Chemoselective Reductive Heterocyclization by Controlling the Binomial Architecture of Metal Particles and Acid-Base Properties of the Support

Article abstract of DOI:10.1021/acscatal.7b01841

2,1-Benzisoxazoles have been selectively synthesized through reductive heterocyclization of 2-nitroacylarenes using Pt-supported nanoparticles. The reaction involves a cascade process in which the first step is the reduction of the nitro group into hydroxylamine followed by heterocyclization through the nucleophilic attack of the hydroxylamine group to the carbonyl of the acyl group and further dehydration. The reaction was performed on Pt/C, Pt/TiO₂, and Pt/MgO using hydrogen as the reducing agent under mild reaction conditions. The results showed that Pt/MgO was the most active and selective catalyst. The study of the influence of the crystal size of the metal on the activity and selectivity, combined with the reaction mechanism examined by in situ Fourier transform infrared spectroscopy of the adsorbed reactant, showed that the maximum activity and selectivity to the target compound can be achieved by controlling the architecture of metal particles and acid-base properties of the support. The effect of temperature on selectivity, the stability of the Pt/MgO catalyst, and the scope of the reaction have been studied. Finally, reductive heterocyclization using different metals (Pd and Au) supported on MgO has also been performed.

Full text of DOI:10.1021/acscatal.7b01841

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Article
Chemoselective reductive heterocyclization by controlling the binomial
architecture of metal particles and acid-base properties of the support
Laura Martí, Laura Sanchez, Maria Jose Climent, Avelino Corma,
Sara Iborra, Gustavo P Romanelli, and Patricia Concepción
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b01841 • Publication Date (Web): 26 Sep 2017
Downloaded from http://pubs.acs.org on September 26, 2017
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Chemoselective Reductive Heterocyclization By Controlling
The Binomial Architecture Of Metal Particles And AcidꢀBase
Properties Of The Support
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L. Martia, L.M. Sanchezb, Maria J. Climenta*, A. Cormaa*, S. Iborraa, G. P.
Romanellib, P. Concepciona
aInstituto de Tecnología Química (UPV-CSIC), Universitat Politècnica de València,
46022, Valencia, Spain
bCentro de Investigación y Desarrollo en Ciencias Aplicadas ‘Dr. J. J. Ronco’
(CINDECA), Departamento de Química, Universidad Nacional de La Plata,1900, La
Plata, Argentina.
* To whom correspondence should be addressed
E-mail
acorma@itq.upv.es
mjcliol@qim.upv.es
Fax:
(+34) 963877809
(+34) 963877800
Phone:
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ABSTRACT
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2,1ꢀBenzisoxazoles have been selectively synthesized through reductive
heterocyclization of 2ꢀnitroacylarenes using Pt supported nanoparticles. The
reaction involves a cascade process in which the first step is the reduction of
the nitro group into hydroxylamine followed by heterocyclization through the
nucleophilic attack of the hydroxylamine group to the carbonyl of the acyl group
and further dehydration. The reaction was performed on Pt/C, Pt/TiO2 and
Pt/MgO using hydrogen as reducing agent under mild reaction conditions. The
results showed that Pt/MgO was the most active and selective catalyst. The
study of the influence of the crystal size of the metal on the activity and
selectivity, combined with the reaction mechanism by in situ FTIR spectroscopy
of the adsorbed reactant, showed that maximum activity and selectivity to the
target compound can be achieved by controlling the architecture of metal
particles and acidꢀbase properties of the support. The effect of the temperature
on the selectivity, the stability of Pt/MgO catalyst, as well as the scope of the
reaction have been studied. Finally, the reductive heterocyclization using
different metals (Pd and Au) supported on MgO has been also performed.
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Keywords: reductive heterocyclization, 2,1ꢀbenzisoxazole, Pt/MgO, 2ꢀ
nitroacylarenes, cascade process.
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INTRODUCTION
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2,1ꢀBenzisoxazoles (anthranils) are fused heteroaromatic systems useful as
building blocks to prepare a broad class of compounds with important biological
properties and industrial applications. For instance, 2,1ꢀbenzisoxazole
derivatives are employed in the treatment of some disorders of the central
nervous system, as for instance Alzheimer’s disease, other forms of dementia,
and cerebral infarct.1 They are also used as antiplasmodial, antimicrobial2 and
antiꢀinflammatory agents.3 Anthranils and their salts can also be used as
starting materials to prepare other heterocyclic systems for tranquilizers drugs
such as Valium,4 or acridones (in the production of dyes and pharmaceutical
products.5
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Different approaches can be used to synthesize 2,1ꢀbenzisoxazoles as, for
instance, the reaction of substituted nitroarenes and arylacetonitriles in
concentrated strong base alcoholic solution,6 and in the presence of silylating
agents,7 heterocyclization of 2ꢀazido aryl ketones,8 and addition of glyoxylate
esters to nitrosoarenes catalyzed by Lewis acid.9 However, the most common
method to prepare 2,1ꢀbenzisoxazoles involves the reductive heterocyclization
of 2ꢀnitroacylbenzene derivatives. This transformation occurs through the partial
reduction of the nitro group to the hydroxylamine function followed by
heterocyclization through the nucleophilic attack of the hydroxylamine group to
the carbonyl of the acyl group and further dehydration10 (see Scheme 1).
Classically, the reaction is carried out using Sn or SnCl2 in concentrated
HCl,10,11 although other approaches use SnCl2 2H2O12 or indium metal with
different additives in water or methanol to promote the reductive
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heterocyclization of 2ꢀnitroacylbenzenes. However, temperature and
concentration of reducing agent should be controlled since overꢀreduction of
2,1ꢀbenzisoxazole into the corresponding 2ꢀaminoacyl compound by reductive
cleavage can occur yielding the corresponding 2,1ꢀbenzisoxazoles in low
selectivity13 (Scheme 2).
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In general, through the above methods, 2,1ꢀbenzisoxazole derivatives are
obtained after long reaction times and with nonꢀreusable catalysts. Therefore a
sustainable route to prepare 2,1ꢀbenzisoxazole derivatives involving the use of
an active, selective and reusable heterogeneous catalyst based on metal
supported nanoparticles and hydrogen as reducing agent would be of interest.
However, this route is not easy because the catalytic hydrogenation can
promote not only the reductive cleavage of 2,1ꢀbenzisoxazoles into to 2ꢀ
aminoacylbenzenes but also the complete and fast reduction of the nitro into
amino group as well as, the reduction of the carbonyl group of the
nitroacylarene. In fact, in the reports on hydrogenation of 2ꢀnitroacylarene
derivatives using Pt (colloidal Pt solution)14 or Pd/C15 catalysts a mixture of 2,1ꢀ
benzisoxazole and 2ꢀaminoacyl derivative, with low selectivity to the former are
obtained. It appears that to perform successfully the reaction to obtain high
yield and selectivity to the 2,1ꢀbenzisoxazol, a catalyst is required that promotes
the formation of the hydroxylamine intermediate and the fast nucleophilic attack
to the carbonyl group of the acyl group, while avoiding the reductive cleavage of
the 2,1ꢀbenzisoxazole.
In the present work we will show that by controlling the binomial architecture of
the metal nanoparticles and the nature of the support a non selective catalyst
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such as Pt, can be transformed to obtain, 2,1ꢀbenzisoxazoles in excellent yields
and selectivity by reductive heterocyclization of 2ꢀnitroacylarenes.
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EXPERIMENTAL SECTION
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2ꢀNitroacylarenes (>99%), Toluene (≥99%), and Dodecane ((≥99%), were
purchased from Aldrich. Gold(III) chloride trihydrate (99.9%), platinum (II)
acetylacetonate (97%), palladium (II) acetylacetonate (99%), were purchased
from Aldrich. MgO sample with a surface area of 670 m2gꢀ1 was purchased
from NanoScale Materials. TiO2 (Pꢀ25, Degussa) and active carbon (Darco KBꢀ
B) supports were supplied by Evonik Industries and Aldrich, respectively.
0.2wt%Pt/TiO2, sample with a Pt crystal size of 1.5 nm was prepared by
incipient wetness following previously reported procedure16 and reduced at
450oC.
Pt/MgO samples with different Pt loading were prepared by impregnation of the
support with the corresponding amount of a solution of platinum (II)
acetylacetonate, in water free toluene (12.5 mL) which was added to 1 g of
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 3.5 h at 550 oC with an N2 flow of 100 mLminꢀ1 and
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activated by calcination at 450 C with an H2 flow of 100 mLminꢀ1 during 3 h.
Pd/MgO and Au/MgO samples were prepared following the same procedure.
A sample of 0.1 wt% of Pt onto MgO was prepared using a solution of
H2PtCl6—6H2O (2.8 mg) in acetone ( 25 mL) by impregnation of 1g of MgO. 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
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calcined 3.5 h at 550 C with an N2 flow of 100 mLminꢀ1 and activated by
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calcination at 450 C with an H2 flow of 100 mL minꢀ1 during 3 h. The average
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mean diameter of metal nanoparticles, measured by HRTEM images, was 1.2
nm.
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A sample with 0.2 wt% of Pt onto porous active carbon (Darco KBꢀB, 100 mesh)
was obtained by incipient wetness impregnation with a aqueous solution (2mL)
containing the desired amount of metal (10.56 mg of H2PtCl6—6H2O) to form a
thick paste (2 g). The catalyst paste was mixed thoroughly with a spatula for
10min. Then, the sample was dried at 100ºC for 12h. The final catalyst was
activated by reduction in a fix bed reactor with an H2 flow of 100mL/min at
450ºC for 3h.
The amount of metal supported on the different catalysts was determined by
ICP analysis in a Varian SpectrAAꢀ10 Plus. Average mean diameter of metal
nanoparticles of the different catalysts was measured by HRTEM images, which
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.
Platinum dispersions were determined by H2 chemisorption at 35°C in an ASAP
2010C Micromeritics equipment by extrapolating the total gas uptakes in the
adsorption isotherms at zero pressure. Prior to the measurements the samples
(about 300 mg) were reduced under flowing pure H2 at 450 °C for 3 h. Active
metal surface area of each sample was estimated from the total amount of
chemisorbed H2, assuming an adsorption stoichiometry Pt/H of 2, the Pt content
(from ICPꢀOES), and considering spherical particle geometry with a surface
atomic density of 8 nm2/atom.
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Powder XꢀRay diffraction patterns were collected in Philips X’ PERT
diffractometer equipped with a proportional detector and a secondary graphite
monochromator. Data were collected stepwise over the 2o ≤2θ ≤ 40o angular
region, with steps of 0.02o 2θ , 20s/step accumulation time and Cu KR (λ =
1.54178 Å) radiation.
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In situ FTIR experiments have been performed with a Nexus 8700 FTIR
spectrometer using a DTGS detector and acquiring at 4 cm−1 resolution. For the
in situ catalytic IR experiments a quartz IR cell allowing in situ treatments in
controlled atmosphere and temperatures from 25 ºC to 600 ºC has been
connected to a vacuum system with gas dosing facility. Prior to the adsorption
experiments the samples were treated at 120 ºC in H2 flow (20 ml—minꢀ1) for 1.5
h followed by evacuation at 10ꢀ5 mbar at the same temperature for 1h.Then the
samples were cooled down to 25 ºC under dynamic vacuum conditions followed
by coꢀadsorption of 2ꢀnitrobenzaldehyde (8 mbar) and H2 (40 mbar). IR spectra
were recorded with time. For the IR studies of CO adsorption a homemade
stainless steel IR cell allowing in situ treatments in controlled atmosphere and
temperatures from ꢀ170 ºC to 500 ºC has been used. Samples have been
activated as before, followed by cooling down to ꢀ170ºC under dynamic vacuum
conditions. CO dosing are performed at ꢀ170ºC and at increasing pressure
(0.05ꢀ0.5 mbar). IR spectra were recorded after each dosage. Origin software
has been used for spectra treatment.
General procedure for reduction of 2-nitroacylarenes . In a 5 mL autoclave, the
catalyst and a solution of 2ꢀnitroacylarene (1 mmol), dodecane as internal standard
(40 mg, 0.23 mmol) in 2 mL of toluene were placed. The autoclave was pressurized
at 9 bar of hydrogen and heated at 30 oC under vigorous stirring.
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In all reactions, samples were taken at regular intervals, diluted with
dichloromethane and analyzed by GC equipped with a HP5 capillary column of 30
m x 0.25mm and 0.25mm crossꢀlinked 5% phenylmethylsiloxane and a FID as the
detector. In all cases the molar balance was ≥ 95%. Mass spectra were performed
by GC–MS HP Agilent 5973 with a 6980 mass selective detector.
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The products were purified by recrystallization from ethanol and identified by
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GCꢀMS and C and H NMR. 1H NMR spectra were recorded at 300 MHz and
13C at 75 MHz in a Bruker Avance 300 spectrometer, and the chemical shifts in
parts per million (ppm) were reported to internal TMS.
For catalyst recycling studies, the solid was collected by filtration, washed
thoroughly with CH2Cl2 and calcined at 550 ºC in nitrogen flow during 3 h and then
with hydrogen flow 3 h more.
A large scale experiment was performed using 5 mmol of 2ꢀnitroacetophenone, 10
mL of toluene, 0.1wt%Pt/MgO (200 mg) at 9 bar of H2 and 30 oC.
Hg(0) poisoning experiment: 0.1wt%Pt/MgO (40 mg), 2ꢀnitroacetophenone (1mmol),
Hg(0) (200 mg) and dodecane as internal standard (40 mg, 0.23 mmol) in 2 mL of
toluene were placed in an autoclave, which was pressurized at 9 bar of hydrogen
and heated at 30 oC under vigorous stirring during 2h.
NMR data
3-Methyl-2,1-benzoisoxazole (2a):
1HꢀNMR (CDCl3, 300MHz): δ 7.45 (d, 8.82 Hz, 1H); 7.32 (d, 9.09 Hz, 1H); 7.16
(dd, 9.09, 6.3 Hz, 1H); 6.92 (dd, 8.82, 6.3 Hz, 1H); 3.14 (s, 3H). 13CꢀNMR
(CDCl3, 75MHz): δ 165.6 (C), 157.1 (C), 130.8 (CH), 122.8 (CH), 119.8 (CH),
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115.6 (CH), 114.9 (C), 11.9 (CH3). MS m/z (%)M+— 133(100), 104(60), 90(10),
78(27), 62(16), 51(10), 43(49), 15(1).
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2,1-Benzoisoxazole (2b):
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1HꢀNMR (CDCl3, 300MHz): δ 9.12 (s, 1H); 7.60 (d, 9.09 Hz, 1H); 7.53 (d, 8.82
Hz, 1H); 7.29 (dd, 9.09, 6.4 Hz, 1H); 6.98 (dd, 8.82, 6.4 Hz, 1H); 13CꢀNMR
(CDCl3, 75MHz): δ 156.1 (CH), 154.5 (C), 130.8 (CH), 124.4 (CH), 119.6 (CH),
118.2 (C), 115.0 (CH). MS m/z (%)M+— 119(87), 92(100), 64(60), 38(18), 28(49).
3-methyl-[1,3]dioxolo[4',5':4,5]benzoisoxazole (2c):
1HꢀNMR (CDCl3, 300MHz): δ 6.62 (,s 1H); 6.45 (s, 1H); 5.88 (s, 2H); 3.22 (s,
3H); 13CꢀNMR (CDCl3, 75MHz): δ 162.7 (C), 156.3 (C), 152.9 (C), 146.5 (C),
101.6 (CH2), 92.4 (CH), 89.5 (CH), 112.2 (C), 12 (CH3). MS m/z (%)M+—177(69),
148(100), 121(7), 105(7), 91(10), 77(12), 68(12), 53(22), 43(43), 28(27).
5-methoxy-2,1,benzoisoxazole (2d):
1HꢀNMR (CDCl3, 300MHz): δ 8.91 (s, 1H); 7.51 (d, 9.57 Hz, 1H); 7.0 (dd, 9.57,
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2.2 Hz, 1H); 6.59 (s, 1H); 3.79 (s, 3H); CꢀNMR (CDCl3, 75MHz): δ 156.1 (C),
154.3 (C), 152.3 (CH), 128.2 (CH), 118.3 (C), 116.4 (CH), 92.8 (CH), 55.3
(CH3). MS m/z (%) M+— 149 (54), 133 (7), 122 (19), 106(100), 79(19), 52(19),
29(7).
5-bromo-3-methyl-2,1-benzoisoxazole (2e):
1HꢀNMR (CDCl3, 300MHz): δ 7.52 (s, 1H); 7.31 (d, 9.42 Hz, 1H); 7.18 (dd, 9.42,
1.59 Hz, 1H); 2.66 (s, 3H); 13CꢀNMR (CDCl3, 75MHz): 165.4 (C), 155.4 (C),
134.6 (CH), 121.8 (CH), 116.7(CH), 116.6 (CH), 116.1 (C), 12.0 (CH3). MS m/z
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(%) M+—212(79), 211(84), 183(91), 182(98), 158(19), 156(28), 132(5), 117(10),
104(19), 90(25), 77(31), 61(25), 50(13), 43(100), 38(13), 15(3).
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RESULTS AND DISCUSSION
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It has been reported in literature that for the reduction of nitroaromatics into
phenylhydroxylamine derivatives using catalyst based on Pd and, especially, Pt
are preferred over supported metals such as Rh, Ir, Ru, and Os due to the
higher activity and selectivity of the former.17 In fact, we recently showed that
0.2wt%Pt/C controlled crystal sizes is an efficient catalyst for the coupling of
nitroarenes with aldehydes in the presence of H2 to obtain nitrones18 in where
the mechanism involves the condensation of the hydroxylamine intermediate
generated in situ with the benzaldehyde in a cascade type reaction. It was
demonstrated that the formation of the hydroxylamine intermediate is favored by
the presence of highly unsaturated Pt species. Furthermore, it has been
reported recently in an interesting work that nitroaromatics can be
chemoselectively reduced into phenylhydroxylamines in high yields using
nanoparticles of Pt supported on carbon.19
From these precedents and considering that the reductive heterocyclization of
2ꢀnitroacylarenes to 2,1ꢀbenzisoxazol involves the cyclization of the
hydroxylamine intermediate by attack of the hydroxylamine group to the
carbonyl group at the 2ꢀposition (see Scheme 1), we envisaged that a properly
designed Pt/C catalyst could be a selective catalysts to prepare 2,1ꢀ
benzisoxazol derivatives by reductive heterocyclization of 2ꢀnitroacylarenes
through a cascade type process.
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Thus, taking 2ꢀnitroacetophenone as reactant model, we tested first 0.2wt%Pt/C
(average crystal size of 1.6 nm) that was active for preparing nitrones.18 The
reduction was performed at 30 oC under 9 bar of H2 in toluene as a solvent and
in Figure 1 the kinetic plot of the reaction is presented. As can be observed
there, the 2ꢀaminoacetophenone appears as a primary and secondary product
which can be formed by fast hydrogenation of the 2ꢀnitroacetophenone into
amino (primary character), as well as by further reduction of the desired 2,1ꢀ
benzisoxazole (see Scheme 2), that appears as a primary and unstable
product,
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From these results we can conclude that although the 0.2wt%Pt/C catalyst
promotes the formation of 2,1ꢀbenzisoxazole through the formation of the
hydroxylamine intermediate, under our reaction conditions, this intermediate
undergoes a fast reduction into 2ꢀaminoacetophenone. Moreover, the catalyst
also promotes the reductive cleavage of 2,1ꢀbenzisoxazole in high extension.
Similar results were obtained when the hydrogenation was performed with Pt
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supported on TiO2 (0.2wt%Pt/TiO2) activated at 450 C in the presence of
hydrogen (see Figure 2), although in this case the results are not surprising due
to the role attributed to TiO2 in minimizing the formation of hydroxylamine
intermediate during the hydrogenation of nitro compounds.20
It has been demonstrated in our previous study21 that the basicity of surface
oxygen species favors the stabilization of nitroso and hydroxylamine
intermediate compounds. Then, in an attempt to stabilize the intermediate
hydroxylamine, enhancing the cyclization reaction, we have selected MgO as a
basic support for Pt.
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Then, a catalyst was prepared that contains 0.2wt% of Pt on MgO
(0.2wt%Pt/MgO). The average Pt crystallite size in this catalyst was 2.4 nm (see
Table S1). The catalytic results given in Figure 3 show that the concentration of
2,1ꢀbenzisoxazole reach a maximum yield of approximately 80% at 100 %
reactant conversion when working with the Pt/MgO catalyst. Longer reaction
times lead to further hydrogenation of 2,1ꢀbenzisoxazole into 2ꢀ
aminoacetophenone, which correspondingly, show a marked character as
secondary product. Moreover, a minor amount of a compound which was
tentatively assigned to a dimmer of the nitrosobenzene intermediate
(azodioxide) was also detected during the reaction.
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Notice that in the case of 0.2wt%Pt/MgO which gives better catalytic results
than 0.2wt%Pt/C, not only the support has been changed, but the average of
crystallite size of the Pt was also different.
Therefore we cannot conclude if the improvement is only due to an intrinsic
effect of the support on the catalytic process or to an indirect effect of the
support on metal dispersion. To gain a better physicoꢀchemical understanding
of our catalytic system, while improving its catalytic behavior, different Pt on
MgO catalysts were prepared in where, the Pt dispersion was changed. By
doing this we could have Pt/MgO samples with different average metal Pt
crystallite sizes. Thus, by changing the metal crystallite size, one can not only
change the ratio of exposed to non exposed metal atoms, that may reflect on
total conversion, but it will also change the relative ratio of accessible Pt atoms
located at the crystal corners (less saturated metal atoms) versus the
accessible Pt atoms located on crystal faces, being this ratio higher when
smaller is the crystal size. Since the electronic properties of those more
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unsaturated Pt atoms should be different, the activity (as per turnover
frequency) and selectivity of the final catalyst could be modified by changing the
crystal size of the metal nanoparticle.
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Then three additional Pt/MgO samples with 0.1, 0.5 and 1 wt% of Pt were
prepared (see experimental section) in which average crystallite sizes obtained
from the corresponding histograms are given in Table S1.
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Kinetic curves for the conversion of 2ꢀnitroacetophenone with these new
samples are given in Figures S1ꢀS4. In Table 1 are summarized the results of
the turnover frequency (TOF), conversion and selectivity to 3ꢀmethylꢀ1,2ꢀ
benzoisoxazole obtained with the different catalysts. It can be seen from those
that the TOF (calculated as initial rate of formation of benzisoxazole divided by
mole of surface Pt atoms) increases when decreasing the Pt metal crystallite
size. This would indicate that the less saturated Pt metal atoms located at the
corners play a key role in this multistep reaction. Very importantly, the maximum
yield of the 3ꢀmethylꢀ2,1ꢀbenzisoxazole (2) (94%) obtained at 100% conversion
of 2ꢀnitroacetophenone is obtained with the Pt/MgO catalyst (TON of 4700) with
the smallest crystallite size (1.1 nm). From these results, we can then conclude
that when the crystal size of the metal Pt decreases and the relative amount of
less saturated Pt atoms on the surface increases the catalyst became more
active for the reductive heterocyclization and less active for the reductive
cleavage that shows a marked sensitiveness to the architecture of the Pt
nanoparticles.
Nevertheless, we want to point out that while the average crystallite size
of the most active and selective Pt/MgO (1.1 nm) is not that different of that of
Pt/C (1.6 nm), TOF and selectivity to 2,1ꢀbenzisoxazole is much lower in the
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second one (990 hꢀ1 and 5% selectivity at 100% conversion for the Pt/C versus
7220 hꢀ1 and 94% selectivity at the same conversion for the Pt/MgO). This
observation indicates either a direct effect of the support or an indirect effect
where the support may influence the shape of the Pt crystals. In order to discern
between both effects, a detailed spectroscopic study based on IR spectroscopy
have been performed on the 0.2wt%Pt/C and 0.2wt%Pt/MgO samples.
Differences in particle shape are hard to be visualized by means of our HRTEM
study; therefore we have used IR spectroscopy of CO adsorption as a more
convenient way to titrate the nature of surface sites. The IR spectra of CO
adsorption (Figure 4) shows less saturated Pt surface sites on the 0.2wt%Pt/C
sample (IR band at 2040 cmꢀ1) than on the 0.2wt%Pt/MgO sample (IR band at
2060 cmꢀ1), being the last one more selective to 2,1ꢀbenzisoxazole. Thus we
can say that the selectivity to 2,1ꢀbenzisoxazole is not only related to the
presence of unsaturated surface sites and has to be related to other factors
than particle size and shape.
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To unravel this behavior, the reaction mechanism has been followed in situ by
IR spectroscopy taking 2ꢀnitrobenzaldehyde as reactant model. Thus, 2ꢀ
nitrobenzaldehyde and H2 have been coꢀadsorbed in the presence of the
catalyst, and the evolution of reaction intermediate surface species monitored
with time by means of IR spectroscopy. On the 0.2wt%Pt/C sample (Figure 5)
2ꢀaminobenzaldehyde has been detected on the catalyst surface in the first
minutes of the reaction (IR bands at 1601, 1570 and 1558 cmꢀ1) while no other
intermediate products could be visualized, indicating a fast hydrogenation rate
of the nitro to amino group.
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In opposite, on the 0.2wt%Pt/MgO sample (Figure 6), nitrosobenzaldehyde (IR
band at 1485 cmꢀ1) and hydroxylamine (1490 cmꢀ1) are detected in the first
minutes of the reaction (see inset of Figure 6), while at increasing reaction time
new IR bands at 1638, 1539, 1515 and 1482 cmꢀ1 could be envisage,
corresponding to 2,1ꢀbenzisoxazole. 2ꢀAminobenzaldehyde was hard to detect,
specifically considering the bad quality of the IR spectra due to the high amount
of carbonate species on the support.
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According to previous studies performed in our group,21 the higher basicity of
the MgO support, may explain the stabilization of the hydroxylamine
intermediate compound, where accumulation of hydroxylamine on the catalyst
surface would favor their cyclization versus hydrogenation. In a similar way, the
basicity of the support enhances stabilization of 2,1ꢀbenzisoxazole. This has
been proved by a control experiment where 2,1ꢀbenzisoxazole has been
adsorbed on a fresh 0.2wt%Pt/MgO sample where it remains stable even after
vacuum treatment (see supporting information for details Figure S5) and in the
presence of H2 as observed in figure 6.
From these results we can then conclude that the higher basicity of the MgO
support plays a key role enhancing the selectivity to 2,1ꢀbenzisoxazole.
Moreover, the higher rate of 2ꢀaminoacylarene formation observed on the
0.2wt%Pt/C sample, in both the IR as in the catalytic studies, can be related to
a more pronounce activation of the carbonyl functional group in the case of the
0.2wt%Pt/C sample. Indeed, the carbonyl group of adsorbed 2ꢀ
nitrobenzaldehyde is shifted to lower frequencies in the 0.2wt%Pt/C sample
(1695 cmꢀ1) versus the 0.2wt%PtMgO sample (1702 cmꢀ1) (see Figure S6). In
this case, we can assume that activation of the carbonyl group causes an
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electronic withdrawing effect that enhances the electrophylicity of the nitro
group increasing their hydrogenation rate to amino group. Similar effects have
already been reported in the literature.19
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On the other hand, it is interesting to point out that for the preparation of Pt/MgO
samples we selected platinum (II) acetylacetonate as a source of Pt instead of
H2PtCl6 considering the results previously reported by M. A. Aramendía et al.22
In this work the authors found that the use of chlorineꢀcontaining metal
precursors (H2PtCl6) to prepare Pt/MgO had an adverse effect on the chemical
and textural properties of the resulting solid, decreasing specific surface area
and basicity of the support. Therefore, in order to see the possible role of metal
precursor on the catalytic activity of Pt/MgO, we prepared a 0.1wt%Pt/MgO
sample using H2PtCl6 as Pt source. The sample, with a metal size determined
by TEM of 1.2 nm, was tested in the reductive heterocyclization of 2ꢀ
nitroacetophenone under the same reaction conditions (Figure S7). The results
showed that the catalytic activity and selectivity to 3ꢀmethylꢀ2,1ꢀbenzisoxazole
are very different to those obtained with 0.1wt%Pt/MgO (prepared with
platinum (II) acetylacetonate, see Figure S1). Thus, with the catalyst prepared
with H2PtCl6 the rate of appearance of the 2,1ꢀbenzisoxazole was lower, while
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the selectivity at 100 % conversion was only 76%.
Influence of the Temperature of Reaction
In order to study the influence of the reaction temperature on the selectivity, the
o
process was performed at increased temperatures (50, 70 and 90 C) using
0.1wt%Pt/MgO sample. In Figure 7 is presented the yield of 3ꢀmethylꢀ2,1ꢀ
benzisoxazole versus conversion. As can be observed, an increase of
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temperature leads to a decrease in selectivity to 2,1ꢀbenzisoxazole, indicating
that the reductive cleavage should have a higher activation energy.
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To investigate if the catalytic process involves possible Pt leached into the
solution, an additional experiment was carried out where the reduction of 2ꢀ
nitroacetophenone with 0.2wt%Pt/MgO was stopped after 30 min. At this point,
the catalyst was filtered off in hot and the reaction was continued for an
additional 1h, but no further conversion was detected (Figure S8).
Additionally a Hg(0) poisoning test was performed to corroborate the
heterogeneous nature of the active species. Hg(0) poisons metal(0) catalysts by
forming an amalgam with the metal and/or adsorbing onto the metal surface. 23
Then, the heterocyclization of 2ꢀnitroacetophenone was performed using
0.1wt%Pt/MgO in the presence of 200 mg of Hg, and after 2h the conversion
was only of 2 %. The strong inhibition of the reaction on addition of Hg(0) is
indicative of the heterogeneous nature of the active species.
To check the reusability of the catalyst, after a first run, the 0.1wt%Pt/MgO
sample was recovered by filtration, washed thoroughly with dichloromethane
and used in a second cycle. The results showed an important decrease in
activity (only 10 % yield of 2,1ꢀbezisoxazole was obtained) indicating strong
catalyst deactivation, which could be caused by strong adsorption of organic
material on the catalyst surface. Indeed the TG analysis of the used catalyst
showed that 32 wt% (with respect to the amount of catalyst) of organic material
remained on the catalyst. However, another possible cause of catalyst
deactivation could be the existence of structural changes of the support. XRD
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analysis of the used catalyst showed the appearance of diffraction peaks
corresponding to Mg(OH)2 (see Figure S9) which will be produced by
hydration of MgO by the water produced during reaction. These observations
suggest that deactivation of the catalyst could be originated not only by
adsorption of organic material but also by changes in basicity of the support as
Mg(OH)2 is less basic than MgO.24 However the initial catalytic activity could be
recovered by submitting the catalyst to calcination at 550 ºC under air flow
followed by reduction under H2 flow at 450 ºC. Following this protocol, the
catalyst could be reused three consecutive cycles without loss of activity and
selectivity (see Figure 8). Moreover, the ICP analysis of the catalyst after
reaction showed that the amount of Pt on the catalyst remains constant during
the three cycles.
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The average mean diameter of metal nanoparticles was also measured by
HRTEM after each cycle (see Table S2). The results showed that there is a
slightly increase of the metal size after each cycle, which has not effect on
conversion and selectivity.
Since other metals such as Au and Pd have been reported as potential
chemoselective catalyst for hydrogenation of nitro groups 0.1wt%Pd/MgO and
0.1wt%Au/MgO were prepared following the same methodology and tested in
the reduction of 2ꢀnitroacetophenone. However, as can be observed in Table 2
0.1wt%Pd/MgO (1.9 nm Pd crystal size) was less active than Pt/MgO although
the selectivity to 2,1ꢀbenzoisoxazole was rather acceptable, while the Au/MgO
(2.3 nm Au crystal size) showed very low activity in this reaction
.
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Scope of the reaction
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The 0.1wt%Pt/MgO catalyst was tested for the reductive heterocyclization of
various 2ꢀnitroarylketone and 2ꢀnitrobenzaldehyde derivatives (Table 3). Good
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conversion and selectivities to the corresponding
2,1ꢀbenzoisoxazole
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derivatives were obtained with substrates bearing electronꢀdonating groups in
the aromatic ring (entries 3 and 4) or with withdrawing groups such as Br (entry
5) while in this case dehalogenation as side reaction was not observed.
However, when the carbonyl group in ortho position is integrated in an ester
group the reductive heterocyclization was not observed at all, and the only
observed compound was the corresponding 2ꢀaminoester (entry 6). This result
agrees with the previously reported results using SnCl2 for reducing 2ꢀ
nitroesters.12
Finally, a large scale experiment was performed using 5 mmol of 2ꢀ
nitroacetophenone using 0.1wt%Pt/MgO catalyst (see experimental section).
The results showed that after 4h reaction time a conversion of 100 % with 90 %
selectivity to 3ꢀmethylꢀ2,1benzisoxazole can be achieved.
CONCLUSIONS
2,1ꢀBenzisoxazoles have been obtained by reductive heterocyclization of 2ꢀ
nitroacylarenes using supported Pt nanoparticles. The reductive
heterocyclization of 2ꢀnitroacetophenone performed with Pt nanoparticles on
different supports (C, TiO2 and MgO) showed that Pt/MgO was the most active
and selective catalyst. Kinetic experiments combined with Operando IR
spectroscopy and HRTEM showed that while small Pt nanoparticles (~1nm) are
necessary for a successful catalyst, this is not the only requisite to achieve high
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activity and selectivity. The reaction mechanism studied by in situ IR
spectroscopy of the adsorbed reactant, showed that the reduction of the nitro
group on the Pt goes through the formation of the corresponding nitroso,
hydroxylamine and aniline derivatives. However, the relative rate of the different
hydrogenation steps can be modified by the basicity of the support. Thus, it is
possible to stabilize the hydroxylamine intermediate on the Pt/MgO surface
favoring their cyclization to the target compound versus hydrogenation.
Moreover, the basicity of the support enhances the stabilization of the desired
2,1ꢀbenzisoxazole avoiding their further reductive cleavage. Then, maximum
activity and selectivity to the target compound can be achieved by controlling
the architecture of metal particles and acidꢀbase properties of the support. The
optimized Pt/MgO catalyst could be reused several times without loss of activity
and could be applied to the synthesis of a variety of 2,1ꢀbenzisoxazole
derivatives with high yields.
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Supporting Information. TEM images and average particle size of the Pt
supported catalysts, kinetic data, XRD patterns of the used and regenerated
catalyst, IR spectra of adsorbed species.
ACKNOWLEGEMENTS
Spanish MICINN Project (CTQꢀ2015ꢀ67592ꢀP), Generalitat Valenciana
(Prometeo Program), and Severo Ochoa Program are gratefully acknowledged.
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R1
R1
HO
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Reduction
R2
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NO2
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O
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ꢀH2O
N
Scheme 1. Mechanism of the reductive heterocyclization of 2ꢀnitroacylarenes
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Scheme 2. Pathway of the reduction of 2ꢀnitroacylarenes
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Figure 1. Hydrogenation of 2ꢀnitroacetophenone using 0.2wt%Pt/C as catalyst;
2ꢀnitroacetophenone
(■),3ꢀmethylꢀ2,1ꢀbenzoisoxazole
(ꢀ),
2ꢀ
aminoacetophenone (●).
Reaction conditions: 0.2wt%Pt/C (40 mg), 2ꢀ
nitroacetophenone (1 mmol), Toluene (2 mL), 9 bar H2 at 30 oC.
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Figure 2. Hydrogenation of 2ꢀnitroacetophenone using 0.2wt%Pt/TiO2 catalyst;
2ꢀnitroacetophenone (■), 2ꢀaminoacetophenone (●), 3ꢀmethylꢀ2,1ꢀ
benzoisoxazole (ꢀ). Reaction conditions: 0.2wt%Pt/TiO2, (40 mg), 2ꢀ
nitroacetophenone (1 mmol), Toluene (2 mL), 9 bar H2, at 30 oC.
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Figure 3. Hydrogenation of 2ꢀnitroacetophenone using 0.2wt%Pt/MgO as a catalyst; 2ꢀ
nitroacetophenone (■), 3ꢀmethylꢀ2,1ꢀbenzoisoxazole (ꢀ), 2ꢀaminoacetophenone (●),
azodioxide (Mr=266 g/mol) (ꢁ).Reaction conditions: 0.2wt%Pt/MgO (40 mg), 2ꢀ
nitroacetophenone (1 mmol), Toluene (2 mL), 9 bar H2 at 30 oC;
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A
0.2wt%Pt/MgO
2060
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Wavenumber (cmꢀ1)
B
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2040
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Wavenumber (cmꢀ1)
Figure 4. IR spectra of CO adsorption on 0.2wt%Pt/MgO (A) and 0.2wt% Pt/C (B)
acquired at ꢀ170 ºC and 0.5 mbar CO.
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0.1
1524
υ(ΝΟ2)as
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1341
υ(ΝΟ2)s
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υ(C
=Ο)
1601
time
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1500
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1300
Wavenumber (cmꢀ1)
Figure 5. Time evolution of IR surface species on the 0.2wt%Pt/C catalyst during the
hydrogenation of 2ꢀnitrobenzaldehyde (8mbar 2ꢀnitrobenzaldehyde and 40 mbar H2 at
25 ºC). In black thin line the sample before reaction and in bold line the sample during
the reaction. Spectra are acquired at 7 min, 52 min and 150 min of reaction. IR bands
at 1695, 1524 and 1341 cmꢀ1 are due to 2ꢀnitrobenzaldehyde.
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