest irradiation time with a low-pressure mercury lamp at 15 °C, the relative proportions are 1 1 10 40 2. The major product is the 2,5 l, 4 -adduct (301) and the next most prolific is the 2,3 l, 2 -adduct (302). Adduct (301) is unreactive to dienophiles but gives adduct (302) by Cope reaction at 60-70 °C. This reaction can also be achieved by irradiation of a cyclohexane solution of (301). Adduct (302) reacts readily with dienophiles in ethereal solution to form Diels-Alder adducts. The minor adducts possess structures (303), (304) and (305). The reaction is thought to involve the first excited triplet of benzene or an excited state complex. A [ .4s+ .4g] photoadduct (306) is formed... 

For fiirther reactions of this type see <95CC2025>. The synthesis of l,4-dihydrofurano[3,4-d]-3,2-oxathiine-2-oxides, precursors for nonclassical heteroaromatic o-quinodimethanes, and their application in the Diels-Alder reaction were reported <95CC2537>. The intramolecular Diels-Alder reaction with furans (e. g., 47) offers a rapid access to highly functionalized isoquinolines <95 JCS(P 1)2393>. 

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