Asymmetric Michael addition reactions catalyzed by a novel upper-rim functionalized calix[4]squaramide organocatalyst

Article abstract of DOI:10.1016/j.cclet.2020.02.057

A novel upper-rim functionalized calix[4]squaramide organocatalyst bearing bis-squaramide and cyclohexanediamine scaffolds was designed and prepared to catalyse a serial of asymmetric Michael addition of 1,3-dicarbonyl compounds to α,β-unsaturated carbony

Full text of DOI:10.1016/j.cclet.2020.02.057

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Asymmetric Michael addition reactions catalyzed by a novel upper-rim
functionalized calix[4]squaramide organocatalyst
Ke Yang, Zhiyan Ma, Hong-Xiao Tong, Xiao-Qiang Sun, Xiao-Yu Hu,
Zheng-Yi Li
PII:
S1001-8417(20)30117-0
https://doi.org/10.1016/j.cclet.2020.02.057
CCLET 5498
DOI:
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Chinese Chemical Letters
Received Date:
Revised Date:
Accepted Date:
6 January 2020
18 February 2020
28 February 2020
Please cite this article as: Yang K, Ma Z, Tong H-Xiao, Sun X-Qiang, Hu X-Yu, Li Z-Yi,
Asymmetric Michael addition reactions catalyzed by a novel upper-rim functionalized
calix[4]squaramide organocatalyst, Chinese Chemical Letters (2020),
doi: https://doi.org/10.1016/j.cclet.2020.02.057
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Chinese Chemical Letters
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Communication
Asymmetric Michael addition reactions catalyzed by a novel upper-rim functionalized calix[4]squaramide
organocatalyst
Ke Yang a, Zhiyan Ma a, Hong-Xiao Tong a, Xiao-Qiang Sun a,, Xiao-Yu Hu a,b, Zheng-Yi Li a,*
a Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, School of Petrochemical
Engineering, Changzhou University, Changzhou 213164, China
b College of Material Science and Technology, Nanjing University of Aeronautics and Astronautics,
Nanjing 211100, China
Corresponding authors.
E-mail addresses: xqsun@cczu.edu.cn (X.Q. Sun), zyli@cczu.edu.cn (Z.Y. Li)
ARTICLE INFO-ABSTRACT
Article history:
Received 6 January 2020
Received in revised form 18 February 2020
Accepted 26 February 2020
Available online-A novel upper-rim functionalized calix[4]squaramide organocatalyst bearing bis-
squaramide and cyclohexanediamine scaffolds was designed and prepared to catalyse a serial of
asymmetric Michael addition of 1,3-dicarbonyl compounds to α,β-unsaturated carbonyl compounds in high
yields (up to 99%) and good to excellent enantiomeric excesses (up to 99% ee). The comparative
experiments indicated that the cooperative effect between calixarenes cavitives and chiral catalytic centers
on this calix[4]squaramide catalyst could promote these reactions. Moreover, this strategy also provides
valuable and easy access to chiral chromene, naphthoquinone and acetylacetone derivatives, which are
important skeletons in biological and pharmaceutical compounds.
Keywords:Calix[4]squaramide;; Supramolecular catalyst; Asymmetric catalysis; Michael addition;
Organic synthesis-
In recent years, asymmetric Michael reactions have become a powerful strategy to construct C-C bonds
in organic chemistry [1-8]. Among them, the organocatalytic Michael addition of 1,3-dicarbonyl
compounds to α,β-unsaturated carbonyl compounds has attracted much attention due to it offers a facile,
green and effective way to synthesize various important chiral biological and pharmaceutical skeletons [9-
13]. Meanwhile, squaramide is also a very important scaffold in this process due to its rigid four-
membered ring, higher acidity and the appropriate distance between two donor hydrogens [14-18].
Although the significant progress has been made in this research field, the development of a novel and
efficient chiral organic squaramide catalyst for asymmetric Michael addition is a challenging issue.
Calixarenes, as the ideal supramolecular catalysts, have been widely used in asymmetric Michael
reactions because of their tunable three-dimensional molecular platforms with the relatively easy
modification at the lower and upper rims [19-25]. In 2016, Durmaz group demonstrated the synthesis of a
lower-rim functionalized calix[4]squaramide organocatalyst (Fig. 1a) and its catalytic performance in the
asymmetric Michael addition of acetylacetone to nitroolefins [26]. In the past decade, our group also
prepared a series of lower- and upper-rim functionalized calix[4]arene organocatalysts to achieve the
different asymmetric organic reactions in good yields and enantioselectivities [27-31]. It is worth noting
that preparing the cavity of upper-rim functionalized calixarene is much more valuable and difficult than
the lower-rim in the cone conformation of calixarene, because the synergistic effect between calixarene
cavitive and chiral catalytic center could lead the better catalytic performance. In our continuing efforts for
———

developing novel types of chiral organocatalysts, herein the novel upper-rim functionalized
calix[4]squaramide cyclohexanediamine catalyst (Fig. 1b) has been synthesized to catalyze a serial of
asymmetric Michael addition of 1,3-dicarbonyl compounds to α,β-unsaturated carbonyl compounds.
The chemical structures and synthetic pathways for catalysts 1 and 2 are shown in Scheme 1. The upper
rim-functionalized calix[4]arene-based cyclohexanediamine catalyst 1 has been prepared by the following
methods. First of all, calix[4]arene derivative I with amino group on upper rim was obtained according to
literature report [32]. Then the amino group was converted to squaramide group to obtain compound II.
Subsequently, chiral cyclohexanediamine derivatives were reacted with calix[4]arene-based compound II
to form squaramide groups, producing the corresponding calix[4]squaramide cyclohexanediamine catalyst
1. Moreover, in order to investigate the role of the cavity of calix[4]arene, a model catalyst 2 was also
obtained through the similar synthetic methods. Catalysts 1 and 2 were well characterized by NMR and
HRMS analyses, more details are deposited in Supporting information.
Fig. 1. The lower-rim and upper-rim functionalized calix[4]squaramide organocatalyst.
Our investigation began with the Michael addition reaction of ethyl (E)-2-oxo-4-phenylbut-3-enoate 3a
to cyclohexane-1,3-dione 4a in the presence of catalytic calix[4]squaramide cyclohexanediamine 1 (2.5
mol%) in the water at 25 °C. The desired product 5a was detected in 79% yield and 74% ee (Table 1, entry
1). The subsequent examination of different solvents revealed that this process could be obtained in an
improved yield (98% yield) and enantioselectivity (90% ee) in the solvent of DCM (entries 2-10). Next,
decreasing the amount of calix[4]squaramide cyclohexanediamine to 1.0 mol% gave the desired product in
90% yield and 82% ee. However, further optimization showed that the amount of catalyst was increased to
5.0% without an apparent effect on the reaction. Additionally, decreasing the reaction temperature to 0 °C
or -10 °C also showed no apparent effect on this process. Finally, the comparative experiment
demonstrated that the low yield and poor enantioselectivity of desired product 5a was obtained in the
presence of catalyst 2, and these results further confirm the cooperative effect between calixarenes
cavitives and chiral catalytic centers in this catalytic process (entry 15).

Scheme 1. The chemical structures and synthetic pathways for catalysts 1 and 2.
Table 1
Optimization of reaction conditions.a
Entry Catalyst
(mol%)
Yield ee (%)c
Solvent
(%)b
79
1
2
3
4
5
6
7
1 (2.5) H2O
74
52
62
65
82
75
1 (2.5) DMSO
1 (2.5) CH3OH
1 (2.5) CH3CN
1 (2.5) THF
98
92
91
98
1 (2.5) Et2O
98
1,4-
Dioxane
1 (2.5)
90
79
8
9
1 (2.5) PhMe
1 (2.5) DCM
1 (2.5) CHCl3
1 (1.0) DCM
1 (5.0) DCM
1 (2.5) DCM
1 (2.5) DCM
2 (2.5) DCM
95
98
98
90
98
95
92
70
83
90
85
82
90
90
90
80
10
11
12
13d
14e
15
a Reagents and conditions: 3a (0.5 mmol), 4a (0.55 mmol), catalyst, solvent (4.0 mL), 25 oC and 6 h.
b Isolated yield.
c Determined by chiral HPLC analysis.
d 0 oC.
e -10 oC.

With the optimized reaction conditions in hand, we investigated the scope of asymmetric Michael
addition reactions of β–unsaturated α–keto esters and 1,3-dicarbonyl compounds. As shown in Scheme 2,
different β–unsaturated α–keto esters reacted smoothly with cyclohexane-1,3-dione 4a to afford the
corresponding products (5a-d) in excellent isolated yield (85%-98%) and good enantioselectivities (75%-
90% ee). Furthermore, various other cyclic 1,3-dicarbonyl compounds, including dimedone and 2-
hydroxy-1,4-naphthoquinone, have also been used to construct the corresponding products. Using
dimedone as the starting material, the corresponding product 5e was obtained in 98% yield and 73% ee. To
our delight, using 2-hydroxy-1,4-naphthoquinone as the reaction partner, excellent enantioselectivity and
especially high efficiency was achieved. Then, several aromatic β–unsaturated α–keto esters reacted
smoothly with 2-hydroxy-1,4-naphthoquinone to afford the desired products in excellent yields (92%-99%)
and enantioselectivities (83%-99% ee). Moreover, using chalcone as the substrate to react with different
1,3-dicarbonyl compounds such as cyclohexane-1,3-dione, dimedone, 2-hydroxy-1,4-naphthoquinone or
acetylacetone, however, no desired products could be isolated in current conditions.
Scheme 2. The asymmetric Michael addition reaction of β–unsaturated α–keto esters and 1,3-dicarbonyl
compounds. Reagents and conditions: 3 (0.5 mmol), 4 (0.55 mmol), 1 (2.5 mol%), DCM (4.0 mL) and 25
oC. Isolated yield. The ee value was determined by chiral HPLC analysis.
Besides, the asymmetric Michael additions of aryl nitroolefins (6a-6i) with acetylacetone 7 were also
employed to explore the generality of this protocol. The results are summarized in Scheme 3. Although
product 8a obtained from nitrostyrolene only gave the moderate enantioselectivity (63% ee), electronic
effects of the substituents on the phenyl ring exhibited a significant influence on this process. Both
electron-donating (Me and MeO) and electron-withdrawing groups (Cl, Br, NO2 and CF3) at the para-
position on the phenyl ring of nitroolefins were all compatible in the current reaction system, affording the
corresponding products (8b-g) in high yields (81%-98%) and moderate to good enantioselectivities (51%-
94% ee). It was also noticed that the strong electron-withdrawing groups (NO2 and CF3) afforded
obviously better enantioselective products than others. Furthermore, (E)-1-nitro-2-(2-nitrovinyl)benzene
was also tolerated under the current catalytic system to afford the desired product 8h in 80% yield and 61%
ee. However, meta-nitro-substituted nitrostyrolene only gave the desired product 8i in 82% yield and 25%
ee.

Scheme 3. The asymmetric Michael addition of aryl nitroolefins with acetylacetone. Reagents and
o
conditions: 6 (0.5 mmol), 7 (0.55 mmol), 1 (2.5 mol%), DCM (4.0 mL) and 25 C. Isolated yield. The ee
value was determined by chiral HPLC analysis.
On the basis of the above results and the previous asymmetric Michael reactions [33-35], a possibly
synergistic catalytic transition-state model was proposed in Scheme 4. The α-keto ester group of the
substrate 3a is activated via double hydrogen bonding with the one squaramide moiety, while its benzene
group is held by π···π stacking supramolecular host-guest interaction with the calixarene cavities.
Meanwhile, the deprotonated form of the substrate 4a is assumed to interact with the protonated tertiary
amine group of the other squaramide moiety, leading the corresponding transition-state. The cooperative
effect between calixarene cavity and squaramide moieties facilitates the substrate 4a to stereoselectively
attack 3a to form the desired product 5a in good yield and enantioselectivity.
Scheme 4. The possible transition-state model.
In summary, a novel upper rim-functionalized calix[4]arene-based chiral cyclohexanediamine
squaramide catalyst 1 as multiple H-bond donor–acceptor organocatalyst for the enantioselective Michael
reactions of 1,3-dicarbonyl compounds and α,β-unsaturated carbonyl compounds. These Michael reactions
were performed smoothly in DCM at room temperature by using 2.5 mol% of chiral catalyst 1, leading to
the Michael adducts in good yields (up to 99%) and enantioselectivities (up to 99% ee). Moreover, the
scaffold of calixarene, especially its hydrophobic cavity of catalyst 1 played important roles in controlling
reaction activities and enantioselectivities by comparing with model catalyst 2. Further study on this
reaction mechanism in detail is ongoing in our laboratory.

Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that
could have appeared to influence the work reported in this paper.
Acknowledgments
We gratefully acknowledge the financial support from the National Natural Science Foundation of China
(Nos. 21572026 and 21702019), Advanced Catalysis and Green Manufacturing Collaborative Innovation
Center, Changzhou University, and the Priority Academic Program Development of Jiangsu Higher
Education Institutions.
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