Catalytic Asymmetric Synthesis of Substituted 3‐Hydroxy‐2‐Oxindoles

Abstract

Substituted 3-hydroxy-2-oxindoles are important core structures found in many natural products [1] and pharmaceutical lead compounds. [2] Despite the prevalence of bioactive oxindole structures, there is not currently a general asymmetric method for the addition of a broad range of unactivated electron-rich p nucleophiles to isatins (indole-2,3-diones). [3, 4] Although the development of an asymmetric reaction is the primary challenge, the addition of electron-rich arenes is further complicated by the competing formation of achiral 3,3-diaryl oxindole products (such as B, Scheme 1). [5,6] Herein, we compare the activity and selectivity of diverse Lewis acid catalysts and show that chiral scandium(III) and indium(III) complexes offer a general method to control both the reactivity of the direct monoaddition of indole and arene nucleophiles to isatins and the absolute configuration of the product. Reactions involving catalytic asymmetric addition to isatins have been reported previously; however, this direct method is the first catalytic asymmetric addition of indole nucleophiles to an isatin.We examined a series of Lewis acid catalysts (Pd II , Cu II , In III , Sc III , La III , and Y III complexes) capable of activating 1,2dicarbonyl electrophiles to classify the effects of the metal, ligand, and temperature for addition reactions of nucleophiles to isatins. We used the addition of N-methylindole (2) to 5bromo-N-methylisatin (1 a) as a model reaction and evaluated three criteria: reactivity, selectivity for the monoaddition product 3, and enantioselectivity (Table 1). Metal complexes with slower reaction rates were observed to be active for the addition reaction with limited (or no) formation of the 3,3'bisindolyl product 4; however, both the use of a low temperature and the presence of a chiral ligand also promoted the Scheme 1. Competing formation of monoaddition (A) and doubleaddition (B) oxindole products in the Lewis acid catalyzed addition of nucleophiles to isatin. TMS = trimethylsilyl. Table 1: Metal and ligand effects for the addition of N-methylindole. [a] M(OTf) n Ligand T [8C] t [h] Yield [%] [b] ee [%] [c] 3 a 4

Catalytic Stereoselective Synthesis of Diverse Oxindoles and Spirooxindoles from Isatins

“…8 The strategy we envisioned utilizes a common set of N -propargylated isatins 3 to access diverse oxindole scaffolds through a series of mechanistically-distinct nucleophilic addition pathways. Each resulting oxindole scaffold contains an alkyne group that provides further opportunities for structural diversification with triazole heterocycles using the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction.…”

A catalytic, mild and efficient protocol for the C-3 aerial hydroxylation of oxindoles

“…11 Also of note are the recent reports by Franz, 12 who has reported the asymmetric direct addition of nucleophiles to isatins using chiral Lewis acids, and Shibata and Toru who have reported the asymmetric C-3 hydroxylation of oxindoles also using chiral Lewis acids, with an oxaziridine as the stoicheiometric oxidant. 13 Thus owing to the significance of the oxindole structural motif, the development of catalytic methods for the synthesis of oxindoles bearing a C-3 hydroxy quaternary centre is highly desirable.…”

Asymmetric Addition of Indoles to Isatins Catalysed by Bifunctional Modified Cinchona Alkaloid Catalysts

“…[14] In conclusion, we have developed the first highly enantioselective organocatalytic Friedel-Crafts-type addition of indole to isatin. It is important to note that this new catalytic asymmetric reaction can be used for substituted isatin and indole derivatives under ambient conditions.…”

“…[13] During the preparation of this manuscript, a metal-complex-catalysed reaction of isatin with indole was reported by Franz and co-workers. [14] Herein, we report the first asymmetric organocatalytic reaction of isatin derivatives with indole for procuring optically active 3-(indolyl)hydroxyoxindole derivatives.…”