Synthesis of MeO-PEG2000-supported chiral ferrocenyl oxazoline carbinol ligand and its application in asymmetric catalysis

Article abstract of DOI:10.1016/j.tetasy.2016.08.018

A simple method for the synthesis of a MeO-PEG-supported chiral ferrocenyl oxazoline carbinol ligand has been developed. The chiral ligand was successfully applied to the catalytic asymmetric addition of diethylzinc to aryl aldehydes, affording secondary alcohols in high yields and with excellent enantioselectivities (up to 94% ee). The chiral ligand can be recovered and reused twice with no apparent loss of catalyst efficiency.

Full text of DOI:10.1016/j.tetasy.2016.08.018

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of MeO-PEG2000-supported chiral ferrocenyl oxazoline
carbinol ligand and its application in asymmetric catalysis
⇑
⇑
Wen-Xian Zhao , Guan-Jun Liu, Jingjing Wang, Feng Li, Lantao Liu
College of Chemistry and Chemical Engineering, Shangqiu Normal University, 298 Wenhua Road, Shangqiu, Henan 476000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple method for the synthesis of a MeO-PEG-supported chiral ferrocenyl oxazoline carbinol ligand
has been developed. The chiral ligand was successfully applied to the catalytic asymmetric addition of
diethylzinc to aryl aldehydes, affording secondary alcohols in high yields and with excellent enantiose-
lectivities (up to 94% ee). The chiral ligand can be recovered and reused twice with no apparent loss of
catalyst efficiency.
Received 8 August 2016
Accepted 7 September 2016
Available online xxxx
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
asymmetric catalysis have been the subject of increasing interest
in organometallic chemistry, materials science, and catalysis.6
The development of more efficient and environmentally
friendly methodologies in asymmetric catalysis is a very important
area of research in organic chemistry. One area that has attracted a
great deal of interest in recent years is combining asymmetric
catalysis and polymer-supported transition metals.1–3 Chiral cata-
lyst immobilization can overcome problems that traditionally pla-
gue chiral catalysts, such as difficult separation and recycling.2
However, immobilized ligands and catalysts often exhibit lower
enantioselectivities and efficiencies than their non-immobilized
counterparts. Therefore, one of the main challenges of immobilized
chiral ligands is to maintain their activities and selectivities while
facilitating their recovery and recyclability.
Among them, the ferrocenyl-oxazoline carbinols7 and ferrocenyl-
oxazoline silanol8 developed by Bolm et al. were proven to be effi-
cient catalysts for asymmetric arylation reaction of benzaldehydes.
However, only a few reports on soluble polymer supported ferro-
cenyl oxazoline have been reported.9
The monomethyl ether of PEG (MeO-PEG) has been successfully
used to support chiral ligands in some asymmetric reactions.10
Recently, Zhou et al. reported a simple synthesis and application of
MeO-PEG-supported chiral N,P-ligands and N,S-ligands containing
a
ferrocenyl oxazoline moiety.9b Although these results are
important, further investigations are still needed and new
applications remain to be explored. Herein, we report the synthesis
Recently, expensive chiral catalysts have been recovered and
recycled by utilizing soluble PEG polymers as supports. These
PEG-supported catalysts have higher catalytic activities and better
enantioselectivities than those immobilized on other solid materi-
als. PEG-supported catalysts can be easily separated from the reac-
tion mixture by filtration, extraction or precipitation.3
of a MeO-PEG-supported chiral ferrocenyl oxazoline carbinol
ligand and its preliminary application in catalytic asymmetric
additions of diethylzinc to aldehydes, affording secondary alcohols
in high yields and with excellent enantioselectivities. The chiral
ligand can be recovered and reused twice without apparent loss of
catalyst efficiency (see Fig. 1).
In addition to its unique sandwich structure, ferrocene has
many ideal properties such as low cost, thermal stability, planar
chirality, rigid bulkiness, and ease of derivatization.4 These charac-
teristics make ferrocene suitable for its use as a scaffold for chiral
ligands,5 and it may also be beneficial for the new chiral ligand
design. Recently, ferrocene and its derivatives with planar chiral
ferrocenyl oxazoline ligands being the most widely used in
O
N
O-PEG2000-OMe
OH
Fe
Ph
Ph
⇑
Corresponding authors.
E-mail addresses: zhwx2595126@163.com (W.-X. Zhao), liult05@iccas.ac.cn
(L. Liu).
Figure 1. MeO-PEG-supported chiral ferrocenyl-oxazoline carbinol ligand.
http://dx.doi.org/10.1016/j.tetasy.2016.08.018
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
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2
W.-X. Zhao et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Table 1
2. Results and discussion
Optimization of the reaction conditionsa
MeO-PEG-supported chiral ferrocenyl oxazoline carbinol ligand
12 was synthesized from the chiral amino alcohol 6, which was
prepared from inexpensive and readily available L-tyrosine 1. As
O
OH
Et2Zn, 12
toluene, 48 h
H
Ph
13a
Ph
14a
shown in Figure 2, the steps for the synthesis of 6 include esterifi-
cation, protection of the amino group, phenolic hydroxyl protec-
tion, reduction, and removal of the Boc-protecting group.11
Figure 3 shows the synthetic steps for converting amino alcohol
6 into MeO-PEG-supported chiral ligand 12. First, amino alcohol 6
reacted with ferrocene carboxylic acid to form oxazoline 9 accord-
ing to the known procedure.6a,12 Compound 10 was then formed in
moderate yield by ortho-lithiation of ferrocenyl oxazoline 9 by
using s-BuLi at À78 °C in THF, followed by the addition of Ph2CO.
The absolute configuration of 10 was assigned as (Rp,S) by X-ray
crystallographic analysis.13 Compound 10 was then converted into
chiral ferrocenyl oxazoline ligand 11 by removal of the TBS pro-
tecting group. Finally, ligand 11 was reacted with poly(ethylene
glycol) 2000 monomethyl ether mesylate with Cs2CO3 as the base
in DMF to afford the desired MeO-PEG-supported chiral ligand 12
in 90% yield.14
Entry
12 (mol %)
Temp (°C)
Yield (%)b
ee (%)c
Configd
1
2
3
4
5
6
7e
5
3
1
0.1
1
0
0
0
>99
>99
>99
69
90
60
87
88
89
40
84
26
91
(R)
(R)
(R)
(R)
(R)
(R)
(R)
0
À10
20
0
1
1
99
a
Conditions: benzaldehyde (0.5 mmol), Et2Zn (2 mmol), ligand 12 (0.005 mmol)
in toluene at 0 °C for 48 h.
b
Isolated yields.
c
Determined by chiral HPLC.
The configuration of the major products is (R).15
d
e
Ligand 10 was used instead of ligand 12.
and enantioselectivity, these results demonstrate that the opti-
mum amount of chiral ligand 12 was 1 mol %. Next, the effect of
temperature was examined. The product was obtained with 84%
ee and in 90% yield at À10 °C (Table 1, entry 5). When the temper-
ature was increased to 20 °C, the ee decreased to 26% (Table 1,
entry 6). In addition, the reaction of the ligand 10 was also carried
out under the same reaction conditions. Compared with ligand 12,
the product was obtained in 99% yield, while the ee value did not
change significantly (Table 1, entry 7). Thus, the optimal conditions
for the model system were established as 1 mol % ferrocene 12 as
the catalyst and 0 °C.
With chiral ligand 12 in hand, the asymmetric addition of
diethylzinc to aryl aldehydes was carried out to check its catalytic
properties under various reaction conditions and the results are
summarized in Table 1.
Initially, benzaldehyde and diethylzinc (Et2Zn) were chosen as
the model system,16 and the effect of the catalyst loading was next
examined. In the presence of 5 mol % of chiral ligand 12 at 0 °C the
reaction preceded well to give the desired product with 87% ee and
in 99% yield (Table 1, entry 1). When the catalyst loading was
reduced to 3 mol %, (R)-1-phenylpropan-1-ol was obtained without
a significant increase in the ee value (Table 1, entry 2). When the
catalyst loading was further reduced to 1 mol %, the ee increased
slightly to 89% (Table 1, entry 3). The yield and the ee of the pro-
duct decreased significantly when the catalyst loading was
reduced to 0.1 mol % (Table 1, entry 4). In view of the reactivity
After optimizing the reaction conditions, the reactions of
diethylzinc with aryl aldehydes with various steric and electronic
properties were explored and the results are shown in Table 2.
As shown previously, the reaction of benzaldehyde with diethylz-
COOCH3
COOCH3
NH2.HCl
COOH
NH2
SOCl2
Boc2O, NaHCO3
H2O
TBSCl
HN
dry CH3OH
imidazole
HO
HO
HO
Boc
1
2
3
O
OH
OCH3
NaBH4, CaCl2
THF, EtOH
OH
PTSA
THF, CH2Cl2
HN
HN
NH2
TBSO
TBSO
Boc
TBSO
Boc
4
5
6
Figure 2. Synthesis of chiral amino alcohol 6.
OTBS
O
O
COOH
1. s-BuLi, THF, -78 oC
1. (COCl)2
2. Et3N, DCM, 6
Et3N, DMAP, DCM
TsCl, RT, 24 h
N
H
N
OTBS
Fe
Fe
2. Ph2CO
Fe
OH
Ph
7
8
9
O
N
O
O
N
O-PEG2000-OMe
N
OH
OTBS
TBAF
THF
MeO-PEG2000-OMs
o
OH
Ph
OH
Ph
Fe
Fe
OH
Ph
Ph
ꢀꢁ'0)
Cs2CO3, 65 C
Fe
Ph
10
11
Figure 3. Synthesis of MeO-PEG-supported chiral ligand 12.
12
(Rp,S)-
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W.-X. Zhao et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
Table 2
Table 3
Asymmetric alkyl transfer reaction to substituted benzaldehydes 13 using chiral
Recycling experimentsa
ligand 12 and Et2Zna
O
OH
Et2Zn, 12
O
OH
Et2Zn, 1 mol% 12
toluene, 48 h, 0 o
H
Ph
13a
toluene, 48 h
Ph
H
Ar
C
14a
ee (%)c
Ar
13
14
Run
Ligand
Yield (%)b
Config.d
Entry
Ar
Ph
Yield (%)b
ee (%)c
Configd
1
2
3
4
12
12
12
12
>99
97
97
88
83
81
62
(R)
(R)
(R)
(R)
1
2
3
4
5
9914a
9714b
9514c
6114d
6614e
88
84
81
70
62
(R)
(R)
(R)
(R)
(R)
4-CH3Ph
54
4-CH3OPh
3-CH3OPh
2-CH3OPh
a
Conditions: benzaldehyde (0.5 mmol), Et2Zn (2 mmol), ligand 12 (0.005 mmol)
in toluene at 0 °C for 48 h.
b
Isolated yields.
Determined by HPLC.
The major product had an (R)-configuration.
6
>9914f
82
(R)
c
d
7
>9914g
59
(R)
O
8
>9914h
87
(R)
3. Conclusion
O
9
10
11
Fc
2-ClPh
4-ClPh
>9914i
6814j
6914k
94
52
61
(R)
(R)
(R)
In conclusion, the synthesis of MeO-PEG-supported chiral ferro-
cenyl-oxazoline carbinol ligand 12 has been described and its cat-
alytic use in asymmetric alkyl-transfer reactions to substituted
benzaldehydes has been demonstrated. High yields and good enan-
tioselectivities were achieved in all of the reactions. Furthermore,
the catalyst can be easily recovered and reused in successive cat-
alytic additions, while maintaining its enantioselectivity even at
the third cycle. We are currently exploring the potential use of this
new class of ligands in other enantioselective reactions.
a
Conditions: aldehyde (0.5 mmol), Et2Zn (2 mmol), ligand 12 (0.005 mmol) in
toluene at 0 °C for 48 h.
b
Isolated yields.
Determined by chiral HPLC.
The major product had an (R)-configuration.
c
d
inc proceeded smoothly to give the corresponding products 14a
with 88% ee in 99% yield (Table 2, entry 1). p-Tolualdehyde also
reacted with diethylzinc to give the desired product 14b with
84% ee in 97% yield (Table 2, entry 2). p-Anisaldehyde showed good
enantioselectivity (Table 2, entry 3). However, when a MeO group
was at the meta- or ortho-positions, the ee of the reaction product
decreased dramatically to 70% or 62%, respectively (Table 2, entries
4 and 5). These results suggest that the steric effect of the aldehyde
is a key factor for controlling the reactivity. b-Naphthaldehyde also
exhibited excellent reactivity and gave the desired products 14f
with 82% ee in 99% yield (Table 2, entry 6). The reaction of
4. Experimental
4.1. General
Unless otherwise noted, all catalytic reactions were carried out
under an atmosphere of dry N2 with oven-dried glassware and
anhydrous solvents. 1H and 13C NMR spectra were obtained on a
Bruker 400 MHz spectrometer with CDCl3 as the solvent. Chemical
shifts were measured relative to tetramethylsilane as an internal
reference. IR spectra were recorded on Nicolet-NEXUS 670 FT-IR
spectrometer. Melting points were determined using a Beijing
X-5 melting point apparatus and were uncorrected. Mass spectra
were recorded on a Bruker esquire-3000. Enantiomeric excesses
were determined by HPLC (Chiralcel-OD and Chiralcel-OB col-
umns) with UV detection and an i-PrOH/hexane mobile phase.
Toluene was distilled under an N2 atmosphere after drying with
sodium/benzophenone. Diethylzinc (1.0 M solution in hexane)
was purchased from Aldrich, and used directly. (S)-2-Amino-3-[4-
(tert-butyldimethylsilyloxy)-phenyl]-propan-1-ol 6 was prepared
according to the procedure in the literature.11 Other chemicals
and reagents were obtained from commercial sources and used
directly.
a-naphthaldehyde with diethylzinc led to products with lower ee
values (Table 2, entry 7), indicating that the reaction was very sen-
sitive to the steric hindrance of the aldehyde substrate. Benzo[d]
[1,3]dioxole-5-carbaldehyde also reacted with diethylzinc to give
the desired product 14h with 87% ee in 99% yield (Table 2, entry
8). The product for the addition of diethylzinc to ferrocenecarbox-
aldehyde gave the best ee (94%) with an isolated yield of 99%
(Table 2, entry 9). When a benzaldehyde with a halide substituent
was used as the substrate, the activity of the catalyst significantly
decreased. For example, benzaldehyde with a Cl substituent at the
2- or 4-position reacted with diethylzinc to give 14j and 14k with
52% and 61% ee in 68% and 69% yields, respectively (Table 2, entries
10 and 11). This indicates that the electronic effect also plays an
important role in this reaction.
The recyclability of MeO-PEG-supported chiral ligand 12 was
also studied and the results are presented in Table 3. After the reac-
tion was completed, diethyl ether (Et2O) was added to the reaction
system. Since MeO-PEG supported ligand 12 does not dissolve in
Et2O, it precipitated from the reaction mixture. The catalyst was
then recovered by filtration and the recovered chiral ligand 12
was used for another catalytic cycle. The catalyst maintained good
enantioselectivity even after being recovered and reused twice. For
the fourth run, the activity of the catalyst decreased a great deal. It
should be noted that the reaction protocol as well as the separation
and recycling method are simple and efficient.
4.2. Typical procedure for the preparation of MeO-PEG-
supported ligand 12
4.2.1. Synthesis of the compound 8
Oxalyl chloride (0.72 mL, 7.5 mmol) was added via syringe to a
stirred suspension of ferrocenecarboxylic acid
3.56 mmol) in CH2C12 (25 mL) at room temperature under nitro-
gen. This mixture was allowed to react for 2 h and then evaporated
to dryness to give a purple solid. The resultant crude ferrocenyl
chloride was dissolved in CH2C12 and added dropwise to a solution
of (S)-2-amino-3-[4-(tert-butyldimethylsilyloxy)-phenyl]-propan-
1-ol 6 (1.8 g, 6.3 mmol) and triethylamine (1.1 mL, 7.2 mmol) in
7
(0.82 g,
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W.-X. Zhao et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
20 mL of CH2C12 in an ice-water bath under a nitrogen atmo-
sphere. The reaction mixture was stirred at room temperature
overnight. The reaction mixture was washed with H2O and satu-
rated aqueous NaCl, dried over MgSO4, filtered and evaporated in
vacuo. The crude product was purified by column chromatography
(1:1 EtOAc/petroleum ether) to give product 8 as an orange solid
4.2.4. Synthesis of compound 11
A solution of TBAF (1.8 mL of 1.0 M solution in THF solution) in
10 mL of THF was added to a round bottom flask. Compound 10
(0.6 g, 0.91 mmol) in THF (10 mL) was then added dropwise, and
the mixture was stirred until the reaction was complete. The sol-
vents were removed under reduced pressure after which water
was added to the residue. The aqueous layer was extracted twice
with EtOAc, and the combined organics were dried with MgSO4, fil-
tered, and concentrated. The residue was purified on silica gel to
(1.17 g, 66.5%). [
a]
D = À1.2 (c 1.03, CHCl3); mp 120–121 °C; 1H
NMR (400 MHz, CDCl3) d: 7.15 (d, J = 8.4 Hz, 2H), 6.84 (d,
J = 8.4 Hz, 2H), 5.88 (d, J = 6.6 Hz, 1H), 4.62 (s, 1H), 4.49 (s, 1H),
4.32 (d, J = 6.4 Hz, 2H), 4.26 (t, J = 10.6 Hz, 1H), 4.08 (s, 5H), 3.77
(d, J = 10.6 Hz, 1H), 3.68 (s, 1H), 3.50 (s, 1H), 2.95 (dd, J = 14.0,
6.3 Hz, 1H), 2.79 (dd, J = 14.0, 8.4 Hz, 1H), 1.06–0.92 (m, 9H), 0.17
(d, J = 2.7 Hz, 6H); 13C NMR (100 MHz, CDCl3) d: 171.69, 154.61,
130.08, 120.42, 75.31, 70.64, 69.81, 68.54, 67.68, 65.49, 53.40,
36.33, 30.96, 25.66, 18.18, À4.41; HRMS (ESI) m/z: Calcd for
give the desired product 11 (0.47 g, yield 95%). [
a]
D = À1.4 (c 0.1,
CHCl3); mp 179–181 °C; 1H NMR (400 MHz, CDCl3) d: 9.22 (s,
1H), 7.51–7.49 (m, 2H), 7.30 (t, J = 6.4 Hz, 2H), 7.25–7.22 (m, 1H),
7.20–7.04 (m, 7H), 6.87–6.76 (m, 2H), 5.36 (s, 1H), 4.73 (dd,
J = 2.6, 1.6 Hz, 1H), 4.25 (t, J = 2.6 Hz, 1H), 4.22 (s, 5H), 4.18–4.01
(m, 2H), 3.97 (d, J = 2.9 Hz, 1H), 3.68 (dd, J = 2.6, 1.6 Hz, 1H),
3.03–2.92 (m, 1H), 2.77–2.66 (m, 1H); HRMS (ESI) m/z: Calcd for
C
26H35FeNO3Si [M+H]+: 494.1814; found: 494.1816.
C
33H29FeNO3 [M+H]+: 544.1575; found: 544.1562.
4.2.2. Synthesis of compound 9
The above product 8 (2.3 g, 4.6 mmol) was dissolved in 50 mL
CH2C12 and then 1.3 mL (2 equiv) Et3N was added. After stirring
for 2 h, TsCl (0.98 g, 1.1 equiv) and a catalytic amount DMAP were
added and the solution was stirred at room temperature under
nitrogen overnight. Next, 50 mL of CH2C12 were added, and the
resulting solution was washed with saturated ammonium chloride
solution and saturated aqueous NaHCO3. After extracting with
CH2C12, the organics were dried over MgSO4, filtered and concen-
trated. The residue was purified using silica gel column chromatog-
raphy (1:3 EtOAc/petroleum ether) to afford the pure product 9
4.2.5. Synthesis of compound 12
Nitrogen gas was bubbled through a solution of the above pro-
duct 11 (0.4 g) in DMF (20 mL). Next, Cs2CO3 (0.6 g) and MeO-PEG-
OMs (1.55 g) were added to the solution. The mixture was heated
to 65 °C until the reaction was complete. After removal of DMF in
vacuo, HCl (2 M) was added and the mixture was extracted with
CH2C12. The combined organics were washed with saturated NaCl
solution, dried with MgSO4, filtered, and concentrated. Next, Et2O
(25 mL) was added slowly with vigorous stirring at 0 °C. The pre-
cipitate formed was isolated by filtration and then dried in vacuo
(2.0 g, 91%) as a yellow solid. [
a
]
D = À1.5 (c 0.67, CHCl3); mp 78–
to give the MeO-PEG derivatives 12 (yield 90%). [
a
]
D = À17.2 (c
80 °C; 1H NMR (400 MHz, CDCl3) d: 7.10 (d, J = 8.4 Hz, 2H), 6.79
(d, J = 8.4 Hz, 2H), 4.75 (t, J = 1.8 Hz, 2H), 4.44–4.37 (m, 1H),
4.36–4.33 (m, 2H), 4.31 (d, J = 6.9 Hz, 1H), 4.23 (t, J = 8.7 Hz, 1H),
4.18 (s, 5H), 4.10–4.00 (m, 1H), 3.17 (dd, J = 13.9, 4.5 Hz, 1H),
2.60 (dd, J = 13.7, 9.3 Hz, 1H), 0.98 (s, 9H), 0.19 (s, 6H); 13C NMR
(100 MHz, CDCl3) d: 154.18, 130.61, 130.14, 120.05, 71.36, 70.27,
69.62, 68.93, 67.89, 40.97, 25.63, À4.46; HRMS (ESI) m/z: Calcd
for C26H33FeNO2Si [M+H]+: 476.1708; found: 476.1693.
0.53, CHCl3); mp 43–45 °C; 1H NMR (400 MHz, CDCl3) d: 9.08 (s,
1H), 7.51 (d, J = 7.5 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.25–7.23 (m,
1H), 7.19–7.08 (m, 7H), 6.89 (d, J = 8.6 Hz, 2H), 4.73–4.70 (m,
1H), 4.25 (dd, J = 4.8, 2.2 Hz, 1H), 4.21 (s, 5H), 4.11–4.07 (m, 4H),
4.01–3.92 (m, 1H), 3.82 (dd, J = 9.1, 4.3 Hz, 3H), 3.72–3.68 (m,
4H), 3.68–3.57 (m, 171H), 3.55 (dd, J = 5.7, 3.6 Hz, 2H), 3.49–3.44
(m, 2H), 3.38 (s, 3H), 3.05 (dd, J = 16.8, 6.8 Hz, 1H), 2.70 (dd,
J = 14.0, 7.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) d: 168.27,
157.53, 149.28, 146.53, 130.45, 129.67, 127.21, 127.08, 126.59,
126.32, 114.80, 100.35, 75.13, 71.95, 70.82, 70.79, 70.67, 70.66,
70.58–70.44, 69.74, 68.13, 67.45, 66.73, 65.66, 59.04, 40.24.
4.2.3. Synthesis of compound 10
A yellow/orange stirred solution of 9 (0.998 g, 2.1 mmol) in THF
(20 mL) under nitrogen was cooled to À78 °C in a Schlenk tube.
Next, s-BuLi (2.52 mL, 1.2 equiv, 1 M in hexane) was added drop-
wise to the solution. After stirring at À78 °C for 2 h, the Schlenk
tube was heated to À60 °C and stirring was maintained for another
15 min. Next Ph2CO (574 mg, 3 mmol) was added and the reaction
mixture was allowed to warm to room temperature. Finally the
reaction mixture was quenched with saturated ammonium chlo-
ride and diluted with ether. The two layers were separated and
the aqueous phase was extracted with Et2O. The organics were
combined, dried over MgSO4, filtered and evaporated. The crude
product was purified by column chromatography to afford 10 as
a red crystalline solid. Recrystallisation from hexane and CH2C12
gave pure 10 as a single diastereo-isomer. Mp 192–194 °C; 1H
NMR (400 MHz, CDCl3) d: 9.06 (s, 1H), 7.52 (d, J = 7.3 Hz, 2H),
7.33 (t, J = 7.5 Hz, 2H), 7.28–7.22 (m, 2H), 7.20–7.04 (m, 7H),
6.83–6.75 (m, 2H), 4.72 (dd, J = 2.5, 1.6 Hz, 1H), 4.25 (d,
J = 2.8 Hz, 1H), 4.22 (s, 5H), 4.12–4.03 (m, 2H), 4.00–3.92 (m, 1H),
3.70 (dd, J = 2.5, 1.6 Hz, 1H), 3.05 (dd, J = 13.6, 4.0 Hz, 1H),
2.66 (dd, J = 13.6, 7.2 Hz, 1H), 0.97 (d, J = 2.9 Hz, 9H), 0.17
(s, 6H); 13C NMR (100 MHz, CDCl3) d: 168.24, 154.32, 149.33,
146.56, 130.58–130.41, 130.26, 127.89, 127.53, 127.14, 126.58,
126.30, 120.16, 100.42, 75.15, 71.20, 70.85, 70.46, 68.12, 66.80,
65.70, 40.47, 25.70, 18.19, À4.39; HRMS (ESI) m/z: Calcd for
4.2.6. Typical procedure for the addition of diethylzinc to
aldehydes using MeO-PEG-supported ferrocene 12
Chiral ligand 12 (0.005 mmol) was placed in a dried Schlenk
tube under
a nitrogen atmosphere. Freshly distilled toluene
(2.0 mL) was then added followed by diethylzinc (2.0 mL, 1 M in
hexane). The resulting solution was cooled to 0 °C and stirred for
approximately 30 min. The aldehyde (0.5 mmol) was then added
and the reaction mixture was stirred for 48 h. The reaction was
quenched with saturated ammonium chloride solution (4.0 mL).
The mixture was then extracted with diethyl ether, and the organic
portion was washed with saturated aqueous NaCl. The combined
organics were then dried over anhydrous MgSO4 and concentrated
in vacuo. The crude compound was purified by flash chromatogra-
phy to give the final product.
4.2.7. 1-Phenylpropan-1-ol 14a
99% yield, 88% ee, [a]
20 = +27.7 (c 2.2, CHCl3), [Determined by
D
HPLC analysis Chiralcel OD-H column, Hexane/i-PrOH = 100/2,
Flow rate: 1 mL/min, UV detection at 254 nm, Retention time:
tmajor = 13.31 min, tminor = 17.24 min]; 1H NMR (400 MHz, CDCl3)
d 0.90 (t, 3H), 1.71–1.92 (m, 2H), 1.96 (br, 1H), 4.51–4.72 (m,
1H), 7.25–7.40 (m, 5H); 13C NMR (100 MHz, CDCl3) d 144.8,
128.4, 127.4, 126.2, 75.9, 31.9, 10.2.
C
39H43FeNO3Si [M+H]+: 658.2440; found: 658.2436.
Please cite this article in press as: Zhao, W.-X.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.08.018

W.-X. Zhao et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
4.2.8. 1-(p-Tolyl)propan-1-ol 14b
97% yield, 84% ee, [
20 = +33.9 (c 5.0, CHCl3), [Determined by
d 0.90 (t, J = 7.4 Hz, 3H), 1.79–2.01 (m, 2H), 1.89 (s, 1H), 4.57 (t,
J = 6.5 Hz, 1H), 5.98 (s, 2H), 6.73–6.80 (m, 2H), 6.85 (s, 1H); 13C
NMR (100 MHz, CDCl3) d 148.3, 147.5, 139.5, 120.1, 108.7, 106.8,
101.6, 76.8, 32.3, 10.7.
a]
D
HPLC analysis Chiralcel OB-H column, Hexane/i-PrOH = 95/5, Flow
rate: 0.5 mL/min, UV detection at 254 nm, Retention time:
tmajor = 7.92 min, tminor = 5.95 min]; 1H NMR (400 MHz, CDCl3) d
0.90 (t, J = 7.3 Hz, 3H), 1.63–1.92 (m, 2H), 2.31 (s, 3H), 2.49 (br s,
1H), 4.45 (t, J = 6.8 Hz, 1H), 7.10 (d, J = 8.6 Hz, 2H), 7.20 (d,
J = 8.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 142.8, 137.8, 129.9,
127.1, 76.6, 32.8, 22.1, 10.8.
4.2.15. (1-Hydroxypropyl)ferrocene 14i
99% yield, 94% ee, [Determined by HPLC analysis Chiralcel OD-H
column, Hexane/i-PrOH = 100/2, Flow rate: 1.0 mL/min, UV
detection at 254 nm, Retention time: tmajor = 12.93 min,
tminor = 14.02 min]; 1H NMR (400 MHz, CDCl3) d 0.88 (t, J = 7.4 Hz,
3H), 1.55–1.65 (m, 2H), 1.93 (d, J = 3.2 Hz, 1H), 4.05–4.18 (m,
9H); 13C NMR (100 MHz, CDCl3) d 94.6, 71.6, 68.8, 68.4, 68.1,
67.5, 65.8, 31.6, 10.9.
4.2.9. 1-(4-Methoxyphenyl)propan-1-ol 14c
95% yield, 81% ee, [a]
20 = +30.5 (c 2.6, CHCl3), [Determined by
D
HPLC analysis Chiralcel OD-H column, Hexane/i-PrOH = 100/1,
Flow rate: 1 mL/min, UV detection at 254 nm, Retention time:
tmajor = 33.05 min, tminor = 38.07 min]; 1H NMR (400 MHz, CDCl3)
d 0.83 (t, J = 7.3 Hz, 3H), 1.56–1.87 (m, 2H), 1.99 (br s, 1H), 3.73
(s, 3H), 4.44 (t, J = 6.8 Hz, 1H), 6.79 (d, J = 8.8 Hz, 2H), 7.21 (d,
J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 158.1, 135.8, 126.7,
112.7, 74.9, 54.7, 31.2, 9.6.
4.2.16. 1-(2-Chlorophenyl)propan-1-ol 14j
68% yield, 52% ee, [a]
20 = +28.9 (c 0.69, CHCl3), [Determined by
D
HPLC analysis Chiralcel OB-H column, Hexane/i-PrOH = 95/5, Flow
rate: 0.5 mL/min, UV detection at 254 nm, Retention time:
tmajor = 13.22 min, tminor = 10.25 min].
4.2.10. 1-(3-Methoxyphenyl)propan-1-ol 14d
4.2.17. 1-(4-Chlorophenyl)propan-1-ol 14k
61% yield, 70% ee, [
a
]
D
20 = +19.9 (c 0.5, CHCl3), [Determined by
69% yield, 61% ee, [a]
20 = +27.8 (c 3.2, CHCl3), [Determined by
D
HPLC analysis Chiralcel OD-H column, Hexane/i-PrOH = 100/2,
Flow rate: 1 mL/min, UV detection at 254 nm, Retention time:
tmajor = 28.16 min, tminor = 33.43 min]; 1H NMR (400 MHz, CDCl3)
d 0.87 (t, J = 7.3 Hz, 3H), 1.61–1.79 (m, 2H), 2.58 (br s, 1H), 3.75
(s, 3H), 4.50 (t, J = 6.6 Hz, 1H), 6.76 (dd, J = 8.3 Hz, 2.4 Hz, 1H),
6.85–6.87 (m, 2H), 7.21 (dd, J = 8.3 Hz, 8.3 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 160.3, 146.9, 130.0, 118.9, 113.7, 112.2, 15.8,
55.8, 32.6, 10.7.
HPLC analysis Chiralcel OB-H column, Hexane/i-PrOH = 95/5, Flow
rate: 0.5 mL/min, UV detection at 254 nm, Retention time:
tmajor = 14.67 min, tminor = 12.66 min]; 1H NMR (400 MHz, CDCl3)
d 0.91 (t, J = 7.3 Hz, 3H), 1.63–1.92 (m, 2H), 2.37 (d, J = 2.6 Hz,
1H), 4.50 (t, J = 6.6 Hz, 1H), 7.21–7.32 (m, 4H); 13C NMR
(100 MHz, CDCl3) d 143.9, 133.8, 129.5, 128.3, 76.1, 32.7, 10.9.
Acknowledgement
This work was supported by National Natural Science
Foundation of China (Nos. 20972091, 21172139 and 21202095).
4.2.11. 1-(2-Methoxyphenyl)propan-1-ol 14e
66% yield, 62% ee, [a]
20 = +12.6 (c 4.1, CHCl3), [Determined by
D
HPLC analysis Chiralcel OD-H column, Hexane/i-PrOH = 100/1,
Flow rate: 1 mL/min, UV detection at 254 nm, Retention time:
tmajor = 21.74 min, tminor = 20.71 min]; 1H NMR (400 MHz, CDCl3)
d 0.98 (t, J = 7.4 Hz, 3H), 1.80–1.87 (m, 2H), 2.82 (d, J = 6.1 Hz,
1H), 3.86 (s, 3H), 4.80–4.85 (m, 1H), 6.89–7.35 (m, 4H); 13C NMR
(100 MHz, CDCl3) d 156.4, 132.4, 128.0, 126.9, 120.5, 110.4, 71.9,
55.1, 30.1, 10.3.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.08.
018.
References and notes
4.2.12. 1-(Naphthalen-2-yl)propan-1-ol 14f
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99% yield, 82% ee, [a]
20 = +31.1 (c 2.4, CHCl3), [Determined by
D
HPLC analysis Chiralcel OD-H column, Hexane/i-PrOH = 90/10,
Flow rate: 0.5 mL/min, UV detection at 254 nm, Retention time:
tmajor = 22.42 min, tminor = 19.54 min]; 1H NMR (400 MHz, CDCl3)
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99% yield, 59% ee, [a]
20 = +32.8 (c 2.5, CHCl3), [Determined by
D
HPLC analysis Chiralcel OD-H column, Hexane/i-PrOH = 95/5, Flow
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tmajor = 27.53 min, tminor = 13.38 min]; 1H NMR (400 MHz, CDCl3)
d 1.03 (t, J = 7.4 Hz, 3H), 1.87–2.02 (m, 2H), 2.94 (br, 1H), 5.32 (t,
J = 6.2 Hz, 1H), 7.46–8.11 (m, 7H); 13C NMR (100 MHz, CDCl3) d
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123.8, 73.5, 32.1, 11.4.
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