From 2-Vinylindoles

The regioisomer 3-demethoxycarbazomycin A was prepared starting from indolyl(methoxy)methylcarbenium tetrafluoroborate (91) which was deprotonated in situ to provide a 3-vinylindole (91a). This on trapping with dimethyl acetylenedicarboxylate and subsequent dehydrogenation and reduction gave 3-demethoxycarbazomycin A (90) through (92). 

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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). 

A rare Diels-Alder/aza-Michael/aldol cascade allows the formation of tetracyclic pyridocarbazoles derivatives from 3-vinylindoles and o,p-unsaturated aromatic aldehydes (Scheme 7.33) [51]. In this triple cascade, six stereogenic centers are formed, as well several new C-C bonds and one C-N bond, all with great efficiency and high stereoselectivities. 

Formation of a cation radical of the diene may catalyze Diels-Alder reactions with certain dienophiles thus oxidation of substituted vinylindoles to the cation radical in the presence of a push-pull dienophile may form different heterocyclic compounds by the Diels-Alder reaction, for instance pyrido[l,2i7]indoles from vinylindoles and yS-enamino-esters [33]. Similarly, anodic oxidation in MeCN of certain oxazolidines in presence of vinyl ether leads to derivatives of oxazepines in a catalytic reaction in which the ring-opened radical cation of the oxazolidine adds to the vinyl ether and the radical cation of the resulting oxazepine oxidizes the oxazolidine [34]. 

In some cases it is possible to obtain Diels-Alder adducts from vinylindole intermediates which are generated in situ. The yields in such reactions are usually not very high but the simplicity of operation is a compensating factor. For example, heating indole, a ketone and maleic acid together gives l,2,3,4-tetrahydrocarbazole-2-carboxylic acids in around 20% yield (Equation (143))... 

This asymmetric version of Levy s disconnection exploits diaryl prolinol 141 as a catalyst to induce the enantioselective formation of tetra-hydro(iminoethano)carbazole 142 from vinylindole 139 and trans-formyla-crylate 140. The sequence proceeds via a similar mechanism as that seen in Scheme 9. 

In a related study, 161 was reported from a dimerization of a 3-vinylindole precursor (61JOC4254). Previously, a compound with the structure 162 had been suggested as a product originating from a dimerization of an alcohol precursor under acidic conditions (63G238). It has recently been demonstrated that the alcohol 163, when treated with aluminum trichloride in the presence of acetic anhydride, produced the indolocarbazole 160, which could be isolated in 41% yield as an 83 17 mixture of cis and trans isomers (98JOC2909). 

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). 

Tetrahydrocarbazoles have been prepared in one-flask syntheses from indoles, ketones and maleic anhydride, with acid catalysis. The reactions involve a condensation of the indole 121 with the ketone or aldehyde, followed by in situ trapping of the vinylindole 122 with maleic anhydride to afford tetrahydrocarbazoles 123 after double bond isomerization <96T4555>. 

Although harmine 52 is frequently obtained by isolation (or purchase order), a synthesis of this compound as well as a number of analogs has recently appeared [47,48]. The key step to this synthesis was the thermal electrocyclization of oxime intermediate 55, which was prepared by acylation of vinylindole derivative 54 followed by treatment with hydroxylamine hydrochloride. Neither oxime 55 nor its ketone precursor were isolated— instead, the crude reaction mixture was heated at reflux in o-dichlorobenzene to ultimately yield harmine in 56% yield overall starting from 54 (Fig. 18). 

Miki effected Pd-catalyzed cross-coupling between dimethyl 7-bromoindole-2,3-dicarboxylate and both tributylvinyltin and tributyl-1-ethoxyvinyltin to yield the expected 7-vinylindoles [197]. Hydrolysis of the crude reaction product from using tributyl-1-ethoxyvinyltin gave the 7-acetylindole. Sakamoto used dibromide 192, which was prepared by acylation of 7-bromoindole, in a very concise and efficient synthesis of hippadine [36]. The overall yield from commercial materials is 39%. Somewhat earlier, Grigg employed the same strategy to craft hippadine from the diiodoindoline version of 192 using similar cyclization reaction conditions ((Me3Sn)2/Pd(OAc)2), followed by DDQ oxidation (90%) [198]. 

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). 

Hibino et al. reported the total synthesis of carbazomycin G (269) by the regioselective addition of methyllithium onto 3-methoxy-2-methylcarbazole-l,4-quinone (941) (653). The required immediate precursor of carbazomycin G, carbazole-l,4-quinone 941, was obtained from 3-(2-methoxyethenyl)-N-(phenylsul-fonyDindole (986). The benzannulation involves an allene-mediated electrocyclic reaction of a 67t-electron system generated from the 2-propargylindole 989, which was derived from the 3-vinylindole 986 in three steps. 

Beccalli et al. reported a new synthesis of staurosporinone (293) from 3-cyano-3-(lH-indol-3-yl)-2-oxo propionic acid ethyl ester (1464) (790). The reaction of 1464 with ethyl chlorocarbonate and triethylamine afforded the compound 1465, which, on treatment with dimethylamine, led to the corresponding hydroxy derivative 1466. The triflate 1467 was prepared from 1466 by reaction with trifluoromethanesulfonic anhydride (Tf20) in the presence of ethyldiisopropylamine. The palladium(O)-catalyzed cross-coupling of the triflate 1467 with the 3-(tributylstannyl)indole 1468 afforded the vinylindole 1469 in 89% yield. Deprotection of both nitrogen atoms with sodium ethoxide in ethanol to 1470, followed by photocyclization in the presence of iodine as the oxidizing agent provided the indolocarbazole 1471. Finally, reductive cyclization of 1471 with sodium borohydride-cobaltous chloride led to staurosporinone (293) in 40% yield (790) (Scheme 5.248). 

Pindur et al. reported the synthesis of carazostatin (247) starting from the 2-vinylindole 958, which previously served as the key building block in the total synthesis of carbazoquinocin C (274) (see Scheme 5.130). The 2-vinylindole (958), readily available in four steps starting from Af-(phenylsulfonyl)indole (956), was transformed to the indolylacetic acid (1568) by treatment with KCN and paraformaldehyde followed by alkaline hydrolysis. Subsequent acid-catalyzed polar cyclization of 1568 led to carazostatin (247) (648) (Scheme 6.1). 

Polyfl-benzyl-5-vinylindole) (29), prepared from the monomer via either radical or anionic polymerization, has been used to prepare polymeric analogues of a variety of biologically active indole derivatives (77MI11101). 

The facile acid-catalyzed elimination of the elements of water from the carbinols derived from 2-methylindole and 1,3-dicarbonyl compounds, such as ethyl acetoacetate or pentane-2,4-dione, yields the 3-vinylindole derivatives (122) (B-70MI30500). Pyrroles tend to form 2 1 adducts with 1,3-diketones. For example, cyclohexane-1,3-dione produces the bispyrrolyl derivatives (121) (B-77MI30502). 

Substituted 2-vinylindoles yield the di- and tetra-hydrocarbazoles with JV-methyl-maleimide and maleic anhydride, and with DMAD, respectively (81UP30500, 82CJC419) and the expected cycloadducts are obtained from the reaction of 4-(2-indolyl)-l,2,5,6-tetrahy-dropyridines with iV-phenylmaleimide and with acrylonitrile (68HCA264). Both l-(l-methyl-... 

An interesting paper reports the combined synthesis of 3-vinylindoles from ketones with the vinylindole synthesis of tetrahydrocarbazoles in one flask by using indole (1 equivalent) and excess ketone precursor as the solvent, usually at reflux with maleic acid (1 equivalent), both as the catalyst for 3-vinylindole formation and as the dienophile for the Diels-Alder reaction. These reactions constitute an in situ vinylindole synthesis of tetrahydrocarbazoles (79JOC4402). 

The parent 2-vinylindole and 2-(2-methylvinyl)indole also reacted with the carbodienophiles methyl-(E)-3-benzoylacrylate, l-penten-3-one, and methyl acrylate these reactions proceeded through a Diels-Alder step to produce the corresponding carbazoles (90JOC5368). The unsymmetrical dienophiles reacted regioselectively in accordance with the predictions of the FMO concept. In none of these reactions was it possible to detect either a betaine intermediate originating from a stepwise process or a Michael-type adduct. The stereochemistry of the cycloadducts was not changed when the reactions were carried out in the polar solvent... 

Starting from indolylallyl alcohol 315, several compounds containing a diene-dienophile in their structures were prepared. The 3-vinylindole 316 underwent an intramolecular Diels-Alder reaction when heated in bromo-benzene at 156°C, affording cycloadducts 317 and 318 (89CZ273). 

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. 

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