Chiral Phosphoric Acid-Catalyzed C6 Functionalization of 2,3-Disubstituted Indoles for Synthesis of Heterotriarylmethanes

Abstract

The direct regio- and enantioselective C6 functionalization of 2,3-disubstituted indoles with azadienes has been developed using chiral phosphoric acid as catalyst, providing a convenient approach to synthesize the optically active heterotriarylmethanes with excellent yields, broad substrate scope, and up to 98% ee. Mechanistic studies revealed that N-alkylation of 2,3-disubstituted indoles with azadienes would be reversible, and enantioselective C6 functionalization could be enabled.

Solvent-Mediated Tunable Regiodivergent C6- and N1-Alkylations of 2,3-Disubstituted Indoles with p-Quinone Methides

“…19 However, the enantioselective C6-functionalization of 2,3disubstituted indoles with benzofuran-derived azadienes using chiral phosphoric acid led to a range of enantioenriched heterotriarylmethanes. 20 Recently, electrophiles such as ohydroxybenzyl alcohol, 21 trifluoromethylated 3-indolylmethanol, 22 and carbene 23 have been utilized in the Friedel−Craftstype C6-alkylations of 2,3-disubstituted indoles. p-Quinone methides (p-QMs) have attracted considerable attention as powerful acceptors in 1,6-nucleophilic conjugate addition reactions with a wide range of carbon and heteroatom nucleophiles.…”

“…Limited elegant approaches, such as template-assisted C6-olefination, ligand-controlled C6-borylation, C6-arylation via a transient mediator, and C6-alkylation with σ-activation, are available for the remote C­(sp 2 )–H activation (Scheme a, middle side). In addition, Lewis and Bronsted acid promoted Friedel–Crafts-type reactions were also reported for the C6–H alkylation (Scheme a, right side). − Within this scope, Zheng, You, and co-workers, pioneers in the field, first described scandium triflate-catalyzed direct C6 alkylation of 2,3-disubstituted indoles with aziridines via Friedel–Crafts-type functionalization . Subsequently, Shi and co-workers reported another pioneering study via chemo- and regiospecific C6-alkylation of 2,3-disubstituted indoles using 3-indolylmethanols with organocatalysts .…”

Brønsted acid catalyzed remote C6 functionalization of 2,3-disubstituted indoles with β,γ-unsaturated α-ketoester

“… Simonetti et al (2017) Frost’s group used C3 ester groups with auxiliary coordination orientation and strong coordination orientation of pyrimidine groups on N atoms as the reaction substrate, and achieved selective C-H bond alkylation of indole C6 in Ru catalysis ( Scheme 2C ). ( Leitch et al (2017) Recently, the groups of Zhang ( Zhou et al, 2019 ) ( Scheme 2D ) and Zhou ( Huang et al, 2021 ) ( Scheme 2E ) have independently developed C6-enantioselective C−H functionalization of 2,3-disubstituted indoles via chiral phosphoric acid catalysis. However, the development of efficient methods for the facile access to metal-free and highly selective C6 functionalization of indole in a sustainable fashion under mild conditions is still highly desirable.…”

Chiral-Phosphoric-Acid-Catalyzed C6-Selective Pictet–Spengler Reactions for Construction of Polycyclic Indoles Containing Spiro Quaternary Stereocenters

“…In recent years, the direct C6 functionalization of 2,3disubstituted indoles has been studied by several groups. 11−13 However, the direct asymmetric C6 functionalizations of 2,3disubstituted indoles has remained a challenge and was only realized by Zhang 12 and our group 13 Initially, the model substrate 2-(1H-indol-7-yl)anilines 1 could be conveniently prepared from 7-bromoindoles and (2aminophenyl)boronic acid via Suzuki coupling in good yields.…”

“…In recent years, the direct C6 functionalization of 2,3-disubstituted indoles has been studied by several groups. − However, the direct asymmetric C6 functionalizations of 2,3-disubstituted indoles has remained a challenge and was only realized by Zhang and our group via chiral phosphoric acid catalysis. Very recently, we reported chiral-phosphoric-acid-catalyzed regioselective and enantioselective reactions of 2-(1 H -indolyl)­aniline derivatives and ketones for the synthesis of indole N -alkylated aminals , and C3-alkylated spiro-indolin-2-ones .…”