Highly efficient polymer supported phase-transfer catalysts containing hydrogen bond inducing functional groups

Article abstract of DOI:10.1016/j.tetlet.2007.12.077

Merrifield resin supported cinchona ammonium salts bearing 2′-fluorobenzene, 2′-cyanobenzene and 2′-N-oxypyridine groups were prepared and applied to the phase-transfer catalytic alkylation of N-(diphenylmethylene)glycine tert-butyl ester for the enantios

Full text of DOI:10.1016/j.tetlet.2007.12.077

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1380–1383
Highly efficient polymer supported phase-transfer catalysts
containing hydrogen bond inducing functional groups
a
b
b
b
b
Qinghua Shi , Yeon-Ju Lee , Mi-Jeong Kim , Mi-Kyung Park , Kyoungyim Lee ,
a
a
c
Hongrui Song , Maosheng Cheng , Byeong-Seon Jeong ,
b,
b,
*
*
Hyeung-geun Park , Sang-sup Jew
a
Shenyang Pharmaceutical University, Shenyang Wenhua Road 103, China
Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
b
c
College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea
Received 18 November 2007; revised 13 December 2007; accepted 17 December 2007
Available online 23 December 2007
Abstract
0
0
0
Merrifield resin supported cinchona ammonium salts bearing 2 -fluorobenzene, 2 -cyanobenzene and 2 -N-oxypyridine groups were
prepared and applied to the phase-transfer catalytic alkylation of N-(diphenylmethylene)glycine tert-butyl ester for the enantioselective
synthesis of a-amino acids (76–96% ee).
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Phase-transfer catalyst; Enantioselective synthesis; Polymer-supported catalyst; Cinchona alkaloid
Quaternary ammonium salts derived from cinchona
alkaloids have been developed as efficient chiral phase-
transfer catalysts (PTCs), which have been successfully
applied to various organic reactions, such as alkylation,
ported catalyst might have far more advantage of a large
scale production from both practical and economical view-
points. Based on the connection site to resin, the polymer
supported cinchona catalysts can be classified into three
categories (types 6–8 as shown in Fig. 1).
1
Michael reaction, aldol condensation, and epoxidation.
Especially, intensive studies have been performed on asym-
metric alkylation of N-(diphenylmethylene)glycine tert-
butyl ester (4) affording a variety of natural and nonnatural
a-amino acid derivatives where 1–3 have been regarded as
representative cinchona-derived PTCs for this purpose
Generally, type 6 catalysts showed moderate to
good chemical yields with moderate enantioselectivities in
the asymmetric alkylation of N-(diphenylmethylene)glycine
5
a–c
esters.
In case of type 7 catalysts, relatively high
2
–4
R1
(
Scheme 1).
Beyond these solution phase catalysts, many polymer
CD
CD
CD
CD
CD =
X
N+
supported phase-transfer catalysts based on cinchona alka-
loids have been developed and employed to various phase-
n
9
X
R
= Cl or Br
= vinyl or ethyl
= H or allyl
n = 1 or 2
O
R2
1
5
N
2
R
transfer catalytic organic reactions as well. Although
1
2
3
catalytic amount of solution phase catalyst is consumed
in phase-transfer catalytic reaction, reusable polymer sup-
Asymmetric
-Bu PTC Alkylation
Ph
N
CO2
t
Ph
N
CO2
t-Bu
2
H N
2
CO H
*
*
Ph
Ph
R
R
4
5
α-Amino acids
*
Corresponding authors. Tel.: +82 2 880 7871; fax: +82 2 872 9129
(H.P.).
Scheme 1. Representative cinchona phase-transfer catalysts and catalytic
E-mail address: hgpk@snu.ac.kr (H. Park).
asymmetric synthesis of a-amino acids under phase-transfer conditions.
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.077

Q. Shi et al. / Tetrahedron Letters 49 (2008) 1380–1383
1381
CH2Cl2
Br
N+
O
N
N
Br
X
X
X
+
N+
N+
N+
X
r.t., 24 h
Y
X
OH
OH
N
Y
OH
O
OH
N
1
2
13a X-Y = C-H
N
N
14a 92%
b
c
d
X-Y = C-F
X-Y = C-CN
X-Y = N -O
b
c
d
94%
94%
93%
+
-
6
7
8
Fig. 1. Polymer supported cinchona phase-transfer catalysts.
Br
N+
Merrifield resin (Br)
0.902 mmol/g)
15a 86% (0.59 mmol/g)
(
enantioselectivities with moderate chemical yields were
b
c
d
85% (0.59 mmol/g)
82% (0.56 mmol/g)
90% (0.61 mmol/g)
X
O
Y
n-Bu4NBr, 50% KOH
CH Cl , r.t., 24 h
observed at ꢀ50 °C, which may be less practical for large
N
2
2
5
d,e
scale production.
Type 8 catalysts provided relatively
low enantioselectivities even at the condition of ꢀ78 °C
5
f
and solid CsOH base. In this Letter, we report a new series
of polymer supported cinchona-derived ammonium salts in
which hydrogen bonding capable functional groups are
incorporated in N -arylmethyl group, and their application
to asymmetric alkylation of N-(diphenylmethylene)glycine
tert-butyl ester (4).
Scheme 2. Preparation of Merrifield resin-supported catalysts.
+
respectively (92–94%) followed by the attachment of 14b–d
8
to Merrifield resin. It should be noted that the activation
of Merrifield resin, a halide exchange from chloride to bro-
mide with 2.0 equiv of sodium bromide and 0.1 equiv of
tetrabutylammonium bromide (TBAB) in refluxing tolu-
ene–water (volume ratio = 10:1), is essential before cou-
pling it with cinchona PTCs 14. Without this activation
process, a retardation of coupling process and low yield
was observed. Coupling of activated Merrifield resin and
the corresponding cinchona units 14b–d was carried out
in the presence of 10 equiv of 50% potassium hydroxide
and 0.1 equiv of TBAB in dichloromethane for 24 h at
room temperature to give 15b–d (82–90%), respectively.
It has been proposed that the high enantioselective cat-
alytic efficiency of cinchona PTCs (1–3) is due to steric
+
bulkiness of the N -arylmethyl group in the catalyst, which
enables the E-enolate anion of 4 approach only from the
+
6
opposite direction to N -arylmethyl group. However,
recent studies from our laboratory demonstrated that the
+
electronic effect of the N -arylmethyl unit in the catalyst
is also responsible for high enantioselectivity. Catalysts
0
0
0
+
ꢀ
9
–11 containing 2 -F, 2 -CN, and 2 -N –O functional
groups showed enhanced enantioselectivity compared to
0
0
0
0
0
the 2 -H, 2 -CꢁCH, and 2 -pyridine analogues, respec-
To confirm the electronic effect of 2 -fluoro, 2 -cyano, and
0
tively, while they exert virtually the same steric effect
Fig. 2).
2 -N-oxide functional groups, benzyl analogue 15a was pre-
pared as a reference by these procedures.
7
(
We have proposed that the high enantioselectivities
might be due to more rigid conformations of catalysts
caused by hydrogen bonding (or induced dipole–dipole
Table 1
Enantioselective phase-transfer catalytic benzylation of N-(diphenyl
methylene)glycine tert-butyl ester (4)
0
0
a
interaction) involving water between C(9)–O and 2 -F, 2 -
0
+
ꢀ
7
CN, or 2 -N –O in each catalyst. We made an attempt
to apply the electronic functional group effect into polymer
supported phase-transfer catalysts.
Ph
N
CO
2
t-Bu
PTC, PhCH
Br, 50% KOH
Ph
N
CO
Ph
2
t-Bu
2
Ph
PhMe/CHCl (7:3), 0
3
ºC
Ph
4
5d
Among the three kinds of polymer supported phase-
transfer catalysts (6–8, Fig. 1), type 7 afforded the highest
enantioselectivity in the alkylation of 4, which led us to
choose C(9)–O-connected catalyst 7 as a basic template.
We employed Merrifield resin as a solid supporting mate-
rial. Catalysts 15b–d were prepared in two step sequence
from (ꢀ)-hydrocinchonidine based on the previous meth-
b
c,d
ee (%)
Entry
PTC (mol %)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
a
15a (20)
15b (20)
15c (20)
15d (20)
15d (2.5)
15d (5.0)
15d (10)
15d (40)
22
7
82
88
83
81
74
82
83
81
69 (S)
91 (S)
93 (S)
14
10
48
22
14
8
e
95 (S)
90 (S)
91 (S)
92 (S)
93 (S)
4
,7
ods (Scheme 2). The treatment of (ꢀ)-hydrocinchonidine
(
12) with benzyl bromide analogues (13b–d) in dichloro-
The reaction was carried out with 5.0 equiv of benzyl bromide and
0.0 equiv of 50% KOH in the presence of catalyst in PhMe–CHCl (7:3)
atb 0 °C.
Isolated yields.
Enantiopurity was determined by HPLC analysis using a chiral col-
umn (Chiralcel OD-H) with hexanes–2-propanol as eluents.
methane at room temperature (24 h) afforded 14b–d,
2
3
c
Br
N+
O
Ar =
N+
d
Ar
Absolute configuration was assigned by comparison of retention times
F
NC
O
2–4
of both enantiomers determined previously.
e
N
9
10
11
It was reported that the PTC 11, the unsupported counterpart of 15d,
gave 5d in 94% chemical yield and 96% ee under the same conditions (the
7
b
Fig. 2. Electronically modified cinchona PTCs.
reaction time: 5 h).

1382
Q. Shi et al. / Tetrahedron Letters 49 (2008) 1380–1383
1
00
30
in asymmetric phase-transfer catalytic alkylation. The best
yield (%)
catalyst 15d was chosen for investigation of the optimal
amount of catalyst loading. As shown in Table 1, the opti-
mal amount of 15d was 20 mol %. Generally, the larger
amount of the catalyst showed the faster reaction rate with
slightly increased enantioselectivity except for 40 mol %
loading (93% ee), which showed slightly decreased enantio-
selectivity than 20 mol % (95% ee).
ee (%)
reaction time (h)
9
9
5
0
25
20
%
85
15 hours
Our next focus was on the reusability of 15d. After the
first benzylation (10 h, 81%, 95% ee) of 4 in the presence
of 20 mol % of 15d, the catalyst was recovered and subse-
quently used in the second benzylation. No decrease of
enantioselectivity (12 h, 88%, 95% ee) was observed with
the recovered 15d (Fig. 3). Even the 5th recycle of the cat-
alyst conserved enantioselectivity (13 h, 80%, 94% ee). The
reusability of 15d without any decrease of enantioselectivty
demonstrates 15d as an efficient and economical polymer
supported phase-transfer catalyst.
8
7
7
0
5
0
10
5
0
1
2
3
4
5
Number of use of PTC 15d
Fig. 3. Relationship between chemical/optical yield and reaction time
according to the number of use of the PTC 15d.
Further alkylation with various alkylating reagents
under the optimal reaction condition using 15d was per-
formed. High enantioselectivities (76–96% ee) shown in
Table 2 indicate that the polymer supported recyclable
PTC 15d is a very efficient catalyst for the practical asym-
metric synthesis of a-amino acids.
The capability of the catalysts 15b–d along with 15a was
evaluated by the benzylation of 4 with 20 mol % of each
solid supported catalyst, benzyl bromide, and 50% KOH
9
in toluene–chloroform (volume ratio = 7:3) at 0 °C. As
shown in Table 1, all of the functional group incorporated
catalysts (15b–d) showed quite enhanced enantioselectivity
with faster reaction rate compared to the reference 15a,
In conclusion, we developed a series of Merrifield resin
supported hydrocinchonidine-derived ammonium salts
15b–d incorporated the functional groups having an ability
of hydrogen bonding. Very high enantioselectivities were
obtained in the alkylation of N-(diphenylmethylene)glycine
tert-butyl ester (4) under mild reaction conditions, and 15d
showed the highest catalytic efficiency. The easy prepara-
tion and recyclable capability without decrease of enanti-
oselectivity of 15d make this catalyst very practical for
the synthesis of optically active a-amino acids in industrial
process. Further application to other phase-transfer cata-
lytic reactions is currently under investigation.
7
which is in agreement with previous results. Among the
catalysts, N-oxy derivative 15d showed the highest enantio-
selectivity (15b, 91% ee; 15c, 93% ee; 15d, 95% ee). These
cumulative findings along with our previous results
strongly support that the electronic effects of the functional
groups play integral role of increasing of enantioselectivity
Table 2
a
Enantioselective phase-transfer catalytic alkylation of 4
Ph
N
CO
2
t-Bu
15d, RX, 50% KOH
PhMe/CHCl (7:3), 0 ºC
Ph
N
2
CO t-Bu
3
Ph
Ph
R
Acknowledgment
4
5
b
c,d
Entry RX
Time (h) Yield (%) ee (%)
This work was supported by Grant (E00257) from the
Korea Research Foundation (2006).
a
b
c
d
e
f
g
h
i
Iodomethane
Allyl bromide
2-Methylallyl bromide
Benzyl bromide
2-Methylbenzyl bromide
3-Methylbenzyl bromide
4-Methylbenzyl bromide
4-Fluorobenzyl bromide
2-Nitrobenzyl bromide
2-Chlorobenzyl bromide
3-Chlorobenzyl bromide
48
14
12
10
14
14
15
7
60
75
78
81
84
87
81
84
76
80
76
78
76 (S)
88 (S)
90 (S)
95 (S)
94 (S)
95 (S)
90 (S)
90 (S)
90 (S)
96 (S)
92 (S)
94 (S)
References and notes
1
. (a) O’Donnell, M. J. Aldrichim. Acta 2001, 34, 3; (b) Maruoka, K.; Ooi,
T. Chem. Rev. 2003, 103, 3013; (c) O’Donnell, M. J. Acc. Chem. Res.
2
004, 37, 506; (d) Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37,
8
8
8
5
18; (e) Ooi, T.; Maruoka, K. Acc. Chem. Res. 2004, 37, 526; (f) Ooi,
j
k
l
T.; Maruoka, K. Angew. Chem., Int. Ed. 2007, 46, 1433.
2
. (a) O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc. 1989,
2-Bromomethylnaphthalene 11
1
11, 2353; (b) O’Donnell, M. J.; Wu, S.; Huffman, J. C. Tetrahedron
a
The reaction was carried out with 5.0 equiv of alkylating reagents and
0.0 equiv of 50% KOH in the presence of 20 mol % of 15d in toluene–
1994, 50, 4507; (c) O’Donnell, M. J.; Wu, S.; Esikova, I.; Mi, A. U.S.
Patent 5,554,753, 1996; (d) O’Donnell, M. J.; Delgado, F.; Hostettler,
C.; Schwesinger, R. Tetrahedron Lett. 1998, 39, 8775; (e) O’Donnell,
M. J.; Delgado, F.; Pottorf, R. S. Tetrahedron 1999, 55, 6347; (f)
Najera, C.; Sansano, J. M. Chem. Rev. 2007, 107, 4584.
2
chloroform (7:3) at 0 °C.
b
Isolated yields.
c
Enantiopurity was determined by HPLC analysis using a chiral col-
umn (Chiralcel OD-H) with hexane–2-propanol as eluents.
3. (a) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595; (b)
Lygo, B.; Crosby, J.; Peterson, J. A. Tetrahedron Lett. 1999, 40, 1385;
(c) Lygo, B. Tetrahedron Lett. 1999, 40, 1389; (d) Lygo, B.; Crosby, J.;
d
Absolute configuration was assigned by comparison of retention times
2–4
of both enantiomers determined previously.

Q. Shi et al. / Tetrahedron Letters 49 (2008) 1380–1383
filtered, and successively washed with water, dioxane, CH
1383
Peterson, J. A. Tetrahedron Lett. 1999, 40, 8671; (e) Corey, E. J.; Xu,
F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414; (f) Corey, E. J.;
Noe, M. C.; Xu, F. Tetrahedron Lett. 1998, 39, 5347; (g) Corey, E. J.;
Bo, Y.; Busch-Peterson, J. J. Am. Chem. Soc. 1998, 120, 13000.
. (a) Jew, S.-s.; Jeong, B.-S.; Yoo, M.-S.; Huh, H.; Park, H.-g. Chem.
Commun. 2001, 1244; (b) Park, H.-g.; Jeong, B.-S.; Yoo, M.-S.; Park,
M.-K.; Huh, H.; Jew, S.-s. Tetrahedron Lett. 2001, 42, 4645; (c) Park,
H.-g.; Jeong, B.-S.; Yoo, M.-S.; Lee, J.-H.; Park, M.-K.; Lee, Y.-J.;
Kim, M.-J.; Jew, S.-s. Angew. Chem., Int. Ed. 2002, 41, 3036.
2
Cl
2
, and
MeOH. The solid was dried in vacuo for 14 h at room temperature and
for 2 h at 100 °C to afford 15d. IR (KBr): 3434, 3024, 2920, 1633, 1492,
ꢀ
1
1451, 1026, 758, 698, 545 544 cm ; Elemental Anal: N, 2.50%,
4
5
loading: 0.61 mmol/g, 90% yield.
9. Procedure of the asymmetric benzylation of 4 under phase-transfer
conditions: To an ice-cooled mixture of N-(diphenylmethylene)glycine
tert-butyl ester (4) (25 mg, 0.085 mmol) and 15d (30 mg, 0.017 mmol)
in toluene–chloroform (7:3, 0.6 mL) was added benzyl bromide (50 lL,
0.43 mmol) at 0 °C. Then 50% aq potassium hydroxide (0.1 mL) was
added and the resulting mixture was stirred at 0 °C until the starting
material 4 had been consumed. The suspension was filtered, and the
filter cake was washed with ethyl ether to afford the recovered catalyst
15d. The filtrate was washed with water, and the combined filtrate and
. (a) Chinchilla, R.; Maz o´ n, P.; N a´ jera, C. Tetrahedron: Asymmetry
2
2
000, 11, 3277; (b) Chinchilla, R.; Maz o´ n, P.; N a´ jera, C. Molecules
004, 9, 349; (c) Thierry, B.; Plaquevent, J.-C.; Cahard, D. Tetra-
hedron: Asymmetry 2001, 12, 983; (d) Thierry, B.; Perrard, T.;
Audouard, C.; Plaquevent, J.-C.; Cahard, D. Synthesis 2001, 1742;
(e) Thierry, B.; Plaquevent, J.-C.; Cahard, D. Tetrahedron: Asymmetry
4
washings was dried over MgSO , filtered, and concentrated. Purifi-
2
003, 14, 1671; (f) Danelli, T.; Annunziata, R.; Benaglia, M.; Cinquini,
cation of the residue by flash column chromatography (hexanes–
1
M.; Cozzi, F.; Tocco, G. Tetrahedron: Asymmetry 2003, 14, 461.
. Lipkowitz, K. B.; Cavanaugh, M. W.; Baker, B.; O’Donnell, M. J. J.
Org. Chem. 1991, 56, 5181.
. (a) Jew, S.-s.; Yoo, M.-S.; Jeong, B.-S.; Park, I. Y.; Park, H.-g. Org.
Lett. 2002, 4, 4245; (b) Yoo, M.-S.; Jeong, B.-S.; Lee, J.-H.; Park,
H.-g.; Jew, S.-s. Org. Lett. 2005, 7, 1129.
EtOAc = 50:1) afforded the benzylated imine 5d (26.3 mg, 81%).
NMR (300 MHz, CDCl ) d 7.58–7.54 (m, 2H), 7.38–7.22 (m, 6H),
7.20–7.17 (m, 3H), 7.12–7.02 (m, 2H), 6.8 (d, J = 7.0 Hz, 2H), 4.08 (dd,
H
6
7
3
1
3
J = 4.4, 4.8 Hz, 1H), 3.25–3.10 (m, 2H), 1.43 (s, 9H) ppm; C NMR
(100 MHz, CDCl ) d 170.8, 170.3, 139.6, 138.4, 136.4, 130.0, 129.9,
3
128.7, 128.2, 128.1, 128.0, 127.9, 127.7, 126.1, 81.1, 67.9, 39.6,
+
8
. Representative procedure for the preparation of Merrifield resin
28.0 ppm; MS (FAB): m/z 386 [M+H] . The enantiomeric excess of
supported catalyst (15d): To a suspension of Merrifield resin (Br)
the product was determined by a chiral HPLC analysis [Chiralcel
OD-H column, hexanes–2-propanol = 500:2.5, flow rate = 1.0 mL/
min, 23 °C, k = 254 nm, retention times R (minor) 10.6 min, S (major)
23.2 min, 95% ee]. The absolute configuration was determined by
comparison of the HPLC retention times with the reported data of an
(1.0 g, 0.90 mmol), tetrabutylammonium bromide (30.0 mg,
0.09 mmol), and N-(1-oxypyridin-2-ylmethyl)hydrocinchonidinium
bromide (14d) (8.89 g, 1.8 mmol) in dichloromethane (20 mL) was
added 50% aq potassium hydroxide (1.0 mL, 9.0 mmol). The resulting
mixture was stirred at room temperature for 24 h. The solid was
2
–5
authentic sample.