Scheme 1. Synthetic Route to Substrates 1
Screening of various solvents revealed that less polar
aromatic solvents were the most effective for giving 2a
with high enantioselectivity and an acceptable yield
(Table 1, entries 6À9). The fact that the reaction in a protic
solvent resulted in poor yield and enantioselectivity implies
the crucial role of hydrogen bonding in the catalysis mode
of this reaction (Table 1, entry 5). As a longer reaction time
led to lower enantioselectivity, which was likely due to the
competing noncatalytic reaction (Table 1, entry 10), 10 mol %
3a was employed to improve the yield (Table 1, entry 11). On
decreasing the reaction temperature to 0 °C, the yield was
considerably reduced, albeit with a slight increase in the
enantioselectivity (Table 1, entry 12). The use of urea catalyst
3b instead of thiourea catalyst 3a largely improved both the
yield and enantioselectivity (Table 1, entry 13). Substrates
with other protecting groups (1b, 1c) gave poorer results
(Table 1, entries 14 and 15). Furthermore, the screening of
urea catalysts showed that quinine-derived 3d was an efficient
catalyst for obtaining the opposite enantiomer of 2a with
good enantioselectivity (Table 1, entry 17).14
Figure 1. Representative indoline derivatives in natural products.
hetero-Michael addition.9 This methodology utilizes mul-
tipoint recognition by bifunctional aminothiourea cata-
lysts through hydrogen bonding.10,11 Thus, we attempted
to use this efficient cyclization approach in order to devel-
op a novel asymmetric intramolecular aza-Michael addi-
tion reaction for generating a variety of 2-substituted
indolines.12 The potential versatility of this type of cata-
lysis, utilizing noncovalent interactions, was demonstrated
using a range of different substrates.
The starting materials 1 were prepared through the
synthetic route indicated in Scheme 1.13 The investigation
was initiated using substrate 1a with 5 mol % quinidine-
derived bifunctional thiourea catalyst 3a in cyclopentyl
methyl ether (CPME) at 25 °C, and indoline product 2a
was obtained enantioselectively (Table 1, entry 1).
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could be successfully applied to was explored using the
optimized conditions (Table 2). Although urea catalyst 3b
exhibited low reactivity for an electron-rich enone, thiourea
catalyst 3a proved to be more suitable in this case for
improving the yield while giving a similarly good enantiomeric
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