Direct asymmetric aldol reaction of cyclohexanone with aldehydes catalyzed by chiral trans-cyclohexanediamine l-tartrate salt

Article abstract of DOI:10.1007/s00706-012-0821-6

The stable and commercially available catalyst (1R,2R)-(+)-1,2- cyclohexanediamine l-tartrate complex was used for asymmetric aldol reaction in high yields (up to 99 %) and enantioselectivities [up to 94 % enantiomeric excess (ee)]. The catalyst was obtai

Full text of DOI:10.1007/s00706-012-0821-6

Monatsh Chem (2013) 144:381–386
DOI 10.1007/s00706-012-0821-6
ORIGINAL PAPER
Direct asymmetric aldol reaction of cyclohexanone with aldehydes
catalyzed by chiral trans-cyclohexanediamine L-tartrate salt
•
Shengying Wu Limin Wang Jun Tang
•
•
•
Dan Mao Xin Liu
Received: 18 November 2011 / Accepted: 7 July 2012 / Published online: 18 August 2012
Ó Springer-Verlag 2012
Abstract The stable and commercially available catalyst
(1R,2R)-(?)-1,2-cyclohexanediamine L-tartrate complex
was used for asymmetric aldol reaction in high yields (up
to 99 %) and enantioselectivities [up to 94 % enantiomeric
excess (ee)]. The catalyst was obtained easily and reused
three times.
reaction with the aim of increasing reactivity and stereo-
selectivity [6].
Recently, primary amine based organocatalysts have
also been investigated as effective tools in asymmetric
aldol condensation [7–11]. Among them, chiral cyclohex-
anediamine catalysts with diverse functional features have
been designed, with excellent results. For example, Luo
and Cheng [12] reported the primary–tertiary diamine
catalyst 2, which showed excellent selectivity in cross aldol
condensation; the Shao group [13] synthesized the catalyst
3 in combination of binaphthyl unit; the primary amine–
thiourea catalysts 4 and 5 were introduced by Jacobsen [14]
and Tsogoeva [15], respectively. However, most of these
catalysts need multi-step and time-consuming preparation,
or were generated in situ with unstable properties.
Keywords Chiral resolution Á Asymmetric aldol
condensation Á Green chemistry Á Cyclohexanediamine
catalyst Á Stable and recoverable
Introduction
Asymmetric direct aldol reactions have tremendous syn-
thetic utility and have received considerable attention as
one of the most ubiquitous C–C bond-forming reactions in
modern organic synthesis [1–4]. They provide an atom-
economic approach to access chiral b-hydroxycarbonyl
compounds, which are versatile synthetic motifs for bio-
logically active natural products and pharmaceutical
intermediates. Since List and co-workers [5] reported an
L-proline-catalyzed direct asymmetric intermolecular aldol
reaction, a large number of secondary amine derived cat-
alysts, such as 1 (Fig. 1), have been developed for this
In 2006, the List group introduced asymmetric count-
eranion-directed catalysis (ACDC) as a new concept in
organocatalysis [16–18]. They demonstrated that salts
made from a chiral primary amine and a chiral phosphoric
acid could function as highly enantioselective iminium
catalysts in the reduction of a,b-unsaturated aldehydes with
Hantzsch esters. Recently, chiral diaminocyclohexane
itself, with different acids as additives generating ion pair
salts such as 6, in aldol or other reactions were also
reported [12, 19–22]. However, in view of the rules of
green chemistry, it is necessary to develop a stable and
recoverable catalyst to overcome the major drawbacks
associated with the exorbitant cost and technical difficulty
of large-scale production. As is well known, racemic trans-
cyclohexane-1,2-diamine was resolved easily by L-tartaric
acid giving ditartrate (R,R)-7 [23]. This salt is stable,
cheap, and easy to prepare on a large scale. Herein, we report
(1R,2R)-(?)-1,2-cyclohexanediamine L-tartrate ((R,R)-7,
Scheme 1) as an efficient counteranion-directed catalyst for
direct asymmetric aldol reaction.
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-012-0821-6) contains supplementary
material, which is available to authorized users.
S. Wu Á L. Wang (&) Á J. Tang Á D. Mao Á X. Liu
Shanghai Key Laboratory of Functional Materials
Chemistry and Institute of Fine Chemicals, East China
University of Science and Technology, 130 Meilong Road,
Shanghai 200237, People’s Republic of China
e-mail: wanglimin@ecust.edu.cn
123

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S. Wu et al.
Fig. 1 Examples of chiral
catalysts for asymmetric aldol
reaction
Scheme 1
Table 1 Influence of the solvent on the asymmetric template-aldol reaction
O
OH
O
OH
O
O
Catalyst
H
Solvent
NO2
O2N
O2N
anti (major)
syn (minor)
8a
9a
Entry
Solvent
Time/h
Yield/%a
ee % (anti)
ee % (syn)
dr (anti/synb)
1
2
3
4
5
6
7
8
H2O
24
[99
[99
[99
83
24
43
58
69
–
4
50/50
55/45
67/33
75/25
–
EtOH
24
32
38
40
–
EtOH/H2O = 4/1
Neat
24
72
DCM
120
120
120
12
n.r.
DMF
n.r.
–
–
–
THF
Brinec
n.r.
–
–
–
[99
76
21
74/26
Reaction conditions: aldehyde (0.5 mmol) and cyclohexanone (2 mmol) in the presence of 7 (0.1 mmol) in different solvents (1 cm3) at room
temperature
ee Enantiomeric excess
a
Isolated combined yields of anti- and syn-b-hydroxyketones
1
Determined by H NMR
b
c
Saturated brine
Results and discussion
hydroxyl group on the molecule, which could act with
hydrogen bonding. Therefore, we studied tartrate salt 7
(Scheme 1) in the aldol reaction of cyclohexanone with
p-nitrobenzaldehyde. First, we prepared (R,R)-7 from
L-Tartaric acid combining cyclohexanediamine might be
suitable for the activation of ketones due to their double
123

Direct asymmetric aldol reaction of cyclohexanone with aldehydes
383
Table 2 Screening of alcohol-brine co-solvent systems
Entry
Solvent
Yield/%a
ee % (anti)
ee % (syn)
dr (anti/synb)
1
EtOH/brine = 4/1
EtOH/brine = 3/2
EtOH/brine = 1/1
EtOH/brine = 2/3
EtOH/brine = 1/4
i-PrOH/brine = 4/1
t-BuOH/brine = 4/1
EtOH/CaCl2 = 4/1
EtOH/NH4Cl = 4/1
EtOH/Na2SO4 = 4/1
EtOH/Na2CO3 = 4/1
[99
[99
[99
[99
[99
[99
[99
[99
[99
[99
[99
85
63
55
58
47
44
45
57
40
60
30
52
70/30
67/33
70/30
72/28
67/33
58/42
67/33
70/30
70/30
63/37
33/67
2
83
3
83
4
82
5
78
6
72
7
75
8
80
9
83
10
11
70
Racemic
Reaction conditions: aldehyde (0.5 mmol) and cyclohexanone (2 mmol) in the presence of 7 (0.1 mmol) in alcohol/brine (1 cm3) co-solvent at
room temperature (25 °C) for 12 h
a
Isolated combined yields of anti- and syn-b-hydroxyketones
1
Determined by H NMR
b
brine to afford improved enantioselectivity and diastereo-
selectivity (anti/syn = 74/26, ee = 76 %/21 %; Table 1,
entry 8).
Table 3 Optimization of catalyst loading
Entry Catalyst
amount/%
Time/h Yield/%a ee % ee % dr (anti/
(anti) (syn) synb)
Subsequently, to improve selectivity of the aldol reac-
tion, the reaction was carried out in EtOH/brine co-solvent,
screening different ratios of EtOH/brine. As shown in
Table 2, a ratio of 4/1 (EtOH/brine) was found to be the
most suitable (anti/syn ratio = 70/30, ee = 85 %/63 %;
Table 2, entry 1). A variety of alcohols with brine as co-
solvents, as well as ethanol with several saturated aqueous
solutions of inorganic salts, were also studied and no better
selectivities were observed (Table 2, entries 6–11). Nota-
bly, in the case of saturated aqueous sodium carbonate
solution and ethanol as co-solvent, a reverse effect on
diastereoselectivity was observed, and syn-9a was obtained
as the main product in 52 % ee (Table 2, entry 11).
Having established ethanol and brine (4/1) as a good
solvent system, we then investigated catalyst loading.
Dropping catalyst loading resulted in a longer reaction time
for full conversion of p-nitrobenzaldehyde, and the ee
value of the product was slightly improved (Table 3,
entries 1–4). We were delighted to find that 7 mol % cat-
alyst loading resulted in the best result after 48 h reaction
(99 % yield, anti/syn ratio = 74/26, ee = 92 %/81 %;
Table 3, entry 4). Decreasing the catalyst loading to
5 mol % led to decreased enantioselectivity and diastere-
oselectivity (Table 3, entry 5).
1
2
3
4
5
40
20
10
7
5
97
82
85
91
92
88
45
63
80
81
78
66/34
70/30
70/30
74/26
71/29
12
24
48
120
[99
[99
[99
[99
5
Reaction conditions: aldehyde (0.5 mmol) and cyclohexanone
(2 mmol) in the presence of 7 in EtOH-brine (4/1, 1 cm3) at room
temperature
a
Isolated combined yields of anti- and syn-b-hydroxyketones
1
Determined by H NMR
b
cyclohexanediamine and L-tartaric acid by stirring in water/
acetic acid (Scheme 1). With catalyst 7 in hand, initially
we investigated water as a reaction medium, because of its
favorable characteristics, such as non-toxic, safe, eco-
nomic, and environmentally benign nature. Gratifyingly,
(R,R)-7 was found to act as a catalyst to give the desired
product 9a in nearly quantitative yield (Table 1, entry 1).
Unfortunately, the diastereoselectivity and enantioselec-
tivity were very low [anti/syn ratio = 50/50, enantiomeric
excess (ee) = 24 %/4 %]. Then, ethanol was tried as a
solvent, which led to increased enantioselectivity still with
excellent yield (anti/syn ratio = 55/45, ee = 43 %/32 %).
The reaction proceeded rather slowly under neat condi-
tions, and no product was found in the case of DCM, DMF,
and THF (Table 1, entries 4–7). As reported previously
[24–26], brine was found to be a suitable solvent in the
aldol condensation. Thus, we conducted the reaction in
Next, the temperature effect was also examined, as
shown in Table 4. Dropping the reaction temperature did
not have a significant effect on the ee value; however, the
reaction became sluggish. For simplicity, room tempera-
ture was used in all further experiments (Table 4, entry 6).
123

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S. Wu et al.
Table 4 Temperature effect catalyzed with 7 mol % of catalyst
Entry
T/°C
Time/h
Yield/%a
ee % (anti)
ee % (syn)
dr (anti/synb)
1
2
3
4
5
6
-10
-5
0
120
96
80
72
60
48
64
73
84
89
86
87
88
92
52
45
50
20
71
81
72/28
82/18
72/28
65/35
74/26
70/30
78
5
85
10–15
r.t.
99
[99
Reaction conditions: aldehyde (0.5 mmol), and cyclohexanone (2 mmol) in the presence of 7 (0.035 mmol) in EtOH/brine (1 cm3) co-solvent at
different temperatures
a
Isolated combined yields of anti- and syn-b-hydroxyketones
1
Determined by H NMR
b
With the optimized conditions in hand, the scope of the
in the heterogeneous system. The catalyst could be
recycled by simple filtration and reused three times
without significant loss of reactivity and enantioselectivity
(Table 5, entry 6).
reaction was then explored and the results are shown in
Table 5 (entries 1–5). It appears that aromatic aldehydes 8
with electron-withdrawing groups could react with cyclo-
hexanone affording the corresponding products 9 in good
yields (73–99 %) with moderate-to-high diastereoselectiv-
ity and good enantioselectivity.
To gain a better understanding of the reaction, the fol-
lowing experiments were carried out: (1) L-tartaric acid
with cyclohexylamine as an achiral primary amine, and (2)
the chiral diamine in combination with malonic acid as an
achiral carboxylic acid. The results are shown in Table 6.
Both cases were effective in giving the desired product;
however, the yields and enantioselectivities were lower
Based on previous studies [27–30], the recycling and
reuse of the catalyst was also desired on account of high
catalyst loading. The L-tartrate complex has weak solu-
bility in EtOH-brine as co-solvent; the reaction proceeded
Table 5 Substrate scope for enantioselective organocatalytic aldol reaction
OH
O
OH
O
O
O
Cat. (7 mol%)
H
EtOH / brine = 4/1, r.t.
R
R
R
anti (major)
syn (minor)
8
9
Entry
Ra
Yield/%b
ee % (anti)
ee % (syn)
dr (anti/sync)
1
2
3
4
5
6d
a
2-NO2
3-NO2
4-CN
[99
96
91
75
99/1
84
70
74/26
89
81
81
60/40
4-CF3
2-CF3
4-NO2
84
70
31
61/39
73
94
75
[99/1
70/30 (71/29, 68/32)
96 (81, 67)
90 (87, 83)
80 (76, 70)
Reaction conditions: aldehyde (0.5 mmol) and cyclohexanone (2 mmol) in the presence of 7 (0.035 mmol) in EtOH/brine (4/1, 1 cm3) co-
solvent at room temperature
b
Isolated combined yields of anti- and syn-b-hydroxyketones
1
Determined by H NMR
c
d
Recycled and reused for three times
123

Direct asymmetric aldol reaction of cyclohexanone with aldehydes
385
Table 6 Catalyst screening of aldol reaction
Entry
1a
Acid
Amine
Yield/%c
ee % (anti)
ee % (syn)
dr (anti/synd)
[99
92
81
70/30
HO
CO2H
CO2H
HO
H2N
NH2
2b
95
83
70
68/32
NH2
HO
HO
CO2H
CO2H
3a
92
73
60
60/40
COOH
COOH
H2N
NH2
Reaction conditions: aldehyde (0.5 mmol) and cyclohexanone (2 mmol) in the presence of the catalyst (0.035 mmol) in EtOH-brine (4/1, 1 cm3)
at room temperature for 48 h
a
Generated in situ
b
Catalyst 7
c
Isolated combined yields of anti- and syn-b-hydroxyketones
1
Determined by H NMR
d
than the value catalyzed by the titled L-tartrate salt
(Table 6, entries 1–3).
[19–30]. All the detailed data and spectra are shown in the
supplementary material.
In conclusion, we developed (1R,2R)-(?)-1,2-cyclo-
hexanediamine L-tartrate for an efficient direct asymmetric
aldol reaction in EtOH/brine (4/1) as co-solvent, giving the
products in good enantiomeric excess (up to 94 %) and
excellent diastereoselectivities (up to 99 %). The diamine
tartrate solid is stable, easy to handle, and commercially
available, and could be a powerful catalyst in amino-cat-
alyzing reactions in the future.
General procedure for asymmetric aldol reaction
Aromatic aldehyde (0.5 mmol) was introduced to a mixture
of a catalytic amount of catalyst (0.05 mmol, 10 mol %)
and neat cyclohexanone (2.0 mmol) in 0.1 cm3 EtOH-brine
(4/1) co-solvent. The reaction mixture was stirred at room
temperature for the time indicated in Table 3. The catalyst
was recycled by simple filtration. The reaction mixture was
subsequently filtered, extracted with ethyl acetate, and
dried over anhydrous Na2SO4. The organic layers were
evaporated under reduced pressure. The crude aldol pro-
duct was purified by flash column chromatography on silica
gel to afford the aldol adducts as a white or pale yellow
Experimental
Unless otherwise stated, materials were purchased from
commercial suppliers and used without purification. 1H
NMR spectra were recorded on a Varian 400 (400 MHz)
spectrometer. Flash column chromatography was per-
formed using 200–300 mesh silica gel. Chiral HPLC was
performed on Waters 2487 series with chiral columns
(Chiralcel AD-H/OD-H). (1R,2R)-(?)-1,2-Cyclohexanedi-
amine L-tartrate was prepared following reported procedures
[23]. All products are known compounds; 1H NMR and other
characterization data matched data reported in literature
1
solids, and then analyzed by H NMR spectroscopy and
chiral HPLC.
General procedure for racemic samples
Electron-withdrawing aromatic aldehyde (0.5 mmol), neat
ketone, and weak base additives (TEA, EDA, or K2CO3 if
necessary) were mixed in EtOH-brine (4/1) co-solvent and
123

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S. Wu et al.
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stirred magnetically at room temperature for 48 h. The
reaction mixture was filtered and extracted with ethyl
acetate, and then dried over anhydrous Na2SO4. The
organic layers were evaporated under reduced pressure.
The crude residue was purified by flash column chroma-
tography and analyzed by chiral HPLC.
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Acknowledgments This research was supported financially by the
National Nature Science Foundation of China (20672035) and Key
Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences.
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