Remote C6-Enantioselective C–H Functionalization of 2,3-Disubstituted Indoles through the Dual H-Bonds and π–π Interaction Strategy Enabled by CPAs

Abstract

A versatile dual H-bonds and π–π interaction strategy that enables enantioselective remote C6-selective C–H functionalization of 2,3-disubstituted indoles was first reported. The N–H bond of indole was pivotal to achieve the C6 functionalization with excellent yield and enantioselectivity. Furthermore, this methodology leads to the efficient construction of numerous enantioenriched C6-functionalized indole products under mild reaction conditions employing different electrophiles. Preliminary cell proliferation investigations revealed that the synthesized chiral C6-substituted indole derivatives had potential anticancer activities.

Ruthenium(II)-Catalyzed Highly Chemo- and Regioselective Oxidative C6 Alkenylation of Indole-7-carboxamides

“…This is mainly due to two reasons, first, the inert nature of the C6 C–H bond and, second, the interference by C2, C3, and C7 C–H bonds make the C6 functionalization of indole a challenging task. Till now, the C6 functionalization of indoles has been attained either through electrophilic substitution on C2–C3 disubstituted indoles using Lewis acid and Brønsted acid catalysts or using metal-catalyzed chelation-assisted remote functionalization methods. Metal-catalyzed strategies include iridium­(I)-catalyzed ligand-controlled C6 borylation of tryptophans by Baran and co-workers .…”

Chiral Spirocyclic Phosphoric Acids and Their Growing Applications

“…Zhang developed the direct enantioselective C6‐selective C—H functionalization of 2,3‐disubstituted indoles in the presence of ( S ) ‐ SPA 5 through dual H‐bonds and π–π interaction strategy (Scheme 16). [ 21a ] The N—H bond of indole was the key to afford the C6‐functionalized indoles under mild reaction conditions employing different electrophiles with excellent yield (up to 99%) and enantioselectivity (up to 98% ee). In addition, numbers of C6‐functionalization products exhibited exceedingly potent cytotoxicities for the intended purposes.…”

“…Tan and Shi reported SPAs‐ catalyzed enantioselective aza ‐Friedel−Crafts reaction of isatin‐derived imines with 2‐substituted 3,3’‐bisindoles through dual H‐bonds interaction for an atroposelective synthesis of a new class of 3,3’‐bisindoles bearing axial and central chirality. [ 21b ]…”

Enantioselective Synthesis of 3‐Amino‐3’‐carbazole Oxindole Derivatives via Friedel‐Crafts Aminoalkylation Reaction

“…Comprising the biological important of these architectures, efficient enantioselective synthetic protocols for carbazoles have been explored through [4+2] cycloaddition, [7] intramolecular hydroarylation, [8] C−H activation, [9] photoactive intramolecular iminium‐ion based electron donor acceptor (EDA) complex, [10] N‐propargylation [11] . 3‐amino substituted oxindole syntheses were demonstrated using organocatalysts through aza‐Friedel–Crafts, [12] aza‐Henry, [13] Mannich, [14] Strecker reactions, [15] C−H Functionalization, [16] C−H Aminoalkylation [17] . Continuation of those efforts oxindole derived N‐Boc ketimines [18] were used in combination with 1,3 diketones and nitroolefins to construct structurally diverse 3‐aminooxindoles [19] .…”