A Nickel-Bisdiamine Porous Organic Polymer as Heterogeneous Chiral Catalyst for Asymmetric Michael Addition to Aliphatic Nitroalkenes

Article abstract of DOI:10.1002/adsc.202000875

We report a polystyrene-incorporated chiral nickel(II)-bisdiamine complex, which is accessible on gram-scale. This metal complex functions as a heterogeneous catalyst for the enantioselective Michael addition between malonates and aliphatic nitroalkenes,

Full text of DOI:10.1002/adsc.202000875

Title: A Nickel-Bisdiamine Porous Organic Polymer as Heterogeneous
Chiral Catalyst for Asymmetric Michael Addition to Aliphatic
Nitroalkenes
Authors: Mikkel Buendia, Søren Kegnæs, and Soren Kramer
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000875
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10.1002/adsc.202000875
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
A Nickel-Bisdiamine Porous Organic Polymer as Heterogeneous
Chiral Catalyst for Asymmetric Michael Addition to Aliphatic
Nitroalkenes
Mikkel B. Buendia,a Søren Kegnæs,a* Søren Kramera*
a
Department of Chemistry, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark
E-mail: skk@kemi.dtu.dk; E-mail: sokr@kemi.dtu.dk
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Several homogeneous catalytic systems have been
nickel(II)-bisdiamine complex, which is accessible on developed for this transformation[5], however,
gram-scale. This metal complex functions as
Abstract. We report a polystyrene-incorporated chiral
a
successful reactions for nitroalkenes bearing aliphatic
substituents are still rare.[6] In contrast to reactions
using homogeneous catalysts for the asymmetric
Michael addition between malonates and nitroalkenes,
reactions employing heterogeneous catalysts are
much less investigated, especially for metal-based
chiral catalysts.[4,7,8] In 2012, two groups
independently reported the first organometallic
heterogeneous catalysts for this reaction.[4a,7a]
Kobayashi and co-workers reported a polystyrene-
bound Pybox-CaCl2 catalyst, which displayed good
enantioselectivity for aromatic nitroalkenes.[4a] Liu,
Li, and co-workers reported a chiral nickel(II)-
bisdiamine complex heterogenized by incorporation
in periodic mesoporous organosilica. This catalyst
system also provided good enantioselectivities for
aromatic nitroalkenes.[7a] In 2016, Bellemin-
Laponnaz et al. incorporated a similar nickel complex
into a self-supported polymerized catalyst, which
showed good reusability and enantioselectivity for
aromatic nitroalkenes.[7b] All the important advances
mentioned above focus on aromatic nitroalkenes;
aliphatic nitroalkenes were either unsuccessful or not
included in these reports. Finally, in 2019, Kobayashi
and co-workers reported the use of a catalyst
consisting of a chiral nickel(II)-bisdiamine complex
impregnated onto silica.[7c] Good yields and
enantioselectivities were achieved for a range of
substrates including six aliphatic nitroalkenes without
heterogeneous catalyst for the enantioselective Michael
addition between malonates and aliphatic nitroalkenes, and
it provides yields and enantioselectivities on par with
homogeneous catalysts. Good functional group tolerance is
reported for this reaction. Upon recycling, the catalyst
achieves significantly higher TONs than previously
reported. We demonstrate scalability to multigram-scale,
compatibility with continuous flow production (4.43 gram),
and application to the synthesis of the blockbuster drug
Pregabalin. Finally, a new tandem reaction is disclosed.
Keywords: Asymmetric Catalysis; Heterogeneous
Catalysis; Porous Organic Polymer; Michael Addition;
Continuous Flow
The continuous demand for enantiopure compounds
by the agrochemical, fragrance, and pharmaceutical
industries necessitates more efficient syntheses of
optically pure compounds. Asymmetric catalysis is
one of the most powerful methods for obtaining
enantiopure
compounds,
and
homogeneous
asymmetric catalysis has experienced astounding
advancements over the past decades.[1] However, for
industrial purposes heterogeneous catalysis is
generally preferred due to the ease of catalyst
separation from the reaction medium and recycling.[2]
For asymmetric catalysis, the benefits of the last
feature are even more pronounced as the chiral
ligands are often very expensive. Despite the
development of several heterogenization strategies,
covalent and non-covalent, it remains a challenge to
obtain heterogeneous, recyclable catalysts which
displays activity and enantioselectivity on par with
the corresponding homogeneous catalysts.[3]
functional
groups.
Furthermore,
recycling
experiments demonstrated loss of activity already in
the second run caused by leaching of the chiral ligand
due to the non-covalent support attachment.
Herein, we report a new heterogeneous catalyst for
the asymmetric Michael addition of malonates to
aliphatic nitroalkenes. The catalyst represents the first
incorporation of
a
chiral nickel(II)-bisdiamine
The asymmetric Michael addition reaction of
malonates to nitroalkenes is a highly attractive
reaction as the resulting products are easily converted
into biologically active γ-amino acid derivatives, such
as the pharmaceuticals Pregabalin and Rolipram.[4]
complex in a polystyrene porous organic polymer
(POP). Due to the attachment of the ligands to the
support by strong covalent bonds, no ligand leaching
can take place. The heterogeneous nature of the
catalyst makes it compatible with continuous flow
1
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10.1002/adsc.202000875
Advanced Synthesis & Catalysis
production. Furthermore,
a
substrate scope
Table 1. Evaluation of activity and enantioselectivity for
POPs, containing different ligands, and the corresponding
homogeneous catalysts.
investigation demonstrates – for the first time – good
functional group tolerance for the challenging
aliphatic nitroalkenes, manifested by high yields and
enantioselectivities. Finally, a novel tandem reaction
for a substrate bearing a pendant alkyne was
discovered.
As part of our interest in asymmetric catalysis,
Entry Catalyst System
Yield [%]a)
ee [%]b)
catalysis
with
3d
transition-metals,
and
heterogeneous catalysis, we set out to develop a
highly efficient chiral heterogeneous metal catalyst
for the challenging asymmetric Michael addition of
malonates to aliphatic nitroalkenes.[9] We envisioned
that the covalent incorporation of the ligands of a
nickel(II)-bisdiamine catalyst into a polystyrene-POP
would prevent undesired ligand leaching despite the
fact that ligand dissociation is an integral part of the
elucidated reaction mechanism for the homogeneous
reaction.[5g] Recently, polystyrene-POP-based metal
catalysts have received significant attention as their
swelling properties allow for quasi-homogeneous
catalyst behaviour while still facilitating easy catalyst
separation and recycling.[9d,10] The typical approach to
chiral ligand-containing POP metal catalysts is
polymerization of the ligands followed by post-
polymerization metalation. This strategy has so far
mostly focused on [ML] systems, typically with
ligands within the PyBox, BINAP, and salen families
1
2
NiL12-POP
NiL22-POP
NiI2 / L1
NiI2 / L2
NiI2
69
49
68
47
0
90
89
90
88
-
3c)
4c)
5
Reaction conditions: 1a (0.25 mmol), 2 (0.35 mmol), and 1
mol% catalyst in toluene (1.0 mL) at 60 °C for 5 h. a) Yield
determined by 1H NMR analysis using an internal standard.
b)
Enantiomeric excess determined by HPLC with a chiral
stationary phase. c) NiI2 (1 mol%) and ligand (2.5 mol%).
the synthesis of functionalized ligands suitable for
POP-incorporation typically introduces several
additional steps to already tedious synthetic
routes.[3a,10] In contrast, the straightforward route to
NiL2-POPs allowed for easy preparation of almost 3
grams of catalyst material in one batch.
With the chiral heterogeneous catalysts in hand, we
evaluated their performance in the asymmetric
Michael addition of malonates to aliphatic
nitroalkenes (Table 1). To allow for activity
comparison, the reaction outcome was examined at
partial conversion (5 hours) with low catalyst loading
(1 mol%). The comparable activities and
enantioselectivities for polystyrene-bound and
homogeneous complexes containing the same ligand
highlight the quasi-homogeneous nature of the
polystyrene-bound catalysts (entries 1–4). Although
the rate-limiting steps for the homogeneous system
involves ligand dissociation[5g], which incorporation
into a polymer could potentially influence, we
hypothesize that the extreme flexibility and quasi-
homogeneous nature of the polystyrene support in
toluene makes the entropy-penalty for ligand
dissociation very close to that of the homogeneous
system.[12] Both the polystyrene-bound and the
homogeneous L1-complexes demonstrated improved
activity compared to the L2-complexes. Thus, our
study was continued with NiL12-POP.[13] A control
experiment showed that NiI2 is not active without
diamine ligands (entry 5). Finally, evaluation of
different malonates showed that methyl, ethyl, and
iso-propyl malonates provided comparable activities,
yields, and enantioselectivities, while the use of a
tert-butyl malonate decreased the activity without
affecting the enantioselectivity.[14]
(PyBox:
2,6-bis(4,5-dihydrooxazol-2-yl)pyridines;
BINAP:
2,2’-bis(diphenylphosphino)-1,1’-
binaphthyl;
salen:
N,N’-
bis(salicylidene)ethylenediamine).[3,9d,10] To date, no
examples of polystyrene-bound, co-polymerized
[ML2] catalysts bearing chiral ligands exist.
We initiated our study by preparing two
polystyrene-POP catalysts by co-polymerization of
vinyl-functionalized nickel(II)-bisdiamine complexes
(Scheme 1). Thus, these materials can be classified as
polystyrene-bound, co-polymerized [ML2] catalysts
bearing two chiral ligands. The complete synthesis
route is short and simple, adding only
a
polymerization step in comparison to the synthesis of
the corresponding homogeneous complexes.[11] The
direct synthesis of these POP-catalysts is notable as
Next, different ligand/support ratios and nickel
halide salts were evaluated (Table 2). Simply
polymerizing the vinyl-functionalized NiL12 complex
without styrene and DVB led to a catalyst displaying
comparable activity but decreased enantioselectivity
(entry 1). The addition of styrene and DVB to the
Scheme 1. Preparation of polystyrene-incorporated NiL2-
POPs.
(DVB
=
divinylbenzene,
AIBN
=
azobisisobutyronitrile, DIPEA = diisopropylethylamine).
2
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10.1002/adsc.202000875
Advanced Synthesis & Catalysis
Table 2. Evaluation of ligand/support ratios and
counterion effects.
Figure 1. Recycling experiments including activity tests
for the reaction between 1a and 2. Reactions conditions as
Table 2, entry 2.
Entry A:B:C
X
Yield [%]a) ee [%]b)
1
2
1:0:0
1:42:1 (“NiL12-
POP”)
I
I
66
69
85
90
3
4
5
1:84:1
1:42:1
1:42:1
I
Br
Cl
53
41
21
90
89
90
after 22 hours corresponded to 0.7% of the original
nickel content in the catalyst material, hence very
limited nickel leaching is taking place.[16]
Reaction conditions: 1a (0.25 mmol), 2 (0.35 mmol), and 1
mol% catalyst in toluene (1.0 mL) at 60 °C for 5 h. a) Yield
determined with 1H NMR analysis using an internal
standard. b) Enantiomeric excess determined by HPLC with
a chiral stationary phase.
With the optimized catalyst in hand, we
investigated the recyclability of the heterogeneous
chiral catalyst. At the end of a reaction, NiL12-POP is
easily recovered by centrifugation after addition of
ether/hexane. Using this method, five consecutive
runs were performed with the same catalyst material
(Figure 1). For all five runs, the enantioselectivity
remained constant at 90% ee. Furthermore, the
NiL12-POP displayed no loss of activity during the
first three runs (yields after 5 hours). Although the
activity started to decrease after three consecutive
reactions, a turnover number (TON) of 450 was
obtained after five runs. This TON is almost five
times higher than any previously reported TON.[17]
TEM images after the fifth consecutive run did not
show any metal nanoparticle formation. In
combination with the very limited nickel leaching,
the origin of the deactivation is not clear at this point.
Encouraged by the high performance of NiL12-
POP as heterogeneous catalyst, in terms of yield,
enantioselectivity and TON, we continued by
investigating the substrate scope for the nitroalkenes.
So far, aliphatic nitroalkenes bearing functional
groups have not been reported for the asymmetric
Michael addition of malonates.[5,6,7] Accordingly, we
decided to examine both the tolerance to different
carbon scaffolds and functional groups in order to
improve the utility of this reaction (Table 3). First,
the sensitivity to length and sterical hindrance of the
alkyl substituent was evaluated. The reaction
efficiency was not affected by increasing the length
of an unbranched alkyl moiety (3b–3d). Also,
introduction of the bulkier iso-propyl group did not
affect the reaction outcome significantly, while the
use of a cyclohexyl-bearing substrate led to a small
decrease in yield (3e–3f). The sterically highly
challenging tert-butyl group was tolerated but led to
lower yield and enantioselectivity (3g). Importantly,
the reaction was found to tolerate a broad range of
functional groups including sensitive functional
polymerization improved the enantioinduction of the
catalyst without affecting activity (entry 2). However,
the use of additional styrene had a negative effect on
the activity (entry 3). Notably, the halide counterion
had significant impact on the activity as a decrease
was observed when moving up in the periodic table
(entries 4–5). The remaining study was performed
with the NiL12-POP catalyst in entry 2.[15]
Before further catalytic evaluations were
performed, the optimized NiL12-POP was
characterized.[11] 13C-1H CP/MAS NMR spectroscopy
of the catalyst material in the solid state clearly
showed ligand incorporation into the polystyrene
backbone. Transmission electron microscopy (TEM)
confirmed the absence of metal nanoparticles in the
material, and energy-dispersive X-ray spectroscopy
proved the presence of both nickel and iodide. The
nickel content was determined to be 1.07 wt.% by
inductively coupled plasma optical emission
spectroscopy
(ICP-OES).
Thermogravimetric
analysis indicated that the NiL12-POP is stable in air
up to 300 °C. Scanning electron microscopy (SEM)
showed that NiL12-POP consisted of both hollow
sheets, in the size range 10 µm to 50 µm, and spheres
with a broad size distribution ranging from 50 nm to
a 1 µm. The NiL12-POP had a negligible surface area
and pore volume of 24 m2/g and 0.049 cm3/g,
respectively. These results suggest that the high
catalytic activity of NiL12-POP is caused by its
swelling properties. In fact, during catalysis, the
reaction mixture is a clear solution thus indicating the
quasi-homogeneous nature of the catalysis.[11] Finally,
we tested nickel leaching during a catalytic reaction
by ICP-OES. The nickel content in the liquid phase
3
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10.1002/adsc.202000875
Advanced Synthesis & Catalysis
Table 3. Substrate scope for nitroalkenes. The listed yields are isolated yield of purified product. Reaction conditions: 1
(0.375 mmol), 2 (0.525 mmol), and 1 mol% catalyst in toluene (1.5 mL) at 60 °C for 22 h. Enantiomeric excess
determined by HPLC with a chiral stationary phase. a) 2 mol% NiL12-POP, 72 h. b) Room temperature.
groups, and all these substrates afforded high
enantioselectivities (≥90% ee). Primary alkyl
bromides and chlorides were tolerated (3h–3i), as
4.43 grams of (R)–3a in 90% ee. Again, the catalyst
efficiency was remarkably high, and a TON of 173
was obtained which is almost three times higher than
well as an ester (3j), ethers (3k–3l), a silyl ether (3m), previously reported.[20]
a phthalimide-protected amine (3n), an amide (3o),
and terminal alkene (3p). The absolute
stereochemistry
The opposite enantiomer of NiL12-POP is easily
a
accessible using the same synthesis route (Scheme 1).
As expected, the use of Ni(ent-L1)2-POP afforded the
opposite enantiomer of product in essentially
was
assigned
by
X-ray
crystallographic analysis of 3n (Figure 2).[11] Three
(hetero)aromatic nitroalkenes were also included in
the substrate scope investigation in order to illustrate
the generality of the developed catalyst (3q–3s).
Next, the scalability of the developed method was
examined. A gram-scale reaction was performed
using 1 mol% of NiL12-POP in undried toluene and
under air (Scheme 2a). Pleasingly, using this protocol,
the desired product was obtained in a quantitative
yield (2.20 gram) and with 90% ee. Subsequently, we
proceeded to evaluate the compatibility of the
heterogeneous catalyst with a continuous flow setup
(Scheme 2b).[18] The adaptation proceeded smoothly,
and the catalyst showed good stability for more than
five continuous days of operation which produced
Scheme 2. Application of the developed method (a) on
gram-scale, (b) in continuous flow production, and (c) for
enantioselective synthesis of the pharmaceutical Pregabalin.
Figure 2. X-ray crystal structure of 3n (ellipsoids are
shown at 50% probability, and most hydrogens are omitted
for clarity).[19]
4
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10.1002/adsc.202000875
Advanced Synthesis & Catalysis
identical yield and enantioselectivity compared to
NiL12-POP (Scheme 2c). In just two steps from this
product, (S)–3a, the blockbuster drug Pregabalin was
synthesized in 90% yield and 90% ee, thus
highlighting the relevance of the reaction and
products for medicinal chemistry.[21,22]
separation and recycling as well as application in
continuous flow production.
Experimental Section
In air, NiL12-POP (23.4 mg, 1.0 mol%), dimethyl
malonate (60.0 µL, 0.575 mmol), nitroalkene (0.375
mmol) and toluene (1.5 mL) were added to a 4 mL vial.
The vial was capped with a PTFE-lined septum cap and the
reaction stirred for 22 hours at 60 °C. After cooling to
room temperature, the reaction mixture was directly
purified by flash chromatography.
Finally, during the investigation of the substrate
scope, an unprecedented tandem reaction was
discovered for a substrate bearing a pendant alkyne
(1t) (Scheme 3). The formal [4+1] annulation affords
98%
yield
of
the
enantioenriched
exo-
methylenecyclopentane 3t. The reaction proceeds by
an initial enantioselective Michael addition followed
by a Conia-ene reaction.[23] Build-up of the
intermediate from the Michael addition is observed
during the reaction suggesting that the Conia-ene
cyclization is the slowest step. Furthermore, no
cyclization of the isolated intermediate was observed
in the absence of NiL12-POP indicating that the
nickel complex is responsible for catalyzing both
steps. It is rare that both steps of a tandem Michael
addition/Conia-ene sequence is catalyzed by the same
catalyst.[23] Notably, there are no previous reports on
racemic or enantioselective [4+1] annulation between
malonates and alkyne-bearing nitroalkenes.[24]
Acknowledgements
The authors are grateful for funding from the Independent
Research Fund Denmark (grant no. 6111-00237), from Villum
Foundation (grant no. 13158), and from Haldor Topsøe A/S. S.
Kramer is deeply appreciative of generous financial support from
the Lundbeck Foundation (grant no. R250-2017-1292). The
authors thank David B. Christensen for assistance with TEM, Dr.
Farnoosh Goodarzi for assistance with SEM, Dr. Mariusz Kubus
for assistance with X-ray crystallography, and Dr. Kasper
Enemark-Rasmussen at the DTU NMR center supported by the
Villum foundation for aid with solid-state NMR.
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POP.
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In conclusion, we have prepared a polystyrene-
incorporated chiral nickel(II)-bisdiamine metal
complex, which can be used as a heterogeneous
catalyst for the challenging asymmetric Michael
addition of malonates to aliphatic nitroalkenes. The
catalyst provides high yields and enantioselectivities
for this reaction. Our protocol was found to tolerate a
broad range of functional groups, including sensitive
groups. Importantly, the catalyst displayed good
recyclability, and a TON almost five times higher
than previously reported was obtained by recycling in
batch. Furthermore, the reaction is scalable to
multigram-scale both in batch and in a continuous
flow setup. The relevance of the transformation and
products for medicinal chemistry was highlighted
with the synthesis of Pregabalin. Finally, we have
discovered an unprecedented tandem reaction
between malonates and alkyne-functionalized
nitroalkenes leading to an enantioenriched exo-
methylenecyclopentane. Overall, we have reported a
heterogeneous catalyst displaying activity and
enantioselectivity on par with the homogeneous
catalysts, and we have illustrated advantages of the
heterogeneous catalyst such as easy catalyst
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Advanced Synthesis & Catalysis
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butyl: 80% yield, 90% ee. For more details, see Table
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[15] The use of ethyl acetate or THF as solvent, under the
reaction conditions in Table 2, entry 2, provided
inferior results after 5 h: EtOAc, 31% yield, 89% ee;
THF, 45% yield, 81% ee.
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the catalytic activity is not caused by leached
homogeneous species (See Figure S8).
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[17] The best previously reported TON for heterogeneous
catalysts with malonates and aliphatic nitroalkenes in
batch is 95. See ref. 7c.
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[13] A NiL12-POP made by post-polymerization
metalation led to essentially identical activity and
enantioselectivity (5 h: 65% yield, 90% ee; see Table
S3). The similar activities and enantioselectivities for
6
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10.1002/adsc.202000875
Advanced Synthesis & Catalysis
UPDATE
A Nickel-Bisdiamine Porous Organic Polymer as
Heterogeneous Chiral Catalyst for Asymmetric
Michael Addition to Aliphatic Nitroalkenes
Adv. Synth. Catal. Year, Volume, Page – Page
Mikkel B. Buendia, Søren Kegnæs,* Søren
Kramer*
7
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