C3-symmetrical cinchonine-squaramide as new highly efficient, and recyclable organocatalyst for enantioselective michael addition

Article abstract of DOI:10.1002/adsc.201100066

A novel and recyclable catalyst, a C₃-symmetrical cinchonine-squaramide, has been developed for the asymmetric Michael addition of 1,3-dicarbonyl compounds to nitroalkenes. When using only 1 mol% of catalyst 1a for the reaction, high reaction y

Full text of DOI:10.1002/adsc.201100066

FULL PAPERS
DOI: 10.1002/adsc.201100066
C3-Symmetrical Cinchonine-Squaramide as New Highly
Efficient, and Recyclable Organocatalyst for Enantioselective
Michael Addition
Chang Min,a Xin Han,a Zongquan Liao,a Xiangfei Wu,a Hai-Bing Zhou,a
and Chune Donga,*
a
College of Pharmacy, State Key Laboratory of Virology, Wuhan University, Wuhan 430072, Peopleꢀs Republic of China
Fax : (+86)-27-6875-9850; phone: (+86)-27-6875-9586; e-mail: cdong@whu.edu.cn
Received: January 26, 2011; Revised: June 14, 2011; Published online: October 11, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100066.
Abstract: A novel and recyclable catalyst, a C3-sym- esters are the best ever achieved. Moreover, 1a can
metrical cinchonine-squaramide, has been developed be easily recovered by simple precipitation and was
for the asymmetric Michael addition of 1,3-dicarbon- used for six cycles without losing any selectivity and
yl compounds to nitroalkenes. When using only activity.
1 mol% of catalyst 1a for the reaction, high reaction
yields with excellent enantioselectivities and diaste- Keywords: asymmetric Michael addition; C3-sym-
reoselectivities (up to 96% yield,>99% ee,>99:1 dr) metrical species; catalyst recycling; cinchonine-squar-
were achieved, in which the results for cyclic keto amide
Introduction
efficient, recyclable chiral catalysts for the asymmetric
Michael addition reaction are highly desirable.
Currently, C3-symmetrical chiral molecules have
The asymmetric Michael addition has emerged as one
À
of the most efficient and powerful tools to C C bond drawn much attention in the area of supramolecular
formation in organic synthesis.[1] In particular, the coordination chemistry,[7] molecular recognition,[8] and
asymmetric Michael addition of 1,3-dicarbonyl com- material sciences.[9] As far as asymmetric catalysis is
pounds to nitroalkenes catalyzed by organocatalysts concerned, it is generally believed that C3-symmetri-
such as diamine,[2] amine-thiourea,[3] Cinchona deriva- cal ligands can reduce the number of possible diaste-
tives[4] etc. is one of the most important methods for reomers in catalytic intermediates, and create a more
the preparation of optically active nitro carbonyl com- sterically encumbered chiral space as well, which
pounds,[5] which are the key intermediates for prepa- might reduce disadvantages such as rotation and flexi-
ration of a large number of pharmaceutical substan- bility in enantiofacial control. In addition, C3-symmet-
ces. In 2008, the chiral squaramide organocatalysts rical ligands can also be synthesized in a direct or
pioneered by Rawalꢀs group have been demonstrated modular way, which can greatly improve the ligand di-
to be a new family of efficient and versatile bifunc- versity and provides access to ligands capable of
tional organocatalysts for asymmetric additions of 1,3- achieving excellent selectivity for a wide range of
dicarbonyl compounds to nitrostyrenes with excellent asymmetric reactions. Since 1998, the chiral C3-sym-
enantioselectivity.[6] Despite important progress in this metrical ligands have been assayed in reactions such
area, there is still room for improvement regarding as asymmetric cyclopropanation, allylic oxidation, al-
this type of asymmetric Michael addition reaction. kynylation of aldehydes, allylic alkylation, and asym-
For example, slight erosions in enantioselectivities metric borane reduction of proketones giving modest
and diastereoselectivities in addition to heterocyclic to good enantioselectivities.[10] More recently, Reetz
nitroolefins are still a challenge. Furthermore, due to and co-workers reported the use of the C3-symmetri-
the difficulty in catalyst recycling, the applications of cal monodentate phosphate ligand in the Rh-cata-
these catalytic systems in pharmaceutical production lyzed enantioselective hydrogenation of homoallylic
have been limited. Therefore, new strategies to design alcohols.[11] Meanwhile, squaric acid has long been
Adv. Synth. Catal. 2011, 353, 2715 – 2720
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Chang Min et al.
FULL PAPERS
known as an aromatic compound with a unique char-
acter and wide applications,[12] its rigid ring provides
an efficient environment for coordination of the sub-
strates and the reagents in asymmetric reactions.[13,14]
In consideration of the excellent performance of the
squarACHTUNGTRENNUNGamide organocatalysts developed by Rawalꢀs
group and later exploited by other groups,[6,13] we an-
ticipated that the synthesis of C3-symmetrical catalysts
with a squaric acid moiety, would not only provide a
unique chiral environment in asymmetric transforma-
tion, but also open a new way for the design and syn-
thesis of novel organocatalysts. To the best of our
knowledge, there is no report on the C3-symmetrical
chiral molecules of squaric acid for use in asymmetric
catalysis so far. Our interest is to explore the synthesis
and application of C3-symmetrical squaramides in the
enantioselective Michael addition. For this purpose,
our initial efforts focused on the synthesis of C3-sym-
metrical cinchonine-squaramides starting with com-
mercially available squaric acid and cinchonine. We
envisioned that the combination of a cinchonine
framework and a squaric acid skeleton would enhance
the enantioselectivity. Moreover, the poor solubility
of the C3-symmetrical squaramide in organic solvents
enabled its easy recovery by a simple precipitation
method, allowing its operational recycling. Herein, we
describe the first C3-symmetrical cinchonine-squara-
mide as a new robust, highly efficient, recyclable cata-
lyst for the enantioselective Michael addition of 1,3-
dicarbonyl compounds to nitroalkenes.
On the basis of the above considerations and from
the viewpoint of synthetic simplicity, three C3-sym-
metrical cinchonine-squaramides 1a–c were designed,
in which the three chiral subunits of the catalysts
were connected with each other via a C3-symmetrical
triamine core through a squaramide linker. As illus-
trated in Scheme 1, compounds 1a–c were prepared in
two steps via the coupling of diethyl squarate with
cinchonine-derived amine, and subsequent condensa-
tion with amines 4a–c in good yields under mild con-
ditions. In a similar way, the corresponding bis- and
monocinchonine-squaramides were also prepared for
comparison.[15]
Scheme 1. Preparation of C3-symmetrical cinchonine-squara-
mides 1a--c.
Table 1. Optimization and catalyst screening for the Michael
addition of 5a with 6a.
Entry Catalyst (mol%) Solvent Yield [%][c] ee [%][d]
1[a]
1a (0.5)
1a (1.0)
1a (2.0)
1a (5.0)
1a (1.0)
1a (1.0)
1a (1.0)
1a (1.0)
1b (1.0)
1c (0.5)
1c (1.0)
1c (5.0)
DCM
DCM
DCM
DCM
DCM
toluene 91
THF 95
ethanol 73
DCM
DCM
DCM
DCM
91
98
95
97
93
86
89
66
55
97
85
81
85
63
82
83
62
2[a]
3[a]
4[a]
5[b]
6[b]
7[b]
8[b]
9[a]
Results and Discussion
89
93
97
95
10[a]
11[a]
12[a]
With catalysts 1a–c in hand, an evaluation of their
catalytic activities in the asymmetric Michael addition
of 1,3-dicarbonyl compounds to nitroolefins was un-
dertaken. Initially, 2,4-pentanedione (5a) and b-nitro-
styrene (6a) were chosen as substrates for this study.
After a brief survey of reaction conditions (Table 1),
we found that the catalyst, solvent, and catalyst load-
ing are critical determinants of the reaction efficiency.
When the reaction was catalyzed by 1.0 mol% 1a in
CH2Cl2 with 1.1 equivalents of 5a and 1.0 equivalent
[a]
Reaction conditions: 0.5 mmol of 5a, 0.25 mmol of 6a, in-
dicated amount of catalysts in 1.5 mL CH2Cl2, room tem-
perature, 12 h.
Reaction conditions: 0.275 mmol (1.1 equiv.) of 5a,
0.25 mmol of 6a, indicated catalyst in 0.1 mL of solvent,
room temperature, 12 h.
[b]
[c]
[d]
Isolated yield.
Determined by HPLC with an OD-H column.
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C3-Symmetrical Cinchonine-Squaramide as New Highly Efficient, and Recyclable Organocatalyst
Table 2. Asymmetric Michael addition of 1,3-dicarbonyl
compounds 5 with nitroalkenes 6 catalyzed by catalyst 1a.[a]
of 6a, 7a was obtained in high yield (93%) and excel-
lent enantioselectivity (97% ee) (Table 1, entry 5). In-
terestingly, the catalyst loading of 1a dramatically in-
fluenced the enantioselectivity of the product; in-
creasing the loading of 1a led to decreased enantiose-
lectivity (Table 1, entries 3 and 4). While other sol-
vents (e.g., THF, toluene, ethanol) and catalysts all
provided inferior results (Table 1, entries 6–8). When
1c was used instead of 1a under the same reaction
conditions, a decreased enantioselectivity (83% ee)
was observed (Table 1, entry 11); on switching from
1c to 1b, the enantioselectivity of the reaction was
even poorer (63% ee) (Table 1, entry 9). This implied
that a steric effect was an important factor for enan-
tioselectivity. Bearing three methyl groups on the
phenyl ring, the steric hindrance of 1b might prevent
the suitable transition-state geometry to be attained
easily. Under the same reaction conditions, in compar-
ison with 1a, both bissquaramide and monosquara-
mide gave moderate enantioselectivity (see Support-
ing Information). The results indicated that the C3-
symmmetrical squaramide 1a was more effective in
the Michael addition reaction.
Entry
5
Nitroolefin 6
Product Yield ee
[%][b] [%][c]
1
2
3
4
5
6
7
8
9
5a R1 =Ph (6a)
7a
7b
93
87
89
83
94
88
94
90
87
97
89
90
91
90
93
96
94
95
5a R1 =4-Me-C6H4 (6b)
5a R1 =4-MeO-C6H4 (6c) 7c
5a R1 =2-MeO-C6H4 (6d) 7d
5a R1 =4-Br-C6H4 (6e)
5a R1 =2-Br-C6H4 (6f)
5a R1 =4-F-C6H4 (6g)
5a R1 =2-Cl-C6H4 (6h)
5a R1 =2,4-di-Cl-C6H3
(6i)
7e
7f
7g
7h
7i
10
11
12
5a R1 =2-thienyl (6j)
5b R1 =2-thienyl (6j)
5b R1 =Ph (6a)
7j
7k
7l
96
91
92
>99
95
91
[a]
With the optimized reaction conditions in hand, the
scope and limitation of our catalytic system to in
enantioselective Michael reactions of various nitroole-
fins with 1,3-dicarbonyl compounds was investigated,
the results are summarized in Table 2.
As demonstrated in Table 2, with using 1 mol% 1a,
the reactions of all b-nitrostyrenes, bearing ortho or
para electron-donating or electron-withdrawing sub-
Unless otherwise noted, the reactions were carried out
with 0.275 mmol of 5, 0.25 mmol of 6 in 0.1 mL of
CH2Cl2 in the presence of 1 mol% of catalyst 1a for 12–
24 h.
[b]
[c]
Isolated yield.
Values were determined by HPLC using a chiralpac AD-
H column.
stitutents, with 2,4-pentanedione 5a proceeded results,[6,16] suggesting that the C3-symmetrical chiral
smoothly, and afforded the corresponding Michael ad- catalyst would likely enhance the enantioselectivity
ducts 7a–i in high yield (up to 94%) with excellent and diastereoselectivity for this asymmetric transfor-
enantioselectivities (up to 97%) (Table 2, entries 1–9). mation. For example, the reactions of the keto ester
This observation suggests that the nature of the nitro- 8e with nitroolefins 6h and 6j were completed within
olefins has no significant influence on the enantiose- 12 h affording 9l and 9m in >99% dr with almost one
lectivities. Meanwhile, a heteroaromatic nitroolefin, enantiomer only (>99% ee) (Table 3, entries 12 and
such as 6j, displayed high activity in this reaction. For 13). To the best of our knowledge, these results for
example, the reaction of 5a with 6j furnished 7j in cyclic keto esters are the best ever achieved. Further-
96% yield with >99% ee (Table 2, entry 10). Further- more, the substituted group at the phenyl ring of ni-
more, 5b reacted with 6a forming 7l in 92% yield and trostyrene can also be varied without affecting the ef-
91% ee, respectively (entry 12).
ficiency of the reaction: 4-methoxynitrostyrene 6c and
Encouraged by these results, the substrate scope of 2-chloronitrostyrene 6h reacted smoothly with 8d
the reaction with several b-keto esters was also inves- leading to the corresponding products 9e and 9h in
tigated (Table 3). As shown in Table 3, in all cases, 99% dr and 97% ee, respectively (Table 3, entries 5
the Michael adducts were obtained in high yields with and 8). Also, we were delightful to find that the
predominately the syn diastereomer, and good to ex- heteroACHTUNTRGNEUNGaromatic nitroolefin 6k, bearing a furyl group,
cellent enantioselectivity. The reaction of b-nitrostyr- reacted with ethyl aceoacetate 8a to give the desired
ene (6a) and keto esters 8a–c provided the corre- product 9n in 93% ee (Table 3, entry 14).
sponding products 9a–c in good yields and enantiose-
The nice enantioselectivity for heteroaromatic ni-
lectivities, but the diastereoselectivities were moder- troolefins was further demonstrated by the reaction
ate (Table 3, entries 1–3). However, excellent diaste- of 6k with 2-ethoxycarbonycyclohexanone 8e. Under
reoselectivities (>99:1) and enantioselectivities (> the optimal conditions, the target compound 9o was
99%) were obtained when cyclic b-keto esters 8d and obtained in 84% yield with 95% ee of the syn diaste-
8e were used in these asymmetric transformations reomer
dominating
(syn/anti=98:2)
(Table 3,
(entries 4–13), which is in sharp contrast to previous entry 15).
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Table 3. Variation of nucleophiles in reaction with 6 catalyzed Table 4. Recycling experiments of catalyst 1a in the Michael
by 1a.[a]
addition of 5b with 6a.[a]
Cycle no. Catalyst recovery rate [%] Yield [%][b] ee [%][c]
Entry Keto
ester
Nitroolefin Product Yield
[%][b]
dr[c]
ee
[%][d]
1
2
3
4
5
6
92
91
89
87
85
83
94
93
96
91
93
90
91
90
90
91
92
90
1
8a
8b
8c
8d
8d
8d
8d
8d
8d
8e
8e
8e
8e
8a
8e
6a
6a
6a
6a
6c
6d
6e
6h
6j
9a
9b
9c
9d
9e
9f
9g
9h
9i
93
91
87
93
89
85
95
87
92
92
95
91
90
83
84
1.2:1 88
1.3:1 97
4:1
2
3
4
5
89
>99:1 94
>99:1 97
>99:1 94
>99:1 97
>99:1 97
>99:1 98
>99:1 93
>99:1 95
>99:1 >99
>99:1 >99
1.3:1 93
[a]
6
7
8
9
All reactions were carried out with 1.1 mmol of 5b,
1 mmol of 6a, in 0.5 mL of CH2Cl2 in the presence of 1
mol% of catalyst 1a for 12 h.
[b]
[c]
Isolated yield.
10
11
12
13
14
15
6a
6e
6h
6j
6k
6k
9j
Values were determined by HPLC using a chiralpac AD-
H column.
9k
9l
9m
9n
9o
98:2
95
[a]
Unless otherwise noted, the reactions were carried out with
0.275 mmol of 8, 0.25 mmol of 6 in 0.1 mL of CH2Cl2 in the
presence of 1 mol% of catalyst 1a for 12–24 h.
Isolated yield.
[b]
[c]
[d]
The syn/anti ratio was determined by 1H NMR.
Values of syn-isomer were determined by HPLC using a
chiralpac AD-H or OD-H column.[5f,n]
Scheme 2. Proposed transition state of Michael addition cat-
alyzed by C3-symmetrical squaramide.
To determine the recyclability of the catalyst, 1a chonine moiety interacted through hydrogen bonding
was recovered after the catalytic process by precipita- with nitroolefin and 1,3-diketone simultaneously. The
tion from the reaction mixture with the addition of di- tertiary amine of cinchonine moiety plays the role of
ethyl ether, and then was reused in the Michael addi- the base to deprotonate a-carbon of the carbonyl
tion of 5b with 6a under the optimized reaction condi- group, forming the enolate to attack the electrophile.
tions (Table 4). It is important to note that the cata- Meanwhile, the two NH groups of the squaramide
lyst can tolerate recycling, and the recovery rate was moiety provide hydrogen bondings to activate the
up to 83% after six cycles. Meanwhile, we were grati- nitro group of the olefin. Since catalyst 1b, bearing
fied to observe that the recovered catalyst retained its three methyl groups on the phenyl ring, gave sharp
high activity and high level of enantioselectivity (90– decrease in enantioselectivity, this implies that the
92% ee) even after six cycles. This promising advant- steric hindrance of the methyl group might disturb
age will make this approach suitable not only for lab- this interaction. However, a precise description of the
oratory-scale research but also for industrial applica- reaction mechanism still requires a more comprehen-
tions.
Based on the observed stereoselectivity, we propose
a plausible dual activation model for this Michael ad-
sive mechanistic study.
dition. The possible transition state for binding of a Conclusions
nitroolefin and a diketone is shown in Scheme 2.
First, the scaffold of C3-symmetrical catalyst was as- In summary, we have prepared the new C3-symmetri-
sumed to create three equal reaction sites surrounded cal cinchonine-squaramides by simple condensation of
by two squaramides,[10c] in which squaramide and cin- a cinchonine-derived amine and diethyl squarate in
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C3-Symmetrical Cinchonine-Squaramide as New Highly Efficient, and Recyclable Organocatalyst
two steps with excellent yields. Catalyst 1a, represen- General Procedure for the Enantioselective Michael
tative of a new class of C3-symmetrical bifunctional Addition Reactions
organocatalyst promoted the asymmetric Michael ad-
dition of various 1,3-dicarbonyl compounds to nitroal-
To a vial with nitroolefin (0.25 mmol) in CH2Cl2 (0.1 mL)
was added catalyst 1a (1 mol%, 0.0025 mmol), and the mix-
kenes leading to the respective products in excellent
enantioselectivities and diastereoselectivities. Mean-
while, 1a could be reused for up to six times without a
distinct decrease in catalyst activity and enantioselec-
tivity. So far, 1a is the first example of a highly effi-
cient, and recyclable C3-symmetrical catalyst for an
asymmetric Michael addition reaction. Further inves-
tigations to clarify the mechanism and explore appli-
cations in other asymmetric transformations are cur-
rently underway.
ture was stirred for 5 min under an N2 atmosphere. Then
1,3-dicarbonyl compound (0.275 mmol) was added to the
mixture. Upon consumption of nitroolefin substrate (moni-
tored by TLC), the reaction mixture was concentrated and
purified by column chromatography to afford the conjugate
addition product.
Procedure for Recycling of the Catalyst
For the catalyst recycling experiment, dry diethyl ether was
added to the reaction mixture after Michael addition until
no additional precipitate appeared. Then the mixture was
centrifuged and the catalyst deposited at the bottom of the
vial. The liquid layer was siphoned out; the residual solid
was washed again until no more compounds were detected
by TLC. Then the vial with remaining catalyst was dried
under vacuum. According to the amount of catalyst, the ni-
troolefin 6a and dicarbonyl compound 5b were then charged
for another round of the Michael addition reaction.
Experimental Section
Unless otherwise noted, reagents and materials were ob-
tained from commercial suppliers and were used without
further purification. All solvents were purified according to
reported procedures. Reactions were monitored by thin
layer chromatography (TLC) and column chromatography
purifications were performed using 230–400 mesh silica gel.
Acknowledgements
Procedure for the Synthesis of 3
This work is supported by National Nature Science Founda-
tion of China (20972121, 20872116, 91017005), the Science
Foundation of Ministry of Education for the New Teacher at
the University of China (20090141120058), the Ministry of
Education of China (NCET-10-0625) and the National Mega
Project on Major Drug Development (2009ZX09301-014-1).
To a solution of diethyl squarate (935 mg, 5.5 mmol) in etha-
nol (10 mL) was added a solution of cinchonine-derived
amine (1.465 g, 5 mmol) in ethanol (10 mL) under an N2 at-
mosphere. After 12 h, the reaction was completed (as moni-
tored by TLC), then the mixture was concentrated and puri-
fied by column chromatography (CH2Cl2:CH3OH=15:1) to
afford the yellow solid 3; yield: 1.93 g (93%). 1H NMR
(400 MHz, CDCl3): d=0.97 (d, J=11.7 Hz, 2H), 1.52 (m,
1H), 1.62 (s, 3H), 1.70 (s, 1H), 2.35 (d, J=7.7 Hz, 1H), 3.00
(m, 5H), 4.06 (br, 2H), 5.15 (d, J=17.4 Hz, 1H), 5.21 (d,
J=10.3 Hz, 1H), 5.93 (m, 1H), 7.39 (s, 1H), 7.63 (m, 1H),
7.77 (t, J=7.7 Hz, 1H), 8.17 (m, 2H), 8.92 (d,=4.4 Hz, 1H).
References
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Catalysts 1a
To a solution of 3 (0.31 mmol) in MeOH (3 mL) was added
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MeOH (2 mL) under an N2 atmosphere. After 12 h, the re-
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1a: 83%; yellow solid; mp 255–2568C; IR (KBr): n=3435,
2938, 1797, 1661, 1589, 1536 cmÀ1
;
1H NMR (400 MHz,
DMSO-d6): d=0.88 (br, 6H), 1.47 (s, 9H), 2.17 (s, 3H), 2.76
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5.08 (d, J=12 Hz, 3H), 5.13 (d, J=16 Hz, 3H), 5.79 (br,
3H), 6.04 (s, 3H), 7.16 (s, 3H), 7.70 (m, 13H), 7.90 (br, 3H),
8.06 (d, J=8 Hz, 3H), 8.41 (d, J=4 Hz, 3H), 8.9d (br, 3H);
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38.63, 45.81, 46.66, 48.89, 59.30, 114.51, 119.28, 123.25,
126.31, 126.64, 127.04, 129.43, 129.92, 139.54, 140.51, 145.48,
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Chang Min et al.
FULL PAPERS
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[15] Bisquaramide and monosquaramide were also prepared
for comparison. Both gave inferior enantioselectivity.
See the Supporting Informations for details.
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2720
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Adv. Synth. Catal. 2011, 353, 2715 – 2720