Highly efficient and recoverable dendritic organocatalyst from click chemistry for the asymmetric michael addition of ketones to nitroolefins without the use of organic solvent

Article abstract of DOI:10.1016/j.tetasy.2008.10.016

A series of pyrrolidine-triazole based dendritic catalysts have been synthesized and applied directly in the asymmetric Michael addition of ketones to nitroolefins without the use of an organic solvent. Good yields (up to 99%), and high diastereoselectivi

Full text of DOI:10.1016/j.tetasy.2008.10.016

Tetrahedron: Asymmetry 19 (2008) 2568–2572
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Highly efficient and recoverable dendritic organocatalyst from click
chemistry for the asymmetric michael addition of ketones to
nitroolefins without the use of organic solvent
*
Guanghua Lv, Rizhe Jin, Wenpeng Mai, Lianxun Gao
State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences,
Graduate School of Chinese Academy of Sciences, Changchun 130022, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 September 2008
Accepted 7 October 2008
A series of pyrrolidine-triazole based dendritic catalysts have been synthesized and applied directly in
the asymmetric Michael addition of ketones to nitroolefins without the use of an organic solvent. Good
yields (up to 99%), and high diastereoselectivities (up to syn/anti = 45:1) and enantioselectivities (up to
95% ee) have been obtained. Furthermore, the third generation catalyst can be reused at least five times
without significant loss of catalytic activity.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
prepare via a click reaction, show high catalytic activity and
enantioselectivity.9
Interest has greatly increased in the recent years on develop-
ment of organocatalysts for organic reactions because they are
environmentally benign, easy to handle, and highly efficient. Sev-
eral excellent organocatalysts for asymmetric reactions that
achieve high enantioselectivities have been reported.1 Though
the advances are great, there are still disadvantages associated
with the use of organocatalysts. One major limitation of organocat-
alyzed reactions is the high-catalyst loadings that are generally
required (10–30 mol %) to complete the reactions thoroughly. This
causes cost problems, especially in industrial applications when a
large amount of expensive chiral raw materials are needed to pre-
pare the catalysts. Thus, the development of recyclable organocat-
alysts is of great significance to expand upon the scope to
encompass further industrial applications. Recently, great efforts
have been devoted to immobilizing and further recycling these
organocatalysts using supports such as ionic liquids,2 polysty-
renes,3 flourous tags,4 PEG,5 silica gel,6 and dendrimers.7
Dendrimers are well-defined macromolecules with tunable
structures, shapes, sizes, and solubilities. Since the first report in
1994, dendritic catalysts have been become a subject of intensive
research.10 Such novel catalysts can be used under homogeneous
conditions, and be readily recovered via simple precipitation or
nanofiltration methods. To the best of our knowledge, a dendritic
organocatalyst system has yet to be investigated in the asymmetric
Michael addition of ketones to nitroolefins. Therefore, we
attempted to anchor the pyrrolidine derivates to dendrimers via a
click reaction, and investigate their catalytic activity in asymmetric
Michael addition of ketones to nitroolefins. Herein, we report den-
dritic catalysts derived from pyrrolidine derivates via a click reac-
tion which are highly active and selective for the asymmetric
Michael addition of ketones to nitroolefins. Moreover, the catalysts
can be easily recovered after the reaction is over, and recycled up
to five times with only a slight loss in catalytic activity.
The asymmetric Michael addition of ketones or aldehydes to
nitroolefins is a powerful method for the construction of enantio-
merically enriched nitroalkanes, which are versatile synthetic
intermediates in organic synthesis. Over the past decade, great
progress has been made in the organocatalytic asymmetric version
of these reactions to give synthetically useful products with high
enantiopurities.8 Within these reported catalysts, pyrrolidine
derivates bearing 1,2,3-triazole substituents, which are easy to
2. Results and discussion
The synthetic route to a series of polyether dendrimers-sup-
ported pyrrolidine-triazole organocatalysts 5a–c is shown in
Scheme 1. Azidomethylpyrrolidine 1 was prepared according to a
reported literature method.9a On the other hand, brominated
polyether dendrimers 2a–c are treated with 4-ethynylbenzyl alco-
hol 3 under basic conditions (NaH, DMF/THF = 1:1) to give alkyne-
functionalized polyether dendrimers 4a–c. Azide 1 was then
grafted to dendrimers 4a–c by a Cu(I)-catalyzed click reaction to
afford the desired dendrimer-supported organocatalysts 5a–c.
The detailed experimental procedures and the spectroscopic data
* Corresponding author. Tel.: +86 431 8526 2259; fax: +86 431 8568 5653.
E-mail address: lxgao@ciac.jl.cn (L. Gao).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.10.016

G. Lv et al. / Tetrahedron: Asymmetry 19 (2008) 2568–2572
2569
OBn
OBn
O
O
O
BnO
BnO
BnO
Br
a
O
b
BnO
O
n
n
2a
2b
2c
n=0
n=1
n=2
4a n=0
4b n=1
4c n=2
OBn
OBn
N
H
OBn
N
N
N
O
O
BnO
BnO
O
n
5a n=0
5b n=1
5c n=2
OBn
Scheme 1. Reaction and conditions: (a) 4-ethynylbenzyl alcohol 3, NaH, DMF/THF = 1:1, rt, 24 h; (b) azidomethylpyrrolidine 1, CuI, DIPEA, toluene/t-BuOH = 4:1.
are summarized in Section 4. These catalysts were purified by
flash column chromatography, and were characterized by 1H
NMR/13CNMR spectroscopy and elemental analysis.
To establish the scope of the reaction with 5c, a series of sub-
strates were tested under the optimized reaction conditions, and
the results are summarized in Table 2. b-Nitroolefins, which pos-
sess either neutral (entries 1 and 8), electron- withdrawing (entries
2, 3 and 7), or -donating (entries 4–6), and heterocyclic groups
The catalytic activity of 5a–c for the asymmetric Michael addi-
tion of ketones to nitroolefins is investigated by performing a
model reaction of trans-b-nitrostyrene with cyclohexanone under
various reaction conditions. The results are summarized in Table
1. As can be seen from Table 1, with dendritic catalysts 5a–c, the
Michael addition reaction proceeded smoothly with trifluoroacetic
acid (TFA) as an additive under neat conditions; the syn-Michael
adducts were obtained as the major products in excellent yields
(96–99%) and with high diastereoselectivity and enantioselectivity
(entries 1–3). Notably, the third generation catalyst 5c provides the
best results in terms of the catalytic activity and selectivity under
the same reaction conditions. Therefore, 5c was chosen for the sub-
sequent studies of the effects of other conditions on the reaction.
First, the influence of catalyst loading was examined (entries 4–
6). It is found that no change had been observed by increasing
the amount of 5c to 20%. A sharp drop in both the yield and the
enantioselectivity was observed when reducing the catalyst load-
ing to 5% and further to 2%. Attention was also paid to the effect
of reactant ratios on the reaction (entries 7–9). The results in Table
1 show that 5 equiv of cyclohexanone to 1 equiv of trans-b-nitro-
styrene gave the best results. We also studied the effect of water
on the reaction (entries 10 and 11); this showed that a slight drop
in enantioselectivity but a sharp increase in diastereoselectivity
was observed in the presence of water when using 5 equiv of cyclo-
hexanone. Thus, the optimum reaction conditions were obtained
by performing the reaction of 5 equiv of cyclohexanone with
1 equiv of nitroolefin, 10 mol % 5c, and 2.5 mol % of TFA as additive
without the use of an organic solvent.
Table 1
Optimization of the reaction conditionsa
O
O
Ph
Ph
cat/2.5%TFA
NO2
+
neat
NO2
Entry
Catalyst
Catalyst
loading (%)
Reactant
ratiosb
Time
(h)
Yieldc
(%)
syn/antid
eee
(%)
1
2
3
4
5
6
7
8
9
5a
5b
5c
5c
5c
5c
5c
5c
5c
5c
5c
10
10
10
20
5
20
20
20
20
20
20
10
5
18
18
18
18
18
18
18
18
18
24
24
96
96
99
98
89
78
98
98
96
98
97
40:1
42:1
45:1
45:1
35:1
26:1
45:1
45:1
25:1
>99:1
22:1
91
91
94
94
89
86
94
94
90
90
89
2
10
10
10
10
10
2
5
2
10f
11f
a
b
c
d
e
f
Unless otherwise stated, all the reactions were performed with 2.5% TFA.
Cyclohexanone/trans-b-nitrostyrene.
Isolated yield.
Determined by 1H NMR of the crude product.
Determined by HPLC analysis of the syn-product (chiral pak AD-H column).
0.25 mL water was added.

2570
G. Lv et al. / Tetrahedron: Asymmetry 19 (2008) 2568–2572
Table 2
yield but a dramatic drop in both enantioselectivity and diastereo-
Substrate scope of dendritic catalyst 5ca
selectivity. With acetone and butanone, the desired adducts were
produced with moderate yields but low enantioselectivities.
The recovery and the reuse of the catalyst 5c were also investi-
gated (Table 4). After reaction, the unreacted cyclohexanone was
removed in vacuo, followed by the addition of ether (5 times) to
extract the product thoroughly. The catalyst is almost quantita-
tively left in the reaction vessel, and is used directly in the next
run. The catalyst can be used for four consecutive runs with no
decrease in the isolated yield of adduct 6a or in the stereoselectivity;
however, in the fifth run a slight loss of product yield was observed
while high levels of enantioselectivity and diastereoselectivity still
remain even in the sixth run.
O
Ar
O
Ar
NO2
+
NO2
6
Entry
Ar
Product
Yieldb (%)
syn/antic
eed (%)
1
2
3
4
5
6
7
8
9
C6H5–
4-ClC6H4–
4-BrC6H4–
6a
6b
6c
6d
6e
6f
6g
6h
6i
99
93
94
92
96
94
91
99
93
95
45:1
40:1
45:1
35:1
45:1
35:1
35:1
25:1
25:1
16:1
93
93
95
91
92
88
93
92
92
89
2,4-MeO2C6H3–
4-MeC6H4–
4-MeOC6H4–
3-O2NC6H4–
2-Naphthyl–
2-Furanyl–
2-Thiophenyl–
3. Conclusions
10
6j
In conclusion, a highly efficient, dendritic organocatalyst for the
diastereo- and enantioselective Michael addition of ketones to
nitroolefins has been developed using a click chemistry method.
The catalyst system represents the first dendritic organocatalyst
for this type of reaction. The catalyst can be easily separated from
the reaction system, and reused for several runs without significant
loss in both the catalytic activity and the stereoselectivity. Due to
the importance of the reuse of the organocatalyst, the development
and application of other dendritic organocatalysts are currently in
progress.
a
Reaction condition: 5c (0.025 mmol), TFA (0.00625 mmol), b-nitroolefin
(0.25 mmol), and cyclohexanone (0.14 mL, 1.25 mmol) at rt for 18 h.
b
Isolated yield.
c
Determined by 1H NMR of the crude product.
d
Determined by HPLC analysis of the syn-product (chiral pak AD-H column).
Table 3
The reactions of other Michael donors with trans-b-nitrostyrene catalyzed by 5c
O
O
Ph
Ph
5c
10%
4. Experimental
4.1. General
NO2
+
NO2
R1
R2
2.5% TFA
r.t
R1
R2
All commercial reagents were used as received, and all reactions
were carried out directly under open air, unless otherwise stated.
All solvents were dried before use. Flash chromatography was per-
formed on silica from QingDao Haiyang chemical Co.Ltd. FT-IR
spectra were recorded on a Boi-Rad FTS135 infrared spectrometer.
1H NMR and 13C NMR spectra were recorded on a Bruker AV400.
Chemical shifts were reported in ppm using tetramethylsilane
(TMS, 0.00 ppm) as internal standard. Elemental analyses were car-
ried out in a GmbH VarioEL V2.8 instrument. Optical rotations
were measured with Perkin–Elmer digital polarimeter. High per-
formance liquid chromatography (HPLC) was performed on Shima-
dzu L6AD, using Chiralpak AD-H column.
6
Entry
R1, R2
Product
Yielda (%)
syn/antib
eec (%) syn/anti
1
2
3
R1, R2 = CH2CH2
6k
6l
6m
58
65
60
7:4
—
8:1
72/66
38
68
R1, R2 = H, H
R
1 = H, R2 = Me
a
b
c
Isolated yield.
Determined by 1H NMR of the crude product.
Determined by HPLC analysis of the syn-product (chiral pak AD-H column).
(entries 9 and 10) and contain a variety of substitution patterns
(ortho- and meta-, entries 4 and 7), were all tested as Michael
acceptors. The results showed that the reactions proceeded effi-
ciently (92–99% yield) with high to excellent levels of enantioselec-
tivity (88–95% ee) and diastereoselectivity (syn/anti = 45:1),
regardless of the electronic or steric properties of the substrate.
The use of ketones other than cyclohexanone as Michael donors
was evaluated as well, and the results are shown in Table 3. The
use of cyclopentanone as a Michael donor resulted in a moderate
4.2. General procedure for the synthesis of 4a–c
Typical procedure: To a suspension of sodium hydride (60% dis-
persion in mineral oil; 0.16 g, 4 mmol) in a mixture of THF (10 mL)
and DMF (10 mL) under nitrogen was added 4-ethynylbenzyl alco-
hol (0.396 g, 3 mmol) at 0 °C. The mixture was allowed to warm to
room temperature, and stirred for 1 h. Compound 2a–c (2 mmol)
was then added at 0 °C. The mixture was then allowed to warm
to room temperature and stirred for 24 h. The mixture was cooled
to 0 °C and water (0.5 mL) was added to quench the reaction, and
then the residue was purified by flash chromatography on silica
gel (CH2Cl2) to give 4a–c.
Compound 4a: Prepared according to the above general proce-
dure, the resulting residue was purified by column chromatogra-
phy on silica gel (CH2Cl2) to give 4a as a white liquid. Yield: 90%;
1H NMR (CDCl3, 400 MHz): d (ppm) 3.09 (s, 1H), 4.51 (s, 2H),
4.53 (s, 2H), 5.05 (s, 4H), 6.58 (s, 1H), 6.63 (s, 2H), 7.29–7.51 (m,
14H). 13C NMR (CDCl3, 100 MHz): d (ppm) 70.06, 71.51, 72.15,
83.54, 101.44, 106.63, 127.5, 128, 128.6, 132.2, 136.9, 139.1,
140.5, 160.1. Anal. Calcd for C30H26O3: C, 82.92; H, 6.03. Found:
C, 82.96; H, 6.00.
Table 4
Recycling of dendritic catalyst 5c in the asymmetric catalysis of the reaction of trans-
b-nitrostyrene with cyclohexanonea
Run
Time (h)
Yieldb (%)
syn/antic
eed (%)
1
2
3
4
5
6
18
18
18
24
30
36
98
95
95
93
88
80
45:1
45:1
45:1
42:1
40:1
40:1
94
92
93
91
92
90
a
Reaction conditions: 5c (0.025 mmol), TFA (0.00625 mmol), b-nitrostyrene
(0.25 mmol), cyclohexanone (0.14 mL, 1.25 mmol) at rt.
b
Isolated yield.
c
Determined by 1H NMR of the crude product.
d
Determined by HPLC (chiral pak AD-H column).

G. Lv et al. / Tetrahedron: Asymmetry 19 (2008) 2568–2572
2571
Compound 4b: Prepared according to the above general proce-
dure, the resulting residue was purified by column chromatogra-
phy on silica gel (CH2Cl2) to give 4b as a white foam. Yield: 83%;
1H NMR (CDCl3, 400 MHz): d (ppm) 3.07 (s, 1H), 4.50 (s, 2H),
4.52 (s, 2H), 4.98 (s, 4H), 5.04 (s, 8H), 6.58 (s, 1H), 6.59 (s, 2H),
6.61 (s, 2H), 6.69 (s, 4H), 7.31–7.47 (m, 24H). 13C NMR (CDCl3,
100 MHz): d (ppm) 70.00, 70.1, 71.53, 72.15, 83.55, 101.44,
101.56, 106.35, 106.66, 127.55, 128.00, 128.6, 132.2, 136.8, 139.3,
140.5, 160.0, 160.1. Anal. Calcd for C58H50O7: C, 81.10; H, 5.87.
Found: C, 81.23; H, 5.79.
53.43, 58.44, 69.92, 70.03, 71.71, 72.01, 101.42, 101.57, 106.02,
106.34, 106.60, 125.64, 127.49, 127.92, 128.21, 128.51, 129.61,
136.72, 138.21, 139.19, 139.31, 140.70, 147.27, 159.95, 160.01,
160.09. Anal. Calcd for C119H108N4O15: C, 77.93; H, 5.94; N, 3.05.
Found: C, 77.86; H, 5.87; N, 3.13.
4.4. General procedure for the dendritic catalysts 5a–c
catalyzed Michael addition reaction of ketones with
nitroolefins
Compound 4c: Prepared according to the above general proce-
dure, the resulting residue was purified by column chromatogra-
phy on silica gel (CH2Cl2) to give 4b as a white foam. Yield: 75%;
1H NMR (CDCl3, 400 MHz): d (ppm) 3.08 (s, 1H), 4.50 (s, 2H),
4.52 (s, 2H), 4.99–5.05 (m, 28H), 6.60–6.72 (m, 21H), 7.31–7.50
(m, 44H). 13C NMR (CDCl3, 100 MHz): d (ppm) 70.00, 70.1, 71.51,
72.11, 83.52, 101.38, 101.58, 106.37, 106.63, 127.51, 127.95,
128.54, 132.14, 136.75, 139.04, 139.18, 139.28, 140.52, 160.04,
160.13. Anal. Calcd for C114H98O15: C, 80.17; H, 5.78. Found: C,
80.21; H, 5.81.
Nitroolefin (0.25 mmol) and 5c (45.6 mg, 10 mol %) were mixed
with ketones (1.25 mmol) in the presence of TFA (2.5 mol %)11 at
room temperature. The homogeneous reaction mixture was stirred
at room temperature for 18 h. The unreacted cyclohexanone was
removed in vacuo, followed by the addition of ether (5 ꢁ 20 mL)
to extract the product thoroughly. The ether solution was com-
bined, and the solvent was reduced under reduced pressure and
was loaded onto a silica gel column to afford the Michael adducts
6a–j as a white solid.
References
4.3. General procedure for the synthesis of 5a–c
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(1 mL), the reaction mixture was stirred at room temperature over-
night. After removal of the solvents, the resulting residue was puri-
fied by flash chromatography on silica gel (MeOH–CH2Cl2 = 1:100)
to give 5a–c as a pale yellow foam.
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Compound 5a: Prepared according to the above general proce-
dure, the resulting residue was purified by column chromatogra-
phy on silica gel (MeOH–CH2Cl2 = 1:100) to give 5a as a pale
yellow foam. Yield: 72%; ½a D20
ꢀ
¼ þ9:1 (c 1, CH2Cl2), 1H NMR (CDCl3,
400 MHz): d (ppm) 1.53 (m, 1H), 1.78 (m, 2H), 1.98 (m, 1H), 2.99
(m, 2H), 3.69 (m, 1H), 4.30 (m, 1H), 4.45 (m, 1H), 4.50 (s, 2H),
4.54 (s, 2H), 5.03 (s, 4H), 6.56 (s, 1H), 6.63 (s, 2H), 7.29–7.43 (m,
12H), 7.80 (d, 2H), 7.95 (s, 1H). 13C NMR (CDCl3, 100 MHz): d
(ppm) 25.14, 28.94, 29.66, 46.40, 54.60, 59.19, 70.04, 71.74,
72.03, 101.38, 106.63, 125.69, 127.49, 127.93, 128.25, 128.54,
129.89, 136.84, 138.15, 140.65, 147.3, 160.04. Anal. Calcd for
C35H36N4O3: C, 74.98; H, 6.47; N, 9.99. Found: C, 74.87; H, 6.41;
N, 10.08.
Compound 5b: Prepared according to the above general proce-
dure, the resulting residue was purified by column chromatogra-
phy on silica gel (MeOH–CH2Cl2 = 1:100) to give 5b as a pale
yellow foam. Yield: 56%; ½a D20
ꢀ
¼ þ4:5 (c 1, CH2Cl2), 1H NMR (CDCl3,
400 MHz): d (ppm) 1.58 (m, 1H), 1.83 (m, 2H), 2.03 (m, 1H), 3.05
(m, 2H), 3.77 (m, 1H), 4.47 (m, 2H), 4.51 (s, 2H), 4.54 (s, 2H),
4.98 (s, 4H), 5.03 (s, 8H), 6.54 (s, 1H), 6.58 (s, 2H), 6.63 (s, 2H),
6.69 (s, 4H), 7.30–7.42 (m, 42H), 7.72 (d, 2H), 7.88 (s, 1H). 13C
NMR (CDCl3, 100 MHz): d (ppm) 25.12, 28.93, 29.62, 46.38, 54.60,
59.19, 69.93, 70.04, 71.76, 72.03, 101.43, 101.57, 106.34, 106.64,
125.70, 127.53, 127.96, 128.27, 128.54, 129.89, 136.76, 138.19,
139.32, 140.68, 147.3, 159.96, 160.14. Anal. Calcd for
C63H60N4O7: C, 76.81; H, 6.14; N, 5.69. Found: C, 76.76; H, 6.09;
N, 5.81.
6. (a) Zhang, Y. G.; Zhao, L.; Lee, S. S.; Ying, J. Y. Adv. Synth. Catal. 2006, 348, 2027;
(b) Selkala, S. A.; Tois, J.; Pihko, P. M.; Koskinen, A. M. P. Adv. Synth. Catal. 2002,
344, 941; (c) Li, P. H.; Wang, L.; Zhang, Y. C.; Wang, G. W. Tetrahedron 2008, 64,
7633; (d) Zhao, Y. B.; Zhang, L. W.; Wu, L. Y.; Li, R.; Ma, J. T. Tetrahedron:
Asymmetry 2008, 19, 1352.
7. (a) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S. W. Org. Lett. 2006, 8, 4417; (b)
Liu, Y. H.; Shi, M. Adv. Synth. Catal. 2008, 350, 122; (c) Li, Y. W.; Liu, X. Y.; Zhao,
G. Tetrahedron: Asymmetry 2006, 17, 2034.
8. For selected examples of the organocatalytic asymmetric Michael addition to
nitroolefins, see: (a) Andrey, O.; Alexakis, A.; Bernardinelli, G. Org. Lett. 2003, 5,
2559; (b) Tian, S.; Ran, H.; Deng, L. J. Am. Chem. Soc. 2003, 125, 9900; (c) Tian, S.
K.; Chen, Y. G.; Hang, J. F.; Tang, L.; McDaid, P.; Deng, L. Acc. Chem. Res. 2004, 37,
621; (d) Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng,
L. Angew. Chem., Int. Ed. 2005, 44, 105; (e) Okino, T.; Hoashi, Y.; Furukawa, T.;
Compound 5c: Prepared according to the above general proce-
dure, the resulting residue was purified by column chromatogra-
phy on silica gel (MeOH–CH2Cl2 = 1:100) to give 5c as a pale
yellow foam. Yield: 40%; ½a D20
ꢀ
¼ þ2:8 (c 1, CH2Cl2), 1H NMR (CDCl3,
400 MHz): d (ppm) 1.53 (m, 1H), 1.77 (m, 2H), 1.98 (m, 1H), 2.99
(m, 2H), 3.71 (m, 1H), 4.37 (m, 2H), 4.47 (s, 2H), 4.50 (s, 2H),
4.93 (s, 8H), 4.94 (s, 4H), 4.98 (s, 16H), 6.53 (m, 6H), 6.61 (m,
3H), 6.65 (m, 12H), 7.30–7.39 (m, 22H), 7.77 (d, 2H), 7.96 (s, 1H).
13C NMR (CDCl3, 100 MHz): d (ppm) 24.77, 28.67, 29.65, 46.18,

2572
G. Lv et al. / Tetrahedron: Asymmetry 19 (2008) 2568–2572
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11. A stock solution of TFA in ketones.