L. M. Lutete et al. / Tetrahedron Letters 57 (2016) 1220–1223
1221
N
aromatic nucleophiles (Table 4). The reaction with ketones bearing
–NO2 and –CF3 groups on the aromatic ring afforded excellent
yields with moderate enantiomeric excess (entries 1 and 2). The
observed shorter time, compared to that of the reaction with ace-
tophenone (Table 3, entry 1), may be attributed to the higher reac-
N
CF3
CF3
MeO
S
MeO
S
H
H
N
N
N
H
N
H
CF3
N
H
N
H
CF3
4a
4b
tivity due to the increased acidity of the
a proton. On the other
hand, when ketones bearing electron rich aromatic rings were used
as nucleophiles the corresponding products were obtained in good
to excellent yields with good enantioselectivity (entries 3–5). It is
noteworthy that, while electron deficient ketones favored the reac-
tion rate, the highest levels of enantiomeric excess were achieved
when electron rich donors were used (entries 1 and 2 vs. 3–5). Sim-
ilarly, 3l was obtained in excellent yield albeit with a lower enan-
tiomeric excess, perhaps due to the relatively small size of the furyl
group (entry 6).
CF3
CF3
S
S
N
N
CF3
N
H
N
H
CF3
H
H
N
N
4c
4d
CF3
CF3
S
Ph
S
The S configuration of the products was determined by compar-
ison of the optical rotation of 3d with that reported in the
literature.7b
Ph
N
H
N
H
CF3
N
H
N
H
CF3
N
N
4e
4f
Recent investigations on amino thiourea catalysis carried out by
various research groups have shown that the dual activation of the
nucleophile and the electrophile may take place via different path-
ways.11 Based on the insights provided by these studies, three pos-
sible transition states are proposed to account for the reactivity
and enantioselectivity observed in the present reaction (Fig. 2).
In A, the generally accepted Takemoto model, acetophenone is acti-
vated by the tertiary amine in the catalyst skeleton via deprotona-
tion and subsequent hydrogen bonding of the resulting enolate
with the protonated amine. Besides, the thiourea moiety forms
two hydrogen bonds with the carbonyl group of 2,2,2-trifluoroace-
tophenone.12 These hydrogen bonds activate the electrophile and
direct its position during the nucleophilic approach. The re attack
is preferred since the interaction of the aromatic ring of 2,2,2-tri-
fluoroacetophenone with the enolate is avoided and leads to the
formation of the major S enantiomer. In B, the Papai model, an
opposite coordination pattern is displayed in which the thiourea
binds and activates the nucleophile while the protonated amine
activates the electrophile and directs its position. Finally, in C,
the Wang model, the deprotonated nucleophile is engaged in two
hydrogen bond interactions involving the protonated amine and
the proximal thiourea N–H while the distal thiourea N–H activates
the electrophile.
Bn
Bn
O
O
S
N
N
N
H
H
N
4g
Figure 1. Bifunctional catalysts employed in this study.
the highest levels of chemical yield and enantiomeric excess (entry
6).
The optimized conditions were then extended to other sub-
strates.10 First, acetophenone as the nucleophile was reacted with
a variety of aromatic electrophiles (Table 3). Ketones having elec-
tron withdrawing groups on the aromatic rings afforded the aldol
products in good to excellent yields with good enantiomeric excess
(Table 3, entries 1–3). Low chemical yields were obtained when
electrophiles with electron rich aromatic rings were used (entries
5 and 6). The somewhat lower enantiomeric excess of 3f may be
attributed to the relatively small size of the thienyl group. From
these results it appears that electron deficient acceptors facilitate
the reaction while this electronic effect has no significant impact
on the enantioselectivity. Next, 30,50-dichloro-2,2,2-trifluoroace-
tophenone as the electrophile was treated with a variety of
Table 2
Screening of solvents for the reaction of acetophenone with 30,50-dichloro-2,2,2-
trifluoroacetophenonea
Table 1
Screening of catalysts for the asymmetric addition of acetophenone to 30,50-dichloro-
2,2,2-trifluoroacetophenonea
Cl
Cl
Cl
Cl
4c (20 mol%)
solvent, 25䰳
F3C
+
4a - 4g (20 mol%)
toluene, 25
Cl
Cl
F3C
+
F C
3a
Cl
O
3
OH
Cl
O
O
䰳
F C
OH
3a
O
3
O
O
Entry
Solvent
Toluene
Chlorobenzene
THF
CPME
Diisopropyl ether
n-Bu2O
MTBE
DMSO
CHCl3
n-BuCl
Yieldb (%)
eec (%)
Entry
Catalyst
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
90
90
71
85
83
96
84
54
78
92
76
73
66
74
74
76
73
22
73
70
1
2
3
4
5
6
7
8
None
4a
4b
4c
4d
4e
4f
0
29
64
90
55
44
38
61
—
62
ꢀ70
76
68
54
63
4g
49
a
Reaction conditions: acetophenone (1.0 mmol), 30,50-dichloro-2,2,2-trifluo-
roacetophenone (1.0 mmol), catalyst (0.2 mmol) and toluene (1.0 mL) at 25 °C for
a
Reaction conditions: acetophenone (1.0 mmol), 30,50-dichloro-2,2,2-trifluo-
48 h.
roacetophenone (1.0 mmol), 4c (0.2 mmol) and a solvent (1.0 mL) at 25 °C for 48 h.
b
b
Isolated yield.
Isolated yield.
c
c
Determined by chiral HPLC analysis.
Determined by chiral HPLC analysis.