A chiral benzoylthiourea-pyrrolidine catalyst for the highly enantioselective Michael addition of ketones to chalcones

Article abstract of DOI:10.1016/j.bmcl.2014.04.005

A benzoylthiourea-pyrrolidine catalyst was developed for the asymmetric Michael addition of ketones to chalcones. The corresponding products were obtained in high yields with high level of diastereoselectivities (up to 99:1 dr) and high level of enantioselectivities (up to 94% ee) under mild conditions.

Full text of DOI:10.1016/j.bmcl.2014.04.005

Bioorganic & Medicinal Chemistry Letters xxx (2014) xxx–xxx
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Bioorganic & Medicinal Chemistry Letters
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A chiral benzoylthiourea–pyrrolidine catalyst for the highly
enantioselective Michael addition of ketones to chalcones
a
a
a,
Shu-rong Ban a,b, , Xi-xia Zhu , Zhi-ping Zhang , Qing-shan Li
⇑
⇑
a School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, People’s Republic of China
b Department of Chemistry, McGill University, Montreal, Quebec H3A 0B8, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
A benzoylthiourea–pyrrolidine catalyst was developed for the asymmetric Michael addition of ketones to
chalcones. The corresponding products were obtained in high yields with high level of diastereoselectiv-
ities (up to 99:1 dr) and high level of enantioselectivities (up to 94% ee) under mild conditions.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 21 January 2014
Revised 19 March 2014
Accepted 2 April 2014
Available online xxxx
Keywords:
Benzoylthiourea–pyrrolidine
Enantioselective
Michael addition
Ketones
Chalcones
The formation of carbon–carbon bonds is central to organic
chemistry, indeed to chemistry in general.1 One essence of syn-
thetic organic chemistry leading to the formation of various valu-
able molecules is how to efficient generation of a carbon–carbon
bond. For a long time chemists have focused considerable and con-
sistent attentions on the development of efficient and operation-
ally simple protocols for the formation of carbon–carbon bonds.2
The Michael reaction is generally regarded as one of the most effi-
cient carbon–carbon bond forming reactions.3 The importance of
this methodology has stimulated significant interest in the devel-
opment of catalytic, asymmetric versions of the process.4,5
Although in 1973 Langstrom and Bergson firstly reported the enan-
tioselective Michael addition catalyzed by 2-(hydroxymethyl)-
quinuclidine,6 organocatalytic Michael reaction has blossomed
rapidly since the turn of the century.7 Forming of iminium8 or
enamine9 intermediate temporarily, hydrogen bonding interac-
tions10 and steric hindrance11 are mainly involved in organocata-
lytic Michael reaction. Chiral proline,8,9 thioureas or ureas,10
cinchona alkaloid6,7a and guanidines12 have been developed and
applied to asymmetric Michael reaction.
properties, including anti-inflammatory, antimicrobial, antifungal,
antioxidant, cytotoxic, antitumor and anticancer activities.13
Organocatalytic Michael additions of nucleophiles (such as nitro-
alkanes,14 malonates,15 cyanoacetates,16 hydroxylamines,17 malon-
onitrile,18 thiols,19 cyanomethylphosphonate,20 butenolide,21 and
sodium bisulfite et al.22) to chalcones have been reported. Asym-
metric addition of simple cyclic ketones with chalcones catalyzed
by organocatalysts, however, still remains a challenge, probably
due to the low reactivity and high steric hindrance of the sub-
strates.23 Wang et al. accomplished the addition of ketones to chal-
cones for the first time with high enantioselectivity using a chiral
pyrrolidinylmethylsulfonamide catalyst and obtained the desired
products with moderate yields and good enantioselectivities and
diastereomeric ratios.23a Wang and co-workers then reported the
Michael addition of cyclohexanone to chalcones catalyzed by a
pyrrolidine-pyridine base.23b Wang et al. developed a C2-symmet-
ric tetraamine catalyst for the asymmetric addition of ketones to
chalcones.23c,d The corresponding adducts were obtained in good
yields with high levels of diastereo- and enantioselectivities under
mild conditions. A proline-based organic phosphane was discov-
ered by Li’group and successfully applied to catalyze the addition
of cyclohexanone or cyclopentanone to chalcones.23e Our group
in 2012 reported the pyrrolidine-based imides which can catalyze
the addition of cyclic ketones to chalcones smoothly.23f
Chalcones, belonging to the flavonoid family, is one of the major
classes of natural products with widespread distribution in fruits,
vegetables, spices, tea and soy based foodstuff. Chalcones and their
structural analogues have been reported to possess many useful
Recently, we have developed the novel bifunctional ben-
zoylthiourea–pyrrolidine 1 (Fig. 1) which was found to be efficient
in the asymmetric Michael reaction of ketones to nitroalkenes.6b
⇑
Corresponding authors. Tel./fax: +86 351 4690322.
E-mail addresses: shurong.ban@mcgill.ca (S. Ban), qingshanl@yahoo.com (Q. Li).
http://dx.doi.org/10.1016/j.bmcl.2014.04.005
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ban, S.-r.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.04.005

2
S. Ban et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
S
O
O
O
O
S
O
while with unsatisfied yield (Table 1, entry 14, 60% yield). Benzoic
acid is the best choice because of the higher of enantioselectivity
and reaction rate (Table 1, entry 9, 96:4 dr, 94% ee). In addition,
decreasing cyclohexanone(5a) loading was deteriorated to the
yield and stereoselectivity of 7a (Table 1, entry 15).
Catalysts 2ꢀ4 were then screened employing above optimized
conditions (Table 1, entry 9), and the results were summarized in
Table 2. Catalysts 2ꢀ4, however, proved incapable of catalyzing
this model reaction. Inefficiency of 2ꢀ4 may be due to their poor
solubility in cyclohexanone(neat) (3 and 4) and/or less of acidic
protons (2 and 4). Catalysts 2, 3 and 4 were then reexamined in
other polar solvents such as DMF, DMSO, and i-PrOH. To our disap-
pointment, solubilities improvement of catalysts did not generate
satisfactory results. Probably polar solvents themselves are against
this catalytic system.
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 ad-
ducts in moderate to excellent yields with excellent diastereoselec-
tivities and enantioselectivities (Table 3, entries 1–13). Excellent
diastereoselectivities (up to >99/1 dr) and enantioselectivities (up
to 94% 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 7 and 11). To our satisfaction, thiophenyl contained
chalcone as Michael acceptor gave good yield and stereoselectivity
(Table 3, entry 13).
Other ketones (cyclopentanone, acetone and cycloheptanone)
were then tested as the Michael donors for this catalytical system
(Fig. 2). Cyclopentanone and acetone gave the adducts with good
enantioselectivities (79% and 50% ee, respectively). However, when
cycloheptanone was used as substrate, the reaction proceeded
slowly and only moderate enantioselectivity was obtained.
On the basis of the experimental results, the possible transition
state for the 1-catalyzed Michael addition was presented. As
N
H
N
H
N
H
N
H
N
H
N
H
3
1
S
O
O
S
O
O
N
H
O
N
H
N
H
N
H
2
4
Figure 1. Bifunctional organocatalysts of 1ꢀ4.
Considering the consistency of catalytic mechanism, herein we
tested the benzoylthiourea/sulfonylurea–pyrrolidine catalysts
1ꢀ4 (Fig. 1) in the addition of cyclic ketones to lower activated Mi-
chael 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 diastereoselec-
tivity (up to 99:1) and excellent enantioselectivity (up to 94% ee)
under mild conditions.
Using 1 as the catalyst, the effects of the solvent, additive, and
the catalyst loading on the model asymmetric Michael addition
of cyclohexanone 5a to chalcone 6a were thoroughly investigated,
and the results are summarized in Table 1. Initially, the reaction
was performed by using 10 mol % of 1 in a few solvents at 20 °C
with benzoic acid as the additive. Among the various organic sol-
vents tested, DCM, toluene, and no solvent(neat) were better in
terms of both the diastereoselectivity and enantioselectivity, with
87% ee, 91% ee and 92% ee in enantioselectivity, respectively
(Table 1, entries 1, 2, and 6). When the reaction proceeded in polar
solvents (DMSO, THF and i-PrOH), almost no product was obtained
(Table 1, entries 3–5). We also found that the yield of 7a was in-
creased obviously by augmenting the catalyst loading from 0.1 to
0.3 equiv (Table 1, entries 7–9). Considering both the reaction rate
and stereoselectivity, neat was then selected as the optimal reac-
tion condition in the study of the influence of the additive. In the
absence of any carboxylic acid or in the presence of TFA, acetic acid
or HCl, the reaction proceeded slowly and the yield of 7a was lower
or very poor (Table 1, entries 10–13). When 2,4-dichlorobenzoic
acid was added as co-catalyst the reaction proceeded smoothly
Table 1
Screening of reaction conditions for the addition of cyclohexanone to chalcone 6aa
Cl
O
O
1
solvent
Ph
O
O
+
additive
(10 mol %)
7d, 20oC
Cl
Ph
5a
6a
7a
Entry
Additive
Catalyst loading (mol %)
Solvent
Yieldb (%)
dr (syn/anti)c
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Benzoic acid
Benzoic acid
Benzoic acid
Benzoic acid
Benzoic acid
Benzoic acid
Benzoic acid
Benzoic acid
Benzoic acid
No additive
TFA
10
10
10
10
10
10
30
30
30
30
30
30
30
30
30
DCM
59
48.1
Trace
0
86:14
94:6
–
–
–
95:5
96:4
96:4
96:4
87:13
–
87
91
–
–
–
92
94
93
94
90
–
Toluene
DMSO
DMF
i-PrOH
Neat
DCM
Toluene
Neat
Neat
Neat
Neat
Neat
0
79
79
68
95
52
0
Trace
0
60
78
Acetic acid
HCl
2,4-Dichlorobenzoic acid
Benzoic acid
–
–
–
–
90
92
Neat
90:10
95:5
Neatd
a
b
c
All reactions were carried out with cyclohexanone (5a; 0.5 mL, absolutely excess) and chalcone (6a; 63 mg, 0.26 mmol) in the presence of catalyst 1.
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.
Cyclohexanone(5a; 0.3 mL), chalcone (6a; 63 mg, 0.26 mmol) in the presence of catalyst 1.
d
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S. Ban et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
3
Table 2
shown in Figure 3, benzoylthiourea–pyrrolidine catalyst 1 was pro-
posed as a bifunctional catalyst. The pyrrolidine reacted with car-
bonyl compounds to form an enamine and the benzoylthiourea-
activated chalcone via N–H hydrogen bonds. The enamine attacked
the chalcone from the si-face to afford the product.
In conclusion, 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 benzoylthiourea–pyrrolidine 1. The
presence of a brønsted acid with proper acidity, such as benzoic
acid, proved to be critical for the excellent performance of this cat-
alyst system. The application of this new type of organocatalyst in
other asymmetric reactions is underway in our laboratory.
Screening of catalystsa
Cl
O
O
catalyst
(30 mol %)
neat
O
O
Ph
+
Ph
benzoic acid
Cl
(10 mol %)
7d, 20oC
5a
7a
6a
Entry
Catalyst
Yieldb (%)
dr (syn/anti)c
eec (%)
1
2
3
4
1
2
3
4
95
0
Trace
0
96:4
94
–
–
–
–
–
–
a
All reactions were carried out with cyclohexanone (5a; 0.5 mL, absolutely
excess) and chalcone (6a; 63 mg, 0.26 mmol) in the presence of catalyst (30 mol %).
Acknowledgments
b
Yield of the isolated product after chromatography on silica gel.
c
Determined by chiral HPLC on a Chiralpak AS-H column with n-hexane and
We gratefully acknowledge the financial support from the Na-
tional Natural Science Foundation of China (No. 81172938), the
Main Cultivate Object of Program for the Top science and Technol-
ogy Innovation Teams of Higher Learning Institutions of Shanxi, the
Scientific and Technological Innovation Programs of Higher Educa-
tion Institutions in Shanxi (No. 2013118) and the Scientific and
Technological Innovation Programs of Shanxi Medical University
(No. C01201009). Prof. Ban thanks the support from Shanxi Schol-
arship Council of China and Shanxi Medical University Program of
Training and Studying Abroad for Young Teachers.
2-propanol as eluents.
Table 3
Catalytic asymmetric Michael addition of cyclohexanone to chalconesa
O
O
Ar1 O
O
1
(30 mol % )
Ar2
+
Ar2
Ar1
benzoic acid
(10 mol % )
5a
6
7
7d, neat, 20 o
C
Entry Ar1
Ar2
Yieldb (%) dr (syn/anti)c eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
4-ClC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
95
98
95
90
88
92
85
94
91
78
66
89
96:4
91:9
87:13
99:1
97:3
95:5
98:2
97:3
96:4
98:2
99:1
98:2
85:15
94
89
87
91
90
90
94
78
87
90
75
87
87
Supplementary data
3-NO2C6H4
2,4-Cl2C6H3
4-BrC6H4
4-FC6H4
4-CH3C6H4
Ph
Ph
Ph
Ph
Ph
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.04.
005.
4-BrC6H4
4-NO2C6H4
4-FC6H4
4-CH3C6H4
4-ClC6H4
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53% yield
32% yield
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