Reversal of Regioselectivity in Catalytic Arene-Ynamide Cyclization: Direct Synthesis of Valuable Azepino[4,5-b]indoles and β-Carbolines and DFT Calculations

Abstract

Ynamides are important building blocks in organic synthesis, and a variety of versatile synthetic methods have been developed in the past decade. Among these, catalytic cyclizations of π-tethered ynamides are particularly attractive, since this approach enables facile access to a diverse array of synthetically useful nitrogen heterocycles. However, due to the fact that the nitrogen atom is able to impose an electronic bias, these cyclizations exclusively occur on the α position of ynamides. Herein, we report the reversal of regioselectivity in arene-ynamide cyclization by copper catalysis, which represents the first catalytic π-tethered ynamide cyclization involving the reversal of regioselectivity. This strategy allows the expedient and practical synthesis of valuable azepino [4,5-b]indoles and β-carbolines in generally high yields under mild conditions. Moreover, the relevant mechanistic rationale for this cyclization, especially for the observed high regioselectivity, is strongly supported by density functional theory (DFT) calculations. The synthetic utility of this chemistry is also indicated by the synthesis of several biologically active compounds and natural product bauerine A.

Brønsted Acid‐Catalyzed Tandem Cyclizations of Tryptamine‐Ynamides Yielding 1H‐Pyrrolo[2,3‐d]carbazole Derivatives

“…Yang and co‐workers reported a gold‐catalyzed intramolecular consecutive annulation of indole‐ynamide to generate a pyrrolidinoindoline by using alcohol as the nucleophile to capture the indoleninium . Recently, Ye and co‐workers described a copper‐catalyzed regioselectivity‐reverse cyclization of an arene‐ynamide . Such examples of tryptamine‐derived ynamide cyclization reactions have demonstrated that the substrates and conditions (i.e., the substitutions, the nucleophiles, the types of catalysts, etc.)…”

Gold-catalyzed intermolecular reaction of ynamides with 3-indolyl azides via an unexpected 1,2-alkyl migration

“…Recently, the generation of a-imino gold carbenes [14][15][16][17][18][19][20][21][22] through gold-catalyzed alkyne amination has gained significant attention, because this strategy offers easy access to a variety of valuable complex nitrogen-containing molecules [23][24][25][26][27][28][29][30][31][32][33]. In our recent study on the ynamide chemistry [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48], we first disclosed that benzyl azides could serve as efficient nitrene transfer reagents to react with ynamides for the intermolecular generation of aimino gold carbenes. As a result, this chemistry has evolved into a robust and reliable method for the construction of versatile 2aminoindoles and 3-amino-b-carbolines (Scheme 2a) [49].…”

Regioselective Direct C‐Alkenylation of Indoles

“…Intramolecular reaction of indole‐based ynamides catalyzed by Cu(OTf) 2 directly affords β‐carboline derivatives as a result of a 6‐endo‐dig process (Scheme ) . The final aromatization process is achieved by elimination of the mesylate anion.…”

“…Under the same reaction conditions described in Scheme for the synthesis of β‐carbolines, indole‐based ynamides can be converted into azepinoindoles (Scheme ) . Starting from enantiopure substrates, the corresponding azepinoindoles are obtained with complete retention of the original configuration.…”