N,N′-Dioxide-scandium(III) complex catalyzed highly enantioselective Friedel-Crafts alkylation of indole to alkylidene malonates

Article abstract of DOI:10.1016/j.tet.2009.12.032

A highly efficient enantioselective Friedel-Crafts alkylation of indoles with alkylidene malonates has been developed using chiral N,N′-dioxide L4-scandium(III) complex as the catalyst, giving the corresponding products in high yields with excellent enant

Full text of DOI:10.1016/j.tet.2009.12.032

Tetrahedron 66 (2010) 1447–1457
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
N,N0-Dioxide–scandium(III) complex catalyzed highly enantioselective
Friedel–Crafts alkylation of indole to alkylidene malonates
*
Yanling Liu, Xin Zhou, Deju Shang, Xiaohua Liu, Xiaoming Feng
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 October 2009
Received in revised form 9 December 2009
Accepted 11 December 2009
Available online 16 December 2009
A highly efficient enantioselective Friedel–Crafts alkylation of indoles with alkylidene malonates has
been developed using chiral N,N0-dioxide L4–scandium(III) complex as the catalyst, giving the corre-
sponding products in high yields with excellent enantioselectivities (up to 99% yield and 95% ee). The
product 3a was facilely converted into several interesting compounds, such as tryptamines, in-
dolepropionic acids and b-carbolines. It is noteworthy that the seven-membered b-carboline-like com-
pound has been synthesized for the first time. Based on the crystal structure of the chiral N,N0-dioxide
L10–scandium(III) complex, the proposed transition state and possible catalytic cycle were presented to
elucidate the reaction mechanism.
Keywords:
Friedel–crafts alkylation
Alkylidene malonates
Indole derivatives
N,N0-Dioxide–scandium(III)
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The Friedel–Crafts alkylation reaction is a powerful carbon–
carbon bond-forming process in the organic synthesis. As
a promising synthetic methodology for the synthesis of chiral
indole derivatives, which has been identified as privileged
structure or pharmacophore in medicinal chemistry,1 the asym-
metric Friedel–Crafts alkylation of indoles with electron-deficient
olefins has recently attracted significant attentions.2 However, to
date, only a few highly enantioselective versions of indoles with
alkylidene malonates have been reported. In 2001, Jørgensen
et al. reported the reaction for the first time using chiral Cu(II)–
bis(oxazolines) complex.3 Subsequently, chiral Cu(II)–tris(oxazo-
line) complex was developed by Tang et al. and showed superior
performance in the reaction.4 Just recently, Reiser et al. disclosed
that the mole ratio of the ligand to copper played a crucial role on
the enantioselectivity of this reaction.5 Despite these advanced
achievement, the development of new and efficient asymmetric
catalytic system is still challenging and interesting. Herein, we
described our detailed effort on the enantioselective Friedel–
Crafts alkylation of indoles with alkylidene malonates using chiral
N,N0-dioxides–scandium(III) complex as the catalyst, giving the
corresponding indole derivatives with high yields and
enantioselectivities.13
2.1. Preliminary experiment results
Since N,N0-dioxide–scandium(III) complexes have been proved
to be effective chiral Lewis acid catalysts,14 L1-Sc(OTf)3 was first
selected for the preliminary investigation on the Friedel–Crafts
alkylation reaction. As shown in Table 1, the reaction proved to be
highly solvent-dependent. Only racemic products were obtained
in toluene, CH2Cl2 and PhOMe (Table 1, entries 1–3), while the
indole derivative 3a with 25% ee was isolated in Et2O (Table 1,
entry 4). Fortunately, better enantioselectivity could be achieved
when the reaction was carried out in alcohols (Table 1, entries
5–12), and the best enantioselectivity was obtained in cyclo-
pentanol (Table 1, entry 11).
2.2. Ligand effect
To further improve the enantioselectivity, various chiral N,N0-
dioxides (Fig.1) were complexed with Sc(OTf)3 in situ to catalyze
the reaction. As far as the chiral backbone of N,N0-dioxide was
concerned, L4 derived from
line derived L2 and -pipecolic acid derived L3 for the reaction
(Table 2, entries 1–3). The chiral N,N0-dioxide L4 derived from
L-ramiprol acid was superior to L-pro-
L
L-
ramiprol acid and diphenylmethyl amine provided the corre-
sponding product with the highest enantiomeric excess (Table 2,
entry 3). In contrast, ligands with smaller or bulkier amide moiety
gave slightly lower enantioselectivities (Table 2, entries 4–6). Linker
* Corresponding author.
E-mail address: xmfeng@scu.edu.cn (X. Feng).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.12.032

1448
Y. Liu et al. / Tetrahedron 66 (2010) 1447–1457
Table 1
2.3. Lewis acid effect
Initial screening of solventsa
A variety of chiral Lewis acid catalysts generated in situ from
metal salts and the L4 were then evaluated, and the results were
summarized in Table 3. When CuOTf, Cu(OTf)2, Zn(OTf)2, Y(OTf)3 or
Sm(OTf)3 was employed as central metal, only negligible enantio-
meric excess or even racemic product was obtained (Table 3, entries
1–5), while in the presence of Sc(OTf)3, La(OTf)3, Yb(OTf)3 or In(OTf)3,
indole reacted well with alkylidene malonate 2a, giving the desired
product in poor to moderate enantioselectivity (Table 3, entries 6–9).
Entry
Solvent
Yieldb (%)
Eec (%)
1
2
3
4
5
6
7
8
Toluene
CH2Cl2
PhOMe
Et2O
MeOH
96
74
81
85
83
57
70
39
37
85
64
48
0
0
0
Table 3
Investigations on the metal sourcesa
25(R)
30(R)
41(R)
32(R)
33(R)
42(R)
34(R)
45(R)
34(R)
EtOH
iPrOH
n-butanol
n-propanol
t-butanol
Cyclopentanol
Cyclohexanol
9
10
11
12
a
Entry
Metal
Yieldb (%)
traced
4
Eec (%)
Unless otherwise noted, reactions were carried out with L1 (10 mol %), Sc(OTf)3
(10 mol %), 2a (0.125 mmol), and 1a (0.15 mmol) in solvent (0.5 mL) at 45 ꢀC for
36 h.
1
2
3
4
5
6
7
8
9
CuOTf
2
0
0
5(S)
2
69(R)
13(S)
15(R)
14(R)
Cu(OTf)2
Zn(OTf)2
Y(OTf)3
Sm(OTf)3
Sc(OTf)3
La(OTf)3
Yb(OTf)3
In(OTf)3
b
Isolated yield.
Determined by HPLC using chiral OD-H column.
7
c
70
25
81
62
85
13
a
Unless otherwise noted, reactions were carried out with L4 (10 mol %), metal
(10 mol %), 2a (0.125 mmol), and 1a (0.15 mmol) in cyclopentanol (0.2 mL) at 45 ꢀC
for 36 h.
b
Isolated yield.
Determined by HPLC using chiral OD-H column.
Not detected.
c
d
2.4. Solvent effect
Figure 1. Chiral N,N0-dioxide ligands evaluated.
Considering that different chiral Lewis acid catalysts may exhibit
a distinct performance in solvent in some case, we reexamined the
reaction solvents. In all cases, L4–Sc(OTf)3 complex achieved
better enantioselectivities compared with the catalyst L1-Sc(OTf)3
(Table 4 vs Table 1). Furthermore, instead of cyclopentanol, the best
length of the N,N0-dioxide was also investigated. Unfortunately,
shorting or increasing the linker all led to a significant decrease on
enantioselectivity (Table 2, entries 7 and 8). The investigations on
the relationship between the ligands and the enantioselectivities of
the reaction obviously disclosed a cooperative effect of amino acid
moiety, amide part and linker of N,N0-dioxide in creating a excellent
chiral Lewis acid catalyst.
Table 4
Effect of solvents using chiral L4-Sc(OTf)3 as the catalysta
Table 2
Investigations on the ligands effecta
Entry
Solvent
Yieldb (%)
Eec (%)
1
2
3
4
5
6
7
8
Toluene
CH2Cl2
PhOMe
Et2O
EtOH
66
85
48
99
57
77
81
96
90
39
81
88
55(R)
64(R)
47(R)
63(R)
64(R)
40(R)
68(R)
64(R)
57(R)
74(R)
69(R)
63(R)
Entry
Ligand
Yieldb (%)
Eec (%)
1
2
3
4
5
6
7
8
L2
L3
L4
L5
L6
L7
L8
L9
65
64
81
68
42
22
96
68
32(R)
29(R)
69(R)
19(R)
64(R)
26(R)
57(R)
19(R)
MeOH
iPrOH
n-butanol
n-propanol
t-butanol
Cyclopentanol
Cyclohexanol
9
10
11
12
a
a
Unless otherwise noted, reactions were carried out with Ligand (10 mol %),
Sc(OTf)3 (10 mol %), 2a (0.125 mmol), and 1a (0.15 mmol) in cyclopentanol (0.2 mL)
at 45 ꢀC for 36 h.
Unless otherwise noted, reactions were carried out with L4 (10 mol %), Sc(OTf)3
(10 mol %), 2a (0.125 mmol), and 1a (0.15 mmol) in solvent (0.2 mL) at 45 ꢀC for
36 h.
b
b
Isolated yield.
Determined by HPLC using chiral OD-H column.
Isolated yield.
Determined by HPLC using chiral OD-H column.
c
c

Y. Liu et al. / Tetrahedron 66 (2010) 1447–1457
1449
enantioselectivity was obtained using tert-butanol as the solvent
2.7. Temperature effect
albeit with lower yield (Table 1, entries 10 and 11 vs Table 4, entries
10 and 11).
The reaction was extremely sensitive to the temperature. Low-
ering the reaction temperature, the enantioselectivity was further
improved to 85% ee, which was accompanied with an obvious loss
in reactivity (Table 7, entry 4). Considering the excellent reactivity
and good enantioselectivity when the reaction proceeded in Et2O
and tBuOH, respectively (Table 4, entries 5 and 10), the reaction was
then performed in Et2O at ꢁ20 ꢀC after the catalyst was prepared in
tBuOH at 35 ꢀC. It is delightful that both the yield and enantiose-
lectivity were improved, giving the corresponding product 3a in
94% yield with 90% ee (Table 7, entry 5). This finding clearly dis-
2.5. Ratio of ligand/metal and catalyst loading effect
The ratio of ligand and Sc(OTf)3 strongly influenced the enan-
tioselectivity of the reaction. In the presence of equivalent or an
excess of ligand, the yield and enantioselectivity were basically
maintained (Table 5, entries 1–3). An excess of Sc(OTf)3 led to im-
provement of the yield with some loss in enantioselectivity of the
reaction (Table 5, entries 4 and 5). Moreover, changing the catalyst
loading had no benefit effect on the enantioselectivity (Table 5,
entries 6 and 7).
t
closed the decisive role of BuOH in the generation of catalytically
active species.
Table 7
Table 5
Investigation of the reaction temperaturea
Study on the ratio of Ligand/Metal and catalyst loadinga
Entry
Temp (ꢀC)
Yieldb (%)
Eec (%)
Entry
L4 (mol %)
Sc(OTf)3 (mol %)
Yieldb (%)
Eec (%)
1
2
3
45
25
0
94
68
46
31
94
74(R)
77(R)
81(R)
85(R)
90(R)
1
2
3
4
5
6
7
10
11
13
10
10
5.5
22
10
10
10
11
13
5
39
39
39
46
90
37
59
74(R)
76(R)
76(R)
71(R)
0
4
ꢁ20
5d
ꢁ20
a
Unless otherwise noted, reactions were carried out with L4 (11 mol %), Sc(OTf)3
(10 mol %), 2a (0.125 mmol), and 1a (0.25 mmol) in t-butanol (0.1 mL) at indicated
temperature.
72(R)
50(R)
20
a
b
Unless otherwise noted, reactions were carried out with L4, Sc(OTf)3, 2a
(0.125 mmol), and 1a (0.15 mmol) in t-butanol (0.2 mL) at 45 ꢀC for 36 h.
Isolated yield.
c
Determined by HPLC using chiral OD-H column.
b
d
Catalyst was prepared in tBuOH at 35 ꢀC and the reaction was carried out in Et2O.
Isolated yield.
Determined by HPLC using chiral OD-H column.
c
2.8. Effect of ester group
2.6. Substrate concentration effect
Given alkylidene malonate coordinated with Sc(OTf)3 in a biden-
tate manner,4b,7 we envisioned that the size of the ester group of the
alkylidene malonate might affect the enantioselectivity of the re-
action. Thus, a number of benzylidene maonates with different ester
groups were tested. A suitable steric hindrance of the ester groups
played a crucial role on the reactivity and enantioselectivy (Table 8).
Though diisopropyl benzylidenemalonate showed a slightly higher
enantioselectivity, the yield was extremely poor compared with that
of diethyl benzylidenemalonate (Table 8, entry 2 vs 4).
The substrate concentration was an important parameter for the
reaction of indole 1a and alkylidene malonate 2a. High concen-
tration was beneficial for the yield of the reaction (Table 6). The
yield could be increased to 68% without considerable loss in
enantioselectivity the substrate concentration of the reaction in-
creased to 1.25 M (Table 6, entry 2). Furthermore, when the molar
ratio of indole to alkylidene malonate 2a was raised from 1.2:1 to
2:1, the yield of 3a was remarkably improved from 68% to 94%,
while the enantioselectivity was maintained (Table 6, entry 2 vs 8).6
Table 8
Effect on ester moiety of benzylidene maonatesa
Table 6
Effect of the substrate concentration a
Entry
R
Yieldb (%)
Eec (%)
Entry
Concentration (mmol/mL)
Yieldb (%)
Eec (%)
1
2
3
Me
Et
12
46
20
6
4
59
64
81(R)
80
1
2
3
5
2.50
1.25
0.63
0.31
0.21
1.25
68
68
41
22
13
94
72(R)
74(R)
75(R)
75(R)
76(R)
73(R)
nPr
4
iPr
83
5d
6d
tBu
PhCH2
3e
7
71
8d
a
Unless otherwise noted, reactions were carried out with L4 (11 mol %), Sc(OTf)3
(10 mol %), 2 (0.125 mmol), and 1a (0.25 mmol) in t-butanol (0.1 mL) at 0 ꢀC for 84 h.
a
Unless otherwise noted, reactions were carried out with L4 (11 mol %), Sc(OTf)3
(10 mol %), 2a (0.125 mmol), and 1a (0.15 mmol) in t-butanol at 45 ꢀC for 36 h.
b
Isolated yield.
Determined by HPLC using chiral OD-H column.
The reaction was carried out at 45 ꢀC.
b
c
Isolated yield.
Determined by HPLC using chiral OD-H column.
0.25 mmol indole was used.
c
d
d
e
Reversed configuration of product was obtained.

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Y. Liu et al. / Tetrahedron 66 (2010) 1447–1457
Table 10
2.9. Substrate scope
Catalytic enantioselective Friedel–Crafts reaction of indole 1a with alkylidene mal-
onates 2a
To study the generality of this reaction, a variety of indoles were
examined (Table 9, entries 1–5) under the optimal reaction con-
ditions (Table 7, entry 5). The reaction was found to be sensitive to
the position of substituents on indoles. 4-MeO or 5-MeO indole
gave good enantioselectivities and excellent yields (Table 9, entries
2 and 3). However, when the same substituent was introduced into
indole ring at position 6, the yield was dramatically decreased
(Table 9, entry 4). Furthermore, a C(5) bromine substituent facili-
tated the reaction to give the desired product 3af with 84% ee (Table
9, entry 5).
Entry
R2
Product
Yieldb (%)
Eec (%)
1
2
3
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
94
84
59
90
90
73
97
84
98
97
74
92
55
87
97
71
77
92
72
83
90(R)f
90
92
93
92
82
92
87
83
80
71
80
75
82
80e
62
88
83
80
71
3-MeC6H4
3-MeOC6H4
3-PhOC6H4
3-CF3C6H4
3-NO2C6H4
3-BrC6H4
3-ClC6H4
4
5
6
7
Table 9
Catalytic enantioselective Friedel–Crafts reaction of indoles 1 with alkylidene malo-
nate 2aa
8d
9d
10
11e
12d
13
14
15
16
17
18
19e
20
4-FC6H4
4-BrC6H4
4-NO2C6H4
4-ClC6H4
4-CNC6H4
4-CF3C6H4
4-CH3C6H4
2-ClC6H4
3-PhO-4-FC6H3
3,4-Cl2C6H3
2-naphthyl
2-thienyl
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
Entry
R1
Product
Yieldb (%)
Eec (%)
1
2
3
4
5
7-CH3
4-MeO
5-MeO
6-MeO
5-Br
3ab
3ac
3ad
3ae
3af
96
99
95
32
98
85
81
92(R)e
80
84d
21
3u
57
43
a
Unless otherwise noted, reactions were carried out with L4 (11 mol %), Sc(OTf)3
(10 mol %), 2a (0.125 mmol), and 1 (0.25 mmol) in Et2O (0.1 mL) at ꢁ20 ꢀC. Catalyst
a
t
Unless otherwise noted, reactions were carried out with L4 (11 mol %), Sc(OTf)3
(10 mol %), 2 (0.125 mmol), and 1a (0.25 mmol) in Et2O (0.1 mL) at ꢁ20 ꢀC. Catalyst
was prepared in BuOH at 35 ꢀC.
b
Isolated yield.
Determined by HPLC using chiral OD-H column.
The reaction was carried out at 0 ꢀC.
t
was prepared in BuOH at 35 ꢀC.
c
b
d
Isolated yield.
Determined by HPLC using chiral OD-H column.
0.5 mmol indole was used.
The reaction was carried out at 0 ꢀC.
c
e
The absolute configuration was determined by comparing with literature data.
d
e
f
The absolute configuration was determined by comparing with literature data.
Alkylidene malonates with different structures were next eval-
uated, giving the corresponding products with good to excellent
enantioselectivities (up to 92% ee). The enantioselectivity of the
reaction was found to be insensitive to the steric and electronic
properties of meta-substituents on the phenyl ring in arylidene
malonate (Table 10, entries 2–8), which was different from the
catalytic systems of chiral Cu(II)-oxazoline.8 The para-substituted
arylidene malonates were also efficient for the reaction with
moderate to good enantioselectivities (Table 10, entries 9–15), al-
beit the ortho-substituted one showed a reduced enantioselectivity
(Table 10, entry 16), which might be attributed to the steric hin-
drance effect of ortho-position. It was noteworthy that the reaction
could also be extended to condensed-ring, heterocyclic and di-
substituted arylidene malonates with good to excellent enantio-
selectivities (Table 10, entries 17–20). Unfortunately, only moderate
yield and enantioslectivity were obtained for the cyclohexylidene
malonate (Table 10, entry 21).
material in the presence of L4–Sc(OTf)3 complex. The correspond-
ing product (R)-3a could be isolated in 72% yield with 86% ee. After
a single recrystallization, optically pure product 3a could be
obtained (Scheme 1).
Table 11
Catalytic enantioselective Friedel–Crafts reaction of indoles 1 with alkylidene malo-
nates 2a
Entry
R1
R2
Product
Yieldb(%)
Eec(%)
In addition, it was found that when 5-MeO indole reacted with
different arylidene malonates, alkylation adducts were obtained
with better enantioselectivities (Table 10, entries 2, 4, 6–8, 17 and
20 vs Table 11, entries 2–7 and 9). The enantioselectivity was in-
creased to 92% ee when the reaction of 5-Br indole and meta-bro-
mine substituted arylidene malonate were examined (Table 9,
entry 9 vs Table 11, entry 1).
1
2
3
4
5
6
7
8
9
5-Br
3-BrC6H4
3-PhOC6H4
3-ClC6H4
3-PhO-4-FC6H3
3-BrC6H4
3-NO2C6H4
3-CH3C6H4
4-PhC6H4
2-thienyl
3jf
77
75
78
74
89
65
99
73
98
92
95
88
92
92
84
92
86
80
5-MeO
5-MeO
5-MeO
5-MeO
5-MeO
5-MeO
5-MeO
5-MeO
3cd
3hd
3qd
3jd
3fd
3bd
3vd
3td
a
Unless otherwise noted, reactions were carried out with L4 (11 mol %), Sc(OTf)3
(10 mol %), 1 (0.125 mmol), and 2 (0.25 mmol) in Et2O (0.1 mL) at ꢁ20 ꢀC. Catalyst
2.10. Product elaboration
t
was prepared in BuOH at 35 ꢀC.
b
In order to exploit the synthetic potential of the current catalyst
system, the reaction was scaled up to 2.5 mmol of the starting
Isolated yield.
c
Determined by HPLC using chiral OD-H column.

Y. Liu et al. / Tetrahedron 66 (2010) 1447–1457
1451
2.11. Reaction mechanism
Although the preparation of the single crystal of L4–Sc(OTf)3
complex failed, the structure of the complex L10–Sc(OTf)3, as its
monohydrate L10-Sc(OTf)3$(H2O) was determined by X-ray crys-
tallography (Fig. 2).12 Not only the oxygens of N-oxide but also
carbonyl oxygens coordinated with Sc(III) in a tetradentate manner.
Based on this observation, a possible transition state was proposed
(Fig. 3). In this transition state, Sc(III) coordinated in a hexadentate
way with L4 and alkylidene malonate. The Re face of the alkylidene
malonate was blocked by the bulky diphenylmethyl group. There-
fore, indole attacked from the Si face to give the corresponding
product with R configuration. The transition state may help to ex-
plain the behaviour that only racemic product with moderate yield
was afforded when the precursor of N,N0-dioxide L4 was
employed.12
Scheme 1. Scaled up version of the Friedel–Crafts reaction.
Furthermore, the Friedel–Crafts alkylation product could be
easily transformed to some useful intermediates for the synthesis
of biologically active compounds, such as tryptamines,1a 3-indo-
lepropionic acids1k and 1,2,3,4-tetrahydro- -carbolines.1e As
b
shown in Scheme 2, the adduct 3a underwent decarboxylation
smoothly to give the monoester 4 in good yield.3,4c Treatment of 4
with NaOH in the mixed solvent of THF and EtOH provided the
potent neuroprotective agent 5 in high yield. The reaction of acid 5
with diphenylphosphoryl azide gave the corresponding acylazide,
which was subjected to
a Curtius rearrangement to give
isocyanate.1f,9 By the addition of tert-butyl alcohol, isocyanate was
then transformed into carbamate ester, which was converted into
the tryptamine 6 after removal of the Boc group. The crude
product 6 then underwent Pictet–Spengler cyclization10 with
benzaldehyde to furnish the 1,2,3,4-tetrahydro-b 7
-carboline2e,11
as a 92:8 mixture of diastereoisomers. On the other hand,
reduction of ester 4 proceeded smoothly to give the corresponding
alcohol 9 in quantitative yield, which then underwent the esteri-
fication, nucleophilic substitution and reduction to give the
serotonin analogue 12.1j,15 The amine 12 has been embedded in
numerous indole alkaloids. It is noteworthyl that the seven-
Figure 2. Crystal structure of L10–Sc(OTf)3$(H2O).
membered b-carboline-like compound 13 was synthesized for the
first time via a Pictet–Spengler reaction. The relative stereo-
chemistry of 13 was tentatively assigned as 1,5-trans by means of
NOE experiments. All the reactions proceeded well with no
erosion in enantiomeric excess.
Figure 3. Proposed transition state.
As depicted in Figure 4, a catalytic cycle was also proposed to
t
elucidate the reaction mechanism. First, the introduction of BuOH
to the mixture of L4 and Sc(OTf)3 generates the catalytically active
species T1. After ligands exchange, the alkylidene malonate is in-
troduce into the chiral environment to give the activated substrate–
catalyst complex T2. Then, indole attack the Si face of the alkylidene
malonate followed by the H-transfer and decomplexation of the
desired product from the central metal to regenerate the in-
termediate T2. The catalytic cycle is thus completed.
3. Conclusions
In summary, we have developed an efficient catalytic enantio-
selective Friedel–Crafts alkylation of different indoles with a series
of alkylidene malonates using chiral L4–Sc(OTf)3 complex as cata-
lyst. All of the condensed-ring, heterocyclic and different
substituted arylidene malonates could be tolerated. Moreover, the
products could be easily transformed into serotonin analogue 12
Scheme 2. Derivation of the Friedel–Crafts adduct 3a. Conditions: (a) NaCl, DMSO, H2O,
reflux, 66%; (b) THF, EtOH, H2O, 2 N NaOH, reflux, 97%; (c) Curtius rearrangement, Et3N,
DPPA, tBuOH, toluene, reflux; TFA, CH2Cl2, rt, 28%; (d) Pictet–Spengler cyclization, TFA,
benzaldehyde, CH3CN, reflux, 88%; (e) LiAlH4, THF, rt, quantitativeyield; (f) TsCl, pyridine,
CH2Cl2, 50 ꢀC, 72%; (g) DMF, NaN3, 50 ꢀC, 97%; (h) Pd/C (10%), H2, MeOH, 64%; (i) Pictet–
Spengler cyclization, TFA, benzaldehyde, CH3CN, reflux, 44%. DPPA¼diphenylphosphoryl
azide; (j) TsCl, Et3N, CH2Cl2, rt, 84%.
and seven-membered
b-carboline-like 13. Based on the X-ray
structure of the Sc(OTf)3 complex, a possible transition state was

1452
Y. Liu et al. / Tetrahedron 66 (2010) 1447–1457
propanol 90:10, 1.0 mL/min, 254 nm; tr (major)¼10.878 min, tr
(minor)¼12.883 min) gave the isomeric composition of the
23
product: 90% ee, mp 152–154 ꢀC; [
NMR (400 MHz, CDCl3):
a
]
ꢁ51.4 (c 0.218, CHCl3); 1H
D
d
¼8.07 (s, br s, 1H), 7.58 (d, J¼8.0 Hz, 1H),
7.39 (d, J¼6.8 Hz, 2H), 7.14–7.32 (m, 6H), 7.04–7.08 (m, 1H), 5.11
(d, J¼11.6 Hz, 1H), 4.32 (d, J¼12.0 Hz, 1H), 4.00–4.05 (m, 4H),
1.00–1.05 (m, 6H) ppm.
4.2.2. Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(m-methylphenyl) pro-
panoate 3b13. White solid; HPLC analysis (AS-H column, hexane/2-
propanol 90:10, 1.0 mL/min, 254 nm; tr (minor)¼10.907 min, tr
(major)¼12.300 min) gave the isomeric composition of the prod-
26
uct: 90% ee, mp 90–91 ꢀC; [
a]
ꢁ60.5 (c 0.200, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3):
d
¼8.20 (s, br s,1H), 7.63 (d, J¼8.0 Hz,1H), 7.30 (d,
J¼8.4 Hz, 1H), 7.06–7.23 (m, 6H), 7.00 (d, J¼7.2 Hz, 1H), 5.10 (d,
J¼12.0 Hz, 1H), 4.35 (d, J¼11.6 Hz, 1H), 4.00–4.07 (m, 4H), 2.30 (s,
3H), 1.06 (t, J¼7.2 Hz, 3H), 1.00 (t, J¼7.2 Hz, 3H) ppm.
4.2.3. Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(m-methoxylphenyl)
propanoate 3c13. White solid; HPLC analysis (OD-H column, hex-
ane/2-propanol 90:10, 1.0 mL/min, 254 nm; tr (major)¼14.939 min,
tr (minor)¼19.784 min) gave the isomeric composition of the
ꢁ49.55 (c 0.222, CH2Cl2); 1H
27
product: 92% ee, mp 97–99 ꢀC; [
a]
Figure 4. Proposed catalytic cycle.
D
NMR (400 MHz, CDCl3):
d¼8.13 (s, br s, 1H), 7.60 (d, J¼7.6 Hz, 1H),
proposed to explain the absolute configuration observed. The
proposed catalytic cycle has also been introduced to demonstrate
the mechanism of reaction.
7.28–7.31 (m, 1H), 7.13–7.20 (m, 3H), 7.04–7.08 (m, 1H), 7.00 (d,
J¼8.0 Hz, 1H), 6.94 (t, J¼2.0 Hz, 1H), 6.71 (dd, J¼2.4, 8 Hz, 1H), 5.08
(d, J¼11.6 Hz, 1H), 4.32 (d, J¼12.0 Hz, 1H), 3.98–4.07 (m, 4H), 3.76 (s,
3H), 1.07 (t, J¼7.2 Hz, 3H), 1.00 (t, J¼7.2 Hz, 3H) ppm.
4. Experimental
4.2.4. Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(m-phenoxylphenyl)
propanoate 3d13. White solid; HPLC analysis (OD-H column, hex-
ane/2-propanol 90:10, 1.0 mL/min, 254 nm; tr (major)¼12.699 min,
4.1. General information
1H NMR spectra were recorded on commercial instruments
(400 MHz). Chemical shifts were reported in part per million from
tetramethylsilane with the solvent resonance as the internal stan-
tr (minor)¼17.033 min) gave the isomeric composition of the prod-
27
uct: 93% ee, mp 118–119 ꢀC; [
a
]
ꢁ39.92 (c 0.258, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3):
d
¼8.12 (s, br s, 1H), 7.57 (d, J¼8.0 Hz, 1H), 7.28–
dard (CDCl3,
d
¼7.26). Spectra are reported as follows: chemical shift
7.34 (m, 3H), 7.06–7.24 (m, 7H), 6.95 (dd, J¼0.8, 7.6 Hz, 2H), 6.81 (dt,
J¼1.2, 8 Hz, 1H), 5.09 (d, J¼12.0 Hz, 1H), 4.32 (dt, J¼1.6, 12.0 Hz, 1H),
3.99–4.10 (m, 4H), 1.11 (t, J¼7.2 Hz, 3H), 1.00 (t, J¼7.2 Hz, 3H) ppm.
(
d
ppm), multiplicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet,
m¼multiplet), coupling constants (Hz) and integration. 13C NMR
spectra were collected on commercial instruments (100 MHz) with
complete proton decoupling. Chemical shifts are reported in part
per million from the tetramethylsilane with the solvent resonance
4.2.5. Ethyl
2-ethoxycarbonyl-3-(3-indolyl)-3-(m-trifluoromethyl-
phenyl) propanoate 3e13. White solid; HPLC analysis (OJ-H column,
hexane/2-propanol 95:5,1.0 mL/min, 254 nm; tr (major)¼37.180 min,
as internal standard (CDCl3,
were determined by HPLC analysis on chiral DAICEL CHIRALCEL
AD-H, OJ-H, OD-H and AS-H column. Optical rotations were mea-
sured on a commercial polarimeter and reported as follows: [a]
D
(c g/100 mL, solvent). Reagents obtained from commercial sources
were used without further purification. CH2Cl2 was distilled over
CaH2 before use. The other solvents were distilled over metal
sodium before use. Melting points (mp) were measured on elec-
trothermal digital melting point apparatus and were uncorrected.
d
¼77.0). The enantiomeric excesses
tr (minor)¼46.858 min) gave the isomeric composition of the prod-
23
uct: 92% ee, mp 85–86 ꢀC; [
a]
D
ꢁ58.30 (c 0.204, CH2Cl2); 1H NMR
T
(400 MHz, CDCl3):
d
¼8.17 (s, br s, 1H), 7.67 (s, 1H), 7.59 (d, J¼7.6 Hz,
1H), 7.54 (d, J¼7.6 Hz,1H), 7.45 (d, J¼7.6 Hz,1H), 7.38 (d, J¼7.6 Hz,1H),
7.33–7.35 (m, 1H), 7.22 (d, J¼2.4 Hz, 1H), 7.16–7.20 (m, 1H), 7.06–7.10
(m, 1H), 5.18 (d, J¼11.6 Hz, 1H), 4.33 (d, J¼12.0 Hz, 1H), 4.00–4.07 (m,
4H), 1.04 (t, J¼7.2 Hz, 3H), 1.03 (t, J¼7.2 Hz, 3H) ppm.
4.2.6. Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(m-nitrophenyl) pro-
panoate 3f4b. Yellow solid; HPLC analysis (AS-H column, hexane/2-
propanol 80:20, 1.0 mL/min, 254 nm; tr (minor)¼10.269 min, tr
4.2. Typical experimental procedure for the enantioselective
Friedel–Crafts alkylation of indoles with alkylidene malonates
(major)¼11.783 min) gave the isomeric composition of the product:
22
The mixture of ligand L4 (9.8 mg, 0.0138 mmol), Sc(OTf)3
(6.2 mg, 0.0125 mmol) and indole 1a (29.3 mg, 0.25 mmol) in
tBuOH (0.1 mL) was stirred at 35 ꢀC for 1 h under nitrogen atmo-
sphere. After the solvent was removed under vacuo, Et2O (0.1 mL)
was added. The reaction mixture was cooled to ꢁ20 ꢀC and alkyli-
dene malonate 2a (0.125 mmol) was added under stirring. The re-
action mixture was stirred at ꢁ20 ꢀC for 84 h and directly purified
by flash chromatography on silica gel to obtain the desired product
3a in 94% yield with 90% ee.
82% ee, mp 106–108 ꢀC; [
a
]
D
ꢁ28.82 (c 0.170, CHCl3); 1H NMR
(400 MHz, CDCl3):
d
¼8.26 (t, J¼2.0 Hz), 8.21 (s, br s, 1H), 8.04 (ddd,
J¼1.2, 2.4, 8.0 Hz, 1H), 7.76–7.78 (m, 1H), 7.51 (d, J¼8.0 Hz, 1H), 7.44
(t, J¼8.0 Hz, 2H), 7.34 (d, J¼8.0 Hz, 1H), 7.17–7.21 (m, 1H), 7.06–7.10
(m, 1H), 5.23 (d, J¼11.6 Hz, 1H), 4.35 (d, J¼11.6 Hz, 1H), 4.02–4.09
(m, 4H), 1.09 (t, J¼7.2 Hz, 3H), 1.04 (t, J¼7.2 Hz, 3H) ppm.
4.2.7. Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(m-bromophenyl) pro-
panoate 3g13. White solid; HPLC analysis (AS-H column, hexane/2-
propanol 90:10, 1.0 mL/min, 254 nm; tr (minor)¼27.957 min, tr
4.2.1. (R)-Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-phenyl propanoate
(major)¼31.480 min) gave the isomeric composition of the
25
3a13. White solid; HPLC analysis (Chiralcel OD-H, hexane/2-
product: 92% ee, mp 92–93 ꢀC; [
a
]
ꢁ57.21 (c 0.222, CH2Cl2); 1H
D

Y. Liu et al. / Tetrahedron 66 (2010) 1447–1457
1453
NMR (400 MHz, CDCl3):
d
¼8.25 (s, br s, 1H), 7.54–7.57 (m, 2H),
2H), 1.08 (t, J¼7.2 Hz, 3H), 1.02 (t, J¼7.2 Hz, 3H) ppm. 13C NMR
7.28–7.36 (m, 3H), 7.07–7.20 (m, 4H), 5.10 (d, J¼11.6 Hz, 1H), 4.31 (d,
J¼11.6 Hz, 1H), 4.01–4.09 (m, 4H), 1.10 (t, J¼7.2 Hz, 3H), 1.02 (t,
J¼7.2 Hz, 3H) ppm.
(100 MHz, CDCl3):
d¼167.53, 167.48, 147.19, 136.24, 132.22, 129.08,
126.29, 122.59, 121.25, 119.83, 118.91, 118.79, 115.43, 111.30, 110.58,
61.78, 61.75, 57.67, 42.74, 13.85, 13.74 ppm; ES-HRMS calcd for
[C23H22N2O4þNaþ] 413.1472, found: 413.1477.
4.2.8. Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(m-chlorophenyl) pro-
panoate 3h13. White solid; HPLC analysis (AS-H column, hexane/2-
propanol 90:10, 1.0 mL/min, 254 nm; tr (minor)¼11.463 min, tr
4.2.14. Ethyl
2-ethoxycarbonyl-3-(3-indolyl)-3-(p-trifluoromethyl-
phenyl) propanoate 3n. White solid; HPLC analysis (OJ-H column,
hexane/2-propanol 90:10, 1.0 mL/min, 254 nm; tr (major)
(major)¼12.648 min) gave the isomeric composition of the prod-
26
uct: 87% ee, mp 82–94 ꢀC; [
a
]
ꢁ58.45 (c 0.284, CH2Cl2); 1H NMR
¼17.064 min, tr (minor)¼21.494 min) gave the isomeric composi-
D
25
(400 MHz, CDCl3):
d
¼8.20 (s, br s, 1H), 7.56 (d, J¼7.6 Hz, 1H), 7.38 (t,
tion of the product: 82% ee, mp 111–112 ꢀC; [
a]
D
ꢁ45.92 (c 0.294,
J¼1.6 Hz 1H), 7.28–7.33 (m, 2H), 7.14–7.21 (m, 4H), 7.06–7.10 (m,
1H), 5.10 (d, J¼11.6 Hz, 1H), 4.30 (d, J¼12.0 Hz, 1H), 4.00–4.08 (m,
4H), 1.09 (t, J¼7.2 Hz, 3H), 1.02 (t, J¼7.2 Hz, 3H) ppm.
CH2Cl2); 1H NMR (400 MHz, CDCl3):
d
¼8.27 (s, br s, 1H), 7.54 (d,
J¼11.2 Hz, 1H), 7.33 (d, J¼8.0 Hz, 1H), 7.16–7.20 (m, 2H), 7.09–7.11
(m, 1H), 7.31 (t, J¼8.8 Hz, 2H), 7.04 (t, J¼7.6 Hz, 1H), 6.94 (t, J¼7.6 Hz,
1H), 5.20 (d, J¼11.6 Hz, 1H), 4.36 (d, J¼11.6 Hz, 1H), 4.05 (q, J¼7.2 Hz,
2H), 4.04 (q, J¼7.2 Hz, 2H), 1.05 (t, J¼7.2 Hz, 3H), 1.03 (t, J¼7.2 Hz
4.2.9. Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(p-fluorophenyl) pro-
panoate 3i13. White solid; HPLC analysis (AS-H column, hexane/2-
propanol 90:10, 1.0 mL/min, 254 nm; tr (minor)¼12.492 min, tr
3H) ppm. 13C NMR (100 MHz, CDCl3):
d
¼167.78, 167.67, 145.67,
136.26, 128.52 (J¼32 Hz), 128.59, 126.42, 125.38 (J¼4 Hz), 125.31
(J¼4 Hz), 122.50, 121.16, 119.74, 115.96, 111.23, 61.71, 61.67, 57.96,
42.62, 13.73 ppm; ES-HRMS calcd for [C23H22F3NO4þNaþ] 456.1393,
found: 456.1366.
(major)¼18.614 min) gave the isomeric composition of the product:
26
83% ee, mp 114–116 ꢀC; [
a
]
ꢁ77.32 (c 0.216, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3):
d
¼8.15 (s, br s, 1H), 7.52 (d, J¼8.0 Hz, 1H), 7.28–
7.38 (m, 3H), 7.15–7.18 (m, 2H), 7.04–7.08 (m, 1H), 6.92–6.70 (m,
2H), 5.11 (d, J¼12.0 Hz,1H), 4.28 (d, J¼11.6 Hz,1H), 4.03 (q, J¼7.2 Hz,
2H), 4.04 (q, J¼7.2 Hz, 2H), 1.07 (t, J¼7.2 Hz, 3H), 1.03 (t, J¼7.2 Hz,
3H) ppm.
4.2.15. Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(p-methylphenyl) pro-
panoate 3o5a. White solid; HPLC analysis (AS-H column, hexane/2-
propanol 95:5, 1.0 mL/min, 254 nm; tr (minor)¼15.076 min, tr
(major)¼17.795 min) gave the isomeric composition of the product:
ꢁ30.45 (c 0.220, CH2Cl2); 1H NMR
25
4.2.10. Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(p-bromophenyl) pro-
panoate 3j4b. White solid; HPLC analysis (AS-H column, hexane/2-
propanol 90:10, 1.0 mL/min, 254 nm; tr (minor)¼11.100 min, tr
80% ee, mp 100–102 ꢀC; [
a]
D
(400 MHz, CDCl3):
d
¼8.07 (s, br s, 1H), 7.58 (d, J¼7.6 Hz, 1H), 7.26–
7.31 (m, 2H), 7.13–7.17 (m, 2H), 7.03–7.07 (m, 3H), 5.07 (d, J¼11.6 Hz,
1H), 4.31 (d, J¼12 Hz, 1H), 4.00–4.05 (m, 4H), 2.24 (s, 3H), 1.06 (t,
J¼7.2 Hz, 3H), 1.00 (t, J¼7.2 Hz, 3H) ppm.
(major)¼12.721 min) gave the isomeric composition of the prod-
22
uct: 80% ee, mp 104–106 ꢀC; [
a
]
ꢁ23.26 (c 0.288, CHCl3); 1H NMR
D
(400 MHz, CDCl3):
d
¼8.10 (s, br s, 1H), 7.51 (d, J¼8.0 Hz, 1H), 7.28 (t,
J¼2.0 Hz, 1H), 7.26 (t, J¼2.0 Hz, 1H), 7.15–7.19 (m, 2H), 7.04–7.08 (m,
1H), 5.07 (d, J¼12 Hz, 1H), 4.27 (d, J¼11.6 Hz, 1H), 4.04 (q, J¼7.2 Hz,
2H), 4.03 (q, J¼7.2 Hz, 2H), 1.08 (t, J¼7.2 Hz, 3H), 1.02 (t, J¼7.2 Hz,
3H) ppm.
4.2.16. Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(2-chlorophenyl) pro-
panoate 3p13. White solid; HPLC analysis (OD-H column, hexane/2-
propanol 90:10, 1.0 mL/min, 254 nm; tr (major)¼11.163 min, tr
(minor)¼16.864 min) gave the isomeric composition of the prod-
uct: 62% ee, 1H NMR (400 MHz, CDCl3):
7.73 (m,1H), 7.40–7.43 (m,1H), 7.32–7.35 (m,1H), 7.26–7.28 (m,1H),
7.11–7.18 (m, 5H), 5.71 (d, J¼12.0 Hz, 1H), 4.30 (d, J¼11.6 Hz, 1H),
3.96–4.07 (m, 4H), 0.95–1.07 (m, 6H) ppm.
d
¼8.25 (s, br s, 1H), 7.69–
4.2.11. Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(p-nitrophenyl) pro-
panoate 3k4b. Yellow solid; HPLC analysis (AS-H column, hexane/
2-propanol 80:20, 1.0 mL/min, 254 nm; tr (minor)¼11.460 min, tr
(major)¼14.889 min) gave the isomeric composition of the
product: 71% ee, 1H NMR (400 MHz, CDCl3):
d
¼8.12–8.15 (m,
4.2.17. Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(4-fluoro-3-phenoxy-
phenyl) propanoate 3q13. White solid; HPLC analysis (AS-H column,
hexane/2-propanol 90:10, 1.0 mL/min, 254 nm; tr (minor)-
3H), 7.56–7.58 (m, 2H), 7.49 (d, J¼8.0 Hz, 1H), 7.35 (d, J¼8.4 Hz,
1H), 7.25 (d, J¼2.4 Hz, 1H), 7.17–7.21 (m, 1H), 7.06–7.10 (m, 1H),
5.22 (d, J¼11.6 Hz, 1H), 4.34 (d, J¼11.6 Hz, 1H), 4.05 (q, J¼7.2 Hz,
2H), 4.04 (q, J¼7.2 Hz, 2H), 1.09 (t, J¼7.2 Hz, 3H), 1.03 (t, J¼7.2 Hz,
3H) ppm.
¼14.765 min, tr (major)¼19.311 min) gave the isomeric composi-
21
tion of the product: 88% ee, mp 148–150 ꢀC; [
a
]
D
ꢁ49.60 (c 0.258,
CH2Cl2); 1H NMR (400 MHz, CDCl3):
d
¼8.09 (s, br s, 1H), 7.48 (d,
J¼7.6 Hz, 1H), 7.28–7.33 (m, 3H), 7.04–7.20 (m, 7H), 6.89–6.92 (m,
2H), 5.05 (d, J¼11.6 Hz, 1H), 4.22 (d, J¼12.0 Hz, 1H), 4.00–4.09 (m,
4H), 1.12 (t, J¼7.2 Hz, 3H), 1.01 (t, J¼7.2 Hz, 3H) ppm.
4.2.12. (R)-Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(p-chlorophenyl)
propanoate 3l4b. White solid; HPLC analysis (OD-H column, hex-
ane/2-propanol 95:5, 1.0 mL/min, 254 nm; tr (major)¼22.380 min,
tr (minor)¼25.276 min) gave the isomeric composition of the
4.2.18. Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(3,4-dichlorophenyl)
propanoate 3r13. White solid; HPLC analysis (AS-H column, hexane/
2-propanol 95:5, 1.0 mL/min, 254 nm; tr (minor)¼17.102 min, tr
26
product: 80% ee, mp 116–118 ꢀC; [
a]
ꢁ46.15 (c 0.208, CH2Cl2); 1H
D
NMR (400 MHz, CDCl3):
d¼8.10 (s, br s, 1H), 7.51 (d, J¼8.0 Hz, 1H),
7.28–7.34 (m, 3H), 7.15–7.24 (m, 4H), 7.04–7.08 (m, 1H), 5.09 (d,
J¼11.6 Hz, 1H), 4.27 (d, J¼11.6 Hz, 1H), 4.00–4.06 (m, 4H), 1.08 (t,
J¼7.2 Hz, 3H), 1.02 (t, J¼7.2 Hz, 3H) ppm.
(major)¼19.594 min) gave the isomeric composition of the prod-
26
uct: 83% ee, mp 107–108 ꢀC; [
a
]
D
ꢁ42.79 (c 0.208, CH2Cl2); 1H NMR
(400 MHz, CDCl3):
d
¼8.21 (s, br s, 1H), 7.47–7.52 (m, 2H), 7.28–7.35
(m 2H), 7.17–7.26 (m, 3H), 7.07–7.11 (m, 1H), 5.08 (d, J¼11.6 Hz, 1H),
4.27 (dd, J¼1.6, 11.6 Hz, 1H), 4.02–4.11 (m, 4H), 1.12 (t, J¼7.2 Hz, 3H),
1.03 (t, J¼7.2 Hz, 3H) ppm.
4.2.13. Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(p-cyanophenyl) pro-
panoate 3m. White solid; HPLC analysis (AD-H column, hexane/2-
propanol 85:15, 1.0 mL/min, 254 nm; tr (major)¼26.424 min, tr
(minor)¼32.077 min) gave the isomeric composition of the prod-
4.2.19. Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(2-naphthly) prop-
anoate 3s13. White solid; HPLC analysis (Chiralcel AD-H, hexane/
2-propanol 80:20, 1.0 mL/min, 254 nm; tr (minor)¼34.252 min, tr
25
uct: 75% ee, mp 119–121 ꢀC; [
a
]
ꢁ24.38 (c 0.320, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3):
d
¼8.30 (s, br s, 1H), 7.48–7.56 (m, 5H), 7.34 (d,
J¼8.0 Hz, 1H), 7.16–7.20 (m, 2H), 7.05–7.09 (m, 1H), 5.17 (d, J¼12 Hz,
1H), 4.32 (d, J¼11.6 Hz, 1H), 4.05 (q, J¼7.2 Hz, 2H), 4.04 (q, J¼7.2 Hz,
(major)¼36.852 min) gave the isomeric composition of the
24
product: 80% ee, mp 173–174 ꢀC; [
a
]
ꢁ38.4 (c 0.320, CH2Cl2); 1H
D

1454
Y. Liu et al. / Tetrahedron 66 (2010) 1447–1457
NMR (400 MHz, CDCl3):
d
¼8.08 (s, br s, 1H), 7.88 (d, J¼0.8 Hz, 1H),
(m, 2H), 7.24–7.28 (m, 2H), 7.15–7.20 (m, 3H), 6.99 (d, J¼2.4 Hz, 1H),
6.81 (dd, J¼2.4, 6.4 Hz, 1H), 5.05 (d, J¼11.6 Hz, 1H), 4.29 (d,
J¼12.0 Hz, 1H), 3.98–4.07 (m, 4H), 3.80 (s, 3H), 1.03 (t, J¼7.2 Hz, 3H),
1.02 (t, J¼7.2 Hz, 3H) ppm; ES-HRMS calcd for [C23H25NO5þNa]þ
418.1625, found: 418.1635.
7.80–7.81 (m, 1H), 7.75–7.77 (m, 1H), 7.72 (d, J¼8.4 Hz, 1H), 7.60
(d, J¼8.0 Hz, 1H), 7.40–7.50 (m, 3H), 7.31 (d, J¼8.0 Hz, 1H), 7.25 (d,
J¼2.4 Hz, 1H), 7.12–7.16 (m, 1H), 7.01–7.05 (m, 1H), 5.29 (d,
J¼11.6 Hz, 1H), 4.44 (d, J¼11.6 Hz, 1H), 4.04 (q, J¼7.2 Hz, 2H),
3.92–4.00 (m, 2H), 1.03(t, J¼7.2 Hz, 3H), 0.94 (t, J¼7.2 Hz, 3H)
ppm.
4.2.25. Ethyl 2-ethoxycarbonyl-3-[3-(6-methoxyindolyl)]-3-phenyl
propanoate 3ae. White solid; HPLC analysis (Chiralcel OD-H, hex-
ane/2-propanol 90:10, 1.0 mL/min, 254 nm; tr (major)¼17.037 min,
4.2.20. Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(2-thienyl) propanoate
3t. White solid; HPLC analysis (AS-H column, hexane/2-propanol
85:15, 1.0 mL/min, 254 nm; tr (minor)¼9.096 min, tr (major)¼
tr (minor)¼21.476 min) gave the isomeric composition of the
23
product: 80% ee, mp 126–128 ꢀC; [
a
]
D
ꢁ55.34 (c 0.206, CH2Cl2); 1H
12.284 min) gave the isomeric composition of the product: 71% ee,
NMR (400 MHz, CDCl3):
d
¼7.96 (s, br s,1H), 7.36–7.42 (m, 3H), 7.23–
29
mp 88–90 ꢀC; [
CDCl3):
a
]
D
ꢁ52.34 (c 0.214, CH2Cl2); 1H NMR (400 MHz,
7.28 (m, 2H), 7.14–7.18 (m, 1H), 7.06 (d, J¼2.4 Hz, 1H), 6.79 (d,
J¼2.0 Hz,1H), 6.72 (dd, J¼2.4, 6.4 Hz,1H), 5.05 (d, J¼12 Hz,1H), 4.28
(d, J¼12 Hz, 1H), 4.04 (q, J¼7.2 Hz, 2H), 4.00 (q, J¼7.2 Hz, 2H), 3.81
(s, 3H), 1.04 (t, J¼7.2 Hz, 3H), 1.03 (t, J¼7.2 Hz, 3H) ppm. 13C NMR
d
¼8.11 (s, br s, 1H), 7.63 (d, J¼8.0 Hz, 1H), 7.31 (d, J¼8.0 Hz,
1H), 7.14–7.18 (m, 2H), 7.06–7.10 (m, 2H), 7.00 (d, J¼3.6 Hz, 1H), 6.86
(dd, J¼1.6, 3.6 Hz, 1H), 5.39 (d, J¼11.2 Hz, 1H), 4.32 (dd, J¼0.8,
10.4 Hz, 1H), 4.11 (q, J¼7.2 Hz, 2H), 3.94 (q, J¼7.2 Hz, 2H), 1.14 (t,
J¼7.2 Hz, 3H), 0.92 (t, J¼7.2 Hz, 3H) ppm. 13C NMR (100 MHz,
(100 MHz, CDCl3):
d
¼168.06, 167.86, 156.61, 141.43, 136.99, 128.32,
128.17, 126.73, 121.15, 119.98, 119.61, 117.03, 109.47, 94.51, 61.46,
61.38, 58.40, 55.60, 42.95, 13.78 ppm; ES-HRMS calcd for
[C23H25NO5þNaþ] 418.1625, found: 418.1621.
CDCl3):
d
¼167.90, 167.64, 145.87, 136.26, 126.53, 125.18, 124.38,
122.44, 121.71, 119.76, 119.51, 116.63, 111.23, 61.77, 61.60, 59.46,
38.09, 14.02, 13.75 ppm; ES-HRMS calcd for [C20H21NO4SþNaþ]
394.1083, found: 394.1084.
4.2.26. Ethyl 2-ethoxycarbonyl-3-[3-(5-bromoindolyl)]-3-phenyl pro-
panoate 3af13. White solid; HPLC analysis (Chiralcel OD-H, hexane/
2-propanol 90:10, 1.0 mL/min, 254 nm; tr (major)¼10.460 min, tr
4.2.21. Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(cyclohexyl) pro-
panoate 3u. White solid; HPLC analysis (AS-H column, hexane/2-
propanol 90:10, 1.0 mL/min, 254 nm; tr (minor)¼6.961 min, tr
(minor)¼16.491 min) gave the isomeric composition of the prod-
(minor)¼12.545 min) gave the isomeric composition of the prod-
25
uct: 84% ee, mp 154–156 ꢀC; [
a
]
þ4.72 (c 0.212, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3):
d
¼8.13 (s, br s, 1H), 7.68 (d, J¼2.0 Hz, 1H), 7.33–
uct: 43% ee, 1H NMR (400 MHz, CDCl3):
d¼8.17 (s, br s, 1H), 7.69 (d,
7.36 (m, 2H), 7.14–7.27 (m, 6H), 5.00 (d, J¼11.6 Hz, 1H), 4.25 (d,
J¼12.0 Hz, 1H), 3.95–4.04 (m, 4H), 1.02 (t, J¼7.2 Hz, 3H), 1.01 (t,
J¼7.2 Hz, 3H) ppm.
J¼7.6 Hz, 1H), 7.33 (d, J¼8.0 Hz, 1H), 7.10–7.20 (m, 2H), 7.02 (s, 1H),
4.23(t, J¼7.2 Hz, 1H), 4.04 (d, J¼11.2 Hz, 1H), 3.79–3.85 (m, 3H),
1.54–1.79 (m, 7H), 1.13–1.30 (m, 5H), 0.90–1.04 (m, 3H), 0.77 (t,
J¼7.2 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3):
d¼169.09, 168.44,
4.2.27. Ethyl 2-ethoxycarbonyl-3-[3-(5-bromoindolyl)]-3-(m-bromo-
phenyl) propanoate 3jf13. White solid; HPLC analysis (Chiralcel
OD-H, hexane/2-propanol 90:10, 1.0 mL/min, 254 nm; tr
135.62, 128.54, 122.82, 121.70, 119.78, 119.22, 113.94, 110.82, 61.38,
60.95, 55.93, 41.89, 40.99, 32.28, 28.50, 26.60, 26.35, 26.21, 14.09,
13.45 ppm; ES-HRMS calcd for [C22H29NO46þNaþ] 394.1989,
found: 394.2012.
(major)¼10.650 min, tr (minor)¼12.777 min) gave the isomeric
27
composition of the product: 92% ee, mp 122–124 ꢀC; [
a]
þ32.59 (c
D
0.224, CH2Cl2); 1H NMR (400 MHz, CDCl3):
d
¼8.21 (s, br s, 1H), 7.68
4.2.22. Ethyl 2-ethoxycarbonyl-3-[3-(7-methylindolyl)]-3-phenyl pro-
panoate 3ab4c. White solid; HPLC analysis (Chiralcel OD-H, hexane/
2-propanol 90:10, 1.0 mL/min, 254 nm; tr (major)¼9.897 min, tr
(d, J¼2.0 Hz, 1H), 7.48 (t, J¼2.0 Hz, 1H), 7.33 (dd, J¼2.0, 6.0 Hz, 2H),
7.26 (dd, J¼2.0, 7.2 Hz,1H), 7.17–7.21 (m, 2H), 7.14–7.16 (m, 1H), 5.00
(d, J¼12.0 Hz, 1H), 4.23 (d, J¼11.6 Hz, 1H), 4.00–4.08 (m, 4H), 1.09 (t,
J¼7.2 Hz, 3H), 1.03 (t, J¼7.2 Hz, 3H) ppm.
(minor)¼11.959 min) gave the isomeric composition of the prod-
22
uct: 85% ee, mp 91–93 ꢀC; [
a]
ꢁ74.1 (c 0.348, CHCl3); 1H NMR
D
(400 MHz, CDCl3):
d
¼7.93 (s, br s, 1H), 7.34–7.40 (m, 3H), 7.19–7.24
4.2.28. Ethyl 2-ethoxycarbonyl-3-[3-(5-methoxyindolyl)]-3-(p-phenyl-
phenyl)propanoate 3vd13. White solid; HPLC analysis (AD-H column,
hexane/2-propanol 90:10, 1.0 mL/min, 254 nm; tr (minor)-
(m, 3H), 7.10–7.14 (m, 1H), 6.92–6.97 (m, 2H), 5.06 (d, J¼11.6 Hz,
1H), 4.29 (d, J¼11.6 Hz, 1H), 3.94–4.04 (m, 4H), 2.43 (s, 3H), 0.98–
1.04 (m, 6H) ppm; ES-HRMS calcd for [C23H25NO4þNaþ] 402.1676,
found: 402.1683.
¼29.577 min, tr (major)¼36.887 min) gave the isomeric composi-
25
tion of the product: 86% ee, mp 146–147 ꢀC; [
a]
þ62.78 (c 0.266,
D
CH2Cl2); 1H NMR (400 MHz, CDCl3):
d
¼8.00 (s, br s, 1H), 7.30–7.54
4.2.23. Ethyl 2-ethoxycarbonyl-3-[3-(4-methoxyindolyl)]-3-phenyl
propanoate 3ac4b. White solid; HPLC analysis (Chiralcel OD-H,
hexane/2-propanol 90:10, 1.0 mL/min, 254 nm; tr (major)¼
(m, 9H), 7.18–7.20 (m, 2H), 7.02 (d, J¼2.4 Hz, 1H), 6.81 (dd, J¼2.4,
6.4 Hz,1H), 5.10 (d, J¼12.0 Hz,1H), 4.32 (d, J¼11.6 Hz,1H), 4.00–4.07
(m, 4H), 3.81 (s, 3H),1.03 (t, J¼7.2 Hz, 3H),1.02 (t, J¼7.2 Hz, 3H) ppm.
21.703 min, tr (minor)¼25.372 min) gave the isomeric composition
23
of the product: 81% ee, mp 106–108 ꢀC; [
a
]
ꢁ50 (c 0.226, CHCl3);
4.2.29. Ethyl 2-ethoxycarbonyl-3-[3-(5-methoxyindolyl)]-3-(m-methyl-
phenyl) propanoate 3bd13. White solid; HPLC analysis (OD-H
column, hexane/2-propanol 90:10, 1.0 mL/min, 254 nm; tr
D
1H NMR (400 MHz, CDCl3):
d
¼8.01 (s, br s, 1H), 7.36 (d, J¼7.2 Hz,
2H), 7.22 (t, J¼7.2 Hz, 2H), 7.11–7.13 (m, 2H), 7.04 (t, J¼8.0 Hz, 1H),
6.90 (d, J¼8.0 Hz,1H), 6.43 (d, J¼8.0, Hz,1H), 5.52 (d, J¼12.4 Hz,1H),
4.30 (d, J¼12 Hz, 1H), 3.95–4.07 (m, 4H), 3.87 (s, 3H), 0.99–1.03 (m,
6H) ppm; ES-HRMS calcd for [C23H25NO5þNaþ] 418.1625, found:
418.1572.
(minor)¼12.214 min, tr (major)¼14.926 min) gave the isomeric
25
composition of the product: 92% ee, mp 60–62 ꢀC; [
a
]
þ6.64 (c
D
0.226, CH2Cl2); 1H NMR (400 MHz, CDCl3):
d
¼7.98 (s, br s, 1H),
7.34 (s, 1H), 7.11–7.19 (m, 5H), 7.00 (d, J¼2.0 Hz, 1H), 6.79 (dd,
J¼2.4, 6.4 Hz, 1H), 4.99 (d, J¼12.0 Hz, 1H), 4.27 (d, J¼12.0 Hz,
1H), 3.97–4.03 (m, 4H), 3.79 (s, 3H), 2.27 (s, 3H), 0.97–1.04 (m,
6H) ppm.
4.2.24. (R)-Ethyl 2-ethoxycarbonyl-3-[3-(5-methoxyindolyl)]-3-phenyl
propanoate 3ad13. White solid; HPLC analysis (Chiralcel OD-H,
hexane/2-propanol 90:10, 1.0 mL/min, 254 nm; tr (major)¼
13.173 min, tr (minor)¼16.208 min) gave the isomeric composition
4.2.30. Ethyl 2-ethoxycarbonyl-3-[3-(5-methoxyindolyl)]-3-(m-bromo-
phenyl) propanoate 3jd13. White solid; HPLC analysis (OD-H
column, hexane/2-propanol 90:10, 1.0 mL/min, 254 nm; tr
22
of the product: 92% ee, mp 120–122 ꢀC; [
a]
ꢁ11.60 (c 0.328,
D
CHCl3); 1H NMR (400 MHz, CDCl3):
d
¼7.97 (s, br s, 1H), 7.37–7.40

Y. Liu et al. / Tetrahedron 66 (2010) 1447–1457
1455
(major)¼12.806 min, tr (minor)¼16.073 min) gave the isomeric
13.85, 13.77 ppm; ES-HRMS calcd for [C23H24N2O7ꢁHþ] 439.1511,
27
composition of the product: 92% ee, mp 91–92 ꢀC; [
0.472, CH2Cl2); 1H NMR (400 MHz, CDCl3):
a]
þ6.36 (c
found: 439.1497.
D
d
¼8.02 (s, br s, 1H), 7.51
(t, J¼1.6 Hz, 1H), 7.09–7.32 (m, 5H), 6.94 (d, J¼2.4 Hz, 1H), 6.81 (dd,
J¼2.4, 6.4 Hz, 1H), 5.00 (d, J¼11.6 Hz, 1H), 4.23 (d, J¼11.6 Hz, 1H),
4.00–4.05 (m, 4H), 3.80 (s, 3H), 1.06 (t, J¼7.2 Hz, 3H), 1.00 (t,
J¼7.2 Hz, 3H) ppm.
4.3. Data for alkylation derivatives
4.3.1. Ethyl-3-(1H-indol-3-yl)-3-phenylpropanoate 413. To a suspen-
sion of NaCl (787 mg, 13.11 mmol) and 3a (2.396 g, 6.56 mmol,
>99% ee after recrystallization) in anhydrous DMSO (40 mL) was
4.2.31. Ethyl 2-ethoxycarbonyl-3-[3-(5-methoxyindolyl)]-3-(m-chloro-
phenyl) propanoate 3hd13. White solid; HPLC analysis (OD-H
column, hexane/2-propanol 90:10, 1.0 mL/min, 254 nm; tr
added H2O (525 mL). The resulting mixture was refluxed for 26 h
and then stirred at 80 ꢀC for 12 h. After cooling to room tempera-
ture, to the reaction solution was added 100 mL of distilled water
and extracted with CH2Cl2 (3ꢂ50 mL). The combined organic ex-
tracts were washed with saturated solution of NaCl, dried with
anhydrous MgSO4, filtered through cotton and concentrated under
vacuo. The monoester 4 was obtained after purification by flash
(minor)¼14.123 min, tr (major)¼18.111 min) gave the isomeric
25
composition of the product: 88% ee, mp 72–74 ꢀC; [
a]
ꢁ1.55
D
(c 0.194, CH2Cl2); 1H NMR (400 MHz, CDCl3):
d
¼8.00 (s, br s, 1H),
7.34 (s, 1H), 7.11–7.27 (m, 5H), 6.93 (d, J¼2.0 Hz, 1H), 6.80 (dd, J¼2.4,
6.4 Hz, 1H), 5.00 (d, J¼11.6 Hz, 1H), 4.22 (d, J¼12.0 Hz, 1H), 4.02 (q,
J¼7.2 Hz, 2H), 4.01 (q, J¼7.2 Hz, 2H), 3.79 (s, 3H), 1.05 (t, J¼7.2 Hz,
3H), 1.00 (t, J¼7.2 Hz, 3H) ppm.
chromatography (CH2Cl2/petroleum ether, 1:1) as white solid
26
(1.26 g, 66% yield);
(400 MHz, CDCl3):
[
a]
ꢁ53.45 (c 0.290, CHCl3); 1H NMR
D
d
¼7.99 (s, br s, 1H), 7.42 (d, J¼7.6 Hz, 1H), 7.24–
7.34 (m, 5H), 7.13–7.19 (m, 2H), 7.00–7.06 (m, 2H), 4.80 (t, J¼7.6 Hz,
1H), 4.04 (q, J¼7.6 Hz, 1H), 4.03 (q, J¼7.6 Hz, 1H), 3.15 (dd, J¼7.6,
15.2 Hz, 1H), 3.01 (dd, J¼8.0, 15.2 Hz, 1H), 1.11 (t, J¼7.2 Hz, 3H) ppm.
4.2.32. Ethyl 2-ethoxycarbonyl-3-[3-(5-methoxyindolyl)]-3-(4-fluoro-
3-phenoxyphenyl) propanoate 3qd13. White solid; HPLC analysis
(AS-H column, hexane/2-propanol 90:10, 1.0 mL/min, 254 nm; tr
(minor)¼16.500 min, tr (major)¼22.334 min) gave the isomeric
4.3.2. 3-(1H-indol-3-yl)-3-phenylpropionic acid 513. To a solution of
ethyl-3-(1H-indol-3-yl)-3-phenylpropanoate (548.6 mg, 1.87 mmol)
in 19 mL of mixed solvent of THF and ethanol (1/1, v/v) was added
a solution of 2 N NaOH (2.8 mL) and H2O (3.7 mL). The resulting so-
lution was refluxed for 3 h. After cooling to room temperature, to the
reaction solution was added 0.5 N HCl till pH¼1 and extracted with
ethyl acetate (3ꢂ30 mL). The combined extracts were dried over
25
composition of the product: 92% ee, mp 92–94 ꢀC; [
a
]
ꢁ10.39
D
(c 0.520, CH2Cl2); 1H NMR (400 MHz, CDCl3):
d
¼7.97 (s, br s, 1H),
7.02–7.29 (m, 9H), 6.88 (d, J¼8.0 Hz, 3H), 6.80 (dd, J¼2.4, 6.4 Hz,
1H), 4.96 (d, J¼12 Hz, 1H), 4.16 (d, J¼11.6 Hz, 1H), 4.03 (d, J¼7.2 Hz,
2H), 4.00 (d, J¼7.2 Hz, 2H), 3.76 (m, 1H), 1.09 (t, J¼7.2 Hz, 3H), 0.99
(t, J¼7.2 Hz 3H) ppm.
anhydrous Na2SO4. After removal of solvent, the crude product 5 was
27
4.2.33. Ethyl 2-ethoxycarbonyl-3-[3-(5-methoxy-indolyl)]-3-(m-pheno-
xylphenyl) propanoate 3cd13. White solid; HPLC analysis (OD-H col-
umn, hexane/2-propanol 90:10, 1.0 mL/min, 254 nm; tr
obtained as a pale yellow solid (480 mg, 97%); [
a
]
ꢁ39.58 (c 0.720,
D
MeOH); 1H NMR (400 MHz, CDCl3):
d
¼7.98 (s, br s, 1H), 7.56 (d,
J¼8.0 Hz,1H), 7.24–7.41 (m, 4H), 7.10–7.20 (m, 3H), 6.97–7.06 (m, 2H),
4.80 (t, J¼8.0 Hz, 1H), 3.18 (dd, J¼8.0, 15.2 Hz, 1H), 3.05 (dd, J¼7.6,
15.6 Hz, 1H) ppm.
(major)¼15.127 min, tr (minor)¼19.639 min) gave the isomeric
23
composition of the product: 95% ee, mp 81–82 ꢀC; [
a
]
þ13.3 (c
D
0.278, CH2Cl2); 1H NMR (400 MHz, CDCl3):
d
¼7.94 (s, br s,1H), 7.26–
7.31 (m, 2H), 7.17–7.22 (m, 2H), 7.05–7.13 (m, 4H), 6.90–6.95 (m,
3H), 6.78–6.82 (m, 2H), 5.00 (d, J¼12.0 Hz, 1H), 4.23 (d, J¼11.6 Hz,
1H), 4.04 (q, J¼7.2 Hz, 2H), 4.00 (q, J¼7.2 Hz, 2H), 3.78 (s, 3H), 1.08
(t, J¼7.2 Hz, 3H), 0.99 (t, J¼7.2 Hz, 3H) ppm.
4.3.3. 2-(1H-indol-3-yl)-2-phenylethanamine 613. To a suspension
of 5 (264 mg, 1 mmol) in dry toluene was added Et3N (153
1.1 mmol) and diphenylphosphoryl azide (DPPA) (237
1.1 mmol). The reaction mixture was stirred at 110 ꢀC for 4 h under
m
m
L,
L,
nitrogen atmosphere, then tert-butyl alcohol (141 mL, 1.5 mmol)
4.2.34. Ethyl 2-ethoxycarbonyl-3-[3-(5-methoxyindolyl)]-3-(2-thienyl)
propanoate 3td13. White solid; HPLC analysis (AS-H column, hex-
ane/2-propanol 85:15, 1.0 mL/min, 254 nm; tr (minor)¼10.430 min,
was added and the heating was continued for 32 h. After evapo-
ration of the solvent, the residue was dissolved in CH2Cl2 (20 mL),
and the solution was washed with 5% citric acid, brine and satu-
rated K2CO3 solution, dried over MgSO4. The organic phase was
filtered and evaporated affording the tert-butyl 2-(1H-indol-3-yl)-
2-phenylethylcarbamate as white solid. The crude product was
dissolved in CH2Cl2 (10 mL), and TFA (1.0 mL) was added into the
solution. Then the reaction mixture was stirred at room tempera-
ture for 12 h and concentrated in vacuo. After the addition of H2O,
the solution was added 2 N NaOH till pH¼11–12 and extracted with
CH2Cl2 (3ꢂ15 mL). The combined extracts were washed with brine
and dried over MgSO4. After removal of solvent, the crude product 6
was obtained as pale yellow solid (61 mg, 28% yield); The crude
product was used in the next steps without further purification. 1H
tr (major)¼13.032 min) gave the isomeric composition of the
25
product: 80% ee, mp 54–56 ꢀC; [
a
]
D
ꢁ24.28 (c 0.486, CH2Cl2); 1H
NMR (400 MHz, CDCl3):
d
¼8.05 (s, br s, 1H), 7.18 (d, J¼8.8 Hz, 1H),
7.15 (d, J¼2.4 Hz, 1H), 7.10 (dd, J¼1.2, 4.0 Hz, 1H), 7.03 (d, J¼2.4 Hz,
1H), 6.99 (d, J¼3.2 Hz, 1H), 6.86 (dd, J¼1.6, 3.6 Hz, 1H), 6.81 (dd,
J¼2.4, 6.4 Hz, 1H), 5.34 (d, J¼11.6 Hz, 1H), 4.28 (d, J¼11.2 Hz, 1H),
4.11 (q, J¼7.2 Hz, 2H), 3.96 (q, J¼7.2 Hz, 2H), 3.81 (s, 3H), 1.14 (t,
J¼7.2 Hz, 3H), 0.93 (t, J¼7.2 Hz, 3H) ppm.
4.2.35. Ethyl 2-ethoxycarbonyl-3-[3-(5-methoxyindolyl)]-3-(m-nitro-
phenyl) propanoate 3fd. Yellow solid; HPLC analysis (AS-H column,
hexane/2-propanol 80:20, 1.0 mL/min, 254 nm; tr (minor)-
NMR (400 MHz, DMSO):
d
¼10.94 (s, br s, 1H), 7.13–7.37 (m, 9H),
¼10.707 min, tr (major)¼12.550 min) gave the isomeric compo-
7.02 (t, J¼7.6 Hz, 1H), 6.88 (t, J¼7.6 Hz, 1H), 4.20 (s, br s, 1H), 3.35 (s,
26
sition of the product: 84% ee, mp 118–119 ꢀC; [
a
]
þ2.27 (c
br s, 3H) ppm.
D
0.220, CH2Cl2); 1H NMR (400 MHz, CDCl3):
d
¼8.24 (s, br s, 1H),
8.13 (s, 1H), 8.03 (dd, J¼1.2, 6.8 Hz, 1H), 7.74 (d, J¼7.6 Hz, 1H), 7.42
(t, J¼8.0 Hz, 1H), 7.21 (t, J¼2.4 Hz, 2H), 6.91 (d, J¼2.4 Hz. 1H), 6.82
(dd, J¼2.0, 6.4 Hz, 1H), 5.15 (d, J¼11.6 Hz, 1H), 4.30 (d, J¼11.6 Hz,
1H), 4.00–4.07 (m, 4H), 3.79 (s, 3H), 1.06 (t, J¼7.2 Hz, 3H), 1.02 (t,
4.3.4. 1,4-Diphenyl-1,2,3,4-tetrahydro-
solution of crude product 6 (47 mg, 0.199 mmol) in dry CH3CN
(3 mL), were sequentially added TFA (30 L, 0.398 mmol) and
benzaldehyde (21 L, 0.211 mmol). The resulting solution was
b
-carboline 713. To a stirred
m
m
J¼7.2 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3):
d
¼167.47, 154.18,
refluxed for 32 h. After cooling to room temperature, the mixture
was quenched by addition of saturated NaHCO3 and extracted with
CH2Cl2 (3ꢂ15 mL). The combined organic layers were washed with
148.27, 143.83, 134.69, 131.37, 129.28, 126.71, 122.99, 121.95,
121.92, 115.20, 112.76, 112.00, 100.75, 61.79, 57.80, 55.87, 42.28,

1456
Y. Liu et al. / Tetrahedron 66 (2010) 1447–1457
brine, dried over Na2CO3, filtered and concentrated giving crude
product as a mixture of diastereoisomers. The crude product was
purified by chromatography on silica gel (petroleum ether/ethyl
acetate, 2:1) to give the product in 68% yield and with anti/syn¼92/
DMSO):
d
¼10.95 (s, br s,1H), 7.41 (d, J¼8.0 Hz,1H), 7.34–7.36 (m, 4H),
7.24–7.28 (m, 2H), 7.14 (t, J¼7.6 Hz 1H), 7.02–7.06 (m, 1H), 6.88–6.92
(m, 1H), 4.28 (t, J¼8.0 Hz, 1H), 3.24–3.31 (m, 2H), 2.38–2.47 (m, 1H),
2.20–2.30 (m, 1H) ppm.
8. The ee of the major diastreoisomer isolated by chromatography
23
was determined on the corresponding sulfonamide derivative. [
a
]
4.3.9. 3-(1H-indol-3-yl)-3-phenylpropan-1-amine 1213. To a solution
of 3-(3-azido-1-phenylpropyl)-1H-indole 11 (78 mg, 0.282 mmol) in
MeOH (1 mL) was added activated Pd/C (10%,10 mg) and the mixture
was stirred under hydrogen atmosphere at room temperature for
41 h, and then filtered on a Celite pad. The pad was washed four times
with CH2Cl2. After evaporation of the solvent, the crude product was
D
þ59.3 (c 0.440, CHCl3); 1H NMR (400 MHz, CDCl3):
¼7.63 (s, br s,
d
1H), 7.17–7.44 (m, 11H), 7.08–7.12 (m, 1H), 6.84–6.93 (m, 2H), 5.32
(t, J¼2.0 Hz, 1H), 4.41 (m, 1H), 3.58 (dd, J¼5.2, 12.4 Hz, 1H), 3.07 (dd,
J¼8.8, 12.8 Hz, 1H), 1.96 (s, br s, 1H).
4.3.5. 1,4-Diphenyl-2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-
line 810b. To a stirred solution of 1,4-diphenyl-1,2,3,4-tetrahydro-
carboline (36 mg, 0.111 mmol) in CH2Cl2 (2 mL) was added Et3N
(23 L, 0.166 mmol) and TsCl (32 mg, 0.166 mmol). The reaction
b
-carbo-
purified by chromatography on silica gel (CH2Cl2/MeOH, 9:1) in 64%
25
b-
yield as a white solid. [
a
]
ꢁ20.63 (c 0.320, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3):
d
¼8.16 (s, br s,1H), 7.43 (d, J¼8.0 Hz,1H), 7.22–7.32
m
(m, 3H), 6.98–7.17 (m, 6H), 4.26 (d, J¼7.2 Hz,1H), 2.76 (s, br s, 2H), 2.35
(s, br s, 1H), 2.18 (d, J¼7.2 Hz, 1H), 1.80 (s, br, 2H) ppm.
mixture was then stirred for 17 h at room temperature, then directly
purified by chromatography on silica gel (CH2Cl2/petroleum ether,
3:1) to give the title product in 84% yield with 99% ee as a white solid.
The ee of the product was determined by chiral HPLC analysis on
a Daicel Chiralpak AD-H column (n-hexane/i-PrOH¼70:30), Flow
4.3.10.
12 (40 mg, 0.163 mmol) in dry CH3CN (2 mL), were sequentially
added TFA (37 L, 0.489 mmol) and benzaldehyde (26 L,
b
-carboline-like 1313. To a stirred solution of crude product
m
m
rate¼1.0 mL/min, UV¼254 nm, tr (major)¼8.949 min, tr (minor)-
0.261 mmol). The resulting solution was refluxed for three days.
After cooling to room temperature, the mixture was quenched by
addition of satd NaHCO3 and extracted with CH2Cl2 (3ꢂ15 mL). The
combined organic layers were washed with brine, dried over
Na2CO3, filtered and concentrated giving crude product as a mix-
ture of diastereoisomers. The crude product was purified by chro-
27
¼25.548 min. [
a
]
ꢁ88.6(c0.720, CHCl3);1HNMR(400 MHz,CDCl3):
D
d
¼7.73 (s, br s,1H), 6.95–7.31 (m, 16H), 6.87 (d, J¼8.4 Hz, 2H), 6.25 (s,
1H), 4.38 (d, J¼2.0 Hz, 1H), 3.93 (ddd, J¼1.6, 4.4, 13.2 Hz, 2H), 2.27 (s,
3H) ppm.
4.3.6. 3-(1H-indol-3-yl)-3-phenylpropan-1-ol 913. To a stirred solu-
tion of LiAlH4 (409 mg, 10.76 mmol) in THF (25 mL) was added the
Ethyl-3-(1H-indol-3-yl)-3-phenylpropanoate (789 mg, 2.69 mmol in
15 mL THF) dropwise at 0 ꢀC. In order to neutralize the residual hy-
dride, after 18 h of stirring at 0 ꢀC to room temperature, the reaction
mixture was quenched by addition of H2O (0.4 mL), NaOH (0.4 mL,
2 N) and H2O (1.2 mL) orderly. The resulting suspension was filtered
through ashortpadofCelite, Thepad washedseveraltimeswithEt2O.
After drying (MgSO4) of the combined organic fractions and filtration,
the solvent was evaporated under reduced pressure. The crude
reaction mixture was purified by chromatography on silica gel
matography on silica gel (petroleum ether/ethyl acetate, 2:1) to
29
give the product 7 in 44% yield; [
(400 MHz, CDCl3):
a
]
þ8.0 (c 0.100, CHCl3); 1H NMR
D
d
¼7.76 (dd, J¼7.6 Hz, 1H), 6.97–7.56 (m, 14H),
5.37 (s, 1H), 4.78 (t, J¼4.4 Hz, 1H), 3.22 (dt, J¼4.4, 14.4 Hz, 1H), 3.03–
3.09 (m, 1H), 2.45–2.48 (m, 2H), 1.79(s, br s, 1H).
Acknowledgements
We appreciate the National Natural Science Foundation of China
(No. 20732003), PCSIRT (No. IRT0 846) and the State Basic Research
and Development Program (No.2010CB833302) for financial sup-
port. We also thank Sichuan University Analytical & Testing Centre
for NMR analysis.
(petroleum ether/ethyl acetate, 2:1) to give the title product 9
27
quantitatively. [
a
]
ꢁ25.0 (c 0.364, CH2Cl2); 1H NMR (400 MHz,
D
CDCl3):
d
¼8.05 (s, br s, 1H), 7.49 (d, J¼8.0 Hz, 1H), 7.28–7.37 (m, 5H),
7.16–7.23 (m, 2H), 7.03–7.07 (m, 2H), 4.42 (t, J¼8.0 Hz, 1H), 3.66–3.75
(m, 2H), 2.46–2.54 (m, 1H), 2.27–2.35 (m, 1H), 1.52 (s, br s, 1H). ppm.
References and notes
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H. J.; Zhao, B. T.; Zuo, G. Y.; Pittman, C. U.; Dai, W. M.; Hao, X. J. Tetrahedron:
4.3.7. 3-(1H-indol-3-yl)-3-phenylpropyl 4-methylbenzenesulfonate
1013. To a stirred solution of 9 (130.9 mg, 0.521 mmol) in CH2Cl2
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0.525 mmol) at 0 ꢀC. The reaction mixture was then stirred at 50 ꢀC
for 23 h, then directly purified by chromatography on silica gel
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Asymmetry 2001, 12, 2613–2619; (c) Fınaru, A.; Berthault, A.; Besson, T.; Guil-
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27
yield as a white solid. [
(400 MHz, CDCl3):
a]
ꢁ33.3 (c 0.720, CH2Cl2); 1H NMR
D
d
¼7.97 (s, br s, 1H), 7.21 (d, J¼8.4 Hz, 2H), 7.33 (t,
J¼7.6 Hz, 2H), 7.12–7.26 (m, 8H), 6.97–7.01 (m, 2H), 4.29 (t, J¼7.6 Hz,
1H), 3.97–4.27 (m, 2H), 2.51–2.58 (m, 1H), 2.42 (s, 3H), 2.30–2.37
(m, 1H) ppm.
4.3.8. 3-(3-azido-1-phenylpropyl)-1H-indole 1113. Sodium azide
(67 mg,1.03 mmol) was added to a solution of the 3-(1H-indol-3-yl)-
3-phenylpropyl 4-methylbenzenesulfonate 10 (207 mg, 0.511 mmol)
in DMF (4 mL) at room temperature. The resulting mixture was
warmed to 50 ꢀC and maintained at that temperature for 10 h. The
solutionwas then cooled, poured into water and extracted with ether
(4ꢂ15 mL). The combined organic phases were washed successively
with satd NaCl and water, dried over Na2SO4, and then concentrated.
The crude product was purified by silica gel column chromatography
(petroleum ether/CH22C8l2, 2:1) to give the product as colourless thick
oil in 98.6% yield. [
a
]
ꢁ42.5 (c 1.12, CH2Cl2); 1H NMR (400 MHz,
D

Y. Liu et al. / Tetrahedron 66 (2010) 1447–1457
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