3- Vinylindole, cycloaddition reactions Diels-Alder reaction

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). 

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. 

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). 

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). 

First asymmetric Diels-Alder reactions in the vinylhetarene series cycloaddition with vinylindoles to enantiomerically pure carbazole derivatives [133]... 

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>. 

Cycloadditions, in particular Diels-Alder reactions, have proven to be extremely powerful methods for the efficient constmction of complex polycyclic derivatives [1-8], The indole moiety, with its ability to serve as both a diene and a dienophile, thus provides an ideal starting point for the assembly of a variety of alkaloid natural products. With the electron-rich nature of the indole 2,3-bond, indoles are particularly suited as dienophiles for inverse electron demand Diels-Alder reactions. Various vinylindole derivatives, on the other hand, have been proven to be excellent dienes for [4-1-2] cycloadditions. 

Blechert and coworkers have developed a very efficient one-pot synthesis of 2-vinylindole derivatives, starting from an aldehyde, phenyUiydroxylamine, and cyanoallene [64], These 2-vinyl indole species have demonstrated good synthetic utility in constructing linear carbazole skeletons that could be useful as key intermediates in the assembly of indole alkaloids [65]. Early on, it was discovered that the Diels-Alder reactions of the 2-vinylindole species 150 did not proceed under thermal conditions, and the use of Lewis acids did not offer any advantages. However, cycloadditions with electron-deficient dienophiles 151 (at room temperature in chloroform/dichloromethane and in the presence of trifluoroacetic acid), followed by aromatization, led to the formation of the tetrahydrocarbazole structures 152 (Scheme 38). These reactions were found to proceed with high selectivity for the endo products. The tetrahydrocarbazoles 152 could then be oxidized with DDQ to form the corresponding carbazoles in good yields. 

Diels-Alder reactions using 2-vinylindoles as the diene were used as the key step in syntheses of olivacine derivatives (155), ellipticine derivatives (157), and ( )-3-epi-dasycarpidone (162) [65] (Scheme 39). In the synthesis of ( )-3-epi-dasycarpidone, the appropriate 2-vinylindole 159 was prepared via a one-pot procedure, and then subjected to deprotection of the aUyl carbamate, and subsequent enamine formation, followed by an intramolecular Diels-Alder reaction to produce 161, thereby producing the indole alkaloid framework in three steps from a rather simple starting material, 158. The attempted cycloaddition reaction... 

Bailly and coworkers were interested in synthesizing structures containing a carbazole nucleus with a fused imide ring and examining their effects on DNA, human topoisomerases, and P388 leukemia cells [104]. Thus, the Diels-Alder reaction between the 3-vinylindole species 292 and DMAD (221) was used as the key synthetic step to provide the cycloaddition product 293. This cycloadduct was in turn oxidized to the carbazole moiety 294, bearing a diester functionality that could then be cyclized with an appropriate amine 295 to produce the A-substituted imide ring in the final product 296 (Scheme 62). 

Greico and Kaufman used a similar strategy, this time involving the Diels-Alder reaction of 3-vinylindole with an appropriately tethered imine, to construct the pentacyclic ebumamonine structure in a very efficient manner [108] (Scheme 65). At first attempt, the thermal Diels-Alder reaction of imine 307 in 1,2-dichlorobenzene at 180°C afforded the cycloadduct 308 in only 32% yield, and without the formation of ebumamonine (309). Next, cycloadditions under acidic conditions were examined. The optimal conditions were found to involve conducting the reaction at 5 M lithium perchlorate-diethyl ether with 0.1 equivalent of cam-phorsulfonic acid, thus affording the Diels-Alder product 308 in 96% yield. 

Another pioneer in the Diels-Alder reactions of vinylpyrroles was Noland, who also developed the reactions of vinylindoles to yield carbazoles. Some examples of the former are shown in Scheme 2 (equations 1 and 2) [4-7], Jones and his colleagues were equally active in this cycloaddition chemistry of vinylpyrroles (equations 3 and 4) [8-12], These workers measured the rates of the reaction between 1-methyl-2-vinylpyrrole and seven dienophiles, with maleic anhydride being 4800 to 50,000 times more reactive than the other dienophiles (DMAD, maleonitrile, fumaronitrile, dimethyl maleate, methyl acrylate, and acrylonitrile) [8], In a clever tactic to thwart the formation of dihydroindoles, Jones used an excess of methyl propio-late to convert the initial adduct to a second Diels-Alder cycloadduct that subsequently loses ethene by a retro-Diels-Alder reaction to afford the dimethyl 1-methyl (phenyl)-4,7-dicarboxylates (equation 4). The reactions are concerted and were consistent with FMO calculations (HOMO[vinylpyrrole]-LUMO[alkene]). The yields are 54% to 81%, but attempts to dehydrogenate the tetrahydroindole products to indoles were unsuccessful. 2-Vinylpyrrole itself undergoes Michael additions and polymerization with these dienophiles. Domingo, Jones, and coworkers subsequently... 

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. 

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). 

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 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]. 

Saracoglu and Cavdar investigated the Diels-Alder cycloadditions of 2-vinylindoles with various substituted quinone compounds [66] (Scheme 40). Thus, the cycloaddition reaction between 2-vinylindole 163 and naphthoquinone (166), followed by a [l,3]-hydrogen shift, provided compound 167. Similar to what was seen previously, the secondary orbital interactions between the diene and the dienophile lead to the formation of the endo product. Other quinone dienophUes, such as p-benzoquinone (164) and DDQ (168), also participated in similar cycloaddition reactions to produce quinolinocarbazole derivatives. In the case of DDQ, overoxidation by elimination of 2 moles of HCl from the cycloaddition product led to the formation of compound 169. 

Cycloaddition reactions and the related electrocyclization reactions rank at or near the top of the hierarchy of organic synthesis. Several clever adaptations of these reactions have been described for the synthesis of indoles. Methods that originate with an intact indole ring—for example, to give carbazoles—are not included in this chapter. Thus, the several elegant Diels-Alder cycloadditions of vinylindoles to give carbazoles are not covered. 

Like the Diels-Alder cycloaddition reaction of 2- and 3-vinylindoles to give carbazoles, the cycloaddition of 2- and 3-vinylpyrroles to give indoles is a well-established methodology [1],... 

In the last decade, several excellent results were also published in the area of enantioselective nickel-catalysed Diels-Alder cycloadditions. Among them, the reactions of cyclopentadiene with 3-alkenoyloxazolidin-2-ones induced by (i )-BINIM-2QN provided cycloadducts in up to >99% yield, >98% de, and 96% ee. Another excellent result was achieved by using a chiral iV,iV -oxide-derived nickel catalyst in Diels-Alder cycloadditions of 3-vinylindoles with methyleneindolinones for the construction of chiral spiro[carbazole-oxindoles] in up to 97% yield, >98% de, and 98% ee. Moreover, the use of the chiral DBFOX-Ph ligand has allowed an inverse-electron-demand Diels-Alder reaction of a range of Af-sulfonyl-l-azadienes with vinyl ethers to be achieved, providing highly functionalised piperidines in up to 75% yield, 96% de, and 92% ee. 

Minfiensine, a secoiridoid indole alkaloid, was isolated from the African plant Strychnos minfiensis by Massiot and co-workers in 1989. The unique structure feature of the 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9//-carbazole has received much attention for the synthetic efforts and has culminated in several elegant total syntheses. For example. Overman et al. reported on the first and second total synthesis of (-l-)-minfiensine. " In addition, Qin et al. revealed a synthesis of ( )-minfiensine in 2008. Recently, MacMillan and co-workers reported on a nine-step enantiose-lective total synthesis of (-l-)-minfiensine via the key step reaction of organocatalytic Diels-Alder cyclization and amine heterocyclization cascade (Scheme 21.32). For the key step reaction in their approach, reaction of 2-vinylindole 139 and 3 equivalents of propynal in the presence of secondary amine catalyst 140 followed by the addition of NaBH4, stereoselective afforded the tricyclic alcohol 142 via a iminium activated endo-selectiye Diels-Alder cycloaddition and a 5-exo amine heterocy cliz ation. 

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