Asymmetric trifluoromethylation of aromatic aldehydes by cooperative catalysis with (IPr)CuF and quinidine-derived quaternary ammonium salt

Article abstract of DOI:10.1039/c2ob26827b

A general enantioselective trifluoromethylation of aldehydes has been developed using (IPr)CuF and quinidine-derived quaternary ammonium salt as the cooperative catalyst. Thus, a wide range of aromatic aldehydes have been converted to the corresponding products in up to 92% yield and 81% ee at 2 mol% of catalyst loading. The greatly enhanced activity and enantioselectivity result from the initiative generation of active [(IPr)CuCF₃] as well as additional coordination activation of other copper species.

Full text of DOI:10.1039/c2ob26827b

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Asymmetric trifluoromethylation of aromatic aldehydes by cooperative
catalysis with (IPr)CuF and quinidine-derived quaternary ammonium salt†
Shaoxiang Wu, Wei Zeng, Qi Wang and Fu-Xue Chen*
Received 18th September 2012, Accepted 9th October 2012
DOI: 10.1039/c2ob26827b
were less than 60%; accordingly, in the case of electron-rich sub-
strates, around 40% ee values were recorded. Using 1 mol% of
chiral crown ether and 10 mol% of base as catalyst, about 40%
ee was obtained by Shibata et al.9 In contrast to the enantioselec-
tive trifluoromethylation of ketones,2e,10 how to improve the
catalytic activity and enantioselectivity of the reaction using
aldehydes still remains challenging. Herein, we report an effec-
tive cooperative catalyst composed of (IPr)CuF (IPr = 1,3-bis
(2′,6′-diisopropylphenyl)imidazol-2-ylidene) and a quaternary
ammonium salt for the enantioselective trifluoromethylation
reaction of a wide range of aldehydes with up to 81% ee at
2 mol% of catalyst loading within 2 h.
Initially, a model reaction was performed with 2-naphthalde-
hyde (1a) and Me3SiCF3 (2 equiv.) in toluene at −78 °C. In the
present of (IPr)CuF (10 mol%), a series of Cinchona alkaloid-
derived quaternary ammonium salts (3–8) were examined
(Fig. 1). As shown in Table 1, all reactions can be finished
quickly. Firstly, a catalytic amount of 3a (10 mol%) derived
from quinidine and 4-methylbenzyl bromide was used, and the
desired product was obtained in 87% yield and 20% ee (Table 1,
A general enantioselective trifluoromethylation of aldehydes
has been developed using (IPr)CuF and quinidine-derived
quaternary ammonium salt as the cooperative catalyst. Thus,
a wide range of aromatic aldehydes have been converted to
the corresponding products in up to 92% yield and 81% ee
at 2 mol% of catalyst loading. The greatly enhanced activity
and enantioselectivity result from the initiative generation of
active [(IPr)CuCF3] as well as additional coordination acti-
vation of other copper species.
Fluorinated chemicals have attracted ever-increasing interest in
the fields of pharmaceuticals, agrochemicals, and materials.1
Trifluoromethyl-containing alcohols represent an interesting sub-
class of this type of structure providing unique biological activi-
ties due to the special properties of the trifluoromethyl group.
Among the literature approaches, addition of Ruppert–Prakash
(Me3SiCF3) reagent to carbonyl compounds appears the most
straightforward operation to prepare the chiral trifluoromethyl
alcohols.2 The activation of Me3SiCF3 has been accomplished
with fluoride sources,3 such as CsF,3a n-Bu4NF,3b–d and KF.3e
Despite the wealth of syntheses of racemic trifluoromethylated
alcohols,4 the asymmetric trifluoromethylation of aldehydes has
been less explored.
In 1994, Kobayashi et al. reported the first example of asym-
metric addition of Me3SiCF3 to aldehydes using N-[4-(trifluoro-
methyl)benzyl]cinchonium fluoride (20 mol%), giving the
corresponding alcohols in high yields and 40–50% ee.5 In the
following years, similar results were obtained with different
chiral ammonium salt, triaminosulfonium salt in low to moderate
enantioselectivity.6 Prakash and Hu found N-benzylquinidinium
fluoride was very effective for the trifluoromethylation of
9-anthraldehyde; however, high enantioselectivity was observed
only for this substrate.7 Feng et al. discovered a combination use
of 10 mol% of sodium (R)-binaphtholate and Cinchona alkaloid-
derived quaternary ammonium salt yielding up to 71% ee for
2-naphthaldehyde.8 However, the ee values of other substrates
Department of Applied Chemistry, School of Chemical Engineering &
the Environment, Beijing Institute of Technology, No. 5 South
Zhongguancun Street, Haidian District, Beijing 100081, P. R. China.
E-mail: fuxue.chen@bit.edu.cn; Fax: +86 10 68918296
†Electronic supplementary information (ESI) available: Experimental
procedure and characterization data. See DOI: 10.1039/c2ob26827b
Fig. 1 Structure of catalysts.
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Table 1 Optimization of the cooperative catalyst efficiency for the
Table 2 Substrate scopea
model reactiona
Entry
1
Ar
Time (h)
Yieldb (%)
eec (%)
1
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
2-Naphthyl
1-Naphthyl
C6H5
4-BrC6H4
3-BrC6H4
4-ClC6H4
4-MeC6H4
4-PhC6H4
3-PhOC6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
3,4-O(CH2)C6H3
3,4-O(CH2)2C6H3
4-(C3H5O)C6H4
4-EtSC6H4
1
2
2
2
2
2
1
1
1
1
1
1
2
2
2
2
90
88
80
81
82
83
88
90
87
85
89
88
92
92
80
85
75(98)d
60
60
57
51
52
68
66
60
67
74
74
81
79
66
74
Ammonium salt
(mol%)
[IPrCuF]
(mol%)
Time
(h)
Yieldb
(%)
eec,d
(%)
2
Entry
3e
4
1
2
3
4
5
6
7
8
3a(10)
3b(10)
3c(10)
3d(10)
3e(10)
3g(10)
4(10)
5(10)
6(10)
7(10)
8(10)
3e(2)
3e(1)
3e(1)
3e(2)
3e(2)
3e(2)
3e(2)
3e(2)
3e(2)
10
10
10
10
10
10
10
10
10
10
10
2
1
1
2
2
2
2
2
2
1
1
1
1
1
1
1
4
1
12
12
1
4
4
1
1
4
2
87
90
90
93
92
86
93
45
85
43
37
92
52
50
90
92
37
88
41
87
20(R)
35
2
5
6e
7
57
69
63
−8
21
45
17
21
68
66
67
75
47
6
8
9
10
11
12
13
14
15
16
9
10
11
12
13
14e
15f
16f,g
17f,h
18f,i
19f,j
20f,k
a Reaction conditions: 1a–p (0.2 mmol), (IPr)CuF (0.004 mmol, 2 mol
%), 3e (0.004 mmol, 2 mol%), Me3SiCF3 (0.4 mmol, 2 equiv.), [1] =
0.33 M in toluene (0.6 mL), −78 °C, stirring under Ar atmosphere.
b Isolated yield. c Determined by HPLC analysis (Chiralcel OJ-H, OD-H,
AD-H, or AS-H). The absolute configuration of 2a was assigned by
comparing HPLC retention time and the sign of optical rotation value
with that of literature [ref. 10]. Others 2b–p are assumed by analogy.
d The ee value in parentheses was obtained after recrystallization. e The
reaction was carried out at −20 °C.
29
37
40
4
1
a Reaction conditions: 1a (0.2 mmol), Me3SiCF3 (0.4 mmol, 2 equiv.),
[1a] = 0.25 M in toluene (0.8 mL), −78 °C, stirring under Ar
atmosphere. b Isolated yield. c Determined by chiral HPLC on Chiralcel
OJ-H. d The absolute configuration of 2a was assigned by comparing
HPLC retention time and the sign of the optical rotation value with that
of literature [ref. 10]. e 0.4 mL toluene was used, [1a] = 0.50 M. [1a] =
f
0.33 M. g The reaction was carried out at −40 °C. h n-Hexane. i THF.
j Et2O. k CH2Cl2. TBAF = tetrabutylammonium fluoride.
promote the reaction to give 2a with 17% and 21% ee, respect-
ively (entries 10, 11). The unfavourable effect is probably due to
the fact that hydroxyl at C-6′ disturbs the π–π interaction.
Subsequently, other reaction parameters were optimized.
Decreasing the catalyst loading down to 2 mol% did not erode
the enantioselectivity (entry 12). A further decrease of catalyst
loading leads to a longer reaction time (entry 13) even with a
more concentrated reaction (entry 14), yielding moderate conver-
sion and similar ee values. The highest enantioselectivity is
obtained as 75% ee at 2 mol% of catalyst loading with an alde-
hyde concentration of 0.33 M in toluene (entry 15). A higher
reaction temperature (−40 °C) erodes the enantioselectivity
obviously to 47% ee (entry 16). Besides, solvents exhibit a
strong effect on the catalyst capability. In n-hexane, the coopera-
tive catalyst nearly loses its enantioselective capability (entry
17). In polar solvents such as THF and CH2Cl2, low enantio-
selectivities are recorded (entries 18–20). Consequently, the
optimal reaction conditions for the cooperative catalyst are as
follows: 2 mol% of (IPr)CuF and 2 mol% of 3e, a substrate con-
centration 0.33 M in toluene, and −78 °C.
Under the optimal reaction conditions, the substrate scope of
the enantioselective trifluoromethylation of aromatic aldehydes
has been investigated using the cooperative catalyst of (IPr)CuF
and 3e. As shown in Table 2, the standard substrate 1a gives
75% ee, and 98% ee can be reached after simple recrystallization
(entry 1). 1-Naphthylaldehyde (1b) and benzaldehyde (1c)
exhibit good yields and moderate enantioselectivities (entries 2, 3).
entry 1). Replacing the CH3 on the aromatic ring by CF3, 3b cata-
lyzes the reaction in 90% yield and 35% ee (entry 2). However,
using hindered planar 9-anthryl (3c) instead of phenyl decreases
asymmetric inductive capability (entry 3). It is noteworthy that
electron-deficient 2,4,5-trifluorobenzyl ammonium salt 3d
improves the enantioselectivity to 57% ee (entry 4). Delightedly,
3,5-bis(trifluoromethyl)benzyl-derived 3e greatly increases the
enantioselectivity to 69% ee (entry 5). The more bulky 3g shows
slightly decreased enantioselectivity and activity (entry 6). The
quasi-enantiomeric catalyst 4 derived from quinine is inferior to
its quinidine counterpart (entry 7 vs. 5). Dimeric ammonium salt
5 derived from quinidine with a 1,3-dimethylene phenyl linker
did not show any improvement in enantioselectivity (entry 8).
Notably, C-9-protected catalyst 6 leads to a decreased yield
and low ee value of 45% (entry 9). The contrast between this
result and previous observations11 suggests that a hydrogen bond
may be formed and it favours π–π stacking of the benzyl moiety
and the aromatic portion of the substrate.11h Considering the
indispensability of the free hydroxyl group of the quinidine-
derived quaternary ammonium salt for achieving high enantio-
control, ammonium salts 7 and 8 bearing hydroxyls at C-6′ had
been prepared to promote the enantioselectivity. However, they
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Table 3 Control experimentsa
Scheme 1 Transformations of (IPr)CuX.
Ammonium salt (IPr)CuX
Time Yieldb eec
aldehyde. Subsequently, the quaternary ammonium salt2c–e,8,10
and carbene copper alkoxides12b,c catalyze the reaction and give
the desired product.
Entry (mol%)
(mol%)
(h)
(%)
(%)
1
2
3
4
5
6
7
3e(2)
–
—
4
4
1
4
4
36
48
NR
Trace
90
57
NR
87
—
ND
75
45
—
57
67
(IPr)CuF (2)
(IPr)CuF (2)
(IPr)CuOt-Bu (2)
(IPr)CuCl (2)
—
3e(2)
3e(2)
3e(2)
3f(5)
3f(5)
Conclusions
In summary, we have developed a general catalytic enantioselec-
tive trifluoromethylation of aromatic aldehydes using (IPr)CuF
and quinidine-derived quaternary ammonium salt as the coopera-
tive catalyst. The methodology described is significant as (i) a
wide range of trifluoromethylated alcohols with the highest
levels of enantiomeric excess can be prepared; (ii) the lowest
catalyst loading (2 mol%) reported for enantioselective trifluoro-
methylation of aromatic aldehydes thus far has been used; and
(iii) the high capability in both catalytic activity and enantio-
selectivity results from an initiative transmetallation of
Me3SiCF3 with (IPr)CuF affording active [(IPr)CuCF3] and
weak coordination activation of aldehydes with other copper
species. Further effort will be focused on higher enantio-
selectivity and mechanism elucidation.
(IPr)CuCl (5)
84
a Reaction conditions: 1a (0.2 mmol), Me3SiCF3 (0.4 mmol, 2 equiv.),
toluene (0.6 mL), −78 °C, stirring under Ar atmosphere. b Isolated yield.
c Determined by HPLC analysis on Chiralcel OJ-H. ND = not detected.
NR = no reaction.
Those aldehydes bearing electron-withdrawing substituents, such
as bromide and chloride, provide the products in moderate
enantioselectivities (51–57% ee) (entries 4–6). Gratifyingly, sub-
strates with electron-donating groups which have caused more
problems in previous studies2e have been proved appropriate for
our catalyst system (entries 7–16). Compared with the previously
reported methodology,8 for those aldehydes with electron-donat-
ing methoxy groups on the aromatic rings, higher enantio-
selectivities, up to 74% ee, are obtained (entries 7–12). Similar
catalytic efficiency is observed for other electron-rich aldehydes
(entries 13–16). The highest enantioselectivity of 81% ee is
recorded in the case of 1m compared to 46% ee in the literature8
(entry 13). To the best of our knowledge, this cooperative cata-
lyst exhibits the most general process for the trifluoromethylation
of aromatic aldehydes with the highest capability in both cataly-
tic activity and enantioselectivity to date.
Acknowledgements
We thank National Natural Science Foundation of China
(20972016, 21172018) and Beijing Institute of Technology for
the financial support.
Notes and references
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control experiments were carried out under the optimal reaction
conditions (Table 3). It was not surprising that neither (IPr)CuF
nor quaternary ammonium salt 3e produced any products even
after 4 h (entries 1–2 vs. entry 3). Subsequently, by changing the
counter-ion from F− to t-BuO− or Cl− both yields and ee values
decreased stepwise to zero (entries 3–5).
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vs. 1). After combination with (IPr)CuCl rather than (IPr)CuF,
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(IPr)CuF generated from a slow equilibrium between (IPr)CuCl
and 3f (Scheme 1, eqn (1)). These observations indicate that
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