Chiral amine-polyoxometalate hybrids as highly efficient and recoverable asymmetric enamine catalysts

Article abstract of DOI:10.1021/ol701685y

Chiral amine and polyoxometalate (POM) acids were combined to give highly efficient, stereoselective, and recoverable enamine-based catalysts. Less than 1 mol % of chiral amine loading was sufficient for good catalytic activity, and the catalyst could be

Full text of DOI:10.1021/ol701685y

ORGANIC
LETTERS
2
007
Vol. 9, No. 18
675-3678
Chiral Amine−Polyoxometalate Hybrids
3
as Highly Efficient and Recoverable
Asymmetric Enamine Catalysts
Sanzhong Luo,*,† Jiuyuan Li, Hui Xu, Long Zhang, and Jin-Pei Cheng*
†
†
‡
,‡
Beijing National Laboratory for Molecular Sciences (BNLMS), Center for Chemical
Biology, Institute of Chemistry, Chinese Academy of Science, Beijing, 100080, China,
and Department of Chemistry and State Key Laboratory of Elemento-organic
Chemistry, Nankai UniVersity, Tianjin, 300071, China
luosz@iccas.ac.cn; chengjp@mail.most.goV.cn
Received July 17, 2007
ABSTRACT
Chiral amine and polyoxometalate (POM) acids were combined to give highly efficient, stereoselective, and recoverable enamine-based catalysts.
Less than 1 mol % of chiral amine loading was sufficient for good catalytic activity, and the catalyst could be recovered and reused 6 times
with unchanged enantioselectivity and slightly decreased activity.
1
Ever since the debut of asymmetric organocatalysts, im-
mobilization of these small molecular catalysts has attracted
extensive research activities in regard to solve some bottle-
neck problems such as low efficacy, high catalyst loading,
effective than their nonimmobilized small-molecular coun-
terparts. As a result, large amounts of supported organo-
(
3) For recent examples, see: (a) Annunziata, R.; Benaglia, M.; Cozzi,
F.; Tocco, G. Org. Lett. 2000, 2, 1737-1739. (b) Benaglia, M.; Celentano,
G.; Cozzi, F. AdV. Synth. Catal. 2001, 343, 171-173. (c) Benaglia, M.;
Celentano, G.; Cinquini, M.; Puglisi, A.; Cozzi, F. AdV. Synth. Catal. 2002,
2
and problems related to catalyst recovery and recycling.
Various immobilizing strategies, including attaching the
3
44, 149-152. (d) Benaglia, M.; Cinquini, M.; Cozzi, F.; Puglisi, A.;
3
4
catalysts to supports, adsorbing them onto solid surfaces,
Celentano, G. AdV. Synth. Catal. 2002, 344, 533-542. (e) Benaglia, M.;
5
Cinquini, M.; Cozzi, F.; Puglisi, A.; Celentano, G. J. Mol. Catal. A: Chem.
and biphasic catalysis using ionic liquids and fluorous tags,
2
003, 204, 157-163. (f) Pozzi, G.; Cavazzini, M.; Quici, S.; Benaglia, M.;
have been explored for this end. Although good stereose-
lectivity has been achieved in several cases,2c,6 most of the
immobilized organocatalysts often show reduced activity and
enantioselectivity and limited reusability and are also less
Dell’Anna, G. Org. Lett. 2004, 6, 441-443. (g) Puglisi, A.; Benaglia, M.;
Cinquini, M.; Cozzi, F.; Celentano, G. Eur. J. Org. Chem. 2004, 567-
5
73. (h) Selk a¨ l a¨ , S. A.; Tois, J.; Pihko, P. M.; Koskinen, A. M. P. AdV.
Synth. Catal. 2002, 344, 941-945. (i) Ogawa, C.; Sugiura, M.; Kobayashi,
S. Chem. Commun. 2003, 192-193. (j) Kim, H. S.; Song, Y. M.; Choi, J.
S.; Yang, J. W.; Han, H. Tetrahedron 2004, 60, 12051-12057. (k) Andreae,
M. R. M.; Davis, A. P. Tetrahedron: Asymmetry 2005, 16, 2487-2492.
(l) Akagawa, K.; Sakamoto, S.; Kudo, K. Tetrahedron Lett. 2005, 46, 8185-
8187. (m) Revell, J. D.; Gantenbein, D.; Krattiger, P.; Wennemers, H.
Biopolymers 2006, 84, 105-113. (n) Font, D.; Jimeno, C.; Peric a` s, M. A.
Org. Lett. 2006, 8, 4653-4655. (o) Zhang, Y.; Zhao, L.; Lee, S. S.; Ying,
J. Y. AdV. Synth. Catal. 2006, 348, 2027-2032. (p) Giacalone, F.;
Gruttadauria, M.; Marculescu, A. M.; Noto, R. Tetrahedron Lett. 2007, 48,
255-259. (q) Gu, L.; Wu, Y.; Zhang, Y.; Zhao, G. J. Mol. Catal. A: Chem.
2007, 263, 186-194. (r) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S.
Org. Lett. 2006, 8, 4417-4420. (s) Liu, X.; Li, Y.; Wang, G.; Chai, Z.;
Wu, Y.; Zhao, G. Tetrahedron: Asymmetry 2006, 17, 750-755. (t) Li, Y.;
Liu, X.; Zhao, G. Tetrahedron: Asymmetry 2006, 17, 2034-2039.
†
Institute of Chemistry.
Nankai University.
‡
(1) For selected reviews of organocatalysis, see: (a) Dalko, P. I.; Moisan,
L. Angew. Chem., Int. Ed. 2004, 43, 5138. (b) Berkessel, A.; Groger, H.
Asymmetric Organocatalysis; Wiley-VCH: Weinheim, 2005. (c) Seayad,
J.; List, B. Org. Biomol. Chem. 2005, 3, 719-724. (d) List, B. Chem.
Commun. 2006, 819-824. (e) Lelais, G.; MacMillan, D. W. C. Aldrichimica
Acta 2006, 39, 79-87.
(
2) For reviews, see: (a) Benaglia, M.; Puglisi, A.; Cozzi, F. Chem. ReV.
2
1
003, 103, 3401-3429. (b) Benaglia, M. New J. Chem. 2006, 30, 1525-
533. (c) Cozzi, F. AdV. Synth. Catal. 2006, 348, 1367-1390.
1
0.1021/ol701685y CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/07/2007

catalysts in terms of both weight and molar ratio are normally
required to achieve reasonable yields. A new immobilization
strategy that overcomes the above shortcomings is therefore
highly desirable.
and the proven catalytic capability of chiral diamines
(Scheme 1). The chiral diamine moieties would also
1
2
Polyoxometalates (POMs) belong to a large family of
metal-oxide clusters that have diverse catalytic applications
due to their intrinsic properties such as high acidity and
Scheme 1. Strategy for the Construction of CA-POM and the
Synthesized CA-POMs
7
favorable redox potentials. Besides serving as catalysts,
POMs can also act as supports for catalysts via ion-pair
interaction or by covalent immobilization. Such constructed
POM hybrids combine these two types of catalytically active
species in one and, also, can be recycled and reused many
times by taking advantage of the large framework of POMs.
For example, transition metal-POM hybrids have been used
as effective and recoverable catalysts in hydrogenation
8
reactions and aerobic oxidations. Lanthanide-POM hybrids
9
were recently reported as reusable Lewis acid catalysts.
However, to the best of our knowledge, there are only a
few reports on asymmetric catalysis involving POMs despite
the numerous catalytic applications of POMs and their hybrid
1
0
compounds. In addition, though organic modifications of
POMs are well applied to tune their physical properties and/
or structural diversity to improve the performance and
reusability of the catalysts, the catalytic potentials of organic
groups in organic-POM hybrids remain unexplored. Thus,
we envisaged that if POMs were combined with function-
alized chiral organocatalysts the assemblies may be able to
act as recoverable asymmetric organocatalysts. This design
is based on the well-applied “acid-base” strategy in orga-
nocatalysis by utilizing the intrinsic high acidity of POMs
function as solubility modulators for the resulting hybrids
to render biphasic organocatalysis, so that the chiral amine-
POM (CA-POM) hybrids can be separated by precipitation
with ether or by nanofiltration. Indeed, we found that CA-
POM hybrid catalysts such as 2 and 3 were highly efficient
11
13
and reusable asymmetric enamine-based catalysts with only
1
mol % of loading (loading amount based on chiral amines).
The CA-POM hybrids were obtained by slow addition
of a POM acid into a solution of chiral amine in THF. After
removal of the solvent, the resulting powders were washed
with ethyl ether and dried under a vacuum. NMR studies
and elemental analysis confirmed that the compositions of
the hybrid compounds were consistent with the structures
shown in Scheme 1. In general, the hybrid solids, for
example, 2 and 3, have biphasic characteristics and are
soluble in polar organic solvents such as acetone, DMF, and
DMSO but insoluble in less polar solvents like hexane,
toluene, and ethyl ether. These properties, together with their
easy preparations, suffice for practical applications in bi-
phasic asymmetric organocatalysis.
(
4) For examples, see: (a) Gruttadauria, M.; Riela, S.; Aprile, C.; Meo,
P. L.; D’Anna, F.; Noto, R. AdV. Synth. Catal. 2006, 348, 82-92. (b) An,
Z.; Zhang, W. H.; Shi, H. M.; He, J. J. Catal. 2006, 241, 319-327. (c)
Gruttadauria, M.; Riela, S.; Meo, P. L.; D’Anna, F.; Noto, R. Tetrahedron
Lett. 2004, 45, 6113.
(5) For examples, see: (a) Kotrusz, P.; Kmentova, I.; Gotov, B.; Toma,
Sˇ .; Sol cˇ a´ niov a´ , E. Chem. Commun. 2002, 2510-2511. (b) Loh, T.-P.; Feng,
L.-C.; Yang, H.-Y.; Yang, J.-Y. Tetrahedron Lett. 2002, 43, 8741-8743.
(
1
c) Chowdari, N. S.; Ramachary, D. B.; Barbas, C. F., III. Synlett 2003,
906-1909. (d) Kotrusz, P.; Toma, S.; Schmalz, H.-G.; Adler, A. Eur. J.
Org. Chem. 2004, 1577-1583. (e) Guo, H. M.; Cun, L. F.; Gong, L. Z.;
Mi, A. Q.; Jiang, Y. Z. Chem. Commun. 2005, 1450-1452. (f) Kotrusz,
P.; Alemayehu, S.; Toma, T.; Schmalz, H. G.; Adler, A. Eur. J. Org. Chem.
2
3
005, 4904-4911. (g) C o´ rdova, A. Tetrahedron Lett. 2004, 45, 3949-
952. (h) Rasalkar, M. S.; Potdar, M. K.; Mohile, S. S.; Salunkhe, M. M.
J. Mol. Catal. A: Chem. 2005, 235, 267-270. (i) Dere, R. T.; Pal, R. R.;
Patil, P. S.; Salunkhe, M. M. Tetrahedron Lett. 2003, 44, 5351-5353. (j)
Guo, H. M.; Niu, H. Y.; Xue, M. X.; Guo, Q. X.; Cun, L. F.; Mi, A. Q.;
Jiang, Y. Z.; Wang, J. J. Green Chem. 2006, 8, 682-684. (k) Zu, L.; Wang,
J.; Li, H.; Wang, W. Org. Lett. 2006, 8, 3077-3079. (l) Zu, L.; Li, H.;
Wang, J.; Yu, X.; Wang, W. Tetrahedron Lett. 2006, 47, 5131-5134.
The hybrid catalysts were then examined for the direct
aldol reaction of acetone and p-nitrobenzaldehyde. Some
screening results are listed in Table 1. To our delight, the
(6) For the use of chiral ionic liquids as reusable organocatalysts with
good stereoselectivity, see: (a) Luo, S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.;
Cheng, J.-P. Angew. Chem. Int. Ed. 2006, 45, 3093-3097. (b) Miao, W.
S.; Chan, T. H. AdV. Synth. Catal. 2006, 348, 1711-1718.
(11) For recent examples, see: (a) Ritchie, C.; Burkholder, E. M.; Long,
D.; Adam, D.; K o¨ gerler, P.; Cronin, L. Chem. Commun. 2007, 468-470.
(b) Haimov, A.; Cohen, H.; Neumann, R. J. Am. Chem. Soc. 2004, 126,
11762-11763. (c) Vasylyev, M. V.; Neumann, R. J. Am. Chem. Soc. 2004,
126, 884-890. (d) Zeng, H.; Newkome, G. R.; Hill, C. L. Angew. Chem.,
Int. Ed. 2000, 39, 1772-1774. (e) Bareyt, S.; Piligkos, S.; Hasenknopf, B.;
Gouzerh, P.; Lac oˆ te, E.; Thorimbert, S.; Malacria, M. J. Am. Chem. Soc.
2005, 127, 6788-6794. (f) Hamamoto, H.; Suzuki, H.; Yamada, Y. M. A.;
Tabata, H.; Takahashi, H.; Ikegami, S. Angew. Chem., Int. Ed. 2005, 44,
4536-4538. (g) Bareyt, S.; Piligkos, S.; Hasenknopf, B.; Gouzerh, P.;
Lac oˆ te, E.; Thorimbert, S.; Malacria, M. Angew. Chem., Int. Ed. 2003, 42,
3404-3406.
(
7) For reviews, see: (a) Kozhevnikov, I. V. Catalysis by Polyoxometa-
lates; Wiley: Chichester, England, 2002. (b) Neumann, R. In Modern
Oxidation Methods; B a¨ ckvall, J. E., Eds; Wiley-VCH: Weinheim, 2004;
pp 223-251. (c) Hill, C. L. In ComprehensiVe Coordination Chemistry II;
Wedd, A. G., Ed.; Elsevier: Oxford, 2004; Vol. 4, pp 679-759. For other
applications of POMs, see: Chem. ReV. 1998, 98, (1)-thematic issue.
(
8) (a) Bar-Nahum, I.; Neumann, R. Chem. Commun. 2003, 2690-2691.
b) Bar-Nahum, I.; Khenkin, A. M.; Neumann, R. J. Am. Chem. Soc. 2004,
26, 10236-10237.
9) Boglio, C.; Lemi e` re, G.; Hasenknopf, B.; Thorimbert, S.; Lac oˆ te,
E.; Malacria, M. Angew. Chem., Int. Ed. 2006, 45, 3324-3327.
10) (a) Augustine, R.; Tanielyan, S.; Anderson, S.; Yang, H. Chem.
(
1
(
(12) (a) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570-579.
(b) Nakadai, M.; Saito, S.; Yamamoto, H. Tetrahedron 2002, 58, 8167-
8177.
(
Commun. 1999, 1257-1258. (b) Augustine, R. L.; Mahata, P. G. N.; Reyes,
C.; Tanielyan, S. K. J. Mol. Catal. A: Chem. 2004, 216, 189-197.
(13) Witte, P. T.; Chowdhury, S. R.; ten Elshof, J. E.; Sloboda-Rozner,
D.; Neumann, R.; Alsters, P. L. Chem. Commun. 2005, 1206.
3676
Org. Lett., Vol. 9, No. 18, 2007

Table 1. Selected Screening Resultsa
Table 2. CA-POM Hybrid 3 Catalyzed Aldol Reactions of
Acetonea
X (mol %)b
yield (%)c
ee (%)d
entry
R
time (h)
yield (%)b
ee (%)c
entry catalyst
time (h)
1
2
3
4
5
6
7
8
9
2-NO2Ph
3-NO2Ph
4-CF3Ph
4-CNPh
4-ClPh
2-ClPh
3-BrPh
2-BrPh
Ph
22
24
48
48
96
72
90
72
6d
6d
82 (78)
86 (73)
90 (77)
86 (80)
73 (64)
91 (84)
88 (46)
92 (87)
37 (14)
11
91 (86)
89 (90)
90 (90)
91 (91)
88 (90)
92 (87)
90 (90)
90 (89)
90 (89)
87
1
2
3
4
5
6
7
8
9
0
1
2
3
4
1a
1b
1c
1d
1e
2
3
3
4
3
10
10
10
10
10
5
5
1
1
1
10
15
15
15
19
12
7
24
24
24
24
26
30
30
87
78
78
79
84
86
86
87
78
82
78
70
70
67
90
86
89
84
75
90
92
91
91
92
91
92
91
92
e
e
e
e
e
10
4-MeOPh
1
1
1
1
1
3
3
3
3
1
1
1
1
a
Reaction in neat acetone (0.5 M) with 0.33 mol % of 3 (equal to 1
mol % of chiral amine). Data in the parentheses refer to that obtained with
catalyst 4 under identical conditions. b Isolated yields. c Determined by
chiral HPLC.
a
b
Reaction in neat acetone (0.5 M). Refers to the loading of chiral
amine. c Isolated yields. Determined by chiral HPLC. Second-sixth
reuse of the catalyst 3 in entry 8.
d
e
using the nonsupported catalyst 4 were also listed in Table
2
(see also Table 3, entry 1). Obviously, catalyst 3 performed
better in all the cases examined, again highlighting a
synergistic effect of the POM supports. Other aldol donors
including cyclic ketones, linear ketones, and aldehydes also
worked very well in the catalysis of CA-POM, and the
desired products were obtained with excellent yields and
enantioselectivity (51-99% yield, 95 to >99% ee, Table 3).
In the cases of cyclic ketones, catalyst 2 gave the best results
in terms of both reactivity and stereoselectivity (for screening
details, see Supporting Information).
CA-POM hybrids do effectively catalyze the asymmetric
reactions. Among a series of commercially available POMs,
3
the hybrid catalyst with H PW12O40 gave the best results
(Table 1, entry 5). Subsequent screening of a range of chiral
amines led to an optimal hybrid catalyst 3 for the model
reaction (Table 1, entry 7; for details see Supporting
Information). Significantly, the loading of chiral amine (of
catalyst 3) could be reduced to as low as 1 mol % while
still maintaining very good activity (24 h, 87%, 91% ee;
Table 1, entry 8). In comparison, the nonsupported catalyst
Table 3. CA-POM Hybrid 2 or 3 Catalyzed Aldol Reactions
4
9
gave 78% yield under identical conditions (Table 1, entry
). The dehydration bypathway normally observed in the
of Various Aldol Donorsa
catalysis of 4 was considerably diminished in the reactions
catalyzed by 3, and the only detected byproduct is a bisaldol
adduct (see Supporting Information). These results highlight
the synergistic effect by combining chiral amine and POMs
together. More importantly, the CA-POM hybrid catalysts
could be easily recycled from the homogeneous reaction by
precipitation with diethyl ether. The enantioselectivity ob-
tained using the recovered catalyst 3 maintained the same
enantioselectivity after six runs with slightly reduced activity
time yield
(h)
drc
anti/syn
ee
(%)
1
2
R3
(%)b
d
entry
1
R , R
-(CH2)4- 4-NO2Ph
-(CH2)4- 3-NO2Ph
16 99 (99)e 87:13
80:20)e
83:17 >99
87:13 98
90:10 >99
99 (97)e
(
2
3
4
5
6
7
8
9
19 94
-(CH2)4- 2- NO2Ph 24 92
(
Table 1, entries 10-14). 14 To our knowledge, this represents
-(CH2)4- 4-CF3Ph
-(CH2)4- 4-ClPh
-(CH2)4- Ph
-(CH2)3- 4-NO2Ph
-(CH2)3- 4-CNPh
30 94
96 95
96 51
the first example of a highly efficient and reusable asym-
metric organocatalyst with a chiral amine loading as low
as 1 mol %.
The scope of the hybrid catalyst was then examined with
a series of aldehyde acceptors (Table 2) and aldol donors
88:12
87:13
77:23
75:25
90:10
-
98
96
95
94
98 (94)
98
6
86
19 91
19 59 (40)
72 90
f
f
Me, Me
4-NO2Ph
4-NO2Ph
g
10
H
(Table 3). In the presence of 0.33 mol % of 3, acetone reacted
a
Reaction with 10-20 equiv of ketones under neat conditions with
.33 mol % of 2 (equal to 1 mol % of chiral amine). Isolated yields.
Determined by H NMR. Determined by HPLC. Reaction with catalyst
under identical conditions. Data for the linear product in the presence
of 1.67 mol % of 3 (equal to 5 mol % of chiral amine). Isobutyraldehyde
was used as a donor in the presence of 1.67 mol % of 3 (equal to 5 mol %
of chiral amine).
with various aromatic aldehydes to afford the desired
products with high yields and enantioselectivity (Table 2).
For comparison, the results obtained from the same reactions
b
c
0
1
d
e
f
4
g
(14) The formation of the bisaldol byproduct was increased. 1st run, 7%;
2
nd run, 10%; 3rd run, 16%; 4th run, 16%; 5th run, 20%; 6th run, 18%.
Org. Lett., Vol. 9, No. 18, 2007
3677

Homogeneous or semihomogeneous solutions were gener-
ally observed in all the cases examined under neat conditions,
proving the biphasic characteristics of the CA-POM hybrid
In conclusion, we have developed a new and very facile
approach for deriving efficient and recoverable asymmetric
enamine-based catalysts by combining chiral amines and the
POM acids. The CA-POM hybrid catalysts demonstrated
high activity, excellent stereoselectivity, and good reusability
in asymmetric direct aldol reactions for a broad range of
substrates. As low as 1 mol % of chiral amine loading was
sufficient for effective catalysis. This study provided a new
strategy to the development of practical asymmetric orga-
nocatalytic synthesis. Further applications of this strategy
in other organocatalytic systems and the development of
15
catalysis. The absolute configurations of the aldol products
were determined to be the same as those obtained from the
catalysis of 4 by comparison of their HPLC spectra;
therefore, the reaction mode of the present catalysis should
be consistent with that in previous publications.1
,12
17
heterogeneous CA-POM catalysts will be reported shortly.
Acknowledgment. This work was supported by the
Natural Science Foundation of China (NSFC 20421202,
2
0632060, and 20542007), the Ministry of Science and
Technology (MoST), and the Chinese Academy of Sciences.
We thank Prof. Fan Qinghua for helpful discussions.
To further demonstrate the potentials of our strategy, CA-
POM hybrids were tested in asymmetric Michael addition
Note Added after ASAP Publication. There were spelling
errors in author names in refs 3h, 9, 11e, and 11g in the
version published ASAP August 7, 2007; the revised version
was published ASAP August 14, 2007.
(
eq 1). An initial quick screening identified our first hit,
hybrid catalyst 5, that catalyzed the reaction with as little as
mol % of chiral amine loading, affording the desired
products with comparable yield (91%) and stereoselectivity
syn/anti, 94:6, 89% ee) but significantly improved activity
over the corresponding nonsupported chiral-diamine ana-
logue catalysts.16 The catalyst can also be readily recycled
by precipitation with ether and reused.
5
Supporting Information Available: Experimental details
and characterization of catalysts. This material is available
free of charge via the Internet at http://pubs.acs.org.
(
OL701685Y
(16) For a recent review on asymmetric Michael addition, see: Sulzer-
Mosse, S.; Alexakis, A. Chem. Commun. 2007, DOI: 10.1039/b701216k.
(17) For examples on heterogeneous asymmetirc metal-organic hybrid
catalysts, see: Ding, K.; Wang, Z.; Wang, X.; Liang, Y.; Wang, X. Chem.-
Eur. J. 2006, 12, 5188-5197.
(
15) No reaction or slow reactions were normally observed under
heterogeneous conditions in less polar organic solvents such as ethyl ether,
hexane, or toluene. See Supporting Information for details.
3678
Org. Lett., Vol. 9, No. 18, 2007