A green and efficient asymmetric aldol reaction catalyzed by a chiral anion modified ionic liquid

Article abstract of DOI:10.1002/ejoc.201000304

A chiral anion modified ionic liquid derived from L-proline proves as a green, and efficient asymmetric organocatalyst for direct asymmetric aldol reactions in [BMIm]BF₄ at room, temperature. The corresponding aldol products with moderate to go

Full text of DOI:10.1002/ejoc.201000304

FULL PAPER
DOI: 10.1002/ejoc.201000304
A Green and Efficient Asymmetric Aldol Reaction Catalyzed by a Chiral
Anion Modified Ionic Liquid
Yunbo Qian,[a] Xin Zheng,[a] and Yongmei Wang*[a]
Keywords: Asymmetric synthesis / Ionic liquids / Organocatalysis / Aldol reactions / Chirality
A chiral anion modified ionic liquid derived from
L
-proline
tivities (up to 97:3), and excellent enantioselectivities (up to
99%ee) were afforded. Recycling of the catalyst and solvent
([BMIm]BF4) was possible up to four runs with a slight re-
duction in activity.
proves as a green and efficient asymmetric organocatalyst
for direct asymmetric aldol reactions in [BMIm]BF4 at room
temperature. The corresponding aldol products with moder-
ate to good isolated yields (up to 99%), anti-diastereoselec-
Introduction
developed a functional ionic liquid by using -proline
as an anion, but the enantiomeric excess values were less
than 10% when the CIL was applied to direct aldol reac-
tions.
The asymmetric aldol reaction is one of the most impor-
tant carbon–carbon bond-forming reactions in organic syn-
thesis[1] for the production of enantiomerically enriched β-
hydroxy ketones. Since List and Barbas III[2] reported 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.[3,4] How-
ever, the enantio- and diastereoselectivities were not good
enough for their restricted substrate applicability in some
cases. In addition, the organic solvents employed in this re-
action, DMSO and DMF, are not environmentally friendly
and make recycling of the catalyst difficult.
Over the last decade, room-temperature ionic liquids
(ILs) have attracted much attention as an environmentally
benign reaction media because of their fascinating and
characteristic properties.[5] They have also been used as a
substitution for organic solvents in direct aldol reactions
mainly as green and recoverable solvents.[4c,6] Furthermore,
chiral ionic liquids (CILs) have recently emerged as a hot
research focus.[7] Due to their facile chemical modification,
ILs with chiral cations derived from (S)-proline were suc-
cessfully utilized as highly enantioselective organocata-
lysts[4a,8] for aldol reactions, whereas there are only a few
CILs modified on the anion structure.[9] In 2007, Han[10]
Previously, we reported that the anion-modified CIL 1-
ethyl-3-methylimidazolium-(S)-2-pyrrolidinecarboxylic acid
salt [EMIm][Pro][11] (1) could efficiently catalyze the asym-
metric Michael addition reaction through an enamine
mechanism with a catalyst loading of 200 mol-%.[12] Herein,
as a continuation of our work, we would like to disclose the
application of 1 as a green and efficient organocatalyst for
direct asymmetric aldol reactions. Compared to the (S)-pro-
line-catalyzed aldol reaction in organic solvent,[2b] more
convincing results were obtained. When a catalyst loading
of 30 mol-% was used, the corresponding aldol products
were obtained in moderate to excellent yields (up to 99%),
low to high diastereoselectivities (up to 97:3), and good to
excellent enantiomeric excesses (up to 99%). As [BMIm]-
BF4 was used as the solvent, a green and efficient system
was developed, and it could be reused up to four times with
only a slight decrease in activity. To the best of our knowl-
edge, this is the first asymmetric aldol reaction induced by
an anion modified CIL with satisfactory enantioselectivi-
ties, which may greatly expand the scope of the design and
application of CILs.
Results and Discussion
[a] Department of Chemistry, The Key Laboratory of Elemento-
Organic Chemistry, Nankai University,
Tianjin 300071, China
Originally, the model reaction of 4-nitrobenzaldehyde
with cyclohexanone (3 equiv.) was carried out in various
solvents at room temperature by using 1 (30 mol-%) as the
catalyst (Table 1).
Fax: +86-22-2350-2654
E-mail: ymw@nankai.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000304.
3672
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3672–3677

A Green and Efficient Asymmetric Aldol Reaction
Table 1. Optimization of reaction conditions.
To broaden the scope of this transformation, a variety of
aromatic aldehydes were tested with cyclohexanone under
the optimized conditions. As illustrated in Table 2, the reac-
tion of various substituted benzaldehydes bearing an elec-
tron-withdrawing group proceeded smoothly in moderate to
good diastereoselectivities (up to 3:97) and excellent
enantioselectivities (up to 98%) to furnish the anti isomer
of the aldol adducts (Table 2, Entries 1–8), whereas for the
neutral and electron-rich aromatic aldehydes (Table 2, En-
tries 9–11), the reactions commonly required a longer time
(108 h). Lower isolated yields and enantioselectivities were
obtained for p-tolualdehyde and anisaldehyde (Table 2, En-
tries 10 and 11). Other aromatic aldehydes, such as, 2-fural-
dehyde, 2-thenaldehyde, and 2-pyridinylaldehyde, under-
went the aldol reactions as well and generated the corre-
sponding adducts with good enantioselectivities for the
major isomer. Dramatically, the reaction with furfural pri-
marily produced the syn isomer, whereas the diastereoselec-
tivity was disappointingly low for 2-pyridinylaldehyde
(Table 2, Entries 12–14).
Entry
Solvent
Yield[a][%] dr[b] (syn/anti) ee[b][%](syn/anti)
1
2
3
4
5
6
7
8
DMSO
DMF
cyclohexanone
hexane
95
87
98
82
90
75
87
85
77
95
97
97
90
90
46:54
55:45
58:42
36:64
46:54
52:48
45:55
37:63
39:61
22:78
26:74
25:75
22:78
33:67
rac/–11
4/–11
rac
rac
toluene
CH3OH
CH2Cl2
H2O
[BMIm]PF6
[BMIm]BF4
[BMIm]BF4
[BMIm]BF4
[BMIm]BF4
[BMIm]BF4
–10/–18
–20/–30
–21/–27
16/4
–6/–9
94/97
77/93
86/93
89/93
80/91
9
10
11[c]
12[d]
13[e]
14[f]
[a] Isolated yield. [b] Determined by chiral HPLC analysis.
[c] Water (100 mol-%) was added. [d] Cyclohexanone (2 equiv.) was
used. [e] Cyclohexanone (5 equiv.) was used. [f] 20 mol-% of cata-
lyst 1 was used.
To further investigate the generality of the current pro-
cess, several different cycloketones were examined with 4-
nitrobenzaldehyde (Table 2, Entries 15–19). Each reaction
gave the aldol product in good yield except cycloheptanone
(Table 2, Entry 16). Although the diastereoselectivities were
When the reaction was performed in DMSO or DMF, not satisfactory, moderate to excellent enantioselectivities
which are usually used in aldol reaction, almost racemic were attained in almost all cases. When applying 4-methyl-
aldol product 4a was obtained, although an excellent yield cyclohexanone in the present reaction, one more chiral cen-
was obtained after 12 h (Table 1, Entries 1 and 2). Other ter was introduced into the structure of the product
organic solvents and solvent-free conditions were also (Table 2, Entry 19). Predominantly one single syn isomer
tested, but no good results were acquired (Table 1, En- with excellent enantioselectivity (99%ee) was obtained with
tries 3–7). Reactions occurring in toluene, CH3OH, or a ratio of 71:29 to all other isomers. Reaction with acetone
CH2Cl2 exhibited inverted enantioselectivities compared was also carried out, and the adduct was produced with a
with proline-catalyzed reactions; the diastereoselectivities similar ee value (74%) compared to that[2a] obtained with
and ee values were far from satisfactory (Table 1, Entries 5– the proline-catalyzed reaction (Table 2, Entry 20). Signifi-
7). At best, only a slight improvement in the diastereoselec- cantly, no dehydrated products were produced in any of the
tivities was observed with water and [BMIm]PF6, and the reactions listed in Table 2.
enantioselectivities were still disappointing.
After completion of the reaction and subsequent extrac-
However, dramatic changes occurred when the ionic li- tion of the product with ether, catalyst 1 remaining in
quid [BMIm]BF4 was employed in conjunction with cata- [BMIm]BF4 can be reused directly in subsequent reactions.
lyst 1: the aldol adduct was afforded in 98% yield with Table 3 showed that the catalyst and the solvent could be
moderate diastereoselectivity (78:22) and excellent ee value recycled together four times with a slight decrease in ac-
(97%/94%) for both isomers. Moreover, no inverted tivity and stereoselectivity.
enantioselectivity was observed with the use of [BMIm]BF4.
A proline–imidazole conjugate catalysis has also been
Thus, the unique ionic liquid [BMIm]BF4 when used as a proposed as a probable transition state of the asymmetric
solvent plays a crucial role in the stereoselectivity of this aldol reaction (Figure 1). As major product 4a had (2S,1ЈR)
[2b]
reaction. Although the solvent effect between [BMIm][BF4]
absolute stereochemistry, the enamine intermediate of
and [BMIm][PF6] was not clear at this stage, we proposed
–
–
that because BF4 was more electronegative than PF6 , the
BF4– ion has a much stronger ionicity, which could stabilize
the enamine transition state. Water was added to improve
the diastereoselectivity, but no obvious effect was detected
(Table 1, Entry 11). Examination of the ratio of the reac-
tants indicated that 3 equivalents of donor cyclohexanone
to 1 equivalent of acceptor aldehyde gave the best results
(Table 1, Entries 12 and 13). Reducing the catalyst loading
to 20 mol-% resulted in a lower dr value (33:67; Table 1,
Entry 14).
Figure 1. Proposed transition state.
Eur. J. Org. Chem. 2010, 3672–3677
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3673

Y. Qian, X. Zheng, Y. Wang
FULL PAPER
Table 2. Screening of different aromatic aldehydes with cyclic ketones.
[a] Isolated yield. [b] Determined by chiral HPLC analysis. [c] Determined by 1HNMR spectroscopic analysis. [d] Not detected. [e] Inverted
diastereoselectivity was observed.
Table 3. Recycling study of [EMIm][Pro] (1) using the model reac- and the imidazolium moiety of the catalyst is expected to
tion.
stabilize the transition state and make the selectivity pos-
sible.
dr[b]
(syn/anti)
ee[b] [%]
(syn/anti)
Entry
Reuse
t [h] Yield[a][%]
1
2
3
4
5
6
95
90
91
89
93
22:78
30:70
33:67
40:60
32:68
94/97
69/91
75/87
56/79
70/85
1
2
3
4
12
12
24
24
Conclusions
To conclude, we have applied the anion-modified CIL
[EMIm][Pro] (1) as a green and efficient asymmetric
organocatalyst in direct aldol condensation reactions. It
broadly expands the substrate applicability with close to
[a] Isolated yield. [b] Determined by chiral HPLC analysis.
the reaction favored Re facial attack on the arylaldehyde. perfect diastereo- and enantioselectivities. The employment
An electrostatic interaction between the aromatic aldehyde of the ionic liquid as either a catalyst or the solvent made
3674
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3672–3677

A Green and Efficient Asymmetric Aldol Reaction
(2S,1ЈR)-2-{Hydroxy[p-(trifluoromethyl)phenyl]methyl}cyclohexan-
1-one:[14,18] Yield: 23.1 mg, 85 % (Table 2, Entry 4). 1H NMR
(400 MHz, CDCl3): δ = 7.60 (d, J = 7.8 Hz, 2 H, Ar), 7.44 (d, J =
7.9 Hz, 2 H, Ar), 4.84 (d, J = 8.2 Hz, 1 H, CH), 4.04 (br. s, 1 H,
OH), 2.32–2.62 (m, 3 H, CH, CH2), 2.08–2.12 (m, 1 H, CH), 1.49–
1.82 (m, 4 H, CH2), 1.28–1.38 (m, 1 H, CH) ppm. HPLC (Chi-
ralpak AD-H column, hexane/2-propanol = 90:10, ow rate =
1.0 mLmin–1, λ = 254 nm): tR = 10.52 (minor), 12.86 min (major).
the aldol process environmentally benign and more atom
economical. Moreover, the system can be reused over four
runs with only a slight decrease in activity. As a result, this
procedure was proved to be a green and attractive alterna-
tive to the existing methods for the synthesis of β-hydroxy
ketones. Further investigations on the design of similar
CILs that may influence the outcome of asymmetric reac-
tions are underway.
(2S,1ЈR)-2-[Hydroxy(p-fluorophenyl)methyl]cyclohexan-1-one:[14,18]
Yield: 16.2 mg, 73 % (Table 2, Entry 5). 1H NMR (400 MHz,
CDCl3): δ = 7.26–7.30 (m, 2 H, Ar), 7.01–7.06 (m, 2 H, Ar) 4.78
(d, J = 8.8 Hz, 1 H, CH), 4.00 (br. s, 1 H, OH), 2.32–2.62 (m, 3 H,
CH, CH2), 2.08–2.12 (m, 1 H, CH), 1.57–1.89 (m, 4 H, CH2), 1.23–
1.34 (m, 1 H, CH) ppm. HPLC (Chiralpak AD-H column, hexane/
Experimental Section
General Methods: Commercial reagents were used as received, un-
less otherwise stated. 1H and 13C NMR spectra were recorded with
either a Bruker-DPX 300 or AV-400 spectrometer. Chemical shifts
are reported in ppm from tetramethylsilane with the solvent reso-
nance as the internal standard. HPLC analysis was performed with
a Shimadzu CTO-10AS by using a Chiralpak AD-H or OD-H col-
umn purchased from Daicel Chemical Industries.
2-propanol = 90:10, ow rate = 1.0 mLmin–1, λ = 254 nm): tR
=
12.93 (minor), 13.98 min (major).
(2S,1ЈR)-2-[Hydroxy(p-chlorophenyl)methyl]cyclohexan-1-one:[15,18]
Yield: 19.9 mg, 84 % (Table 2, Entry 6). 1H NMR (400 MHz,
CDCl3): δ = 7.31–7.33 (m, 2 H, Ar), 7.23–7.27 (m, 2 H, Ar), 4.76
(d, J = 8.7 Hz, 1 H, CH), 4.01 (s, 1 H, OH), 2.32–2.59 (m, 3 H,
CH, CH2), 2.08–2.12 (m, 1 H, CH), 1.49–1.87 (m, 4 H, CH2), 1.24–
1.34 (m, 1 H, CH) ppm. HPLC (Chiralpak AD-H column, hexane/
Typical Procedure for Direct Asymmetric Aldol Reaction: Cyclo-
hexanone (29.5 mg, 0.3 mmol) was injected into a vial containing
catalyst 1 (6.7 mg, 0.03 mmol) in [BMIm]BF4 (0.25 mL) at room
temperature. The mixture was then stirred for 30 min before p-ni-
trobenzaldehyde (15.1 mg, 0.1 mmol) was added. The mixture was
vigorously stirred and monitored by TLC. When the reaction was
complete, the mixture was extracted with diethyl ether and then
purified by flash silica gel chromatography (ethyl acetate/hexane,
1:3) to afford the product as a white solid. Yield: 23.6 mg (95%);
22:78 dr (determined by HPLC) and 94:97%ee. HPLC (Chiralpak
2-propanol = 90:10, ow rate = 1.0 mLmin–1, λ = 254 nm): tR
=
13.65 (minor), 15.58 min (major).
(2S,1ЈR)-2-[Hydroxy(o-chlorophenyl)methyl]cyclohexan-1-one:[14]
Yield: 21.4 mg, 90 % (Table 2, Entry 7). 1H NMR (400 MHz,
CDCl3): δ = 7.54–7.56 (m, 2 H, Ar), 7.22–7.34 (m, 2 H, Ar), 5.36
(d, J = 7.7 Hz, 1 H, CH), 4.04 (s, 1 H, OH), 2.34–2.71 (m, 3 H,
CH, CH2), 2.10–2.12 (m, 1 H, CH), 1.57–1.84 (m, 5 H, CH, CH2)
ppm. HPLC (Chiralpak AD-H column, hexane/2-propanol =
90:10, ow rate = 1.0 mLmin–1, λ = 254 nm): tR = 12.96 (minor),
11.43 min (major).
(2S,1ЈR)-2-[Hydroxy(p-bromophenyl)methyl]cyclohexan-1-one:[14,18]
Yield: 23.9 mg, 85 % (Table 2, Entry 8). 1H NMR (400 MHz,
CDCl3): δ = 7.45–7.49 (m, 2 H, Ar), 7.17–7.21 (m, 2 H, Ar), 4.75
(dd, J = 8.7, 2.4 Hz, 1 H, CH), 4.01 (s, 1 H, OH), 2.31–2.59 (m, 3
H, CH, CH2), 2.07–2.13 (m, 1 H, CH), 1.49–1.87 (m, 4 H, CH2),
1.25–1.34 (m, 1 H, CH) ppm. HPLC (Chiralpak AD-H column,
hexane/2-propanol = 90:10, ow rate = 1.0 mLmin–1, λ = 254 nm):
tR = 14.73 (minor), 17.04 min (major).
AD-H column, hexane/2-propanol
= 90:10, flow rate =
1.0 mLmin–1, λ = 254 nm): tR (syn isomer) = 21.85 (minor),
19.04 min (major); tR (anti isomer) = 24.25 (minor), 32.28 min
(major).
(2S,1ЈR)-2-[Hydroxy(p-nitrophenyl)methyl]cyclohexan-1-one:[13–15]
Yield: 23.6 mg, 95 % (Table 2, Entry 1). 1H NMR (400 MHz,
CDCl3): δ = 8.22 (d, J = 7.9 Hz, 2 H, Ar), 7.51 (d, J = 8.0 Hz, 2
H, Ar), 4.90 (d, J = 7.9 Hz, 1 H, CH), 4.09 (s, 1 H, OH), 2.58–
2.62 (m, 1 H, CH), 2.49–2.52 (m, 1 H, CH), 2.36–2.41 (m, 1 H,
CH), 2.11–2.14 (m, 1 H, CH), 1.35–1.85 (m, 5 H, CH, CH2) ppm.
HPLC (Chiralpak AD-H column, hexane/2-propanol = 90:10, ow
rate = 1.0 mLmin–1, λ = 254 nm): tR = 24.25 (minor), 32.28 min
(major).
(2S,1ЈR)-2-[Hydroxy(phenyl)methyl]cyclohexan-1-one:[13–15] Yield:
1
8.3 mg, 41% (Table 2, Entry 9). H NMR (400 MHz, CDCl3): δ =
7.30–7.36 (m, 5 H, Ar), 4.79 (d, J = 8.6 Hz, 1 H, CH), 3.97 (s, 1
H, OH), 2.33–2.67 (m, 3 H, CH, CH2), 2.07–2.11 (m, 1 H, CH),
1.51–1.81 (m, 4 H, CH2), 1.23–1.37 (m, 1 H, CH) ppm. HPLC
(Chiralpak OD-H column, hexane/2-propanol = 95:5, ow rate =
1.0 mLmin–1, λ = 254 nm): tR = 17.26 (minor), 12.29 min (major).
(2S,1ЈR)-2-[Hydroxy(p-tolyl)methyl]cyclohexan-1-one:[16,18] Yield:
8.5 mg, 39% (Table 2, Entry 10). 1H NMR (400 MHz, CDCl3): δ
= 7.15–7.22 (m, 4 H, Ar), 4.79 (d, J = 8.5 Hz, 1 H, CH), 3.93 (s, 1
H, OH), 2.40–2.64 (m, 3 H, CH, CH2), 2.34 (s, 3 H, CH3), 2.09–
2.10 (m, 1 H, CH), 1.60–1.80 (m, 4 H, CH, CH2), 1.27–1.34 (m, 1
H, CH) ppm. HPLC (Chiralpak OD-H column, hexane/2-propanol
= 90:10, ow rate = 1.0 mLmin–1, λ = 254 nm): tR = 9.18 (minor),
7.46 min (major).
(2S,1ЈR)-2-[Hydroxy(m-nitrophenyl)methyl]cyclohexan-1-one:[13–15]
Yield: 22.8 mg, 92 % (Table 2, Entry 2). 1H NMR (400 MHz,
CDCl3): δ = 8.21 (m, 1 H, Ar), 8.16–8.18 (m, 1 H, Ar), 7.67–7.69
(m, 1 H, Ar), 7.52–7.56 (m, 1 H, Ar), 4.90 (d, J = 8.5 Hz, 1 H,
CH), 4.14 (br. s, 1 H, OH), 2.59–2.68 (m, 1 H, CH), 2.49–2.53 (m,
1 H, CH), 2.34–2.42 (m, 1 H, CH), 2.10–2.15 (m, 1 H, CH), 1.82–
1.87 (m, 1 H, CH), 1.52–1.77 (m, 3 H, CH, CH2), 1.37–1.44 (m, 1
H, CH) ppm. HPLC (Chiralpak AD-H column, hexane/2-propanol
= 92:8, ow rate = 1.0 mLmin–1, λ = 254 nm): tR = 24.61 (major),
31.29 min (minor).
(2S,1ЈR)-2-[Hydroxy(o-nitrophenyl)methyl]cyclohexan-1-one:[14,18]
Yield: 21.9 mg, 88 % (Table 2, Entry 3). 1H NMR (400 MHz,
CDCl3): δ = 7.76–7.86 (m, 2 H, Ar), 7.66 (m, 1 H, Ar), 7.43–7.45
(m, 1 H, Ar), 5.45 (d, J = 6.5 Hz, 1 H, CH), 4.14 (br. s, 1 H, OH),
2.74–2.78 (m, 1 H, CH), 2.44–2.46 (m, 1 H, CH), 2.31–2.37 (m, 1
(2S,1ЈR)-2-[Hydroxy(p-methoxyphenyl)methyl]cyclohexan-1-
one:[13,18] Yield: 7.9 mg, 34 % (Table 2, Entry 11). 1H NMR
H, CH), 1.84–1.87 (m, 1 H, CH), 1.53–1.78 (m, 5 H, CH, CH2) (400 MHz, CDCl3): δ = 7.23–7.24 (m, 2 H, Ar), 6.88–6.90 (m, 2 H,
ppm. HPLC (Chiralpak AD-H column, hexane/2-propanol = 92:8,
ow rate = 1.0 mLmin–1, λ = 254 nm): tR = 24.76 (major), 26.92 min
(minor).
Ar), 4.75 (d, J = 8.3 Hz, 1 H, CH), 3.94 (s, 1 H, OH), 3.81 (s, 3 H,
OCH3), 2.33–2.63 (m, 3 H, CH, CH2), 2.08–2.11 (m, 1 H, CH),
1.57–1.80 (m, 4 H, CH2), 1.24–1.32 (m, 1 H, CH) ppm. HPLC
Eur. J. Org. Chem. 2010, 3672–3677
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3675

Y. Qian, X. Zheng, Y. Wang
FULL PAPER
(Chiralpak AD-H column, hexane/2-propanol = 95:5, ow rate =
(400 MHz, CDCl3): δ = 8.20 (d, J = 8.7 Hz, 2 H, Ar), 7.49 (d, J =
8.6 Hz, 2 H, Ar), 5.48 (br. s, 1 H, CH), 3.15 (s, 1 H, OH), 2.66–
2.72 (m, 1 H, CH), 2.37–2.56 (m, 2 H, CH2), 2.02–2.06 (m, 1 H,
CH), 1.77–1.97 (m, 2 H, CH2) 1.57–1.63 (m, 1 H, CH), 1.36–1.52
(m, 1 H, CH), 0.93 (d, J = 6.5 Hz, 3 H, CH3) ppm. HPLC (Chi-
ralpak AD-H column, hexane/2-propanol = 92:8, ow rate =
1.0 mLmin–1, λ = 254 nm): tR = 23.58 (minor), 22.54 min (major).
(R)-4-Hydroxy-4-(p-nitrophenyl)butan-2-one:[3,15] Yield: 19.0 mg,
91% (Table 2, Entry 20). 1H NMR (400 MHz, CDCl3): δ = 8.21 (d,
J = 8.7 Hz, 2 H, Ar), 7.54 (d, J = 8.7 Hz, 2 H, Ar), 5.26 (d, J =
8.0 Hz, 1 H, CH), 3.60 (s, 1 H, OH), 2.82–2.85 (m, 2 H, CH2), 2.20
(s, 3 H, CH3) ppm. HPLC (Chiralpak AD-H column, hexane/2-
propanol = 90:10, ow rate = 0.6 mLmin–1, λ = 254 nm): tR = 25.86
(minor), 26.81 min (major).
1.0 mLmin–1, λ = 254 nm): tR = 31.38 (minor), 33.01 min (major).
(2R,1ЈR)-2-[Hydroxy(furan-2-yl)methyl]cyclohexan-1-one:[18] Yield:
1
14.7 mg, 76% (Table 2, Entry 12). H NMR (400 MHz, CDCl3): δ
= 7.32 (m, 1 H, Ar), 6.25–6.32 (m, 2 H, Ar), 5.29 (br. s, 1 H, CH),
4.05 (s, 1 H, OH), 2.32–2.95 (m, 3 H, CH, CH2), 2.04–2.17 (m, 1
H, CH), 1.60–1.89 (m, 4 H, CH2), 1.30–1.44 (m, 1 H, CH) ppm.
HPLC (Chiralpak AD-H column, hexane/2-propanol = 95:5, ow
rate = 1.0 mLmin–1, λ = 254 nm): tR = 20.45 (minor), 22.59 min
(major).
(2S,1ЈR)-2-[Hydroxy(thien-2-yl)methyl]cyclohexan-1-one:[17,21]
Yield: 11.9 mg, 57 % (Table 2, Entry 13). 1H NMR (400 MHz,
CDCl3): δ = 7.3 (m, 1 H, Ar), 6.93–6.96 (m, 2 H, Ar), 5.09 (d, J =
8.2 Hz, 1 H, CH), 4.11 (s, 1 H, OH), 2.33–2.70 (m, 3 H), 2.10–2.13
(m, 1 H), 1.63–1.86 (m, 4 H), 1.34–1.40 (m, 1 H) ppm. HPLC
(Chiralpak AD-H column, hexane/2-propanol = 90:10, ow rate =
1.0 mLmin–1, λ = 254 nm): tR = 14.65 (minor), 13.25 min (major).
Supporting Information (see footnote on the first page of this arti-
cle): Selected 1H NMR spectroscopic data for diastereoisomers and
HPLC data for enantiomers of aldol adducts.
(2S,1ЈR)-2-[Hydroxy(pyrid-2-yl)methyl]cyclohexan-1-one:[19] Yield:
20.2 mg, 99% (Table 2, Entry 14). H NMR (400 MHz, CDCl3): δ
1
Acknowledgments
= 8.53–8.55 (m, 1 H, Ar), 7.68–7.72 (m, 1 H, Ar), 7.48 (d, J =
7.8 Hz, 1 H, Ar), 7.17–7.21 (m, 1 H, Ar), 4.91 (br. s, 1 H, CH),
4.31 (s, 1 H, OH), 2.97–3.10 (m, 1 H, CH), 2.33–2.49 (m, 2 H,
CH2), 2.07–2.10 (m, 1 H, CH), 1.82–1.89 (m, 1 H, CH), 1.46–1.77
(m, 4 H, CH2) ppm. HPLC (Chiralpak AD-H column, hexane/2-
propanol = 99:1, ow rate = 1.0 mLmin–1, λ = 254 nm): tR = 68.24
(minor), 66.12 min (major).
The work was financially supported by the National Natural Sci-
ence Foundation of China (973 Project no. 2010CB833300) and
The Research Fund for the Doctoral Program of Higher Education
(no. 20090031110019, China). We also thank the Nankai Univer-
sity State Key Laboratory of Elemento-Organic Chemistry for sup-
port.
(2S,1ЈR)-2-[Hydroxy(p-nitrophenyl)methyl]cyclopentan-1-one:[13–15]
Yield: 23.0 mg, 98 % (Table 2, Entry 15). 1H NMR (400 MHz,
CDCl3): δ = 8.22 (d, J = 8.7 Hz, 2 H, Ar), 7.51 (d, J = 8.6 Hz, 2
H, Ar), 4.85 (d, J = 9.2 Hz, CH), 4.79 (s, 1 H, OH), 2.34–2.51 (m,
2 H, CH2), 1.96–2.18 (m, 2 H, CH2), 1.53–1.77 (m, 3 H, CH, CH2)
ppm. HPLC (Chiralpak AD-H column, hexane/2-propanol = 95:5,
ow rate = 1.0 mLmin–1, λ = 254 nm): tR = 44.18 (minor), 44.91 min
(major).
[1] a) C. H. Heathcock in Comprehensive Organic Synthesis (Eds.:
B. M. Trost, I. Fleming, C. H. Heathcock), Pergamon, Oxford,
1991, vol. 2, ch. 1.5 and 1.6; b) R. Mahrwald in Modern Aldol
Reactions (Ed.: R. Mahrwald) Wiley-VCH, Weinheim, 2004,
vols. 1 and 2.
[2] a) B. List, R. A. Lerner, C. F. Barbas III, J. Am. Chem. Soc.
2000, 122, 2395–2396; b) K. Sakthivel, W. Notz, T. Bui, C. F.
Barbas III, J. Am. Chem. Soc. 2001, 123, 5260–5267.
[3] a) Reviews: S. Mukherjee, J. W. Yang, S. Hoffmann, B. List,
Chem. Rev. 2007, 107, 5471–5569; b) G. Guillena, C. Nájera,
D. J. Ramón, Tetrahedron: Asymmetry 2007, 18, 2249–2293; c)
B. List, Tetrahedron 2002, 58, 5573–5590; d) W. Notz, F.
Tanaka, C. F. Barbas III, Acc. Chem. Res. 2004, 37, 580–591.
[4] a) Examples: M. Lombardo, S. Easwar, F. Pasi, C. Trombinia,
Adv. Synth. Catal. 2009, 351, 276–282; b) S.-P. Zhang, X.-K.
Fu, S.-D. Fu, J.-F. Pan, Catal. Commun. 2009, 10, 401–405; c)
J. Shah, H. Blumenthal, Z. Yacob, J. Liebscher, Adv. Synth.
Catal. 2008, 350, 1267–1270; d) H. Inoue, M. Kikuchi, J. Ito,
H. Nishiyama, Tetrahedron 2008, 64, 493–499; e) D. E. Siyut-
kin, A. S. Kucherenko, M. I. Struchkova, S. G. Zlotin, Tetrahe-
dron Lett. 2008, 49, 1212–1216; f) J. Huang, X. Zhang, D. W.
Armstrong, Angew. Chem. Int. Ed. 2007, 46, 9073 –9077; g) B.
Rodríguez, A. Bruckmann, C. Bolm, Chem. Eur. J. 2007, 13,
4710–4722; h) S. Luo, J. Li, H. Xu, L. Zhang, J.-P. Cheng, Org.
Lett. 2007, 9, 3675–3678.
[5] a) T. Welton, Chem. Rev. 1999, 99, 2071–2084; b) J. Dupont,
R. F. de Souza, P. A. Z. Suarez, Chem. Rev. 2002, 102, 3667–
3692; c) P. Wasserscheid, W. Keim, Angew. Chem. Int. Ed. 2000,
39, 3772–3789; d) J. Levillain, D. Cahard, A.-C. Gaumont, J. C.
Plaqueventa, Tetrahedron: Asymmetry 2003, 14, 3081–3093.
[6] a) M. Lombardo, S. Easwar, F. Pasi, C. Trombinia, D. D.
Dhavale, Tetrahedron 2008, 64, 9203–9207; b) H.-M. Guo, L.-
F. Cun, L.-Z. Gong, A.-Q. Mi, Y.-Z. Jiang, Chem. Commun.
2005, 1450–1452; c) Y.-H. Liu, Y.-W. Zhang, Y.-P. Ding, Z.-X.
Shen, X.-Q. Luo, Chin. J. Chem. 2005, 23, 634–636; d) A.
Córdova, Tetrahedron Lett. 2004, 45, 3949–3952; e) T.-P. Loh,
L.-C. Feng, H.-Y. Yang, J.-Y. Yang, Tetrahedron Lett. 2002, 43,
8741–8743; f) P. Kotrusz, I. Kmentová, B. Gotov, S. Toma, E.
Solcániová, Chem. Commun. 2002, 2510–2511.
(2S,1ЈR)-2-[Hydroxy(p-nitrophenyl)methyl]cycloheptan-1-one:[15,18]
Yield: 8.1 mg, 31 % (Table 2, Entry 16). 1H NMR (400 MHz,
CDCl3): δ = 8.22 (d, J = 8.7 Hz, 2 H, Ar), 7.53 (d, J = 8.6 Hz, 2
H, Ar), 4.92 (dd, J = 6.4, 5.0 Hz, CH), 3.72–3.74 (s, 1 H, OH),
2.96–3.00 (m, 1 H, CH), 2.44–2.60 (m, 2 H, CH2), 1.26–1.90 (m, 8
H, CH2) ppm. HPLC (Chiralpak AD-H column, hexane/2-propa-
nol = 90:10, ow rate = 1.0 mL min–1, λ = 254 nm): tR = 18.89
(minor), 45.66 min (major).
(2S,1ЈR)-2-[Hydroxy(p-nitrophenyl)methyl]tetrahydro-4-H-pyran-4-
one:[16] Yield: 26.4 mg, 99 % (Table 2, Entry 17). 1H NMR
(400 MHz, CDCl3): δ = 8.23 (d, J = 8.7 Hz, 2 H, Ar), 7.52 (d, J =
8.6 Hz, 2 H, Ar), 5.00 (d, J = 7.7 Hz, CH) 4.19–4.27 (s, 1 H, OH),
3.71–3.88 (m, 3 H, CH, CH2), 3.46 (t, J = 10.54, 10.54 Hz, 1 H,
CH), 2.46–2.95 (m, 3 H, CH, CH2) ppm. HPLC (Chiralpak AD-
H column, hexane/2-propanol = 90:10, ow rate = 1.0 mLmin–1, λ
= 254 nm): tR = 47.41 (minor), 56.11 min (major).
(2S,1ЈR)-2-[Hydroxy(p-nitrophenyl)methyl]tetrahydrothiopyran-4-
one:[15,16] Yield: 25.8 mg, 97 % (Table 2, Entry 18). 1H NMR
(400 MHz, CDCl3): δ = 8.24 (d, J = 8.7 Hz, 2 H, Ar), 7.54 (d, J =
8.6 Hz, 2 H, Ar), 5.05 (dd, J = 8.0, 3.6 Hz, CH), 3.64 (d, J =
3.8 Hz, 1 H, OH), 2.65–3.05 (m, 6 H, CH, CH2), 2.51–2.53 (m, 1
H, CH) ppm. HPLC (Chiralpak AD-H column, hexane/2-propanol
= 90:10, ow rate = 1.0 mLmin–1, λ = 254 nm): tR = 59.88 (minor),
71.04 min (major).
(2R,4S)-2-[(R)-Hydroxy(p-nitrophenyl)methyl]-4-methylcyclo-
hexanone:[20] Yield: 22.3 mg, 85% (Table 2, Entry 19). 1H NMR
3676
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3672–3677

A Green and Efficient Asymmetric Aldol Reaction
[7] a) P. S. Schulz, N. Müller, A. Bösmann, P. Wasserscheid, An-
gew. Chem. Int. Ed. 2007, 46, 1293–1295; b) R. Gausepohl, P.
Buskens, J. Kleinen, A. Bruckmann, C. W. Lehmann, J. Klank-
ermayer, W. Leitner, Angew. Chem. Int. Ed. 2006, 45, 3689–
3692; c) J. Ding, V. Desikan, X. Han, T. L. Xiao, R. Ding, W. S.
Jenks, D. W. Armstrong, Org. Lett. 2005, 7, 335–337; d) J.
Ding, D. W. Armstrong, Chirality 2005, 17, 281–292; e) C. Bau-
dequin, 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. Gau-
mont, Chem. Commun. 2003, 2914–2915; g) J.-C. Plaquevent,
J. Levillain, F. Guillen, C. Malhiac, A.-C. Gaumont, Chem.
Rev. 2008, 108, 5035–5060; h) K. Bica, P. Gaertner, Eur. J. Org.
Chem. 2008, 3235–3250; i) X. Chen, X. Li, A. Hu, F. Wang,
Tetrahedron: Asymmetry 2008, 19, 1–14; j) H. Ohno, K. Fuku-
moto, Acc. Chem. Res. 2007, 40, 1122–1129.
[8] a) D. E. Siyutkin, A. S. Kucherenko, S. G. Zlotin, Tetrahedron
2009, 65, 1366–1372; b) L. Zhang, S. Luo, X. Mi, S. Liu, Y.
Qiao, H. Xu, J.-P. Cheng, Org. Biomol. Chem. 2008, 6, 567–
576; c) D. E. Siyutkin, A. S. Kucherenko, M. I. Struchkova,
S. G. Zlotin, Tetrahedron Lett. 2008, 49, 1212–1216; d) C. Ap-
rile, F. Giacalone, M. Gruttadauria, A. M. Marculescu, R.
Noto, J. D. Revell, H. Wennemers, Green Chem. 2007, 9, 1328–
1334; e) M. Lombardo, F. Pasi, S. Easwar, C. Trombini, Adv.
Synth. Catal. 2007, 349, 2061–2065; f) L. Zhou, L. Wang,
Chem. Lett. 2007, 36, 628–629; g) S. Luo, X. Mi, L. Zhang, S.
Liu, H. Xu, J.-P. Cheng, Tetrahedron 2007, 63, 1923–1930; h)
W. Miao, T. H. Chan, Adv. Synth. Catal. 2006, 348, 1711–1718;
i) M. Gruttadauria, S. Riela, C. Aprile, P. L. Meo, F. D’Anna,
R. Noto, Adv. Synth. Catal. 2006, 348, 82–92; j) S. Luo, X. Mi,
L. Zhang, S. Liu, H. Xu, J.-P. Cheng, Angew. Chem. Int. Ed.
2006, 45, 3093–3097.
[9]
a) W. Zhou, L.-W. Xu, H.-Y. Qiu, G.-Q. Lai, C.-G. Xia, J.-X.
Jiang, Helv. Chim. Acta 2008, 91, 53–59; b) H. Zhao, L. Jack-
son, Z. Song, O. Olubajo, Tetrahedron: Asymmetry 2006, 17,
1549–1553; c) M. Bian, F. Xu, C. Ma, Synthesis 2007, 19,
2951–2956; d) L. C. Branco, P. M. P. Gois, N. M. T. Lourenço,
V. B. Kurteva, C. A. M. Afonso, Chem. Commun. 2006, 22,
2371–2372.
S. Hu, T. Jiang, Z. Zhang, A. Zhu, B. Han, J. Song, Y. Xie, W.
Li, Tetrahedron Lett. 2007, 48, 5613–5617.
K. Fukumoto, M. Yoshizawa, H. Ohno, J. Am. Chem. Soc.
2005, 127, 2398–2399.
Y. Qian, S. Xiao, L. Liu, Y. Wang, Tetrahedron: Asymmetry
2008, 19, 1515–1518.
[10]
[11]
[12]
[13]
[14]
Y.-C. Teo, G.-L. Chua, Tetrahedron Lett. 2008, 49, 4235–4238.
C. Wang, Y. Jiang, X. Zhang, Y. Huang, B. Li, G. Zhang, Tet-
rahedron Lett. 2007, 48, 4281–4285.
B. Rodríguez, A. Bruckmann, C. Bolm, Chem. Eur. J. 2007, 13,
4710–4722.
[15]
[16] L. He, J. Jiang, Z. Tang, X. Cui, A.-Q. Mi, Y.-Z. Jiang, L.-Z.
Gong, Tetrahedron: Asymmetry 2007, 18, 265–270.
[17] H. Jiang, Z. Liang, X. Wu, Y. Lu, Chem. Commun. 2006, 2801–
2803.
[18] Y. Wu, Y. Zhang, M. Yu, G. Zhao, S. Wang, Org. Lett. 2006,
8, 4417–4420.
[19] S. S. Chimni, D. Mahajan, Tetrahedron 2005, 61, 5019–5025.
[20] S. Luo, H. Xu, J. Li, L. Zhang, X. Mi, X. Zheng, J.-P. Cheng,
Tetrahedron 2007, 63, 11307–11314.
[21] M. Kawai, M. Onaka, Y. Izumi, Bull. Chem. Soc. Jpn. 1988,
61,1237–1245.
Received: March 4, 2010
Published Online: May 12, 2010
Eur. J. Org. Chem. 2010, 3672–3677
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3677