Efficient 1,6-addition reactions of 3-substituted oxindoles: Access to isoxazole-fused 3,3′-disubstituted oxindole scaffolds and hexahydro-1h-pyrido[2,3-b]indol-2-one scaffolds

ABSTRACT

Developed herein is a new methodology for a hybrid of two pharmacophoric oxindole and isoxazole motifs to construct isoxazole-fused 3,3′-disubstituted oxindole scaffolds via an efficient 1,6-addition reaction of 3-substituted oxindoles to 3-methyl-4-nitro-5-alkenylisoxazoles, which might generate novel drug-like molecules for biological screenings. The method gives an easy access to a series of isoxazole-fused 3,3′-disubstituted oxindoles with 26 examples in high yields (up to 92% yield) and good diastereoselectivity (up to >20:1), which makes possible the synthesis of libraries under similar circumstances. Subsequently, a sequential Michael addition/amidation/reductive cyclization process was designed for accessing this hexahydro-1H-pyrido[2,3-b]indol-2-one scaffold, which is a key structural skeleton found in a large number of biologically active natural products and pharmaceutical compounds. Hexahydro-1H-pyrido[2,3-b]indol-2-one scaffold 7cg could be obtained in 42.5% overall yield after 4 steps.

GRAPHICAL ABSTRACT

KEYWORDS:

• 1,6-Addition reactions
• 3-methyl-4-nitro-5-alkenylisoxazoles
• hexahydro-1h-pyrido[2,3-b]indol-2-one scaffolds
• isoxazole-fused 3,3′-disubstituted oxindole scaffolds

Supplementary Information

CCDC 1569850, 1569851 and 1574678 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Additional information

Funding

We are grateful for the financial support from the National Natural Science Foundations of China (No. 81560563, No. 81660576 and No. 81760625); Excellent creative talents of guizhou province (Qian Jiao He KY Zi [(2015)491] and Qian Ke He Zi [2015]4032, [2017]5609); Project of Guizhou province (Qian Ke He Zi ([2016]5623 and [2015]4010); Innovation Fund for graduate students of Guizhou University (2017027) and Major project of the graduate student education teaching reform (Qian Jiao Yan He JG Zi)[2016]06.