Indolo carbazole, synthesis

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 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). 

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 yellow colored, sparcely soluble 5-ethyl-2-methyl-l l/f-pyrido[3,4-u] carbazolium 347 isolated from Aspidosperma gilbertii exists as a hydroxide after filtration of the corresponding iodide over basic aluminum oxide. A short synthesis was described (80CB3245). The Pyrido[3,4-a]carbazole ring system is present in the alkaloid AG-1, whereas Cryptolepine (348) possesses the indolo[3,2-b]quinoline moiety (65MI1). 

Saulnier expanded this reaction to an elegant synthesis of indolo[2,3-a]carbazole 355, featuring a polyannulation from the diacetylene as shown [315]. 

The double iron-mediated arylamine cyclization provides a highly convergent route to indolo[2,3-fc]carbazole (Scheme 16). Double electrophilic substitution of m-phenylenediamine 34 by reaction with the complex salt 6a affords the diiron complex 35, which on oxidative cyclization using iodine in pyridine leads to indolo[2,3-b]carbazole 36 [98].Thus,ithasbeen demonstrated that the bidirectional annulation of two indole rings can be applied to the synthesis of indolocarbazoles. 

The application of indolo-2,3-quinodimethanes and their cyclic analogs in the synthesis of carbazole alkaloids has attracted wide interest since they could undergo Diels-Alder reactions with a wide variety of dienophiles to afford functionalized carbazole derivatives. This represents the shortest and most elegant method for the preparation of selectively functionalized carbazole derivatives (514). 

The reactive indolo-2,3-quinodimethanes are generated in situ generally from N-protected 2,3-disubstituted indoles (514,515). Generation of reactive indolo-2,3-quinodimethanes was achieved by fluoride-induced, 1,4-elimination of silylated indolyl ammonium salts, and was applied in the synthesis of substituted tetrahydrocarbazoles (516). Subsequently, the iodide-induced 1,4-elimination of ]V-benzoyl-2,3-bis(bromomethyl)indole (534) methodology was developed for the synthesis of reactive indolo-2,3-quinodimethanes and was applied for the first time in the synthesis of substituted carbazoles (e.g., 536) (517) (Scheme 5.14). 

Later, independently, different anionic indolo-2,3-quinodimethanes which exhibit pronounced diene reactivity were developed from 2-cyano-l-methylindole-3-acetonitrile (537) (518,519) and l,2-dimethylindole-3-carboxaldehyde (539) (520) by reacting with strong base. These quinodimethanes were used in the synthesis of polyfunctionalized carbazole derivatives (538 and 541) (Scheme 5.15). 

An extension of this methodology led to another indolo[2,3-fl]carbazole, AT2433-B1 (341). For this synthesis, the required bisindolylsuccinimide (1455) was obtained through a catalytic hydrogenation of the readily available N-methylarcyriarubin A (1454). TFA-promoted Mannich cyclization of 1455 afforded the hexacyclic... 

Somei et al. reported the total synthesis of the cytotoxic and antiviral 5-cyano-6-methoxy-ll-methylindolo[2,3-fl]carbazole (357) starting from indigo (1458) (786,787). A reduction of indigo (1458) with tin in acetic acid/acetic anhydride afforded 3-acetoxy-2,2 -bisindolyl (1459) in 88% yield. Heating of 1459 with dichloroacetyl chloride in ethyl acetate under reflux provided 3-acetoxy-3 -dichloroacetyl-2,2 -bisindolyl (1460), which was treated with aqueous ammonia in methanol/DMF at room temperature to give the indolo[2,3-fl] carbazole derivative 1461. N-Methylation... 

Recently, Moody et al. reported a biomimetic synthesis of calothrixin B (378) by oxidation of Hibino s 6-formylindole[2,3-fl]carbazole 1555 (870). The key intermediate 6-formyl-indole[2,3-fl]carbazole was readily obtained in six steps from indigo (1458). Using Somei s procedure, indigo (1458) was transformed to the cis-chlorohydrin 1461 in three steps and 50% overall yield (see Scheme 5.247). The reduction of the chlorohydiin 1461 gave 5-hydroxy-indolo[2,3-fl]carbazole 1564, and subsequent Vilsmeier formylation delivered the desired 6-formyl-indole[2,3-fl]carba-zole 1565 in 45% yield. Reaction of hydroxy-indolocarbazole 1565 with an excess of chloromethyl methyl ether (MOMCI) afforded the tiis-MOM-protected compound 1555. Following Hibino s approach, the tris-MOM-protected indolocarbazole 1555... 

The synthesis of substituted indolo[3,2-ib]carbazoles is presented in Scheme 4.4. Parent indolo[3,2-jb]carbazole can be first prepared by double Fisher indolization to... 

New approaches to the indole nucleus are continuously developed, providing aceess to indoles which are difficult to prepare using the well established reactions, such as the Fischer indole synthesis. Nevertheless, this classic reaction is still often used for constructing more complex systems, as exemplified by the preparation of 2-(pyrimidin-4-yl)indoles <03CPB975>, or indolo[3,2-i)]carbazoles possessing new substitution patterns <03T1265>. 

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