Chiral bronsted acid directed iron-catalyzed enantioselective friedelcrafts alkylation of indoles with β-aryl α'-hydroxy enones

Article abstract of DOI:10.1002/chem.200902705

A cooperative catalytic system established by the combination of an iron salt and a chiral Bronsted acid has proven to be effective in the asymmetric Friedel-Crafts alkylation of indoles with β-aryl α'-hydroxy enones. Good to excellent yields and enatioselectivities were observed for a variety of α'-hydroxy enones and indoles, particularly for the β-aryl α'-hydroxy enones bearing an electron-with-drawing group at the para position of the phenyl ring (up to 90% yield and 91 % ee). The proton of the chiral Bronsted acid, the Lewis acid activation site, as well as the inherent basic site for the hydrogen-bonding interaction of the Bronsted acid are responsible for the high catalytic activities and enantioselectivities of the title reaction. A possible reaction mechanism was proposed. The key catalytic species in the catalytic system, the phosphate salt of Fe^III, which was thought to be responsible for the high activity and good enantioselectivity, was then confirmed by ESIMS studies.

Full text of DOI:10.1002/chem.200902705

DOI: 10.1002/chem.200902705
Chiral Brønsted Acid Directed Iron-Catalyzed Enantioselective Friedel–
Crafts Alkylation of Indoles with b-Aryl a’-Hydroxy Enones
Lei Yang, Qiming Zhu, Shengmei Guo, Bo Qian, Chungu Xia,* and Hanmin Huang*[a]
Abstract:
A
cooperative catalytic
drawing group at the para position of
the phenyl ring (up to 90% yield and
91% ee). The proton of the chiral
Brønsted acid, the Lewis acid activa-
tion site, as well as the inherent basic
site for the hydrogen-bonding interac-
tion of the Brønsted acid are responsi-
ble for the high catalytic activities and
enantioselectivities of the title reaction.
A possible reaction mechanism was
proposed. The key catalytic species in
the catalytic system, the phosphate salt
of FeIII, which was thought to be re-
sponsible for the high activity and good
enantioselectivity, was then confirmed
by ESIMS studies.
system established by the combination
of an iron salt and a chiral Brønsted
acid has proven to be effective in the
asymmetric Friedel–Crafts alkylation
of indoles with b-aryl a’-hydroxy
enones. Good to excellent yields and
enatioselectivities were observed for a
variety of a’-hydroxy enones and in-
doles, particularly for the b-aryl a’-hy-
droxy enones bearing an electron-with-
Keywords: alkylation · asymmetric
catalysis · Brønsted acids · iron ·
proton acceleration
Introduction
fast proton transfer from the indole moiety to newly gener-
ated enolate components is required, but this step is often
slow and catalyst turnover is limited significantly. To over-
come this problem, some proton sources such as alcohols
and protic acids have usually been applied as additives to
accelerate the proton-transfer step and thus facilitate the
catalytic turnover.[7] Given that Lewis acid metal complexes
can catalyze Friedel–Crafts reactions and that an appropri-
ate proton source might facilitate the catalytic turnover, we
envisioned that this kind of asymmetric reaction could be
realized by using a cooperative catalytic system with a
Lewis acid site for activating the electrophile, a base site for
activating the nucleophile through a hydrogen-bonding in-
teraction, and a free proton source for accelerating the
proton transfer. All these can be incorporated into one
chiral platform to achieve high asymmetric induction. As
shown in Scheme 1, once the chiral phosphoric acid used as
Brønsted acid,[8] the Lewis acid activation site, and the free
proton source could be constructed through anion metathe-
Cooperative asymmetric catalysis through the combination
of metal complexes and organocatalysts has experienced sig-
nificant growth over the last several years,[1] as this strategy
has the ability to realize some new asymmetric transforma-
tions by mutual activation and organization of reactants that
are different to those promoted by the metal catalysts or or-
ganocatalysts alone. Both transition-metal catalysis and or-
ganocatalysis have been applied to a broad range of organic
transformations in synthetic organic chemistry,[2] but asym-
metric catalysis by using this strategy is still in its develop-
mental stages by comparison.[3]
Proton transfer is among the most elementary of reaction
steps in many chemical reactions that have played an impor-
tant role in both chemistry and biology.[4] In Lewis acid cata-
lyzed Michael-type Friedel–Crafts alkylation of indoles with
a,b-unsaturated compounds, which is among the most im-
portant C C bond-forming reactions in organic synthesis,
[5,6]
À
[a] Dr. L. Yang, Q. Zhu, S. Guo, B. Qian, C. Xia, Prof. H. Huang
State Key Laboratory for Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics
Lanzhou, 730000 (P.R. China)
Fax : (+86)931-4968129
E-mail: hmhuang@licp.cas.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902705.
Scheme 1. Proposed cooperative catalytic system.
1638
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 1638 – 1645

FULL PAPER
sis of the Brønsted acid and Lewis acid metal salt, the inher-
ent Brønsted base site can activate the nucleophile through
a
hydrogen-bonding interaction. The interaction would
allow the reaction to proceed under a chiral environment
regulated by the chiral conjugated base. To ascertain the
feasibility of this hypothesis, we aimed to develop a chiral
Brønsted acid controlled, iron-catalyzed[9] enantioselective
Friedel–Crafts alkylation of indoles with a’-hydroxy
enones,[10] which was first developed by Palomo and co-
workers, who used chiral bis(oxazoline)/CuACTHNUGTRENUNG(OTf)2 (2–30
mol%; OTf=trifluoromethanesulfonate) as a catalyst.[6h]
Based on the cooperative working hypothesis proposed
above, we assumed the reaction would be performed accord-
ing to the catalytic cycle depicted in Scheme 2.
Results and Discussion
To validate our hypothesis, we attempted the reaction of 4-
chlorophenyl-substituted a’-hydroxy enone (2a) with indole
(3a) in the binary catalytic system to provide the Friedel–
Crafts product (4aa). Our initial experiment was carried out
Scheme 2. Proposed proton-accelerated asymmetric Friedel–Crafts reac-
tion process.
using CuACHTUNGTRENNUNG(OTf)2 (5 mol%) as Lewis acid and 1a as Brønsted
acid (5 mol%) to establish a binary catalyst. The reaction
was carried out at room temperature in dichloromethane for
24 h, and only moderate yield (52%) and poor enantioselec-
of indole (3a) and 4-chlorophenyl-substituted a’-hydroxy
enone (2a). As shown in Table 1, the reaction could be cata-
lyzed by all the binary catalysts combined with FeCl3 and
the phosphoric acids that were tested here. Among the
phosphoric acids examined, 1a (bearing 2-naphthyl groups)
and 1b (bearing 9-phenanthryl groups) exhibited high enan-
tioselectivities of 53 and 55% ee with high reactivities (up to
94% yield; Table 1, entries 1 and 7). The existence of the
tivity (3% ee) were observed. Further screening of
a
number of other metal salts under the same reaction condi-
tions showed that no transformation occurred at all when
Zn
(OAc)2 were used as Lewis acids (Figure 1; OAc=
O2CCH3). The partners InCl3/
1a and Ti(O-iPr)4/1a could give
ACHTUNGTRENNUNG(OTf)2, MgACHTUNGTRENNUNG(ClO4)2, NiCATHNUGTRNE(UNGN ClO4)2·6H2O, AgOAc, and Pd-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
the desired product in 40%
yield, but an almost racemic
product was observed. To our
delight, the inexpensive FeCl3
was found to be the best part-
ner of 1a and provided 96%
yield with 53% ee for 4aa
(Figure 1).
To optimize the reaction con-
ditions, we first investigated the
effects of solvents with 1a/
FeCl3 as the binary catalyst at
room temperature (typically
15–208C). The results in
Table 1
demonstrated
that
CH2Cl2 was the best choice. We
then concentrated on the modi-
fication of the chiral phosphoric
acid for the binary catalyst. A
series of chiral phosphoric acids
(1) with different substituents
at the 3,3’-positions of the bi-
naphthyl scaffold were pre-
Figure 1. Screening of metal salts for the asymmetric Friedel–Crafts alkylation of indole with 1a as Brønsted
pared and tested in the reaction acid.
Chem. Eur. J. 2010, 16, 1638 – 1645
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1639

C. Xia, H. Huang et al.
Table 1. Enantioselective Friedel–Crafts alkylation of indole with 2a cat-
led to lower activity and ee values under the same reaction
conditions and showed the importance of the proton for this
trifunctional catalyst system. The transformation became
slow (24 h, 85% yield) when only using FeCl3 as the catalyst
(Table 1, entry 14). Virtually no reaction occurred when
phosphoric acid 1a alone was used as the catalyst (Table 1,
entry 15). These results demonstrate that both the phospho-
ric acid and FeCl3 are essential for this cooperative catalytic
process and also suggest that the Brønsted acid here not
only acts as chiral counteranion but also provides a free
proton source for facilitating catalytic turnover through ac-
celerating the proton-transfer step of the Friedel–Crafts re-
action, which led the FeCl3-catalyzed nonenantioselective
background reaction to be suppressed.
To further optimize the enantioselectivity of the reaction,
a number of different iron salts were subsequently investi-
gated with phosphoric acid 1a as Brønsted acid under the
above reaction conditions, and some selected results are
summarized in Table 2. It appears that the binary catalyst
with FeIII induces higher enantioselectivity and activity than
the catalyst with FeII. The anions of the iron salts are crucial
for the performance of this binary catalytic system. For ex-
alyzed by different phosphoric acid/FeCl3 combinations.[a]
Entry
Catalyst
Solvent
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1a/FeCl3
1a/FeCl3
1a/FeCl3
1a/FeCl3
1a/FeCl3
1a/FeCl3
1b/FeCl3
1c/FeCl3
1d/FeCl3
1e/FeCl3
1 f/FeCl3
1g/FeCl3
1h/FeCl3
FeCl3
CH2Cl2
CH2ClCH2Cl
toluene
THF
3
4
6
24
24
24
6
94
90
91
20
54
35
91
75
66
76
80
45
61
85
trace
53
46
30
10
À3
27
55
40
À3
16
31
35
19
–
dioxane
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
8
9
24
24
48
48
24
24
24
10
11
12
13
14
15
1a
–
ample, with covalent-type iron salts such as [FeACHTUNGTRENNUNG(acac)3]
[a] General conditions: 1 (5 mol%), FeCl3 (5 mol%), enone (0.2 mmol),
indole (0.3 mmol), CH2Cl2 (1 mL), RT (15–208C). [b] Isolated yield.
[c] Determined by chiral HPLC.
(acac=acetylacetonate) as precatalyst, no reaction occurred.
Among the simple iron salts tested, FeCl3 was found to be
optimal. To further improve the enantioselectivity, silver
salts with different anions as additives were screened, and
AgOTf showed positive effects (65% ee; Table 2 entry 12).
Other silver additives such as AgSbF6, AgBF4, and
Ag3PW12O40 could give good yields, but negative effects on
the enantioselectivity were observed. An increase in the
loading of silver additive could be favorable for obtaining
higher enantioselectivity (70% ee; Table 2, entry 16). Fur-
ther screening of the reaction conditions revealed that a
lower temperature could improve the enantioselectivity
(Table 2, entries 17 and 18).
phosphate salt of FeIII in the catalytic system of 1b/FeCl3
might be responsible for the high activity and good enantio-
selectivity, a postulation that was confirmed by ESIMS stud-
ies (Figure 2). To further clarify the mechanism of the reac-
tion, control experiments were carried out. Chiral silver
phosphate salt 1h without an acidic proton was prepared
and combined with FeCl3 to act as the binary catalyst. This
Under the optimized conditions
(at À408C and with CH2Cl2 as
solvent), 4aa was obtained in
83% yield with 90% ee when
the
combination
of
1b
(5 mol%)/FeCl3
(5 mol%)/
AgOTf (30 mol%) was used as
catalyst (Table 2, entry 19).
Having succeeded in devel-
oping an efficient enantioselec-
tive catalyst, we then turned
our attention to the substrate
scope (Table 3). For the enone
2j, which had no substituent on
the phenyl ring, and enones
such as 2a and 2c–h, which
bore an electron-withdrawing
group at the meta or para posi-
tion of the phenyl ring, the re-
actions went smoothly and af-
forded the products with high
Figure 2. Confirmation of the existence of iron phosphate salt 1b/FeCl3.
1640
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 1638 – 1645

Friedel–Crafts Alkylation of Indoles
FULL PAPER
Table 2. Enantioselective Friedel–Crafts alkylation of indole with 2a cat-
yields and good to excellent enantioselectivities (84–
91% ee). However, by contrast, ortho substitutents in the b-
aryl a’-hydroxy enones strongly diminished the enantioselec-
tivity of the reaction, which may be due to steric interaction
of the o-substituent to the indole during the reaction. For
example, the reaction of 2-chloro-substituted b-aryl a’-hy-
droxy enone 2i under the optimized conditions generated
the Friedel–Crafts product in only 69% ee (Table 3, entry 9).
By introducing an electron-donating group into the b-aryl
a’-hydroxy enone, we observed a drop in the enantioselec-
tivity. In the case of 2b, which has a 4-OCH3 group, 73% ee
was obtained (Table 3, entry 2). Besides the substituted
phenyl enones, the naphthyl enone 2k also gave the asym-
metric Friedel–Crafts product in good yield and enantiose-
lectivity (Table 3, entry 11). Unfortunately, when b-enones
derived from heteroaromatic or alkyl aldehyde compounds
such as 2l and 2m were tested, only moderate enantioselec-
tivity was obtained (Table 3, entries 12 and 13).[11] Finally,
various substituted indoles were also investigated in the
Friedel–Crafts reaction with 4-chlorophenyl-substituted a’-
hydroxy enone 2a. Similarly, the indole bearing an electron-
withdrawing group gave the corresponding adduct in high
yield and enantioselectivity, but upon introducing an elec-
tron-donating group into the indole, we also observed a dra-
matic drop in the enantioselectivity (Table 3, entry 14 vs.
15). When N-methylindole (3d) was prepared and treated
with b-aryl a’-hydroxy enone (2a), a very low ee value was
observed (Table 3, entry 16), thereby demonstrating that the
hydrogen atom on the N atom of the indole moiety is crucial
for obtaining high enantioselectivity. This observation fur-
ther suggests that the hydrogen-bonding interaction site is
important for our cooperative catalytic system. The absolute
configuration of 4ea was assigned as R by X-ray diffraction
analysis (Figure 3).
alyzed by different iron salt/phosphoric acid combinations.[a]
Entry Catalyst
t
Yield
ee
[h] [%][b]
[%][c]
1
2
3
4
5
6
7
8
1a/FeCl3
1a/FeCl3·6H2O
1a/FeCl2·4H2O
3
3
94
90
53
51
47
43
52
47
43
19
43
37
–
96 30
24 45
18 95
24 80
24 82
24 90
24 80
18 88
1a/Fe
1a/Fe
1a/Fe
1a/Fe
1a/Fe
2A
(NO3)3·9H2O
(ClO4)3·xH2O
(ClO4)3
(OTf)2·2CH3CN
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
9
1a/FeBr3
1a/Fe(OTs)3 (Ts=tosyl)
1a/[Fe(acac)3]
1a/FeCl3 (5 mol%)/AgOTf (15 mol%) 22 88
10
11
12
13
14
ACHTUNGTRENNUNG
G
24
–
65
20
10
1a/FeCl3 (5 mol%)/AgBF4 (15 mol%)
1a/FeCl3 (5 mol%)/AgSbF6
(15 mol%)
5
92
22 83
15
1a/FeCl3 (5 mol%)/Ag3PW12O40
(15 mol%)
24 64
42
16
1a/FeCl3 (5 mol%)/AgOTf (30 mol%) 24 90
1a/FeCl3 (5 mol%)/AgOTf (30 mol%) 24 87
1a/FeCl3 (5 mol%)/AgOTf (30 mol%) 24 85
1a/FeCl3 (5 mol%)/AgOTf (30 mol%) 24 83
70
17
75[d]
88[d]
90[e]
18[f]
19[f]
[a] General conditions: 1a (5 mol%), iron salt (5 mol%), enone
(0.2 mmol), indole (0.3 mmol), CH2Cl2 (1 mL), RT. [b] Isolated yield.
[c] Determined by chiral HPLC. [d] The reaction was run at À208C.
[e] The reaction was run at À408C. [f] Compound 1b was used as Brønst-
ed acid.
Table 3. Enantioselective Friedel–Crafts alkylation of indoles 3 with vari-
ous b-aryl a’-hydroxy enones 2.[a]
Entry R1
R2
T
Product (Yield
ee
[8C] [%])[b]
[%][c]
1
2
4-ClC6H4 (2a)
4-MeOC6H4
(2b)
H (3a)
H (3a)
À40 4aa (83)
À20 4ba (76)
90
73
3
4
5
6
7
8
9
10
11
12[d]
13
4-CF3C6H4 (2c) H (3a)
À40 4ca (90)
À40 4da (84)
À40 4ea (80)
À40 4 fa (68)
À20 4ga (82)
À40 4ha (82)
À40 4ia (75)
À40 4ja (70)
À40 4ka (66)
À20 4la (70)
À40 4ma (95)
91
85
90
84
85
84
69
86
80
43
47
4-FC6H4 (2d)
4-BrC6H4 (2e)
H (3a)
H (3a)
4-NO2C6H4 (2 f) H (3a)
3-ClC6H4 (2g)
3-FC6H4 (2h)
2-ClC6H4 (2i)
C6H5 (2j)
H (3a)
H (3a)
H (3a)
H (3a)
2-naphthyl (2k) H (3a)
2-furan (2l)
C6H5CH2CH2
(2m)
H (3a)
H (3a)
14[e]
15[e]
4-ClC6H4 (2a)
4-ClC6H4 (2a)
5-Br (3b) À20 4ab (82)
72
24
2-Me
(3c)
À20 4ac (86)
À40 4ad (92)
16
4-ClC6H4 (2a)
N-Me
(3d)
12
[a] General conditions: 1b (5 mol%), FeCl3 (5 mol%), AgOTf
(30 mol%), enone (0.2 mmol), indole (0.3 mmol), CH2Cl2 (1 mL), 24 h.
[b] Isolated yield. [c] Determined by chiral HPLC. [d] For 36 h. [e] Com-
pound 1a was used as Brønsted acid.
Figure 3. X-ray structure of 4ea.
Chem. Eur. J. 2010, 16, 1638 – 1645
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1641

C. Xia, H. Huang et al.
CDCl3): d=212.6, 143.6, 136.6, 128.5, 127.8, 126.6, 126.4, 122.3, 121.2,
119.6, 119.5, 118.9, 111.2, 76.4, 42.4, 37.9, 26.1, 26.0 ppm.
Conclusion
Compound 4ba: The title compound was prepared according to the gen-
eral procedure and purified by chromatography to give a white solid,
which was an unknown compound. Chiral HPLC was performed using an
HP series 1200 (Chiralpak AD-H column; hexane/2-propanol 90:10;
In summary, a cooperative catalytic system has been suc-
cessfully established by the combination of an iron salt and
a chiral phosphoric acid through taking advantage of the
fact that the free proton source could promote the catalytic
turnover for the Friedel–Crafts reaction. This newly pre-
pared catalytic system has proven to be effective in the
enantioselective Friedel–Crafts alkylation of indoles with b-
aryl a’-hydroxy enones. Further studies of the reaction
mechanism and the applicability of this concept involving
other asymmetric transformations are currently being inves-
tigated in our laboratory and will be reported in due course.
1.0 mLminÀ1
,
254 nm):
t
G
tRACTHNGUTERN(UNG minor)=50.13 min,
73% ee; [a]2D0 =À16.7 (c=0.12 in CH2Cl2). The absolute configuration
was assigned as R by analogy. 1H NMR (400 MHz, CDCl3): d=7.92 (br,
1H), 7.35 (d, J=7.6 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.13–7.19 (m, 2H),
7.07–7.11 (m, 1H), 6.94–6.98 (m, 1H), 6.90 (s, 1H), 6.71–6.75 (m, 1H),
4.83 (t, J=7.2 Hz, 1H), 3.69 (s, 3H), 3.58 (s, 1H), 3.25 (dd, 1J=8.0 Hz,
2J=5.2 Hz, 2H), 1.19 (s, 3H), 1.06 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=212.7, 158.1, 136.6, 135.7, 128.8, 126.4, 122.3, 121.0, 119.5,
119.3, 113.8, 111.2, 76.4, 55.2, 42.5, 37.1, 26.1, 25.9 ppm; HRMS (ESI):
m/z: calcd for C21H23NO3 [M+H]+: 338.1751; found: 338.1757.
Compound 4ca: The title compound was prepared according to the gen-
eral procedure and purified by chromatography to give a white solid,
which was an unknown compound. Chiral HPLC was performed using an
HP series 1200 (Chiralpak AD-H column; hexane/2-propanol 85:15;
Experimental Section
1.0 mLminÀ1
,
254 nm):
t
G
tRACTHNGUTERN(UNG minor)=12.08 min,
91% ee; [a]2D0 =À23.3 (c=0.24 in CH2Cl2). The absolute configuration
was assigned as R by analogy. 1H NMR (400 MHz, CDCl3): d=7.97 (br,
1H), 7.30 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.17–7.22 (m, 2H),
7.07–7.12 (m, 1H), 6.94–6.98 (m, 1H), 6.84–6.90 (m, 3H), 4.86 (t, J=
7.2 Hz, 1H), 3.55 (s, 1H), 3.25 (d, J=7.6 Hz, 2H), 1.19 (s, 3H), 1.06 ppm
(s, 3H); 13C NMR (100 MHz, CDCl3): d=212.4, 162.7, 160.3, 139.4 (d, J=
31 Hz), 136.6, 129.3 (d, J=80 Hz), 126.3, 122.4, 121.1, 119.6, 119.4, 118.8,
115.3 (d, J=212 Hz), 111.3, 76.4, 42.5, 37.1, 26.1, 25.9 ppm; HRMS (ESI):
m/z: calcd for C21H20NO2F3 [M+H] +: 376.1519; found: 376.1513.
General: All reactions were performed in sealed oven-dried glass tubes
under an atmosphere of argon unless otherwise noted. All common re-
agents were obtained from commercial suppliers and used without fur-
ther purification. All solvents before use were dried and degassed by
standard methods and stored under nitrogen. a’-Hydroxy enones were
prepared following literature procedures.[12] Chiral 1,1’-bi-2-naphthol
(BINOL)-derived phosphoric acids and the silver phosphate salt were
prepared according to or analogously to the reported procedures.[13]
Thin-layer chromatography (TLC) was performed on silica gel GF254
with a mixture of petroleum and ethyl acetate as the eluent unless other-
wise noted. Column chromatography was carried out using silica gel
(200–300 mesh) and petroleum/ethyl acetate as the eluent. NMR spectra
were obtained using a Bruker DRX spectrometer operating at 400 MHz
for 1H and 100 MHz for 13C in CDCl3 unless otherwise noted. Coupling
constants (J) are reported in Hz and refer to apparent peak multiplica-
Compound 4da: The title compound was prepared according to the gen-
eral procedure and purified by chromatography to give a white solid,
which was an unknown compound. Chiral HPLC was performed using an
HP series 1200 (Chiralpak IA column; hexane/2-propanol 85:15;
1.0 mLminÀ1
,
254 nm):
t
G
tRACTHNGUTERN(UNG minor)=15.17 min,
85% ee; [a]2D0 =À35.7 (c=0.14 in CH2Cl2). The absolute configuration
was assigned as R by analogy. 1H NMR (400 MHz, CDCl3): d=7.99 (br,
1H), 7.45 (d, J=8.4 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.27–7.33 (m, 4H),
7.09–7.13 (m, 1H), 6.94–7.00 (m, 1H), 6.93 (s, 1H), 4.94 (t, 1H, J=
7.2 Hz), 3.46 (s, 1H), 3.25–3.37 (m, 2H), 1.21 (s, 3H), 1.11 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=212.1, 147.8, 136.6, 128.2, 126.2, 125.5,
125.4, 122.6, 121.2, 119.8, 119.2, 118.1, 111.3, 76.4, 42.1, 37.5, 26.2,
26.1 ppm; HRMS (ESI): m/z: calcd for C20H20NO2F [M+H]+: 326.1551;
found: 326.1544.
tions. High-resolution mass spectra (HRMS) were obtained using
a
Bruker Apex II instrument (ESI). The ESIMS was performed using
Micro-QOF-II instrument. Enantiomeric excess (ee) values were deter-
mined by HPLC analysis using an Agilent HP-1200. Optical rotations
were measured on a Perkin–Elmer polarimeter (model 341LC).
General procedure for the enantioselective Friedel–Crafts alkylation of
indoles with b-aryl a’-hydroxy enones: An oven-dried Schlenk tube was
charged with AgOTf (30 mol%) and FeCl3 (5 mol%). The tube was
evacuated and refilled with Ar, and this process was repeated three
times. Then CH2Cl2 (1 mL) was injected. The reaction mixture was
heated at 508C and stirred vigorously for 2 h. After cooling to RT, 2a
(0.2 mmol) was added and the mixture was stirred for 20 min at RT, and
then chiral phosphoric acid 1b (5 mol%) was added into the reaction
mixture. After 10 min of being stirred at the same temperature, the reac-
tor was cooled to À408C. Compound 3a (0.3 mmol) was added directly
into the reaction mixture at À408C. After 24 h, the mixture was then di-
luted with NH4Cl (10 mL) and extracted with CH2Cl2 (3ꢁ10 mL). The or-
ganic layers were combined, dried over anhydrous NaSO4, and concen-
trated. Subsequent purification by flash chromatography using silica gel
(ethyl acetate/petroleum, ca. 1:10 to 1:3) to afford the chiral product 4aa.
Compound 4ea: The title compound was prepared according to the gen-
eral procedure and purified by chromatography to give a white solid,
which was an unknown compound. Chiral HPLC was performed using an
HP series 1200 (Chiralpak AD-H column; hexane/2-propanol 85:15;
1.0 mLminÀ1
,
254 nm):
t
G
tRACTHNGUTERN(UNG minor)=19.33 min,
90% ee; [a]2D0 =À14.2 (c=0.12 in CH2Cl2). The absolute configuration
was assigned as R by using X-ray crystallography. 1H NMR (400 MHz,
CDCl3): d=7.98 (br, 1H), 7.25–7.31 (m, 4H), 7.08–7.18 (m, 3H), 6.90–
6.99 (m, 1H), 6.89 (s, 1H), 4.84 (t, J=7.2 Hz, 1H), 3.51 (s, 1H), 3.20–3.29
(m, 2H), 1.19 (s, 3H), 1.09 ppm (s, 3H); 13C NMR (100 MHz, CDCl3):
d=212.3, 142.7, 136.6, 131.6, 129.6, 126.2, 122.5, 121.2, 120.3, 119.7, 119.3,
118.4, 111.3, 76.4, 42.2, 37.2, 26.1, 26.0 ppm; HRMS (ESI): m/z: calcd for
C20H20NO2Br [M+H]+: 386.0750; found: 386.0747.
Compound 4aa: The title compound was prepared according to the gen-
eral procedure and purified by chromatography to give a white solid,
which was a known compound. Chiral HPLC was performed using an
HP series 1200 (Chiralpak AD-H column; hexane/2-propanol 85:15;
Crystal data for 4ea: Mr =386.28; crystal size 0.38ꢁ0.35ꢁ0.31 mm; ortho-
rhombic; space group P212121; a=9.6040(6), b=11.5562(7), c=
15.9003(10) ꢂ; a=90, b=90, g=908; V=1764.71(19) ꢂ3; Z=4; l=
0.71073 ꢂ; m=2.341 mmÀ1; 1calcd =1.454 mgmÀ3; T=296(2) K; F
ACHTUNGTRENNUNG(000)=
1.0 mLminÀ1
,
254 nm):
t
G
tRACTHNGUTERN(UNG minor)=18.55 min,
90% ee; [a]2D0 =À18.7 (c=0.32 in CH2Cl2). The absolute configuration
was assigned as R by comparison of the optical rotation with the reported
value (ref. [6h]: [a]2D5 =À12.3 (c=1.0 in CH2Cl2), 83% ee for R isomer).
1H NMR (400 MHz, CDCl3): d=7.95 (br, 1H), 7.35 (d, J=8.0 Hz, 1H),
7.23–7.26 (m, 2H), 7.17–7.20 (m, 2H), 7.06–7.12 (m, 2H), 6.93–6.98 (m,
1H), 6.89 (s, 1H), 4.88 (t, J=7.2 Hz, 1H), 3.59 (s, 1H), 3.27 (d, J=
7.6 Hz, 2H), 1.18 (s, 3H), 1.06 ppm (s, 3H); 13C NMR (100 MHz,
792; 3463 independent reflections (Rint =0.0282); 9923 collected reflec-
tions; refinement method: full-matrix least-squares on F2; goodness-of-fit
on F2: 1.037; final R indices (I>2s(I)) R1=0.0327, wR2=0.0687; R indi-
ces (all data): R1=R1=0.0495 and wR2=0.0741; absolute structure pa-
rameter was 0.000(9); largest difference peak and hole: 0.290 and
À0.419 eꢂÀ3, respectively. CCDC-749512 (4ea) contains the supplemen-
tary crystallographic data for this paper. These data can be obtained free
1642
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 1638 – 1645

Friedel–Crafts Alkylation of Indoles
FULL PAPER
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
1.08 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=212.3, 141.1, 135.2,
128.6, 128.2, 127.7, 126.8, 125.2, 122.3, 121.9, 118.6, 112.8, 112.7, 76.4,
42.4, 37.6, 26.1, 25.9 ppm; HRMS (ESI): m/z: calcd for C20H21NO2
[M+H]+: 308.1645; found: 308.1639.
Compound 4 fa: The title compound was prepared according to the gen-
eral procedure and purified by chromatography to give a white solid,
which was an unknown compound. Chiral HPLC was performed using an
HP series 1200 (Chiralpak IA column; hexane/2-propanol 85:15;
Compound 4ka: The title compound was prepared according to the gen-
eral procedure and purified by chromatography to give a white solid,
which was an unknown compound. Chiral HPLC was performed using an
HP series 1200 (Chiralpak OD-H column; hexane/2-propanol 80:20;
1.0 mLminÀ1
,
254 nm):
t
(major)=19.50 min,
tRACTHNGUTERN(UNG minor)=26.51 min,
84% ee; [a]2D0 =À2.6 (c=0.15 in CH2Cl2). The absolute configuration was
1
assigned as R by analogy. H NMR (400 MHz, CDCl3): d=8.08 (br, 1H),
1.0 mLminÀ1
,
254 nm):
t
G
tRACTHNGUTERN(UNG major)=22.49 min,
8.03–8.05 (m, 2H), 7.41 (d, J=8.8 Hz, 2H), 7.28 (t, J=7.2 Hz, 2H), 7.09–
7.13 (m, 1H), 6.95–6.99 (m, 2H), 4.97 (m, 1H), 3.27–3.41 (m, 3H), 1.19
(s, 3H), 1.14 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=211.9, 151.6,
146.6, 136.6, 128.8, 126.0, 123.8, 122.7, 121.3, 119.9, 119.0, 117.4, 111.5,
76.4, 41.9, 37.6, 26.2 ppm; HRMS (ESI): m/z: calcd for C20H20N2O4
[M+H]+: 353.1496; found: 353.1501.
80% ee; [a]2D0 =À12.8 (c=0.18 in CH2Cl2). The absolute configuration
was assigned as R by analogy. 1H NMR (400 MHz, CDCl3): d=7.95 (br,
1H), 7.66–7.71 (m, 4H), 7.33–7.39 (m, 4H), 7.27 (d, J=8.0 Hz, 1H),
7.06–7.10 (m, 1H), 6.92–6.96 (m, 2H), 5.06 (t, J=7.2 Hz, 1H), 3.54 (s,
1H), 3.33–3.43 (m, 2H), 1.19 (s, 3H), 1.07 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=212.5, 142.0, 136.6, 133.4, 132.3, 128.2, 127.8,
127.6, 126.5, 126.4, 126.0, 125.9, 125.5, 122.3, 121.3, 119.6, 119.4, 118.8,
111.2, 76.4, 42.2, 37.9, 26.1, 26.0 ppm; HRMS (ESI): m/z: calcd for
C24H23NO2 [M+H]+: 358.1802; found: 358.1800.
Compound 4ga: The title compound was prepared according to the gen-
eral procedure and purified by chromatography to give a white solid,
which was an unknown compound. Chiral HPLC was performed using an
HP series 1200 (Chiralpak AD-H column; hexane/2-propanol 80:20;
Compound 4la: The title compound was prepared according to the gen-
eral procedure and purified by chromatography to give a white solid,
which was an unknown compound. Chiral HPLC was performed using an
HP series 1200 (Chiralpak OD-H column; hexane/2-propanol 90:10;
1.0 mLminÀ1
,
254 nm):
t
G
tRACTHNGUTERN(UNG minor)=10.25 min,
85% ee; [a]2D0 =À23.1 (c=0.13 in CH2Cl2). The absolute configuration
was assigned as R by analogy. 1H NMR (400 MHz, CDCl3): d=7.99 (br,
1H), 7.34 (d, J=7.6 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.21 (s, 1H), 7.06–
7.16 (m, 4H), 6.91–6.99 (m, 1H), 6.90 (s, 1H), 4.85 (t, 1J=7.2 Hz, 2J=
7.2 Hz, 1H), 3.53 (s, 1H), 3.20–3.31 (m, 2H), 1.19 (s, 3H), 1.09 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=212.2, 145.8, 136.6, 134.3, 129.8,
127.9, 126.8, 126.2, 126.1, 122.5, 121.2, 119.7, 119.3, 118.2, 111.3, 76.4,
42.2, 37.5, 26.1, 26.0 ppm; HRMS (ESI): m/z: calcd for C20H20NO2Cl
[M+H]+: 342.1255; found: 342.1251.
1.0 mLminÀ1
,
254 nm):
t
G
tRACTHNGUTERN(UNG major)=34.05 min,
43% ee; [a]2D0 =+12.0 (c=0.10 in CH2Cl2). 1H NMR (400 MHz, CDCl3):
d=8.00 (br, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.23–7.27 (m, 2H), 7.08–7.13
(m, 1H), 6.96–6.99 (m, 2H), 6.18–6.20 (m, 1H), 5.98 (d, J=3.2 Hz, 1H),
4.94 (t, J=7.2 Hz, 1H), 3.64 (s, 1H), 3.33 (dd, 1J=8.0 Hz, 2J=17.2 Hz,
1H), 3.14 (dd, 1J=6.8 Hz, 2J=16.8 Hz, 1H), 1.20 (s, 3H), 1.08 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=212.4, 156.2, 141.2, 136.4, 125.9,
122.3, 122.1, 119.6, 119.2, 116.1, 111.4, 110.3, 105.9, 76.5, 40.6, 32.1, 26.1,
25.8 ppm; HRMS (ESI): m/z: calcd for C18H19NO3 [M+H]+: 298.1438;
found: 298.1435.
Compound 4ha: The title compound was prepared according to the gen-
eral procedure and purified by chromatography to give a white solid,
which was an unknown compound. Chiral HPLC was performed using an
HP series 1200 (Chiralpak AD-H column; hexane/2-propanol 85:15;
Compound 4ma: The title compound was prepared according to the gen-
eral procedure and purified by chromatography to give a white solid,
which was a known compound. Chiral HPLC was performed using an
HP series 1200 (Chiralpak OD-H column; hexane/2-propanol 80:20;
1.0 mLminÀ1
,
254 nm):
t
G
tRACTHNGUTERN(UNG minor)=15.19 min,
84% ee; [a]2D0 =À28.3 (c=0.18 in CH2Cl2). The absolute configuration
was assigned as R by analogy. 1H NMR (400 MHz, CDCl3): d=8.13 (br,
1H), 7.33 (d, J=7.6 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.03–7.18 (m, 3H),
6.81–6.99 (m, 3H), 6.76–6.79 (m, 1H), 4.87 (t, J=7.6 Hz, 1H), 3.30 (s,
1H), 3.25–3.27 (m, 2H), 1.19 (s, 3H), 1.09 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=212.3, 164.1, 161.7, 146.4 (d, J=66 Hz), 136.6,
129.9 (d, J=82 Hz), 126.3, 123.6 (d, J=27 Hz), 122.4, 121.2, 119.4 (d, J=
335 Hz), 118.2, 114.7 (d, J=221 Hz), 113.4 (d, J=210 Hz), 111.3, 76.4,
42.3, 37.5, 26.1, 26.0 ppm; HRMS (ESI): m/z: calcd for C20H20NO2F
[M+H]+: 326.1551; found: 326.1545.
1.0 mLminÀ1
,
254 nm):
t
G
tRACTHNGUTERN(UNG minor)=10.15 min,
47% ee; [a]2D0 =+10.5 (c=0.19 in CH2Cl2). The absolute configuration
was assigned as S by comparison of the optical rotation with the reported
value (ref. [6h]: [a]2D5 =+27.2 (c=1.0 in CH2Cl2), 98% ee for S isomer).
1H NMR (400 MHz, CDCl3): d=8.07 (s, 1H), 7.64 (d, J=8.0 Hz, 1H),
7.34 (d, J=8.0 Hz, 1H), 7.08–7.25 (m, 7H), 7.06 (d, J=2.4 Hz, 1H), 3.70
(s, 1H), 3.58–3.65 (m, 1H), 3.07 (dd, J=6.8 Hz, 1H), 2.88 (dd, J=6.8 Hz,
1H), 2.50–2.57 (m, 2H), 2.02–2.19 (m, 2H), 1.29 (s, 3H), 1.04 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=213.5, 142.2, 136.6, 128.4, 128.3,
126.3, 125.7, 122.0, 121.6,119.4, 119.3, 118.2, 111.4, 76.3, 42.6, 36.9, 34.1,
32.5, 26.2, 25.8 ppm.
Compound 4ia: The title compound was prepared according to the gen-
eral procedure and purified by chromatography to give a white solid,
which was an unknown compound. Chiral HPLC was performed using an
HP series 1200 (Chiralpak AD-H column; hexane/2-propanol 90:10;
Compound 4ab: The title compound was prepared according to the gen-
eral procedure and purified by chromatography to give a white solid,
which was an unknown compound. Chiral HPLC was performed using an
HP series 1200 (Chiralpak AD-H column; hexane/2-propanol 90:10;
1.0 mLminÀ1
,
254 nm):
t
G
tRACTHNGUTERN(UNG minor)=34.15 min,
69% ee; [a]2D0 =À35.8 (c=0.12 in CH2Cl2). The absolute configuration
was assigned as R by analogy. 1H NMR (400 MHz, CDCl3): d=7.97 (br,
1H), 7.42 (d, J=8.0 Hz, 1H), 7.30–7.32 (m, 1H), 7.24 (d, J=8.0 Hz, 1H),
7.16–7.18 (m, 1H), 7.03–7.11 (m, 3H), 6.87–7.00 (m, 1H), 6.88 (s, 1H),
5.35 (t, J=7.2 Hz, 1H), 3.57 (s, 1H), 3.37 (dd, 1J=7.8 Hz, 2J=17.6 Hz,
1H), 3.22 (dd, 1J=6.8 Hz, 2J=17.6 Hz, 1H), 1.24 (s, 3H), 1.23 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=211.9, 141.0, 136.5, 133.7, 129.9,
128.8, 127.8, 126.9, 126.5, 122.4, 121.7, 119.7, 119.4, 117.5, 111.2, 76.3,
41.3, 34.2, 26.5, 26.4 ppm; HRMS (ESI): m/z: calcd for C20H20NO2Cl
[M+H]+: 342.1255; found: 342.1261.
1.0 mLminÀ1
,
254 nm):
t
G
tRACTHNGUTERN(UNG minor)=23.26 min,
72% ee; [a]2D0 =+23.1 (c=0.13 in CH2Cl2). 1H NMR (400 MHz,
CD3COCD3): d=10.37 (br, 1H), 7.61 (s, 1H), 7.42–7.46 (m, 3H), 7.37 (d,
J=8.8 Hz, 1H), 7.30–7.33 (m, 2H), 7.19–7.22 (m, 1H), 4.86 (t, J=7.2 Hz,
1H), 4.38 (s, 1H), 3.51–3.63 (m, 2H), 1.23 (s, 3H), 1.22 ppm (s, 3H);
13C NMR (100 MHz, CD3COCD3): d=213.3, 144.9, 136.5, 132.1, 130.6,
129.5, 125.0, 124.3, 122.2, 118.9, 114.1, 112.5, 77.2, 43.2, 37.5, 26.7,
26.6 ppm; HRMS (ESI): m/z: calcd for C20H19NO2BrCl [M+H]+:
420.0360; found: 420.0357.
Compound 4ja: The title compound was prepared according to the gen-
eral procedure and purified by chromatography to give a white solid,
which was an unknown compound. Chiral HPLC was performed using an
HP series 1200 (Chiralpak IA column; hexane/2-propanol 85:15;
Compound 4ac: The title compound was prepared according to the gen-
eral procedure and purified by chromatography to give a white solid,
which was an unknown compound. Chiral HPLC was performed using an
HP series 1200 (Chiralpak AD-H column; hexane/2-propanol 90:10;
1.0 mLminÀ1
,
254 nm):
t
(major)=10.56 min,
tRACTHNGUTERN(UNG minor)=13.47 min,
86% ee; [a]2D0 =À28.3 (c=0.12 in CH2Cl2). The absolute configuration
was assigned as R by analogy. 1H NMR (400 MHz, CDCl3): d=8.04 (br,
1H), 7.46 (d, J=2.0 Hz, 1H), 7.10–7.22 (m, 8H), 6.92 (d, J=2.4 Hz, 1H),
4.81 (t, J=7.2 Hz, 1H), 3.53 (s, 1H), 3.21–3.29 (m, 2H), 1.19 (s, 3H),
1.0 mLminÀ1
,
254 nm):
t
(minor)=18.31 min,
tRACTHNGUTERN(UNG major)=24.42 min,
Chem. Eur. J. 2010, 16, 1638 – 1645
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1643

C. Xia, H. Huang et al.
2
1J=6.0 Hz, J=16.8 Hz, 1H), 2.36 (s, 3H), 1.19 (s, 3H), 0.79 ppm (s, 3H);
[6] For selected examples of Friedel–Crafts alkylation of indoles with
a,b-unsaturated compounds, see: a) W. Zhuang, T. Hansen, K. A.
Jørgensen, Chem. Commun. 2001, 347; b) K. B. Jensen, J.
Thorhauge, R. G. Hazell, K. A. Jørgensen, Angew. Chem. 2001, 113,
164; Angew. Chem. Int. Ed. 2001, 40, 160; c) J. F. Austin, D. W. C.
MacMillam, J. Am. Chem. Soc. 2002, 124, 1172; d) J. Zhou, Y. Tang,
J. Am. Chem. Soc. 2002, 124, 9030; e) D. A. Evans, K. A. Scheidt,
K. R. Fandrick, H. W. Lam, J. Wu, J. Am. Chem. Soc. 2003, 125,
10780; f) D. A. Evans, K. R. Fandrick, H.-J. Song, J. Am. Chem. Soc.
2005, 127, 8942; g) R. P. Herrera, V. Sgarzani, L. Bernardi, A. Ricci,
Angew. Chem. 2005, 117, 6734; Angew. Chem. Int. Ed. 2005, 44,
6576; h) C. Palomo, M. Oiarbide, B. G. Kardak, J. M. Garcꢃa, A.
Linden, J. Am. Chem. Soc. 2005, 127, 4154; i) D. A. Evans, K. R.
Fandrick, H.-J. Song, J. Org. Chem. 2006, 71, 75; j) S. Yamazaki, Y.
Iwata, J. Org. Chem. 2006, 71, 739; k) R. Rasappan, M. Hager, A.
Gissibl, O. Reiser, Org. Lett. 2006, 8, 6099; l) Y. X. Jia, S. F. Zhu, Y.
Yang, Q. L. Zhou, J. Org. Chem. 2006, 71, 75; m) J. Itoh, K. Fuchibe,
T. Akiyama, Angew. Chem. 2008, 120, 4080; Angew. Chem. Int. Ed.
2008, 47, 4016; n) H. Yang, Y. T. Hong, S. Kim, Org. Lett. 2007, 9,
2281; o) M. Rueping, B. J. Nachtsheim, S. A. Moreth, M. Bolte,
Angew. Chem. 2008, 120, 603; Angew. Chem. Int. Ed. 2008, 47, 593;
p) H.-Y. Tang, A.-D. Lu, Z.-H. Zhou, G.-F. Zhao, L.-N. He, C.-C.
Tang, Eur. J. Org. Chem. 2008, 1406.
13C NMR (100 MHz, CDCl3): d=213.0, 142.1, 135.4, 132.0, 131.8, 128.8,
128.4, 126.9, 121.1, 119.4, 118.9, 112.4, 110.6, 76.5, 40.5, 36.2, 26.1, 25.6,
12.1 ppm; HRMS (ESI): m/z: calcd for C21H22NO2Cl [M+H]+: 356.1412;
found: 356.1409.
Compound 4ad: The title compound was prepared according to the gen-
eral procedure and purified by chromatography to give a white solid,
which was an unknown compound. Chiral HPLC was performed using an
HP series 1200 (Chiralpak OD-H column; hexane/2-propanol 80:20;
1.0 mLminÀ1
,
254 nm):
t
G
tRACTHNGUTERN(UNG major)=16.62 min,
12% ee; [a]2D0 =À4.1 (c=0.22 in CH2Cl2). 1H NMR (400 MHz, CDCl3):
d=7.30 (d, J=8.0 Hz, 1H), 7.11–7.21 (m, 6H), 7.94–7.98 (m, 1H), 6.74 (s,
1H), 4.84 (t, J=7.2 Hz, 1H), 3.67 (s, 3H), 3.51 (s, 1H), 3.25 (d, J=
7.2 Hz, 2H), 1.20 (s, 3H), 1.09 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=212.3, 142.3, 137.3, 132.1, 129.2, 128.6, 126.6, 125.9, 121.9,
119.4, 119.1, 116.9, 109.4, 76.3, 42.3, 37.2, 32.8, 26.1, 26.0 ppm; HRMS
(ESI): m/z: calcd for C21H22NO2Cl [M+H]+: 356.1412; found: 356.1410.
Acknowledgements
[7] a) J. Zhou, M.-C. Ye, Z. Z. Huang, Y. Tang, J. Org. Chem. 2004, 69,
1309; b) J. Zhou, Y. Tang, Chem. Commun. 2004, 432; c) T. Arai, N.
Yokoyama, Angew. Chem. 2008, 120, 5067; Angew. Chem. Int. Ed.
2008, 47, 4989.
This work was supported by the Chinese Academy of Sciences, National
Natural Science Foundation of China (nos. 20802085, 20625308). We
thank Dr. Chensong Pan in the Beijing office of Bruker Daltonics, Inc.
for ESIMS analysis. H.H. gratefully acknowledges Professor Huilin Chen
at DICP for his encouragement and important suggestions.
[8] For reviews, see: a) P. R. Schreiner, Chem. Soc. Rev. 2003, 32, 289;
b) P. M. Pihko, Angew. Chem. 2004, 116, 2110; Angew. Chem. Int.
Ed. 2004, 43, 2062; c) J. Seayad, B. List, Org. Biomol. Chem. 2005, 3,
719; d) M. S. Taylor, E. N. Jacobsen, Angew. Chem. 2006, 118, 1550;
Angew. Chem. Int. Ed. 2006, 45, 1520; e) S. J. Connon, Angew.
Chem. 2006, 118, 4013; Angew. Chem. Int. Ed. 2006, 45, 3909; f) T.
Akiyama, J. Itoh, K. Fuchibe, Adv. Synth. Catal. 2006, 348, 999; g) T.
Akiyama, Chem. Rev. 2007, 107, 5744; h) A. D. Doyle, E. N. Jacob-
sen, Chem. Rev. 2007, 107, 5713; i) M. Terada, Chem. Commun.
2008, 4097.
[9] For selected reviews of iron-catalyzed organic reactions, see: a) C.
Bolm, J. Legros, J. Le Paih, L. Zani, Chem. Rev. 2004, 104, 6217;
b) A. Correa, O. Garcꢃa MancheÇo, C. Bolm, Chem. Soc. Rev. 2008,
37, 1108; c) B. D. Sherry, A. Fꢄrstner, Acc. Chem. Res. 2008, 41,
1500; d) S. Gaillard, J. L. Renaud, ChemSusChem 2008, 1, 505; e) A.
Fꢄrstner, Angew. Chem. 2009, 121, 1390; Angew. Chem. Int. Ed.
2009, 48, 1364.
[10] For selected examples of using a’-hydroxy enones as substrate, see:
a) C. Palomo, M. Oiarbide, J. M. Garcꢃa, A. Gonzꢅlez, E. Arceo, J.
Am. Chem. Soc. 2003, 125, 13942; b) C. Palomo, M. Oiarbide, E.
Arceo, J. M. Garcꢃa, R. Lꢆpez, A. Gonzꢅlez, A. Linden, Angew.
Chem. 2005, 117, 6343; Angew. Chem. Int. Ed. 2005, 44, 6187; c) C.
Palomo, M. Oiarbide, R. Halder, M. Kelso, E. Gꢆmez-Bengoa, J. M.
Garcꢃa, J. Am. Chem. Soc. 2004, 126, 9188; d) C. Palomo, R. Pazos,
M. Oiarbide, J. M. Garcꢃa, Adv Synth. Catal. 2006, 348, 1161; e) S.
Lee, C. Lim, S. Kim, R. Subramaniam, J. Zimmerman, M. P. Sibi,
Org. Lett. 2006, 8, 4311; f) D. Monge, E. M. -Zamora, J. Vꢅzquez,
Ma. Alcarazo, E. ꢇlvarez, R. Fernꢅndez, J. M. Lassaletta, Org. Lett.
2007, 9, 2867; g) J. M. Garcꢃa, A. Gonzꢅlez, B. G. Kardak, J. M.
Odriozola, M. Oiarbide, J. Razkin, C. Palomo, Chem. Eur. J. 2008,
14, 8768.
[11] It should be noted that the OH group of the a’-hydroxy enones is
also important for obtaining high enantioselectivity of the Friedel–
Crafts alkylation products. When the OH was replaced with OCH3,
only low ee values were obtained (À208C, 48 h, 80% yield, 18% ee).
[12] a) C. Palomo, M. Oiarbide, H. Raijkumar, M. Kelso, E. Gꢆmez-
Bengoa, J. M. Garcꢃa, J. Am. Chem. Soc. 2004, 126, 9188; b) C.
Palomo, M. Oiarbide, B. G. Kardak, J. M. Garcꢃa, A. Linden, J. Am.
Chem. Soc. 2005, 127, 4154; c) P. Chiang, M. Rommel, J. W. Bode, J.
Am. Chem. Soc. 2009, 131, 8714.
[1] For reviews, see: Y. J. Park, J. W. Park, C. H. Jun, Acc. Chem. Res.
2008, 41, 222. For selected examples, see: a) M. Nakoji, T. Kanaya-
ma, T. Okino, Y. Takemoto, Org. Lett. 2001, 3, 3329; b) V. Koman-
duri, M. J. Krische, J. Am. Chem. Soc. 2006, 128, 16448; c) V. Ko-
manduri, M. J. Krische, J. Am. Chem. Soc. 2006, 128, 16448; d) M.
Rueping, A. P. Antonchick, C. Brinkmann, Angew. Chem. 2007, 119,
7027; Angew. Chem. Int. Ed. 2007, 46, 6903; e) A. Yamaguchi, S.
Matsunaga, M. Shibasaki, Org. Lett. 2008, 10, 2319; f) S. B. J. Kan,
R. Matsubara, F. Berthiol, S. Kobayashi, Chem. Commun. 2008,
6354; g) W. H. Hu, X. F. Xu, J. Zhou, W. J. Liu, H. X. Huang, J. Hu,
L. P. Yang, L. Z. Gong, J. Am. Chem. Soc. 2008, 130, 7782; h) X. F.
Xu, J. Zhou, L. P. Yang, W. H. Hu, Chem. Commun. 2008, 6564.
[2] a) E. N. Jacobsen, A. Pfaltz, H. Yamamoto, Comprehensive Asym-
metric Catalysis, Springer, Heidelberg, 1999; b) M. Beller, C. Bolm,
Transition Metals for Organic Synthesis: Building Blocks and Fine
Chemicals, Vols. 1 and 2, 2nd ed., Wiley-VCH, Weinheim 2004;
c) A. Berkessel, H. Groger, Asymmetric Organocatalysis-From Bio-
mimetic Concepts to Powerful Methods for Asymmetric Synthesis,
Wiley-VCH, Weinheim, 2005.
[3] a) Z.-Y. Han, H. Xiao, X.-H. Chen, L.-Z. Gong, J. Am. Chem. Soc.
2009, 131, 9182; b) T. Yang, A. Ferrali, F. Sladojevich, L. Campbell,
D. J. Dixon, J. Am. Chem. Soc. 2009, 131, 9140; c) M. E. Muratore,
C. A. Holloway, A. W. Pilling, R. I. Storer, G. Trevitt, D. J. Dixon, J.
Am. Chem. Soc. 2009, 131, 10796; d) Y. Lu, T. C. Johnstone, B. A.
Arndtsen, J. Am. Chem. Soc. 2009, 131, 11284.
[4] Electron and Proton Transfer in Chemistry and Biology (Ed.: A.
Muller), Elsevier, Amsterdam, 1992.
[5] For recent reviews of Friedel–Crafts alkylation reactions, see:
a) G. A. Olah, R. Krishnamurti, G. K. S. Prakash, Comprehensive
Organic Synthesis, Vol. 3, 1st ed. (Eds.: B. M. Trost, I. Fleming), Per-
gamon, Oxford, 1991, p. 293; b) R. M. A. Roberts, A. Khalaf, Frie-
del–Crafts Alkylation Chemistry: A Century of Discovery, Marcel
Dekker, New York, 1984; c) K. A. Jørgensen, Synthesis 2003, 1117;
d) M. Bandini, A. Melloni, A. Umani-Ronchi, Angew. Chem. 2004,
116, 560; Angew. Chem. Int. Ed. 2004, 43, 550; e) M. Bandini, A.
Melloni, S. Tommasi, A. Umani-Ronchi, Synlett 2005, 1199; f) S.
Cacchi, G. Fabrizi, Chem. Rev. 2005, 105, 2873; g) S. B. Tsogoeva,
Eur. J. Org. Chem. 2007, 1701; h) T. B. Poulsen, K. A. Jørgensen,
Chem. Rev. 2008, 108, 2903.
[13] a) T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew. Chem. 2004,
116, 1592; Angew. Chem. Int. Ed. 2004, 43, 1566; b) D. Uraguchi, M.
1644
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 1638 – 1645

Friedel–Crafts Alkylation of Indoles
FULL PAPER
Terada, J. Am. Chem. Soc. 2004, 126, 5356; c) T. Akiyama, H.
Morita, J. Itoh, K. Fuchibe, Org. Lett. 2005, 7, 2583; d) D. Uraguchi,
K. Sorimachi, M. Terada, J. Am. Chem. Soc. 2005, 127, 9360; e) D.
Uraguchi, K. Sorimachi, M. Terada, Angew. Chem. 2006, 118, 2312;
Angew. Chem. Int. Ed. 2006, 45, 2254; f) J. Jiang, J. Yu, X.-X. Sun,
Q.-Q. Rao, L.-Z. Gong, Angew. Chem. 2008, 120, 2492; Angew.
Chem. Int. Ed. 2008, 47, 2458. also see: g) M. Terada, D. Uraguchi,
K. Sorimachi, H. Shimizu, PCT Int. Appl. WO 2005070875, 2005;
h) T. Akiyama, PCT Int. Appl. WO 200409675, 2004; i) G. L. Hamil-
ton, E. J. Kang, M. Mba, F. D. Toste, Science 2007, 317, 496.
Received: October 1, 2009
Published online: December 23, 2009
Chem. Eur. J. 2010, 16, 1638 – 1645
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1645