Gold Nanoparticles Supported on a Layered Double Hydroxide as Efficient Catalysts for the One-Pot Synthesis of Flavones

Article abstract of DOI:10.1002/anie.201507134

Flavones are a class of natural products with diverse biological activities and have frequently been synthesized by step-by-step procedures using stoichiometric amounts of reagents. Herein, a catalytic one-pot procedure for the synthesis of flavone and its derivatives is developed. In the presence of gold nanoparticles supported on a Mg-Al layered double hydroxide (Au/LDH), various kinds of flavones can be synthesized starting from 2′-hydroxyacetophenones and benzaldehydes (or benzyl alcohols). The present one-pot procedure consists of a sequence of several reactions, and Au/LDH can catalyze all these different types of reactions. The catalysis is shown to be truly heterogeneous, and Au/LDH can be readily recovered and reused. Go for gold: In the presence of gold nanoparticles supported on a Mg-Al layered double hydroxide (Au/LDH), various flavones were obtained from the corresponding 2′-hydroxyacetophenones and benzaldehydes (or benzyl alcohols). All three (four) steps of this one-pot process are catalyzed by Au/LDH in a truly heterogeneous fashion.

Full text of DOI:10.1002/anie.201507134

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Angewandte
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International Edition: DOI: 10.1002/anie.201507134
German Edition: DOI: 10.1002/ange.201507134
One-Pot Synthesis Very Important Paper
Gold Nanoparticles Supported on a Layered Double Hydroxide as
Efficient Catalysts for the One-Pot Synthesis of Flavones
Takafumi Yatabe, Xiongjie Jin, Kazuya Yamaguchi, and Noritaka Mizuno*
Abstract: Flavones are a class of natural products with diverse
biological activities and have frequently been synthesized by
step-by-step procedures using stoichiometric amounts of
reagents. Herein, a catalytic one-pot procedure for the synthesis
of flavone and its derivatives is developed. In the presence of
gold nanoparticles supported on a Mg-Al layered double
hydroxide (Au/LDH), various kinds of flavones can be
synthesized starting from 2’-hydroxyacetophenones and ben-
zaldehydes (or benzyl alcohols). The present one-pot proce-
dure consists of a sequence of several reactions, and Au/LDH
can catalyze all these different types of reactions. The catalysis
is shown to be truly heterogeneous, and Au/LDH can be
readily recovered and reused.
F
lavones are a class of flavonoids with a 2-phenylchromen-4-
one skeleton and present in many fruits and vegetables.
[1]
Scheme 1. Synthetic procedures for flavones.
They possess a variety of biological activities that are due to
the basic skeleton and have especially been found to be
effective for several diseases related to oxidative stress, such
as arteriosclerosis, diabetes, cancer, Alzheimerꢀs disease, and
2’-hydroxychalcone intermediates can be readily synthesized
by a base-catalyzed Claisen–Schmidt condensation of readily
[
1]
[3]
Parkinsonꢀs disease. Their activities and targets are largely
available 2’-hydroxyacetophenones and benzaldehydes.
[
1]
dependent on their substitution patterns. Therefore, to
discover flavone-based prominent lead compounds for vari-
ous diseases, it is very important to not only investigate their
structure–activity relationships in detail but also develop new
efficient procedures for their synthesis and structural modi-
fication.
However, the oxidative dehydrogenation step in route B is
still problematic, and halogen-based, organic, or metal-based
oxidants, such as Br , I , I /dimethyl sulfoxide (DMSO), 2,3-
2
2
2
dichloro-5,6-dicyano-para-benzoquinone (DDQ), and SeO ,
2
[
3]
have generally been utilized. Although a homogeneous
copper-catalyzed aerobic oxidative cyclization of 2’-hydrox-
ychalcones to flavones promoted by ionic liquids has recently
been developed, their direct synthesis from 2’-hydroxyaceto-
phenones and benzaldehydes has not been reported, and the
Thus far, various kinds of flavones have been synthesized
by utilizing two major routes (routes A and
B
in
[1–4]
Scheme 1).
Route A (the b-diketone route) is the tradi-
[3k]
tional and most frequently utilized choice. The Baker–
Venkataraman reaction and the Allan–Robinson reaction
2’-hydroxychalcones thus have to be separately prepared.
Recently, heterogeneous catalysts have been increasingly
used for liquid-phase fine-chemical synthesis, and numerous
[2]
belong to this category. The reaction typically proceeds
through the condensation of 2’-hydroxyacetophenones with
acid chlorides (or anhydrides) followed by rearrangement to
produce the b-diketone intermediates in the presence of
strong bases. Then, acid-catalyzed cyclodehydration of the
b-diketones gives the corresponding flavones. Route A is
intrinsically a step-by-step procedure, and strong acids, strong
bases (typically in superstoichiometric amounts), and pre-
[
5,6]
powerful catalytic systems have been developed to date.
Despite the advantages of heterogeneous catalysts, most of
the previously reported systems for the synthesis of flavones
[1–4]
are homogeneous.
Therefore, if the above-mentioned
route B could be realized as a heterogeneously catalyzed
one-pot procedure using molecular oxygen as the terminal
oxidant, it would be one of the greenest and most powerful
procedures for the synthesis of flavones.
Herein, we have developed the first efficient heteroge-
neously catalyzed one-pot synthesis of flavones starting
directly from 2’-hydroxyacetophenones and benzaldehydes
[2]
activated substrates are required. Route B (the chalcone
route) is an attractive procedure because the
[
*] T. Yatabe, Dr. X. Jin, Dr. K. Yamaguchi, Prof. Dr. N. Mizuno
Department of Applied Chemistry, School of Engineering
The University of Tokyo
(or benzyl alcohols) in the presence of gold nanoparticles
supported on a Mg-Al layered double hydroxide (Au/
[
7]
LDH). The present one-pot process consists of a Claisen–
Schmidt condensation (base catalysis), an intramolecular oxa-
Michael addition (base catalysis), and an aerobic oxidative
dehydrogenation of chromanones (gold catalysis; route B in
7
-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656 (Japan)
E-mail: tmizuno@mail.ecc.u-tokyo.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507134.
1
3302
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Angewandte
Chemie
[8–10]
Scheme 1).
When benzyl alcohols are used as the starting
desired product 3aa was obtained in 76% yield when the Au/
materials, the sequence begins with aerobic oxidation of the
LDH catalyst was used (entry 1). When the reaction was
carried out with Au/LDH under an argon atmosphere, the
yield of 3aa decreased to 24% (entry 9). In this case, the
hydrogenation of the C=C bond of 4aa also proceeded to
[7]
alcohol (gold catalysis). The Au/LDH catalyst plays multi-
ple roles in this process, catalyzing all the different types of
reactions included in this sequence. The catalysis is shown to
be truly heterogeneous, and the Au/LDH catalyst can be
reused without a severe loss of catalytic performance. The
present procedure possesses several noteworthy features, for
example, 1) the use of a reusable heterogeneous catalyst,
some extent. Therefore, molecular oxygen (in air) acted as the
[13]
terminal oxidant in the present system. The effect of the
gold supports was significant, and LDH showed the best
performance among the supports examined (entries 1 and 6–
8). The basicity of LDH possibly plays an important role for
not only catalyzing the Claisen–Schmidt condensation and the
2
) simple one-pot operation and avoidance of tedious iso-
lation steps, 3) the use of the greenest oxidant, namely
molecular oxygen (in air), as the terminal oxidant, 4) readily
available starting materials, 5) no need for additives, and
[12]
oxa-Michael addition,
but also promoting the oxidative
dehydrogenation of 5aa (see below).
6
) the formation of water as the theoretically only by-product.
To begin with, we prepared various kinds of supported
To determine whether the active catalyst was solid Au/
LDH or a leached metal species (gold, magnesium, and/or
aluminum), Au/LDH was removed by hot filtration during
the reaction when 3aa had been formed in approximately
50% yield; then the reaction was repeated with the filtrate
under the same reaction conditions. As shown in the
Supporting Information, Figure S1, the production of 3aa
was completely stopped by removal of Au/LDH. Further-
more, we confirmed by inductively coupled plasma atomic
emission spectroscopy (ICP-AES) analysis that gold, magne-
sium, and aluminum species were hardly present in the filtrate
metal catalysts (referred to as metal/support, see the Sup-
[
11]
porting Information), and they were tested for the direct
one-pot synthesis of flavone (3aa) starting from 2’-hydroxy-
acetophenone (1a) and benzaldehyde (2a). The reactions
were carried out in mesitylene at 1308C in open air (1 atm)
using an equimolar mixture of 1a and 2a. Under these
reaction conditions, the desired compound 3aa was not
produced at all in the absence of catalyst (Table 1, entry 11).
(
Au: < 0.003%, Mg: < 0.02%, Al: < 0.4%). The above
[
a]
Table 1: Synthesis of flavone (3aa) using various catalysts.
experimental results rule out that metal species that had
leached into the reaction solution contribute to the observed
catalysis, which is thus truly heterogeneous.
[14]
After the
reaction of 1a and 2a was completed, the Au/LDH catalyst
could be readily retrieved from the reaction mixture by
simple filtration. It could then be reused for the same reaction
Entry
Catalyst
Conv. [%]
Yield [%]
[15]
1
a
2a
3aa
4aa
5aa
without a severe loss of catalytic performance (Table S1).
Next, we examined the scope of the present Au/LDH-
catalyzed one-pot procedure. Under the optimized reaction
conditions, various structurally diverse flavones could be
synthesized starting directly from 2’-hydroxyacetophenones
1
2
3
4
5
6
7
8
Au/LDH
Ru/LDH
Rh/LDH
Pd/LDH
Pt/LDH
Au/Al O
>99
70
79
84
91
79
46
40
97
78
74
>99
96
83
56
78
>99
90
65
76
<1
<1
2
<1
58
34
3
24
<1
<1
<1
5
20
2
20
2
<1
<1
15
31
<1
<1
16
39
22
44
[16]
and benzaldehydes. The products were readily isolated by
3
2
3
simple column chromatography on silica gel (see the Sup-
porting Information), and the yields of isolated products are
given in Scheme 2. The reaction of 1a with benzaldehydes
with either electron-donating or electron-withdrawing sub-
stituents at various positions of the aryl rings efficiently
produced the corresponding flavones (3aa–3ag). In the case
of para-tolualdehyde, the undesirable oxidation of the
benzylic methyl group hardly proceeded (3ab). Furthermore,
various substituted 2’-hydroxyacetophenones were suitable
reaction partners for benzaldehydes (3ba, 3ca, and 3cb). By
utilizing the present Au/LDH-catalyzed one-pot procedure,
various halogen-substituted flavones could be efficiently
synthesized. These halide functional groups could then be
used for further derivatization of these flavone molecules.
Aside from benzaldehydes, aliphatic aldehydes could be
employed; for example, the reaction of 1a with n-octanal
afforded the corresponding chromone (3ah). Furthermore, by
using 2’-(methylamino)acetophenone and 2a as the starting
materials, the present Au/LDH-catalyzed one-pot procedure
could successfully construct the corresponding 4-quinolone
skeleton (3da). It is known that Au/LDH can act as an
efficient heterogeneous catalyst for the aerobic oxidation of
Au/TiO2
<1
<1
34
59
<1
Au/CeO2
Au/LDH
LDH
[
b]
9
1
1
>99
>99
9
0
1
–
[
a] Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), catalyst
(
(
130 mg), mesitylene (2 mL), 1308C, open air (1 atm), 24 h. Benzoic acid
formed by the oxidation of 2a) was formed as a side product. When
supported gold catalysts were used, aurone (possibly by dehydrogen-
ation of the 5-exo-trig oxa-Michael adduct) was formed as a side product
(<5%). Yields were determined by GC analysis using biphenyl as an
internal standard. [b] Ar atmosphere (1 atm).
Although the Claisen–Schmidt condensation product 4aa and
the oxa-Michael addition product 5aa were formed when
[
12]
using just LDH, the oxidative dehydrogenation of 5aa to
aa did not take place at all (entry 10). In the presence of Ru/
3
LDH, Rh/LDH, Pd/LDH, or Pt/LDH, 3aa was barely
produced even though the Claisen–Schmidt condensation
and the oxa-Michael addition proceeded (entries 2–5), thus
indicating that these supported metals are intrinsically
inactive for the oxidative dehydrogenation. Fortunately, the
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(Table S2) in the presence of Au/LDH. Therefore, the present
one-pot procedure consists of a Claisen–Schmidt condensa-
tion of the 2’-hydroxyacetophenones (1) with the benzalde-
hydes (2) to yield 2’-hydroxychalcones (4), an intramolecular
oxa-Michael addition of intermediates 4 to form chroma-
nones (5), and the oxidative dehydrogenation of 5, which
affords the desired flavones (3). The LDH can act as a solid
base catalyst of the Claisen–Schmidt condensation and the
[12]
oxa-Michael addition. When benzyl alcohols are used as
the starting materials, the sequence begins with aerobic
alcohol oxidation by a typical alkoxide formation/hydride
[7,17]
elimination mechanism.
To elucidate the roles of the catalyst in the oxidative
dehydrogenation step in more detail, several experiments
were carried out. First, the oxidative dehydrogenation of 5aa
to 3aa was performed with various supported metal catalysts.
Ru/LDH, Rh/LDH, Pd/LDH, and Pt/LDH were inactive for
the dehydrogenation, whereas supported gold catalysts gave
3
aa in significant yields (Table S2). These results are con-
sistent with those described in Table 1. The effect of the gold
support was also significant; the catalytic performance
depended on the kind of support and was independent of
[18]
the specific surface area (Table S2). Therefore, we conclude
that the basicity of LDH assists the gold-catalyzed oxidative
dehydrogenation likely by promoting the deprotonation of
Scheme 2. Substrate scope. Reaction conditions: 1 (0.3 mmol), 2
(
(
0.6 mmol), Au/LDH (100 mg), mesitylene (2 mL), 1308C, open air
1 atm). Yields (based on 1) of isolated products are given. [a] Au/
5
aa. The oxidative dehydrogenation of 5aa was not influ-
enced by the presence of an equimolar amount of the radical
scavenger 2,6-di-tert-butyl-4-methylphenol (BHT) with
respect to 5aa (Figure S3), indicating that radical species
are not involved in the present transformation. Next, the
oxidative dehydrogenation of 5aa was carried out with
2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO). TEMPO is
also a radical scavenger and known to be an effective
hydrogen atom abstractor. Furthermore, it has been reported
that TEMPO can abstract a hydrogen atom (one electron and
one proton) from a AuÀH species with concomitant
LDH (200 mg). [b] 3aa was also formed (8%). [c] The product was
isolated as a monohydrate.
[7]
alcohols. Therefore, we expected that benzyl alcohols
instead of benzaldehydes) could also be utilized as the
(
starting materials for the present Au/LDH-catalyzed one-pot
flavone synthesis. As shown in Scheme 3, several substituted
flavones could indeed be synthesized directly from 1a and
benzyl alcohols. To the best of our knowledge, such a hetero-
geneously catalyzed direct one-pot flavone synthesis was
hitherto unknown.
The reaction profile for the Au/LDH-catalyzed trans-
formation of 1a and 2a revealed that 4aa and 5aa are initially
produced followed by the formation of 3aa (Figure S2).
Furthermore, it was confirmed by separate experiments that
formation
of
1-hydroxy-2,2,6,6-tetramethylpiperidine
[17]
(TEMPOH). When the Au/LDH-catalyzed oxidative dehy-
drogenation of 5aa was carried out in the presence of an
equimolar amount of TEMPO with respect to 5aa, the
reaction was somewhat faster than without TEMPO, and the
formation of TEMPOH was observed (Figure S3). This result
clearly supports the formation of a AuÀH species during the
3
aa can be synthesized starting from 4aa (Scheme S1) or 5aa
catalytic cycle.
Based on the above-mentioned experimental results, we
now propose a possible mechanism for the gold-catalyzed
oxidative dehydrogenation of 5 (Scheme S2). The direct
hydrogen atom abstraction pathway can be excluded because
the reaction rates did not decrease in the presence of radical
scavengers such as BHT and TEMPO. Therefore, we believe
that the dehydrogenation possibly proceeds by a deprotona-
tion/hydride elimination mechanism. The relatively acidic
hydrogen atom at the 3-position of 5 is abstracted as a proton
in a process that is promoted by the LDH, and the proton is
temporarily stored on the basic LDH surface. The hydrogen
at the 2-position is eliminated as a hydride to form a transient
AuÀH species. As mentioned above, molecular oxygen (in
Scheme 3. One-pot synthesis of flavones starting from 1a and benzyl
alcohols. Reaction conditions: 1a (0.5 mmol), 6 (0.5 mmol), Au/LDH
[13]
air) acts as the terminal oxidant in the present system and
regenerates the active gold species by removing the hydrogen
(130 mg), mesitylene (2 mL), 1308C, open air (1 atm). Yields were
determined by GC analysis using biphenyl as an internal standard.
1
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atom from the AuÀH species via the formation of a hydro-
[7] For the use of Au/LDH for aerobic alcohol oxidation, see: a) T.
[
17]
Mitsudome, A. Noujima, T. Mizugaki, K. Jitsukawa, K. Kaneda,
Adv. Synth. Catal. 2009, 351, 1890; b) T. Mitsudome, A. Noujima,
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peroxide. The proton stored on LDH is consumed for the
production of water.
In conclusion, we have described the first heterogeneously
catalyzed synthesis of flavones in a one-pot process from 2’-
hydroxyacetophenones and benzaldehydes (or benzyl alco-
hols). Gold nanoparticles supported on a layered double
hydroxide catalyzed all three (four) steps of the overall
process. Owing to the practical reaction conditions, we hope
that this transformation will find wide application for the
synthesis of flavone derivatives and related compounds.
7
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Keywords: flavones · gold catalysis · heterogeneous catalysis ·
layered double hydroxides · one-pot synthesis
How to cite: Angew. Chem. Int. Ed. 2015, 54, 13302–13306
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K. Yamaguchi, K. Mori, T. Mizugaki, K. Ebitani, Catal. Surv.
Jpn. 2000, 4, 31.
6] For excellent reviews on one-pot syntheses using heterogeneous
catalysts, see: a) M. J. Climent, A. Corma, S. Iborra, Chem. Rev.
[13] The Au/LDH-catalyzed oxidative dehydrogenation of 5aa under
the conditions described in Table S2 gave 3aa in 66% yield.
Under an argon atmosphere, the yield of 3aa decreased to 4%,
2
2
011, 111, 1072; b) H. Miyamura, S. Kobayashi, Acc. Chem. Res.
014, 47, 1054.
Angew. Chem. Int. Ed. 2015, 54, 13302 –13306
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Angewandte
Communications
and the hydrogenation of 4aa (formed by a retro-Michael
addition) was observed.
14] R. A. Sheldon, M. Wallau, I. W. C. E. Arends, U. Schuchardt,
Acc. Chem. Res. 1998, 31, 485.
surface (Figure S7). Therefore, the deactivation of Au/LDH is
not caused by a change in the size of the gold nanoparticles but
by the adsorption of carboxylic acids.
[
[
[16] A larger (5 mmol) scale synthesis was also effective and gave 3aa
in 64% yield under the conditions described in Scheme S3.
[17] M. Conte, H. Miyamura, S. Kobayashi, V. Chechik, J. Am. Chem.
Soc. 2009, 131, 7189.
15] The yield of 3aa gradually decreased for each reuse experiment
(
Table S1). The average particle size of gold in the fresh Au/
LDH sample was 4.2 nm (s = 1.2 nm) and was unchanged after
the second reuse experiment (4.3 nm, s = 1.2 nm; Figure S4). It
was confirmed by X-ray photoelectron spectroscopy (XPS)
analysis that the oxidation state of gold was still zero after the
reaction (Figure S5). X-ray diffraction (XRD) analysis revealed
that the structure of LDH had been almost preserved after the
[18] The influence of the particle size of the gold nanoparticles was
also studied (Table S2). In our previous study, we had observed
that the gold-catalyzed oxidative dehydrogenation of such
compounds tends to become slower as the average gold particle
[9]
size increases.
reaction (Figure S6). The IR spectrum of Au/LDH after the
À1
second reuse experiment showed a band around 1600 cm
,
which was attributed to carboxylate species, suggesting the
adsorption of carboxylic acids (formed by oxidation of the
aldehyde substrates and/or mesitylene) on the basic LDH
Received: July 31, 2015
Revised: August 21, 2015
Published online: September 14, 2015
1
3306 www.angewandte.org
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Angew. Chem. Int. Ed. 2015, 54, 13302 –13306