Chiral Nanoparticles/Lewis Acids as Cooperative Catalysts for Asymmetric 1,4-Addition of Arylboronic Acids to α,β-Unsaturated Amides

Article abstract of DOI:10.1002/anie.201601559

Cooperative catalysts consisting of chiral Rh/Ag nanoparticles and Sc(OTf)₃have been developed that catalyze asymmetric 1,4-addition reactions of arylboronic acids with α,β-unsaturated amides efficiently. The reaction has been considered one of

Full text of DOI:10.1002/anie.201601559

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201601559
German Edition: DOI: 10.1002/ange.201601559
Asymmetric Catalysis
Chiral Nanoparticles/Lewis Acids as Cooperative Catalysts for
Asymmetric 1,4-Addition of Arylboronic Acids to a,b-Unsaturated
Amides
Tomohiro Yasukawa, Yuuki Saito, Hiroyuki Miyamura, and Sh u¯ Kobayashi*
Abstract: Cooperative catalysts consisting of chiral Rh/Ag
Consequently, reported examples required relatively high
loading (> 3 mol%) of unrecoverable homogeneous catalysts
and substrate generality was limited. Herein, we report the
use of chiral Rh NPs/Lewis acids as powerful heterogeneous
and recoverable catalysts for asymmetric 1,4-addition reac-
tions of arylboronic acids with a,b-unsaturated amides.
We selected N-benzyl crotonamide (1a) and phenylbor-
onic acid (2a) as model compounds, and several reaction
conditions were examined (Table 1). First, the reaction was
nanoparticles and Sc(OTf) have been developed that catalyze
3
asymmetric 1,4-addition reactions of arylboronic acids with
a,b-unsaturated amides efficiently. The reaction has been
considered one of the most challenging reactions because of the
low reactivity of the amide substrates. The new catalysts
provide the desired products with outstanding enantioselectiv-
ities (> 98% ee) in the presence of low loadings (< 0.5 mol%)
of the catalyst.
T
he development of efficient catalysts for asymmetric
Table 1: Optimization of reaction conditions of asymmetric 1,4-addition.
carbon–carbon bond (CÀC bond) formation is one of the
most important research themes in synthetic organic chemis-
try. We have focused on the use of metal nanoparticles (NPs)
as novel heterogeneous catalysts because they offer advan-
tages, such as ease of heterogenization, robustness, and
[1]
unique activity. The application of chiral ligand-modified
metal NPs (chiral metal NPs) in asymmetric catalysis is
particularly attractive. Indeed, the great potential of such
chiral catalysts as an alternative to conventional metal-
complex catalysts has been recognized. We have also used
polymer incarceration (PI) methods to construct several
achiral and chiral heterogeneous NP catalysts immobilized on
a nanocomposite of polystyrene-based copolymers with cross-
linking moieties and carbon black (PI/CB catalyst). Metal
NPs in PI/CB catalysts are stabilized by weak but multiple
interactions with polymer network, and cannot aggregate and
leach out, resulting in high catalytic activity and robustness.
Chiral amides constitute a class of key skeletons of
biologically active compounds. Aryl amides that bear
a chiral center at the b-position could be synthesized by
asymmetric 1,4-addition of arylboronic acids to a,b-unsatu-
rated amides. Early examples of such reactions using Rh
complexes as catalysts were reported by Hayashi and Miyaura
[
2]
[
a]
[b]
[c]
Entry Additive [mol%]
Yield [%]
ee [%]
Rh leaching [%]
1
2
3
4
5
6
7
–
37
42
74
79
98
97
96
99
98
97–99
98
ND
ND
ND
ND
–
K CO (10)
K
Sc(OTf) (1)
Cu(OTf) (1)
Other M(OTf) (1) 27–49
Sc(OTf) (1)
2
3
[3]
CO
(100)
2
3
3
63
2
[
[
e]
f]
[d]
–
ND
n
93
3
[4]
[a] Isolated yield. [b] Determined by HPLC analysis. [c] Determined by
ICP analysis (ND=not detected). The values express the percentage of
the total amount of Rh that was employed in the reaction. Detection limit
1
of Rh leaching was 0.3–0.4%. [d] Determined by H NMR analysis.
[e] M=Mg, Ca, Ba, La, Ce, Sm, Y, Yb. [f] Reaction time was 24 h and 4
(0.1 mol%) was used.
[5]
in 2001. Since then, tremendous progress in asymmetric 1,4-
addition reactions has been achieved over almost two
decades; however, surprisingly, there have been only a few
conducted with a chiral metal nanoparticle system consisting
[
6]
of Rh/Ag bimetallic NP catalyst prepared by our polymer
[
4a,7]
[9a]
examples of the reactions with a,b-unsaturated amides.
incarceration methods (PI/CB Rh/Ag)
and secondary
These reactions are challenging because of the low reactivity
of amide substrates caused by higher LUMO energy com-
pared with those of the corresponding ketones and esters.
amide substituted chiral diene 4 under the best conditions
for asymmetric 1,4-addition to a,b-unsaturated esters.
Under these conditions, the desired product was obtained in
low yield, although excellent enantioselectivity was obtained
[
9b]
[8]
(
Table 1, entry 1). Addition of a base improved the yield;
[
*] Dr. T. Yasukawa, Y. Saito, Dr. H. Miyamura, Prof. Dr. S. Kobayashi
Department of Chemistry, School of Science
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
however, a stoichiometric amount of base was necessary and
the enantioselectivity decreased slightly (entries 2 and 3).
Given that these unsatisfactory results were clearly ascribed
to the low reactivity of the amide substrate, we then
considered methods to activate the a,b-unsaturated amide
by using a second catalyst.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201601559.
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When two or more catalysts are applied together to
Table 2: Substrate scope.
a reaction system, the catalytic performance is sometimes
enhanced by a synergistic effect to give a better result. This
strategy has been explored for several combinations of
[10]
catalysts such as metal complexes and non-metal catalysts.
In contrast, this approach has been less well explored for
[
11]
metal NP catalysts, probably because these catalysts are
[
12]
1
2
[a]
[b]
often incompatible with other catalysts. To our knowledge,
there had been no example of synergistic effects between
chiral NP catalysts and other types of catalyst. Quite recently,
our group reported a synergistic effect between Au/Pd
bimetallic NP catalysts and metal Lewis acid catalysts for
Entry R , R
Ar
3
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
CH , H (1a)
CH , H
CH , H
CH
CH , H
CH , H
CH , H
CH , H
CH , H (1b)
C H , H (1c) Ph
(4-Me)C
1d)
Ph
3aa 93
3ab 88
3ac 85
3ad 90
3ae 85
98
3
[
[
c]
(2-OMe)C H
(3-OMe)C H
(4-OMe)C
(3-Me)C H
(4-Me)C H
(4-Cl)C H
(4-F)C H
Ph
>99.5
98
3
6
4
4
4
d]
[e]
3
6
[e,f]
, H
H
98
99
98
99
98
98
99
99
3
6
[13]
hydrogen autotransfer processes. From these findings, we
envisioned that cooperative catalyst systems of chiral metal
NP catalysts and metal Lewis acids may give a new oppor-
tunity to develop highly active asymmetric catalysis.
3
6
4
3af
84
3
6
4
[
d]
3ag 77
3ah 81
3ba 61
3ca 88
3da 69
3
6
4
[d]
[g]
3
6
4
[h]
3
n
[e]
[e]
We then examined the use of metal Lewis acid cocatalysts
to activate the amide substrate. After screening several Lewis
10
11
5
11
[
[
[
d]
i]
H
4
, H Ph
6
(
acids, it was found that Sc(OTf) gave the best result (Table 1,
3
i
[e]
12
13
14
15
C H , H (1e)
Ph
Ph
(4-F)C H
3ea 72
3 fa
3 fh 72
3ga 35
99
99
99
99
3
7
entries 4–6); when 1 mol% Sc(OTf) was employed, the yield
3
[
e]
-(CH ) - (1 f)
-(CH ) -
-(CH ) - (1g)
56
2
2
improved dramatically (entry 4). It is remarkable that chiral
d]
2
2
6
4
NPs were compatible with Sc(OTf) and a synergistic effect
[d,j]
[e]
3
Ph
2
1
was found to enhance the catalytic performance significantly.
This is in marked contrast to the fact that acidic additives
sometimes inhibit these types of reactions using Rh-BINAP
[
1
a] Isolated yield. [b] Determined by HPLC analysis. [c] PI/CB Rh/Ag (Rh:
mol%) and 4 (0.4 mol%) were used. [d] PI/CB Rh/Ag (Rh: 0.5 mol%)
1
and 4 (0.2 mol%) were used. [e] Calculated by H NMR analysis after
isolation of the mixture of the product and the starting material.
[f] 1.07m. [g] Toluene/H O=3:1 and 0.36 m. [h] Crotonamide (1b) was
used. [i] 1.6 m. [j] Toluene/H O=2:1 and 0.4m. The concentrations were
2
[5b]
complex systems and that most Rh-catalyzed asymmetric
,4-addition reactions tend to be performed under either basic
conditions. This result may be ascribed to the unique
1
2
[14]
calculated based on the amount of toluene.
character of Sc(OTf)3. We expected that Sc(OTf) lowered
3
the LUMO level of the amide substrate to accelerate the CÀC
bond-forming step. At the same time, a second role of
Sc(OTf) , such as acceleration of a protonation (product
substrate 1e, and cyclic substrate with a six-membered ring
1 f, were converted into the corresponding 1,4-addition
products in good yields with outstanding enantioselectivities
(entries 10–13). The application of the reaction conditions to
the formal synthesis of a pharmacologically important com-
3
release and catalyst regeneration) step by inner-sphere water
ligands of the water-compatible Lewis acid, was also
[14]
assumed.
increased and the reaction time was extended, the desired
,4-addition product was obtained in 93% yield with 98% ee
entry 7). Notably, no metal leaching was identified by ICP
When the loading of the chiral diene was
[
15]
1
(
pound, Paroxetine, was demonstrated by the reaction of 1 f
with 4-fluorophenylboronic acid (Scheme 1). The product
analysis under any of the conditions.
Substrate generality was surveyed under the optimized
conditions (Table 2). Arylboronic acids with either electron-
donating or electron-withdrawing groups were tested for the
reaction with 1a (Table 2, entries 1–8). The presence of
a substituent at the ortho-position decreased the reactivity
significantly, but an increase in the catalyst loading gave the
product in high yield with outstanding enantioselectivity
Scheme 1. Formal synthesis of pharmacologically important com-
pound.
(
entry 2). The reactions with arylboronic acids bearing an
electron-donating substituent at the meta- or para-position
proceeded smoothly to afford the products in high yields with
excellent enantioselectivities (entries 4–6). The reactions with
arylboronic acids bearing an electron-withdrawing substitu-
ent also afforded the products in high yields with excellent
enantioselectivities, when the catalyst loading was slightly
increased (entries 3, 7, and 8). Notably, the primary amide
could be applied directly, and the desired product was
obtained in 61% yield with 98% ee when a toluene major
cosolvent system was used (entry 9). Several N-benzyl
unsaturated amides, including aliphatic substrate 1c, aromatic
substrate 1d, sterically bulky isopropyl group-substituted
3 fh, which can be converted into Paroxetine by using
[
15]
a reported method, was obtained in 72% yield with 99%
ee (entry 14). On the other hand, conducting the reaction with
1g, a cyclic substrate with a five-membered ring, gave the
desired product in 35% yield with 99% ee (entry 15). In this
reaction, formation of ortho-disubstituted benzene side
product 5 was observed, which was presumably generated
[16]
through sequential 1,4-addition to 1g, 1,4-migration of Rh,
and further 1,4-addition to another molecule of 1g. In this
2
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[
18]
substrate survey, it is noted that outstanding enantioselectiv-
ities (> 98% ee) were obtained under any of the condi-
tions.
with that of Rh/Ag NPs. Further investigations to clarify
the structure of the cooperative catalysts are ongoing.
In summary, we have developed cooperative catalysts
consisting of chiral Rh/Ag NPs and Sc(OTf) for asymmetric
3
1
,4-addition reactions of arylboronic acids with a,b-unsatu-
rated amides. The reactions with unreactive amide substrates
were successfully conducted by using the new catalyst, and the
desired products were obtained in high yields with outstand-
ing enantioselectivities (> 98% ee) in the presence of low
catalyst loading (< 0.5 mol%). The catalyst could be recov-
ered and reused by a simple procedure without significant loss
of activity. No metal leaching occurred, which was carefully
confirmed by ICP analysis. In addition to a remarkable
activity of the cooperative catalyst, it is notable that, whereas
most homogeneous rhodium-complex-catalyzed asymmetric
arylation reactions are performed under basic conditions, the
chiral Rh/Ag NPs reported herein showed compatibility with
a Lewis acid. Furthermore, it was found that the heteroge-
neous NP catalyst system enhanced the efficiency of the
cooperative catalysis. These cooperative catalysts may pro-
vide new possibilities for asymmetric catalysis and heteroge-
neous NP catalysis.
It was confirmed that the asymmetric 1,4-addition reac-
tion could be successfully conducted on a gram scale (Table 3,
run 1). The PI/CB Rh/Ag catalyst was then recovered by
simple filtration. After washing with organic solvents and
water followed by heating at 1508C, the recovered catalyst
Table 3: Recovery and reuse of the catalyst.
Experimental Section
Typical procedure (Table 2, entry 5): (E)-N-Benzylbut-2-enamide 1a
(
52.4 mg, 0.3 mmol), 3-methylphenylboronic acid 2e (70.8 mg,
Parameter
Run
2
[
c]
[d]
[d]
[e]
[e]
0.6 mmol), PI/CB Rh/Ag (4.3 mg, Rh: 0.25 mol%) and chiral diene
4
tube, toluene (0.375 mL) was added and the mixture was stirred for
1
1
3
4
5
À1
(3.93 mgmL in toluene, 0.02 mL) were combined in a Carousel
[
a]
Yield (%)
87 (1.32 g)
99
82
99
53
98
75
99
75
99
[
b]
ee (%)
À1
min. Sc(OTf) (14.8 mgmL in water, 0.1 mL) and water (0.65 mL)
3
were added and the mixture was stirred and heated to 1008C under an
Ar atmosphere for 24 h. The mixture was allowed to cool and diethyl
ether was added to quench the reaction. The mixture was filtered
through a membrane filter to remove residual solids and the solution
was transferred to a separating funnel. The aqueous layer was
extracted with diethyl ether and the organic layer was washed with
brine. The combined organic layer was dried over sodium sulfate and
the conversion of 1a and the yield of 3ae were determined by
[
a] Isolated yield. [b] Determined by HPLC analysis. [c] 40 h. [d] The
recovered catalyst was washed with water and THF then heated at 1508C
for 3 h before use. [e] The recovered catalyst was first washed with THF/
1
m TfOH aq.=99:1, water, and THF and heated at 1508C for 3 h before
use. New portions of diene 4 and Sc(OTf) were added in every run.
3
1
was reused in the same reaction of 1a and 2a with new
H NMR analysis with reference to 1,1,2,2-tetrachloroethane as
portions of chiral diene 4 and Sc(OTf) to afford the desired
internal standard. The crude product was purified by preparative
TLC (dichloromethane/acetone = 49:1) to afford 68.4 mg (85%
yield) of 3ae. The ee of the product was determined by chiral
HPLC analysis.
3
product 3aa with similar yield and enantioselectivity (run 2).
The same recovery and reuse experiments were then con-
tinued further. Whereas the yield decreased in the 3rd run
(
run 3), the catalyst was successfully reactivated by treatment
[
17]
with trifluoromethanesulfonic acid,
and good yields and
Acknowledgements
excellent enantioselectivities were observed again in the 4th
and 5th runs (runs 4 and 5).
This work was partially supported 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 have some information on the structure of the key
cooperative catalysts consisting of chiral Rh/Ag NPs and
Sc(OTf) . We assumed that Sc(OTf) was easily accessible
into amphiphilic polymer matrix consisting of benzene rings
and polyethylene glycol moieties to locate closely to Rh/Ag
NPs, creating efficient asymmetric environments for catalysis.
Indeed, it was confirmed that the Rh/Ag NPs/Sc(OTf)3
cooperative catalyst gave a higher yield than simple combi-
nation of a homogeneous Rh complex and Sc(OTf)3
3
3
Keywords: cooperative effects · heterogeneous catalysis ·
Lewis acid · nanoparticles · Rh catalysis
(
Table S2, in the Supporting Information). When an excess
amount of Sc(OTf) was added to a reaction system, Rh
3
leaching was observed (Table S1) suggesting that the stabili-
zation of Sc(OTf) from polymer matrix may be competitive
3
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Received: February 13, 2016
Revised: March 11, 2016
Published online: && &&, &&&&
[
4
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Angewandte
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Communications
Asymmetric Catalysis
T. Yasukawa, Y. Saito, H. Miyamura,
S. Kobayashi*
&&&& — &&&&
Chiral Nanoparticles/Lewis Acids as
Cooperative Catalysts for Asymmetric 1,4-
Addition of Arylboronic Acids to a,b-
Unsaturated Amides
It can abide amides: Cooperative cata-
lysts consisting of heterogeneous chiral
Rh/Ag nanoparticles and a metal Lewis
for asymmetric 1,4-addition reactions of
arylboronic acids with a,b-unsaturated
amides. The reaction is regarded as
challenging owing to low reactivity of the
amide substrates.
acid, Sc(OTf) show high catalytic activ-
3
ities and outstanding enantioselectivities
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