The synthesis of novel chiral N,O-ferrocenyl ligands and their application in the addition of diethylzinc to aldehydes

Article abstract of DOI:10.1016/S0957-4166(99)00512-1

Novel chiral N,O-ferrocenyl ligands, in which N and O groups were attached to two different Cp rings of ferrocene, were synthesized from easily available ferrocene, and applied to the asymmetric diethylzinc addition to aldehydes. High chemical yields and good enantioselectivities (up to 90.9% ee) were obtained by using ferrocene ligand 6. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(99)00512-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 4689–4693
The synthesis of novel chiral N,O-ferrocenyl ligands and their
application in the addition of diethylzinc to aldehydes
∗
Wei-Ping Deng, Xue-Long Hou and Li-Xin Dai
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
3
54 Fenglin Lu, Shanghai 200032, China
Received 7 October 1999; accepted 9 November 1999
Abstract
Novel chiral N,O-ferrocenyl ligands, in which N and O groups were attached to two different Cp rings of
ferrocene, were synthesized from easily available ferrocene, and applied to the asymmetric diethylzinc addition to
aldehydes. High chemical yields and good enantioselectivities (up to 90.9% ee) were obtained by using ferrocene
ligand 6. © 2000 Published by Elsevier Science Ltd. All rights reserved.
1
. Introduction
The ferrocene-based chiral ligand has became a noteworthy class of ligand in asymmetric catalysis and
1
at least two of them have been used in industrial processes. In recent years, much effort has been made
to study chiral 1,2-disubstituted bidentate ferrocene ligands because of the inherent nature of their planar
2
3
4
0
chirality, for example compounds 1, 2 and 3 (Scheme 1). However, the study of 1,1 -disubstituted
5
0
bidentate ferrocene ligands has rarely been reported. We report herein the synthesis of novel chiral 1,1 -
disubstituted bidentate ferrocene ligands 4–7, and their application in the ligand-accelerated addition of
4
diethylzinc to aldehydes.
Scheme 1.
∗
Corresponding author. E-mail: xlhou@pub.sioc.ac.cn
0
957-4166/99/$ - see front matter © 2000 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00512-1
tetasy 3147

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W.-P. Deng et al. / Tetrahedron: Asymmetry 10 (1999) 4689–4693
2. Results and discussion
Quite recently, Ahn and Bryce5b,6 synthesized ferrocene derivative 8a with a versatile functional group
(bromine) on the second Cp ring of the ferrocene. It seems that the bromo–lithium exchange followed
by trapping with various electrophiles such as PhSSPh, Ph PCl, Ph CO, etc., should give a series of
2
2
0
1
,1 -disubstituted ferrocenyloxazolines which could be used as chiral ligands in asymmetric catalysis. In
fact, compound 8a is equal to a key intermediate to afford all kinds of ligands. In order to realize this
6
new idea, firstly, compound 8a was synthesized with high yield according to Bryce’s method, then this
0
method was successfully extended to the synthesis of a series of 1 -bromo-ferrocenyloxazolines 8c–d,
with different substituents on the oxazoline ring, in high chemical yields. Ferrocene derivatives 8a–d
were then treated with n-BuLi in THF at −78°C for 30 min followed by trapping with benzophenone, as
we expected, to afford the target products 4–7 in reasonable yields (Scheme 2).
Scheme 2.
In order to examine the effectiveness of these ligands, the addition of diethylzinc to aldehyde as a
model reaction was tested. Table 1 shows that this kind of ligand showed good catalytic activities and
enantioselectivities.
In pursuit of a good enantioselective and high-yielding catalytic system, we examined the effects of
a variety of reaction conditions including solvent, temperature, ligand and the amount of ligand (entries
1
–7). After much experimentation, it was found that the use of 5 mol% ferrocene 6 as the ligand in
toluene at 0°C gave the best result (98% yield, 88.6% ee, entry 6).
Next, the standard set of reaction conditions was applied to the addition of diethylzinc to various
aldehydes. In all cases, the ligand 6 proved to be effective to induce formation of the secondary alcohols
of (R)-configuration with high chemical yields and moderate to good enantioselectivity (up to 90.9%
ee). Moreover, for aromatic aldehydes, an electron-donating group on the benzene ring turned out to
slightly reduce the level of asymmetric induction (entries 9, 11 and 15). For aliphatic aldehydes, moderate
enantioselectivity was obtained (71.7% ee, 64.2% ee).
In summary, novel N,O-ferrocenyl ligands 4–7 in which the N- and the O-groups were attached to
the two different Cp rings of ferrocene were synthesized. With this novel kind of ligand, the addition of
diethylzinc to aldehyde was carried out in high chemical yield and with good ee values. Further studies
on the preparation of these kinds of novel N,O-ferrocenyl ligands and their applications in asymmetric
synthesis are in progress.

W.-P. Deng et al. / Tetrahedron: Asymmetry 10 (1999) 4689–4693
4691
Table 1
a
Enantioselective addition of diethylzinc to aldehydes using 4–7 as ligand
3. Experimental
3.1. General
All of the reactions were performed under a dry argon atmosphere. Toluene, hexane and THF were
freshly distilled from sodium. The commercially available reagents were used as received without
1
further purification. Melting points are uncorrected. H NMR spectra were recorded on a Bruker AMX-
3
00 (300 MHz) spectrometer in CDCl at room temperature. Chemical shifts are given in parts per
3
million downfield from tetramethylsilane. Optical rotations were measured on a Perkin–Elmer 241 MC
polarimeter with a thermally jacketed 10 cm cell at 25°C (concentration c given as g/100 mL). IR spectra
−
1
were recorded in KBr and measured in cm , using a Shimadzu IR-440 infrared spectrophotometer.
Mass spectra and high-resolution mass spectra were taken using HP 5989A and Finnigan MAT mass

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W.-P. Deng et al. / Tetrahedron: Asymmetry 10 (1999) 4689–4693
spectrometers, respectively. Elemental analyses were performed on a Foss–Heraeus Vario EL instrument.
Enantiomeric excesses were determined by chiral HPLC on a Chiralcel OD column.
0
3
.2. 1-[(S)-4-Isopropyl-2,5-oxazolinyl]-1 -(α-diphenylhydroxymethyl)ferrocene 4
To a solution of 8a (113 mg, 0.3 mmol) in THF (4 mL) was added n-butyllithium (1.6 M in hexane,
0.2 mL, 0.32 mmol) at –78°C. The reaction mixture was stirred for an additional 30 min and then
trapped with benzophenone (109 mg, 0.6 mmol) at this temperature. After stirring at 0°C for 20 min,
the reaction mixture was washed with water and then with brine and dried over Na SO After the
2
4.
solvent was removed under reduced pressure, the residue was purified by column chromatography with
ethyl acetate:petroleum (60–90°C, 1:3) as an eluent to afford 4 (133 mg, 93%) as an orange solid. M.p.
2
5
1
9
1
(
7–98°C. [α] =−86.0 (c 0.2, EtOH). H NMR δ 0.92 (d, J=6.74 Hz, 3H), 1.06 (d, J=6.74 Hz, 3H),
D
.84 (m, 1H), 3.95–4.20 (m, 6H), 4.30–4.46 (m, 3H), 4.76 (s, 3H), 7.17–7.38 (m, 10H). MS m/z 479
M , 100.0), 249 (83.8), 163 (67.8), 229 (65.3), 230 (43.3), 228 (41.9). IR (KBr) 3441, 2955, 1643,
+
1
485, 1117, 753, 768, 485. Anal. calcd for C H NO Fe: C, 72.66; H, 6.10; N, 2.92. Found: C, 72.72;
29 29 2
H, 6.14; N, 3.17.
0
3
.3. 1-[(S)-4-Benzyl-2,5-oxazolinyl]-1 -(α-diphenylhydroxymethyl)ferrocene 5
Compound 8b (212 mg, 0.5 mmol) was allowed to react according to the procedure for 4 to afford 5
2
5
1
(
216 mg, 82%) as an orange solid. M.p. 64–65°C. [α] =−51.0 (c 0.22, EtOH). H NMR δ 2.69 (dd,
D
J=8.94, 13.69 Hz, 1H), 3.25 (dd, J=4.98, 13.7 Hz, 1H), 4.03–4.13 (m, 3H), 4.13–4.21 (m, 2H), 4.25–
+
4
9
7
2
.39 (m, 3H), 4.42–4.56 (m, 1H), 4.62 (br, 1H), 4.77 (s, 2H), 7.19–7.36 (m, 15H). MS m/z 527 (M ,
1.4), 297 (100.0), 279 (51.2), 229 (81.1), 188 (64.5), 91 (67.8). IR (KBr) 2924, 1645, 1489, 1445, 1122,
51, 700, 496. Anal. calcd for C H NO Fe: C, 75.15; H, 5.54; N, 2.66. Found: C, 75.15; H, 5.55; N,
2
9
29
2
.56.
0
3
.4. 1-[(S)-4-tert-Butyl-2,5-oxazolinyl]-1 -(α-diphenylhydroxymethyl)ferrocene 6
Compound 8c (195 mg, 0.5 mmol) was allowed to react according to the procedure for 4 to afford 6
2
5
1
(
9
220 mg, 90%) as an orange solid. M.p. 137–138°C. [α] =−125.0 (c 0.2, EtOH). H NMR δ 0.96 (s,
D
H), 3.97 (dd, J=8.04, 9.71 Hz, 1H), 4.05–4.23 (m, 5H), 4.25–4.35 (m, 2H), 4.38 (s, 1H), 4.75 (d, J=9.25
Hz, 2H), 4.91 (br, 1H), 7.15–7.46 (m, 10H). MS m/z 493 (M , 24.4), 311 (26.4), 310 (95.2), 254 (100.0),
26 (42.4), 211 (53.26). IR (KBr) 3283, 2965, 1648, 1486, 1123, 957, 754, 703, 499 cm . Anal. calcd
+
−
1
2
for C H NO Fe: C, 73.03; H, 6.33; N, 2.84. Found: C, 73.00; H, 6.32; N, 3.12.
2
9
29
2
0
3
.5. 1-[(R)-4-Phenyl-2,5-oxazolinyl]-1 -(α-diphenylhydroxymethyl)ferrocene 7
Compound 8d (205 mg, 0.5 mmol) was allowed to react according to the procedure for 4 to afford 7
2
5
1
(
(
186 mg, 73%) as an orange solid. M.p. 139–140°C. [α] =+98.6 (c 0.21, EtOH). H NMR δ 4.08–4.27
D
m, 5H), 4.37 (dd, J=1.2, 23.1 Hz, 3H), 4.73 (t, J=9.02 Hz, 1H), 4.87 (d, J=11.2 Hz, 2H), 5.27 (t, J=8.26
Hz, 1H), 7.18–7.47 (m, 15H). MS m/z 513 (M , 99.2), 283 (39.9), 229 (57.9), 193 (100.0), 163 (36.6).
IR (KBr) 3260, 1637, 1446, 1121, 1023, 749, 709, 491 cm . Anal. calcd for C H NO Fe: C, 74.86;
+
−1
2
9
29
2
H, 5.30; N, 2.73. Found: C, 74.90; H, 5.29; N, 2.76.

W.-P. Deng et al. / Tetrahedron: Asymmetry 10 (1999) 4689–4693
4693
3.6. General procedure for catalytic asymmetric addition of diethylzinc to various aldehydes
To a solution of ferrocene ligand 6 (0.05 mmol) in toluene (2.5 mL) was added Et Zn (2.0 mL, 2.0
2
mmol, 1 M in hexane) at room temperature. After 30 min, the reaction system was cooled to 0°C, and the
aldehyde (1.0 mmol) was added under an argon atmosphere. After being stirred for the appropriate time,
the reaction was quenched with 3N HCl. The mixture was extracted with ether. The organic layer was
washed with brine, dried and evaporated under reduced pressure to give an oily residue. Purification of the
residue by preparative TLC gave the optically active alcohol. The enantiomeric excess was determined
by HPLC analysis using a Chiralcel OD column. Configurations were assigned by comparison with the
sign of specific rotation of known compounds.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (project 29790127 and
29872045), the Chinese Academy of Sciences and the Shanghai Committee of Science and Technology
(project 99JC14025).
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