Diels-Alder reaction, with furans

A review on fliran and its derivatives in the synthesis of other heterocycles was published <95CHE1034>. Furan decomposes on Pd(lll) at 300 K to form H, CO and CjH, which can dimerize to benzene at 350 K <96JA907>. Again, a considerable number of Diels-Alder reactions with furan and fiiran derivatives was reported. The synthesis of 2-pyridinyl-7-oxabicyclo[2.2.1]heptanes (e.g., 3, 4) was accomphshed via zinc chloride-mediated Diels-Alder reaction of furan with 2-vinylpyridines <96SL703>. 

Radialenes 86 were obtained when bis(l-diazo-2-oxoalkyl)silanes 84 were decomposed with copper or palladium catalysts60,61. The assumption, that the heterocyclic [3]cumulene 85 is the immediate precursor of 86, is corroborated by its trapping in a Diels-Alder reaction with furan. 

Bicyclopropylidene (1) does not undergo an intermolecular Diels-Alder reaction with furan and 2-methoxyfuran even under high pressure. Intramolecular cycloadditions of compounds 160 with a furan tethered to bicyclopropylidene, however, were easily brought about under high pressure (10 kbar) and gave cycloadducts 161 stereoselectively in yields ranging from 32 to 95% (Scheme 35) [58]. 

Diketone 829 closely parallels 820 in its chemical reactivity. Introduction of a functionalized bridging carbon can be achieved with ethyl formate and base . The acetate group in 8JO 6 is remarkably easily replaced with retention by simple nucleophiles, e.g, the conversion to 8JI. The implicated peristyl-3-ene-2,6-dione (8J2) can in fact be obtained as a colorless crystalline compound. Also, 8J0a spontaneously dehydrates during ketalization to produce 8JJ. The strained double bond in 832 enters readily into Diels-Alder reaction with furan to furnish a 3 1 mixture of 834a and 834b. 

Diels-Alder reactions with furans constitute a major class of cycloaddition reactions, which have been used for the preparation of a variety of new compounds. Some examples will be given in this section. A one-pot stereoselective synthesis of tricyclic -y-lactones was achieved via Diels-Alder reactions of 2-methoxyfuran with masked o-benzoquinones, which are in turn available from the corresponding 2-methoxyphenols <99CC713>. 

This effect cannot be explained by simply considering differences in frontier orbital energies. A useful monofluorinated dienophile has been prepared [364] using metallated difluoroenol carbamate chemistry (Eq. 143) cycloaddition occurred smoothly with a range of dienes, and desulfination could be achieved under mild conditions without loss of the fluorine atom. Wakselman and co-workers [365] synthesised a rare competent difluorinated dienophile. Lewis acid catalysed Diels-Alder reaction with furan afforded an acceptable yield of (unfortunately) unstable cycloadduct which decomposed to a phenolic product via a dehydrofluorination reaction, circumscribing its utility (Eq. 144). 

Diastereoselective Diels-Alder reactions The (S)- and (R)-3-(2-pyridylsul-finyl)acrylates (1) are obtained by addition of 2-mercaptopyridine to ( + )-menthyl propiolate followed by oxidation and fractional crystallization of the diastereoiso-meric sulfoxides. In the presence of (QH AIG, both undergo highly diastereoselective Diels-Alder reactions with furan to give mainly endo-adducts without epimerization of the sulfoxide group. The products are converted as shown into ( + )- and ( - )-ewdo-2-hydroxymethyl-7-oxabicyclo[2.2.1]heptane (2). 

Diels-Alder reactions with furans.2 This sulfonate ester undergoes cycloaddition to furans at room temperature. 

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>. 

In order to introduce functionality at key positions, an intramolecular Diels-Alder reaction with furan as the diene component was planned. Suzuki coupling of the previously mentioned 105 with furan-3-boronic acid 106 gave compound 107, which was N-tosylated to 108. Construction of the dienophile portion was performed as in the previous case, by addition of vinylmagne-sium bromide to give 109, followed by MnC>2 oxidation to give the cyclization precursor, which was immediately heated at 120 °C in toluene and afforded compound 110, which incorporates an oxygen atom at both the ketone and vinyl chloride positions of welwistatin (Scheme 24). 

Furan is an excellent diene in a wide variety of Diels-Alder reactions, providing oxabicyclic compounds with useful synthetic applications. However, Diels-Alder reactions with furans are often reversible and require a highly reactive dienophile in order to provide useful yields of the cycloadduct. As shown in Scheme 17, furans have now been shown to undergo synthetically useful Diels-Alder reactions with azirines. The reaction of furan with azirine 91 provides cycloadduct 92 in 100% yield <1998J(P1)299>. Aziridine 92, while crystalline, is moisture sensitive, decomposing to aziridine 93. An X-ray structure of 92 was obtained which confirmed the exo-natute of the cycloaddition reaction in contrast to the r/o-cycloadditions seen in the formation of 88 <2001J(P1)2969>. 

Furthermore, the photoreaction of 2-cyano-3-methyl- and 3-cyano-4-methylthio-phene gives the same Dewar isomer, 3-cyano-4-methyl Dewar thiophene, which can be isolated at room temperature. The Diels-Alder reaction with furan affords a mixture of two adducts. This implies that an equilibrium exists between the three Dewar thiophenes through the migration or walk of the sulfur. The equilibrium is shifted to the 3-cyano-4-methyl Dewar thiophene due to the electronic pull-push effects of the two substituents, although this isomer is less reactive than 3-eyano-2-methyl Dewar thiophene in the Diels-Alder reaction U2). 

The readily accessibile 3-bromothiophene (80 % overall yield from thiophene [142]) makes this exchange reaction an attractive route to 3-substituted thiophenes. 3-Bromofuran can be synthesized from furan, but a rather lengthy route must be followed (involving inter alia a Diels-Alder reaction with furan and cyclopentadiene... 

Diels-Alder reactions with furans can be very problematic due to the thermal sensitivity of the cycloadduct and their tendency for cycloreversion, which is due to the strain inherent to the 7-oxabicycloheptane cycloadduct (128) as well as the aromatic character of the furan. As shown in Table 11.9, high pressure significantly increases the yield of Diels-Alder adduct with furan derivatives. 2-Methylfuran is more reactive than furan but substituents on the alkene (dienophile) lower the... 

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). 

The introduction of a nitro or trifluoromethyl group at the C-3 position on the pyridine ring in 3-(2-pyridylsulfinyl)acrylates has been shown to enhance the reactivity and diastereoselectivity of the dienophile in the Diels-Alder reaction with furan and its derivatives [171]. Such a modification of the dienophile renders the addition of diethylaluminium chloride unnecessary in order to achieve the desired asymmetric cycloaddition. The cycloadduct (207), prepared with high stereoselectivity from the asymmetric Diels-Alder reaction between (5)-menthyl 3-(3-trifluoromethylpyrid-2-ylsulfinyl)acrylate (194) and 2-methoxyfuran (208), was converted in seven steps to the glyoxalase I inhibitor (209) [171] (Scheme 5.67). 

SCHEME 12.10 Diels-Alder reactions with furans. 

Van Royen, L.A. Mijngheer, R. De Clercq, P.J., Intramolecular Diels-Alder reaction with furan-diene. Total synthesis of ( )-l 1-ketotestosterone and ( )-adrenosterone. Tetrahedron, 1985,41,4667-80. 

Wong also successfully generated 87 from the dibromide 86 [43]. It was found that 87 underwent Diels-Alder reaction with furan to give the endoxide 88. Upon reduction with low-valent titanium, 81 was eventually furnished in... 

A1 1 cage complex of tetragonal coordination capsule 581 with an encapsulated furane molecule (Scheme 5.83) is described in [83] to slowly dissociate in aqueous solution, whereas in the presence of benzene as concurrent guest, it releases furane into bulk solution during 1 h. Addition of maleimide resulted in its Diels-Alder reaction with furane in this solution [83]. 

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