Enantioselective Friedel-Crafts alkylation of indoles with β,γ-unsaturated α-ketoesters catalyzed by new squaramide-linked bisoxazoline-Zn(OTf)2 complexes

Article abstract of DOI:10.1016/j.tetasy.2014.05.011

Enantioselective Friedel-Crafts alkylation reactions of indoles with β,γ-unsaturated α-ketoesters catalyzed by novel chiral C ₂-symmetric squaramide-linked bisoxazoline-Zn(OTf)₂ complexes were investigated. The corresponding indole k

Full text of DOI:10.1016/j.tetasy.2014.05.011

Tetrahedron: Asymmetry 25 (2014) 980–988
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective Friedel–Crafts alkylation of indoles with
b,c-unsaturated a-ketoesters catalyzed by new squaramide-linked
bisoxazoline–Zn(OTf)2 complexes
⇑
Sheng-Jian Jia, Da-Ming Du
School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing 100081, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 April 2014
Accepted 16 May 2014
Enantioselective Friedel–Crafts alkylation reactions of indoles with b,c-unsaturated a-ketoesters
catalyzed by novel chiral C2-symmetric squaramide-linked bisoxazoline–Zn(OTf)2 complexes were inves-
tigated. The corresponding indole ketoesters were obtained in good to excellent yields (up to 98%) and
with high enantioselectivities (up to 94% ee). This is the first report on the use of chiral squaramide-
linked bisoxazoline SQBOX in a catalytic enanitioselective Friedel–Crafts alkylation reaction.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
catalysts.7 Thereafter, a binary chiral phosphoric acid/MgF2 catalyst
has been applied to the same reaction,8 and afforded relatively lower
Many scientists have focused on the catalytic enantioselective
Friedel–Crafts reaction because this reaction is a versatile and
powerful carbonAcarbon bond-forming method in organic synthe-
sis.1,2 In medicinal chemistry and complex target synthesis, the
framework of indole has a structural motif of particular value.3
Among the various types of substrates used in enantioselective
enantioselectivities (82–92% ee) than those obtained using Lewis
acid catalysts. In 2012, using heteroarylidene–tethered bisoxazoline
copper complexes, Fu et al. expanded upon these asymmetric Fri-
edel–Crafts alkylations of indoles with b,c-unsaturated a-ketoesters
to unprotected pyrroles, the 3-indolyl adducts were achieved with
excellent enantioselectivities, but 2-pyrrolyl adducts were obtained
in lower enantioselectivities than the indole derivatives.9
Friedel–Crafts alkylation, the reactions of indoles, b,c-unsaturated
a
-ketoesters are important substrates for the synthesis of enantio-
Although a number of methods have already been published
that describe high to excellent enantioselectivities for this reaction
using various catalysts, the development of inexpensive and facile
synthesized ligands remains a challenge. Meanwhile, this well-
established Friedel–Crafts reaction can be used as an evaluation
platform for new catalysts’ development in a modular manner.10
Oxazoline is a significant type of ‘privileged ligand’ due to its mod-
ular nature and has been successfully applied to various catalytic
asymmetric reactions.11 The reported results have demonstrated
that the linker in bioxazoline ligands may have an important influ-
ence on the catalytic performance.2e,12 Meanwhile, squaramides
have been demonstrated to be exceptionally versatile scaffolds
and efficient catalysts in asymmetric organocatalysis.13 We envi-
sioned that the modular assembly of the oxazoline and squaramide
moieties together will provide a facile method for the rapid synthe-
sis of squaramide-linked bisoxazoline SQBOX ligands.
merically enriched indole derivatives. The indole derivatives of
these alkylation reactions can be readily functionalized into the
corresponding amino acids or
reactions have attracted much attention over the past decade.
In recent years, there have been a few reports based on chiral
metal complexes for the asymmetric Friedel–Crafts alkylation of
indoles with b,
workers reported on the first enantioselective Friedel–Crafts reaction
a
-hydroxy acids,4 and these
c-unsaturated a
-ketoesters.5–9 Jørgensen and co-
of aromatic CAH bonds to b,c-unsaturated a-ketoesters catalyzed by
chiral bisoxazoline (BOX)–Cu(II) complexes.5 Desimoni and co-work-
ers reported on the asymmetric Friedel–Crafts reaction between a
series of substituted indoles and b,c-unsaturated a-ketoesters cata-
lyzed by the pybox–Sc(OTf)3 complexes, and the alkylated products
were obtained with high to excellent enantioselectivities (up to
99% ee).6 In 2010, Feng and co-workers reported on the first example
of central metal controlled reversal of enantioselectivity in asymmet-
Herein we report the modular synthesis of a series of squaramide-
linked bisoxazoline ligands. Their primary application in catalytic
ric Friedel–Crafts alkylation of indoles with b,c-unsaturated a-keto-
esters using the N,N0-dioxide–AgAsF6 or Sm(OTf)3 complexes as
asymmetric Friedel–Crafts alkylations of indoles with b,
c-unsatu-
rated -ketoesters was evaluated, and the corresponding substituted
a
4-(indol-3-yl)-2-oxo-4-arylbutyric acid esters were obtained in good
to excellent yields and with high enantioselectivities (up to 94% ee).
⇑
Corresponding author. Tel.: +86 10 68914985.
E-mail address: dudm@bit.edu.cn (D.-M. Du).
http://dx.doi.org/10.1016/j.tetasy.2014.05.011
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

S.-J. Jia, D.-M. Du / Tetrahedron: Asymmetry 25 (2014) 980–988
981
O
O
O
O
O
O
NH
HN
N
H
NH
N
H
HN
O
O
O
O
O
O
N
N
N
N
N
N
Ph
Ph
Bn
Bn
L1
L2
L3
O
O
O
O
Bn
Bn
Bn
Bn
N
H
HN
NH
HN
O
O
O
O
N
N
N
N
Ph
Ph
L5
L4
Figure 1. Squaramide-linked bisoxazoline ligands.
in the enantioselectivity (entries 15 and 18). From the above eval-
uation, the L1–Zn(OTf)2 complex was chosen as the best catalyst
and employed in subsequent optimization reactions.
2. Results and discussion
Firstly, 2-(aminomethyl)oxazoline modules 1 were synthesized
following the literature.13 A small library of C2-symmetric modular
squaramide-linked bisoxazoline ligands L1–L5 (Fig. 1) was then
easily synthesized from the reaction of 2-(aminomethyl)oxazolines
1 and dimethyl squarate (Scheme 1). These squaramide-linked bis-
oxazolines were used as organocatalysts to catalyze asymmetric
In order to further optimize the reaction conditions, the effect of
solvents, the amount of indole, catalyst loading, and reaction tem-
perature were then evaluated and the results are summarized in
Table 2. The solvents had a significant effect on the yields and
enantioselectivity. When the reaction was carried out in chloro-
form or acetonitrile, the product was obtained in excellent yields
(97% and 99%), but the enantioselectivities were moderate (Table 2,
entries 7 and 8). while other solvents such as THF, dichlorometh-
ane (DCM), ether, ethyl acetate, acetone, and xylene gave moderate
yields and enantioselectivities. 1,2-Dichloroethane and toluene
were more suitable for this reaction in terms of enantioselectivity,
and the best results (80% yield and 86% ee) were obtained in tolu-
ene (Table 2, entry 1). In order to evaluate the influence of the
mixed solvent, we tested the mixed solvent effect at different tem-
peratures. Poor results (69% yield and 40% ee) were obtained in
THF–PhMe (1:1) solvent (Table 2, entry 12). The DCM–PhMe
(1:1) mixed solvent afforded good to high enantioselectivities
(81–88% ee, Table 2, entries 13–15), and the best result (93% yield
and 90% ee) was obtained at room temperature. When the reaction
was performed in CHCl3–PhMe (1:1) mixed solvent, preferable
enantioselectivities (86–93% ee) were obtained (Table 2, entries
16–18); the best result (89% yield and 93% ee) was obtained at
0 °C. In general, the reaction temperature had no obvious effect
on the enantioselectivities. Lowering the reaction temperature to
ꢀ10 °C, led to a similar enantioselectivity (92% ee) (Table 2, entry
17), while the yield slightly decreased to 87%.
The different structures of the ligands had distinct effects on the
enantioselectivity. The effect of different ligands was then evalu-
ated in this reaction using CHCl3–PhMe (1:1) mixed solvent at °C
(Table 2, entries 18–22). Ligand L2 afforded the product with very
low enantioselectivity, while ligands L3–L5 gave moderate to good
enantioselectivities. The best result was obtained with ligand L1.
Reducing the catalyst loading to 5 mol %, gave a similar yield
(97%, Table 2, entry 23), while the enantioselectivity slightly
decreased to 87% ee. When 1 equiv of indole was used, 93% ee
and 48% yield were obtained (Table 2, entry 24). From the above
evaluation, the optimized reaction conditions were found to be a
combination of 10 mol % of L1 with 10 mol % of Zn(OTf)2, and
1.5 equiv of indole in CHCl3–PhMe (1:1) (2 mL) at 0 °C.
Friedel–Crafts alkylations of indole 2a with a-ketoester 3a, the cor-
responding product was obtained in very low yield in racemic
form. Next, the catalytic performance of these squaramide-bisox-
azoline ligand metal complexes in the asymmetric Friedel–Crafts
alkylation of indoles with b,
investigated.
c
-unsaturated a-ketoesters was
O
O
R1
O
O
R1
R1
O
N
MeOH
O
NH
HN
+
O
NH2
R2
MeO
OMe
N
N
R2
R2
L
1
Scheme 1. Modular synthesis of squaramide-linked bisoxazoline ligands.
In order to optimize the reaction conditions, ligand L1 was first
chosen to explore the effect of Lewis acids at 10 mol % catalyst
loading. The effect of the Lewis acid was firstly screened in the
model alkylation reaction of indole 2a with 2-oxo-4-phenyl-but-
3-enoic acid methyl ester 3a in toluene at room temperature,
and the results are summarized in Table 1. According to the initial
experiment, Zn(OTf)2 gave the most promising results of 86% ee
and 80% yield (Table 1, entry 1). In most cases, the presence of a
catalytic amount of Lewis acid (10 mol %) was found to remarkably
accelerate the reaction. However, the enantioselectivities varied
greatly (0–86% ee) depending on the Lewis acid used. Most of the
Lewis acids examined only afforded 4a in nil or modest ee values
(entries 3–18). The results also indicate that the anion in the Lewis
acid plays a prominent role in the catalysis. For instance, the cata-
lyst generated from Zn(OTf)2 and ligand L1 afforded the product 4a
with 86% ee (Table 1, entry 1), whereas changing the anion of the
zinc salt to either a chloride or perchlorate anion led to an erosion
Under the optimal reaction conditions, the substrate scope of
the asymmetric Friedel–Crafts alkylation reaction of indoles with

982
S.-J. Jia, D.-M. Du / Tetrahedron: Asymmetry 25 (2014) 980–988
Table 1
Screen of Lewis acid for catalytic enantioselective Friedel–Crafts reaction of indole 2a with b,
c
-unsaturated a-ketoester
3aa
Ph
O
L1
10 mol%
CO2Me
O
OMe
10 mol% Lewis acid
+
Ph
toluene
N
H
N
H
O
2a
4a
3a
Entry
Lewis acid
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Zn(OTf)2
La(OTf)3
PdCl2
Mg(OTf)2
Pd(OAc)2
Cu(OTf)2
Sc(OTf)3
80
11
53
78
66
33
49
20
21
25
20
7
77
40
96
66
49
43
86
68
8
20
4
3
3
1
4
5
2
0
20
15
11
39
3
CuOTfꢁ1/2C6H6
AgOTf
Yb(OTf)3
In(OTf)3
LiOTf
Ag2CO3
AgPF4
ZnCl2
Ni(ClO4)2ꢁH2O
Pd(PPh3)4
Zn(ClO4)2ꢁH2O
20
a
Unless otherwise noted, reactions were carried out with L1 (10 mol %), Lewis acid (10 mol %), 2a (0.3 mmol) and
3a (0.2 mmol) in PhMe (2.0 mL) at room temperature for 4–10h.
b
Isolated yield.
c
Determined by chiral HPLC analysis. The absolute configuration was assigned by comparison with literature
data.5,6
Table 2
Optimization of the reaction conditions for catalytic enantioselective Friedel–Crafts alkylation of indole 2a with b,
c-unsaturated
a
-ketoester 3aa
Ph
O
10 mol% ligand
OMe
CO2Me
10 mol% Zn(OTf)2
solvent
+
Ph
O
N
H
O
N
H
2a
3a
4a
Entry
Ligand
Solvent
T (°C)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L1
L1
PhMe
THF
DCM
EtOAc
CH3COCH3
Et2O
CHCl3
CH3CN
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
ꢀ10
rt
ꢀ10
0
0
0
80
64
48
72
63
61
99
97
72
66
77
69
93
79
82
90
87
89
82
81
85
87
97
48
86
33
65
73
67
55
77
39
82
63
0
40
88
87
81
86
92
93
20
83
65
62
87
93
9
ClCH2CH2Cl
Xylene
MeOH
10
11
12
13
14
15
16
17
18
19
20
21
22
23d
24e
THF/PhMe = 1:1
DCM/PhMe = 1:1
DCM/PhMe = 1:1
DCM/PhMe = 1:1
CHCl3/PhMe = 1:1
CHCl3/PhMe = 1:1
CHCl3/PhMe = 1:1
CHCl3/PhMe = 1:1
CHCl3/PhMe = 1:1
CHCl3/PhMe = 1:1
CHCl3/PhMe = 1:1
CHCl3/PhMe = 1:1
CHCl3/PhMe = 1:1
0
0
0
0
a
Unless otherwise noted, reactions were carried out with L1 (10 mol %), Lewis acid (10 mol %), 2a (0.3 mmol), and 3a (0.2 mmol) in PhMe (2.0 mL) at room temperature for
4–12h.
b
Isolated yield.
c
d
e
Determined by chiral HPLC analysis.
5 mol % ligand-Lewis acid was used.
0.2 mmol indole was used.

S.-J. Jia, D.-M. Du / Tetrahedron: Asymmetry 25 (2014) 980–988
983
b,
are summarized in Table 3. We first studied a variety of b,
urated -ketoesters bearing different substituents in the benzene
ring (Table 3, entries 1–9). All of these substrates reacted with
the indole and afforded the corresponding products 4a–4i in good
to excellent yields (74–98%) and with good to high enantioselectiv-
ities (71–94% ee). The steric and electronic nature of the substitu-
c
-unsaturated
a
-ketoesters was investigated further. The results
4 was assigned as (S) by comparison with previous literature
reports.5,6
c
-unsat-
a
Further substrate scope with other non-indole nucleophiles was
also investigated. When pyrrole was used, the product was
obtained as complex mixtures. As shown in Scheme 2, when
3-methoxyphenol was used, the corresponding product 4r was
obtained with excellent enantioselectivity (95% ee) but with very
lower reactivity (35% yield).
ents in the benzene ring of the b,c-unsaturated a-ketoesters, only
slightly affected the yields and enantioselectivities. The strong
electron-withdrawing substituent NO2 led to a lower yield and
enantioselectivity (Table 3, entries 7 and 8). The substrate scope
of the reaction was further demonstrated by varying the substitu-
ent of the indoles. When various indole derivatives bearing either
electron-donating or electron-withdrawing substituents at the
5-position were used, the reaction proceeded smoothly and affor-
ded the corresponding products 4k–4l in good yields and with high
enantioselectivities (Table 3, entries 11–13). However, when N-Me
indole was used, the enantioselectivity decreased to 32% ee
(Table 3, entry 10). Extending the substrates to ester groups, the
corresponding reactions also proceeded well and gave the alkyl-
ation products 4n–4q in high yields and with high enantioselectiv-
ities (Table 3, entry 14–17). The absolute configuration of products
As a control experiment, (2S)-2-methyl-1-((4S)-4-phenyl-4,5-
dihydro-oxazol-2-yl)propylamine 1a was also used as the ligand
in the model reaction under the optimized reaction; 1a–Zn(OTf)2
complexes afforded the corresponding product in 37% yield and
with 20% ee. This result demonstrates that the squaramide linker
is crucial for generating a synergistic catalytic effect. A tentative
transition state (Fig. 2) has been proposed to explain the observed
stereochemical outcome. The b,
nates to the zinc center in an approximately tetrahedral geometry
in the L1–Zn(OTf)2 complex, and the indole attacks the b, -unsat-
urated -ketoesters preferably from the Si face, leading to predom-
c-unsaturated a-ketoester coordi-
c
a
inant formation of the (S)-configured adduct. The high
enantioselectivity comes from the well-defined squaramide-bisox-
azoline chiral environment around the zinc center.
Table 3
Catalytic enantioselective Friedel–Crafts reaction of indoles 2 with b,
c
-unsaturated a
-ketoesters 3a
Ph
N
R1
O
L1
10 mol%
10 mol% Zn(OTf)2
CO2R4
OR4
R1
O
R3
+
PhCH3/CHCl3, 0 o
C
N
R2
O
R2
3
2
4
Entry
2
R1
R2
3
R3
R4
Time (h)
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2a
2a
2a
2a
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
3a
3a
3a
3a
3j
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
4
4
4
12
4
4
12
12
12
8
8
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
89
98
82
92
86
98
83
74
92
87
86
87
87
83
84
81
86
93
88
81
89
89
91
79
71
89
32
91
83
94
89
85
86
89
4-ClC6H4
4-BrC6H4
4-FC6H4
4-MeOC6H4
4-MeC6H4
4-NO2C6H4
2-NO2C6H4
H
H
3,4-(MeO)2C6H3
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5-Me
5-Cl
5-MeO
H
H
H
8
6
6
6
3k
3l
3m
Bn
i-Pr
Vinyl
H
6
a
b
c
Unless otherwise noted, reactions were carried out with L1 (10 mol %), Zn(OTf)2 (10 mol %), 2 (0.3 mmol), and 3 (0.2 mmol) in 2 mL of PhMe–CHCl3 (1:1) at 0 °C.
Isolated yield.
Determined by chiral HPLC analysis, the absolute configuration was determined by comparison with literature data.5,6
OMe
O
L1
10 mol%
10 mol% Zn(OTf)2
OMe
+
OMe
Ph
HO
O
PhCH3/CHCl3, 0 o
C
O
Ph
CO2Me
OH
3a
2f
4r
35% yield, 95% ee
Scheme 2. Further investigation of substrate scope.

984
S.-J. Jia, D.-M. Du / Tetrahedron: Asymmetry 25 (2014) 980–988
(380.3 mg, 74% yield). Following this typical procedure, the other
following ligands L2–5 were prepared.
O
O
HN
N
O
4.2.2. 3,4-Bis((S)-1-((S)-4,5-dihydro-4-phenyloxazol-2-yl)-2-me-
thylpropylamino)cyclobut-3-ene-1,2-dione L1
HN
HN
74% yield, mp 114–116 °C, [
a
]
D
19 = ꢀ6.0 (c 0.10, CH2Cl2). 1H
Zn
O
NMR (400 MHz, DMSO-d6): d 8.15–8.02 (m, 2H, NH), 7.36–7.32
(m, 4H, ArH), 7.29–7.24 (m, 6H, ArH), 5.29–5.23 (m, 2H, CH),
4.90–4.82 (m, 2H, CH), 4.78–4.74 (m, 2H, CH), 4.17–4.04 (m, 2H,
CH), 2.23–2.13 (m, 2H, CH), 0.97 (d, J = 6.8 Hz, 12H, CH3) ppm.
13C NMR (100 MHz, DMSO-d6): d 182.6, 167.3, 165.6, 142.2,
128.45, 128.40, 127.2, 126.6, 126.5, 126.4, 74.6, 68.3, 56.5, 31.9,
O
MeO
N
O
O
O
Ph (S)
OMe
Si
Ph
N
H
30.5, 18.4, 17.3 ppm. IR (KBr):
m 3252, 3063, 3030, 2965, 2903,
2877, 1799, 1669, 1590, 1526, 1494, 1454, 1390, 1371, 1344,
1311, 1148, 1080, 987, 927, 758, 700 cmꢀ1. HRMS (ESI): m/z calcd
for C30H35N4O4 [M+H]+ 515.26528, found 515.26559.
Figure 2. The proposed transition state for stereochemical control.
3. Conclusion
4.2.3. 3,4-Bis((S)-1-((S)-4-tert-butyl-4,5-dihydrooxazol-2-yl)-2-
methylpropylamino)cyclobut-3-ene-1,2-dione L2
19 = ꢀ71.3 (c 0.085, CH2Cl2). 1H
In conclusion, a series of novel modular C2-symmetric squara-
mide-linked bisoxazoline ligands have been synthesized. These
squaramide-linked bisoxazoline–Zn(OTf)2 complexes have been
applied to enantioselective Friedel–Crafts reactions of indoles with
99% yield, mp 99–102 °C, [
a]
D
NMR (400 MHz, DMSO-d6): d 8.00–7.83 (m, 2H, NH), 4.69 (dd,
J1 = 5.8 Hz, J2 = 9.8 Hz, 2H, CH), 4.25 (t, J = 9.6 Hz, 2H, CH), 4.11 (t,
J = 8.4 Hz, 2H), 3.84 (t, J = 9.0 Hz, 2H, CH), 2.10–2.04 (m, 2H, CH),
0.91 (d, J = 6.8 Hz, 12H, CH3), 0.81 (s, 18H, CH3) ppm. 13C NMR
(100 MHz, DMSO-d6): d 182.6, 167.5, 164.2, 74.3, 68.6, 56.6, 33.2,
b,c-unsaturated a-ketoesters, and the corresponding alkylation
products were obtained in good to excellent yields (up to 98%)
and with high enantioselectivities (up to 93% ee). This enantiose-
lective protocol provides practical and efficient access to indole
derivatives bearing a chiral tertiary carbon center and ketoester
functional groups, which may be further transformed into types
of potential chiral intermediates and functional materials. Further
investigations on the applications of novel chiral C2-symmetric
squaramide-bisoxazoline ligands in other asymmetric catalytic
reactions are currently in progress in our laboratory.
31.7, 25.5, 18.6, 17.2 ppm. IR (KBr):
m 3148, 2962, 2905, 2873,
1803, 1671, 1587, 1534, 1465, 1393, 1360, 1245, 1209, 1151,
1098, 1046, 984, 929, 915, 840, 767, 739, 684 cmꢀ1. HRMS (ESI):
m/z calcd for C26H43N4O4 [M+H]+ 475.32788, found 475.32895.
4.2.4. 3,4-Bis((S)-1-((S)-4-benzyl-4,5-dihydrooxazol-2-yl)-2-me-
thylpropylamino)cyclobut-3-ene-1,2-dione L3
75% yield, mp 134–136 °C, [
a
]
19 = ꢀ61.1 (c 0.11, CH2Cl2). 1H
D
NMR (400 MHz, DMSO-d6): d 8.07–7.94 (m, 2H, NH), 7.29–7.16
(m, 10H, ArH), 4.74–4.66 (m, 2H, CH), 4.47–4.28 (m, 4H, CH2),
4.04–3.97 (m, 2H, CH), 2.94–2.72 (m, 2H, CH), 2.09–2.03 (m, 2H,
CH), 0.92–0.87 (m, 12H, CH3) ppm. 13C NMR (100 MHz, DMSO-
d6): d 182.4, 167.1, 164.6, 137.8, 129.3, 129.2, 129.1, 128.2, 128.1,
128.0, 126.1, 71.7, 71.6, 66.4, 66.3, 56.3, 40.7, 31.8, 18.4,
4. Experimental
4.1. General methods
Commercially available compounds were used without further
purification. Column chromatography was carried out using silica
gel (200–300 mesh). Melting points were measured with an XT-4
melting point apparatus without correction. The 1H NMR spectra
were recorded with a Varian Mercury-plus 400 MHz or Bruker
400 MHz spectrometer, while 13C NMR spectra were recorded at
100 MHz. Infrared spectra were obtained on a Perkin Elmer Spec-
trum One FT-IR spectrometer. The high resolution mass ESI-HRMS
spectra were obtained using electron spray ionization (ESI) with a
Bruker APEX IV FTMS spectrometer. Optical rotations were mea-
sured on a WZZ-3 polarimeter at the indicated concentration with
unit g per 100 mL. The enantiomeric excesses of the products were
determined by chiral HPLC analysis using Agilent 1200 LC instru-
ment with Daicel Chiralpak AD-H, IA, IB or AS-H column.
17.1 ppm. IR (KBr):
m 3243, 3060, 3027, 2964, 2932, 2875, 1799,
1671, 1591, 1527, 1496, 1453, 1390, 1371, 1344, 1311, 1243,
1205, 1150, 1095, 1073, 1029, 985, 948, 850, 752, 701 cmꢀ1. HRMS
(ESI): m/z calcd for C32H39N4O4 [M+H]+ 543.29658, found
543.29622.
4.2.5. 3,4-Bis((S)-1-((S)-4,5-dihydro-4-phenyloxazol-2-yl)-2-phe
nylethylamino)cyclobut-3-ene-1,2-dione L4
45% yield, mp 121–124 °C, [a]
19 = +19.6 (c 0.105, CH2Cl2). 1H
D
NMR (400 MHz, DMSO-d6): d 8.10–7.96 (m, 2H, NH), 7.49–6.93
(m, 20 H, ArH), 5.24–5.16 (m, 4H, CH2), 4.74 (dd, J1 = 9.2 Hz,
J2 = 18.4 Hz, 2H, CH2), 4.05 (t, J = 8.4 Hz, 2H, CH), 3.26–3.07 (m,
4H, CH) ppm. 13C NMR (100 MHz, CDCl3): d 183.3, 167.3, 141.3,
135.45, 129.6, 129.4, 128.71, 128.69, 128.56, 128.48, 127.8, 127.7,
127.1, 127.0, 126.6, 126.5, 75.8, 75.7, 69.0, 53.3, 52.8, 40.2 ppm.
4.2. Materials
IR (KBr):
m 3125, 3029, 2935, 1800, 1676, 1655 1575, 1550, 1492,
2-(Aminomethyl)oxazolines 1 were prepared by following a
1455, 1268, 1242, 1214, 1166, 1123 1080, 1029, 1001, 917, 851,
previously reported method.14
757, 739, 700 cmꢀ1
. HRMS (ESI): m/z calcd for C38H35N4O4
[M+H]+ 611.26528, found 611.26486.
4.2.1. Typical procedure for the preparation of squaramide-bis-
oxazoline ligand
4.2.6. 3,4-Bis((S)-1-((S)-4,5-dihydro-4-isopropyloxazol-2-yl)-2-
A mixture of (2S)-2-methyl-1-((4S)-4-phenyl-4,5-dihydro-oxa-
zol-2-yl)propylamine 1a (479.6 mg, 2.2 mmol) and dimethyl squa-
rate (142.0 mg, 1 mmol) in MeOH (5 mL) was stirred at room
temperature for 4 h. The solvent was evaporated and the crude res-
idue material was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate, 1:1) to afford a white solid L1
phenylethylamino)cyclobut-3-ene-1,2-dione L5
37% yield, mp 126–139 °C, [
a]
19 = ꢀ52.3 (c 0.135, CH2Cl2). 1H
D
NMR (400 MHz, DMSO-d6): d 7.87 (d, J = 6.8 Hz, 2H, NH), 7.66–
6.97 (m, 10H, ArH), 5.05 (br s, 2H, CH), 4.32 (t, J = 9.2 Hz, 2H, CH),
4.03 (t, J = 7.8 Hz, 2H, CH), 3.93–3.76 (m, 2H, CH), 3.11 (dd,
J1 = 13.6 Hz, J2 = 5.6 Hz, 2H, CH2), 3.01 (dd, J1 = 13.6 Hz, J2 = 7.6 Hz,

S.-J. Jia, D.-M. Du / Tetrahedron: Asymmetry 25 (2014) 980–988
985
2H, CH2), 1.63–1.58 (m, 2H, CH), 0.86 (d, J = 6.4 Hz, 6H, CH3), 0.79 (d,
J = 6.4 Hz, 6H, CH3) ppm. 13C NMR (100 MHz, DMSO-d6): d 182.5,
166.8, 164.0, 136.0, 129.3, 128.3, 126.6, 71.2, 70.2, 52.3, 48.6, 31.9,
4.3.4. (S)-4-(1H-Indol-3-yl)-2-oxo-4-(4-florophenyl)butyric acid
methyl ester 4d7
Compound 4d was obtained according to the general procedure
18.4, 18.0 ppm. IR (KBr):
m
3157, 3059, 3029, 2956, 1802, 1675,
as a white solid (59.0 mg, 92% yield). Mp 110–113 °C, [a]
20 = +41.7
D
1649, 1570, 1495, 1467, 1386, 1240, 1223, 1116, 1006, 978, 953,
(c 3.00, CH2Cl2). The ee was determined by HPLC analysis (Daicel
Chiralpak AD-H column, n-hexane–2-propanol 80:20, flow rate
1.0 mL/min, detection at 254 nm): tR (minor) = 12.0 min, tR
(major) = 16.4 min, 89% ee. 1H NMR (400 MHz, CDCl3): d 8.05 (s,
1H, NH), 7.39–7.26 (m, 4H, ArH), 7.17 (t, J = 7.6 Hz, 1H, ArH),
7.03–6.92 (m, 4H, ArH), 4.90 (t, J = 7.4 Hz, 1H, CH), 3.78 (s, 3H,
OCH3), 3.67 (dd, J1 = 17.0 Hz, J2 = 7.0 Hz, 1H, CH2), 3.58 (dd,
914, 855, 776, 751, 726, 698 cmꢀ1. HRMS (ESI): m/z calcd for
C
32H39N4O4 [M+H]+ 543.29658, found 543.29739.
4.3. General procedure for the enantioselective Friedel–Crafts
alkylation reaction
A mixture of ligand L1 (10.4 mg, 0.02 mmol), Zn(OTf)2 (7.2 mg,
J1 = 17.2 Hz, J2 = 8.0 Hz, 1H, CH2) ppm. IR (KBr): m 3375, 3141,
0.02 mmol) and b,
c
-unsaturated
a
-ketoester
3
(0.2 mmol) in
2960, 2927, 2893, 1742, 1732, 1603, 1505, 1459, 1428, 1391,
CHCl3–PhMe (1:1) mixed solvent (2 mL) was stirred at room tem-
perature for 0.5–1 h under an argon atmosphere. Next, indole 2
(0.3 mmol) was added with stirring. The reaction mixture was stir-
red for the indicated time and then directly purified by flash chro-
matography on silica gel (petroleum ether–ethyl acetate, 4:1) to
give product 4.
1337, 1286, 1241, 1218, 1069, 1015, 962, 834, 743, 705, 677 cmꢀ1
.
4.3.5. (S)-4-(1H-Indol-3-yl)-2-oxo-4-(4-methoxyphenyl)butyric
acid methyl ester 4e7
Compound 4e was obtained according to the general procedure
as a white solid (65.0 mg, 86% yield). Mp 98–103 °C, [
a]
20 = +24.1
D
(c 2.85, CH2Cl2). The ee was determined by HPLC analysis (Daicel
Chiralpak AS-H column, n-hexane–2-propanol 85:15, flow rate
1.0 mL/min, detection at 230 nm): tR (minor) = 23.5 min, tR
(major) = 29.0 min, 89% ee. 1H NMR (400 MHz, CDCl3): d 8.12 (s,
1H, NH), 7.41 (d, J = 7.6 Hz, 1H, ArH), 7.31 (d, J = 8.4 Hz, 1H, ArH),
7.25–7.19 (m, 2H, ArH), 7.14 (t, J = 7.4 Hz, 1H, ArH), 7.03–6.96
(m, 2H, ArH), 6.85–6.73 (m, 2H, ArH), 4.86 (t, J = 7.2 Hz, 1H, CH),
3.76 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.67 (dd, J1 = 17.2 Hz,
J2 = 7.2 Hz, 1H, CH2), 3.57 (dd, J1 = 16.8 Hz, J2 = 8.0 Hz, 1H, CH2)
4.3.1. (S)-4-(1H-Indol-3-yl)-2-oxo-4-phenylbutyric acid methyle
ster 4a9
Compound 4a was obtained according to the general procedure
as a white solid (54.0 mg, 89% yield). Mp 99–102 °C, [a]
20 = +26.3
D
(c 3.15, CH2Cl2). The ee was determined by HPLC analysis (Daicel
Chiralpak AD-H column, n-hexane–2-propanol 80:20, flow rate
1.0 mL/min, detection at 254 nm): tR (minor) = 12.4 min, tR
(major) = 14.5 min, 93% ee. 1H NMR (400 MHz, CDCl3): d 8.03 (s,
1H, NH), 7.41 (d, J = 8.0 Hz, 1H, ArH), 7.22–7.33 (m, 5H, ArH),
7.18–7.11 (m, 2H, ArH), 7.03–6.97 (m, 2H, ArH), 4.91 (t,
J = 7.6 Hz, 1H, CH), 3.74 (s, 3H, OCH3), 3.67 (dd, J = 17.0, 7.6 Hz,
1H, CH2), 3.59 (dd, J1 = 17.0 Hz, J2 = 7.8 Hz, 1H, CH2) ppm. IR
ppm. IR (KBr):
1398, 1338, 1289, 1247, 1174, 1072, 1038, 840, 770, 748, 706,
677 cmꢀ1
m 3366, 2949, 2832, 1747, 1737, 1611, 1510, 1460,
.
(KBr):
m
3401, 3021, 2956, 1729, 1717, 1602, 1491, 1459, 1434,
4.3.6. (S)-4-(1H-Indol-3-yl)-2-oxo-4-(4-methylphenyl)butyric acid
methyl ester 4f6
1417, 1335, 1298, 1204, 1100, 1065, 822, 777, 759, 750, 700 cmꢀ1
.
Compound 4f was obtained according to the general procedure
4.3.2. (S)-4-(1H-Indol-3-yl)-2-oxo-4-(4-chlorophenyl)butyric acid
methyl ester 4b7
as a white solid (63.0 mg, 98% yield). Mp 125–127 °C, [a]
20 = +28.0
D
(c 1.20, CH2Cl2). The ee was determined by HPLC analysis (Daicel
Chiralpak AD-H column, n-hexane–2-propanol 80:20, flow rate
1.0 mL/min, detection at 254 nm): tR (minor) = 13.7 min, tR
(major) = 17.2 min, 91% ee. 1H NMR (400 MHz, CDCl3): d 8.04 (s,
1H, NH), 7.42 (d, J = 7.6 Hz, 1H, ArH), 7.28 (d, J = 8.0 Hz, 1H, ArH),
7.23–7.18 (m, 2H, ArH), 7.15–7.11 (m, 1H, ArH), 7.06 (d,
J = 8.0 Hz, 2H, ArH), 7.03–6.99 (m, 1H, ArH), 6.98 (d, J = 2.0 Hz,
1H, ArH), 4.87 (t, J = 7.6 Hz, 1H, CH), 3.74 (s, 3H, OCH3), 3.67 (dd,
J1 = 17.0 Hz, J2 = 7.4 Hz, 1H, CH2), 3.57 (dd, J1 = 16.8 Hz, J2 = 8.0 Hz,
Compound 4b was obtained according to the general procedure
as a white solid (66.9 mg, 98% yield). Mp 148–150 °C, [a]
20 = +20.9
D
(c 3.35, CH2Cl2). The ee was determined by HPLC analysis (Daicel
Chiralpak AD-H column, n-hexane–2-propanol 80:20, flow rate
1.0 mL/min, detected at 254 nm): tR (minor) = 13.2 min, tR
(major) = 19.9 min, 88% ee. 1H NMR (400 MHz, CDCl3): d 8.05 (s,
1H, NH), 7.39–7.14 (m, 7H, ArH), 7.05–6.96 (m, 2H, ArH), 4.89 (t,
J = 7.4 Hz, 1H, CH), 3.78 (s, 3H, OCH3), 3.66 (dd, J1 = 17.2 Hz,
J2 = 7.2 Hz, 1H, CH2), 3.57 (dd, J1 = 17.2 Hz, J2 = 8.0 Hz, 1H, CH2)
1H, CH2), 2.27 (s, 3H, CH3) ppm. IR (KBr):
m 3361, 3043, 3018,
ppm. IR (KBr):
1458, 1437, 1418, 1399, 1338, 1285, 1255, 1235, 1219, 1091,
1071, 1015, 969, 943, 834, 820, 791, 761, 749, 727, 702, 668 cmꢀ1
m
3364, 3061, 2956, 2876, 1746, 1638, 1547, 1489,
2951, 2921, 2879, 1747, 1734, 1618, 1511, 1459, 1437, 1402,
1337, 1288, 1256, 1236, 1221, 1072, 973, 828, 770, 743, 724,
.
702, 676 cmꢀ1
.
4.3.3. (S)-4-(1H-Indol-3-yl)-2-oxo-4-(4-bromophenyl)butyric acid
methyl ester 4c7
4.3.7. (S)-4-(1H-Indol-3-yl)-2-oxo-4-(4-nitrophenyl)butyric acid
methyl ester 4g7
Compound 4c was obtained according to the general procedure
Compound 4g was obtained according to the general procedure
as a white solid (63.0 mg, 82% yield). Mp 153–154 °C, [
a
]
D
20 = +11.9
as a white solid (58.0 mg, 83% yield). Mp 153–155 °C, [a]
20 = +13.6
D
(c 3.15, CH2Cl2). The ee was determined by HPLC analysis (Daicel
Chiralpak AD-H column, n-hexane–2-propanol 80:20, flow rate
1.0 mL/min, detection at 254 nm): tR (minor) = 13.7 min, tR
(major) = 20.9 min, 81% ee. 1H NMR (400 MHz, CDCl3): d 8.05 (s,
1H, NH), 7.39–7.32 (m, 4H, ArH), 7.21–7.14 (m, 3H, ArH), 7.03 (t,
J = 7.4 Hz, 2H, ArH), 4.88 (t, J = 7.4 Hz, 1H, CH), 3.79 (s, 3H, OCH3),
3.67 (dd, J1 = 17.2 Hz, J2 = 7.2 Hz, 1H, CH2), 3.57 (dd, J1 = 17.2 Hz,
(c 1.70, CH2Cl2). The ee was determined by HPLC analysis (Daicel
Chiralpak AD-H column, n-hexane–2-propanol 80:20, flow rate
1.0 mL/min, detection at 254 nm): tR (minor) = 24.9 min, tR
(major) = 32.8 min, 79% ee. 1H NMR (400 MHz, CDCl3): d 8.18 (s,
1H, NH), 8.11 (d, J = 8.8 Hz, 2H, ArH), 7.50 (d, J = 8.8 Hz, 2H, ArH),
7.34 (t, J = 8.2 Hz, 2H, ArH), 7.20–7.15 (m, 1H, ArH), 7.09 (d,
J = 1.6 Hz, 1H, ArH), 7.05–7.01 (m, 1H, ArH), 5.02 (t, J = 7.4 Hz, 1H,
CH), 3.81 (s, 3H, OCH3), 3.74 (dd, J1 = 17.6, J2 = 6.8 Hz, 1H, CH2),
J2 = 8.0 Hz, 1H, CH2) ppm. IR(KBr):
m 3362, 3048, 2953, 2899,
2877, 1746, 1737, 1637, 1547, 1486, 1458, 1437, 1419, 1400,
3.64 (dd, J1 = 18.0 Hz, J2 = 8.0 Hz, 1H, CH2) ppm. IR (KBr):
3115, 3074, 2957, 2881, 1745, 1608, 1598, 1520, 1459, 1401,
1349, 1284, 1255, 1068, 947, 859, 785, 754, 716, 663 cmꢀ1
m 3371,
1337, 1283, 1255, 1235, 1220, 1071, 1012, 970, 943, 831, 788,
767, 750, 725, 675 cmꢀ1
.
.

986
S.-J. Jia, D.-M. Du / Tetrahedron: Asymmetry 25 (2014) 980–988
4.3.8. (S)-4-(1H-Indol-3-yl)-2-oxo-4-(2-nitrophenyl)butyric acid
methyl ester 4h
(major) = 14.1 min, 91% ee. 1H NMR (400 MHz, CDCl3): d 7.91 (s,
1H, NH), 7.34–7.31 (m, 2H, ArH), 7.27–7.24 (m, 2H, ArH), 7.21–
7.14 (m, 3H, ArH), 6.98–6.95 (m, 2H, ArH), 4.89 (t, J = 7.6 Hz, 1H,
CH), 3.76 (s, 3H, OCH3), 3.66 (dd, J1 = 17.0 Hz, J2 = 7.4 Hz, 1H,
CH2), 3.59 (dd, J = 17.0 Hz, J2 = 7.8 Hz, 1H, CH2), 2.37 (s, 3H, CH3)
Compound 4h was obtained according to the general procedure
as a white solid (52.0 mg, 74% yield). Mp 172–174 °C, [a]
20 = +64.8
D
(c 1.70, CH2Cl2). The ee was determined by HPLC analysis (Daicel
Chiralpak IA column, n-hexane–2-propanol 80:20, flow rate
1.0 mL/min, detection at 254 nm): tR (minor) = 13.4 min, tR
(major) = 21.4 min, 71% ee. 1H NMR (400 MHz, CDCl3): d 8.11 (s,
1H, NH), 7.83–7.80 (m, 1H, ArH), 7.44–7.38 (m, 2H, ArH), 7.35–
7.29 (m, 3H, ArH), 7.17–7.13 (dt, J1 = 7.6 Hz, J2 = 0.8 Hz, 1H, ArH),
7.12 (d, J = 1.6 Hz, 1H, ArH), 7.03–6.98 (m, 1H, ArH), 5.57 (t,
J = 7.4 Hz, 1H, CH), 3.829 (s, 3H, OCH3), 3.825 (dd, J1 = 17.4 Hz,
J2 = 8.0 Hz, 1H, CH2), 3.56 (dd, J1 = 17.4 Hz, J2 = 7.0 Hz, 1H, CH2)
ppm. 13C NMR (100 MHz, CDCl3): d 191.5, 161.1, 149.6, 137.6,
136.5, 132.8, 130.0, 127.5, 126.2, 124.4, 122.6, 122.0, 119.9,
ppm. IR (KBr):
m 3443, 3111, 3056, 3024, 2949, 2886, 2829, 1728,
1652, 1614, 1603, 1547, 1486, 1477, 1453, 1437, 1397, 1374,
1328, 1296, 1258, 1228, 1192, 1152, 1134, 1120, 1085, 1064,
1037, 1013, 945, 931, 915, 844, 823, 764, 744, 703, 668, 599,
567 cmꢀ1
.
4.3.12. (S)-4-(5-Chloro-1H-indol-3-yl)-2-oxo-4-phenylbutyric acid
methyl ester 4l6
Compound 4l was obtained according to the general procedure
as
a
yellow solid (58.0 mg, 87% yield). Mp 100–102 °C,
[a]
20 = +75.0 (c 3.05, CH2Cl2). The ee was determined by HPLC
D
119.2, 116.5, 111.2, 53.1, 45.3, 32.4 ppm. IR (KBr):
m
3459, 3445,
3062, 2953, 1732, 1605, 1525, 1458, 1437, 1417, 1399, 1359,
1295, 1254, 1068, 945, 857, 790, 741, 708, 667 cmꢀ1. HRMS
(ESI): m/z calcd for C19H17N2O5 [M+H]+ 353.11320, found
353.11338; calcd for C19H20N3O5 [M+NH4]+ 370.13975, found
370.13944.
analysis (Daicel Chiralpak IA column, n-hexane–2-propanol
85:15, flow rate 1.0 mL/min, detection at 254 nm): tR (min-
or) = 19.6 min, tR (major) = 23.4 min, 83% ee. 1H NMR (400 MHz,
CDCl3): d 8.11 (s, 1H, NH), 7.37 (d, J = 2.0 Hz, 1H, ArH), 7.30–7.24
(m, 4H, ArH), 7.21–7.16 (m, 2H, ArH), 7.08 (dd, J1 = 8.4 Hz,
J2 = 2.0 Hz, 1H, ArH), 7.04 (d, J = 2.0 Hz, 1H, ArH), 4.84 (t,
J = 7.6 Hz, 1H, CH), 3.78 (s, 3H, OCH3), 3.65 (dd, J1 = 17.2 Hz,
J2 = 7.6 Hz, 1H, CH2), 3.57 (dd, J1 = 17.2 Hz, J2 = 7.8 Hz, 1H, CH2)
4.3.9. (S)-4-(1H-Indol-3-yl)-2-oxo-4-(3,4-dimethoxyphenyl)but-
yric acid methyl ester 4i
Compound 4i was obtained according to the general procedure
ppm. IR (KBr):
1437, 1418, 1395, 1303, 1279, 1237, 1101, 1069, 964, 944, 898,
863, 812, 754, 705, 687, 667 cmꢀ1
m 3348, 3021, 2954, 2894, 1741, 1614, 1494, 1464,
as a white solid (67.0 mg, 92% yield). Mp 233–235 °C, [a]
20 = +80.7
D
(c 3.35, CH2Cl2). The ee was determined by HPLC analysis (Daicel
Chiralpak IB column, n-hexane–2-propanol 80:20, flow rate
1.0 mL/min, detection at 230 nm): tR (minor) = 19.6 min, tR
(major) = 23.8 min, 89% ee. 1H NMR (400 MHz, CDCl3): d 8.10 (s,
1H, NH), 7.44 (d, J = 8.0 Hz, 1H, ArH), 7.31 (d, J = 8.4 Hz, 1H, ArH),
7.17–7.12 (m, 1H, ArH), 7.05–7.01 (m, 1H, ArH), 6.99 (d,
J = 2.0 Hz, 1H, ArH), 6.86–6.84 (m, 2H, ArH), 6.75 (d, J = 8.8 Hz,
1H, ArH), 4.87 (t, J = 7.6 Hz, 1H, CH), 3.81 (s, 3H, OCH3), 3.80 (s,
3H, OCH3), 3.76 (s, 3H, OCH3), 3.65 (dd, J1 = 16.8 Hz, J2 = 6.8 Hz,
1H, CH2), 3.59 (dd, J1 = 16.8 Hz, J2 = 7.8 Hz, 1H, CH2) ppm. 13C
NMR (100 MHz, CDCl3): d 192.7, 161.3, 148.8, 147.6, 136.6, 135.7,
126.3, 122.2, 121.4, 119.6, 119.45, 119.35, 118.5, 111.3, 111.13,
.
4.3.13. (S)-4-(5-Methoxy-1H-indol-3-yl)-2-oxo-4-phenylbutyric
acid methyl ester 4m6
Compound 4m was obtained according to the general proce-
dure as a yellow oil (64.0 mg, 87% yield). [a]
20 = +96.1 (c 4.35,
D
CH2Cl2). The ee was determined by HPLC analysis (Daicel Chiralcel
AD-H column, n-hexane–2-propanol 80:20, flow rate 1.0 mL/min,
detection at 254 nm): tR (minor) = 15.6 min, tR (major) = 23.2 min,
94% ee. 1H NMR (400 MHz, CDCl3): d 7.97 (s, 1H, NH), 7.34–7.29
(m, 2H, ArH), 7.28–7.22 (m, 2H, ArH), 7.18–7.14 (m, 2H, ArH),
6.97 (d, J = 2.4 Hz, 1H, ArH), 6.82 (d, J = 2.4 Hz, 1H, ArH), 6.80 (dd,
J1 = 2.4, J2 = 8.8 Hz, 1H, ArH), 4.85 (t, J = 7.4 Hz, 1H, CH), 3.75 (s,
3H, OCH3), 3.71 (s, 3H, OCH3), 3.67 (dd, J1 = 17.2, J2 = 7.2 Hz, 1H,
111.09, 55.8, 52.9, 45.7, 37.5 ppm. IR (KBr):
m 3372, 2934, 2837,
1730, 1593, 1515, 1460, 1420, 1261, 1140, 1075, 1024, 857, 809,
745 mꢀ1
.
HRMS (ESI): m/z calcd for C21H22NO5 [M+H]+
CH2), 3.58 (dd, J1 = 17.2, J2 = 7.8 Hz, 1H, CH2) ppm. IR (KBr): m
3365, 3081, 3038, 2996, 2837, 1745, 1711, 1627, 1580, 1483,
368.14925, found 368.14927; calcd for C21H25N2O5 [M+NH4]+
385.17580, found 385.17559.
1455, 1443, 1396, 1303, 1287, 1240, 1207, 1174, 1099, 1069,
1039, 968, 947, 922, 847, 806, 755, 720, 709, 641,586 cmꢀ1
.
4.3.10. (S)-4-(1-Methyl-1H-indol-3-yl)-2-oxo-4-phenylbutyric acid
methyl ester 4j5,6
4.3.14. (S)-4-(1H-Indol-3-yl)-2-oxo-4-phenylbutyric acid ethyl
ester 4n7
Compound 4j was obtained according to the general procedure as
a yellow solid (64.0 mg, 87% yield). Mp 106–108 °C, [
a]
20 = +18.7 (c
Compound 4n was obtained according to the general procedure
D
3.20, CH2Cl2). The ee was determined by HPLC analysis (Daicel Chir-
alpak AS-H column, n-hexane–2-propanol 80:20, flow rate 1.0 mL/
min, detection at 230 nm): tR (minor) = 8.7 min, tR (major) = 10.0 -
min, 32% ee. 1H NMR (400 MHz, CDCl3): d 7.42 (d, J = 8.0 Hz, 1H,
ArH), 7.33 (d, J = 7.2 Hz, 2H, ArH), 7.27–7.23 (m, 3H, ArH), 7.19–
7.14 (m, 2H, ArH), 7.03–6.99 (m, 1H, ArH), 6.86 (s, 1H, ArH), 4.91
(t, J = 7.6 Hz, 1H, CH), 3.75 (s, 3H, OCH3), 3.71 (s, 3H, NCH3), 3.67
(dd, J1 = 17.2, J2 = 7.2 Hz, 1H, CH2), 3.59 (dd, J1 = 17.2, J2 = 7.8 Hz,
as a white solid (53.3 mg, 83% yield). Mp 87–89 °C, [a]
20 = +35.4 (c
D
2.79, CH2Cl2). The ee was determined by HPLC analysis (Daicel
Chiralpak AD-H column, n-hexane–2-propanol 80:20, flow rate
1.0 mL/min, detection at 254 nm), tR (minor) = 12.5 min, tR
(major) = 14.7 min, 89% ee. 1H NMR (400 MHz, CDCl3): d 8.01 (s,
1H, NH), 7.42 (d, J = 8.0 Hz, 1H, ArH), 7.32 (t, J = 7.2 Hz, 3H, ArH),
7.27–7.24 (m, 2H, ArH), 7.20–7.12 (m, 2H, ArH), 7.02 (d,
J = 7.4 Hz, 2H, ArH), 4.92 (t, J = 7.4 Hz, 1H, CH), 4.21 (q, J = 7.2 Hz,
2H, CH2), 3.68 (dd, J1 = 16.8, J2 = 7.2 Hz, 1H, CH2), 3.59 (dd,
J1 = 17.0, J2 = 7.8 Hz, 1H, CH2), 1.27 (t, J = 7.0 Hz, 3H, CH3) ppm. IR
1H, CH2) ppm. IR (KBr):
m 1729, 1477, 1374, 1329, 1296, 1258,
1085, 1063, 744, 703, 668 cmꢀ1
.
(KBr):
1423, 1388, 1339, 1297, 1260, 1106, 1088, 1057, 1007, 944, 842,
827, 753, 744, 736, 704, 648 cmꢀ1
m 3410, 3115, 3053, 2987, 2932, 1720, 1601, 1492, 1458,
4.3.11. (S)-4-(5-Methyl-1H-indol-3-yl)-2-oxo-4-phenylbutyric acid
methyl ester 4k7
.
Compound 4k was obtained according to the general procedure
as a white solid (60.0 mg, 86% yield). Mp 125–126 °C, [
a
]
20 = +11.1
4.3.15. (S)-4-(1H-Indol-3-yl)-2-oxo-4-phenylbutyric acid benzyl
ester 4o
D
(c 3.00, CH2Cl2). The ee was determined by HPLC analysis (Daicel
Chiralpak AD-H column, n-hexane–2-propanol 80:20, flow rate
1.0 mL/min, detection at 254 nm): tR (minor) = 11.0 min, tR
Compound 4o was obtained according to the general procedure
as
a
white solid (64.1 mg, 84% yield). Mp 123–125 °C,

S.-J. Jia, D.-M. Du / Tetrahedron: Asymmetry 25 (2014) 980–988
987
[
a
]
20 = +35.1 (c 3.45, CH2Cl2). The ee was determined by HPLC anal-
J = 8.0 Hz, 1H, ArH), 6.35 (d, J = 2.4 Hz, 1H, ArH), 6.31 (dd, J = 8.4,
2.4 Hz, 1H, ArH), 4.91 (t, J = 7.6 Hz, 1H, CH), 4.73 (s, 1H, OH), 3.81
(s, 3H, OCH3), 3.73 (s, 3H, OCH3), 3.61 (dd, J = 16.8, 7.6 Hz, 1H),
3.45 (dd, J = 16.8, 7.6 Hz, 1H) ppm.
D
ysis (Daicel Chiralpak AD-H column, n-hexane–2-propanol 85:15,
flow rate 1.0 mL/min, detection at 254 nm): tR (minor) = 24.0 min,
tR (major) = 25.4 min, 85% ee. 1H NMR (400 MHz, DMSO-d6): d
10.95 (s, 1H, NH), 7.39–7.31 (m, 10H, ArH), 7.24 (t, J = 7.2 Hz, 2H,
ArH), 7.09 (t, J = 7.0 Hz, 1H, ArH), 7.03 (t, J = 7.4 Hz, 1H, ArH), 6.91
(t, J = 7.4 Hz, 1H, ArH), 5.24 (s, 2H, CH2), 4.76 (t, J = 7.2 Hz, 1H, CH),
3.78 (dd, J1 = 17.4, J2 = 7.4 Hz, 1H, CH2), 3.63 (dd, J1 = 17.6,
J2 = 7.2 Hz, 1H, CH2) ppm. 13C NMR (100 MHz, DMSO-d6): d 192.3,
160.2, 144.3, 136.3, 134.9, 128.4, 128.34, 128.31, 128.1, 127.5,
126.1, 126.0, 122.0, 121.0, 118.5, 118.3, 117.0, 111.3, 67.1, 45.1,
Acknowledgment
We are grateful for the financial support from the National Nat-
ural Science Foundation of China (Grant Nos. 21072020 and
21272024).
37.0 ppm; IR (KBr):
m 3448, 3022, 1717, 1603, 1492, 1458, 1412,
References
1338, 1275, 1239, 1095, 1075, 1051, 1009, 907, 808, 768, 752,
698 cmꢀ1
.
HRMS (ESI): m/z calcd for C25H22NO3 [M+H]+
1. For recent reviews on asymmetric Friedel–Crafts alkylation reactions, see: (a)
Poulsen, T. B.; Jørgensen, K. A. Chem. Rev. 2008, 108, 2903; (b) Jørgensen, K. A.
Synthesis 2003, 7, 1117; (c) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew.
Chem., Int. Ed. 2004, 43, 550; (d) Bandini, M.; Melloni, A.; Tommasi, S.; Umani-
Ronchi, A. Synlett 2005, 1199; (e) Bandini, M.; Cozzi, P. G.; Melchiorre, P.;
Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004, 43, 84; (f) Almasi, D.; Alonso, D.;
Nájera, A. C. Tetrahedron: Asymmetry 2007, 18, 299; (g) Bandini, M.; Eichholzer,
A. Angew. Chem., Int. Ed. 2009, 48, 9608; (h) You, S.-L.; Cai, Q.; Zeng, M. Chem.
Soc. Rev. 2009, 38, 2190.
384.15942, found 384.15940; calcd for C25H25N2O3 [M+NH4]+
401.18597, found 401.18626.
4.3.16. (S)-4-(1H-Indol-3-yl)-2-oxo-4-phenylbutyric acid isopro
pyl ester 4p
Compound 4p was obtained according to the general procedure
as
a
white solid (54.0 mg, 81% yield). Mp 120–122 °C,
[a]
20 = +136.0 (c 3.40, CH2Cl2). The ee was determined by HPLC
D
2. For selected examples of asymmetric Friedel–Crafts alkylations, see: (a)
Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem., Int. Ed. 2005,
44, 6576; (b) Jia, Y.-X.; Zhu, S.-F.; Yang, Y.; Zhou, Q.-L. J. Org. Chem. 2006, 71, 75;
(c) Lu, S.-F.; Du, D.-M.; Xu, J. Org. Lett. 2006, 8, 2115; (d) Liu, H.; Xu, J.; Du, D.-M.
Org. Lett. 2007, 9, 4725; (e) Liu, H.; Lu, S.-F.; Xu, J.; Du, D.-M. Chem. Asian J. 2008,
3, 1111; (f) Madhu, G.; Daniel, S. J. Am. Chem. Soc. 2008, 130, 16464; (g)
Akiyama, T.; Fuchibe, K.; Itoh, J. Angew. Chem., Int. Ed. 2008, 47, 4016; (h) Trost,
B. M.; Mueller, C. J. Am. Chem. Soc. 2008, 130, 2438; (i) Sheng, Y.-F.; Gu, Q.;
Zhang, A.-J.; You, S.-L. J. Org. Chem. 2009, 74, 6899; (j) McKeon, S. C.; Müeller-
Bunz, H.; Guiry, P. J. Eur. J. Org. Chem. 2009, 4833; (k) Yokoyama, N.; Arai, T.
Chem. Commun. 2009, 3285; (l) Liu, H.; Du, D.-M. Adv. Synth. Catal. 2010, 352,
1113; (m) Liu, H.; Du, D.-M. Eur. J. Org. Chem. 2010, 2121; (n) Sohtome, Y.; Shin,
B.; Horitsugi, N.; Takagi, R.; Noguchi, K.; Nagasawa, K. Angew. Chem., Int. Ed.
2010, 49, 7299; (o) Marques-Lopez, E.; Alcaine, A.; Tejeo, T.; Herrera, R. P. Eur. J.
Org. Chem. 2011, 3700.
3. (a) Nicolaou, K. C.; Snyder, S. A. Classics in Total Synthesis II; Wiley-VCH:
Weinheim, 2003; (b) Borschberg, H. J. Curr. Org. Chem. 2005, 9, 1465; (c)
Kleeman, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical Substances, 4th
ed.; Thieme: New York, 2001; (d) Rawson, D. J.; Dack, K. N.; Dickinson, R. P.;
James, K. Bioorg. Med. Chem. Lett. 2002, 12, 125; (e) Kinsman, A. C.; Kerr, M. A. J.
Am. Chem. Soc. 2003, 125, 14120; (f) Chang-Fang, J.; Rangisetty, J. B.; Dukat, M.;
Setola, V.; Raffay, T.; Roth, B.; Glennon, R. A. Bioorg. Med. Chem. Lett. 2004, 14,
1961.
analysis (Daicel Chiralpak AD-H column, n-hexane–2-propanol
80:20, flow rate 1.0 mL/min, detection at 254 nm): tR (min-
or) = 8.6 min, tR (major) = 10.3 min, 86% ee. 1H NMR (400 MHz,
CDCl3): d 8.04 (s, 1H, NH), 7.42 (d, J = 8.0 Hz, 1H, ArH), 7.33–7.23
(m, 5H, ArH), 7.19–7.12 (m, 2H, ArH), 7.04–7.00 (m, 2H, ArH),
5.07–5.00 (m, 1H, CH), 4.91 (t, J = 7.4 Hz, 1H, CH), 3.66 (dd,
J1 = 16.8, J2 = 7.6 Hz, 1H, CH2), 3.57 (dd, J1 = 16.8, J2 = 8.0 Hz, 1H,
CH2), 1.26 (d, J = 6.0 Hz, 3H, CH3), 1.22 (d, J = 6.4 Hz, 3H, CH3)
ppm. 13C NMR (100 MHz, CDCl3): d 193.5, 160.5, 143.2, 136.5,
128.5, 127.7, 126.5, 126.3, 122.1, 121.6, 119.5, 119.4, 119.3,
118.2, 111.1, 70.7, 45.6, 37.8, 21.5, 21.4 ppm. IR (KBr):
m 3410,
3115, 3053, 2987, 2932, 1720, 1601, 1492, 1458, 1423, 1388,
1339, 1297, 1260, 1106, 1088, 1057, 1007, 944, 842, 753, 744,
736, 704, 648 cmꢀ1. HRMS (ESI): m/z calcd for C21H22NO3 [M+H]+
336.15942, found 336.15951.
4. Rueping, M.; Nachtsheim, B. J.; Moreth, S. A.; Bolte, M. Angew. Chem., Int. Ed.
2008, 47, 593.
5. Jensen, K. B.; Thorhauge, J.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2001, 40, 160.
6. Desimoni, G.; Faita, G.; Toscanini, M.; Boiocchi, M. Chem. Eur. J. 2008, 14, 3630.
7. Liu, Y.-L.; Shang, D.-J.; Zhou, X.; Zhu, Y.; Lin, L.-L.; Liu, X.-H.; Feng, X.-M. Org.
Lett. 2010, 12, 180.
4.3.17. (S)-4-(1H-Indol-3-yl)-2-oxo-4-phenylbutyric acid allyl
ester 4q
Compound 4q was obtained according to the general procedure
as a yellow oil (57.3 mg, 86% yield). [a]
20 = +34.4 (c 3.45, CH2Cl2).
D
The ee was determined by HPLC analysis (Daicel Chiralpak AD-H
column, n-hexane–2-propanol 85:15, flow rate 1.0 mL/min, detec-
tion at 254 nm): tR (minor) = 12.9 min, tR (major) = 14.4 min, 89%
ee. 1H NMR (400 MHz, CDCl3): d 8.01 (s, 1H, NH), 7.42 (d,
J = 8.0 Hz, 1H, ArH), 7.34–7.24 (m, 5H, ArH), 7.19–7.13 (m, 2H,
ArH), 7.02 (t, J = 7.4 Hz, 2H, ArH), 5.91–5.81 (m, 1H, CH), 5.32 (d,
J = 17.2 Hz, 1H, @CH2), 5.26 (d, J = 6.4 Hz, 1H, @CH2), 4.92 (t,
J = 7.4 Hz, 1H, CH), 4.63 (d, J = 5.6 Hz, 2H, CH2), 3.68 (dd, J1 = 16.8,
J2 = 7.2 Hz, 1H, CH2), 3.57 (dd, J1 = 16.8, J2 = 7.8 Hz, 1H, CH2) ppm.
13C NMR (100 MHz, CDCl3): d 192.7, 160.5, 143.1, 136.5, 130.6,
128.5, 127.7, 126.6, 126.4, 122.2, 121.5, 119.9, 119.5, 119.2,
8. Lv, J.; Li, X.; Zhong, L.; Luo, S. Z.; Cheng, J.-P. Org. Lett. 2010, 12, 1096.
9. Liu, L.; Ma, H.; Xiao, Y.; Du, F.; Qin, Z.; Li, N.; Fu, B. Chem. Commun. 2012, 9281.
10. For examples, see: (a) Popa, D.; Puigjaner, C.; Gómez, M.; Benet-Buchholz, J.;
Vidal-Ferran, A.; Pericàs, M. A. Adv. Synth. Catal. 2007, 349, 2265; (b) Dieguez,
M.; Pamies, O. Chem. Eur. J. 2008, 14, 3653; (c) Velder, J.; Robert, T.; Weidner, I.;
Neudoerfl, J.-M.; Lex, J.; Schmalz, H.-G. Adv. Synth. Catal. 2008, 350, 1309; (d)
Langlotz, B. K.; Wadepohl, H.; Gade, L. H. Angew. Chem., Int. Ed. 2008, 47, 4670;
(e) Fernandez-Perez, H.; Pericàs, M. A.; Vidal-Ferran, A. Adv. Synth. Catal. 2008,
350, 1984; (f) Zhao, B.-G.; Liang, J.-J.; Yang, J.; Jia, C.-D.; Yang, X.-J.; Zhang, H.-R.;
Tang, N.; Janiak, C. Chem.-Eur. J. 2008, 14, 7847; (g) Nagel, U.; Diez, C. Eur. J.
Inorg. Chem. 2009, 1248; (h) Popa, D.; Marcos, R.; Sayalero, S.; Vidal-Ferran, A.;
Pericàs, M. A. Adv. Synth. Catal. 2009, 351, 1539.
11. For selected recent reviews, see: (a) Johnson, J. S.; Evans, D. A. Acc. Chem. Res.
2000, 33, 325; (b) Rechavi, D.; Lemaire, M. Chem. Rev. 2002, 102, 3467; (c)
Desimoni, G.; Faita, G.; Quadrelli, P. Chem. Rev. 2003, 103, 3119; (d) Zhou, J.;
Tang, Y. Chem. Soc. Rev. 2005, 34, 664; (e) Desimoni, G.; Faita, G.; Jørgensen, K.
A. Chem. Rev. 2006, 106, 3561; (f) Nishiyama, H. Chem. Soc. Rev. 2007, 36, 1133;
(g) Hargaden, G. C.; Guiry, P. J. Chem. Rev. 2009, 109, 2505.
12. (a) Gómez, M.; Jansat, S.; Muller, G.; Maestro, M. A.; Mahía, J. Organometallics
2002, 21, 1077; (b) Du, X.; Liu, H.; Du, D.-M. Tetrahedron: Asymmetry 2010, 21,
241; (c) Jin, Y.; Du, D. M. Tetrahedron 2012, 68, 3633; (d) Yamagishi, T.; Ohnuki,
M.; Kiyooka, T.; Masui, D.; Sato, K.; Yamaguchi, M. Tetrahedron: Asymmetry
2003, 14, 3275; (e) Braunstein, P.; Naud, F.; Pfaltz, A.; Rettig, S. J.
Organometallics 2000, 19, 2676; (f) Castillo, M. R.; Castillón, S.; Claver, C.;
Fraile, J. M.; Gual, A.; Martín, M.; Mayoral, J. A.; Sola, E. Tetrahedron 2011, 67,
5402.
13. For selected examples of asymmetric reactions using squaramides, see: (a)
Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416; (b)
Zhu, Y.; Malerich, J. P.; Rawal, V. H. Angew. Chem., Int. Ed. 2010, 49, 153; (c) Xu,
D. Q.; Wang, Y.-F.; Zhang, W.; Luo, S.-P.; Zhong, A.-G.; Xia, A.-B.; Xu, Z.-Y.
118.2, 111.1, 66.8, 45.7, 37.7 ppm. IR (KBr):
m 3405, 3356, 3057,
3024, 1733, 1648, 1618, 1492, 1458, 1420, 1337, 1279, 1254,
1232, 1098, 1057, 997, 938, 760, 743, 700 cmꢀ1. HRMS (ESI): m/z
calcd for C21H20NO3 [M+H]+ 334.14377, found 334.14379.
4.3.18. (S)-Methyl 4-(2-hydroxy-4-methoxyphenyl)-2-oxo-4-phe
nylbutanoate 4r8
Compound 4r was obtained according to the general procedure
as a yellow oil (22.0 mg, 35% yield). [
a
]
21 = ꢀ2.5 (c 0.40, CH2Cl2).
D
The ee was determined by HPLC analysis (Daicel Chiralpak AD-H
column, n-hexane–2-propanol 90:10, flow rate 1.0 mL/min, detec-
tion at 254 nm): tR (major) = 26.3 min, tR (minor) = 29.6 min, 95%
ee. 1H NMR (400 MHz, CDCl3): d 7.28–7.22 (m, 5H, ArH), 6.89 (d,

988
S.-J. Jia, D.-M. Du / Tetrahedron: Asymmetry 25 (2014) 980–988
Chem.-Eur. J. 2010, 16, 4177; (d) Qian, Y.; Ma, G.; Lv, A.; Zhu, H.-L.; Zhao, J.;
Commun. 2011, 12706; (j) Min, C.; Han, X.; Liao, Z. Q.; Wu, X. F.; Zhou, H.-B.;
Dong, C. Adv. Synth. Catal. 2011, 353, 2715; (k) Bae, H. Y.; Some, S.; Lee, J. H.;
Kim, J.-Y.; Song, M. J.; Lee, S.; Zhang, Y. J.; Song, C. E. Adv. Synth. Catal. 2011, 353,
3196.
Rawal, V. H. Chem. Commun. 2010, 3004; (e) Konishi, H.; Lam, T. Y.; Malerich, J.
P.; Rawal, V. H. Org. Lett. 2010, 12, 2028; (f) Yang, W.; Du, D.-M. Org. Lett. 2010,
12, 5450; (g) Pansare, S. V.; Paul, E. K. Chem. Commun. 2011, 1027; (h) Yang, W.;
Du, D.-M. Adv. Synth. Catal. 2011, 353, 1241; (i) Yang, W.; Du, D.-M. Chem.
14. Västilä, P.; Pastor, I. M.; Adolfsson, H. J. Org. Chem. 2005, 70, 2921.