Chiral Bronsted acid-catalyzed enantioselective friedel-crafts reaction of 4,7-dihydroindoles with trifluoromethyl ketones

Article abstract of DOI:10.1002/adsc.201000510

In the presence of chiral phosphoric acid, an enantioselective Friedel-Crafts reaction of 4,7-dihydroindoles with aromatic trifluoromethyl ketones and ethyl 4,4,4-trifluoroacetoacetate has been realized. A series of 2-substituted 4,7-dihydroindoles with a trifluoromethylated tertiary alcohol moiety were obtained in 45-95% yields with 60-93% ee. Furthermore, 2-functionalized indole derivatives could be produced through a one-pot process.

Full text of DOI:10.1002/adsc.201000510

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DOI: 10.1002/adsc.201000510
Chiral Brønsted Acid-Catalyzed Enantioselective Friedel–Crafts
Reaction of 4,7-Dihydroindoles with Trifluoromethyl Ketones
Teng Wang,a Guang-Wu Zhang,a Yuou Teng,a Jing Nie,a Yan Zheng,a
and Jun-An Maa,b,*
a
Department of Chemistry, Tianjin University, Tianjin 300072, Peopleꢀs Republic of China
Fax : (+86)-22-2740-3475; e-mail: majun_an68@tju.edu.cn
State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, People Republic of China
b
Received: June 30, 2010; Published online: October 26, 2010
Abstract: In the presence of chiral phosphoric acid,
an enantioselective Friedel–Crafts reaction of 4,7-
dihydroindoles with aromatic trifluoromethyl ke-
tones and ethyl 4,4,4-trifluoroacetoacetate has been
realized. A series of 2-substituted 4,7-dihydroin-
doles with a trifluoromethylated tertiary alcohol
moiety were obtained in 45–95% yields with 60–
93% ee. Furthermore, 2-functionalized indole deriv-
atives could be produced through a one-pot pro-
cess.
On the other hand, considerable advancement has
been made during the past decades for catalytic asym-
metric Friedel–Crafts reactions of pyrroles at the 2-
position.[6] Recently, SaraÅoglu and co-worker report-
˘
ed that the Friedel–Crafts reaction of 4,7-dihydroin-
dole (2,3-disubstituted pyrrole) with enones, followed
by a p-benzoquinone oxidation, gave 2-substituted in-
doles in moderate yields.[7] Subsequently, two research
groups developed the asymmetric version of this reac-
tion by utilizing chiral Lewis acid catalysts, providing
easy access to enantioenriched 2-substituted indole
derivatives.[8] More recently, enantioselective Friedel–
Crafts reactions of 4,7-dihydroindoles with imines and
a,b-unsaturated carbonyl compounds activated by
chiral organocatalysts have been described by You[9a,b]
and Wang.[9c] In contrast, little progress has been
made in the development of trifluoromethyl ketones
as electrophilic reagents in the Friedel–Crafts reaction
Keywords: Brønsted acids; 4,7-dihydroindoles;
enantioselectivity; Friedel–Crafts reaction; tri-
fluoromethyl-substituted compounds
Chiral compounds with a trifluoromethyl-substituted of 4,7-dihydroindoles, and only one example by Pedro
tertiary alcohol moiety have a considerable impor- and co-workers has addressed 2,2,2-trifluoroacetophe-
tance in the field of biological and medicinal chemis- none as an electrophilic species.[8d] We were delighted
try.[1] In particular, the application of Mosherꢀs acid[2a] to find that chiral Brønsted acids 1 serve as efficient
and some drugs such as Efavirenz (anti-HIV)[2b] or organocatalysts in the Friedel–Crafts reaction of 4,7-
CJ-17,493 (NK-1 receptor antagonists),[2c] chiral tri- dihydroindoles with aromatic trifluoromethyl ketones
fluoromethyl tertiary alcohols in which the CF3 and ethyl 4,4,4-trifluoroacetoacetate for the synthesis
moiety is located at a stereogenic tetrasubstituted of 2-substituted indoles with a trifluoromethyl-substi-
carbon atom, has stimulated investigations in this tuted tertiary alcohol moiety.
area. One of the methods to synthesize chiral tri-
We initially investigated the reaction of 4,7-dihy-
ACHTUNGTRENNUNGfluoromethylated alcohols is by asymmetric addition droindole (2a) with 2,2,2-trifluoroacetophenone (3a)
of various nucleophiles to trifluoromethyl ketones.[3] in the presence of readily available BINOL-derived
We have demonstrated that chiral phosphoric acids[4] phosphoric acid 1a (10 mol%) in toluene (Scheme 1).
can efficiently promote the enantioselective additions The starting material 2a disappeared almost com-
of indoles to trifluoroacetaldimines and trifluorometh- pletely within 30 h (detected by TLC), however, the
yl ketones.[5] However, due to the dramatic difference desired adduct 4a was obtained only in moderate
in reactivity between the 2- and 3-positions of indole, yield (48%) with poor enantioselectivity. Interestingly,
these successful examples are limited to the formation the racemic by-product 5a was observed (43%). A ki-
of 3-substituted indoles with a trifluoromethyled netic profile was then obtained for these transforma-
amine or alcohol moiety. Therefore, we have an inter- tions (Figure 1). Accompanied by a slow drop in the
est in developing a suitable protocol for the synthesis concentration of 4,7-dihydroindole 2a, an increase in
of trifluoromethylated 2-indolylmethanol derivatives.
the concentration of the desired product 4a occurs
gradually. A significant increase in the concentration
Adv. Synth. Catal. 2010, 352, 2773 – 2777
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Teng Wang et al.
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Scheme 1. Brønsted acid 1a-catalyzed Friedel–Crafts reaction of 4,7-dihydroindole 2a with 2,2,2-trifluoroacetophenone 3a.
Table 1. Optimization of the reaction conditions.
Figure 1. In the graph, the relative concentrations, moni-
Entry Catalyst
(mol%)
Solvent
T
Yield
ee
&
^
tored by HPLC, of 2a ( ), product 4a ( ), and by-product
[8C] [%][a]
[%][b]
~
5a ( ) under standard conditions are compared to the rela-
tive concentrations of the same compounds.
1
2
3
4
5
6
7
8
1a (10)
1b (10)
1c (10)
1d (10)
1e (10)
1f (10)
1g (10)
1h (10)
1i (10)
1j (10)
1i (15)
1i (10)
1i (10)
1i (10)
1i (10)
1i (10)
1i (10)
1i (10)
1i (10)
1i (10)
1i (10)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
benzene
xylene
xylene
mesitylene
CH2Cl2
ClCH2CH2Cl 25
CHCl3
xylene
xylene
xylene
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
86
62
67
56
56
76
52
55
58
45
40
47
68
53
43
61
74
42
58
67
75
<5
<5
<5
<5
<5
6
<5
48
60
<5
60
50
85
93
67
48
50
40
80
60
79
of the undesired product 5a was observed with pro-
longed reaction times. In the control reaction, the iso-
lated adduct 4a was rapidly converted into 5a with a
catalytic amount of 1a (10 mol%). This is a strong in-
dication that by-product 5a could be formed through
dehydration and oxidation of the alkylation product
4a. Thus, screening experiments were carried out for
24 h with respect to the yield of the desired adduct.
A further screening of catalysts has been carried
out and the results are shown in Table 1 (entries 1–
11). It was found that phosphoric acid 1i, with bulky
4-adamantanyl-2,6-diisopropylphenyl groups at the
3,3’-positions of the binaphthyl scaffold, gave the
9
10
11
12
13
14[c]
15
16
17
18
25
15
0
highest enantioselectivity (60% ee) (entry 9). Subse- 19
20
21
quently, an optimization of the reaction solvents was
undertaken (entries 12–18). Among the solvents
tested, xylene was found to be the best with respect
to catalytic activity and asymmetric induction (en-
tries 13 and 14). Substantial changes in reaction tem-
perature had s significant effect on the enantioselec-
tivity (entries 19–21 vs. 14). Good results were at-
tained when the reaction were carried out at room
temperature for 28 h.
40
[a]
[b]
Isolated yield.
Enantiomeric excess was determined by chiral HPLC
analysis.
Reaction time: 28 h.
[c]
yl ketones and substituted 4,7-dihydroindoles has
With the optimal conditions established, the scope been examined in the presence of 1i. The results are
of the Friedel–Crafts reaction between trifluorometh- summarized in Table 2. A series of aromatic trifluoro-
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Adv. Synth. Catal. 2010, 352, 2773 – 2777

Chiral Brønsted Acid-Catalyzed Enantioselective Friedel–Crafts Reaction of 4,7-Dihydroindoles
Table 2. Enantioselective Friedel–Crafts reaction of 4,7-dihydroindoles with aromatic trifluoromethyl ketones.
Entry
R
Ar
Product 4
Product 5
Yield [%][a]
ee [%][b]
Yield [%][a]
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
C6H5 (3a)
53 (4a)
45 (4b)
54 (4c)
54 (4d)
57 (4e)
69 (4f)
47 (4g)
55 (4h)
55 (4i)
45 (4j)
93
66
61
61
73
65
72
60
90
67
46 (5a)
45 (5b)
42 (5c)
43 (5d)
30 (5e)
4-FC6H4 (3b)
4-ClC6H4 (3c)
4-BrC6H4 (3d)
4-MeC6H4 (3e)
3,5-Me2C6H3 (3f)
4-PhC6H4 (3g)
2-naphthyl (3h)
C6H5 (3a)
[c]
–
50 (5g)
[c]
–
Me
Me
43 (5i)
51 (5j)
10
4-MeC6H4 (3e)
[a]
Isolated yield.
[b]
[c]
Enantiomeric excess was determined by chiral HPLC analysis.
No isolation.
Scheme 2. Organocatalytic enantioselective Friedel–Crafts reaction of 4,7-dihydroindoles with ethyl trifluoroacetoacetate 7.
Scheme 3. Friedel–Crafts reaction of 4,7-dihydroindoles with trifluoromethyl ketones and p-benzoquinone oxidation. The ab-
solute configuration of 9a was determined by comparison of retention time and specific rotation with those reported in the
literature.[8d] The absolute configuration of adduct 9b was assigned on the basis of an analogy with the study of 9a.
methyl ketones has been tested in the reaction with tions to afford the adducts 8a and 8b in high yields
4,7-dihydroindole 2a. Moderate yields and good to and enantioselectivities (Scheme 2).
high enantioselectivities were achieved for the adduct
Subsequently, we developed a one-pot procedure
4a–h (entries 1–8). When 5-methyl-4,7-dihydroindole including the Friedel–Crafts reaction of 4,7-dihydroin-
2b was used as a substrate, the desired products 4i doles with trifluoromethyl ketones and further oxida-
and 8j were also obtained with 90% ee and 67% ee, tion of the resulting adducts with p-benzoquinone.
respectively (entries 9 and 10). Accordingly, in most The corresponding trifluoromethyl-substituted 2-in-
cases the by-products 5 were isolated in moderate dolyl compounds 9a and 9b were obtained smoothly
yields. It was noteworthy that the reaction of 4,7-dihy- with high enantioselectivities (92% ee for 9a and 90%
droindoles 2a and 2b with ethyl trifluoroacetoacetate ee for 9b, respectively) (Scheme 3). This is a strong in-
7 proceeded well under our current reaction condi- dication that the current methodology is suitable for
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Teng Wang et al.
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methyl-substituted tertiary alcohol moiety.
In summary, we have developed a catalytic enantio-
selective Friedel–Crafts reaction of 4,7-dihydroindoles
with trifluoromethyl ketones by employing BINOL-
derived phosphoric acids as organocatalysts. The reac-
tion takes place with good to high enantioselectivities
(up to 93% ee). Furthermore, the resulting 4,7-dihy-
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of p-benzoquinone with high enantioselectivity. Fur-
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Experimental Section
Typical Procedure
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(9.4 mg, 0.01 mmol), 4,7-dihydroindole 2a (11.9 mg,
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Acknowledgements
We gratefully appreciate the National Natural Science Foun-
dation of China (No. 20772091 and 20902067) for generous
financial support.
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