Process Intensification with Bifunctional Heterogeneous Catalysts: Selective One-Pot Synthesis of 2′-Aminochalcones

Article abstract of DOI:10.1021/cs5011713

(Chemical Equation Presented) 2′-Aminochalcones of pharmaceutical and commercial interest have been obtained in high yields and selectivities through a one-pot process using a bifunctional heterogeneous catalyst bearing base and metal active sites. This is a physical mixture material formed by a high-surface-area MgO and Pt on TiO₂. The process involves as the first step the Claisen-Schmidt condensation between o-nitroacetophenone and benzaldehyde derivatives on the basic catalytic function. This is followed by a chemoselective hydrogenation of the nitro group in the presence of the carbonyl and double-bond carbon-carbon groups within the molecule. Using the bifunctional catalyst and the reaction system proposed here, it is possible to produce, under mild reaction conditions and short reaction times, 2′-aminochalcones with higher yields and selectivities than those obtained by conventional multistep methods.

Full text of DOI:10.1021/cs5011713

Research Article
pubs.acs.org/acscatalysis
Process Intensification with Bifunctional Heterogeneous Catalysts:
Selective One-Pot Synthesis of 2′-Aminochalcones
,†
,†,‡
†
†
M. J. Climent,* A. Corma,* S. Iborra, and L. Martí
†
Instituto de Tecnología Química (UPV-CSIC), Universitat Politec
́
nica de Valen
King Fahd University of Petroleum and Minerals, P.O. Box 989, Dhahran 31261, Saudi Arabia
S Supporting Information
̀
cia, Avda dels Tarongers s/n, 46022 Valencia, Spain
‡
*
ABSTRACT: 2′-Aminochalcones of pharmaceutical and commercial interest have been obtained in high yields and selectivities
through a one-pot process using a bifunctional heterogeneous catalyst bearing base and metal active sites. This is a physical
mixture material formed by a high-surface-area MgO and Pt on TiO . The process involves as the first step the Claisen−Schmidt
2
condensation between o-nitroacetophenone and benzaldehyde derivatives on the basic catalytic function. This is followed by a
chemoselective hydrogenation of the nitro group in the presence of the carbonyl and double-bond carbon−carbon groups within
the molecule. Using the bifunctional catalyst and the reaction system proposed here, it is possible to produce, under mild reaction
conditions and short reaction times, 2′-aminochalcones with higher yields and selectivities than those obtained by conventional
multistep methods.
KEYWORDS: heterogeneous catalysis, 2′-aminochalcones, fine chemicals, cascade process, bifunctional catalyst
1
. INTRODUCTION
However, the synthesis of 2′-aminochalcones by Claisen−
Schmidt condensation between o-aminoacetophenones and
benzaldehyde derivatives is not an easy-to-perform process
because in the presence of strong bases, besides the typical
possible side reactions such as the Cannizaro reaction and the
self-aldol condensation of acetophenones, oligomerization
reactions of amino compounds can also take place easily,
Chalcones (1,3-diaryl-2-propen-1-ones), which belong to the
flavonoid family, are abundant in edible plants where they serve
different physiological functions such as UV photoprotectors,
1
insect repellents, and attractants of pollinators. A huge number
of chalcone derivatives have attracted increasing attention
because of their potential pharmacological applications such as
anticancer (inhibiting tubulin polymerization), diuretic, choler-
etic, spasmolytic, bactericidal, antiinflammatory, antimalarial,
and antifungal properties. Among them, 2′-aminochalcone
derivatives are interesting compounds because they exhibit
antitumor activity and because of their high UV−visible
extinction coefficient are useful as photoprotectors in sunscreen
formulations as well as in textile polymers or fibers.
The most general method of obtaining chalcones is by
Claisen−Schmidt condensation between substituted acetophe-
nones and substituted benzaldehydes in the presence of
conventional homogeneous bases, such as aqueous alkali
metal hydroxide solutions. In recent years, heterogeneous
catalysts have gained importance mainly because of environ-
mental and economical factors. Then, a variety of solid acid
catalysts such as zeolites, silica−H SO , and Montmorillonite
KSF (clay) and base heterogeneous catalysts such as MgO,
Al/Mg mixed oxides, activated Ba(OH)
carbons (Na- and Cs-Norit), hydroxyapatite, and KF-
considerably decreasing the final yield of the 2′-amino-
14,15
chalcones.
For example, a 52−72% yield of 2′-amino-
chalcone has been reported, starting from o-aminoacetophe-
2
none and benzaldehyde in aqueous or ethanolic solutions of
14,16
NaOH or KOH (10−15 wt %) and 5−25 °C.
A higher
3
17
yield (94%) were reported by Lee et al., although a higher
concentration of a strong base (25 wt % MeONa), a lower
temperature (0 °C), and a toxic solvent such as THF were
required. To overcome these difficulties, other strategies have
been reported. For instance, a 68−84% yield of 2′-amino-
chalcones can be obtained by protecting the amino group of the
acetophenone by acetylation with acetic anhydride before the
condensation reaction. However, in this case, an additional
process of hydrolysis of the resulting 2′-acetamidochalcones
4
1
18
was required. Another procedure for obtaining 2′-amino-
chalcones consists of reducing the corresponding 2′-nitro-
chalcone. Nevertheless, the presence of different reducible
5
6
2
4
7
8
9
10
basic activated
2
,
11
12
Received: August 11, 2014
Revised: November 13, 2014
1
3
supported alumina have been evaluated for the synthesis of
chalcones.
©
XXXX American Chemical Society
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Research Article
functions such as the CC bond and carbonyl group within
the molecule makes the process difficult, giving a low selectivity
to the corresponding 2′-aminochalcone. For instance, different
homogeneous catalysts have been employed for the reduction
of 2′-nitrochalcones such as iron−acetic acid, ferrous hydroxide,
sodium hydrogen sulfide, and stannous chloride−hydrochloride
2. EXPERIMENTAL SECTION
.1. Materials and Methods. Benzaldehyde was purified
2
by distillation (≥99.5%). Biphenyl (99.5%), o-nitroacetophe-
none (95%), o-aminoacetophenone (98%), o-xylene (≥99%),
magnesium nitrate hexahydrated (≥99%), aluminum nitrate
nonahydrate (≥98%), sodium carbonate (≥99.5%), and
sodium hydroxide (≥95%) were purchased from Aldrich.
Gold(III) chloride trihydrate (99.9%), platinum(II) acetylacet-
onate (97%), and palladium(II) acetylacetonate (99%) were
purchased from Aldrich. Titanium dioxide P-25 Degussa and
aluminum oxide nanopowder were purchased by Evonik
Industries and NanoScale Materials, respectively.
1
9
acid. Thus, in the presence of the most satisfactory catalyst,
stannous chloride in hydrochloride acid, 2′-nitrochalcone was
reduced to 2′-aminochalcone with a 45% yield. After this
reduction process, an additional step using excess aqueous
ammonia followed by extraction with boiling acetone is
required. Moreover, this route requires as a previous step the
synthesis of the corresponding 2′-nitrochalcone through the
Claisen−Schmidt condensation between o-nitroacetophenones
and benzaldehydes. Unfortunately, this condensation under a
homogeneous catalysis (NaOH) gives a low yield of the
Al/Mg hydrotalcite was prepared by following a previously
9b
reported procedure. An Mg−Al hydrotalcite with a Mg/Al
ratio of 3 was prepared from gels produced by mixing two
20
solutions: solution A containing 2.25 moles of Mg(NO ) and
corresponding 2′-nitrochalcone (∼60%). Then, if both steps
are combined for the production of 2′-aminochalcones,
maximum yields of about 25% can be obtained using a
conventional homogeneous catalyst (Scheme 1).
3 2
0
.75 mol of Al(NO ) in an Al + Mg concentration of 1.5 mol/
3 3
L for a ratio of 0.25 and another solution B of 6.75 moles of
NaOH and 2 moles of Na CO dissolved in the same volume of
solution A. Both solutions are coadded at a rate of 1 mL min
2
3
−1
under vigorous mechanical stirring at room temperature. The
suspension was left for 18 h at 60 °C. The hydrotalcite was
filtered and washed until pH 7 was achieved, and the solid was
dried at 60 °C. The hydrotalcite was calcined at 450 °C in dry
nitrogen for 6 h in order to obtain the corresponding Al/Mg
Scheme 1. Synthesis of 2′-Aminochalcone from Nitro or
Aminoacetophenones and Benzaldehyde Using
Conventional Methods
2
−1
mixed oxide (HTc) with a surface area of 267 m g . The
hydrated Al/Mg mixed oxide (HTr) was obtained by directly
adding 36 wt % water over the HTc just before the reaction
2
−1
(
SBET = 30 m g ).
A MgO sample with a surface area of 670 m g was
2
−1
purchased from NanoScale Materials. Prior to each experiment,
the catalyst was calcined at 450 °C for 10 h first in a stream of
air and finally in a stream of nitrogen to remove any absorbed
impurities and carbonates. The KF−Al O sample with 40 wt %
2
3
KF was supplied by Aldrich.
Au−TiO (1.5 wt %) was supplied by Strem Chemicals, Inc.
2
Pt−TiO (0.2 wt %) and Pt−Al O (0.2 wt %) samples were
2
2
3
As described above, these methods suffer from unsatisfactory
yields, use expensive and sometimes corrosive reagents, give
residual wastes salts and effluent-polluting chemicals, and
require various purification steps with the corresponding energy
consumption. Therefore, there is an incentive to develop a
catalytic process able to produce 2′-aminochalcones by
environmentally friendly methods while minimizing the
number of reaction steps.
prepared by incipient wetness following previously reported
2
2
procedure. Pt−TiO catalyst (0.2 wt %) was prepared by
2
supporting nanosized crystals of Pt on TiO and decorating the
2
exposed (111) and (110) Pt crystal faces with TiO from the
2
−1
support by activation under hydrogen flow (100 mL min ) at
50 °C for 3 h. The same pretreatment was used for Pt−Al O .
4
2
3
Pd−MgO (0.5 wt %) and Pt−MgO (0.5 wt %) with different
Pt loadings were prepared by the impregnation of the support
with the corresponding amount of a solution of palladium(II)
acetylacetonate or platinum(II) acetylacetonate, respectively, in
water-free toluene (12.5 mL) that was added to 1 g of an oxide
support. The mixture was stirred for 12 h at room temperature,
and the solvent was removed at reduced pressure and dried
overnight under vacuum. The samples were calcined for 3.5 h at
In this work, we have studied for the first time the possibility
to produce 2′-aminochalcones through a one-pot process using
a bifunctional heterogeneous catalyst that combines basic and
metal functions. The process involves as a first step the
Claisen−Schmidt condensation between o-nitroacetophenone
and benzaldehyde derivatives catalyzed by the basic sites with
the selective hydrogenation of the nitro into the amino group
on the metal sites (Scheme 2).
2
1
−1
550 °C with an N flow of 100 mL min and actived by
2
Scheme 2. One-Pot Process for the Synthesis of 2′-Aminochalcone Using a MgO/Pt−TiO Catalyst
2
1
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Research Article
calcination at 450 °C with a mixture of hydrogen and nitrogen
2.2.2. Reduction of 2′-Nitrochalcone (3) to 1-(2-Amino-
phenyl)-3-phenylprop-2-en-1-one (2′-Aminochalcone, 4)
(General Procedure). In a 3 mL autoclave we placed the
−1
(
H /N 90/10 at a flow rate of 100 mL min ) for 2 h.
2 2
Au−MgO (0.5 wt %) was prepared following the Pd−MgO
procedure but using HAuCl ·3H O as a source of Au. The
catalyst (Pt−TiO , 30 mg) and a solution of 2′-nitrochalcone
4
2
2
catalyst was actived at 250 °C with a mixture hydrogen and
(0.5 mmol, 126 mg) and 1,1′-biphenyl as an internal standard
(72 mg, 0.5 mmol) in 0.5 mL of o-xylene. The autoclave was
pressurized at 9 bar of hydrogen and held at 70 °C under
vigorous stirring.
−1
nitrogen (H /N 90/10 at a flow rate of 100 mL min ) for 3 h.
2
2
Au(1 wt %)−Pt−MgO(100 ppm) was prepared by the
impregnation of the support with an aqueous solution (25 mL)
of platinum(II) acetylacetonate (1 mg) and HAuCl ·3H O (40
2.2.2.1. One-Pot Procedure: Preparation of 1-(2-Amino-
phenyl)-3-phenylprop-2-en-1-one (4). Typically, a solution of
o-nitroacetophenone (165 mg, 1 mmol), benzaldehyde (106
mg, 1 mmol), 1,1′-biphenyl as an internal standard (72 mg, 0.5
mmol), and 0.5 mL of o-xylene was added to a physical mixture
4
2
mg), which was added to 2 g of oxide support. The mixture was
stirred for 12 h at room temperature, and the solvent was
removed at reduced pressure. The sample was calcined for 3.5 h
−
1
at 450 °C with an N flow of 100 mL min and then reduced
2
−1
with hydrogen (H flow rate of 100 mL min ) for 2 h. A
of calcined MgO (30 mg) and 0.2 wt % Pt−TiO (30 mg). The
2
2
Au(0.7 wt %)−Pt(0.45 wt %) sample was prepared following
the same methodology.
reaction mixture was heated to 90 °C under vigorous stirring.
When the maximum yield of 2′-nitrochalcone was achieved
(98%), the temperature was set to 70 °C and the autoclave was
pressurized at 9 bar of hydrogen. After reaction, the catalyst was
collected by vacuum filtration, and the product mixture was
analyzed by GC-MS.
The amount of metal supported was determined by ICP
analysis in a Varian SpectrAA-10 Plus. The average metal size of
the different catalysts was measured with TEM images that
were acquired by using a JEM 1010 transmission electron
microscopy operated at 100 kV. The samples were prepared
directly by dispersing the powders onto carbon copper grids.
Physicochemical characteristics of metal-supported catalysts are
summarized in Table 1.
In all reactions, samples were taken at regular intervals,
diluted with acetonitrile, and analyzed by GC equipped with a
Biorad column (30 m × 0.25 mm × 0.25 μm) and an FID as
the detector. In all cases, the molar balance was ≥95%.
2
.2.2.2. Recycling of the MgO/Pt−TiO Physical Mixture.
2
After reaction, the catalyst was recovered by filtration and
calcined at 450 °C for 7 h in the presence of air, followed by a
stream of nitrogen (3 h). Before each cycle, the catalyst was
actived at 450 °C under hydrogen flux for 3 h. The amount of
reactants was readjusted to the acatalyst weight to maintain the
initial ratios.
Table 1. Physicochemical Characteristics of Metal-
Supported Catalysts
catalyst
Pd−MgO
metal content (wt %)
metal particle size (nm)
0.5
0.05
0.1
0.2
0.5
1
3−5
1.5
1.7
2.4
3
0.05Pt−MgO
0.1Pt−MgO
0.2Pt−MgO
0.5Pt−MgO
1Pt−MgO
2.2.2.3. Synthesis of 2′-Aminochalcones under Homoge-
neous Catalysis. The synthesis of 2′-aminochalcones using a
homogeneous catalyst was performed following the procedure
described in ref 15. Typically, 2′-aminoacetophenone (2 mmol)
was added to a solution of benzaldehyde (2 mmol) in 15 mL of
ethanol containing 15 wt % NaOH and stirred at 25 °C for 16
h.
8.7
8.5
12.3
12.1
3−6
1.5
4
Au−MgO
Au−Pt−MgO(1)
Au−Pt−MgO(2)
0.5
1
a
b
0.7
1.5
0.2
Au−TiO2
Pt−TiO2
2
The 2′-nitrochalcone and 2′-aminochalcone derivatives that
were synthesized were isolated by liquid chromatography using
silica gel and a mixture of hexane−ethyl acetate with different
polarities as the eluent. The compounds were further purified
by recrystallization in ethanol. The identification of the
products was carried out by MS-GS (Agilent MDS-5973 with
an HP5 capillary column) and NMR spectroscopy with a
Pt−Al O3
0.2
a
b
The catalyst contains 100 ppm Pt. The catalyst contains 0.45 wt %
Pt with a crystal size of 2.3 nm.
1
Powder X-ray diffraction patterns were collected with a
Philips X’PERT diffractometer equipped with a proportional
detector and a secondary graphite monochromator. Data were
collected stepwise over the 2° ≤ 2θ ≤ 40° angular region with
steps of 0.02° 2θ, a 20 s/step accumulation time, and Cu KR (λ
Bruker Avance 300 spectrometer working at 300 MHz for H
and at 75 MHz for 13C. The H and C NMR spectra of the
1
13
products were recorded using CDCl as the solvent and TMS
3
as the internal reference. A coupling constant of approximately
1
of 16 Hz for the CHCH protons in the H NMR spectrum
=
1.54178 Å) radiation.
.2. Reaction Procedure. 2.2.1. Synthesis of 1-(2-
Nitrophenyl)-3-phenylprop-2-en-1-one (2′-Nitrochalcone, 3)
General Procedure). The Claisen−Schmidt condensation was
of the 2′-aminochalcones indicates the trans geometry for the
chalcone.
2
ESI−HRMS (electrospray ionization−high-resolution mass
spectrometry). Samples were diluted in acetonitrile and
analyzed by means of a Waters ACQUITY XevoQToF
spectrometer (Waters Corp.) through direct infusion of the
liquid sample in an ESI interface. The ESI source was operated
in positive ionization mode with the capillary voltage at 1.5 kV.
The temperature of the source and desolvation were set at 100
and 400 °C, respectively. The cone and desolvation gas flows
(
performed in a 3 mL autoclave containing 30 mg of basic
catalyst under a nitrogen atmosphere. Then a solution of o-
nitroacetophenone (165 mg, 1 mmol) and benzaldehyde (106
mg, 1 mmol) in 0.5 mL of o-xylene was added, and 1,1′-
biphenyl was used as an internal standard. The reaction mixture
was heated to 90 °C under vigorous stirring. After reaction, the
catalyst was filtered off, and the solvent was eliminated by
heating under reduced pressure. The 2′-nitrochalcone (3) was
crystallized in ethanol as white needles.
−1
were 100 and 800 L h , respectively. All data collected in
centroid mode were acquired by using the Masslynx software
(Waters Corp.). Leucine enkephalinephalin was used as the
1
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dx.doi.org/10.1021/cs5011713 | ACS Catal. 2015, 5, 157−166

ACS Catalysis
lock mass generating an [M + H] ion (m/z = 556.2771) at a
concentration of 2 ng mL and a flow rate of 50 mL min to
ensure accuracy during the MS analysis.
Research Article
+
131 (CH), 130 (CH), 129 (CH), 128 (3CH), 126 (C), 123
−1
−1
+
(CH), 117 (CH), 116 (CH). MS m/z (%) 222 (M − 1, 89),
1
94 (12), 146 (100), 120 (15), 92 (21), 65 (24), 39 (7).
2
.2.2.4. Spectral Characteristics Data. 2.2.2.4.1. trans-1-(2-
2
.2.2.4.8. 1-(2-Aminophenyl)-3-phenylpropan-1-one. 1H
NMR (CDCl , 300 MHz): δ 7.66 (dd, 8.01, 1.41 Hz, 1H);
1
Nitrophenyl)-3-phenylprop-2-en-1-one (3). H NMR (CDCl ,
3
3
3
7
7
7
00 MHz): δ 8.19 (ddd, 8.10, 1.32, 0.38 Hz, 1H); 7.77 (td,
.54, 1.32 Hz, 1H); 7.66 (ddd, 9.04, 7.54, 1.51 Hz, 1H); 7.53−
.47 (m, 3H); 7.42−7.35 (m, 3H); 7.24 (d, 16.20 Hz, 1H);
7
1
2
(
1
.25−7.1 (m, 6H); 6.57 (d, 8.34 Hz, 1H); 6.54 (td, 7.08 Hz,
H); 6.1 (broad, 2H); 3.25 (t, 8.4 Hz, 2H); 3 (t, 8.34 Hz,
H). C NMR (CDCl , 75 MHz): δ 201 (C), 150 (C), 142
13
1
3
3
.01 (d, 16.20 Hz, 1H). C NMR (CDCl , 75 MHz): δ 192
3
C), 141 (C), 134 (CH), 131 (CH), 129 (CH), 128 (CHx2),
27 (CH), 126 (CH), 117 (CH), 116 (CH), 41 (CH ), 30
(
(
(
C), 146 (C), 146 (CH), 136 (C), 134 (CH), 133 (C), 131
CH), 130 (CH), 129 (CH), 128 (2CH), 126 (CH), 124
CH). MS m/z (%) 253 (M , 6), 207 (36), 191 (4), 147 (16),
2
+
(CH2).
.2.2.4.9. trans-1-(2-Aminophenyl)-3-(4-chlorophenyl)-
prop-2-en-1-one (4a). H NMR (CDCl , 300 MHz): δ 7.75
2
1
19 (16), 105 (67), 77 (93), 51 (36), 28 (28).
1
2
.2.2.4.2. trans-3-(4-Chlorophenyl)-1-(2-nitrophenyl)prop-
3
1
(
dd, 8.43, 1.53 Hz, 1H); 7.55 (q, 15.6 Hz, 2H); 7.45 (dt, 84,
2
-en-1-one (3a). H NMR(CDCl , 300 MHz): δ 8.2 (dd, 8.2, 1
3
Hz, 1H); 7.8 (td, 7.5, 1.2 Hz, 1H); 7.7 (ddd, 8.1, 7.5, 1.5 Hz,
H); 7.5 (dd, 7.8, 1.5 Hz, 1H); 7.4 (dt, 8.4, 2.1 Hz, 2H); 7.3
dt, 8.4, 2.1 Hz, 2H); 7.2 (d, 16.2 Hz, 1H); 6.95 (d, 16.2 Hz,
H). 13C NMR (CDCl 75 MHz): δ 192(C), 145 (CH), 139
1,7.1 Hz, 2H); 7.30 (dt, 8.49, 1.83 Hz, 2H); 7.20 (td, 8.37, 1.5
Hz, 1H); 6.61 (tt, 7.14, 1.14 Hz, 1H); 6.62 (dd, 8.28, 1.26 Hz,
1
(
1H); 6.27 (broad, 2H). 13C NMR (CDCl , 75 MHz): δ 191
3
1
(C), 151 (C), 141 (CH), 136 (C), 134 (CH), 133 (C), 131
CH), 129 (CH × 2), 123 (CH), 119 (C), 117 (C), 116 (C).
MS m/z (%) 256 (M − 1, 33), 146 (100), 120 (9), 92 (13), 65
12), 39 (3).
.2.2.4.10. trans-1-(2-Aminophenyl)-3-(4-fluorophenyl)-
3
,
(
(
C), 138 (C), 137 (CH), 136 (CH), 130 (CH), 128 (CH), 125
CH), 118 (C), 115 (C).
(
+
2
.2.2.4.3. trans-3-(4-Fluorophenyl)-1-(2-nitrophenyl)prop-
(
1
2
-en-1-one (3b). H NMR (n, 300 MHz): δ 8.1 (dd, 8.2, 1 Hz,
2
1H); 7.75 (td, 7.5, 1.1 Hz, 1H); 7.63 (8.0, 1.05 Hz, 1H); 7.45
1
prop-2-en-1-one (4b). H NMR (CDCl , 300 MHz): δ 7.7
3
(
1
1
dd, 7.5, 1.4 Hz, 1H); 7.3−7.1 (m, 4H); 7 (td, 8.31, 2.46 Hz,
(
6
1
(
2
1
dd, 8.4, 1.14 Hz, 1H); 7.55 (q, 15.6 Hz, 2H); 7.35−7 (m, 5H);
1
3
H); 6.8 (d, 16.2 Hz, 1H). C NMR (CDCl , 75 MHz): δ
3
13
.65−6.6 (m, 2H); 6.26 (s, 2H). C NMR (CDCl , 75 MHz): δ
3
93(C), 164 (C), 161 (C), 146 (CH), 144 (CH), 136 (C), 134
91 (C), 164 (C), 161 (C), 151 (C), 141 (CH), 136 (C),134
(
(
CH), 130 (CH), 127 (C), 128 (CH), 127 (C), 125 (CH), 124
CH), 117 (CH), 115 (CH), 114 (CH). MS m/z (%) 260 (6),
CH), 131 (CH), 130 (CH), 124 (CH), 118 (C), 117 (CH ×
+
), 116 (CH), 115 (CH), 114 (CH). MS m/z (%) 240 (M −
2
(
23 (10), 207 (67), 191 (9), 165 (4), 147 (31), 124 (100), 122
99), 119 (25), 95 (81), 75 (28), 44 (24), 28 (33).
.2.2.4.4. trans-4-(3-(2-Nitrophenyl)-3-oxoprop-1-en-1-yl)-
, 39), 212 (6), 146 (100), 120 (16), 92 (13), 65 (13), 39 (4).
+
2
MS m/z (%) 240 (M − 1, 39), 212 (6), 146 (100), 120 (16),
1
benzonitrile (3c). H NMR (CDCl , 300 MHz): δ 8.15 (dd,
92 (13), 65 (13), 39 (4).
3
8
7
.2, 1 Hz, 1H); 7.75 (td, 7.5, 1.2 Hz, 1H); 7.7−7.65 (m, 3H);
2.2.2.4.11. trans-4-(3-(2-Aminophenyl)-3-oxoprop-1-en-1-
1
.55 (d, 16.56 Hz, 2H); 7.45 (dd, 7.4, 1.5 Hz, 1H); 7.2 (d, 16.3
yl)benzonitrile (4c). H NMR (CDCl , 300 MHz): δ 7.76 (dd,
3
1
3
Hz, 1H); 6.95 (d, 16.3 Hz, 1H). C NMR (CDCl 75 MHz):
3
,
8.7, 1.5 Hz, 1H); 7.63 (s, 4H); 7.61 (s, 2H); 7.40 (d, 15.51 Hz,
δ 192(C), 146 (C), 142 (CH), 138 (C), 136 (C), 134 (CH),
32 (CH), 130 (CH), 128 (CH), 125 (CH), 118 (C), 115 (C).
.2.2.4.5. trans-3-(4-Methoxyphenyl)-1-(2-nitrophenyl)-
1
H); 7.24 (td, 8.3, 1.5 Hz, 1H); 6.63 (m, 2H); 6.3 (broad, 2H).
1
13
C NMR (CDCl , 75 MHz): δ 191 (C), 151 (C), 140 (CH),
3
2
1
(
39 (C), 135 (CH), 133 (CH), 131 (CH), 128 (CH), 126
CH), 119 (C), 118 (C), 117 (CH), 116 (CH), 113 (C).
.2.2.4.12. trans-1-(2-Aminophenyl)-3-(4-methoxyphenyl)-
1
prop-2-en-1-one (3d). H NMR (CDCl , 300 MHz): δ 8.20
3
(dd, 8.13, 1.08 Hz, 1H); 7.75 (td, 7.47, 1.26 Hz, 1H); 7.64 (td,
2
7
1
(
.53, 1.56 Hz, 1H); 7.50 (dd, 7.47, 1.44 Hz, 1H); 7.45 (dt, 8.64,
1
prop-2-en-1-one (4d). H NMR (CDCl , 300 MHz): δ 7.80
(dd, 8.4, 1.56 Hz, 1H); 7.65 (d, 15.51 Hz, 1H); 7.50 (dt, 9.63,
3
.86 Hz, 1H); 7.20 (d, 16.2 Hz, 1H); 6.9−6.86 (m, 3H); 3.81
s, 3H). 1 C NMR (CDCl 75 MHz): δ 193 (C), 162 (CH),
3
3
,
2
1
.88 Hz, 2H); 7.40 (d, 15.51 Hz, 1H); 7.20 (dd, 7.05, 1.44 Hz,
H); 6.8 (dt, 9.63, 2.88 Hz, 2H); 6.62 (td, 7.1, 1.14 Hz, 1H);
1
46 (C), 136 (C), 134 (CH), 130 (CH × 2), 129 (CH), 127
(C), 124 (CH × 2), 114 (CH), 55 (CH3).
2
.2.2.4.6. trans-1-(2-Nitrophenyl)-3-(p-tolyl)prop-2-en-1-
6.61 (dd, 8.25, 1.24 Hz, 1H); 6.20 (broad, 2H); 2,30 (s, 3H).
1
13
one (3e). H NMR (CDCl , 300 MHz): δ 8.18 (dd, 8.1, 1.2
C NMR (CDCl , 75 MHz): δ 192(C), 161 (C), 151 (C), 143
3
3
Hz, 1H); 7.76 (td, 7.5, 1.2 Hz, 1H); 7.65 (dd, 7.5, 1.5 Hz, 1H);
(CH), 134 (CH), 131 (CH), 130 (CH), 128 (C), 121 (CH),
7
.50 (dd, 7.2, 1.5 Hz, 1H); 7.39 (d, 8.1 Hz, 2H); 7.22 (d, 16.2
Hz, 1H) 7.21 (d, 7.8 Hz, 2H); 6.96 (d, 16.2 Hz, 1H); 2,37 (s,
H). 13C NMR (CDCl 75 MHz): δ 193 (C), 147 (C), 146
1
19 (C), 117 (CH), 116 (CH), 114 (CH), 55 (CH ). MS m/z
3
+
(
%) 252 (M − 1, 100), 236 (31), 209 (22), 180 (13), 164
3
3
,
(
10), 146 (99), 120 (22), 92 (31), 65 (25), 39 (6).
(
1
CH), 142 (C), 136 (C), 134 (CH), 131 (C), 130 (CH × 2),
2
.2.2.4.13. trans-1-(2-Aminophenyl)-3-(p-tolyl)prop-2-en-
29 (CH), 128 (CH × 2), 125 (CH), 124 (CH), 21 (CH3).
1
1
1
7
6
-one (4e). H NMR (CDCl , 300 MHz): δ 7.80 (dd, 8.4,
+
3
MS m/z (%) 267 (M , 4), 252 (7), 223 (100), 207 (49), 179
67), 146 (22), 121 (49), 105 (60), 93 (39), 77 (51), 51 (24),
8 (54), 18 (51).
.2.2.4.7. trans-1-(2-Aminophenyl)-3-phenylprop-2-en-1-
.5 Hz, 1H); 7.65 (d, 15.54 Hz, 1H); 7.50 (d, 15.54 Hz, 1H);
.45 (s, 1H); 7.20 (td, 8.4, 1.5 Hz, 2H); 7.15 (d, 8.1 Hz, 2H);
.62 (td, 8.28, 1.14 Hz, 1H); 6.61 (dd, 8.28, 1.2 Hz, 1H); 6.22
(
2
2
13
1
(broad, 2H); 2,30 (s, 3H). C NMR (CDCl , 75 MHz): δ
one (4). H NMR (CDCl , 300 MHz): δ 7.875 (dd, 8.29,
3
3
1
92(C), 151 (C), 142 (CH), 140 (C), 136 (CH), 135 (C), 132
1
7
8
.32 Hz, 1H); 7.75 (d, 15.45 Hz, 1H); 7.65−7.59 (m, 3H);
(
CH), 129 (CH), 128 (CH), 122 (CH), 119 (CH), 117 (C),
.44−7.39 (m, 3H); 7.31 (dd, 15.45, 1.51 Hz, 1H); 6.72 (td,
.29, 1.13 Hz, 2H); 6.51 (s.a, 2H). 1 C NMR (CDCl , 75
3
+
115 (CH), 21(CH
(100), 115 (16), 92 (13), 65 (18), 39 (4).
). MS m/z (%) 236 (M − 1, 81), 146
3
3
MHz): δ 192 (C), 150 (C), 143 (CH), 135 (C), 134 (CH),
1
60
dx.doi.org/10.1021/cs5011713 | ACS Catal. 2015, 5, 157−166

ACS Catalysis
. RESULTS AND DISCUSSION
Research Article
3
bands of this layered material that disappear after calcination,
showing the typical bands of the Al/Mg mixed oxide (Figure
The study was started by selecting an adequate solid base
catalyst able to perform the first step efficiently, i.e., the
Claisen−Schmidt condensation between o-nitroacetophenone
and benzaldehyde to obtain the corresponding 2′-nitro-
chalcone, which was taken as a reaction model (Scheme 2).
The mechanism generally accepted for the Claisen−Schmidt
condensation in basic media involves the formation of the
anion of o-nitroacetophenone. It is followed by an attack of the
carbonyl group of benzaldehyde to give the aldol intermediate,
which dehydrates to the corresponding 2′-nitrochalcone. Thus,
different solids with basic sites able to abstract the proton in the
methyl group of acetophenone, such as an Al/Mg mixed oxide
1
c). After hydration, the Al/Mg mixed oxide partially recovers
its initial lamellar structure (Figure 1d).
The Claisen−Schmidt condensation was carried out using
equimolar amounts of o-nitroacetophenone and benzaldehyde
in o-xylene as a solvent at 90 °C and in the presence of 10 wt %
of either HTc or the corresponding hydrated sample (HTr). As
can be observed in Figure 2, only maximum yields of 77 and
(HTc), a rehydrated Al/Mg mixed oxide (HTr), and MgO,
were selected as catalysts. Al/Mg mixed oxides possess strong
2
−
+2
23
Lewis basic sites associated with O M ion pairs that are
9
able to perform the Claisen−Schmidt condensation and
24
related aldol condensations. However, it has been demon-
strated that when the Al/Mg mixed oxide is hydrated with a
controlled amount of water, its catalytic activity can be
considerably increased for a variety of aldol-type condensa-
2
5
tions. The increased activity of the hydrated Al/Mg oxides is
attributed to the partial restoration of the layered structure of
the hydrotalcite in which some of the CO3 compensation
2−
−
anions in the interlayer space are replaced by OH anions that
26
act as strong Bronsted basic sites.
Figure 2. Kinetic curves of aldol condensation between o-nitro-
acetophenone and benzaldehyde in the presence of MgO (•), HTc
We have previously shown that Al/Mg mixed oxides
produced from the calcination of Al/Mg hydrotalcites (HTc)
and particularly their hydrated forms (with a 36 wt % water
content, HTr) are excellent and reusable catalysts for the
synthesis of chalcones through the Claisen−Schmidt con-
densation between acetophenone and benzaldehyde deriva-
tives. Then, in order to test the catalytic activity of these
materials for the aldol condensation of o-nitroacetophenone
and benzaldehyde, an Al/Mg hydrotalcite (Mg/Al molar ratio
of 3) was calcined at 450 °C to obtain the corresponding Al/
Mg mixed oxide (HTc). By the hydration of this material with
(
▲), HTr (■), and KF-Al O (◆).
2 3
4
2
0% trans-2′-nitrochalcone were achieved, respectively (Table
), which can be attributed to catalyst deactivation. To confirm
9
c
Table 2. Results of the Claisen−Schmidt Condensation of
Benzaldehyde and o-Nitroacetophenone Using Different
a
Solid Base Catalysts
2
4
r × 10
r × 10 (mmol conv
yield
selec
o
o
entry catalyst (mmol min−1)
min
−1
m )
−2
(%) 1 (%) 3 (%) 3
3
6 wt % CO -free water, the hydrated sample was obtained
2
1
2
3
4
MgO
HTc
HTr
KF-
10.60
6.00
1.33
0.44
1.6
99
78
41
34
98
77
40
29
99
99
99
86
(HTr). In Figure 1 the XRD of the samples is given. The as-
2.2
4.4
synthesized Al/Mg hydrotalcite (Figure 1b) presents the typical
Al O3
2
a
Reaction conditions: Molar ratio of benzaldehyde/o-nitroacetophe-
none = 1, 10 wt % catalyst, o-xylene as a solvent, at 90 °C, results given
at 1 h.
this point and after the condensation reaction, catalysts were
washed with dichloromethane and reused in a second cycle. As
can be seen in Figure S1 (Supporting Information), an
important decrease in catalytic activity was observed for both
catalysts, confirming that a strong deactivation of the samples is
taking place during the reaction. Neither benzoic acid or
benzylic alcohol were detected in the reaction media, indicating
that the Cannizaro reaction does not take place under these
conditions and that the production of benzoic acid is not the
cause of the catalyst deactivation (Figure 2). Moreover, in the
case of the rehydrated HTr sample, we performed the XRD
analysis of the used catalyst (Figure S2), and it was confirmed
that the lamellar structure of the starting material is preserved
after use, indicating that deactivation is not due to changes in
the catalyst structure. Then, the catalyst decay should be
attributed to a strong adsorption of reactants and/or product
Figure 1. Powder X-ray diffraction (XRD) patterns of (a) MgO, (b)
Al/Mg hydrotalcite, (c) Al/Mg mixed oxide (HTc), and (d)
rehydrated HTc (HTr) samples.
1
61
dx.doi.org/10.1021/cs5011713 | ACS Catal. 2015, 5, 157−166

ACS Catalysis
Research Article
on the catalyst surface. In fact, the solid−liquid extraction of the
two samples with a Soxhlet apparatus showed that the organic
material that was extracted was composed mainly of 2′-
nitrochalcone.
Because adsorption is an exothermic process, an increase in
temperature should favor desorption. To determine this, we
carried out the reaction at 120 °C using HTc as catalyst, but
unfortunately, only a 25% yield of 2′-nitrochalcone was
detected after 8 h of reaction because of the oligomerization
of the enone, which is favored at higher temperature.
The TG analysis of the used catalysts after Soxhlet extraction
showed that the amount of organic material adsorbed on HTr
strong adsorption of the organic material on the catalyst
surface. In fact, the thermogravimetric analysis of MgO showed
that 22 wt % of organic material with respect to the weight of
the catalyst remains adsorbed on the solid after Soxhlet
extraction. The greater amount of organic material retained on
MgO with respect to HTc and HTr samples should be
2
attributed to its higher surface area (670 m /g). However, the
organic material can be burned off by calcination at 450 °C in
air, and the catalyst can be reused in five consecutive cycles,
practically maintaining its initial catalytic performance (Figure
3
).
(10 wt %) was similar to the amount of organic material
detected on the HTc catalyst (11%). However, considering the
2
differences in surface area of both catalysts (267 and 30 m /g
for HTc and HTr, respectively), the amount of organic material
2
retained per m on HTr is about 10 times higher than on HTc.
These results can explain the fast deactivation observed with
the hydrated sample and can be related to its greater polar
character.
Because of the strong deactivation exhibited by the
hydrotalcite-based catalysts (HTc and HTr), MgO was tested
as catalyst because it presents strong Lewis basicity with good
27
activity for aldol-type condensations. The basic sites able to
2
+
2−
abstract protons are those associated with Mg O ion pairs, in
which O2 acts as a Lewis basic site. Furthermore, we have
previously demonstrated that the aldol condensation is a
reaction sensitive to the structure of MgO: the basic sites
associated with corners and edges, which are the most basic, are
−
Figure 3. Reuses of MgO in the Claisen−Schmidt condensation of o-
nitroacetophenone and benzaldehyde after catalyst calcination at 450
°C.
28
the most active sites, and the number of such sites can be
increased by decreasing the crystal size of MgO. Considering
these results, we selected an MgO sample with a crystallite size
3
.1. Reduction of 2′-Nitrochalcone to 2′-Amino-
chalcone. As mentioned above, the final objective of this
work is directed to opening a new reaction route to produce the
most interesting 2′-aminochalcones directly from o-nitro-
acetophenone and benzaldehyde derivatives by means of a
one-pot process. The process will involve the basic catalyzed
Claisen−Schmidt condensation to give 2′-nitrochalcone,
followed by the selective hydrogenation of the nitro group of
the 2′-nitrochalcone.
2
of 3 nm and a 670 m /g surface area to perform the aldol
condensation between o-nitroacetophenone and benzaldehyde.
As can be seen in Figure 2 and Table 2, MgO results in the
most active catalyst when compared to HTc and HTr.
However, if the surface area is taken into consideration, it
can be seen that the initial activity of the HTr sample bearing
Bronsted basic sites is considerably superior to the Lewis basic
catalyst, which is in good agreement with previously reported
It has recently been reported that Pd, Pt, and Au
nanoparticles supported on different metal oxides can be
chemoselective catalysts for reducing nitro into amino groups
9
c
results. However, MgO shows a much slower deactivation
rate being possible to achieve 98% yield of the corresponding
chalcone within a 1 h reaction time. For comparison purposes,
the reaction was also performed using KF/Al O , which is
2
2,29
in a variety of organic compounds.
According to the
2
3
previous results, a series of bifunctional metal−MgO catalysts
were prepared and tested for the hydrogenation step (Scheme
2). (The characteristics of the catalysts are given in the
Experimental Section.)
recognized as a strong Lewis base catalyst. In this case, a lower
initial reaction rate and a higher deactivation rate were
observed.
Considering that the 2′-nitrochalcone has pharmacological
interest because it is a potent inhibitor of the biosynthesis of
the release of Interleukin-1 and is currently used for the
treatment of chronic inflammatory diseases (such as
rheumatoid arthritis and septic shock), we can conclude
that MgO is an excellent catalyst for producing 2′-nitrochalcone
in a selective way. Notice that the yield achieved using NaOH
as homogeneous catalyst was considerably lower (59% after 2
h).
To study the reusability of the MgO catalyst after the
reaction, the catalyst was filtered and submitted to a solid−
liquid extraction (Soxhlet equipment) using dichloromethane
as a solvent for 10 h. When the catalyst was used in a second
experiment, only 5% of nitrochalcone was achieved after 8 h of
reaction, indicating that an important deactivation of the
catalysts occurs during the reaction, which can be attributed to
The reduction process was first carried out using Pd on MgO
(0.5 wt % Pd−MgO) at 70 °C and 9 bar of hydrogen pressure
and using o-xylene as a solvent (Table 3, entry 1). Under these
conditions, a moderate yield of 2′-aminochalcone was obtained
(43%), whereas a compound assigned by MS-GC to the
nitrosochalcone intermediate was formed in considerable
amounts (Figure S3, Supporting Information). Moreover, the
reduction of the CC bond of the 2′-aminochalcone to give 1-
(2-aminophenyl)-3-phenylpropanone also occurs to a consid-
erable extent. This not surprising if one takes into account that
Pd−MgO is a selective catalyst for the reduction of the CC
20
2
8
bond in α,β-conjugated enones. When 1 wt % Pt−MgO was
tested as a catalyst for the reduction of 2′-nitrochalcone (Table
3, entry 2), low activity (TOF) and selectivity for the desired
product 4 was obtained (58%), again as a result of the
competitive hydrogenation of the CC bond of the 2′-
1
62
dx.doi.org/10.1021/cs5011713 | ACS Catal. 2015, 5, 157−166

ACS Catalysis
Research Article
Table 3. Results of the Hydrogenation of 2′-Nitrochalcone
catalyst bearing 100 ppm of Pt on the Au/MgO catalyst was
prepared and tested in the reaction (entry 8). In this case,
neither the activity nor selectivity could be improved, achieving
similar results to those observed when using 0.05 wt % Pt−
MgO sample (entry 6). When the crystal size of Pt was
increased (2.3 nm) by preparing a sample of Au−Pt−MgO
bearing 0.45 wt % Pt, a higher selectivity for 2′-aminochalcone
was achieved (69%); however, the yield of 2′-aminochalcone
was not high (69%; Table 3, entry 9; Figure S11) and was
similar to those obtained with samples 0.2Pt−MgO and 0.5Pt−
MgO (Table 2, entries 3 and 4).
The results obtained so far, preclude the use of the metal on
MgO (M-MgO in were M is Pt, Pd or Au) to catalyze the
desired one-pot process for the synthesis of 2′-aminochalcones.
At this point, we thought that another possibility for
performing the one-pot process could be based on a physical
mixture catalyst formed by a highly chemoselective catalyst for
a
(3) in the Presence of Different Metal-Supported Catalysts
TOF
conv
yield
selc
−
1
b
c
d
entry
catalyst
S/C
(h
)
t (h)
(%) 3 (%) 4 (%) 4
1
2
3
Pd−MgO
1Pt−MgO
550
233
421
1130
555
0.50
0.33
0.33
100
100
100
43
58
69
43
58
69
0.5Pt−
1897
MgO
4
5
6
0.2Pt−
647
1209
2248
1830
4029
3705
0.42
1
100
100
100
70
71
31
70
71
31
MgO
0.1Pt−
MgO
0.05Pt−
1.83
MgO
7
8
Au−MgO
250
276
167
35
8
8
28
5
17
25
Au−Pt−
100
25
MgO(1)
9
Au−Pt−
234
1490
0.33
100
69
69
MgO(2)
reducing nitro groups and MgO as a basic catalyst. To do that,
10
11
12
13
Au−TiO2
229
1176
980
76
5
100
100
96
96
51
90
83
96
51
94
83
29,30
gold nanoparticles supported on TiO (Au/TiO )
were
2
2
Pt−Al O3
3868
1565
1108
0.33
0.42
5
2
first studied for the chemoselective hydrogenation of 2′-
nitrochalcone. Results given in Table 3 (entry 10) indicate a
Pt−TiO2(d)
e
Pt−
1000
100
good activity and selectivity of the Au/TiO catalyst, although a
2
TiO
2(nd)
high catalyst/substrate ratio and longer reaction time were
a
Reaction conditions: 2′-nitrochalcone (0.5 mmol) and o-xylene (0.5
required.
mL) at 70 °C and 9 bar H . Substrate/catalyst ratio (S/C) (mol/mol).
22
2
b
−1
However, it has been previously reported that nanocrystals
TOF is calculated as the initial rate (mmol h ) of disappearance of 3
c
of Pt decorated with TiOx species can selectively reduce the
nitro groups in a wide range of substituted nitro aromatic
compounds under mild reaction conditions. The catalyst was
divided by mmols of metal. Time at which the maximum yield of 2′-
aminochalcone was detected. In all cases, 1-(2-aminophenyl)-3-
d
phenylpropanone formed by the hydrogenation of the CC bond of
the 2′-aminochalcone and intermediate 2′-nitrosochalcone were the
prepared by supporting nanosized crystals of Pt on TiO and
2
e
byproducts (Figures S3−S15, Supporting Information). Pt−TiO2
decorating the exposed (111) and (110) Pt crystal faces with
activated at 200 °C in the presence of hydrogen.
TiO from the support simply by treating the material at 450
2
°
C in the presence of hydrogen. Therefore, we thought that this
material would be an excellent candidate for performing the
aminochalcone that takes place to a considerable extent. In a
first approximation to increase the hydrogenation selectivity, we
have attempted to modify the metal crystal size by changing the
platinum content. Then, four samples with different Pt loadings
reduction of 2′-nitrochalcone. As shown in Table 3, the higher
temperature pretreated Pt−TiO (entry 12) resulted in an
2
active and selective catalyst giving 94% selectivity at almost
complete conversion under mild reaction conditions. It is
interesting that with a conventional hydrogenation catalyst such
(0.5 wt % Pt−MgO, 0.2 wt % Pt−MgO, 0.1 wt % Pt−MgO,
and 0.05 wt % Pt−MgO) were prepared and tested in the
reduction reaction. As can be seen in Table 3 (entries 2−6), the
decrease in particle size significantly improves the catalytic
activity and the selectivity for 2′-aminochalcone. Thus, when
the metal crystal size was reduced from 8.7 to 3 nm, the
selectivity for 2′-aminochalcone was considerably increased
as Pt/Al
O
or with nondecorated Pt−TiO (activated at 200
2
3
2
°C) (Table 3, entries 11 and 13) complete conversion can be
achieved, though the selectivities for 2′-aminochalcone are
sensibly lower.
The reusability of the decorated Pt−TiO was studied by
2
(
6
entries 2 and 3), achieving a yield for 2′-aminochalcone of
regenerating the catalyst by calcination at 450 °C under
hydrogen and performing the reduction of 2′-nitrochalcone
during five consecutive cycles without an appreciable loss of
activity (Figure S16). Additionally, the catalyst could also be
regenerated by simply washing with dichoromethane. In Figure
S17 it can be observed that the catalytic activity was practically
maintained during four consecutive cycles.
9% with the sample with a Pt content of 0.5 wt % (entry 3),
and remains similar at lower Pt content (entries 4 and 5).
Further diminution of the Pt content (entry 6) decreases the
selectivity to 2′-aminochalcone because in this case the 2′-
nitrosochalcone intermediate was the main product formed
(Figure S8, Supporting Information).
In previous work, we studied the selective hydrogenation of
nitrostyrene in the presence of Au nanoparticles on different
Several reaction parameters such as the amount of metal on
the catalyst may influence the catalytic activity in the one-pot
synthesis of 2′-aminochalcone. To study the optimal amount of
metal catalyst in the hydrogenation of 2′-nitrochalcone using
supports such as TiO , Fe O , SiO , and carbon. It was found
2
2
3
2
that gold on TiO and Fe O were chemoselective catalysts for
2
2
3
the reduction of the nitro group, whereas when inert supports
Pt−TiO , we carried out the hydrogenation with different
2
such as silica and carbon were used, the chemoselectivity
molar ratios of 2′-nitrochalcone/Pt (S/C). The plot of the
initial rate formation of 2′-aminochalcone versus S/C (Figure
4) indicates good activity when working between 1000 and
2700 mol of reactant per mol of Pt. Working at S/C molar
3
0
decreased.
Here, we have explored the possibility of gold on MgO (Au−
MgO) as a catalyst for the cascade synthesis of 2′-amino-
chalcone. Results in Table 3, entry 7 clearly indicate that gold
on MgO is even less active and selective for the formation of 2′-
aminochalcone than Pd/MgO or Pt/MgO. With the aim of
improving the hydrogen dissociation, a bimetallic Au−Pt−MgO
−1
ratios of 2700 and 5000 mol mol , we found that the
maximum selectivities for 2′-aminochalcone of 95 and 90%
were achieved, respectively. Therefore, an S/C molar ratio of
2700 was chosen for the subsequent experiments.
1
63
dx.doi.org/10.1021/cs5011713 | ACS Catal. 2015, 5, 157−166

ACS Catalysis
Research Article
With the 1:1 MgO/TiO physical mixture catalyst and a
2
substrate-to-Pt molar ratio of 2700, the one-pot reaction was
performed (Figure 5). The procedure was as follows: The
Figure 4. Initial hydrogenation reaction rate of 2′-nitrochalcone into
2
′-aminochalcone with Pt−TiO versus the S/C molar ratio.
2
3
.2. One-Pot Process. In consideration of the above
Figure 5. Kinetics of the one-pot reaction using a physical mixture of
findings, a bifunctional catalyst containing MgO and Pt−TiO2
has been used for the condensation and reduction steps,
respectively, for the one-pot synthesis of 2′-aminochalcones.
This catalyst matches the reaction conditions required for the
two reactions. With this in mind, we prepared a bifunctional
catalyst by combining different weight ratios of MgO and 0.2 wt
MgO and Pt−TiO . o-Nitroacetophenone (▲), 2′-nitrochalcone (•),
2
and 2′-aminochalcone (◆). Reaction conditions: o-nitroacetophenone
(
1 mmol) and benzaldehyde (1 mmol) in 0.5 mL of o-xylene. First
o
o
step: 90 C under a N atmosphere. Second step: 70 C at 9 bar
2
hydrogen. Catalysts: MgO (30 mg) and Pt−TiO (30 mg).
2
%
Pt−TiO components. The results presented in Table 4
2
condensation of o-nitroacetophenone and benzaldehyde was
carried out at 90 °C in o-xylene as a solvent, and when a 98%
yield of 2′-nitrochalcone was achieved, the reaction temper-
ature was decreased to 70 °C and the reactor was pressurized at
9 bar of hydrogen. After 1.5 h of reaction time, a yield of 97%
Table 4. Results of the Claisen−Schmidt Condensation of o-
Nitroacetophenone and Benzaldehyde Using the Physical
Mixture MgO/Pt−TiO Catalyst
a
2
(
98% selectivity) of 2′-aminochalcone was achieved, with a 95%
MgO/Pt−TiO (wt
yield
selec
2
entry
catalyst
MgO
ratio)
t (h)
3 (%)
3 (%)
final yield for the process. These results show that the one-pot
procedure presented here (Scheme 2) is highly effective for the
synthesis of 2′-aminochalcones and it is possible to achieve a 3-
fold higher yield than when using previously reported methods
(25%) that involve a multistep process (Scheme 1) .
b
1
1
2
98
98
99
99
c
2
MgO/Pt−
1/1
1/2
2/1
TiO
2
c
3
MgO/Pt−
8.25
3
55
97
1
100
97
TiO
2
To show if there is a possible benefit in selectivity when the
c
4
MgO/Pt−
physical mixture of MgO/Pt−TiO is used in the one-pot
2
TiO
2
b
process, we have performed an additional experiment under the
same reaction conditions but carrying out the two reaction
steps in separated vessels. Thus, the synthesis of 2′-nitro-
chalcone was performed first only with MgO, and when the
reaction was completed, the catalyst was filtered off and the
5
TiO2
8
100
a
Reaction conditions: benzaldehyde (1 mmol), o-acetophenone (1
mmol), and o-xylene (0.5 mL) at 90 °C. 10 wt % catalyst. 20 wt %
b
c
physical mixture (MgO and Pt−TiO ) catalyst with respect to the total
2
weight of reactants.
resulting reaction product was hydrogenated with the Pt−TiO
2
catalyst. The results presented in Figure S18 show that whereas
the catalytic activity for the hydrogenation increases with
respect to that for the one-pot system, the chemoselectivity is
sensibly lower (87 instead of 98%). From these results, we
speculate that the increase in selectivity observed during the
one-pot process could be due to a selective deactivation of Pt
by undetectable amounts of impurities formed during the
reaction. That assumption could explain the decrease in activity
and the increase in selectivity during the one-pot process.
3.3. Stability and Reuse of the Catalyst. Finally, the
recyclability of the MgO/Pt−TiO2 catalyst was tested by
performing successive reuses of the catalyst in the one-pot
reaction. After the reaction, the catalyst was recovered, calcined,
and used in subsequent runs as explained in the Experimental
Section. Results of the conversion, yield, and selectivity for 2′-
aminochalcone are displayed in Figure 6, and as can be seen, no
loss of activity was observed after three consecutive cycles.
Additionally, XRD analysis of the fresh and used catalyst was
performed, and as can be observed in Figure S19, the structure
of each catalyst is preserved after use and calcination.
showed that the physical mixture (MgO/Pt−TiO ) prepared at
2
a 1:1 wt ratio is the most active catalyst, giving a 98% yield with
9
9% selectivity for 2′-nitrochalcone in a 2 h reaction time.
When the weight ratio of MgO/TiO was 1:2, a decrease in the
2
reaction rate was observed, which could be attributed to a
competitive adsorption of reactants on TiO , which is not basic
2
enough to promote the condensation reaction (Table 4, entry
5
). When the catalyst was formed with 2:1 a weight ratio of
MgO/Pt−TiO , high yield and selectivity for 2′-nitrochalcone
2
could also be achieved; however, longer reaction times (3 h)
were required. In this case, the excess MgO promotes the
Cannizaro reaction producing benzylic alcohol and benzoic
acid, which were detected in small amounts in the reaction
media. The formation of benzoic acid promotes the
deactivation of the basic component of the catalyst, with a 3
h reaction time necessary to obtain results similar to those
obtained in 2 h when the weight ratio of the two components
of the catalysts was 1:1.
1
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Research Article
that good to moderate yields of 2′-aminochalcones can be
obtained in short reaction times using the one-pot protocol.
For comparison purposes, the synthesis of 2′-amino-
chalcones starting from o-aminoacetophenone and substituted
benzaldehydes was carried out in the homogeneous phase using
NaOH as a catalyst. As can be observed in Table 6, yields and
Table 6. Synthesis of 2′-Aminochalcones by the Claisen−
Schmidt Condensation of 2′-Aminoacetophenone and
Benzaldehyde Derivatives Using NaOH as a Homogeneous
a
Catalyst
Figure 6. Reuses of the MgO/Pt−TiO2 catalyst in the one-pot
b
b
entry
R
t (h) conversion (%) yield (%) 4 selectivity (%) 4
process.
1
2
3
4
5
H
4
100
75
80
88
60
50
55
61
51
60
66
68
69
55
Cl
16
16
16
18
3
.4. Scope of the Catalytic System. Different 2′-
CN
aminochalcones were synthesized by reacting substituted
OCH3
CH3
benzaldehydes and o-nitroacetophenone in the presence of
90
physical mixture MgO/Pt−TiO (Table 5). In general, it is
a
2
Reaction conditions: 2′-aminoacetophenone (2 mmol) benzaldehyde
observed that electron-withdrawing groups (i.e., Cl, −CN) in
the aromatic ring of benzaldehyde favor the Claisen−Schmidt
condensation with respect to electron-donating groups, in good
derivative (2 mmol) in 15 mL of ethanol containing 15 wt % NaOH at
2
b
5 °C. Data of conversion and yields from GC analysis.
9a,31
agreement with previously reported results.
The higher
yield of 2′-nitrochalcone compared to those obtained with
nitrochalcones bearing electron-withdrawing groups cannot be
attributed to electronic effects but is probably related to
geometric effects associated with diffusional problems or/and
geometrical restrictions in the adequate adsorption config-
uration caused by the presence of larger substituents on the
aromatic ring.
selectivities of the corresponding 2′-aminochalcones were in all
cases lower, and longer reaction times than those obtained
through the one-pot process presented here were required.
4
. CONCLUSIONS
Chalcones are molecules of industrial interest, and different
procedures and catalysts have been developed through the
years. This is especially true for the synthesis of 2′-
aminochalcones. The synthesis reported until now requires a
multistep process with low final yields of the desired products.
A catalyst has been prepared here that can perform the
synthesis of 2′-aminochalcones in one pot starting from easily
It is interesting that the hydrogenation of the nitrile group
entry 4) and the hydrodehalogenation of halogenated
(
derivatives (entries 2 and 3) were not observed and that the
chemoselective hydrogenation of the 2′-nitrochalcones is
maintained for all reactants. Then, results from Table 5 show
a
Table 5. One-Pot Synthesis of Different 2′-Aminochalcones Using the MgO/Pt−TiO Catalyst
2
step I
step II
selec (%) 4−4e
c
c
c
R
t (h)
yield (%) 3−3e
select (%) 3−3e
t (h)
yield (%) 4−4e
total yield (%)
H
Cl
F
2
98
90
93
83
80
80
99
97
99
100
98
98
1.5
97
73
65
93
91
71
98
71
68
92
90
92
95 (84)
65 (58)
60 (53)
77 (67)
73 (67)
57 (49)
3.5
2
0.5
0.75
0.75
1.15
0.75
b
CN
2
b
OCH3
CH3
7
8
a
Reaction conditions. First step: o-nitroacetophenone (1 mmol), benzaldehyde derivative (1 mmol), 30 mg of MgO, 30 mg of 0.2% PtTiO , 0.5 mL
2
b
c
of o-xylene, 90 °C, N atmosphere. Second step: 70 °C, 9 bar of H . 90 °C was the reaction temperature in the second step. Data from GC analysis.
2
2
Isolated yield in parentheses.
1
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Research Article
accessible o-nitroacetophenone and benzaldehydes. When the
one-pot process is used, a bifunctional catalyst that is a physical
mixture material formed by high-surface-area MgO together
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With the bifunctional catalyst and the reaction system
proposed here, under mild reaction conditions it is possible to
produce 2′-aminochalcones in high yields and selectivities in a
one-pot reaction system. This result considerably improves the
values reported previously with the multistep synthesis
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■
*
S
Supporting Information
The following file is available free of charge on the ACS
Publications website at DOI: 10.1021/cs5011713.
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AUTHOR INFORMATION
■
*
*
Corresponding Authors
Fax: (+34) 963877809. E-mail: mjcliol@qim.upv.es.
Fax: (+34) 963877809. E-mail: acorma@itq.upv.es
(24) (a) Vaccari, A.; Zicmanis, A. Catal. Commun. 2004, 5, 145−150.
(
b) Tichit, D.; Coq, B. Cattech 2003, 7, 206−217.
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1
998, 173, 115−121. (b) Climent, M. J.; Corma, A.; Iborra, S.; Epping,
Notes
K.; Velty, A. J. Catal. 2004, 225, 316−326. (c) Climent, M. J.; Corma,
A.; Iborra, S.; Velty, A. Green Chem. 2002, 4, 474−482. (d) Hora, L.;
Kelbichova, V.; Kikhtyanin, O.; Bortnovskly, O.; Kubicka, D. Catal.
Today 2014, 223, 138−147.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(26) (a) Roelofs, J.C.A.A; Lendsveld, D. J.; van Dillen, A. J.; de Jong,
Financial support from Consolider-Ingenio 2010 (project
MULTICAT), Spanish MICINN (project CTQ-2011-27550),
Generalitat Valenciana (Prometeo program), and Program
Severo Ochoa is gratefully acknowledged. L.M. thanks Spanish
Ministry of Education and Science for fellowships.
P. J. Catal. 2001, 203, 184−191. (b) Abello, S.; Medina, F.; Tichit, D.;
Perez-Ramirez, J.; Cesteros, Y.; Salagre, P.; Sueiras, J. E. Chem.
Commun. 2005, 1453−1455. (c) Abello, S.; Medina, F.; Tichit, D.;
Perez-Ramirez, J.; Sueiras, J. E.; Salagre, P.; Cesteros, Y. Appl. Catal. B:
Environmental 2007, 70, 577−584.
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