Insertion reactions functionalized indoles synthesis

The classical Fischer indole synthesis has persisted as a commonly used procedure due to its working simplicity. However, this method suffers some drawbacks, such as the need for strong acids, poor selectivity with unsymmetrical ketones, and poor functional group tolerance. Huang et al. developed an alternative synthetic strategy for the synthesis of unprotected indoles a tandem ortho-C-H activation and annulation by using triazenyl arenes and alkynes. This reaction involves a ring contraction by a 1,2-Rh shift and an N=N insertion (Eq. (5.12))... 

Reaction of the cyclometallated derivative of phenyl-2-pyridylketone 73 leads to indenol-chelated, palladium-containing derivatives 74. Here, incorporating an electrophilic (CO) function in the starting palladacycle signifies that, following alkyne insertion in the Pd-C bond, an intramolecular attack of the vinyl palladated unit on the metal-bound, activated CO function occurs. This is in sharp contrast to the reaction described in Scheme 9 whereby incorporating a nucleophilic, masked, secondary amine function leads to indole derivatives 40 and to the azepinium synthesis from the metallated benzylpyridine complex 34. Therefore, these reactions are rather sensitive to the nature of other potentially reactive functions within the metallacyclic framework. 

In 2013, Takemoto and co-workers developed a palladium-catalyzed isocyanide insertion and alkyne functionalization for the synthesis of 2-arylindole derivatives, including tetracyclic carbazoles (Scheme 2.105). In this process, the formation of two C-C bonds via isocyanide insertion was achieved, and isocyanide was effectively used by incorporating both the C and N atoms as components of the indole skeleton. Regarding the reaction mechanism, the reaction started with the oxidative addition of Pd(0) to aryl... 

The rapid development of C-H functionalization has helped in accomplishing the synthesis of a variety of complex heterocycles from simple precursors. Recendy, Ramana and co-worker demonstrated a simple one-pot procedure for the Cu(I)-catalyzed SNAr reaction of o-bromochalcones 1 with sodium azide followed by intramolecular cyclization through nitrene C-H insertion to provide 2-aroylindole derivatives 2 [56] (Scheme 7.1) on the basis of their previous work [57]. Furthermore, this methodology is also applicable with the 2 -bromocinnamates giving the indole-2-carboxylates. 

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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