Synthesis of cinchona alkaloid-derived chiral polymers by Mizoroki-Heck polymerization and their application to asymmetric catalysis

Article abstract of DOI:10.1021/ma5001018

To facilitate the asymmetric catalysis process, we designed novel polymeric chiral catalysts. Since quaternary ammonium salts of cinchona alkaloid derivatives show efficient catalytic activity in various asymmetric transformations, we have synthesized nov

Full text of DOI:10.1021/ma5001018

Article
pubs.acs.org/Macromolecules
Synthesis of Cinchona Alkaloid-Derived Chiral Polymers by
Mizoroki−Heck Polymerization and Their Application to Asymmetric
Catalysis
Md. Masud Parvez, Naoki Haraguchi, and Shinichi Itsuno*
Department of Environmental & Life Sciences, Toyohashi University of Technology, Toyohashi 441-8580, Japan
ABSTRACT: To facilitate the asymmetric catalysis process, we designed novel polymeric chiral catalysts. Since quaternary
ammonium salts of cinchona alkaloid derivatives show efficient catalytic activity in various asymmetric transformations, we have
synthesized novel chiral polymer catalysts containing cinchonidinium moieties in the main chain of the polymer. Repetitive
Mizoroki−Heck coupling reactions between the cinchona alkaloid-derived dimer and diiodide afforded the chiral polymer
catalysts, which were subsequently used as catalysts in asymmetric benzylation reactions to yield the corresponding phenylalanine
derivatives in higher yields and levels of enantioselectivity than can be obtained with a monomeric catalyst. Because of the
insolubility of the polymeric catalysts, they were easily recovered from the reaction mixture and reused several times.
INTRODUCTION
attachment of cinchona derivatives onto the side chain of
polymers, resulting in chiral polymers containing randomly
attached cinchona moieties on the cross-linked polymer
■
Cinchona alkaloids have been utilized for the preparation of
various types of chiral catalysts. Some cinchona alkaloid
1
9
supports. However, most of these polymer-immobilized
derivatives can be utilized as chiral ligands for transition metal
2
3
cinchona derivative catalysts possess lower catalytic activities
and enantioselectivities as compared with the low-molecular-
catalysis and organo/metal cooperative catalysis, but the most
important application of cinchona alkaloids is their use as chiral
10
1
,4,5
weight cinchona-derived catalysts in solution.
organocatalysts.
A number of asymmetric catalysis experi-
We have recently investigated novel polymeric cinchona-
derivative catalysts, in which the organocatalyst is incorporated
ments have been performed with chiral organocatalysts derived
from cinchona alkaloids. Typical examples include chiral base
5
11
into the polymer main chain as a repeating unit. Since
cinchona alkaloids contain several functionalities such as a
quinuclidine tertiary nitrogen, a secondary alcohol, a quinoline
nitrogen, and vinyl group, various types of polycondensation
reactions that use these functionalities can be applied to
cinchona alkaloid dimers. For example, polymerization between
cinchonidine dimers and dihalide linkers yielded a polymer
containing cinchonidinium salts in its main chain unit, which
catalysis with cinchona alkaloids. A large number of chiral
quaternary ammonium salts have also been designed and
synthesized from cinchona alkaloids. In most cases, due to the
6
relatively lower catalytic activities of chiral quaternary
ammonium salts as compared to transition metal catalysts,
over 10 mol % of the catalyst is usually required to facilitate a
reaction at a reasonable rate. The amphiphilic nature of these
chiral quaternary ammonium salts is necessary for their
12
7
we termed quaternization polymerization. By utilizing the
secondary alcohol functionality of the cinchona alkaloid,
etherification polymerization of cinchona alkaloid dimers and
performance as phase transfer catalysts; however, this property
can sometimes complicate isolation of the desired reaction
products from the reaction mixture and cause decreases in
yield. Moreover, recovery and reuse of the catalyst are usually
difficult. One effective solution is to immobilize the catalyst on
a solid support, and several approaches to immobilize cinchona-
13
dihalide linkers yielded yet another class of chiral polymer.
Received: January 14, 2014
Revised: March 2, 2014
Published: March 11, 2014
8
derived organocatalysts onto polymers have been reported. In
most cases, the immobilization strategy employed involves
©
2014 American Chemical Society
1922
dx.doi.org/10.1021/ma5001018 | Macromolecules 2014, 47, 1922−1928

Macromolecules
Article
Another method of polymerization is to use an ion exchange
reaction between cinchonidinium halide dimers and aromatic
chromatography (SEC) was obtained with Tosoh instrument with
HLC 8020 UV (254 nm) or refractive index detection. DMF was used
as a carrier solvent at a flow rate of 1.0 mL/min at 40 °C. Two
polystyrene gel columns of bead size 10 μm were used. A calibration
curve was made to determine number-average molecular weight (Mn)
and molecular weight distribution (M /M ) values with polystyrene
1
4
dihalide linkers. These chiral polymers were applied to
asymmetric catalysis, some of which showed excellent catalytic
activity in asymmetric alkylation reactions. However, no other
polymerization reaction has been developed by using the vinyl
group of cinchona alkaloids except for the radical copoly-
merization of cinchona alkaloids and acrylonitrile to give chiral
polymers possessing cinchona moieties as the side-chain
w
n
standards.
Synthesis of 2. A mixture of (−)-cinchonidine (1.47 g, 5.0 mmol)
with benzyl bromide (0.89 g, 5.2 mmol) was stirred in a mixture of 20
mL (ethanol:DMF:CHCl /5:6:2) at 100 °C for 6 h. After completion
3
1
5
pendant groups.
of the reaction, the reaction mixture was cooled to room temperature.
After cooling, the reaction mixture was added dropwise to ether (300
mL) with stirring. The solid precipitate was filtered and washed with
In this paper, we report that the vinyl group of cinchonidine
easily reacted with aromatic iodide under the conditions of the
Mizoroki−Heck coupling reaction. Mizoroki−Heck coupling is
one of the most efficient C−C bond formation reactions of
1
ether (100 mL) and hexane to afford 1 (2.25 g, 88% yield). H NMR
(
DMSO-d , 300 MHz) δ: 8.98 (d, J = 4.5 Hz, 1H), 8.31 (d, J = 8.1 Hz,
6
16
1H), 8.11 (d, J = 8.4 1H), 7.87−7.80 (m, 2H), 7.77−7.73 (m, 3H),
olefinic compounds with aromatic halides. Our strategy was
to use the Mizoroki−Heck coupling reaction between
cinchonidine dimers and diiodide linkers in the presence of
7
5
4
.58−7.56 (m, 3H), 6.67 (d, J = 4.5 Hz, 1H), 6.56 (d, J = 3.6 Hz, 1H),
.73−5.62 (m, 1H), 5.21−5.13 (m, 2H), 5.05 (d, J = 12.3 Hz, 1H),
.94 (d, J = 10.5 Hz, 1H), 4.32−4.25 (m, 1H), 3.97−3.91 (m, 1H),
Pd(OAc) . Since the Mizoroki−Heck reaction is relatively
3.78 (d, J = 12.3 Hz, 1H), 3.26−3.18 (m, 2H), 2.69 (s, 1H), 2.15−1.99
(m, 3H), 1.85−1.77 (m, 1H), 1.32−1.24 (m, 1H). C NMR (DMSO-
2
13
tolerant of many functional groups, this polymerization has an
advantage in the synthesis of various kinds of cinchona alkaloid
polymers including quaternary ammonium catalyst and free
amine base catalyst. Repetitive Mizoroki−Heck coupling
affords chiral polymers containing the cinchonidine moiety in
its main chain. Several examples of Mizoroki−Heck polymer-
ization for achiral monomers have been reported for the
synthesis of the corresponding polymers containing trans
d
1
5
1
, 100 MHz) δ: 150.1, 147.4, 145.5, 138.0, 133.8, 130.1, 129.6, 129.5,
28.9, 128.0, 127.4, 124.3, 123.9, 120.1, 116.4, 67.5, 64.0, 62.4, 59.1,
6
0.6, 36.8, 25.9, 24.2, 21.0. IR (KBr) ν: 3296, 3090, 2922, 2190, 1967,
2
5
663, 1608, 1587, 1510, 1458, 1343, 1214, 1127, 939, 799. [α]
=
D
−
123 (c 1.0, DMSO).
A mixture of 1 (0.93 g, 2.0 mmol) with iodobenzene (0.45 g, 2.2
mmol) in the presence of 3 mol % Pd (OAc) (0.06 mmol 0.01 g) and
2
Et N (0.2 mL, 2.0 mmol) was stirred in 10 mL of dry DMF at 100 °C
3
1
7−19
double bonds in the main chain.
Recently, chiral
for 12 h. After completion of reaction, the reaction mixture was cooled
to room temperature. The reaction mixture was filtered by filter paper
and poured into ether (300 mL) with stirring. The solid precipitate
conjugated polymers have been prepared by Mizoroki−Heck
polymerization of divinyl compounds with chiral aromatic
2
0
dihalide linkers. However, no chiral polymeric catalysts have
been synthesized by means of a Mizoroki−Heck polymer-
ization. In this article, we discuss a novel chiral polymer
synthesis involving cinchona alkaloid derivatives by using
Mizoroki−Heck polymerization and the application of this
polymer to asymmetric organocatalysis.
was filtered, washed with water, ether, ethyl acetate, and hexane to
1
afford 2 (1.09 g, 94% yield). H NMR (DMSO-d , 400 MHz) δ: 8.99
6
(
7
(
3
d, J = 4.0 Hz, 1H), 8.36 (d, J = 7.6 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H),
.81 (d, J = 12.2 Hz, 1H), 7.58 (s, 3H), 7.25−7.14 (m, 4H), 6.72−6.50
m, 2H), 6.23−6.06 (m, 1H), 5.41−4.96 (m, 2H), 4.29−3.84 (m, 2H),
.45−3.39 (m, 1H), 3.12−3.10 (m, 2H), 2.96−2.91 (m, 2H), 2.08 (d, J
13
=
13.2, 2H), 1.86−1.46 (m, 1H), 1.20−1.16 (m, 5H). C NMR
(DMSO-d , 100 MHz) δ: 150.6, 148.0, 146.0, 137.0, 134.3, 131.36,
6
EXPERIMENTAL SECTION
1
30.7, 130.4, 130.2, 130.0, 129.5, 128.9, 128.5, 128.0, 127.9, 126.6,
■
Materials and General Considerations. Unless otherwise stated,
all commercial reagents were purchased from Aldrich, Wako, or TCI
Chemicals and were used as received. Reactions were monitored by
thin layer chromatography using Merck precoated silica gel plates
124.9, 124.4, 120.6, 68.4, 64.6, 63.3, 60.4, 51.3, 37.2, 27.0, 24.8, 21.6.
IR (KBr) ν: 3231, 2943, 1590, 1508, 1388, 1233, 1160, 1032, 758, 701.
[α]25
= 94.70 (c 1.0, DMSO).
D
Synthesis of Cinchonidinium Salt Dimer D1. A mixture of 1
(
Merck 5554, 60F254). Column chromatography separations were
(1.21 g, 2.60 mmol) with 2,7-naphthalene disodium disulfonate (0.42
performed with a silica gel column (Wakogel C-200, 100−200 mesh).
Melting points were taken on a Yanaco micro melting apparatus and
are uncorrected. Optical rotations were measured on a JASCO DIP-
g, 1.25 mmol) was stirred in a mixture of CH Cl (20 mL) and H O
2 2 2
(10 mL) at room temperature for 30 min. After completion of
reaction, the reaction mixture was filtered through a glass filter and
washed with CH Cl , water, and hexane. The solid obtained was dried
1
40 digital polarimeter with a 10 cm thermostated microcell. NMR
2
2
1
1
spectra were registered in a Varian Mercury 300 (300 MHz ( H))
under vacuum at 40 °C to afford 1.20 g (91% yield) of D1a. H NMR
(DMSO-d , 300 MHz) δ: 8.98 (d, J = 4.5 Hz, 1H), 8.27 (d, J = 8.4 Hz,
1
spectrometer or a JEOL JNM-ECS400 (400 MHz ( H)) spectrometer
6
in CDCl or DMSO-d at room temperature operating at 300 or 400
1H), 8.11 (s, 2H), 7.86−7.82 (m, 3H), 7.77−7.69 (m, 4H), 7.56 (s,
3H), 6.79 (d, 1H), 6.57 (s, 1H), 5.76−5.61 (m, 1H), 5.16−5.10 (m,
2H), 4.99−4.92 (m, 2H), 4.24 (s, 1H), 3.94−3.88 (m, 1H), 3.71 (d, J
= 11.1 Hz, 1H), 3.32−3.20 (m, 2H), 2.68 (s, 1H), 2.15−1.98 (m, 3H),
3
6
1
13
1
MHz ( H) and 100 MHz ( C{ H}). TMS was used as internal
1
13
standard for H NMR and CDCl for C NMR. Chemical shifts are
3
reported in ppm referred to TMS, and the J values were recorded in
hertz. IR spectra were recorded with a JEOL JIR-7000 Fourier
transform infrared spectrometer and were reported in reciprocal
13
1.84−1.76 (m, 1H), 1.32−1.24 (m, 1H). C NMR (DMSO-d , 100
6
MHz) δ: 150.2, 147.6, 145.9, 145.4, 138.6, 133.8, 132.6, 131.3, 130.2,
129.9, 129.5, 129.0, 127.9, 127.3, 124.6, 124.4, 123.6, 120.1, 116.4,
67.6, 64.2, 62.9, 59.2, 50.6, 36.9, 25.9, 24.2, 20.9. IR (KBr) ν: 3209,
3006, 2849, 1935, 1845.54, 1640, 1590, 1509, 1498, 1459, 1422, 1267,
−
1
centimeters (cm ). Elemental analyses (carbon, hydrogen, and
nitrogen) were performed on a Yanaco-CHN coder MT-6 analyzer.
GC analyses were performed with a Shimadzu capillary gas
chromatograph GC-2014 equipped with a capillary column (SPERCO
β-DEX 325, 30 m × 0.25 mm). High-performance liquid
chromatography (HPLC) analyses were performed with a Jasco
HPLC system composed of a DG-980-50 three-line degasser, a PU
1062, 779, 698. [α]25 = −122 (c 1.0, DMSO); mp 230−232 °C.
D
Synthesis of Main-Chain Chiral Polymers P1a from Ionic
Dimer D1a Using Mizoroki−Heck Reaction. A mixture of ionic
dimer D1a (0.53 g, 0.5 mmol) with 4,4′-diiodobiphenyl (0.20 g, 0.5
mmol) in the presence of 3 mol % Pd (OAc) and Et N (0.07 mL, 0.5
980 HPLC pump, and a CO-965 column oven equipped with a chiral
2
3
column (Chiralcell OD-H, Daicel) with hexane/2-propanol as an
eluent. A Jasco UV-975 UV detector was used for the peak detection.
Optical rotations were recorded with a JASCO DIP-149 digital
polarimeter, using a 10 cm thermostated microcell. Size exclusion
mmol) was stirred in 15 mL of dry DMF at 100 °C for 24 h. After
completion of the reaction, the reaction mixture was cooled to room
temperature. The reaction mixture was then added dropwise into
water (400 mL) with stirring. The solid precipitate was filtered and
1
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Article
washed with water, ether, ethyl acetate, CH OH, and hexane to afford
3
Scheme 1. Mizoroki−Heck Phenylation of Cinchonidinium
Salt 1
0
1
1
1
2
1
.42 g (70% yield) of the product. 13C NMR (DMSO-d , 100 MHz) δ:
6
50.2, 147.6, 145.9, 145.5, 138.3, 137.7, 135.6, 133.8, 132.6, 131.3,
30.5, 130.2, 129.9, 129.5, 129.0, 128.6, 127.9, 127.3, 126.7, 126.5,
26.4, 124.6, 123.7, 120.1, 68.0, 64.2, 63.1, 60.0, 50.9, 36.9, 26.5, 24.4,
1.0. IR (KBr) ν: 3230, 2948, 1919, 1700, 1655, 1591, 1508, 1457,
25
316, 1217, 1180, 1101, 1026, 699. [α] = −135 (c 1.0, DMSO); Mn
D
3
(
SEC) = 7.0 × 10 ; M /M = 1.71, dp = 6.
w n
Mizoroki−Heck Phenylation of Cinchonidine Dimer D2b. A
14
mixture of cinchonidine dimer D2b (0.85 g, 1.0 mmol) with
iodobenzene (0.45 g, 2.2 mmol) in the presence of 3 mol % Pd(OAc)2
and Et N (0.14 mL, 1.0 mmol) was stirred in 15 mL dry DMF at 100
3
°
C for 12 h. The reaction mixture was then cooled to room
In order to apply the Mizoroki−Heck coupling reaction for
the synthesis of chiral polymers, cinchonidinium salt dimers D1
and D2 were prepared according to literature procedures
temperature and poured into ether (400 mL) with stirring. The solid
precipitated was filtered and washed with water, ether, ethyl acetate,
and hexane to afford 0.96 g (96% yield) of D2bPh. H NMR (DMSO-
d6, 400 MHz) δ: 8.99 (d, J = 4.4 Hz, 1H), 8.40 (d, J = 8.0 Hz, 1H),
8
7
2
1
14
(
Schemes 2 and 3).
In a previous paper, we found that the ion exchange reaction
of cinchonidinium bromide 1 and sodium sulfonate occurred
.13−8.09 (m, 1H), 8.01−7.93 (m, 1H), 7.84−7.78 (m, 3H), 7.32−
.15 (m, 4H), 7.04−6.20 (m, 3H), 5.39−4.93 (m, 3H), 4.39−3.61 (m,
H), 3.40 (s, 4H), 3.22−2.91 (m, 1H), 2.29−1.80 (m, 4H), 1.49−1.43
14
smoothly to afford the cinchonidinium sulfonate. When
disodium disulfonate 3 was used, the corresponding cinchoni-
dium ionic dimer D1 was formed in quantitative yield (Scheme
13
(
m, 1H), 1.21−1.16 (m, 1H). C NMR (DMSO-d , 100 MHz) δ:
6
1
1
5
1
50.3, 147.7, 145.4, 145.0, 136.5, 134.2, 130.8, 129.9, 129.4, 128.5,
28.4, 127.4, 126.1, 124.4, 124.2, 123.8, 120.1, 68.6, 68.1, 64.2, 62.4,
9.8, 36.7, 26.6, 24.1, 21.4. IR (KBr) ν: 3227, 2945, 1653, 1591, 1509,
2
). Cinchonidinium dimers D2 were prepared by quaterniza-
tion of cinchonidine 4 with dihalide 5 (Scheme 3) according to
a previously reported procedure. The corresponding
455, 1233, 1162, 954. [α]25 = 50.8 (c 1.0, DMSO).
D
14
Synthesis of Main-Chain Chiral Polymer P2a from Cincho-
phenylated derivative of D2, D2bPh, was also prepared in
96% yield by using the Mizoroki−Heck reaction (Scheme 4).
Since the Mizoroki−Heck reaction proceeded quantitatively
on the vinyl positions in these cinichonidinium salts, we
investigated the synthesis of chiral polymers by means of a
repetitive Mizoroki−Heck coupling reaction. The Mizoroki−
Heck coupling of dimer D1 and 4,4′-diiodobiphenyl occurred
smoothly in DMF to provide chiral polymers P1 containing
cinchonidinium repeating units in its main chain (Scheme 5).
Under the same reaction conditions, the Mizoroki−Heck
coupling of dimer D2 with 4,4′-diiodobiphenyl affords chiral
polymer P2 (Scheme 6).
Next, we examined various reaction conditions for the
Mizoroki−Heck polymerization of chiral dimer D2 and 4,4′-
diiodobiphenyl. Table 1 summarizes the result of the
Mizoroki−Heck polymerization. Polymerization in refluxing
THF failed to yield polymer even after 24 h (entry 1). The
polymerization proceeded smoothly in DMF to provide the
corresponding chiral polymer P2. The polymerization temper-
ature was found to significantly influence the degree of
nidine Dimer D2a Using Heck Reaction. A mixture of
cinchonidine dimer D2a (0.86 g, 1.0 mmol) with 4,4′-diiodobi-
phenyl (0.41 g, 1.0 mmol) in the presence of 3 mol % Pd(OAc) and
14
2
Et N (0.14 mL, 1.0 mmol) was stirred in 15 mL of dry DMF at 100 °C
3
for 24 h. After completion of the reaction, the reaction mixture was
cooled to room temperature. The reaction mixture was then added
dropwise into water (400 mL) with stirring. The solid precipitate was
filtered and washed with water, ether, ethyl acetate, and hexane to
afford 0.7 g (71% yield) of the product. C NMR (DMSO-d , 100
MHz) δ: 150.3, 147.7, 146.7, 138.2, 135.9, 130.5, 129.9, 129.4, 127.1,
1
5
3
13
6
27.1, 127.1, 127.0, 126.9,126.8, 126.5, 126.4, 124.7, 123.6, 119.1, 66.2,
9.9, 53.9, 43.0, 37.8, 36.7, 27.3, 27.3, 23.9, 18.1. IR (KBr) ν: 3309,
024, 2944, 1734, 1699, 1654, 1592, 1508, 1457, 1376, 1024, 807, 755.
25
4
[α] = 58.7 (c 1.0, DMSO); M = 1.4 × 10 , M /M = 1.71, dp = 14.
D
n
w
n
General Procedure for Catalytic Enantioselective Benzyla-
tion of N-Diphenylmethylidene Glycine tert-Butyl Ester. Chiral
polymeric catalyst (10 mol %) and N-diphenylmethylidene glycine
tert-butyl ester 6 (0.53 g, 1.78 mmol) were added to a mixed solvent of
toluene (7 mL) and chloroform (3 mL). 50 wt % aqueous KOH
solution (2.5 mL) was added to the above mixture. Benzyl bromide
(
0.37 g, 2.14 mmol) was then added dropwise at 0 °C to the mixture.
The reaction mixture was stirred vigorously for 8 h. Saturated sodium
chloride solution (10 mL) was then added, and the organic phase was
extracted with ethyl acetate and concentrated in vacuo to give the
crude product as colorless oil. Purification of the residual oil by
column chromatography on silica gel (ether−hexane = 1:10 as eluent)
gave (S)-tert-butyl N-(diphenylmethylidene)phenylalanine 7. The
enantiomeric excess (91% ee) was determined by HPLC analysis
polymerization. Lower molecular weight P2d (M = 5600)
n
was obtained at 80 °C (entry 2), whereas higher molecular
weight P2d (M = 37 000) could be obtained at 100 °C (entry
n
3). Under this polymerization condition, other dimers D2 also
gave the corresponding polymers P2 with high molecular
weight (entries 4−6). The use of PdCl as a catalyst during the
2
(
Daicel Chiralcel OD-H, hexane-2-propanol = 100:1, flow rate = 0.3
reaction at 100 °C afforded a lower molecular weight polymer
−1
mL min , retention time: R enantiomer = 27.6 min, S enantiomer =
7.9 min). The absolute configuration was determined by comparison
of the HPLC retention time with the authentic sample independently
(
entry 7). The polymerization reaction in DMSO at 100 °C
4
resulted in the same chiral polymer with lower molecular
weight (entry 8).
21
synthesized by the reported procedure.
In order to evaluate the catalytic activity of the resulting
cinchonidinium salts containing chiral polymers P1 and P2, the
enantioselective alkylation of N-diphenylmethylene glycine tert-
butyl ester 6 was investigated with these chiral quaternary
ammonium salts in a biphasic system comprising organic and
aqueous layers. Table 2 summarizes the results for the
asymmetric benzylation of 6 with monomeric catalysts 1 and
2, dimeric catalysts D1, and polymeric catalysts P1. From
entries 1 and 2, it can be seen that the Mizoroki−Heck
modification on the cinchonidine double bond (C10−C11)
RESULTS AND DISCUSSION
■
Synthesis of Cinchonidium Dimers and Polymers by
Mizoroki−Heck Polymerization. As a model reaction of
Mizoroki−Heck polymerization, N-benzylcinchonidinium bro-
mide 1 was allowed to react with iodobenzene in the presence
2
2
of Pd(OAc)2. Mizoroki−Heck coupling occurred smoothly to
provide 11-phenyl-modified cinchonidinium salt 2 in 90%
isolated yield (Scheme 1).
1
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Scheme 2. Synthesis of Cinchonidinium Ionic Dimer D1
Scheme 3. Synthesis of Cinchonidinium Dimer D2
high catalytic activity in the alkylation reaction. In the presence
of the chiral polymeric catalyst P1, N-diphenylmethylene
glycine tert-butyl ester 6 was smoothly benzylated to afford
the chiral product 7 in quantitative yield although with
somewhat decreased enantioselectivities (entries 6−8).
Table 3 summarizes the results for the asymmetric
benzylation of 6 with dimeric catalysts D2 and polymeric
catalysts P2. Dimeric catalysts D2 exhibited a better catalytic
performance in the enantioselective benzylation of 6 (entries
1
−4). Phenylated dimer D2bPh also showed high catalytic
activity (entry 5). Polymeric catalysts P2 also demonstrated
high levels of catalytic activity similar to the P1 catalysts. In the
presence of P2b, ester 6 was asymmetrically benzylated to
provide 7 in 83% yield with 91% ee (entry 7), which is much
higher than that obtained for the low-molecular-weight catalysts
in solution (80% ee for the corresponding dimeric (entry 2)
and 71% ee for the monomeric catalyst (Table 1, entry 2)).
Although there is no clear explanation why P2b showed higher
enantioselectivity in the asymmetric reaction, conformational
modifications on the catalytic site may occur during polymer
formation. P2b might have a suitable conformation for the
asymmetric catalysis. Moreover, P2b was easily separated from
the reaction mixture and reused. The polymeric catalyst could
be reused at least twice without loss of the catalytic activity
Scheme 4. Mizoroki−Heck Phenylation of D2
(
entries 8 and 9).
had no significant influence on the asymmetric benzylation
reaction. The same enantioselectivity (71%) was observed for
either monomeric catalyst. The dimeric catalysts D1 afforded
somewhat higher enantioselectivities (entries 3−5). Chiral
polymers P1 derived from dimer D1 were then used as catalysts
in the same reaction. Although the chiral polymers were not
soluble in either the organic or aqueous phase, they showed
Chiral polymers P2 can be prepared by the quaternization
polymerization of dimeric cinchonidine D3 with dihalide
instead of the Mizoroki−Heck polymerization of D2 with
diiodide (Scheme 7). Dimer D3 was prepared by the
Mizoroki−Heck reaction of cinchonidine with 4,4′-diiodobi-
phenyl, and equimolar amounts of dihalide 5d was allowed to
react with D3 to afford the corresponding quaternized polymer
Scheme 5. Mizoroki−Heck Polymerization of D1
1
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Scheme 6. Mizoroki−Heck Polymerization of D2
Table 1. Synthesis of Chiral Polymer P2 by Mizoroki−Heck Polymerization
a
a
entry
dimer D2
polymer P2
Pd catalyst
solvent
temp (°C)
reaction time (h)
yield (%)
Mn
M /M
w
n
1
2
3
4
5
6
7
8
D2d
D2d
D2d
D2a
D2b
D2c
D2d
D2d
P2d
P2d
P2d
P2a
P2b
P2c
P2d
P2d
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
THF
75
80
24
48
24
24
24
24
24
24
0
75
76
71
85
80
70
72
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
5 600
37 000
14 000
29 000
24 000
6 600
1.21
1.43
1.71
1.66
1.58
1.21
1.20
100
100
100
100
100
100
Pd(OAc)2
6 500
a
Determined by SEC measurement using DMF as a solvent at a flow rate of 1.0 mL/min at 40 °C.
Table 2. Asymmetric Benzylation of N-Diphenylmethylene
Glycine tert-Butyl Ester 6 with Cinchonidine-Based
Catalysts
Table 3. Asymmetric Benzylation of N-Diphenylmethylene
Glycine tert-Butyl Ester 6 with D2 and P2
a
a
b
c
d
entry
catalyst
time (h)
conv (%)
yield (%)
ee (%)
b
c
d
e
entry
catalyst
time (h)
conv (%)
yield (%)
ee (%)
1
D2a
D2b
D2c
D2d
D2bPh
P2a
6
8
4
4
5
6
8
8
8
4
5
5
100
100
100
100
100
100
100
100
100
100
100
100
88
91
90
89
85
75
83
85
80
69
83
84
86
80
84
83
83
64
91
90
91
76
82
72
f
2
1
2
3
4
5
6
7
8
1
5
5
4
4
4
5
5
5
100
100
100
100
100
100
100
100
91
89
88
90
84
83
83
85
71
71
78
79
76
70
66
65
g
3
2
4
5
6
7
D1a
D1b
D1c
P1a
P1b
P1c
P2b
P2b
P2b
P2c
h
8
i
9
a
10
Reactions were performed with catalyst (0.178 mmol), N-diphenyl-
methylene glycine tert-butyl ester (6, 1.78 mmol), and benzyl bromide
2.14 mmol) in toluene/CHCl (7/3, 10 mL) in the presence of 50 wt
1
1
1
2
P2d
j
P2d
(
3
KOH aqueous solution (2.5 mL). Determined by 1H NMR
b
a
%
Reactions were performed with catalyst (0.178 mmol), N-diphenyl-
methylene glycine tert-butyl ester (6, 1.78 mmol), and benzyl bromide
c
d
spectroscopy. Isolated yield of 7. Determined by HPLC (Chiralcel
OD-H).
(2.14 mmol) in toluene/CHCl (7/3, 10 mL) in the presence of 50 wt
3
b
1
%
KOH aqueous solution (2.5 mL). Determined by H NMR
c d
spectroscopy. Isolated yield of 7. Determined by HPLC (Chiralcel
e
f
g
h
P2d. P2d, prepared by the quaternized polymerization, was
used as a catalyst for the benzylation reaction and lead to lower
enantioselectivity (entry 10) when compared with the P2d
obtained from the strategy employed in Scheme 6 (entry 9).
Having selected chiral polymer P2b as the best catalyst, we
investigated the effects of reaction temperature and solvent
employed in asymmetric benzylation of ester 6, and the results
are summarized in Table 4. Lowering the reaction temperature
to −20 °C resulted in a somewhat higher enantioselectivity in
toluene−chloroform (entry 3). Further lowering the reaction
temperature to −40 °C led to a considerable reduction in the
OD-H). Reference 23. Reference 14a. Reference 24. P2b used in
i j
entry 7 was reused. P2b used in entry 8 was reused. Prepared by
quaternization polymerization shown in Scheme 7.
reaction rate, as reflected in the 58% yield with 93% ee after 72
h (entry 4). The toluene:chloroform ratio was also found to
affect the catalytic activity. The optimum solvent ratio for the
reaction with polymeric catalyst P2b was found to be 5:5
toluene:chloroform. In this equivolume mixed solvent system,
enantioselective benzylation of 6 provided high yields of
product 7 in 95% ee at −20 °C (entry 6).
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Macromolecules
Article
Scheme 7. Quaternization Polymerization of D3
ACKNOWLEDGMENTS
■
This work has been supported by JSPS KAKENHI (Grant-in-
Aid for Scientific Research) Grant Number 23350053 and
MEXT KAKENHI (Grant-in-Aid for Scientific Research on
Innovative Areas) Grant Number 25102515.
REFERENCES
■
(
1) For reviews about cinchona alkaloids based organocatalysts, see:
a) Cinchona Alkaloids in Synthesis and Catalysis; Song, C. E., Ed.;
(
Wiley-VCH: Weinheim, 2009. (b) Singh, R. P.; Deng, L. In Science of
Synthesis, Asymmetric Organocatalysis 2; List, B., Maruoka, K., Eds.;
Thieme: Stuttgart, 2012; pp 41−117.
(2) (a) Hentges, S. G.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
4
263. (b) Berrisford, D. J.; Bolm, C.; Sharpless, K. B. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1059. (c) Zielinska-Blajet, M.; Siedlecka, R.;
Skarzewski, J. Tetrahedron: Asymmetry 2007, 18, 131−136.
Table 4. Solvent and Temperature Effect on Asymmetric
Benzylation of Ester 6 with Catalyst P2b
(
3) Yang, T.; Ferrali, A.; Sladojevich, F.; Campbell, L.; Dixon, D. J. J.
a
Am. Chem. Soc. 2009, 131, 9140−9141.
4) (a) Jianga, L.; Chen, Y.-C. Catal. Sci. Technol. 2011, 1, 354−365.
b) Yeboah, E. M. O.; Yeboah, S. O.; Singh, G. S. Tetrahedron 2011,
(
(
6
1
(
7, 1725−1762. (c) Marcelli, T. WIREs Comput. Mol. Sci. 2011, 1,
42−152.
5) Ingemann, S.; Hiemstra, H. In Comprehensive Enantioselective
Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH: Weinheim, 2013; pp
b
c
entry
solvent
toluene
temp (°C) time (h) yield (%) ee (%)
1
19−160.
1
2
3
4
5
6
7
8
0
0
10
8
84
83
99
58
99
93
84
80
72
91
94
93
93
95
92
90
(6) Enantioselective Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH:
toluene:CHCl = 7:3
Weinheim, 2007.
7) Asymmetric Phase Transfer Catalysis; Maruoka, K., Ed.; Wiley-
VCH: Weinheim, 2008.
8) (a) Itsuno, S.; Haraguchi, N. In Science of Synthesis, Asymmetric
3
(
toluene:CHCl = 7:3
−20
−40
0
24
72
6
3
toluene:CHCl = 7:3
3
(
toluene:CHCl = 5:5
3
Organocatalysis 2; List, B., Maruoka, K., Eds.; Thieme: Stuttgart, 2012;
pp 673−696. (b) Haraguchi, N.; Itsuno, S. In Polymeric Chiral Catalyst
Design and Chiral Polymer Synthesis; Itsuno, S., Ed.; Wiley: Hoboken,
NJ, 2011; pp 17−61.
toluene:CHCl = 5:5
−20
0
24
6
3
toluene:CHCl = 3:7
3
CHCl3
0
6
a
Reactions were performed with catalyst P2b (0.178 mmol), N-
diphenylmethylene glycine tert-butyl ester (6, 1.78 mmol), and benzyl
bromide (2.14 mmol) in solvent (10 mL) in the presence of 50 wt %
KOH aqueous solution (2.5 mL). 100% conversion of 6 was attained
́ ́
(9) (a) Chinchilla, R.; Mazon, P.; Najera, C. Tetrahedron: Asymmetry
2000, 11, 3277−3281. (b) Thierry, B.; Plaquevent, J. C.; Cahard, D.
Tetrahedron: Asymmetry 2001, 12, 983−986. (c) Thierry, B.; Perrard,
T.; Audouard, C.; Plaquevent, J. C.; Cahard, D. Synthesis 2001, 11,
1742−1746. (d) Thierry, B.; Plaquevent, J. C.; Cahard, D. Mol.
Diversity 2005, 9, 277−290. (e) Shi, Q.; Lee, Y. J.; Song, H.; Cheng,
M.; Jew, S. S.; Park, H. G.; Jeong, B. S. Chem. Lett. 2008, 37, 436−437.
b
c
for all entries. Isolated yield of 7. Determined by HPLC (Chiralcel
OD-H).
(
10) Recently, helical poly(phenylacetylene)s bearing cinchona
alkaloid pendants showed higher enantioselectivities compared with
that of the monomeric catalyst; see: Tang, Z.; Iida, H.; Hu, H.-Y.;
Yashima, E. ACS Macro Lett. 2012, 1, 261−265.
In conclusion, we have successfully synthesized chiral
quaternized polymers by means of a Mizoroki−Heck coupling
reaction. The alkene moiety of cinchonidinium dimers
smoothly reacted with aromatic diiodides to form the chiral
polymers. These polymers exhibited excellent catalytic activities
in the enantioselective benzylation of N-diphenylmethylene
glycine tert-butyl ester 6, and high levels of enantioselectivity
were obtained from the polymeric catalyst derived from
cinchonidinium dimer D2. In the presence of P2b, the
enantioselective benzylation of 6 occurred smoothly to give 7
in higher yields and enantioselectivities (up to 95% ee) than
those obtained from the corresponding low-molecular-weight
catalyst in solution. We are currently surveying the catalytic
activity of the chiral quaternized polymers in various
asymmetric transformations other than benzylation.
(11) Itsuno, S.; Parvez, M. M.; Haraguchi, N. Polym. Chem. 2011, 2,
1
(
942−1949.
12) (a) Ahamed, P.; Haque, M. A.; Ishimoto, M.; Parvez, M. M.;
Haraguchi, N.; Itsuno, S. Tetrahedron 2013, 69, 3978−3983.
(b) Haraguchi, N.; Ahamed, P.; Parvez, M. M.; Itsuno, S. Molecules
2012, 17, 7569−7583.
(13) Itsuno, S.; Paul, D. K.; Ishimoto, M.; Haraguchi, N. Chem. Lett.
2
(
010, 39, 86−87.
14) (a) Itsuno, S.; Paul, D. K.; Salam, M. A.; Haraguchi, N. J. Am.
Chem. Soc. 2010, 132, 2864−2865. (b) Parvez, M. M.; Haraguchi, N.;
Itsuno, S. Org. Biomol. Chem. 2012, 10, 2870−2877. (c) Parvez, M. M.;
Salam, M. A.; Haraguchi, N.; Itsuno, S. J. Chin. Chem. Soc. 2012, 59,
8
(
15−821.
15) Kobayashi, N.; Iwai, K. J. Am. Chem. Soc. 1978, 100, 7071−7072.
(16) (a) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971,
4, 581. (b) Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem. 1972, 37,
320−2322. (c) Heck, R. F. Palladium-Catalyzed Vinylation of
4
2
AUTHOR INFORMATION
■
Organic Halides. Org. React. 1982, 27, 345−390.
Corresponding Author
(17) (a) Zhu, Y.; Heim, I.; Tieke, B. Macromol. Chem. Phys. 2006,
2
07, 2260−2214. (b) Mikroyannidis, J. A.; Yu, Y.-J.; Lee, S.-H.; Jin, J.-I.
J. Polym. Sci., Part A: Polym. Chem. 2006, 44, 4494−4507.
18) Diaz, C.; Alzate, D.; Rodriguez, R.; Ochoa, C.; Sierra, C. A.
Synth. Met. 2013, 172, 32−36.
*E-mail: itsuno@ens.tut.ac.jp (S.I.).
Notes
(
The authors declare no competing financial interest.
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Article
(
19) Xie, N.; Wang, J.; Guo, Z.; Chen, G.; Li, Q. Macromol. Chem.
Phys. 2013, 214, 1710−1723.
20) (a) Cheng, Y.; Zou, X.; Zhu, D.; Zhu, T.; Liu, Y.; Zhang, S.;
Huang, H. J. Polym. Sci., Part A: Polym. Chem. 2007, 45, 650−660.
b) Song, J.; Cheng, Y.; Chen, L.; Zou, X.; Zhiliu, W. Eur. Polym. J.
006, 42, 663−669. (c) Zong, L.; Miao, Q.; Liu, Y.; Xu, J.; Huang, X.;
Cheng, Y. Chin. J. Chem. 2009, 27, 1179−1185.
21) O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc.
989, 111, 2353−2355.
22) The Mizoroki-Heck reactions on cinchona alkaloids have been
(
(
2
(
1
(
reported, see: Dinio, T.; Gorka, A. P.; McGinniss, A.; Roepe, P. D.;
Morgan, J. B. Bioorg. Med. Chem. 2002, 20, 3292−3297.
(
23) Chinchilla, R.; Mazon, P.; Najera, C. Tetrahedron: Asymmetry
2
(
002, 13, 927−931.
24) Lee, J.-H.; Yoo, M.-S.; Jung, J.-H.; Jew, S.-s.; Park, H.-g.; Jeong,
B.-S. Tetrahedron 2007, 63, 7906−7915.
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