Furans Diels-Alder cycloadditions with

An electron-withdrawing group on the alkenyl double bond has been shown to greatly facilitate the Diels-Alder cycloaddition with furan as depicted below < 00TL9387>. 

The diacetylene 15 readily underwent Diels-Alder cycloaddition with furan to furnish the endoxide 16, which was hydrogenated catalytically to the tetrahydro compound 17. Dehydration of 77 with polyphosphoric acid gave 1 in 16% yield (Eq. 7) Alternatively, deoxy nation of 16 with low valent titanium generated by reducing titanium tetrachloride with lithium aluminium hydride also afforded 7 in 50% yield... 

The enantiomerically pure, doubly activated a, /j-olefinic sulfoxides 46-5095 98 undergo highly diastereoselective Diels-Alder cycloadditions with cyclopentadiene, and pyridyl vinylic sulfoxide 5199 reacts diastereoselectively with furan. It is noteworthy that olefins singly-activated by only a sulfinyl group are not effective partners in Diels-Alder cycloadditions, as we have found after many attempts and as has been reported recently98. 

MCP (1) is not known to undergo [4 + 2] cycloadditions. The substitution of two, or more, ring protons with fluorine atoms, however, seems to improve dramatically the dienophilic reactivity of the exocyclic double bond. 2,2-Di-fluoromethylenecyclopropane (5) is a quite reactive dienophile in Diels-Alder cycloadditions. With cyclopentadiene (6) and furan (7), it formed two isomeric adducts (Scheme 1) [9]. In both cases the adduct with the endo CF2 group is the major isomer. 

Notice that the a-acetoxyacrylonitrile is in fact a "ketene equivalent" [30] in the Diels-Alder condensation with furan, since ketene itself undergoes [2 + 21-cycloadditions rather than [4 + 2] cycloadditions. 

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]. 

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). 

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

The Diels-Alder reaction of a difluorinated dienophile with furans produced cycloadducts which could be converted to difluorinated cyclohexane or cyclohexane polyols.181 Heptaleno[l,2-c]furans undergo Diels-Alder cycloaddition with electron-deficient dienophiles (DMAD, DCE) to produce the corresponding... 

Scheme 25 Synthesis of ROMP monomers via Diels-Alder cycloaddition of furan with different dienophiles [26]...

The inter- and intramolecular Diels-Alder reactions of furans, and their applications to the synthesis of natural products as well as synthetic materials, were reviewed <1997T14179>. HfCU promoted the endo-seXccuve. inter-molecular Diels-Alder cycloadditions of furans with a,/3-unsaturated esters <2002AGE4079>. The cycloaddition between furan and methacrylate was also achieved under these conditions, providing, however the o-isomer as the major cycloadduct. A catalytic enantioselective Diels-Alder reaction between furan and acryloyl oxazolidinone to provide the < 46i-adduct in 97% ee was achieved by using the cationic bis(4-fer7-butyloxazoline)copper(ll) complex 55, as shown in Equation (41) <1997TL57>. 

A complexation-induced intramolecular Diels-Alder cycloaddition of furan is depicted in Scheme 34. Upon exposure to silica gel, the alkyne-Co2(CO)6 complex 61 was transformed to the cycloadduct that contained a seven-membered ring <20000L871>. This facile process was supposed to be arisen from the bending of the linear triple bond to a structure with a 140° angle between the two carbon substituents in the cobalt complex 61. 

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>. 

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. 

The bisiodonium ethyne 24 is even more reactive than 18 and readily undergoes Diels-Alder cycloaddition with cyclopentadiene and furans as shown in equation 41. The remarkable fact of the cycloaddition of 24 is that, unlike the usual Diels-Alder reactions that require extensive heating and/or pressure, these reactions occur in a matter of minutes at -35 °C. 

Imembrine, a tropolone natural product related to colchicine was also synthesized via an oxazole-acetylene Diels-Alder reaction followed by a [4 -H 3]-oxyallyl cycloaddition.Here, 8-iodo-5,6,7-trimethoxyisoquinoline 269 was converted to 5-substituted oxazole 270 in four steps and 42% overall yield (Fig. 3.81). Thermolysis of 270 in refluxing o-dichlorobenzene effected the desired intramolecular Diels-Alder cycloaddition with concomitant loss of the Boc-protecting group to afford the tetracyclic furan 271 in 90% yield. At this point, 271 was subjected to the [4 + 3] cycloaddition in the presence of l,3,3-trichloro-2-propanone and 2,2,2-trifluoroethanol. Subsequent dechlorination of the intermediate (not shown) with zinc provided the oxabicyclic 272 as a single regioisomer in 73% yield. The synthesis of imembrine was completed in three steps from 272. 

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). 

A nice measure of the aromatic, i.e. non-diene-like character of thiophene can be gained from a comparison (Scheme 4) of the conditions necessary to force it to participate as a 1,3-diene in a Diels-Alder cycloaddition with maleic anhydride [7], compared with the classical reaction of furan. Lu et al. [8] shows how S-oxidation of thiophenes (utilisation of the pair of electrons on sulfur that is not involved in the aromatic sextet) reduces the aromaticity and allows cycloadditions to occur easily. 

Singlet oxygen reacted stereospecifically with 2-vinyl-thiophens in a 1,4-cycloaddition to give thermally stable 1,4-endoperoxides (147). The previously discovered [2 + 2] photoaddition of benzophenone to 2,5-dimethylthiophen to give oxetans has been extended to other carbonyl derivatives. Mechanisms explaining the formation of pyrroles, obtained by u.v. irradiation of a number of thiophens in the presence of propylamine, have been discussed. Irradiation of (148) led to the Dewar thiophen (149). The structures of dimerization products and Diels-Alder adducts with furans were elucidated. ... 

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