Polysilane-Immobilized Rh-Pt Bimetallic Nanoparticles as Powerful Arene Hydrogenation Catalysts: Synthesis, Reactions under Batch and Flow Conditions and Reaction Mechanism

Article abstract of DOI:10.1021/jacs.8b06015

Hydrogenation of arenes is an important reaction not only for hydrogen storage and transport but also for the synthesis of functional molecules such as pharmaceuticals and biologically active compounds. Here, we describe the development of heterogeneous Rh-Pt bimetallic nanoparticle catalysts for the hydrogenation of arenes with inexpensive polysilane as support. The catalysts could be used in both batch and continuous-flow systems with high performance under mild conditions and showed wide substrate generality. In the continuous-flow system, the product could be obtained by simply passing the substrate and 1 atm H₂ through a column packed with the catalyst. Remarkably, much higher catalytic performance was observed in the flow system than in the batch system, and extremely strong durability under continuous-flow conditions was demonstrated (>50 days continuous run; turnover number >3.4 × 10⁵). Furthermore, details of the reaction mechanisms and the origin of different kinetics in batch and flow were studied, and the obtained knowledge was applied to develop completely selective arene hydrogenation of compounds containing two aromatic rings toward the synthesis of an active pharmaceutical ingredient.

Full text of DOI:10.1021/jacs.8b06015

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Article
Polysilane-Immobilized Rh-Pt Bimetallic Nanoparticles as
Powerful Arene Hydrogenation Catalysts: Synthesis, Reactions
under Batch and Flow Conditions, and Reaction Mechanism
Hiroyuki Miyamura, Aya Suzuki, Tomohiro Yasukawa, and Shu Kobayashi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b06015 • Publication Date (Web): 06 Aug 2018
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Journal of the American Chemical Society
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Polysilane-Immobilized Rh-Pt Bimetallic Nanoparticles as Powerful
Arene Hydrogenation Catalysts: Synthesis, Reactions under Batch and
Flow Conditions, and Reaction Mechanism
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Hiroyuki Miyamura, Aya Suzuki, Tomohiro Yasukawa and Shū Kobayashi*
Department of Chemistry, School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
*Corresponding author. E-mail: shu_kobayshi@chem.s.u-tokyo.ac.jp
Arene hydrogenation, Heterogeneous catalyst, Flow reaction, Drug synthesis, Selective hydrogenation
ABSTRACT: Hydrogenation of arenes is an important reaction not only for hydrogen storage and transport but also for the
synthesis of functional molecules such as pharmaceuticals and biologically active compounds. Here, we describe the
development of heterogeneous Rh-Pt bimetallic nanoparticle catalysts for the hydrogenation of arenes with inexpensive
polysilane as support. The catalysts could be used in both batch and continuous-flow systems with high performance under
mild conditions and showed wide substrate generality. In the continuous-flow system, the product could be obtained by
simply passing the substrate and 1 atm H2 through a column packed with the catalyst. Remarkably, much higher catalytic
performance was observed in the flow system than in the batch system, and extremely strong durability under continuous-
flow conditions was demonstrated (>50 days continuous run; turnover number >106). Furthermore, details of the reaction
mechanisms and the origin of different kinetics in batch and flow were studied, and the obtained knowledge was applied to
develop completely selective arene hydrogenation of compounds containing two aromatic rings toward the synthesis of an
active pharmaceutical ingredient.
almost no reports on a general theory for selective arene
hydrogenation of more complex compounds that contain
Introduction
more than two aromatic moieties in different chemical
environments. If this kind of selective hydrogenation is
feasible and the selectivity is predictable, it would be
possible to introduce a new synthetic strategy in which
selective arene hydrogenation could be conducted at a final
stage of synthesis of a complex compound, so-called late-
stage selective arene hydrogenation. Moreover, an ideal
catalytic arene hydrogenation system would function in
continuous-flow under atmospheric and mild conditions,
since continuous-flow synthesis is in great demand in the
field of hydrogen storage and the synthesis of APIs. Although
several arene hydrogenation protocols are applied in flow
Hydrogenation of arenes and heteroarenes is an
important reaction in a variety of fields such as organic
synthesis, including drug and natural product synthesis,1
and petroleum chemistry,2 as well as for the transition to a
hydrogen-based
society.3
In
addition,
selective
hydrogenation of arene and heteroarene moieties in more
complex compounds bearing various functionalities is a
challenge necessary for the synthesis of biologically active
compounds such as active pharmaceutical ingredients
(APIs).1c, 4 However, functional groups that are found in such
compounds include highly polar and coordinative
functionalities, such as pyridine, amide, ester, carboxylic
acid, amine, and alcohol, and these substrates and the
corresponding products obtained after hydrogenation might
strongly interact and poison the catalysts. Although
hydrogenation of simple alkylarenes, especially benzene and
toluene,5 has been developed through the use of transition
metals, including bimetallic catalysts in both heterogeneous
and homogeneous systems,6 heterogeneous catalysts that
can be useful for hydrogenation of highly functionalized
arenes are very limited compared with those of simple alkyl-
4, 7b,
8
systems,1c,
there are no reports that evaluate and
compare catalytic performances directly and quantitatively
between continuous-flow and batch systems in terms of
durability of catalyst and catalytic turnover number (TON)
and turnover frequency (TOF).
Here, we describe the development of high-performance
polysilane-immobilized Rh-Pt bimetallic nanoparticle
catalysts that perform in both continuous-flow and batch
systems for arene hydrogenation under mild conditions.
These catalysts showed not only very high catalytic activity
and robustness but also high tolerance for various
functionalities to realize broad substrate scope, including
highly functionalized arenes, for the synthesis of
1c, 4,
7
substituted arenes.
Furthermore, these catalysts
require very harsh conditions and show limited catalytic
turnover, and catalyst deactivation and leaching of metals
are also sometimes problematic. In addition, there are
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Page 2 of 13
pharmaceuticals and biologically active compounds. In and 4). The alloyed structure of the Rh-Pt bimetallic
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addition, remarkably high catalytic TOFs were
demonstrated in flow processes compared with batch
systems, especially for arenes containing polar and
coordinative functionalities that usually act as catalyst
poisons. Moreover, the predictable selective arene
hydrogenation of complex compounds that contain more
than two aromatic moieties based on mechanistic studies is
demonstrated.
nanoparticles was confirmed by scanning transmission
electron microscopy (STEM) and energy–dispersive X-ray
spectroscopy (EDS) line/mapping analyses. In addition, the
EDS analysis clarified that polysilane and alumina formed
composite supports but nanoparticles located mostly at the
silicon part (SI Figures 5 and 6).9d H2 pulse chemisorption
analysis revealed that the active site (total mol of adsorbed
hydrogen in unit gram of catalyst) in Rh-Pt/(DMPSi-Al2O3)
was calculated as 0.0155 mmol/g.
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Results and Discussion
We evaluatedthe performance ofthe prepared catalysts in
the hydrogenation of toluene to afford methylcyclohexane
(MCH) in atmospheric hydrogen under neat conditions and
at ambient reaction temperature (Table 2). When single-
metal nanoparticle catalysts of Rh, Pt, or Pd immobilized on
DMPSi were used, the Rh catalyst showed moderate activity,
whereas the Pt and Pd catalysts showed almost no activity
(entries 1–3). Interestingly, when a bimetallic catalyst of Rh
and Pt (Rh-Pt/(DMPSi-Al2O3)) was used, a significant
increase in activity was observed; MCH was obtained in 76%
yield with only 0.025 mol% Rh (entry 4). This result might
be explained by a synergistic effect of the two metals on the
surface of the alloyed nanoparticles. Indeed, we previously
demonstrated a number of unique effects in bimetallic
systems that were absent from their monometallic
counterparts.12 The use of Rh-Pt/(MPPSi-Al2O3) also led to
comparable results under the same reaction conditions
(entry 5). We then raised the reaction temperature from 30
to 50 °C in an attempt to increase the reactivity. We
compared the activities of bi- and tri-metallic catalysts. Rh-
Pt/(DMPSi-Al2O3) showed higher activity than Rh-
Pd/(DMPSi-Al2O3) and Rh-Pt-Pd/(DMPSi-Al2O3) (eintries 6-
8). We were pleased to find that the use of Rh-Pt/(DMPSi-
Al2O3) under these conditions gave an excellent yield of MCH
(entry 9). However, such high performance was not realized
by the use of Rh-Pt/(MPPSi-Al2O3) (entry 10). The catalyst
loading of Rh-Pt/(DMPSi-Al2O3) was then reduced to
0.00625 mol% in an attempt to achieve higher catalytic
turnover. This led to almost full conversion with Rh-
Pt/(DMPSi-Al2O3) at 50 °C for 60 h; TON of 16,000 (198,193
per active site) (entry 11).
Catalyst preparation and arene hydrogenation in a
batch system
We have developed polysilane-encapsulated Pd
nanoparticle catalysts for the hydrogenation of C–C double
bonds, triple bonds, and nitro groups in both batch and flow
systems.9 Polysilane is a polymer with interesting electronic
properties, derived from s-conjugaed electrons of the silicon
backbone.10 s-Conjugated electrons show reduction ability
to generate metal nanoparticles from metal salts and
stabilize metal nanoparticles by multiple, weak interactions.
Polysilane is also commercially available and inexpensive. In
addition, polysilane is a highly stable and safe material that
does not swell with organic solvents; the latter feature is
highly beneficial for continuous-flow systems because
almost no pressure increases or clogging occurs, especially
under multi-phase flow conditions of gas and liquid.9,
11
Therefore, we chose polysilane as a support to generate
heterogeneous metal catalysts for the hydrogenation of
arenes. In this context, we first prepared single and
bimetallic metal nanoparticle catalysts (Rh, Pt, Pd, and bi-
and tri-metallic) using NaBH4 as an external reductant to
facilitate the formation of metal(0) nanoparticles in the
presence of two types of polysilane supports:
dimethylpolysilane (DMPSi) and methylphenyl polysilane
(MPPSi) (Table 1). Metal salts were dropwise into the
mixture of polisilane and NaBH4 and metal nanoparticles
were generated immediately under reductive conditions.
The generated nanoparticles were deposited and stabilized
by the polysilane through electronic interactions. Alumina
was added as a second support to stabilize the catalyst
structure in the following step. Methanol that is a poor
solvent for polysilane was added to form polysilane
encapsulated metal nanoparticles. The obtained mixture
was heated under vacuum, and partial inter-crossliking of
polysilane and alumina proceeded through oxygen bond
because a part of Si-Si bond was converted to Si-O-Si bond
during the reduction of the metal. This inter-crossliking
between the primary support (polysilane) and the
secondary support (alumina) is important for the stability of
the catalyst and prevention of metal leaching.9b
Table 1. Preparation of catalysts
NaBH4 (x equiv.)
/diglyme
metals
(1 equiv. each)
Me
MeOH
Al2O3
2 h
Si
R
1) filtration
2) wash
(acetone, H2O)
THF, 0 ºC, 1 h
n
R = Me: M/(DMPSi-Al2O3)
R = Ph:
dry
1) filtration
2) wash
(H2O, THF, CH2Cl2)
neat, 100 ºC
5 h, in vacuo
M/(MPPSi-Al2O3)
Metal
2/(3)
Metal 1
Metal 1 / Metal 2 /
(Metal 3)
M
R
x
(mmol/g)
(mmol/g)
These catalysts were composed of metal nanoparticles
with an average size of approximately 5–6 nm (SI Figures 3
Rh
Me Rh(OAc)2
6
0.011
–
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Poisoning of the catalyst, either by a small amount of
Pt
Me Na2PtCl6
Me Pd(OAc)2
12 0.061
–
–
1
2
3
4
5
6
7
8
impurity or by solvent molecules that are adsorbed on metal
nanoparticles during the work-up process, may account for
the slight loss of catalytic activity. These molecules would be
removed by heating the catalyst to revive the catalytic
activity. We thus demonstrated the robustness of the Rh-Pt
nanoparticle catalyst during this reuse investigation; a total
TON of 42,480 was achieved. We also confirmed, by ICP
analysis of the reaction mixture, that no measurable leaching
of either of the metals (Rh or Pt) occurred during the
recovery and reuse investigation. STEM analysis revealed
that the size of the nanoparticles remained small during
recovery and reuse, even after the regeneration process
under heating (SI Figures 11-14).
We then investigated the scope ofthe reaction in the batch
system with respect to the substrate (Figure 1 and Table 4).
Arenes with less bulky substituents, such as toluene (1a),
benzene (1b), and ethyl benzene (1c), were fully
hydrogenated under the optimized conditions (entries 1–3).
Cumene (1d) and tert-butyl benzene (1e), which have bulky
substituents, required 40 h (entries 4 and 5). Arene with a
long alkyl chain (1f) afforded the desired product
quantitatively, even with 0.1 mol% catalyst loading in 64 h
(entry 6). The p-, m-, and o-xylenes 1g, 1h, and 1i required
longer reaction times; full conversions were obtained with
enriched cis configurations, albeit with slightly different
diastereoselectivities (entries 7–9). The tendency to form
the cis isomer has been noted previously for arene
hydrogenation when using metal nanoparticles.6b, 6d, 6f, 6i, 6l, 6n,
6q, 6t, 6x This might be caused by steric repulsion between the
surface of the nanoparticles and the methyl groups in the
partially reduced intermediates. The presence of the trans
isomers in these three cases suggests that partially reduced
intermediates might disaggregate from the surface of the
nanoparticles at least once before complete hydrogenation.
For mesitylene (1j), moderate yield was observed, probably
because of its high steric bulk (entry 10).
Tetrahydronaphthalene (1k) was hydrogenated to decaline
under relatively harsh conditions (entry 11).
Pd
6
0.067
0.080–
0.096
0.025–
0.031
Rh-Pt
Me Rh(OAc)2/Na2PtCl6 18
Rh-Pt
Ph Rh(OAc)2/Na2PtCl6 18 0.100
Me Rh(OAc)2/Pd(OAc)2 18 0.074
Rh(OAc)2/Na2PtCl6/
Rh-Pd
0.036
0.025/0.0
42
Rh-Pt-Pd Me
18 0.068
Pd(OAc)2
9
Table 2. Optimization of reaction in the batch system
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M/(DMPSi-Al2O3) or M/(MPPSi-Al2O3) (x mol%)
T ºC, H2 (1 atm), 20 h, neat
Tem
p
(°C)
Catalyst
(M; R)
Rh (M)
Entr
y
Yield
(%)[a]
TON[d]
(x, mol%)
1
Rh; Me
0.025
0.025
0.025
30
30
30
40
2
1,600
64 (/Pt)
0
2
Pt; Me
3
Pd; Me
0
4
Rh-Pt; Me
Rh-Pt; Ph
Rh-Pt; Me
0.025(0.008 Pt) 30
0.025(0.008 Pt) 30
76
72
>99
65
3,020
2,880
1,000
650
5
6[c]
7[c]
0.1 (0.033 Pt)
50
50
Rh-Pd; Me 0.1 (0.05 Pd)
Rh-Pt-Pd;
Me
0.1 (0.037 Pt)
(0.062 Pd)
8[c]
50
53
530
9
Rh-Pt; Me
Rh-Pt; Ph
0.025(0.008 Pt) 50
0.025(0.008 Pt) 50
99
77
3,960
3,080
16,000
10
0.00625
50
11[c] Rh-Pt; Me
>99
(198,193)
(0.0021Pt)
[e]
[a] Determined by GC. [b] Reaction time 24 h. [c] Reaction time 60
h. [d] Defined as moles of reacted toluene per mole of Rh. [e] De-
fined as moles of reacted H2 per mole of active site of catalyst.
Table 3. Recovery and reuse of the catalyst
Rh-Pt/(DMPSi-Al2O3) (0.025 mol% as Rh)
50 ºC, H2 (1 atm), 24 h, neat
Run
Yield (%)[a]
1
2
3
4
5[b] 6[b] 7[b] 8[b] 9[b] 10[b]
We then investigated the electronic effects of directly
connected substituents on the aromatic ring. Aromatic
99 99 97 88 96 97 97 98 97 96
compound 1l, with
a
strong electron-withdrawing
[a] Yield determined by GC analysis. [b] After the fourth run, the
catalyst was heated under Ar before use at 100 °C for 7 h.
trifluoromethyl group, gave anexcellent yield (Table 4, entry
12). Free carboxylic acid derivatives 1m and 1n afforded
excellent yields in cyclopentyl methyl ether (CPME) and
moderate diastereoselectivity was observed for 1n (entries
13 and 14). Ethyl benzoate (1o) and benzamide (1p) were
hydrogenated quantitatively while preserving the
functionalities (entries 15 and 16). We then investigated the
compatibility of the reaction conditions towards functional
groups. Arenes with carboxylic acid, hydroxyl, primary
amine, and N-Boc-protected amine groups (1q, 1r, 1s, 1t)
were reduced to the corresponding cyclohexyl compounds
Recovery and reuse of Rh-Pt/(DMPSi-Al2O3) were then
investigated (Table 3). Rh-Pt/(DMPSi-Al2O3) was recovered
by simple filtration of the reaction mixture and drying in
vacuoat room temperature. High yields were maintained for
the initial three runs; however, the catalytic activity
decreased slightly in the fourth run. Catalytic activity was
regenerated in the fifth run after reviving the catalyst by
heating under anAratmosphere. Recycling andregeneration
of the catalyst by heating after each run was continued, and
almost full conversion was maintained until the tenth run.
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with retention of these functionalities (entries 17–20). N- much attention because the hydrogenated products can be
1
Boc-protected phenyl glycine (1u) and its methyl ester (1v)
were reduced to the corresponding cyclohexane derivative
while maintaining the optical purity and preserving the Boc-
protecting group (entry 21 and 22). N-Boc-protected
anthranilic acid (1w) was hydrogenated smoothly, retaining
the functionalities (entry 23). Phenol (1x) was smoothly
reduced to cyclohexanol without formation of either
cyclohexanone or cyclohexenone (entry 24). Hydroquinone
(1y) was fully hydrogenated in isopropanol to afford 1,4-
dihydroxy cyclohexane with almost 1:1 ratio of cis-trans
isomers. The low diastereoselectivity can be explained by
the formation of a stable intermediate involving a ketone
moiety that can be easily detached from the catalyst surface
before the next hydrogenation (entry 25). Anisole (1z), n-
butyl phenyl ether (1æ), and isopropyl phenyl ether (1aa)
were fully reduced to the corresponding cyclohexyl ethers,
quantitatively without cleavage of the ether bond (entries
26–28). On the other hand, cyclopentyl phenyl ether (1ab)
afforded not only cyclohexyl cyclopentyl ether but also
cyclohexanol (21%) and cyclopentanol (24%) (see SI, Table
6). Interestingly, a slight increase in hydrogen pressure (3.9
atm) prevented ether cleavage; cyclohexyl cyclopentyl ether
was obtained as the sole product (entry 29). Diphenyl ether
(1ac) afforded dicyclohexyl ether in76% yield under slightly
pressurized conditions, accompanied by the formation of
cyclohexanol (entry 30).
Primary, secondary, and tertiary aniline derivatives were
also investigated. Aniline (1ad) was fully hydrogenated;
however, cyclohexylamine was obtained in moderate yield
because of the formation of dicyclohexylamine (41%) (entry
31). On the other hand, methylaniline (1ae) was smoothly
reduced to the corresponding cyclohexylamine derivative
under pressurized conditions (entry 32). Dimethylaniline
(1af) required harsher reaction conditions (20 atm H2, 120
°C) for full reduction, probably because the catalytic activity
was diminished by the strong coordinating nature of tertiary
amines (entry 33). Protected anilines, acetanilide (1ag) and
N-boc aniline (1ah), were converted into the corresponding
cyclohexylamine derivatives in excellent yields while
maintaining the protecting group (entries 34 and 35). The
protection of amine group may mitigate its coordinating
ability on the nanoparticle surface, thereby allowing milder
reaction conditions compared with those required for
alkylated aniline derivatives. Heteroaromatic compounds
such as furan (1ai) and dimethyl furan (1aj) were smoothly
reduced to the corresponding tetrahydrofuran derivatives
under mild conditions, and the latter gave the cis isomer as
the major product (entries 36 and 37). Although pyridine
(1al) could be reduced under atmospheric conditions (entry
39), pyrrole (1ak) required 10 atm of hydrogen (entry 38).
Hydrogenation of substituted pyridines, especially those
containing an ester group at the meta-position, attracts
easily converted into valuable pharmaceuticals. Of these
processes, full hydrogenation of ethyl 3-nicotinate (1am) is
one of the most challenging tasks. In earlier studies,1c, 4 very
harsh conditions (100 atm H2) were typically required.
Interestingly, Rh-Pt/(DMPSi-Al2O3) was found to be a highly
active catalyst for this transformation; quantitative
conversion into ethyl nipecotinate (2am) was achieved with
partially reduced product 3am under 10 atm H2 at 100 °C in
hexane (entry 40). A pyridine derivative with a dimethyl
acetal moiety (1an) was successfully reduced to the
corresponding piperidine derivative in excellent yield with
retention of the acetal moiety (entry 41). Ethyl 4-nicotinate
(1ao) was also hydrogenated smoothly under mild
conditions to afford the fully reduced product in excellent
isolated yield (entry 42). Quinoline (1ap) and isoquinoline
(1aq) afforded tetrahydroquinoline almost quantitatively at
80 °C under pressurized conditions without formation of full
hydrogenated compounds (entries 43 and 44). Difficulty in
full hydrogenation of these bicyclic structure might be
caused by the steric repulsion of initially hydrogenated cycle,
as 1k also required harsh conditions.
2
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Me
Me
R
iPr
tBu
Me
Me
R=M 1a
1b
1d
1e
1f
H
Me
Me
Me
Me
Me
n-Octyl
Et 1c
1g
1j
1h
1i
COOEt
1k
CF3
O
COOH
COOH
COOH
NH2
1p
1q
1l
1m
OH
1n
1o
H
N
O
H
N
MeOOC
OtBu
HOOC
OtBu
OtBu
NH2
N
H
O
O
1r
1s
1t
1v
1u
COOH
O
OH
OH
OMe
O
O
nBu
N
H
OtBu
HO
1y
1æ
1aa
1w
1x
1z
H
N
Me Me
Me
H
NH2
HN
N
OtBu
N
1ag
OMe
O
O
O
O
1ah
1ab
1ac
1ad
1ae
1af
O
O
OEt
OEt
N
H
1ak
OMe
N
1an
O
O
N
1al
N
1am
1aj
1ai
N
1ao
OH
OH
N
N
H
H
H
1ap
2ap
H
H
H
H
HO
HO
N
NH
1ar
2ar
1aq
2aq
Figure 1. List of substrates.
Table 4. Substrate scope in the batch system
Rh-Pt/(DMPSi-Al2O3) (x mol% as Rh)
aromatic compounds
saturated compounds
T °C, H2 (P atm), t h, neat or solvent
Entry Substrate
x
P
T
(°C)
t
(h)
Solvent Yield
(%)[a]
(mol%) (atm)
1
2
3
4
1a
1b
1c
1d
0.1
0.1
0.1
0.1
1
1
1
1
50 24 neat
50 24 neat
50 24 neat
50 40 neat
>99[b]
>99[b]
>99[b]
94[c]
5
1e
0.1
1
50 40 neat
94
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6
1f
0.1
0.1
1
1
50 64 neat
50 48 neat
99
The utility of arene hydrogenation catalyzed by Rh-
Pt/(DMPSi-Al2O3) is highlighted in the synthesis of
intermediates of drugs and biologically active compounds
(Scheme 1). Cyclohexane carboxylic acid derivative 2n was
obtained from commercially available benzoic acid
derivative 1n in 87% yield, and 2n can be converted into
nateglinide by using a reported method (Scheme 1 (a)). N-
Boc-protected phenyl glycine was hydrogenated
quantitatively, and the resulting product can be converted
into melagatran by following the reported procedure
(Scheme 1 (b)). As noted above, ethyl 3-nipecotinate (2am)
is an intermediate for several pharmaceuticals, such as
tiagabine (Scheme 1 (c)). Pyridine derivative 1ao could be
hydrogenated to the corresponding piperidine derivative,
which is an intermediate for the synthesis of donepezil, in
1
2
3
4
5
6
7
8
7
8
9
1g
>99[b,
d]
1h
1i
0.1
0.1
1
1
50 48 neat
50 144 neat
>99[b,
e]
>99[b,
f]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
1j
0.1
0.1
0.03
0.1
0.1
0.1
0.1
0.3
0.1
0.1
0.3
1.7
1.7
1.7
0.03
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.13
0.27
0.1
0.1
0.1
0.1
0.1
2.6
1
1
50 24 neat
80 24 neat
50 64 neat
45[c, g]
85
9
1k
10
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1l
94
1m
1n
1
50 24 CPME 98
80 36 CPME 87[h]
10
1
1o
50 24 neat
80 24 EtOH
99
1p
10
1
>99
excellent yield (Scheme 1 (d)).
Scheme 1. Application to the preparation of intermedi-
1q
50 24 CPME >99
1r
10
10
1
80 24 neat
80 24 neat
52[c]
54[c]
ates for drug synthesis (cat. = Rh-Pt/(DMPSi-Al2O3))
(a)
1s
cat. (0.1 mol%)
H
N
CO2Me
Ph
1n
2n
1t
50 24 CPME 99
80 48 EtOAc 81
50 48 EtOAc 99
80 24 EtOAc 93[i]
H2 (10 atm), 80 ºC
CPME, 24 h, 87%
O
Nateglinide
1u
10
1
R. Yahalomi, et al. European Patent, EP1487782 (A1) (2002)
1v
O
O
H
(b)
N
CO2H
cat. (1.7 mol%)
N
N
1w
1x
10
10
1
H
2u
H2N
1u
H2 (10 atm), 80 ºC
EtOAc, 48 h, 99%
NH
80 26 neat
81
Melagatran
50 24 i-PrOH 85[j]
L.A. Sobrera, et al. Drugs Future 2002, 27, 201.
1y
O
(c)
(d)
1z
1
50 24 neat
50 120 neat
50 24 neat
80 24 neat
80 24 neat
80 24 neat
80 24 neat
120 48 neat
99
cat. (0.1 mol%)
N
OH
1am
S
2am
H
2 (10 atm), 100 ºC
hexane, 24 h, 99%
1æ
1aa
1ab
1ac
1ad
1ae
1af
1ag
1ah
1ai
1aj
1ak
1al
1am
1an
1ao
1ap
1aq
1
74
S
(R)-Tiagabine
1
76
Knutsen, L. J. S. et al., J. Med. Chem. 1993, 36, 1716.
OMe
3.9
3.9
10
10
20
1
86
cat. (3 mol%)
O
1ao
2ao
OMe
Ph
N
H2 (10 atm), 100 ºC
hexane, 24 h, 99%
76[c]
59[c]
91
Donepezil
A. Imai, A. et al. European Patent, EP1911745 (A1) (2008)
Arene hydrogenation in a continuous-flow system
83
50 46 CPME 95
50 46 CPME 95
We applied Rh-Pt/(DMPSi-Al2O3) to continuous-flow
hydrogenation systems (Figure 2, SI Figure 15). Toluene and
hydrogen, as liquid and gas substrates, respectively, were
simultaneously passed through a column containing Rh-
Pt/(DMPSi-Al2O3) without a backpressure controller at the
outlet (i.e., open to the atmosphere). The inlet of the column
was constructed as a double-layered structure with a
metallic mesh through which both the liquid and gas
components pass and intermix well before entering the
catalyst-packed region (SI Figure 17). Using Rh-Pt/(DMPSi-
Al2O3) as catalyst, reaction conditions were optimized under
the multiphase continuous-flow conditions, changing
parameters of substrate and hydrogen flow rates, and
column heating temperature (SI Table 2). When the liquid
substrate was delivered with a flow rate of 0.05 mL/min
together with 63 mL/min hydrogen (corresponding to 1.86
equiv. of the amount theoretically required for quantitative
conversion) through Rh-Pt/(DMPSi-Al2O3) (666 mg), packed
1
1
50 24 neat
50 24 neat
80 24 neat
50 37 neat
99[b]
1
81[k]
83
10
1
93
10
10
1
100 24 hexane 99
80 48 neat
50 36 neat
80 24 neat
120 24 neat
97
90
96
76
0.1
0.1
10
20
[a] Isolated yield. [b] Determined by GC analysis. [c] Determined
by 1H NMR analysis. [d] cis/trans = 68:32 [e] cis/trans = 78:22 [f]
cis/trans = 92:8
67:33 [i] cis/trans = 80:20 [j] cis/trans = 57:43 [k] cis/trans = 97:3
[g]
[h]
all-cis/cis-cis-trans = 88:12
cis/trans =
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Journal of the American Chemical Society
Page 6 of 13
in a stainlesscolumn maintainedat 70°C, using analuminum flow conditions as those used for toluene (entries 4 and 5).
1
2
3
4
5
6
7
8
heating block, toluene was fully converted and analytically
pure MCH was obtained quantitatively, without the
requirement for purification. The reaction systems reached
steady state very rapidly (within 10 min). We alsomonitored
the pressure at the peristaltic pump and verified that almost
no increase in pressure was observed (<20 KPaG); thus, the
reaction took place under essentially atmospheric pressure,
even under continuous-flow conditions.
We then investigated the durability of this continuous-
flow hydrogenation system (Figure 2). Remarkably, the
conversion ratio of the flow reaction, which was analyzed at
regular intervals, was maintained quantitatively throughout
a run of 1,214 h (>50 days); a total TON of 347,149
(99,815,534 reacted H2/active site) was achieved. Notably,
no regeneration of the catalyst packed in the column was
required during the long-period continuous-flow
hydrogenation reaction, although catalyst regeneration was
p-, m-, and o-Xylenes 1g, 1h, and 1i were also good
substrates for flow systems. Full conversions were obtained
under the same optimized reaction conditions used for
toluene, although very long reaction periods (2–6 days)
were required to obtain full conversion in the batch
reactions, even with higher catalyst loadings than in the case
of toluene (Table 5, entries 7–9). Aromatic compound 1f,
with a long alkyl chain, required a longer reaction period in
the batch system (Table 4, entry 6). However, the use of flow
conditions led to quantitative conversion of this difficult
substrate while maintaining a high TOF (Table 5, entry 6).
Although mesitylene (1j) showed very poor reactivity in the
batch system, the saturated compound was obtained
quantitatively when using the flow system (entry 10).
Aromatic compounds 1l, 1o, and 1z, with both electron-
withdrawing and electron-donating groups, were also
investigated. Solid substrate 1y was also hydrogenated using
i-PrOH as solvent (entry 13). Again, flow conditions gave
excellent to quantitative conversions with high TOFs,
irrespective ofthe nature of the substituents on the aromatic
ring (entries 11–14). n-Butyl phenyl ether (1æ) was also an
excellent substrate in the flow system, and quantitative
conversion was observed (entry 15).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
required in batch reactions for the recovery and reuse.
mass flow controller
1 atm
63 mL/min
peristaltic pump
0.05 mL/min
H2
aluminium heating
block at 70 ºC
neat
temperature
controller
Heteroaromatic compounds were then investigated.
Dimethyl furan (1aj) could be reduced to the corresponding
tetrahydrofuran derivative quantitatively under flow
conditions, with the cis isomer being formed as the major
product (entry 16). Using the batch system under
atmospheric hydrogen conditions, almost no reactions
proceeded for pyrrole (1ak); this substrate required
pressurized conditions (10 atm of H2). Notably, pyrrole
(1ak) could be fully reduced under atmospheric conditions
when using the flow system (entry 17). Pyridine (1al) was
smoothly reduced under the optimized flow conditions
(entry 18). Ethyl 4-nicotinate (1ao) was also hydrogenated
smoothly under flow conditions, using hexane as solvent, to
afford fully reduced product in excellent yield (entry 19).
Flow hydrogenation of ethyl 3-nicotinate was performed
using hexane as solvent at 100 °C using 10 atm of H2 (entry
20). Notably, only 10 atm H2 was sufficient to afford 2am
with almost quantitative conversion under continuous-flow
conditions. This is in contrast to previously reported flow
systems that required 100 atm H2.1c, 4 A large molecule, such
as b-estradiol (1ar), can be hydrogenated to the
corresponding saturated product (2ar) as a mixture of
diastereomers smoothly under flow conditions, while almost
no hydrogenation of this complex compound proceeded
under batch conditions (entry 21).
Rh-Pt/(DMPSi-Al2O3)
666 mg in 5φ x 5 cm column
>99% conversion was maintained for 1214 h (>50 days).
Figure 2. Schematic representation of the continuous-
flow reactor (hourly yield; SI Table 5)
We also compared this flow system with the
corresponding
batch
system
using
the
same
substrate/catalyst ratio for >50 days under the optimized
reaction conditions of the batch system, except for the
catalyst loading. Conversion of <10% was observed in the
batch system, thereby confirming the advantage of using the
continuous-flow system. We also conducted control
experiments using polysilane or alumina packed column as
reactor and no conversion of toluene wasconfirmed. Neither
polysilane, alumina nor SUS-column were active for
hydrogenation.
Next, we investigated the scope of the reaction with
respect to substrate in a continuous-flow system and
compared the results with those of a batch system (Table 4
vs. Table 5). Aromatic compounds with less bulky
substituents, such as toluene (1a), benzene (1b), and ethyl
benzene (1c), were fully hydrogenated to afford the
corresponding cyclohexane derivatives under the optimized
flow conditions for toluene (Table 5, entries 1–3). Although
aromatic compounds with bulky substituents, cumene (1d)
and tert-butyl benzene (1e), exhibited lower reactivity and
required longer reaction times in the batch system, these
substrates could be fully reduced using the same optimized
The remarkably enhanced catalytic activity for various
substrates in the continuous-flow system with respect to
increased catalytic TOF andreduced hydrogen pressure may
be explained by efficient mixing of the gas and liquid
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Journal of the American Chemical Society
substrates within the column packed with Rh-Pt/(DMPSi- was 0.1–0.3 mol%, the rate-limiting step is mainly the
1
2
3
4
5
6
7
8
Al2O3), which is a fine powder that swells very little in the
presence of organic materials. Notably, in the relatively
simple system shown in Figure 2, the heterogeneous catalyst
is simply packed in the column, providing an ideal reaction
environment for gas–liquid–solid multiphase reactions.
dissolving and diffusion of hydrogen from the gas to the
liquid phase (Scheme 2, step A). The rate-limiting step then
gradually shifted to the step of the hydrogen adsorption to
the surface of the nanoparticles. The reaction kinetics were
first-order in catalyst when <0.0125 mol% of Rh was used
(Scheme 2, step B). In the case of 0.00625 mol%, the TOF
(/h) (moles of reacted hydrogen (mol)/mole of Rh used
(mol)/1 (h)) was calculated as 662 (/h).
Table 5. Substrate scope in the continuous-flow system
(for detailed information about reaction conditions of
each substrate and hourly yields, see SI Table 4)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Next, we investigated the kinetics under the continuous-
flow conditions. We defined the moles hourly space velocity
(MHSV) relating tothe weight hourly space velocity (WHSV),
as shown in the equation below.
MHSV (/h) = substrate (mol)/(catalyst (mol) ´ time (h))
(/h)
MHSV is the contact frequency between a catalyst (surface
of metal nanoparticles) and a substrate in a unit of time.
Therefore, 1/MHSV (h) is described using flow rate F (L/h)
and concentration C (mol/L) of substrate, as shown below.
1/MHSV (h) = (catalyst (mol) ´ time (h))/substrate (mol)
= catalyst (mol)/(C ´ F (mol/h)),
where C ´ F = mole flow rate (mol/h). 1/MHSV is also
understood as the average contact time of one substrate to a
catalyst. In flow systems, the reaction kinetics can be
determined by varying the flow rate of a substrate and
hydrogen and fixing the catalyst amount in the column.
Kinetic parameters are calculated by plotting conversion
against 1/MHSV as determined by the mole flow rate.14 Rh-
Pt/(DMPSi-Al2O3) (99 mg) was packed in a reactor column
held at 50 °C and the substrate flow rate was varied from
0.05 to 0.15 mL/min. The hydrogen flow rate was also
changed, keeping 6 equiv. to substrate (2 equiv. for
theoretically consumable hydrogen amount). Plots followed
zero-order kinetics for the substrate, as observed in the
batch system. TOF was calculated to be 1189 (/h), which is
5.4 times greater thanthat of the batch system (SIFigure 27).
Similar kinetic studies in both batch and flow systems
were conducted for o-xylene, N-methyl aniline, and pyrrole.
In the cases of o-xylene and N-methyl aniline, plots of both
batch and flow systems obeyed zero-order kinetics (SI
Figures 21, 22, 29, 30). In the case of pyrrole, plots obeyed
zero-order kinetics within low conversion (<20%), while
saturation kinetics were observed at >20% conversion,
probably because of the inhibition effect of the produced
pyrrolidine (SI Figures 23, 31). TOF values of both batch and
flow systems, for these substrates, are summarized in Table
Rh-Pt/(DMPSi-Al2O3)
(600–800 mg)
aromatic compound
0.025–0.05 mL/min
saturated compound
70 ºC, H2 (1 atm,
32–63 mL/min), neat
Substrat Yield
e
Entr
y
Substra Yield
Entry
(%)[a]
>99[b]
>99[b]
>99
>99[b]
>99
te
(%)[a]
1
2
3
4
5
6
7
8
9
10
1a
1b
1c
1d
1e
1f
11
12
13
14
15
16
1l
>99
1o
98[c]
>99[i]
>99[c]
>99
1y
1z
1æ
1aj
1ak
1al
1ao
1am
1ar
>99
>99[j]
1g
1h
1i
>99[b,e]
>99[b,f]
>99[b,g]
>99[h]
17
18
19
20
21
99
95
>99[c]
98[k]
92[l]
1j
[a] Isolated yield of fractions collected during steady state. [b] De-
termined by GC analysis. [c] In hexane (0.24 M) at 100 °C. [d] In i-
[e]
[f]
[g]
PrOH (0.1 M).
cis/trans = 64:36.
cis/trans = 77:23
cis/trans = 89:11. [h] cis/trans = 75:25. [i] cis/trans = 61:39. [j]
cis/trans = 91:9. [k] In hexane (0.24 M), H2 (10 atm), at 100 °C;
for optimization detail of 1am, see SI Table 3. [l] In i-PrOH (0.03
M) at 50 ºC.
Comparison of reaction kinetics between batch and
flow systems
In the substrate scope study, it was established that
reactivity is highly dependent on the functionality of the
arenes. However, reactivity tendency was sometimes very
different between the batch system and the flow system. We
were initially interested in the origin of this difference and
hence decided to observe the reaction kinetics in both batch
and flow systems. In all kinetic experiments, 1 atm H2 was
used.
First, reaction profiles, using toluene as substrate in a
batch system, were recorded; these followed zero-order
kinetics with respect to the substrate (SI Figure 19).6z, 13
When 0.1–0.3 mol% of Rh-Pt/(DMPSi-Al2O3) as Rh loading
was used, only a slight increase in the reaction rate was
observed. When the catalyst loading was reduced to 0.025,
0.0125, and 0.00625 mol%, the reaction rate gradually
decreased in proportion to the amount of Rh (SI Figure 20).
Fromthese results, it appears that, whenthe catalyst loading
6.
Table 6. Comparison of TOFs for different substrates in
batch and flow systems
En Substr Produc TOF[a] in TOF[a] in TOFin flow/
try ate
t
batch (/h) flow (/h) TOF in batch
1
2
1a
1i
2a
2i
198
30
1189
213
5.4
7.1
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Journal of the American Chemical Society
Page 8 of 13
in batch system
3
4
1ae
1ak
2ae
2ak
14
22[b]
378
593[b]
27
27
rate-limiting step of catalyst
loading: <0.0125 mol%
rate-limiting step of catalyst
loading: 0.1–0.3 mol%
1
Step A
Step B
2
3
4
5
6
7
H2 (gas)
H2 (solution)
v = α [cat.]
v = a (constant)
[a] TOF is defined as moles of reacted substrate/mole of Rh in 1
h, and calculated from the value of the slope of linear regression
H2 (on catalyst)
Step C
v = β [1/MHSV]
in flow system
H2 (gas)
obtained from the reaction profile (batch) or relationship be-
hydrogenation
[b]
tween conversion and 1/MHSV (flow). See SI Eq. 1.
lated from the data points <20% conversion.
Calcu-
substrate (solution)
substrate (on catalyst)
8
9
In the batch system, reaction rates for o-xylene, N-methyl
aniline, and pyrrole were significantly decreased compared
with toluene (Table 6, entries 1 and 2). In the flow system,
the reaction rate of o-xylene was decreased while high TOFs
for N-methyl aniline and pyrrole were observed. For N-
methyl aniline and pyrrole, TOFs were 27 times greater in
flow than in batch systems (entries 3 and 4).
Understanding the functionality-dependent reactivity
and selectivity based on adsorption strength of
substrates
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To understandthe origin of the difference in reaction rates
among the substrates, competition experiments were
conducted (Table 7). Competition experiments between
monosubstituted alkyl arenes with different bulkiness have
been investigated previously.16 However, to our knowledge,
there are no such experiments using different categories of
arenes.
TOFs of flow systems were much greater than those of
batch systems for all substrates, while a limited amount (2
equiv. relative to the theoretically required amount) of
hydrogen was used in the flow system. It was expected that
hydrogen adsorption on the surface of the catalyst was the
rate-limiting step, and that this adsorption was competitive
to substrate adsorption. When hydrogen is adsorbed on the
surface of the catalyst, the first hydrogenation proceeds to
afford an intermediate on the surface. Generally, the second
and third hydrogenations are much faster than the first.15
Enhanced catalytic activity in flow systems can be
explained by the difference in the pathway of hydrogen
access onto the surface of the nanoparticles from the gas
phase (Scheme 2, steps A and B vs. C). In the batch system, a
catalyst exists with a liquid substrate, and only dissolved
hydrogen in the solution can access the surface of the
nanoparticles (steps A and B). On the other hand, in the flow
system, hydrogen gas and liquid substrate are directly
introduced to the column packed with solid catalyst, and
hydrogen can access the surface of the nanoparticles from
the gas phase hydrogen directly (step C). In the cases of N-
methyl aniline and pyrrole, stronger adsorption of
substrates and products to the surface of the catalyst is
expected compared with the case of toluene because of the
influence of the heteroatom. Therefore, the efficiency of
First, a 1:1 molar ratio of toluene and o-xylene was used in
a batch system and the reaction was monitored (SI Figure
24). The reduction of toluene proceeded selectively and
almost no conversion of o-xylene was observed (Table 7,
entry 5). Reaction rates of toluene hydrogenation for only
toluene and a toluene/o-xylene mixture were compared; a
decrease was observed in the reaction rate in the case of the
toluene/o-xylene mixture system (entry 1 vs. 5, SI Figures19
vs. 24). Judging from these results, both toluene and o-xylene
would be adsorbed onthe catalyst surface. It is expected that
bis-substituted arenes afford a more sterically hindered
intermediate after the reaction with one molecule of
hydrogen and the rate of the hydrogenation is much slower
than that of monosubstituted arenes.17 The reaction rate of
toluene was significantly decreased. Toluene and o-xylene
would compete for the available reaction sitesof the catalyst,
since hydrogen solubility to toluene and xylene is almost
similar at ambient temperature.18 The adsorbed hydrogen
selectively reacted with the more reactive adsorbed toluene,
over the unreactive o-xylene, leading to complete
suppression of o-xylene reduction.
Table 7. Comparison of reactivity and selectivity be-
tween pure and mixed substrates at selected reaction
time points (see SI for full monitoring of reactions: SI
hydrogen
adsorption
that
is
competing
with
substrate/product adsorption has a greater impact on the
reaction rate, and a much higher catalytic enhancement in
the flow system is observed. Although hydrogen adsorption
is accelerated in the flow system, it still might be the rate-
limiting step because the kinetic behavior is zero order with
respect to the substrate.
Scheme 2. Difference in hydrogen access pathway be-
tween batch and flow systems
Figures 21–26)
Rh-Pt/(DMPSi-Al2O3) (0.001x mmol Rh)
a
+
b
A
+
B
H2 (1 atm), 50 ºC
x mmol x mmol
(a: hydrogenated A, b: hydrogenated B)
Entry A
B
Yield
(%)[a]
a Yield
(%)[a]
b
1
2
3
4
toluene
o-xylene
pyrrole
-
-
-
-
56
-
-
-
-
18
14
21[b], 37[c]
N-methyl
aniline
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Journal of the American Chemical Society
would proceed at the initial stage. N-Methyl aniline could
5
toluene
toluene
o-xylene 14
pyrrole
pyrrole 4, 43[d]
0.9
1
2
3
4
5
6
7
8
then be gradually adsorbed to reach steady–state conditions
for competing adsorption, resulting in constant reaction
rates for both substrates. When only N-methyl aniline was
hydrogenated, there was no induction period. Adsorption of
N-methyl aniline might be prevented by rapidly adsorbed
pyrroles. Thus, this induction period was observed only in
the competitive experiment.
Hydrogenation of a mixture of pyrrole and N-methyl
aniline was conducted ina flow system, and only pyrrole was
hydrogenated selectively; almost full recovery of N-methyl
aniline was observed, and zero-order correlation was
observed for pyrrole (SI Figure 32). In the flow system, the
residence time of substrates is less than a few minutes, and
pyrrole could be preferentially hydrogenated, probably
because it could be quickly adsorbed on the surface of the
nanoparticles, over N-methyl aniline, which could not be
adsorbed in an appropriate manner for hydrogenation
within this short residence time. These results strongly
supported the scenario proposed above.
Based on the mechanistic knowledge obtained thus far,
selective hydrogenation of one of the aromatic substituents
in one molecule that has two aromatic functionalities under
different electronic and steric environments might be
possible. If we can predict and control selective
hydrogenation of one or more of the aromatic rings within
one relatively large molecule containing several aromatic
functionalities, such methodology will be very powerful in
synthetic organic chemistry.
To validate this hypothesis, we prepared three different
molecules containing two monosubstituted arenes; one an
aniline-based structure and the other an alkyl-substituted
phenyl group. Compound 4a has a shorter alkyl linkage
(three methylenes) between these two arene moieties,
whereas 4b has a longer one (eight methylenes). Compound
4c is a 4b analogue with N-Boc protection. For compounds
4a and 4b, partially hydrogenated compounds with
cyclohexyl amine moieties (5a and 5b) were obtained as
major products, and fully hydrogenated compounds (7a and
7b) were obtained as minor products, without formation of
partially hydrogenated compounds retaining aniline
moieties (6a and6b) (Table 8, entries 1 and 2). Substrate 4b,
with the longer alkyl chain, gave better selectivity than 4a,
with the shorter alkyl chain. Interestingly, when N-Boc-
protected compound 4c was used, selectivity was
completely reversed, and only partially hydrogenated
compound 6c, retaining an aniline moiety, was obtained;
there was no formation of other hydrogenated products (5c
and 7c) (entry 3).
6
7
0
38
17, 53[d]
N-methyl
aniline
[a] At 6 h. [b] At 11 h. [c] At 23.5 h. [d] At 29 h.
Next, we monitored the reduction of a mixture of toluene
and pyrrole (SI Figure 25). Pyrrole was selectively reduced
and no conversion oftoluene was observed, althougha much
higher reactivity of toluene compared with pyrrole was
recorded when pure substrates were used (entry 6).
Surprisingly, the reaction rate of pyrrole hydrogenation was
much faster than in the case where pyrrole was used as pure
starting material (entries 3 vs. 6, SI Figures 23 vs. 25). The
increased catalytic turnover rates are a remarkable
phenomenon, but it is difficult to explain at this stage.
Hydrogenation of a mixture of pyrrole and N-methyl
aniline was also monitored (SI Figure 26). In this case, both
substrates reacted; however, the kinetic behaviors differed,
especially at the initial stage (entry 7). Pyrrole had a higher
reaction rate at the initial stage, whereas N-methyl aniline
had an induction period of 4–5 h. After 6 h, the reaction rates
of both substrates were constant and almost equal (SI Figure
26).
To evaluate adsorption strength (binding ability to the
catalyst surface), catalyst poisoning effects by o-xylene and
pyrrole were investigated. The catalyst was first stirred in o-
xylene or pyrrole for 1 h at room temperature, and then
these compounds were evaporated and catalysts were
thoroughly dried in vacuo at room temperature.
Hydrogenation of toluene was monitored by using these
catalysts (SI Figure 27). When the catalyst was treated with
toluene, the reaction rate of toluene hydrogenation was
slower in the initial period (ca. 1 h), and then the reaction
rate became almost the same as that observed with the
untreated catalyst. On the other hand, catalyst treated with
pyrrole showed no trace of activity for toluene
hydrogenation, even after complete removal of pyrrole
under vacuum.
o-Xylene might remain on the catalyst surface after
evaporation and disturb toluene hydrogenation, then a
slower reaction rate might be observed during the initial 1 h.
In this period, o-xylene adsorbed on the catalyst surface may
be either hydrogenated or desorbed from the catalyst
surface. On the other hand, pyrrole might have a much
stronger adsorption ability than o-xylene and toluene, and
the generated pyrrolidine may also prevent toluene
adsorption; toluene hydrogenation is then completely
suppressed. On the other hand, pyrrole and N-methyl aniline
might have different adsorption rates, but might also have
comparable adsorption ability under thermodynamic
conditions. Pyrrole would be adsorbed quickly compared
with N-methyl aniline, and selective pyrrole hydrogenation
9
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These results may be explained by different strengths of
the adsorption ability of each arene functionality. In
substrates 4a and 4b, the aniline moiety preferentially
interacts with the surface of the nanoparticles, compared
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with alkyl benzene moieties, and selective hydrogenation of Al2O3) under atmospheric hydrogen at 50 °C, completely
1
this functionality proceeds. Judging from the absence of
partially hydrogenated compounds keeping aniline moieties
(6a and 6b), full hydrogenation proceeds only from 5a and
5b, probably maintaining the interaction between the
cyclohexylamine moietyandthe surface ofthe nanoparticles
as an ‘anchor’. This second hydrogenation was faster, with a
shorter alkyl chain, because of the probability of interaction
between the alkyl benzene moiety and the surface of the
nanoparticles with the ‘anchoring amine’ being entropically
favored by a shorter rather than a longer chain length.
Therefore, more selective hydrogenation wasrealized for 4b
with a longer alkyl chain. On the other hand, the aniline
moiety with N-Boc protection could not be hydrogenated,
and an opposite selectivity was obtained in the case of 4c.
The steric bulk of N-Boc protection might prevent
hydrogenation of the aniline moiety. Completely selective
hydrogenation of the alkyl benzene moiety was realized.
Next, we focused on obtaining a fully hydrogenated
compound selectively. We have demonstrated the powerful
hydrogenation ability under continuous-flow conditions
regardless of functionalities. As we expected, full
hydrogenation of 4a proceeded smoothly under the
continuous-flow conditions, and 7a was obtained
quantitatively (Scheme 3).
selective hydrogenation of the pyridine moiety and the C–C
double bond was realized under these ambient and neutral
conditions, and the other aromatic functionality and ketone
remained perfectly intact (analytically pure 8 was obtained
after removal of the catalyst by filtration). Notably, almost
perfect reactivity and selectivity of Rh-Pt/(DMPSi-Al2O3) for
3 could be achieved using standard conditions for other
typical substrates without any specific optimizations.
Although a similar approach for hydrogenation of 3 using
Pd/C was previously investigated using harsher and acidic
conditions, very careful tuning of reaction conditions was
indispensable because the reaction suffered from the
formation of undesired byproducts 9 and 10, which were
never observed in our case.19 The perfect selectivity toward
the synthesis of Donepezil 11 in our catalytic system can be
explained by strong and selective interaction between the
pyridine moiety and the catalyst surface, which is preferable
for selective hydrogenation. On the other hand, the di-
substituted bicyclic aromatic (dimethylresorcinol) moiety
may cause the steric repulsion to prevent hydrogenation, as
other bicyclic structures are also difficult substrates; 1k
required very harsh conditions and no full hydrogenation
from 1ap, 1aq and 1ar was observed in batch. Finally,
benzylation was successfully conducted under atmospheric,
ambient, and one-pot conditions, even without removal of
the heterogeneous catalyst, to afford Donepezil (11) directly
in two-steps from 3 in 87% isolated yield, which is much
higher than previously reported one (56% yield)19 (Scheme
4).
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
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50
51
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53
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60
Table 8. Selective partial hydrogenation of substrates
containing two aromatic substituents
R
N
R
N
R
N
R
N
Rh-Pt/(DMPSi-Al2O3) (0.5 mol% Rh)
Ph
Ph
Cy
Cy
Ph
Cy
Ph
Cy
iPrOH, H2 (1 atm), 50 ºC, 24 h
n
n
n
n
4a-c
5a-c
6a-c
7a-c
7 yield[b]
Thus, we have demonstrated the totally controlled
hydrogenation of compounds containing two aromatic
functionalities with different chemical environments. The
results of these investigations also strongly supported our
proposed mechanistic scenario for the functionality-
dependent reactivity and selectivity in arene hydrogenation
using Rh-Pt/(DMPSi-Al2O3).
Entry Substrate R, n
5
yield 6 yield
[a]
1
4a
4b
4c
H, 3
H, 8
80%
85%
<5%[b]
<5%[b]
99 %[a]
17%
7%
2
3c
Boc, 8 0%
0%
[a] Isolated yield. [b] Determined by 1H NMR. [c] Neat, 45 h.
Scheme 4. One-pot synthesis of Donepezil (11)
Scheme 3. Full hydrogenation of a compound with two
different types of arene moieties under continuous-
flow conditions
O
OMe
OMe
Ph
1) Rh-Pt/(DMPSi-Al2O3) (3 mol%)
H2 (1 atm), 50 ºC, iPrOH, 144 h
O
N
N
OMe
2) BnBr (1.05 eq.), Na2CO3 (2.7 eq.)
50 ºC, iPrOH, 12 h
3
Donepezil (11)
H
N
OMe
OMe
OMe
Rh-Pt/(DMPSi-Al2O3) (863 mg in column)
H2 (1 atm, 31 mL/min), 50 ºC
H
N
One-pot, two steps: 87% (Isolated)
3
Never observed undesired products
OMe
3
OMe
OMe
O
HN
4a
in iPrOH 0.1 M, 0.05 mL/min
7a
>99% (Isolated)
OMe
HN
HN
8
10
9
Finally, the knowledge obtained in these selective arene-
hydrogenation studies using model substrates was applied
to actual synthesis of an API (Donepezil (11)) under one-pot
and two-step conditions (Scheme 4). Adduct 3 can be
prepared from inexpensive commercially available
substrates through aldol condensation. Compound3 has two
aromatic rings; the first is a pyridine moiety and the second
is a tetrasubstituted benzene. When compound 3 was
hydrogenated in isopropyl alcohol using Rh-Pt/(DMPSi-
Conclusion
We have developed new Rh-Pt bimetallic nanoparticle
catalysts for the hydrogenation of arenes using readily
available polysilane as a support. The catalystscould be used
to achieve high levels of performance in both batch and
continuous-flow systems. In the batch system, the catalyst
showed very high activity under very mild conditions (30–
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Journal of the American Chemical Society
(4)
Irfan, M.; Petricci, E.; Glasnov, T. N.; Taddei, M.; Kappe, C.
50 °C, 1 atm H2), and recovery of the catalyst could be
O. Eur. J. Org. Chem. 2009, 2009, 1327.
1
2
3
4
5
6
7
8
achieved without loss of activity or leaching of metals. In the
continuous-flow system, products could be obtained in pure
form under mildconditions bysimply passing both substrate
and 1 atm H2 through a column packed with the catalyst. The
output of the system was stable and the high conversion
ratio could be maintained over an extended period of time
(50 days; TON 347,149). The scope of the reaction with
respect to substrate is broad and the conditions are
compatible with various functional groups, such as alcohol,
amine, ether, acetal, carboxylic acid, ester, amide, carbamate,
phenol, aniline derivatives, and heteroaromatic compounds,
including application to the synthesis of fine chemicals.
A clear contrast between the batch and flow systems was
confirmed in kinetic studies. Remarkable increases in
catalytic performance under the flow conditions were
demonstrated with variouscategory of substrates, especially
those containing strongly coordinative substrates, which
otherwise exhibited lower reactivity in the batch system.
Furthermore, competition experiments using different
categories of arenes revealed factors that govern selectivity:
adsorption strengths and steric factor. Based on these
mechanistic studies, we demonstrated the totally controlled
selective partial and full hydrogenation of substrates that
contain two aromatic functionalities, including a highly
practical API (Donepezil) synthesis. We believe the late-
stage arene hydrogenation strategy that has been
demonstrated in this study will open up more efficient
synthetic routes and continuous-flow syntheses for fine
chemicals and APIs.
(5)
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ASSOCIATED CONTENT
Supporting Information
Reaction procedures and spectra are available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
shu_kobayashi@chem.s.u-tokyo.ac.jp
ACKNOWLEDGMENT
Thiswork wassupported in part by a Grant-in-Aid for Scientific
Research from JSPS, the University of Tokyo, and MEXT (Japan),
JST. We thank Mr. Noriaki Kuramitsu (University of Tokyo) for
STEM and EDS analyses.
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1
2
3
4
5
>99% yield for >50 days
under continuous-flow
R
R
R
R
X
X
Hn
X
X
Hm
6
7
8
H2
Batch
vs.
up to 27 times faster TOF
reaction
9
Boc
N
H
N
Boc
N
H
N
controlled
selectivity
10
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n
n
n
n
O
O
HN
N
OMe
OMe
OMe
OMe
13
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