Compared to the widely reported aldol reaction, in which
water is used as solvent,5 only limited success has been
obtained for the efficient Michael addition quite recently.6
For these reported cases, the organocatalysts were specifically
designed to be less water soluble or even water insoluble
with a large hydrophobic group (Figure 1, modes A-B),
In this report, the catalysts 1-2 were readily prepared by
a straightforward route from 1-methylimidazole and Boc-L-
proline methyl ester in three steps with 32-35% overall
yields (Scheme 1). These catalysts were conceived based on
Scheme 1. Synthesis of Di(methylimidazole)prolinol Silyl Ether
Figure 1. Various designs of organocatalysts for aqueous environ-
ments.
an intuition that the bimethylimidazole group would enhance
the hydrophilic interaction when the reaction is done in water
and should also act as an effective steric controller due to
the bulky group near the catalytic site of the catalyst (Mode
C in Figure 1).
A model reaction was carried out in aqueous solution of
valeraldehyde and trans-ꢀ-nitrostyrene in the presence of 10
mol % of catalysts 1 and 2 separately; the screening results
are shown in Table 1. As can be seen, our first attempt in
which accurately served as a “concentrated organic phase”,
whereby the hydrophobicity of catalysts can aggregate
organic reactants and drive the formation of enamine
intermediate away from water. To the best of our knowledge,
there is no water-soluble organocatalyst with large hydro-
philic group (Figure 1, mode C), which gives high enanti-
oselectivity for this reaction in water. However, it is still
appealing to study the efficiency of water-soluble organo-
catalysts that influence the outcomes of the asymmetric
Michael reactions. In this communication, we describe the
study of water-soluble di(methylimidazole)prolinol silyl ether
that catalyze highly enantioslective Michael addition reac-
tions of aldehydes with nitroolefins using water as only
solvent.
Table 1. Optimization of the Michael Reaction Conditionsa
(5) Aldol reactions in aqueous media, see: (a) Dickerson, T. J.; Janda,
K. D. J. Am. Chem. Soc. 2002, 124, 3220. (b) Torii, H.; Nakadai, M.;
Ishihara, K.; Saito; Yamamoto, S. H. Angew. Chem., Int. Ed. 2004, 43,
1983. (c) Cordova, A.; Zou, W.; Ibrahem, I.; Reyes, E.; Engqvist, M.; Liao,
W.-W. Chem. Commun. 2005, 3586. (d) Samanta, S.; Liu, J.; Dodda, R.;
Zhao, C.-G. Org. Lett. 2005, 7, 5321. (e) Dziedzic, P.; Zou, W.; Hafren, J.;
Cordova, A. Org. Biomol. Chem. 2006, 4, 38. (f) Pihko, P. M.; Laurikainen,
K. M.; Usano, A.; Nyberg, A. I.; Kaavi, J. A. Tetrahedron 2006, 62, 317.
(g) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.;
Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 734. (h) Hayashi, Y.;
Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M. Angew.
Chem., Int. Ed. 2006, 45, 958. (i) Hayashi, Y.; Aratake, S.; Okano, T.;
Takahashi, J.; Sumiya, T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 5527.
(j) Font, D.; Jimeno, C.; Perica`s, M. A. Org. Lett. 2006, 8, 4653. (k) Wu,
Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S. Org. Lett. 2006, 8, 4417. (l)
Chen, X.-H.; Luo, S.-W.; Tang, Z.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.;
Gong, L.-Z. Chem.sEur. J. 2007, 13, 689. (m) Huang, W.-P.; Chen, J.-R.;
Li, X.-Y.; Cao, Y.-J.; Xiao, W.-J. Can. J. Chem. 2007, 85, 208. (n) Maya,
V.; Raj, M.; Singh, V. K. Org. Lett. 2007, 9, 2593. (o) Wu, X.; Jiang, Z.;
Shen, H.-M.; Lu, Y. AdV. Synth. Catal. 2007, 349, 812. (p) Aratake, S.;
Itoh, T.; Okano, T.; Usui, T.; Shoji, M.; Hayashi, Y. Chem. Commun. 2007,
2524. (q) Guizzetti, S.; Benaglia, M.; Raimondi, L.; Celentano, G. Org.
Lett. 2007, 9, 1247. (r) Font, D.; Sayalero, S.; Bastero, A.; Jimeno, C.;
Perica`s, M. A. Org. Lett. 2008, 10, 337. (s) Zu, L.; Xie, H.; Li, H.; Wang,
J.; Wang, W. Org. Lett. 2008, 10, 1211.
entry solvent additive time (h) yieldb (%) eec (%) syn/antid
e
e
e
e
e
e
1
2
3
4
5
6
7
8
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
none
TsOH
96
96
96
96
96
96
96
96
96
48
48
<10
0
0
CF3CO2H
NaHCO3
Na2CO3
Li2CO3
K2CO3
65
85
40
77
45
93
90
90
97
94
96
95
95
98
99
96
94/6
95/5
93/7
91/9
96/4
98/2
91/9
91/9
KHCO3
9
brine none
brine NaHCO3
brine NaHCO3
10
11f
a Aldehyde (5 equiv) and additive (0.2 equiv) were used. b Isolated yield.
c Determined by chiral HPLC. d Determined by 1H NMR. e Not determined.
f Catalyst 2 was used.
water gave very poor yield using 1 as catalyst (Table 1, entry
1). It has been reported that the addition of an acid to the
Michael reaction can improve chemical yields by acceleration
of enamine formation.8 However, no product was observed
using TsOH or TFA as additive (Table 1, entries 2-3). To
our surprise, the addition of 20 mol % NaHCO3 gave the
desired Michael adduct 5a in 65% yield with excellent
enantioselectivity (97% ee) and high diastereoselectivity (syn/
anti 94/6) (Table 1, entry 4). When a little stronger base
(6) Michael reactions in aqueous media, see: (a) Mase, N.; Watanabe,
K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc.
2006, 128, 4966. (b) Luo, S.; Mi, X.; Liu, S.; Xu, H.; Cheng, J.-P. Chem.
Commun. 2006, 3687. (c) Zu, L.; Wang, J.; Li, H.; Wang, W. Org. Lett.
2006, 8, 3077. (d) Yan, Z.-Y.; Niu, Y.-N.; Wei, H.-L.; Wu, L.-Y.; Zhao,
Y.-B.; Liang, Y.-M. Tetrahedron: Asymmetry 2006, 17, 3288. (e) Cao, Y.-
J.; Lai, Y.-Y.; Wang, X.; Li, Y.-J.; Xiao, W.-J. Tetrahedron Lett. 2007, 48,
21. (f) Singh, V.; Singh, V. K. Org. Lett. 2007, 9, 1117. (g) Palomo, C.;
Landa, A.; Mielgo, A.; Oiarbide, M.; Puente, A.; Vera, S. Angew. Chem.,
Int. Ed. 2007, 46, 8431. (h) Zhu, S.-L.; Yu, S.-Y.; Ma, D.-W. Angew. Chem.,
Int. Ed. 2008, 47, 545. (i) Alza, E.; Cambeiro, X. C.; Jimeno, C.; Perica`s,
M. A. Org. Lett. 2007, 9, 3717.
(7) Mannich reaction in aqueous media, see Cheng, L.; Wu, X.; Lu, Y.
Org. Biomol. Chem. 2007, 5, 1018.
(8) Mase, N.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2003, 5, 4369.
Org. Lett., Vol. 11, No. 15, 2009
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