Synthesis of main-chain chiral quaternary ammonium polymers for asymmetric catalysis using quaternization polymerization

Article abstract of DOI:10.3390/molecules17067569

Main-chain chiral quaternary ammonium polymers were successfully synthesized by the quaternization polymerization of cinchonidine dimer with dihalides. The polymerization occurred smoothly under optimized conditions to give novel type of main-chain chiral quaternary ammonium polymers. The catalytic activity of the polymeric chiral organocatalysts was investigated on the asymmetric benzylation of N-(diphenylmethylidene)glycine tert-butyl ester.

Full text of DOI:10.3390/molecules17067569

Molecules 2012, 17, 7569-7583; doi:10.3390/molecules17067569
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of Main-Chain Chiral Quaternary Ammonium
Polymers for Asymmetric Catalysis Using Quaternization
Polymerization
Naoki Haraguchi *, Parbhej Ahamed, Md. Masud Parvez and Shinichi Itsuno
Department of Environmental and Life Sciences, Graduate School of Engineering,
Toyohashi University of Technology, 1-1 Hibarigaoka, Tenpaku-cho, Toyohashi,
Aichi 441-8580, Japan
*
Author to whom correspondence should be addressed; E-Mail: haraguchi@ens.tut.ac.jp;
Tel.: +81-532-44-6812; Fax: +81-532-48-5833.
Received: 27 April 2012; in revised form: 4 June 2012 / Accepted: 13 June 2012 /
Published: 19 June 2012
Abstract: Main-chain chiral quaternary ammonium polymers were successfully
synthesized by the quaternization polymerization of cinchonidine dimer with dihalides.
The polymerization occurred smoothly under optimized conditions to give novel type
of main-chain chiral quaternary ammonium polymers. The catalytic activity of the
polymeric chiral organocatalysts was investigated on the asymmetric benzylation of
N-(diphenylmethylidene)glycine tert-butyl ester.
Keywords: chiral polymer; quaternization polymerization; organocatalysis; cinchona
alkaloid; quaternary ammonium salt
1
. Introduction
Cinchona alkaloids are among the most attractive chiral molecules because they represent readily
available and inexpensive natural chiral amino alcohols with pseudo-enantiomer forms. Cinchona
alkaloids and their derivatives have been widely applied as chiral organocatalysts for some asymmetric
reactions [1–3]. Among them, the quaternary ammonium salts of cinchona alkaloids [1–4] are widely
used for asymmetric reactions such as alkylations [5,6], aldol reactions [7–9], nitroaldol reactions [7],
Mannich reactions [10], nitro-Mannich reactions [11], Darzens reactions [12], Strecker reactions [13],

Molecules 2012, 17
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α-hydroxylations [14], α-fluorinations [15], Michael reactions [16,17], epoxidations [18,19],
aziridations [20,21], and reductions [22,23].
From the viewpoint of the practical use of cinchona alkaloid quaternary ammonium salts, some
issues exist. For example, compared with transition metal based catalysts, large amounts (1–20 mol%)
of organocatalyst molecule are generally required to complete the reaction, and only a few active
cinchona alkaloid quaternary ammonium salts are reported. Moreover, due to the amphiphilicity of the
quaternary ammonium salt, the catalyst separation might be difficult in some cases. One potential
solution to the last problem is the immobilization on the catalyst on a polymer [1,4,24–27]. Several
examples of polymer-immobilized chiral quaternary ammonium salts have been developed and
successfully used as catalysts for asymmetric synthesis [28–39]. In these polymeric catalyst examples
the catalyst was immobilized on the side-chain of the support polymer.
In addition of these polymer-immobilized chiral quaternary ammonium salts, we have recently
developed main-chain chiral polymers with chiral organocatalysts [40–45]. Some useful polymerization
techniques such as etherification polymerization [40], ion exchange polymerization [41–44], and
neutralization polymerization [45] were used for the synthesis of main-chain chiral polymers with
chiral organocatalysts. Interestingly, some main-chain chiral polymers showed higher enantioselectivity
than the corresponding monomeric catalysts.
In this article, some main-chain chiral quaternary ammonium polymers were synthesized by a
quaternization polymerization of cinchonidine dimer with dihalides. The resulting main-chain chiral
quaternary ammonium polymers were used as polymeric chiral organocatalysts for the asymmetric
benzylation of N-(diphenylmethylidene)glycine tert-butyl ester.
2
. Results and Discussion
2.1. Synthesis of Thiolated Cinchonidine Quaternary Ammonium Dimers 5
We have firstly prepared some thiolated cinchonidine quaternary ammonium salt dimers as model
compounds. The synthetic scheme followed is shown in Scheme 1. The thiolated cinchonidine
quaternary ammonium dimers 5 were prepared in two steps from cinchonidine (1), thiols 2 and
dihalides 4. The first thiol-ene click reaction of methyl-3-mercaptopropionate (2) and 1 was carried out
in the presence of AIBN in CHCl at 70 °C for 24 h [46]. The reaction proceeded quantitatively and
3
the thiolated cinchonidine 3 was obtained in 90% isolated yield.
Dimerization of cinchona alkaloids was versatile because of the presence of some functional groups
such as hydroxyl groups, the quinuclidine framework amine and even double bonds in cinchona
alkaloids. Cinchona alkaloids are generally dimerized by etherification with dihalide to afford chiral
diamine derivatives. The other dimerization method is a quaternization of cinchona alkaloids with
dihalides to give chiral quaternary ammonium dimers. We employed the quaternization reaction for the
synthesis of chiral quaternary ammonium dimers. The quaternization reaction was carried out at 100 °C
using 2.2 equivalents of 3 to 4. The reaction was complete within 6 h when the mixed solvent of
ethanol/DMF/chloroform (5/6/2) was used. The isolated yields of 5a–d were 92–96%. We found that
cinchonidine could be easily modified with thiol via thiol-ene click reaction and the thiolated
cinchonidine could be dimerized with dihalides by the quaternization reaction.

Molecules 2012, 17
Scheme 1. Synthesis of cinchonidine quaternary ammonium dimers 5.
7571
5
a : R =
, X = Br
, X = Cl
MeO
S
CH3OCO(CH)2SH, AIBN
O
N
N
2
OH
OH
o
CHCl3, 70 C, 24 h
5b : R =
N
N
1
3
MeO
S
5
c : R =
, X = Br
X
R
X
R X
O
N
N
4
HO
3
OH
EtOH:DMF:CHCl3 = 5:6:2
(2.2 equiv.)
N
N
o
O
1
00 C, 6 h
5d : R =
, X = Br
X
S
OMe
5
2
.2. Synthesis of Cinchonidine Dimers 7 Using Thiol-Ene Click Reaction
Another useful dimerization method we focused on here is the use of the double bond in cinchona
alkaloids. Some useful coupling reactions such as thiol-ene click reaction [47–50] are available for the
dimerization reaction. We tried to synthesize cinchonidine dimers 7a and 7b by the thiol-ene click
reaction of 1 and dithiols 6, as illustrated in Scheme 2.
Scheme 2. Synthesis of cinchonidine dimers 7.
The thiol-ene click reaction of two equivalents of cinchonidine with dithiol was carried out in the
3
presence of AIBN in CHCl at 70 °C. Compared with the reaction of 1 and 2 in the synthesis of
monothiolated cinchonidine 3, the reaction with 6 was slow. In addition, we were faced with a problem
in the purification of 7a and 7b by silica gel column chromatography. Large amounts of the product
interacted with the stationary phase of column chromatography, which led to a decrease in the isolated
yield of 7a and 7b.

Molecules 2012, 17
7572
2
.3. Synthesis of Main-Chain Chiral Quaternary Ammonium Polymers 8 Using Quaternization
Polymerization
We next tried to synthesize main-chain chiral quaternary ammonium polymers 8 using the
thiolinked cinchonidine dimers 7. The synthesis of 8 using quaternization polymerization is illustrated in
Scheme 3. The procedure is quite simple. Compound 7 and equimolar dihalide 4 were reacted in DMSO
at 90 °C. Neither initiator of the polymerization nor additives is necessary. In fact, the corresponding
main-chain chiral quaternary ammonium polymers 8a–h were obtained in high yield. In all cases
polymeric products were precipitated into diethyl ether, which could be easily isolated by filtration.
Scheme 3. Synthesis of main-chain chiral quaternary ammonium polymers 8.
n
M values of these polymers can be measured by SEC. The measured values in the elemental
analysis of 8 were somewhat different from the calculated ones, possibly because of the hydrophilicity
1
of the quaternary ammonium moiety and the low degree of polymerization. In the H-NMR spectra of
the polymers, proton signals assigned to the quinuclidine framework and the dihalide disappeared
completely. On the other hand, some signals assigned to the quaternary ammonium salt were
alternatively observed. These results clearly indicated that successive intermolecular quaternization

Molecules 2012, 17
7573
reaction occurred without side reaction participation to afford main-chain chiral quaternary ammonium
polymers 8. Due to the simplicity of the quaternization polymerization, various kinds of main-chain
chiral quaternary ammonium polymers can be easily prepared by this method. In addition, this is the
first successful report of the synthesis of main-chain polymers of cinchonidine quaternary ammonium
salts using the double bond, in which the cinchonidine quaternary ammonium salts were incorporated
uniformly into the main-chain of the polymer.
2.4. Asymmetric Benzylation of N-(Diphenylmethylidene)glycine tert-butyl Ester 9 Catalyzed by
Main-Chain Chiral Quaternary Ammonium Polymers 8
Since these main-chain chiral quaternary ammonium polymers contain chiral quaternary ammonium
structures in their repeating units, the polymers should have catalytic activity in some asymmetric
transformations. In order to evaluate the catalytic activity of the new chiral ionic polymers, we
chose the asymmetric benzylation of N-(diphenylmethylidene)glycine tert-butyl ester 9 as a typical
asymmetric transformation using chiral quaternary ammonium salt. We designed and synthesized
some main-chain chiral quaternary ammonium polymers based on various combinations of thiolinked
cinchonidine dimers and dihalides to investigate the effect of the structure on the catalytic activity and
the enantioselectivity.
At first, we have tested the asymmetric benzylation reaction with the chiral quaternary ammonium
dimers 5a–d. The results of the asymmetric reaction are summarized in Table 1. The substrate 9 was
allowed to react in an organic solvent with benzyl bromide in the presence of the chiral quaternary
ammonium dimer 5 and aqueous potassium hydroxide. In all cases, the asymmetric reaction took place
smoothly in the two phase system. For example, chiral quaternary ammonium dimer 5a catalyzed the
benzylation to give the corresponding chiral (S)-phenylalanine derivative 10 in 97% yield with 84% ee
(
Table 1, entry 1). The structure of the spacer (R) between two chiral quaternary ammonium salts in
the dimeric catalyst influences the enantioselectivity. When anthracenyl or naphthyl moieties were
introduced as spacer, higher enantioselectivity (up to 90% ee) was observed (entries 2,3,4). In contrast,
thiolated cinchonidine 3 and thiolinked cinchonidine dimers 7 did not show any catalytic activity at all.
We thus confirmed that the chiral quaternary ammonium salt framework was essential to catalyze the
asymmetric benzylation.
Table 1. Asymmetric benzylation of glycine derivative using chiral quaternary ammonium dimer 5.

Molecules 2012, 17
7574
Table 1. Cont.
a
b
Entry
Catalyst
R
Time (h)
Yield (%)
ee (%)
1
5a
5b
5c
5d
4
97
84
2
3
4
4
4
4
92
91
92
90
88
90
a
1
b
Determined by H-NMR; Determined by HPLC (CHIRALCEL OD-H column).
Encouraged by these results in the asymmetric benzylation using chiral quaternary ammonium
dimers 5, main-chain chiral quaternary ammonium polymers 8a–h were used as polymeric chiral
organocatalysts in the asymmetric benzylation reaction under similar conditions in order to investigate
their catalytic activity. The reaction conditions are as same as those using the dimeric catalyst. These
results were summarized in Table 2. Compounds 8a–h were not soluble, but were suspended in a
mixed solvent of toluene/chloroform and aqueous potassium hydroxide. The benzylation reaction
proceeded quantitatively without side reactions within 11 h. After the asymmetric benzylation reaction
was complete, chiral product 10 was easily obtained by extracting the mixture with dichloromethane.
Since these polymeric chiral catalysts were not soluble in the mixed solvent used in the reaction, these
polymers could be easily separated from the reaction mixture. When 8a was used as a polymeric chiral
organocatalyst, the reaction occurred smoothly to afford 10 in 88% yield with 86% ee (entry 1).
Unfortunately, the enantiomeric excess of 10 decreased to 79% when 8b,c were used (entries 2 and 3).
When 8d with an ether linkage was used instead of 8a with an alkyl one, both the yield and
enantioselectivity increased slightly (cf. entry 1 vs. 4).
Table 2. Asymmetric benzylation of 9 using main-chain chiral quaternary ammonium polymer 8.

Molecules 2012, 17
7575
Table 2. Cont.
1
2
a
b
Entry Catalyst
R
R
Time (h)
Yield (%)
ee (%)
1
8a
8
88
86
2
8b
8
8
84
86
79
79
3
8c
4
5
8d
8e
11
5
89
53
87
71
6
7
8
8f
8g
8h
8
11
8
75
80
85
80
88
88
a
1
b
Determined by H-NMR; Determined by HPLC (CHIRALCEL OD-H column).
1
2
Using the ether linkage as R , the effect of R on the catalytic activity was also investigated.
Enantioselectivity decreased significantly with the use of m-xylene-linked 8e (entry 4 vs. 5). In
contrast, naphthyl-linked 8g,h showed higher enantioselectivity, which is comparable to the
corresponding dimeric catalyst 5c (entries 7 and 8). These results clearly indicated that these main-chain
chiral quaternary ammonium polymers 8 showed good catalytic activity in the asymmetric benzylation
1
of N-(diphenylmethylidene)glycine tert-butyl ester (9) and the modification of the structure of R
2
and R in 8 is of significant importance for the design of main-chain chiral quaternary ammonium
polymers as polymeric chiral catalysts. The catalytic activity of 8 was comparable to that of the other
main-chain chiral quaternary ammonium polymers that were prepared by a successive etherification of
cinchonidine quaternary ammonium salt dimers with dihalides [40].

Molecules 2012, 17
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3. Experimental
3.1. General
All solvents and reagents were purchased from Sigma-Aldrich, Wako Pure Chemical Industries,
Ltd., or Tokyo Chemical Industry Co., Ltd. at the highest available purity and used as is, unless noted
otherwise. Reactions were monitored by thin-layer chromatography (TLC) using Merck precoated
silica gel plates (Merck 5554, 60F254). Column chromatography was performed on a silica gel
column (Wakogel C-200, 100–200 mesh). Melting points were recorded using a Yanaco micro
1
13
melting apparatus and are uncorrected. H- (300 MHz) and C-NMR (75 MHz) spectra were
measured on a Varian Mercury 300 spectrometer. Peaks were referenced to the (CH Si) (TMS)
peak at δ = 0 ( H) or the solvent peak [i.e., the CDCl one at δ = 77. 1 ( C) or the DMSO ones at
3 4
)
1
13
3
1
13
δ = 2.5 ( H)/39.5 ( C)]. The J values are reported in Hertz. IR spectra were recorded with a JEOL
−
1
JIR-7000 FT-IR spectrometer and are reported in reciprocal centimeters (cm ). Elemental
analyses were performed at the Microanalytical Center of Kyoto University. Size exclusion
chromatography (SEC) was performed with a 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
n w n
determine number-average molecular weight (M ) and molecular weight distribution (M /M ) values
with polystyrene standards. HPLC analyses were performed with a JASCO HPLC system composed of
a 3-line degasser DG-980, HPLC pump PV-980, column oven CO-965, equipped with a chiral column
(CHIRALCEL OD-H or OD, Daicel) using hexane/2-propanol as eluent. A UV detector (JASCO
UV-975 for the JASCO HPLC system) was used for the peak detection. Optical rotations were
recorded with a JASCO DIP-149 digital polarimeter using a 10 cm thermostated microcell.
3
.2. Preparation of Thiolated Chiral Quaternary Ammonium Salt Dimer 5
.2.1. Preparation of Thiolated Cinchonidine 3
3
A mixture of cinchonidine (1, 3.53 g, 12.0 mmol), methyl-3-mercaptopropionate (2, 2.16 g, 18.0 mmol),
and AIBN (0.039 g, 0.24 mmol) was stirred at 70 °C for 30 h. After the removal of the solvent under
high vacuum, the residue was washed several times with hexane. The product 3 (4.48 g, 90% yield)
2
5
was used for next reaction without further purification. m.p. 142 °C; [α]
D
= −52.50 (1.0, DMSO);
1
3
H-NMR (CDCl , TMS): δ = 1.38–1.55 (m, 4H), 1.63 (s, 1H), 1.74–1.80 (m, 3H), 2.31–2.38 (m, 3H),
2
7
1
3
1
.43–2.56 (m, 2H), 2.67–2.73 (m, 2H), 2.98–3.06 (m, 2H), 3.40–3.51 (m, 1H), 5.63–5.73 (m, 1H),
.34–7.40 (m, 1H), 7.55 (d, J = 4.8 Hz, 1H), 7.60–7.66 (m, 1H), 7.95 (d, J = 8.1 Hz, 1H), 8.05–8.08 (m,
1
3
3
H), 8.79 (d, J = 4.8 Hz, 1H); C-NMR (CDCl ): δ = 20.97, 25.76, 27.10, 28.02, 30.19, 34.42, 34.60,
4.67, 43.28, 51.87, 58.22, 60.27, 71.52, 118.40, 123.05, 125.64, 126.71, 129.11, 130.09, 148.04,
50.02, 172.43; IR (KBr): ν = 1,585 (C=N), 1,220 (C-N), 1,130 (C-O), 750 (C-S); Elem. Anal. calc.
30 2 3
for C23H N O S: C 66.64, H 7.29, N 6.76; found C 66.50, H 7.27, N 6.62.

Molecules 2012, 17
7577
3.2.2. Preparation of Thiolated Chiral Quaternary Ammonium Salt Dimer 5
A mixture of 3 (0.456 g, 1.10 mmol) and 4 (0.50 mmol) in EtOH/DMF/CHCl
3
= 5:6:2 mixed
solvent (3 mL) was stirred at 100 °C for 6 h. After cooling the reaction mixture to room temperature,
the mixture was dissolved in MeOH (2.5 mL) and poured into Et O (20 mL). The mixture was stirred
2
2
at room temperature for 1 h and filtered. The resulting solid was washed with Et O several times to
give the product 5.
2
D
5
Thiolated chiral quaternary ammonium salt dimer 5a: 96% yield. m.p. 189 °C; [α] = −102.63 (1.0,
1
DMSO); H-NMR (DMSO-d
6
): δ = 1.44 (br, 3H), 1.79 (br, 1H), 2.03 (br, 4H), 2.34–2.40 (m, 2H),
2.52–2.58 (m, 2H), 3.98 (d, J = 7.2 Hz, 2H), 4.32 (br, 2H), 5.02 (d, J = 11.4 Hz, 1H), 5.30 (d,
J = 12.3 Hz, 1H), 6.65 (s, 1H), 7.04 (s, 1H), 7.88 (br, 3H), 7.96–8.00 (m, 2H), 8.21–8.24 (m, 1H), 8.45
1
3
(
d, J = 8.4 Hz, 1H), 9.14 (d, J = 4.2 Hz, 1H); C-NMR (DMSO-d ): δ = 20.50, 23.39, 24.36, 25.73,
6
28.00, 32.19, 32.33, 33.79, 61.02, 61.63, 63.92, 67.15, 120.20, 124.09, 124.30, 126.46, 128.10, 129.40,
1
30.86, 133.73, 143.53, 147.75, 149.31, 171.55; IR (KBr): ν = 1,730 (-COOR), 1,633 (C=N), 1,218
(
C-N), 1,040 (C-O), 759 (C-S); Elem. Anal. calc. for C H Br N O S : C 59.33, H 6.27, N 5.13;
54 68 2 4 6 2
found C 58.49, H 6.34, N 5.14.
2
5
Thiolated chiral quaternary ammonium salt dimer 5b: 92% yield. m.p. 166 °C; [α]
D
= −215.81 (1.0,
1
DMSO); H-NMR (DMSO-d
6
): δ = 1.19 (br, 3H), 1.43–1.51 (m, 3H), 1.86–1.96 (br, 2H), 2.18–2.25
(
br, 2H), 2.40–2.44 (br, 2H), 4.48–4.55 (br, 2H), 5.93–5.98 (br, 1H), 6.36–6.55 (br, 1H), 7.11 (br, 1H),
7
9
2
6
1
.72–8.04 (m, 5H), 8.14 (br, 1H), 8.25–8.33 (m, 1H), 8.79–8.84 (m, 1H), 8.97 (d, J = 7.5 Hz, 1H),
1
3
6
.06–9.12 (m, 1H), 9.20 (d, J = 3.9 Hz, 1H); C-NMR (DMSO-d ): δ = 17.03, 21.22, 22.46, 24.04,
4.72, 25.82, 28.10, 31.96, 32.35, 32.78, 33.72, 33.83, 51.09, 54.33, 59.01, 62.02, 65.02, 65.60,
7.06, 119.02, 120.61, 123.89,124.65, 125.73, 126.29, 128.16, 131.14, 131.53, 132.52, 143.63, 147.45,
50.48, 171.53; IR (KBr): ν = 1,730 (-COOR), 1,625 (C=N), 1,215 (C-N), 1,038 (C-O), 779 (C-S);
Elem. Anal. calc. C62
H72Cl
2
N
4
O
6
S
2
: C 67.43, H 6.57, N 5.07; found C 65.95, H 7.03, N 4.98.
1
Thiolated chiral quaternary ammonium salt dimer 5c: 93% yield. m.p. 192 °C; H-NMR (DMSO-d ):
6
δ = 1.46 (br, 4H), 1.72 (br, 1H), 2.05 (br, 5H), 2.37–2.41 (m, 2H), 2.57 (d, J = 6.0 Hz, 2H), 4.01 (br,
1
H), 4.38 (br, 1H), 5.12 (d, J = 12.9 Hz, 1H), 5.37 (d, J = 12.9 Hz, 1H), 6.63 (s, 1H), 6.79 (s, 1H), 7.74
(
d, J = 6.0 Hz, 1H), 7.84 (d, J = 3.9 Hz, 2H), 7.94 (d, J = 7.8 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.22 (d,
1
3
J = 7.8 Hz, 1H), 8.33 (d, J = 7.8 Hz, 2H), 9.01 (d, J = 3.9 Hz, 1H); C-NMR (DMSO-d
6
): δ = 20.52,
2
1
1
3.53, 24.54, 25.74, 28.02, 32.00, 32.47, 33.85, 50.58, 51.12, 61.19, 62.32, 63.79, 67.40, 119.97,
23.64, 124.17, 126.24, 127.05, 128.03, 129.18, 129.53, 131.48, 131.85, 134.14, 145.14, 147.33,
49.89, 171.62; IR (KBr): ν = 1,730 (-COOR), 1,617 (C=N), 1,235 (C-N), 1,022 (C-O), 777 (C-S);
Elem. Anal. calc. C58
H70Br
2
N
4
O
6
S
2
: C 60.94, H 6.17, N 4.90; found C 59.81, H 6.29, N 4.91.
1
Thiolated chiral quaternary ammonium salt dimer 5d: 96% yield. m.p. 190 °C; H-NMR (DMSO-d ):
6
δ = 1.41–1.46 (m, 4H), 1.74 (br, 1H), 1.97–2.03 (br, 4H), 2.18 (br, 1H), 2.32 (d, J = 6.3 Hz, 2H), 4.26
(br, 1H), 4.41 (br, 1H), 5.37 (d, J = 12.9 Hz, 1H), 5.81 (d, J = 12.0 Hz, 1H), 6.78 (s, 1H), 6.93 (d,
J = 3.9 Hz, 1H), 7.79–7.90 (m, 4H), 8.13–8.16 (m, 2H), 8.44 (d, J = 8.4 Hz, 1H), 8.64 (br, 1H), 9.03
1
3
(
6
d, J = 4.5 Hz, 1H); C-NMR (DMSO-d ): δ = 20.78, 23.16, 24.53, 25.84, 28.12, 32.39, 32.61, 33.84,

Molecules 2012, 17
7578
5
1
1
0.76, 51.14, 58.74, 61.49, 64.18, 67.43, 120.11, 123.90, 124.27, 125.13, 126.97, 127.25, 128.99,
29.56, 133.37, 133.64, 146.16, 146.69, 149.56, 171.60; IR (KBr): ν = 1,730 (-COOR), 1,632 (C=N),
,235 (C-N), 1,062 (C-O), 758 (C-S); Elem. Anal. calc. C58 : C 60.94, H 6.17, N 4.90;
2 4 6 2
H70 Br N O S
found C 59.77, H 6.18, N 4.96.
3
.3. Preparation of Main-Chain Chiral Quaternary Ammonium Polymers 8
.3.1. Preparation of Cinchonidine Dimer 7
3
A mixture of cinchonidine 1 (1.18 g, 4.00 mmol), dithiol (2.00 mmol), AIBN (6.4 mg, 0.04 mmol),
and CHCl (6 mL) was stirred at 70 °C. During the reaction AIBN (0.04 mmol) was added three times
3
successively. The residue after the removal of solvent under high vacuum was purified by column
chromatography to give the product 7.
2
5
1
Cinchonidine dimer 7a: 40% yield. m.p. 116 °C; [α]D = −59.56 (1.0, DMSO); H-NMR (CDCl ,
3
TMS): δ = 1.32–1.56 (m, 5H), 1.61–1.64 (m, 4H), 1.72–1.79 (m, 3H), 2.29–2.48 (m, 6H), 2.92–3.02
(
m, 2H), 3.44–3.46 (m, 1H), 5.05 (s, 1H), 5.62 (s, 1H), 7.33–7.41 (m, 1H), 7.52–7.55 (m, 1H),
1
3
7
3
.59–7.66 (m, 1H), 7.96–7.98 (m, 1H), 7.98–8.08 (m, 1H), 8.73–8.78 (m, 1H); C-NMR (CDCl ):
δ = 20.54, 25.55, 27.84, 28.36, 29.87, 31.57, 34.57, 43.07, 49.81, 58.08, 60.08, 71.11, 118.27, 122.91,
1
25.46, 126.52, 128.94, 129.65, 147.65, 149.65, 150.40; IR (KBr): ν = 1,580 (C=N), 1,225 (C-N),
,120 (C-O), 755 (C-S); Elem. Anal. calc. C42 : C 70.95, H 7.65, N 7.88; found C 70.39,
1
54 4 2 2
H N O S
H 8.01, N 7.71.
2
5
1
Cinchonidine dimer 7b: 37% yield (for 70 h). m.p. 109 °C; [α]
CDCl , TMS): δ = 1.37–1.49 (br, 4H), 1.58–1.76 (br, 5H), 2.30–2.42 (m, 4H), 2.54–2.58 (m, 2H),
.91–3.02 (m, 2H), 3.46–3.52 (m, 4H), 5.35 (s, 1H), 5.65 (s, 1H), 7.35–7.40 (m, 1H), 7.54 (d, J = 4.2,
D
= −52.57 (1.0, DMSO); H-NMR
(
3
2
1
2
1
13
3
H), 7.61–7.66 (m, 1H), 7.99–8.07 (m, 2H), 8.72 (d, J = 4.5, 1H); C-NMR (CDCl ): δ = 20.89,
5.64, 28.02, 30.63, 31.61, 34.61, 38.56, 43.23, 58.23, 60.24, 69.22, 70.76, 70.86, 71.40, 118.42,
23.04, 125.66, 126.74, 129.14, 129.98, 147.93, 149.90, 150.28; IR (KBr): ν = 1,590 (C=N), 1,235
54 4 3 2
(C-N), 1,100 (C-O), 760 (C-S); Elem. Anal. calc. C42H N O S : C 69.38, H 7.49, N 7.71; found
C 69.02, H 7.70, N 7.61.
3
.3.2. Preparation of Main-Chain Chiral Quaternary Ammonium Polymers 8
A mixture of cinchonidine dimer 7 (0.500 mmol), dihalide 4 (0.500 mmol) in DMSO (2 mL) was
stirred at 90 °C for 10 h. The residue after the removal of solvent under high vacuum was dissolved in
MeOH (5 mL) and poured into Et O (120 mL). After the filtration of the mixture, the solid was washed
with hexane and ethyl acetate, and was dried under high vacuum to give the polymer 8.
2
2
D
5
Main-chain chiral quaternary ammonium polymers 8a: 88% yield. [α]
(SEC) = 3.1 kg/mol; Elem. Anal. calc. C50 : C 61.59, H 6.41, N 5.75; found C 61.56,
H 6.42, N 5.75.
= −117.1 (1.0, DMSO);
M
n
2 4 2 2
H62Br N O S

Molecules 2012, 17
7579
Main-chain chiral quaternary ammonium polymers 8b: 84% yield. M
n
(SEC) = 2.8 kg/mol; Elem.
Anal. calc. C70
2 4 2 2
H64Cl N O S : C 70.64, H 6.75, N 5.68; found C 69.93, H 6.75, N 5.68.
2
D
5
Main-chain chiral quaternary ammonium polymers 8c: 93% yield. [α]
= −146.22 (1.0, DMSO);
M (SEC) = 3.6 kg/mol; Elem. Anal. calc. C H Br N O S : C 63.27, H 6.29, N 5.47; found C 62.47,
n
54 64
2
4
2 2
H 6.62, N 5.46.
2
D
5
Main-chain chiral quaternary ammonium polymers 8d: 96% yield. [α]
= −120.1 (1.0, DMSO);
M (SEC) = 10.8 kg/mol; Elem. Anal. calc. C H Br N O S : C 60.60, H 6.31, N 5.65; found C 60.78,
n
50 62
2
4
3 2
H 6.23, N 5.62.
2
D
5
Main-chain chiral quaternary ammonium polymers 8e: 96% yield. [α]
= −131.24 (1.0, DMSO);
M (SEC) = 6.8 kg/mol; Elem. Anal. calc. C H Br N O S : C 60.60, H 6.31, N 5.65; found C 61.10,
n
50 62
2
4
3 2
H 6.21, N 5.61.
n
Main-chain chiral quaternary ammonium polymers 8f: 67% yield. M (SEC) = 2.8 kg/mol; Elem. Anal.
2 4 3 2
calc. C58H66Cl N O S
: C 69.51, H 6.64, N 5.59; found C 70.54, H 6.54, N 5.53.
2
D
5
Main-chain chiral quaternary ammonium polymers 8g: 90% yield. [α]
(SEC) = 3.7 kg/mol; Elem. Anal. calc. C54 : C 62.30, H 6.20, N 5.38; found C 62.43,
H 6.22, N 5.48.
= −135.48 (1.0, DMSO);
M
n
2 4 3 2
H64Br N O S
2
D
5
Main-chain chiral quaternary ammonium polymers 8h: 96% yield. [α]
(SEC) = 4.3 kg/mol; Elem. Anal. calc. C54 : C 62.30, H 6.20, N 5.38; found C 62.23,
H 6.22, N 5.39.
= −139.7 (1.0, DMSO);
M
n
2 4 3 2
H64Br N O S
3
.4. General Procedure for Asymmetric Benzylation of N-(Diphenylmethylidene)glycine tert-butyl
Ester 9 Catalyzed by Main-Chain Chiral Quaternary Ammonium Polymers 8
Main-chain chiral quaternary ammonium polymer 8 (0.018 mmol) and N-(diphenyl-
methylidene)glycine tert-butyl ester (9, 0.053 g, 0.180 mmol) were added into 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 (0.037 g, 0.216 mmol) was then added dropwise at 0 °C to the
mixture. The reaction mixture was stirred vigorously at 0 °C. The reaction was monitored by TLC.
After completion of the reaction, 10 mL of saturated sodium chloride solution was added, and the
mixture was subsequently filtered to recover 8, which was washed with water and dichloromethane
several times. The organic phase was separated, and the aqueous phase was extracted with
4
dichloromethane. The organic extracts were washed with brine and dried over MgSO . Evaporation
of solvents and purification of the residual oil by column chromatography on silica gel (diethyl
ether:hexane = 1:10 as eluent) gave (S)-phenylalanine derivative 10. The enantiomeric excess
was determined by HPLC analysis (Daicel Chiralcel OD-H, hexane/2-propanol = 100:1, flow
rate = 0.3 mL/min, retention time: R enantiomer = 27.6 min, S enantiomer = 47.9 min). The absolute
configuration was determined by comparison of the HPLC retention time with the authentic sample
independently synthesized by the reported procedure [6].

Molecules 2012, 17
. Conclusions
We have designed novel main-chain chiral quaternary ammonium salt polymers using thiol-ene
7580
4
click reaction followed by quaternization polymerization. The resulting main-chain chiral quaternary
ammonium salt polymers have successfully been applied as polymeric chiral organocatalysts for the
asymmetric benzylation of glycine derivatives. Thiolinked cinchonidine dimer could be synthesized by
the thiol-ene click reaction of cinchonidine with dithiol. The quaternization polymerization with
dihalide proceeded smoothly without side reactions to afford main-chain chiral quaternary ammonium
salt polymers. We found that these main-chain chiral quaternary ammonium polymers showed good
catalytic activity in the asymmetric benzylation of N-(diphenylmethylidene)glycine tert-butyl ester.
1
2
Furthermore, the modification of the structure of R and R in 8 was significantly important for the
design of main-chain chiral quaternary ammonium polymers as polymeric chiral catalysts. The effect
of hydroxyl group functionalization and the reusability of the main-chain chiral quaternary ammonium
salt polymers are now under investigation.
Acknowledgments
This work was partially supported by a Grant-in-Aid for Scientific Research on Innovative Areas
“
Advanced Molecular Transformations by Organocatalysts” (No. 24105514) and by a Grant-in-Aid
for Scientific Research on Innovative Areas “Molecular Activation Directed toward Straightforward
Synthesis” (No. 2335003) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
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Sample Availability: Samples of the compounds of are available from the authors.
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2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
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