Cinchona alkaloid-derived quaternary ammonium salt combined with NaH: a facile catalyst system for the asymmetric trifluoromethylation of ketones

Article abstract of DOI:10.1016/j.tetlet.2009.05.041

Enantioselective trifluoromethylation of aromatic ketones promoted by the cinchona alkaloid-derived ammonium bromide and sodium hydride was described. A series of trifluoromethyl-substituted aryl alcohols could be obtained in up to 82% ee with 98% yield u

Full text of DOI:10.1016/j.tetlet.2009.05.041

Tetrahedron Letters 50 (2009) 4378–4380
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Tetrahedron Letters
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Cinchona alkaloid-derived quaternary ammonium salt combined with NaH:
a facile catalyst system for the asymmetric trifluoromethylation of ketones
*
Xiaolei Hu, Jun Wang, Wei Li, Lili Lin, Xiaohua Liu, Xiaoming Feng
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantioselective trifluoromethylation of aromatic ketones promoted by the cinchona alkaloid-derived
ammonium bromide and sodium hydride was described. A series of trifluoromethyl-substituted aryl alco-
hols could be obtained in up to 82% ee with 98% yield under mild conditions. A possible catalytic cycle
was also presented.
Received 3 April 2009
Revised 12 May 2009
Accepted 15 May 2009
Available online 20 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Cinchona alkaloid
Ketones
Quaternary ammonium salt
Sodium hydride
Trifluoromethylation
Since
a
-trifluoromethylated alcohols play special roles in the
has described that disodium (R)-binaphtholate combined with the
chiral quaternary ammonium bromide to promote the enantiose-
lective addition of TMSCF3 to aromatic aldehydes.12 Herein, we
present another efficient FÀ free catalyst system comprising qua-
ternary ammonium bromide of cinchona alkaloid and NaH for
the enantioselective trifluoromethylation of aryl ketones with
TMSCF3.
fields of pharmacy and agrochemistry,1 great effort has been paid
to preparing these compounds.2 Among the developed strategies,3
employing Ruppert–Prakash reagent (TMSCF3)4 to react with car-
bonyl compounds had attracted great attention. Although the
non-asymmetric synthesis of trifluoromethylated alcohols has
been well developed,5 the catalytic asymmetric version of tirfluo-
romethylation of carbonyl compounds remains a challenge. In
1994, enantioselective trifluoromethylation using chiral quater-
nary ammonium fluoride was investigated by Iseki et al.6a Then,
Iseki et al. designed chiral triamino sulfonium salts for the enantio-
selective trifluoromethylation of aldehydes.7 After that, asymmet-
ric trifluoromethylation of ketones and aldehydes catalyzed by
chiral ammonium fluorides was described by Caron et al.8 Re-
cently, the combination of biscinchoninium and TMAF (tetrameth-
ylaminofluoride) was established by Shibata and coworkers to
promote the trifluoromethylation of ketones, giving the desired
product in up to 94% ee.9c
Initial studies started from that in the presence of catalytic
amount of base and quinidine-derived ammonium bromide 3a,
the reaction of 2-acetonaphthone 1a and 1.2 equiv TMSCF3 under-
went smoothly at À20 °C in Et2O.13 To our delight, the base screen-
ing showed that NaH gave the best result of 87% yield and 53% ee
(Table 1, entries 1–3). Then, the quaternary ammonium salts de-
rived from other cinchona alkaloids and 3,5-bis(trifluoromethyl)
benzyl bromide were examined (Fig. 1). It was indicated that the
quaternary ammonium salt 3b derived from cinchonine could en-
hance the enantioselectivity to 80% ee (Table 1, entry 4). Further-
more, 3c–e synthesized from cinchonine and some other alkyl
bromides were evaluated, but unsatisfactory results were given
(Table 1, entries 7–9). Configuration inversion of the product was
observed, when 3 was replaced by 4 (Table 1, entries 5 and 6).
Next, the influence of amount of NaH was studied. The reaction
rate was gradually enhanced by increasing the amount of NaH
from 5 mol % to 50 mol % without any loss of enantioselectivity
(Table 1, entry 10). Further increasing the amount from 50 mol %
to 100 mol % exhibited no difference in both reactivity and enanti-
oselectivity. However, 200 mol % NaH resulted in a sharp diminu-
tion of ee value (Table 1, entry 11). Therefore, 50 mol % NaH was
suitable for the reaction.
Quaternary ammonium salts have been demonstrated as one of
the most efficient catalyst system for the trifluoromethylation of
aldehydes and ketones. Noteworthily, for most of these catalysts,
employing FÀ as the counter ion was crucial to ensure the good
performance.6,8–10 Recently, some interesting and appealing FÀ free
catalyst system has been developed. Mukaiyama et al. reported
that the cinchonidine-derived chiral quaternary ammonium phen-
oxides were efficient for trifluoromethylation.11 As well, our group
* Corresponding author. Tel./fax: +86 28 85418249.
E-mail address: xmfeng@scu.edu.cn (X. Feng).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.041

X. Hu et al. / Tetrahedron Letters 50 (2009) 4378–4380
4379
Table 1
Table 2
Catalyst screeninga
Optimization for enantioselective trifluoromethylation of ketones catalyzed by chiral
ammonium bromidea
3
4
a) 5 mol % or
OH
O
5mol % base
Et2O, -20 o
∗
C
OH
O
CF3
∗
TMSCF3
a) 5 mol % 3b, 50 mol % NaH
b) TBAF.H2O, THF, rt
CF3
+
TMSCF3
b) TBAF.H2O, THF, rt
1a
2a
1a
2a
Yieldb (%)
eec(%)
Entry
Ammonium salt
Base
Yieldb (%)
eec (%)
Entry
Catalyst (mol %)
Solvent
1
2
3
3a
3a
3a
3b
4a
4b
3c
3d
3e
3b
3b
Na2CO3
t-BuOK
NaH
NaH
NaH
NaH
NaH
NaH
NaH
—
89
87
96
64
90
77
90
87
97
97
—
51
53
80
27
70
20
54
56
80
43
1
2
3
4
5
6
7
8
9
5
5
5
5
5
5
5
2
10
5
PhCH3
CH2Cl2
THF
47
97
94
37
93
56
96
28
98
32
96
95
—
59
53
25
72
77
70
81
82
76
82
73
75
—
4
Hexane
t-BuOCH3
PhOCH3
(i-Pr)2O
(i-Pr)2O
(i-Pr)2O
(i-Pr)2O
(i-Pr)2O
(i-Pr)2O
(i-Pr)2O
5d
6d
7
8
9
10e
11f
NaH
NaH
10d
11e
12f
13g
5
5
5
a
Unless otherwise noted, the reaction was carried out with 5 mol % 3 or 4,
5 mol % NaH and 1.2 equiv TMSCF3 at À20 °C in Et2O under Ar, substrate concen-
tration = 0.3 M. t = 12 h. The absolute stereochemistry of the newly generated ste-
reocenter in 2a was R which was determined by comparing specific rotation
reported by Shibata et al.9c
a
Unless otherwise noted, the reaction was carried out with 5 mol % 3, 50 mol %
NaH and 1.2 equiv TMSCF3 at À20 °C under Ar, substrate concentration = 0.3 M,
t = 12 h. The absolute stereochemistry of the newly generated stereocenter in 2a
was R which was determined by comparing specific rotation reported by Shibata
et al.9c
b
Isolated yield.
c
Determined by HPLC analysis using a Chiralcel OD-H with hexane/2-propanol
b
as an eluent.
Isolated yield.
d
c
The configuration of the product was S.
50 mol % NaH was used, t = 6 h.
200 mol % NaH was used, t = 6 h.
Determined by HPLC analysis using a Chiralcel OD-H with hexane/2-propanol
e
as an eluent.
f
d
The substrate concentration was 0.1 M.
The substrate concentration was 0.5 M.
The reaction temperature was 0 °C.
The reaction temperature was À45 °C.
e
f
g
H
N
N
HO
HO
Br
R2
Br
Table 3
R1
Substrate scope for the catalytic asymmetric trifluoromethylation of ketonesa
H
R1
R2
N
N
O
3b,
OH
a) 5 mol %
50 mol % NaH
3
isopropyl ether, -20 oC
4
∗
TMSCF3
3a: R1
= MeO
R2
= 3,5-di(trifluoromethyl)phenyl
.
R
b) TBAF H2O, THF, rt
R
CF3
3b: R1 = H
3c: R1 = H
3d: R1 = H
3e: R1 = H
4a: R1 = MeO
4b: R1 = H
R2 = 3,5-di(trifluoromethyl)phenyl
R2 = phenyl
1
2
R2 = 3,5-di(methoxyl)phenyl
R2 = 1-naphthyl
Entry
R
Product
Time (h)
Yieldb (%)
eec (%)
R2 = 3,5-di(trifluoromethyl)phenyl
R2 = 3,5-di(trifluoromethyl)phenyl
1d
2
3
4
5
6
7
8
2-Naphthyl
1-Naphthyl
2-FC6H4
3-ClC6H4
4-ClC6H4
2a
2b
2c
2d
2e
2f
2g
2h
2i
6
6
96
98
47
96
83
43
30
64
38
70
31
81(R)
82
68
68
61
60
68(R)
50
58
67
19
19
19
48
48
24
96
3
Figure 1. Structure of catalysts.
4-BrC6H4
3-NO2C6H4
4-NO2C6H4
3-MeOC6H4
4-MeC6H4
(E)PhCH@CH
Solvent screening manifested that ethers except THF were suit-
able solvents, while toluene, CH2Cl2, and hexane gave poor results
(Table 2, entries 1–7). Especially, the best result was achieved in
isopropyl ether which was chosen as the optimal solvent afterward
(Table 2, entry 7). Then, different catalyst loading, concentration
and reaction temperature were examined (Table 2, entries 8–13).
Lowering the catalyst loading to 2 mol %, the reactivity suffered
(Table 2, entry 8). Increasing the catalyst loading and concentration
led to high yield but low ee. In addition, the reaction was extre-
mely sensitive to the temperature. Descending ee was obtained
at 0 °C, and no reaction occurred at À45 °C (Table 2, entries 12
and 13). Consequently, the optimal reaction conditions were iden-
tified as: 0.2 mmol ketone, 1.2 equiv TMSCF3, 5 mol % 3b, 50 mol %
NaH in (i-Pr)2O (0.67 mL) at À20 °C.
9d
10
11
2j
2k
22
59
a
Unless otherwise noted, the reaction was carried out with 5 mol % 3b, 50 mol %
NaH and 1.2 equiv TMSCF3 at À20 °C in (i-Pr)2O under Ar, substrate
concentration = 0.3 M.
b
Isolated yield.
c
Determined by HPLC analysis using Chiral columns with hexane/2-propanol as
an eluent.
d
The absolute configurations of 2a and 2i were determined by comparing spe-
cific rotation reported by Shibata et al.9 and Mukaiyama et al.,11 respectively. The
stereochemistry of other trifluoromethylated alcohols 2 was tentatively assumed by
analogy.
ties (Table 3, entries 1 and 2). Substituted acetophenones gave
moderate to good results as well (Table 3, entries 3–8). Especially,
when 1k was subjected to the trifluoromethylation, 1,2-addition
Under the optimized conditions, the substrate scope was ex-
plored (Table 3). 1- and 2-Acetonaphthone were converted to the
corresponding products in high yields with good enantioselectivi-

4380
X. Hu et al. / Tetrahedron Letters 50 (2009) 4378–4380
Br
OTMS
Br
∗
N
+
CF3
B
R
N
MeO
F3C
CF3
∗
H
R
O
CH3
Br
H3C Si
N
N
CF3
CH3
5
B
OH
* CF3
O
O
a) 5 mo l% 5, 50 mol % NaH
isopropyl ether, -20 ºC
R
+ TMSCF3
.
b) TBAF H2O, THF, rt
63% ee, 90% yield
B
Br
CH3
CH3
Scheme 1. Control experiment.
H3C Si
F3C
N
A
)
(
O
CF3
CH3
R
O
R
for financial support. We also thank Sichuan University Analytical
and Testing Center for NMR analysis.
N
H3C
Si
CH3
Br
B
(B)
References and notes
Figure 2. Proposed catalytic cycle.
1. (a) Meissner, R. S.; Perkins, J. J.; Kim, Y.; Hanney, B.; McVean, C. A. WO20070
16358, 2007.; (b) Powers, J. P.; Degraffenreid, M. R.; He, X.; Julian, L.; McMinn,
D. L.; Sun, D.; Rew, Y.; Yan, X. WO2006138508, 2006.; (c) Degraffenreid, M. R.;
He, X.; Powers, J. P.; Sun, D.; Yan, X. WO2005063247, 2005.; (d) Bilder, D. M.
WO2002078628, 2002.; (e) Obach, R.S.; Scully, D. A. WO2000071538, 2000.; (f)
Satake, K. WO 9925714, 1999; (g) Young, S. D.; Britcher, S. F.; Payne, L. S.; Tran,
L. O.; Lumma, W. C., Jr. WO9520389, 1995.
2. For a review see: (a) Farnham, W. B. Chem. Rev. 1996, 96, 1633; (b) Prakash, G.
K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757; (c)Morden Fluoroorganic Chemistry
Synthesis, Reactivity, Applications; Kirsch, P., Ed.; Wiley-VCH Verlag GmbH &
Co.: Weinheim, Germany, 2004; (d) Billard, T.; Langlois, B. R. Eur. J. Org. Chem.
2007, 6, 891; (e) Shibata, N.; Mizuta, S.; Kawai, H. Tetrahedron: Asymmetry
2008, 19, 2633.
3. (a) Kitazume, T.; Ishikawa, N. Chem. Lett. 1982, 1453; (b) Billard, T.; Bruns, S.;
Langlois, B. R. Org. Lett. 2000, 2, 2101; (c) Aït-Mohand, S.; Takechi, N.;
Médebielle, M.; Dolbier, R., Jr. Org. Lett. 2001, 3, 4271; (d) Billard, T.; Langlois, B.
R.; Blond, G. Eur. J. Org. Chem. 2001, 8, 1467; (e) Prakash, G. K. S.; Hu, J. B.; Olah,
G. A. Org. Lett. 2003, 5, 3253; (f) Yamauchi, Y.; Kawate, T.; Katagiri, T.; Uneyama,
K. Tetrahedron 2003, 59, 9839; (g) Martina, S. L. X.; Jagt, R. B. C.; De Vries, J. G.;
Feringa, B. L.; Minnaard, A. J. Chem. Commun. 2006, 4093; (h) Wang, X. J.; Zhao,
Y.; Liu, J. T. Org. Lett. 2007, 9, 1343.
4. Rupport, I.; Schlich, K.; Volbach, W. Tetrahedron Lett. 1984, 25, 2195.
5. (a) Prakash, G. K. S.; Krishnamurthi, R.; Olah, G. A. J. Am. Chem. Soc. 1989, 111,
393; (b) Stahly, G. P.; Bell, D. R. J. Org. Chem. 1989, 54, 2873; (c) Singh, R. P.;
Kirchmeier, R. L.; Shreeve, J. M. J. Org. Chem. 1999, 64, 2579; (d) Prakash, G. K. S.;
Mandal, M.; Panja, C.; Mathew, T.; Olah, G. A. J. Fluorine Chem. 2003, 123, 61; (e)
Song, J. J.; Tan, Z. L.; Reeves, J. T.; Gallou, F.; Yee, N. K.; Senanayake, C. H. Org.
Lett. 2005, 7, 2193; (f) Prakash, G. K. S.; Panja, C.; Vaghoo, H.; Surampudi, V.;
Kultyshev, R.; Mandal, M.; Rasul, G.; Mathew, T.; Olah, G. A. J. Org. Chem. 2006,
71, 6806; (g) Pedrosa, R.; Sayalero, S.; Vicente, M.; Maestro, A. J. Org. Chem.
2006, 71, 2177; (h) Demir, A. S.; Eymur, S. J. Org. Chem. 2007, 72, 8527.
6. (a) Iseki, K.; Nagai, T.; Kobayashi, Y. Tetrahedron Lett. 1994, 35, 3137; (b) Iseki,
K.; Kobayashi, Y. Rev. Heteroat. Chem. 1995, 12, 211.
occurred, furnishing
(Table 3, entry 11).
a-trifluoromethyl allylic alcohol 2k in 59% ee
As depicted in Figure 2, a catalytic cycle was proposed to eluci-
date the reaction mechanism. First, ketone was effectively acti-
vated by the chiral N+ cation in quaternary ammonium salt to
form the intermediate A.14 Meanwhile, discrimination of the enan-
tiotopic faces of ketones happened in this step. Second, the nucle-
ophilic reagent TMSCF3 was activated by Lewis base to generate
the intermediate B.15 Then, the activated carbonyl group was easily
attacked by CF3À, after which, trimethylsilylation of the resulted
alkoxide quickly underwent to furnish the desired product and
regenerate the catalyst.
It should be noted that there were two possible species that
might act as Lewis base to activate TMSCF3. One was HÀ from
NaH. The other was ROÀ which might be produced from the depro-
tonation of hydroxy on quaternary ammonium salt by NaH. How-
ever, the control experiment showed that when the hydroxyl in 3b
was methylated, the reaction still proceeded smoothly and enanti-
oselectively, affording the product in 63% ee and 90% yield (Scheme
1). Additionally, in the absence of NaH, 5 could not catalyze the
reaction. Based on these observations, it was reasonable to deduce
that the hydride ion in sodium hydride might serve as the efficient
Lewis base to activate TMSCF3.
In conclusion, the combined use of cinchonine-derived quater-
nary ammonium salt 3b and NaH was established as the effective
and FÀ free catalytic system for the catalytic asymmetric trifluo-
romethylation of ketones. Adducts bearing electron-donating and
electron-withdrawing groups could be obtained in moderate to
good ee (up to 82%) and yield (up to 98%). Moreover, a plausible
catalytic cycle was proposed to explain the mechanism.
7. Kuroki, Y.; Iseki, K. Tetrahedron Lett. 1999, 40, 8231.
8. Caron, S.; Do, N. M.; Arpin, P.; Larivée, A. Synthesis 2003, 11, 1693.
9. (a) Shibata, N.; Toru, T. JP 2005306769, 2005.; (b) Mizuta, S.; Shibata, N.;
Hibino, M.; Nagano, S.; Nakamura, S.; Toru, T. Tetrahedron 2007, 63, 8521; (c)
Mizuta, S.; Shibata, N.; Akiti, S.; Fujimoto, H.; Nakamura, S.; Toru, T. Org. Lett.
2007, 9, 3707.
10. Prakash, G. K. S.; Hu, J. B. In Fluorine-Containing Synthons; Soloshonok, V. A., Ed.;
ACS Symposium Series 911; American Chemical Society: Washington, 2005; pp
16–56.
11. Nagao, H.; Yamane, Y.; Mukaiyama, T. Chem. Lett. 2007, 36, 666.
12. Zhao, H. T.; Qin, B.; Liu, X. H.; Feng, X. M. Tetrahedron 2007, 63, 6822.
13. The reaction could not proceed smoothly in the presence of 5 mol % quaternary
ammonium 3a or 3b independently.
14. Ooi, T.; Maruoka, K. Angew. Chem., Int. Ed. 2007, 46, 4222.
15. Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, 1560.
Acknowledgments
We appreciate the National Natural Science Foundation of China
(No. 20732003) and the Ministry of Education (No.20070610019)