Synthesis of new C2- Symmetric fluoren-9-ylidene malonate derived bis(oxazoline) ligands and their application in friedel-crafts reactions

Article abstract of DOI:10.3390/molecules15128582

A series of new C₂-symmetric fluoren-9-ylidene malonate-derived bis(oxazoline) ligands were synthesized from fluoren-9-ylidene malonate and enantiomerically pure amino alcohols via a convenient route. Their asymmetric catalytic properties in th

Full text of DOI:10.3390/molecules15128582

Molecules 2010, 15, 8582-8592; doi:10.3390/molecules15128582
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
Synthesis of New C2- Symmetric Fluoren-9-ylidene Malonate
Derived Bis(oxazoline) Ligands and Their Application in
Friedel-Crafts Reactions
Jing Li, Hong-Liang Chen, Lei Liu and Bin Fu *
Department of Applied Chemistry, China Agricultural University, Beijing 100193, China;
E-Mails: lijing_19901210@126.com (J.L.); chenhongliang1016@yahoo.cn (H.-L.C.);
LiuLei-111@163.com (L.L.)
* Author to whom correspondence should be addressed; E-Mail: fubinchem@cau.edu.cn.
Received: 10 November 2010; in revised form: 18 November 2010 / Accepted: 23 November 2010 /
Published: 26 November 2010
Abstract:
A
series of new C2-symmetric fluoren-9-ylidene malonate-derived
bis(oxazoline) ligands were synthesized from fluoren-9-ylidene malonate and
enantiomerically pure amino alcohols via a convenient route. Their asymmetric catalytic
properties in the Friedel-Crafts reactions of indoles with arylidene malonates were
evaluated, and the Cu(OTf)2 complex of a fluoren-9-ylidene malonate-derived
bis(oxazoline) bearing a phenyl group showed moderate to good enantioselectivity (up to
88% ee).
Keywords: bis(oxazoline); fluoren-9-ylidene; asymmetric catalysis; Friedel-Crafts
1. Introduction
During the past two decades, a plethora of bis(oxazoline) ligands have been synthesized and
successfully applied in a variety of asymmetric catalytic reactions [1-3]. For bis(oxazoline) (BOX)
ligands derived from malonate and its analogues, the bridge angle φ, correlating with the bite angle θ
of the BOX-metal complex, is an important structural factor influencing the enantioselectivity of the
catalysis [4-6]. In recent years, one straightforward strategy to tune the bridge angle was introduced to
BOX ligands, in which two oxazoline rings are attached to a sp2 hybridized carbon and then provide a
larger bridge angle than those with sp3 hybridized bridge carbon. So far several examples involving

Molecules 2010, 15
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this type of BOX ligand have appeared, such as I and II (Figure 1) [7-9]. Recently, we reported that
heteroarylidene malonate-derived bis(oxazoline) ligand III-copper(II) complexes demonstrated
excellent enantioselectivities (up to >99% ee) in the catalytic Friedel-Crafts reactions between indoles
and diethyl alkylidenemalonates [10]. As a continuation of our ongoing endeavor to explore these
novel chiral ligands and their application in synthetic methodology, herein we wish to document the
synthesis and application of fluoren-9-ylidene malonate derived bis(oxazoline) 1.
Figure 1. Typical alkylidene and arylidene malonate-type bis(oxazoline) ligands.
R
X
O
O
O
O
O
O
O
O
N
N
N
N
N
N
N
N
R
R
R
R
R
R
R
R
I
III
II
1
2. Results and Discussion
The requisite chiral bis(oxazolines) 1 were conveniently synthesized from the commercially
available starting material diethyl fluoren-9-ylidene malonate (2) in a four step sequence as illustrated
in Scheme 1 [10]. Hydrolysis of diethyl dicarboxylates 2 by the solution of NaOH in a mixture of
water and methanol gave the corresponding dicarboxylic acid, which reacted with oxalyl chloride in
the presence of DMF to afford the diacyl chloride. The diacyl chloride condensed with chiral β-amino
alcohols in the presence of Et3N to give the corresponding chiral intermediate dihydroxydiamides 3 in
good yields, which were treated with methanesulfonyl chloride and excess Et3N in dichloromethane to
afford the desired bis(oxazoline)s 1a~d in good yield (75-84%).
Scheme 1. Synthesis of chiral bis(oxazolines) 1.
a. R = iPr
i, ii, iii
iv
O
O
b. R = iBu
c. R = Bn
d. R = Ph
H
H
N
N
OH
HO
N
N
EtOOC
COOEt
R
R
O
O
R
R
3
1
2
Reagents and conditions: i) NaOH, MeOH; ii) (COCl)2, DCM, DMF; iii) L-amino alcohol, Et 3N,
DCM; iv) MsCl, Et 3N, DCM.
With these new ligands in hand, we evaluated their catalytic activity in the Cu(II) catalyzed Friedel-
Crafts (F-C) alkylation of indole with arylidene malonates according to our previous reports (Scheme
2) [10]. The asymmetric Friedel-Crafts alkylation of indoles with arylidene malonates affords an
efficient methodology to prepare indole derivatives [11-17]. The F-C alkylation was performed in iso-
butanol at room temperature employing Cu(OTf)2-bis(oxazoline) complexes 1a~d (10 mol%) as

Molecules 2010, 15
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catalysts (Scheme 2). The experimental results are outlined in Table 1. Ligand 1d showed the best
enantioselectivity (78% ee) among the four Cu(OTf)2-ligand complexes, while 1a~c gave low catalytic
enantioselectivities (entries 1, 2 and 3). When Cu(ClO4)2x6H2O was used in this teaction, the ee was
decreased to 34% (entry 5). Subsequently, the effect of solvents were examined. In isopropanol or
ethanol, almost the same catalytic activities and enantioselectivities were exhibited (entries 6 and 7),
however in methanol the enantioselectivity was reduced to 40% ee (Entry 8). When dichloromethane
was used in this reaction, both a high yield and low enantioselectivity were obtained (90% yield and
20% ee, entry 9), which was not in accordance with our previous report that the use of
dichloromethane as solvent led to the product with the the opposite configuration being obtained
[10,15].
Scheme 2. Friedel-Crafts alkylations catalyzed by Cu(OTf)2-bis(oxazoline) complexes 1a~d.
COOC2H5
Ph
COOC2H5
COOC2H5
Ligand-Cu(II)
+
Ph
N
COOC2H5
Ligand =
H
N
H
1a~d
Table 1. Effect of ligands and solvent in Cu(II)-catalyzed Friedel-Crafts alkylations. a
Entry Ligands
Solvent
Salt
Yield (%)b
Ee (%)c
39
1
2
3
4
5
6
7
8
9
isobutanol
isobutanol
isobutanol
isobutanol
isobutanol
isopropanol
ethanol
Cu(OTf)2
Cu(OTf)2
1a
1b
1c
99
99
99
99
99
99
99
99
90
16
57
78
34
77
Cu(OTf)2
1d
1d
1d
1d
1d
1d
Cu(OTf)2
Cu(ClO4)2xH2O
Cu(OTf)2
Cu(OTf)2
78.
methanol
CH2Cl2
Cu(OTf)2
40
25
Cu(OTf)2
a All the reactions were conducted under nitrogen for 24 h using 10 mol% of catalyst at room
temperature; b Isolated yield. c Determined by chiral HPLC.
Next the reactions of various indoles and alkylidene malonates were investigated under the optimal
reaction conditions (Table 1, Entry 4). As shown in Table 2, different reactivities were observed for
different substrates. The benzylidene malonates with ortho-ClPh and ortho-MePh groups afforded
much lower yields after reacting 48 h (60% and 65%, respectively). The enantioselectivity of the
reactions was found to depend significantly on the different substituents on the substrates (entries 1~5).
The best result was achieved (up to 88% ee) when diethyl ortho-Cl-benzylidene malonate reacted with
indole (Entry 4). On the other hand, in the reaction of various substituted indoles with diethyl
benzylidene malonates, inferior enantioselectivities (10~45% ee, entries 6~9) resulted for the adducts
of the benzylidene malonate reacting with 5-methoxyindole, 5-methylindole, 5-chloroindole and 6-
chloroindole, although high yields were obtained.

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Scheme 3. F-C alkylations of different indoles and malonates.
COOC2H5
COOC2H5
R2
COOC2H5
1d-Cu(OTf)2
R1
R2
+
R1
N
COOC2H5
N
H
H
Table 2. 1d-Cu(OTf)2 catalyzed Friedel-Crafts reaction of indole derivatives with
alkylidene malonates. a
Entry
R1
R2
Time (h)
Yield (%)b
eec (%)
Config.
1
2
3
4
5
6
7
8
9
H
H
p-MeC6H4
p-FC6H4
m-BrC6H4
o-ClC6H4
o-MeC6H4
C6H5
24
24
48
48
48
24
24
48
48
99
90
95
60
65
99
99
90
80
37
31
52
88
15
41
47
45
10
S
S
S
S
S
S
S
S
S
H
H
H
5-MeO
5-Me
5-Cl
6-Cl
C6H5
C6H5
C6H5
a
All reactions were conducted in isobutanol under nitrogen using 10 mol% catalyst at room
temperature; b Isolated yield; c Determined by chiral HPLC.
3. Experimental
3.1. General
Melting points were measured on an XT-4 melting point apparatus and are uncorrected. NMR
spectra were recorded with a Bruker Avance DPX300 spectrometer with tetramethylsilane as the
internal standard. Infrared spectra were obtained on a Nicolet AVATAR 330 FT-IR spectrometer;
Optical rotations were measured on a Perkin–Elmer 341 LC polarimeter. Elemental analyses were
carried out on an Elementar Vario EL instrument. The enantiomeric excesses of (R)- and (S)-ethyl-2-
ethoxycarbonyl-3-(3-indolyl)-3-arylpropanoate were determined by HPLC analysis over a chiral
column (Daicel Chiralcel OD-H; n-hexane/i-PrOH 90:10, 0.8 mL/min; UV detector, 254 nm). The
absolute configuration of the major enantiomer was assigned by comparison with literature [10,15].
3.2. Synthesis and characterization of dihydroxydiamides 3a-d
3.2.1. (S,S)-N,N-bis(2-hydroxy-1-isopropyl)-2-(fluoren-9-ylidene) malonamide (3a)
To a solution of diethyl fluoren-9-ylidene malonate 2a (1.0 g, 3.10 mmol) in CH3OH (10 mL) was
added a NaOH solution (10 mL, 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). The

Molecules 2010, 15
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acidified mixture was extracted with ethyl acetate (10 mL × 3), and the combined organic phase was
washed with brine, dried over Na2SO4 and evaporated to give yellow solid, which was directly added
to a solution of CH2Cl2 (20 mL) and DMF (0.1 mL), subsequently at 0 °C oxalyl chloride (1.20 g,
9.44 mmol) was slowly injected and then the mixture stirred for 3 h. Removal of the excess oxalyl
chloride in vacuo afforded the diacyl dichloride as a yellow solid. The diacyl dichloride in CH2Cl2
(20 mL) was added dropwise to a solution of L-valinol (0.75 g, 7.28 mmol) and Et3N (4 mL,
28.9 mmol) in CH2Cl2 (20 mL) at 0 °C and stirred at room temperature for 4 h. The reaction mixture
was washed with water (5 mL × 2). The organic layer was dried over Na2SO4 and concentrated to give
crude solid. Purification by silica gel column chromatography (70% ethyl acetate in petroleum ether)
afforded the dihydroxydiamide 3a. Yield: 1.16 g (86%) as a yellow solid. m.p. 238.0~239.5 °C;
25
[α]D = +66.0 (c = 0.10, CH2Cl2). IR (cm-1): 3252, 3061, 2962, 1633, 1540, 1449, 1317, 1057, 725;
1H-NMR (DMSO): δ 8.22 (d, J = 8.88 Hz, 2H, NH), 7.83 (dd, J = 7.50, 11.70 Hz, 4H, ArH), 7.43-7.38
(m, 2H, ArH), 7.27-7.22 (m, 2H, ArH), 4.60(s, 2H, OH), 3.89-3.85 (m, 2H, CHNH), 3.54-3.41 (m, 4H,
CH2O), 1.99-1.93 (m, 2H, CHMe2), 0.91 (d, J = 6.87 Hz, 6H, CH3), 0.85 (d, J = 6.87 Hz, 6H, CH3);
13C-NMR (DMSO): δ 165.2, 139.9, 135.7, 134.5, 131.7, 129.5, 127.5, 124.9, 120.0, 61.1, 56.1, 28.3,
19.9, 17.6; Anal. Calcd. for C26H32N2O4 (436.55): C 71.53, H 7.39, N 6.42; Found: C 71.79, H 7.65, N 6.33.
3.2.2. (S,S)-N,N-bis(2-hydroxy-1-isobutyl)-2-(fluoren-9-ylidene) malonamide (3b)
25
Prepared according to procedure 3.2.1. Yield: 1.20 g (84%). m.p. 223~224.5 °C; [α]D = +84.4
(c = 0.15, CH2Cl2); IR (cm-1): 3254, 3060, 2956, 2870, 1638, 1542, 1449, 1385, 1367, 1320, 1064,
774, 725; 1H-NMR (DMSO): δ 8.21(d, J = 11.70 Hz, 2H, NH), 7.84 (dd, J = 7.35, 12.60 Hz, 4H, ArH),
7.43-7.38 (m, 2H, ArH), 7.26-7.21 (m, 2H, ArH), 4.81(s, 2H, OH), 4.05-4.04 (m, 2H, CHNH), 3.50
(dd, J = 5.10, 10.20 Hz, 2H, CH2O), 3.35-3.27(m, 2H, CH2O), 1.70-1.61(m, 2H, CHCH2), 1.43-1.29
(m, 4H, CH2), 0.92 (dd, J = 6.48 Hz, 6H, CH3), 0.88 (dd, J = 6.60 Hz, 6H, CH3); 13C-NMR (DMSO): δ
164.9, 139.9, 135.7, 134.4, 131.8, 129.5, 127.3, 124.8, 120.1, 63.7, 49.3, 24.1, 23.8, 21.8; Anal. Calcd.
for C28H36N2O4 (464.60): C 72.39, H 7.81, N 6.03; Found: C 72.54, H 7.68, N 6.31.
3.2.3. (S,S)-N,N-bis(2-hydroxy-1-benzyl)-2-(fluoren-9-ylidene) malonamide (3c)
25
Prepared according to procedure 3.2.1. Yield: 1.45 g (88 %). m.p. 197.5~198.5 °C; [α]D = +23.0
(c = 0.45, CH2Cl2). IR (cm-1): 3423, 1637, 1627, 1537, 1449, 1035, 775, 727, 701; 1H-NMR (DMSO):
δ 8.43-8.41(d, J = 8.40 Hz, 2H, NH), 7.78 (d, J = 7.50 Hz, 2H, ArH), 7.48-7.45(d, J = 7.80 Hz, 2H,
ArH), 7.37-7.17(m, 10H, ArH), 7.05(t, J = 7.50 Hz, 2H, ArH), 4.92 (t, J = 5.25 Hz, 2H), 4.24-4.19 (m,
2H, CHNH), 3.52-3.45 (m, 2H, CH2O), 3.42-3.35(m, 2H, CH2O), 2.94 (dd, J = 6.09, 13.50 Hz, 2H,
CH2Ph), 2.74 (dd, J = 7.80, 13.80 Hz, 2H, CH2Ph); 13C-NMR (DMSO): δ 164.8, 139.9, 139.0, 135.5,
133.8, 132.5, 129.4, 129.3, 128.4, 127.5, 126.3, 124.7, 119.9, 62.2, 53.0, 36.6; Anal. Calcd. for
C34H32N2O4 (532.63): C 76.67, H 6.06, N 5.26; Found: C 76.62, H 6.20, N 5.37.
3.2.4. (S,S)-N,N-bis(2-hydroxy-1-phenyl)-2-(fluoren-9-ylidene) malonamide (3d)
25
Prepared according to procedure 3.2.1. Yield: 1.33g (85%). m.p. 238~239 °C; [α]D = +40.0
1
(c = 0.1, CH2Cl2). IR (cm-1): 3436, 1639, 1532, 1449, 1040, 720, 700; H-NMR (DMSO): δ 9.05 (d,

Molecules 2010, 15
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J = 8.10 Hz, 2H, NH), 7.81 (d, J = 7.50 Hz, 2H, ArH), 7.45-7.30 (m, 12H, ArH), 7.01-6.96 (m, 2H,
ArH), 5.08 (dd, J = 7.50, 13.50 Hz, 2H, CHNH), 5.02 (t, J = 5.10 Hz, 2H, OH), 3.71-3.65 (m, 4H,
CH2O); 13C-NMR (DMSO): δ 164.5, 140.3, 139.9, 135.4, 133.6, 132.6, 129.5, 128.3, 127.4, 127.4,
127.2, 124.8, 119.9, 64.5, 55.6; Anal. Calcd. for C32H28N2O4 (504.58): C 76.17, H 5.59, N 5.55;
Found: C 76.01, H 5.70, N 5.27.
3.3. The synthesis and characterization of bis(oxazoline) ligands 1a-d
3.3.1. Bis[(S)-4-iso-propyloxazoline-2-yl]-2-(fluoren-9-yl)-ethene (1a)
MsCl (0.30 g, 2.63 mmol) was slowly added to an ice-cooled solution of the dihydroxydiamide 3a
(0.50 g, 1.15 mmol) and Et3N (4 mL, 28 mmol) in CH2Cl2 (20 mL). The mixture was allowed to warm
to room temperature and stirred for 12 h. The mixture was washed with water (2 × 5 mL). The organic
layer was dried over anhydrous Na2SO4 and concentrated to dryness in vacuo, the residue was purified
by flash chromatography on silica gel (ethyl acetate/petroleum ether, 1/1, v/v) to afford 1a as a yellow
25
solid. Yield: 0.36 g (78%); m.p. 163~164.5 °C; [α]D = -88.6 (c = 0.50, CH2Cl2). IR (cm-1): 2956,
1
2874, 1652, 1609, 1481, 1447, 1370, 1016, 946, 785, 732; H-NMR (CDCl3): δ 7.73 (d,
J = 7.46 Hz, 2H), 7.58 (d, J = 7.50Hz, 2H), 7.35-7.30 (m, 2H, ArH), 7.21-7.15 (m, 2H, ArH),
4.51-4.46 (m, 2H, CHN=), 4.26-4.15 (m, 4H, CH2O), 1.96 (t, J = 6.63 Hz, 2H, CHMe), 1.06 (d,
13
J = 6.75 Hz, 6H, CH3), 0.99 (d, J = 6.75 Hz, 6H, CH3); C-NMR (CDCl3): δ 161.3, 144.8, 141.5,
136.5, 130.2, 127.2, 125.9, 119.5, 115.1, 73.4, 70.3, 32.7, 19.1, 18.3; Anal. Calcd. for C26H28N2O2
(400.51): C 77.97, H 7.05, N 6.99; Found: C 77.98, H 7.24, N 7.07.
3.3.2. Bis[(S)-4-iso-butyloxazoline-2-yl]-2-(fluoren-9-yl)-ethene (1b)
Prepared according to procedure 3.3.1, starting from 3b (0.5 g, 1.08 mmol) and MsCl (0.28 g,
2.46 mmol) in CH2Cl2 (15.0 mL); yellow solid; yield: 0.39 g (84 %); m.p. 67.0~68.5 °C; [α]D25 = -88.8
(c = 0.25, CH2Cl2). IR (cm-1): 2955, 1648, 1468, 1449, 1368, 1276, 1152, 1040, 1003, 938, 786, 728;
1H-NMR (CDCl3): δ 7.75 (d, J = 7.80 Hz, 2H, ArH), 7.58 (d, J = 7.50 Hz, 2H, ArH), 7.36-7.30 (m, 2H,
ArH), 7.21-7.16 (m, 2H, ArH), 4.59-4.53 (dd, J = 7.80, 9.60 Hz, 2H, CH2O), 4.48-4.40 (m, 2H,
CHN=), 4.05 (t, J = 7.80 Hz, 2H, CH2O), 1.90-1.78 (m, 4H, CH2), 1.52-1.41 (m, 2H, CHMe2), 0.99 (t,
13
J = 6.0 Hz, 12H, CH3); C-NMR (CDCl3): δ 161.1, 144.8, 141.5, 136.4, 130.2, 127.1, 125.9, 119.4,
114.9, 73.2, 70.3, 65.6, 44.9, 25.3, 22.6, 22.6; Anal. Calcd. for C28H32N2O2 (428.57): C 78.47, H 7.53,
N 6.54. Found: C 78.66, H 7.75, N 6.57.
3.3.3. Bis[(S)-4-benzyloxazoline-2-yl]-2-(fluoren-9-yl)-ethene (1c)
Prepared according to the procedure 3.3.1, starting from 3c (0.50 g, 0.94 mmol) and MsCl (0.25 g,
2.19 mmol) in CH2Cl2 (15.0 mL); yellow solid; yield: 0.36g (77%); m.p. 120.0~122.0 °C;
25
[α]D = -108.8 (c = 0.25, CH2Cl2). IR (cm-1): 2957,1649, 1614, 1496, 1449, 1309, 1228, 1147, 1018,
1
977, 783, 728, 700; H-NMR (CDCl3): δ 7.61 (d, J = 7.84 Hz, 2H), 7.56 (d, J = 7.23 Hz, 2H, ArH),
7.35-7.21 (m, 12H, ArH), 7.16-7.11(m, 2H), 4.79-4.68 (m, 4H, CHN=), 4.45(t, J = 8.74 Hz, 2H,
CH2O), 4.18 (t, J = 8.44 Hz, 2H, CH2O), 3.32 (dd, J = 5.18, 13.81Hz, 2H, CH2Ph), 2.90 (dd, J = 8.60,
13
13.80 Hz, 2H, CH2Ph); C-NMR (CDCl3): δ 162.0, 145.4, 141.6, 137.6, 136.4, 130.4, 129.4, 128.6,

Molecules 2010, 15
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127.3, 126.6, 126.0, 119.5, 114.4, 72.0, 68.5, 41.1; Anal. Calcd. for C34H28N2O2 (496.60): C 82.23, H
5.68, N 5.64. Found: C 82.47, H 5.77, N 5.47.
3.3.4. Bis[(S)-4-phenyloxazoline-2-yl]-2-(fluoren-9-yl)-ethene (1d)
Prepared according to the procedure 3.3.1, starting from 3d (0.50 g, 0.99 mmol) and MsCl (0.25 g,
2.19 mmol) in CH2Cl2 (15.0 mL); yellow solid; yield: 0.35 g (75 %); m.p. 167.5~168.5 °C;
25
[α]D = -104.4 (c = 0.45, CH2Cl2); IR (cm-1): 1653, 1448, 1356, 1268, 1204, 1145, 1017, 957, 938,
1
786, 735, 701; H-NMR (CDCl3): δ 7.79 (d, J = 7.83 Hz, 2H, ArH), 7.60 (d, J = 7.47 Hz, 2H, ArH),
7.42-7.26 (m, 12H, ArH), 7.18-7.15(m, 2H, ArH), 5.57 (dd, J = 8.64, 10.26 Hz, 2H, CHN=), 4.90 (dd,
13
J = 8.61, 10.32 Hz, 2H, CH2O), 4.38 (t, J = 8.61 Hz, 2H, CH2O); C-NMR (CDCl3): δ 162.9, 146.1,
141.7, 141.6, 136.40, 130.6, 128.8, 127.7, 127.4, 126.9, 126.2, 119.6, 114.0, 74.8, 70.7; Anal. Calcd.
for C32H24N2O2 (468.55): C 82.03, H 5.16, N 5.98; Found: C 82.22, H 5.27, N 5.89.
3.4. General procedure for the asymmetric F-C alkylation of indoles with alkylidenemalonates
Cu(OTf)2 (0.025 mmol) was added to a Schlenk tube, followed by ligand 1d (0.0275 mmol) in
iso-butanol (1.0 mL) under N2, the solution was stirred for 1.5 h at room temperature, a mixture of the
appropriate diethyl arylidenemalonate (0.25 mmol) in the above solvent (1.0 mL) was added. After
stirring for 30 min the indole (0.25 mmol) was added. After stirring for 24~48 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 in high yield; the
enantiomeric excesses of all adducts were determined by HPLC with a chiral column (Daicel Chiralcel
OD-H; hexane-isopropyl alcohol 90:10; flow rate 0.8 mL/min; 254 nm).
3.4.1. (S)–Ethyl 2–ethoxycarbonyl–3–(3–indolyl)–3–phenyl propanoate
Prepared according to the general procedure from diethyl benzylidenemalonate and indole to
25
provide the pure product as a white solid; m.p. 172-176 °C; [α]D = + 33.6 (c = 0.45, CH2Cl2);
1H-NMR (CDCl3): δ 8.04 (brs, 1H, NH), 7.55 (d, J = 8.0 Hz, 1H, ArH), 7.09-7.37 (m, 8H, ArH),
7.00-7.07(m, 1H, ArH), 5.07 (d, J = 11.7 Hz, 1H, CH), 4.28 (d, J = 11.7 Hz, 1H, CH), 3.93-4.04 (m,
13
4H, OCH2), 0.96-1.03 (m, 6H, CH3); C-NMR (CDCl3): δ 168.1, 167.9, 141.4, 136.2, 128.4, 128.2,
126.8, 126.7, 122.3, 120.9, 119.5, 119.4, 117.0, 111.0, 61.5, 61.4, 58.4, 42.9, 13.8. HPLC analysis: tr
(minor) = 12.43 min, tr (major) = 15.14 min, 78% ee.
3.4.2. (S)–Ethyl 2–ethoxycarbonyl–3–(3–indolyl)–3–(p-methylphenyl) propanoate
Prepared according to the general procedure from diethyl p-methylbenzylidenemalonate and indole
25
1
to provide the pure product as a white solid; m.p. 137-139 °C; [α]D = +10.5 (c = 0.50, CH2Cl2); H-
NMR (CDCl3): δ 7.97 (s, 1H, NH), 7.54 (d, J = 7.80 Hz, 1H, ArH), 7.29-7.23 (m, 3H, ArH), 7.16-7.09
(m, 2H, ArH), 7.04-6.99 (m, 2H, ArH), 5.03 (d, J = 11.70 Hz, 1H, CH), 4.26 (d, J = 11.70 Hz, 1H,
13
CH), 2.24 (s, 3H, CH3), 1.03 (t, J = 6.90 Hz, 3H, CH3), 0.97 (t, J = 6.90 Hz, 3H, CH3). C-NMR
(CDCl3): δ 168.1, 167.9, 138.4, 136.2, 136.2, 129.0, 128.0, 126.7, 122.2, 120.8, 119.5, 119.5, 117.3,

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110.9, 61.4, 61.4, 58.4, 42.4, 21.0, 13.8. HPLC analysis: tr (minor) = 14.99 min, tr (major) = 16.28 min,
37% ee.
3.4.3. (S)–Ethyl 2–ethoxycarbonyl–3–(3–indolyl)–3–(p-fluorophenyl)) propanoate
Prepared according to the general procedure from diethyl p-fluorobenzylidenemalonate and indole
25
to provide the pure product as a white solid; m.p. 132.5-134 °C; [α]D = +22.0 (c = 0.50, CH2Cl2);
1H-NMR (CDCl3): δ 8.03 (s, 1H, NH), 7.62 (d, J = 8.10 Hz, 1H, ArH), 7.32-7.05 (m, 5H, ArH), 6.98
(d, J = 2.76 Hz, 1H, ArH), 6.84 (dd, J = 3.90, 5.10 Hz, 1H, ArH), 5.38 (d, J = 11.40 Hz, 1H, CH), 4.29
(d, J = 11.40 Hz, 1H, CH), 4.10(q, J = 7.20 Hz, 2H, OCH2), 3.93 (q, J = 6.99 Hz, 2H, OCH2), 1.13 (t,
J = 6.84 Hz, 3H, CH3), 0.91 (t, J = 7.08 Hz, 3H, CH3); 13C-NMR (CDCl3): δ 168.0, 167.8, 161.7, 137.5,
137.6, 136.4, 129.9, 129.8, 126.6, 122.5, 120.9, 119.8, 119.4, 116.9, 115.5, 115.2, 111.2, 61.8, 61.7,
58.5, 42.5, 13.9, 13.8. HPLC analysis: tr (minor) = 15.57 min, tr (major) = 18.19 min, 31% ee.
3.4.4. (S)–Ethyl 2–ethoxycarbonyl–3–(3–indolyl)–3–(m-bromophenyl) propanoate
Prepared according to the general procedure from diethyl m-bromobenzylidenemalonate and indole
25
1
to provide the pure product as a white solid; m.p. 123-124 °C; [α]D = +24.0 (c = 0.20, CH2Cl2); H-
NMR (CDCl3): δ 8.05(s, 1H, NH), 7.50 (dd, 2H, ArH), 7.32-7.02 (m, 7H, ArH), 5.04 (d, J = 12.0 Hz,
1H, CH),4.23 (d, J = 12.0 Hz, 1H), 4.05-3.98 (m, 4H, OCH2), 1.08-0.96 (m, 6H, CH3); 13C-NMR
(CDCl3): δ 167.8, 167.7, 146.9, 146.3, 131.3, 129.9, 127.0, 126.5, 122.4, 122.4, 121.1, 119.6, 119.1,
116.1, 111.2, 61.7, 58.2, 42.4, 13.9, 13.7. HPLC analysis: tr(minor) = 15.31 min, tr (major) = 20.64 min),
52% ee.
3.4.5. (S)–Ethyl 2–ethoxycarbonyl–3–(3–indolyl)–3–(o-chlorophenyl) propanoate
Prepared according to the general procedure from diethyl o-chlorobenzylidenemalonate and indole
25
1
to provide the pure product as a white solid; m.p. 125-127 °C; [α]D = +22.6 (c = 0.50, CH2Cl2); H-
NMR (CDCl3): δ 8.15 (s, 1H, NH), 7.68 (d, J = 7.80 Hz, 1H, ArH), 7.40-7.23(m, 3H, ArH), 7.14-7.04
(m, 5H, ArH), 5.66 (d, J = 11.70 Hz, 1H, CH), 4.40 (d, J = 11.70 Hz, 1H, CH), 4.04-3.92 (m, 4H,
13
OCH2), 1.01 (t, J = 6.90 Hz, 3H, CH3), 0.94 (t, J = 6.90 Hz, 3H, CH3); C-NMR (CDCl3): δ 168.1,
167.7, 139.3, 136.2, 134.2, 129.9, 129.0, 128.1, 126.9, 126.8, 122.3, 122.2, 119.6, 119.7, 115.8, 111.3,
61.7, 57.8, 38.9, 13.8, 13.7. HPLC analysis: tr (minor) = 15.88 min, tr (major) = 20.63 min, 88% ee.
3.4.6. (S)–Ethyl 2–ethoxycarbonyl–3–(3–indolyl)–3–(o-methylphenyl) propanoate
Prepared according to the general procedure from diethyl o-methylbenzylidenemalonate and indole
to provide the pure product as a white solid; m.p. 94-95 °C; [α]D25 = +1.5 (c = 0.20, CH2Cl2). 1H-NMR
(CDCl3): δ 7.87 (s, 1H, NH), 7.82 (d, J = 7.50 Hz, 2H, ArH), 7.64-7.62 (m, 1H, ArH), 7.37-7.25 (m,
3H), 7.20-7.00 (m, 3H, ArH), 5.31(d, J = 12.0 Hz, 1H, CH), 4.33(d, J = 12.0 Hz, 1H, CH), 4.00-3.86
13
(m, 4H, OCH2), 1.01-0.85 (m, 6H, CH3); C-NMR (75MHz, CDCl3): δ 168.4, 167.9, 140.1, 136.3,
135.9, 130.7, 126.8, 126.4, 126.3, 126.0, 122.3, 122.1, 119.5, 119.3, 116.5, 110.9, 61.4, 61.3, 58.5,
38.0, 19.9, 13.7, 13.6. HPLC analysis: tr (minor) = 12.21 min, tr (major) = 15.39 min, 15% ee.

Molecules 2010, 15
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3.4.7. (S)–Ethyl 2–ethoxycarbonyl–3–[3–(5-methoxyindolyl)]–3–phenylpropanoate
Prepared according to the general procedure from diethyl benzylidenemalonate and
5-methoxyindole to provide the pure product as a white solid; m.p. 143-145 °C; [α]D25 = +6.0 (c = 0.20,
CH2Cl2); 1H-NMR (CDCl3): δ 7.91(s, 1H, NH), 7.38-7.34 (m, 2H, ArH), 7.25-7.11 (m, 4H, ArH), 6.96
(d, J = 2.40Hz, 1H, ArH), 6.78 (dd, J = 2.40 Hz, 9.0 Hz, ArH), 5.01 (d, J = 12.0 Hz, CH), 4.25 (d,
J = 12.0 Hz, CH), 4.05-3.94 (m, 4H, 2×CH2), 3.78 (s, 3H, OCH3), 1.00 (t, J = 7.20 Hz, 6H, 2×CH3).
13C-NMR (CDCl3): δ 168.1, 167.6, 140.8, 139.6, 131.5, 128.7, 127.4, 127.3, 126.7, 120.8, 111.7, 101.3,
61.6, 61.5, 58.4, 55.8, 42.5, 13.8. HPLC analysis: tr (minor) = 20.40 min, tr (major) = 27.86 min, 41% ee.
3.4.8. (S)–Ethyl 2–ethoxycarbonyl–3–[3–(5-methylindolyl)]–3–phenylpropanoate
Prepared according to the general procedure from diethyl benzylidenemalonate and 5-methylindole
25
to provide the pure product as a white solid; m.p. 176.5-178 °C; [α]D = +24.0 (c = 0.50, CH2Cl2);
1H-NMR (CDCl3): δ 7.89 (s, 1H, NH), 7.38-7.33 (m, 3 H, ArH), 7.26-7.13 (m, 5H, ArH), 5.04 (d,
J = 11.70 Hz, 1H, CH), 4.26 (d, J = 11.70 Hz, 1H, CH), 4.03-3.93(m, 4H, 2×CH2), 2.38 (s, 3H, CH3),
1.02-0.97 (m, 6H, 2×CH3); 13C-NMR (CDCl3): δ 167.9, 167.8, 141.3, 134.3, 128.5, 128.2, 128.0, 126.7,
126.6, 123.7, 120.8, 118.7, 116.3, 110.4, 76.6, 61.3, 61.2, 58.3, 42.6, 21.5, 13.5, 13.6. HPLC analysis:
tr (minor) = 13.28 min, tr (major) = 16.45 min, 47% ee.
3.4.9. (S)–Ethyl 2–ethoxycarbonyl–3–[3–(5-chloroindolyl)]–3–phenylpropanoate
Prepared according to the general procedure from diethyl benzylidenemalonate and 5-chloroindole
25
to provide the pure product as a white solid; m.p. 190-192 °C; [α]D = -6.0 (c = 0.20, CH2Cl2);
1H-NMR (CDCl3): δ 8.03 (s, 1H, NH), 7.51 (d, J = 1.80 Hz, 1H, ArH), 7.36-7.06 (m, 7H, ArH), 6.91
(d, J = 2.49 Hz, 1H, ArH), 5.00 (d, J = 12.0 Hz, 1H, CH), 1.03-0.98 (m, 6 H, 2×CH3); 13C-NMR
(CDCl3): δ 167.9, 167.8, 141.1, 134.9, 128.6, 128.5, 128.1, 127.1, 125.4, 122.3, 122.1, 116.8, 113.1,
112.6, 77.4, 61.6, 61.5, 58.6, 42.7, 13.9. HPLC analysis: tr (minor) = 14.88 min, tr (major) = 20.25 min,
45% ee.
3.4.10. (S)–Ethyl 2–ethoxycarbonyl–3–[3–(6-chloroindolyl)]–3–phenylpropanoate
Prepared according to the general procedure from diethyl benzylidenemalonate and 6-chloroindole
25
to provide the pure product as a white solid; m.p. 203-205 °C; [α]D = +20.0 (c = 0.25, CH2Cl2);
1H-NMR (CDCl3): δ 8.02 (s, 1H, NH), 7.42 (d, J = 8.40 Hz, 1H, ArH), 7.35-7.15 (m, 7H, ArH), 5.02
(d, J = 11.70 Hz, 1H, CH), 4.25 (d, J = 12.0 Hz, 1H, CH), 4.04-3.94 (m, 4 H, 2×CH2), 1.00 (t,
J = 7.20 Hz, 2×CH3); 13C-NMR (CDCl3): δ 167.9, 167.7, 141.1, 136.5, 128.4, 128.2, 128.1, 126.9,
125.3, 121.5, 120.3, 120.2, 117.2, 110.9, 77.4, 61.5, 61.4, 58.3, 42.7, 13.7. HPLC analysis:
tr(minor) = 14.93 min, tr (major) = 17.95 min, 10% ee.
4. Conclusions
In summary, a series of novel C2-symmetric fluoren-9-ylidene malonate-derived bis(oxazoline)
ligands were synthesized in good yields for the first time from diethyl fluoren-9-ylidene malonate and

Molecules 2010, 15
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chiral amino alcohols. Their application in the asymmetric catalytic Friedel-Crafts reaction of indoles
and alkylidene malonates was examined. The copper complex of ligand 1d bearing a phenyl group
showed moderate to good enantioselectivity. Further experiments to extend the scope of use of these
catalysts are currently in progress in our laboratory.
Acknowledgements
We are grateful for financial support from the Chinese Universities Scientific Fund (NO.2009JS31)
and the Innovation Programme for National Undergraduate Students.
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