Organic Letters
Letter
a
Scheme 3. Scope of Reactions
Scheme 4. Gram-Scale Preparation and Synthetic Utility of
3a
Having established an optimal protocol for this reaction
(Table 1, entry 10), we then examined the substrate generality
(Scheme 3). First, a number of 2-(1-alkynyl)-2-alken-1-ones 1
were investigated by reacting with 2a. For the alkynyl moiety in
substrate 1, both electron-rich and electron-deficient sub-
stituted aromatic rings were accommodated, resulting in the
anticipated products 3a−i in good yields with excellent ee
values. When aliphatic substituents such as n-butyl and
cyclopropyl were incorporated, perhaps due to the low
reactivity, a higher temperature (60 °C) had to be applied to
achieve the full consumption of the starting materials
(products 3j,k). The ring size of substrate 1 can be modified.
Under the standard reaction conditions, cyclopentenone- and
cycloheptenone-derived 2-(1-alkynyl)-2-alken-1-ones fur-
nished the corresponding 1,4-DHPs 3l and 3m in 57% yield
with 92% ee and in 57% yield with 83% ee, respectively. Next,
a series of 3-aminobenzofurans 2 were surveyed by reacting
with 1a. The use of 5-Me-, 5-OMe-, and 6-Me-substituted
benzofurans in the reaction all proceeded smoothly, producing
the desired products 3n−p in good yields with excellent
enantioselectivities. Halogen substituents (5-Cl, 5-Br, 6-F, and
6-Cl), which can be utilized for further derivatizations, were
well tolerated in this reaction, as products 3q−t were
successfully obtained. The protecting group on the amine
part was also probed. An electron-donating group such as a 4-
OMe-substituted reactant gave product 3u with similar ee, but
when an electron-withdrawing group such as 4-NO2 was
employed, the ee value of product 3v dropped to 90%.
a
Reaction conditions unless otherwise specified: 1 (0.1 mmol), 2
(0.12 mmol), D (0.02 mmol), and toluene (1 mL) at 40 °C under a
b
nitrogen atmosphere for 72 h. Isolated yields based on 1. These
reactions were carried out at 60 °C for 72 h.
To figure out the stereochemistry of the C4 position in the
major enantiomer of compound 3o, a single crystal was grown
and tested. The X-ray crystallographic analysis of this crystal
unequivocally confirmed that the absolute configuration of the
newly formed stereocenter was S (Figure 2). The config-
urations of other chiral 1,4-DHPs were assigned on the
assumption of a uniform mechanistic pathway.
The practicability of this formal [3 + 3] annulation reaction
was displayed by gram-scale synthesis and further elaboration
of 1,4-DHP 3a. Under the optimal reaction conditions, simple
amplification of the model reaction to the 3 mmol scale
straightforwardly produced >1 g of 3a without losing efficiency
(Scheme 4, top). In the presence of a catalytic amount of
sulfuric acid, 3a directly underwent Fischer indole synthesis
with phenylhydrazine to provide hexacyclic compound 4
(Scheme 4, bottom, left). The tosyl group was removed by
treating 3a with sodium hydroxide under reflux conditions to
Figure 2. ORTEP diagram of 3o (ellipsoid contour at 30%
probability).
proven to be compatible with the current reaction, as they all
smoothly delivered the corresponding product 3a (entries 5−
9). Among them, toluene showed the highest efficiency by
forming 3a in 65% yield with 95% ee. Moreover, with D as the
catalyst and toluene as the solvent, we also evaluated the
temperature influence. When the model reaction was
performed at 40 °C, the yield of 3a was enhanced to 77%
without a loss of enantioselectivity (entry 10), but when the
temperature was further lowered to 25 °C, a slight drop in
yield was observed (entry 11). Finally, the use of cinchonine-
derived thiourea catalyst E14 furnished 3a in 68% yield with
−93% ee, indicating that in the current reaction, both of the
enantiomeric series of the products were accessible (entry 12).
6393
Org. Lett. 2021, 23, 6391−6395
Li, Zhanhuan
