Table 1. Screening of the reaction conditions.[a]
tioselectivity (Table 1, entry 15 vs. entry 7). Therefore, the
optimal conditions were found to be the use of 10 mol% of
catalyst G in toluene at room temperature.
Based on the established optimal reaction conditions, we
explored the scope of the cascade aza-Michael–Michael
process by using a variety of ortho-amino-substituted a,b-
unsaturated ketones and nitroalkenes in toluene at room
temperature (Table 2). In most cases, it was found that the
reactions provided the corresponding products with excel-
lent yields and enantioselectivities. R1 groups containing a
variety of substituents on the aromatic ring, including elec-
tron-donating (Table 2, entries 2–5) and electron-withdraw-
ing (Table 2, entries 6–9) groups could efficiently participate
in this reaction. However, the reaction proceeded faster
with substrates containing electron-donating substituents
than with those containing electron-withdrawing substitu-
ents (Table 2, entries 2 to 5 vs. entries 6 to 9). This observa-
tion could be attributed to the higher nucleophilic activity
of aromatic amines containing a,b-unsaturated ketones with
electron-donating substituents than those with electron-
withdrawing substituents. A heteroaromatic group could
also be employed to provide the product with excellent
enantioselectivity (Table 2, entry 10). Furthermore, substi-
tuted anilines were also suitable for this cascade process
(Table 2, entries 11–13). In this cascade reaction, diaster-
eomers formed from ortho-halogen-substituted nitroalkenes
could be isolated by flash column chromatography (Table 2,
entries 1–17, 19, and 20), but diastereomers formed from
other types of nitroalkene, including meta- and para-halo-
gen-substituted nitroalkenes and ortho-substituted, nonhalo-
genated nitroalkenes only show one spot in TLC, which
means that they could not be isolated by column chromatog-
raphy (Table 2, entry 18). Noticeably, aliphatic a,b-unsatu-
rated ketones proceeded smoothly to provide the desired
products in good yields, albeit with moderate enantioselec-
tivities (Table 2, entries 19 and 20). Furthermore, the reac-
tion of a nitroalkene containing an alkyl group, such as cy-
clohexyl, gives the corresponding product with high yield
and excellent enantioselectivity (Table 2, entry 21).
Entry
Catalyst
Solvent
Time
[h][b]
Yield
[%][c]
d.r.[d]
ee
[%][e]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15[f]
A
B
C
D
E
F
G
H
G
G
G
G
G
G
G
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Et2O
xylene
CH2Cl2
THF
CHCl3
CH3CN
toluene
72
72
18
96
96
72
48
48
48
48
60
84
60
72
60
95
95
94
88
80
96
96
93
94
87
90
74
92
86
93
67:33
67:33
80:20
50:50
67:33
75:25
83:17
83:17
80:20
67:33
67:33
67:33
67:33
50:50
83:17
95
96
75
77
67
96
98
98
94
90
82
81
79
86
98
[a] Unless otherwise specified, all reactions were carried out with 1a
(0.1 mmol), 2a (0.12 mmol), and the organocatalyst (20 mol%) in the in-
dicated solvent (1.0 mL) at room temperature. [b] Reaction time was de-
termined by TLC. [c] Combined yields of the diastereomers after flash
column chromatography. [d] Determined by 1H NMR analysis of the
crude products. [e] Refers to major compound 3a; determined by chiral-
phase HPLC analysis (AD-H column). [f] The reaction was carried out
with 10 mol% catalyst.
To determine the absolute configuration of the cascade
reaction product, the X-ray crystal structure of compound
3o, containing a bromine atom, was obtained (Figure 1).[9]
As shown in Figure 1, the newly formed stereogenic centers
in 3o were confirmed to be 2R,3S,4R. Similarly, the absolute
several catalysts were screened for this reaction (Table 1, en-
tries 2–8). It was found that all of these catalysts catalyzed
the reaction to provide the desired product. Among these
catalysts, chiral bifunctional tertiary amine thioureas G and
H gave the best diastereoselectivity (d.r. 83:17) and enantio-
selectivity (98% ee). We then studied the effect of the sol-
vent on the reaction and tested a variety of polar and non-
polar solvents (Table 1, entries 9–14). In summary, the reac-
tions in less polar solvents, such as toluene, CH2Cl2, Et2O,
and THF, generally proceeded with relatively high yield and
enantioselectivity. If the catalyst loading was further reduced
from 20 to 10 mol%, it did not influence the yield or enan-
Figure 1. The X-ray crystal structure of the compound 3o.
&
2
&
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!