Unusual Olefinic C-H Functionalization of Simple Chalcones toward Aurones Enabled by the Rational Design of a Function-Integrated Heterogeneous Catalyst

Article abstract of DOI:10.1021/acscatal.8b00727

Flavonoids, which are ubiquitous plant secondary metabolites obtained from chalcones, mostly possess 6-membered C-rings derived from 6-endo-trig cyclization of chalcones. However, aurones, which are a class of flavonoids that rarely occur naturally, possess unusual 5-membered C-rings biosynthesized from chalcones by mainly performing B-ring oxidation. Therefore, the chemical catalytic transformation from simple chalcones into aurones is attractive, because it overcomes the drawback of known limited enzyme catalysis. The catalytic transformation, however, has not yet been reported because of the preferential 6-membered ring formation as with the biosynthesis and the need for rare intramolecular olefinic C-H functionalization. Here, we developed the catalytic olefinic C-H functionalization of simple chalcones toward various aurones enabled by the rational design of a function-integrated heterogeneous catalyst - a Pd-on-Au bimetallic nanoparticle catalyst supported on CeO₂ - using O₂ in air as the sole oxidant without any additives. In this system, the four conditions that were required for the challenging transformation toward aurones were achieved by the respective components of the catalyst: (a) a supported Pd catalyst: a catalyst for the olefinic C-H functionalization of chalcones toward aurones, (b) an Au promoter: an improvement in the catalytic activity by stabilizing Pd(0), (c) a CeO₂ support: the inhibition of the 6-endo-trig cyclization utilizing the adsorption of chalcones, and (d) a Pd-on-Au structure: the inhibition of Au-catalyzed flavone synthesis. This catalytic transformation will promote not only the pharmaceutical study of aurones but also the rational design of a heterogeneous catalyst for the development of organic reactions that are not yet realized by homogeneous catalysts or biocatalyst.

Full text of DOI:10.1021/acscatal.8b00727

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Unusual Olefinic C–H Functionalization of Simple
Chalcones Toward Aurones Enabled by the Rational
Design of a Function-Integrated Heterogeneous Catalyst
Takafumi Yatabe, Xiongjie Jin, Noritaka Mizuno, and Kazuya Yamaguchi
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00727 • Publication Date (Web): 12 Apr 2018
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Unusual Olefinic C–H Functionalization of Simple Chalcones Toward Aurones
Enabled by the Rational Design of a FunctionꢀIntegrated Heterogeneous Catalyst
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Takafumi Yatabe,† Xiongjie Jin,‡ Noritaka Mizuno,† and Kazuya Yamaguchi*,†
†Department of Applied Chemistry, School of Engineering, The University of Tokyo, 7ꢀ3ꢀ1
Hongo, Bunkyoꢀku, Tokyo 113ꢀ8656, Japan
‡Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo,
7ꢀ3ꢀ1 Hongo, Bunkyoꢀku, Tokyo 113ꢀ8656, Japan
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ABSTRACT
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Flavonoids, which are ubiquitous plant secondary metabolites obtained from chalcones, mostly
possess 6ꢀmembered Cꢀring derived from 6ꢀendo-trig cyclization of chalcones. However, aurones,
which are a class of flavonoids that rarely occur naturally, possess unusual 5ꢀmembered Cꢀring
biosynthesized from chalcones by mainly performing B ring oxidation. Therefore, the chemical
catalytic transformation from simple chalcones into aurones is attractive, because it overcomes the
drawback of known limited enzyme catalysis. The catalytic transformation, however, has not yet
been reported because of the preferential 6ꢀmembered ring formation as with the biosynthesis and
the need for rare intramolecular olefinic C–H functionalization. Here, we developed the catalytic
olefinic C–H functionalization of simple chalcones toward various aurones enabled by the rational
design of a functionꢀintegrated heterogeneous catalyst—a PdꢀonꢀAu bimetallic nanoparticle catalyst
supported on CeO2—using O2 in the air as the sole oxidant without any additives. In this system, the
four conditions that were required for the challenging transformation toward aurones were achieved
by the respective components of the catalyst—a) a supported Pd catalyst: a catalyst for the olefinic
C–H functionalization of chalcones toward aurones, b) an Au promoter: an improvement in the
catalytic activity by stabilizing Pd(0), c) a CeO2 support: the inhibition of the 6ꢀendo-trig cyclization
utilizing the adsorption of chalcones, and d) a PdꢀonꢀAu structure: the inhibition of Auꢀcatalyzed
flavone synthesis. This catalytic transformation will promote not only the pharmaceutical study of
aurones but also the rational design of a heterogeneous catalyst for the development of organic
reactions that are not yet realized by homogeneous catalysts or biocatalyst
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KEYWORDS
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C–H functionalization, heterogeneous catalyst, palladium, gold, bimetallic nanoparticle, ceria,
chalcone, aurone
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INTRODUCTION
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Flavonoids—ubiquitous plant secondary metabolites possessing a C6–C3–C6 skeleton, which
originates from chalcones (2ꢀbenzylideneꢀ2ʹꢀhydroxyacetophenone and its derivatives)—exhibit
various biological activities such as antiꢀoxidant, antiꢀoncogenic, antiꢀinflammatory, cardiovascular
action, and so on.1 Almost all of the flavonoids possess 6ꢀmembered Cꢀring that was derived from
flavanone through 6ꢀendo-trig cyclization of the chalcones that were easily catalyzed by chalcone
isomerase (CHI) (Figure 1, I).1
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However, aurones (2ꢀbenzylideneꢀcoumaranꢀ3ꢀone and its derivatives), a class of minor
flavonoids naturally that occur in limited plants such as Antirrhinum majus and Cosmos, possess an
unusual 5ꢀmembered Cꢀring because of an exceptional mechanism (Figure 1, I).1,2 Aurones are
biosynthesized directly from chalcones via the oxidation of Bꢀrings2a mainly by polyphenol oxidases
(PPO), such as aureusidin synthase (AmAS1)2b,c and aurone synthase (AUS1)2d, or by peroxidases
(PRX), such as MtPRXs.2e,f Therefore, the chemical catalytic transformation from simple chalcones
into aurones that do not occur naturally is attractive, which overcomes the drawback of known
limited enzyme catalysis. Further, the aboveꢀmentioned transformation is one of the most useful
synthetic methods to produce aurones as compared with that of the other synthetic methods3–6
because chalcones are easily available through synthesis from simple aldehydes and ketones via the
Claisen–Schmidt condensation or by extracting from the plants. Recently, various biological
activities of aurones have also been revealed along with that of other flavonoids,2g–k which have
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elevated the importance of the transformation into novel aurones in terms of their pharmaceutical
application.
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However, the literature contains no report about the catalytic transformation from simple
chalcones into aurones.7 For one thing, the control of 5ꢀexo/6ꢀendoꢀtrig cyclization of chalcones is
quite difficult; only 6ꢀendo-trig cyclization—i.e. intramolecular oxaꢀMichael addition—proceeds to
produce flavanones8 that is similar to the biosynthesis of flavonoids in nature; to the best of our
knowledge, the literature contains no reports about the 5ꢀexo-trig cyclization. Thus, the direct
oxidative cyclization of chalcones, 5ꢀmembered/6ꢀmembered oxidative cyclization, is also difficult
to control; 6ꢀmembered oxidative cyclization dominantly proceeds to produce flavones via
6ꢀendo-trig cyclization (Figure 1, IIꢀa).9 Only when (super)stoichiometric amounts of metal oxidants,
typically Hg(OAc)2, are used, does the 5ꢀmembered oxidative cyclization into aurones proceed
because of the intermediate formed by the coordination of a chalcone to a metal species to inhibit the
6ꢀmembered cyclization (Figure 1, IIꢀa).6 For another thing, the catalytic transformation from
chalcones into aurones is regarded as “intramolecular αꢀolefinic C–H functionalization” (including
formal C–H functionalization; in this manuscript, an olefinic C–H bond closer to a directing group is
defined as αꢀolefinic C–H), which has been rarely reported. To the best of our knowledge, a formal
intramolecular αꢀolefinic C–H functionalization even via Pdꢀcatalyzed Wackerꢀtype cyclization has
never been reported.10 Recently, a Rhꢀcatalyzed pioneering formal intramolecular αꢀolefinic C–H
functionalization of βꢀsubstitutedꢀ2ʹꢀhydroxyacrylophenone was reported by Glorius et al; however,
the system could not be applied to the transformation of chalcones into aurones that was observed in
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the literature (Figure 1, IIꢀb).11 As for intramolecular directed αꢀolefinic C–H functionalization, a
recent report by Yu et al. to synthesize 4ꢀiminoꢀβꢀlactams was observed to be pioneering,12 while
numerous examples of βꢀolefinic C–H functionalization have been reported.13 Therefore, the
development of innovative multifunctional catalysts to control difficult cyclization and rare C–H
functionalization is indispensable to achieve this challenging catalytic transformation into aurones.
Novel difficult organic transformations have been mostly developed on the basis of
homogeneous catalysts; however, in terms of the integration of multiple functions to achieve unusual
reactions, heterogeneous catalysts also exhibit considerable potential. Indeed, as for comparatively
typical organic syntheses, the literature contains several reports about tandem reactions and
concerted catalysis via functionꢀintegrated heterogeneous catalysts.14 Heterogeneous catalysts are
mainly composed of a) a main active species for the target reactions, b) a promoter for the catalysis,
and c) a support to disperse and stabilize the active species.15 Furthermore, the design of d) the
morphology of these three components enables control of catalytic activity, selectivity, and longevity,
which can lead to a novel unique catalysis that differs from homogeneous catalysis.
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Herein, through the rational design of a functionꢀintegrated heterogeneous catalyst based
on the aforementioned components, four requirements for the catalytic transformation of chalcones
into aurones were achieved—a) a supported Pd catalyst: a catalyst for αꢀolefinic C–H
functionalization of chalcones, b) an Au promoter: an improvement of the catalytic activity by the
stabilization of Pd(0), c) a CeO2 support: the inhibition of the 6ꢀendo-trig cyclization utilizing the
adsorption of chalcones, and d) a PdꢀonꢀAu structure: the inhibition of Auꢀcatalyzed flavone
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synthesis (Figure 1, III). That is, we have successfully developed an unusual catalytic transformation
from simple chalcones into aurones over PdꢀonꢀAu bimetallic nanoparticles supported on CeO2
(Pd/Au/CeO2) using O2 in air as the sole oxidant without any additives for the first time.
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I) Biosynthesis of Flavonoids
II) Key Problems of Catalytic Transformation from Chalcones into Aurones
Flavonoids with 6-membered C ring derived from flavanone
a) Preferential 6-membered cyclization: No report for catalytic transformation into aurones
O
O
O
O
B
O
CoA
S
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6-membered
oxidative cyclization
5-membered
oxidative cyclization
OH
O
H
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C
C
C
A
A
A
HO
O
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O
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O
4-Coumaroyl-CoA
B
B
catalytically
well-established
H
stoichiometric
Hg(OAc)2
O
Flavone
Isoflavone
Flavonol
OH
Chalcone
3 Malonyl-CoA
Flavone
Aurone
Chalcone
Isomerase
(CHI)
O
O
O
OH
O
O
β
Preferential
6-endo-trig
cyclization
2
6'
A
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Intermediate to inhibit
6-endo-trig cyclization
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OH
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A
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Hg
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Chalcone
Major Route
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B
B
B
Dihydroflavonol
Leuco-anthocyanidin
Flavanone
Phlobaphene
Backbone of Flavonoids
Exceptional
Route
b) Rare “α-olefinic C–H functionalization”: Glorius’s pioneering work inapplicable to chalcones
Condensed Tannin
Anthocyanin
O
O
O
H
(Cp⋆RhCl2)2
3 O
4
A
7
H
EWG
5
6
α
2
C
H
O
■
Minor flavonoid with 5-membered C ring: Limited abundance
Requirement of B ring oxidation for typical aurone biosynthesis
Formal α-olefinic
C–H functionalization
O
1' 2'
EWG
OH
O
1
6'
5'
3'
B
Aurone
■
4'
Aurone
III) This Work: Design of a Function Integrated Heterogeneous Catalyst for Unusual a-Olefinic C–H Functionalization of Chalcones Toward Aurones
O
1/2O2
O
H
R1
a) Pd Catalyst
b) Au Promoter
R2
R1
H
O
OH
Chalcone
R2
−H2O
Aurone
c) CeO2 Support
O
O
O
d) Pd-on-Au Morpology
R1
R1
O
R2
R2
Flavanone
Flavone
Figure 1. Overview of the transformation from chalcones into aurones: I) Biosynthetic routes of flavonoids from chalcones that includes the exceptional route toward aurones; II)
Key problems of chemical catalytic transformation into aurones; a) difficulty with 5ꢀmembered ring formation from chalcones and b) rare “intramolecular αꢀolefinic C–H
functionalization”; III) Strategy used in this work: Design of a functionꢀintegrated heterogeneous catalyst controlling each reaction to achieve the four requirements; a) novel catalysis
for transformation into aurones, b) improvement of catalytic activity, c) inhibition of 6ꢀendo-trig cyclization, and d) inhibition of flavone synthesis.
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RESULTS AND DISCUSSION
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Catalyst Preparation and Characterization. Hutchings et al. reported Au@Pd core–shell
structures formed from Au and Pd species impregnated on metal oxides by calcination at
approximately 200–400 °C.16 Referring to the report, in the present work, we prepared Pd/Au/CeO2
through calcination at 300 °C for 2 h after Au and Pd species were supported on CeO2 separately in
this order via a deposition–precipitation method (see Experimental Section). Transmission electron
microscopy (TEM) images of the Pd/Au/CeO2 revealed that the metal species were dispersedly
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supported on CeO2 as nanoparticles with a mean diameter of 2.2 nm (σ = 1.0 nm) (Figure 2a,b). The
highꢀangle annular darkꢀfield scanning transmission electron microscopy (HAADFꢀSTEM) image in
Figure 2c and STEM energyꢀdispersive Xꢀray spectroscopy (STEMꢀEDS) mapping images
(Figure 2d–f) indicate that the nanoparticles consisted of both Au and Pd. Each particle observed by
HAADFꢀSTEM possessed almost the same structure, though clear direct observation of the
PdꢀonꢀAu structure was quite difficult because of the small nanoparticle size (Figure S1). In addition,
Xꢀray photoelectron spectroscopy (XPS) spectra of the freshly prepared Pd/Au/CeO2 catalyst
indicate a Pd valence of II and an Au valence of 0 (Figure 2g,h). Given the aforementioned results,
the proposed structure of Pd oxides covering the surface of Au nanoparticles is valid. According to
the Xꢀray diffraction (XRD) (Figure S2) and Ce LIIIꢀedge Xꢀray absorption near edge structure
(XANES) analyses (Figure S3), the structure of the CeO2 support was not affected by the preparation.
Thus, the PdꢀonꢀAu bimetallic nanoparticle catalyst supported on CeO2 was successfully prepared.
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a)
b)
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0
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7
Particle size [nm]
c)
d)
e)
f)
g)
h)
Pd (II)
342.3
Pd (0)
340.6
Au(0) 4f5/2
86.6
Au(0) 4f7/2
82.8
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330
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78
Binding Energy [eV]
Binding Energy [eV]
Figure 2. Characterization of Pd/Au/CeO2: a), b) TEM images and nanoparticle size distributions of
Pd/Au/CeO2 (mean diameter: 2.2 nm, = 1.0 nm). The size distributions were determined using 200
σ
particles; c) HAADFꢀSTEM image and STEMꢀEDS mapping images of Pd/Au/CeO2, showing the
distributions of d) Pd (yellow), e) Au (magenta) and f) Au and Pd together; g), h) XPS spectra of
Pd/Au/CeO2 around the Pd 3d region and Au 4f region, respectively; peak positions were calibrated
using the C 1s peak (284.2 eV).
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Catalyst Design and Optimization of Conditions for Aurone Synthesis. We attempted the
transformation from 2ʹꢀhydroxychalcone (1a) into aurone (2a) using various catalysts in butyl
acetate (BuOAc) at 100 °C under an open air atmosphere (Table 1). Although homogeneous Pd
species catalytically produced 2a, the yield was not satisfactory (entry 1, Table 1); the production of
2a stopped in the middle with the formation of Pd black (Figure S4), and the formation of flavanone
(4a) could not be suppressed. To stabilize Pd species and to inhibit the 6ꢀendo-trig cyclization, we
prepared supported Pd catalysts (represented as Pd/support). Pd/Al2O3 and Pd/TiO2 effectively
increased the 2a yield, although flavanone 4a was still formed to some extent (entries 3 and 4,
Table 1). Pd/CeO2 effectively inhibited 4a production; however, 2a was obtained in a low yield
(entry 2 vs entry 11, Table 1). The inhibition of 4a was possibly due to the coordination of phenoxide
species derived from 1a toward Ce species, analogous to the typical aurone synthesis using
stoichiometric reagents such as Hg(OAc)2.6 In fact, when 1a and the CeO2 support were mixed under
the same conditions described in Table 1, the CeO2 support was colored, as revealed by both its
appearance and its DR UV–Vis spectrum, suggesting that the phenoxide species derived from 1a
was adsorbed onto CeO2 (Figure S5).17 When only the CeO2 support was used, 2a was not produced
at all (entry 1, Table S1). Among the other metal catalysts (Au, Cu, Ru, Rh, and Ni) supported on
CeO2, only Au showed the catalytic activity toward the synthesis of 2a (entry 5, Table 1 and entries
2–5, Table S1); however, the selectivity toward 2a was remarkably low because of the dominant
formation of flavone (3a) catalyzed by Au.9c Bimetallic nanoparticles composed of Pd and the other
metal species (i.e. Pt–Pd, Cu–Pd, Rh–Pd, Ni–Pd, Pb–Pd, and Zn–Pd) supported on CeO2 did not
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improve the 2a yield (entries 6–12, Table S1). Exceptionally, Au–Pd bimetallic nanoparticles
supported on CeO2 (Au–Pd/CeO2) boosted the production of 2a concomitantly with considerable 3a
production by Au catalysis (entry 6, Table 1). The physical mixture of Au/CeO2 and Pd/CeO2 also
promoted the production of 2a; however, the yield was not comparable to that achieved using Au–
Pd/CeO2 and 3a production was dominant because of the bare Au catalyst (entry 7, Table 1). Thus,
the PdꢀonꢀAu bimetallic nanoparticle catalyst supported on CeO2 (Pd/Au/CeO2) was designed to
retain the Au promotion effect while inhibiting the Au catalysis toward 3a production; this catalyst
resulted in a high yield of and high selectivity toward 2a (entry 8, Table 1).18 The inhibition effect of
Pd/Au/CeO2 on the production of 3a was also observed when the reaction was carried out starting
from 4a instead of 2a (Figure S6).
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59
60
The effect of solvents was also very significant (Table S2). In lowꢀpolarity solvents such as
toluene and diglyme, the production of 3a and 4a was substantially suppressed; however, the yields
of 2a were low. In polar solvents such as alcohols, N,Nꢀdimethylacetamide (DMA), and
N,Nꢀdimethylformamide (DMF), the yields of 2a were comparably high; however, considerable
amounts of 3a and 4a were produced. BuOAc was the most suitable solvent for the efficient
transformation into 2a with simultaneous suppression of 3a and 4a production. With optimization of
the reaction temperature (Table S3), the ratio of Au and Pd (Figure S8), and the amount of catalysts,
the yield of 2a reached 79% (entry 9, Table 1). Under an Ar atmosphere, 2a was hardly obtained,
which revealed that O2 in air functioned as the sole oxidant in this system (entry 10, Table 1).
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Table 1. Effect of catalysts on the transformation from 2ʹꢀhydroxychalcone (1a) into aurone
(2a)a
8
9
O
O
O
O
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
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49
50
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53
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59
60
O
O
O
OH
1a
2a
3a
4a
Conv. (%)
Yield (%)
Entry
Catalyst
1a
38
7
2a
12
3
3a
2
4a
16
4
1
2b
3b
4b
5
Pd(TFA)2
Pd/CeO2
<1
1
Pd/TiO2
37
47
>99
90
94
60
94
21
16
19
16
6
13
25
8
Pd/Al2O3
3
Au/CeO2
80
22
51
6
6
Au–Pd/CeO2
Au/CeO2 + Pd/CeO2
Pd/Au/CeO2
Pd/Au/CeO2
Pd/Au/CeO2
None
52
32
46
79
1
8
7
14
9
8
9c
10c,d
11
11
<1
<1
5
13
16
<1
aReaction conditions: 1a (0.3 mmol), catalyst (Au and/or Pd: 2 mol%), BuOAc (2 mL), open air
b
(1 atm), 100 °C, 24 h. Yields and conversions were determined by GC. Supported Pd catalyst
c
d
(50 mg, Pd: 1 mol%). Catalyst (100 mg, Au: 5 mol%, Pd: 5 mol%). Under Ar (1 atm). TFA =
trifluoroacetate.
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Heterogeneous Catalysis and Catalyst Reuse. To verify whether the observed catalytic reaction
occurred on solid Pd/Au/CeO2 or arose from leached metal species (Au and/or Pd) in the solution,
Pd/Au/CeO2 was removed by hot filtration during the reaction and the reaction was again carried out
with the filtrate under the same conditions. The production of 2a completely stopped with the
removal of Pd/Au/CeO2 (Figure S8). In addition, Au and Pd species in the filtrate after the reaction
were not detected by inductively coupled plasma atomic emission spectroscopy (ICPꢀAES) (Au:
<0.003%, Pd: <0.02%). Therefore, the observed catalysis to perform the current transformation into
aurones is truly heterogeneous. After the reaction under the optimized conditions, Pd/Au/CeO2 could
be readily retrieved from the reaction mixture by simple filtration. The retrieved Pd/Au/CeO2
catalyst could be reused without a severe loss of its catalytic activity after it was calcined at 300 °C
for 2 h, although the catalytic activity decreased when the calcination was not performed (Figure S9).
TEM observations suggested that the size of the nanoparticles slightly increased during the reaction
and was not affected by the calcination (Figure S10). Thus, the activity loss without calcination in
the second reaction was not caused by an increase in nanoparticle size. XRD patterns and FTꢀIR
spectra revealed no change of the basic structure of CeO2 (Figures S11 and S12). However, in the
FTꢀIR spectra collected after the reaction, peaks were observed at 1456 cm−1 and 1418 cm−1, which
are possibly attributable to phenylꢀring stretching vibrations. These peaks disappeared after the
catalyst was calcined at 300 °C. On the basis of these results, the adsorption of organic compounds
onto the catalyst was likely the main reason for the loss of catalytic activity when the recovered
catalyst was not calcined.
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Substrate Scope and Limitation. We examined the scope of the present Pd/Au/CeO2ꢀcatalyzed
transformation into aurones. Under the optimized reaction conditions, various aurones could be
synthesized in a (Z)ꢀselective fashion starting from simple chalcones (Table 2). The desired products
were isolated by simple column chromatography on silica gel (see Experimental Section).19 The
conversions of chalcones (1) and the yields of aurones (2), flavones (3), and flavanones (4)
determined by gas chromatography (GC) are summarized in Table S4. When 2ʹꢀhydroxychalcones
substituted with a methoxy group at their 2ꢀ, 3ꢀ, or 4ꢀposition were used as the substrates, the
corresponding aurones (2b–2d) were synthesized. In the case of 2ʹꢀhydroxyꢀ4ꢀmethylchalcone,
4ʹꢀmethylaurone (2e) was obtained without benzylic oxidation of the methyl group. The chalcone
with a 2ꢀnaphthyl group as the B ring was converted into the corresponding aurone (2f). The use of
chalcones with various substituents at these A rings was also possible (2g–2j). In particular,
5ʹꢀfluoroꢀ2ʹꢀhydroxychalcone was efficiently transformed into the corresponding aurone with a
fluoro group (2g), which is an important group in the pharmaceutical field.20 Thus, a novel aurone
with potential medicinal applications, e.g. 5ꢀfluoroꢀ3ʹꢀmethoxyaurone (2k), was also successfully
synthesized. In addition, as a demonstration of using plantꢀderived substrates, we used flavokavain A
(2ʹꢀhydroxyꢀ4,4ʹ,6ʹꢀtrimethoxychalcone), which is a flavonoid extracted from kava plants, as the
substrate to obtain the corresponding aurone efficiently (2l). However, this system was inapplicable
to some substrates (2m–2o), possibly because their hydroxy groups could not easily access the Pd
catalysts coordinated by the other groups.
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Table 2. Scope of transformation into aurones (2)a
O
O
8
9
R1
R2
R1
O
OH
R2
10
11
12
13
14
15
16
17
18
19
20
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1
2
O
O
O
OMe
O
O
O
OMe
2c
61% (38%)b
Ratio: 67%, E/Z = 2/98
2a
2b
46% (37%)b
Ratio: 67%, E/Z = 3/97
79% (64%)
Ratio: 83%, E/Z = 3/97
O
O
O
O
O
O
2d
2e
2f
OMe
41% (31%)c
Ratio: 45%, E/Z = 3/97
29% (20%)b,c
Ratio: 44%, E/Z = 3/97
45% (37%)c
Ratio: 70%, E/Z = <1/>99
O
O
O
F
O
O
MeO
Cl
O
2g
2h
80% (60%)d
Ratio: 84%, E/Z = 3/97
2i
84% (39%)
Ratio: 86%, E/Z = 1/99
36% (16%)b,c
Ratio: 43%, E/Z = <1/>99
O
O
OMe
O
Cl
F
O
O
O
2l
MeO
OMe
Cl
2j
2k
28% (19%)b,e
Ratio: 45%, E/Z = <1/>99
68% (36%)
Ratio: 73%, E/Z = 1/99
80% (72%)b,f
Ratio: 88%, E/Z = 7/93
OMe
O
O
O
Br
O
O
O
O
2o
2m
2n
4%
Cl
2%
<1%
aReaction conditions: 1 (0.3 mmol), Pd/Au/CeO2 (100 mg, Au: 5 mol%, Pd: 5 mol%), BuOAc
(2 mL), open air (1 atm), 100 °C, 24 h. Ratio of 2 = 2 × 100/(2 + 3 + 4) (%). The E/Z ratios were
determined by GC analysis using biphenyl as an internal standard. The GC yields including the (E)
b
isomer are shown. The values in parentheses are the isolated yields of the (Z) isomer. 48 h.
cPd/Au/CeO2 (200 mg, Au: 9 mol%, Pd: 9 mol%). d50 h. eDMA (2 mL). fThe isolated yield including
the (E) isomer.
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Mechanistic Studies. The present transformation into aurones possibly proceeds through one of the
following three paths (Scheme 1): directed αꢀolefinic C–H activation/reductive elimination (Path A),
migratory insertion/βꢀhydride elimination (Path B), or single electron transfer (SET)/radical
cyclization/hydrogenꢀatom transfer (HAT) (Path C).21 The directed αꢀolefinic C–H activation
included in Path A has rarely been reported;12 however, the reductive elimination from the
6ꢀmembered palladacycle was the major reaction mechanism proposed in reported aurone syntheses
from ynones.3 The reaction in Path B is well known as the Wackerꢀtype cyclization;10 however, a
formal intramolecular αꢀolefinic C–H functionalization via Pdꢀcatalyzed Wackerꢀtype cyclization
has, to our knowledge, never been reported. Path C was declared in previous reports for aurone
synthesis using a stoichiometric oxidant such as Pb(OAc)4 or Mn(OAc)3.6d,e
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O
C–H
Activation
Reductive
Elimination
O
O
O
O
Path A
O
Pd
Pd
Pd
O
(Z)-Aurone
β-Hydride
Elimination
O
O
O
Insertion
Insertion
SET
H
O
O
Pd
Pd
(E)-Aurone
Isomerization
Path B
O
O
β-Hydride
Elimination
O
Pd
H
O
O
OH
O
(Z)-Aurone
O
5-Exo-Trig
Cyclization
O
O
Path C
O
HAT
Pd
O
Aurone
Scheme 1. Possible paths of transformation from chalcones into aurones.
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First, to verify whether a radical species is involved in this system, we carried out the
reaction under the optimized conditions in the presence of an equimolecular amount of
2,2,6,6ꢀtetramethylpiperidine 1ꢀoxyl (TEMPO) or 2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylphenol (BHT) as a
radical scavenger with respect to 1a (Figure S13). The production rates of 2a from 1a did not
decrease, indicating that radical species are irrelevant to this reaction; thus, Path C was excluded.
Next, to verify whether the reaction proceeds through Path A or Path B, we conducted the
following control experiments (Figure 3): a) the reaction using [αꢀD]ꢀ2ʹꢀhydroxychalcone
([αꢀD]ꢀ1a) or [βꢀD]ꢀ2ʹꢀhydroxychalcone ([βꢀD]ꢀ1a) as the substrate to confirm a scrambling of
deuterium atoms; b) isomerization of (Z)ꢀaurone; c) oxidative cyclization of 2ꢀallyl phenol and the
reaction of 1a under the reported Wackerꢀtype cyclization conditions;10a and d) oxidative cyclization
of 2ꢀallyl phenol and the reaction of 1a under the present aurone synthesis conditions.
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If the βꢀhydride elimination included in Path B occurs, the deuterium atoms would likely
be scrambled between the aurones and Pd catalysts to produce partially Dꢀlabeled or nonꢀlabeled
1
aurones when using [αꢀD]ꢀ1a or [βꢀD]ꢀ1a, respectively (Figure 3a). H NMR analyses of the
reaction solutions after the reactions indicated no scrambling of the deuterium atoms in this system
(Figure S14)—hence, the existence of Path B cannot be confirmed. If reductive elimination included
in Path A occurs, only (Z)ꢀaurone should be produced. In the present system, the aurone was
obtained in a (Z)ꢀselective fashion, whereas small amounts of (E)ꢀaurones were produced in the case
of several substrates (E/Z = 1/99–7/93), which are derived from βꢀhydride elimination included in
Path B or natural isomerization of (Z)ꢀaurones.3d The (Z)ꢀisomer of 2a was treated under the
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optimized reaction conditions for 24 h, resulting in isomerization into the (E)ꢀisomer whose ratio
was approximately the same as that of the product synthesized from 1a (Figure 3b). Thus, the small
amounts of (E)ꢀisomers are possibly produced by isomerization after the (Z)ꢀselective aurone
formation through Path A. As previously reported,10a the oxidative cyclization of 2ꢀallyl phenol
efficiently proceeded reproducibly under the Wackerꢀtype cyclization conditions using PdCl2. The
production of 2a from 1a, however, did not proceed at all under the Wackerꢀtype cyclization
conditions (Figure 3c). By contrast, under the aurone synthesis conditions using Pd/Au/CeO2 in
DMA, 2a was produced from 1a, whereas the Wackerꢀtype cyclization of 2ꢀallyl phenol hardly
proceeded (Figure 3d).
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On the basis of the aforementioned results, the present transformation from chalcones into
aurones likely proceeds through Path A (Figure 3e). After the coordination of deprotonated 1 to the
Pd center, intramolecular olefinic αꢀC–H activation directed by the phenoxide group occurs to
produce a 6ꢀmembered palladacycle. Then, 2 is produced through reductive elimination from the
palladacycle with concomitant formation of a reduced Pd species, e.g., Pd(0), which is then
reꢀoxidized by O2 in air to complete the catalytic cycle. Under an O2 atmosphere instead of an open
air atmosphere, the production rate of 2a increased (Figure S15). Moreover, as shown in Figure S13,
TEMPO possibly worked as the reꢀoxidant of the reduced Pd species to promote the production rate
of 2a, although only TEMPO did not produce 2a at all.9c,22 These results suggest that the
reꢀoxidation of the Pd species is included in the turnoverꢀlimiting step of the present transformation
into aurones under an open air atmosphere.
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Finally, to demonstrate the effect of Au, we measured the reaction profiles for the
transformation from 1a into 2a using Pd/CeO2 or Pd/Au/CeO2 under an open air atmosphere or an
O2 atmosphere (Figure S16). Compared with the catalyst with only Pd, that with coexisting Pd and
Au exhibited improved catalytic activity and catalyst longevity. Moreover, in the absence of Au, the
production rate of 2a was independent of the O2 partial pressure. XPS spectra revealed that Pd(II)
species were stabilized in Pd/CeO2 (Figure S17), which is consistent with previous reports23
indicating that the reductive elimination step is difficult to induce. By contrast, when Pd/Au/CeO2
was used, as previously mentioned, the reꢀoxidation of the reduced Pd species was included in the
turnoverꢀlimiting step. Furthermore, Pd(0) species considerably formed in Pd/Au/CeO2 after the
reaction, whereas no Pd(0) species were present before the reaction (Figure S18). Therefore, Au
species likely contributed to the stabilization of Pd(0)24 during the reaction to promote the reductive
elimination step.
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a)
b)
O
O
O
Pd/Au/CeO2
100 mg
H
D
D
H
O
O
Pd/Au/CeO2
100 mg
O
D
O
O
BuOAc 2 mL
Open air, 100 °C, 24 h
OH
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O
O
[α-D]-1a
BuOAc 2 mL
Open air, 100 °C, 24 h
O
(E)-Aurone
(Z)-Aurone
O
O
O
D
(Z)-Aurone
Pd/Au/CeO2
100 mg
E/Z = 2/98
O
O
BuOAc 2 mL
Open air, 100 °C, 24 h
OH
[β-D]-1a
c)
e)
O
O
77%
OH
PdCl2 5 μmol
NaOAc 0.1 mmol
2-allyl phenol
OH
Chalcone (1)
DMA 3 mL
O2 6 atm, 80 °C,4 h
O
H2O
O
Pd(II)
Reoxidation
O
Deprotonation
Coordination
1/2O2
2H+
OH
1a
<1%
Pd(0)
O
d)
H
O
O
OH
2-allyl phenol
Pd/Au/CeO2
50 mg
O
Pd
1%
Directed α-Olefinic
C–H Activation
DMA 2 mL
Open air, 100 °C, 24 h
O
O
O
O
Aurone (2)
Reductive
Elimination
Pd
O
O
Palladacycle
OH
1a
46%
Figure 3. Overview of the mechanistic studies on the transformation into aurones: a) Scrambling of deuterium using [αꢀD]ꢀ1a or [βꢀD]ꢀ1a as a substrate
under the optimized reaction conditions; b) Isomerization of (Z)ꢀaurone under the optimized reaction conditions; c) Oxidative cyclization of 2ꢀallyl phenol
or 1a under the reported Wackerꢀtype cyclization conditions as shown in the figure; d) Oxidative cyclization of 2ꢀallyl phenol or 1a on the aurone
synthesis conditions as shown in the figure; e) Proposed mechanism of transformation into aurones in this system.
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CONCLUSION
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We have achieved the first catalytic transformation from simple chalcones into various aurones over
PdꢀonꢀAu bimetallic nanoparticles supported on CeO2 through the rational design of a
functionꢀintegrated heterogeneous catalyst; the designed system included the following four roles
indispensable for the catalytic transformation—a) a supported Pd species: a novel catalyst for aurone
synthesis via rare directed αꢀolefinic C–H functionalization, b) an Au promoter: an improvement of
catalytic activity as a result of stabilization of Pd(0), c) a CeO2 support: the inhibition of the
6ꢀendo-trig cyclization on the surface, and d) a PdꢀonꢀAu structure: the inhibition of Auꢀcatalyzed
flavone synthesis. This catalysis was confirmed to be heterogeneous, and the catalysts could be
reused. In addition, O2 served as the sole oxidant and no additives were needed, making this system
truly environmentally friendly. This system was also significantly useful as an aurone synthesizing
method; various aurones were synthesized starting from simple chalcones, including a natural
compound extracted from plants, which will promote the pharmaceutical study of aurones. This
study demonstrates the considerable potential of a heterogeneous catalyst design for novel difficult
organic syntheses that have not yet been achieved using homogeneous catalysts or biocatalysts.
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EXPERIMENTAL SECTION
Preparation of Pd/Au/CeO2
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The PdꢀonꢀAu bimetallic nanoparticle catalyst supported on CeO2 (Pd/Au/CeO2) was prepared as
follows. CeO2 (2 g) was added to an aqueous solution of HAuCl4 (3 mM, 100 mL), and the slurry
was stirred for 2 min, followed by the addition of 10% aqueous NH3 (360 ꢁL). After stirring for 14 h,
the resulting mixture was filtered, washed with deionized water (1 L), and dried in vacuo, affording
a supported Au precursor. This Au precursor was then dispersed in an aqueous solution of K2PdCl4
(3 mM), which was generated in situ from a mixture of PdCl2 (0.3 mmol) and KCl (1.2 mmol) in
100 mL water, and stirred for 10 min. The pH of the solution was adjusted to 12.3 using an aqueous
solution of NaOH (2 M). After the reaction mixture was stirred for 14 h, the precursor was filtered,
washed, and dried in the aforementioned manner to give a supported Au–Pd precursor. After
calcination of the Au–Pd precursor at 300 °C for 2 h, the desired Pd/Au/CeO2 (Pd: 1.5 wt%, Au: 2.7
wt%) was obtained as a black powder. The catalysts for which the Pd/Au ratio is 1/3 (Pd: 0.7 wt%,
Au: 4.0 wt%) or 3/1 (Pd: 2.2 wt%, Au: 1.2 wt%) were prepared using a similar procedure after
adjusting the initial concentrations of metal sources to obtain the desired ratios. Similarly,
Au/Pd/CeO2 was prepared, by simply reversing the aforementioned order of the supporting metal
species.
Catalytic reaction
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The catalytic reaction was typically carried out according to the following procedure. Into a Pyrex
glass reactor (volume: ca. 20 mL) were successively added Pd/Au/CeO2 (100 mg, Au: 5 mol%, Pd:
5 mol%), biphenyl (0.1 mmol, internal standard), 2ʹꢀhydroxychalcone (1a, 0.3 mmol), BuOAc
(2 mL), and a Teflonꢀcoated magnetic stir bar; the mixture was then stirred at 100 °C under an open
air atmosphere. The yields of products were determined by GC analysis using biphenyl as an internal
standard. With respect to the isolation of products, after the reaction, the catalyst was removed by
simple filtration and the filtrate was then concentrated by evaporation of BuOAc or DMA. The crude
product was subjected to column chromatography on silica gel (typically using hexane/EtOAc = 8/2
as an eluent), giving the pure aurones.
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ASSOCIATED CONTENT
The supporting information is available free of charge on the ACS Publication website.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: kyama@appchem.t.uꢀtokyo.ac.jp
Fax: +81ꢀ3ꢀ5841ꢀ7220
Notes
The authors declare no competing financial interests.
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ACKNOWLEDGMENTS
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We thank Mr. Hiroyuki Oshikawa (The University of Tokyo) for his assistance with the
HAADFꢀSTEM and EDS analyses. This work was financially supported by JSPS KAKENHI Grant
No. 15H05797 in Precisely Designed Catalysts with Customized Scaffolding and the Mitsubishi
Foundation. A part of this work was conducted at the Advanced Characterization Nanotechnology
Platform of the University of Tokyo, supported by “Nanotechnology Platform” of the Ministry of
Education, Culture, Sports, Science and Technology (MEXT), Japan. The XANES measurements
with the help of Dr. Yoshiyuki Ogasawara (The University of Tokyo) were carried out under the
approvals of the Photon Factory Program Advisory Committee (Proposal No. 2015G698). The
authors would like to thank Enago (www.enago.jp) for the English language review. Takafumi
Yatabe was supported by the JSPS through the Research Fellowship for Young Scientists (Grant No.
17J08127) and the Program for Leading Graduate Schools (MERIT program).
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Supporting Information. Brief statement in nonꢀsentence format listing the contents of the material
supplied as Supporting Information.
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