Silica-supported pyrrolidine-triazole, an insoluble, recyclable organocatalyst for the enantioselective Michael addition of ketones to nitroalkenes

Article abstract of DOI:10.1016/j.tetasy.2008.05.011

A highly efficient, silica-supported organocatalyst for the Michael addition of ketones to nitroalkenes is successfully developed. A 1,2,3-triazole ring, constructed via a click 1,3-dipolar cycloaddition, plays a dual role of grafting the chiral pyrrolidi

Full text of DOI:10.1016/j.tetasy.2008.05.011

Tetrahedron: Asymmetry 19 (2008) 1352–1355
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Silica-supported pyrrolidine–triazole, an insoluble, recyclable organocatalyst
for the enantioselective Michael addition of ketones to nitroalkenes
*
Ya-Bin Zhao, Lin-Wei Zhang, Lu-Yong Wu, Xing Zhong, Rong Li, Jian-Tai Ma
College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient, silica-supported organocatalyst for the Michael addition of ketones to nitroalkenes is
successfully developed. A 1,2,3-triazole ring, constructed via a click 1,3-dipolar cycloaddition, plays a
dual role of grafting the chiral pyrrolidine onto the silica surface and of providing a structural element
complementary to the pyrrolidine. The supported catalyst demonstrated high activity and enantioselec-
tivity; furthermore, it can be readily reused four times without significant loss of catalytic activity.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 11 April 2008
Accepted 13 May 2008
Available online 10 June 2008
1. Introduction
Recently, attempts to work with supported chiral pyrrolidine–
triazole14,15 catalysts in asymmetric Michael additions have shown
Organocatalytic, asymmetric carbon–carbon and carbon–het-
eroatom bond-forming reactions have been extensively investi-
gated in recent years.1 Within this field, the organocatalyzed
asymmetric Michael addition remains an important challenge,2
the conjugate addition of ketones to nitroalkenes is particularly
interesting and challenging because it can generate two contiguous
stereocenters in a single step. These Michael adducts are versatile
building blocks for the preparation of agricultural and pharmaceu-
tical compounds.3 As a result, different catalysts, quite often based
on proline, have been developed, providing useful solutions for al-
most every reaction involving classical carbonyl chemistry.4
Recently, a significant amount of effort has been devoted to-
wards modification of the proline motif. A series of proline deriva-
tives, particularly chiral pyrrolidine–triazoles, which are made
through copper-mediated 1,3-dipolar cycloaddition between
azides and alkynes (click chemistry),5 have been found to be very
effective in asymmetric Michael addition reactions.6,7 These organ-
ocatalysts are generally considered environmentally benign
because the use of metals is avoided. However, it would be even
more desirable and economical to develop an immobilized, easily
recoverable, and reusable catalyst to perform this reaction.8
improved catalytic properties over homogeneous counterparts and
have led to high enantioselectivities, while offering important
operational advantages.16
The stereoselective reaction in water or neat environments is
another important research area, which avoids the problems of
waste disposal that are inherent with organic solvents. However,
the asymmetric reaction in water has proven to be very difficult,
although a small amount of water is beneficial in some proline
derivative-mediated reactions. We found that the pyrrolidine–tria-
zole substituted proline, especially bridged with amine, is capable
of catalyzing asymmetric Michael addition reaction under environ-
mentally benign conditions, with high diastereoselectivity and
enantioselectivity. These findings and our current interest in the
application of solid-supported ligands in the asymmetric Michael
addition led us to explore silica-supported triazole–pyrrolidine 1,
(Fig. 1) connecting through an amine tether as a recyclable catalyst.
For optimal performance, ligands to be supported must be de-
signed to allow anchoring through positions remote from the cat-
alytic sites, in this way, interference by the bulky solid backbone
will be avoided. We envisioned that the implementation of a
click-reaction in the synthetic scheme towards a ligand should lead
to a novel class of chiral silica-supported pyrrolidine-type triazoles
1, which would catalyze the Michael addition of carbonyl com-
pounds to nitroalkenes.
Since Benaglia et al. utilized PEG-supported
L-proline-catalyzed
asymmetric aldol condensations,9 much effort has been devoted to
the recovery of the L
-proline-based organocatalysts.10 Different
types of supports, such as PEG, mesoporous, and ionic liquids,11,12
have been used in connection with organocatalysts recovery.
Unfortunately, most insoluble solid-supported chiral catalysts
often suffer from low catalytic activity and enantioselectivity.13
N
N
N
2
N
HN
1
* Corresponding author. Tel.: +86 931 8912596; fax: +86 931 8912582.
E-mail address: majiantai@lzu.edu.cn (J.-T. Ma).
Figure 1.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.05.011

Y.-B. Zhao et al. / Tetrahedron: Asymmetry 19 (2008) 1352–1355
1353
Table 1
2. Results and discussion
Optimization of the reaction conditionsa
O
As has been mentioned in the preceding section, we have re-
cently described the synthesis and application of a new type of sil-
ica-supported catalyst 1 (shown in Scheme 1). Compound 3 was
prepared from Boc-(S)-proline in four steps.6,7,17 The other cou-
pling partner, 3-aminopropyl functionalized silica 4 was treated
with propargyl bromide under basic conditions (K2CO3 in acetone)
to provide the alkyne-functionalized silica 5. Azide 2 was then
grafted onto 5 by a Cu(I)-catalyzed Huisgen cycloaddition to afford,
upon deprotection with TFA, immobilized catalyst 1.
O
Ph
NO2
1
10 mol%
r.t.
NO2
Ph
Entry
Solvent
Additive
Yieldc (%)
dr (syn/anti)d
eef (%)
1
2
3
4
5
6
7
8
9e
DMSO
H2O
CHCl3
No solvent
CHCl3
H2O
DMSO
No solvent
No solvent
—
—
—
—
80
83
Trace
97
Trace
75
70
88
65
94:6
93:7
—
96:4
—
93:7
93:7
96:4
95:5
89
90
—
91
—
82
87
88
90
The catalytic activity of the silica-supported organocatalyst 1
was evaluated in the Michael addition reaction of cyclohexanone
to b-nitrostyrene at room temperature. Initial attempts to carry
out the reaction in DMSO led to incomplete conversion of b-nitro-
styrene (Table 1, entry 1). Variation of the solvent to H2O or CHCl3
did not improve the yield of reaction (entries 2 and 3); interest-
ingly, the best conversion and highest enantioselectivities with
catalyst 1 were achieved under neat conditions. The addition of
5 mol % of TFA decreased the reaction yield18 (entries 5–8), while
decreasing the catalyst loading led to lower yield, although the dia-
stereoselectivity and ee were maintained (Table 1, entry 9).
Under the optimized conditions, a variety of nitroalkenes and
ketones were investigated to establish the generality of this meth-
odology (Table 2). All reactions were performed at room tempera-
ture in the presence of 10 mol % of 1 for 72 h. As shown in Table 2,
all aromatic b-nitroalkenes are good acceptors and give the desired
syn adducts in good yields with high diastereo- and enantioselec-
tivity. No significant dependence on the electronic or steric proper-
ties of the substrate was observed (entries 1–10), with the
exception of 2-naphthyl-nitroalkene, where a slight decrease in
enantioselectivity was observed, whereas the reaction yield re-
mained excellent (entry 11). Unfortunately, attempts using ali-
phatic nitroalkenes gave lower yields and ees. On the other hand,
the use of ketones other than cyclohexanones had a dramatic effect
on the performance of the catalyst. Thus, the use of cyclopentanone
and 3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-9-one as a Michael
donor resulted in a significant drop in both yield and enantioselec-
tivity (entries 13 and 14), acetone also proved to be a suitable Mi-
chael donor providing good yield with moderate enantioselectivity
(entry 12).
TFAb
TFA
TFA
TFA
—
a
Unless otherwise noted, the reaction was conducted using cyclohexanone
(2 mmol), b-nitrostyrene (0.1 mmol), 10 mol % catalyst 1, and reaction mixture was
stirred at room temperature for 72 h.
b
TFA = trifluoroacetic acid, 0.005 mmol was used.
c
Isolated yield.
Determined by 1H NMR.
d
e
5 mol % catalyst was used.
Determined by chiral HPLC analysis (Chiralpak AD-H, hexane-2-
f
propanol = 90:10).
model study. Thus, after the reaction mixtures were quenched by
filtration, the catalyst was washed with EtOAc and simply dried
for reuse. As shown in Table 3, the supported catalyst exhibited
good catalytic activity with high diastereo- and enantioselectivity
up to the fourth cycle.
3. Conclusion
In conclusion, a new silica-supported organocatalyst has been
prepared and successfully applied to the asymmetric Michael addi-
tion reaction of ketones to nitroalkenes. The reactions proceeded
smoothly at room temperature to give high yields (up to 98%),
excellent diastereoselectivities (syn/anti ratio up to 20:1), and
excellent enantioselectivities (ee up to 93%). Furthermore, this pro-
cedure permits extensive recycling of the catalyst without substan-
tial loss of activity. On the basis of the current work, it seems likely
that a number of asymmetric reactions could be performed equally
well with this immobilized organocatalyst. The design of the
In addition to these characteristics, the recyclability and reus-
ability of silica-supported catalyst 1 is noteworthy (Table 3). The
reaction of cyclohexanone and b-nitrostyrene was chosen as a
(1) BH3 SMe2
CO2H
TFA
N3
N3
N
(2) TsCl, (3) NaN3
N
N
H
3
Boc
Boc
2
propargyl bromide
NH2
N
4
acetone, K2CO3
5
N
(1) i-Pr2NEt, CuI
N
5
2
N
(2) TFA, CH2Cl2
N
HN
2
1
Scheme 1.

1354
Y.-B. Zhao et al. / Tetrahedron: Asymmetry 19 (2008) 1352–1355
Table 2 (continued)
Table 2
Scope of different ketone with nitroolefinsa
Entry
Product
Yieldb (%)
dr (syn/anti)c
eed (%)
O
R
Br
O
NO2
1
10 mol%
r.t.
NO2
9
96
96:4
89
R
O
NO2
NO2
Entry
1
Product
Yieldb (%)
dr (syn/anti)c
eed (%)
O
97
96:4
91
O
O
O
NO2
10
11
97
94
94:6
88
77
Cl
2
3
4
97
97
98
>20:1
88
87
84
O
O
Cl
NO2
>20:1
NO2
NO2
NO2
93:7
12
95
—
40
O
O
NO2
NO2
OCH3
13
55
23:14
43:56e
>20:1
O
O
NO2
O
NO2
Cl
14
68
95:5
65
5
96
>20:1
89
NO2
O
O
Cl
a
Reactions were performed on a 0.1 mmol nitroalkene, 2 mmol ketone and
10 mol % catalyst 1.
6
97
>20:1
93
b
O
Isolated yield.
c
Determined by 1H NMR.
NO2
NO2
d
Determined by chiral HPLC analysis (Chiralpak AD-H).
ee (%) is syn:anti.
e
Table 3
Recycling studies of silica-supported catalyst 1 in the Michael reaction of cyclohex-
anone to b-nitrostyrene
7
98
96:4
85
O
O
Cycle
1
2
3
4
Yielda (%)
dr (syn/anti)b
eec (%)
97
96:4
91
96
97:3
90
93
95:5
90
95
94:6
91
a
Isolated yield.
Determined by 1H NMR.
Determined by chiral HPLC analysis (Chiralpak AD-H).
Br
b
c
8
97
>20:1
87
NO2
improved catalysts and their application to other types of reactions
are currently underway in our laboratory.

Y.-B. Zhao et al. / Tetrahedron: Asymmetry 19 (2008) 1352–1355
1355
4. Experiment
4.1. General
References
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open air, unless otherwise stated. 1H NMR spectra were recorded
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13C NMR spectra at 75 MHz or 100 MHz. Mass spectra were re-
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4.2. General procedure for the asymmetric Michael addition
reactions of ketones to nitroalkenes
To
a mixture of nitroalkenes (0.1 mmol), the catalyst 1
(0.01 mmol) was added to ketone (2 mmol). The suspension was
stirred vigorously at room temperature and monitored by TLC. After
the reaction, the mixture was filtrated, the catalyst was washed with
AcOEt (3 Â 15 mL), and simply dried for reuse. The organic layer was
separated and rotary evaporated, and purified by flash column chro-
matography on silica gel using a mixture of ethyl acetate/petroleum
ether = 1:20 to 4:1 to give the Michael adduct.
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Xu, H.; Cheng, J.-P. Chem. Eur. J. 2008, 14, 1273–1281; For enantioselective a-
(a) 3-Aminopropyl functionalized silica catalyst 4.19
Elemental analysis (%): N, 1.71, C, 6.55, H, 1.68; Loading:
1.22 mmol/g.
(b) Silica-supported catalyst 5.
3-Aminopropyl functionalized silica (1 g, loading = 1.22
mmol/g) was treated with propargyl bromide (4.3 g,
36.6 mmol), K2CO3 (1.2 equiv) and refluxed in acetone for
48 h. The reaction mixture was then filtered and sequentially
washed with water (250 mL), DMF (250 mL), THF (250 mL),
THF–MeOH 1:1 (250 mL), MeOH (250 mL), and THF
(250 mL). The solid was dried in vacuo for 24 h at 40 °C. Ele-
mental analysis (%): N, 1.27, C, 15.58, H, 2.07; Loading:
0.91 mmol/g.
(c) Cycloaddition of 5 with N-Boc-(2S)-2-azidomethyl-pyrrol-
idine 2.
aminoxylation of aldehydes and ketones with
a
polymer-supported
organocatalyst, see: (g) Font, D.; Bastero, A.; Sayalero, S.; Jimeno, C.; Pericas,
M. A. Org. Lett. 2007, 9, 1943–1946.
N-Boc-(2S)-2-Azidomethyl-pyrrolidine
2
(181 mg, 0.8
mmol), N,N-diisopropylethylamine (1.12 mL, 6.4 mmol),
and copper(I) iodide (0.006 g, 0.003 mmol) were added to a
suspension of 5 (1 g, loading = 0.91 mmol/g) and stirred in
DMF–THF 1:1 (20 mL) at 35 °C for 24 h, then collected by fil-
tration and sequentially washed with water (250 mL), DMF
(250 mL), THF (250 mL), THF–MeOH 1:1 (250 mL), MeOH
(250 mL), and THF (250 mL). The solid was dried in vacuo
for 24 h at 40 °C. Elemental analysis (%): N, 3.23, C, 18.73,
H, 2.50; Loading: 0.26 mmol/g.
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1996, 47, 1–15; (b) Salvadori, P.; Pini, D.; Petri, A. Synlett 1999, 1181–1190; (c)
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18. It should be noted that the addition of TFA had little effect on the
diastereoselectivity and enantioselectivity, presumably because the
(d) Deprotection.
Firstly, 1 g (loading = 0.26 mmol/g) of the silica resulting
from the previous step was immersed with 10 mL of CH2Cl2.
After 10 min, 10 mL of trifluoroacetic acid was added and
stirred for 24 h, after which the reaction mixture was fil-
tered. After filtration, silica-supported proline 1 was sequen-
tially washed with THF (with 2% of Et3N, 250 mL), water
(250 mL), THF (250 mL), THF–MeOH 1:1 (250 mL), MeOH
(250 mL), and THF (250 mL). The solid was dried in vacuo
for 24 h at 40 °C. Elemental analysis (%): N, 3.15, C, 15.60,
H, 2.17; Loading: 0.25 mmol/g.
stereogenic center
a to the carbonyl carbon is prone to racemization. This
would be even faster in water or aqueous acidic condition, however, the
system used is neat and without acid, thus can avoid this undesired reaction
and give high diastereo- and enantioselectivity.
19. The silica gel used is 60–100 (mesh size). For preparation of 3-aminopropyl
functionalized silica, see: (a) Maria Chong, A. S.; Zhao, X. S. J. Phys. Chem. B
2003, 107, 12650–12657; (b) Cauvel, A.; Renard, G.; Brunel, D. J. Org. Chem.
1997, 62, 749–751.