Enantioselective Michael addition of dicyanoolefins to α,β- unsaturated aldehydes in aqueous medium

Article abstract of DOI:10.1002/adsc.200800145

A pool of water-compatible catalysts, namely dialkyl-(S)-prolinols, has been developed for the enantioselective direct vinylogous Michael addition reaction of vinylmalononitriles to α,β-unsaturated aldehydes in aqueous medium. In many cases, the products can be obtained in almost optically pure form (>96% ee) after a single recrystallization.

Full text of DOI:10.1002/adsc.200800145

COMMUNICATIONS
DOI: 10.1002/adsc.200800145
Enantioselective Michael Addition of Dicyanoolefins to
a,b-Unsaturated Aldehydes in Aqueous Medium
Jun Lu,a Feng Liu,a and Teck-Peng Loha,*
a
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological
University, 1 Nanyang Link, Singapore 637371
Fax : (+65)-6791-1961; phone: (+65)-6316-8899; e-mail: teckpeng@ntu.edu.sg
Received: March 11, 2008; Published online: July 24, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A pool of water-compatible catalysts,
namely dialkyl-(S)-prolinols, has been developed
for the enantioselective direct vinylogous Michael
addition reaction of vinylmalononitriles to a,b-un-
saturated aldehydes in aqueous medium. In many
cases, the products can be obtained in almost opti-
cally pure form (>96% ee) after a single recrystalli-
zation.
with excellent diastereoselectivities and enantioselec-
tivities. Thereafter, many organocatalysts have been
designed for different enantioselective reactions
under aqueous conditions, for example, chiral dialkyl-
prolinol derivatives have been applied in asymmetric
conjugate additions to provide high enantioselectivi-
ties using water as the only solvent.[6]
Very recently, it has been reported that a,a-dicya-
noolefin compounds can selectively behave as accept-
ors or vinylogous donors in Michael reactions under
easily controllable conditions, which simultaneously
give multifunctional products with two vicinal chiral
tertiary carbon centers.[7] Although a similar reaction
has been reported to work in organic solvent,[7a] ex-
tending this method to aqueous medium requires the
use of new organic catalysts. In conjunction with our
Keywords: dicyanoolefins; enantioselective Michael
addition; organocatalysts; unsaturated aldehydes;
water
Organic reactions in water have attracted tremendous interest in the development of new organic reactions
attention because of the many advantages that they in aqueous media for the functionalization of biomol-
offer.[1] For example, organic reactions in/on water ecules,[8] our group has extensively studied the enan-
allow multistep syntheses to be carried out more effi- tioselective direct vinylogous Michael addition reac-
ciently without the need for protection-deprotection tion of vinylmalononitriles to a,b-unsaturated alde-
of the functional groups containing acidic protons. hydes in water. Herein, we report that the water-com-
Furthermore compounds containing water molecules patible catalysts derived from l-proline catalyze
or biomolecules can also be used directly.
highly diastereo- and enantioselective direct vinylo-
In the field of asymmetric synthesis, the develop- gous Michael addition reactions in water, resulting in
ment of water-compatible catalytic methods still re- the corresponding anti-Michael addition products in
mains a challenge, because most metal catalysts are high enantioselectivities [Eq. (1)].
unstable toward hydrolysis.[2] Water can also interfere
with organocatalysis[3] given its capacity for disrupting
hydrogen bonds and other polar interactions. To
ACHTREUNGachieve highly catalytic activity and excellent enantio-
selectivity of organic reactions in water, much effort
has been devoted to understanding the nature of the
interrupting ionic interactions, hydrogen bonds, and
hydrophobic interactions in aqueous media. Just re-
cently, breakthrough contributions were made by the
We envisaged that dialkyl-(S)-prolinols with alkyl
groups of Barbas,[4] Takabe,[4] and Hayashi.[5] They chains as hydrophobic groups should assemble with
used proline-derived catalysts in the presence of hydrophobic reactants in water and sequester the
water to demonstrate the direct asymmetric aldol re- transition state from water and, therefore, high asym-
action and the Michael reaction with high yields and metric induction may be achieved in water. Thus, we
Adv. Synth. Catal. 2008, 350, 1781 – 1784
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1781

Jun Lu et al.
COMMUNICATIONS
decrease in yield (Table 1, entry 3). However, when
the reaction was carried out for 36 h under the same
conditions, the product could be obtained in good
yield and high enantioselectivity (Table 1, entry 11).
Inferior results were obtained when the reactions
were catalyzed by other catalysts (Table 1, entries 4–
7). In all the reactions tested, only the anti-Michael
addition products were obtained. Notably, catalyst 2
Figure 1. Structures of chiral dialkyl-(S)-prolinols.
synthesized a series of chiral dialkyl-(S)-prolinols bearing a hexyl group provided the best results in
(Figure 1) derived from l-proline and investigated both isolated yield and enantioselectivity.
their catalytic activities in asymmetric direct vinylo-
gous Michael addition reactions in water.
Thus, catalyst 2 was selected for the subsequent
studies. First, the influence of catalyst loading on the
The catalytic activity of catalysts 1–5 for the asym- reaction was examined (Table 1, entry 8 vs. 3). It was
metric direct vinylogous Michael addition reaction found that there was no significant increase in the
was investigated by performing a model reaction of yield and enantioselectivity by increasing the catalyst
the vinylmalononitrile 6a and crotonaldehyde 7a in amount to 30 mol%. However, the reaction proceed-
aqueous medium. The results are summarized in ed sluggishly with a significant drop in enantioselec-
Table 1.
tivity when the catalyst loading was reduced to 10
It is interesting to find that the vinylogous Michael mol%. By decreasing the reaction temperature fur-
addition reaction proceeds efficiently in water/brine ther to À108C, a comparable enantioselectivity was
in the presence of catalyst 2/PNBA (20 mol%) at found, but there was a significant drop in yield
room temperature, the desired products were ob- (Table 1, entry 10). Therefore, the optimum reaction
tained with comparable yield and enantioselectivity conditions were achieved by performing the reaction
(Table 1, entries 1 and 2). In order to increase the of 1 equiv. of dicyanoolefin with 4 equiv. of a,b-unsa-
enantioselectivity, we hypothesized the reaction turated aldehyde and 20 mol% catalyst loading at
should be carried out at lower temperature. There- 08C in brine.
fore, brine was chosen as the solvent for further stud-
ies. By lowering the temperature to 08C, a significant
To examine the scope of the direct vinylogous
ACHTREMUNG ichael addition reactions by using the catalyst 2 in
increase in enantioselectivity was observed, but with a brine, a series of a,a-vinylmalononitriles (Figure 2)
and a,b-unsaturated aldehydes were evaluated under
the optimized reaction conditions, and the results are
summarized in Table 2. In general, regardless of the
alkyl- and aryl-, or heteroaryl-substituted a,b-unsatu-
Table 1. Screening of chiral dialkyl-(S)-prolinols for the vi-
nylogous Michael addition reaction.[a]
rated aldehydes, the reaction proceeded smoothly to
afford the Michael adducts in 36 h with good diaste-
reoselectivities and enantioselectivities. When cyclic
substrates were used, only the anti-products were
formed. When the acyclic substrate 6f was tested, a
major product was obtained in 75% ee. While the
other diastereomer was found in 8% yield and 30%
ee. Many of these products can be obtained in almost
Entry Catalyst Solvent Temperatue Time Yield ee
[8C]
[h]
[%]
[%][d]
1
2
3
4
5
6
7
2
2
2
1
3
4
5
2
2
2
2
water
brine
brine
brine
brine
brine
brine
brine
brine
brine
brine
r.t.
r.t.
0
0
0
0
0
0
0
16
16
16
16
16
16
16
16
16
16
36
88
92
72
51
61
32
65
76
38
45
82
72
73
88
64
86
85
85
89
56
88
90
8[b]
9[c]
10
11
À10
0
[a]
The reaction was performed with 6a (0.1 mmol), 7a
(0.4 mmol), brine (0.5 mL), and catalyst/PNBA
(0.02 mmol).
30 mol% of catalyst was used in this reaction.
10 mol% of catalyst was used in this reaction.
Determined by chiral-phase HPLC analysis.
[b]
[c]
[d]
Figure 2. Structures of vinylmalononitriles 6.
1782
asc.wiley-vch.de
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 1781 – 1784

Enantioselective Michael Addition of Dicyanoolefins to a,b-Unsaturated Aldehydes
COMMUNICATIONS
Table 2. Asymmetric vinylogous Michael addition of dicya-
noolefins 6 to a,b-unsaturated aldehydes 7.[a]
Entry
6
R
Product Yield ee
[%][b] [%][c]
1
2
3
4
5
6
7
8
6a M e (7a)
6b M e (7a)
6c M e (7a)
6d M e (7a)
6e M e (7a)
6f M e (7a)
6a Et (7b)
6b Et (7b)
6c Et (7b)
6d Et (7b)
6a n-Pr (7c)
6b n-Pr (7c)
6c n-Pr (7c)
6a C6H5 (7d)
6b C6H5 (7d)
8aa
8ba
8ca
8da
8ea
8fa
8ab
8bb
8cb
8db
8ac
8bc
8cc
8ad
8bd
82
79
90
54
46
43/8
81
85
58
64
80
84
86
83
81
76
74
90 (96)[d]
Figure 3. X-ray crystallographic structure of 8cb.
92 (98)[d]
91 (98)[d]
88
87
75
Experimental Section
Typical Procedure for Direct Vinylogous Michael
Addition Reaction: (Table 2, entry 1)
84
88
9
90 (>99)[d,e]
A mixture of 6a (19.4 mg, 0.1 mmol), 7a (32 mL, 0.4 mmol),
10
11
12
13
14
15
16
17
84
85
87
84
85
87
catalyst
2
(5.4 mg, 0.02 mmol) and PNBA (3.4 mg,
0.02 mmol) in brine (0.5 mL) was stirred for 36 h at 08C.
Then the reaction was quenched by adding 0.5 mL 1 MHCl.
The mixture was extracted with EtOAc, dried with anhy-
drous sodium sulfate. The crude product was purified by
column chromatography on silica gel to give the desired
product 8aa in 82% yield with 90% ee, as determined by
HPLC (Chiralpak AS, 0% 2-propanol/hexane, 1 mLminÀ1):
6b 4-ClC6H4 (7e) 8be
6b 4-BrC6H4 (7f) 8bf
88 (98)[d]
85 (96)[d]
[a]
t
minor =18.756 min, tmajor =26.674 min.
Reactions performed with 0.1 mmol of 6, 0.4 mmol of 7,
20 mol% of catalyst and 20 mol% PNBA in 0.5 mL of
brine at 08C for 36 h.
Isolated yield.
Determined by HPLC analysis on a chiral phase.
After recrystallization with i-PrOH.
Crystallographic Data
[b]
[c]
[d]
[e]
Crystal data for 8cb: C17H16N2OS, M=296.38, orthorhombic,
space group P212121, a=7.2773(3), b=8.1433(4), c=
25.9326(12) Š, V=1536.80(12) Š 3, Z=4, crystal size 0.28”
0.24”0.04 mm, T=223(2) K, Siemens P4 diffractometer, ab-
sorption coefficient 0.211 mmÀ1, reflections collected 3002,
independent reflections 2640 (Rint =0.00572), refinement by
full-matrix least-squares on F2, data/restraints/parameters
2640/0/191, goodness-of-fit on F2=1.080, final R indices [I>
2s(I)]: R1=0.0604, wR2=0.1621, R indices (all data): R1 =
0.0511, wR2 =0.1411. Crystallographic data for the structure
8cb have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication no.
CCDC 668757. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
The absolute configuration was determined to be C-11: S,
C-13: R by X-ray crystallographic analysis.
optically pure form after a single crystallization from
isopropyl alcohol (Table 2, entries 1, 2, 3, 9, 16, 17).
Enantiopure 8cb (>99% ee), which contains a
sulfur atom, was obtained by crystallizing slowly from
isopropyl alcohol and the crystals were suitable for X-
ray structural analysis. The relative and absolute con-
figurations of the two contiguous stereogenic carbons
in 8cb could easily be determined by X-ray crystallo-
graphic analysis. As shown in Figure 3, the two newly
created stereocenters of 8cb were revealed to possess
the (11S,13R)-configuration with an anti-relative ste-
reochemistry.
Supporting Information
Additional experiment procedures, 1H and 13C NMR, and
HPLC spectra for reaction products are available as Sup-
porting Information.
In conclusion, we have developed new chiral water-
compatible dialkylprolinol organocatalysts for the
highly enantioselective direct vinylogous Michael ad-
dition reaction of vinylmalononitriles to a,b-unsatu-
rated aldehydes in aqueous medium. Further work on
applying this kind of chiral water-compatible organo-
catalyst for other organic transformations is in prog-
ress.
Acknowledgements
We gratefully acknowledge Biomedical Research Council
(A*STAR grant M47110003) for funding of this research and
we thankDr. Y.-X. Li for X-ray support.
Adv. Synth. Catal. 2008, 350, 1781 – 1784
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1783

Jun Lu et al.
COMMUNICATIONS
References
T. Okano, J. Takahashi, T. Sumiya, M. Shoji, Angew.
Chem. 2006, 118, 5653; Angew. Chem. Int. Ed. 2006, 45,
5527.
[1] a) C. J. Li, Acc. Chem. Res. 2002, 35, 533; b) C. I. Herre-
rías, X. Q. Yao, Z. P. Li, C. J. Li, Chem. Rev. 2007, 107,
2546; c) K. K. Chauhan, C. G. Frost, J. Chem. Soc.
Perkin Trans. 1 2000, 3015; d) B. C. Ranu, Eur. J. Org.
Chem. 2000, 2347; e) G. Babu, P. T. Perumal, Aldrichimi-
ca Acta 2000, 33, 16; f) T. P. Loh, in: Science of Synthesis,
(Ed.: H. Yamamoto), Vol. 7, Georg Thieme Verlag
Stuttgart, New York, 2004, p 413; g) C. J. Li, T. H. Chan,
Tetrahedron 1999, 55, 11149; h) C. J. Li, Chem. Rev.
2005, 105, 3095; i) C. J. Li, Chem. Rev. 1993, 93, 2023;
j) C. J. Li, L. Chen, Chem. Soc. Rev. 2006, 35, 68; k) D.
Dallinger, C. O. Kappe, Chem. Rev. 2007, 107, 2563; l) S.
Kobayashi, A. K. Manabe, Acc. Chem. Res. 2002, 35,
209; m) U. M. Lindstrom, Chem. Rev. 2002, 102, 2751;
n) A. P. Brogan, T. J. Dickerson, K. D. Janda, Angew.
Chem. 2006, 118, 8278; Angew. Chem. Int. Ed. 2006, 45,
8100; o) Y. Hayashi, Angew. Chem. 2006, 118, 8281;
Angew. Chem. Int. Ed. 2006, 45, 8103.
[2] a) Aqueous-Phase Organometallic Catalysis, (Eds.: B.
Cornils, W. A. Herrman), Wiley-VCH, Weinheim, 1998;
b) S. Kobayashi, C. Ogawa, Chem. Eur. J. 2006, 12, 5954;
c) S. Kobayashi, M. Sugiura, H. Kitagawa, W. W. L.
Lam, Chem. Rev. 2002, 102, 2227; d) D. Sinou, Adv.
Synth. Catal. 2002, 344, 221.
[3] a) P. I. Dalko, L. Moisan, Angew. Chem. 2001, 113, 3840;
Angew. Chem. 2001, 113, 3840; Angew. Chem. Int. Ed.
2001, 40, 3726; b) E. R. Jarvo, S. J. Miller, Tetrahedron
2002, 58, 2481; c) P. I. Dalko, L. Moisan, Angew. Chem.
2004, 116, 5248; Angew. Chem. Int. Ed. 2004, 43, 5138;
d) J. Seayad, B. List, Org. Biomol. Chem. 2005, 3, 719;
e) A. Berkessel, H. Grçger, Asymmetric Organocataly-
sis: From Biomimetic Concepts to Applications in Asym-
metric Synthesis, Wiley-VCH, Weinheim, 2005.
[6] a) X. Y. Wu, Z. Q. Jiang, H. M. Shen, Y. X. Lu, Adv.
Synth. Catal. 2007, 349, 812; b) Z. Q. Jiang, Z. A. Liang,
X. Y. Wu, Y. X. Lu, Chem. Commun. 2006, 2801; c) S. Z.
Luo, X. L. Mi, S. Liu, H. Xu, J.-P. Cheng, Chem.
Commun. 2006, 3687; d) Y. Y. Wu, Y. Z. Zhang, M. L.
Yu, G. Zhao, S. W. Wang, Org. Lett. 2006, 8, 4417; e) D.
Font, C. Jimeno, M. A. Pericus, Org. Lett. 2006, 8, 4653;
f) S. L. Zhu, S. Y. Yu, D. W. Ma, Angew. Chem. Int. Ed.
2008, 47, 545; g) J. M. Huang, X. T. Zhang, D. W. Arm-
strong, Angew. Chem. 2007, 119, 9231; Angew. Chem.
Int. Ed. 2007, 46, 9073; h) C. Palomo, A. Landa, A.
Mielgo, M. Oiarbide, A. Puente, S. Vera, Angew. Chem.
2007, 119, 8583; Angew. Chem. Int. Ed. 2007, 46, 8431;
i) V. Maya, M. Raj, V. K. Singh, Org. Lett. 2007, 9, 2593;
j) S. Aratake, T. Itoh, T. Okano, N. Nagae, T. Sumiya,
M. Shoji, Y. Hayashi, Chem. Eur. J. 2007, 13, 10246.
[7] a) J. W. Xie, L. Yue, D. Xue, X. L. Ma, Y. C. Chen, Y.
Wu, J. Zhu, J. G. Deng, Chem. Commun. 2006, 1563;
b) Y. C. Chen, D. Xue, J. G. Deng, X. Cui, J. Zhu, Y.-Z.
Jiang, Tetrahedron Lett. 2004, 45, 1555; c) D. Xue, Y. C.
Chen, X. Cui, Q. W. Wang, J. Zhu, J. G. Deng, J. Org.
Chem. 2005, 70, 3584; d) D. Xue, Y. C. Chen, L. F. Cun,
Q. W. Wang, J. Zhu, J. G. Deng, Org. Lett. 2005, 7, 5293;
e) J. W. Xie, W. Chen, R. Li, M. Zeng, W. Du, L. Yue,
Y. C. Chen, Y. Wu, J. Zhu, J. G. Deng, Angew. Chem.
2007, 119, 393; Angew. Chem. Int. Ed. 2007, 46, 389.
[8] a) R. B. Wang, C. M. Lim, C. H. Tan, B. K. Lim, K. Y.
Sim, T. P. Loh, Tetrahedron: Asymmetry 1995, 6, 1825;
b) X. R. Li, T. P. Loh, Tetrahedron: Asymmetry 1996, 7,
1535; c) T. P. Loh, G. Q. Cao, J. Pei, Tetrahedron Lett.
1998, 39, 1453; d) T. P. Loh, X. R. Li, Eur. J. Org. Chem.
1999, 1893; e) T. P. Loh, J. R. Zhou, Z. Yin, Org. Lett.
1999, 1, 1855; f) T. P. Loh, J. R. Zhou, Tetrahedron Lett.
1999, 40, 9115; g) T. P. Loh, J. R. Zhou, Tetrahedron
Lett. 2000, 41, 5261; h) T. P. Loh, J. M. Huang, K. C. Xu,
Tetrahedron Lett. 2000, 41, 6511; i) T. P. Loh, H. Y. Song,
Synlett 2003, 2119; j) T. P. Loh, Z. Yin, H. Y. Song, K. L.
Tan, Tetrahedron Lett. 2003, 44, 911; k) J. M. Huang,
K. C. Xu, T. P. Loh, Synthesis 2003, 755.
[4] a) N. Mase, Y. Nakai, N. Ohara, H. Yoda, K. Takabe, F.
Tanaka, C. F. Barbas III, J. Am. Chem. Soc. 2006, 128,
734; b) N. Mase, K. Watanabe, H. Yoda, K. Takabe, F.
Tanaka, C. F. Barbas III, J. Am. Chem. Soc. 2006, 128,
4966.
[5] a) Y. Hayashi, T. Sumiya, J. Takahashi, H. Gotoh, T. Ur-
ushima, M. Shoji, Angew. Chem. 2006, 118, 972; Angew.
Chem. Int. Ed. 2006, 45, 958; b) Y. Hayashi, S. Aratake,
1784
asc.wiley-vch.de
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 1781 – 1784