Bifunctional Thiourea Catalyzed Asymmetric Mannich Reaction Using Trifluoromethyl Aldimine as Trifluoromethyl Building Blocks

Article abstract of DOI:10.1055/s-0034-1380693

An efficient bifunctional thiourea catalyzed asymmetric Mannich reaction with trifluoromethyl aldimine as trifluoromethyl building block was achieved to give the products in good diastereoselectivity and enantioselectivity.

Full text of DOI:10.1055/s-0034-1380693

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1725–1731
letter
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Letter
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Bifunctional Thiourea Catalyzed Asymmetric Mannich Reaction
Using Trifluoromethyl Aldimine as Trifluoromethyl Building
Blocks
Shilong Jia
Ahmed Ebrahim Alkhalila
Yingpeng Su*a
Xiaowen Xiaa
Siying Chonga
Ke-Hu Wanga
Danfeng Huanga
Ying Fua
O
O
O
R3
DIPEA
catalyst (10%)
OR2
CF3
O
H
N
H
N
N
N
F3C
R1
R1
+
*
n
*
i-Pr2O
n
OR2
F3C
S
OMe
NHR3
CF3
n = 1, 2
up to 95% yield
up to 94% ee
N
R1 = H, Me, MeO, Cl, Br
R2 = Me, Et, t-Bu, Bn
R3 = 4-MeOC6H4, 4-ClC6H4, 4-BrC6H4
catalyst
Yulai Hu*a,b
a College of Chemistry and Chemical Engineering, Northwest Normal University, 967 Anning Road (E.), Lanzhou, Gansu 730070, P. R. of China
huyl@nwnu.edu.cn
suyp51@nwnu.edu.cn
b State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Received: 11.02.2015
Accepted after revision: 06.04.2015
Published online: 21.05.2015
On the other hand, organocatalysis has developed into
an essential asymmetric catalysis that complements the
fields of metal and enzyme catalysis in the last decade.18 It
has also been used in enantioselective fluorination and tri-
fluoromethylation reactions.19,20 Our research group also
engaged in enantioselective fluorination and trifluoro-
methylation reactions, and firstly demonstrated that
thiourea-based bifunctional organocatalysts have been suc-
cessfully applied in the enantioselective fluorination reac-
tions of β-keto esters using NFSI as fluorination reagents
with the enantiomeric excess of the products up to 99%.20
Herein, we wish to report the bifunctional thiourea cata-
DOI: 10.1055/s-0034-1380693; Art ID: st-2015-w0095-l
Abstract An efficient bifunctional thiourea catalyzed asymmetric
Mannich reaction with trifluoromethyl aldimine as trifluoromethyl
building block was achieved to give the products in good diastereose-
lectivity and enantioselectivity.
Key words thiourea catalysts, trifluoromethyl aldimine, β-keto esters,
Mannich reaction, bifunctional organocatalyst
In recent years, trifluoromethyl compounds have re-
ceived much attention in pharmaceuticals and agrochemi-
cals because of the unique impact of the CF3 group on the
enhancement and modification of their original biological
activities.1–3 Among these useful fluorine-containing or-
ganic compounds, the trifluoromethylated organic com-
pounds have played increasing important roles in the phar-
maceutical area.1,2,4 In particular, some of the trifluoro-
methylated drugs bear chiral trifluoromethyl stereocenters
(Figure 1).1,5 Consequently, numerous methodologies have
been developed in the area of trifluoromethylation using
nucleophilic,6,7 electrophilic,8–10 and radical6,9,11 trifluoro-
methylation reagents as well as transformations of prochi-
ral trifluoromethylated substrates.12 Furthermore, enan-
tioselective introduction of a CF3 group into organic mole-
cules was also achieved with the traditional
trifluoromethylation reagents13 such as Umemoto,14 Tog-
ni,10,15 and Ruppert–Prakash16 reagents. Trifluoromethyl
building blocks were another useful tool for enantioselec-
tive construction of CF3-containing stereocenters because
of their easy availability and low cost.17
F
Me
Me
CF3
H
F3C
N
CN
N
H
Cl
O
O
N
O
H
MeO2S
efavirenz
HIV reverse transcriptase inhibitor
odanacatib
cathepsin K inhibitor
MeO
O
HO
CF
O
3 H
N
H
N
O
N
O
CF3
N
Ph
H
O
ZK-216348
a selective glucocorticoid receptor agonist
CJ-17493
NK-1 receptor antagonist
Figure 1 Examples of trifluoromethylated drugs
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1725–1731

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Table 1 Screening of Thiourea Catalysts for Asymmetric Mannich Re-
lyzed Mannich reaction for enantioselective trifluorometh-
ylation of β-keto esters using trifluoromethyl aldimine as
trifluoromethyl building blocks.
actiona
O
O
*
O
*
catalyst 1 (10 mol%)
Our initial investigation started with the trifluorometh-
ylation of β-keto ester 2a with N-(2,2,2-trifluorometh-
ylidene)anisidine (3) in Et2O at room temperature. Various
thioureas (Figure 2) were screened, and the results are
summarized in Table 1. It is shown that the catalysts 1a–g
derived from (+)-quinidine gave the products in low to
moderate yields with moderate diastereomeric ratio and
low to moderate enantiomeric excess (Table 1, entries 1–7).
However, the catalysts 1h,i,j,k gave racemic products or the
products with poor enantiomeric excess (Table 1, entries 8–
11). Furthermore, we examined the catalysts 1l–n derived
from the chiral amino acids, which still provided the race-
mic products (Table 1, entries 12–14). Thus, the catalyst 1g
(Table 1, entry 7) was regarded as the best catalyst and used
for further optimization of other reaction conditions.
The solvent effects were checked next (Table 2). The re-
sults showed that the diastereoselectivities of the reactions
were almost the same in different solvents when 1g was
used as the catalyst for the reaction between 2a and 3.
However, the solvents influenced the enantioselectivity
greatly. For example, the enantiomeric excess of the prod-
uct can reach to 84% when i-Pr2O was used as solvent (Table
2, entry 7). However, when the protic solvent such as meth-
anol was used, the product was obtained in low enantiose-
lectivity (Table 2, entry 1). There were no improvement in
the yield and enantioselectivity when the THF or dioxane
was used as solvent (Table 2, entries 2 and 3). The reaction
O
Et3N (1.5 equiv)
PMP
OMe
CF3
+
N
Et2O
OMe
F3C
NHPMP
4a
2a
3
Entry
Cat.
Yield (%)
drb
80:20
Major ee (%)b Minor ee (%)b
1
2
1a
1b
1c
1d
1e
1f
41
26
66
48
39
30
85
26
30
30
39
26
47
68
17
0
19
0
70:30
81:19
82:18
77:23
65:35
77:23
70:30
79:21
85:15
84:16
78:22
82:18
83:17
3
13
5
14
17
24
48
69
0
4
5
24
16
70
0
6
7
1g
1h
1i
8
9
0
0
10
11
12
13
14
1j
27
0
23
0
1k
1l
0
0
1m
1n
60
0
2
0
a The reactions were carried out under argon atmosphere by addition of a
solution of 2a (0.158 mmol) to a mixture of 3 (1.2 equiv), catalyst (10
mol%), and Et3N (1.5 equiv) in Et2O (3 mL) at r.t. for 72 h.
b The enantiomeric excesses and diastereomeric ratios of 4a were deter-
mined by HPLC analysis with a Chiralcel AD-H column, 2-PrOH–hexane
(1:9), 1.0 mL/min, λ = 254 nm.
H
H
N
H
N
H
N
H
N
N
N
N
O
N
Ar
S
OMe
S
OMe
S
OMe
MeO
Me
OMe
N
N
N
1h
1i
1a Ar = 4-MeOC6H4
1b Ar = Ph
1c Ar = 4-ClC6H4
1d Ar = 1-Naph
1e Ar = 2-Naph
1f Ar = t-Bu
1g Ar = 3,5-(F3C)2C6H3
OMe
Cl
Cl
S
S
S
H
H
N
HN
N
H
N
N
HN
N
N
N
Ar
H
H
Me
O
OMe
S
OH
Ph
Me
O
O
Ph
N
1l
1m
1n
1j Ar = 4-ClC6H4
1k Ar = 4-MeOC6H4
Figure 2 Catalysts used in this research work
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1725–1731

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in toluene or Et2O gave better yield and enantioselectivity
(Table 2, entries 4–8). Thus, mixed solvents of toluene and
ether were tested in order to improve the yield and enanti-
oselectivity further (Table 2, entries 9–11), but there were
no improvements in yield and enantioselectivity. Thus, i-
Pr2O was determined as the best solvent finally.
firmed as 10 °C (Table 3, entries 2 and 13–15). Therefore,
the optimized reaction conditions were 10 mol% 1g and 1.5
equivalents Hünig’s base in i-Pr2O at 10 °C.
Table 3 The Effect of Base and Temperature on the Reactiona
O
*
O
O
*
base,
catalyst 1g
PMP
O
Table 2 Effects of Solvents on the Reaction Using 1g as Catalystsa
OMe
CF3
N
+
i-Pr2O
OMe F3C
catalyst 1g
(10 mol%)
Et3N (1.5 equiv)
O
*
O
O
NHPMP
4a
O
2a
3
PMP
OMe
CF3
+
N
*
solvent
OMe
F3C
Entry Base
Yield Cat.
(%)
Temp drb
(mol%) (°C)
Major ee Minor ee
NHPMP
(equiv)
(%)b
(%)b
2a
3
4a
1
2
Et3N (1.5)
72
80
10
10
10
10
10
10
10
10
10
10
5
20
10
20
20
20
20
20
20
20
20
20
20
20
0
78:22
79
84
64
58
34
15
36
41
87
79
51
86
73
70
58
84
88
66
59
38
0
Entry Solvent
Yield (%) drb
Major ee Minor ee
DIPEA (1.5)
80:20
80:20
77:23
67:33
37:63
78:22
61:39
77:23
78:22
74:26
76:24
77:23
73:27
77:23
(%)b
(%)b
3
sparteine (1.5) 60
1
2
MeOH
THF
20
40
15
65
70
85
80
20
60
70
85
71:29
34
44
19
65
71
70
79
77
70
53
67
25
49
29
84
70
69
84
82
75
70
82
4
DABCO (1.5)
DMAP (1.5)
DBU (1.5)
50
47
80
56
50
77
82
62
82
90
70
50
76:24
76:24
72:28
76:24
77:23
78:22
78:22
75:25
78:22
75:25
5
3
dioxane
toluene
CH2Cl2
Et2O
6
4
7
K2CO3 (1.5)
DIPEA (1.0)
DIPEA (2.0)
DIPEA (3.0)
DIPEA (1.5)
DIPEA (1.5)
DIPEA (1.5)
DIPEA (1.5)
DIPEA (1.5)
46
62
88
82
67
89
80
51
45
5
8
6
9
7
i-Pr2O
TBME
10
11
12
13
14
15
8
9
i-Pr2O–Et2O (1:1)
25
10
10
10
10
11
Et2O–toluene(1:1)
i-Pr2O–toluene (1:1)
a The reactions were carried out under argon atmosphere by addition of a
solution of 2a (0.158 mmol) to a mixture of 3 (1.2 equiv), 1g (10 mol%), and
Et3N (1.5 equiv) in solvent (3 mL) at r.t. for 72 h.
–10
a The reactions were carried out under argon atmosphere by addition of a
solution of 2a (0.158 mmol) to a mixture of 3 (1.2 equiv) and 1g for 72 h.
b The enantiomeric excesses and diastereomeric ratios of 4a were deter-
mined by HPLC analysis with a Chiralcel AD-H column, 2-PrOH–hexane (1:9),
1.0 mL/min, λ = 254 nm.
b The enantiomeric excesses and diastereomeric ratios of 4a were deter-
mined by HPLC analysis with a Chiralcel AD-H column, 2-PrOH–hexane (1:9),
1.0 mL/min, λ = 254 nm.
In our previous study, we found that the base used in
the reaction played an important role in bifunctional
thiourea catalyzed asymmetric fluorination of β-keto es-
ters.20 Thus, different bases were examined again based on
the above optimized catalyst and solvent (Table 3, entries
1–7). After carefully screening, it was found that the best
base for the reaction was DIPEA, which afforded the prod-
uct in 80:20 diastereomeric ratio, up to 84% enantiomeric
excess for the major product and 88% enantiomeric excess
for the minor product (Table 3, entry 2). The amount of
DIPEA also had influence on the reaction. The yield and en-
antioselectivity of the reaction would increase when the
amount of DIPEA increased. However, the yield and enanti-
oselectivity were almost the same when DIPEA was used
above 1.5 equivalents (Table 3, entries 2, 9 and 10). Investi-
gation of catalyst loading also showed that 10 mol% of cata-
lyst was suitable for the reaction (Table 3, entries 2 and 11
and 12). Moreover, the reaction temperature was con-
With the optimized reaction conditions in hand, the
asymmetric trifluoromethylation via a Mannich reaction
was exploited with various 1,3-dicarbonyl compounds
(Scheme 1).21 The different kinds of alkoxy groups in in-
danonecarboxylates were tested (Scheme 1, 4a–d). It was
found that the alkoxy groups such as MeO, EtO, t-BuO, or
BnO in indanonecarboxylates had little influence on the en-
antiomeric excess of the products. What was worth noticed
was that tertiary butyl ester 2c gave single diasteroisomer
4c in 76% enantiomeric excess and 72% yield. However, te-
tralone derivatives such as 2j did not afford the product 4j.
Cyclopentane derivative 4k, acyclic 4l and 4m could not be
obtained either under the standard reaction conditions.
Then, the scope of different trifluoroalkyl aldimines was
examined. Although various anilines were used to prepare
the corresponding perfluoroalkyl aldimines with trifluoro-
acetaldehyde hemiacetal, just 4-Cl and 4-Br anilines gave
desired aldimines. 4-Toluidine and aniline as well as ben-
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zylamine did not supply the corresponding aldimines. Thus,
the aldimines obtained were used for Mannich reaction and
provided 4n and 4o in excellent enantiomeric excess and
diastereomeric ratio with good yield. Furthermore, it was
found that, when the product in Table 3, entry 2 was recrys-
tallized from isopropanol, the diastereomeric ratio would
increase to 98:2, and the enantiomeric excess would in-
crease to 97% for the major product and 73% for the minor
product.
Based on the experimental results and related litera-
tures,20,22 a mechanism was proposed for the reaction as
shown in Scheme 2.
Firstly, the reaction is initiated by deprotonation of 2a to
form the enolate, which can interact with bifunctional
thiourea via the hydrogen bond to furnish the intermediate
A. Then, intermediate B was formed from A and trifluoro-
methyl aldimine by hydrogen bond. Enolate attacked the al-
dimine in intermediate B to produce finally the trifluoro-
methylated product.
O
*
O
O
catalyst 1g (10 mol%)
R3
O
OR2
OR2
CF3
DIPEA
N
R1
R1
+
*
i-Pr2O
CF3
NHR3
2
3
4
Me
O
*
O
*
O
O
O
*
Me
Me
O
O
O
O
OEt
NHPMP
OMe
NHPMP
OBn
NHPMP
NHPMP
*
*
*
*
*
F3C
F3C
F3C
F3C
4a
4b
4c
4d
yield: 80%
dr: 80:20
major ee: 84%
minor ee: 88%
yield: 85%
dr: 86:14
major ee: 77%
minor ee: 80%
yield: 72%
ee: 76%
yield: 81%
dr: 81:19
major ee: 79%
minor ee: 65%
O
O
O
*
O
O
O
O
O
MeO
Me
OMe
NHPMP
OBn
NHPMP
OMe
NHPMP
OMe
NHPMP
*
*
*
*
*
*
*
Cl
Br
F3C
F3C
F3C
4g
F3C
4h
4e
4f
yield: 93%
dr: 81:19
yield: 82%
dr: 87:13
yield: 78%
dr: 73:27
yield: 85%
dr: 59:41
major ee: 76%
minor ee: 84%
major ee: 86%
minor ee: 47%
major ee: 30%
minor ee: 35%
major ee: 25%
minor ee: 10%
O
*
O
O
O
O
O
O
O
OMe
NHPMP
Me
OMe
NHPMP
OBn
NHPMP
OEt
*
*
*
*
*
*
*
Cl
CF3
F3C
NHPMP
CF3
4k
F3C
4i
4j
4l
yield: 0%
yield: 80%
yield: 0%
yield: 0%
dr: 72:28
major ee: 81%
minor ee: 65%
O
O
O
O
O
OEt
NHPMP
OMe
CF3
OMe
CF3
*
*
*
*
*
*
O
CF3
NH
NH
Me
Cl
Br
4m
4n
4o
yield: 0%
yield: 83%
yield: 95%
dr: 97:3
major ee: 94%
minor ee: 42%
dr: 85:15
major ee: 94%
minor ee: 90%
Scheme 1 Scope of substrates
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O–
O
i-Pr2NEt
O
O
OMe
OMe
+
2a
i-Pr2NHEt
N
CF3
N
H
H
i-Pr2NEt
F3C
N
N
S
OMe
F3C
S
OMe
N
N
H
H
+
N
PMP
CF3
N
N
A
1g
3
H
O–
H
CF3
O
O
O
N
CF3
MeO
OMe
CF3
*
S
N
*
OMe
NHPMP
4a
F3C
N
H
N
H
+
B
N
PMP
H
O
O–
F3C
H
MeO
Scheme 2 Plausible reaction mechanism
In conclusion, we have identified an efficient bifunc-
tional thiourea catalyzed asymmetric trifluoromethylation
of β-keto esters with trifluoromethyl aldimine as trifluoro-
methyl building block to provide the products with vicinal
chiral centers in good distereoselectivity and enantioselec-
tivity. It proves that bifunctional thiourea catalysts can be
successfully used in construction of CF3-containing stereo-
center using trifluoromethyl aldimine as trifluoromethyl
building block.
References and Notes
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We are thankful for financial support from the National Natural Sci-
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Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380693.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
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Letter
Synlett
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1 H), 7.55–7.53 (d, J = 8.0 Hz, 1 H), 7.43–7.39 (t, J = 7.6 Hz, 1 H),
6.81 (s, 4 H), 5.23–5.15 (m, 1 H), 4.07–4.03 (d, J = 17.2 Hz, 1 H),
3.76 (s, 3 H), 3.71–3.68 (d, J = 11.6 Hz, 1 H), 3.56 (s, 3 H), 3.43–
3.39 (d, J = 17.2 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
196.7, 167.5, 153.7, 152.3, 139.4, 135.8, 133.9, 129.4–120.9 (q,
JC–F = 284.3 Hz), 128.0, 126.4, 125.1, 116.1, 114.7, 63.9, 60.9–
60.1 (q, JC–F = 27.8 Hz), 55.5, 53.3, 31.4 ppm. 19F NMR (376 MHz,
CDCl3): δ = –70.36 to –70.38 (d, J = 6.8 Hz) ppm. ESI-HRMS: m/z
calcd for C20H18F3NO4 [M + H]+: 394.1261; found: 394.1258. IR
(thin film): 3370, 3032, 2961, 1745, 1514, 1465, 1245, 1033,
828, 760 cm–1. HPLC: major ee = 84%; minor ee = 88%; dr =
80:20 [Chiralpak AD-H, n-hexane–i-PrOH (90:10), 1 mL/min,
254 nm]: t1 (major isomer) = 17.70 min, t2 (major isomer) =
29.28 min; t3 (minor isomer) = 11.97 min, t4 (minor isomer) =
22.82 min.
(20) Xu, J.; Hu, Y.; Huang, D.; Wang, K.-H.; Xu, C.; Niu, T. Adv. Synth.
Catal. 2012, 354, 515.
(21) General Procedure for Preparing 4
To the mixture of 2 (0.158 mmol, 1 equiv) and 3 (0.189 mmol,
1.2 equiv) in i-Pr2O (2 mL), DIPEA (0.237 mmol, 1.5 equiv) and
thiourea catalyst 1g (9.4 mg, 10 mol%) were added successively
into a flame-dried flask at 10 °C under Ar atmosphere. The
mixture was stirred at 10 °C for 72 h. When the reaction was
completed, the mixture was concentrated under reduced pres-
sure. The residue was purified by flash column chromatography
using PE–EtOAc–CH2Cl2 (7:1:1) as eluent to obtain the desired
product 4.
Data of Compound 4a
(22) (a) Matsubara, R.; Berthiol, F.; Kobayashi, S. J. Am. Chem. Soc.
2008, 130, 1804. (b) Nakano, J.; Masuda, K.; Yamashita, Y.;
Kobayashi, S. Angew. Chem. Int. Ed. 2012, 51, 9525.
Yield 80%; white solid; mp 148–150 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.80–7.78 (d, J = 7.6 Hz, 1 H), 7.68–7.64 (t, J = 7.6 Hz,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1725–1731