Our initial investigation of the asymmetric Mannich reaction of indole 2a with phenyl α-amidosulfone 3a is summarized in Table 1. The effect of catalyst structure on the reaction outcome was first investigated at 10 mol% catalyst loading in toluene (Table 1, Entries 1–5). As we expected, based on our knowledge of the catalytic performance of chiral oligoEG 1, the ether chain length (Entries 1–3) as well as suitable acidity of the phenolic protons (Entry 2 vs. Entries 4 and 5) are critical for the catalytic performance in this reaction. Consistently, catalyst 1b bearing iodine atom at the 3 and 3′ positions of the binaphthyl scaffold showed the best results in terms of catalytic activity (70% yield) and enantioselectivity (98% ee) (Entry 2, Table 1). In further experiments using (R)-1b as the optimal catalyst, different solvents were examined (Entries 6–10). In general, excellent enantioselectivity was obtained in all the solvents tested in this study. Among them, m-xylene proved to be the best in terms of yield (75%) and asymmetric induction (99% ee) (Entries 8–10). Further improvement of the yield was achieved by increasing the equivalents of indole (83% yield and 99% ee, Entry 11).
Table 1. Optimization of the BINOL-based polyether catalyzed asymmetric Friedel-Crafts (FC) reactions of indole [a]
Entry Catalyst Indole 2a (equiv.) Solvent Yield (%)[b] ee (%)[c]
1 (R)-1a 1.0 Toluene 68 61
2 (R)-1b 1.0 Toluene 70 98
3 (R)-1c 1.0 Toluene 59 80
4 (R)-1d 1.0 Toluene 24…