Asymmetric Synthesis of C2-Quaternary Indolin-3-ones Enabled by N-Heterocyclic Carbene Catalysis

Abstract

An N-heterocyclic carbene (NHC)-catalyzed formal [4 + 2] annulation of 2-aryl-3H-indol-3-ones with α,β-unsaturated carboxylic acids bearing γ-H was developed via an in situ activation strategy. The reaction involves the γ-addition of vinyl enolates to the unique cyclic ketimines to afford chiral tricyclic indolin-3-ones with a quaternary carbon center at 2-position. This protocol provides a rapid and enantioselective pathway to access a novel class of structurally important C2-quaternary indolin-3-ones that might be useful for drug discovery.

Synthesis of N‐Fused Seven‐Membered Indoline‐3‐ones via a Palladium‐Catalyzed One‐Pot Insertion Reaction from 2‐Alkynyl Arylazides and Cyclic β‐Diketones

“…[13b] Basic conditions produce the 2‐phenyl‐3 H ‐indol‐3‐one G via 1,3‐Ts shift of E and further reductive desulfonation of α‐amino sulfone F . Nucleophilic addition of 3a to G afforded the complex H , which resulted in a four‐membered ring complex I after intramolecular addition . Finally, the desired product 4aa was obtained by protonation of complex J , which was generated from the ring expansion of I…”

“…Recently, Fu's group demonstrated a synthetic strategy of imidazo[1,5‐a]indol‐3‐ones by chiral phosphoric acid catalyzed sequential additions of G , aldehydes and diethyl 2‐aminomalonate [Scheme , (1)]. Later, an NHC‐catalyzed [4 + 2] annulation reaction of G with α,β ‐unsaturated carboxylic acids to produce N ‐fused six‐membered indoline‐3‐ones has been developed by Du's group [Scheme , (2)]. In 2012, Lavilla and co‐workers reported a method for the synthesis of dihydropyrimido[1,6‐a]indoline‐3‐ones through multicomponent reaction between dihydropyran, nitrile and G with Sc(OTf) 3 catalysis [Scheme , (3)].…”

Recent advances of N-heterocyclic carbenes in the applications of constructing carbo- and heterocyclic frameworks with potential biological activity

“…Besides, by taking advantage of chiral NHC catalysis cooperated with pyBOP strategy, Du et al reported the [4 + 2] annulation of α,β-unsaturated carboxylic acids 52 bearing γ-H and 2-aryl-3 H -indol-3-ones 51 to afford C2-quaternary indolin-3-ones 53 ( Scheme 13 ). 35 The cycloadducts were obtained in good yields with good to excellent enantioselectivities. A wide variety of substituted 2-aryl-3 H -indol-3-ones and α,β-unsaturated carboxylic acids were well tolerated under the optimized reaction conditions.…”

Regioselective Cross-Coupling of Isatogens with Boronic Acids to Construct 2,2-Disubstituted Indolin-3-one Derivatives

“…2,2-Disubstituted indolin-3-ones are one of the privileged structural units found in natural alkaloids and bioactive molecules, such as aristotelone, (+)-austamide, halichrome A, mitragynine, (−)-trigonoliimine C, and (−)-isatisine A . Consequently, substantial synthetic efforts have been devoted to construct these important molecules. − These methods could be divided into three main strategies: (1) oxidative dearomatization of indoles, (2) cyclization of preprepared substrates, and (3) nucleophilic additions to 3 H -indol-3-ones or indolone- N -oxides . Indolone- N -oxides (also known as isatogens) have important applications in medicinal chemistry, and they can also be used as intermediates to synthesize natural alkaloids or bioactive molecules .…”