Polysulfonate supported chiral diamine-nickel catalysts: Synthesis and applications

Article abstract of DOI:10.1016/j.tetlet.2020.152792

A series of chiral polysulfonate cyclohexyldiamine-Ni(II) catalysts were prepared via sulfur (VI) fluoride exchange click-reactions. The catalysts exhibited good catalytic activity and enantioselectivity in the Michael addition of malonates to nitroalkene

Full text of DOI:10.1016/j.tetlet.2020.152792

Tetrahedron Letters 65 (2021) 152792
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Polysulfonate supported chiral diamine-nickel catalysts: Synthesis
and applications
⇑
⇑
Jing-xuan Zhou, Dong-yu Zhu, Jie Chen, Xue-jing Zhang , Ming Yan , Albert S.C. Chan
Guangdong Provincial Key Laboratory of Chiral Molecules and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of chiral polysulfonate cyclohexyldiamine-Ni(II) catalysts were prepared via sulfur (VI) fluoride
exchange click-reactions. The catalysts exhibited good catalytic activity and enantioselectivity in the
Michael addition of malonates to nitroalkenes. The excellent recyclability of the catalysts was demon-
strated via the reuse of the privileged catalyst 7a for ten times. The results provide a new strategy for
the immobilization of chiral homogeneous catalysts.
Received 19 November 2020
Revised 16 December 2020
Accepted 18 December 2020
Available online 11 January 2021
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Catalyst immobilization
Chiral dimamine-nickel catalyst
Polysulfonate
Asymmetric conjugate addition
c
-Aminobutyric acid drug
Introduction
In 2007, Evans and co-workers found that chiral cyclohexyl-
diamine-Ni(II) complexes are efficient catalysts for the enantiose-
Asymmetric catalysis is the most powerful method to prepare
optically active compounds. Tremendous progresses have been
made in last four decades [1]. In most cases, chiral homogeneous
catalysts have been applied taking advantage of excellent catalytic
activity and structural diversity. However, these catalysts fre-
quently suffer from the poor-recyclability, high cost and the con-
tamination of heavy metals in the products. Immobilization of
homogeneous chiral catalysts provides a practical solution of these
drawbacks and is extremely attractive for the industrial applica-
tions and the flow chemistry. Great efforts have been made to
develop various immobilization methods [2]. Usually, the immobi-
lization on the surface of solid materials such as silica gel, molec-
ular sieves, polystyrene beads are preferred via the covalent or
non-covalent interaction. In addition, the polymerization of the
functionalized ligand monomers had also been used. After the
coordination with transition metals, the immobilized catalysts
were obtained. In most cases, polystyrene was selected for this
purpose. Another interesting strategy, named self-immobilization,
was also developed via the dynamic generation of metallopoly-
mers. Despite the efforts, further improvements are still required
in terms of the catalytic activity, recyclability, the chemical and
mechanical stability, and the cost.
lective Michael addition of 1,3-dicarbonyl substrates to
nitroalkenes [3]. The catalysts are readily prepared from cheap chi-
ral cyclohexyldiamines. The reaction was applicable for a large
number of nitroalkenes with excellent yields and enantioselectivi-
ties. The products could be transformed to chiral
acid derivatives after subsequent steps [4]. These features are
attractive for the industrial preparation of chiral -amino butyric
c-amino butyric
c
acid drugs [5]. The immobilization of cyclohexyldiamine-Ni(II) cat-
alysts can provide additional benefits to decrease the catalyst cost
and the contamination of nickel, and to facilitate the workup of the
products. In 2012, Li, Liu and co-workers reported the immobiliza-
tion of cyclohexyldiamine-Ni(II) catalysts on a periodic meso-
porous silica gel. The resulted catalyst could be recycled for nine
times without obvious loss of the yields and enantioselectivities
[6]. Later, Bellemin-Laponnaz and co-workers designed a dynamic
self-supported cyclohexyldiamine-Ni(II) catalyst with a chiral dito-
pic cyclohexyldiamine ligand. This catalyst was recycled up to ele-
ven times with excellent yields and enantioselectivities [7]. In
2019, Kobayashi and co-workers reported that the composites of
chiral diamine-Ni(II) complexes and mesoporous silica MCM-41
exhibited excellent catalytic activity and enantioselectivity for
the conjugate addition of malonates to nitroalkenes [8]. MCM-41
seemed to enhance the catalytic activity of the chiral diamine-Ni
(II) complex that resides within its pores. The catalyst could be
reused for three times with keeping the same levels of yield and
⇑
Corresponding authors.
E-mail addresses: zhangxj33@mail.sysu.edu.cn (X.-j. Zhang), yanming@mail.
sysu.edu.cn (M. Yan).
https://doi.org/10.1016/j.tetlet.2020.152792
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

Jing-xuan Zhou, Dong-yu Zhu, J. Chen et al.
Tetrahedron Letters 65 (2021) 152792
enantioselectivity, but the significant loss of the yield was
observed from the fourth cycle.
by ICP analysis. The structure, yield and Ni loading of catalysts 7a-
7e are summarized in Scheme 1. Although the similar reaction con-
ditions were adopted, the degree of polymerization is much lower
In recent years, Sharpless and co-workers developed a series of
sulfur (VI) fluoride exchange (SuFEx) click-reactions [9]. Among
them, the reaction of aromatic bis(silyl ethers) and bisfluorosul-
fates provided polysulfonates in excellent yields [10]. We speculate
that a new immobilization of chiral diamine-Ni(II) catalysts may be
achieved taking the advantage of SuFEx reaction. In this paper, we
would like to report the synthesis of polysulfonate supported chiral
diamine-Ni(II) catalysts and their applications in the enantioselec-
tive addition of malonates to nitroalkenes. Excellent yields, enan-
tioselectivities and recyclability were obtained using the
immobilized catalysts.
Table 1
Enantioselective addition of diethyl malonate 9a to b-phenylnitroethene 8a.a
EtOOC
COOEt
NO2
NO2
catalyst
rt, 24 h
+
EtOOC
COOEt
8a
10a
9a
Solvent
Entry
Cat.
Yield (%)b
Ee (%)c
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
DCM
DCM
DCM
DCM
DCM
CHCl3
DCE
95
94
91
71
87
92
83
91
81
50
37
79
73
34
84
99
92
85
84
87
73
92
89
89
74
78
55
64
62
38
89
92
Results and discussion
The synthesis of polysulfonate supported chiral cyclohexyl-
diamine-Ni(II) catalysts is outlined in Scheme 1. The reaction of
4-hydroxylbenzaldehyde with t-butyl-dimethylsilyl chloride
(TBSCl) in the presence of imidazole and DMAP gave 4-(t-
butyldimethylsilyl)oxy benzaldehyde 2 with excellent yield. The
reductive amination of aldehyde 2 with (1S,2S)-1,2-cyclohexanedi-
amine provided chiral diamine 3 in a 64% yield. On the other hand,
a number of bisphenols 4a-4e were treated with SO2F2 to give aro-
matic bisfluorosulfonates 5a-5e. The subsequent SuFEx reaction of
3 and 5a-5e in DMF afforded polysulfonate supported chiral dia-
mine ligands 6a-6e. GPC analysis showed average molecular
weight (Mn) ranged from 3625 to 8068 Da. The further reaction
with NiBr2 in DMF provided the catalysts 7a-7e, which were pre-
cipitated as dark-red solids via the addition of EtOAc/hexane. The
Ni loadings were ranged from 0.34 to 1.34 mmol/g as determined
THF
9
1,4-Dioxane
EtOAc
Toluene
CH3CN
MeOH
DMF
10
11
12
13
14
15d
16e
DCM
DCM
a
Reaction conditions: b-nitrostyrene 8a (0.2 mmol), diethyl malonate 9a
(0.3 mmol), and 7a-7e (10 mg) in solvent (1.0 mL) at rt for 24 h.
b
Isolated yields.
Determined by chiral HPLC analysis.
5 mg of 7a was used.
20 mg of 7a was used.
c
d
e
OTBS
CHO
CHO
O
NH
NH
Imidazole, DMAP
H2N
NH2
+
TBS Cl
DCM
95% yield
MeOH, NaBH4
64% yield
OH
1
TBS
2
3
OTBS
SO2F2 (balloon)
HO Ar OH
FO2SO Ar OSO2F 1.DBU,150°C
Et3N, DCM
92-99% yield
2.DMF
5a-5e
4a-4e
82-90% yield
NH
HN
N
H
Br
N
NiBr2, DMF
150°C
H
Ni
Br
O
S
O
O
S
O
O
O
O
O
O
O
S
S
O
O
O
O
O
O
n
n
7a-7e
6a-6e
R
R
Ar =
7b
R = CF3, 96%
7a
, 95%
7d
, 94%
1.09 mmol Ni/g
7e
, 94%
0.34 mmol Ni/g
0.67 mmol Ni/g
1.34 mmol Ni/g
7c
R = CH3, 95%
0.81 mmol Ni/g
Scheme 1. Synthesis, structure, yield and Ni loading of catalysts 7a-7e.
2

Jing-xuan Zhou, Dong-yu Zhu, J. Chen et al.
Tetrahedron Letters 65 (2021) 152792
than that achieved in the study of Sharpless, Fokin and co-workers
[10]. The steric hindrance of bis(silyl ether) precursor 3 may ham-
per the polymerization. In addition, the structure of the bisphenol
also exerted the effect on the degree of polymerization and the Ni
loading.
9–14). The effect of the catalyst loading was also explored. 84%
yield was obtained while 5 mg of 7a was used (Table 1, entry
15). In contrast, the yield increased to 99% while 20 mg of 7a
was used (Table 1, entry 16).
With the optimized reaction conditions in hand, the substrate
scope was then explored. The reactions of b-aryl-nitroethenes 8b-
8m with malonates 9a-9b were investigated and the results are
summarized in Scheme 2. Good yields and enantioselectivities were
obtained for halogen substituted b-phenyl-nitroethenes 8b-8f. The
position of the halogen on the phenyl group did not influence the
enantioselectivity. The reactions of b-phenyl-nitroethenes 8g-8j,
substituted with electron withdrawing or electron donating groups,
were equally efficient. Lower enantioselectivity was obtained for b-
naphthyl-nitroethene 8k, probably due to the increased steric hin-
drance. The reactions of b-furyl-nitroethene 8l and b-indoyl-
nitroethene 8m provided the products with good yields and enan-
tioselectivities. The reaction of diethyl 2-methylmalonate provided
the product 10n with good enantioselectivity, but in a reduced yield.
An aliphatic nitroalkene (cyclohexyl nitroethene) was also tested in
the reaction, but no reaction was observed. The lower reactivity of
the aliphatic nitroalkene accounted for the result.
Catalysts 7a-7e were examined in asymmetric conjugate addi-
tion of diethyl malonate to b-phenyl-nitroethene and the results
are summarized in Table 1. While 7a was used as the catalyst,
the product 10a was obtained, with excellent yield and enantiose-
lectivity (Table 1, entry 1). For catalysts 7b and 7c, although excel-
lent yields were achieved, the enantioselectivity was reduced
(Table 1, entries 2–3). The catalysts 7d showed lower catalytic
activity (Table 1, entry 4). On the other hand, much lower enantios-
electivity was observed using 7e as the catalyst (Table 1, entry 5).
The results demonstrated that the structure of the bisphenol moi-
ety affects both the catalytic activity and enantioselectivity. Using
7a as the selected catalyst, a variety of reaction solvents were
screened. Similar enantioselectivity and slightly lower yield were
obtained in chloroform (Table 1, entry 6). While using dichlor-
oethane (DCE) or THF as the solvent, inferior yield and enantiose-
lectivity were observed (Table 1, entries 7–8). Other solvents
such as dioxane, ethyl acetate, toluene, acetonitrile, methanol,
and DMF are unsuitable for this reaction. Both the yield and the
enantioselectivity were decreased significantly (Table 1, entries
We then examined the recyclability of 7a in the reaction of 8a
and diethyl malonate 9a. For the convenience of experiment oper-
ation, the reaction was carried out in a centrifuge tube. Because
O
O
O
O
R'
7a
R
R
Ar
R
R
+
O
O
NO2
8a-8m
O
O
DCM, rt, 24 h
NO2
R'
Ar
9a-9b
10a-10n
O
O
O
O
O
O
O
O
O
Et
Et
Et
Et
Et
Et
Et
Et
Et
O
O
O
O
O
O
O
NO2
NO2
NO2
NO2
Cl
F
Cl
10a
99% yield, 92% ee
10c
90% yield, 88% ee
10b
96% yield, 91% ee
10d
95% yield,89% ee
O
O
O
O
O
O
O
O
Et
Et
Et
Et
Et
Et
Et
O
O
O
O
O
O
O
O
NO2
NO2
NO2
NO2
Cl
10e
99% yield, 89% ee
F3C
Br
MeO
10h
10f
10g
87% yield, 91% ee
97% yield, 92% ee
96% yield, 87% ee
O
O
Et
Et
O
O
O
O
O
O
O
O
NO2
Et
Et
Et
Et
Et
Et
O
O
O
O
O
O
O
MeO
NO2
NO2
NO2
O
10j
89% yield, 91% ee
10k
90% yield, 73% ee
10i
10l
94% yield, 90% ee
93% yield, 89% ee
O
O
O
O
Et
Et
Et
Et
O
O
O
O
NO2
NO2
NH
10m
10n
79% yield, 87% ee
89% yield, 85% ee
Scheme 2. Substrate scope of the reaction. Reaction conditions: b-aryl-nitroethene 8a-8m (0.2 mmol), diethyl malonate 9a-9b (0.3 mmol), and 7a (20 mg) in DCM (1 mL) at rt
for 24 h. The yield was determined after the chromatographic purification. The enantiomeric excess was determined by chiral HPLC analysis.
3

Jing-xuan Zhou, Dong-yu Zhu, J. Chen et al.
Tetrahedron Letters 65 (2021) 152792
catalyst 7a is slightly soluble in dichloromethane, hexane was
added to precipitate 7a after the reaction. The reaction mixture
was centrifugated and the supernatant was taken out to obtain
the product 10a. The residual catalyst 7a in the bottom of the cen-
trifugation tube was used for next run. To our surprise, the yield
and enantioselectivity decreased sharply in the second and third
runs (see details in SI). We speculated that the p-hydroxy-benzy-
lamine moiety in the catalysts 7a is prone to the oxidation under
an air atmosphere during the long reaction period. Then the recy-
cling experiment was examined under an argon atmosphere and
the results are summarized in Table 2. The yields of 10a were lower
than that obtained in Scheme 2 due to the inferior stirring effect in
the centrifuge tube, but were well kept during the eight recycles.
Only slight decrease in the yield and enantioselectivity were
observed in the ninth and the tenth recycle. The results demon-
strated the excellent recyclability of polysulfonate supported dia-
mine-Ni(II) catalyst.
Chiral
for the synthesis of
strate the utility of the catalyst 7a, three
c
-nitro carbonyl compounds are valuable intermediates
c
-aminobutyric acid analogs [5]. To demon-
-aminobutyric acid drugs
c
(phenibut, balcofen and rolipram) were prepared and the results
are listed in Scheme 3. Phenibut and balcofen were obtained start-
ing from compound 10a and 10c respectively. The hydrogenation
of the nitro group was achieved in the presence of Raney-Ni. The
spontaneous lactamation provided the products 11a and 11c. The
subsequent hydrolysis with HCl gave phenibut and balcofen in
good yields. The similar reaction of 10j provided the lactam 11j.
After the decarboxylation, rolipram was obtained with a good
yield.
Conclusion
In summary, we designed and synthetized a series of polysul-
fonate supported chiral diamine-Ni(II) catalysts via SuFEx reaction.
The catalysts exhibited good catalytic activity and excellent enan-
tioselectivity in the asymmetric Michael addition of malonates to
nitroalkenes. The catalyst 7a could be recycled for ten times with-
out obvious loss of its catalytic activity and enantioselectivity. Fur-
thermore, the reaction products were successfully applied for the
synthesis of three c-aminobutyric acid drugs. To the best of our
knowledge, this is the first example that chiral homogeneous cat-
alyst is immobilized on polysulfonate chain.
Table 2
Recyclability of catalyst 7a.a
EtOOC
COOEt
NO2
NO2
7a
+
EtOOC
COOEt
DCM, rt, 24 h
under argon
10a
9a
8a
Yield%b
Ee/%c
Declaration of Competing Interest
Run
1st
89
90
91
92
92
92
91
90
88
87
92
92
92
91
91
91
90
90
90
90
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
2nd
3rd
4th
5th
6th
7th
8th
9th
Acknowledgements
We acknowledge the National Natural Science Foundation of
China (21772240), the Fundamental Research Funds for the Central
Universities (20ykpy120) and Guangdong Provincial Key
Laboratory of Chiral Molecules and Drug Discovery
(2019B030301005) for the financial support.
10th
a
Reaction conditions: b-nitrostyrene 8a (0.5 mmol), diethylmalonate 9a
(0.75 mmol), and 7a (50 mg) in DCM (2.5 mL), at room temperature under an argon
atmosphere. Isolated yields. Determined by chiral HPLC analysis.
b
c
a)
EtOOC
O
COOEt
NO2
EtOOC
Raney Ni
, H
6 M HCl
NH
EtOH
92%
reflux
94%
2
HOOC
NH3Cl
phenibut
10a
11a
Cl
b)
EtOOC
O
COOEt
NO2
EtOOC
Raney Ni
, H
6 M HCl
NH
EtOH
94%
reflux
95%
2
HOOC
baclofen
NH3Cl
Cl
10c
11c
c)
O
O
O
O
O
EtOOC
Et
O
Et
NH
NH
NO2
Raney Ni
, H
1.LiOH, HCl
EtOH
94%
2. PhMe, reflux, 12 h
94%
2
MeO
MeO
MeO
O
O
O
rolipram
10j
11j
Scheme 3. Synthesis of
c-aminobutyric acid drugs.
4

Jing-xuan Zhou, Dong-yu Zhu, J. Chen et al.
Tetrahedron Letters 65 (2021) 152792
Franconetti, G. de Gonzalo, ChemCatChem 2018, 10, 5554–5572; e) K. Zheng,
X. Liu, X. Feng, Chem. Rev. 2018, 118, 7586–7656.
[3] D.A. Evans, D. Seidel, J. Am. Chem. Soc. 127 (2005) 9958–9959.
[4] D.A. Evans, S. Mito, D. Seidel, J. Am. Chem. Soc. 129 (2007) 11583–11592.
[5] a R. Baran, E. Veverková, A. Škvorcová, R. Šebesta, Org. Biomol. Chem. 11
(2013) 7705–7711;
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152792.
b P.S. Hynes, P.A. Stupple, D.J. Dixon, Org. Lett. 10 (2008) 1389–1391;
c A.B. Hughes, Amino Acids, Peptides and Proteins in Organic Chemistry,
Wiley-VCH (2010);
References
d R.T. Owen, Drugs Today 43 (2007) 601–610;
[1] a) A. Berkessel, H. GrÖger, Asymmetric Organocatalysis-From Biomimetic
Concepts to Applications in Asymmetric Synthesis, 1st ed., Wiley, 2005;
b) R.E. Gawley, J. Aubé, Principles of Asymmetric Synthesis, 2nd Ed., Elsevier,
2012;
e A. Trabocchi, F. Guarna, A. Guarna, Curr. Org. Chem. 9 (2005) 1127–1153.
[6] R. Jin, K. Liu, D. Xia, Q. Qian, G. Liu, H. Li, Adv. Synth. Catal. 354 (2012) 3265–
3274.
[7] D. Bissessar, T. Achard, S. Bellemin-Laponnaz, Adv. Synth. Catal. 358 (2016)
1982–1988.
c) G.L. David Krupadanam, Fundamentals of Asymmetric Synthesis, 1st ed.,.,
CRC Press, 2014;
[8] H. Ishitani, K. Kanai, W. Yoo, T. Yoshida, S. Kobayashi, Angew. Chem. Int. Ed. 58
(2019) 13313–13317.
d) M. Christmann, S. Brase, Asymmetric Synthesis II: More Methods and
Applications, 1st ed., Wiley-VCH, 2012;
[9] J. Dong, L. Krasnova, M.G. Finn, K.B. Sharpless, Angew. Chem. Int. Ed. 53 (2014)
9430–9448.
[10] J. Dong, K.B. Sharpless, L. Kwisnek, J.S. Oakdale, V.V. Fokin, Angew. Chem. Int.
Ed. 53 (2014) 9466–9470.
e) J. Alemán, S. Cabrera, Applications of asymmetric organocatalysis in
medicinal chemistry, Chem. Soc. Rev. 42 (2013) 774–793.
[2] a) M. Benaglia, A. Puglisi, Catalyst Immobilization: Methods and Applications.
Wiley, 2019; b) M. Bartók, Catal. Rev. Sci. Eng. 2015, 57, 192–255; c) M. A. E.
Sater, N. Jaber, E. Schulz, ChemCatChem 2019, 11, 3662–3687; d) A.
5