Reusable nano-sized chiral bisoxazoline catalysts

Article abstract of DOI:10.1016/j.tetlet.2005.08.100

The nano-sized gold particle-based chiral catalyst having two kinds of alkyl thiol spacers, one of which is substituted with the chiral bisoxazoline/copper(II) complex at the end, behaves as reusable homogeneous catalyst. This gold particle complex acts as nearly homogeneous catalyst in the ene reaction between 2-phenylpropene and ethyl glyoxylate in dichloromethane, while it undergoes dense aggregation when diluted with hexane so as to be separated by simple filtration. Thus, the catalyst can be recovered after the completion of reaction by the repeated sequences of solvent exchange, centrifugal treatment, and decantation, followed by the recharge of substrates, and the situation is ready for the second reaction.

Full text of DOI:10.1016/j.tetlet.2005.08.100

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7623–7626
Reusable nano-sized chiral bisoxazoline catalysts
Fumiyasu Ono,b Shuji Kanemasaa,* and Junji Tanakaa
aInstitute for Materials Chemistry and Engineering, CREST of JST (Japan Science and Technology Agency),
Kyushu University, 6-1 Kasugakoen, Kasuga 816-8580, Japan
bDepartment of Molecular and Material Sciences, Graduate School of Engineering Sciences, Kyushu University, 6-1 Kasugakoen,
Kasuga 816-8580, Japan
Received 30 July 2005; revised 20 August 2005; accepted 22 August 2005
Available online 13 September 2005
Abstract—The nano-sized gold particle-based chiral catalyst having two kinds of alkyl thiol spacers, one of which is substituted with
the chiral bisoxazoline/copper(II) complex at the end, behaves as reusable homogeneous catalyst. This gold particle complex acts as
nearly homogeneous catalyst in the ene reaction between 2-phenylpropene and ethyl glyoxylate in dichloromethane, while it under-
goes dense aggregation when diluted with hexane so as to be separated by simple filtration. Thus, the catalyst can be recovered after
the completion of reaction by the repeated sequences of solvent exchange, centrifugal treatment, and decantation, followed by the
recharge of substrates, and the situation is ready for the second reaction.
Ó 2005 Elsevier Ltd. All rights reserved.
Unlike homogeneous molecular catalysts, immobilized
heterogeneous catalysts have a great synthetic advan-
tage that these can be recovered through filtration after
the completion of reaction and further can be reused for
the next reaction. However, the limited mobility brings
about a serious decrease of catalytic activity. Thus, the
effective reuse of reactive catalysts has been achieved
at the expense of catalytic activity.1–4 This dilemma
has remained unsolved.5
In this letter, we will report new types of nano-sized gold
particle catalysts, which are modified with two alkyl
chains, one with simple alkyl sulfides and the other with
alkyl sulfides having copper(II) complexes of chiral bis-
oxazoline ligands 2–5 at the terminal (Fig. 1). These
catalysts are highly dispersed in dichloromethane, but
aggregate in hexane so that these can be separated from
the solvent through simple filtration. Ene reactions
between 2-phenylpropene and ethyl glyoxylate were cat-
alyzed by the nano-sized complex catalysts Au-n/Cu(II)
giving high yields of ene-reaction product with satisfac-
tory enantioselectivity. Repeated use of the catalysts was
performed without serious loss of catalytic activity.
The authors have noticed that the metal complexes
derived from nano-sized particles, the surface of which
is modified with alkyl chains having a ligand at the ter-
minus, would work as effective catalysts.2–4 High syn-
thetic advantage can be expected for such catalysts due
to the mobility and immobility properties. They would
act as nearly homogeneous catalysts at the stage of reac-
tion in one solvent, and at the work-up stage they are
aggregated in another solvent so that the catalysts can
be separated through filtration from the products, which
are soluble in the solvent. If the complex catalysts are
stable enough to be isolated, repeated use of the cata-
lysts may be attained. However, to the best of our
knowledge, no precedent reports are known for such
effective usage of nano-sized particle catalysts.
Some examples are known for the heterogeneous chiral
catalysts, which have been used in the catalyzed enantio-
selective ene reactions. Ene reaction between 2-phenyl-
propene and ethyl glyoxylate in the presence of the
PEG-anchored (R)-BOX/Ph complex of Cu(OTf)2 gave
a satisfactory result for both yield and enantioselectiv-
ity.6 Recently, Cu-exchanged zeolite Y modified by
(R)-BOX/Ph ligand was examined in the same ene
reaction, however, the recovered catalyst was much less
reactive than the initial one showing a lower enantio-
selectivity in the second reaction (80–65% ee).7
Bisoxazoline ligands 2–5 were synthesized starting from
diethyl methylmalonate (6). One typical example is
shown for the synthesis of 5 in Scheme 1. Methylmalonate
Keywords: Nano-sized particle; Chiral catalyst.
*
Corresponding author. Tel.: +81 925837802; fax: +81 925837875;
e-mail: kanemasa@cm.kyushu-u.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.100

7624
F. Ono et al. / Tetrahedron Letters 46 (2005) 7623–7626
Me
(CH2)nSH
O
O
N
N
Au
Au
Au
Au
2-5
Ph
Me(CH2)5SH
Ph
1
Au-n (2-3 nm)
Figure 1. Au-modified chiral catalysts.
O
O
O
O
Ph
O
O
Ph
a, b
c
d
EtO
OEt
Me
Cl
Cl
N
H
N
H
Me
Me
7(85%)
Me (CH2)nBr
OH
Me
8 (75%)
OH
6
Me (CH2)nSCOMe
O O
O
O
O
O
g
e, f
N
N
N
N
N
N
Ph
Ph
Ph
Ph
Ph
Ph
9 (65%)
10 (n = 10, 45%)
11 (n = 10, quant)
Me (CH2)nSH
O
O
h
N
N
Ph
Ph
2-5 (n = 10, quant)
Scheme 1. Reagents and conditions: (a) KOH, H2O–EtOH = 1:3 v/v, reflux, 4 h; (b) SOCl2 (2.2 equiv), reflux, 3 h; (c) (R)-2-phenylglycinol (2 equiv),
Et3N (2 equiv), CH2Cl2, rt, 12 h; (d) MsCl (2 equiv), Et3N (2 equiv), CH2Cl2, rt, 16 h; (e) n-BuLi (1.1 equiv), À78 °C, THF; (f) Br(CH2)10Br (4
equiv), rt, 6 h; (g) MeCOSK (1.1 equiv), DMF, rt, 15 min; (h) NaOH, MeOH, rt, 15 min.
ester 6 was hydrolyzed with aqueous potassium hydrox-
ide and chlorinated with thionyl chloride giving meth-
ylmalonyl chloride (7), which was then reacted with (R)-
phenylglycinol to give bisamide 8. Amide 8 was mesyl-
ated and cyclized into bisoxazoline 9.8 Deprotonation
of 9 with butyllithium at À78 °C, followed by the alkyl-
ation with 1,10-dibromodecane, gave x-bromodecanyl
bisoxazoline 10. Treatment of 10 with a potassium thio-
acetate led to thioacetate derivative 11, which was then
exposed to alkaline hydrolysis at room temperature for
15 min to give the target chiral ligand 5 in 19% of the
total yield starting from 6. Other chiral bisoxazoline
ligands having C4 2 (n = 4), C6 3 (n = 6), and C8 linkers
4 (n = 8) were similarly synthesized.
Hexanethiol-modified nanoparticle (diameter: 2–3 nm)
1,9 which was prepared by reduction of HAuCl4Æ4H2O
with sodium borohydride in the presence of hexane-
thiol,10 was treated with bisoxazoline 5 by stirring at
room temperature for 24 h giving the hybrid chiral
ligand Au-10, which contains 0.32 mmol/g of bisoxazo-
line ligand.11,12 Although hexanethiol-modified gold
particle 1 forms highly stabilized dispersion both in
dichloromethane and hexane, bisoxazoline-modified
particle Au-10 readily aggregates in hexane as less polar
Figure 2. Dispersion and aggregation property of Au particles in
different solvents.
solvent (top two in Fig. 2). The size of particles included

F. Ono et al. / Tetrahedron Letters 46 (2005) 7623–7626
7625
in the high dispersion was smaller than 5 nm, but that
of Au-10 in hexane was estimated to be ca. 3 lm.13
Copper(II) triflate complex derived from Au-4 in dichlo-
romethane was stable enough to keep high dispersion at
least 6 h at room temperature, but the complex of Au-10
was readily converted into dense aggregation under
similar conditions (bottom two in Fig. 2), indicating that
the dispersion degree of copper(II) complex catalysts of
Au-n depends upon the length of the spacer.
ethyl 4-phenyl-4-pentenoate (14) as the ene reaction
product in 99% yield with an enantioselectivity of 86%
ee.14 A comparable result was obtained in the same reac-
tion in the presence of the molecular catalyst derived
from BOX/Ph ligand and copper(II) triflate.15
On the other hand, the residue including the catalyst was
dissolved in dichloromethane. A clear solution is obtained
through sonication for 5 min and the resulting catalyst
solution could be reused for the second reaction. This
procedure was repeated five times as shown in Scheme
2. Although yields of the ene product 14 gradually de-
creased in the late reactions, enantioselectivity remained.
Copper(II) triflate complex prepared from Au-4 was suc-
cessfully applied to the enantioselective ene reaction
between 2-phenylpropene (12) and ethyl glyoxylate
(13) (Scheme 2). The typical procedure is as follows: A
mixture of 12, 13, and Au-4ÆCu(OTf)2 (10 mol % each)
in dichloromethane was stirred at room temperature
for 5 h. After the reaction is complete (checked by
TLC), hexane is added (hexane/CH2Cl2 = 3:1 v/v) and
shaken well. The resulting aggregation was centrifuged
(10,000 rpm/10 min) and the upper clear solution was
separated by decantation. The residue was washed with
the combined solvent of hexane/CH2Cl2 and centrifugal
separation was applied. After this washing and separa-
tion procedure was repeated three times, the extract
and washings were combined and evaporated to give
A variety of hybrid chiral ligands Au-4, Au-6, Au-8, and
Au-10 having spacers of different chain lengths were
converted into copper(II) triflate complexes and used
in the ene reactions between 12 and 13 (Scheme 3). As
apparent by comparison of the results shown in Scheme
3, the copper(II) complex derived from Au-4, having the
shortest spacer of n = 4, showed the most effective cata-
lytic activity and recyclic utility. Probably, Au-4Æcop-
per(II) complex shows the highest dispersion, and
hence the minimized aggregation in dichloromethane
solution, since the complex parts are buried in an array
OH
COOEt
a
+
O=CHCOOEt
14
12
13
reaction
shake
recycle yield/%
ee %
hexane
0
1
2
3
4
99
94
90
87
80
86
84
85
84
84
centrifuge (10,000 / 10 min)
3 times
CH2Cl2 / hexane = 1/3 v/v
decantation
a:
Au-4 / Cu(OTf)2 (10 mol%
each), CH2Cl2, rt, 5 h.
shake
centrifuge (10,000 / 5 min)
CH2Cl2
sonication (5 min)
substrates
next reaction
Scheme 2.
a
a: Au-n / Cu(OTf)2 (10 mol% each), CH2Cl2, rt
+
12
13
14
Au-4
Au-6
Au-8
Au-10
time/h yield/%
(% ee)
time/h yield/%
(% ee)
time/h yield/%
(% ee)
time/h yield/%
(% ee)
recycle
0
1
2
3
5
10
13
24
99 (86)
99 (84)
94 (85)
92 (86)
9
20
20
95 (85)
98 (86)
73 (85)
11
20
20
97 (85)
90 (86)
55 (84)
16
20
20
93 (85)
80 (85)
39 (86)
Scheme 3.

7626
F. Ono et al. / Tetrahedron Letters 46 (2005) 7623–7626
5. Discovery of a complex catalyst that is soluble only in
the presence of substrates has been recently reported
Dioumaev, V. K.; Bullock, R. M. Nature 2003, 424, 530–
532.
6. Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.;
Pitillo, M. J. Org. Chem. 2001, 66, 3160–3166.
7. Caplan, N. A.; Hancock, F. E.; Bulman Page, P. C.;
Hutchings, G. J. Angew. Chem., Int. Ed. 2004, 43, 1685–
1688.
of neighboring hexanethiol ligands. However, this com-
plex shows the effective aggregation in hexane solution
to make large sized particles, which are separable by
filtration. This indicates that the size matching of the
spacers included in the chiral ligand and the aggrega-
tion-inhibiting hexanethiol ligands is essential to attain
the homogeneous reusable catalysts.
In conclusion, we have succeeded to develop a new type
of gold particle-based chiral copper(II) complex cata-
lyst, which works as almost homogeneous catalyst in
the ene reaction between 2-phenylpropene and ethyl gly-
oxylate in dichloromethane. When the reaction is over,
the catalyst can be separated simply by dilution with
hexane and centrifugal treatment.
8. Bourguignon, J.; Bremberg, U.; Dupas, G.; Hallman, K.;
Hagberg, L.; Hortala, L.; Levacher, V.; Lutsenko, S.;
´
Macedo, E.; Moberg, C.; Queguiner, G.; Rahm, F.
Tetrahedron 2003, 59, 9583–9589.
9. Size of particles 1 and Au-10 was based upon the TEM
analysis.
10. Brust, M.; Walker, M. J. Chem. Soc., Chem. Commun.
1994, 801–802.
11. The ligand content was based on elemental analysis.
12. Boal, A. K.; Rotello, V. M. J. Am. Chem. Soc. 1999, 121,
4914–4915.
References and notes
13. Size of the particles in solution was determined by
dynamic light scattering analysis (DLS).
1. Bartz, M.; Kuther, J.; Seshadri, R.; Tremel, W. Angew.
¨
Chem., Int. Ed. 1998, 37, 2466–2468.
2. Li, H.; Luk, Y.-Y.; Mrksich, M. Langmuir 1999, 15, 4957–
4958.
3. Marubayashi, K.; Takizawa, S.; Kawakusu, T.; Arai, T.;
Sasai, H. Org. Lett. 2003, 5, 4409.
14. Ene reaction was carried out in a centrifuge tube in open
air. Stirring was made by a magnetic stirring bar.
15. Although the reaction between 12 and 13 under the
catalysis of the BOX/PhÆCu(OTf)2 complex (10 mol %)
was previously reported (20 h at rt, 14: 66% (80% ee)), 7 we
have reexamined in the present work: 4 h at rt, 14: quant
(86% ee).
4. Beiser, T.; Sto¨hr, M.; Pfalz, A. J. Am. Chem. Soc. 2005,
127, 8720–8731.