Asymmetric Friedel-Crafts Alkylations Of Indoles With Ethyl Glyoxylate Catalyzed By Lewis Acid

Friedel-Crafts alkylation reactions have been recognized as one of the most fundamental C-C bond-forming reactions in organic synthesis. Among the aromatic systems suitable for Friedel-Crafts alkylations, indole has received much attention because of its widespread applications in material science, agrochemicals, and Pharmaceuticals. Furthermore, regioselective Friedel-Crafts alkylation at the 3-position of indoles represents one of the most straightforward methods for the synthesis of many naturally occurring alkaloids. In this context, we document the Friedel-Crafts alkylations of a variety of indoles with ethyl glyoxylate.I. Lewis acid catalyzed-Friedel-Crafts alkylations of indoles with ethyl glyoxylate have been successfully carried out with the use of chiral (S)-BINOL-Ti (IV) complex(10 mol%). Under optimal conditions, the corresponding optically active ethyl 3-indolyl-hydroxyacetate, an important building block for organic synthesis, was formed in good yields(up to 88%) and with high enantiomeric excess (up to 96%).II. The absolute configuration of the products was determined by X-ray crystallography. A possible reaction mechanism was proposed.III. It was found that HOAc could be used as a catalyst in the Friedel-Crafts alkylations of indoles with ethyl glyoxylate in Et₂O at 0°C. An attempt to carry out the organocatalytic asymmetric version of this reaction has also been examined.All target compounds were characterized by ¹H NMR, ¹³C NMR, MS and element analysis.