Asymmetric Electrophilic α-cyanation Reaction Of 3-phenyloxindole

Organic cyanide, also known as nitrile, is widely applied in biology, pharmaceuticals, pesticides, daily chemical articles, new materials, etc, and can be transformed into other compounds, thus it is widely used in the synthesis of chemical products such as food additives, medicine and its intermediate, dyes. The synthesis of nitrile by nucleophilic reaction is mature, while there are a few examples on the synthesis of nitrile by electrophilic reactions. So far there is only one report on the catalytic asymmetric electrophilic cyanation reaction. Therefore, the synthesis of new nitrile not only has important methodological significance, but also has potential applications on pharmaceuticals.Oxindole, an important heterocyclic compound, is the functional moiety of many natural products and pharmaceutical molecules. And chiral oxindoles bearing C-3 chiral carbon centers possess vital bioactivity and drug activities. Thus catalytic asymmetric syntheses of oxindoles bearing 3, 3-disubstituted chiral carbon stereocenters have attracted many focus in recent years.This research synthesized a novel cyano oxindole structure with chiral quaternary carbon center by asymmetric electrophilic α-cyanation reaction for the first time. Adopting 3-phenyloxindole as the substrate and cationic cyanide as the source of cyano group, this research explored alkaloid and chiral Lewis acid catalyst system, and finally established thiophene dicarboxylic acid cuprous(CuTc) and chiral oxazoline complex as Lewis acid catalyst system. The catalyst efficiency was optimized by structure of catalyst, nature of Lewis acid, the property of cyano reagents and reaction parameters.The optimal reaction conditions are: in situ generated catalyst from CuTc(5 mol%) and chiral oxazoline ligand Box-1(6 mol%) for 2 h in CH2Cl2 at r.t., 4-acetylphenyl cyanate(2.0 equiv) and 3-phenyloxindole(0.25 M) in CH2Cl2 at 0 ?C for 1 d. Under these optimal conditions, the desired product was obtained in 31% yield and 50% ee. Besides, during optimization process, the highest enantioselectivity was approached to 54% ee.