Indoles benzene ring functionalization

Regioselective lithiations have also been utilized to prepare other benzene-ring functionalized indoles. For example, the selective halogen-metal exchange of 4,7-dibromoindole 152 led to the formation of 7-lithioindole intermediate 153, which in turn gave indole-7-carboxaldehyde 154 upon treatment with DMF <03TL5987>. 

The corresponding benzo-analogs (IH-indole, benzofuran, and benzo-thiophene), however, react preferentially via the C3-position. This can be rationahzed by the Wheland intermediates originating from electrophilic substitution on the C2- and C3-position. For the latter, one more resonance structure can be drawn without loss of aromaticity of the annulated benzene ring (Figure 4). C2-functionalization is less favored but can take place when the C3-position is blocked for instance (either via direct attack at C2 or via initial attack at C3 followed by 1,2-migration). 

After this work, the more challenging synthesis of arene-alkynylated indoles was investigated. Because of the enhanced reactivity of the pyrrole ring, the direct functionalization of indoles on the benzene ring is highly challenging. A domino process to access these compounds would therefore be very useful. They were able... 

Another intramolecular Heck reaction could be called a heteroaryl Heck reaction because the C-C bond formation involves a benzene and an indole ring. The resulting phenylcarbazoles are potential anti-cancer agents functioning as DNA topoisomerase I inhibitors. 

Fused indole 232 resulted from the reaction of a donor-acceptor cyclopropane with an indole bearing a Michael acceptor at C2.The products were obtained in good yield with high diastereoselectivity (16 examples, 64-90% yield) (140L3954). Tetracyclic-fused indole 233 was prepared by a [3+3]-cycloaddition of an indol-2-yl carbinol with an azadiene (11 examples, 42-90% yield). This could be followed by an oxidative ring expansion promoted by (bis(trifluoroacetoxy)iodo)benzene to produce a series of indole azepinones (6 examples, 59-71% yield) (14CC11181). Fused indole 234 was synthesized by the first calcium(II)-promoted Nazarov cyclization (87% yield).The substituent a to the ester functionality could vary electron-rich arenes, heteroarenes, and secondary alkyl... 

In 2005, Ohno et al. reported a cascade intramolecular carbopalladation/aromatic C-H bond activation for the synthesis of tri- or tetracyclic heterocycles 174 in the presence of palladium species [70] (Scheme 6.48). The authors proposed that this domino reaction might proceed through the oxidative addition of bromoenyne 173 to Pd(0), insertion of the alkyne into the C-Pd bond of intermediate 175, followed by C-H bond functionalization of the aromatic ring. Not only benzene-substituted substrates but also heteroaromatic rings such as benzofuran and indole, could be introduced efficiently to this reaction. Similar work was reported by Chernyak and Gevorgyan [71]. 

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