An immobilization method of chiral quaternary ammonium salts onto polymer supports

Article abstract of DOI:10.1002/anie.200802800

(Chemical Equation Presented) Direct support: The title compounds have been used as polymeric organocatalysts (see structure) in the asymmetric alkylation of a glycine derivative to give the corresponding phenylalanine with high enantioselectivity. The po

Full text of DOI:10.1002/anie.200802800

Communications
DOI: 10.1002/anie.200802800
Polymeric Catalysts
An Immobilization Method of Chiral Quaternary Ammonium Salts
onto Polymer Supports**
Yukihiro Arakawa, Naoki Haraguchi, and Shinichi Itsuno*
[15]
Asymmetric transformations by means of a chiral quaternary
ammonium salt acting as the organocatalyst have been
extensively studied. Since the pioneering work by a research
group at Merck in 1984,[1] cinchona-alkaloid-derived quater-
nary ammonium salts have been widely used as chiral
organocatalyst in various asymmetric reactions.[2] The enan-
tioselective alkylation of glycinate Shiff base in the presence
of an enantiopure quaternary ammonium salt is a typical
asymmetric synthesis of chiral a-amino acids.[3] From the
viewpoint of reaction efficiency, polymer-immobilized chiral
catalysts which have been used for asymmetric reactions are
of considerable interest in organic synthesis. Although
numerous polymer-immobilized chiral catalysts have been
developed, but so far, there have been limited reports on
polymer-immobilized chiral quaternary ammonium salts.[4]
First examples were reported by Chiellini and Solaro in
1977[5] and Colonna et al. in 1978.[6] In 1981, Kobayashi and
Iwai reported asymmetric catalysis by quinium salts immobi-
lized onto polystyrene.[7] Hodge et al. also reported the
quaternary ammonium salts of polymer-immobilized cin-
chona alkaloids [8] where the polymers were simply prepared
through quaternarization of the cinchona alkaloid with
partially chloromethylated cross-linked polystyrene. Najera
and co-workers used the same type of polymeric cinchona-
alkaloid quaternary ammonium salt for the enantioselective
alkylation of N-diphenylmethylene glycine esters.[9] Cahard
and co-workers have developed a similar type of polystyrene-
immobilized chiral quaternary ammonium salts that have a
spacer arm.[10] Furthermore, hydrocinchonidinium salts were
immobilized onto Merrifield resin and used for the same
alkylation reaction.[11] Poly(ethylene glycol) was also utilized
as a polymer support of a chiral quaternary ammonium
salt.[12–14] All of the above examples involve a covalent bond
between the polymer and the chiral quaternary ammonium
salt. We have found that quaternary ammonium sulfonate is
quite stable and that polymers possessing sulfonate groups
can immobilize quaternary ammonium cations through ionic
bonding.
To our knowledge, this is a new type of
immobilization comprising of an ionic bond between a
chiral catalyst and a polymer. We have developed two
methods of the ionic immobilization: the first involves the
polymerization of a chiral quaternary ammonium sulfonate
monomer, and the second is the immobilization of a chiral
quaternary ammonium salt onto a sulfonated polymer
through an ion exchange reaction. These polymeric chiral
quaternary ammonium salts were successfully used as poly-
meric organocatalysts in the asymmetric alkylation of a
glycine derivative. This is the first example of the immobili-
zation of quaternary ammonium salt through an ionic
interaction.
As chiral quaternary ammonium sulfonates can be easily
prepared from cinchonidine, we have prepared our styrene
sulfonate monomers from this substrate (Scheme 1). N-
Benzylcinchonidinium chloride (1a) was treated with
sodium p-styrene sulfonate (2b) in water, and subsequent
extraction with dichloromethane gave the chiral quaternary
ammonium monomer 3b. The chiral monomer was copoly-
merized with styrene and divinylbenzene under radical
condition to give the corresponding polymeric chiral quater-
nary ammonium salt 4aA. By using this method, any type of
chiral quaternary ammonium salt can be transformed into its
corresponding monomer. This method is an easier way to
obtain the chiral quaternary ammonium salt polymers in
comparison to the conventional covalent bonding method. By
means of this method, the original chiral quaternary ammo-
nium structure can always be maintained in the polymer, as no
chemical modification on the chiral ammonium moiety is
required.
On the other hand, the same polymeric chiral quaternary
ammonium salts can be readily prepared from polymers
having sulfonate pendant groups (Scheme 1). An ion
exchange reaction of 8 with a chiral quaternary ammonium
salt gave the polymeric ammonium salts 4. If difficulty in the
chiral monomer synthesis is encountered or if functionalities
contained in the quaternary ammonium moiety hinder the
polymerization reaction, then the ion exchange reaction of
polymeric sulfonate is a suitable method for the preparation
of these polymers.
The chiral polymers mentioned above were then used as a
catalysts for the asymmetric alkylation of N-diphenylmethy-
lene glycine tert-butyl ester (5; Scheme 2). In the presence of
4aA, prepared by polymerization, benzylation smoothly
afforded the corresponding phenylalanine derivative with
78% ee (Table 1, entry 3). Under the same reaction condi-
tions, the unsupported catalyst 3a showed 68% ee (Table 1,
entry 2) and the original chloride catalyst 1a gave 69% ee
(Table 1, entry 1). The enantioselectivity obtained by using
[*] Y. Arakawa, Dr. N. Haraguchi, Prof. S. Itsuno
Department of Materials Science
Toyohashi University of Technology
Tempaku-cho, Toyohashi 441-8580 (Japan)
Fax: (+81)532-44-6813
E-mail: itsuno@tutms.tut.ac.jp
Homepage: http://material.tutms.tut.ac.jp/STAFF/ITSUNO/
index.html
[**] This work was financially supported by a Grant-in-Aid from the
Ministry of Education, Culture, Sports, Science, and Technology
(Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802800.
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Chemie
Table 1: Asymmetric benzylation of N-diphenylmethylene glycine tert-
butyl ester (5).[a]
Entry
Catalyst
t [h]
Yield [%][b]
ee [%][c,d]
1
2
3
1a
3a
4aA
4aA
4aA
7
0.5
0.5
15
15
15
24
24
0.5
10
24
22
24
24
24
78
88
66
66
65
72
0
86
84
73
74
70
70
61
69
68
78
79
80
75
–
93
94
95
95
96
96
96
4[e]
5[f]
6
7[g]
8
7
3c
9
4bA
4bB
4bB
4bB
4bB
4bB
10[h]
11[i]
12[j,k]
13[j,k]
14[h,j]
[a] The reaction was carried out with benzyl bromide (1.2 equiv) in the
presence of catalyst (10 mol%) in 50 wt% aqueous KOH/toluene at 08C.
[b] The yields were determined by 1H NMR spectroscopy. [c] The
ee values were determined by HPLC on a chiral stationary phase using
a Chiralcel OD-H column; eluent: 2-propanol/n-hexane(1:100). [d] All
products have S configuration. [e] The polymer recovered from entry 3
was reused. [f] The polymer recovered from entry 4 was reused. [g] The
polymer recovered from entry 6 was reused. [h] The polymer recovered
from entry 10 was reused. [i] The reaction was carried out at À208C.
[j] The polymer recovered from entry 12 was reused. [k] The polymer
recovered from entry 13 was reused.
Scheme 1. Preparation of the polymer-supported chiral quaternary
ammonium catalysts. AIBN=2,2’-azobisisobutyronitrile, DMF=N,N-
dimethylformamide.
Figure 1. Polymer-supported chiral quaternary ammonium carboxylate
catalyst 7.
Scheme 2. Asymmetric benzylation of N-diphenylmethylene glycine
tert-butyl ester (5).
chiral quaternary salt into the solution during the asymmetric
reaction and could not be reused (Table 1, entry 7). This result
shows that the sulfonate group gives considerable stability
and is essential as a counter anion for the polymeric
ammonium salt.
The 9-anthracenemethyl derivative of the cinchonidine-
based quaternary ammonium salt 1b was originally intro-
duced by Lygo and co-workers as a powerful catalyst for the
above mentioned asymmetric alkylation.[16] Enantioselectiv-
ity increased to 91% using 1b[16] and the sulfonated catalyst
3c was also active for the same reaction to give 93% ee
(Table 1, entry 8). When the polymer-immobilized version of
the catalyst 4bA was employed a similar enantioselectivity
(94% ee) was obtained (Table 1, entry 9). Other alkyl halides
were used as alkylating agent, and in all cases somewhat
higher enantioselectivities were obtained with the polymer-
supported catalyst (Table 2).
the polymeric catalyst was higher than those obtained from
the unsupported catalyst 1a and 3a. Interestingly, the
polymeric catalyst immobilized through the quaternary
ammonium sulfonate substrate was unexpectedly stable.
After the reaction the polymeric catalyst was easily separated
and quantitatively recovered. No elimination of the chiral
quaternary ammonium moiety was observed in solution. The
recovered polymeric catalyst was successfully used again for
the same reaction (Table 1, entries 4 and 5). Next, the
carboxylate polymer 7 (Figure 1) was prepared by polymer-
ization from the corresponding chiral monomer. The carbox-
ylate counter anion of 7 had no obvious influence on the
reactivity and enantioselectivity on the asymmetric benzyla-
tion reaction (Table 1, entry 6). However, in contrast to the
sulfonated polymeric catalysts, 7 thoroughly released the
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Communications
Table 2: Asymmetric alkylation of N-diphenylmethylene glycine tert-butyl
ester (5) using polymeric catalyst 4bA.[a]
Although the reaction mechanism is not clear at this
moment, we believe that aggregated ion pairs seem to be
involved (Scheme 3; see the Supporting Information). The
results obtained from the polymer-immobilized catalysts
leads to the assumption that the polymeric sulfonate must
be closely involved in the transition state. Owing to the strong
affinity between the sulfonate anion and ammonium cation,
the polymeric quaternary ammonium sulfonate catalyst is
always recovered.[18]
Entry
Alkyl halide
t [h]
Yield [%][b,c]
ee [%][c,d]
1
2
3
4
benzyl bromide
4-methyl-benzyl bromide
4-bromo-benzyl bromide
allyl bromide
allyl iodide
methyl iodide
10
5
12
6
16
19
84 (86)
90 (90)
95 (92)
85 (85)
74 (89)
45 (53)
94 (93)
97 (96)
91 (87)
98 (95)
80 (91)
70 (85)
5
6[e]
[a] See Table 1 for reaction conditions. [b] The yields were determined by
1H NMR spectroscopy. [c] Data in parenthesis were obtained using 3c.
[d] All products have S configuration. [e] Polymeric catalyst 4bB was
used.
Polymer-supported quaternary ammonium salts were also
prepared by reaction of the sulfonated polymer 8 with a chiral
quaternary ammonium salt. By using this method, any kind of
chiral quaternary ammonium salt can be attached onto a
polymer. The polymeric sulfonate catalyst 4bB was used for
the asymmetric benzylation to give the product with 95% ee
(Table 1, entry 10). This polymeric catalyst was recycled and
reused and it showed the same catalytic activity (Table 1,
entry 11).
Scheme 3. A proposed reaction mechanism.
Since this immobilization method can be applied to any
kind of chiral ammonium salt, we chose to look at the
excellent catalyst developed by Maruoka.[17] The chiral
quaternary ammonium salt of polymer 9 (Figure 2) is one of
In conclusion, we have developed a novel immobilization
method for chiral organocatalysts onto a polymer through
ionic bonds to sulfonate groups. By using this method, any
type of chiral quaternary ammonium organocatalyst can be
easily immobilized onto a polymer support. Somewhat higher
enantioselectivities were obtained in most cases by using this
type of polymeric catalyst compared to the unsupported
catalysts in homogeneous solution systems. The polymeric
catalyst can be reused without the need for the regeneration
of the catalyst.
Experimental Section
Preparation of 4aA: A glass ampoule equipped with a magnetic
stirring bar was charged with DMF (0.62 g), 3b (228 mg, 0.4 mmol),
styrene (366 mg, 3.52 mmol), divinylbenzene (10.4 mg, 0.08 mmol),
and AIBN (13.2 mg, 80 mmol). The ampoule was sealed after three
freeze-pump-thaw cycles. Copolymerization was carried out at 608C
for 4 days. The ampoule was opened and the resulting mixture was
poured into methanol (50 mL). The polymer was then collected and
washed with dichloromethane and methanol, then dried in vacuo
(93%, 0.66 molequiv nitrogen per gram of polymer). Elemental
analysis calcd for C10.6H10.8N0.2O0.4S0.1: C 84.56%, H 7.23%, N 1.85%:
found: C 84.38%, H 7.09%, N 2.03%.
Preparation of 9: A biphasic water (2 mL) and dichloromethane
(5 mL) solution of (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-
Figure 2. Polymer-supported Maruoka catalyst 9.
dihydro-3H-dinaphtho[2,1-c:1’,2’-e]azepinium
bromide
(0.1 g,
0.13 mmol) and 8 (128 mg, 0.11 mmol) was stirred at room temper-
ature for 22 h. The resulting polymer was collected and washed with
dichloromethane, water, and methanol, then dried in vacuo (166 mg,
56% conversion, 0.38 molequiv nitrogen per gram of polymer).
Elemental analysis found C 82.55%, H 6.70%, N 0.52%.
Asymmetric benzylation of 5: A mixture of N-diphenylmethylene
glycine tert-butyl ester (5; 0.53 g, 1.78 mmol), 9 (47 mg, 17.8 mmol),
50 wt% aqueous KOH solution (2.5 mL), and toluene (10.5 mL) was
cooled to 08C. After stirring for 15 min, benzyl bromide (0.37 g,
2.14 mmol) was added and the reaction mixture stirred vigorously for
21 h. Saturated sodium chloride solution was then added, and the
mixture was subsequently filtered to recover 9, which was washed
the most effective catalysts for the asymmetric alkylation
reaction. Our method is the only the way to prepare the
polymer-supported Maruoka catalyst without modification of
its original structure. By using 1 mol% of 9 in the reaction of 5
with benzyl bromide, the chiral product 6 was obtained in
84% yield with 98% ee. The polymer was fully recovered
after the reaction and reused twice to give the same yields and
enantioselectivities (for the second and third uses: 84% yield,
98% ee).
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Angewandte
Chemie
with water and dichloromethane several times. The organic phase was
separated and concentrated in vacuo to give a colorless liquid 6. The
yield was determined by 1H NMR spectroscopy (84%). The ee value
(98%) was determined by HPLC on a chiral stationary phase using a
Chiralcel OD-H column; eluent: 2-propanol/n-hexane (1:100); flow
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rate: 0.3 mLminÀ1
,
l = 254 nm, 228C; retention times: R enan-
tiomer= 27.6 min, S enantiomer= 47.9 min.
Received: June 13, 2008
Published online: September 22, 2008
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Keywords: alkylation · polymers · quaternary ammonium salts ·
sulfonates
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