Highly enantioselective yttrium(III)-catalyzed Friedel-Crafts alkylation of β-trichloro(trifluoro)methyl aryl enones with indoles

Article abstract of DOI:10.1039/c1cc12306h

An efficient yttrium(iii)-catalyzed highly enantioselective Friedel-Crafts alkylation of β-trichloro(trifluoro)methyl aryl enones is described. The reaction delivered a series of functionalized indoles with a chiral tertiary carbon center bearing a trichloro(trifluoro)methyl group in excellent results (up to 96% ee and 99% yield) under mild conditions.

Full text of DOI:10.1039/c1cc12306h

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COMMUNICATION
Highly enantioselective yttrium(III)-catalyzed Friedel–Crafts alkylation of
b-trichloro(trifluoro)methyl aryl enones with indolesw
Wentao Wang, Xiangjin Lian, Donghui Chen, Xiaohua Liu, Lili Lin and Xiaoming Feng*
Received 20th April 2011, Accepted 20th May 2011
DOI: 10.1039/c1cc12306h
An efficient yttrium(III)-catalyzed highly enantioselective
Friedel–Crafts alkylation of b-trichloro(trifluoro)methyl aryl
enones is described. The reaction delivered a series of functional-
ized indoles with a chiral tertiary carbon center bearing a
trichloro(trifluoro)methyl group in excellent results (up to 96%
ee and 99% yield) under mild conditions.
activities, including antitumor, anti-HIV and analgesic activities.7
Herein, we wish to report an efficient yttrium(III) complex-
catalyzed highly enantioselective Friedel–Crafts alkylation
of b-trichloro(trifluoro)methyl aryl enones with indoles to
address these issues.
Initially, we selected the Friedel–Crafts alkylation of indole
1a with b-trichloromethyl-a,b-enone 2a as the model reaction,
which would readily give access to many bioactive indole
derivatives. Using 5 mol% of N,N0-dioxide L1–Y(OTf)3 as
the catalyst,8 the reaction proceeded sluggishly to afford the
corresponding (R)-adduct 3a with 9% yield and 80% ee
(Table 1, entry 1). The outcome of each asymmetric reaction
may be different depending on the relative steric hindrance and
electronic property of the ligand. Therefore, further optimization
of the reaction conditions was then aimed at exploring the
efficacy of Y(OTf)3 with other N,N0-dioxide ligands (Table 1,
entries 2–8). It was found that the steric effect of the amide
moiety (Fig. 1) played a crucial role in the activity and
enantioselectivity of the reaction. For example, when the
ligand L5 having a bulkier isopropyl group at the ortho
position of aniline was employed, the product 3a was obtained
Enantiomerically pure trichloro(trifluoro)methylated compounds
are fascinating in the field of biological and medicinal
chemistry, and are also utilized as versatile building blocks
in modern organic synthesis.1 Among them, especially those
featuring a trichloro(trifluoro)methyl group at an all-C
tertiary chiral carbon center remain challenging synthetic
targets.2 On the other hand, the indole framework is considered
to be one of the ‘‘privileged’’ structures in pharmaceutical
chemistry.3 In this context, to introduce these simple structures to
complex molecules would not only have potential biological
applications but also represent a significant contribution to
synthetic methodologies. The Friedel–Crafts alkylation4,5 of
indoles with trichloro(trifluoro)methyl olefins represents a
direct and promising route to this class of compounds, and
the development of asymmetric catalysts for such processes
has been the focus of recent research effort. In 2010, Shibata
and co-workers reported the first enantioselective Friedel–
Crafts reaction of b-trifluoromethylated acrylates with pyrroles
and indoles promoted by 20 mol% of bis(oxazoline)–
Zn(NTf2)2 complex at ꢀ75 1C.6a Very recently, Pedro et al.
described a highly enantioselective Friedel–Crafts alkylation
of b-trifluoromethyl-a,b-unsaturated ketones with indoles
using 20 mol% of zirconium(IV) complex.6b Although the
impressive advances have been made in this area,6c searching
for efficient catalysts that could achieve high reactivity and
enantioselectivity under mild reaction conditions and extending
the substrate scope are still desirable and challenging.
Furthermore, to our knowledge to date, there is no report in
which trichloromethyl olefins are employed. Nevertheless
trichlorinated molecules exhibit a wide range of biological
Table 1 Evaluation of reaction parameters
Entrya
Ligand
Metal
Time/h
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
L5
L5
L5
L5
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Sc(OTf)3
La(OTf)3
Sm(OTf)3
Y(OTf)3
30
30
26
45
45
30
49
45
30
36
36
52
9
8
80 (R)
65 (R)
90 (S)
93 (S)
94 (S)
0
85 (S)
91 (S)
76 (S)
—
55
67
75
16
31
76
82
NRd
NRd
89
9
10
11
12e
—
94 (S)
Key Laboratory of Green Chemistry & Technology,
Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, China. E-mail: xmfeng@scu.edu.cn;
Fax: +86 28-8541-8249
w Electronic supplementary information (ESI) available: CCDC
807085. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c1cc12306h
a
Unless otherwise noted, reactions were carried out with 5 mol% of
L–metal (1 : 1), 1a (0.12 mmol) and 2a (0.10 mmol) in CH2Cl2
b
c
(0.25 mL) at 35 1C. Isolated yield. Determined by chiral HPLC
analysis. NR = No reaction. CH2Cl2 (0.15 mL) was used.
d
e
c
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Chem. Commun., 2011, 47, 7821–7823 7821

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Table
2
Catalytic enantioselective Friedel–Crafts alkylation of
indoles 1 with b-trichloromethyl aryl enones 2
Entrya
R
Ar
Product Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
89
87
95
77
92
71
97
95
96
96
99
95
65
84
94
95
94
99
98
78
68
40
85
94 (S)
91
92
88
95
90
92
93
91
96
90
94
91
85
90
90
86
4-FC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
4-MeC6H4
3-ClC6H4
3-NO2C6H4
2-ClC6H4
2-FC6H4
Fig. 1 Screened ligands in this study.
with opposite configuration in 75% yield and 94% ee (Table 1,
entry 5). Decreasing the steric hindrance of the amide moiety
led to poor results (Table 1, entry 2). However, a racemic product
was obtained when 1-adamantylamine-derived N,N0-dioxide
L6 was used as the chiral ligand (Table 1, entry 6). As for the
chiral backbone moiety, L-pipecolic acid-derived N,N0-dioxide
L5 was superior to both L7 (derived from L-proline) and L8
(derived from L-ramipril acid) (Table 1, entry 5 vs. entries 7
and 8). Subsequently, we surveyed other rare earth metal salts
and found that Sc(OTf)3 exhibited higher activity, whereas the
enantioselectivity of the reaction was lower than Y(OTf)3
(Table 1, entries 9–11). To our delight, the moderate yield of
3a could be overcome to some extent by prolonging the
reaction time and increasing the concentration, and the
enantiomeric excess remained the same (Table 1, entry 12, 89%
yield, 94% ee). Therefore, the optimal reaction conditions
were as follows: 5 mol% of L5–Y(OTf)3 (1 : 1), 1 (0.12 mmol)
and 2 (0.10 mmol) in CH2Cl2 at 35 1C.
9
10
11
12d
13d
14
15
16
17
18
19
20
21
22
23e
3j
3,4-Cl2C6H3 3k
2-Naphthyl
1-Naphthyl
2-Thienyl
Ph
Ph
Ph
3l
3m
3n
3o
3p
3q
3r
3s
3t
5-Me
6-Me
7-Me
5-MeO Ph
7-Et Ph
6-MeO Ph
5-Cl
5-F
H
93
83
90
72
82
93 (S)
Ph
Ph
Ph
3u
3v
3a
a
Unless otherwise noted, reactions were carried out with 5 mol% of
L5–Y(OTf)3 (1 : 1), 1 (0.12 mmol) and 2 (0.10 mmol) in CH2Cl2
(0.15 mL) at 35 1C for 26–74 h. Isolated yield. c Determined by chiral
HPLC analysis; the absolute configuration of 3a was determined to be S by
X-ray crystallographic analysis. Indole (0.2 mmol) was used. e The
b
d
Under the optimal reaction conditions (Table 1, entry 12),
various b-trichloromethyl aryl enones 2 and indoles 1 were
screened, giving the desired products with high to excellent
enantioselectivities (up to 96% ee).9 It was noteworthy that
either the electronic nature or the position of the substituents
at the phenyl ring of enones had little influence on the
enantioselectivity and activity of the reaction (Table 2, entries
1–11, 88–96% ee, 71–99% yield). Moreover, heteroaromatic
and fused ring substrates were also applicable, giving the
desired products with good results (Table 2, entries 12–14).
With regard to the indole ring containing electron-donating
groups (CH3 or CH3O), the reaction also proceeded smoothly
to afford trichloroalkylated indoles in excellent yields with up
to 93% ee (Table 2, entries 15–20). However, in the case of
halogen-substituted indoles, moderate reactivities and enantio-
selectivities were obtained (Table 2, entries 21 and 22). Notably,
by treatment of 1.0 mmol of starting materials under the
optimal reaction conditions, the reaction still worked well to
afford 3a in 85% yield with 93% ee (Table 2, entry 23). The
absolute configuration of the product 3a was determined to
be S by X-ray crystallography analysis.
reaction was conducted on a 1.0 mmol scale, for details see ESI.w
Table 3 Catalytic enantioselective Friedel–Crafts alkylation of indoles 1
with b-trifluoromethyl aryl enones 4
Entrya
R
Ar
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
5-Me
6-Me
5-MeO
6-MeO
5-F
H
Ph
5a
5b
5c
5d
5e
5f
5g
5h
5i
96
99
95
99
96
96
88
99
87
99
99
60
99
94 (S)
96
93
96
92
80
86
81
90
96
96
79
94 (S)
4-NO2C6H4
4-MeC6H4
3-NO2C6H4
2-FC6H4
4-ClC6H4
2-Naphthyl
Ph
Ph
Ph
Ph
Ph
9
10
11
12
13d
5j
5k
5l
Ph
5a
Encouraged by the above good performance of the current
catalyst system, its general applicability in the Friedel–Crafts
reaction of indoles with b-trifluoromethyl-enones was also
examined under the same reaction conditions.9 As shown in
Table 3, usually, the b-trifluoromethyl aryl enones 4 exhibited
higher activity than b-trichloromethyl aryl enones 2. It seems
that the CF3 group favors the Friedel–Crafts reaction due to
a
Unless otherwise noted, reactions were carried out with 5 mol% of
L5–Y(OTf)3 (1 : 1), 1 (0.12 mmol) and 4 (0.10 mmol) in CH2Cl2
b
c
(0.25 mL) at 35 1C for 17–30 h. Isolated yield. Determined by chiral
HPLC analysis; the absolute configuration of 5a was determined to be S
by comparison with the reported value of optical rotation.6b d The
reaction was conducted on a 1.0 mmol scale, for details see ESI.w
c
7822 Chem. Commun., 2011, 47, 7821–7823
This journal is The Royal Society of Chemistry 2011

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Fig. 2 Proposed working model and X-ray crystallographic structure
of 3a.
its higher electron-withdrawing character. And the corres-
ponding trifluoromethylated indoles were obtained in high to
excellent yields and enantioselectivities (Table 3, entries 1–12,
60–99% yield, 79–96% ee). In addition, when the reaction was
scaled up tenfold with 5 mol% of L5–Y(OTf)3 complex,
excellent results (99% yield and 94% ee) were still maintained
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Based on the absolute configuration of the product 3a and
our previous studies on N,N0-dioxide–metal complexes,8e,f
a
possible working model was proposed (Fig. 2). As shown in
Fig. 2, the oxygens of N,N0-dioxide, amide oxygens coordinated
to Y(III) in a tetradentate manner to form two six-membered
chelate rings, and the enone 2a can coordinate to Y(III) from
the more accessible side. The incoming indole prefers to attack
the Re face rather than the Si face of the enone 2a because the
latter is strongly shielded by the nearby 2,6-diisopropylphenyl
group of N,N0-dioxide L5, which results in the S-configured
product.
In conclusion, we have developed a highly enantioselective
Friedel–Crafts alkylation of b-trichloro(trifluoro)methyl aryl
enones with indoles promoted by 5 mol% of N,N0-dioxide
L5–Y(OTf)3 complex under mild conditions. The reaction not
only provides a wide variety of biologically interesting indoles
with high to excellent yields (up to 99%) and excellent
enantioselectivities (up to 96% ee), but also opens a new entry
to construct tertiary carbon stereogenic centers bearing a CCl3
group. Further applications of the methodology are currently
underway in our laboratory.
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We appreciate the National Natural Science Foundation of
China (Nos 20732003 and 21021001), and the Basic Research
Program of China (973 Program: 2011CB808600) for financial
support. We also thank Sichuan University Analytical &
Testing Center for NMR and X-ray analysis, and the State
Key Laboratory of Biotherapy for HRMS analysis.
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9 For the results of sub-optimal substrates, see ESIw (page 20–22).
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 7821–7823 7823