An efficient ionic liquid additive for proline-catalyzed direct asymmetric aldol reactions between cyclic ketones and aromatic aldehydes

Article abstract of DOI:10.1246/cl.2009.576

An ionic liquid [EMIm][CF₃COO] proved to be an efficient additive for proline-catalyzed direct asymmetric aldol reactions between cyclic ketones and aromatic aldehydes in [BMIm]BF₄ at room temperature. Corresponding aldol products in

Full text of DOI:10.1246/cl.2009.576

576
Chemistry Letters Vol.38, No.6 (2009)
An Efficient Ionic Liquid Additive for Proline-catalyzed Direct Asymmetric Aldol Reactions
between Cyclic Ketones and Aromatic Aldehydes
Yunbo Qian, Xin Zheng, Xu Wang, Shiyong Xiao, and Yongmei WangÃ
Department of Chemistry, The Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. China
(Received March 23, 2009; CL-090284; E-mail: ymw@nankai.edu.cn)
An ionic liquid [EMIm][CF3COO] proved to be an efficient
additive for proline-catalyzed direct asymmetric aldol reactions
between cyclic ketones and aromatic aldehydes in [BMIm]BF4
at room temperature. Corresponding aldol products in low to
good yields (trace–93%) and excellent enantiomeric excesses
(up to 98%) were afforded. Recycling of the catalyst and addi-
tive together with the solvent ([BMIm]BF4) was possible up to
5 runs with only slight reduction in activity.
catalyzed by proline with the addition of [EMIm][CF3COO].
Table 1 summarized the results. Compared to reactions using
organic solvent DMSO or cyclohexanone, reactions performed
in [BMIm]BF4 gave the best result (Table 1, Entry 8). In the
presence of 10 equiv of water, the aldol product could be ob-
tained in 87% overall yield together with a 16:84 dr (diastereo-
mer ratio) value and up to 97% ee for the anti isomer. Reaction
without the addition of 1 in the presence of water was also
carried out, the stereoselectivity was not satisfied (Table 1,
Entry 10). When the ionic liquid 1 was used directly as a solvent
(Table 1, Entry 11), there was also a slight decrease in the enan-
tioselectivity. Entry 12 showed that an increased amount of
cyclohexanone (5 equiv) improved the yield slightly but led to
moderate dr value (32:68). Based on this result, it is also impor-
tant to control the ratio of the substrates.
With the optimized conditions in hand, we then examined a
variety of aromatic aldehydes and cyclic ketones to establish the
general efficacy of the catalytic transformation. As illustrated
in Table 2, the reaction was dramatically dependent on the elec-
tronic effects of the aldehyde. Aromatic aldehydes with electron-
withdrawing groups in the para position reacted smoothly with
cyclohexanone, giving the corresponding aldol products in good
yield and excellent ee for anti isomers. (Table 2, Entries 1 and 4–
6). As a result of the steric hindrance, the aldehyde bearing a ni-
tro group in the ortho position showed lower reactivity, the prod-
uct was isolated in 34% yield with a weak diasteroselectivity
(Table 2, Entry 2). Unsubstituted aromatic aldehyde also gave
The asymmetric aldol reaction is one of the most important
carbon–carbon bond-forming reactions in organic synthesis1 for
the production of enantiomerically enriched ꢀ-hydroxy ketones
which are essential building blocks in the synthesis of polyfunc-
tional compounds and natural products.2 Since Barbas et al.3 re-
ported the direct aldol reaction catalyzed by (S)-proline under
mild conditions, the use of small organic molecules as catalysts
has received great attention. Over the past few years, (S)-proline
and its structural analogues have been continuously developed
for direct asymmetric aldol reactions.4,5
During the last decade, room temperature ionic liquids (ILs)
have attracted much attention as environmentally benign reac-
tion media because of their fascinating and characteristic proper-
ties.6 Ionic liquids have also been introduced into direct aldol re-
actions mainly as green solvents to replace organic solvents such
as DMF or DMSO.7 Recently, chiral ionic liquids (CILs) have
become a research focus of increasing importance owing to their
potential for chiral discrimination in asymmetric synthesis and
optical resolution of racemates.8 However, there are few exam-
ples reported using ionic liquid as an additive in a catalytic
amount. Furthermore, proline-catalyzed direct asymmetric aldol
reactions between cyclic ketones and aromatic aldehydes in
ionic liquid have not been systemically investigated. Herein,
we would like to report the application of [EMIm][CF3COO]
(1) (Scheme 1) as an efficient additive for proline-catalyzed
direct asymmetric aldol reactions in [BMIm]BF4. Although the
exact role of 1 is still under investigation, we assume that an in-
teraction exists between proline and the anion CF3COOÀ, which
could stabilize the enamine intermediate of the aldol reaction.
The ionic liquid [EMIm][CF3COO] (1) could be easily
obtained in 100% overall yield according to the reference9
(Scheme 1).
Table 1. The model reaction of 4-nitrobenzaldehyde and cyclo-
hexanone in the presence of [EMIm][CF3COO] (1)
H2O Yielda
(equiv) /% (syn/anti) (syn/anti)
drb
eeb/%
Entry
Solvent
e
1
2
3
4
5
6
7
8
9
DMSO
DMSO
—
15
—
5
15
—
5
10
15
10
10
10
89
97
98
94
90
87
71
87
82
85
91
91
44:56
44:56
43:57
37:63
32:68
33:67
23:77
16:84
34:66
32:68
19:81
32:68
68/75
88/88
86/89
87/93
86/91
65/95
72/96
58/97
85/94
67/89
80/82
75/93
e
e
cyclohexanone
cyclohexanone
cyclohexanone
[BMIm]BF4
[BMIm]BF4
[BMIm]BF4
[BMIm]BF4
[BMIm]BF4
Originally, a model reaction of 4-nitrobenzaldehyde and 3.5
equiv of cyclohexanone was carried out at room temperature
10c
11 [EMIm][CF3COO]
12d
[BMIm]BF4
aIsolated yields after column chromatography. bDetermined by
HPLC analysis on a chiral AD-H column. cNo [EMIm][CF3COO]
Scheme 1. Synthesis of ionic liquid: 1-Ethyl-3-methylimidazo-
lium trifluoroacetate ([EMIm][CF3COO]).
d
e
was added. 5 equiv of cyclohexanone was added. Not added.
Copyright ꢀ 2009 The Chemical Society of Japan

Chemistry Letters Vol.38, No.6 (2009)
577
Table 2. Proline-catalyzed direct aldol reaction of cyclic ke-
tones with aromatic aldehydes in the presence of [EMIm]-
[CF3COO] (1)
cellent enantiomeric excesses (up to 98%) were afforded. Recy-
cling of the catalyst and additive together with the solvent
([BMIm]BF4) was possible up to 5 runs with only slight reduc-
tion in activity.
References and Notes
1
a) C. H. Heathcock, in Comprehensive Organic Synthesis, ed.
by B. M. Trost, I. Fleming, Pergamon, Oxford, 1991, Vol. 2.
b) Modern Aldol Reactions, ed. by R. Mahrwarld, Wiley-
VCH, Weinheim, 2004, Vol. 1.
T
Yielda drb
eec/%
(syn/anti) (syn/anti)
Entry
R
X
/h /%
2
a) P. Decker, H. Schweer, Origins Life Evol. Biosphere 1984,
14, 335. b) T. Mukaiyama, Tetrahedron 1999, 55, 8609.
c) K. C. Nicolaou, D. Vourloumis, N. Winssinger, P. S. Baran,
Angew. Chem., Int. Ed. 2000, 39, 44.
a) B. List, R. A. Lerner, C. F. Barbas, III, J. Am. Chem. Soc.
2000, 122, 2395. b) K. Sakthivel, W. Notz, T. Bui, C. F.
Barbas, III, J. Am. Chem. Soc. 2001, 123, 5260.
1
2
3
4
5
6
7
8
9
10
11
12
13
14f
15f
16f
17f
18f,g
p-NO2 CH2
o-NO2 CH2
m-NO2 CH2
12 87
72 34
72 62
48 85
72 77
72 74
72 59
72 <10
12 93
72 67
16:84
40:60
19:81
16:84
19:81
12:88
15:85
/97
/97
/96
/92
/94
/89
/94
p-CF3
p-Br
p-Cl
H
CH2
CH2
CH2
CH2
3
4
h
h
p-OMe CH2
—
—
´
´
Reviews: a) G. Guillena, C. Najera, D. J. Ramon, Tetrahedron:
Asymmetry 2007, 18, 2249. b) B. List, Synlett 2001, 1675. c) B.
List, Tetrahedron 2002, 58, 5573. d) W. Notz, F. Tanaka, C. F.
Barbas, III, Acc. Chem. Res. 2004, 37, 580.
p-NO2
p-NO2
—
S
64:36b,c
50:50b,c
29:71d
81/89
94/97
98e
p-NO2 CHCH3 48 75
p-NO2 (CH2)2 72 trace
p-NO2 acetone 12 92
p-NO2 CH2
p-NO2 CH2
p-NO2 CH2
p-NO2 CH2
p-NO2 CH2
h
h
—
—
—
74
5
Examples: a) J. Huang, X. Zhang, D. W. Armstrong, Angew.
Chem., Int. Ed. 2007, 46, 9073. b) F. Wang, Y. Xiong, X.
Liu, X. Feng, Adv. Synth. Catal. 2007, 349, 2665. c) H. Inoue,
M. Kikuchi, J. Ito, H. Nishiyama, Tetrahedron 2008, 64, 493.
d) S. Luo, J. Li, H. Xu, L. Zhang, J.-P. Cheng, Org. Lett. 2007,
9, 3675. e) V. Maya, M. Raj, V. K. Singh, Org. Lett. 2007,
9, 2593. f) J. Shah, H. Blumenthal, Z. Yacob, J. Liebscher,
Adv. Synth. Catal. 2008, 350, 1267. g) D. E. Siyutkin, A. S.
Kucherenko, M. I. Struchkova, S. G. Zlotin, Tetrahedron Lett.
2008, 49, 1212. h) M. Lombardo, S. Easwar, F. Pasi, C.
Trombini, Adv. Synth. Catal. 2009, 351, 276. i) S.-P. Zhang,
X.-K. Fu, S.-D. Fu, J.-F. Pan, Catal. Commun. 2009, 10,
401. j) S. Aratake, T. Itoh, T. Okano, T. Usui, M. Shoji, Y.
Hayashi, Chem. Commun. 2007, 2524. k) Y. Hayashi, T.
Sumiya, J. Takahashi, H. Gotoh, T. Urushima, M. Shoji,
Angew. Chem., Int. Ed. 2006, 45, 958.
i
12 91
12 92
12 88
12 90
12 93
24:76
28:72
31:69
38:62
29:71
86/95
72/94
68/96
82/94
78/94
aIsolated yields after column chromatography. bDetermined by
1H NMR of the crude product. Determined by HPLC analysis on
c
a chiral AD-H column. dThe ratio of the major isomer shown with
all the other isomers. eThe major isomer. fReuse conditions. g9 mL
water (5 equiv) was added. No data. No dr value.
h
i
good stereoselectivity in moderate yield (Table 2, Entry 7).
There was almost no product obtained (yield < 10%) when p-
methoxylbenzaldehyde reacted with cyclohexanone even for
72 h (Table 2, Entry 8).
Other cyclic ketones were also tested with p-nitrobenzalde-
hyde, each reaciton gave aldol product in good yield except cy-
cloheptanone (Table 2, Entries 9–12). Although good to excel-
lent ee values were attained in almost all cases, the diastereoselc-
tivities were not satisfactory. Acetone was also tested, but the
enantioselectivity of 74% ee did not show any improvement
although with a high yield (Table 2, Entry 13).
Recycling of catalyst and solvent was investigated in terms
of green chemsitry. (Table 2, Entries 14–18). We carried out our
study by using a model reaction. After the reaction was com-
pleted, the product and the remained substrates were extracted
by ether. The residue was dried and reused directly as catalyst
and solvent for the next time. When recycling repeated four
times, about equal amounts of the product was produced with
a slight decrease in the enantioselectivity. Entry 18 in Table 2
proved that the decreased diastereoselectivity was partly attrib-
uted to loss of water.
6
7
a) T. Welton, Chem. Rev. 1999, 99, 2071. b) P. Wasserscheid,
T. Welton, Ionic Liquids in Synthesis, Wiley-VCH, Weinheim,
Germany, 2003. c) P. Wasserscheid, W. Keim, Angew. Chem.,
Int. Ed. 2000, 39, 3772.
´
a) A. Cordova, Tetrahedron Lett. 2004, 45, 3949. b) H.-M.
Guo, L.-F. Cun, L.-Z. Gong, A.-Q. Mi, Y.-Z. Jiang, Chem.
Commun. 2005, 1450. c) J. Shah, H. Blumenthal, Z. Yacob,
J. Liebscher, Adv. Synth. Catal. 2008, 350, 1267. d) Y.-H.
Liu, Y.-W. Zhang, Y.-P. Ding, Z.-X. Shen, X.-Q. Luo, Chin.
J. Chem. 2005, 23, 634.
8
a) R. Gausepohl, P. Buskens, J. Kleinen, A. Bruckmann, C. W.
Lehmann, J. Klankermayer, W. Leitner, Angew. Chem., Int.
Ed. 2006, 45, 3689. b) P. S. Schulz, N. Muller, A. Bosmann,
¨
¨
P. Wasserscheid, Angew. Chem., Int. Ed. 2007, 46, 1293.
c) J. Ding, V. Desikan, X. Han, T. L. Xiao, R. Ding, W. S.
Jenks, D. W. Armstrong, Org. Lett. 2005, 7, 335. d) J. Ding,
D. W. Armstrong, Chirality 2005, 17, 281. e) C. Baudequin,
D. Bregeon, J. Levillain, F. Guillen, J.-C. Plaquevent, A.-C.
Gaumont, Tetrahedron: Asymmetry 2005, 16, 3921. f) J.
Levillain, G. Dubant, I. Abrunhosa, M. Gulea, A.-C. Gaumont,
Chem. Commun. 2003, 2914.
To conclude, we have applied the ionic liquid [EMIm]-
[CF3COO] as an efficient additive for proline-catalyzed direct
asymmetric aldol reactions between cyclic ketones and aromatic
aldehydes in [BMIm]BF4 at room temperature. The correspond-
ing aldol products with low to good yields (trace–93%) and ex-
9
K. K. Laali, V. J. Gettwert, J. Org. Chem. 2001, 66, 35.
Published on the web (Advance View) May 16, 2009; doi:10.1246/cl.2009.576