Malonate-type bis(oxazoline) ligands with sp2 hybridized bridge carbon: Synthesis and application in Friedel-Crafts alkylation and allylic alkylation

Article abstract of DOI:10.1016/j.tet.2011.09.106

A series of simple and new C₂-symmetric diphenylmethylidene malonate-type bis(oxazoline) ligands were synthesized and applied to the Friedel-Crafts reaction and allylic alkylation. The Cu(II) complex of ligand 4b bearing the benzyl group afford

Full text of DOI:10.1016/j.tet.2011.09.106

Tetrahedron 67 (2011) 9602e9608
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Malonate-type bis(oxazoline) ligands with sp2 hybridized bridge carbon:
synthesis and application in FriedeleCrafts alkylation and allylic alkylation
*
Hongliang Chen, Fengpei Du, Lei Liu, Jing Li, Qiuying Zhao, Bin Fu
Department of Applied Chemistry, China Agricultural University, Beijing 100193, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 July 2011
Received in revised form 16 September 2011
Accepted 23 September 2011
Available online 29 September 2011
A series of simple and new C2-symmetric diphenylmethylidene malonate-type bis(oxazoline) ligands
were synthesized and applied to the FriedeleCrafts reaction and allylic alkylation. The Cu(II) complex of
ligand 4b bearing the benzyl group afforded good to excellent enantioselectivity for the FeC adducts (up
to >99% ee) between indole and alkylidene malonate, and the palladium complex of ligand 4c bearing
the phenyl group afforded excellent enantioselectivity (up to 94% ee) for the allylic alkylation product.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Bis(oxazoline)
Asymmetric catalysis
FriedeleCrafts
Allylic alkylation
1. Introduction
substituents on the oxazoline rings and the heterocycles attached
to the other end of the double bond play important roles in
In the past two decades, chiral bis(oxazoline) (BOX) ligands have
received a great deal of attention and become one of the most
successful and versatile classes of ligands in catalytic asymmetric
synthesis. As a result, bis(oxazoline) ligands with diverse skeleton
and backbone have been reported.1 Among them, malonate-type
BOX, which is derived from malonate and its analogues, is one of
the most typical class.2 In this class of ligands, the bridge
angle, correlating with the bite angle of BOXemetal complex, is
considered as an important structural factor influencing the
enantioselectivity.3
asymmetric catalysis owing to their different steric and electronic
effects. In our effort to develop highly enantioselective reactions
using simple and cheap chiral catalytic systems, the novel C2-
symmetric diphenylmethylidene malonate derived bis(oxazoline)
ligands 4 were demonstrated to be efficient in the Cu(II)-catalyzed
asymmetric FriedeleCrafts alkylation and the Pd-catalyzed asym-
metric allylic alkylation. Herein, we would like to report our pre-
liminary results.
A straightforward strategy to tune the bridge angle has been
intentionally or accidentally introduced in alkylidene- and
arylidene-linked BOX ligands such as 1, 2, and 3 (Fig. 1). The oxa-
zoline rings attached to an sp2 hybridized bridge carbon can pro-
vide a larger bridge angle than those with sp3 hybridized bridge
carbon. In 2005, Burke et al. first reported a family of alkylidene-
linked BOX ligands 1 and arylidene-linked BOX 2,4 which gave
moderate to high ee (up to 89%) in the Cu(I)-catalyzed asymmetric
cyclopropanation reaction. Recently, our group showed that ligand
3 with furan and thiophene unit in the backbone provides excellent
asymmetric catalytic property in the Cu(II) catalyzed FriedeleCrafts
alkylation of indole derivatives with arylidene malonates (99% yield
and up to >99% ee).5 In this type of BOX ligand both the
Ph
N
Ph
N
H
N
H
N
X
O
O
O
O
O
O
O
O
N
N
N
N
R
R
R
R
R
R
R
R
4
1
3
2
a. R = i-Pr; b. R = Bn; c. R = Ph
Fig. 1. The alkylidene and arylidene malonate-type bis(oxazoline) ligands.
2. Results and discussion
2.1. Synthesis of new bis(oxazoline) ligands
The novel chiral bis(oxazoline) ligands 4 were conveniently
synthesized in four steps, as illustrated in Scheme 1, based on our
previous reported procedure.5 After the saponification of the di-
ester 5, the dicarboxylic acid was treated with oxalyl chloride in
* Corresponding author. Tel.: þ86 10 62732873; fax: þ86 10 62732948; e-mail
address: fubinchem@cau.edu.cn (B. Fu).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.106

H. Chen et al. / Tetrahedron 67 (2011) 9602e9608
9603
Table 1
CH2Cl2 to yield the diacyl chloride. The catalytic amount of DMF
Effect of ligands in the Cu(OTf)2 catalyzed FriedeleCrafts alkylationa
was critical for the smooth conversion. The desired ligands 4 can be
obtained through amide bond condensation and methanesulfonyl
chloride mediated oxazoline ring formation in good yields
Entry
Ligands
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
4a
4b
4c
1b
4b
4b
iso-Butanol
iso-Butanol
iso-Butanol
iso-Butanol
iso-Propanol
Ethanol
99
99
99
d
83
>99
98
(74e81%). The structure of the ligands 4 and bis(
b-hydroxylamide)
intermediates 6 were finely characterized and confirmed.
d
99
99
>99
>99
Ph
Ph
Ph
N
Ph
N
a
All the reactions were conducted under nitrogen for 24 h using 10 mol % of
catalyst at room temperature.
O
O
Ph
Ph
O
O
a. R =i-Pr
b. R = Bn
c. R = Ph
R
NH
b
HN
i, ii, iii
R
Isolated yield.
Determined by chiral HPLC.
EtOOC
COOEt
c
HO
R
R
OH
5
6
4
iv) MsCl. Et3N, CH2Cl2
i) NaOH, C2H5OH ii) (COCl)2, DMF, CH2Cl2 iii) amino alcohol, Et3N
both electron-donating and electron-withdrawing substituents at
the para-position reacted smoothly with indole to yield the alkyl-
ation products in excellent yields with high enantioselectivities
(entries 1e3). However, for ortho-substituted benzylidene malo-
nates, the reaction time has to be prolonged to 72 h to overcome
their low reactivity (entries 4e6). The high enantioselectivity can
be retained in the case of fluoro-substituted benzylidene malonates
owing to the smaller size of F than Cl and methyl group (>99% ee,
entry 5). The reaction of the less hindered meta-substituted sub-
strates can be finished within 48 h, but significant decrease of the
enantioselectivities was observed (entries 7 and 8). The effect of
substituents on the indole ring was also investigated. The catalytic
efficiency varied significantly for differently substituted indoles.
Generally, introduction of electron-withdrawing group deactivates
indole and leads to lower enantioselectivity (entries 12e14). For
indoles with electron-donating group, high reactivity and excellent
enantioselectivity can be achieved in 99% yield and more than 98%
ee regardless of the position of the substituents (entries 9e11).
Interestingly, when 5-MeO indole reacted with ortho-Me benzyli-
dene malonate, the alkylation adduct was also obtained in excellent
yield and enantioselectivity (99% yield and 91% ee, entry 15).
Scheme 1. Synthesis of new bis(oxazoline) ligands. (i) NaOH, C2H5OH; (ii) (COCl)2,
DMF, CH2Cl2; (iii) amino alcohol, Et3N; (iv) MsCl$Et3N, CH2Cl2.
2.2. Cu(II)-catalyzed asymmetric FriedeleCrafts alkylation
The FriedeleCrafts reaction is one of the most powerful car-
bonecarbon bond formation methodology in synthetic organic
chemistry.6 The asymmetric FriedeleCrafts alkylation of indole
derivatives and alkylidene malonates has been investigated
by Jørgenson et al.,7 Tang et al.,8 Reiser et al.,9 and Feng et al.10
Based on their pioneering contributions, we recently reported
the application of simple heteroarylidene malonate derived
bis(oxazoline)(3)eCu(II) complexes in asymmetric FriedeleCrafts
alkylation of indole derivatives with alkylidene malonates. Excel-
lent yields and enantioselectivities can be obtained even at room
temperature. Considering the structural similarity between ligands
3 and 4, we first examined the catalytic property of 4 in this model
system (Scheme 2).
COOC2H5
Ph
COOC2H5
COOC2H5
COOC H
2 5
2
Ligand-Cu(II)
+
R
Ph
N
COOC2H5
COOC H
H
2
5
N
COOC H
1
2
5
4b-Cu(OTf)
2
+
R
2
R
H
1
R
Ligand = 4 or 1
N
COOC H
2
5
H
N
H
Scheme 2.
Scheme 3.
The results of the catalytic FriedeleCrafts reaction using indole
and diethyl benzylidene malonate as model substrates are sum-
marized in Table 1. Under the catalysis of 10 mol % ligandeCu(OTf)2
complexes, quantitative yields can be achieved in iso-butanol for
ligands 4aec (entries 1e3), while the highest enantioselectivity
(>99% ee) was afforded by 4b with benzyl substituent on the
oxazoline ring (entry 2). This is slightly different from our previous
finding, in which both of the ligand 3 with iso-propyl or benzyl
substituents gave the same highest catalytic enantioselectivity.5 For
comparison, the dimethylmethylidene bis(oxazoline) ligand 1b was
also synthesized and tested in this reaction.4a To our surprise, no
reaction occurred after being stirred for 6 days under the same
condition (entry 4). This result suggested that not only the sub-
stituents on the oxazoline rings but also the moiety attached to the
other end of the double bond have remarkable impact on the re-
activity. When iso-propanol and ethanol were used as solvents,
similar results (99% yield and >99% ee) can be achieved for the
optimized ligand 4b (entries 5 and 6).
Table 2
Complex 4beCu(OTf)2 catalyzed FeC reaction of indole derivatives with alkylidene
malonatesa
Entry
R1
R2
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
p-MeC6H4
p-FC6H4
p-BrC6H4
o-ClC6H4
o-FC6H4
o-MeC6H4
m-FC6H4
m-MeC6H4
C6H5
24
24
48
72
72
72
48
48
24
24
24
48
48
48
24
99
99
90
75
80
90
99
90
99
99
99
90
90
90
99
96
98
98
87
99
79
78
79
>99
>99.9
98
75
70
9
5-MeO
5-Me
7-Me
5-Cl
6-Cl
6-COOMe
5-MeO
10
11
12
13
14
15
C6H5
C6H5
C6H5
C6H5
With these encouraging results, we selected ethanol as the
solvent in subsequent experiments due to its low cost, non-toxicity,
and equal efficiency to iso-butanol. The scope of the 4beCu(OTf)2
catalyst in FriedeleCrafts alkylation was further investigated using
a variety of structurally different indole derivatives and arylidene
malonates (Scheme 3, Table 2). The benzylidene malonates bearing
C6H5
82
91
o-MeC6H4
a
All reactions were conducted in ethanol under nitrogen using 10 mol % catalyst
at room temperature.
b
Isolated yield.
Determined by chiral HPLC.
c

9604
H. Chen et al. / Tetrahedron 67 (2011) 9602e9608
2.3. Palladium-catalyzed asymmetric allylic alkylation
indicate that the substituents attached to the double bond evi-
dently affected the reactivity and enantioselectivity in asymmetric
catalysis. An accurate diagram of the precise coordination sphere
around Cu or Pd for this type of ligands is still being pursued.
As an important enantioselective CeC bond formation process,
the palladium-catalyzed asymmetric allylic alkylation reaction has
attracted a great deal of attention from synthetic chemists over the
past three decades.11 A plethora of efficient chiral ligands with P, N,
and S as coordinating atoms have been synthesized and applied to
this transformation.12 In general, N,N-chelating ligands for catalytic
allylic alkylation are less common than other types of ligands. Only
limited number of BOX ligands have been reported to give high
reactivity and enantioselectivity in this reaction.13
3. Conclusions
In conclusion, a series of novel chiral bis(oxazoline) ligands
4aec were conveniently synthesized from diphenyl methylene
malonate and chiral amino alcohols. Their application in the
asymmetric FriedeleCrafts alkylation of indole derivatives with
arylidene malonates was investigated. The Cu(OTf)2 complex of li-
gands 4b with the benzyl group afforded excellent enantiose-
lectivity (up to >99% ee). In the palladium-catalyzed allylic
alkylation, the palladium complex of ligand 4c bearing phenyl
group afforded the highest 94% ee, which is comparable to the re-
sults obtained by other reported BOX ligands.13 Our results indicate
that both the reactivity and the enantioselectivity of asymmetric
induction were not only dependent on the substituents on the
oxazoline ring, but also the moieties attached to the distal terminus
of the double bond in the ligand skeleton. The preliminary evalu-
ation for this type of BOX ligands shows promising application in
asymmetric catalysis, and provides a new clue for the development
of new chiral ligands. Further study to extend this catalytic system
to other asymmetric reactions is now in progress in our group.
The novel chiral bis(oxazoline) ligands 4aec were also applied
to the palladium-catalyzed asymmetric allylic alkylation of 1,3-
diphenyl-2-propen-1-yl acetate with dimethyl malonate, which is
commonly used as model substrate in literature for evaluation of
chiral catalysts.14 The reaction was catalyzed by 5 mol % complexes
generated in situ from 2.5 mol % of [Pd(h
3-C3H5)Cl]2, 6 mol % of the
chiral ligands, in the presence of N,O-bis(trimethylsilyl)acetamide
(BSA) and 20 mol % of KOAc in dichloromethane. As summarized in
Table 3, the reaction proceeded smoothly and the product was
obtained in high yields after 48 h (entries 1e3). Highly asymmetric
induction was observed for all tested ligands, and the best 90% ee
was provided by ligand 4c with phenyl substituent on the oxazoline
ring. The enantioselectivity can be further improved to 94% at 0 ꢀC,
though the reaction became slightly sluggish (entry 4). In contrast
to our ligands,1c and 2c with similar skeleton gave lower yields and
enantioselectivities (entries 5 and 6). Reactions in other solvents
than CH2Cl2 were also examined, inferior yields and enantiose-
lectivities were obtained (entries 7e10) (Scheme 4).
4. Experimental section
4.1. General
NMR spectra were recorded with a Bruker Avance DPX300
spectrometer with tetramethylsilane as the internal standard. In-
frared spectra were obtained on a Nicolet AVATAR 330 FT-IR
spectrometer. Mass spectra were obtained on Bruker APEX II FT-
ICRMS mass spectrometer. Optical rotations were measured on
a PerkineElmer 341 LC polarimeter. The enantiomeric excesses of
(R)- and (S)-enantiomer were determined by HPLC analysis over
a chiral column (Daicel Chiralcel OD-H and AD-H; eluted with
hexane/iso-propyl alcohol; UV detector, 254 nm). The absolute
configuration of the major enantiomer was assigned by comparison
with literature. Solvents were purified and dried by standard
procedures.
Table 3
Effect of ligands and solvent in the Pd-catalyzed allylic alkylationa
Entry
Ligands
Solvent
Temp (ꢀC)
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
4a
4b
4c
4c
1c
2c
4c
4c
4c
4c
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
THF
Toluene
CH3CN
25
25
25
0
25
25
25
25
25
25
48
48
48
72
72
48
48
48
48
48
90
90
90
85
20
60
90
60
70
65
86
78
90
94
75
45
85
77
71
34
10
a
All the reactions were conducted under nitrogen using 2.5 mol % of catalyst.
Isolated yield.
Determined by chiral HPLC.
b
c
4.2. General procedure I: synthesis and characterization of
(S,S)-N,N-bis(2-hydroxy-1-iso-propyl)-2-diphenylmethylidene
malonamide 6a
MeOOC
Ph
COOMe
Ph
To a solution of diethyl diphenylmethylidene malonate 5 (1.0 g,
3.09 mmol) in CH3
OH (10 mL) was added NaOH solution (10 mL,
COOMe
COOMe
OAc
Ph
η
Pd ( -C H )Cl - ligand
3
3
5
2
+
BSA, KOAc
Scheme 4.
2.0 M). The mixture was refluxed for 8 h, then the methanol was
removed in vacuo. The residue was cooled to 0 ꢀC and acidified with
aqueous HCl (6 M), extracted with ethyl acetate (10 mLꢁ3), dried
over Na2SO4, and evaporated to give the white solid, which directly
reacted with oxalyl chloride (0.98 g, 0.77 mmol) and DMF (0.1 mL)
in CH2Cl2 (20 mL) at 0 ꢀC for 3 h, after removing the excess oxalyl
chloride in vacuo the diacyl dichloride was afforded. Subsequently
the diacyl dichloride in CH2Cl2 (20 mL) was added dropwise to
Ph
The X-ray structure of the Cu(OTf)2eligand 4b or [Pd(h
3-C3H5)
Cl]2eligand 4c complex would be helpful to elucidate the observed
asymmetric induction. However, we have not yet obtained such
structure after extensive attempts. Two single crystals of the li-
gands 4b and 4c were cultivated from their solution in hexane/ethyl
acetate and analyzed by X-ray diffraction.15 As can be seen from the
crystallography diagram of ligand 4b or 4c shown in Fig. 2, the four
rings (two oxazoline rings and two phenyl rings) attaching to the
double bond are clearly not co-planar, but distorted around the
double bond due to steric repulsion. The sp2 hybridized bridging
carbon results in 114.13ꢀ and 115.46ꢀ bridge angles for 4b and 4c,
respectively, then the geometry of ligand 4emetal complex should
be different from that of the bis(oxazoline) ligand with sp3
hybridized bridge carbon.3,16 Besides, the experimental results
a
solution of L-valinol (0.64 g, 6.20 mmol) and Et3N (4 mL,
28.9 mmol) in CH2Cl2 (20 mL) at 0 ꢀC and stirred at room temper-
ature for 4 h. The reaction mixture was washed with water
(5 mLꢁ2), dried over Na2SO4, and concentrated to give the crude
solid. Purification by silica gel column chromatography (70% ethyl
acetate in petroleum ether) afforded the dihydroxy diamide 6a
(1.16 g, 86.0%) as a white solid. Mp 177e178 ꢀC. [
a
]
25 ꢂ15.7 (c 0.30,
D
CH2Cl2). IR: 3258, 3060, 2961, 1633, 1540, 1449, 1317, 1056, 725. 1H
NMR (300 MHz, DMSO-d6):
d
7.45 (d, J¼9.20 Hz, 2H, NH), 7.32e7.21

H. Chen et al. / Tetrahedron 67 (2011) 9602e9608
9605
Fig. 2. The X-ray structure of 4b and 4c.
(m, 10H, ArH), 4.49 (t, J¼5.40 Hz, 2H, OH), 3.50e3.45 (m, 2H,
CHNH), 3.29e3.18 (m, 4H, CH2O), 1.73e1.66 (m, 2H, CHMe2), 0.59 (t,
residue was purified by flash chromatography on silica gel (ethyl
acetate/petroleum ether, 1:1, v/v) to afford a white solid 4a (0.41 g,
25
J¼6.89 Hz, 12H, CH3). 13C NMR (75 MHz, DMSO-d6):
d
165.86,
73.2%). Mp 111.5e113.0 ꢀC. [
a
]
D
þ26.4 (c 0.25, CH2Cl2). IR: 2955,
140.51, 135.58, 129.07, 128.00, 127.82, 61.06, 55.62, 27.76, 19.56,
17.53. HRMS (ESI): m/z calcd for C26H35N2O4 (MþHþ): 439.25913;
found: 439.25837.
2875, 1652, 1609, 1448, 1370, 1016, 946, 785, 732. 1H NMR
(300 MHz, CDCl3): 7.31e7.21 (m, 10H, ArH), 4.08e4.00 (m, 2H,
d
CHN]), 3.92e3.84 (m, 4H, CH2O), 1.65e1.59 (m, 2H, CHMe2), 0.80
(d, J¼6.75 Hz, 6H), 0.76 (d, J¼6.75 Hz, 6H). 13C NMR (75 MHz,
4.2.1. (S,S)-N,N-Bis(2-hydroxy-1-benzyl)-2-diphenylmethylidene
CDCl3): d 162.16,155.04,140.92, 129.41,128.53, 127.75, 117.44, 72.48,
malonamide 6b. Using the same procedure as described in general
69.82, 32.30, 18.80, 18.16. HRMS (ESI): m/z calcd for C26H35N2O4
procedure I: diethyl diphenylmethylidene malonate
3.09 mmol), oxalyl chloride (0.98 g, 0.77 mmol), -phenylalaninol
(0.94 g, 6.20 mmol), and Et3N (4 mL, 28.9 mmol) to afford the
5 (1.0 g,
(MþHþ): 439.25913; found: 439.25837.
L
4.3.1. Bis[(S)-4-benzyloxazoline-2-yl]-2,20-diphenyethene 4b. Using
the same procedure as described in general procedure II: from
dihydroxy diamide 6b (0.50 g, 0.94 mmol), MsCl (0.25 g,
2.20 mmol), and Et3N (4 mL, 28 mmol) to afford 4b (0.38 g, 81.2%)
dihydroxy diamide 6b (1.26 g, 76.4%) as
a white solid. Mp
187e189 ꢀC. [
a
]
D
25 þ10.2 (c 0.10, CH2Cl2). IR: 3422, 1627, 1537, 1449,
1035, 775, 726, 701. 1H NMR (300 MHz, DMSO-d6):
d 7.68 (d,
J¼8.25 Hz, 2H, NH), 7.27e7.05 (m, 20H, ArH), 4.66 (t, J¼5.38 Hz, 2H,
as a white solid. Mp 120.0e121.0 ꢀC. [
a
]
D
25 þ19.0 (c 0.20, CH2Cl2). IR:
OH), 3.83e3.76 (m, 2H, CHN), 3.20e3.03 (m, 4H, CH2O), 2.61e2.42
3035, 1648, 1614, 1496, 1474, 1449, 1309, 1228, 1147, 1018, 976, 960,
(m, 4H, CH2Ph). 13C NMR (75 MHz, DMSO-d6):
d
165.40, 142.98,
932, 783, 728, 700. 1H NMR (CDCl3, 300 MHz):
d 7.34e7.19 (m, 16H,
140.25, 140.30, 138.86, 134.99, 129.17, 129.08, 128.20, 127.89, 125.95,
79.50, 79.06, 78.62, 61.34, 52.45, 35.91. HRMS (ESI): m/z calcd for
C34H35N2O4 (MþHþ): 535.25913; found: 535.25853.
ArH), 7.08e7.05 (m, 4H, ArH), 4.44e4.34 (m, 2H, CHN]), 4.06 (t,
J¼8.65 Hz, 2H, CH2O), 3.85 (dd, J¼6.96, 8.42 Hz, 2H, CH2O), 2.92 (dd,
J¼5.63,13.66 Hz, 2H, CH2Ph), 2.50 (dd, J¼8.62,13.65 Hz, 2H, CH2Ph).
13C NMR (75 MHz, CDCl3):
d 162.78, 155.79, 140.84, 137.93, 129.48,
4.2.2. (S,S)-N,N-bis(2-hydroxy-1-phenyl)-2-diphenylmethylidene
malonamide 6c. Using the same procedure as described in general
129.17, 128.78, 128.37, 127.79, 126.30, 116.94, 71.60, 67.79, 40.82.
HRMS (ESI): m/z calcd for C34H35N2O4 (MþHþ): 535.25913; found:
535.25853.
procedure I: diethyl diphenylmethylidene malonate
3.09 mmol), oxalyl chloride (0.98 g, 0.77 mmol), -phenyl glycinol
(0.85 g, 6.20 mmol), and Et3N (4.0 mL, 28.9 mmol) to afford the
5 (1.0 g,
L
4.3.2. Bis[(S)-4-phenyloxazoline-2-yl]-2,20-diphenyethene 4c. Using
the same procedure as described in general procedure II: from
dihydroxy diamide 6c (0.50 g, 0.99 mmol), MsCl (0.26 g,
2.28 mmol), and Et3N (4 mL, 28 mmol) to afford 4c (0.44 g, 76.2%)
dihydroxy diamide 6c (1.22 g, 78.2%) as
a white solid. Mp
211e211.5 ꢀC. [
a
]
D
25 þ28.9 (c 0.15, CH2Cl2). IR: 3436,1639,1532,1449,
1106, 1040, 700. 1H NMR (300 MHz, DMSO-d6):
d
8.23 (d, J¼8.13 Hz,
2H), 7.31e7.15 (m, 16H, ArH), 6.97e6.94 (m, 4H, ArH), 4.78e4.69 (m,
as a white solid. Mp 173.0e174.5 ꢀC. [
a
]
25 þ37.7 (c 0.30, CH2Cl2). IR:
D
4H, CHN and OH), 3.41 (t, J¼5.70 Hz, 4H). 13C NMR (75 MHz, DMSO-
3015, 2346, 1653, 1448, 1357, 1269, 1204, 1145, 1017, 957, 938, 786,
d6):
d
165.49, 142.97, 140.59, 140.30, 134.86, 129.17, 128.30, 128.08,
735, 701. 1H NMR (300 MHz, CDCl3):
d 7.33e7.31 (m, 10H, ArH),
128.03,127.97,127.02,126.67, 64.41, 54.89. HRMS (ESI): m/z calcd for
7.24e7.20 (m, 6H, ArH), 7.08e7.05 (m, 4H, ArH), 5.24 (dd, J¼8.10,
C32H31N2O4 (MþHþ): 507.22783; found: 507.22817.
9.90 Hz, 2H, CHN]), 4.47 (dd, J¼8.36, 10.20 Hz, 2H, CH2O), 3.96 (t,
J¼8.25 Hz, 2H, CH2O). 13C NMR (75 MHz, CDCl3):
d 163.82, 156.13,
142.02, 140.83, 129.47, 128.82, 128.44, 128.04, 127.25, 126.73, 116.84,
74.60, 69.84. HRMS (ESI): m/z calcd for C32H31N2O4 (MþHþ):
507.22783; found: 507.22817.
4.3. General procedure II: bis[(S)-4-iso-propyloxazoline-2-yl]-
2,20-diphenyethene 4a
To an ice-cooled solution of the dihydroxy diamide 6a (0.5 g,
1.14 mmol) and Et3N (4 mL, 28 mmol) in CH2Cl2 (20 mL) was added
MsCl (0.34 g, 3.0 mmol) slowly. The mixture was allowed to warm
to room temperature and was stirred for 12 h. The mixture was
washed with water (2ꢁ5 ml). The organic layer was dried over
anhydrous Na2SO4 and concentrated to dryness in vacuo, the
4.4. General procedure for asymmetric FeC alkylation of
indoles with alkylidene malonates
To a Schlenk tube Cu(OTf)2 (0.025 mmol) was added, followed
by ligand 4b (0.0275 mmol) in the solvent ethanol (1.0 mL) under

9606
H. Chen et al. / Tetrahedron 67 (2011) 9602e9608
N2, the solution was stirred for 1.5 h at room temperature, a mix-
ture of diethyl arylidenemalonate (0.25 mmol) in the above solvent
(1.0 mL) was added. After stirring for 30 min, indole (0.25 mmol)
was added. After stirring for 24e72 h at room temperature, the
solution was concentrated in vacuo. The crude product was purified
by flash column chromatography on silica gel [eluted with ethyl
acetate/petroleum ether (1:5, v/v)] to afford the (S)-ethyl
2-ethoxycarbonyl 3-(3-indolyl)-3-arylpropanoate as a white solid.
The enantiomeric excesses were determined by HPLC with a chiral
column (Daicel Chiralcel OD-H; hexane/iso-propanol 90:10; flow
rate 0.8 mL/min; 254 nm).
CH2Cl2). 1H NMR (300 MHz, CDCl3):
d 8.25 (s, 1H, NH), 7.68 (d,
J¼7.50 Hz, 1H, ArH), 7.39e7.19 (m, 3H, ArH), 7.14e7.00 (m, 5H, ArH),
5.67 (d, J¼11.70 Hz, 1H, CH), 4.46 (d, J¼11.70 Hz, 1H, CH), 4.02 (q,
J¼7.20 Hz, 2H, CH2), 3.93 (q, J¼7.20 Hz, CH2), 1.01 (t, J¼7.20 Hz, 3H,
CH3), 0.90 (t, J¼7.20 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3):
d
167.90, 167.55, 139.05, 135.97, 133.91, 129.73, 128.87, 127.73,
126.77, 126.55, 122.01, 121.97, 119.40, 119.31, 115.41, 111.05, 61.46,
57.60, 38.53, 13.61, 13.56. HRMS (ESI): m/z calcd for C22H22ClKNO4
(MþKþ): 482.03638; found: 482.03650. HPLC analysis tR (minor)¼
16.84 min, tR (major)¼27.56 min, 87% ee.
4.4.6. (S)-Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(o-fluorophenyl)
25
4.4.1. (S)-Ethyl
anoate. White solid. Mp: 179e180 ꢀC. [
1H NMR (300 MHz, CDCl3):
2-ethoxycarbonyl-3-(3-indolyl)-3-phenyl
prop-
propanoate. White solid. Mp 154e156 ꢀC. [
a
]
þ10.6 (c 0.20,
D
25
a
]
þ42.2 (c 0.50, CH2Cl2).
CH2Cl2). 1H NMR (300 MHz, CDCl3):
d 8.05 (s, 1H, NH), 7.50 (d,
D
d
8.06 (br s, 1H), 7.54 (d, J¼8.0 Hz, 1H),
J¼7.50 Hz, 1H, ArH), 7.37 (d, J¼1.80 Hz, 1H, ArH), 7.29e7.22
(m, 2H, ArH), 7.16e6.96 (m, 5H, ArH), 5.35 (d, J¼12.0 Hz, 1H, CH),
4.46 (d, J¼12.0 Hz, 1H, CH), 4.03 (q, J¼7.20 Hz, 2H, CH2), 3.97 (q,
J¼7.08 Hz, CH2), 1.03 (t, J¼10.10 Hz, 3H, CH3), 0.97 (t, J¼7.11 Hz,
7.09e7.37 (m, 8H), 7.02 (t, J¼7.50 Hz, 1H), 5.07 (d, J¼11.82 Hz, 1H),
4.28 (d, J¼11.82 Hz, 1H), 3.94e4.03 (m, 4H), 0.95e1.02 (m, 6H). 13C
NMR (75 MHz, CDCl3):
d 168.02, 167.83, 141.41, 136.20, 128.30,
128.17, 126.8, 126.70, 122.21, 120.88, 119.49, 119.38, 116.99, 110.96,
61.43, 61.37, 58.39, 42.86, 13.75, 13.71; HRMS (ESI): m/z calcd for
C22H23KNO4 (MþKþ): 404.12587; found: 404.12590. HPLC analysis
(Chiralcel OD-H, n-hexane/2-PrOH, 90:10, 0.8 mL/min, 254 nm): tR
(minor)¼13.71 min, tR (major)¼15.65 min; >99% ee.
3H, CH3). 13C NMR (75 MHz, CDCl3):
d 167.84, 167.67, 162.28,
159.01, 135.89, 129.75, 129.70, 129.0, 128.68, 128.50, 128.40,
128.29, 126.64, 124.06, 124.01, 122.17, 121.40, 119.54, 118.97,
115.82, 115.61, 110.98, 61.47, 56.9, 56.89, 36.30, 36.27, 13.68. HRMS
(ESI): m/z calcd for C22H22FKNO4 (MþKþ): 422.11644; found:
422.11670. HPLC analysis tR (minor)¼15.74 min, tR (major)¼
21.09 min, 99.5% ee.
4.4.2. (S)-Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(p-methylphenyl)
25
propanoate. White solid. Mp 147e149 ꢀC. [
a
]
þ22.6 (c 0.20,
D
CH2Cl2). 1H NMR (300 MHz, CDCl3):
d
8.06 (s, 1H, NH), 7.54 (d,
4.4.7. (S)-Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(o-methylphenyl)
25
J¼7.80 Hz, 1H, ArH), 7.26e7.22 (m, 3H, ArH), 7.13e7.08 (m, 2H, ArH),
7.04e6.99 (m, 2H, ArH), 5.03 (d, J¼11.85 Hz, 1H, CH), 4.27 (d,
J¼11.80 Hz, 1H, CH), 2.23 (s, 3H, CH3), 1.03 (t, J¼7.11 Hz, 3H, CH3),
propanoate. Colorless oil. [
(300 MHz, CDCl3):
a
]
þ15.2 (c 0.30, CH2Cl2). 1H NMR
D
d
8.27 (s, 1H, NH), 8.05 (d, J¼0.81 Hz, 1H, ArH),
7.74e7.71 (m, 1H, ArH), 7.58 (d, J¼8.40 Hz, 1H, ArH), 7.37e7.34 (m,
3H, ArH), 7.26e7.21 (m, 1H, ArH), 7.18e7.13 (m, 2H, ArH), 5.08 (d,
J¼12.0 Hz, 1H, CH), 4.28 (d, J¼12.0 Hz, 1H, CH), 4.02e3.93 (m, 4H,
CH2), 3.90 (s, 3H, CH3),1.01 (t, J¼6.90 Hz, 3H, CH3), 0.96 (t, J¼7.11 Hz,
0.96 (t, J¼7.11 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3):
d 168.10,
167.88, 138.42, 136.20, 136.12, 128.97, 127.96, 126.68, 122.11, 120.84,
119.40, 119.36, 117.12, 110.94, 61.36, 61.33, 58.43, 42.43, 20.92, 13.75,
13.67. HRMS (ESI): m/z calcd for C23H25KNO4 (MþKþ): 418.14152;
found: 418.14176. HPLC analysis tR (minor)¼15.01 min, tR (major)¼
13.78 min, 96% ee.
3H, CH3). 13C NMR (75 MHz, CDCl3):
d 168.39, 167.88,140.08, 136.29,
135.99, 130.68,126.75,126.42,126.30, 125.96,122.27,122.03,119.46,
119.28, 116.47, 110.97, 61.40, 61.28, 58.48, 38.05, 19.89, 13.68, 13.57.
HRMS (ESI): m/z calcd for C23H25KNO4 (MþKþ): 418.14152; found:
418.14178. HPLC analysis tR (minor)¼11.02 min, tR (major)¼
13.21 min, 79% ee.
4.4.3. (S)-Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(p-fluorophenyl)
25
propanoate. White solid. Mp 130e132 ꢀC. [
a]
þ14.2 (c 0.20,
D
CH2Cl2). 1H NMR (300 MHz, CDCl3):
d 8.05 (s, 1H, NH), 7.48 (d,
J¼7.80 Hz, 1H, ArH), 7.35e7.29 (m, 3H, ArH), 7.19e7.12 (m, 2H, ArH),
7.11e7.10 (m,1H, ArH), 6.91 (d, J¼8.70 Hz,1H, ArH), 6.84 (dd, J¼3.90,
5.10 Hz, 1H), 5.06 (d, J¼12.0 Hz, 1H, CH), 4.23 (d, J¼12.0 Hz, 1H, CH),
4.03 (q, J¼4.80 Hz, 2H, CH2), 3.97 (q, J¼4.80 Hz, 2H, CH2), 1.03 (t,
J¼7.20 Hz, 3H, CH3), 0.99 (t, J¼7.20 Hz, 3H, CH3). 13C NMR (75 MHz,
4.4.8. (S)-Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(m-fluorophenyl)
25
propanoate. White solid. Mp 144e146 ꢀC. [
a
]
þ8.4 (c 0.20,
D
CH2Cl2). 1H NMR (300 MHz, CDCl3):
d 8.05 (s, 1H, NH), 7.55 (d,
J¼8.40 Hz, 1H, ArH), 7.32e7.29 (m,1H, ArH), 7.21e7.17 (m, 4H, ArH),
7.07e7.02 (m, 2H, ArH), 6.82 (t, J¼6.30 Hz, 1H, ArH), 5.08 (d,
J¼11.76 Hz, 1H, CH), 4.25 (d, J¼11.70 Hz, 1H, CH), 4.03 (q, J¼2.40 Hz,
2H, CH2), 3.98 (q, J¼2.40 Hz, 2H, CH2), 1.04 (t, J¼7.24 Hz, 3H, CH3),
CDCl3):
d 167.86, 167.74, 163.26, 160.01, 137.20, 137.16, 136.27,
129.82, 129.71, 126.55, 122.36, 120.79, 119.59, 119.27, 116.83, 115.24,
114.96, 111.04, 61.51, 61.47, 58.43, 42.12,13.80, 13.72. HRMS (ESI): m/
z calcd for C22H22FKNO4 (MþKþ): 422.11644; found: 422.11655.
HPLC analysis tR (minor)¼13.78 min, tR (major)¼15.61 min, 98% ee.
0.99 (t, J¼7.24 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3):
d 167.72,
167.62, 164.37, 161.12, 144.14, 144.11, 136.19, 134.2, 129.79, 129.69,
126.53, 123.95, 123.92, 122.3, 122.42, 120.92, 119.67, 119.23, 116.42,
116.39, 115.29, 115.01, 113.82, 113.56, 111.04, 61.53, 58.13, 42.48,
13.79, 13.72. HRMS (ESI): m/z calcd for C22H22FKNO4 (MþKþ):
422.11644; found: 422.11649. HPLC analysis tR (minor)¼12.52 min,
tR (major)¼16.22 min, 78% ee.
4.4.4. (S)-Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(p-bromophenyl)
25
propanoate. White solid. Mp 141e142 ꢀC. [
a]
þ28.5 (c 0.20,
D
CH2Cl2). 1H NMR (300 MHz, CDCl3):
d 8.08 (s, 1H, NH), 7.48 (d,
J¼7.50 Hz, 1H, ArH), 7.36e7.23 (m, 5H, ArH), 7.18e7.12 (m, 2H, ArH),
7.06e7.01 (m, 1H, ArH), 5.04 (d, J¼11.70 Hz, 1H, CH), 4.23 (d,
J¼11.70 Hz, 1H, CH), 4.03 (q, J¼7.20 Hz, 2H, CH2), 3.98 (q, J¼6.90 Hz,
2H, CH2), 1.07 (t, J¼7.20 Hz, 3H, CH3), 0.99 (t, J¼7.20 Hz, 3H, CH3).
4.4.9. (S)-Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(m-methylphenyl)
25
propanoate. White solid. Mp 106e108 ꢀC. [
a]
þ11.2 (c 0.20,
D
CH2Cl2). 1H NMR (300 MHz, CDCl3):
d 8.00 (s, 1H, NH), 7.57 (d,
13C NMR (75 MHz, CDCl3):
d
167.75, 167.64, 140.55, 136.23, 131.41,
J¼8.10 Hz, 1H, ArH), 7.30e7.26 (m,1H, ArH), 7.18e7.05 (m, 5H, ArH),
7.03e7.00 (m, 1H, ArH), 6.94 (d, J¼7.24 Hz, 1H, ArH), 5.03 (d,
J¼12.00 Hz,1H, CH), 4.27 (d, J¼12.00 Hz,1H, CH), 4.01 (q, J¼4.32 Hz,
2H, CH2), 3.96 (q, J¼1.26 Hz, 2H, CH2), 2.26 (s, 3H, CH3), 1.01 (t,
J¼5.67 Hz, 3H, CH3), 0.97 (t, J¼7.20 Hz, 3H, CH3). 13C NMR (75 MHz,
129.96, 126.47, 122.42, 120.89, 120.58, 119.65, 119.20, 116.43, 111.06,
61.55, 61.7, 58.07, 42.23, 13.80, 13.71; HRMS (ESI): m/z calcd for
C22H22BrKNO4 (MþKþ): 422.11644; found: 422.11655. HPLC anal-
ysis tR (minor)¼14.73 min, tR (major)¼16.04 min, 98% ee.
CDCl3):
d 168.04, 167.83, 141.32, 137.75, 136.20, 128.95, 128.17,
4.4.5. (S)-Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-(o-chlorophenyl)
127.48, 126.79, 125.11, 122.22, 120.87, 119.51, 119.47, 117.22, 110.90,
61.37, 61.32, 58.44, 42.75, 21.42, 13.77, 13.72. HRMS (ESI): m/z calcd
25
propanoate. White solid. Mp 123e125 ꢀC. [
a
]
þ24.8 (c 0.50,
D

H. Chen et al. / Tetrahedron 67 (2011) 9602e9608
9607
for C23H25KNO4 (MþKþ): 418.14152; found: 418.14184. HPLC anal-
ysis tR (minor)¼13.60 min, tR (major)¼15.67 min, 78% ee.
1H, ArH), 5.10 (d, J¼12.0 Hz, 1H, CH), 4.29 (d, J¼12.0 Hz, 1H, CH),
4.04e3.93 (m, 4H, 2ꢁCH2), 3.91 (s, 3H, CH3), 1.02 (t, J¼7.20 Hz, 3H,
CH3), 0.96 (t, J¼7.20 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3):
4.4.10. (S)-Ethyl 2-ethoxycarbonyl-3-[3-(5-methoxyindolyl)]-3-
d 168.02, 167.83, 167.62, 141.04, 138.65, 128.46, 128.02, 126.90,
25
phenylpropanoate. White solid. Mp 147e148.5 ꢀC. [
a]
D
þ17.5 (c
126.32, 123.74, 122.30, 122.24, 121.77, 118.47, 110.74, 61.49, 58.45,
51.83, 51.80, 42.44, 13.76, 13.70. HRMS (ESI): m/z calcd for
C24H25KNO6 (MþKþ): 462.13135; found: 462.13253. HPLC analysis
tR(minor)¼23.92 min, tR (major)¼28.11 min, 82% ee.
0.20, CH2Cl2). 1H NMR (300 MHz, CDCl3):
d 7.96 (s,1H, NH), 7.37e7.35
(m, 2H, ArH), 7.25e7.12 (m, 4H, ArH), 6.96 (s, 1H, ArH), 6.78 (dd,
J¼2.40 Hz, 9.00 Hz, ArH), 5.01 (d, J¼11.76 Hz, CH), 4.25 (d, J¼11.76 Hz,
CH), 4.05e3.94 (m, 4H, 2ꢁCH2), 3.77 (s, 3H, OCH3), 0.99 (t, J¼6.00 Hz,
6H, 2ꢁCH3).13C NMR(75 MHz, CDCl3):
d
168.05,167.85,153.94,141.37,
4.4.16. (S)-Ethyl 2-ethoxycarbonyl-3-[3-(5-methoxyindolyl)]-3-(p-
131.36, 128.31, 128.16, 127.16, 126.72, 121.59, 116.76, 112.46, 111.62,
101.28, 61.45, 61.38, 58.38, 55.82, 42.86, 13.75. HRMS (ESI): m/z calcd
for C23H25KNO5 (MþKþ):434.13643;found:434.13697. HPLCanalysis
tR (minor)¼17.39 min, tR (major)¼22.18 min, >99% ee.
methylphenyl)propanoate. White solid. Mp 105e107 ꢀC. [
a
]
25 þ13.5
D
(c 0.20, CH2Cl2). 1H NMR (300 MHz, CDCl3):
d 7.92 (s, 1H, NH), 7.36
(d, J¼7.50 Hz, 1H, ArH), 7.16e6.97 (m, 6H, ArH), 6.77 (dd, J¼2.37,
8.70 Hz, 1H, ArH), 5.26 (d, J¼11.80 Hz, 1H, CH), 4.31 (d, J¼11.80 Hz,
1H, CH), 3.99 (q, J¼7.08 Hz, 2H, CH2), 3.91 (q, J¼7.11 Hz, 2H, CH2),
3.80 (s, 3H, CH3), 2.47 (s, 3H, CH3), 0.99 (t, J¼7.11 Hz, 3H, CH3), 0.91
4.4.11. (S)-Ethyl 2-ethoxycarbonyl-3-[3-(5-methylindolyl)]-3-
25
phenylpropanoate. White solid. Mp 181e182 ꢀC. [
a]
þ18.2 (c
(t, J¼7.14 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3):
d 168.45, 167.89,
D
0.20, CH2Cl2). 1H NMR (300 MHz, CDCl3):
d
7.94 (s, 1H, NH),
153.92, 140.03, 136.31, 131.15, 130.70, 127.17, 126.44, 126.29, 125.93,
122.98, 116.25, 112.31, 111.61, 101.16, 61.42, 61.29, 58.34, 55.77, 38.17,
19.89, 13.70, 13.62. HRMS (ESI): m/z calcd for C24H27KNO5 (MþKþ):
448.152085; found: 448.15218. HPLC analysis tR(minor)¼12.70 min,
tR (major)¼15.63 min, 91% ee.
7.38e7.33 (m, 3H, ArH), 7.26e7.13 (m, 5H, ArH), 6.94 (d, J¼8.40 Hz,
1H, ArH), 5.04 (d, J¼11.70 Hz, 1H, CH), 4.26 (d, J¼11.70 Hz, 1H, CH),
4.03e3.93 (m, 4H, 2ꢁCH2), 2.38 (s, 3H, CH3), 1.02e0.97 (m, 6H,
2ꢁCH3). 13C NMR (75 MHz, CDCl3):
d 167.99, 167.86, 141.51, 134.52,
128.68, 128.29, 128.17, 126.97, 126.65, 123.88, 120.97, 118.95, 116.53,
110.58, 61.39, 61.34, 58.50, 42.80, 21.49, 13.76, 13.71. HRMS (ESI): m/
z calcd for C23H25KNO4 (MþKþ): 418.14152; found: 418.14193. HPLC
analysis tR (minor)¼11.93 min, tR (major)¼15.39 min, >99.9% ee.
4.5. General procedure for catalytic asymmetric allylic
alkylation
To
a flame dried Schlenk tube, [Pd(h
3-C3H5)Cl]2 (4.6 mg,
4.4.12. (S)-Ethyl 2-ethoxycarbonyl-3-[3-(7-methylindolyl)]-3-
0.0125 mmol), anhydrous KOAc (10 mg, 0.10 mmol), and ligand 4c
(13.1 mg, 0.03 mmol) were added under nitrogen, followed by addi-
tion of CH2Cl2 (2.0 mL). The solution was stirred at room temperature
for 0.5 h. then a solution of (E)-1,3-diphenylprop-2-en-1-yl acetate
(126 mg, 0.50 mmol) in CH2Cl2 (1 mL) was added, and the mixture was
stirred for 10 min before the addition of dimethyl malonate (0.17 mL,
1.5 mmol) and BSA (0.37 mL, 1.5 mmol). After being stirred for
48e72 h at room temperature or 0 ꢀC, water was added and the
mixture was extracted with EtOAc (2ꢁ10 mL), and the combined or-
ganic phase was dried over anhydrous Na2SO4. The solvent was re-
moved in vacuo and the residue was purified by flash chromatography
to afford a colorless oil. This is a known compound.1H NMR (300 MHz,
25
phenylpropanoate. White solid. Mp 125e126 ꢀC. [
a]
þ23.5 (c
D
0.20, CH2Cl2). 1H NMR (300 MHz, CDCl3):
d 7.97 (s, 1H, NH),
7.41e7.34 (m, 3H, ArH), 7.25e7.09 (m, 4H, ArH), 6.97e6.91 (m, 2H,
ArH), 5.05 (d, J¼11.70 Hz, 1H, CH), 4.28 (d, J¼11.70 Hz, 1H, CH),
4.04e3.93 (m, 4H, 2ꢁCH2), 2.42 (s, 3H, CH3), 1.04e0.97 (m, 6H,
2ꢁCH3). 13C NMR (75 MHz, CDCl3):
d 168.01, 167.83, 141.43, 135.78,
128.26, 128.16, 126.64, 126.21, 123.7, 122.70, 120.53, 120.06, 119.57,
117.46, 117.10, 61.41, 61.33, 58.37, 42.97, 16.43, 13.72. HRMS (ESI): m/
z calcd for C23H25KNO4 (MþKþ): 418.14152; found: 418.14172. HPLC
analysis tR (minor)¼12.64 min, tR (major)¼15.32 min, 99% ee.
4.4.13. (S)-Ethyl 2-ethoxycarbonyl-3-[3-(5-chloroindolyl)]-3-
CDCl3):
d
7.35e7.17 (m,10H, ArH), 6.47 (d, J¼15.75 Hz,1H, eCH]), 6.32
25
phenylpropanoate. White solid. Mp 196e198 ꢀC. [
a
]
ꢂ4.4 (c 0.20,
D
(dd, J¼8.43, 15.90 Hz, 1H, CH]), 4.26 (dd, J¼8.43, 10.80 Hz, 1H, CH),
3.95 (d, J¼10.80 Hz,1H, CH), 3.71(s,3H, CH3O), 3.52(s, 3H, CH3O). HPLC
analysis (Chiralcel AD-H, n-hexane/2-PrOH, 90:10, 1.0 mL/min,
254 nm): tR (minor)¼14.43 min, tR (major)¼19.77 min; 94% ee.
CH2Cl2). 1H NMR (CDCl3, 300 MHz):
d 8.17 (s, 1H, NH), 7.51 (d,
J¼1.98 Hz,1H, ArH), 7.35e7.05 (m, 8H, ArH), 5.00 (d, J¼12.00 Hz,1H,
CH), 4.25 (d, J¼12.00 Hz,1H), 4.03e3.94 (m, 4H, CH2), 1.03e0.97 (m,
6H, 2ꢁCH3). 13C NMR (75 MHz, CDCl3):
d 167.92, 167.65, 140.99,
134.50, 128.45, 128.04, 127.74, 126.91, 125.32, 122.62, 122.39, 118.77,
116.76, 112.04, 61.52, 61.47, 58.36, 42.60, 13.74, 13.71. HRMS (ESI):
m/z calcd for C22H22ClKNO4 (MþKþ): 438.08689; found: 438.08762.
HPLC analysis tR(minor)¼12.79 min, tR(major)¼16.45 min, 75% ee.
Acknowledgements
We are grateful for financial support by the Ministry of Science
and Technology of China (No. 2009BAK61B04), Chinese Universities
Scientific Fund Project (No. 2010JS030) and the Innovation Project
for National Undergraduated Students.
4.4.14. (S)-Ethyl 2-ethoxycarbonyl-3-[3-(6-chloroindolyl)]-3-
25
phenylpropanoate. White solid. Mp 208e210 ꢀC. [
a]
D
þ42.2 (c
0.20, CH2Cl2).1H NMR (300 MHz, CDCl3):
d 8.09 (s,1H, NH), 7.44e7.14
Supplementary data
(m, 8H, ArH), 7.01e6.97 (m, 1H, ArH), 5.03 (d, J¼11.70 Hz, 1H, CH),
4.25 (d, J¼11.70 Hz, 1H, CH), 4.04e3.94 (m, 4H, 2ꢁCH2), 1.00 (t,
J¼7.14 Hz, 2ꢁCH3). 13C NMR (75 MHz, CDCl3):
d 167.95, 167.69,
Supplementary data associated with this article can be found in
online version, at doi:10.1016/j.tet.2011.09.106.
141.09, 136.53, 128.41, 128.09, 126.89, 125.31, 121.54, 120.34, 120.24,
117.28,110.95, 77.20, 61.51, 61.46, 58.30, 42.70,13.76. HRMS (ESI): m/z
calcd for C22H22ClKNO4 (MþKþ): 438.08689; found: 438.08746.
HPLC analysis tR(minor)¼13.13 min, tR (major)¼15.79 min, 70% ee.
References and notes
1. (a) Hargaden, G. C.; Guiry, P. J. Chem. Rev. 2009, 109, 2505e2550; (b) Desimoni,
G.; Faita, G.; Jørgensen, K. A. Chem. Rev. 2006, 106, 3561e3651; (c) Mcmanus, H.
A.; Guiry, P. J. Chem. Rev. 2004, 104, 4151e4202; (d) Johnson, J. S.; Evans, D. A.
Acc. Chem. Res. 2000, 33, 325e335; (e) Ghosh, A. K.; Mathivannan, P.; Cappiello,
J. Tetrahedron: Asymmetry 1998, 9, 1e45.
2. (a) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M. J. Am. Chem. Soc.
1991, 113, 726e728; (b) Corey, E. J.; Imai, N.; Zhang, H.-Y. J. Am. Chem. Soc. 1991,
113, 728e729.
4.4.15. (S)-Ethyl 2-ethoxycarbonyl-3-[3-(6-methoxycarbony-
25
lindolyl)]-3-phenylpropanoate. White solid. Mp 146e147 ꢀC. [
a]
D
þ8.2 (c 0.20, CH2Cl2). 1H NMR (300 MHz, CDCl3):
d 8.37 (s, 1H, ArH),
8.26 (s, 1H, NH), 7.84 (dd, J¼2.40, 8.70 Hz, 1H, ArH), 7.41 (dd, J¼1.92,
7.85 Hz, 2H, ArH), 7.34e7.22 (m, 4H, ArH), 7.27 (dd, J¼1.80, 7.24 Hz,

9608
H. Chen et al. / Tetrahedron 67 (2011) 9602e9608
3. (a) Davies, I. W.; Gerena, L.; Castonguay, L.; Senanayake, C. H.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J. Chem. Commun. 1996, 1753e1754; (b) Davies, I. W.;
Deeth, R. J.; Larsen, R. D.; Reider, P. J. Tetrahedron Lett. 1999, 40, 1233e1236; (c)
Denmark, S. E.; Stiff, C. M. J. Org. Chem. 2000, 65, 5875e5878.
4. (a) Carreiro, E. P.; Chercheja, S.; Burke, A. J.; Ramalho, J. P.; Rodrigues, A. P. J. Mol.
Catal. A: Chem. 2005, 236, 38e45; (b) Carreiro, E. P.; Chercheja, S.; Moura, N.;
Gertrudes, S. C.; Burke, A. J. Inorg. Chem. Commun. 2006, 9, 823e826; (c) Burke,
A. J.; Carreiro, E. P.; Chercheja, S.; Moura, N. M. M.; Ramalho, J. P.; Rorigues, A. I.;
Santos, C. I. M. J. Organomet. Chem. 2007, 692, 4863e4874.
Moberg, C. Acc. Chem. Res. 2004, 37, 159e167; (d) Trost, B. M.; Crawley,
M. L. Chem. Rev. 2003, 103, 2921e2943; (e) Trost, B. M.; van Vranken, D. L.
Chem. Rev. 1996, 96, 395e422; (f) Pfaltz, A. Acc. Chem. Res. 1993, 26,
339e345.
ꢀ
12. (a) Liu, D. L.; Xie, F.; Zhang, W.-B. J. Org. Chem. 2007, 72, 6992e6997; (b) Pamies,
ꢀ
O.; Dieguez, M.; Claver, C. J. Am. Chem. Soc. 2005, 127, 3646e3647; (c) Tanaka,
Y.; Mino, T.; Akita, K.; Sakamoto, M.; Fujita, T. J. Org. Chem. 2004, 69,
6679e6687; (d) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029e3069; (e) Dai,
L. X.; Tu, T.; You, S. L.; Deng, W. P.; Hou, X. L. Acc. Chem. Res. 2003, 36, 659e667;
(f) McCarthy, M.; Guiry, P. J. Tetrahedron 2001, 57, 3809e3844; (g) Evans, D. A.;
Campos, K. R.; Tedrow, J. S.; Michael, F. E.; Gagne, M. R. J. Am. Chem. Soc. 2000,
122, 7905e7920; (h) Trost, B. M.; Radinov, R. E.; Grenzer, M. J. Am. Chem. Soc.
1997, 119, 7879e7880.
5. Sun, Y.-J.; Li, N.; Zheng, Zh.-B.; Liu, L.; Yu, Y.-B.; Qin, Zh.-H.; Fu, B. Adv. Synth.
Catal. 2009, 351, 3113e3117.
6. For recent reviews on the asymmetric FriedeleCrafts reaction, see: (a) Sheng,
Y.-F.; Li, G.-Q.; Kang, Q.; Zhang, A.-J.; You, S.-L. Chem.dEur. J. 2009, 15,
3351e3354; (b) Cui, H. L.; Feng, X.; Peng, J.; Lei, J.; Jiang, K.; Chen, Y. C.
Angew. Chem. 2009, 121, 5847e5849; Angew. Chem., Int. Ed. 2009, 48,
5737e5739; (c) Lin, S.-Zh.; You, T.-P. Tetrahedron 2009, 65, 1010e1016; (d)
Poulsen, T. B.; Jørgensen, K. A. Chem. Rev. 2008, 108, 2903e2915; (e) Liu, H.;
Lu, S. F.; Xu, J. X.; Du, D. M. Chem. Asian J. 2008, 3, 1111e1121; (f) Kang, Q.;
Zheng, X.-J.; You, S.-L. Chem.dEur. J. 2008, 14, 3539e3542; (g) Kang, Q.;
Zhao, Z.-A.; You, S.-L. J. Am. Chem. Soc. 2007, 129, 1484e1485; (h) Jia, Y.-X.;
Zhong, J.; Zhu, S.-F.; Zhang, C.-M.; Zhou, Q.-L. Angew. Chem. 2007, 119,
5661e5663; Angew. Chem., Int. Ed. 2007, 46, 5565e5567; (i) Evans, D. A.;
Fandrick, K. R.; Song, H.-J.; Scheidt, K. A.; Xu, R. J. Am. Chem. Soc. 2007, 129,
10029e10041.
13. (a) Du, X.; Liu, H.; Du, D.-M. Tetrahedron: Asymmetry 2010, 21, 241e246; (b)
ꢀ
Aït-Haddou, H.; Hoarau, O.; Cramailere, D.; Pezet, F.; Daran, J.-C.; Balavoine,
G. G. A. Chem.dEur. J. 2004, 10, 699e707; (c) Bayardon, J.; Sinou, D.; Guala,
M.; Desimoni, G. Tetrahedron: Asymmetry 2004, 15, 3195e3200; (d) Bayardon,
ꢀ
J.; Sinou, D. J. Org. Chem. 2004, 69, 3121e3128; (e) Pericas, M. A.; Puigjaner, C.;
ꢀ
ꢀ
Riera, A.; Vidal-Ferran, A.; Gomez, M.; Jimenez, F.; Muller, G.; Rocamora, M.
Chem.dEur. J. 2002, 8, 4164e4178; (f) Glos, M.; Reiser, O. Org. Lett. 2000, 2,
2045e2048.
14. For recent literatures on recent allylic alkylations: (a) Kultyshev, R. G.;
Miyazawa, A. Tetrahedron 2011, 67, 2139e2148; (b) Dugal-Tessier, J.; Dake,
G. R.; Gates, D. P. Org. Lett. 2010, 12, 4667e4669; (c) Thiesen, K. E.;
Maitra, K.; Olmstead, M. M.; Attar, S. Organometallics 2010, 29,
7. Zhuang, W.; Hansen, T.; Jørgensen, K. A. Chem. Commun. 2001, 347e349.
8. (a) Zhou, J.; Tang, Y. J. Am. Chem. Soc. 2002, 124, 9030e9031; (b) Zhou, J.; Ye, M.-
C.; Huang, Z.-Z.; Tang, Y. J. Org. Chem. 2004, 69, 1309e1320; (c) Zhou, J.; Tang, Y.
Chem. Commun. 2004, 432e434.
€
ꢀ
6334e6342; (d) Cattoen, X.; Pericas, M. A. Tetrahedron 2009, 65,
8199e8205; (e) Tian, F.-T.; Yao, D.-M.; Zhang, Y.-J.; Zhang, W.-B. Tetra-
ꢀ
ꢀ
hedron 2009, 65, 9609e9615; (f) Dieguez, M.; Pamies, O. Chem.dEur. J.
2008, 14, 3653e3669; (g) Vargas, F.; Sehnem, J. A.; Galetto, F. Z.; Braga,
A. L. Tetrahedron 2008, 64, 392e398.
9. (a) Rasappan, R.; Hager, M.; Gissibl, A.; Reiser, O. Org. Lett. 2006, 8, 6099e6102;
€
(b) Schatz, A.; Rasappan, R.; Hager, M.; Gissibl, A.; Reiser, O. Chem.dEur. J. 2008,
14, 7259e7266.
15. Crystallographic Data Centre as supplementary publication number CCDC
822096 and 829376. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. Fax: þ44 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk.
10. (a) Liu, Y.-L.; Shang, D.-J.; Zhou, X.; Liu, X.-H.; Feng, X.-M. Chem.dEur. J. 2009,
15, 2055e2058; (b) Liu, Y.-L.; Zhou, X.; Shang, D.-J.; Liu, X.-H.; Feng, X.-M.
Tetrahedron 2010, 66, 1447e1457.
11. (a) Hartwig, J. F.; Stanley, L. M. Acc. Chem. Res. 2010, 43, 1461e1475; (b)
Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 258e297; (c) Belda, O.;
16. Trost, B. M.; Van Vranken, D. L.; Bingel, C. J. Am. Chem. Soc. 1992, 114,
9327e9343.