Enantioselective reduction of oxime ethers with borane catalyzed by polymer-supported 2-piperazinemethanol

Full text of DOI:10.1021/jo0007837

J . Org. Chem. 2000, 65, 5879-5881
5879
tion of oxime ethers in homogeneous system,3 we have
designed a novel chiral monomer 1. In the reaction of
4-vinylbenzenesulfonyl chloride with enantiopure O-
protected 2-piperazinemethanol, the sulfonyl group was
regioselectively introduced to the less hindered amino
group of the piperazine to give (R)-1. This chiral monomer
was then subjected to polymerization with styrene and
divinylbenzene under the suspension polymerization
condition in water to give the chiral polymer beads 2,
which were converted into 3 by treatment with tetrabu-
tylammonium fluoride in THF (Scheme 1). By means of
the polymerization method shown in Scheme 1, the
loading of chiral ligand and the degree of cross-linking
can be readily controlled by regulating the fractions of
chiral monomer and divinylbenzene. To understand the
effect of polymeric catalyst on the asymmetric reduction,
we have prepared several chiral polymers (3a -e) con-
taining different loadings and degrees of cross-linking.
En a n tioselective Red u ction of Oxim e
Eth er s w ith Bor a n e Ca ta lyzed by
P olym er -Su p p or ted 2-P ip er a zin em eth a n ol
Shinichi Itsuno,*,† Takeshi Matsumoto,†
Daisuke Sato,‡ and Tsutomu Inoue‡
Department of Materials Science, Toyohashi University of
Technology, Toyohashi 441-8580, J apan, and Research &
Planning Laboratory, Odawara Research Center, Nippon
Soda Co., Ltd., 345 Takada, Odawara,
Kanagawa 250-0280, J apan
itsuno@tutms.tut.ac.jp
Received May 22, 2000
In tr od u ction
The enantioselective reduction of the CdN double bond
is an important synthetic strategy for the preparation of
optically active amines and has received much attention
over the past few years, in both academic and industrial
research.1,2 Recently, we described new chiral ligands
derived from enantiopure 2-piperazinemethanol, which
are effectively used for the borane reduction of imines
and oximes as well as ketones.3 For example, by using
(S)-4-(p-toluenesulfonyl)-2-piperazinemethanol as a chiral
ligand, acetophenone O-methyloxime was reduced with
borane to give (S)-1-phenylethylamine in 84% ee at 50
°C.
On the other hand, asymmetric syntheses achieved
using polymer-supported chiral catalysts are a particu-
larly attractive type of organic reaction.4 Polymer-sup-
ported catalysis is receiving considerable and ever in-
creasing interest as a useful tool for automated reactions
with unique microenvironments for stereoselective reac-
tions.5 Because of the various advantages of supported
catalysts, we have prepared a polymer-supported chiral
ligand containing the 2-piperazinemethanol structure.
We now report an enantioselective borane reduction of
oxime ethers using the polymer-supported oxazaboroli-
dine catalyst.6 The reusability of the polymeric chiral
ligand has also been demonstrated.
In the first place, chiral polymer 3a was suspended in
THF, which was allowed to react with BH3 to form the
supported chiral oxazaborolidine.7 The polymeric chiral
oxazaborolidine was then used for the borane reduction
of acetophenone O-methyloxime (4a ) to give chiral pri-
mary amine 5 (Scheme 2). By using 3a , the borane
reduction occurred smoothly at 50 °C, the oxime ether
being consumed completely in 24 h to afford the corre-
sponding primary amine in 56% yield with 72% ee. The
lower isolated yield of primary amine was caused by
difficulties in the removal of byproducts including meth-
oxyamine. Using the oxazaborolidine prepared from
trimethyl borate,8 a somewhat lower ee was obtained
(entry 4, Table 1). Using polymeric chiral ligands 3a and
3b as well as model ligand in the homogeneous system,
no reaction occurred below room temperature. Interest-
ingly, when the polymer 3c containing 20 mol % of chiral
ligand was used, the reduction occurred even at room
temperature to give the corresponding enantioenriched
amine in 82% ee (entry 6). This polymeric oxazaborolidine
showed apparently higher activity than that of the low
molecular weight counterpart in the homogeneous sys-
tem. In the case of lightly cross-linked polymer 3d having
the same content of chiral ligand, higher enantioselec-
tivity (96% ee) was achieved at room temperature. Some
other ketoxime O-methyl ethers were also asymmetri-
cally reduced using 3d to give the amines in high ees.
Heavily loaded polymer 3e gave poorer results probably
due to the rigidity of the catalyst site (entry 14). Although
no reaction took place at -78 °C with the polymeric
oxazaborolidine 3d , the reduction occurred at 0 °C. At
this temperature almost perfect enantioselectivity was
obtained (99% ee) in the reduction of 4a (entry 12).
Although it is not clear why high activity appears in these
cross-linked polymeric oxazaborolidines, our discovery
Resu lts a n d Discu ssion
Based on the results using 4-(p-toluenesulfonyl)-2-
piperazinemethanol as a chiral ligand in borane reduc-
* To whom corresponding should be addressed. Phone and fax: +81
532 44 6813.
† Toyohashi University of Technology.
‡ Nippon Soda Co.
(1) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895.
(2) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069.
(3) Inoue, T.; Sato, D.; Komura, K.; Itsuno, S. Tetrahedron Lett.
1999, 40, 5379.
(4) Reviews of polymer-supported chiral catalysts: (a) Itsuno, S. In
Polymeric Materials Encyclopedia; Synthesis, Properties and Applica-
tions; Salamone, J . C., Ed.; CRC: Boca Raton, FL, 1996; Vol. 10, p
8078. (b) Blossey, E. C.; Ford, W. T. In Comprehensive Polymer Science.
The Synthesis, Characterization, Reactions and Applications of Poly-
mers; Allen, G., Bevington, J . C., Eds.; Pergamon: New York, 1989;
Vol. 6, p 81. (c) Pu, L. Chem. Eur. J . 1999, 5, 2227.
(5) Itsuno, S. In Handbook on Lewis Acid - Application in Organic
Synthesis; Yamamoto, H., Ed.; Wiley-VCH: in press.
(6) (a) Itsuno, S. Org. React. 1998, 52, 395. (b) Itsuno, S. In
Comprehensive Asymmetric Catalysis; J acobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 1, Chapter 1, p 289.
(c) Corey, E. J .; Helal, C. J . Angew. Chem., Int. Ed. 1998, 37, 1987.
(7) For other examples of supported chiral oxazaborolidines, see: (a)
Itsuno, S.; Nakano, M.; Ito, K.; Hirao, A.; Owa, M.; Kanda, N.;
Nakahama, S. J . Chem. Soc., Perkin Trans. 1 1985, 2615. (b) Caze,
C.; El Moualij, N.; Hodge, P.; Lock, C. J .; Ma, J . J . Chem. Soc., Perkin
Trans. 1 1995, 345. (c) Franot, C.; Stone, G. B.; Engeli, P.; Spo¨ndlin,
C.; Waldvogel, E. Tetrahedron: Asymmetry 1995, 6, 2755. (d) Felder,
M.; Giffels, G.; Wandrey, C. Tetrahedron: Asymmetry 1997, 8, 1975.
(e) Giffels, G.; Beliczey, J .; Felder, M.; Kragl, U. Tetrahedron: Asym-
metry 1998, 9, 691.
(8) Masui, M.; Shioiri, T. Tetrahedron Lett. 1998, 39, 5199.
10.1021/jo0007837 CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/17/2000

5880 J . Org. Chem., Vol. 65, No. 18, 2000
Notes
Sch em e 1
Sch em e 2
system, the chiral product in solution can be separated
and remaining polymeric oxazaborolidine can be reused
without regeneration in subsequent reactions (recycle
method B in Experimental Section). The same level of
enantioselectivities (94-96% ee) were achieved by this
recycling method.
In summary, we have developed a polymer-supported
version of 2-piperazinemethanol, which was efficiently
used in the enantioselective borane reduction of oxime
ethers to give enantioenriched primary amines. By ap-
propriately balancing the content of the chiral ligand and
the degree of cross-linking in the polymer support, it is
possible to obtain a highly active catalyst. It is notewor-
thy that this chemistry shows a remarkable example of
the polymer effect on catalysts to increase both reactivity
and selectivity.
Ta ble 1. En a n tioselective Red u ction of Oxim e Eth er
w ith BH3‚THF Ca ta lyzed by P olym er -Su p p or ted Ch ir a l
Ca ta lysta
oxime polymeric
T
(°C)
time yield eeb
entry ether
ligand
(h)
(%)
(%) confignc
1
2
3
4e
5
6
7
8
9
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
4a
4a
4a
d
3a
3a
3a
3b
50
50
rt
50
50
rt
rt
rt
rt
rt
6
12
24
12
12
24
24
24
24
24
24
48
48
36
61
56
0
84
72
S
R
40
77
60
65
64
75
81
63
70
0
54
60
82
96
96
86
93
88g
99
R
R
R
R
S
R
R
R
R
Exp er im en ta l Section
3c
3d
Gen er a l P r oced u r es. All reactions were carried out under
an atmosphere of dry nitrogen. Tetrahydrofuran (THF) and
diethyl ether were freshly distilled from sodium benzophenone
ketyl under nitrogen immediately before use. Flash column
chromatography was performed over Wako silica gel (Wakogel
C-200, 100-200 mesh). NMR spectra were obtained in CDCl3
at 270 MHz for 1H and 67.8 MHz for 13C.
(S)-3d f
3d
10
3d
3d
3d
3d
11
12
13
14
rt
0
-78
rt
(R)-2-(ter t-Bu t yld im et h ylsiloxy)m et h yl-4-(4-vin ylb en -
zen esu lfon yl)p ip er a zin e 1. To a solution of (R)-2-(tert-butyl-
dimethylsiloxy)methylpiperazine (2.89 g, 12 mmol) and triethyl-
amine (4.55 g, 45 mmol) in chloroform (15 mL) at 0 °C was added
dropwise a chloroform (15 mL) solution of 4-vinylbenzenesulfonyl
chloride9 (2.42 g, 12 mmol) prepared from sodium 4-styrene-
sulfonate and thionyl chloride. The mixture was stirred at room
temperature for 12 h. Water (40 mL) was then added, and the
aqueous phase was extracted with chloroform. The organic layers
were combined and dried over MgSO4, filtered, and concentrated.
Flash chromatography (hexane/ethyl acetate ) 1:5) gave 3.40 g
3e
37
90
R
a
b
2.23 equiv of the polymeric chiral ligand was used. The
enantiomeric excess of 5. Determined by GC analysis with a chiral
stationary phase column unless otherwise noted. See the Experi-
mental Section. c The absolute configurations of 5a ,10 5c,11 and
5d 12 were determined by the comparison of optical rotation with
the literature values. The configuration of 5b was assumed to be
d
R from a similarity of the elution order in GC analysis. (S)-4-
(p-Toluenesulfonyl)-2-piperazinemethanol was used.3 e Oxazaboro-
lidine generated from trimethyl borate and 3a was used. f (S)-3d
was prepared from (S)-2-(tert-butyldimethylsilyloxy)methyl-
piperazine. g Determined by HPLC analysis with a chiral station-
ary phase column. See the Experimental Section.
(70%) of 1 as colorless oil: [R]23 +41 (c 0.845, CHCl3); 1H NMR
D
(CDCl3) δ 0.03 (s, 6H), 0.86 (s, 9H), 1.75 (br, 1H), 1.98-2.13 (m,
1H), 2.28-2.42 (m, 1H), 2.81-3.09 (m, 3H), 3.37-3.63 (m, 4H),
5.54 (J ) 10.7 Hz, 1H), 5.88 (d, J ) 17.6 Hz, 1H), 6.75 (dd, J )
10.7, J ) 17.6 Hz, 1H), 7.53 (d, J ) 8.5 Hz, 2H), 7.69 (d, J ) 8.5
Hz, 2H); 13C NMR (CDCl3) δ -5.0, 18.8, 26.4, 45.1, 47.1, 48.8,
56.3, 65.1, 117.9, 127.1, 128.6, 135.0, 135.8, 142 5; IR (neat) 1351,
1166 cm-1. Anal. Calcd for C19H32N3O3SSi: C, 57.54; H, 8.13;
N, 7.06. Found: C, 57.50; H, 8.09; N, 7.12.
belongs to the rare class of catalysts that are more active
on support than in solution.
To show that the polymeric chiral ligand can be
recycled a number of times, the borane reduction of 4a
using 3d was repeated five times at room temperature
(recycle method A in Experimental Section). The enan-
tioselectivities remain around 95% ee (96, 93, 98, 95, and
96% ee, respectively) clearly illustrating the reusability
of the chiral ligand. Polymer-supported oxazaborolidine
could be reused even without its regeneration. In such a
(9) Ishizone, T.; Tsuchiya, J .; Hirao, A.; Nakahama, S. Macromol-
ecules 1992, 25, 4840.
(10) Theilaker, W.; Winkler, H. G. Chem. Ber. 1954, 87, 691.
(11) Warren, M. E.; Smith, H. E. J . Am. Chem. Soc. 1965, 87, 1757.
(12) Yamamoto, Y.; Shimoda, H.; Oda, J .; Inoue, Y. Bull. Chem. Soc.
J pn. 1976, 49, 3247.

Notes
P olym er -Su p p or ted Ch ir a l Liga n d 3d . To a well-stirred
J . Org. Chem., Vol. 65, No. 18, 2000 5881
mixture was treated with 1 N HCl (15 mL) and filtered through
a glass filter. The filtrate was washed with ether and neutralized
with aqueous ammonia. The aqueous phase was extracted with
ether, and then the combined organic layers were dried over
MgSO4, filtered, and concentrated. Flash chromatography (ether)
gave 0.24 g (65%) of 1-phenylethylamine (5a ) as a colorless oil.
The enantioselectivity (96% ee) was determined for its trifluo-
roacetylated derivative by GC analysis using a chiral stationary-
phase column (Astec Chiraldex G-TA, 30 m × 0.25 mm) at 110
°C; tR ) 25.3 min (R), tR ) 27.1 min (S). For 5b: tR ) 44.9 min,
tR ) 46.1 min at 130 °C. For 5c: tR ) 36.3 min (R), tR ) 38.0
min (S) at 110 °C. The enantioselectivity of 5d was determined
for its trifluoroacetylated derivative by HPLC analysis using
Chiralcel OD (flow rate 0.5 mL/min, hexane/2-propanol ) 95:5,
column temperature; 30 °C); tR ) 15.8 min (R), tR ) 17.1 min
(S).
solution of poly(vinyl alcohol) 0.6 g, degree of polymerization:
2000, 78-82% hydrolyzed) in 300 mL of water cooled to 0 °C
was added a solution of 1 (3.25 g, 8.0 mmol), styrene (3.25 g,
31.2 mmol), divinylbenzene (0.10 g, 0.8 mmol), and 2,2′-azobis-
(4-methoxy-2,4-dimethylvaleronitrile) (0.13 g, 0.5 mmol) in
benzene (3 mL). After 1 h of stirring at 0 °C to homogenize the
particle size, the temperature was raised to 80 °C and the
reaction mixture was stirred vigorously (400 rpm) for 48 h at
the same temperature. The resulting polymer beads were filtered
and washed with water, methanol, THF-methanol, THF, and
methanol, respectively. After the beads were dried in vacuo at
40 °C, 5.62 g (85%) of polymer 2d was obtained: IR (KBr) 1352,
1166 cm-1. Anal. Calcd for (C19H32N2O3SSi)0.20(C8H8)0.78(C10
H10 0.02: C, 75.38; H, 7.93; N, 3.43. Found: C, 75.45; H, 8.01; N,
3.38.
-
)
2d was then suspended in THF (35 mL), and n-Bu4NF (10.1
mL, 1.0 M) was added. The mixture was stirred at 50 °C for 20
h. The polymer beads were collected on the glass filter and
washed with water, THF, and methanol. After the beads were
dried in vacuo at 40 °C for 24 h, 4.75 g (100% from 2d ) of polymer
3d was obtained. From the elemental analysis data shown below,
the functional group substitution of 3d was calculated to be 0.71
mmol/g: IR (KBr) 1331, 1164 cm-1. Anal. Calcd for (C13H18N2-
Recycle Meth od A. The polymeric chiral ligand 3d separated
through glass filter was neutralized with ammonia and washed
with water, THF, and methanol. After being dried in vacuo at
40 °C for 24 h, 3d was used for the second reaction.
Recycle Meth od B. A flask equipped with a glass frit was
used for the recycle use of the polymeric oxazaborolidine without
its regeneration. After the reaction was completed, the product
in solution was separated by filtration through fritted glass
attached to the flask. The second reaction was performed by
using the polymeric oxazaborolidine left in the flask.
O3S)0.20(C8H8)0.78(C10H10)0.02: C, 77.38; H, 7.21; N, 3.99. Found:
C, 77.41; H, 7.19; N, 3.95.
Gen er a l P r oced u r e of En a n tioselective Bor a n e Red u c-
tion of Oxim e Eth er Usin g P olym er -Su p p or ted Ca ta lyst.
To a suspension of polymer-supported chiral ligand 3d (4.79 g,
6.7 mmol) in 25 mL of dry THF was added dropwise BH3‚THF
(9.0 mL, 1.0 M in THF). The reaction was stirred at 50 °C for
15 h. The excess borane and THF were removed in vacuo. The
resulting polymeric oxazaborolidine was suspended in dry THF
(25 mL), and acetophenone O-methyloxime (0.45 g, 3 mmol) was
added. BH3‚THF (6.0 mL, 1.0 M) was then added to the above
mixture and stirred at room temperature for 24 h. The reaction
Ack n ow led gm en t. This work was supported in part
by a Grant-in-Aid for Scientific Research from the
Ministry of Education, Science, and Culture of J apan.
Financial support from the Ogasawara Foundation for
the Promotion of Science & Technology is also greatly
acknowledged.
J O0007837