The Highly Enantioselective Friedel-Crafts Reaction Of Isatins-derived N-Boc Imines Catalysed By Chiral Phosphoric Acid

Chiral 3-amino-2-oxindoles are important structural motifs in many natural products and biologically active compounds, so the synthesis of compounds bearing these motifs is very significant. The asymmetric addition reaction of imine is a very effective method to synthesis many amino compound, and the synthesis of imines derived from isatins is a challenging work. In order to construct these 3-amino-2-oxindole motifs, we have overcomed the synthetical method of isatins-derived N-Boc imines.In view of the following reasons, we developed an aza-Friedel-Crafts reaction of N-methylindole to these isatins-derived N-Boc imines. Firstly, aza-Friedel-Crafts reaction is a impactful method for formation of C-C bonds. Secondly, bisindolyl scaffold is also a popular structure in many drug compoud and natural products. Finally, several valid catalytic systems have been developed for the research of asymmetric aza-Friedel-Crafts reaction was very prevalent. Compared with the catalytic effect between metal chiral bisoxazoline complexes and chiral phosphoric acid, we chose chiral BINOL derived phosphoric acid as catalyst, and high yields and excellent enantioselectivities were obtained. Then we researched the asymmetric addition of pyrrole and 4,7-dihydroindole to these imines in the same catalytic system. The enantioselectivities and yield up to 99% ee were observed with 1 mol% phosphoric acid in moderate temperature.Moreover, we also researched the addition of N-methylindole to 3-N-phenyliminoisatin, but a bisindoly product was generated, and no quaternary 3-amino-2-oxoindole was observed, then a possible reaction mechanism was proposed.