Combining Indolizines and Isatins via Brønsted-Acid Catalyzed Friedel-Crafts Alkylation in Water

The controlled mono-addition of indolizines to isatins under very mild conditions is described. The reaction occurs in water using diphenylphosphate (DPP) as catalyst and is dramatically accelerated by adding a surfactant (sodium dodecyl sulfate – SDS). Using this methodology, 19 new 3-hydroxy-3-indolizinyl-2-oxindoles scaffolds were synthesized (up to >99% yield). Notably, in organic solvents only bis-addition products were observed, in poor yields and in prolonged times. The very low solubility of the mono-addition product in water was determinant for the observed selectivity .