3- Vinylindole, cycloaddition reactions

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). 

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

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). 

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. 

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... 

Examples with 2-vinylindoles are also found. Thus, the reaction of N-methyl-2-(2-methoxyvinyl)indole, as a cis-trans mixture, with acrylonitrile and ethyl and methyl acrylate gives the corresponding Diels-Alder compounds [83IJC(B)846]. With N-methyl-2-(2-nitrovinyl)indole as diene, similar reactions occur with methyl acrylate, acrylonitrile, and acrolein acetal but in these cases, the fully aromatic compounds were isolated. The cycloaddition reaction with acrolein acetal was nonregioselective and the isolated adducts had a CHO group, indicating that the acetal had been hydrolyzed (presumably during work-up). 

The reaction of 2- and 3-vinylindoles with dienophile 214 constitutes the first example of an asymmetric Diels-Alder reaction of vinyl heterocycles. From 3-vinylindoles, enantiomerically pure carbazoles 215a-c were obtained, whereas from the vinylindole 197 together with 215d, diastereomer 216 was obtained as a minor product. Conversely, 2-vinylindoles provided inseparable mixtures of diasteromeric carbazoles. On the other hand, the cycloaddition reactions of 3-vinylindoles with 217 furnish the tetrahy-drocarbazoles 218 with endo-diastereoselectivity (93T2863). 

Blechert and coworkers have extended synthetic methods involving generation and cycloaddition reactions of ct-cyanovinylindoles. The cyanovinyl indoles can be generated from arylhydroxylamines by reaction with an aldehyde and cyanoallene. <95S592> The resulting vinylindoles were used as precursors of several kinds of alkaloid structures. 

Enaminoesters, -ketones, and -nitriles have also successfully been applied in electro-chemically induced radical cation cycloaddition reactions, especially with 2-vinylindoles or 2-vinylpyrroles. Some examples are given in Eq. (31). Depending on the structures, the reaction starts with the formation of either the vinylindole or vinylpyrrole radical cation or the radical cation of the enamidoester, -ketone, or -nitrile. In Eq. (32), a representative reaction pathway for the cycloaddition between a 2-vinylpyrrole and an acceptor-substituted enamine is formulated via the enamine radical cation [159]. 

In the electron-transfer-sensitized reaction of the 2-vinylindole 27 with dienes it has been found that the indole rather than the diene usually [41c], although not always [41b], becomes the diene partner in the 2-1-4 cycloaddition reaction styrenes also add to 27 in this manner and the initial adducts are further oxidized to the carbazole 28 under the reaction conditions (Scheme 11) [41c]. Formation of the indole radical cation and its attack on the styrene to give intermediate 29 explains the regioselectivity observed. 

The most fully explored synthetic applications of Diels-Alder reaction in annotation of pyrroles and indoles involves use of vinyl derivatives. Because of the donor character of the heteroaromatic ring, vinylpyrroles and vinylindoles react as electron-rich dienes. Various aspects of both the synthesis and cycloaddition reactions of vinylindoles have been reviewed. <85JHC585, 86CZ95, 88H(27)1253>. 

The 2,3-bond in the indole nucleus can participate in cycloaddition reactions in a variety of capacities. In a previous section, we have reviewed the role of the 2,3-bond as the dienophile in Diels-Alder chemistry. In addition, the 2,3-bond may also be combined with a vinyl group in either the second or third position of the indole nucleus and thus take part as the diene in Diels-Alder cycloadditions. These vinylindole species are very useful synthetically and provide access to complex poIycycUc structures in a very efficient manner. This section will mostly cover research published over the past 15 years. Readers interested in earlier work on this chemistry are referred to the excellent reviews by Pindur [58, 59]. 

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