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 III , and Y III complexes) capable of activating 1,2-dicarbonyl 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 5-bromo-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.

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

The indium(III)-catalyzed enantioselective and regioselective addition of pyrroles to isatins is described. The effects of metal and solvent on the reactivity and selectivity are compared and discussed, demonstrating that the indium(III)-indapybox complex provides the most effective catalyst. A case of divergent reactivity between pyrroles and indoles is presented.

Catalytic Asymmetric Synthesis of Substituted 3-Hydroxy-2-oxindoles. -Chiral scandium(III) and indium(III) complexes successfully catalyze the direct asymmetric addition of indoles and electron-rich arenes to isatins. The competing double-addition pathway is suppressed. This operationally simple method does not require the use of activated arenes or transmetalation conditions. - (HANHAN, N. V.; SAHIN

Enantioselective and Regioselective Indium(III)-Catalyzed Addition of Pyrroles to Isatins. -The reaction requires an excess of pyrrole to provide the addition products with high yields and enantioselectivities. No reaction takes place for the 4-chloroisatin (Ic) although the product is obtained enantioselectively when indole (IV) is used instead of the pyrrole [cf. (V)]. For a pyrrole with 2-substitution, the conditions can control whether a mono-[cf. (XI)] or dipyrrolyloxindole (XII) is formed. -(GUTIERREZ, E. G.; WONG, C. J.; SAHIN, A. H.; FRANZ*, A. K.; Org. Lett. 13 (2011) 21, 5754-5757, http://dx.doi.org/10.1021/ol202329s ; Dep. Chem., Univ. Calif., Davis, CA 95616, USA; Eng.) -R. Steudel