Synthesis of New C₂- Symmetric Fluoren-9-ylidene Malonate Derived Bis(oxazoline) Ligands and Their Application in Friedel-Crafts Reactions

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).

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 [1,2,3]. 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 [4,5,6]. 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 this type of BOX ligand have appeared, such as I and II (Figure 1) [7,8,9]. 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.

Figure 1. Typical alkylidene and arylidene malonate-type bis(oxazoline) ligands.

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.

Scheme 1. Synthesis of chiral bis(oxazolines) 1.

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 [11,12,13,14,15,16,17]. The F-C alkylation was performed in iso-butanol at room temperature employing Cu(OTf)₂-bis(oxazoline) complexes 1a~d (10 mol%) as 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)₂6H₂O 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.

Scheme 2. Friedel-Crafts alkylations catalyzed by Cu(OTf)₂-bis(oxazoline) complexes 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
1	1a	isobutanol	Cu(OTf)2	99	39
2	1b	isobutanol	Cu(OTf)2	99	16
3	1c	isobutanol	Cu(OTf)2	99	57
4	1d	isobutanol	Cu(OTf)2	99	78
5	1d	isobutanol	Cu(ClO4)2H2O	99	34
6	1d	isopropanol	Cu(OTf)2	99	77
7	1d	ethanol	Cu(OTf)2	99	78.
8	1d	methanol	Cu(OTf)2	99	40
9	1d	CH2Cl2	Cu(OTf)2	90	25

^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.

Table 1. Effect of ligands and solvent in Cu(II)-catalyzed Friedel-Crafts alkylations. ^a

Entry	Ligands	Solvent	Salt	Yield (%)b	Ee (%)c
1	1a	isobutanol	Cu(OTf)2	99	39
2	1b	isobutanol	Cu(OTf)2	99	16
3	1c	isobutanol	Cu(OTf)2	99	57
4	1d	isobutanol	Cu(OTf)2	99	78
5	1d	isobutanol	Cu(ClO4)2H2O	99	34
6	1d	isopropanol	Cu(OTf)2	99	77
7	1d	ethanol	Cu(OTf)2	99	78.
8	1d	methanol	Cu(OTf)2	99	40
9	1d	CH2Cl2	Cu(OTf)2	90	25

^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.

Scheme 3. F-C alkylations of different indoles and malonates.

Scheme 3. F-C alkylations of different indoles and malonates.

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	H	p-MeC6H4	24	99	37	S
2	H	p-FC6H4	24	90	31	S
3	H	m-BrC6H4	48	95	52	S
4	H	o-ClC6H4	48	60	88	S
5	H	o-MeC6H4	48	65	15	S
6	5-MeO	C6H5	24	99	41	S
7	5-Me	C6H5	24	99	47	S
8	5-Cl	C6H5	48	90	45	S
9	6-Cl	C6H5	48	80	10	S

^a All reactions were conducted in isobutanol under nitrogen using 10 mol% catalyst at room temperature; ^b Isolated yield; ^c Determined by chiral HPLC.

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	H	p-MeC6H4	24	99	37	S
2	H	p-FC6H4	24	90	31	S
3	H	m-BrC6H4	48	95	52	S
4	H	o-ClC6H4	48	60	88	S
5	H	o-MeC6H4	48	65	15	S
6	5-MeO	C6H5	24	99	41	S
7	5-Me	C6H5	24	99	47	S
8	5-Cl	C6H5	48	90	45	S
9	6-Cl	C6H5	48	80	10	S

^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 invacuo. The residue was cooled to 0 °C and acidified with aqueous HCl (6 M). The 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; [α]_D²⁵ = +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)

Prepared according to procedure 3.2.1. Yield: 1.20 g (84%). m.p. 223~224.5 °C; [α]_D²⁵ = +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)

Prepared according to procedure 3.2.1. Yield: 1.45 g (88 %). m.p. 197.5~198.5 °C; [α]_D²⁵ = +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)

Prepared according to procedure 3.2.1. Yield: 1.33g (85%). m.p. 238~239 °C; [α]_D²⁵ = +40.0 (c = 0.1, CH₂Cl₂). IR (cm^-1): 3436, 1639, 1532, 1449, 1040, 720, 700; ¹H-NMR (DMSO): δ 9.05 (d, 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 drynessinvacuo, the residue was purified by flash chromatography on silica gel (ethyl acetate/petroleum ether, 1/1, v/v) to afford 1a as a yellow solid. Yield: 0.36 g (78%); m.p. 163~164.5 °C; [α]_D²⁵ = -88.6 (c = 0.50, CH₂Cl₂). IR (cm^-1): 2956, 2874, 1652, 1609, 1481, 1447, 1370, 1016, 946, 785, 732; ¹H-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, J = 6.75 Hz, 6H, CH₃), 0.99 (d, J = 6.75 Hz, 6H, CH₃); ¹³C-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, J = 6.0 Hz, 12H, CH₃); ¹³C-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; [α]_D²⁵ = -108.8 (c = 0.25, CH₂Cl₂). IR (cm^-1): 2957,1649, 1614, 1496, 1449, 1309, 1228, 1147, 1018, 977, 783, 728, 700; ¹H-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, 13.80 Hz, 2H, CH₂Ph); ¹³C-NMR (CDCl₃): δ 162.0, 145.4, 141.6, 137.6, 136.4, 130.4, 129.4, 128.6, 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; [α]_D²⁵ = -104.4 (c = 0.45, CH₂Cl₂); IR (cm^-1): 1653, 1448, 1356, 1268, 1204, 1145, 1017, 957, 938, 786, 735, 701; ¹H-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, J = 8.61, 10.32 Hz, 2H, CH₂O), 4.38 (t, J = 8.61 Hz, 2H, CH₂O); ¹³C-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 provide the pure product as a white solid; m.p. 172-176 °C; [α]_D²⁵ = + 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, 4H, OCH₂), 0.96-1.03 (m, 6H, CH₃); ¹³C-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: t_r (minor) = 12.43 min, t_r (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 to provide the pure product as a white solid; m.p. 137-139 °C; [α]_D²⁵ = +10.5 (c = 0.50, CH₂Cl₂); ¹H-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, CH), 2.24 (s, 3H, CH₃), 1.03 (t, J = 6.90 Hz, 3H, CH₃), 0.97 (t, J = 6.90 Hz, 3H, CH₃). ¹³C-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, 110.9, 61.4, 61.4, 58.4, 42.4, 21.0, 13.8. HPLC analysis: t_r (minor) = 14.99 min, t_r (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 to provide the pure product as a white solid; m.p. 132.5-134 °C; [α]_D²⁵ = +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: t_r (minor) = 15.57 min, t_r (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 to provide the pure product as a white solid; m.p. 123-124 °C; [α]_D²⁵ = +24.0 (c = 0.20, CH₂Cl₂); ¹H-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: t_r(minor) = 15.31 min, t_r (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 to provide the pure product as a white solid; m.p. 125-127 °C; [α]_D²⁵ = +22.6 (c = 0.50, CH₂Cl₂); ¹H-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, OCH₂), 1.01 (t, J = 6.90 Hz, 3H, CH₃), 0.94 (t, J = 6.90 Hz, 3H, CH₃); ¹³C-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: t_r (minor) = 15.88 min, t_r (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 (m, 4H, OCH₂), 1.01-0.85 (m, 6H, CH₃); ¹³C-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: t_r (minor) = 12.21 min, t_r (major) = 15.39 min, 15% ee.

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: t_r (minor) = 20.40 min, t_r (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 to provide the pure product as a white solid; m.p. 176.5-178 °C; [α]_D²⁵ = +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: t_r (minor) = 13.28 min, t_r (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 to provide the pure product as a white solid; m.p. 190-192 °C; [α]_D²⁵ = -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: t_r (minor) = 14.88 min, t_r (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 to provide the pure product as a white solid; m.p. 203-205 °C; [α]_D²⁵ = +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: t_r(minor) = 14.93 min, t_r (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 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.