Ionic liquid-immobilized quinuclidine-catalyzed Morita-Baylis-Hillman reactions

Article abstract of DOI:10.1021/jo048391d

(Chemical Equation Presented) The ionic liquid-bound quinuclidine catalyzed Baylis-Hillman reactions were investigated. The IL-supported catalyst showed equally good catalytic activity as compared with its nonimmobilized counterpart. The corresponding Bay

Full text of DOI:10.1021/jo048391d

7
8
Ionic Liquid-Immobilized
Quinuclidine-Catalyzed
2
PPh Me, and imidazoles. In most cases, stoichiometric
or excess amount of Lewis bases is required to facilitate
faster reactions. It is therefore of interest to develop
recyclable and reusable Baylis-Hillman catalysts, which
will make the reaction more atom-economic and efficient.
Morita-Baylis-Hillman Reactions
†
‡
,†,‡
Xueling Mi, Sanzhong Luo, and Jin-Pei Cheng*
9
10
Shi and Corma independently investigated the use of
commercially available poly-DMAP as the recyclable
Baylis-Hillman catalyst. Those heterogeneous catalyses
were quite slow (generally required several days to
achieve acceptable yields), probably due to resin retarda-
tion effect. In fact, it has been demonstrated that Baylis-
Hillman reaction under homogeneous conditions had
faster rate and higher yields compared to the reaction
under heterogeneous conditions.11 Further, Shi and co-
workers reported the PEG-bound alkyl diphenylphos-
phines as recyclable Baylis-Hillman catalysts and in-
deed observed faster reaction. However, an additional
activating step was required in order for the immobilized
catalyst to be reused.
Department of Chemistry and State Key Laboratory of
Elemento-organic Chemistry, Nankai University,
Tianjin 300071, China, and Center for Molecular Science,
Institute of Chemistry, Chinese Academy of Sciences,
Beijing 100080, China
jpcheng@nankai.edu.cn
Received September 13, 2004
9
As a continuation of our work in Baylis-Hillman
reactions8 and applications of ionic liquids (ILs), we
have designed and synthesized a series of ionic liquid-
linked catalysts on the basis of the biphasic strategy, i.e.,
homogeneous reaction and heterogeneous separation.
Herein we wish to report the first example of this type
of Baylis-Hillman catalyst, the ionic liquid-supported
quinuclidine, and its efficient applications in the Baylis-
Hillman reactions.
a-c
12
The ionic liquid-bound quinuclidine catalyzed Baylis-Hill-
man reactions were investigated. The IL-supported catalyst
showed equally good catalytic activity as compared with its
nonimmobilized counterpart. The corresponding Baylis-
Hillman adducts were obtained in moderate to high yields
in all the cases tested. The IL-supported quinuclidine can
be readily recovered and reused six times without significant
loss of catalytic activity.
The so-called room temperature ionic liquids, especially
those derived from 1-n-alkyl-3-methylimidazolium cat-
ions, have demonstrated to have versatile applications
13,14
in organic synthesis as reaction media.
Earlier work
has shown that ionic liquid as reaction media can
accelerate Baylis-Hillman coupling in the presence of
DABCO.15 Later, Aggarwal and co-workers pointed out
that the imidazolium-containing ionic liquid was not inert
under the reaction conditions. In our examination of the
stability of the synthesized IL-bound catalysts, we found,
16
The Morita-Baylis-Hillman reaction is one of the
most versatile carbon-carbon bond-forming reactions in
modern organic synthesis and has drawn considerable
attention in the past decades due to its many advantages
in regard to atomic economy, nonmetal catalysis, mild
conditions, compatibility of multiple functional groups,
(
(
5) Shi, M.; Xu, Y.-M.; Eur. J. Org. Chem. 2002, 696.
6) (a) Yamada, Y. M. A.; Ikegami, S. Tetrahedron Lett. 2000, 41,
1
and so on. This reaction is usually carried out under
2
165. (b) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295. (c)
homogeneous conditions in the presence of Lewis base
Jenner, G. Tetrahedron Lett. 2000, 41, 3091. (d) Genski, T.; Taylor, R.
J. K. Tetrahedron Lett. 2002, 43, 3573.
2
3
4
5
6
3 3
catalysts such as DABCO, DMAP, DBU, PPh , PBu ,
(
7) (a) Shi, M.; Xu, Y.-M. Tetrahedron: Asymmetry 2002, 13, 1195.
(
b) Shi, M.; Zhao, G.-L. Tetrahedron Lett. 2002, 43, 4499.
†
Nankai University.
(8) (a) Luo, S. Z.; Zhang, B. L.; He, J. Q.; Janczuk, A.; Wang, P. G.;
‡
Chinese Acadamy of Sciences.
Cheng, J.-P. Tetrahedron Lett. 2002, 43, 7369. (b) Luo, S. Z.; Wang, P.
G.; Cheng, J.-P. J. Org. Chem. 2004, 69, 555. (c) Luo, S. Z.; Mi, X. L.;
Wang, P. G.; Cheng, J.-P. Tetrahedron Lett. 2004, 45, 5171. (d) Gatri,
R.; El Gaied, M. M. Tetrahedron Lett. 2002, 43, 7835.
(9) Huang, J.-W.; Shi, M. Adv. Synth. Catal. 2003, 345, 953.
(10) Corma, A.; Garc ´ı a, H.; Leyva, A. Chem. Commun. 2003, 2806.
(11) (a) Yu, C.; Liu, B.; Hu, L. J. Org. Chem. 2001, 66, 5413. (b) Yu,
C.; Hu, L. J. Org. Chem. 2002, 67, 219. (c) Cai, J.; Zhou, Z.; Zhao, G.;
Tang, C. Org. Lett. 2002, 4, 4723.
(
1) For reviews, see: (a) Ciganek, E. Org. React. 1997, 51, 201. (b)
Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103,
11. (c) Langer, P. Angew. Chem., Int. Ed. 2000, 39, 3049. (d)
8
Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001.
(
(
e) Marko, I. E.; Giles, P. G.; Hindley, N. J. Tetrahedron 1997, 53, 1015.
f) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653.
(
2) (a) Baylis, A. B.; Hillman, M. E. D. German Patent 2155113,
1
3
972. (b) Baylis, A. B.; Hillman, M. E. D. Chem. Abstr. 1972, 77,
4174q. (c) Aggarwal, V. K.; Tarver, G. J.; McCague, R. Chem.
(12) Mi, X. L.; Luo, S. Z.; He, J. Q.; Cheng, J.-P. Tetrahedron Lett.
2004, 45, 23, 4567.
Commun. 1996, 2713. (d) Aggarwal, V. K.; Mereu, A.; Tarver, G. J.
McCargue, R. J. Org. Chem. 1998, 63, 7183. (e) Yu, C.; Hu, L. J. Org.
Chem. 2002, 67, 219. (f) Lee, W.-D.; Yang, K.-S.; Chen, K. Chem.
Commun. 2001, 1612.
(13) For reviews, see: (a) Wasserscheid, P.; Keim, W. Angew. Chem.,
Int. Ed., 2000, 39, 3772. (b) Welton, T. Chem. Rev. 1999, 99, 2071. (d)
Wilkes, J. S. Green Chem. 2002, 4, 73.
(
3) (a) Rezgui, F.; El Gaied, M. M. Tetrahedron Lett. 1998, 39, 5965.
b) Lee, K. Y.; Gong, J. H.; Kim, J. N. Bull. Korean Chem. Soc. 2002,
3, 659; (c) Octavio, R.; de Souza M. A.; Vasconcellos, M. L. A. A. Synth.
Commun. 2003, 33, 8, 1383.
4) (a) Aggarwal, V. K.; Mereu, A. Chem. Commun. 1999, 2311. (b)
Shi, M.; Xu, Y. M.; Zhao, G. L.; Wu, X. F. Eur. J. Org. Chem. 2002, 21,
666.
(14) Sheldon, R. Chem. Commun. 2001, 2399.
(
2
(15) Rosa, J. N.; Afonso, C. A. M.; Santos, A. G. Tetrahedron 2001,
57, 4189. For other later examples, see: (a) Hsu, J.-C.; Yen, Y.-H.; Chu,
Y.-H. Tetrahedron Lett. 2004, 45, 4673. (b) Kim, E. J.; Ko, S. Y. Helv.
Chim. Acta 2003, 86, 3, 894.
(
(16) Aggarwal, V. K.; Emme, I.; Mereu, A. Chem. Commun. 2002,
1612.
3
10.1021/jo048391d CCC: $30.25 © 2005 American Chemical Society
2338
J. Org. Chem. 2005, 70, 2338-2341
Published on Web 02/02/2005

SCHEME 1
TABLE 1. Reactions of p-Chlorobenzaldehyde with
Methyl Acrylate in Various Media at Room
Temperaturea
b
entry
catalyst
solvent
CH3CN
CH2Cl2
CHCl3
THF
yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1b
1b
1b
1b
1b
18
5
9
8
EtOH
MeOH
36
37
46
52
84
71
13
26
13
21
15
SCHEME 2
c
MeOH
d
MeOH
MeOH
MeOH
d
d
0
1
2
3
4
5
e
f
[BMIM]BF4
[BMIM]BF4
f,g
[BMIM]PF6
h
[bupy]BF4
however, that the ionic liquid tags were actually quite
i
[BMMIM]BF4
stable under the Baylis-Hillman reaction conditions
a
when methanol was used as the reaction medium (see
Carried out on a 0.5 mmol scale in 0.5 mL of solvent (except
the Supporting Information).17 This encouraged us to
those specified) for 8 h in the presence of 0.3 equiv of the catalyst
at room temperature. Molar ratio of p-chloro-benzaldehyde/methyl
pursue the use of ionic liquid as a new support for
Baylis-Hillman catalyst, aiming to develop an effective
catalyst system that can be readily recycled and reused.
Synthesis. The synthesis of IL-supported quinuclidine
was straightforward as depicted in Scheme 1. The reduc-
tive amination of 3-quinuclidinone with amino ionic
liquid afforded the desired IL-bound quinuclidine 1 as a
pale yellow viscous liquid. This new type ionic liquid was
b
c
acrylate ) 1:1.5. Isolated yields of pure product. Aldehyde/
d
e
methanol ) 1:10. Aldehyde/methanol ) 1:2.0. [BMIM]BF4/1-
butyl-3-methylimidazolium tetrafluoroborate. f Aldehyde/ionic liq-
uid ) 1:2.0. g [BMIM]PF6/1-butyl-3-methylimidazolium hexafluoro-
h
phosphate. [bupy]BF4: 1-butylpyridinium tetrafluoroborate.
i
[
bupy]BF4: decomposition occurred during the reaction. [BM-
MIM]BF4: 1-butyl-2,3-dimethylimidazolium tetrafluoroborate.
TABLE 2. Reactions of p-Chlorobenzaldehyde (1.0
1
13
characterized by H NMR and C NMR, IR, and MS.
Catalytic Conditions. The Baylis-Hillman reaction
of p-chlorobenzaldehyde and methyl acrylate was selected
as the model for subsequent screening. The reaction was
conducted in the presence of 0.3 equiv of catalyst 1 at
room temperature (Scheme 2). As shown in Table 1, the
ionic liquid-supported quinuclidine worked well for the
desired Baylis-Hillman reaction and was more efficient
in protic solvents than in aprotic solvents (entries 1-6).
Of the solvents examined, methanol was found to be the
best medium (entry 6). These results are consistent with
previous observations that the Baylis-Hillman reactions
generally proceed faster in protic solvents such as
methanol and water than in aprotic solvents.8 Further
inspection revealed that the amount of methanol also
affected the reaction quite notably. Optimal yield was
achieved in the presence of 2.0 equiv. of methanol in the
reaction mixture (Table 1, entries 6-8).
equiv) and Methyl Acrylate (1.5 equiv) in the Presence of
0
.3 equiv of Different Catalysts in 2.0 equiv of Methanol
a
at Room Temperature
,11
When ionic liquids were used as solvent for the model
reaction instead of methanol, the product yields were
found to be substantially lower than those in methanol
a
b
The reactions were carried out on a 0.5 mmol scale. Isolated
c
d
yields of the pure products. 1 mL of methanol was used. The
e
(Table 1, entries 11-15). This indicates that the ionic
aldehyde used is benzaldehyde. Reuse of catalyst from 1 to 6
runs.
liquid itself does not have a large rate-enhancing effect
on Baylis-Hillman reaction and that the protic solvent
plays a dominant role in accelerating the reaction,
probably via hydrogen bonding.11,18 On the other hand,
catalyst 1b was found to give the best result in terms of
product yield (Table 1, entry 9), so it was selected for the
subsequent catalytic experiments.
results are listed in Table 2. As shown, the IL-supported
catalyst 1b of this work not only exhibited a much better
activity than its parent catalyst 3-quinuclidinone, but
also was shown to be better than DABCO under the same
conditions (Table 2, entries 1-4). The reaction catalyzed
by 3-benzylaminoquinuclidine, a nonbounded analogue
of 1b, gave a slightly higher yield (Table 2, entry 5).
These results are comparable with those obtained from
the reaction catalyzed by quinuclidine, the “optimum”
catalyst claimed by Aggarwal (50 mol % of catalyst, 3 h,
The reactions catalyzed by some conventional catalysts
were also examined for the purpose of comparison. The
(
17) Decomposition does occur after extensive use probably due to
the reactivity of the ionic liquid, but reasonable catalytic activity is
still maintained.
(18) (a) Aggarwal, V. K.; Dean, D. K.; Mereu, A.; Williams, R. J.
8
8%).19 Our present observations indicate that the ionic
liquid-supported quinuclidine is an excellent homogen-
Org. Chem. 2002, 67, 510. (b) Kumar, A.; Pawar, S. S. Tetrahedron
003, 59, 5019.
2
J. Org. Chem, Vol. 70, No. 6, 2005 2339

TABLE 3. Baylis-Hillman Reactions of Aldehydes (1.0
equiv) and Acrylates (1.5 equiv) Catalyzed by Ionic
Liquid-Supported Quinuclidine 1b (0.3 equiv) in 2.0
equiv of Methanol at Room Temperature
TABLE 4. Baylis-Hillman Reactions of Aldehydes (1.0
equiv) and Acrylonitrile (1.5 equiv) in the Presence of 1b
(0.3 equiv) in 2.0 equiv of Methanol at Room
Temperature
R1
time (h)
product
yield (%)
a
entry
1
2
3
4
5
6
Ph
8
9
10
24
0.5
0.5
3a
3b
3c
3d
3e
3f
91
89
83
69
92
97
p-ClPh
p-CH3Ph
p-CH3OPh
p-NO2Ph
2-pyridyl
a
entry
R1
R2
time (h) product yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
n-C3H7
i-C4H9
n-C6H13
Ph
p-ClPh
p-ClPh
p-CH3Ph
p-iPrPh
p-NO2Ph
o-NO2Ph
COOCH3
COOCH3
COOCH3
COOCH3
COOC2H5
COOC4H9
COOCH3
COOCH3
COOCH3
COOCH3
12
12
12
8
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
62
83
84
82
92
84
75
74
97
88
90
96
90
98
90
a
Isolated yields.
SCHEME 3
8
8
10
12
1
0
1
2
3
4
5
0.5
1
0.5
1
m-NO2Ph COOCH3
2-pyridyl
3-pyridyl
4-pyridyl
2-furyl
COOCH3
COOCH3
COOCH3
COOCH3
TABLE 5. Baylis-Hillman Reactions of Aldehydes (1.0
equiv) and Cyclohexenones (1.5 equiv) in the Presence of
0.5
1
1
b (0.3 equiv) in Methanol (2.0 equiv) at Room
Temperature
R1
time (h)
product
yield (%)
a
entry
eous catalyst for Baylis-Hillman reactions. And more
importantly, the use of the ionic liquid-linked catalyst
can facilitate easy product separation and reuse of the
catalyst. After each run, the product was readily separ-
ated by extraction with diethyl ether, and the ionic liquid
residue, i.e., the catalyst, can then be used directly for
next run without further treatment. It was found that
the ionic liquid-supported catalyst could be recycled for
at least six times without too much loss of its activity
1
2
3
4
5
Ph
12
12
24
6
4a
4b
4c
4d
4e
73 (5)
86 (8)
41
69 (27)
32
p-ClPh
p-CH3Ph
p-NO2Ph
piperonal
48
a
Isolated yields. The numbers in parentheses are yields of aldol
products.
SCHEME 4
(Table 2, entries 6-11).
Applicability. Under the optimum conditions estab-
lished above, the 1b-catalyzed Baylis-Hillman reactions
of acrylates with a variety of aldehydes were examined
at room temperature (Table 3). As demonstrated in Table
3
, both aliphatic and aromatic aldehydes can undergo
very efficient Baylis-Hillman reactions with acrylates
in the presence of 0.3 equiv of 1b, giving the correspond-
improve its efficiency.8,20 In our study, we found that the
reactions of 2-cyclohexenone proceeded quite effectively
using 1b as catalyst under the conditions mentioned
above, providing the Baylis-Hillman adducts in fair to
high yields (Table 5). Minor amount of aldol products was
also isolated in some cases probably due to the relatively
strong basicity of the catalyst (Scheme 4).
In summary, we in the present work have investigated
a range of Baylis-Hillman reactions using the ionic
liquid-supported 1b as a new catalyst. Generally, the
reactions demonstrated higher efficiency and gave high
yields in comparison with the cases where other common
homogeneous or heterogeneous catalysts were used. The
ionic liquid-bound catalyst can be readily recovered from
the reaction mixture and be reused several times without
much loss of its activity, thus providing a highly efficient
ing Baylis-Hillman adducts 2b-n in good to excellent
yields (62-98%).1
1,19
No apparent side reaction of alde-
hydes such as aldol condensation was observed under the
conditions of the present study.
The analogous reactions of acrylonitrile were also
investigated. Again, high yields were achieved in shorter
reaction time. As shown in Table 4, the ionic liquid-
supported catalyst was highly effective for all the sub-
strates tested. It was found that the reaction of p-meth-
oxybenzaldehyde, which is usually quite an inert substrate,
could provide a fairly good yield (69%, entry 4) of isolated
Baylis-Hillman adduct under the present conditions,
demonstrating the good activity of the ionic liquid-bound
catalyst synthesized in this work (Scheme 3).
Cyclic enones are poor Michael acceptors, and conse-
quently the Baylis-Hillman reactions involving cyclic
enones were usually observed to be sluggish under
normal conditions. A variety of catalysts have therefore
been employed for this kind of reaction in order to
(20) For examples, see: (a) Li, G. G.; Wei, H. X.; Gao, J. J.; Caputo,
T. D. Tetrahedron Lett. 2000, 41, 1. (b) Sugahara, T.; Ogasawara, K.
Synlett 1999, 419. (c) Kataoka, T.; Iwama, T.; Tsujiyama, S.; Iwamura,
T.; Watanabe, S. Tetrahedron 1998, 54, 11813. (d) Yamada, Y. M. A.;
Ikegami, S. Tetrahedron Lett. 2000, 41, 2165. (e) Pei, W.; Wei, H.-X.;
Li, G. G. Chem. Commun. 2002, 2412. (e) Basavaiah, D.; Sreenivasulu,
B.; Rao, A. J. J. Org. Chem. 2003, 68, 5983. (f) Patra, A.; Batra, S.;
Joshi, B. S.; Roy, R.; Kundu, B.; Bhaduri, A. P. J. Org. Chem. 2002,
67, 5783.
(19) Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J. Org. Chem., 2003,
6
8, 692.
2340 J. Org. Chem., Vol. 70, No. 6, 2005

alternative for the Baylis-Hillman-type synthesis to be
carried out under environmentally more friendly condi-
tions. The design and synthesis of ionic liquid-bound
asymmetric Baylis-Hillman catalyst are currently un-
derway in our laboratory.
product. The remaining layer was further vacuumed to
dryness and the resulting catalyst was reused directly
for the next run. The reactions using the recycled catalyst
were conducted in a similar manner.
Acknowledgment. We are very grateful to the
Experimental Section
Natural Science Foundation of China (NSFC Nos.
2
0452001, 20332020) and the Ministry of Science and
Technology (MoST) of China for financial support.
General Procedure. To the solution of 1b (57 mg,
0
3
.15 mmol) in CH OH (41 µL, 2.0 equiv) were added
aldehyde (0.5 mmol) and activated alkene (0.75 mmol).
The resulting solution was stirred at ambient tempera-
ture and monitored by TLC. After the indicated reaction
time, the solution was concentrated and the residue was
extracted with diethyl ether. The ether extracts were
rotary-evaporated, and the crude product was purified
by flash chromatography on silica gel to afford the desired
Supporting Information Available: The syntheses of
1
a-c, the NMR spectra of 1a-c, the stability study of 1b, and
1
H NMR spectra of all the Baylis-Hillman products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO048391D
J. Org. Chem, Vol. 70, No. 6, 2005 2341