Palladium-catalyzed asymmetric allylic alkylation of indoles by C-N bond axially chiral phosphine ligands

Article abstract of DOI:10.1016/j.tetasy.2013.03.008

Abstract The palladium-catalyzed asymmetric allylic alkylation of indoles with 1,3-diphenyl-2-propenyl acetate using P/N-type ligands such as N-aryl indole, C-N bond axially chiral aminophosphine (aS)-L4, gave the desired products 1 in good yields and wit

Full text of DOI:10.1016/j.tetasy.2013.03.008

Tetrahedron: Asymmetry 24 (2013) 499–504
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Tetrahedron: Asymmetry
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Palladium-catalyzed asymmetric allylic alkylation of indoles by C–N bond
axially chiral phosphine ligands
⇑
Takashi Mino , Miho Ishikawa, Kenji Nishikawa, Kazuya Wakui, Masami Sakamoto
Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 February 2013
Accepted 8 March 2013
The palladium-catalyzed asymmetric allylic alkylation of indoles with 1,3-diphenyl-2-propenyl acetate
using P/N-type ligands such as N-aryl indole, C–N bond axially chiral aminophosphine (aS)-L4, gave
the desired products 1 in good yields and with moderate to high enantioselectivities (up to 90% ee).
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
and 5 mol% of ligand (Pd/ligand = 1/1) as a model reaction (Table 1).
The reaction using (S)-L1 and 2 equiv of K2CO3 as a base in aceto-
Optically active indoles and their derivatives are widely present
in various biologically and medicinally important compounds.1
The asymmetric Friedel–Crafts reaction of indole2 and the metal-
catalyzed allylic alkylation of indole3 gave optically active indole
derivatives. Although many palladium-catalyzed allylic alkylations
of malonates with 1,3-diphenyl-2-propenyl acetate have been re-
ported,4 the synthesis of optically active indoles by the palladium-
catalyzed asymmetric allylic alkylation of indoles5,6 with 1,3-diphe-
nyl-2-propenyl acetate was not achieved until 2007. Chan et al. first
reported the palladium-catalyzed asymmetric allylic alkylation of
indoles with 1,3-diphenyl-2-propenyl acetate using chiral ferroce-
nyl P/S ligands.7 Moreover, the P/S-type sulfur-MOP ligands8
reported by Hoshi et al., and chiral olefin/P-type MOP ligands9 and
phosphorus amidite ligands10 reported by Du et al. also gave good
enantioselectivities. However, P/N-type ligands, such as iPr-PHOX,
were not effective (<10% ee) in this reaction.7 Recently we reported
on P/N-type ligands, such as chiral phosphinohydrazone L1,11 pyrro-
lidinyl-containing chiral aminophosphine L2,12 N-aryl indoline-type
C–N bond axially chiral aminophosphine L3,13 N-aryl indole-type C–
N bond axially chiral aminophosphine L4,14 and acyclic C–N bond
axially chiral aminophosphine L5.15 Herein we report on the palla-
dium-catalyzed asymmetric allylic alkylation of indoles with 1,3-di-
phenyl-2-propenyl acetate using the P/N type-ligands L1–L5 (Fig. 1).
nitrile (0.1 M) at 40 °C for 18 h gave the corresponding product 1a
in 21% yield with moderate enantioselectivity (50% ee) (entry 1).
We tested other ligands and changed the concentration of this
reaction (entries 3–8) and found that (aS)-L4 and (aS)-L5 were
effective ligands. We changed the reaction temperature in the reac-
tion using (aS)-L4. The enantioselectivity of product 1a increased
to 88.5:11.5 e.r. to give a high yield in acetonitrile (1 M) at room
temperature (entry 9). On the other hand, the reaction using
(aS)-L5 scarcely proceeded under these conditions (entry 10). We
investigated the effects of various solvents (entries 11–15). When
using dichloroethane (DCE) as a solvent, the enantioselectivity de-
creased slightly (71% ee) with moderate yield (entry 13). Using tol-
uene as a solvent led to good enantioselectivity (80% ee) with 89%
yield (entry 11). When the reaction was carried out in trifluoro-
methyl benzene instead of toluene, 1a was obtained with a similar
level of enantioselectivity (entry 11 vs. entry 15). When 6 mol% of
(aS)-L4 was used in toluene, the yield of 1a decreased to 63% (entry
16). We also investigated the effect of the base. The reaction pro-
ceeded with low yield using Na2CO3 instead of K2CO3 (entry 17).
When the reaction was carried out at 0 °C, the enantioselectivity
was decreased slightly (entry 18).
2.2. Substrate scope and limitation
Under the optimized reaction conditions (Table 1, entry 11), we
investigated the palladium-catalyzed asymmetric allylic alkylation
of various indoles with 1,3-diphenyl-2-propenyl acetate using
N-aryl indole C–N bond axially chiral aminophosphine (aS)-L4
(Table 2). The reactions with methyl-substituted indoles, except
for N-methylindole, gave the corresponding products in moderate
enantioselectivites but with good yields (entries 2–5). On the other
hand, the reaction using N-methylindole did not give the product
(entry 6). When we used 6-methoxyindole, the reaction gave
product 1g with good enantioselectivity (entry 8). However, the
2. Results and discussion
2.1. Optimization of the reaction conditions
The reaction of indole with 1,3-diphenyl-2-propenyl acetate
was performed in the presence of 2.5 mol% of [Pd(g
3-C3H5)Cl]2,
⇑
Corresponding author. Tel.: +81 43 290 3385; fax: +81 43 290 3401.
E-mail address: tmino@faculty.chiba-u.jp (T. Mino).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.03.008

500
T. Mino et al. / Tetrahedron: Asymmetry 24 (2013) 499–504
OMe
N
N
OTMS
Me
N
N
N
N
F3C
PPh2
PPh2
MeO
PPh2
F3C
PPh2
MeO
PPh2
(aS)-L3
(S)-L1
(S)-L2
(aS)-L4
(aS)-L5
Figure 1. P/N-type ligands L1–L5.
Table 1
Optimization of the palladium-catalyzed asymmetric allylic alkylation of indole with 1,3-diphenyl-2-propenyl acetate
Ph
*
2.5 mol% [Pd(C3H5)Cl]2
Ph
N
H
5 mol% ligand
2 equiv base
+
solv., temp., 18 h
OAc
N
H
Ph
Ph
1.2 equiv
Solv.
1a
Entry
Ligand
Base
Temp (°C)
Yield (%)a
eeb
1
2
3
4
5
6
7
8
(S)-L1
(S)-L2
MeCN (0.1 M)
MeCN (0.1 M)
MeCN (0.1 M)
MeCN (0.1 M)
MeCN (0.1 M)
MeCN (1 M)
MeCN (1 M)
MeCN (1 M)
MeCN (1 M)
MeCN (1 M)
PhMe (1 M)
EtOAc (1 M)
DCE (1 M)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
K2CO3
40
40
40
40
40
40
40
40
rt
rt
rt
rt
rt
21
65
47
96
44
88
88
72
93
Trace
89
91
69
81
92
63
24
91
50 (S)
4 (R)
(aS)-L3
(aS)-L4
(aS)-L5
(aS)-L3
(aS)-L4
(aS)-L5
(aS)-L4
(aS)-L5
(aS)-L4
(aS)-L4
(aS)-L4
(aS)-L4
(aS)-L4
(aS)-L4c
(aS)-L4
(aS)-L4
57 (S)
58 (R)
62 (R)
50 (S)
73 (R)
69 (R)
77 (R)
–
80 (R)
76 (R)
71 (R)
73 (R)
79.8 (R)
78 (R)
77 (R)
75 (R)
9
10
11
12
13
14
15
16
17
18
THF (1 M)
rt
rt
rt
rt
PhCF3 (1 M)
PhMe (1 M)
PhMe (1 M)
PhMe (1 M)
0
a
b
c
Isolated yield.
Determined by HPLC analysis using a chiral column. The absolute configuration was assigned by comparison of the specific rotation with the reported data.9
6 mol % of (aS)-L4 was added.
reaction with 5-methoxyindole and 6-benzyloxyindole led to
moderate enantioselectivities (entries 7 and 9). The reaction with
halogen-substituted indoles gave the corresponding products with
good to high enantioselectivities (entries 10–15). Using 6-bromoin-
dole gave product 1j good yield and with high enantioselectivity
(90% ee) (entry 11). When the reaction of 6-bromoindole was carried
out in trifluoromethyl benzene instead of toluene, the enantioselec-
tivity of 1j was decreased to 86% ee (entry 12). The reaction of
6-chloroindole also gave the corresponding product 1l in high
enantioselectivity (86% ee) (entry 14). On the other hand, reaction
using 6-nitroindole did not proceed under these conditions (entry
16). Finally, we tested the reaction of 2-phenylindole in toluene
and trifluoromethyl benzene. The reactions gave the corresponding
product 1n with 86% ee (entry 17) and 88% ee (entry 18), respec-
tively. The absolute configurations of products 1 were assigned by
comparison of the specific rotation with the reported data9,10 or ten-
tatively assigned by analogy.
2.3. Plausible asymmetric induction process
We suggested a plausible asymmetric induction process for the
palladium-catalyzed asymmetric allylic alkylation of indole
derivatives with 1,3-diphenyl-2-propenyl acetate using chiral ami-
nophosphine (aS)-L4 as shown in Figure 2. There are two candidates,
A and B, which are possible structures formed from chiral ligand
(aS)-L4 in the same way as in the allylic alkylation of malonate.14
Intermediate B could be obtained from A by exchanging the relative
positions of the phosphine and the acetate ligands. However, inter-
mediate B is unstable because of the steric hindrance between the
phenyl rings of the allylic substrate and the indole ring of the ligand.
Therefore, the reaction probably proceeds through M-type interme-
diate A rather than a W-type intermediate B. The nucleophilic attack
of the indole potassium salt occurs predominantly at the allyl termi-
nus trans to the phosphine atom. As a result, the (R)-products 1 were
obtained in this reaction using the chiral ligand (aS)-L4.

T. Mino et al. / Tetrahedron: Asymmetry 24 (2013) 499–504
501
Table 2
Palladium-catalyzed asymmetric allylic alkylation of indoles with 1,3-diphenyl-2-propenyl acetate using (aS)-L4
4
3
5
Ph
2
R
2.5 mol% [Pd(C3H5)Cl]2
5 mol% (aS)-L4
Ph
N
H
6
7
2 equiv K2CO3
+
R
PhMe (1.0 M), rt, 18 h
OAc
N
H
Ph
Ph
1.2 equiv
1
entry
R
Yield (%)a
eeb
1
2
3
4
5
H
89 1a
93 1b
85 1c
76 1d
65 1e
N.R.
80
33
36
33
37
—
4-Me
5-Me
6-Me
7-Me
N-Me
6
7
8
9
5-MeO
6-MeO
6-BnO
5-Br
6-Br
6-Br
5-Cl
6-Cl
6-F
85 1f
69 1g
69 1h
88 1i
80 1j
74 1j
73 1k
77 1l
83 1m
N.R.
40
75
34
58
90
86
80
86
44
—
10
11
12c
13
14
15
16
17
18c
6-NO2
2-Ph
2-Ph
81 1n
88 1n
86
88
a
b
c
Isolated yield.
Determined by HPLC analysis using a chiral column.
PhCF3 was used as a solvent.
10 lmol), [Pd(g lmol), and K2CO3 (55.7 mg,
3-C3H5)Cl]2 (1.8 mg, 5
3. Conclusion
0.4 mol) was added toluene (0.2 mL) at room temperature under
an Ar atmosphere. After stirring for 18 h at room temperature,
the mixture was quenched with water and diluted with diethyl
ether. The organic layer was washed with water and brine, and
dried over MgSO4. The filtrate was concentrated with a rotary
evaporator and the residue was purified by column chromatogra-
phy (elution with n-hexane/EtOAc/Et3N = 40/2/1).
In conclusion, we found that the palladium-catalyzed asymmet-
ric allylic alkylation of indoles with 1,3-diphenyl-2-propenyl ace-
tate using N-aryl indole C–N bond axially chiral aminophosphine
(aS)-L4 as a ligand in toluene gave the desired products 1 in good
yields with moderate to high enantioselectivities (up to 90% ee) at
room temperature.
4.2.1. (R)-(–)-3-[(E)-1,3-Diphenyl-2-propen-1-yl]-1H-indole 1a10
4. Experimental
4.1. General
(Table 2, entry 1)
89% Yield (55.1 mg) as a white solid, 80% ee; ½a D20
¼ ꢁ38:1 (c
ꢀ
0.50, CHCl3); ½a D20
ꢀ
¼ ꢁ46:7 (c 0.50, CH2Cl2);7 mp 112–114 °C; 1H
NMR (CDCl3, 300 MHz)
d 5.11 (d, J = 7.3 Hz, 1H), 6.43 (d,
Melting points were measured on a Asone micromelting point
apparatus and are uncorrected. The 1H and 13C NMR spectra were
recorded in CDCl3 on a Bruker DPX-300 spectrometer. The chemi-
cal shifts of 1H NMR spectra are reported relative to TMS (d 0.00)
and 13C NMR spectra are reported relative to CDCl3 (d 77.0), as
the internal standard. Mass spectra were determined on a Shima-
dzu GCMS-QP5050A using EI, and presented as m/z (% rel inten-
sity). HRMS were recorded on a Thermo Fisher Scientific Exactive
using ESI. Analytical high-performance liquid chromatography
(HPLC) was carried out with a JASCO GULLIVER 900 or 2000 system
coupled with a UV detector using a chiral column. Optical rotations
were measured on JASCO P-2100.
J = 15.8 Hz, 1H), 6.72 (dd, J = 7.4 and 15.8 Hz, 1H), 6.88 (d,
J = 2.3 Hz, 1H), 6.99–7.04 (m, 1H), 7.14–7.43 (m, 13H), 7.96 (br s,
1H); 13C NMR (CDCl3, 75 MHz) d 46.2, 111.1, 118.7, 119.4, 119.9,
122.1, 122.6, 126.3, 126.4, 126.8, 127.1, 128.4, 128.5ꢂ2, 130.5,
132.5, 136.6, 137.4, 143.3; EI-MS m/z (rel intensity) 309 (M+,
100). HPLC (Daicel CHIRALPAKÒ IB, 0.46 / ꢂ 25 cm, UV 254 nm,
hexane/ethanol = 99:1,
0.9 mL/min)
tR = 55.1 min
(major),
tR = 61.4 min (minor).
4.2.2. (R)-(–)-3-[(E)-1,3-Diphenyl-2-propen-1-yl]-4-methyl-1H-
indole 1b10 (Table 2, entry 2)
93% Yield (60.4 mg) as a white solid, 33% ee; ½a D20
¼ ꢁ27:6 (c
ꢀ
0.50, CHCl3); mp 156–158 °C; 1H NMR (CDCl3, 300 MHz) d 2.52
(s, 3H), 5.44 (d, J = 6.4 Hz, 1H), 6.23 (d, J = 15.8 Hz, 1H), 6.71 (d,
J = 6.5 Hz, 1H), 6.75–6.83 (m, 2H), 7.06 (t, J = 7.6 Hz, 1H), 7.16–
7.35 (m, 11H), 7.99 (br s, 1H); 13C NMR (CDCl3, 75 MHz) d 20.4,
46.5, 109.0, 119.0, 121.3, 122.2, 123.5, 125.5, 126.3 ꢂ 2, 127.1,
4.2. General procedure for the palladium-catalyzed asymmetric
allylic alkylation of indoles using (aS)-L4
To a mixture of indole or substituted indole (0.2 mmol), 1,3-di-
phenyl-2-propenyl acetate (60.5 mg, 0.24 mmol), (aS)-L4 (4.4 mg,

502
T. Mino et al. / Tetrahedron: Asymmetry 24 (2013) 499–504
K
N
R
F3C
F3C
Ph
N
N
Ph
(aS)
Ph
Ph
OAc
Ph
Pd(II)
Pd(II)
OAc
Ph
P
P
OAc
A
B
KOAc
R
H
N
Ph
Ph
Ph
F3C
N
R
Ph
Pd(0)
N
H
P
(R)-1
Figure 2. Plausible asymmetric induction process for the palladium-catalyzed asymmetric allylic alkylation using chiral ligand (aS)-L4.
128.3, 128.5, 128.9, 130.7, 131.1, 133.9, 137.0, 137.5, 144.0; EI-MS
m/z (rel intensity) 323 (M+, 100); HPLC (Daicel CHIRALPAKÒ IB,
0.46 / ꢂ 25 cm, UV 254 nm, hexane/ethanol = 99:1, 0.9 mL/min)
tR = 34.6 min (minor), tR = 53.9 min (major).
C
24H21N+H 324.1747, found 324.1739; HPLC (Daicel CHIRALPAKÒ
IB, 0.46 / ꢂ 25 cm, UV 254 nm, hexane/ethanol = 99:1, 0.5 mL/
min) tR = 71.7 min (major), tR = 77.4 min (minor).
4.2.5. (R)-(–)-3-[(E)-1,3-Diphenyl-2-propen-1-yl]-7-methyl-1H-
4.2.3. (R)-(–)-3-[(E)-1,3-Diphenyl-2-propen-1-yl]-5-methyl-1H-
indole 1e9 (Table 2, entry 5)
indole 1c10 (Table 2, entry 3)
65% Yield (42.3 mg) as a brown oil, 37% ee; ½a D20
¼ ꢁ13:3 (c 0.50,
ꢀ
85% Yield (55.6 mg) as a white solid, 36% ee; ½a D20
ꢀ
= –16.6 (c
CHCl3); 1H NMR (CDCl3, 300 MHz) d 2.47 (s, 3H), 5.11 (d, J = 7.4 Hz,
1H), 6.43 (d, J = 15.8 Hz, 1H), 6.72 (dd, J = 7.4 and 15.8 Hz, 1H),
6.89–6.99 (m, 3H), 7.16–7.37 (m, 11H), 7.89 (br s, 1H); 13C NMR
(CDCl3, 75 MHz) d 16.6, 46.3, 117.6, 119.2, 119.6, 120.2, 122.3,
122.6, 126.29, 126.31 ꢂ 2, 127.1, 128.37, 128.44, 128.5, 130.5,
132.5, 136.2, 137.5, 143.4; EI-MS m/z (rel intensity) 323 (M+,
100); HPLC (Daicel CHIRALPAKÒ IB, 0.46 / ꢂ 25 cm, UV 254 nm,
0.50, CHCl3); mp 104–106 °C; 1H NMR (CDCl3, 300 MHz) d 2.36
(s, 3H), 5.09 (d, J = 7.3 Hz, 1H), 6.41 (d, J = 15.8, 1H), 6.71 (dd,
J = 7.3 and 15.8 Hz, 1H), 6.84 (d, J = 2.3 Hz, 1H), 6.99 (d, J = 9.5 Hz,
1H), 7.16–7.37 (m, 12H), 7.88 (br s, 1H); 13C NMR (CDCl3,
75 MHz) d 21.5, 46.0, 110.7, 118.1, 119.3, 122.8, 123.7, 126.3 ꢂ 2,
127.0, 127.1, 128.37, 128.44, 128.5, 128.6, 130.4, 132.7, 134.9,
137.5, 143.4; EI-MS m/z (rel intensity) 323 (M+, 100); HPLC (Daicel
CHIRALCELÒ OZ-3, 0.46 / ꢂ 25 cm, UV 254 nm, hexane/2-propa-
nol = 97:3, 0.5 mL/min) tR = 17.9 min (minor), tR = 20.1 min
(major).
hexane/ethanol = 99:1,
0.9 mL/min)
tR = 54.3 min
(major),
tR = 67.1 min (minor).
4.2.6. (R)-(–)-3-[(E)-1,3-Diphenyl-2-propen-1-yl]-5-methoxy-
1H-indole 1f10 (Table 2, entry 7)
4.2.4. (R)-(–)-3-[(E)-1,3-Diphenyl-2-propen-1-yl]-6-methyl-1H-
85% Yield (57.5 mg) as a yellow oil, 40% ee; ½a D20
¼ ꢁ14:9 (c
ꢀ
indole 1d (Table 2, entry 4)
0.50, CHCl3); 1H NMR (CDCl3, 300 MHz) d 3.71 (s, 3H), 5.07 (d,
J = 7.3 Hz, 1H), 6.44 (d, J = 15.8 Hz, 1H), 6.71 (dd, J = 7.3 and
15.8 Hz, 1H), 6.81–6.87 (m, 3H), 7.17–7.37 (m, 11H), 7.88 (br s,
1H); 13C NMR (CDCl3, 75 MHz) d 46.2, 55.8, 101.8, 111.7, 112.1,
118.3, 123.4, 126.3, 126.4, 127.1, 127.2, 128.4, 128.46, 128.48,
130.5, 131.8, 132.4, 137.5, 143.3, 153.8; EI-MS m/z (rel intensity)
76% Yield (49.3 mg) as a brown solid, 33% ee; ½a D20
¼ ꢁ13:2 (c
ꢀ
0.50, CHCl3); mp 103–105 °C; 1H NMR (CDCl3, 300 MHz) d 2.42
(s, 3H), 5.08 (d, J = 7.3 Hz, 1H), 6.43 (d, J = 15.8 Hz, 1H), 6.71 (dd,
J = 7.3 and 15.8 Hz, 1H), 6.81–6.86 (m, 2H), 7.13–7.37 (m, 12H),
7.82 (br s, 1H); 13C NMR (CDCl3, 75 MHz) d 21.7, 46.2, 111.0;
118.5, 119.5, 121.2, 121.9, 124.6, 126.3 ꢂ 2, 127.1, 128.36,
128.44, 128.5, 130.4, 131.9, 132.6, 137.1, 137.5, 143.4; EI-MS m/z
(rel intensity) 323 (M+, 100); HRMS (ESI-orbitrap) m/z calcd for
339 (M+, 100); HPLC (Daicel CHIRALPAKÒ IB, 0.46
254 nm, hexane/ethanol = 99:1, 0.9 mL/min) tR = 28.0 min (major),
tR = 36.4 min (minor).
u
ꢂ 25 cm, UV

T. Mino et al. / Tetrahedron: Asymmetry 24 (2013) 499–504
503
4.2.7. (R)-(–)-3-[(E)-1,3-Diphenyl-2-propen-1-yl]-6-methoxy-
1H-indole (1g) (Table 2, entry 8)
ꢂ 25 cm, UV 254 nm, hexane/ethanol = 99:1, 0.9 mL/min)
tR = 57.4 min (major), tR = 65.3 min (minor).
69% Yield (47.9 mg) as a white solid, 75% ee; ½a D20
¼ ꢁ37:0 (c
ꢀ
0.50, CHCl3); mp 143–145 °C; 1H NMR (CDCl3, 300 MHz) d 3.81
(s, 3H), 5.06 (d, J = 7.4 Hz, 1H), 6.43 (d, J = 15.8 Hz, 1H), 6.67–6.83
(m, 4H), 7.16–7.37 (m, 11H), 7.87 (br s, 1H); 13C NMR (CDCl3,
75 MHz) d 46.2, 55.6, 94.6, 109.3, 118.6, 120.5, 121.2, 121.4,
126.28, 126.34, 127.1, 128.38, 128.43, 128.44, 130.4, 132.5,
137.39, 137.45, 143.4, 156.4; EI-MS m/z (rel intensity) 339 (M+,
100); HRMS (ESI-orbitrap) m/z calcd for C24H21ON+H 340.1696,
found 340.1689; HPLC (Daicel CHIRALPAKÒ IB, 0.46 / ꢂ 25 cm,
UV 254 nm, hexane/ethanol = 99:1, 0.9 mL/min) tR = 57.0 min (ma-
jor), tR = 61.1 min (minor).
4.2.12. (R)-(–)-6-Chloro-3-[(E)-1,3-diphenyl-2-propen-1-yl]-1H-
indole 1l (Table 2, entry 14)
77% Yield (52.8 mg) as a white solid, 86% ee; ½a D20
¼ ꢁ13:3 (c
ꢀ
0.50, CHCl3); mp 120–122 °C; 1H NMR (CDCl3, 300 MHz) d 5.07 (d,
J = 7.3 Hz, 1H), 6.41 (d, J = 15.8 Hz, 1H), 6.68 (dd, J = 7.3 and
15.8 Hz, 1H), 6.88–6.89 (m, 1H), 6.97 (dd, J = 1.8 and 8.5 Hz, 1H),
7.18–7.37 (m, 12H), 7.97 (br s, 1H); 13C NMR (CDCl3, 75 MHz) d
46.1, 111.0, 118.9, 120.2, 120.8, 123.2, 125.4, 126.3, 126.5, 127.3,
128.0, 128.4, 128.48, 128.49, 130.8, 132.1, 137.0, 137.3, 143.0; EI-
MS m/z (rel intensity) 343 (M+, 100); HRMS (ESI-orbitrap) m/z calcd
for C23H18NCl+H 344.1189, found 344.1201; HPLC (Daicel CHIR-
ALPAKÒ IA-3, 0.46 / ꢂ 25 cm, UV 254 nm, hexane/ethanol = 99:1,
0.5 mL/min) tR = 85.9 min (minor), tR = 91.3 min (major).
4.2.8. (R)-(–)-6-Benzyloxy-3-[(E)-1,3-diphenyl-2-propen-1-yl]-
1H-indole 1h (Table 2, entry 9)
69% Yield (57.4 mg) as a white solid, 34% ee; ½a D20
¼ ꢁ11:6 (c
ꢀ
0.50, CHCl3); mp 128–130 °C; 1H NMR (CDCl3, 300 MHz) d 5.05
(d, J = 7.4 Hz, 1H), 5.06 (s, 2H), 6.42 (d, J = 15.8 Hz, 1H), 6.70 (dd,
J = 7.4 and 15.8 Hz, 1H), 6.75–6.79 (m, 2H), 6.88 (d, J = 2.1 Hz,
1H), 7.16–7.45 (m, 16H), 7.82 (br s, 1H); 13C NMR (CDCl3,
75 MHz) d 46.2, 70.5, 96.0, 110.0, 118.6, 120.5, 121.4, 121.5,
126.28, 126.35, 127.1, 127.4, 127.8, 128.38, 128.435, 128.444,
128.5, 130.5, 132.5, 137.3, 137.4, 137.5, 143.3, 155.6; EI-MS m/z
(rel intensity) 415 (M+, 49); HRMS (ESI-orbitrap) m/z calcd for
4.2.13. (R)-(–)-6-Fluoro-3-[(E)-1,3-diphenyl-2-propen-1-yl]-1H-
indole 1m (Table 2, entry 15)
83% YieldYield (54.8 mg) as a yellow solid, 44% ee; ½a D20
ꢀ
= –14.2
(c 0.50, CHCl3); mp 96–98 °C; 1H NMR (CDCl3, 300 MHz) d 5.07 (d,
J = 7.3 Hz, 1H), 6.42 (d, J = 15.8 Hz, 1H), 6.69 (dd, J = 7.3 and 15.8
HZ, 1H), 6.74–6.81 (m, 1H), 6.86–6.87 (m, 1H), 7.01 (dd, J = 2.2
and 9.6 Hz, 1H), 7.17–7.37 (m, 11H), 7.96 (br s, 1H); 13C NMR
(CDCl3, 75 MHz) d 46.1, 97.4 (d, JC–F = 25.7 Hz), 108.2 (d, JC–
F = 24.2 Hz), 118.8, 120.6 (d, JC–F = 9.9 Hz), 122.8 (d, JC–F = 3.4 Hz),
123.3, 126.3, 126.5, 127.2, 128.4, 128.46, 128.49, 130.7, 132.2,
136.6 (d, JC–F = 12.5 Hz), 137.3, 143.1, 159.9 (d, JC–F = 236.2 Hz);
EI-MS m/z (rel intensity) 327 (M+, 100); HRMS (ESI-orbitrap) m/z
calcd for C23H18NF–H 326.1355, found 326.1351; HPLC (Daicel
CHIRALPAKÒ IA, 0.46 / ꢂ 25 cm, UV 254 nm, hexane/etha-
nol = 99:1, 0.5 mL/min) tR = 77.0 min (minor), tR = 83.0 min (major).
C
30H25ON+H 416.2018, found 416.2009; HPLC (Daicel CHIRALPAKÒ
IA-3, 0.46 / ꢂ 25 cm, UV 254 nm, hexane/ethanol = 99:1, 0.7 mL/
min) tR = 176.9 min (minor), tR = 196.5 min (major).
4.2.9. (R)-(–)-5-Bromo-3-[(E)-1,3-diphenyl-2-propen-1-yl]-1H-
indole 1i10 (Table 2, entry 10)
88% Yield (68.2 mg) as a white solid, 58% ee; ½a D20
¼ ꢁ33:1 (c
ꢀ
0.50, CHCl3); mp 136–138 °C; 1H NMR (CDCl3, 300 MHz) d 5.05
(d, J = 7.2 Hz, 1H), 6.40 (d, J = 15.8 Hz, 1H), 6.68 (dd, J = 7.2 and
15.8 Hz, 1H), 6.90 (d, J = 2.3 Hz, 1H), 7.18–7.37 (m, 12H), 7.53 (s,
1H), 8.02 (br s, 1H); 13C NMR (CDCl3, 75 MHz) d 45.8, 112.5,
112.7, 118.4, 122.3, 123.8, 125.0, 126.3, 126.6, 127.3, 128.37,
128.42, 128.49, 128.50, 130.8, 132.0, 135.2, 137.3, 142.8; EI-MS
m/z (rel intensity) 387 (M+, 100); HPLC (Daicel CHIRALPAKÒ IB,
0.46 / ꢂ 25 cm, UV 254 nm, hexane/ethanol = 99:1, 0.9 mL/min)
tR = 56.6 min (major), tR = 61.8 min (minor).
4.2.14. (R)-(–)-3-[(E)-1,3-Diphenyl-2-propen-1-yl]-2-phenyl-1H-
indole 1n10 (Table 2, entry 18)
This reaction was carried out in trifluoromethyl benzene in-
stead of toluene:88% Yield (68.9 mg) as a yellow solid, 88% ee;
½
a 2D0
ꢀ
¼ ꢁ86:0 (c 0.50, CHCl3); mp 76–78 °C; 1H NMR (CDCl3,
300 MHz) d 5.28 (d, J = 7.3 Hz, 1H), 6.40 (d, J = 15.8 Hz, 1H), 6.89
(dd, J = 7.3 and 15.8 Hz, 1H), 6.97–7.02 (m, 1H), 7.14–7.56 (m,
18H), 8.10 (br s, 1H); 13C NMR (CDCl3, 75 MHz) d 45.1, 110.9,
113.9, 119.7, 121.2, 122.1, 126.1, 126.3, 127.1, 127.9, 128.0,
128.25, 128.28, 128.4, 128.6, 128.8, 131.1, 132.2, 133.0, 135.6,
136.2, 137.5, 143.5; EI-MS m/z (rel intensity) 385 (M+, 100); HPLC
(Daicel CHIRALPAKÒ IB, 0.46 / ꢂ 25 cm, UV 254 nm, hexane/etha-
nol = 99:1, 0.9 mL/min) tR = 21.1 min (minor), tR = 23.3 min
(major).
4.2.10. (R)-(–)-6-Bromo-3-[(E)-1,3-diphenyl-2-propen-1-yl]-1H-
indole 1j10 (Table 2, entry 11)
80% Yield (62.1 mg) as a white solid, 90% ee; ½a D20
¼ ꢁ39:0 (c
ꢀ
0.50, CHCl3); mp 130–132 °C; 1H NMR (CDCl3, 300 MHz) d 5.07
(d, J = 7.3 Hz, 1H), 6.41 (d, J = 15.8 Hz, 1H), 6.68 (dd, J = 7.3 and
15.8 Hz, 1H), 6.86–6.87 (m, 1H), 7.10 (dd, J = 1.7 and 8.5 Hz, 1H),
7.18–7.37 (m, 11H), 7.49 (d, J = 1.5 Hz, 1H), 7.97 (br s, 1H); 13C
NMR (CDCl3, 75 MHz) d 46.0, 114.0, 115.7, 118.9, 121.1, 122.7,
123.2, 125.7, 126.3, 126.5, 127.3, 128.4, 128.488, 128.494, 130.8,
132.0, 137.3, 137.4, 143.0; EI-MS m/z (rel intensity) 387 (M+,
100); HPLC (Daicel CHIRALPAKÒ IA-3, 0.46 / ꢂ 25 cm, UV
254 nm, hexane/2-propanol = 98:2, 0.7 mL/min) tR = 67.2 min
(minor), tR = 74.1 min (major).
Acknowledgements
This work was supported by a Grant-in-Aid for Young Scientists
(WAKATE B-22750082) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan and the COE Start-up Pro-
gram in Chiba University.
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0.50, CHCl3); 1H NMR (CDCl3, 300 MHz) d 5.06 (d, J = 7.3 Hz, 1H),
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