Organic Letters
Letter
a
Given the limited types of synthetic blocks, we considered
that invention of a stable building block could provide an
attractive method, easy to implement, for accessing enantioen-
riched difluoromethyl group-bearing compounds, particularly if
it would facilitate the preparation of a wide array of molecular
Table 1. Screening of Reaction Conditions
architectures containing the CF H groups. Herein, we first
2
reported a building block based on O’Donnell Schiff bases,
condensed by thioisatin and difluoroethylamine, which is an
active methylene compound prone to alkylation with electro-
philes. The block would provide a new, potentially powerful
avenue for the enantioselective synthesis of desired compounds
bearing γ-nitro-β,β-difluoroethylamine units that could be
extended to a series of derivatives possessing useful functional
handles such as α-difluoromethyl amines, β-amino acids, and
β-diamines when nitroalkene derivatives were chosen as
another candidate substrate.
b
c
d
entry catalyst
solvent
time (h) yield (%)
dr
ee (%)
1
2
3
4
5
6
7
8
C1
C2
C3
C4
C5
C6
C7
C8
C5
C5
C5
C5
C5
C5
C5
C5
C5
C5
C5
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
6
6
6
6
4
4
4
4
85
88
66
80
88
68
77
61
96
93
nr
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
−
92
−84
−88
93
98
−97
−96
94
94
87
−
−
88
89
97
97
97
97
In the past several decades, bifunctional organocatalysts
derived from cinchona alkaloids have shown versatile ability in
asymmetric alkylation of O’Donnell Schiff base deriva-
9
5
6.5
24
10
11
12
13
EA
DCM
3
7−40
tives.
Hence, initial evaluation of the proposed alkylation
MeOH
acetone
acetonitrile
toluene
toluene
toluene
toluene
toluene
24
24
48
6
8
4
nr
−
85
68
82
69
89
69
trace
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
−
14
15
16
17
18
19
e
f
g
h
i
6
9
−
a
Reaction conditions: N-2,2-difluoroethylthioisatin ketimines 1 (0.10
mmol), β-nitrostyrenes 2a (0.15 mmol), catalyst (10 mol %), solvent
1 mL), room temperature. Isolated yield. Determined by chiral
HPLC analysis or H NMR. Determined by chiral phase HPLC
analysis. At 0 °C. At −10 °C. At 35 °C. With 5 mol % catalyst.
b
c
(
1
d
e
f
g
h
i
With 1 mol % catalyst.
with a slight increase or decrease in yield (Table 1, entries 15−
1
7). In addition, an impressive decrease in yields is seen in
Table 1 when a range of lower catalyst loadings were used
Table 1, entries 18 and 19). Under 1% catalyst loading, only
(
Figure 1. Structures of the catalysts.
traces of products were observed (Table 1, entry 19).
The scope of the reaction was investigated (Scheme 1)
under the optimal conditions (Table 1, entry 5) using a wide
range of β-nitrostyrenes possessing halo substituents such as F
(3d, 3f, and 3j), Cl (3c and 3k), and Br (3d, 3g, and 3l) or
alkyl substituents such as OMe (3e, 3h, and 3m) and Me (3n)
on phenyl moieties. Notably, the enantioselectivity of the
asymmetric alkylation process was not influenced by the
electronic effect of the substituents, whereas the reactivities of
2-substituted nitrostyrenes were significantly reduced com-
pared with those of 3- or 4-substituted substituents. This fact
shows that greater steric hindrance might exist when the ortho-
substituted nitroalkenes combined with N-2,2-difluoroethylth-
ioisatin ketimines, and the increase in the reaction energy
barrier resulted in a lower reaction conversion rate. To
determine the absolute configuration of our products, we grew
crystals of compound 3l and subjected them to X-ray
crystallographic analysis (Scheme 1). Regardless, substrates
with strong coordination abilities, such as those with a
trifluoromethyl (3i and 3o) and double halogen atoms (3p
and 3q) on phenyl moieties, still underwent the asymmetric
addition to afford the desired products in good yields and
enantioselectivities. Only when the hydroxyl group was
introduced at the ortho position of the benzene ring did the
yield decrease sharply to 46%.
as the precatalyst and (E)-(2-nitrovinyl)benzene 2a as the
acceptor in toluene at room temperature. Gratifyingly, the
desired product 3a was obtained in 85% yield and 92% ee
(Table 1, entry 1). Further extensive evaluation of different
cinchona-based thiourea and squaramide [C2−C8 (Figure 1)]
provided pretty good yields and enantioselectivity (Table 1,
entries 2−8), and quinine-derived squaramide C5 proved to be
the best (Table 1, entry 5).
The influence of solvents and temperature then was studied,
showing that the enantioselectivity and yields of reactions were
extremely dependent on the solvents used while the ee value of
the products was almost unaffected by temperature. The best
results were obtained in toluene, furnishing stereoisomer 3a in
8
8% yield and 98% ee (Table 1, entry 5). Solvents such as
tetrahydrofuran and ethyl acetate led to good performance in
terms of yields and ee values (Table 1, entries 9 and 10,
respectively). Remarkably, no product was observed in the
polar solvent dichloromethane and the protic solvent methanol
(Table 1, entries 11 and 12, respectively). In the dipolar
solvents acetone and acetonitrile, moderate yields and ee
values were obtained (Table 1, entries 13 and 14, respectively).
In contrast, the reaction enantioselectivity and diastereose-
lectivity remained excellent at different temperatures albeit
2
585
Org. Lett. 2021, 23, 2584−2589
Gao, Fengyun
