Continuous enantioselective kinetic resolution of terminal epoxides using immobilized chiral cobalt-salen complexes

Article abstract of DOI:10.1055/s-2007-965877

Jacobsen's cobalt-salen complex was covalently immobilized on polymer carriers that are part of different technical setups (polymer powder, composite Raschig rings, PASSflow microreactors) and employed for the enantioselective ring opening of terminal epoxides with water and phenols. The polymer-supported catalysts showed good activity and stereoselectivity and could be used repeatedly after a simple reactivation protocol in both batch as well as continuous-flow modes. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-965877

PAPER
583
Continuous Enantioselective Kinetic Resolution of Terminal Epoxides Using
Immobilized Chiral Cobalt–Salen Complexes
Continuous
E
nantiosele
l
c
tive
K
a
inetic Reso
d
T
erm
i
ina
l
E
m
poxides ir Solodenko,a Gerhard Jas,b Ulrich Kunz,c Andreas Kirschning*a
a
Institut für Organische Chemie, Leibniz Universität Hannover, Schneiderberg 1b, 30167 Hannover, Germany
E-mail: andreas.kirschning@oci.uni-hannover.de
b
c
Synthacon GmbH, Alt Fechenheim 34 G58, 60386 Frankfurt, Germany
Institut für Chemische Verfahrenstechnik, Technische Universität Clausthal, Leibnizstr. 17, 38678 Clausthal-Zellerfeld, Germany
Received 2 November 2006
Abstract: Jacobsen’s cobalt–salen complex was covalently immo-
bilized on polymer carriers that are part of different technical setups
(polymer powder, composite Raschig rings, PASSflow microreac-
tors) and employed for the enantioselective ring opening of terminal
epoxides with water and phenols. The polymer-supported catalysts
showed good activity and stereoselectivity and could be used re-
peatedly after a simple reactivation protocol in both batch as well as
continuous-flow modes.
Cl
N
O
N
O
M
(R,R)-2
+
X
t-Bu
t-Bu
t-Bu
(R,R)-1: X = OH, M = H,H
DIPEA, CsI,
DMF, 60 °C,
N2, 21 h
(R,R)-2: X = HOOC(CH2)3COO, M = H, H
(R,R)-3: X = t-Bu, M = Co(OAc)
Key words: catalysis, immobilization, continuous-flow processes,
enantioselective synthesis, microreactor, salen
Immobilization of homogeneous catalysts on insoluble
supports is widely used to improve the efficiency of
chemical processes.1 Indeed, the use of homogeneous cat-
alysts can be hampered by their high price, air sensitivity,
and difficulties when the ligands and their degradation
byproducts as well as residual metals have to be removed
during workup. These aspects may preclude application of
transition-metal-catalyzed reactions on a large scale. Het-
erogenization of homogeneous catalysts allows easy re-
moval of the active species by simple filtration from the
reaction media. Of particular interest is the combination
of a heterogenized homogeneous catalyst incorporated in
a flow-through device. So far, flow-through processes are
restricted to production processes despite the fact that they
assure facile automation, reproducibility, safety, and pro-
cess reliability. Only recently have chemists begun to fo-
cus on the development of flow-devices for laboratory use
and hence for industrial applications.2
O
O
O
N
N
O
OH HO
t-Bu t-Bu
t-Bu
4
Co(OAc)2⋅4H2O,
MeOH–PhMe (1:1)
O
O
O
O
N
N
Co
O
O
t-Bu
OAc
t-Bu
5
t-Bu
Scheme 1 Covalent immobilization of the salen ligand on the poly-
mer carrier.
Herein, we report on the immobilization of chiral Jacob-
sen’s cobalt–salen complex 3 on chloromethylpolystyrene
(powder), which was prepared by precipitation polymer-
ization as previously described.6 Additionally, the catalyst
was loaded onto in the same material, which is part of a
monolithic glass/polymer composite material shaped in
the form of industrially utilized Raschig rings (Figure 1).
Finally, we incorporate the salen complex inside a PASS-
flow microreactor, which contains the same composite
material. The utility of these immobilized species was
demonstrated in the kinetic resolution of terminal ep-
oxides.
In this context, chiral salen–metal complexes such as
(R,R)-3 (Scheme 1) are among the most versatile catalysts
as they can be utilized in the synthesis of a plethora of
chiral building blocks (important for the fine chemical in-
dustry) and intermediates starting from alkenes and ep-
oxides, respectively.3 Jacobsen and co-workers4 have
developed a synthetic protocol for the immobilization of
salen complexes on hydroxymethylpolystyrene resin as
well as on silica beads by employing unsymmetrically
substituted salen ligands such as (R,R)-1; various immobi-
lized versions of chiral salen complexes have since been
reported.5
Firstly, we immobilized ligand 1 on the model polysty-
rene resin powder bearing active benzyl chloride groups.
The immobilization of chiral ligand (R,R)-2 [prepared by
acylation of ligand (R,R)-1 with glutaric anhydride] was
achieved as shown in Scheme 1 and afforded resin 4
(loading ca. 0.35 mmol/g).7 Treatment with cobalt(II)
acetate afforded catalyst 5.
SYNTHESIS 2007, No. 4, pp 0583–0589
x
x
.
x
x
.2
0
0
7
Advanced online publication: 12.01.2007
DOI: 10.1055/s-2007-965877; Art ID: Z22306SS
© Georg Thieme Verlag Stuttgart · New York

584
W. Solodenko et al.
PAPER
catalytic amount of perfluoro-tert-butyl alcohol accelerat-
ed the reaction dramatically.4
In the case of epichlorohydrin, two products were formed
in 1:1 ratio after complete consumption of phenol. These
products were identified as (R)-1-chloro-3-phenoxypro-
pan-2-ol (15) and (S)-glycidyl phenyl ether [(S)-8], the
latter is formed after ring closure of chlorohydrin 15.
Complete conversion of 15 to (S)-glycidyl phenyl ether
[(S)-8, 86%, 93.2% ee] was achieved in the presence of
solid potassium hydroxide in diethyl ether.
Figure 1 Covalent immobilization of the salen ligand on the poly-
mer carrier (the same approach was applied for polystyrene resin,
Raschig rings, and PASSflow microreactor).
It is noteworthy, that catalyst 5 retains its activity after
multiple use. The same portion of catalyst 5 was success-
fully employed for at least seven different stereoselective
ring-opening reactions of racemic terminal epoxides us-
ing either water or phenols as nucleophiles (Schemes 2
and 3). After each transformation, the immobilized cata-
lyst 5 was washed successively according to the protocol
described in the experimental section.
The functionalized polymer was active in the hydrolytic
kinetic resolution of various terminal epoxides 6–8 and
exerted similar stereoselectivities for both products to
those reported for the homogeneous catalyst (R,R)-38
(Scheme 2).
5 (1–2 mol%),
H2O (0.55 equiv),
THF, r.t.
O
OH
The stereoselectivity of the Jacobsen catalysts is not abso-
lute, and for the hydrolytic kinetic resolution of terminal
epoxides according to Scheme 2, the results (yields and
enantiomeric excess of the products) are essentially de-
pendent on the substrate-to-water ratio and the reaction
time. In contrast, these factors are not important when epi-
bromohydrin is the substrate, as it undergoes dynamic ki-
netic resolution according to Scheme 4 as a result of its
relatively rapid racemization under the conditions em-
ployed.10
O
R
+
OH
R
R
rac
6 R = CH2Cl
7 R = Ph
(S)-6: 27%; ee n.d.
(R)-7: 37%; 87% ee
(S)-8: 34%; 97% ee
(R)-9: 32%; 85% ee
(S)-10: 46%; 90% ee
(R)-11: 49%; 67% ee
8 R = CH2OPh
Scheme 2 Hydrolytic kinetic resolution of terminal epoxides
(yields refer to isolated products).
Functionalized polymer 5 was also utilized in the kinetic
resolution of terminal epoxides initiated by nucleophilic
ring opening with phenols affording phenyl ethers 12–15
with selectivity very close to that for the homogeneous
catalyst (R,R)-39 (Scheme 3). In this case, addition of a
For this reason, this transformation is a convenient model
reaction for the rapid evaluation of the efficiency of vari-
ous immobilized Jacobsen catalysts. The reaction of race-
mic epibromohydrin with water (1.5 equiv) in
tetrahydrofuran in the presence of catalyst 5 (2 mol%)
OH
(S)
O
OH
O
5 (2.8 mol%),
+
(CF3)3COH (0.2 equiv)
THF, r.t.
4 equiv
12 (99%; 99% ee)
OH
(S)
O
OH
O
5 (2.8 mol%),
+
(CF3)3COH (0.2 equiv)
THF, r.t.
5 equiv
13 (93%; 95.5% ee)
OH
OH
OH
(S)
O
O
5 (2.8 mol%),
+
+
(CF3)3COH (0.2 equiv)
THF, r.t.
5 equiv
Me
14 (96%; 98.3% ee)
Me
O
OH
(R)
Cl
(S)
O
O
Cl
O
5 (2.8 mol%),
4 equiv
+
(CF3)3COH (0.2 equiv)
THF, r.t.
15
KOH, Et2O
(S)-8
(86%; 93.2% ee)
Scheme 3 Stereoselective ring opening of epoxides with phenols (yields refer to isolated products).
Synthesis 2007, No. 4, 583–589 © Thieme Stuttgart · New York

PAPER
Continuous Enantioselective Kinetic Resolution of Terminal Epoxides
585
Scheme 4 Dynamic kinetic resolution of epibromohydrin.
gave (R)-3-bromopropane-1,2-diol (16) in 94% yield and
95% ee (Scheme 4), which correlates well with the results
(93% yield and 96% ee) reported for the homogeneous ca-
talysis.10
In the next step, we used the same catalytic species except
that it was incorporated according to Scheme 1 on the po-
rous glass/polymer composite material shaped as a
Raschig ring resembling the situation inside the PASS-
flow microreactors. In this case, a certain degree of cata-
lyst site isolation can be expected, which will effect the
efficiency of the catalytic process because a cooperative
bimetallic mechanism has been discussed.4 However,
with these Raschig rings the dynamic kinetic resolution of
epibromohydrin was carried out on a 10-mmol scale to
yield (R)-3-bromopropane-1,2-diol (16) in 73% isolated
yield and with 95.8% ee.
Figure 3 PASSflow machine.
Thus, we immobilized the salen ligand 1 inside the PASS-
flow reactor bearing benzyl chloride groups. This was ac-
complished by the circulation of an N,N-dimethyl-
formamide solution of ligand (R,R)-2 in the presence of
N,N-diisopropylethylamine and cesium iodide through
the reactor at 60 °C for 28 hours. After loading with co-
balt(II) acetate, the functionalized flow-through reactor
was used for the dynamic kinetic resolution of epibromo-
hydrin under flow-through conditions (Scheme 5).
Four successive runs were performed with the same reac-
tor, the reactor being reactivated after each run by wash-
ing with toluene–acetic acid (9:1). Three runs performed
on the 1-mmol scale were completed within 20 hours for
each run and afforded (R)-diol 16 in 76–87% yield with
constant enantiomeric purity of 91–93% ee. The fourth
run was carried out in a 10-mmol scale and required six
days for completion, (R)-diol 16 was collected in 76%
yield and in 93% ee. Thus, no substantial loss of activity
or reduced enantioselectivity of the Co–salen complex in-
side the PASSflow reactor was observed during these four
experiments.
In summary, we have demonstrated that Jacobsen’s co-
balt–salen complex can be successfully immobilized on
different polymeric phases (powder, composite Raschig
Figure 2 PASSflow setup.
Recently, we developed a novel continuous-flow reactor
device, called PASSflow, which is composed of this
monolithic megaporous glass/polymer composite materi-
al. Shaped as a rod, it is incorporated inside a tube and cas-
ing.6b The polymer can be functionalized including
grafting of catalytic species. This flow device was incor-
porated into a setup that is depicted in Figures 2 and 3.
Both, stoichiometric and catalytic transformations can be
efficiently conducted under continuous-flow conditions.
Importantly, reactions can be scaled up without major op-
timization, which makes this setup ideal for industrial ap-
plications.6,11–13
H
N
H
N
O
O
Co
O
O
t-Bu
OH
O
OAc
t-Bu t-Bu
O
O
(R)
Br
Br
OH
16
H2O (1.5 equiv), THF, r.t.
76–87% yield
91–93% ee
Scheme 5 Dynamic kinetic resolution of epibromohydrin under
continuous-flow conditions using a PASSflow microreactor.
Synthesis 2007, No. 4, 583–589 © Thieme Stuttgart · New York

586
W. Solodenko et al.
PAPER
mmol/g according to weight increase and 0.34 mmol/g according to
elemental analysis (0.94% N).
rings, and inside a PASSflow reactor) thus allowing the
kinetic resolution of terminal epoxides under batch or
continuous-flow conditions. The flow setup has great po- This resin (56 mg) was stirred with a soln of Co(OAc)2·4 H2O (10
mg, 0.04 mmol) in MeOH–toluene (1:1, 1 mL) under N2 for 2 h.
tential for scaling up the reaction and, hence, for applica-
Then, the resin was filtered, washed with MeOH, CH2Cl2, toluene–
tion in the industrial production of chiral building blocks.
AcOH (9:1), CH2Cl2, MeOH, and CH2Cl2, and dried in vacuo to
give catalyst 5 (56 mg) as a greenish-brown powder.
NMR spectra were recorded with a Bruker DPX-400 spectrometer
After each transformation, the immobilized catalyst 5 was washed
at 400 MHz (1H NMR) and at 100 MHz (13C NMR) in CDCl3 using
successively with MeOH, CH2Cl2, toluene–AcOH (9:1), CH2Cl2,
TMS as the internal standard. MS spectra (EI) were obtained at 70
MeOH, and CH2Cl2 and dried in vacuo before use in further exper-
eV with a type VG Autospec apparatus (Micromass). GC analyses
iments.
were conducted using a Hewlett-Packard HP 6890 Series GC Sys-
tem equipped with a SE-54 capillary column (25 m, Macherey-
Nagel) and a FID detector 19231 D/E. Analytical TLC was per-
formed using pre-coated silica gel 60 F254 plates (Merck, Darm-
stadt), and the spots were visualized with UV light at 254 nm or by
staining with H2SO4/4-methoxybenzaldehyde in EtOH. Flash col-
umn chromatography was performed on Merck silica gel 60 (230–
400 mesh). Commercially available reagents and anhyd solvents
were used as received. Most compounds prepared were isolated af-
(S)-Epichlorohydrin [(S)-6] and (R)-3-Chloropropane-1,2-diol
[(R)-9]
A suspension of catalyst 5 (47 mg, 2 mol%), epichlorohydrin (6,
92.5 mg, 1 mmol) and H2O (10 mL, 0.55 mmol) were stirred in an-
hyd THF (0.3 mL) at r.t. for 24 h. CH2Cl2 (10 mL) was added and
the mixture was filtered. The filtrate was washed with H2O (3 × 2
mL) and dried (MgSO4). Careful rotary evaporation (400 mbar, r.t.)
afforded (S)-epichlorohydrin [(S)-6]. The combined aqueous solns
were evaporated in vacuo (65 mbar, 60 °C) to yield (R)-3-chloro-
propane-1,2-diol [(R)-9].
ter filtration and removal of the solvent. Pure homogeneous product
samples were collected after flash chromatography and purity was
analyzed by TLC, GC, and NMR analyses. Characterization was
achieved by appropriate spectroscopic methods (1H and 13C NMR,
(S)-Epichlorohydrin [(S)-6]
Yield: 25 mg (27%) (ee could not be determined with the available
IR, HRMS). Additionally, for known compounds the physical (e.g.,
mp, optical rotation) and spectroscopic data were compared with
chiral columns).
those in the literature. Chiral GC analyses were conducted using the
[a]D20 +15.1 (c 1.1, CH2Cl2) {Lit.14 [a]D23 +20.4 (c 1.02, CH2Cl2)}.
Hewlett-Packard 5890 Series II Gas Chromatograph with H2 as a
carrier gas and the chiral capillary column b-Hydrodex-PM (50
(R)-3-Chloropropane-1,2-diol [(R)-9]
m × 0.25 mm, Macherey-Nagel) at a column head pressure of 20
Yield: 35 mg (32%); 85% ee [b-Hydrodex-PM, 100 °C, tR = 6.99,
7.33 min, as the acetonide prepared using 1% w/v CSA–
Me2C(OMe)2].
[a]D20 –6.0 (c 1.1, MeOH) {Lit.8b [a]D20 –1.24 (neat)}.
1H NMR (200 MHz, DMSO-d6): d = 3.25–3.42 (m, 2 H), 3.43–3.57
(m, 1 H), 3.58–3.70 (m, 2 H), 4.72 (t, J = 5.65 Hz, 1 H), 5.11 (d,
J = 5.14 Hz, 1 H).
psi. Chiral HPLC analyses were performed on the LaChrom HPLC
System (Merck-Hitachi) interfaced with D-7000 HPLC-System-
Manager (Merck) software for data analysis using chiral HPLC col-
umn Chiralcel OD-H (25 × 0.46 cm, Diacel Chemical Industries,
LTD). Optical rotations were measured on a Perkin-Elmer Polarim-
eter 341.
Salen ligand (R,R)-1 was prepared according the literature method.4
The preparation of the polymeric phase as powder as well as glass/
polymer composite materials is given in the literature.6
(R)-Styrene Oxide [(R)-7] and (S)-1-Phenylethane-1,2-diol [(S)-
10]
Preparation of Catalyst 5
A suspension of catalyst 5 (40 mg, 1.1 mol%), styrene oxide (7, 120
mg, 1 mmol) and H2O (9.9 mL, 0.55 mmol) was gently stirred in an-
hyd THF (0.2 mL) at r.t. for 72 h. The mixture was filtered, and the
resin was rinsed with THF (2 × 1 mL) and CH2Cl2 (2 × 1 mL). The
combined filtrates were concentrated in vacuo. Flash chromatogra-
phy of the residue (silica gel, hexane–EtOAc, gradient from 5:1 to
1:2) afforded (R)-7 and (S)-10.
Glutaric anhydride (137 mg, 1.2 mmol) was added to a soln of salen
ligand (R,R)-1 (506 mg, 1 mmol) and DMAP (146 mg, 1.2 mmol)
in CH2Cl2 (5 mL). The mixture was stirred at r.t. for 22 h and then
concentrated in vacuo. Flash chromatography (silica gel, CH2Cl2–
MeOH, 95:5) afforded salen glutarate monoester (R,R)-2 as a yel-
low foam; yield: 411 mg (66%).
1H NMR (400 MHz, CDCl3): d = 1.23 (s, 9 H), 1.37 (s, 9 H), 1.39
(s, 9 H), 1.0–2.10 (m, 10 H), 2.49 (t, J = 7.14 Hz, 2 H), 2.60 (t, J
= 7.27 Hz, 2 H), 3.31 (m, 2 H), 6.75 (d, J = 2.8 Hz, 1 H), 6.91 (d,
J = 2.8 Hz, 1 H), 6.97 (d, J = 2.4 Hz, 1 H), 7.30 (d, J = 2.4 Hz, 1
H), 8.22 (s, 1 H), 8.29 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 24.42, 29.29, 29.58, 31.56, 33.26,
33.35, 34.18, 35.04, 35.09, 72.36, 72.59, 117.91, 118.35, 121.46,
122.85, 126.11, 127.07, 136.55, 138.76, 140.13, 142.57, 158.11,
158.34, 164.79, 166.04, 171.98.
(R)-Styrene Oxide [(R)-7]
Colorless liquid; yield: 44 mg (37%); 87% ee [chiral GC analysis,
chiral capillary column b-Hydrodex PM, 100 °C, isothermal,
tR = 14.45 min (major), 15.13 min (minor)].
[a]D20 +20.3 (c 0.3, CH2Cl2) {Lit.8b [a]D23 +28.6 (neat)}.
1H NMR (400 MHz, CDCl3): d = 2.81 (dd, J = 5.4, 2.5 Hz, 1 H, Ph-
CHCHH), 3.16 (dd, J = 5.4, 4.0 Hz, 1 H, PhCHCHH), 3.87 (dd,
J = 4.0, 2.5 Hz, 1 H, PhCHCH2), 7.30–7.40 (m, 5 H, Ph).
HRMS (ESI): m/z [M + H]+ calcd for C37H53N2O6: 621.3904; found:
621.3914.
13C NMR (100 MHz, CDCl3): d = 51.33, 52.51, 125.65, 128.33,
128.65, 137.75.
LR-MS: m/z = 120 (M+).
Polyvinyl benzyl chloride resin (50 mg, 0.32 mmol) was added to
the soln of salen glutarate monoester (R,R)-2 (93 mg, 0.15 mmol),
CsI (39 mg, 0.15 mmol), and DIPEA (19.4 mg, 0.15 mmol) in anhyd
DMF (2 mL). The mixture was stirred at 60 °C under N2 for 24 h
and filtered. The collected solid was washed with H2O, MeOH, and
CH2Cl2 and dried in vacuo to afford resin 4 (64 mg) as a light-yel-
low powder. The loading of salen ligand was calculated to be 0.37
(S)-1-Phenylethane-1,2-diol [(S)-10]
White solid; yield: 64 mg (46%); mp 62–64 °C; 90% ee [chiral GC,
b-Hydrodex PM, 140 °C, isothermal, tR = 9.53 min (minor), 9.88
min (major), as the acetonide prepared using 1% w/v CSA–
Me2C(OMe)2].
Synthesis 2007, No. 4, 583–589 © Thieme Stuttgart · New York

PAPER
Continuous Enantioselective Kinetic Resolution of Terminal Epoxides
587
[a]D20 +39.2 (c 1.11, EtOH) {Lit.8b [a]D23 +38.4 (c 4.38, EtOH)}.
1H NMR (400 MHz, CDCl3): d = 2.83 (br s, 1 H, OH), 3.22 (br s, 1
H, OH), 3.55–3.80 (m, 2 H, CH2), 4.79 (dd, J = 8.0, 3.5 Hz, 1 H,
PhCHCH2), 7.30–7.45 (m, 5 H, Ph).
13C NMR (100 MHz, CDCl3): d = 14.1, 22.8, 27.8, 32.9, 70.3, 72.3,
114.7, 121.2, 129.6, 158.8.
HRMS (EI): m/z [M]+ calcd for C12H18O2: 194.1307; found:
194.1307.
13C NMR (100 MHz, CDCl3): d = 68.15, 74.83, 126.20, 128.12,
128.66, 140.64.
(S)-1-Phenoxybutan-2-ol (13)
Phenol (18.8 mg, 0.2 mmol), 1,2-epoxybutane (72.1 mg, 1 mmol),
(CF3)3COH (5.6 mL, 0.04 mmol), and catalyst 5 (20 mg, 2.8 mol%)
were stirred in anhyd THF (100 mL) at r.t. for 24 h. The mixture was
filtered, the resin was washed with THF (2 × 1 mL) and CH2Cl2
(4 × 1 mL) and the combined filtrates were concentrated in vacuo.
Flash chromatography of the residue (silica gel, hexane–EtOAc,
5:1) afforded 13 as a colorless liquid; yield: 31 mg (93%); 95.5% ee
(chiral GC, b-Hydrodex PM, 120 °C, isothermal, tR = 44.37, 46.15
min).
LR-MS: m/z = 138 (M+).
(S)-Glycidyl Phenyl Ether [(S)-8] and (R)-3-Phenoxypropane-
1,2-diol [(R)-11]
A suspension of catalyst 5 (55 mg, 1.5 mol%), glycidyl phenyl ether
(8, 150 mg, 1 mmol), and H2O (9.9 mL, 0.55 mmol) were stirred in
anhyd THF (0.2 mL) at r.t. for 67 h. The mixture was filtered, and
the resin was rinsed with THF (2 × 1 mL) and CH2Cl2 (2 × 1 mL).
The combined filtrates were concentrated in vacuo. Flash chroma-
tography of the residue (silica gel, hexane–EtOAc, 5:1, then 1:2) af-
forded (S)-8 and (R)-11.
[a]D20 +24.6 (c 2.04, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 1.04 (t, J = 7.5 Hz, 3 H, CH2CH3,
1.63 (dq, J = 7.5, 6.6 Hz, 2 H, CHCH2CH3), 2.39 (br s, 1 H, OH),
3.84 (dd, J = 8.9, 7.3 Hz, 1 H, PhOCHHCH), 3.90–3.96 (m, 1 H,
CHOH), 3.99 (dd, J = 8.9, 3.0 Hz, 1 H, PhOCHHCH), 6.92 (dd,
J = 8.7, 0.9 Hz, 2 H, Ph), 6.97 (dd, J = 7.4, 7.4 Hz, 1 H, Ph), 7.30
(dd, J = 8.7, 7.4 Hz, 2 H, Ph).
(S)-Glycidyl Phenyl Ether [(S)-8]
Colorless liquid; yield: 51 mg (34%); 97% ee (chiral HPLC, Chiral-
cel OD-H, 10% i-PrOH–hexane, 214 nm, 1 mL/min, tR = 6.72,
11.95 min).
[a]D20 +4.8 (c 1.77, CHCl3) {Lit.8b [a]D23 +5.2 (c 7.5, CHCl3)}.
13C NMR (100 MHz, CDCl3): d = 10.0, 26.3, 71.6, 72.0, 114.7,
121.2, 129.6, 158.8.
1H NMR (400 MHz, CDCl3): d = 2.77 (dd, J = 5.0, 2.7 Hz, 1 H,
CHCHHOepoxy), 2.92 (dd, J = 4.8, 4.2 Hz, 1 H, CHCHHOepoxy),
3.37 (dddd, 5.6, 4.0, 2.9, 2.9 Hz, 1 H, OCH2CHCH2Oepoxy), 3.97 (dd,
J = 11.0, 5.6 Hz, 1 H, PhOCHHCH), 4.22 (dd, J = 11.0, 3.3 Hz, 1
H, PhOCHHCH), 6.97–7.05 (m, 3 H, Ph), 7.22–7.35 (m, 2 H, Ph).
HRMS (EI): m/z [M]+ calcd for C10H14O2: 166.0994; found:
166.0986.
(S)-1-(3-Methylphenoxy)hexan-2-ol (14)
m-Cresol (21.6 mg, 0.2 mmol), 1,2-epoxyhexane (100.2 mg, 1
mmol), (CF3)3COH (5.6 mL, 0.04 mmol), and catalyst 5 (20 mg, 2.8
mol%) were stirred in anhyd THF (100 mL) at r.t. for 24 h. Then, the
mixture was filtered, the resin was rinsed with THF (2 × 1 mL) and
CH2Cl2 (4 × 1 mL), and the filtrates were concentrated in vacuo.
Flash chromatography of the residue (silica gel, hexane–
EtOAc, 5:1) afforded 14 as a colorless liquid; yield: 40 mg (96%);
98.3% ee [chiral HPLC, Chiralcel OD-H, 3% EtOH–hexane, 210
nm, 1 mL/min, tR = 14.29 min (minor), 24.51 min (major)].
13C NMR (100 MHz, CDCl3): d = 44.9, 50.3, 68.8, 114.8, 121.4,
129.7, 158.7.
LR-MS: m/z = 150 (M+).
(R)-3-Phenoxypropane-1,2-diol [(R)-11]
Viscous colorless liquid that crystallizes at standing; yield: 82 mg
(49%); 67% ee (chiral HPLC, Chiralcel OD-H, 10% EtOH–hexane,
260 nm, 1 mL/min, tR = 10.67, 16.91 min).
[a]D20 –6.6 (c 1.9, EtOH) {Lit.8b [a]D23 –10.0 (c 1.9, EtOH)}.
[a]D20 +19.8 (c 1.54, CH2Cl2) {Lit.9 [a]D25 +19.5 (c 1.87, CH2Cl2)}.
1H NMR (400 MHz, CDCl3): d = 3.20 (br s, 1 H, OH), 3.58 (br s, 1
H, OH), 3.65–3.73 (m 1 H, CHHOH), 3.77–3.87 (m, 1 H, CHHOH),
3.98 (d, J = 5.3 Hz, 2 H, PhOCH2), 4.06–4.13 (m, 1 H, CHOH),
6.88 (dd, J = 8.7, 0.9 Hz, 2 H, Ph), 6.95 (dd, J = 7.3, 7.3 Hz, 1 H,
Ph), 7.26 (dd, J = 8.7, 7.3 Hz, 2 H, Ph).
13C NMR (100 MHz, CDCl3): d = 63.8, 69.1, 70.3, 114.7, 121.4,
129.7, 158.5.
1H NMR (400 MHz, CDCl3): d = 0.94 (t, J = 7.1 Hz, 3 H, CH2CH3),
1.35–1.44 and 1.45–1.62 (2 m, 6 H, 3 CH2), 2.34 (s, 3 H, C6H4CH3),
2.38 (d, J = 3.3 Hz, 1 H, CHOH), 3.82 (dd, J = 9.1, 7.4 Hz, 1 H,
ArOCHHCH), 3.97 (dd, J = 9.1, 2.6 Hz, 1 H, ArOCHHCH), 3.96–
4.02 [m, 1 H, CH2CH(OH)CH2], 6.72 (dd, J = 8.3, 2.1 Hz, 1 H, Ar),
6.75 (s, 1 H, Ar), 6.79 (d, J = 7.5 Hz, 1 H, Ar), 7.17 (dd, J = 7.8,
7.8 Hz, 1 H, Ar).
13C NMR (100 MHz, CDCl3): d = 14.1, 21.6, 22.8, 27.8, 32.9, 70.3,
72.3, 111.6, 115.6, 122.1, 129.4, 139.7, 158.8.
LR-MS: m/z = 168 (M+).
HRMS (EI): m/z [M]+ calcd for C13H20O2: 208.1463; found:
(S)-1-Phenoxyhexan-2-ol (12)
Phenol (18.4 mg, 0.196 mmol), 1,2-epoxyhexane (80.1 mg, 0.8
mmol), (CF3)3COH (5.6 mL, 0.04 mmol), and catalyst 5 (20 mg, 2.8
mol%) were stirred in anhyd THF (100 mL) at r.t. After complete
consumption of phenol (17 h, GC monitoring), the mixture was fil-
tered, the resin was rinsed with CH2Cl2 (4 × 1 mL), and the filtrates
were concentrated in vacuo to give pure 12 as a colorless oil; yield:
38 mg (>99%); >99% ee (chiral GC, b-Hydrodex PM, 120 °C, iso-
thermal, tR = 131.4, 134.6 min).
208.1463.
(S)-Glycidyl Phenyl Ether [(S)-8] and (R)-1-Chloro-3-phen-
oxypropan-2-ol (15)
Phenol (18.8 mg, 0.2 mmol), epichlorohydrin (6, 74 mg, 0.8 mmol),
(CF3)3COH (5.6 mL, 0.04 mmol), and catalyst 5 (20 mg, 2.8 mol%)
were stirred in anhyd THF (100 mL) at r.t. After 24 h GC analysis
indicated complete consumption of phenol and the presence of two
products in ca. 1:1 ratio. The mixture was filtered, and the resin was
rinsed with CH2Cl2 (4 × 1 mL). The filtrates were concentrated in
vacuo. Flash chromatography of the residue (silica gel, hexane–
EtOAc, 5:1) afforded (S)-glycidyl phenyl ether [(S)-8] (12 mg,
40%) and (R)-1-chloro-3-phenoxypropan-2-ol (15) (18 mg, 48%).
[a]D20 +19.1 (c 1.45, CH2Cl2) {Lit.9 [a]D25 +18.7 (c 1.25, CH2Cl2)}.
1H NMR (400 MHz, CDCl3): d = 0.94 (t, J = 7.0 Hz, 3 H, CH2CH3),
1.25–1.60 (m, 6 H, 3 CH2), 2.40 (d, J = 3.4 Hz, 1 H, CHOH), 3.84
(dd, J = 9.2, 7.5 Hz, 1 H, PhOCHHCH), 3.99 (dd, J = 9.2, 2.4 Hz,
1 H, PhOCHHCH), 3.98–4.05 (m, 1 H, CHOH), 6.90–6.99 (m, 3 H,
Ph), 7.25–7.33 (m, 2 H, Ph).
Synthesis 2007, No. 4, 583–589 © Thieme Stuttgart · New York

588
W. Solodenko et al.
PAPER
(R)-1-Chloro-3-phenoxypropan-2-ol (15)
1H NMR (200 MHz, CDCl3): d = 2.58 (d, J = 5.9 Hz, 1 H), 3.70–
3.85 (m, 3 H), 4.08–4.18 (m, 2 H), 6.90–7.05 (m, 3 H), 7.25–7.35
(m, 2 H).
mL), H2O (10 mL), MeOH (10 mL), and MeOH–toluene (1:1).
Then, a soln of Co(OAc)2·4 H2O (87.2 mg, 0.35 mmol) in MeOH–
toluene (1:1; 3 mL) was pumped (2 mL/min) through the reactor in
circulating mode at r.t. for 1 h. Finally, the reactor was washed with
MeOH (10 mL), CH2Cl2 (10 mL), toluene–AcOH (9:1, 20 mL),
CH2Cl2 (10 mL), MeOH (10 mL), and CH2Cl2 (10 mL) and dried in
vacuo over P2O5.
LR-MS: m/z = 186 (M+, Cl35), 188 (M+, Cl37)].
(S)-Glycidyl Phenyl Ether [(S)-8]
(R)-15 (17.5 mg) and solid KOH (20 mg) were stirred in Et2O (6
mL) at r.t. for 2.5 h. Filtration of the mixture and removal of the sol-
vent in vacuo provided pure (S)-8 (14 mg). Total yield of (S)-gly-
cidyl phenyl ether [(S)-8] (26 mg, 86%); 93.2% ee (chiral HPLC,
Chiralcel OD-H, 10% i-PrOH–hexane, 210 nm, 1 mL/min, tR =
8.08, 13.31 min).
This loaded and dried reactor was flushed with anhyd THF (20 mL).
Then, a soln of epibromohydrin (137 mg, 1 mmol) and H2O (27 mL,
1.5 mmol) in anhyd THF (0.5 mL) was pumped (2 mL/min) through
the reactor in circulating mode at r.t. for 20 h (GC monitoring). Af-
ter the complete consumption of epibromohydrin, the reactor was
washed with THF (10 mL) and CH2Cl2 (10 mL). The combined or-
ganic solns were concentrated in vacuo (65 mbar, 60 °C) to give
(R)-3-bromopropane-1,2-diol (16) as a clear viscous liquid; yield:
118 mg (76%); 91% ee. Analytical data are described above.
[a]D20 +4.5 (c 0.4, CHCl3) {Lit.8b [a]D23 +5.2 (c 7.5, CHCl3)}.
1H NMR (400 MHz, CDCl3): d = 2.77 (dd, J = 4.8, 2.5 Hz, 1 H,
CHCHHOepoxy), 2.91 (dd, J = 4.7, 4.2 Hz, 1 H, CHCHHOepoxy),
3.36 (dddd, J = 5.6, 4.0, 2.8, 2.8 Hz, 1 H, CH2CHCH2Oepoxy), 3.97
(dd, J = 11.0, 5.6 Hz, 1 H, PhOCHHCH), 4.22 (dd, J = 11.0, 3.2
Hz, 1 H, PhOCHHCH), 6.90–6.99 (m, 3 H, Ph), 7.27–7.32 (m, 2 H,
Ph).
The PASSflow reactor was washed with toluene–AcOH (9:1, 10
mL) followed by anhyd THF (20 mL) and used in the next runs ac-
cording to the procedure described above.
13C NMR (100 MHz, CDCl3): d = 44.9, 50.3, 68.8, 114.8, 121.4,
129.7, 158.7.
Acknowledgment
The work was supported by the Fonds der Chemischen Industrie
and the DFG (Ki 379/6-1). We thank Solvay Pharmaceutical
Research Laboratories, Hannover, for the donation of chemicals.
LR-MS: m/z = 150 (M+).
Preparation of Catalyst 5 Loaded on Raschig Rings and
Dynamic Kinetic Resolution of Epibromohydrin
Six glass/polymer composite Raschig rings (bearing ca. 1 mmol of
benzyl chloride groups) were gently shaken with a soln of (R,R)-2
(207 mg, 0.333 mmol), DIPEA (68.5 mL, 0.4 mmol), and CsI (104
mg, 0.4 mmol) in DMF (7 mL) at 60 °C under N2 for 72 h. After de-
cantation of the soln, the rings were shaken for 5 min with DMF (10
mL) followed by decantation. This procedure was repeated with
DMF (11 × 10 mL), H2O (2 × 10 mL), MeOH (2 × 10 mL), and
CH2Cl2 (2 × 10 mL). After drying in vacuo, the rings were shaken
with a soln of Co(OAc)2·4 H2O (174 mg, 0.7 mmol) in MeOH–tol-
uene (1:1) under N2 for 6 h, then washed with MeOH (2 ×), CH2Cl2
(2 ×), toluene–AcOH (9:1, 3 ×) and finally with CH2Cl2 (2 ×),
MeOH (2 ×), and CH2Cl2 (2 ×). After drying in vacuo, these rings
were gently shaken in a soln of epibromohydrin (1.37 g, 10 mmol)
and H2O (0.27 mL, 15 mmol) in THF (6 mL) at r.t. for 20 h. The
soln was decanted, the rings were washed with THF (5 mL) and
CH2Cl2 (2 × 5 mL), and the combined organic solns were concen-
trated in vacuo. The residue was taken up in CH2Cl2 (10 mL) and
extracted with H2O (3 × 5 mL). The aqueous soln was washed with
CH2Cl2 (5 mL) and concentrated in vacuo to yield (R)-3-bromopro-
pane-1,2-diol (16) as a colorless viscous liquid; yield: 1.134 g
(73%); 95.8% ee [chiral GC, b-Hydrodex PM, 100 °C, isothermal,
tR = 10.92 min (minor), 11.12 min (major), as the acetonide pre-
pared using 1% w/v CSA–Me2C(OMe)2].
References
(1) For recent reviews on immobilized catalysts, see:
(a) Immobilised Catalysts, In Topics in Current Chemistry,
Vol. 242; Kirschning, A., Ed.; Springer: Berlin, 2004.
(b) Solodenko, W.; Frenzel, T.; Kirschning, A. In Polymeric
Materials in Organic Synthesis and Catalysis; Buchmeiser,
M. R., Ed.; Wiley-VCH: Weinheim, 2003, 201–240. (c) Li,
C. Catal. Rev.–Sci. Eng. 2004, 46, 419. (d) Xia, Q. H.; Ge,
H. Q.; Ye, C. P.; Liu, Z. M.; Su, K. X. Chem. Rev. 2005, 105,
1603.
(2) (a) Jas, G.; Kirschning, A. Chem. Eur. J. 2003, 9, 5708.
(b) Kirschning, A.; Solodenko, W.; Mennecke, K. Chem.
Eur. J. 2006, 12, 5972; and references therein.
(3) (a) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691.
(b) Larrow, J. F.; Jacobsen, E. N. Top. Organomet. Chem.
2004, 6, 123.
(4) Annis, D. A.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121,
4147.
(5) For recent publications on immobilized chiral salen
complexes, see: (a) Reger, T. S.; Janda, K. D. J. Am. Chem.
Soc. 2000, 122, 6929. (b) Heckel, A.; Seebach, D. Helv.
Chim. Acta 2002, 85, 9130. (c) Holbach, M.; Weck, M. J.
Org. Chem. 2006, 71, 1825; and references therein.
(6) (a) Kirschning, A.; Altwicker, C.; Dräger, G.; Harders, J.;
Hoffmann, N.; Hoffmann, U.; Schönfeld, H.; Solodenko,
W.; Kunz, U. Angew. Chem. Int. Ed. 2001, 40, 3995.
(b) Kunz, U.; Schönfeld, H.; Solodenko, W.; Jas, G.;
Kirschning, A. Ind. Eng. Chem. Res. 2005, 44, 8458.
(7) The loading with salen ligand was determined by weight
increase and combustion analysis.
(8) (a) Tokunada, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E.
N. Science 1997, 277, 936. (b) Schaus, S. E.; Brandes, B.
D.; Larrow, J. F.; Tokunada, M.; Hansen, K. B.; Gould, A.
E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002,
124, 1307.
[a]D20 –4.4 (c 9.5, MeOH) {Lit.15 [a]D25 –3.94 (c 5.07, CHCl3)}.
1H NMR (200 MHz, DMSO-d6): d = 3.25–3.70 (m, 5 H,
CH2CHCH2), 4.72 (t, J = 5.6 Hz, 1 H, CH2OH), 5.13 (d, J = 4.9
Hz, 1 H, CHOH).
13C NMR (100 MHz, DMSO-d6): d = 37.4, 63.4, 70.9.
Preparation of Catalyst 5 Loaded Inside a PASSflow Reactor
and Dynamic Kinetic Resolution of Epibromohydrin in Contin-
uous-Flow Mode
A homogeneous soln of salen glutarate monoester (R,R)-2 (105 mg,
0.169 mmol), CsI (43.9 mg, 0.169 mmol), and DIPEA (21.8 mg,
0.169 mmol) in anhyd DMF (5 mL) was allowed to circulate (2 mL/
min) through the PASSflow reactor for 28 h (containing ca. 0.4
mmol active benzyl chloride groups), the reactor was heated at
60 °C (external thermostat). The reactor was washed with DMF (10
(9) Ready, J. M.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121,
6086.
(10) Furrow, M. E.; Schaus, S. E.; Jacobsen, E. N. J. Org. Chem.
1998, 63, 6776.
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Continuous Enantioselective Kinetic Resolution of Terminal Epoxides
589
(11) Hodge and co-workers were one of the first groups that
combined solid-phase assisted organic synthesis with
continuous-flow techniques; Hodge, P.; Sung, D. W. L.;
Stratford, P. W. J. Chem. Soc., Perkin Trans. 1 1999, 2335;
and references cited therein.
(12) For related important work in this field refer to: (a) Saaby,
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2005, 2909. (b) Yoswathananont, N.; Nitta, K.; Nishiuchi,
Y.; Sato, M. Chem. Commun. 2005, 40.
(13) Rubin, A. E.; Tummala, S.; Both, D. A.; Wang, C.; Delaney,
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(14) Ready, J. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123,
2687.
(15) Kawakami, Y.; Asai, T.; Umeyama, K.; Yamashita, Y. J.
Org. Chem. 1982, 47, 3581.
Synthesis 2007, No. 4, 583–589 © Thieme Stuttgart · New York