N‐Heterocyclic‐Carbene‐Catalyzed Synthesis of 2‐Aryl Indoles

Abstract

A convergent and efficient transition‐metal‐free catalytic synthesis of 2‐aryl‐indoles has been developed. The interception of a highly reactive and transient aza‐ortho‐quinone methide by an acyl anion equivalent generated through N‐hetereocyclic carbene catalysis is central to this successful strategy. High yields and a wide scope as well as the streamlined synthesis of a kinase inhibitor are reported.

Synthesis of Indoles through Domino Reactions of 2‐Fluorotoluenes and Nitriles

“…[11] Xiao and co-workers developed cascade annulations of sulfur ylides with N-(ortho-chloromethyl)aryl amides (Scheme 1e,t op), [12] while Scheidt and coworkers introduced an N-heterocyclic carbene catalyzed synthesis of 2-aryl indoles with aldehydes (Scheme 1e, bottom). [13] Thes yntheses in Scheme 1e mploy highly functionalized precursors or low temperatures,which are difficult to access on scale.…”

Rate and Equilibrium Constants for the Addition of N‐Heterocyclic Carbenes into Benzaldehydes: A Remarkable 2‐Substituent Effect

“…However, the increased steric hindrance around the nucleophilic carbon of 41 compared with 40 may decrease its relative rate of addition sufficiently to explain the formation of cross-benzoin 37 . [25]…”

Aza‐ortho‐Quinone Methide and Its Conjugated Acid: Reactivity, Stability and Acidity

“…Aza-o-quinone methide (1) and its analogues are important and unstable intermediates. [6][7][8][9][10][11][12][13][14][15][16][17] They may carry out [4 + 1], [6][7][8] [4 + 2] [9][10][11][12][13] and [4 + 3] [14] cycloadditions to form tetrahydroquinolines, [9,[11][12][13] quinolines, [9,10] indoles [6][7][8] and benzotriazepine, [14] which are useful scaffolds to build many drugs and natural products, [9] such as virantmycin, [15] and chartellin. [16] Interestingly, to carry out the cycloaddition reactions, in-situ generated 1 needs to be in alkaline conditions, instead of acidic conditions.…”