Dy(OTf)3/Pybox-catalyzed enantioselective Friedel-Crafts alkylation of indoles with α,β-unsaturated trifluoromethyl ketones

Article abstract of DOI:10.1016/j.tetlet.2010.02.121

The first catalytic enantioselective Friedel-Crafts alkylation of indoles with α,β-unsaturated trifluoromethyl ketones has been accomplished. The reaction was achieved in the presence of the Dy(OTf)₃/Pybox complex, producing the desired product

Full text of DOI:10.1016/j.tetlet.2010.02.121

Tetrahedron Letters 51 (2010) 2326–2328
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Dy(OTf)3/Pybox-catalyzed enantioselective Friedel–Crafts alkylation
of indoles with
a,b-unsaturated trifluoromethyl ketones
*
Shigeru Sasaki, Takayasu Yamauchi, Kimio Higashiyama
Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The first catalytic enantioselective Friedel–Crafts alkylation of indoles with
a,b-unsaturated trifluoro-
Received 28 December 2009
Revised 16 February 2010
Accepted 22 February 2010
Available online 25 February 2010
methyl ketones has been accomplished. The reaction was achieved in the presence of the Dy(OTf)3/Pybox
complex, producing the desired products in high yields (up to 99%) with good enantioselectivities (up to
86% ee). The absolute stereochemistry of the resulting adducts was determined by X-ray analysis.
Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
Keywords:
a,b-Unsaturated trifluoromethyl ketones
Indoles
Enantioselective Friedel–Crafts alkylation
Organic fluorine compounds often show unique bioactivities
and behavior compared with their non-fluorinated parent compo-
uds.1 Currently, about 20–30% of agrochemicals and pharmaceuti-
cals owe their effectiveness due to the presence of one or more
fluorine atoms in their structure. Various organic fluorine com-
nor, and the isopropyl side chain of 4a can be easily changed with
other alkyl substituents.5d The use of the Ln/Pybox system in syn-
thesis methodology has been reported.5 In this work, various
Ln(OTf)3/Pybox 4a systems were applied to the reaction of 1 with
2 (Table 2).
The reaction of 1 with 2 was attempted in the presence of
5 mol % Sc(OTf)3 and 4 in DCM to give the corresponding adduct
3a in good yield and with opposite enantioselectivity (entry 1).
Based on the previous report, the formation of opposite enantio-
pounds have been synthesized,2 for example,
a,b-unsaturated tri-
fluoromethyl ketones have been prepared,3 involving a directly
linking electron-withdrawing trifluoromethyl group with a highly
reactive p-system.
The Friedel–Crafts (F–C) alkylation of indoles4 is of interest be-
cause a number of biologically active derivatives exist as natural
compounds. However, there is yet no report on the F–C alkylation
Table 1
of indoles with a,b-unsaturated trifluoromethyl ketones. Here, we
Acid-catalyzed F–C alkylation of 1 with 2
studied the role of such ketones as Michael acceptors yielding syn-
thetic fluorine-containing indole derivatives.
The reactions of indole 1 with a,b-unsaturated trifluoromethyl
ketones 2 were chosen as models for optimizing the reaction con-
dition. To evaluate the behavior of acid catalysts (Table 1), 1 was
reacted with 1.05 equiv of 2 and a catalytic amount of acids in
dichloromethane (DCM) at room temperature to yield the product
3a. Classical Brønsted (entries 2 and 3) and Lewis (entries 4 and 5)
acid catalysis on F–C alkylation produced unsatisfactory results,
but the one using Sc(OTf)3 catalyst gave the desired adduct 3a in
good yield.
Entry
Catalyst
Conversiona (%)
The above-mentioned result led us to investigate the complexes
of lanthanide (Ln) and Pybox 4a–e (Fig. 1), where the pyridine- and
imine-building blocks support the ligand as a strong electron do-
1
2
3
4
5
6
None
p-TsOH
PPTS
BF3OEt2
Ti(Oi-Pr)4
Sc(OTf)3
5
41
No reaction
Trace
18
81
* Corresponding author. Tel.: +81 3 5498 5770; fax: +81 3 5498 5768.
E-mail address: kimio@hoshi.ac.jp (K. Higashiyama).
a
Calculated by 1H NMR spectra.
0040-4039/$ - see front matter Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.121

S. Sasaki et al. / Tetrahedron Letters 51 (2010) 2326–2328
2327
Table 3
Enantioselective F–C alkylation with Dy(OTf)3/Pybox 4a–e
Figure 1. Pybox 4a–e.
Table 2
Enantioselective F–C alkylation of 1 with 2
Entry
Pybox
Yield of 3aa (%)
eeb (%)
1
2
3
4
5
4a
4b
4c
4d
4e
95
98
62
13
55
84
77
64
13
70
a
Isolated yield.
Determined by HPLC.
b
Table 4
Enantioselective F–C alkylation of indoles 5 with 2
Entry
Ln
Yield of 3aa (%)
eeb (%)
1
2
3
4
5
6
7
8
9
Sc
Y
La
Sm
Eu
Gd
Tb
Dy
Ho
Yb
85
>99
29
>99
>99
84
88
>99
93
À47
84
53
76
83
84
85
87
83
74
10
60
a
Isolated yield.
Determined by HPLC.
b
Entry R1
R2
Conc of 5 (mol/
L)
Reaction
time
Yielda
(%)
eeb
(%)
1
2
3
4
5
6
7
8
9
H
H
H
H
MeO
Me
F
Cl
Br
0.2
0.2
0.2
0.1
0.1
0.4
0.4
0.4
1
20 h
2 d
2 d
18 h
18 h
4 d
4 d
4 d
4 d
4 d
95 (3a)
98 (3b)
77 (3c)
96 (3d)
99 (3e)
91 (3f)
91 (3g)
77 (3h)
97 (3i)
60 (3j)
84
16
16
77
85
72
78
77
19
7
mers by changing the Ln(OTf)3/Pybox catalyst has been already
examined.6 It was assumed that difference lanthanide ion radius
gives different enantioselectivity due to the changing of their coor-
dination with chiral ligand.7 The reaction also proceeded smoothly
in the presence of 5 mol % Y(OTf)3 (entry 2). In contrast, La(OTf)3
promoted no similar reactions (entry 3), although the other
Ln(OTf)3 compounds of f-blocks (except Yb(OTf)3) were shown to
be effective catalysts, yielding the adduct 3a in good yields and
enantioselectivities, and Dy(OTf)3 was found to be the best (entries
4–10). Owing to the insufficient reproducibility of the Dy(OTf)3
system, therefore, we examined the amount of Dy(OTf)3 and Pybox
to determine the optimum synthesis condition (7.5 mol % Dy(OTf)3
and 5 mol % Pybox were used).8
We then turned our attention to the effect of ligand substitution
on the F–C alkylation (Table 3). In terms of enantioselectivity, i-Pr-
Pybox (4a) is clearly the most effective ligand in the Dy(OTf)3-cat-
alyzed F–C alkylation (entry 1). Rather surprisingly, t-Bu and ind-
ano-Pybox (4d, e) gave poor yield and enantioselectivity (entries
4 and 5). In this study we found that the optimum enantioselectiv-
ity was achieved with Dy(OTf)3/i-Pr-Pybox catalyst.
Since the Dy(OTf)3/Pybox 4a system was found useful in the
reaction of 1 with 2, the enantioselective F–C alkylations of various
indole derivatives 5 with 2 were attempted as shown in Table 4. In
all cases, the reactions provided the desired adduct 3a–j in good
yields. However, N-alkylated indoles had a detrimental effect on
enantioselectivity (R1 = Me and Bn; entries 2 and 3). In contrast
to the electron-donating groups, which have a beneficial effect
(R2 = MeO and Me; entries 4 and 5), the electron-withdrawing
groups (R2 = F, Cl, Br, CO2Me, CN) in C-5 of the indole skeleton ap-
pear to result in low reactivities (entries 6–10) and enantioselec-
tivities (entries 9 and 10). The low reactivities were overcome by
Me
Bn
H
H
H
H
H
H
H
CO2Me
CN
10
0.5
a
Isolated yield.
Determined by HPLC.
b
the use of high concentrations of indoles in a longer reaction time
to obtain the products in good yields.
Next, the enantioselective F–C alkylations of various a,b-unsat-
urated trifluoromethyl ketones 6 were attempted in order to deter-
mine the reaction condition (Table 5). The presence of a range of
electron-withdrawing substituents at the aromatic ring had little
influence on enantioselectivity. However, replacing the aromatic
ring with aliphatic groups such as n-C6H13 (entry 12) resulted in
lowering of the enantioselectivity.
The absolute configuration of 3a was determined by X-ray anal-
ysis (see Supplementary data) of the bromo derivative 7k. The
hydrogenolysis of 7k with Pd(OH)2/H2 afforded 3a, and the abso-
lute configuration proposed previously for 3a was validated
(Scheme 1).
In summary, we devised Dy(OTf)3/Pybox as an effective cata-
lytic system for the enantioselective F–C alkylation of indoles with
,b-unsaturated trifluoromethyl ketones furnishing synthetic fluo-
rine-containing indoles in good yields and enantioselectivities. The
catalytic system can be easily obtained from a commercial source,
a

2328
S. Sasaki et al. / Tetrahedron Letters 51 (2010) 2326–2328
Table 5
Supplementary data
Enantioselective F–C alkylation of 1 with 6a–l
Experimental procedures, structural proofs, NMR spectra, HPLC
profiles, and X-ray crystallography data are available. CCDC
730908 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/da-
ta_request/cif. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/j.tetlet.2010.
02.121.
Entry
R
Reaction time
Yielda (%)
eeb (%)
References and notes
1
2
3
4
5
6
7
8
9
o-MeO–Ph (6a)
m-MeO–Ph (6b)
p-MeO–Ph (6c)
o-Me–Ph (6d)
m-Me–Ph (6e)
p-Me–Ph (6f)
p-F–Ph (6g)
o-Cl–Ph (6h)
m-Cl–Ph (6i)
p-Cl–Ph (6j)
4 d
4 d
4 d
3 d
3 d
3 d
22 h
22 h
22 h
22 h
22 h
36 h
98 (7a)
96 (7b)
78 (7c)
90 (7d)
95 (7e)
95 (7f)
93 (7g)
99 (7h)
99 (7i)
94 (7j)
99 (7k)
95 (7l)
72
84
71
81
84
81
79
81
83
80
86
17
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Scheme 1. Determination of absolute configuration of 7k and 3a.
and our simple procedure is particularly suitable for introducing a
trifluoromethyl ketone unit into drug candidates having complex
structures.
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8. The reaction was performed with 2.5 mol % Dy(OTf)3 and 5 mol % i-Pr-Pybox to
give product 3a in low yield and poor enantioselectivity (22%, 42%ee). Though
5 mol % dried Dy(OTf)3 (60 °C, 30 min, under vacuum) was used, the F–C
alkylation did not proceed. Therefore for providing the optimum condition we
should use a little excess Dy(OTf)3 (7.5 mol %) and 5 mol % of i-Pr-Pybox without
purification.
Acknowledgment
This work was supported in part by the Open Research Center
Project.