Enantioselective Friedel-Crafts Reaction of Indoles with N-Tosylimines Employing Takemoto's Organocatalyst

Abstract

The asymmetric Friedel-Crafts reaction of indoles with imines provides a direct approach for the enantioselective construction of 3-indolyl methanamine derivatives. In this paper, a series of thiourea/ urea-tertiary amine derivatives have been used to catalyze the asymmetric F-C reaction of indoles with N-tosylimines. The effect of solvent, temperature and catalyst loading amount were investigated. the optimized conditions were determined to be toluene as the solvent with a 5 mol% loading of Takemoto's catalyst 1c at rt. A wide range of substituted indoles and imines were evaluated to explore the scope and general applicability of this reaction. The enantioselectivities were obviously affected by the position of the substituents on the phenyl ring of imines. 4- electron-donating substituted imines appeared to favor higher enantioselectivities. Moreover, indoles containing either electron-donating groups or electron-withdrawing groups were then investigated for the reaction with imines. In all cases, high yields and excellent enantioselectivities could be achieved. Of all the different substrates, the reaction of the 5-OMe substituted indole with 4-chloride substituted imine afforded an optimal yield and enantiomeric excess. Under the screened optimal condition, optically active 3-indolyl-methanamines were obtained in good yields (70-90%) with high enantioselectivities (up to 98%ee). The catalyst type and the substrate scope were broadened in this methodology.