Highly enantioselective friedel-crafts-type alkylation reactions of indoles with chalcone derivatives using a chiral barium catalyst

Article abstract of DOI:10.1002/asia.201000347

Ba Ba black sheep: We have developed novel barium/binol catalysts prepared from alkaline earth metal amides and chiral binaphthol ligands. These catalysts effectively promoted the asymmetric Friedel-Crafts-type alkylation reactions of indoles with chalcon

Full text of DOI:10.1002/asia.201000347

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DOI: 10.1002/asia.201000347
Highly Enantioselective Friedel–Crafts–type Alkylation Reactions of Indoles
with Chalcone Derivatives using a Chiral Barium Catalyst
Tetsu Tsubogo, Yuichiro Kano, Yasuhiro Yamashita, and Shu Kobayashi*[a]
¯
Alkaline earth metals are abundant, nontoxic and inex-
pensive, and have high coordination numbers. Their salts
have both Brønsted basicity and Lewis acidity. Despite
these characteristic features, only recently have successful
examples using alkaline earth metal compounds as catalysts
in organic synthesis been reported.[1–5] We have developed
anionic chiral calcium catalysts prepared from calcium alk-
oxides or amides and chiral bisoxazoline (box) ligands[4] and
strontium catalysts prepared from strontium alkoxides or
amides and chiral sulfonamides.[2] These catalysts worked
well as Brønsted bases for several catalytic asymmetric
of their versatile synthetic utilities, the use of chalcone de-
rivatives as enones has been limited.[6g]
We considered that alkaline earth metal complexes might
function as chiral Brønsted base catalysts in the Friedel–
Crafts–type reactions of indoles. The reaction of indole 8a
with chalcone 9a was selected as a model reaction, and sev-
eral combinations of alkaline earth amides[9] with chiral li-
gands were tested. First, we examined the combination of al-
kaline earth metal amides with taddols (a,a,a’,a’-tetraaryl-
1,3-dioxolan-4,5-dimethanoles) 1[10] in the model reaction
(Figure 1). When barium amide (barium bis(hexamethyldi-
À
carbon carbon bond-forming reactions. We also found that
a chiral coordinative ligand (pybox)[5] was applicable for
asymmetric 1,4-addition and Mannich-type reactions using a
calcium catalyst. Herein, we report that chiral barium com-
plexes prepared from barium amides and chiral ligands
work well as efficient catalysts for asymmetric Friedel–
Crafts–type alkylation reactions of indoles with chalcone de-
rivatives.
Enantioselective Friedel–Crafts–type alkylation reactions
of indoles provide versatile methods for the preparation of
optically active indole derivatives. As catalytic asymmetric
reactions are ideal from a viewpoint of efficiency, some cata-
lysts for these reactions have been developed recently; how-
ever, most are chiral Lewis acids[6a–g,7a–d] or organocata-
lysts.[6h–k,7e] To the best of our knowledge there are no exam-
ples of Brønsted base catalyzed asymmetric Friedel–Crafts–
type reactions of indoles with enones.[8] Moreover, in spite
Figure 1. Chiral ligands combined with alkaline earth metal compounds.
silazide), [BaACHTNUTRGNEUNG(hmds)2]) and 1 were combined, the desired
adduct was obtained in good yield with low enantioselectivi-
ty (Table 1, entry 1). We then proceeded to use other alka-
line earth metal amides, [Sr
interesting to find that [Sr(hmds)2] gave a racemic product.
The desired alkylated indole was obtained in good yield and
with high enantioselectivity when using [Ca(hmds)2]
(Table 1, entries 3–6). Furthermore, the opposite enantio-
mers were obtained when using [Ba(hmds)2] and [Ca-
(hmds)2] with the same ligand 1. We further optimized the
reaction conditions using [Ca(hmds)2] with 1. As the enan-
tioselectivity decreased in diethyl ether, we elected to use
ether-free [Ca(hmds)2] instead of [Ca(hmds)2]·1.3Et2O and,
ACHUTGTNERN(NGU hmds)2] and [CaACHTUNGTRENN(GUN hmds)2]. It was
AHCTUNGTRENNUNG
[a] T. Tsubogo, Y. Kano, Dr. Y. Yamashita, Prof. Dr. S. Kobayashi
Department of Chemistry
ACHTUNGTRENNUNG
School of Science and Graduate School of Pharmaceutical Sciences
The University of Tokyo
The HFRE Division ERATO
Japan Science Technology Agency (JST)
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax : (+81)3-5684-0634
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
G
ACHTUNGTRENNUNG
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000347.
as expected, the enantioselectivity increased to 94%
1974
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Chem. Asian J. 2010, 5, 1974 – 1977

Table 1. Alkaline earth metal amide/taddol-catalyzed Friedel–Crafts–
type reaction.
the product was racemic. However, to our delight, when
[BaACTHNUTRGNE(NUG hmds)2] was combined with 3,3-substituted H8-Binol
4,[11]the reaction proceeded smoothly to afford the desired
adduct in 96% yield with 72% ee (Table 2, entry 2). We also
examined other alkaline earth metal amides ([Sr
and [Ca(hmds)2]); however, lower yields and enantioselec-
tivities were obtained (Table 2, entries 3 and 4). We then
further optimized the reaction conditions using [Ba(hmds)2]
ACHTUNGTRENNUNG(hmds)2]
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
Entry
M
Conditions
Yield [%]
ee [%]
and 4 in order to improve the enantioselectivity. The choice
of solvent was found to be crucial for the selectivity. The de-
sired product (S)-10aa was obtained in 86% yield with 95%
ee when tBuOMe/THF (9:1) was used as the solvent
(Table 2, entry 14).
We then investigated the substrate scope under optimized
conditions (Table 3). For chalcone derivatives, substrates
bearing both electron-withdrawing and electron-donating
groups in the benzene ring afforded high yields and enantio-
selectivities (Table 3, entries 1–7). As for the effects of the
positions of substituents on the aromatic rings on yield and
enantioselectivity, the para-substituted substrates afforded
the highest enantioselectivity compared with other sub-
strates, whilst meta-substituted substrates afforded lower
1
2
3
4
5
6
Ba
Sr
RT, MS 4 ꢁ
RT, MS 4 ꢁ
RT, MS 4 ꢁ
RT
85
82
70
69
61
61
42[a]
2[a]
84
89
91
Ca[b]
Ca[b]
Ca[b]
Ca
208C
208C
94
[a] The opposite enantiomer (S)-10aa was obtained. [b] [Ca-
ACHTUNGTRENNUNG(hmds)2]·1.3Et2O.
(Table 1, entry 6). We then investigated several other sub-
strates under the optimized conditions. Low yields were re-
corded, even after relatively long reaction times (>48 h),
with low enantioselectivities in most cases. We further tried
to optimize the reaction conditions by including additives
such as metal Brønsted bases, Lewis acids, and organobases,
and so forth, but no improvement was obtained.
Table 3. Substrate scope for indole derivatives.
Next, we examined other chiral ligands combined with al-
kaline earth metal amides (Table 2). As our preliminary
work on direct-type amide aldol reactions showed that a
combination of barium compounds with H8-binol ligands
such as 2 provided promising results,[1b] we first tested the
model reaction of indole 8a with chalcone 9a in the pres-
Entry
8
9
Product
Yield [%]
ee [%]
ence of 10 mol% each of [BaACHTNUGTRNEUNG(hmds)2] and H8-binol 3. The
reaction proceeded in moderate yield, but, disappointingly,
1
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8b
8c
8d
8e
8 f
9a
9b
9c
9d
9e
9 f
9g
9h
9i
10aa
10ab
10ac
10ad
10ae
10af
10ag
10ah
10ai
10aj
10ak
10ba
10ca
10da
10ea
10 fa
86
quant.
97
95
93
91
93
2[a]
3
4
5
6
92
89
96
Table 2. Optimization of reaction conditions.
68(80[b]
80
)
95(92[b]
95
)
7[a]
8
87
81
78
92
90
96
67
88
95
85
89
94
85
93
96
95
9
10
11[a]
12
13
14
15[a]
16[a,c]
9j
9k
9a
9a
9a
9a
9a
Entry
M
Binol
Conditions
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
Ba
Ba
Sr
3
4
4
4
2
5
6
4
4
4
4
4
4
4
THF, 48 h, 0.2m
THF, 48 h, 0.2m
THF, 48 h, 0.2m
THF, 48 h, 0.2m
THF, 48 h, 0.2m
THF, 48 h, 0.2m
THF, 48 h, 0.2m
Et2O, 48 h, 0.2m
tBuOMe, 48 h, 0.2m
Solvent[b], 24 h, 0.2m
Solvent[b], 24 h, 0.1m
Solvent[b], 24 h, 0.1m
Solvent[b], 24 h, 0.05m
Solvent[d], 24 h, 0.05m
58
96
28
13
quant.
80
81
77
71
86
1
72
18[a]
32[a]
67
84
70
Ca
Ba
Ba
Ba
Ba
Ba
Ba
Ba
Ba
Ba
Ba
[a] 60 h. [b] tBuOMe/THF=2:1. [c] Ligand 7 was used.
20
46
80
86
81
90
89
91
9
10
11
12[c]
13[c]
14[c]
91
99
90
86
95
[a] The opposite enantiomer (R)-10aa was obtained. [b] tBuOMe/THF=
2:1. [c] Indole (1.0 equiv) and chalcone (1.2 equiv) were used.
[d] tBuOMe/THF=9:1.
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1975

S. Kobayashi et al.
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enantioselectivity, while maintaining high enantioselectivity
(Table 3, entries 8–10). We also examined several indole de-
rivatives (Table 3, entries 12–16). When 5-chloroindole was
used, the enantioselectivity decreased slightly but the yield
remained high (Table 3, entry 12). In the cases of indoles
with electron-donating groups at the 5-positions, the reac-
tions proceeded smoothly to afford the corresponding ad-
ducts in high yields and with high enantioselectivities
(Table 3, entries 13 and 15). When 4-methoxyindole was
used, the yield decreased slightly, but the enantioselectivity
was still high (Table 3, entry 14). We then conducted the re-
action of 2-methylindole, and found that the reaction pro-
ceeded slowly and the enatioselectivity decreased, presuma-
bly because of steric hindrance at the 2-position (Table 3,
entry 16).
reaction and the catalyst structure, and to develop other re-
actions using alkaline earth metal compounds as catalysts,
are underway.
Experimental Section
A
typical experimental procedure: [BaACHTNGUTERNNU(G hmds)2] (0.015 mmol), 3,3’-
(Ph3Si)2-H8-Binol 4 (0.015 mmol), and M.S. 4 ꢁ (50 mg) were added to a
10 mL flame-dried vial with screw cap under an argon atmosphere. THF
(0.25 mL) was then added and the mixture was stirred for 2 h at room
temperature. Solutions of indole (8a, 0.15 mmol) in tBuOMe (1.4 mL)
and chalcone (9a, 0.18 mmol) in a mixture of THF (0.050 mL) and
tBuOMe (1.3 mL) were then added successively. The mixture was stirred
for 24 h at room temperature and then sat. NH4Cl (aq.) was added to
quench the reaction. After the addition of CH2Cl2 (10 mL), the organic
layer was separated, and the aqueous layer was extracted twice with
CH2Cl2 (15 mLꢂ2). The organic layers were combined and dried over
anhydrous Na2SO4. After filtration and concentration under reduced
pressure, the crude product was purified by preparative TLC (cyclohex-
ane/ether=2:1) to afford the desired product.
As for the catalyst structure, we assumed the formation of
barium phenoxide from barium amide and H8-binol, based
on NMR analyses.[12] A plausible catalytic cycle of this reac-
tion is shown in Figure 2.[13] First, the barium phenoxide de-
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Research from
the Japan Society for the Promotion of Science (JSPS), the Global COE
Program (Chemistry Innovation through Cooperation of Science and En-
gineering), the University of Tokyo, and MEXT (Japan). T.T. thanks the
JSPS Research Fellowship for Young Scientists.
Keywords: alkaline earth metals · alkylation · asymmetric
catalysis · barium · calcium
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an initial Friedel–Crafts adduct. The barium moiety then
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nates the indole to afford the product, along with regenera-
tion of the chiral indole.
In conclusion, we have developed novel barium/binol cat-
alysts prepared from a barium amide and a chiral ligand
(binol). These catalysts effectively promote the asymmetric
Friedel–Crafts–type alkylation reactions of indoles with
chalcone derivatives. To the best of our knowledge, this is
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1976
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Chem. Asian J. 2010, 5, 1974 – 1977

Enantioselective Friedel–Crafts Alkylation of Indoles using Barium Catalysis
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[12] See the Supporting Information.
[13] A similar mechanism was suggested in zinc-catalyzed Friedel–
Crafts–type alkylation reactions of pyrrols: B. M. Trost, C. Mꢅller, J.
Am. Chem. Soc. 2008, 130, 2438.
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a) J. C. Fiaud, A. H. De Gournay, M. Larcheveque, H. B. Kagan, J.
Organomet. Chem. 1978, 154, 175; b) S. Saito, T. Tsubogo, S. Ko-
bayashi, Chem. Commun. 2007, 1236. See also Refs. 1b, 1c and 1e.
[15] We conducted
a Friedel–Crafts–type reaction using N-methyl
indole; however, the reaction didn’t proceed. This may suggest the
formation of a chiral barium/indole complex.
Received: May 11, 2010
Published online: August 2, 2010
Chem. Asian J. 2010, 5, 1974 – 1977
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
1977