3- benzo-furans cycloaddition with

In order to exploit the cycloaddition reactions of 2-vinylbenzofurans for natural product synthesis, the reactions of (E)-2-()S-methoxyvinyI)benzo-furans have been examined. The simplest compound (139, Scheme 36) on reaction with dimethyl acetylenedicarboxylate in boiling toluene gave a mixture of products. The major adduct was not the one expected but was its conjugation product 140. The diene system in 140 is able to react with... 

As mentioned in Section III,A, benzo[c]furan (4) participates in thermal [jt4 -I- TCgJ-cycloadditions. With tropone and substituted tropones, compounds of type 206 (exo R = H, Cl, OMe) have been obtained, and 6,6-dimethylfulvene yielded 207 (endo). The extended Hiickel method and... 

Benzo[ ]furans and indoles do not take part in Diels-Alder reactions. By 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 (184) 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). 

Furans also undergo cycloadditions with o-benzoquinones. Thus furan, 2-methylfuran, 2,5-diphenylfuran and benzo[ >]furan yield dihydrofurobenzodioxins of type (238) with tetrachloro-l,2-benzoquinone (Scheme 83). The reaction of furan with 1,2-benzoquinone affords only a 1% yield of adduct because most of the quinone undergoes polymerization. The reaction with 2-methylfuran produces a 25% yield of adduct, however. The reactions are thought to involve the electrophilic attack of the quinone on the furan to produce a carbonium ion. In the case of 2-methylfuran the more stable carbonium ion (239) is produced. Evidence for a two-step mechanism is the diversion of the intermediate (239) to the addition product (240) which may be isolated when the reaction is conducted in the presence of ethanol (69JCS(C)1694). 

The 8 + 2-cycloaddition of 2//-cy c I o h cpta[h ] furan -2 - one (155) with acyclic 1,3-dienes provides a facile route to bicyclo[5.3.0] ring systems (156) (Scheme 61).291 2H-Benzo[Z>]thiete in the o-quinoid form undergoes 8 + 2-cycloaddition with 1,3-dithiolane-2-thione, l,3-dithiole-2-thiones, and adamantanethione to produce 4//-1,3-benzoditliianes.292... 

As 2-vinylfuran rapidly polymerizes even in a nitrogen atmosphere in the presence of a stabilizer, yields obtained for these Diels-Alder reactions were very low. In fact, when the more stable 5-(4-nitrophenyl)-2-vinylfuran lb reacted with DMAD, the yield of the aromatized cycloadduct, dimethyl 2-(4-nitrophenyl)benzofuran-4,5-dicarboxylate 4b, was 50%. The 4-nitrophenyl group not only deactivated the vinylfuran for oxidation and polymerization, but also deactivated the diene system toward cycloadditions, and the reaction was successful only when conducted in boiling xylene. The decrease in reactivity of the reactive diene may account for the relatively low yield of methyl 2-(4-nitrophenyl)benzo-furan-4-carboxylate 6b obtained in a similar reaction with MP (73-AJC1059). 

Benzo[6]thiophene reacts with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate in a cycloaddition-fragmentation reaction to yield (143), whereas benzo[ ]furan and N- methylindole yield products (144) arising from ring opening and recyclization (76AP679). 

The only other dipolar species that has been added to thiophene is the carbonyl ylide (287). Thus tetracyanoethylene oxide, as the carbonyl ylide, reacts with thiophene to form the adduct (288) in 70% yield (65JA3657,68T2551). Several monosubstituted thiophenes have been used in this reaction. From competitive experiments it has been shown that the rate of cycloaddition to furan and benzo[/>]furan is greater than that to thiophene and benzo[AJthiophene respectively (75ACS(B)441). 

Under similar conditions, a radical-initiated [3-F2] cycloaddition of N-centered radical with benzo[.i]furan 82 was examined. A benzo[. ]furan-derived pyrrolidine 112 was obtained in good yield with again EtsB as a radical initiator (as depicted in Equation 101) <20010L2709>. 

Benzo[ ]furan-based azide was also reported to undergo a 1,3-dipolar cycloaddition with norbornadiene as dipolar-ophile to give a triazole after extrusion of cyclopentadiene (Equation 180) <2001T7729>. 

Vinyl-substituted benzo[c]furans can be prepared by reaction of n-alkynylbenzaldehydes with chromium Fischer carbene complexes. Initially a benzo[c]furan chromiumtricarbonyl complex is believed to be formed which is converted into an alkylidenephthalan derivative or can be trapped with electron-deficient dienophiles with excellent ( 3 ti-selectivity (Equation 128) <20000L1267>. More elaborate vinylidene Fischer carbene complexes yield dienyl benzo[c]furans that undergo [8-1-2] cycloaddition with DMAD to furnish furanophane derivatives <2003JA12720>. An equilibrium between 7] -(o-ethynylbenzoyl)rhenium complexes and rhenium benzo[f]furyl carbene complexes has been observed. These species behave like other benzo[< ]furans in the reaction with DMAD <20040M4121>. 

Furan has been found to form oxetanes with a variety of carbonyl compounds, e.g., ketones,202-205 aldehydes,206 and ethyl cyanofor-mate.207 In most reactions the (2 + 2)-cycloaddition occurred specifically to give a 2,7 dioxabicyclo[3.2.0]hept-3-ene (175) rather than the 2,6-isomer (176). Only the addition of ethyl cyanoformate yielded mixtures of 175 and 176 (R = OEt and R2 = CN), in a ratio of 2 l.207 Two subsequent (2 + 2)-cycloadditions of benzophenone and furans have been reported to give two isomeric products, 177 and 178.205 Substituted furans yielded similar oxetanes.203 Benzo[ >]furans, furo-coumarins, and furochromones also proved to undergo (2 + 2)-cyclo-addition reactions with carbonyl compounds such as ketones, aldehydes, and quinones. Invariably one type of oxetane was formed (179).,37,u3 ,44 200-202 208,20, In the case of 2-methoxycarbonylbenzo[6)-furan, evidence has been provided that the oxetane was produced by addition of the excited triplet state of the olefinic reactant to the ground state of the ketone.208... 

In contrast to furan, the benzene ring in benzo[ ]furan (because of its large resonance energy) is dominant to such an extent that [4+2] cycloadditions are not possible. On the other hand, photochemical [2+2] cycloaddition occurs readily on the C-2/C-3 double bond leading, e.g. with an acetylene di-carboxylic ester, to the cyclobutene derivative 1 ... 

We decided to investigate one final substrate that contained our desired side chain for the intramolecular Diels-Alder cycloaddition as well as a small and removable cyano group. Our synthesis is outlined in Scheme 11. Phenol 53 was alkylated with chloroacetonitrile, then condensed to form 2-cyano benzo-furan 54. Subsequent quatemarization to 56 was accomplished with sodium hydride and a bromocrotcMiate (55) electrophile. Following phenol ether deprotection and reduction of the benzylic ketone with sodium borohydride, we were in a position to evaluate the dearomatization step. Unfortunately, all attempts to access the quinone epoxide 58 under classic or modified Adler-Becker reaction conditions failed. With these results, we closed the book on the second chapter in our vinigrol saga and went back to the drawing board. 

Benzo[c]furans (isobenzofurans) are very reactive but generally unstable dienes which are prepared in situ and trapped. The in ihu-generated isobenzo-furan 33 was trapped by cycloaddition reaction with bis(methyl (S)-lactyl) ester 34 to afford [32] optically active naphthols (Equation 2.12). The cycloaddition was carried out in the presence of a catalytic amount of glacial acetic acid and represents a facile one-pot procedure to synthesize substituted naphthols. 

Takeshita and colleagues299 studied the reactions of 3-bromo-l,5-azulenequinone (478) and 3-bromo-l,7-azulenequinone (484) with benzo[c]furan (479) and 1,3-diphenylbenzo [c]furan (485) by analogy with the reactions previously described by Scott and Adams300. The reaction of 478 with 479 afforded a mixture of four cycloadducts (equation 142), three stereoisomeric [2 + 4]/[6 + 4] tandem adducts (480-482) and one [2 + 4]/[2 + 4]/[6 + 4] triple adduct (483). No mono adduct was isolated, indicative of a fast follow-up cycloaddition. The [6 + 4] cycloadditions all proceeded in an exo fashion, whereas the [4 + 2] cycloaddition proceeded in an endo fashion for 480 and 483, and in an exo fashion for 481 and 482. The reaction of 478 with 485 afforded a mixture of [4 + 2] adducts and [4 + 2]/[8 + 4] tandem adducts. 

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... 

---