Highly enantioselective Michael addition of cyclic ketones to chalcones catalyzed by pyrrolidine-based imides

Article abstract of DOI:10.1016/j.tetlet.2012.05.106

An efficient procedure for asymmetric Michael addition reaction of cyclic ketones with low activated chalcones catalyzed by pyrrolidine-based phthalimide and 1,8-Naphthalimide catalysts was developed. The corresponding products were obtained in high yield

Full text of DOI:10.1016/j.tetlet.2012.05.106

Tetrahedron Letters 53 (2012) 3865–3868
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Tetrahedron Letters
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Highly enantioselective Michael addition of cyclic ketones to chalcones
catalyzed by pyrrolidine-based imides
⇑
⇑
Hong-Yu Xie, Shu-Rong Ban , Ju-Na Liu, Qing-Shan Li
School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient procedure for asymmetric Michael addition reaction of cyclic ketones with low activated
chalcones catalyzed by pyrrolidine-based phthalimide and 1,8-Naphthalimide catalysts was developed.
The corresponding products were obtained in high yields with high diastereoselectivities (up to 99:1
dr) and high enantioselectivities (up to 96% ee) under mild conditions.
Received 9 March 2012
Revised 4 May 2012
Accepted 11 May 2012
Available online 29 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Enantioselective
Michael addition
Cyclic ketones
Chalcones
The most intriguing aspect of organic synthesis of paramount
concern is that of the carbon–carbon bond formation reaction.
The efficient generation of a carbon–carbon bond is the essence of
synthetic organic chemistry leading to the formation of various
valuable molecules. For a long time chemists have focused consid-
erable and consistent attentions on the development of efficient
and operationally simple protocols for the formation of carbon–car-
bon bonds.1 Among many methods of carbon–carbon bond forma-
tion the Michael addition reaction is extremely popular and very
powerful which involves two major reagents: Michael donors and
Michael acceptors.2 The importance of this methodology has stim-
ulated significant interest in the development of catalytic, asym-
metric versions of the process.3,4 Lewis acid-based catalytic5 and
organocatalytic systems6 have been reported. However, most of
the organocatalyzed Michael addition reactions employ highly acti-
vated Michael acceptors, such as nitroalkenes.7 We noticed that
organocatalytic asymmetric Michael addition reactions of simple
cyclic ketones with chalcones still remain a challenge and were
rarely reported, probably due to the low reactivity and high steric
hindrance of the substrates.8 In our previous work the pyrroli-
dine-based phthalimides and 1,8-Naphthalimide (I–III) (Fig. 1)
were synthesized and found to be efficient in the asymmetric
Michael reaction of ketones to nitroalkenes as enamine-type
organocatalysts.9 Considering the consistency of catalytic mecha-
nism, herein we tested these pyrrolidine-based imides (I–III)
in the asymmetric Michael addition of cyclic ketones to lower
R
R
O
N
O
O
NH
R
R
NH
N
O
II
I: R=H
III: R=Cl
Figure 1. Imide catalysts (I–III).
activated Michael acceptors chalcones. The experimental results
showed this catalytic system performed well over a broad scope
of substrates, furnishing various 1,5-diketone compounds in high
diastereoselectivity (up to 99:1) and excellent enantioselectivity
(up to 96% ee) under mild conditions.
Using I as the catalyst, a number of parameters were firstly
screened in the model asymmetric Michael addition of cyclohexa-
none to chalcones. The results are summarized in Table 1. Initially,
the conjugate addition was examined in a few solvents at room
temperature with benzoic acid as additive. Among the various
organic solvents tested, toluene, dichloromethane, THF, and sol-
vent-free were better in terms of both the diastereoselectivity
and enantioselectivity, with 93%, 94% ee, 95% ee, and 95% ee in
enantioselectivity, respectively (Table 1, entries 1, 2, 4, and 7).
When the reaction proceeded in polar solvents (DMSO, t-BuOH,
i-PrOH, and THF), the yields of 3a were very poor (Table 1, entries
3, 4, 5, and 6). Solvent-free was chosen for the following study of
the influence of additive, catalyst, and temperature. The additive
carboxylic acid was found to be an essential factor to this reaction.
⇑
Corresponding authors. Tel./fax: +86 351 4690322.
E-mail addresses:
shurongban@163.com (S.-R. Ban), qingshanl@yahoo.com
(Q.-S. Li).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.106

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H.-Y. Xie et al. / Tetrahedron Letters 53 (2012) 3865–3868
Table 1
Screening of reaction conditions for the conjugate addition of cyclohexanone to chalconea
Cl
O
O
I (10 mol %)
Ph
O
O
+
additive
Cl
(10 mol %)
Ph
1a
2a
3a
c
Entry
Additive
Temp (°C)
Solvent
Time (d)
Yieldb (%)
dr
% ee
1
2
3
4
5
6
7
8
Benzoic acid
Benzoic acid
Benzoic acid
Benzoic acid
Benzoic acid
Benzoic acid
Benzoic acid
2,4-Dichlorobenzoic acid
Trifluoroacetic acid
Acetic acid
Hydrochloric acid
No additive
20
20
20
20
20
20
20
20
20
20
20
20
50
75
Toluene
DCM
DMSO
THF
t-BuOH
i-PrOH
Neat
Neat
Neat
Neat
Neat
12
11
11
12
7
8
11
7
7
7
7
7
11
42
6
18
6
Trace
38
20
0
28
Trace
0
98:2
98:2
99:1
98:2
98:2
—
98:2
98:2
—
99:1
—
—
96:4
67:33
93
94
86
95
77
—
95
91
—
94
—
—
71
62
9
10
11
12
13
14
Neat
Neat
Neat
Benzoic acid
Benzoic acid
7
7
17
11
a
b
c
All reactions were carried out with cyclohexanone (1a; 0.5 mL, absolutely excess) and chalcone (2a; 63 mg, 0.26 mmol) in the presence of catalyst I (10 mol %).
Yield of the isolated product after chromatography on silica gel.
Determined by chiral HPLC on a Chiralpak AS-H column with n-hexane and 2-propanol as eluents.
In the absence of any carboxylic acid or in the presence of CF3COOH
no product was obtained (Table 1, entries 9 and 12). The yield of
the reaction was very low in the presence of hydrochloric acid
(Table 1, entry 11). Almost the same level of diastereoselectivity
was observed for substituted benzoic acid such as benzoic acid
(Table 1, entry 7, 98:2 dr), and 2,4-dichlorobenzoic acid (Table 1,
entry 8, 98:2 dr). Benzoic acid is the best choice because of the
higher enantioselectivity and reaction rate. Increasing reaction
temperature could improve the reaction rate but reduced the ste-
reoselectivity (Table 1, entries 7, 13, and 14) obviously.
Catalysts II and III were then screened employing above
optimized conditions (Table 1, entry 7), and the results are summa-
rized in Table 2. Compounds I and II facilitated the asymmetric
ichael addition of cyclohexanone to chalcone with good to excellent
stereoselectivities while using III as catalyst gave no product. The
possible reason is that catalyst III could not form the transition state
with ketone to chalcone (Fig. 2) because of the high electron-with-
drawing inductive effect. We also found that for catalyst I the yield
was increased slightly by augmenting the catalyst loading from
0.1 equiv to 0.3 equiv (Table 2, entries 1 and 4) but still unsatisfac-
tory (Table 2, entry 4, 45% yield). To our delight, 30% of II had the
right properties to achieve good product formation (Table 2, entry
5) with an excellent yield in 7 d and high enantioselectivity, albeit
with slightly diminished diastereoselectivity (92:8 vs 97:3 dr).
With the optimized reaction conditions in hand, a variety of
chalcones bearing different substituent groups were investigated,
and the results are summarized in Table 3. These chalcones reacted
smoothly with cyclohexanone to provide the corresponding
adducts in moderate to excellent yields with excellent diastereose-
lectivities and enantioselectivities (Table 3, entries 1–15). Excellent
diastereoselectivities (up to >99/1 dr) and enantioselectivities
(81–96% ee) were observed regardless of the electronic nature of
the aromatic substituent. While the nature of the substituent on
the benzene ring exhibited slight influence on the reaction rate
and yield: when electron-donating substituent was introduced to
the benzene ring, low to moderate yields were obtained (Table 3,
entries 8 and 13). Thiophenyl contained chalcone as Michael
acceptor gave low yield (Table 3, entry 15). In addition, acetone-
derived chalcone can also react smoothly with cyclohexanone to
give the corresponding adduct with excellent enantioselectivity
but slower reaction rate (Table 3 entry 16).
Table 2
Screening of catalystsa
Cl
O
O
catalyst
O
O
(10 mol %)
Ph
+
Ph
benzoic acid
(10 mol %)
7d, neat
Cl
1a
3a
2a
c
Entry
Catalyst
Temp (°C)
Yieldb (%)
dr
% ee
1
2
I
20
20
20
20
20
38
51
0
45
91
98:2
97:3
—
98:2
92:8
95
94
—
96
94
II
III
I
3
O
N
4d
5d
II
N
a
O
O
All reactions were carried out with cyclohexanone (1a; 0.5 mL, absolutely
O
H
excess) and chalcone (2a; 63 mg, 0.26 mmol) in the presence of catalysts I–III
O
(10 mol %).
Ar2
b
Yield of the isolated product after chromatography on silica gel.
Determined by chiral HPLC on a Chiralpak AS-H column with n-hexane and
c
Ar1
2-propanol as eluents.
d
30 mol % catalyst was used.
Figure 2. Possible transition state.

H.-Y. Xie et al. / Tetrahedron Letters 53 (2012) 3865–3868
3867
Table 3
Other ketones were also found to be compatible with 1a
under the optimized conditions (Table 4). Reactions with six-mem-
bered ring ketones gave the Michael adducts with excellent enanti-
oselectivities (92–94% ee). However, when cyclopentanone,
cycloheptanone, or acetone was used as substrate, only moderate
enantioselectivity was obtained. The absolute stereochemical
results can be explained by the concept of an acyclic synclinal tran-
sition state, as proposed by Seebach and Golinski.10 It is accepted
that when primary or secondary chiral amines are used as organo-
catalysts, the reaction clearly involves an enamine pathway. As
shown in Figure 2, the possible transition state was presented in
which the imide carbonyl oxygen atom plays an important role in
shielding the si-face of enamine double bond and activating chal-
cones. If the catalyst could not form a transition state, such as III,
the catalyst would not be effective for this reaction.
In summary, we have successfully developed a procedure for
catalytic asymmetric Michael addition reaction of cyclic ketones
with chalcones. Moderate to excellent diastereoselectivities and
enantioselectivities were obtained for the addition of ketones to
a variety of chalcones under the pyrrolidine-based 1,8-Naphthali-
mide catalysis of II. The presence of a brønsted acid with proper
acidity, such as benzoic acid, proved to be critical for the excellent
performance of this catalyst system. The application of this new
type of organocatalyst in other asymmetric reactions is under
way in our laboratory.
Catalytic asymmetric Michael addition of cyclohexanone to chalconesa
O
O
Ar1
O
O
II (30 mol % )
Ar2
+
Ar2
Ar1
benzoic acid
(10 mol % )
1a
2
3
7d, neat, 20 oC
c
Entry
Ar1
Ar2
Yieldb (%)
dr
% ee
1
2
3
4
5
6
7
8
4-ClC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
91
98
77
93
82
95
99
78
99
99
91
78
66
99
67
43
92:8
96:4
99:1
84:16
98:2
88:12
93:7
96:4
77:23
90:10
92:8
95:5
99:1
94
92
95
94
96
95
93
92
91
91
88
91
81
88
91
90
2-NO2C6H4
3-NO2C6H4
2,4-Cl2C6H3
4-BrC6H4
4-FC6H4
4-CH3C6H4
4-NO2C6H4
Ph
Ph
Ph
Ph
Ph
9
Ph
10
11
12
13
14
15
16
4-BrC6H4
4-NO2C6H4
4-FC6H4
4-CH3C6H4
4-ClC6H4
2-Thiophenyl
CH3
93:7
83:17
81:19
2-Thiophenyl
4-ClC6H4
a
All reactions were carried out with cyclohexanone (1a; 0.5 mL, absolutely
excess) and chalcone (2; 0.26 mmol) in the presence of catalyst II (30 mol %).
b
Yield of the isolated product after chromatography on silica gel.
Determined by chiral HPLC on a Chiralpak AS-H column with n-hexane and
c
2-propanol as eluents.
Table 4
Catalytic asymmetric Michael addition reactions of cyclic ketones 1 with chalcone 2aa
Cl
O
O
II (30 mol%)
O
O
Ph
+
Ph
benzoic acid
(10 mol%)
Cl
7d, neat, 20 oC
2a
3
1
c
Entry
1
Ketone 1
Yieldb (%)
dr
% ee
94
O
91
63
92:8
93:7
O
2d
90
O
O
3
4
95
95
96:4
92
73
O
O
61:39
5d
6d
39
40
97:3
—
51
56
O
a
b
c
All reactions were carried out with cyclic ketone (1; 0.5 mL, absolutely excess) and chalcone (2a; 0.26 mmol) in the presence of catalyst II (30 mol %).
Yield of the isolated product after chromatography on silica gel.
Determined by chiral HPLC on a Chiralpak AS-H column with n-hexane and 2-propanol as eluents.
The reaction was carried out in the solvent of DCM.
d

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The authors would like to acknowledge financial supports from
the National Natural Science Foundation of China (No. 81172938),
the Shanxi Province Science Foundation for Youths of China
(No. 2009021041-1) and the Main Cultivate Object of Program
for the Top science and Technology Innovation Teams of Higher
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.05.
106.
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