Chiral Br?nsted acid-catalyzed regio- and enantioselective arylation of α,β-unsaturated trifluoromethyl ketones

Article abstract of DOI:10.1016/j.tetlet.2010.06.132

The interesting examples of chiral phosphoric acid-catalyzed regio- and enantioselective arylation of α,β-unsaturated trifluoromethyl ketones were reported. The reaction proceeded well and the desired products were obtained in good yields (up to 99%) with moderate to good enantioselectivities (up to 88% ee). Several desired products were obtained with excellent optical purities after a single recrystallization. Subsequent reduction of enantiopure products with NaBH₄ afforded two diastereomers of chiral trifluoromethyl-substituted secondary alcohols with high enantioselectivities (98% ee).

Full text of DOI:10.1016/j.tetlet.2010.06.132

Tetrahedron Letters 51 (2010) 4658–4661
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Chiral Brønsted acid-catalyzed regio- and enantioselective arylation
of
a,b-unsaturated trifluoromethyl ketones
*
Zeng-kai Pei, Yan Zheng, Jing Nie, Jun-An Ma
Department of Chemistry, Tianjin University, Tianjin 300072, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The interesting examples of chiral phosphoric acid-catalyzed regio- and enantioselective arylation of a,b-
Received 10 May 2010
Revised 13 June 2010
Accepted 30 June 2010
Available online 17 July 2010
unsaturated trifluoromethyl ketones were reported. The reaction proceeded well and the desired prod-
ucts were obtained in good yields (up to 99%) with moderate to good enantioselectivities (up to 88%
ee). Several desired products were obtained with excellent optical purities after a single recrystallization.
Subsequent reduction of enantiopure products with NaBH4 afforded two diastereomers of chiral trifluo-
romethyl-substituted secondary alcohols with high enantioselectivities (98% ee).
Keywords:
Chiral phosphoric acid
Arylation
Ó 2010 Elsevier Ltd. All rights reserved.
a,b-Unsaturated trifluoromethyl ketones
Reduction
Enantioselectivity
As the most electronegative element, fluorine atom has great
influence on the properties and the reactivity of the molecules.1
Among fluorinated compounds, trifluoromethyl-substituted mole-
cules have gained growing interest during the past decades.2,3
Compared with non-fluorinated analogues, the introduction of a
trifluoromethyl group with strong electron-withdrawing ability
can lead to significant changes in physical, chemical, and biological
properties of the molecules. Therefore, the development of asym-
metric approaches for the synthesis of trifluoromethyl-containing
compounds has been such an important object for organic
chemists.4
Indole represents an attractive structural motif in a variety of
natural bioactive products and therapeutic agents.5,6 In recent
years, particular attention has been paid to the enantioselective
reactions of indoles with various electrophilic substrates to pre-
pare chiral indole-derivatives. For example, many reports involved
chiral metal-complex or small organic molecule-catalyzed asym-
enantioselectivities.24–27 Herein, we would like to report our work
about organocatalyzed regio- and enantioselective arylation of
unsaturated trifluoromethyl ketones with indoles.
a,b-
Based on our previous work, the asymmetric arylation of 1,1,1-
trifluoro-4-phenyl-3-buten-2-one 3a with indole 2a was chosen as
the model reaction for screening the BINOL-derived phosphoric
acid catalysts 1 (Fig. 1). Interestingly, 3-alkylated product 4a of in-
dole was obtained (Table 1, entries 1ꢀ14). Other adducts, such as
1,1,1-trifluoro-4-(1H-indol-2-yl)-4-phenylbutan-2-one, 1,1,1-tri-
fluoro-2-(1H-indol-3-yl)-4-phenylbutan-2-ol, and 1,1,1-trifluoro-
2-(1H-indol-2-yl)-4-phenylbutan-2-ol, were not observed in the
reaction. The best result was obtained using phosphoric acid 1f
with 9-anthracenyl groups at the 3,30-positions of the binaphthyl
scaffold, which gave the desired product 4a in 97% yield and 48%
ee (Table 1, entry 6). Subsequently, the effect of solvents and reac-
tion temperature was examined in the model reaction using 1f as
catalyst (Table 1, entries 16ꢀ22). The reaction proceeded with high
conversion and moderate enantioselectivities in chlorinated al-
kanes (Table 1, entries 6, 20 and 21), while higher enantioselectiv-
ity was observed in CH3CN but with a low yield (Table 1, entry 19).
Finally, the mixture of ClCH2CH2Cl/CH3CN (1:1) was proved to be a
superior co-solvent in which the desired product 4a was obtained
in 96% yield with 53% ee (Table 1, entry 22). When the reaction
temperature was lowered to ꢀ20 °C, the enantioselectivity could
be improved to 72% with the prolonged reaction time (Table 1, en-
try 24).
metric Michael additions of indoles to
a,b-unsaturated carbonyl
compounds.6–18 However, to the best of our knowledge, these
otherwise extensively studied reactions have not been successfully
applied to
a
,b-unsaturated trifluoromethyl ketones.19 BINOL-de-
rived phosphoric acids have been shown to be excellent nonmetal
chiral organocatalysts for vast asymmetric transformations.20–23
Recently, we have demonstrated that chiral phosphoric acids can
catalyze several arylation reactions of trifluoroacetaldimines, tri-
fluoromethyl ketones, ethyl 4,4,4-trifluoroacetoacetate, and ethyl
trifluoropyruvate with electron-rich arenes with good to excellent
With the optimal conditions (10 mol % 1f as the catalyst, at
ꢀ20 °C in ClCH2CH2Cl/CH3CN 1:1) in hand, the scope of the organo-
catalytic enantioselective arylation of
a,b-unsaturated trifluoro-
* Corresponding author.
E-mail address: majun_an68@tju.edu.cn (J.-A. Ma).
methyl ketones 3 was explored with indoles 2 (Table 2).28 In most
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.132

Z. Pei et al. / Tetrahedron Letters 51 (2010) 4658–4661
4659
Figure 1.
Table 1
Optimization of reaction conditions
Ph
O
or
Ph
*
OH
CF3
*
O
catalyst 1
(10 mol %)
N
H
CF3
O
Ph
*
Ph
CF3
Ph
OH
N
H
CF3
N
H
N
H
CF3
*
2a
3a
4a
N
H
Entry
Catalyst
Solvent
Temp (°C)
Time (h)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1f
1f
1f
1f
1f
1f
1f
1f
1f
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
Et2O
THF
1,4-Dioxane
CH3CN
CHCl3
ClCH2CH2Cl
ClCH2CH2Cl/CH3CN
ClCH2CH2Cl/CH3CN
ClCH2CH2Cl/CH3CN
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0
36
36
36
24
24
24
36
24
18
24
24
36
71
36
24
24
168
72
72
24
18
24
72
120
52
84
30
66
70
97
84
70
95
50
84
72
58
91
87
85
38
17
22
90
97
96
71
85
5
31
7
9
8
48
17
25
12
8
23
27
23
3
24
17
37
24
60
38
51
53
49
72
1f
-20
a
Isolated yield.
The ee was determined by chiral HPLC analysis.
b
cases,
a
,b-unsaturated trifluoromethyl ketones bearing either elec-
These adducts are useful synthetic intermediates and can be
readily transformed into trifluoromethyl-substituted secondary
alcohols. For example, direct reduction of enantioriched 4a in the
presence of NaBH4 gave trifluoromethylated syn- and anti-alcohols
(1:1 dr), which were easily isolated through silica gel column chro-
matography in 68% overall yield with excellent enantiomeric puri-
ties (98% ee) (Scheme 1).29
tron-withdrawing groups or electron-donating groups gave the cor-
responding products in good yields (80ꢀ99%) with good
enantioselectivities (56ꢀ88%) (Table 2, entries 1ꢀ9). However,
when 1,1,1-trifluoro-4-biphenyl-3-buten-2-one was employed as
a substrate, the desired product was obtained in a low yield. Proba-
bly, the poor solubility in the mixed solvents decreased the reactiv-
ity of this substrate (Table 2, entry 10). Next, several indoles were
probed (Table 2, entries 11ꢀ14). The reactions took place in good
yields (83ꢀ93%) with moderate to good enantioselectivities
(42ꢀ88% ee). 2-Methylindole provided the desired product with
low enantioselectivity (18% ee) (Table 2, entry 14). It was notewor-
thy that several desired products could be obtained with excellent
optical purities after single recrystallization from CH2Cl2/hexane
(Table 2, entries 1, 4, and 8).
In summary, we have developed an asymmetric arylation reac-
tion of
a,b-unsaturated trifluoromethyl ketones with indoles by
using chiral phosphoric acids as efficient organocatalysts. In most
cases, the transformations proceeded well in good yields (up to
99%) with moderate to good enantioselectivities (up to 88% ee).
Several desired products were obtained with excellent optical puri-
ties (98ꢀ99.9% ee) after a single recrystallization. Moreover, the
arylated products could be transformed into two diastereomers

4660
Z. Pei et al. / Tetrahedron Letters 51 (2010) 4658–4661
Table 2
Scope of chiral Brønsted acid-catalyzed arylation of
a
,b-unsaturated trifluoromethyl ketones
O
Ar
R
O
CF3
R
Catalyst 1f (10 mol %)
Ar
CF3
ClCH2CH2Cl/CH3CN
N
H
4
N
H
(1/1), −20 ºC
2
3
Entry
2
Ar
C6H5
p-MeC6H4
o-MeC6H4
p-MeOC6H4
3,5-Me2C6H3
1-Naphthyl
2-Naphthyl
4-BrC6H4
3,5-(CF3)2C6H3
4-Biphenyl
3,5-(CF3)2C6H3
3,5-(CF3)2C6H3
3,5-(CF3)2C6H3
3,5-(CF3)2C6H3
Time (h)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Indole
Indole
Indole
Indole
Indole
Indole
Indole
Indole
Indole
Indole
5-Me-indole
7-Me-indole
5-Cl-indole
2-Me-indole
120
72
72
72
96
72
72
72
80
120
72
72
72
72
85
87
97
92
99
89
80
86
99
25
85
93
85
83
72 (99.9)c
63
56
60 (98)c
66
79
73
76 (98)c
88
63
62
88
42
18
a
b
c
Isolated yield.
The ee was determined by chiral HPLC analysis. The absolute configuration was assigned according to Ref. 19.
The results in parentheses were obtained after a single recrystallization.
O
1) Catalyst 1f (10 mol %)
ClCH2CH2Cl/CH3CN
O
CF3
(1/1), −20 ºC
CF3
2) Recrystallization
from CH2Cl2/hexane
N
H
N
H
4a 99.9% ee
NaBH4
MeOH
OH
CF3
OH
CF3
N
H
N
H
1
:
1
98% ee
98% ee
Scheme 1.
of chiral trifluoromethyl-substituted secondary alcohols with high
enantioselectivities (98% ee). Further efforts in our laboratory will
be mainly directed toward improving the selectivity and synthetic
application.
References and notes
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Acknowledgments
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The financial support from NSFC (No. 20772091 and 20902067)
and Tianjin Municipal Science & Technology Commission (No.
08JCYBJC09500) is gratefully acknowledged.

Z. Pei et al. / Tetrahedron Letters 51 (2010) 4658–4661
4661
10. Blay, G.; Fernández, I.; Pedro, J. R.; Vila, C. Org. Lett. 2007, 9, 2601–2604.
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petroleum ether (1:20 to 1:7) to afford the desired product 4a. 85% yield,
mp: 93–98 °C; ½a 2D0
ꢁ
ꢀ6.3° (c 1.0, CHCl3) [lit.19 a rDt
½ ꢁ +7.96 (c 1.02, CHCl3, >99%
ee)]; 72% ee, [Daicel Chiralcel OD-H, Hexane/i-PrOH = 90:10, 0.8 mL/min,
254 nm, TR (minor) = 19.06 min, TR (major) = 28.26 min]; 1H NMR (500 MHz,
CDCl3) d (ppm) 3.47–3.52 (dd, J = 18.0 Hz, 1H, CH2), 3.60 (dd, J = 18.0 Hz, 1H,
CH2), 4.96 (t, J = 7.0 Hz, 1H, CH), 6.96 (m, 1H), 7.06–7.09 (t, J = 7.0 Hz, 1H),
7.18–7.26 (m, 2H), 7.29–7.36 (m, 5H), 7.46–7.46 (d, J = 8 Hz, 1H), 8.04 (br s,
1H); 13C NMR (125 MHz, CDCl3) d (ppm) 37.1, 43.2, 77.3, 111.5, 118.1, 119.4,
119.9, 121.4, 122.7, 126.5, 127.1, 127.8, 128.9, 136.8, 142.8, 190; IR (KBr)
m
15. Tang, H.-Y.; Lu, A.-D.; Zhou, Z.-H.; Zhao, G.-F.; He, L.-N.; Tang, C.-C. Eur. J. Org.
Chem. 2008, 1406–1410.
(cmꢀ1) 3400, 2923, 2357, 1762, 1618, 1459, 1128, 1042, 812, 735, 696, 586,
418; MS (ESI) m/z 316.11 [MꢀH]ꢀ.
16. Adachi, S.; Tanaka, F.; Watanabe, K.; Harada, T. Org. Lett. 2009, 11, 5206–5209.
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18. You, S.-L.; Cai, Q.; Zeng, M. Chem. Soc. Rev. 2009, 38, 2190–2201.
19. More recently, a similar communication was published by Higashiyama and
co-workers using Dy(OTf)3–Pybox complex: Sasaki, S.; Yamauchi, T.;
Higashiyama, K. Tetrahedron Lett. 2010, 51, 2326–2328.
20. Akiyama, T. Chem. Rev. 2007, 107, 5744–5758.
29. General procedure for the reduction of arylated product: A mixture of NaBH4
(0.3 mmol) and optically pure 4a (0.1 mmol, >99.9% ee) in methanol (3 mL)
was stirred 24 h under air (monitored by TLC). The diastereoisomers were
purified directly by flash column chromatography with ethyl acetate/
petroleum ether (1:20 to 1:10) to afford the desired product (anti/syn = 1:1).
Total yield: 68%. Diastereomer-1: 98% ee [Daicel Chiralcel OD-H, Hexane/i-
PrOH = 90:10,
0.8 mL/min,
254 nm;
TR
(minor) = 18.078 min,
TR
21. You, S.-L. Chem. Asian J. 2007, 2, 820–827.
22. Terada, M. Chem. Commun. 2008, 4097–4112.
(major) = 33.526 min]. ½a D20
ꢁ
+21.2 (c 1.0, CH2Cl2); 1H NMR (500 MHz, CDCl3) d
(ppm) 1.30 (s, 1H, OH), 2.28–2.32 (m, 1H, CH2), 2.55–2.61 (m, 1H, CH2), 4.00
(dd, J = 7.5 Hz, 1H, CH), 4.60 (dd, J = 11.5, 1H, CH), 7.07–7.10 (m, 2H), 7.19–7.22
(m, 2H), 7.28–7.36 (m, 5H), 7.55–7.56 (d, J = 7.5 Hz, 1H), 8.08 (br s, 1H); 13C
NMR (125 MHz, CDCl3) d (ppm) 35.5, 38.3, 63.6, 77.2, 111.3, 119.7, 121.0,
23. Adair, G.; Mukherjee, S.; List, B. Aldrichim. Acta 2008, 41, 31–39.
24. Zhang, G.-W.; Wang, L.; Nie, J.; Ma, J.-A. Adv. Synth. Catal. 2008, 350, 1457–1463.
25. Nie, J.; Zhang, G.-W.; Wang, L.; Fu, A.; Zheng, Y.; Ma, J.-A. Chem. Commun. 2009,
2356–2358.
26. Nie, J.; Zhang, G.-W.; Wang, L.; Zheng, D.-H.; Zheng, Y.; Ma, J.-A. Eur. J. Org.
Chem. 2009, 3145–3149.
122.5, 127.0, 128.3, 129.0, 136.7, 142.9. IR (KBr)
m
(cmꢀ1) 3421, 3062, 2366,
1618, 1454, 1378, 1157, 1009, 778, 522, 492. MS (ESI) m/z 318.29 [MꢀH]ꢀ.
Diastereomer-2: 98% ee. [Daicel Chiralcel OD-H, Hexane/i-PrOH = 90:10,
27. Zhang, G.-W.; Zheng, D.-H.; Nie, J.; Wang, T.; Ma, J.-A. Org. Biomol. Chem. 2010,
8, 1399–1405.
0.8 mL/min, 254 nm, TR (minor) = 23.033 min, TR (major) = 49.138 min]. ½a D20
ꢁ
+20.3 (c 1.0, CH2Cl2); 1H NMR (500 MHz, CDCl3) d (ppm) 1.65 (s, 1H, OH), 2.37–
2.42 (m, 1H, CH2), 2.45–2.49 (m, 1H, CH2), 3.78 (dd, J = 7.5 Hz, 1H, CH), 4.56
(dd, J = 11.5, 1H, CH), 7.01–7.07 (m, 2H), 7.17–7.26 (m, 2H), 7.31–7.37 (m, 5H),
7.46–7.48 (d, J = 8.0 Hz, 1H), 7.98 (br s, 1H); 13C NMR (125 MHz, CDCl3) d (ppm)
36.3, 38.1, 69.3, 77.5, 111.5, 117.6, 119.5, 119.9, 121.6, 122.6, 126.6, 127.1,
28. General procedure for catalytic asymmetric arylation of
a,b-unsaturated
trifluoromethyl ketones with indole: To a Schlenk tube were added indole 2a
(0.15 mmol), unsaturated trifluoromethyl ketone 3a (0.18 mmol), chiral
phosphoric acid (0.015 mmol), and solvent (ClCH2CH2Cl/CH3CN = 1:1,
0.4 mL). After the solution was stirred for 120 h, the crude product was
purified directly by flash column chromatography with ethyl acetate/
128.8, 136.7, 144.7. IR (KBr)
m
(cmꢀ1) 3425, 3060, 2365, 1600, 1454, 1370,
1150, 1010, 778, 522, 495. MS (ESI) m/z 318.26 [MꢀH]ꢀ.