Rhodium-catalyzed asymmetric 1,4-addition reactions of aryl boronic acids with nitroalkenes: Reaction mechanism and development of homogeneous and heterogeneous catalysts

Article abstract of DOI:10.1039/c7sc03025h

Asymmetric 1,4-addition reactions with nitroalkenes are valuable because the resulting chiral nitro compounds can be converted into various useful species often used as chiral building blocks in drug and natural product synthesis. In the present work, asymmetric 1,4-addition reactions of arylboronic acids with nitroalkenes catalyzed by a rhodium complex with a chiral diene bearing a tertiary butyl amide moiety were developed. Just 0.1 mol% of the chiral rhodium complex could catalyze the reactions and give the desired products in high yields with excellent enantioselectivities. The homogeneous catalyst thus developed could be converted to a reusable heterogeneous metal nanoparticle system using the same chiral ligand as a modifier, which was immobilized using a polystyrene-derived polymer with cross-linking moieties, maintaining the same level of enantioselectivity. To our knowledge, this is the first example of asymmetric 1,4-addition reactions of arylboronic acids with nitroalkenes in a heterogeneous system. Wide substrate generality and high catalytic turnover were achieved in the presence of sufficient water without any additives such as KOH or KHF₂ in both homogeneous and heterogeneous systems. Various insights relating to a rate-limiting step in the catalytic cycle, the importance of water, role of the secondary amide moiety in the ligand, and active species in the heterogeneous system were obtained through mechanistic studies.

Full text of DOI:10.1039/c7sc03025h

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Rhodium-Catalyzed Asymmetric 1,4-Addition Reactions of Aryl
Boronic Acids with Nitroalkenes: Reaction Mechanism and
Development of Homogeneous and Heterogeneous Catalysts
Received 00th January 20xx,
Accepted 00th January 20xx
Hiroyuki Miyamuraa, Kohei Nishinoa, Tomohiro Yasukawaa, and Shū Kobayashia*
DOI: 10.1039/x0xx00000x
Asymmetric 1,4-addition reactions with nitroalkenes are valuable because the resulting chiral nitro compounds can be
converted to various useful species often used as chiral building blocks in drug and natural product synthesis. In the
present work, asymmetric 1,4-addition reactions of arylboronic acids with nitroalkenes catalyzed by a rhodium complex
with a chiral diene bearing a tertiary butyl amide moiety were developed. Just 0.1 mol% of the chiral rhodium complex
could catalyze the reactions and give the desired products in high yields with excellent enantioselectivities. The
homogeneous catalyst thus developed could be converted to a reusable heterogeneous metal nanoparticle system using
the same chiral ligand as a modifier, which was immobilized using a polystyrene-derived polymer with cross-linking
moieties, maintaining the same level of enantioselectivity. To our knowledge, this is the first example of asymmetric 1,4-
addition reactions of arylboronic acids with nitroalkenes in a heterogeneous system. Wide substrate generality and high
catalytic turnover were achieved in the presence of sufficient water without any additives such as KOH or KHF2 in both
homogeneous and heterogeneous systems. Various insights relating to a rate-limiting step in a catalytic cycle, the
importance of water, role of the secondary amide moiety in the ligand, and active species in the heterogeneous system
www.rsc.org/
were
obtained
through
mechanistic
studies.
catalyzed reactions, stoichiometric to substoichiometric
additives, such as KOH or KHF2, were required to achieve an
efficient catalytic turnover.2ꢀ6, 9ꢀ11
Introduction
Asymmetric synthesis is crucial in fine chemical
production, such as synthesis of drugs, biologically active
compounds, and natural products. In particular, asymmetric
carbon–carbon bond formation is useful because both chiral
centers and carbonꢀbased skeletons of target molecules are
constructed simultaneously. Asymmetric 1,4ꢀaddition reactions
with nitroalkenes are valuable because the resulting chiral nitro
compounds can be converted to various useful species often
used as chiral building blocks in drug and natural product
synthesis. The first rhodiumꢀcatalyzed asymmetric 1,4ꢀaddition
reaction of aryl boronic acids with nitroalkenes was reported by
Hayashi et al. and several homogeneous systems for this
transformation have been developed using chiral rhodium and
palladium complexes.1ꢀ12 In the rhodiumꢀcatalyzed 1,4ꢀaddition
reaction of aryl boronic acids with nitroalkenes, it was
suggested that the catalyst regeneration step is relatively slow
because of the strong coordination ability of the generated
nitronate to the rhodium complex. This slow catalytic
regeneration often caused low catalytic turnover and byꢀproduct
formation, and then, in most previously reported rhodiumꢀ
By contrast, to our knowledge, heterogeneous catalyst
systems for this asymmetric reaction have never been
developed hitherto, probably because the strong coordination
ability of the nitro group can induce serious metal leaching and
poisoning of the catalytically active center, which might be
generally less robust compared with that of corresponding
homogeneous complexes. Heterogeneous catalysts have
attracted great attention because of their facile separation from
products, reusability, and application to industrial processes.13ꢀ
17
In general, the strategies to develop heterogeneous metal
catalysts for asymmetric transformations, and immobilized
chiral ligands to form immobilized chiral metal complexes have
been widely explored.18ꢀ21 However, these strategies suffer
from complicated preparation of immobilized ligands, metal
leaching during preparation, and often instability of
immobilized ligands. In addition, immobilized metal catalysts
for organic transformations are generally less active than the
corresponding homogeneous catalysts, and they often suffer
from serious leaching of metals during reactions and decreased
activity during recovery and reuse. As a strategy to convert
homogeneous catalysis to heterogeneous catalysis, use of
heterogeneous metal nanoparticle catalysts is of great interest
because of their reusability, robustness, and high reactivity.22ꢀ25
Recently, several organic transformations originally catalyzed
by homogeneous catalysts have been successfully converted to
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27
heterogeneous metal nanoparticle catalysis.26,
Asymmetric methoxy phenyl boronic acid (2a) with nitrostyrene (1a) using
organic synthesis with heterogeneous metal nanoparticle homogeneous systems of 0.05 mol% of [Rh(C2H4)2Cl]2 (0.1
systems using chiral ligands as chiral modifiers have been mol% of Rh) and different types of chiral diene ligands at 100
investigated, especially in asymmetric hydrogenation reactions C in a 2:1 ratio of toluene and water solvents (Table 1). Chiral
pioneered by Orito et al 28, 29
Several mechanistic studies, even diene ligands with bulky ester moieties (4a and 4b) gave the
“
”
°
.
including theoretical calculations, have been conducted in desired product 3aa in high yields with good
Oritoꢀtype reactions.30ꢀ35 By contrast, asymmetric C–C bond enantioselectivities (entries 1 and 2). The diene ligand with
formation reactions using heterogeneous metal nanoparticle secondary bulky amide 4c gave 3aa with excellent
systems are a very limited and developing field, and their enantioselectivity, even in moderate yield (entry 3). By
reaction mechanisms are obscure in contrast to matured contrast, enantioselectivity was dramatically reduced with
asymmetric hydrogenation reactions.27, 36ꢀ43
chiral diene ligand 4d containing tertiary amide moiety,
In this context, we have developed chirally modified although an excellent yield was observed (entry 4). We
rhodium and bimetallic nanoparticle systems based on polymerꢀ determined ligand 4c as the best in terms of enantioselectivity.
incarcerated (PI) strategy, in which polystyrene derivatives with Next, we investigated the solvent system using phenyl boronic
crossꢀlinking moieties (Figure 1a) are used to immobilize metal acid (2b) as the substrate (Table 2). Phenyl boronic acid (2b
)
nanoparticles. 44ꢀ48 The metal nanoparticles are stabilized with gave a higher yield under the same reaction conditions of Table
weak, but multiple interactions of benzene rings in the polymer 1, entry 3, obtaining an excellent yield (entry 1). When a 1:1
and physical envelopment.49 Chirally modified rhodiumꢀbased ratio of toluene and water maintaining the same concentration
metal nanoparticle systems thus developed can be applied to was employed, the yield was improved slightly (entry 2).
asymmetric 1,4ꢀaddition reactions of aryl boronic acids with Finally, an almost quantitative yield was obtained under twiceꢀ
α
,
β
ꢀunsaturated carbonyl compounds, such as ketones, esters diluted conditions in a 1:1 ratio of toluene and water solvents
and amides. In addition, we have newly developed a chiral even in the presence of 0.1 mol% of the rhodium source under
diene ligand, including secondary amide moiety with almost neutral conditions (entry 3). Remarkably, additives such
a
bifunctionality, interacting with a metal nanoparticle through a as bases were not required in this catalytic system, while
diene moiety and activating a substrate by hydrogen bonding previously developed metal complex systems for asymmetric
(ligand 4c in Figure 1b).45, 50 In the course of these studies, we 1,4ꢀaddition reactions of aryl boronic acids with nitroalkenes
obtained insight into the reaction mechanism of chirally required either basic conditions or higher metal loadings of
modified metal nanoparticle systems, in which active species in more than 3 mol%.2ꢀ6, 9ꢀ12 The rhodium complex of ligand 4c
heterogeneous systems are different from those in would provide an ideal chiral reaction environment for this
corresponding homogeneous systems, and a direct interaction enantioselective transformation.
(a) Copolymer with cross-linking moieties for immobilization
between the chiral ligand and metal nanoparticle surface was
proven.45, 51
x
y
z
x:y:z = 1:1:1
In the present article, we report development of asymmetric
OH
O
O
O
1,4ꢀaddition reactions of aryl boronic acids with nitroalkenes
with a high catalytic turnover and excellent enantioselectivity
using both homogeneous metal complex and heterogeneous
metal nanoparticle systems of chiral diene ligand 4c without
any additives, such as KOH and KHF2. This is the first
heterogeneous system for this asymmetric transformation, and
we have also found various insights into the reaction
mechanism, especially which is different to asymmetric 1,4ꢀ
4
under heating conditions
(b) Ligands
O
O
O
4a: R = 2-naphthyl
4b: R = tBu
4c:
4d:
OR
N
H
N
Me
Figure 1. Copolymer for immobilization and chiral dienes
Table 1. Effect of chiral dienes
addition reactions with α,βꢀunsaturated carbonyl compounds.
Ar
[Rh(C2H4)2Cl]2 (Rh: 0.10 mol%)
diene (0.11 mol%)
NO2
Results and Discussion
Ph
NO2
3aa
Ph
1a
(3-OMe)C6H4B(OH)2 2a (1.5 equiv)
Development of homogeneous reaction systems
toluene:H2O (2:1), 100 °C, Ar, 16 h
Entry
Diene
4a
Yield (%)
ee (%)[a]
A family of chiral dienes with bicyclo[2,2,2]hexadiene
structure were developed independently by Hayashi et al. and
Carreira et al. They have been widely used for transition metalꢀ
catalyzed asymmetric reactions, particularly Rhꢀcatalyzed
asymmetric 1,4ꢀadditionꢀtype reactions.52ꢀ55 We previously
designed and developed chiral diene ligands containing
secondary amide functionality as highly efficient and selective
1
2
3
4
88
71
62
92
71
81
90
7
4b
4c
4d
[a] As determined by HPLC.
bifunctional ligands for asymmetric 1,4ꢀadditions of
α,βꢀ
unsaturated carbonyl compounds in both homogeneous and
heterogeneous systems.45 In this context, we initiated an
investigation of the asymmetric 1,4ꢀaddition reaction of 3ꢀ
2 | J. Name., 2012, 00, 1-3
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desired products in high yields with high enantioselectivities
(entries 15). In these nitroalkenes, bromoꢀsubstituted
Table 2. Optimization of solvent ratio in a homogeneous system
8
–
Ph
[Rh(C2H4)2Cl]2 (Rh: 0.10 mol%)
NO2
nitroalkene could be used to afford the 1,4ꢀadducts in 98%
yield with 90% ee with tolerance of a bromine atom (entries 13
and 14). Twice the amount of chiral rhodium complex could
afford the products in high yields with high enantioselectivities
using heteroaromatic moieties including nitroalkenes (entries
Ar
4c (0.11 mol%)
NO2
3bb
Ar
1b
PhB(OH)2 2b (1.5 equiv)
toluene:H2O, 100 °C, Ar, 16 h
Ar = (4-MeO)C6H4
Entry
Toluene:water for
Yield (%)
ee (%)[a]
0.3 mmol 1b (ꢀL)
750:375
1
2
3
91
93
98
93
93
94
17
reactions proceeded smoothly to afford the products in high
yields with high enantioselectivities (entries 21 24). In the case
of ꢀbutylꢀsubstituted nitroalkene, both yield and
–20). When aliphatic nitroalkenes were examined, the
562:562
1000:1000
–
[a] As determined by HPLC.
n
enantioselectivity were slightly reduced. However, moderate
yields of the desired products were observed and then ee values
were high (entries 25 and 26). We note that no additives were
required for any of these substrates.
Table 3. Substrate scope in the homogeneous system
Ar
[Rh(C2H4)2Cl]2 (Rh: 0.10 mol%)
Discussion of proposed reaction mechanism
NO2
R
4c (0.11 mol%)
NO2
R
1
The assumed catalytic cycle of the asymmetric 1,4ꢀaddition
reactions of arylboronic acids with nitroalkenes is shown in
Figure 2.2
ArB(OH)2 2 (1.5 equiv)
3
toluene:H2O (1:1), 100 °C, Ar, 16 h
Entry
R
Ar
Product
Yield
(%)
ee
(%)
The induction of chirality occurs during the step where the
aryl group is added to the
from the viewpoint of the formation of the chirality in the
product. However, some of the enantioselectivity is determined
β position of nitroalkene (III→IV)
1
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
(3-MeO)C6H4
(4-MeO)C6H4
(4-Cl)C6H4
(4-F)C6H4
(4-Me)C6H4
(2-MeO)C6H4
(2-Me)C6H4
Ph
3aa
3ac
3ad
3ae
3af
3ag
3ah
3cb
3bb
3ba
3db
3ea
3fb
3fa
99
95
87
82
92
88
83
97
98
99
93
94
98
98
96
90
92
88
92
96
89
96
86
80
78
66
91
84
94
94
86
>99
99
92
94
95
91
93
88
90
89
91
94
95
93
94
90
90
90
91
84
86
3
4
in the previous step (II→III); that is, the approach direction of
5
6[b]
nitroalkenes to the rhodium aryl complex II and the stability of
the intermediate III are critical for stereocontrol of the desired
product. A comparison of the yields and the enantioselectivities
7
8
(3-MeO)C6H4
(4-MeO)C6H4
(4-MeO)C6H4
(4-Me)C6H4
(4-Me)C6H4
(4-Br)C6H4
(4-Br)C6H4
(4-F)C6H4
(4-F)C6H4
3-Furyl
using ligands 4b
in Table 1. For comparison, the results of the asymmetric 1,4ꢀ
addition reaction of an arylboronic acid with an ꢀunsaturated
, 4c, and 4d in homogeneous systems is shown
9
Ph
10
11
12
13
14
15
16
17[c]
18[c]
19[c]
20[c]
21
22[c]
23[c]
24[d]
25[c]
26[d]
(3-MeO)C6H4
Ph
α,β
ester in homogeneous systems depending on chiral dienes are
shown in Table 4.45
(3-MeO)C6H4
Ph
OMe
B(OH)2
(3-MeO)C6H4
Ph
3gb
3ga
3hb
3ha
3ib
NO2
OMe
(3-MeO)C6H4
Ph
L
Rh-X
*
L
3-Furyl
(3-MeO)C6H4
Ph
(X = Cl, OH)
I
2-Thienyl
2-Thienyl
Cyclohexyl
Cyclohexyl
i-Pr
B(OH)2X
OMe
H2O
*
(3-MeO)C6H4
Ph
3ia
3jb
L
O
(3-MeO)C6H4
Ph
3ja
L
L
Rh
Rh
3kb
3ka
3lb
N
*
L
O
II
i-Pr
(3-MeO)C6H4
Ph
MeO
n-Bu
NO2
n-Bu
(3-MeO)C6H4
3la
*
IV
[a] As determined by HPLC. [b] 0.25 mol% of [Rh(C2H4)2Cl]2 and 0.55 mol% of the
chiral diene. [c] 0.1 mol% of [Rh(C2H4)2Cl]2 and 0.22 mol% of the chiral diene. [d]
0.15 mol% of [Rh(C2H4)2Cl]2 and 0.33 mol% of the chiral diene.
L
L
NO2
Rh
MeO
Various combinations of nitroalkenes and arylboronic acids
were examined under optimal conditions. In almost all cases,
the products were obtained in more than 90% yield with high
enantioselectivities. Electronꢀrich and ꢀdeficient arylboronic
III
Figure 2. The assumed catalytic cycle
In the case of an asymmetric 1,4ꢀaddition reaction of a
nitroalkene, good to high yields of the desired product were
obtained, while the enantioselectivities of the desired product
were extremely diverse (Table 1). In the case of chiral diene 4b
acids could be used (Table 3, entries 1–7). Orthoꢀsubstituted
arylboronic acids afforded 1,4ꢀadducts with excellent
enantioselectivities (entries 6 and 7). Alternatively, electronꢀ
rich and ꢀdeficient nitroalkenes could be used to give the
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bearing a tertiary butyl ester, the desired product was obtained
By contrast, improvement of the yield was not observed by
with 81% ee (Table 1, entry 2), and the enantioselectivity was the introduction of a secondary amide moiety in the ligand,
90% ee when a chiral diene 4c bearing tertiary butyl amide was unlike the case of the 1,4ꢀaddition to an
α
,β
ꢀunsaturated ester.
used (entry 3). When a ligand lacking a proton on the nitrogen In the case of the 1,4ꢀaddition to an
α,βꢀunsaturated ester,
atom of the amide moiety, chiral diene 4d, was used, the either the approach of the ester to a rhodium aryl complex or
enantioselectivity was dramatically reduced (entry 4). These the 1,4ꢀaddition step is the rateꢀdetermining step and the
results suggest the importance of the presence of an amide secondary amide moiety in the ligand 4c might accelerate these
proton for the enantioselectivities.
By contrast, in the case of the asymmetric 1,4ꢀaddition kinetic behavior (for example, a rateꢀdetermining step) between
reaction of an ꢀunsaturated ester (Table 4), the presence of the case of a nitroalkene and the case of an ꢀunsaturated
steps.43 This difference suggests that there is a variation in
α
,
β
α,β
the proton on the secondary amide notably affects both the ester.
yields and the enantioselectivities (entry 2). It was suggested
Table 4. Comparison of chiral dienes in asymmetric 1,4-addition to an ester
that the amide proton of 4c not only participated in the
stabilization of the ester substrate on the rhodium center
through hydrogen bonding, but also accelerated the 1,4ꢀaddition
step (or both) by its Brønsted acidity.45 Following our
development, similar bifunctional role of diene ligands
containing secondary amide moiety in asymmetric 1,4ꢀaddition
reactions was discussed.9 Similarly, the amide proton in ligand
4c might participate in the rigid fixation of a nitroalkene to
realize high stereoselectivity, stabilizing key intermediate III
more than in the case without hydrogen bonding. Several
assumed transition state models of both desired and undesired
intermediates III with three different ligands are shown in
Figure 3.
entry
diene
4b
yield (%)
ee (%)[b]
94
1
2
3
72
94
69
4c
98
4d
67
[a] As determined by 1H NMR. [b] As determined by HPLC.
In a previous report, it was postulated that hydrolysis of Rh
nitronate would be relatively slow.2 To investigate whether or
not this is true in our present catalytic system, reactions in
nondeuterated water and deuterated water were compared to
In asymmetric 1,4ꢀaddition reactions of arylboronic acids
with nitroalkenes, the major enantiomer formed via the desired
intermediate IIIb is shown in Figure 3. During the approach of
examine whether the protonation step (IV→I) was the rateꢀ
nitroalkenes to the rhodium aryl complex (II
there is a large steric repulsion between the nitro group and the
bulky part of the chiral diene (represented by a gray ball), the
→III), because
determining step (Table 5). If protonation is the rateꢀ
determining step, the initial rate of the reaction in deuterated
water should be slower than that in nondeuterated water
because of the kinetic isotope effect. The reactions were
conducted for 2 h in both cases and the yields and the ee values
of the desired product were examined. There was a clear kinetic
isotope effect, that is, the yield in nondeuterated water (Table 5,
entry 1) was much higher than that in deuterated water (entry
formation of the undesired intermediate (II
→
IIIa) is slower
IIIb). In
than the formation of the desired intermediate (II
→
addition, the stability of the intermediate IIIa may be lower
than that of the intermediates IIIb because of the steric
repulsion. The stereocontrol of the desired products derives
from both the kinetics of the process
thermodynamic stability of intermediate IIIb
(
II
.
→
III
) and
2), and this suggested protonation (IV
determining step. By contrast, in the case of the asymmetric
1,4ꢀaddition of an arylboronic acid to an ꢀunsaturated ester,
no difference in the yields between nondeuterated water and
deuterated water was observed (Scheme 1). From these results,
we concluded that the rateꢀdetermining step of the 1,4ꢀaddition
to a nitroalkene was different from that of the 1,4ꢀaddition to an
→I) as the rateꢀ
Next, the
structures of intermediates IIIb with different chiral dienes are
compared. In the case of chiral diene 4c bearing secondary
amide moiety, the nitroalkene would be fixed as shown by
IIIb-4c in Figure 3 via hydrogen bonding between the oxygens
of the nitro group and the proton of the amide. However, in the
case where the chiral diene 4b bears a tertiary butyl ester
moiety, there is no stabilization by hydrogen bonding.
Therefore, the stability of IIIb-4b could be lower than that of
IIIb-4c, thus resulting in the difference in enantioselectivity. In
the case of the chiral diene 4d bearing tertiary amide moiety,
there is also no stabilization by hydrogen bonding. In addition,
there appears to be steric repulsion between the nitro group and
the methyl group on the amide nitrogen (IIIb-4d). Because of
these factors, the dramatic drop of the enantioselectivity with
chiral diene 4d might be rationalized. That is, in the series of
α,β
α
,
β
ꢀunsaturated ester.
Under conditions with a smaller proportion of water, that is,
a 2:1 ratio of toluene:water, the reaction was much slower than
that in a 1:1 ratio of toluene:water (Table 5, entry 1 [2 h; 74%
yield] vs Table 6, entry 3 [16 h; 62% yield]), probably because
of slower protonation as a result of the lower availability of
water. When we screened additives to enhance the reaction, we
found that adding 0.5 mol% dimethylurea notably accelerated
the reaction under these conditions. The chiral diene bearing
ester moiety 4b, bearing secondary amide moiety 4c, and
bearing tertiary amide moiety 4d were used as ligands and the
effect of dimethylurea is summarized in Table 6. When the
reactions were conducted without dimethylurea (Table 6,
stereoselective pathways (II
→III and stability of III), the
amide proton of chiral diene 4c plays an important role to
achieve excellent enantioselectivities.
entries 1, 3, and 5, as in Table 1, entries 2–4), the yield was
4 | J. Name., 2012, 00, 1-3
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Figure 3. Assumed stereoselective models for intermediate III
lower (1a was remained.) using chiral diene 4c than using
chiral dienes 4b and 4d. When we focus on the rateꢀ
determining step IV, these results may be understood as a
stabilizing effect of the rhodium nitronate intermediate by the
amide proton of chiral diene 4c, which makes the catalytic
regenerations slow. The yields of the desired product were
improved around 20% in the presence of dimethylurea, when
either chiral diene 4b or 4c were used (entries 1 vs. 2 and
entries 3 vs. 4). The enantioselectivities of the desired product
were not associated with the presence of dimethylurea, and they
depend on the structure of chiral dienes in these cases. These
results suggest that dimethylurea affects only the rateꢀ
By contrast, when ligand 4d with its tertiary amide moiety
was used, very high yield was obtained regardless of the
addition of dimethylurea, while enantioselectivities were
extremely poor (Table 6, entries 5 vs. 6). In these cases, an
intermediate before catalyst regeneration step IV might be
already be destabilized by a steric effect of the bulky tertiary
amide moiety, and thus the protonation step (IV
→
I
in Figure 2)
would be sufficiently fast.
Table 5. Reactions in nondeuterated and deuterated water
[Rh(C2H4)2Cl]2 (Rh: 0.10 mol%)
Ar
determining catalytic regeneration step (IV
→I), which is
NO2
4c (0.11 mol%)
Ph
NO2
separated from the chiralꢀinducing step. Based on these
findings, we propose the possible transition states of the
protonation, in which the amide proton of ligand 4c stabilizes
the rhodium nitronate intermediate (Figure 4a) and
dimethylurea accelerates protonation of this intermediate
(Figure 4b, 4c). The role of dimethylurea in accelerating the
regeneration of the catalyst is expected to attract a water
molecule through hydrogenꢀbonding networks near the
intermediate (Figure 4b). Another possible role of dimethylurea
is to perturb the stabilizing effect of the amide proton by a
steric repulsion between the ligand and dimethylurea
interacting with the nitro group (Figure 4c). In both cases,
newly formed hydrogen bonding between the nitro group and
dimethylurea might weaken the existing hydrogen bonding to
the secondary amide proton in ligand 4c and the regeneration of
the catalyst might be facilitated. We note that no acceleration of
the reaction with the addition of dimethylurea was observed
under the optimized conditions (in which toluene:water = 1:1),
probably because the protonation was so fast that the effect of
dimethylurea became undetectable in the presence of sufficient
water (see SI). In other words, our catalytic system involving
diene ligand 4c with the secondary amide moiety possesses
sufficiently high performance to achieve high catalytic turnover
up to 1000 in the presence of sufficient water, even without any
additives, while previously reported rhodiumꢀcatalyzed 1,4ꢀ
addition reaction of aryl boronic acid with nitroalkenes required
such additives to realize efficient catalytic turnover.2ꢀ6, 9ꢀ11
toluene:water (1:1), 100 °C, Ar, 2 h
Ph
1a
3aa
(3-OMe)C6H4B(OH)2 2a (1.5 equiv)
Entry
Water
H2O
Yield (%)
74
ee (%)
90
1
2
D2O
29
90
Scheme 1. Reactions in nondeuterated and deuterated water in the case of
esters
Table 6. Effect of dimethylurea
[Rh(C2H4)2Cl]2 (Rh: 0.10 mol%)
4 (0.11 mol%)
dimethylurea (X mol%)
Ar
NO2
Ph
NO2
3aa
ee (%)
toluene:water (2:1), 100 °C, Ar, 16 h
Ph
1a
(3-OMe)C6H4B(OH)2 2a (1.5 equiv)
Entry
Chiral diene
X (mol%)
Yield (%)
71
1
2
3
4
5
6
4b
4b
4c
4c
4d
4d
0
0.5
0
81
81
90
90
7
88
62
0.5
0
85
91
0.5
92
7
[a] As determined by 1H NMR analysis. Isolated yield in parentheses.
O
Rh
MeO
O
N
X
O
-
O
Rh
+
N
IIIa
IIIb-4c
IIIb-4d
undesired
O
more
stabilization
-
H
MeO
O
O
N
+
N
Rh
MeO
O
Figure 4. Assumed role of dimethylurea in the protonation step (IV
→I)
from this angle
desired with
chiral diene 4c
Development of heterogeneous metal nanoparticle systems
less
stabilization
-
Me
-
O
O
O
O
N
N
O
We next investigated heterogeneous chiral metal
nanoparticle systems for the asymmetric 1,4ꢀaddition of aryl
boronic acids to nitroalkenes. We initiated the study using PI
metal nanoparticle catalysts containing rhodium and silver
bimetallic nanoparticles with different ratios, PI/CB Rh/Ag
+
+
N
O
Rh
Rh
MeO
MeO
O
desired with
desired with
chiral diene 4b
IIIb-4b
chiral diene 4d
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(Table 7).44ꢀ49 The role of silver in the bimetallic nanoparticles example, providing a hydrogenꢀbonding network with water
was found to produce small nanoparticles with good molecules through ether and alcoholic moieties in polymer side
dispersibility in the polymer support.45 We used 1 mol% of Rh chains, and resulting in smooth catalyst regeneration even with
in the heterogeneous catalysts with 0.1 mol% of ligand 4c
,
a smaller proportion of water compared with the homogeneous
because Rh atoms that make up the core of the nanoparticles system.
would not participate in catalysis. When the Rh nanoparticle
Table 8. Effect of the proportion of toluene
catalyst was used under the optimized reaction conditions for
homogeneous catalyst systems, a high yield and excellent
enantioselectivity were observed (entry 1). When the ratio of
silver increased from 2:1 to 1:1, yields were slightly improved
maintaining excellent enantioselectivity (entries 2 and 3).
Further increasing the proportion of silver in the heterogeneous
catalysts resulted in decreased activity (entries 4 and 5). We
considered the heterogeneous catalyst containing a 1:1 ratio of
rhodium and silver as optimized. However, in all cases, a small
amount of rhodium leaching was observed, probably because of
the strong coordination ability of the nitro moiety in the
substrate and the product.
PI/CB Rh/Ag (1/1) (Rh: 1 mol%)
Ar
NO2
4c (0.1 mol%)
Ph
NO2
3aa
toluene:water, 100 °C, Ar, 24 h
Ph
1a
(3-OMe)C6H4B(OH)2 2a (1.5 equiv)
Entry
Ratio
Toluene:
water for
0.3 mmol 1a
(ꢀL)
Yield
(%)
ee
Leaching
(%)[b]
toluene:
water
(%)[
a]
1
2
3
4
5
6
1:2
1:1
1:1
2:1
2:1
5:1
250:500
10
64
86
89
89
90
87
90
90
91
92
92
6.17
2.88
500:500
1000:1000
1000:500
2000:1000
2000:400
2.63
2.09
BLD[c]
BLD[c]
Table 7. Effect of the ratio of Rh:Ag
PI/CB Rh/Ag (Rh: 1 mol%)
Ar
[a] As determined by HPLC. [b] As determined by ICP. [c] BLD = Below the limit of
detection. LD = 0.39%
NO2
4c (0.1 mol%)
Ph
NO2
3aa
toluene:water (1:1), 100 °C, Ar, 24 h
(3-OMe)C6H4B(OH)2 2a (1.5 equiv)
Ph
1a
Under optimized conditions, various combinations of
arylboronic acids and nitroalkenes were examined. The results
are shown in Table 9. Electronꢀrich and ꢀdeficient arylboronic
Entry
Rh:Ag
Yield (%)
ee (%)[a]
Leaching
(%)[b]
2.74
1
2
3
4
5
only Rh
2:1
80
84
86
72
78
90
90
90
90
90
acids were examined (Table 9, entries 1–7). Under the
3.01
optimized conditions, the desired product 3aa was obtained in
90% yield with 92% ee (entry 1); however, other arylboronic
acids afforded the desired products in around 60% yields. A
prolonged reaction time (48 h) afforded the desired products in
1:1
2.63
1:2
3.31
1:3
2.48
[a]
As
determined
by
HPLC. [b]
As
determined
by
ICP.
moderateꢀtoꢀhigh
yields
while
maintaining
high
enantioselectivities (entries
2
–5). In the cases of orthoꢀ
substituted arylboronic acids, the desired products were
obtained with excellent enantioselectivities as observed in the
homogeneous system (entries 6 and 7). In the case of
oꢀ
methoxyphenylboronic acid, 5 mol% of the catalyst and 0.5
mol% of the chiral diene 4c gave only a 36% yield of the
desired product (entry 6). Steric hindrance of the methoxy
group at the orthoꢀposition might make the reaction slower.
Electronꢀrich and ꢀdeficient nitroalkenes were then examined
To suppress rhodium leaching and improve yield, we
(entries 8–15). When phenylboronic acid was used, the desired
investigated solvent systems (Table 8). When concentrated
conditions were employed, the yield decreased and the amount
of leaching increased (entries 2 vs. 3). When the proportion of
toluene was reduced to 1:2, the yield of the product was low,
and a significant amount of rhodium leached out (entry 1).
These results indicate that the heterogeneous catalyst system is
very sensitive to the organic solvent concentration. We
continued careful investigations and decreased the proportion
of water (entry 4), and it was found that diluted conditions
improved both activity and suppressed leaching (entries 4 and
5). Further decreasing of the proportion of water while
maintaining the concentration of toluene (5:1 = toluene:water)
resulted in an excellent yield without rhodium leaching, while
maintaining excellent enantioselectivity as optimized
conditions (entry 6). The amphiphilic nature of the polymer
support might help protonation of rhodium nitronate, for
products were obtained in moderate yields. The reactions were
conducted for prolonged times and the desired products could
be obtained in high yields with high enantioselectivities (entries
8, 9, 12, and 14). In the case of 3ꢀmethoxyphenylboronic acids,
the optimal conditions gave the desired products in high yields
with high enantioselectivities (entries 10, 11, 13, and 15).
Nitroalkenes bearing heteroaromatic moieties also gave the 1,4ꢀ
adducts
in
moderateꢀtoꢀhigh
yields
with
high
enantioselectivities by increasing the loading of the catalyst and
chiral diene 4c (entries 16 and 17). While a sulfur atom can
usually coordinate to metal nanoparticles and might poison the
catalyst, the reaction could be applied to a thienylꢀsubstituted
nitroalkene (entry 17). Next, aliphatic nitroalkenes were
examined. When a cyclohexylꢀsubstituted nitroalkene was used,
the desired product was obtained in 71% yield with 91% ee
6 | J. Name., 2012, 00, 1-3
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washed with
EtOAc, H2O,
acetone
under the optimal conditions (entry 18). In the case of an
isopropylꢀsubstituted nitroalkene, 2 mol% of the catalyst and
0.2 mol% of chiral diene 4c afforded the desired product in
washing
dry in vacuo
filter
reaction
next reaction
on funnel
THF/HCl aq.
70% yield with 90% ee (entry 19). However, in the case of nꢀ
Scheme 2. Method of catalyst recovery
butylꢀsubstituted nitroalkene, the desired product was obtained
in only 25% yield. To improve the yield, we tried prolonging
the reaction time and increasing the catalyst loading; however,
these trials showed no improvement of the yield.
To confirm whether the catalysis proceeds within the solid
phase over the entire period of a reaction, a hot filtration test
was conducted, and no leaching of metals into the final product
was confirmed by ICP. Under optimized conditions, PI/CB
Rh/Ag was removed by filtration at the stage of a 50%
conversion ratio, while maintaining a high reaction temperature
(Figure 5). The reaction in the filtrate after removal of the
catalyst was allowed to continue, but the yield of the product
did not increase any further. This finding clearly demonstrates
that the heterogeneous catalyst was responsible for the reaction.
Table 9. Substrate scope in a heterogeneous system
Ar
PI/CB Rh/Ag (1/1) (Rh: 1 mol%)
NO2
4c (0.1 mol%)
R
NO2
R
1
ArB(OH)2 2 (1.5 equiv)
toluene:H2O (5:1), 100 °C, Ar, 24 h
3
Entry
R
Ar
Product
Yield
(%)
90
73
75
71
90
36
71
96
93
93
89
90
88
87
95
60
88
71
70
25
ee
(%)
92
84
95
94
85
>99
99
92
94
95
93
88
90
89
91
94
94
91
90
85
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
(3-MeO)C6H4
(4-MeO)C6H4
(4-Cl)C6H4
(4-F)C6H4
3aa
3ac
3ad
3ae
3af
3ag
3ah
3cb
3bb
3ba
3ea
3fb
3fa
w/o filtration
filtration at 5 h
2[b]
3[b]
4[b]
5[b]
6[c]
100
90
80
70
60
50
40
30
20
10
0
(4-Me)C6H4
(2-MeO)C6H4
(2-Me)C6H4
Ph
7[b]
8[b]
9[b]
10
(3-MeO)C6H4
(4-MeO)C6H4
(4-MeO)C6H4
(4-Me)C6H4
(4-Br)C6H4
(4-Br)C6H4
(4-F)C6H4
(4-F)C6H4
3-Furyl
Ph
(3-MeO)C6H4
(3-MeO)C6H4
Ph
11
12[b]
13
(3-MeO)C6H4
Ph
14[b]
15
3gb
3ga
3ha
3ia
(3-MeO)C6H4
(3-MeO)C6H4
(3-MeO)C6H4
(3-MeO)C6H4
(3-MeO)C6H4
(3-MeO)C6H4
0
5
10
time (h)
15
20
16[d]
17[e]
18
Figure 5. Hot leaching test (yields were determined by GC using an internal
standard)
2-Thienyl
Cyclohexyl
i-Pr
3ja
19[e]
3ka
3la
The reaction profiles of homogeneous and heterogeneous
catalyst systems were compared (Figure 6). Although the
reaction proceeded smoothly without an induction period in the
case of a homogeneous system, a clear induction period of
around 1 h was observed in the heterogeneous catalyst system.
After the induction period, the yield increased constantly in the
heterogeneous system. In our previous investigation, a similar
induction period was observed for the 1,4ꢀaddition reaction of
an enoate, and it disappeared with preheating with aryl boronic
acid and some reductants.45 In the case of the nitrostyrene 1a, a
similar phenomenon, reducing the induction period, was
effected by preheating with an aryl boronic acid, probably
because of a redox process between the phenyl boronic acid 2a
and metal nanoparticles to generate biphenyl or phenol that
were often observed as small amount of byꢀproduct under
optimized conditions (Figure 7). Generation of an active
species and shortening the induction period by redox processes
were also reported for metal nanoparticle catalysis.56ꢀ58 In order
to understand the nature of the active species further, we
additionally examined several reaction profiles; 1) Monitoring
the reaction profile of recovered catalysts during recovery and
reuse, and 2) Monitoring the profile of the collected catalysts
after a hot filtration test (ESI Figures 7ꢀ9). Monitoring of the
recovered catalyst was conducted under the same reaction
20
n-Bu
[a] As determined by HPLC. [b] 48 h. [c] 5 mol% of PI/CB Rh/Ag and 0.5 mol% of
the chiral diene 4c. [d] 3 mol% of PI/CB Rh/Ag and 0.3 mol% of the chiral diene
4c. [e] 2 mol% of PI/CB Rh/Ag and 0.2 mol% of the chiral diene 4c.
We investigated the recovery and reuse of the PI/CBꢀRh/Ag
catalyst in the asymmetric 1,4ꢀaddition reaction of boronic acid
2a with nitrostyrene 1a. We found that a simple recovery
method including a wash with an acidic solution was effective
for maintaining the high activity of the recovered catalyst
(scheme 2), and the catalytic activity was slightly decreased but
almost maintained for at least five uses without changing the
enantioselectivity (Table 10).
Table 10. Method of catalyst recovery
PI/CB Rh/Ag (1/1) (Rh: 1 mol%)
Ar
NO2
4c (0.1 mol%)
Ph
NO2
3aa
toluene:water (5:1), 100 °C, Ar, 24 h
(3-OMe)C6H4B(OH)2 2a (1.5 equiv)
Ph
1a
Run
1st
93
91
2nd
92
91
3rd
86
92
4th
82
92
5th
75
92
Yield (%)
ee (%)[a]
4c was added in every run. [a] As determined by HPLC.
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conditions as Table 10 (ESI Figure 7). An induction period of
the 2nd run was slightly prolonged and the reaction rate at
steady state was also slightly slower than that of the 1st run. In
the 3rd run, a slower reaction rate at steady state was observed;
however, the desired product was obtained in 85% yield after
24 h. In contrast, the collected catalyst after a hot filtration at 4
h showed almost the same reaction profile as that of the fresh
catalyst during 24 h of reaction time with a similar induction
period (Figure 8). The catalyst was recovered and the reaction
profile was monitored; however, a slower reaction rate than that
of the previous run was observed. The collected catalyst after a
hot filtration at 6 h also gave a similar reaction profile as the 1st
run (ESI Figure 9). The catalyst was again filtered under heated
conditions at 6 h and the next run showed almost a similar
reaction rate. According to the reaction profile of the fresh
catalyst, the reaction rate slowed down after 10 h. We expected
that irreversible deactivation of the catalyst partially occurred
during this period and such deactivated species might not be
activated even an induction period of the next run. On the other
hand, the collected catalyst by a hot filtration at steady state,
where the reaction proceeded at constant rate, showed almost
the same reaction profile including an induction period as the
fresh catalyst. This result indicated that active species could not
be maintained during the filtration process, but returned to
initial potentially active species, which required activation in
the induction period in the next run. Notably, no irreversible
deactivation of the catalyst might proceed during this steady
state. To clarify difference among these catalysts, XPS analyses
of the fresh catalyst, the catalyst after recovery and reuse, the
catalyst collected by a hot filtration during an induction period
(at 1 h) and the catalyst collected by a hot filtration during
steady state (at 5 h) were conducted (ESI Figures 10 and 11).
Both silver and rhodium species were analysed and the peaks of
both rhodium and silver gradually shifted to lower energy
values as the catalyst was used for a longer time. Especially, the
catalyst after recovery and reuse showed the significant peak
shifts. Based on these results, we assumed further reduction of
active species at latter stage of the reaction (after 10 h) to
generate further reduced irreversibly deactivated species. On
the other hand, such deactivation did not proceed during steady
state and active species returned to almost the same metal
species as the fresh catalyst during a recovery process even
when mixtures were filtered under hot filtration conditions.
heterogeneous
homogeneous
100
80
60
40
20
0
0
2
4
time (h)
6
8
Figure 6. Comparison of reaction plots between homogeneous and
heterogeneous catalyst systems
PI/CB Rh/Ag (1/1) (Rh: 1 mol%)
Ar
NO2
4c (0.1 mol%)
Ph
NO2
3aa
toluene:water (5:1), 100 °C, Ar
(3-OMe)C6H4B(OH)2 2a (1.5 equiv)
Ph
1a
Product
Product (pre-heating)
100
80
60
40
20
0
0
1
2
time (h)
3
4
5
Figure 7. Effect of pre-treatment
To understand the similarities and differences between
active species in homogeneous and heterogeneous systems, a
nonlinear effect analysis was conducted for both reaction
systems. Almost linear relationships between the enantiomeric
excess of the ligand and the product were observed in both
reaction systems (Figure 8). This is in clear contrast to the case
of the 1,4ꢀaddition reaction of an enoate in our previous
investigation, in which only a heterogeneous system showed a
positive nonlinear effect.45
PI/CB Rh/Ag (1/1) (Rh: 1 mol%)
Ar
NO2
4c (0.1 mol%)
Ph
NO2
3aa
toluene:water (5:1), 100 °C, Ar
(3-OMe)C6H4B(OH)2 2a (1.5 equiv)
Ph
1a
8 | J. Name., 2012, 00, 1-3
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metal complexes or on very small nanoclusters within the
polymer phase, may be more likely than catalysis (a). In this
case, metal complexes or nanoclusters depart from large
nanoparticles to form active species through redox events that
result in the induction period, and ligand 4c coordinates to these
active species to provide an efficient chiral reaction
environment for asymmetric catalysis. However, the possibility
of catalysis (a) cannot be excluded completely.
heterogeneous
homogeneous
100
80
60
40
20
0
0
20
40
60
80
100
ee of ligand (%)
Figure 8. Nonlinear effect
As a similarity of homogeneous and heterogeneous systems,
the enantioselectivities of the desired product are discussed in
addition to nonlinear effect analysis. In the substrate scopes
examined in homogeneous (Table 3) and heterogeneous (Table
9) systems, the differences in the enantioselectivities of the
desired product from the same combination of the substrates
were within just 1%. These results suggest that reaction
environments of the active species in homogeneous and
heterogeneous systems were almost identical.
The possible catalytic systems explaining how the reaction
occurs on metal nanoparticles catalysis were proposed by
Ananikov and Beletskaya in 201259 and discussed in progress.27
Based on these reports, we propose three possibilities (Figure
9). (a) The reaction proceeds on the surface of the metal
nanoparticles that are partially activated by redox events
without the separation or departure of any atom. (b) Some
metal complexes or nanoclusters depart from the metal
nanoparticles as active species through redox events, but
remain near the metal nanoparticles. The reaction proceeds on
these complexes or nanoclusters, and then these complexes or
nanoclusters return to the metal nanoparticles. This cycle
proceeds within the reaction environment of the polymer phase.
(c) Some metal complexes leach from the nanoparticles through
redox events and the reaction proceeds on both these complexes
and the surface of the metal nanoparticles. The leached metal
complexes do not return to the metal nanoparticles or return
after completion of the reactions.
Figure 9. Possible catalytic systems
Conclusion
In summary, asymmetric 1,4ꢀaddition reactions of
arylboronic acids with nitroalkenes catalyzed by a rhodium
complex of the chiral diene 4c bearing a tertiary butyl amide
moiety were developed, and this complex is more efficient than
previously reported homogeneous catalyst systems. Just 0.1
mol% of the chiral rhodium complex could catalyze the
reactions and afford the desired products in high yields with
excellent enantioselectivities. There was no need for additives
in this catalysis and wide substrate scope was shown.
Mechanistic studies using deuterated water and dimethylurea as
an additive revealed the rateꢀlimiting step in the catalyst system
using the chiral diene 4c to be the protonation step, while
extremely high catalytic turnover was achieved by the
developed catalytic systems without any additives under
optimized conditions using an amount of water sufficient to
accelerate the regeneration step for this catalyst.
The developed homogeneous catalyst systems could be
converted to the heterogeneous metal nanoparticle systems,
maintaining completely the same level of enantioselectivities
with a wide substrate scope without any additives. To our
knowledge, this is the first example of asymmetric 1,4ꢀaddition
In heterogeneous chiral rhodium nanoparticleꢀcatalyzed
asymmetric 1,4ꢀaddition reactions of arylboronic acids with
nitroalkenes, rhodium leaching could be suppressed completely
under optimized conditions. In addition, a hot filtration test
clearly demonstrated the heterogeneity of the reaction
environment where actual catalysis occurred. Moreover, the
catalyst could be recovered and reused at least five times while
maintaining almost the same level of reactivity and excellent
enantioselectivity. From these results, the possibility of (c)
might be excluded.
reactions of arylboronic acids with nitroalkenes in
a
heterogeneous system. In this catalysis, 1 mol% of rhodium
nanoparticle catalyst and 0.1 mol% of chiral diene were
sufficient to obtain excellent enantioselectivities because of a
strong ligandꢀaccelerating effect. The heterogeneous catalyst,
PI/CB Rh/Ag, could be recovered and reused while maintaining
high enantioselectivity. Although several similarities between
homogeneous and heterogeneous systems were demonstrated,
we confirmed that the reaction proceeded within the
environment of the heterogeneous catalyst system by
mechanistic studies. In addition, the catalytic systems
developed here have completely different characters from the
catalytic systems developed for asymmetric 1,4ꢀaddition using
Considering the similarity of the outcomes of
enantioselectivities in homogeneous and heterogeneous systems
as discussed, catalysis (b), in which the reaction proceeds on
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25 D. Astruc, F. Lu and J. R. Aranzaes, Angew. Chem., Int. Ed.,
2005, 44, 7852-7872.
enoates previously reported by our group, in terms of both the
rateꢀlimiting step in the catalytic cycle, and similarities and
differences between homogeneous and heterogeneous systems.
26 H. Cong and J. A. Porco, Acs Catalysis, 2012,
27 T. Yasukawa, H. Miyamura and S. Kobayashi, ACS Catalysis,
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6
28 Y. Orito, S. Imai and S. Niwa, Nippon Kagaku Kaishi, 1979,
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This work was supported in part by a Grant-in-Aid for Science
Research from the Japan Society for the Promotion of Science
(JSPS), the Global COE Program, the University of Tokyo, the
Japan Science and Technology Agency (JST), and the Ministry
of Education, Culture, Sports, Science and Technology (MEXT,
Japan). We also thank Noriaki Kuramitsu (The University of
Tokyo) for STEM and EDS analysis.
34 F. Zaera, J. Phys. Chem. C, 2008, 112, 16196-16203.
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