Indolo indole

The Graebe-Ullman carbazole synthesis has been enmloyed in the preparation of substituted carbolines, as well as indolo[2,3-i] quinolines, which are often difficult to synthesize via other approaches, for example, the Fischer indole process. 

In 1961 Acheson and Hands obtained 3-methyl-l-(2-nitroethyl)-indole (354) in low yield by the addition of nitrocthylene to 3-methyl-indole magnesium iodide. These authors also obtained 5-benzyloxy-l,3-bis(2-nitroethyl)iiidole (355) and 5,6-dimethoxy-3-(2-nitroethyl)-indolo (356) by the action of nitrocthylene on 5-henzyloxy- and 5,G-dimethoxyindolc magnesium iodide, respectively. They excluded the ]jossibility that the products 354, 355, and 356 had the isomeric indolenine structures on the basis of their absorption spectra and chemical properties. 

Conformational study of geissoschizine isomers and their model compounds (geissoschizine is the indolo[2,3-fl]quinolizidine derivative considered to be an important participant of indole alkaloids biogenesis) 99H(51)649. 

In synthesis of the alkaloid tjipanazole E (19b), the required symmetric dichloro-indolo[2,3-fl]carbazole 20a was obtained in a two-step procedure starting fi-om 4-chlorophenylhydrazine hydrochloride and 1,2-cyclohexanedione employing a Fischer indolization. Subsequent attachment of an acetyl-protected glucopyranosyl moiety to one of the nitrogens, followed by cleavage of the protective groups with ammonia in methanol, produced the desired natural product (91X7739). 

Coupling reactions of indole-3-acetic acid derivatives have also p ovided convenient routes to indolo[2,3-a]carbazoles (Scheme 5). An iodine-p-omoted coupling... 

Indole-2,3-quinodimethanes have also been exploited as the key intermediates in indolo[2,3-a]caibazole synthesis, allowing the preparation of several interesting systems. Thus, when the starting materials 74a-b (obtained from the condensation of protected indole-2-carboxaldehydes with 2-aminostyrene) underwent treatment with methyl chloroformate in hot chlorobenzene, the carbamates 75a-b were obtained, and could subsequently be dehydrogenated into the aromatic compounds 76a-b (Scheme 11). However, all functionalization attempts of the methyl... 

A synthesis of an indolo[3,2-fl]carbazole (2) was reported in 1951—the first preparation of a compound belonging to this class (Scheme 13). This was accomplished commencing with cyclohexanone, via conversion to the bishydrazone 108, which underwent Fischer indolization in glacial acetic acid to furnish the octahy-dro derivative 109. After a final dehydrogenation step, the desired product 2 was obtained (51JCS809). 

Indolo[3,2-fl]pyrrolo[3,4-c]carbazoles 120 have been obtained in one step from indole and the corresponding maleimides in acetic acid, with coformation of the Michael adducts 121 (Scheme 15). This reactitai required careful temperature control in order to obtain the desired product ratios. An alternative independent synthesis of compounds 120 could also be accompKshed from 2,3 -biindolyl (115) andsuitable maleimides in hot acetic acid (99T2363). The system 120 where R = H has also been reported as a minor product during studies toward a synthesis of the alkaloid arcyriaflavin A (95TL2689). 

The indol-3-yl-substituted indolo[2,3-()]carbazole 143 has been isolated as a product from the complex mixture generated by the decomposition of urorosein (144) (99CHE561). Interestingly, when subjected to alkylation conditions involving sodium hydride and dimethyl sulfate in THF, 143 was transformed into the N. -dimethyl derivative 145 in 36% yield (00MI2). 

During studies on the acid-induced formation of the alkaloid yuehchukene and related structures from pienylindoles, it was discovered that treatment of indole 173 with p-toluenesulfonic acid and silica gel leads to the formation of indolo-[3,2-b]carbazole 174 and the indole derivative 175 (Scheme 21). Similarly, the disubstituted product 176 could be isolated after TFA treatment of the substrate 177. Detailed mechanistic explanations have also been provided in this work (96T9455). 

Several derivatives of indolo[3,2-fi]carbazole, such as the system 185, have been claimed to arise from the reaction of suitably substituted simple indoles on treatment with thallium triacetate in acetic acid. A compound having the purported structure of 185 was thus isolated when 2,3-dimethylindole was used as the substrate [78UC(B)422]. Many years later, it was demonstrated that this product is in fact a derivative of indolo[2,3-c]carbazole (cf. Section VI) (99T12595). 

Studies on the Bischler-Napieralski cyclization of A -acetyltryptamine in the presence of indole have led to the isolation of numerous products, among which the indolocarbazole 186 could be found in 3.5% yield. This outcome was rationalized as a result of the intermediacy of a spiroindolenine species formed under these conditions [89H(28)175]. During detailed studies on the polymerization of indole, formation of a low yield of the related indolo[3,2-h]carbazole 187 was discovered in the product mixture originating from the treatment of indole with p-toluenesulfonic acid at elevated temperature [88JCS(P1)2387]. In an investigation of the condensation of p-benzoquinone with 4-substituted anilines, an indolo[3,2-h]carbazole derivative has been reported to be formed in 2% yield (80JOC1493). 

Genkina et al. (1979, 1981, 1985) investigated azo coupling reactions of indoles with fused benzo and benzothiopheno rings, namely 4,5- and 6,7-benzindole, 4,5,6,7-dibenzindole (12.42), indolo[6,5]-, -[4,5]-, and -[5,4]-benzo[Z ]thiophene (12.43 to 12.45). Arenediazonium ions reacted with all these indole derivatives at the 3-position. 

The Cacchi group [85] developed a Pd-catalyzed domino process between o-alky-nyltrifluoroacetanilides as 6-157 and aryl or alkenyl halides, which leads to substituted pyrroles within an indole system. This scheme was successfully applied to the preparation of indolo[2,3-a]carbazoles as 6-158 using N-benzyl-3,4-dibro-momaleimide (Scheme 6/1.42). The indolocarbazole is found in several bioactive natural products as arcyriaflavin A and the cytotoxic rebeccamycin. 

The intramolecular Pummerer reaction has been applied to the synthesis of simple quinolizidine alkaloids like lupinine <2000JOC2368>, and also to arenoquinolizine alkaloids. Thus, the 2-(2-piperidyl)indole 284 was converted to indolo[2,3- ]quinolizidine 287 following a protocol that has as the key step the regioselective cyclization onto the indole 3-position of a thionium ion generated by Pummerer reaction from the appropriately substituted compound... 

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