Enantioselective aldol reaction of cyclic ketones with aryl aldehydes catalyzed by a cyclohexanediamine derived salt in the presence of water

Article abstract of DOI:10.1039/b916583e

Water was found to be a suitable reaction medium for the direct asymmetric aldol reaction of various cyclic ketones with aryl aldehydes catalyzed by a primary-tertiary diamine-Bronsted acid. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b916583e

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Enantioselective aldol reaction of cyclic ketones with aryl aldehydes
catalyzed by a cyclohexanediamine derived salt in the presence of water†
Jin-Hong Lin, Cheng-Pan Zhang and Ji-Chang Xiao*
Received 11th August 2009, Accepted 1st September 2009
First published as an Advance Article on the web 11th September 2009
DOI: 10.1039/b916583e
Water was found to be a suitable reaction medium for
the direct asymmetric aldol reaction of various cyclic
ketones with aryl aldehydes catalyzed by a primary-tertiary
diamine-Brønsted acid.
reactions.3h,5 In such situations, it is interesting to investigate
further organocatalytic aldol reactions in the presence of
water.
Recently, we found that an ionic liquid derived from
the
1,1,2,2-tetrafluoro-2-(1,1,2,2,3,3,4,4-octafluorobutoxy)-
The aldol reaction is recognized as one of the most efficient
methods for the formation of carbon-carbon bonds in modern
organic synthesis. It provides an atom-economic approach to
synthesize b-hydroxy carbonyl compounds. Since L-proline was
found by List in 2000 to be able to mimic the catalytic behavior
of type I aldolase in intermolecular aldol reactions,1 much
progress has been made in the development of organocatalysis.2
However, the donors of these aldol reactions are usually used in
a large excess amount, which hampers its practical application.
Therefore, it is necessary to develop more effective ways to lower
the amount of donors.
Water as a reaction medium has attracted both academic
and industrial interests because of its special properties such as
safety, nontoxicity, inflammability, cheapness and environmen-
tal friendliness. While the advantages of water are obvious from
the perspective of green chemistry, there are still many challenges
in the field of organocatalysis in which water is involved.
Water interferes with organocatalysts and disrupts hydrogen
bonds and other polar interactions, accordingly in many cases
deteriorating catalytic activity and stereoselectivity. Even so, the
aldol reaction involving water has developed significantly over
the past several years.3 Interestingly, a hot debate has arisen
recently on the role of water in aldol reactions.4 On the one
hand, Janda didn’t agree that these reactions were truly carried
out “in water” because the reaction system is biphasic.4a As
for the accurate description of the reaction system, Hayashi
proposed that the terminology “in the presence of water” would
best convey the effect of water in these reactions.4b On the
other hand, both Janda and Blackmond didn’t consider that
the aldol reactions carried out in the presence of water were
so green because the donor cyclohexanone was used in a large
amount, even in excess over water, and much organic solvent was
required for extraction work-up.4a,4c Furthermore, cosolvents
were usually employed to improve the stereoselectivity in these
ethanesulfonate anion can act as both the recyclable solvent
and catalyst for Friedel–Crafts alkylations of indoles with
nitroalkenes.6 The good solubility of this kind of ionic
liquid in water and organic solvent prompted us to presume
that organic salts containing this sulfonate might be used
as surfactant-type organocatalysts.7 Thus, a series of salts
having such a sulfonate anion (1a–1f) were synthesized
by direct neutralization of amines with the sulfonic acid
or by neutralization with hydrochloric acid first and then
metathesis with the sulfonate (see ESI).† When these salts were
used as catalysts (10 mol%) for the aldol reaction between
cyclohexanone (1 mmol) and 4-nitrobenzaldehyde (0.5 mmol)
in the presence of water (2 mL), it was found that they exhibited
low stereoselectivity for the transformation (Table 1, entries
1–6). This phenomenon might be ascribed to the large steric
hindrance of the long chain sulfonate anions, which hampered
the hydrogen bonding between catalysts and the substrate.
It seemed that catalysts based on the large sulfonate anion
were not suitable for this reaction. Among the catalysts tested,
1f exhibited higher stereoselectivity for the transformation.
Therefore, 1,2-cyclohexanediamine-derived salts were chosen
as the catalyst for the above aldol condensation (Table 1,
entries 7–10). It can be seen that the stereoselectivity was
greatly improved while decreasing the size of the anion. The
salts with fluorinated anions gave better results (entries 7
and 8) than those nonfluorinated analogues (entries 9 and
10). Comparatively, the triflate salt 1g showed the highest
stereoselectivity (entry 7). Other triflates 1k–1m (entries
11–13) with different lengths of alkyl group on the nitrogen
demonstrated similar stereoselectivity but different catalytic
activity. For those triflates with shorter alkyl chains on the
nitrogen, the reaction proceeded relatively slowly (entries 11
and 12). 1g and 1m exhibited comparable activities (entries
7 and 13). But 1g is viscous liquid while 1m is solid at room
temperature. Thus, the operation of 1m is more convenient.
In addition, the salt form of the 1,2-cyclohexanediamine is
essential for the catalysis. When 1n, the free base form of
1m, was used as the catalyst, the reaction became so sluggish
that only a trace amount of the desired product was formed
(entry 16). Based on a comprehensive consideration of catalytic
activity, stereoselectivity and operational convenience, 1m was
chosen as the catalyst (entry 13).
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai, 200032, P. R. China. E-mail: jchxiao@mail.sioc.ac.cn;
Fax: (+86) 21-6416 6128
† Electronic supplementary information (ESI) available: Experimental
procedures and characterization data. CCDC reference numbers 737246.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/b916583e
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Table 1 Screening of reaction conditions in the direct asymmetric aldol
reaction of cyclohexanone (2a) with 4-nitrobenzaldehyde (3a) in the
presence of watera
Water played an important role in the reaction. Using
cyclohexanone as the solvent, although the reaction proceeded
smoothly without water (entry 17), the stereoselectivity was
slightly improved by the addition of one equivalent of wa-
ter (entry 18). Increasing the amount of water to 10 equiv.
markedly enhanced the stereoselectivity (entry 19). On the
other hand, the amount of cyclohexanone also affected the
selectivity. When the reaction was performed in the presence
of water, the stereoselectivity was considerably improved by
using a large excess of cyclohexanone (entries 20 and 21).
From the green chemistry perspective, 2 : 1 of donor (ketone)
to acceptor (aldehyde) was adopted as the optimum reactant
ratio.
The important feature of this catalytic system is that organic
solvents are not necessary for either the reaction or the
extraction. Since cyclohexanone was used in slight excess over
aryl aldehyde in the presence of water, the reaction system was
biphasic, thus leading to easy separation of the organic product.
Similar work done by Cheng and Luo revealed that large excess
of ketone was used both as the starting material and as the
solvent,2g and an acidic additive was needed to obtain good
stereoselectivity. Therefore, this procedure for aldol reactions
catalyzed by triflate 1m in the presence of water seems very
attractive from a green chemistry perspective.
A series of aryl aldehydes and cyclic ketones were then
subjected to the optimal reaction conditions described above. As
summarized in Table 2, the reaction of cyclohexanone with aryl
aldehydes bearing various substituents afforded high selectivities
of anti-aldol products (entries 1–9). When this procedure was
applied to cyclopentanone (entry 10), the diastereoselectivities
and enantioselectivities became significantly lower. However, in
the case of water miscible tetrahydro-4H-pyran-4-one, excellent
selectivities were obtained (entries 11 and 12).
Entry Catalyst
Time (h) Yield (%)
anti/synb
ee (%)c
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
50
50
60
30
24
40
60
70
36
70
90
90
60
62
85
NR
96
92
88
95
93
96
92
98
43
95
92
91
Trace
97
96
96
95
98
64/36
57/43
—
-35
-48
—
-71
-26
61
96
95
95
93
97
97
95
96
93
—
92
96
69/31
57/43
83/17
94/6
93/7
78/22
88/12
94/6
86/14
95/5
95/5
93/7
—
1g
1h
1i
9d
10d
11
12
13
14
15
16
17e
18f
19g
20h
21i
1j
1k
1l
1m
1m (2nd cycle) 60
1m (3rd cycle) 60
The effectiveness of triflate 1m for the aldol reaction aroused
our interest in this catalyst. The precursor of the catalyst, 1n, has
1n
30
12
12
12
80
24
1m
1m
1m
1m
1m
96/4
98/2
> 99/1
80/20
97/3
98
85
98
Table 2 Asymmetric aldol reaction in the presence of watera
a Reaction conditions: 2a (1 mmol), 3a (0.5 mmol) and catalyst
(0.05 mmol) in the presence of water (2 mL) at room temperature.
b Determined by 1H NMR of the crude product. c Determined by chiral-
phase HPLC analysis of the anti product. d The catalyst was generated
in situ in the reaction system. e Cyclohexanone (2 mL) was used as the
solvent without water. f Cyclohexanone (2 mL) was used as the solvent
with the addition of water (0.5 mmol). g Cyclohexanone (2 mL) was used
as the solvent with the addition of water (5 mmol). h Cyclohexanone
(3 mmol) was used in the presence of water (2 mL). i Cyclohexanone
(5 mmol) was used in the presence of water (2 mL).
Entry
X
n
Y
Time (d) 4, %
anti/synb
ee (%)c
1
2
3
4
5
6
7
8
C
C
C
C
C
C
C
C
C
—
O
O
1
1
1
1
1
1
1
1
1
0
1
1
4-NO2
3-NO2
4-CF3
4-CN
4-Br
2.5
3
4a, 95
95/5
94/6
93/7
90/10
95/5
88/12
99/1
93/7
96/4
79/21
95/5
94/6
95
96
96
86
98
93
97
96
93
84
98
95
4b, 94
4c, 94
4d, 82
4e, 99
4f, 96
4g, 84
4h, 94
4i, 56
4j, 34
4k,57
4l, 75
2
7
4
4
4-Cl
After the completion of the reaction, the organic product
could be readily separated from the reaction mixture by simple
filtration. Further column chromatography afforded the pure
product. In the case of triflate 1m, it was found that a small
amount of catalyst (0.012 mmol) and unreacted cyclohexanone
2,4-Cl2
3,4-Cl2
4-Ph
4-NO2
4-NO2
4-CF3
5.5
7
9
7.5
2
7
10
11
12
7
1
(0.27 mmol) was left in the filtrate, as determined by H and
a Reaction condition: 2 (1 mmol), 3 (0.5 mmol) and catalyst (0.05 mmol)
in the presence of water (2 mL) at room temperature. b Determined by
1H NMR of the crude product. c Determined by chiral-phase HPLC
analysis of the anti product.
19F NMR spectroscopy. After cyclohexanone and catalyst was
supplemented to the original amount, the filtrate can be reused
in the next run, showing no significant decrease in catalytic
performance (entries 14 and 15).
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a primary and a tertiary amino group. Generally, the basicity
of primary amines is stronger than that of tertiary amines.8
The reaction of 1n with trifluoromethanesulfonic acid should
happen preferentially at the primary amine. However, there has
been little investigation into the protonated structure of diamines
containing both primary and tertiary amino groups. Hine once
suggested that the monoprotonated forms of such diamines
exist as internally hydrogen-bonded species.9 Fortunately, single
crystals of 1m suitable for X-ray diffraction studies were
obtained. It was thus proved that the proton is located at the
primary amino group in its solid state.10
Nevertheless, we tend to think that the solvated triflate
1m would take an internally hydrogen-bonded structure A
(Scheme 1), which is very similar to that proposed by Hine.9
A proton is situated between two N atoms, forming a proton
transfer equilibrium between 1m and B. Accordingly, B initiated
the catalytic cycle via nucleophilic addition to the ketone to
give an enamine intermediate C. Hydrogen bonding interaction
between tertiary amino group of C and aldehyde led to the
formation of intermediate D. The cyclic ring of the ketone
effectively screened the Re face of the aryl aldehyde from attack
by enamine. Enamine–aldehyde condensation and subsequent
hydrolysis afforded asymmetrically the aldol product, simulta-
neously generating B for next cycle.
hydrogen-bonded structure of the catalyst was proposed to
explain this direct aldol reaction. Further studies on the catalytic
system to other reactions are currently underway.
Experimental
Typical procedure for the aldol reaction: to a suspension of
catalyst 1m (18.8 mg, 0.05 mmol) in water (2 mL) was added
cyclic ketone (1 mmol). After stirring for one minute, aryl
aldehyde (0.5 mmol) was introduced. Then the reaction was
kept at room temperature for the time indicated in Table 2.
After completion of the reaction, the product precipitated
as a solid. The crude product was collected by filtration.
1
Diastereoselectivity was determined by H NMR analysis of
the crude product. Further column chromatography gave the
pure product.
Acknowledgements
We thank the Chinese Academy of Sciences (Hundreds of
Talents Program) and the National Natural Science Foundation
(20772147) for financial support.
Notes and references
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Scheme 1 Proposed mechanism for the aldol reaction catalyzed by 1m.
In summary, water was found to be a suitable reaction
medium for the direct asymmetric aldol reaction of various cyclic
ketones with aryl aldehydes catalyzed by a primary-tertiary
diamine-Brønsted acid. No organic solvents are necessary for
either the reaction or the extraction. The advantages are clear
from a green chemistry perspective. The protonated structure
of 1,2-cyclohexanediamine was elucidated by single crystal X-
ray analysis. A possible mechanism involving an internally
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737246)†.
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