Exploring the Oxidative Cyclization of Substituted N‐Aryl Enamines: Pd‐Catalyzed Formation of Indoles from Anilines

Abstract

The direct Pd-catalyzed oxidative coupling of two C-H-bonds within N-aryl-enamines 1 allows the efficient formation of differently substituted indoles 2. In this cross-dehydrogenative coupling, many different functional groups are tolerated and the starting material N-aryl-enamines 1 can be easily prepared in one step from commercially available anilines. In addition, the whole sequence can also be run in a one-pot fashion. Optimization data, mechanistic insight, substrate scope, and applications are reported in this full paper.

Iodine-mediated one-pot synthesis of indoles and 3-dimethylaminoindoles via annulation of enaminones

“…At first, αanilinocarbonyl compounds 4a-n were prepared in good to excellent yields (60-99%) under conditions similar to those previously reported (Table 1, entries [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. 21 The mixture of anilines 5a-g, potassium carbonate and potassium iodide were treated with the corresponding methyl bromoacetate (6a) or chloroacetone (6b), in dry acetone as the solvent, at 60 ºC for 12 h. However, for analogues 4o-p, which derive from the 2-bromoacetophenones 6c-d, this method was only able to provide the desired products in low to moderate yields (30-64%).…”

“…For many decades, considerable efforts have been invested in the synthesis 1 and functionalization 2 of the indole core. Even at present, numerous, efficient and elegant approaches are continuously being developed to generate this unique and seminal benzoheterocyclic ring system.…”

“…14 As a consequence of these relevant activities and applications, a great number of synthetic routes leading to 2-substituted indoles have been described in the literature. [1][2][3] However, the protocols reported for the synthesis of 3-aminoindole derivatives are limited in scope, and usually require multistep preparation of the starting materials. 13,15 Therefore, the development of straightforward synthetic approaches to 3-dimethylaminoindoles from easily available starting materials is still a pressing task.…”

Palladium‐Catalyzed Indole Ring Synthesis

“…An important variation of the Mori-Ban-Heck indole synthesis is Pd-catalyzed oxidative cyclization of N-aryl enaminones and enamines, as largely developed by Glorius (Scheme 4, equations 1 and 2) [44][45][46]. The C-2 substituent was easily varied, and the method was extended to imine cyclization (equation 2).…”

Hypervalent Iodine(III)‐Mediated Counteranion Controlled Intramolecular Annulation of Exocyclic β‐Enaminone to Carbazolone and Imidazo[1,2‐a]pyridine Synthesis

“…Åkermark et al., disclosed in 1999 a palladium‐catalyzed cyclization of arylaminoquinones to give biologically important carbazoloquinones, albeit with limited substrate scope . In 2011, Glorius and co‐workers developed a Pd‐catalyzed oxidative coupling of two C−H‐bonds within N ‐arylenamines that allows the efficient formation of differently substituted indoles . In a recent report, He et al., demonstrated a formal [3+2]‐cycloaddition reaction for the synthesis of carbazolequinones through the annulation of aminoquinones with aryne intermediates generated in situ .…”