Development of robust heterogeneous chiral rhodium catalysts utilizing acid?base and electrostatic interactions for efficient continuous-flow asymmetric hydrogenations

Article abstract of DOI:10.1021/jacs.0c08109

Heterogeneous chiral Rh catalysts based on acid?base and electrostatic interactions have been developed. The robust catalysts demonstrate high activity and selectivity in the continuous-flow asymmetric hydrogenation of a wide variety of enamides and dehyd

Full text of DOI:10.1021/jacs.0c08109

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Communication
Development of Robust Heterogeneous Chiral Rhodium
Catalysts Utilizing Acid-base and Electrostatic Interactions
for Efficient Continuous-Flow Asymmetric Hydrogenations
Yuki Saito, and Shu Kobayashi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c08109 • Publication Date (Web): 09 Sep 2020
Downloaded from pubs.acs.org on September 9, 2020
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Development of Robust Heterogeneous Chiral Rhodium Catalysts
Utilizing Acid-base and Electrostatic Interactions for Efficient
Continuous-Flow Asymmetric Hydrogenations
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Yuki Saito and Shū Kobayashi*
Department of Chemistry, School of Science, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
Supporting Information Placeholder
However, such heterogeneous catalysts can only be applied for
reactions with reactive olefins bearing electron-withdrawing
groups. Moreover, metals from the heteropoly acid framework can
leach into a solution, leading to catalyst deactivation.31, 40, 41 This
result suggests insufficient interactions between the heteropoly acid
and the support. We hypothesized that active and robust
heterogeneous catalysts could be prepared if a strong interaction
between the support and the heteropoly acids could be achieved.
Focusing on the strong Brønsted acidity of heteropoly acids, we
designed a support having Brønsted basicity on the surface
(Scheme 1, right). Acid-base interactions would be expected to
hold the heteropoly acid tightly to a support (salt formation), which
would prevent leaching of the active metal species. Moreover, since
heteropoly acids bear multivalent anions, they are expected to form
ion pairs with cationic metal complexes after salt formation. We
selected mesoporous silica as a solid support material because of
its large surface area, high mass transferability, tunable pore size,
and potential for surface functionalization. With catalysts having
these unique features, we investigated asymmetric hydrogenation
of enamides catalyzed by cationic Rh complexes.
ABSTRACT: Heterogeneous chiral Rh catalysts based on acid-
base and electrostatic interactions have been developed. The robust
catalysts demonstrate high activity and selectivity in the
continuous-flow asymmetric hydrogenation of a wide variety of
enamides and dehydroamino acids, providing optically active
amides without leaching of metal species. The chiral environments
can be easily tuned by changing the chiral ligands, demonstrating
the high versatility of the heterogeneous catalysts. By applying
these efficient catalysts, continuous synthesis of several active
pharmaceutical ingredient (API) intermediates was achieved.
Heterogeneous catalysts have gained much attention with respect
to the development of environmentally benign reactions and
processes.1, 2 In such systems the catalysts can be easily separated
from the products (by filtration in many cases) and the catalysts can
be recovered and reused, thereby reducing both the amount of
waste and the energy required. Moreover, heterogeneous chiral
catalysts have recently been successfully applied for continuous-
flow synthesis.3-5 We have been focusing on continuous-flow
reactions as new tools for organic synthesis.6-11 In general,
continuous-flow reactions have advantages over conventional
batch reactions in terms of efficiency, safety, and environmental
compatibility. Among continuous-flow reactions, reactions with
heterogeneous catalysts can achieve greener processes in chemical
transformations because catalyst separation and recycling are
integrated into the process. When such catalysts are applied to
hydrogenation reactions, several additional benefits are expected.12,
13 First, the use of special high-pressure equipment can be avoided,
and it is easier to scale up the process. Second, reactions can be
performed under milder conditions because of the efficient mass
transfer of H2 gas with heterogeneous catalysts. Focusing on these
advantages, we have developed novel, efficient heterogeneous
catalysts, and multistep flow synthesis of complex and valuable
compounds have been achieved.14-20 However, the development of
asymmetric variants remains a challenge because of the lack of
efficient immobilization methods. A novel design of heterogeneous
chiral catalysts that is suitable for continuous-flow reactions is
therefore in high demand.21-33
Scheme 1. Design of Heterogeneous Catalysts
Augustine's Method
This Method
electrostatic
interaction
electrostatic
interaction
R3P
R3P
L
L
Rh
R3P
L
Rh
L
n
R3P
HPA
NH3
O
n
O Si
HPA
O
acid-base
interaction
mesoporous
silica wall
Al2O3
surface
O
O
HN
HN
R2
R2
R1
*
R1
H2
One of the most commonly used heterogenization methods is
Augustine’s method. This method utilizes heteropoly acid (HPA)-
anchored Al2O3 as a support, in which a catalytically active species
is immobilized by ionic interaction (Scheme 1, left).34-39 An
advantage of this method is that cationic metal complexes can be
directly immobilized without modification of the chiral ligand.
Herein, we describe robust heterogeneous chiral Rh catalysts
immobilized on heteropoly acid/amine functionalized
mesoporous silica composite (Scheme 1, right), which promoted
continuous-flow asymmetric hydrogenation reactions of enamides
and dehydroamino acids. The catalyst showed excellent activity
and selectivity as well as long lifetime without leaching of active
a
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species. Continuous synthesis of several intermediates of active
pharmaceutical ingredients (APIs) was also achieved.
H2 (25 mL/min)
= 500 kPa(G)
Rh-QuinoxP*/STA/Support
(200 mg = Rh:0.01 mmol)
+ W-50 (600 mg)
1
2
3
O
O
Considering the size of heteropoly acid and Rh complexes, KIT-
6
was chosen as a
mesoporous silica.42 Surface amine
HN
Ph
HN
functionalization was performed by reaction with aminopropyl
silane (Scheme 2(a)). The obtained material (KIT-6-NH2) was
simply stirred in a solution of silicotungstic acid (STA) to facilitate
salt formation on the surface, giving STA/KIT-6-NH2 as a white
solid (Scheme 2(b)). The latter was finally mixed with chiral Rh
complex that was prepared in situ (Scheme 2(c)). The Rh-
QuinoxP* complex developed by Imamoto et al. was chosen as a
target complex for the immobilization.43 After removal of solvents
and washing, the immobilized catalyst was obtained as an orange
powder.
4
5
6
7
8
9
Ph
0.1 mL/min
2a
1a
Ø10*50 mm, SUS
99% ee
at all points
30 o
C
0.1 M,
Toluene/iPrOH
= 1/1
(a) 1a = 0.1 M
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Scheme 2. Preparation of Heterogeneous Catalysts
(a) Surface amine functionalization
wash/dry
(EtO)3Si
NH2
KIT-6-NH2
+
KIT-6
toluene, reflux, o/n
(1.0 mmol/g)
(b) Salt formation with silicotungstic acid (STA)
STA
iPrOH
wash/dry
(0.1 mmol/g)
STA/KIT-6-NH2
KIT-6-NH2
rt, o/n
(b) 1a = 0.2 M
(c) Immobilization of chiral Rh complex
iPrOH
Rh(nbd)2BF4 + QuinoxP* (0.05 mmol/g)
STA/KIT-6-NH2
rt, o/n
centrifuge
remove supernatant
wash/dry
Rh-QuinoxP*/STA/KIT-6-NH2
The loading concentration of the Rh was determined to be 0.0495
mmol/g by ICP analysis (> 99% of the Rh complex was
immobilized. Almost no immobilization was observed in the
absence of STA or amine functionality. Furthermore, we measured
N2 adsorption/desorption isotherms,44 solid-state NMR
spectroscopy, scanning transmission electron microscopy (STEM)
and energy dispersive X-ray spectroscopy (EDS), and all the
characterization data were consistent with our target structure in
which chiral cationic Rh complexes were immobilized inside
mesopores by ionic interactions with STA. Characterization details
are given in the Supporting Information (SI).
To our delight, the prepared catalyst demonstrated excellent
activity, 90% yield with 99% ee for 22 h flow reaction (Scheme
3(a)). Notably, neither deactivation nor metal leaching was
observed. On the other hand, use of amorphous silica instead of
KIT-6 decreased the lifetime of the catalyst, with deactivation
being observed after 15 h. In contrast, when Al2O3 was used as the
support, a rapid decrease in the yield was observed from 2 h, and
less than 10% yield was observed after 18 h operation. On the other
hand, the enantioselectivity remained stable at 99% ee. We further
examined the effect of mesoporous silica structure (Scheme 3(b)).
It is known that pore diameter, pore size, and surface area can be
controlled by changing the preparation temperature of the
mesoporous silica.42 It was found that the use of KIT-6 prepared at
standard temperature (100 C) led to the highest activity, even with
increased substrate concentration. Neither increasing nor
decreasing the preparation temperature improved the activity(KIT-
6-NH2-H, KIT-6-NH2-L). Considering that the preparation
temperature mainly affects the mesopore diameter, a suitable pore
diameter is required to achieve high activity, which can be
explained by the difference in mass transfer efficiency.
Furthermore, another type of mesoporous silica (SBA-15)42 having
similar pore diameter but different morphology, showed a
decreased lifetime of the catalyst. Although the mechanism of the
With the target catalyst in hand, the system was evaluated in the
asymmetric hydrogenation of enamide 1a under continuous-flow
conditions. A solution of 1a was flowed into a fixed bed reactor
filled with the heterogeneous Rh catalyst (Rh: 0.01 mmol) and W-
50 as a diluent under a flow of H2 gas. The resulting solution was
collected and analyzed and the yield of 2a was plotted against the
operation time (Scheme 3). For comparison, other supports
including Al2O3 and amine-functionalized- amorphous SiO2 were
also assayed under the flow conditions.
Scheme
3.
Evaluation
under
Continuous-flow
Hydrogenation
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catalyst deactivation is still unclear, our current hypothesis is that
a SV = mmol(substrate)/(mmol(catalyst)*h)
1
2
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6
7
rigid fixation of an active species onto a support with a large surface
area may suppress undesirable catalyst-catalyst interaction, which
results in inactive rhodium hydride oligomers or accumulation of a
trace amount of water on the catalyst.44,33 Finally, > 99% yield with
99% enantioselectivity was achieved for 24 h by further
optimization of flow parameters. Under these reaction conditions,
TOF was 120 h–1 and 2640 TON was achieved for the 22 h flow
reaction.
8
9
With optimized reaction conditions in hand, the substrate scope
of the reaction with respect to enamides was examined. The space
velocity (SV) was set to 120 h–1 and the reaction was continued for
22 h (Scheme 4).
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Scheme 4. Scope of the Reaction with Enamides and -/-
(b) -/-Dehydroamino Acids
Dehydroamino Acids
(a) Enamides
H2 (25 mL/min)
= 500 kPa(G)
Rh-QuinoxP*/STA/KIT-6-NH2
H2 (25 mL/min)
(200 mg = Rh:0.01 mmol)
+ W-50 (600 mg)
O
Rh-QuinoxP*/STA/KIT-6-NH2
(200 mg = Rh:0.01 mmol)
+ W-50 (600 mg)
O
= 500 kPa(G)
O
O
HN
HN
Ar
Ar
HN
HN
MeO2C
MeO2C
0.2 mL/min
4
3
Ø10*50 mm, SUS
Ar
Ar
1
0.1 M,
Toluene/iPrOH
= 1/1
or
or
30 o
C
0.2 mL/min
0.1 M,
Toluene/iPrOH
= 1/1
Ø10*50 mm, SUS
O
O
2
30 o
C
SVa = 120 h-1
HN
HN
SVa = 120 h-1
S/C = 2640
S/C = 2640
CO2Me
CO2Me
R
R
5
6
O
O
O
O
O
O
O
HN
HN
HN
HN
OMe
F
NH
NH
NH
MeO2C
MeO2C
MeO2C
MeO
4c
2a
2b
2c
4b
2d
4a
>99% yield
99% ee
>99% yield
99% ee
>99% yield
99% ee
>99% yield
98% ee
98% yield
99% ee
>99% yield
99% ee
>99% yield
98% ee
O
O
O
O
O
O
O
Br
Cl
NH
NH
NH
HN
HN
HN
HN
MeO2C
MeO2C
MeO2C
Br
4d
4e
4f
F
Cl
O
Br
O2N
>99% yield
99% ee
>99% yield
99% ee
>99% yield
99% ee
2e
2f
2g
95% yield
98% ee
2h
>99% yield
97% ee
96% yield
99% ee
>99% yield
99% ee
O
O
HN
Me
HN
CO2Me
CO2Me
HN
Et
Cl
Cl
6a
>99% yield
99% ee from E
98% ee from Z
6b
>99 yield
98% ee from E
97% ee from Z
Bn
Cl
Cl
P
OH
N
H
O
OH
2m
>99% yield
99% ee
CGP-55854
a SV = mmol(substrate)/(mmol(catalyst)*h)
O
Both meta- and para-Me substituted enamides reacted smoothly
to give the corresponding amides 2b and 2c in excellent yields and
selectivities. To check the electronic effect on the aromatic ring,
para-substituted enamides were employed. Electron-donating
groups such as OMe (2d) did not affect either the reactivity or
selectivity. Enamides with an electron-withdrawing group gave the
target products in excellent yields and selectivities (2e–g).
Potentially reactive functional groups such as Br and NO2 survived
under these reaction conditions, and enamides 2g and 2h were
O
N
N
O
HN
MeO
Rivastigmine
Cl
H
N
2n
MeO
>99% yield
96% ee
Tecalcet
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selectively hydrogenated. Finally, two kinds of key intermediates
(a) ortho-Substituted Enamides
1
2
3
4
5
6
7
8
of APIs were synthesized in excellent yields and selectivities.
Amide 2m can be converted into CGP-55845,46 which is a potent
selective GABA-B receptor antagonist. Amide 2n is an
intermediate of two APIs, Rivastigmine47 and Tecalcet.48
O
O
P
OtBu
Next, the scope of the reaction with -dehydroamino acids was
H2 (25 mL/min)
= 500 kPa(G)
examined (Scheme 4(b)).
A
simple phenyl substituted
Rh-L/STA/KIT-6-NH2
(300 mg = Rh:0.015 mmol)
+ W-50 (500 mg)
dehydroamino acid 3a smoothly underwent hydrogenation to give
the optically pure amino acid 4a in quantitative yield under
standard reaction conditions for enamides. Neither electron-
donating nor electron-withdrawing groups at the para-position
changed the outcome of the reaction, and the desired amino acids
4b–e could be obtained in analytically pure quality simply by
removing solvent. This catalyst system could be applied for the
hydrogenation of -dehydroamino acids 5, which are also an
important class of compounds for the synthesis of biologically
active molecules. For this type of substrate, both E- and Z-isomers
are available, and it was found that both isomers showed almost the
same level of excellent enantioselectivity.
O
O
R
HN
R
HN
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0.07 mL/min
Ø10*50 mm, SUS
1
30 o
C
2
0.0125 M,
Toluene/iPrOH
= 1/1
SVa = 3.5 h-1
S/C = 172
O
O
O
O
HN
MeO HN
Cl HN
O2N HN
Although the current catalyst system showed broad substrate
scope for simple enamides and dehydroamino acids, a limitation is
reactions with ortho-substituted enamides. When ortho-methyl
substituted enamide 1i was employed under standard conditions,
the target product was obtained in 31% yield with 30% ee. On the
other hand, one of the advantages of this immobilization method is
that no modification is required for chiral ligands. Therefore, we
decided to use this method as a modular support for various Rh
complexes with a range of chiral ligands. As a proof concept, we
selected a chiral monodentate phosphite developed by Merck
research group.49 This chiral Rh complex could be successfully
immobilized on our composite without any change in the catalyst
preparation protocol. After optimization of the reaction conditions,
the corresponding amide could be obtained in 93–95% yield with
90% ee. Under the optimized reaction conditions, the scope of the
reaction with ortho-substituted enamides was examined (Scheme
5(a)). Similar selectivity was observed in Cl substituted enamides;
however, MeO- and NO2- substitution decreased the selectivity by
10%. This tendency may be explained by considering that oxygen
coordination to the Rh changed the chiral environments in the
transition states, leading to the decrease in enantioselectivity. On
the other hand, such coordination did not affect the reactivity, and
the desired amides were obtained in excellent yields in all cases.
These results not only demonstrate the efficiency of the method for
the preparation of ortho-substituted chiral amides, but also
showcased the generality of this immobilization method.
2i
2j
2k
2l
93-95% yield
90% ee
90-92% yield
70% ee
95-97% yield
85% ee
>99% yield
69% ee
a SV= mmol(substrate)/(mmol(catalyst)*h)
(b) Cinacalcet Intermediates
Me
P
tBu
Me
P
tBu
H2 (25 mL/min)
= 500 kPa(G)
Rh-BenzP*/STA/KIT-6-NH2
(200 mg = Rh:0.01 mmol)
+ W-50 (600 mg)
O
O
HN
HN
0.2 mL/min
Ø10*50 mm, SUS
30 o
C
2o
1o
0.1 M,
Toluene/iPrOH
= 1/1
SVa = 120 h-1
S/C = 2400
90-92% yield
93% ee
H
N
By making use of the easy tunability of chiral ligands, the
hydrogenation of 1-naphthyl substrate 1o would allow access to the
Cinacalcet core structure, which can be used for the treatment of
hyperparathyroidism and hypercalcemia. Since the initial
investigation with QuinoxP* ligand proceeded with relatively low
enantioselectivity, the chiral ligand was changed to BenzP*
reported by Imamoto et al.43 The desired product 2o was obtained
with satisfactory selectivity and excellent yield (Scheme 5(b)).
CF3
Cinacalcet
a SV = mmol(substrate)/(mmol(catalyst)*h)
Finally, to evaluate the lifetime of this catalyst, extended time
operation was performed with model substrate 1a under the
standard reaction conditions (Scheme 6). The activity remained
unchanged during a 90-hour flow reaction without loss of
enantioselectivity, then gradual catalyst deactivation was observed.
At the 90-hour stage, total TON reached as high as 10,800 to give
17.6 g of the enantiomerically pure target compound, which is 10
times higher than that of the reported homogeneous batch system.43
ICP analysis of the crude mixture showed that Rh leaching was
under the limit of detection even after 100 h reaction, which
suggested strong interaction between the Rh complex and the
support. Although the reason for deactivation is still under
investigation, formation of inactive rhodium hydride oligomers,
Scheme 5. Scope of ortho-Substituted Enamides (a) and
Synthesis of Cinacalcet Intermediates (b)
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which is supported by solid 31P NMR analysis (see SI) or
ACKNOWLEDGMENT
1
2
3
4
5
6
7
8
accumulation of a trace amount of water on the catalyst may cause
This work was supported in part by a Grant-in-Aid for Scientific
Research from JSPS, the University of Tokyo, and MEXT (Japan),
JST. We thank Dr. Tei Maki (The University of Tokyo) for STEM
and EDS analyses.
the deactivation.43
Scheme 6. Lifetime Evaluation with 2a
H2 (25 mL/min)
= 500 kPa(G)
O
Rh-QuinoxP*/STA/KIT-6-NH2
(200 mg = Rh:0.01 mmol)
+ W-50 (600 mg)
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9
0.2 mL/min
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a SV = mmol(substrate)/(mmol(catalyst)*h)
In conclusion, we have developed heterogeneous chiral Rh
catalysts for asymmetric hydrogenation of enamides under
continuous-flow conditions. Acid-base and electrostatic
interactions were utilized for the immobilization, and it was
revealed that surface basicity and mesoporous silica structures play
key roles in achieving efficient immobilization of original Rh
complexes and long lifetime after immobilization. The catalysts
showed excellent activity and selectivity for hydrogenation of
various kinds of enamides and dehydroamino acids, providing
optically active amides including API intermediates. Catalyst
deactivation was not observed for a 90-hour reaction, and metal
leaching was completely suppressed. Furthermore, this
immobilization method could be applied for several kinds of Rh
complexes with different chiral ligands to expand the scope of these
reactions. Further study focusing on expansion of this method for
other types of reactions and different metal complexes is ongoing
in our group.
ASSOCIATED CONTENT
Supporting Information.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Catalyst preparation and characterization including ICP, N2
ads./des. isotherm, solid-state NMR, STEM, EDS mapping,
detailed experimental procedures, detailed optimization data,
characterization of products, copies of product NMR spectra and
HPLC charts (PDF)
(18) Saito, Y.; Ishitani, H.; Ueno, M.; Kobayashi, S., Selective
Hydrogenation of Nitriles to Primary Amines Catalyzed by
a
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Conditions. ChemistryOpen 2017, 6, 211-215.
(19) Miyamura, H.; Suzuki, A.; Yasukawa, T.; Kobayashi, S., Polysilane-
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of Hydroquinones from Quinones through Sequential and Continuous-Flow
Hydrogenation-Derivatization Using Heterogeneous Au-Pt Nanoparticles
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AUTHOR INFORMATION
Corresponding Author
* Shū Kobayashi – Department of Chemistry, School of Science,
The University of Tokyo, Tokyo, 113-0033 Japan;
e-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
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