Highly enantioselective Friedel-Crafts alkylation of indole and pyrrole with β,γ-unsaturated α-ketoester catalyzed by chiral dicationic palladium complex

Article abstract of DOI:10.1016/j.tetlet.2011.09.006

The chiral dicationic Pd complexes, bearing sterically demanding diphosphine ligands as Lewis acid catalysts, are shown to catalyze the asymmetric Friedel-Crafts (F-C) alkylations of indoles and pyrroles with β,γ-unsaturated α-ketoesters, to provide the F

Full text of DOI:10.1016/j.tetlet.2011.09.006

Tetrahedron Letters 52 (2011) 6682–6686
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Tetrahedron Letters
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Highly enantioselective Friedel–Crafts alkylation of indole and pyrrole with
b,c-unsaturated
a-ketoester catalyzed by chiral dicationic palladium complex
⇑
Kohsuke Aikawa, Kazuya Honda, Shunsuke Mimura, Koichi Mikami
Department of Applied Chemistry, Tokyo Institute of Technology, Tokyo 152-8552, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 July 2011
Revised 27 August 2011
Accepted 1 September 2011
Available online 5 September 2011
The chiral dicationic Pd complexes, bearing sterically demanding diphosphine ligands as Lewis acid cat-
alysts, are shown to catalyze the asymmetric Friedel–Crafts (F–C) alkylations of indoles and pyrroles with
b,c-unsaturated a-ketoesters, to provide the F–C alkylation products with benzylic stereocenters in high
yields and enantioselectivities. The reactive chelated structure, formed by the chiral dicationic Pd com-
plex and the electrophile, would be important to gain a high level of asymmetric induction in the F–C
alkylation. The F–C products can be readily functionalized to give
metric ene sequences.
a
-hydroxy esters via catalytic asym-
Keywords:
Friedel–Crafts alkylation
Lewis acid
Ó 2011 Elsevier Ltd. All rights reserved.
Indole
Pyrrole
Ene reaction
The Friedel–Crafts (F–C) reaction has undoubtedly been posi-
tioned as one of the most important carbon–carbon bond forming
reactions in modern organic synthesis since first reported in
1877.1 Recently, many researchers have developed the catalytic
asymmetric F–C reaction, because the reaction can readily access
the enantiomerically enriched and synthetically prominent alkyl-
ated aromatic and heteroaromatic derivatives.2,3 The catalytic
asymmetric F–C reactions so far reported can roughly be catego-
rized into two classes: alkylations (1) with activated alkene and
(2) with carbonyl or imine electrophiles. Especially, the former is
efficient in providing a variety of alkylated aromatic and heteroar-
omatic derivatives bearing the chiral benzylic stereocenters with-
out hydroxyl or amino groups.2,3 The suitably designed chiral
organocatalysts and transition-metal complexes for the F–C reac-
tions of indoles and pyrroles as nucleophiles with activated alkenes,
have been developed to attain high levels of asymmetric induc-
tions.4,5 Organocatalysts, such as chiral Brønsted acids and second-
ary amines, can contribute to the operationally simple reactions but
still require high catalyst loading and long reaction time.3 In con-
trast, various transition-metal complexes bearing chiral ligands
for the F–C reactions with activated alkenes have also been de-
signed to give the excellent enantioselectivity and yield. In particu-
lar, the use of Cu as a central metal has played an important role in
the dramatic advance.2 However, to the best of our knowledge, the
report of the asymmetric F–C alkylation with activated alkenes
using the Pd complex as a Lewis acid catalyst is the only one, which
describes the reaction of indoles with b,c-unsaturated a-keto phos-
phonates.6 Herein, we report the chiral dicationic Pd complex as an
efficient Lewis acid catalyst that promotes the asymmetric F–C
alkylation of indole and pyrrole with b,c-unsaturated a-ketoesters
as activated alkenes. Since the indole and pyrrole frameworks are
privileged structures in biologically active natural products and
medicinal agents,7 this F–C alkylation can provide a direct access
to the enantiomerically enriched derivatives. On the other hand,
Hii8 and Sodeoka9 have independently reported the enantioselec-
tive conjugated addition of amines to
a,b-unsaturated carbonyl
compounds catalyzed by chiral di- and monocationic Pd complexes.
We have focused on the development of practical asymmetric
carbon–carbon bond forming reactions with glyoxylate or a-keto-
ester derivatives, which could be catalyzed by the chiral dicationic
Pd complexes as Lewis acid complexes.10 In those cases, it has been
proposed that the coordination of 1,2-dicarbonyl moiety with the
Pd complex could construct the efficient asymmetric environment
through the formation of 1,4-metal chelated species as the reactive
(a) Previous work
(b) This work
Pd2+
O
Pd2+
O
O
O
R'
R'
OR
first Nu
OR
Nu
second Nu
β,γ-unsaturated α-ketoester
α-ketoester
⇑
Corresponding author. Tel./fax: +81 3 5734 2142.
E-mail address: mikami.k.ab@m.titech.ac.jp (K. Mikami).
Figure 1. 1,4-Metal chelated species as the reactive structures.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.006

K. Aikawa et al. / Tetrahedron Letters 52 (2011) 6682–6686
6683
structure (Fig. 1a). Therefore, treatment of b,
c
-unsaturated
a
-keto-
enantioselectivity, the attack of indole 2a to the alkene portion
would be prevented by the equatorial aryl group on the phospho-
rus atom; thus, the attack from the less sterically hindered site
would be favored to provide the corresponding R-product 4a. It
is predicted that DTBM-SEGPHOS ligand could preserve the high
level of asymmetric induction even over the remote alkene posi-
tion from the central metal, due to the more bulky equatorial aryl
group on the phosphorus atom.
esters bearing 1,2-dicarbonyl portion as activated alkenes was also
expected to proceed the F–C alkylations with highly enantioselec-
tive products, which could be transformed into readily functional-
ized
a-hydroxy esters via sequential catalytic carbonyl-ene
reactions (Fig. 1b).10b
Initially, we investigated the reactions of indoles 2 with b,c-
unsaturated
a-ketoesters 3 as activated alkenes under the opti-
mized reaction conditions (Table 1). In the presence of Pd catalyst
1a (5 mol %) at ꢀ78 °C in dichloromethane, 3a smoothly reacted
with N-methyl indole 2a to afford the desired product 4a and its
enol tautomer in good yield but low enantiomeric excess (entry
1). The enol tautomer was readily converted to ketone 4a in dichlo-
romethane solution of silica–gel at room temperature. The aryl
groups on phosphorus atoms of chiral diphosphine ligands affected
the level of enantioselectivity, and consequently catalyst 1d bear-
ing more sterically demanding (R)-DTBM-SEGPHOS ligand led to
the best results (93% yield, 73% ee) (entry 4).11 The absolute config-
uration at the created carbon center was determined to be R in
comparison with the optical rotation of the reported data.4a The
exchange of substituents on nitrogen atom of indole extremely
decreased the enantioselectivites (entries 5 and 6). Unfortunately,
nonprotected indole 2d gave a high yield but a moderate enanti-
oselectivity (entry 7). In contrast, the use of 3b with aliphatic sub-
stituent instead of an aromatic one increased both yield and
enantioselectivity (94% yield, 89% ee) (entry 8). The 1,4-addition
product 4f of 76% ee was obtained by the treatment of 2a and 3f
with dienyl group (entry 9).
In the presence of complex 1d under the same conditions, the
catalytic enantioselective F–C alkylations of N-methyl pyrrole 5
with various b,c-unsaturated a-ketoesters 3 were further exam-
ined (Table 2).12 These results have shown a wide substrate scope.
When the reaction between pyrrole 5 and 3a was carried out at
ꢀ78 °C in dichloromethane, the almost enantiopure product 6a
was provided in a 95% yield (entry 1). In addition, a high yield
and enantioselectivity could be maintained even on catalyst load-
ing of 1 mol % (94% yield, 98% ee) but catalyst loading of 0.5 mol %
decreased both yield and enantioselectivity (85% yield, 89% ee)
(entries 2 and 3). a-Ketoesters 3b–e with not only electron-donating
and -withdrawing aromatic groups but also aliphatic groups on
activated alkene portion were also examined to give the desired
products in excellent stereoselectivities, while the dialkylated
product was obtained by treatment of 3e in a 17% yield (entries
4–8). The use of 3f with dienyl group led to the corresponding
1,4-addition product 6f in high yield and enantioselectivity with-
out the 1,6-addition product (92% yield, 95% ee) (entry 9). Phthal-
oyl group of 3g had no deteriorating effect on the reactivity but
decreased the enantioselectivity (97% yield, 84% ee) (entry 10).
As a demonstration of the synthetic utility of this catalytic
The square planar-like complex as the intermediate is supposed
in this reaction (Fig. 2): the b,
c
-unsaturated
a-ketoester 3a would
process, the F–C product was further transformed to a-hydroxy es-
be activated by complex 1d through not only bidentate coordina-
tion of the two carbonyl oxygen atoms to the central metal, but
also s-cis conformation of the alkene portion. In the sense of
ters bearing a quaternary stereocenter via a sequential catalytic
carbonyl-ene reaction (Scheme 1).10b,f In the presence of
Pd(PPh3)2(SbF6)2 complex, the ene reaction of racemic F–C product
Table 1
Catalytic enantioselective Friedel–Crafts alkylation of indoles using chiral dicationic Pd complexes
1) cat* (5 mol%)
CH2Cl2
-78 °C, 30 min
R1
O
O
OMe
+
OMe
R1
2) silica-gel
CH2Cl2, rt, 2 h
N
X
2a-c
O
O
N
X
3a-b, f
4
Entry
Cat⁄
X
R1
Yield (%)b
ee (%)c
1
2
3
4
5
1a
1b
1c
1d
1d
1d
1d
1d
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Bn (2b)
Boc (2c)
H (2d)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
CH2OBn (3b)
87 (4a)
88 (4a)
77 (4a)
93 (4a)
92 (4b)
16 (4c)
90 (4d)
94 (4e)
38 (R)d
7 (R)d
29 (R)d
73 (R)d
36
6
12
7
62 (R)d
89
8a
Me (2a)
Ph
9
1d
Me (2a)
(3f)
86 (4f)
76
a
b
c
Ketoester 3b with ethyl ester group instead of methyl ester group was used.
Isolated yield.
Enantiopurity was determined by chiral HPLC analysis.
Absolute configuration was assigned by comparison with reported data.
d
O
Ar2
Ar2
P
P
O
Pd2+
Pd2+
P
O
P
-
-
Ar2
2SbF6
Ar2 2SbF6
O
(
(
(
R
R
)-BINAP-Pd (Ar = Ph): 1a
)-Tol-BINAP-Pd (Ar = 4-Me-C 6H4): 1b
R)-DM-BINAP-Pd (Ar = 3,5-Me 2-C6H3): 1c
(
R
)-DTBM-SEGPHOS-Pd: 1d
(Ar = 3,5-tBu2-4-OMe-C6H2)
)-SEGPHOS-Pd (Ar = Ph): 1e
(
R

6684
K. Aikawa et al. / Tetrahedron Letters 52 (2011) 6682–6686
2a
Ph
O
OMe
O
O
R
N
Me
(
S
)-4a
O
R
disfavored
eq.
P
P
Pd
O
O
axi.
R
R
O
Ph
O
OMe
OMe
O
s-cis
Ph
O
N
Me
(
R)-4a
2a
favored
Figure 2. Plausible sense of enantioselectivity in Friedel–Crafts alkylation of indole 2a with b,
c
-unsaturated a-ketoesters 3a.
OTIPS
Ph
O
Pd(PPh3)2(SbF6)2
(5 mol%)
MeN
Ph
HO
OTIPS
OMe
+
(1)
OMe
CH2Cl2, -78 °C, 4 h
NMe
6a
racemic
O
7
O
8a, 99%
anti/syn 43/57
OTIPS
OMe
MeN
Ph
1e (5 mol%)
HO
(2)
(3)
CH2Cl2, -78 °C, 24 h
Ph
O
O
OMe
8a, 81%
anti/syn 92/8
+
7
NMe
6a
>99% ee
O
OTIPS
OMe
ent-1e (5 mol%)
MeN
Ph
HO
CH2Cl2, -78 °C, 24 h
O
8a, 94%
anti/syn 54/46
OTIPS
OEt
MeN
1e (10 mol%)
HO
(4)
BnO
CH2Cl2, -40 °C, 9 h
BnO
O
O
OEt
8b, 92%
+
7
anti/syn 97/3
NMe
O
OTIPS
OEt
6b
ent-1e (10 mol%)
MeN
(5)
HO
98% ee
CH2Cl2, -40 °C, 9 h
BnO
O
8b, 91%
anti/syn 40/60
Scheme 1. Sequential catalytic carbonyl-ene reactions.
6a with acetone silyl enol ether 7 furnished the corresponding
product 8a bearing both quaternary and tertiary stereocenters in
99% yield but low syn-selectivity (Scheme 1, Eq. 1: anti/syn 43/
57). The combination of 6a (>99% ee) and 7 in the presence of
(R)-SEGPHOS-Pd complex 1e (5 mol %) led to the ene product 8a
with a high anti-selectivity (Eq. 2: anti/syn 92/8). In sharp contrast,
the reaction catalyzed by ent-1e bearing (S)-SEGPHOS afforded the
product 8a in a high yield, however, the diastereoselectivity extre-
mely decreased (Eq. 3: anti/syn 54/46). While the use of 1e and 6b
(98% ee) also gave the ene product 8b in high yield and excellent
diastereoselectivity (Eq. 4: anti/syn 97/3), ent-1e led to the low dia-
stereoselectivity (Eq. 5: anti/syn 40/60).
In summary, we have demonstrated a highly enantioselective
Friedel–Crafts alkylation of indole and pyrrole with b,
c-unsatu-
rated -ketoesters catalyzed by the chiral dicationic Pd complexes.
a
The formation of 1,4-metal chelated species as the reactive struc-
ture would be important to gain a high level of asymmetric induc-
tion in this reaction. We have also succeeded in providing a ready
access to functionalized
a-hydroxy esters through the sequential
catalytic carbonyl-ene reaction. Further investigations of the

K. Aikawa et al. / Tetrahedron Letters 52 (2011) 6682–6686
6685
Table 2
Catalytic enantioselective Friedel–Crafts alkylation of N-methyl pyrrole
1) 1d (Y mol%), CH2Cl2
R1
O
O
-78 °C, 30 min
OR2
OR2
+
R1
2) silica-gel
CH2Cl2, rt, 2 h
N
NMe
O
O
Me
3a-g
6a-g
5
Entry
R1
R2
Y
Yield (%)c
ee (%)e
1
5
1
0.5
95
94
85
>99
98
89
2a
Me (3a)
Et (3b)
3b
4
5
1
90
92
98
94
OBn
5a
Me
6
7
Me (3c)
Me (3d)
5
5
83
96
98
95
NO2
60d
92
>99
95
Me
8
9
Et (3e)
5
5
Ph
Me (3f)
O
10
Me (3g)
5
97
84
N
O
a
b
c
Reaction time was 24 h.
Reaction time was 48 h.
Isolated yield.
Dialkylated product was obtained in 17% yield.
Enantiopurity was determined by chiral HPLC analysis.
d
e
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reactions using various nucleophiles with b,c-unsaturated a-keto-
esters are currently in progress.
Acknowledgments
This research was supported in part by a Grant Program ‘‘Col-
laborative Development of Innovative Seeds’’ from the Japan Sci-
ence and Technology Agency (JST). We are grateful to Takasago
International Co. for providing BINAP and SEGPHOS derivatives.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.09.006.
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K. Aikawa et al. / Tetrahedron Letters 52 (2011) 6682–6686
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(19.0 mg, 0.10 mmol) and N-methyl pyrrole (81.1 mg, 1.0 mmol) were added
to the mixture at ꢀ78 °C. The reaction mixture was stirred at ꢀ78 °C for
30 min, and then the reaction mixture was directly loaded onto a silica–gel
column (hexane/AcOEt = 1:1) and evaporated under reduced pressure. The
keto/enol-form products obtained were added to
a solution of silica–gel
(500 mg) in CH2Cl2 (2.0 mL) and stirred at room temperature for 2 h. After
filtration, purification by silica–gel chromatography (hexane/AcOEt = 3:1) gave
the only F–C alkylated product (keto-form) 6a in 95% yield and >99% ee. The
absolute configuration of 6a was tentatively assigned to be R in comparison
with the optical rotation of (R)-4a.
9. Hamashima, Y.; Somei, H.; Shimura, Y.; Tamura, T.; Sodeoka, M. Org. Lett. 2004,
6, 1861.
(R)-4-(1-Methyl-1H-pyrrol-2-yl)-2-oxo-4-phenyl-butyric acid methyl ester (6a):
1H NMR (300 MHz, CDCl3) d 3.36 (s, 3H), 3.41 (dd, J = 18.0, 7.5 Hz, 1H), 3.70 (dd,
J = 18.0, 7.8 Hz, 1H), 3.84 (s, 3H), 4.65 (dd, J = 7.8, 7.5 Hz, 1H), 6.10–6.15 (m,
2H), 6.55 (dd, J = 2.4, 2.1 Hz, 1H), 7.19–7.32 (m, 5H); 13C NMR (75 MHz, CDCl3)
d 33.7, 37.9, 45.8, 52.9, 105.9, 106.4, 122.2, 126.7, 127.7, 128.6, 133.2, 142.1,
161.0, 191.8; HRMS (TOF) calcd for C16H17NNaO4 [M+Na]+: 294.1106, found:
10. (a) Aikawa, K.; Kainuma, S.; Hatano, M.; Mikami, K. Tetrahedron Lett. 2004, 45,
183; (b) Mikami, K.; Kawakami, Y.; Akiyama, K.; Aikawa, K. J. Am. Chem. Soc.
2007, 129, 12950; (c) Aikawa, K.; Hioki, Y.; Mikami, K. J. Am. Chem. Soc. 2009,
131, 13922; (d) Aikawa, K.; Hioki, Y.; Mikami, K. Chem. Asian J. 2010, 5, 2346;
(e) Aikawa, K.; Hioki, Y.; Mikami, K. Org. Lett. 2010, 12, 5716; (f) Aikawa, K.;
Mimura, S.; Numata, Y.; Mikami, K. Eur. J. Org. Chem. 2011, 62.
294.1097; ½a 2D6
ꢀ135.4 (c 2.44, CHCl3), >99% ee (R); HPLC (column, CHIRALPAK
ꢁ
11. X-ray structure of (R)-DTBM-SEGPHOS-Pd(OTf)2: Corkey, B. K.; Toste, F. D. J.
Am. Chem. Soc. 2005, 127, 17168.
AD-3, Hexane/2-Propanol = 95/5, flow rate 0.6 ml/min, 20 °C, detection UV
254 nm) tR of major R-isomer 21.1 min, tR of minor S-isomer 22.7 min.
12. Typical Procedure for Friedel–Crafts alkylation of pyrrole (Table 2, entry 1): To a
solution of PdCl2[(S)-DTBM-SEGPHOS] (6.8 mg, 0.005 mmol) in CH2Cl2 (1.0 mL)