Vinylindoles, cycloaddition

Intramolecular versions of vinylindole cycloaddition can occur with suitable reactants (Equation (144) and Scheme 146) <87JOC466i, 90JOC1624>. 

Two types of cycloaddition reactions have found application for the Synthetic elaboration of indoles. One is Diels-Alder reactions of 2- and 3-vinylindoles which yield partially hydrogenated carbazoles. The second is cycloaddition reactions of 2,3-indolequinodimethane intermediates which also construct the carbazole framework. These reactions arc discussed in the following sections. 

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). 

The Diels-Alder cycloadditions of both 2-vinylindoles and 3-vinylindoles are very attractive methods for preparing [bjannelated indoles to serve as lead substances and as building blocks for alkaloids. Pindur and coworkers [84] have extensively studied the vinylindole Diels Alder chemistry. 

Cycloaddition reactions of 2-vinylindoles 83 with a variety of dienophiles provide a convenient access [85] to carbazoles (Scheme 2.35). 

The reactivity and regioselectivity of the cycloadditions of the 2-vinylindoles are markedly dependent on the substitution pattern as shown by the calculated HOMO energies and coefficients [85a]. 

Noland and coworkers have developed an interesting methodology for the in situ synthesis of carbazoles. This methodology combines the synthesis of 3-vinylindoles from indoles and acyclic ketones with the subsequent Diels-Alder cycloaddition in one flask to produce a variety of tetrahydrocarbazoles [88] (Scheme 2.36). 

Enantiomerically pure tetrahydrocarbazoles have been obtained by asymmetric Diels-Alder reactions [89] of 2- vinyl- and 3-vinylindoles with Oppolzer s acryloylsultam. The results of the [4+2] cycloadditions of 3-vinylindoles (Scheme 2.37) show that the exo-addition is preferred. 

Decomposition of the diazo ester 395 in presence of dirhodium tetraacetate gives the zwitterionic intermediate 396, which undergoes a 1,3-dipolar cycloaddition with the double bond of the adjacent vinylindole. The bridged compound is isolated in good yield when the reaction is carried out at room temperature however, at 50 °C or above, compound 397 is the only compound isolated, again in good yield (Scheme 93) <2005JOC2206>. 

Guertler et al. (1996) described a wide range of cycloaddition reaction between 2-vinyl indoles acting as heterodienes and cyclic or acyclic enamines bearing acceptor groups in (3 positions. The reaction was induced by the formation of 2-vinylindole cation-radicals through anodic oxidation. The synthesis of 4a-carbomethoxy-6-cyano-5,7-dimethylindolo[l,2-a]-l,2,3,4,4a,12a-hexahydro-1,8-naphthyridine can serve as an example (Scheme 7.24). 

The same group studied the radical cation cycloaddition of 2-vinylbenzofti-rans with various alkene and diene compounds initiated by photoinduced electron transfer. Depending on the unsaturated compound used, yields up to 60% were feasible. In contrast to 2-vinylindoles, 2-vinylbenzofurans prefer to react as die-nophiles, very similar to styrenes [82]. 

Diels-Alder reaction of vinylindoles with dienophiles has been established as a versatile and flexible methodology for the synthesis of carbazole alkaloids. Among the two different vinylindoles, 3-vinylindoles were the first to be explored for the Diels-Alder cycloaddition methodology with a range of dienophiles to give polyfunctionalized carbazole derivatives. This reaction is catalyzed by tiifluoroacetic acid, and the yield in the absence of the acidic catalyst is very low. The reaction of substituted 3-vinylindoles 550 and 553 with ethylenic dienophiles 551 and acetylenic dienophiles 535 leads, via a tetrahydrocarbazole and a dihydrocarbazole, to the corresponding carbazoles (552 and 554), respectively (530,531) (Scheme 5.18). 

Beccalli et al. reported a synthesis of carbazomycin B (261) by a Diels-Alder cycloaddition using the 3-vinylindole 831 as diene, analogous to Pindur s synthesis of 4-deoxycarbazomycin B (619). The required 3-vinylindole, (Z)-ethyl 3-[(l-ethoxy-carbonyloxy-2-methoxy)ethenyl]-2-(ethoxy-carbonyloxy)indole-l-carboxylate (831), was synthesized starting from indol-2(3H)one (830) (620). The Diels-Alder reaction of the diene 831 with dimethyl acetylene dicarboxylate (DMAD) (535) gave the tetrasubstituted carbazole 832. Compound 832 was transformed to the acid 833 by alkaline hydrolysis. Finally, reduction of 833 with Red-Al afforded carbazomycin B (261) (621) (Scheme 5.99). 

As was the case with reactions of vinylindoles, the most elaborate synthetic targets approached by the indole-2,3-quinodimethane route have been alka-loids[18]. The route has been applied to aspidosperma[ 19] and kopsine[20] structures. The fundamental reaction pattern is illustrated in equation 16.7. An indole-2,3-quinodimethane is generated by /V-acylation of an AT-(pent-4-enyl)-imine of a 2-methyl-3-formylindole. Intramolecular 2 + 4 cycloaddition then occurs. 

Analogous [ 4 + 2] cycloaddition reactions of DMAD with indoles would disrupt the aromatic character of the fused benzene ring. It is not unexpected, therefore, that indole reacts with two molecules of DMAD to give the dihydrocarbazole derivative (234), via an initial Michael addition reaction, followed by cycloaddition of DMAD to the vinylindole. Aromatization of the 1 2 adduct (234) normally yields the carbazoletetracarboxylic ester... 

Relatively few examples have been reported of cycloaddition reactions of 2-vinylindoles. 

Aromatizations play a particularly prominent role in the synthesis of carbazoles since both the Fischer cyclization (Borsche s method) of cyclohexanones (Section 3.06.3.4.2) and the cycloaddition of 2-vinylindole (Section 3.06.6.1) yield tetrahydrocarbazoles. Both catalytic dehydrogenation over palladium/carbon catalyst and dehydrogenation with chloranil have been employed to effect aromatization (80JA4772,79JOC4402). 

For the indole, methyl sustitution at the 2-position (i.e. 71) appears to sterically block C—C annulation vs C—N annulation (Scheme 46)126a. Note also that electrochemical methods are only useful for the substituted vinylindoles, as unsubstituted indoles passivate the working electrode. The results of cycloadditions of substituted enamines 66 and 69 to vinylindoles 65 and 71 are summarized in Tables 7 and 8. 

The reaction of vinylindoles with dienophiles has been used for the preparation of natural products and synthetic compounds with pharmacological interest because their substituted carbazole structures were more easily accessible by these cycloadditions than by other routes. 

The cycloaddition reactions of 3-vinylindoles with acetylenic esters have been extensively studied. The reaction products generally obtained are [Z ]-annelated indoles, but Michael adducts can be isolated, depending on the substituents on the vinylindole (87HCA1419) (Scheme 1). 

As a result of bond fixation within the indole system, the mesomeric interaction between the 2-vinyl group and the 7r-excessive heteroaromatic system is less than that for the 3-vinylindoles, and in the few reported reactions they have been shown to behave as dienophiles in [4 + 21-cycloaddition reactions (81CC37). 

An interesting reactivity comparison was carried out with l-(l-methyl-2-indolyl)-l-(jV-methyl-2 -pyrrolyl)ethene 57 obtained via the corresponding carbinol. An inspection of its structure suggests that the molecule could react in a cycloaddition reaction as a vinylindole or as a 2-vinylpyrrole. In reactions with dienophiles, which include DMAD, it reacted as a 2-vinylindole, affording a carbazole derivative 58 (89JHC1869). 

Vinylindoles are also efficient 47r-components in cycloaddition reactions and provide the corresponding [c]-annelated carbazoles which react, for example, with NPMI, MA, and quinones [82CJC419 83IJC(B)1004 88HCA1060] (Scheme 6). Although in the more usual cases the result of... 

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