Organocatalyzed Asymmetric Friedel-Crafts Alkylation in the Carbocyclic Ring of Indole

The indole scaffolds are privileged skeletons widely found in many bioactive natural products pharmaceuticals, and material molecules. Indoles show a high nucleophilic reactivity in the azole ring, which preferentially reacts With elecirOrththe aromatic substitution at the C3 position. However, the methods for the enantioselective functionalization of the indole benzene ring are scarce. When hydroxylindoles as nucleophiles have been used in the Friedel-Crafts reaction, the regioseleetive hydroxyalkylation happens in the indole cathocyclic ring due to the advantage of the directing and activating properties of the OH group. Furthermore, the four regioisomeric hydroxylindoles lead to functionalize regioselective every position of the indole benzene ring. In this paper, Cinchona alkaloid derivatives were used to organocatalyze the enantioselective Friedel-Crafts reaction of hydroxylindoles with isatins. The effect of solvent, temperature and catalyst loading were investigated. The optimized conditions were determined to be tetrahydrofuran (THF) as the solvent with a 5%(molar fraction) loading of catalyst 1b at 0 degrees C. The four regioisorneric hydroxylindoles (4-OH, 5-OH, 6-OH and 7-OH indoles) and the different substituted isatins were evaluated to explore the scope and general applicability of this reaction. The resulting products were obtained in good yields (67%-91%) with up to 97% epsilon.epsilon. and excellent regioselectivities (>15 : 1). The enantioselectivities were obviously affected by the position of hydroxyl group. When 4-OH indoles as nucleophiles reacted with 12 isatins, the main C5 substituted products were achieved with moderate to excellent stereoselectivities. The most reaction of 5-OH. indoles got the main product of C4 position substitution with more than 80% e.e.. When 6-OH and 7-OH indoles reacted with isatins, the excellent regioselectivities Were observed. Only C5 substituted products With 88%-93% e. e. were obtained in the reaction of 6-OH indoles, and only C6 substituted products With middle enantioselectivities (72%-78%) were achieved with 7-OH indoles as nucleophiles. The catalyst type and the substrate scope were broadened in this methodology.

Automated summary

In this study, Cinchona alkaloid derivatives were used to catalyze the Friedel-Crafts reaction of hydroxylindoles with isatins, resulting in high yields and excellent regio- and enantioselectivities.