A highly efficient large-scale asymmetric direct intermolecular aldol reaction employing L-prolinamide as a recoverable catalyst

Article abstract of DOI:10.1002/adsc.201000355

A new, simple bifunctional, recoverable and reusable L-prolinamide organocatalyst that promotes aldol reactions while achieving a respectable level of enantioselectivity is reported. This organocatalyst is applicable to the reactions of a wide range of ar

Full text of DOI:10.1002/adsc.201000355

FULL PAPERS
DOI: 10.1002/adsc.201000355
A Highly Efficient Large-Scale Asymmetric Direct Intermolecular
Aldol Reaction Employing l-Prolinamide as a Recoverable
Catalyst
Yang Yang,a,b Yan-Hong He,a,b Zhi Guan,a,* and Wei-Da Huanga
a
School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, Peopleꢀs Republic of China
Fax : (+86)-23-6825-4091; e-mail: guanzhi@swu.edu.cn
These two authors contributed equally to this work
b
Received: May 6, 2010; Revised: August 2, 2010; Published online: September 22, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000355.
Abstract: A new, simple bifunctional, recoverable reused, and only a slight decrease of enantioselectivi-
and reusable l-prolinamide organocatalyst that pro- ty was observed for five cycles. This novel catalyst
motes aldol reactions while achieving a respectable can be efficiently used in large-scale reactions with
level of enantioselectivity is reported. This organoca- the enantioselectivity being maintained at the same
talyst is applicable to the reactions of a wide range level, which offers a great possibility for application
of aromatic and heteroaromatic aldehydes with in industry.
cyclic and acyclic ketones, and the anti-aldol prod-
ucts could be obtained with up to 99:1 anti/syn ratio Keywords: aldol reaction; asymmetric organocataly-
and 98% ee. The catalyst can be easily recovered and sis; large-scale reaction; recoverable catalyst
Introduction
deal of effort is currently being made in the search
for elegant and practical solutions for aldol reaction.
Asymmetric synthesis is dedicated to the preparation Impressive achievements in asymmetric aldol method-
of chiral compounds with defined three-dimensional ology have been made which, in general, rely on the
molecular structures. Its importance is probably best use of the organocatalysts. List et al. reported the in-
appreciated in the context of drug-receptor interac- termolecular direct aldol addition reaction of acetone
tions, because most biological targets are chiral enti- to various aldehydes catalyzed by proline in 2000.[5]
ties.[1] During the past few years, the field of asymmet- Since then, a tremendous amount of research has
ric catalysis, previously dominated by biocatalysis and been directed towards identifying new types of chiral
metal catalysis, has been complemented by organoca- enamine catalysts. Barbas,[6] Hayashi,[7] Gong,[8]
talysis using small organic molecules as a third power- Xiao[9] et al. reported the intermolecular aldol reac-
ful tool. The advent of organocatalysis brought the tions of the ketone-aldehyde type and aldehyde-alde-
prospect of a complementary mode of catalysis, with hyde type catalyzed by l-proline or its derivatives and
the potential for savings in cost, time and energy, an analogues. However, their shortcomings have also
easier experimental procedure, and reductions in been realized. One of the major limitations using or-
chemical waste.[2] On the other hand, the aldol reac- ganocatalyst catalyzed reactions is the high catalyst
tion is one of the most powerful methods for the for- loading (10–30 mol%) generally required to complete
[3]
À
mation of C C bonds in organic synthesis. The clas- the transformations in reasonable timescales. This will
sical aldol reaction is highly atom-economic but suf- raise a cost concern when large amounts of chiral ma-
fers from problems with selectivity, notably, with re- terials are used for a large-scale synthesis in industrial
spect to chemo- and regioselectivity. One of the diffi- applications. In spite of significant efforts devoted to
cult challenge is the design of sustainable the development of highly active organocatalysts
organocatalyzed processes, which are not only more aimed at lowering catalyst loading, it has proved to be
economical but also more benign towards the envi- a significant challenging task, and only limited success
ronment and more practicable in both industry and has been achieved so far. An alternative strategy is to
experiment.[4] Stimulated by this challenge, a great design recyclable and subsequently reusable organo-
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FULL PAPERS
catalysts. Meanwhile efforts also have been made on model reaction to investigate different parameters,
organocatalyst recycling using ionic liquids, solid- such as the catalysts, the cocatalysts, the stoichiometry
phase supports, and fluorous technologies.[10,11] of reactants, loading of the catalysts and cocatalysts
Herein, we wish to report a new, simple bifunctional, and temperature. In our initial investigation l-proline
recoverable and reusable l-prolinamide organocata- and 1a–e were screened as catalysts. As can be seen
lyst that promotes aldol reactions while achieving a from the summarized results in Table 1, all the cata-
respectable level of enantioselectivity, and this cata- lysts can catalyze the asymmetric direct intermolecu-
lyst can be used in large-scale reactions with the enan- lar aldol reaction of 4-nitrobenzaldehyde and cyclo-
tioselectivity being maintained at the same level.
hexanone to give the product in good yields (80–
92%) with different ee values (63–90% ee for anti) in
CH3CN at À208C (Table 1, entries 1–6). The best
enantioselectivity of 90% ee was achieved when 1b
was used, while the more sterically hindered 1c
Results and Discussion
Prolinamides have been popularly designed to modu- showed a lower enantioselectivity (85% ee), which
late the catalystꢀs hydrogen bonding ability to im- suggested that the steric property is essential to maxi-
prove the catalytic activity and stereoselectivity. Xiao mize the enantioselectivity. Moreover, other tested
and co-workers[9] reported a series of bifunctional catalysts including l-proline only gave moderate
prolinamide derivative organocatalysts for the direct enantioselectivities (63–78% ee). Therefore, we chose
asymmetric aldol reaction of various aromatic alde- 1b as a catalyst for the aldol reaction.
hydes and cyclohexanone, and impressive results were
A solvent screening was then performed at room
obtained. Meanwhile, they found that a subtle change temperature to identify the best reaction conditions
in catalyst structure may effect the catalytic activa- (Table 1, entries 7–13 and 17). Among the organic sol-
tion. With this knowledge in mind, we investigated vents tested, THF and CH3CN were slightly better in
some novel (1b–d) and known (1a and 1e) bifunction- terms of both diastereoselectivity and enantioselectiv-
al prolinamide derivative organocatalysts with the ity, and 85% ee and 80% ee were achieved, respec-
aim to develop a practical method for the asymmetric tively (Table 1, entries 13 and 17). When the reaction
aldol reaction. Catalysts 1b and 1c (Figure 1) were was performed in DMSO, DCM, CHCl3, toluene or
prepared in excellent yields by coupling of N-Boc-l- dioxane, the enantioselectivity was slightly inferior to
Pro[12] and mono-protected-(R,R)-1,2-cyclohexandia- the results obtained in THF and CH3CN. Moreover,
mine[13] followed by deprotection with TFA. Com- when water was used as a solvent, the very low ee
pounds 1a and 1e were synthesized following the re- value of 34% was obtained (Table 1, entry 10). Thus,
ported procedure,[14] while 1d was synthesized by cou- we further investigated the reaction in THF and
pling of N-Boc-l-Pro and mono-protected-(R,R)-1,2- CH3CN, respectively, at low temperatures. The enan-
cyclohexandiamine followed by deprotection with tioselectivity increased greatly from 80% ee to 95%
NH2NH2/EtOH.[13]
ee in CH3CN when the reaction temperature was low-
The organocatalyzed aldol reaction was carried out ered from room temperture to À408C (Table 1, en-
using cyclohexanone and 4-nitrobenzaldehyde as a tries 17–19). The ee value in THF was enhanced evi-
dently from 85% to 92% when the temperature was
lowered from room temperture to 08C (Table 1, en-
tries 13 and 14). However, no improvement of ee was
obtained by further lowering the temperature from 0
to À408C (Table 1, entries 14–16). Thus, CH3CN was
selected as the solvent for the aldol reaction.
It is well-known that a Brønsted acid additive
should be involved in the intricate iminium-enamine
equilibrium, and it can also play an important role in
the activation of the aldol acceptor by hydrogen
bonding. Therefore, a series of Brønsted acids was ex-
amined as the cocatalyst in the direct asymmetric
aldol reaction (Table 2). An enantioselectivity/cocata-
lyst profile revealed that optimal enantiocontrol could
be achieved when 3-methylbenzoic acid was used as
the cocatalyst (Table 2, entry 3). Further examinations
documented that the reaction efficiency could be im-
proved if the ratio of 3-methylbenzoic acid to 1b was
changed, but the enantioselectivity was not improved
Figure 1. l-Prolinamide organocatalysts.
when the variation of this ratio was used in this reac-
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A Highly Efficient Large-Scale Asymmetric Direct Intermolecular Aldol Reaction
Table 1. Direct aldol reaction of cyclohexanone and 4-nitrobenaldehyde catalyzed by l-prolinamide derivatives.[a]
Entry
Catalyst
Solvent
Temperature [8C]
Time [h]
Yield [%][b]
dr (anti/syn)[c]
ee [%][c]
1
2
3
4
5
6
7
8
l-proline
1a
1b
1c
1d
1e
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
DCM
CHCl3
water
toluene
dioxane
THF
THF
THF
THF
CH3CN
CH3CN
CH3CN
À20
À20
À20
À20
À20
À20
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
À20
À40
r.t.
0
À40
42
36
20
20
48
24
20
20
20
40
16
16
16
24
30
48
16
20
48
80
85
90
87
82
92
89
93
82
65
87
82
92
94
94
95
90
95
95
84:16
89:11
94:6
94:6
89:11
91:9
89:11
75:25
67:33
67:33
75:25
80:20
94:6
95:5
96:4
96:4
90:10
90:10
95:5
71
78
90
85
63
78
78
77
75
34
77
67
85
92
92
92
80
85
95
9
10
11
12
13
14
15
16
17
18
19
1b
1b
[a]
The reactions were carried out using 4-nitrobenzaldehyde (0.25 mmol) and cyclohexanone (4 equiv.) in the specified sol-
vent (2.0 mL).
Isolated yield after chromatography on silica gel.
Determined by chiral HPLC analysis (AD-H).
[b]
[c]
Table 2. Organocatalyzed direct aldol reactions in the presence of various acid addictives.[a]
Entry
Cocatalyst
Time [h]
Yield [%][b]
dr (anti/syn)[c]
ee [%][c]
1
2
3
4
5
6
7
8
None
48
20
20
20
30
30
40
40
60
30
30
93
90
95
90
85
92
85
92
78
90
93
90:10
94:6
98:2
97:3
96:4
94:6
90:10
91:9
95:5
93:7
93:7
85
91
96
95
73
90
80
78
96
96
96
benzoic acid (10 mol%)
3-methylbenzoic acid (10 mol%)
4-methoxybenzoic acid (10 mol%)
4-nitrobenzoic acid (10 mol%)
4-chlorobenzoic acid (10 mol%)
trifluoroacetic acid (10 mol%)
acetic acid (10 mol%)
3-methylbenzoic acid (5 mol%)
3-methylbenzoic acid (20 mol%)
3-methylbenzoic acid (50 mol%)
9
10
11
[a]
The reaction was carried out using 4-nitrobenzaldehyde (0.25 mmol) and cyclohexanone (4 equiv.) in CH3CN (2.0 mL) at
À208C.
[b]
[c]
Isolated yield after chromatography on silica gel.
Determined by chiral HPLC analysis (AD-H).
tion (Table 2, entries 9–11). Therefore, 3-methylben- the optimal molar ratio of 3-methylbenzoic acid to 1b
zoic acid was chosen as the optimum cocatalyst, and was 1:1.
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Table 3. Effects of ketone and catalyst loading on the organocatalyzed direct aldol reaction.[a]
Entry
Ketone [equiv.]
Catalyst [mol%]
Time [h]
Yield [%][b]
dr (anti/syn)[c]
ee [%][c]
1
2
3
4
5
6
7
8
1
4
10
40
4
4
4
4
10
10
10
10
2
5
15
25
48
36
24
12
48
36
30
18
85
95
95
99
76
95
95
94
95:5
95:5
95:5
95:5
93:7
96:4
95:5
96:4
95
95
95
94
96
96
95
94
[a]
The reaction was carried out using 4-nitrobenzaldehyde (0.25 mmol) and cyclohexanone in CH3CN (2.0 mL) at À208C.
Isolated yields after chromatography on silica gel.
Determined by chiral HPLC analysis (AD-H).
[b]
[c]
Then, using CH3CN as a solvent and 3-methylben- withdrawing groups enhance the electrophilicity of
zoic acid as a cocatalyst with the ratio of 3-methyl- carbonyl carbons in aldehydes which facilitates the re-
benzoic acid to 1b as 1:1, we investigated the effects action, while electron-donating groups lessen the elec-
of ketone and catalyst loading on the reaction of 4-ni- trophilicity. Moreover, the heteroaromatic aldehydes
trobenzaldehyde and cyclohexanone (Table 3). When 2-furaldehyde and 2-thiophenaldehyde both reacted
10 mol% of 1b was used, the reaction could be accel- smoothly with cyclohexanone under optimal condi-
erated by increasing the amount of ketone from 1 to tions to give the corresponding aldol products in good
40 equivalents, but dr and ee values were not im- yields of 90% after 40 h (Table 4, entries 13 and 14).
proved (Table 3, entries 1–4). The aldol product could All the reactions of cyclohexanone with aromatic and
be obtained in high yield with good stereoselectivity heteroaromtic aldehydes provided the corresponding
even with only 4 equivalents of cyclohexanone. Fur- products with good enantioselectivities (89–98% ee
thermore, the effect of catalyst loading was also inves- for anti-isomers) and excellent diastereoselectivities
tigated using 4 equivalents of cyclohexanone. When a (anti/syn 90:10–99:1) (Table 4, entries 1–14). Interest-
large amount of catalyst (25 mol%) was used, the re- ingly, the reaction appears quite tolerant with respect
action was fast but ee value was slightly lower than to the steric contribution of the substituents in substi-
that using lower catalyst loading (Table 3, entries 5– tuted benzaldehydes, and the most sterically hindered
8). Noticeably, using 5 mol% of catalyst after 36 h, we 2,6-dicholobenzaldehyde provided the best enantiose-
obtained a good yield with excellent stereoselectivity lectivity (98% ee) and diastereoselectivity (99:1)
(Table 3, entry 6). Thus, the optimized catalyst loading (Table 4, entry 4). In contrast, the least sterically hin-
was chosen as 5 mol% of 1b.
dered benzaldehyde gave the lowest enantioselectivity
In order to test the substrate generality of this orga- (89% ee) and diastereoselectivity (90:10) (Table 4,
nocatalyzed direct aldol reaction, the reactions of var- entry 12). It seems like that the steric hindrance of
ious aromatic and heteroaromatic aldehydes with the substituents in substituted benzaldehydes has an
cyclic and acyclic ketones were studied under the op- effect on the stereoselectivity. Furthermore, when cy-
timized conditions. The results are summarized in clopentanone was used as an aldol donor, a good
Table 4. It can be seen that a wide range of aromatic yield of 90% with excellent ee (96%) for the anti-
and heteroaromatic aldehydes can effectively partici- isomer was received; however, the diastereomeric
pate in the reaction. In general, the reaction between ratio obtained was only 77:23 (anti/syn) (Table 4,
cyclohexanone and aromatic aldehydes bearing elec- entry 15). In addition, we have examined the feasibili-
tron-withdrawing substituents furnished b-hydroxy ty of using acyclic ketones as aldol donors. Although
carbonyl aldol products in excellent yields (89–97%) longer reaction times were required in comparison
within 32 h (Table 4, entries 1–8). In contrast, longer with cyclic ketones, satisfactory results were obtained.
reaction times (40 h) were required for aromatic alde- Both acetone and diethyl ketone reacted smoothly
hydes containing an electron-donating group to give with 4-nitrobenzaldehyde under optimal conditions to
comparatively lower yields (80–88%) (Table 4, en- give the corresponding aldol products in good yields
tries 9–11). This can be explained in that electron- of 85% (Table 4, entries 16 and 17). In the case of
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A Highly Efficient Large-Scale Asymmetric Direct Intermolecular Aldol Reaction
Table 4. Scope of the organocatalyzed direct aldol reaction under optimal conditions.[a]
Entry
1
Product
No.
Time [h]
30
Yield [%][b]
95
dr (anti/syn)[c]
ee [%][c]
4a
93:7
96
2
3
4
4b
4c
4d
30
30
32
97
90
95
92:8
95:5
99:1
93
90
98
5
6
7
8
9
4e
4f
4g
4h
4i
32
32
32
32
40
90
94
97
89
80
93:7
92:8
95:5
85:15
97:3
90
91
93
92
95
10
11
12
13
14
4j
40
40
32
40
40
88
85
92
90
90
95:5
95:5
90:10
95:5
96:4
94
93
89
93
92
4k
4l
4m
4n
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Table 4. (Continued)
Entry
Product
No.
Time [h]
25
Yield [%][b]
90
dr (anti/syn)[c]
ee [%][c]
15
4o
77:23
96
16
17
4p
60
85
–
79
4q
4r
72
80
85
74
80:20
94:6
85
87
18[d]
[a]
Unless otherwise note, the reactions were carried out using aldehyde (0.5 mmol) and ketone (4 equiv.) in CH3CN
(2.0 mL) at À208C.
[b]
[c]
[d]
Isolated yield after chromatography on silica gel.
Determined by chiral HPLC analysis (AD-H, OD-H, AS-H or OJ-H).
Performed with 10 equivalents of ketone.
tert-butyl ethyl ketone, a higher ketone loading of
Meanwhile, in order to verify that the catalyst 1b
10 equivalents was used to achieve an acceptable could be recovered and reused, we performed a recy-
yield of 74% with benzaldehyde (Table 4, entry 18). cling study of 1b using the aldol reaction between cy-
Notably, acetone as the smallest ketone only gave a clohexanone and 4-nitrobenzaldehyde (Table 5). The
low ee of 79%, while diethyl ketone and tert-butyl catalyst 1b could be easily recovered from the reac-
ethyl ketone gave good ee values of 85% and 87% for tion mixture after completion of the reaction by acid
anti-isomers, respectively. Besides, an excellent diaste- treatment, extraction, alkalization of aqueous phase,
reoselectivity of 94:6 (anti/syn) was obtained using extraction, concentration, and directly used it in sub-
the more sterically hindered tert-butyl ethyl ketone. sequent aldol reaction without adding any new cata-
Meanwhile, the less sterically hindered diethyl ketone lyst. In each reuse, the same amounts of substrates
only gave a moderate dr of 80:20 (anti/syn). The re- were used, and the recovered 1b without further pu-
sults suggested that the steric hindrance of the acyclic rification retained essentially its catalytic activity, and
ketones also has an effect on the stereoselectivity.
only slightly a decrease of enantioselectivity was ob-
served for five cycles (Table 5).
We further performed large-scale asymmetric aldol
reactions with 20 mmol of aldehydes and 4 equiva-
lents of ketones. The same catalyst loading of 5 mol%
as in the experimental scale was used. The large-scale
experiments can be facilely carried out using the
same procedure as for the experimental scale reac-
tions. As can be seen from the results summarized in
Table 6, delightfully, the enantioselectivity maintained
at the same level for the large-scale reactions.
Table 5. Recycling and reuse of catalyst 1b.[a]
Cycle Time [h] Yield [%][b] dr (anti/syn)[c] ee [%][c]
1
2
3
4
5
20
20
20
28
48
95
92
92
90
85
98:2
95:5
95:5
93:7
90:10
96
94
90
88
85
Conclusions
In conclusion, the results from the investigation dem-
onstrate that the l-prolinamide 1b is a robust and ef-
fective catalyst for highly enantioselective aldol reac-
tions. A wide range of aromatic and heteroaromatic
aldehydes with cyclic and acyclic ketones can effec-
tively participate in the reaction. The electronic effect
[a]
The reactions were carried out using 4-nitrobenzaldehyde
(2 mmol) and cyclohexanone (4 equiv.) in CH3CN (8 mL)
at À208C.
[b]
[c]
Isolated yield after chromatography on silica gel.
Determined by chiral HPLC analysis (AD-H).
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A Highly Efficient Large-Scale Asymmetric Direct Intermolecular Aldol Reaction
Table 6. Large-scale asymmetric aldol reactions.[a]
Entry
1
Product
Time [h]
30
Yield [%][b]
89
dr (anti/syn)[c]
ee [%][c]
85:15
93
2
3
36
30
36
91
89
90
90:10
77:23
80:20
95
96
91
4
[a]
The reactions were carried out using aldehyde (20 mmol) and ketone (4 equiv.) in CH3CN (100 mL) at À208C.
Isolated yield after chromatography on silica gel.
Determined by chiral HPLC analysis (AD-H and AS-H).
[b]
[c]
Preparation of Prolinamide 1b[14b]
and steric effect of the substituents in substituted ben-
zaldehydes as well as the steric effect of acyclic ke-
tones have been discussed. The catalyst can be readily
recovered and reused without significant loss of cata-
lytic activity and stereoselectivity. Notably, this orga-
nocatalyzed direct asymmetric aldol reaction can be
performed on a large-scale with the enantioselectivity
being maintained at the same level, which offers a
great possibility for applications in industry.
To a solution of N-Boc-l-proline[12] (4.7 g, 22 mmol) and
TEA (2.3 g, 22 mmol) in dry CH2Cl2 (80 mL) under argon at
08C was added ethyl chloroformate (2.6 g, 24 mmol) drop-
wise over 15 min. The resulting solution was stirred at 08C
for 30 min. Then a solution of 2-[(1R,2R)-2-aminocyclohex-
AHCTUNGTRENNUNG
yl)isoindoline-1,3-dione[13] (4.9 g, 20 mmol) in dry CH2Cl2
(15 mL) was added dropwise over 15 min. The mixture was
allowed to warm to room temperature and further stirred
for 4 h. The mixture was washed with 1M KHSO4, saturated
NaHCO3 and brine, dried over anhydrous Na2SO4 and con-
centrated. The residue was purified by flash chromatography
using EtOAc/petroleum ether (1:3, v/v) as eluent to afford
(S)-tert-butyl
2-[(1R,2R)-2-(1,3-dioxoisoindolin-2-yl)cyclo-
Experimental Section
hexylcarbamoyl]pyrrolidine 1-carboxylate as white solid;
yield: 8.6 g (98%).
To a solution of (S)-tert-butyl 2-[(1R,2R)-2-(1,3-dioxo-
General Remarks
1
NMR data were obtained for H at 300 MHz, and for 13C at
AHCTUNGTRENNUNG
CTHUNGTRENNUNG
75 MHz. Chemical shifts are reported in ppm from tetrame-
thylsilane with the solvent resonance as the internal stan-
dard in CDCl3 solution. High-resolution mass spectra
(Varian 7.0T FTICR-MS) were obtained by use of ESI ioni-
zation sources. In each case, enantiomer ratios were deter-
mined by chiral HPLC analysis on Chiralcel AS-H, AD-H,
OD-H or OJ-H in comparison with authentic racemates.
Amino acids and diamines obtained from commercial sour-
ces were used directly without further purification. tert-
Butyl ethyl ketone was prepared following the reported pro-
cedure.[15] All reactions were monitored by thin-layer chro-
matography (TLC) with Haiyang GF254 silica gel plates.
Flash column chromatography was carried out using 100–
200 mesh silica gel at increased pressure.
(7.5 mL). After stirring at 08C for 2.5 hour, the solution was
concentrated under vacuum to leave a glutinous phase. The
pH of the mixture was brought into the range of ~12 by the
addition of 2M NaOH. The aqueous phase was extracted
with ethyl acetate. The ethyl acetate extracts were pooled,
washed with brine, dried over anhydrous Na2SO4, filtered
off and the solvent was evaporated at low pressure to give a
crude residue that was purified by recrystallization, afford-
ing catalyst 1b as a white solid; yield: 3.1 g (91%).
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Yang Yang et al.
FULL PAPERS
Preparation of Prolinamide 1d[13]
Acknowledgements
A sample of (S)-tert-butyl 2-[(1R,2R)-2-(1,3-dioxoisoindolin-
2-yl)cyclohexylcarbamoyl]pyrrolidine 1-carboxylate (440 mg,
1 mmol) was refluxed with hydrazine hydrate (0.12 mL) in
ethanol (5 mL) for 2 h. After cooling to room temperature
the solution was diluted with diethyl ether to precipitate
phthaloyl hydrazide. The mixture was filtered and the fil-
trate evaporated to dryness. The products were purified by
extraction into the dilute HCl, followed by neutralization
with saturated NaHCO3 solution and back-extraction with
dichloromethane. Yield: 85%.
Financial support from Natural Science Foundation Project
of CQ CSTC (2009A5051) is gratefully acknowledged.
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General Procedure for Aldol Reaction of Ketones
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rification by flash chromatography afforded the correspond-
ing pure products.
Supporting Information
Spectral data for new compounds and HPLC data are avail-
able in the Supporting Information
2586
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Adv. Synth. Catal. 2010, 352, 2579 – 2587
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2587