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,[7] 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).
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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
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