PEG-supported recyclable catalyst for enantioselective ethylations

Article abstract of DOI:10.1080/00397911.2011.625135

A β-amino alcohol derived from 4-hydroxyproline was bound to polyethylene glycol (PEG) and used in the enantioselective ethylation of aryl aldehydes with diethyl zinc. Isolated yields of the corresponding alcohols ranged from 53 to 93% with ee's of 91-97%

Full text of DOI:10.1080/00397911.2011.625135

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PEG-Supported Recyclable Catalyst for
Enantioselective Ethylations
a
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a
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Xiaofeng Zeng , Debasis Malik , Ryan Chen & Edward Lee-Ruff
a
Department of Chemistry, York University, Toronto, Ontario,
Canada
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To cite this article: Xiaofeng Zeng , Debasis Malik , Ryan Chen & Edward Lee-Ruff (2013): PEG-
Supported Recyclable Catalyst for Enantioselective Ethylations, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 43:8, 1168-1172
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Synthetic Communications , 43: 1168–1172, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.625135
PEG-SUPPORTED RECYCLABLE CATALYST FOR
ENANTIOSELECTIVE ETHYLATIONS
Xiaofeng Zeng, Debasis Malik, Ryan Chen, and
Edward Lee-Ruff
Department of Chemistry, York University, Toronto, Ontario, Canada
GRAPHICAL ABSTRACT
Abstract A b-amino alcohol derived from 4-hydroxyproline was bound to polyethylene
glycol (PEG) and used in the enantioselective ethylation of aryl aldehydes with diethyl zinc.
Isolated yields of the corresponding alcohols ranged from 53 to 93% with ee’s of 91–97%.
Full recovery of the catalyst was accomplished by addition of diethyl ether. The polymer-
bound catalyst could be recycled without loss of activity.
Keywords Enantioselective ethylation; PEG; polymer support; soluble polymer-
supported catalyst
INTRODUCTION
The enantioselective alkylations of aldehydes and ketones with chiral catalysts
are convenient for the preparation of secondary and tertiary chiral alcohols, respect-
ively, which are of interest in natural products and pharmaceuticals. The catalysts
were developed by structural modifications and tested on simple aryl aldehyde sub-
[
1]
strates for optimization. Since the pioneering work of Oguni and Omi, numerous
[
2]
chiral ligands have been developed with varying success. Among these, the amino
alcohols are among the best catalysts, allowing the preparation of chiral alcohols in
[3]
good yields and enantiomeric excesses. In a number of instances Ti(IV) is used for
[
cocatalysis in less reactive carbonyl substrates. The use of solid polymer-supported
4]
Received September 7, 2011.
Address correspondence to Edward Lee-Ruff, Department of Chemistry, York University, 4700
Keele Street, Toronto, Ontario M3J 1P3, Canada. E-mail: leeruff@yorku.ca
1
168

SOLUBLE POLYMER-SUPPORTED CATALYST
1169
catalysts has gained increasing popularity for their ease of separation, recyclability,
and their adaptability to flow process operations. However, heterogenous reactions
are, in principle, inherently inefficient. Many of the conventional polystyrene-based
supports suffer from limiting mechanical properties and poor thermo-oxidative sta-
bilities. Solid-phase supports have been used to immobilize pyrrolidinyl methanol
derivatives for catalysis in the enantioselective alkylation of aldehydes with moderate
[
5,6]
success.
The use of soluble polymer supports such as polyethylene glycol (PEG)
has provided an alternative to some of the limiting aspects of solid-phase chemistry
in that homogenous reaction conditions are restored and the polymer support can be
[
7]
readily separated by precipitation with the dilution of an ‘‘antisolvent.’’ Our inter-
[8,9]
est in liquid polymer-support chemistry
caused us to initiate the current study of
their application in immobilizing chiral ligands of the pyrrolidinyl methanol variety
and their use in enantioselective ethylations. One such independent report appeared
recently in which a pyrollidinyl methanol (1) is attached to both an insoluble poly-
styrene resin as well as soluble PEG, the latter via a succinyl ester linkage. Although
the heterogenous reaction showed excellent recyclability, the enantioselective
efficiency was moderate for the diethyl zinc ethylation of aryl aldehydes (34–71%
ee). The PEG-supported ligand, while showing better enantioselectivity (42–90%
ee) than the insoluble counterpart, suffers from the diminishing efficiency even after
[
10]
one recovery cycle (yield 94!17%, ee 90!78%). The reduced efficiency is attrib-
uted to the labile nature of the succinate diester linker under the reaction conditions.
RESULTS AND DISCUSSION
[
10]
We report here the attachment of amino alcohol 1
to MeOPEG2000 via an
ether linkage to give the PEG (MeOPEG2000)–supported ligand 2, which was chosen
for its suitable solubility properties and suitability as an NMR marker (MeO
terminus) for assessing the loading levels of the coupling reaction.
The stability of the ether linkage in 2 under the reaction conditions should
retain the efficacy of this catalyst on recycling in contrast to a previously reported
[
10]
analog, which was attached by a succinate ester linker.
3R,5S)-5-(Hydroxydiphenylmethyl)-1-methylpyrrolidin-3-ol (1) was directly
attached to MeOPEG2000OH via its methanesulfonate ester to give 2 in 97% yield.
[
10]
(
[
9]
The preparation of MeOPEG2000OMs has been previously reported by our group.
To optimize conditions for the catalytic enantioselective ethylation of benzaldehyde
with diethyl zinc, a solvent study using hexane, benzene, and toluene solutions of 2
with substrate was carried out. Slightly better recovered yields of 1-phenyl-1propanol
(3a) and enantioselectivity was observed for benzene solutions (Table 1). All reactions
were run at room temperature for 20 h in an argon atmosphere. The isolated yields

1170
X. ZENG ET AL.
Table 1. Yields and enantioselectivity of arylaldehyde catalytic ethylations with 2
2
3
Aldehyde
(R)
Recycling
times
Isolated
yield (%)
[a]
D
deg
(solvent)
a
b
c
Entry
Solvent
ee (%)
ee (%)
1
2
3
4
5
6
7
8
9
C
C
C
C
C
C
C
C
C
6
6
6
6
6
6
6
6
6
H
H
H
H
H
H
H
H
H
5
5
5
5
5
5
5
5
5
0
0
0
0
0
1
1
2
2
0
0
0
0
0
Hexane
Toluene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
53
69
70
72
76
79
76
57
69
89
93
84
89
73
ꢀ31.83 (CHCl
3
3
)
)
69.9
84.6
85.1
85.1
84.8
80.0
82.3
83.5
83.8
120
ꢀ38.50 (CHCl
ꢀ38 (CHCl
ꢀ38 (CHCl
ꢀ38 (CHCl
ꢀ36 (CHCl
ꢀ37 (CHCl
ꢀ37 (CHCl
ꢀ38 (CHCl
3
3
3
3
3
3
3
)
91.4
)
)
)
)
)
)
1
1
1
1
1
0
1
2
3
4
4-ClC
2-Naphth
(E)-PhCH=CH
6
H
5
ꢀ28 (Benzene)
ꢀ34 (Benzene)
95.8
96.6
94.9
96.5
96.8
86.0
131
ꢀ11 (CHCl
3
)
4-MeOC
4-MeC
6
H
5
ꢀ35 (Benzene)
ꢀ37 (Benzene)
105
92.3
6
H
5
a
b
c
Isolated.
Based on reported specific rotations.
Based on chiral column (Chiralcel 5 micron ChiralPAK) separation and integrations.
[11,12]
.
and enantiomeric excess were reproducible for independent experiments (Table 1,
entries 3–5). Recovery of the catalyst (typically 80%) and enantioselectivity efficiency
was very good (Table 1, entries 6–9) after two recycles of the supported ligand. The
catalyst is readily recovered by concentration of the solution and addition of ether
as the antisolvent. This is in sharp contrast to the observations for the succinate-
appended ligand 1, where a substantial reduction in recovery and loss of enantioselec-
[10]
tivity were observed even after one reuse.
The PEG-attached ligand 2 was also shown to exhibit excellent properties for
the enantiomeric zinc ethylation of other aryl aldehydes (Table 1, entries 10–14) with
recovery yields ranging from 73–93% and ee’s from 95 to 97%. Enantioselectivity
determinations based on optical activity measurements and comparisons with litera-
ture values are prone to errors (entries 10, 12, and 13). Determination of ee’s using
high-performance liquid chromatographic (HPLC) analyses on a chiral column
remains a more reliable method.
The use of soluble polymer-supported reagents and catalysts offers certain
advantages over their insoluble counterparts in bestowing homogenous conditions
for maximizing reaction efficiency. This was seen in the reported enantioselectivities
for the diethyl zinc alkylations of aryl aldehydes catalyzed by 2 when compared
[10]
with the polystyrene-based analogs.
Attachment of ligand 1 to PEG through an
ether linkage imparts greater hydrolytic stability as compared to a diester function,
allowing for the recovery of the catalyst with retention of its efficiency.

SOLUBLE POLYMER-SUPPORTED CATALYST
1171
EXPERIMENTAL
All reactions were done in dried glassware. All solvents used for the reactions
were dried and distilled. Melting points were obtained with a Fisher-Johns melting-
point apparatus and are uncorrected. Ultraviolet (UV) spectra were determined in
MeOH solutions using an Ultraspec 4300 pro UV spectrometer. Infrared (IR) spectra
were recorded on a Pye Unicam SP3-200 spectrometer as thin KBr pellets and are
ꢀ
1
1
reported in cm . Mass spectra were recorded on a QStar Elite spectrometer. H
1
NMR and C NMR spectra were recorded on a Bruker ARX 400-MHz supercon-
3
1
ducting NMR spectrometer. Data for H NMR are referenced relative to residual
6
CDCl proton signals at d 7.27 ppm and to dimethylsulfoxide (DMSO-d ) d at
.50 ppm. Data for C NMR are referenced relative to CDCl at d 77.16 ppm and
to DMSO-d d at 39.52 ppm. Data for H are reported as follows: chemical shift
3
1
3
2
3
6
1
(
ppm), multiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, h ¼ heptet, m ¼
multiplet) and integration. Analytical thin-layer chromatography (TLC) was per-
formed on silica-gel 60 Alugram sheets and silica gel (40–63 mm) was used for column
chromatography. Preparative TLC was conducted using predried glass plates coated
with silica gel (0–20 mm). All reagents employed were purchased from commercial
sources and used without further purification.
Optical rotations were obtained on a Perkin-Elmer 241 polarimeter using 1-dm
cells. Solutions containing 20–30 mg of analyte in 1.2 mL of CHCl were prepared
3
for the measurements..
HPLC analyses were carried out on a Waters 2695 HPLC with a Waters 2996
PDA detector. Approximately 4 mg of the purified sample was dissolved in a 1:1
(v=v) mixture of HPLC-grade hexanes and 2-propanol and further diluted to a con-
centration of ꢁ 2 mg=mL using HPLC-grade hexanes. Samples (injection volume ¼
1
and 2-propanol at 15 C through a Chiralcel ChiralPAK IA column (5 micron,
mL) were run with an isocratic mixture of 99.5:0.5 (v=v) of HPLC-grade hexanes
ꢂ
2
50 mm ꢃ 4.6 mm) using a Waters 2695 HPLC system. Flow rates of individual runs
were reported on the spectra. Enantiomeric excess was determined by integrating UV
response of two peaks originating from the enantiomers of interest at a suitable wave-
length using a Waters 2996 detector (PDA). Purity of individual samples was also
verified with an isocratic run using 65:35 (v=v) mixture of HPLC-grade acetonitrile
and water at 1 mL=min flow rate through a Phenomenex Luna C18(2) HPLC
column (5 microns, 250 mm ꢃ 4.6 mm).
Preparation of Polymer-Supported Catalyst: MeO-PEG-OMs
Mesyl chloride (4 mL, 51.7 mmol) was added dropwise to a stirred solution of
MeO-PEG-OH (20 g, 10 mmol, Mw ¼ 2000) and tripentylamine (8.25 mL, 28.4 mmol)
in CH Cl (100 mL). After stirring for 16 h at room temperature, most of the solvent
2
2
was removed under reduced pressure. Ether (1 L) was added to the residue and cooled
ꢂ
to 0 C with stirring, which was continued for 1 h. The precipitated white solids were
collected by filtering and then redissolved in 20 mL of CH Cl . The solution was
2
2
ꢂ
cooled to 0 C and mixed with ether. After stirring for 1 h, the monomesylated product
(
1
20.1 g, 97%) was collected as a white solid by filtering and drying in air. H NMR
(
400 MHz, CDCl -d, d): 4.37 (m, 2H), 3.80–3.40 (m, 177H), 3.34 (s, 3H), 3.06 (s, 3H).
3

1172
X. ZENG ET AL.
Preparation of 2
MeO-PEG-OMs (13.76 g, 6.62 mmol) was added to a stirred mixture of (3R,5S)-
-(hydroxydiphenylmethyl)-1-methylpyrrolidin-3-ol (1) (2 g, 7.5 mmol), which had
been synthesized following a reported procedure and treated with sodium hydride
0.384 g, 15 mmol) in dry THF (120 mL) for 30 min under reflux in argon. The result-
5
[
10]
(
ing mixture was stirred under reflux overnight, followed by evaporation of solvents
under reduced pressure. The residue was dissolved in 30 mL of water and extracted
with CH Cl2 (3 ꢃ 150 mL). The organic phases were combined and dried over
2
Na SO . Most of the solvents were removed by evaporation under reduced pressure.
2
4
ꢂ
The remaining (ca. 30 mL) was mixed with 1 L of ether and stirred for 1 h at 0 C. The
precipitated solids were filtered off and washed with ether and hexane. The catalyst
1
14 g, 93%) was collected as a white solid after drying in air. H NMR (400 MHz,
(
CDCl -d, d): 7.53–7.08 (m, 10H), 4.02–3.87 (m, 2H), 3.87–3.30 (m, 261H), 3.19–
3
3
.11 (m, 1H), 2.50–2.41 (m, 3H), 1.95–1.74 (m, 2H).
Enantioselective Ethylation of Aryl Aldehydes: General Procedure
Diethylzinc (1.0 M solution in hexane, 2.4 mL) was added to a solution of
ꢂ
catalyst 2 (2.0 g, 7.7 mol%) in anhydrous benzene (10 mL) under argon at 0 C,
and stirred for 20 min. Aldehyde (1.5 mmol) was added, and the mixture was stirred
at room temperature for 20 h. The reaction was quenched by pipetting four drops of
2
was cooled to 0 C, and Et O (50 mL) was added. The precipitated catalyst was
M HCl. Most of the solvents were removed under reduced pressure, the mixture
ꢂ
2
recovered by filtration and air and vacuum dried for subsequent use (recovery of
1.5 to 1.9 g). Evaporation of the filtrate gave the crude product, which was purified
on a silica-gel column to afford the pure sec-alcohol.
ACKNOWLEDGMENT
We thank the Natural Sciences and Engineering Research Council of Canada
NSERC) for financial support.
(
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