Nitrogen-Doped Carbon Enables Heterogeneous Asymmetric Insertion of Carbenoids into Amines Catalyzed by Rhodium Nanoparticles

Article abstract of DOI:10.1002/anie.202102506

Development of stable heterogeneous catalyst systems is a crucial subject to achieve sustainable society. Though metal nanoparticles are robust species, the study of asymmetric catalysis by them has been restricted because methods to activate metal nanopa

Full text of DOI:10.1002/anie.202102506

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Communications
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How to cite:
International Edition: doi.org/10.1002/anie.202102506
German Edition: doi.org/10.1002/ange.202102506
Flow Synthesis
Nitrogen-Doped Carbon Enables Heterogeneous Asymmetric
Insertion of Carbenoids into Amines Catalyzed by Rhodium
Nanoparticles
Ryusuke Masuda, Tomohiro Yasukawa,* Yasuhiro Yamashita, and Shu¯ Kobayashi*
Abstract: Development of stable heterogeneous catalyst sys-
tems is a crucial subject to achieve sustainable society. Though
metal nanoparticles are robust species, the study of asymmetric
catalysis by them has been restricted because methods to
activate metal nanoparticles without causing metal leaching
were limited. We developed Rh nanoparticle catalysts (NCI-
Rh) supported on nitrogen-doped carbon as a solid ligand to
interact with metals for asymmetric insertion of carbenoids into
À
N H bonds cocatalyzed by chiral phosphoric acid. Nitrogen
dopants played a crucial role in both catalytic activity and
enantioselectivity while almost no catalysis was observed with
Rh nanoparticles immobilized on supports without nitrogen
dopants. Various types of chiral a-amino acid derivatives were
synthesized in high yields with high enantioselectivities and
NCI-Rh could be reused in seven runs. Furthermore, we
Scheme 1. Strategy to construct heterogeneous catalysts for asymmet-
ric reactions.
demonstrated the corresponding continuous-flow reaction
using a column packed with NCI-Rh. The desired product
was obtained efficiently for over 90 h through the reactivation
of NCI-Rh and the chiral source could be recovered.
they can be easily prepared and possess high physical stability
considering that they are formed at very high temperatures.
Thus, heterogeneous chiral metal nanoparticle catalysts
would be expected to be suitable for long-term continuous-
flow systems. Indeed, metal nanoparticles with chiral modi-
fiers are applicable to asymmetric catalysis;[5] however,
examples that achieve high enantioselectivity for a wide
variety of substrates are still very limited (Scheme 1b).[6]
Major challenges of metal nanoparticles for asymmetric
catalysis are less flexibility in tuning of the electronic nature
of the active metal species and suppression of metal leaching.
Though some ligand molecules can modify the reactivity of
metal nanoparticles,[7] the available ligands are limited
because strong interactions with ligands often cause metal
leaching.[6i,8] This trade-off between reactivity and stability
limits the choice of chiral ligands for asymmetric metal
nanoparticle catalysis.
We considered that the use of supports bearing coordina-
tion ability to metals could overcome these issues because
interactions from the support were expected to both activate
and stabilize metal nanoparticles simultaneously. Conven-
tional supports that are used for asymmetric metal nano-
particle catalysts, such as carbon black (CB), silica, and metal
oxides, were not expected to interact with the metal
efficiently. We hypothesized that nitrogen-doped carbon
(NDC) would be a good candidate for this purpose.[9] We
recently developed nitrogen-doped carbon-incarcerated
metal nanoparticle catalysts (NCI metal) prepared from
poly(4-vinylpyridine) (PVP) through a polymer-incarceration
methodology, in which metal nanoparticles were encapsu-
lated by NDC layers and stabilized.[10] Using these catalysts,
several oxidative transformations were developed. These
reactions did not proceed in the absence of nitrogen dopants
H
eterogeneous catalysts have advantages over homoge-
neous catalysts with respect to their recovery and reuse.
Moreover, the use of heterogeneous catalysts in continuous-
flow reactions can provide efficient synthetic systems, leading
to enhanced environmental compatibility, efficiency, and
safety.[1] However, the development of heterogeneous chiral
catalysts lags far behind than that of homogeneous chiral
catalysts.[2] Immobilization of chiral ligands on solid supports
is one of the most popular methods to heterogenize chiral
metal complexes (Scheme 1a).[3] While this method is appli-
cable to a variety of ligands, additional synthetic processes are
required to functionalize ligands and the lifetime of the
catalysts depends on that of the metal complexes. In addition,
it is difficult to reactivate catalysts when the complexes
decompose or when catalyst poisons become attached to the
metals. Therefore, these heterogeneous metal complex cata-
lysts still suffer from a relatively short lifetime.
In contrast, heterogeneous metal nanoparticles are
expected to form robust catalyst systems with long lifetimes.[4]
Such catalysts are usually used in bulk chemical synthesis as
[*] R. Masuda, T. Yasukawa, Y. Yamashita, S. Kobayashi
Department of Chemistry, School of Science, The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: t-yasukawa@chem.s.u-tokyo.ac.jp
shu_kobayashi@chem.s.u-tokyo.ac.jp
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202102506.
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Table 1: Screening of Rh catalysts and CPA.
and leaching of metals was suppressed even in the presence of
reactive intermediates such as radical species.[10a] These
findings inspired us to utilize NCI metal nanoparticle catalysts
with an appropriate chiral source for asymmetric reactions. To
our knowledge, there is no example of asymmetric catalysis
using heteroatom-doped carbon-supported catalysts. In addi-
tion, a cooperative catalyst system with metal nanoparticles
and chiral organic molecules that individually activate
substrates would be beneficial because a rate acceleration
by chiral cocatalyst can avoid undesired racemic pathway.
However, such catalyst systems were also less explored.[5]
Chiral a-amino acids are essential building blocks for
peptides, proteins, and many other bioactive compounds;
thus, efficient and enantioselective synthetic methods to
access diverse a-amino acids have been in high demand.[11]
Among synthetic routes, asymmetric insertions of carbenoids
Entry
Rh cat.
CPA
Yield [%][a]
er[b]
1
2
3
4
5
6
7
8
NCI-Rh A
PI/CB-Rh
PSi/Al2O3-Rh
Rh/C (Wako)
CB-Rh[c]
TRIP
TRIP
TRIP
TRIP
TRIP
SCPA
SCPA
SCPA
quant. (95)
58.5:41.5
3
1
N.R.
3
–
–
–
–
NCI-Rh A
88 (82)
47
95
89.5:10.5
74.5:25.5
92:8
NDC-Rh[d]
[Rh(OAc)2]2
À
derived from diazoesters into N H bonds are one of the most
efficient methods,[12] and cooperative systems of transition-
metal catalysts and chiral organocatalysts have been devel-
oped.[13] Although this reaction generates only nitrogen gas as
a by-product and seems to be suitable for flow systems,
effective heterogeneous catalyst systems have not been
established.
Herein, we report novel heterogeneous Rh nanoparticle
catalysts that have high activity, enantioselectivity, and long
lifetime, for the synthesis of chiral a-amino acids even under
continuous-flow conditions.
We explored several kinds of heterogenous Rh nano-
particle catalysts for the asymmetric insertion of diazoesters
[a] Determined by 1H NMR analysis; isolated yield given in parentheses.
[b] Determined by HPLC analysis. [c] Prepared without PVP in prepara-
tion of NCI-Rh A. [d] Prepared from nitrogen-doped carbon instead of
PVP and CB.
À
into N H bonds utilizing 3,3’-bis(2,4,6-triisopropylphenyl)-
1,1’-binaphthyl-2,2’-diylhydrogenphosphates
(TRIP)
as
a chiral phosphoric acid (CPA) cocatalyst that acts as
a proton-transfer shuttle[13c] (Table 1). Methyl phenyldiazoa-
cetate (1a) and p-anisidine (2a) were selected as models.
Nitrogen-doped carbon-incarcerated Rh nanoparticle cata-
lysts (NCI-Rh A) were prepared based on our reported
procedure from 1:1 (w/w) ratio of the polymer and CB.[10b]
A
Rh salt was reduced to form nanoparticles in the presence of
the polymer and CB. A poor solvent was then added to
generate polymer encapsulated nanoparticles as precipitates,
which were further pyrolyzed to give NCI catalysts
(Scheme 2).
Scheme 2. Preparation of NCI catalysts.
NCI-Rh A gave the desired product 3a quantitatively
with low enantioselectivity (Table 1, entry 1). In contrast,
almost no reaction proceeded in the presence of the
previously developed Rh nanoparticle catalysts supported
on polystyrene-based copolymer/carbon black (PI/CB-Rh)[6i]
or polysilane/alumina (PSi/Al2O3-Rh),[6a,14] which could be
used for asymmetric 1,4-addition reactions in the presence of
chiral ligands (entries 2 and 3). Commercially available Rh on
carbon (Rh/C) did not work well either (entry 4). CB-Rh,
which was prepared without PVP by the same method used
for NCI-Rh A, gave almost no product (entry 5). These
results indicated that nitrogen dopants play a key role in the
catalytic activity. We then examined spirobiindane diol
(SPINOL)-derived chiral phosphoric acids (SCPA) as a co-
catalyst based on the literature[13c] and the product 3a was
obtained with 89.5:10.5 er (entry 6). Notably, no leaching of
the metal was confirmed by inductively coupled plasma (ICP)
analysis of the crude solution. To elucidate the effect of our
polymer-incarceration methodology, postdeposition of Rh to
NDC was conducted as a control. The NDC was prepared by
pyrolysis of a mixture of PVP and CB, and NDC-Rh was
prepared from NDC instead of PVP and CB in the
preparation of the NCI catalysts. Interestingly, NDC-Rh
showed lower activity and enantioselectivity (entry 7), indi-
cating that in situ formation of NDC and polymer encapsu-
lation during the catalyst preparation was crucial for high
catalytic activity. It is remarkable that the result of NCI-Rh A
was comparable with that using the corresponding homoge-
neous catalyst (entry 8).
The loading of nitrogen dopant was optimized by chang-
ing the ratios of PVP to CB in NCI-Rh (Table 2). When the
ratio of PVP was decreased (NCI-Rh B), the activity and
enantioselectivity decreased slightly (entry 2). In contrast,
NCI-Rh C, prepared from a larger amount of PVP, improved
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Table 2: Effects of the amount of nitrogen dopants.
Entry
NCI-Rh
(PVP:CB)
Rh loading [m-
molgÀ1 [a]
Yield [%][b]
er[c]
]
1
2
3
4
5
6
NCI-Rh A (1:1)
NCI-Rh B (1:3)
NCI-Rh C (3:1)
NCI-Rh D (5:1)
NCI-Rh E (5:1)
NCI-Rh F (7:1)
0.148
0.158
0.144
0.150
0.072
0.074
82
71
90
trace
91
75
89.5:10.5
88.5:11.5
90.5:9.5
–
91.5:8.5
91:9
[a] Determined by ICP analysis. [b] Isolated yield. [c] Determined by
HPLC analysis.
both yields and enantioselectivities (entry 3). Further
increase in the ratio of PVP led to no activity of the catalyst
(NCI-Rh D), probably because the surface area of the
supports was too small to prevent aggregation of Rh nano-
particles (entry 4). When the loading of Rh was decreased,
keeping the ratio of PVP:CB to 5:1, the catalyst (NCI-Rh E)
gave the highest yield and enantioselectivity without causing
metal leaching (entry 5). NCI-Rh F, which contained the
highest ratio of PVP to CB, showed lower activity compared
with NCI-Rh E (entry 6). These results proved that nitrogen
dopants had highly positive effects on both catalytic activity
and enantioselectivity of NCI-Rh.
To gain more insight into the effect of nitrogen dopants,
we performed X-ray photoelectron spectroscopy (XPS)
analysis (Figures 1a and S2 in the Supporting Information).
The binding energy of Rh 3p/2 in NCI-Rh shifted to higher
energy compared with CB-Rh. The binding energy of N 1s in
NCI-Rh revealed the presence of both pyrrolic and pyridinic
nitrogen, with the latter being the major species (Figures S4
and S5). As both nitrogen species were suggested to work as
an electron acceptor, these results indicate that electron
transfer from Rh to the nitrogen dopant occurred,[9,15] and
that electron-deficient Rh species could facilitate an attack of
a diazo compound on Rh to form a metal carbenoid
intermediate easily. In addition, scanning transmission elec-
tron microscopy (STEM) analysis and Energy dispersive X-
ray spectroscopy (EDS) mapping revealed that nitrogen
dopants contributed to the high dispersion of Rh nano-
particles on all of the supports (Figures 1b–d). The average
size of the particles in NCI-Rh A and NCI-Rh E was 2.9 Æ 0.7
and 3.0 Æ 0.7 nm, respectively (N ꢀ 100) indicating that the
amount of nitrogen dopants did not impact on the particle size
significantly. On the other hand, it was difficult to determine
the average Rh particle size of CB-Rh because of aggregation.
We also performed XPS analysis of NDC-Rh that showed
lower enantioselectivity. The binding energy of Rh 3p/2 was
slightly shifted to higher energy than NCI-Rh (Figure S3) and
the composition of nitrogen species was changed to be rich in
pyrrolic nitrogen (Figure S6). These results indicated that the
nature of nitrogen dopant significantly affected both activity
and enantioselectivity. Brunauer-Emmett-Teller (BET) sur-
face area of these catalysts was analyzed by nitrogen
Figure 1. a) XPS analysis and b) STEM analysis of NCI-Rh E and CB-Rh
c) EDS mapping of NCI-Rh E and d) CB-Rh.
adsorption methods to reveal that NCI-Rh E had a narrower
surface area (158 m2 gÀ1) than that of CB-Rh (386 m2 gÀ1). The
surface area of the catalysts seems not to have strong
influences on catalytic performance.
With the optimized catalyst system in hand, substrate
generality of the asymmetric insertion of carbenoids into
amines was examined (Scheme 3). Various types of protected
amines, p-anisidine, o-anisidine, BocNH2, FmocNH2, and
CbzNH2, afforded the corresponding protected chiral a-
amino acids 3a–e smoothly. Diazo compound with ethyl or
isopropyl ester gave a slightly lower yield and enantioselec-
tivity than methyl ester (3 f, 3g). Other diazo compounds, with
À
substitution on the aryl ring, reacted smoothly to form N H
insertion products in high yields with high enantioselectivity,
regardless of electronic effects or positions of substitutions
(3h–l). 2-Naphthyl-substituted diazoester could also be
utilized for this catalytic system (3m).
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turnover frequency (TOF) was 5.7 hÀ1. SCPA were recovered
(48% yield) successfully from the resin by acidification and
could be reused without loss of either activity or enantiose-
lectivity (Scheme S2). When the recovered NCI-Rh E was
treated at 8008C for 2 h under Ar, restoration of reactivity
was observed. Using the reactivated NCI-Rh E, the second
run of the continuous-flow system was performed. The system
gave the product in high yields with high enantioselectivity for
over 25 h. The TON was 164 and the highest TOF was 6.0 hÀ1.
Through two trials of flow systems, the total TON of 530 was
achieved to produce 15.3 g of the product. These results
demonstrated the efficiency of the continuous-flow system
and the robustness of the metal nanoparticle catalyst.
Finally, stoichiometric reactions under flow conditions
were performed to confirm whether the reaction proceeded
on the heterogeneous phase (Scheme 5). A solution of diazo
Scheme 3. Substrate scope.
NCI-Rh E was easily recovered by centrifugation and
reused for the next run of the model reaction. NCI-Rh E
could be reused in seven runs without loss of either activity or
enantioselectivity and metal leaching (see the Supporting
Information). Additionally, hot filtration tests were per-
formed showing that no further reaction took place in the
filtrate obtained from the middle of the reaction. Based on
the results, the possibility that trace amounts of leached Rh
species catalyzed the reaction was ruled out (Table S3).
NCI-Rh E was applied to a continuous-flow system
(Scheme 4). A solution of substrates and SCPA was flowed
into a column packed with NCI-Rh E. Additionally, we
attempted to recover the chiral source by connecting
a column packed with Amberlite IR 900, which is a basic
resin to trap SCPA. The product was obtained in high yields
with high enantioselectivity from 4 h after starting the system,
which could be run for over 65 h without significant loss of
activity. The turnover number (TON) was 366 and the highest
Scheme 5. Stoichiometric reactions under flow.
substrate 1a was flowed into a column packed with NCI-Rh
E. After washing with an enough amount of dichloromethane,
a solution of amine 2a and SCPA was flowed. The desired
product 3a was obtained in 28% yield corresponding to Rh
amounts. As a control, we examined the flow reactions using
columns packed with nitrogen-doped carbon and no absorp-
tion of 1a in the column was observed. The results suggested
that 1a or an intermediate derived from 1a could stay on the
Rh of the heterogeneous catalyst while 1a could not be
captured by the support itself. We conducted EDS mapping of
NCI-Rh E treated with methyl 2-(4-bromophenyl)-2-diazo-
acetate to detect where the substrate located on the catalyst
(Figure S7). The results showed that Br mainly placed at the
same place of Rh. We think that these results supported that
the reaction proceeded via heterogeneous catalysis pathway
and the formation of Rh carbenoid on the solid state was
proposed.
In conclusion, we have developed NCI-Rh for the
asymmetric insertion of carbenoids derived from diazoesters
À
into N H bonds. Nitrogen dopants played a crucial role in
both activity and enantioselectivity, and that the polymer-
encapsulation protocol for the catalyst preparation was also
important. By employing SCPA as cocatalysts, various types
of a-amino acid derivatives were synthesized in high yields
with high enantioselectivity. In a batch system, NCI-Rh could
be reused for seven runs without any loss of either activity or
enantioselectivity. Furthermore, NCI-Rh was applied success-
fully to a flow system. This system worked efficiently for over
90 h through the reactivation of the catalyst and chiral a-
Scheme 4. Application for continuous-flow system.
4
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the door to asymmetric reactions catalyzed by metal nano-
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Acknowledgements
This work was supported in part by a Grant-in-Aid for
Scientific Research from Japan Society for the Promotion of
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Conflict of interest
The authors declare no conflict of interest.
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Rh nanoparticle
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Manuscript received: February 18, 2021
Accepted manuscript online: March 15, 2021
Version of record online: && &&, &&&&
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Communications
Flow Synthesis
R. Masuda, T. Yasukawa,* Y. Yamashita,
S. Kobayashi*
&&&& — &&&&
Nitrogen-Doped Carbon Enables
Heterogeneous Asymmetric Insertion of
Carbenoids into Amines Catalyzed by
Rhodium Nanoparticles
Rh nanoparticle catalysts supported on
nitrogen-doped carbon were developed
for asymmetric insertions of carbenoids
to promote the reactions. The catalyst
could be reused several times and was
applicable for a continuous-flow reaction
system that produced the desired chiral
amine for over 90 h through reactivation
of the catalyst.
À
derived from diazoesters into N H
bonds cocatalyzed by chiral phosphoric
acid. The nitrogen dopants are essential
6
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