Gold catalysis opens up a new route for the synthesis of benzimidazoylquinoxaline derivatives from biomass-derived products (glycerol)

Article abstract of DOI:10.1002/cctc.201300416

Process intensification by using well-defined solid catalysts able to perform one-pot multistep reactions is one of the open fronts in heterogeneous catalysis. This is even more relevant if new, more efficient synthesis routes are open. Herein, a gold catalyst was used to synthesize benzimidazoylquinoxalines compounds by two efficient and selective novel methods in a multistep one-pot methodology. The first method involved the synthesis of benzimidazoylquinoxaline compounds with the same substituents in both heterocycles through oxidation-cyclization of glycerol with o-phenylenediamine derivatives, whereas the second one allowed the synthesis of benzimidazoylquinoxalines compounds with different substituents in each aromatic ring through coupling of o-phenylenediamine derivatives with glyceraldehyde in a first stage to produce the benzimidazol compound as an intermediate, followed by an oxidation-cyclization with another o-phenylenediamine compound in a second stage. Both stages were performed by using gold nanoparticles supported on nanoparticulated ceria (Au/CeO₂) as the catalyst and air as the oxidant, in absence of any homogeneous reagent. A reaction mechanism has been proposed. A smooth route: Benzimidazoylquinoxaline derivatives can be obtained in good yields through one-pot oxidative coupling of glycerol or glyceraldehydes with 1,2-phenylenediamines in a two-step reaction, using Au/CeO₂ as the catalyst, base-free conditions, mild temperature, and air as the oxidant. Copyright

Full text of DOI:10.1002/cctc.201300416

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DOI: 10.1002/cctc.201300416
Gold Catalysis Opens Up a New Route for the Synthesis of
Benzimidazoylquinoxaline Derivatives from Biomass-
Derived Products (Glycerol)
Marꢀa J. Climent, Avelino Corma,* Sara Iborra,* and Sergio Martꢀnez-Silvestre[a]
Dedicated to Professor Carmen Najera on her 60th birthday.
Process intensification by using well-defined solid catalysts
able to perform one-pot multistep reactions is one of the open
fronts in heterogeneous catalysis. This is even more relevant if
new, more efficient synthesis routes are open. Herein, a gold
catalyst was used to synthesize benzimidazoylquinoxalines
compounds by two efficient and selective novel methods in
a multistep one-pot methodology. The first method involved
the synthesis of benzimidazoylquinoxaline compounds with
the same substituents in both heterocycles through oxidation–
cyclization of glycerol with o-phenylenediamine derivatives,
whereas the second one allowed the synthesis of benzimida-
zoylquinoxalines compounds with different substituents in
each aromatic ring through coupling of o-phenylenediamine
derivatives with glyceraldehyde in a first stage to produce the
benzimidazol compound as an intermediate, followed by an
oxidation–cyclization with another o-phenylenediamine com-
pound in a second stage. Both stages were performed by
using gold nanoparticles supported on nanoparticulated ceria
(Au/CeO2) as the catalyst and air as the oxidant, in absence of
any homogeneous reagent. A reaction mechanism has been
proposed.
Introduction
The use of renewable resources as replacements for fossil fuels
can help to achieve a more sustainable world. In this direction,
biomass can be a renewable source of organic carbon to re-
place fossil fuels and to produce organic chemicals.[1,2]
icals. Here we present a new synthetic application of glycerol
and glycerol derivatives to obtain benzimidazoylquinoxalines
through a cascade reaction process catalyzed by gold.
Compounds possessing the benzimidazole moiety exhibit
significant activity towards several viruses such as human im-
munodeficiency virus (HIV), herpes simplex virus (HSV-1),
human cytomegalovirus (HCMV), and influenza.[8] Bis-benzimi-
dazole is a DNA minor-grove binding agent possessing antitu-
mor activity.[9] Benzymidazoylquinoxaline compounds have
shown properties as a novel class of selective antagonists at
human A1 and A3 adenosine receptors.[10] Methods for the syn-
thesis of these heteroarylquinoxalines are limited. An option
involves the reaction of the corresponding o-phenylenedia-
mine derivative with 3-hydroxyimino-2-butanone and bromine
in a one-pot reaction (Scheme 1).[11] Another possibility is to
react diamine aromatic compounds with quinoxaline-2-carbox-
ylic acid, but this synthetic route needs to be performed in
polyphosphoric acid media at 2008C.[12] A third route is to
react the o-phenylenediamine derivative with quinoxaline-2-
carbaldehyde with acetic acid in ethanol at reflux temperature.
In all three cases the yield of the target product remains very
low.[13]
Oils and fats that do not compete with food will play an
even more important role in chemical industry, owing to their
competitive cost and worldwide availability. Thus, the produc-
tion of biodiesel by transesterification of fatty esters with
methanol and ethanol has been growing in the last years and
co-generates large amounts of glycerol. Because of the over-
supply of glycerol, its price has dropped sharply,[3] and the re-
search for new applications of this versatile molecule has been
an area of growing interests in the last years. Glycerol is a mul-
tifunctionalized compound and a number of conversion pro-
cesses such as oxidations,[4] transesterifications,[5] etherifica-
tions,[6] esterifications,[7] etc. to produce value-added chemicals
have been reported. As a consequence, glycerol has been rec-
ognized as one of the most important building blocks in the
conversion of biomass-derived feedstock to value-added chem-
[a] Prof. Dr. M. J. Climent, Prof. Dr. A. Corma, Prof. Dr. S. Iborra,
S. Martꢀnez-Silvestre
A recent alternative synthetic route for the synthesis of het-
eroarylquinoxalines with higher yields (72–97%) involves the
reaction between 3-alkanoylquinoxalin-2-ones with 1,2-phenyl-
Instituto de Tecnologꢀa Quꢀmica (UPV-CSIC)
Universitat Politꢁcnica de Valꢁncia
Avda dels Tarongers s/n, 46022, Valencia (Spain)
Fax: (+34)963877809
enediamine derivatives through
a novel rearrangement
E-mail: acorma@itq.upv.es
(Scheme 2).[14,15] However the main drawback of this reaction
procedure is the difficult synthesis of the alkanoylquinoxalin-2-
siborra@itq.upv.es
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201300416.
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dazole or quinoxaline com-
pounds by using gold in the
form of nanoparticles as a cata-
lyst, in the absence of base and
under mild reaction condi-
tions.[18,19] Catalyst optimization
studies showed that Au nano-
particles supported on nano-
sized CeO2 (Au/CeO2) were the
most active and selective cata-
lysts to obtain quinoxalines. The
influence of the support on the
rate of the alcohol oxidation by
gold has been ascribed to
changes produced on the crys-
tallite shape as well as to the
participation of the support in
the catalytic cycle.[20] It has been
Scheme 1. Benzimidazoylquinoxaline synthesis routes according to Refs. [11–13].
reported that in the case of
CeO2, its surface saturation by O2
is achieved at relatively low partial pressure of O2,
owing to the excellent capacity of CeO2 to act as an
oxygen pump caused by the presence of surface
oxygen vacancies that arise from the nanometer size
of ceria.[21]
We assumed that by using this catalyst it could be
possible to obtain benzimidazoylquinoxalines
through the oxidative coupling of triol derivatives
with o-phenylenediamine compounds. Thus, the re-
action between 1,2-phenylenediamine (1a) and glyc-
erol (2) was performed with and without Au/CeO2 as
a catalyst in diglyme as a solvent at 1408C. As we
have shown previously,[18] this solvent was able to
dissolve completely both reactants (polyols and 1,2-
phenylenediamine derivatives) and products and al-
Scheme 2. Benzimidazoylquinoxaline synthesis through a novel rearrangement in the re-
actions of 3-alkanoylquinoxalin-2-ones with 1,2-phenylenediamine according to Refs. [14]
and [15].
ones reagents,[15] which are obtained in yields of approximately
30%.
Therefore, there is a clear incentive to develop catalytic pro-
cesses able to produce the benzimidazoylquinoxalines by
more sustainable methods, with high activity and selectivity
whereas minimizing the number of reaction steps. Following
our ongoing program for searching new environmentally
friendly methods for synthesizing fine chemicals,[2,16,17] we
report here a novel straightforward synthetic method of benzi-
midazoylquinoxaline derivatives through oxidative coupling of
glycerol or glyceraldehyde with o-phenylenediamine deriva-
tives in the presence of an Au/CeO2 catalyst.
Results and Discussion
Synthesis of benzimidazoylquinoxalines by oxidative
coupling of glycerol with o-phenylenediamine derivatives
Figure 1. Kinetic plots of the different compounds detected in the oxida-
tion–cyclization reaction of 2 with 1a using Au/CeO2: 1a (&), 3aa (~), 4a
(+), 5a (*), 6a+7a+8a+9aa (X). Reaction conditions: 1a (1.2 mmol), 2
(0.5 mmol), diglyme (1.5 mL), Au/CeO2 (2.33 wt%), 2/Au molar ratio=100, at
1408C.
In earlier work we have performed the oxidative coupling of al-
cohols with o-phenylenediamine derivatives to form benzimi-
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lowed us to work at temperature of 1408C. No reaction was
observed in the absence of a catalyst. However, in the pres-
ence of Au/CeO2, the reaction kinetics given in Figure 1 clearly
revealed the formation of benzimidazoylquinoxaline (3aa) as
the main product, with a yield of 79% after 8 h reaction time.
However, at the beginning of the reaction, the quinoxalin-
2-ylmethanol (4a), formed by oxidative coupling between
glycerol and o-phenylenediamine, and the 1-(1H-benzo-
[d]imidazol-2-yl)ethane-1,2-diol (5a), which could be produced
through the oxidation of one of the primary alcohol groups of
glycerol and subsequent coupling with o-phenylenediamines,
were the predominant products (Scheme 3). Both compounds
(4a and 5a) exhibited a primary and unstable character and
after one hour of reaction, the concentrations of both inter-
mediates began to decrease, which was caused by their con-
version into 2-(1H-benzo[d]imidazol-2-yl)quinoxaline (3aa), pro-
duced through oxidation–cyclization of 4a and 5a with anoth-
er o-phenylenediamine molecule (see Figure 1). Other byprod-
ucts such as 1H-benzo[d]imidazole (6a), quinoxaline (7a), (1H-
benzo[d]imidazole-2-yl)methanol (8a) and 1H,1’H-2,2’-biben-
zo[d]-
imidazole (9aa) were also detected in the reaction media (see
the Supporting Information, Scheme S1).
Taking into account the kinetic behavior of the different
compounds
presented
in
Figure 1, a reaction network is
presented in Scheme 4 in which
glycerol 2 is firstly oxidized to
glyceraldehyde 10 and subse-
quently to the dicarbonyl com-
pound 11 (nondetectable by
GC). Both compounds can con-
densate with the diamine 1 to
produce the imine intermediates
12 and 13, with 12 converted
into product 13 by fast oxidation
of the remaining hydroxyl
group. Later, product 13 follows
a condensation reaction to yield
Scheme 3. Reaction pathway for the benzimidazoylquinoxaline synthesis with glycerol.
Scheme 4. Proposed benzimidazoyquinoxalines (3) synthesis mechanism starting from 1,2-phenylenediamine derivatives and glycerol.
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hydroxymethylquinoxaline intermediate 4, which can
be further oxidized to 2-carbaldehydequinoxaline 14,
which couples with another diamine molecule 1 to
reach the benzimidazoylquinoxaline derivative 3.
Moreover, the imine intermediate 12 can give the di-
hydroxybenzimidazole intermediate 5, which through
a subsequent oxidative coupling with the diamine
1 produces the benzimidazoylquinoxaline derivative
3. On the other hand, the formation of the byprod-
ucts detected could be explained by the oxidative
cleavage of glycerol (2), glyceraldehyde (10), the di-
hydroxybenzimidazole intermediate 5, and the a-hy-
droxycarbonylbenzimidazole intermediate 15 into dif-
ferent carbonyl compounds such as 19, 20, 21, and
22 followed by the coupling with diamine 1 to pro-
duce the byproducts 6, 7, 8, and 9 through cycliza-
tion in minor amounts.
Scheme 5. Possible synthetic routes to yield the intermediate quinoxaline (4a) or benzi-
midazoles (28, 5a).
1,2-phenylenediamine derivative, it was only possible to obtain
regioisomers of the correspondent benzimidazoylquinoxaline
derivatives with the same substituents on the quinoxaline and
on the benzimidazole aromatic rings. Then, in order to expand
Scope of the reaction
The influence of different substituents at position 4 of 1,2-phe-
nylenediamine 1a (i.e., 4-methylbenzene-1,2-diamine 1b, 4-
chlorobenzene-1,2-diamine 1c, 4-nitrobenzene-1,2-diamine 1d,
3,4-diaminobenzonitrile 1e, 4-methoxybenzene-1,2-diamine
1 f, naphthalene-2,3-diamine 1g), on the performance for the
oxidation–cyclization process of glycerol (2), was studied in the
presence of Au/CeO2. As can be seen in Table 1, good yields to
benzimidazoylquinoxaline derivatives were obtained, which
were almost always better than those described in the litera-
ture (compare entries 1–7 with 8–11). However, if electron-
withdrawing substituents such as nitro, chloride, or nitrile
groups were present, the yields of quinoxaline derivatives
were slightly lower with respect to those of 1,2-phenylenedia-
mine or with respect to phenylenediamine molecules with
electron-donating substituents. The same trend has been de-
scribed in the literature for the reaction between a-hydroxycar-
bonyl compounds and 1,2-phenylenediamine derivatives.[18,22]
the synthetic scope, other alternative routes that allow com-
bining different substituents in both heteroaromatic moieties
have been studied. The different strategies studied involved, as
first step, the synthesis of diverse intermediates such as those
showed in Scheme 5, which could be oxidatively coupled with
differently substituted 1,2-phenylenediamine in a second step.
The synthesis of these intermediates (4a, 28, and 5) was per-
formed by oxidative coupling of dihydroxyacetone (26), solke-
tylaldehyde (27), and glyceraldehyde (10) with o-phenylenedia-
mine, respectively, using Au/CeO2 as a catalyst. After optimiza-
tion of the reaction conditions with the different substrates,
the results presented in Table 2 revealed that only the reaction
between glyceraldehyde and 1,2-phenylenediamine (route III)
in the presence of Au/CeO2, oxygen pressure, and at room
temperature, produced the benzimidazole intermediate 5 with
high selectivity at complete conversion. Therefore, the synthe-
sis of the benzimidazole intermediate from glyceraldehyde and
1,2-phenylenediamine derivative was chosen as the optimum
first step of the reaction.
Synthesis of benzimidazoylquinoxalines with different
substituents in heteroaromatic moieties
To develop a new one-pot approach to produce benzimida-
zoylquinoxalines differently substituted in the aromatic rings,
we performed in a first step the oxidative coupling between
glyceraldehyde (10) and 4-methylbenzene-1,2-diamine (1b) in
the presence of Au/CeO2 with pure oxygen (3 bar), at room
temperature, and with water as a solvent. Once complete con-
version of glyceraldehyde was achieved, a solution of 1,2-phe-
nylenediamine (1a) in diglyme was added and the tempera-
ture raised up to 1408C, during which the water was removed
The results presented here demonstrated that our approach
based on the one-pot oxidative coupling of glycerol with 1,2-
phenylenediamines was a straightforward synthetic method
which gave benzimidazoylquinoxaline derivatives in much
higher yields than the conventional synthetic methods report-
ed up to now. However, using this approach, owing to the
rapid oxidative coupling of the intermediate 4 and 5 with the
Scheme 6. New one-pot two-step process to produce benzimidazoylquinoxalines starting from glyceraldehyde (10).
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by a Dean Stark system (Scheme 6). In this
second step, the main product observed at
short times was the desired product 3ba
(Figure 2), formed by oxidation of the hy-
droxyl groups of 5b and subsequent cycli-
zation with o-phenylenediamine (1a). How-
ever, also in this case, byproducts coming
from the oxidative cleavage of the inter-
mediate 1-(5-methyl-1H-benzo[d]imidazol-2-
yl)ethane-1,2-diol (5b), such as 6-methyl-
1H-benzo[d]imidazole (6b), 1H-benzo[d]imi-
dazole (6a), quinoxaline (7a), (1H-benzo[d]i-
midazol-2-yl)methanol (8a) and 6-methyl-
1H,1’H-2,2’-bibenzo[d]imidazole (9ba) were
formed (Scheme S2). From the kinetic be-
havior of the different products obtained in
the second stage (see Figure 2), it can be
seen that all of them were stable products
that were formed from the oxidation–cycli-
zation reaction of 1-(5-methyl-1H-benzo[d]i-
midazol-2-yl)ethane-1,2-diol (5b) or from
the oxidation–cyclization reaction of the by-
products obtained through oxidative cleav-
age of 5b. From the kinetic behavior of
these reactions, a reaction network is pre-
sented in Scheme 7, in which glyceralde-
hyde 10 is firstly cyclized to the benzimida-
zoyl intermediate 5 in the first stage, and
subsequently 5 is oxidatively coupled with
other diamine 1 to produce the benzimida-
zoylquinoxaline derivative 3.
Table 1. Synthesis of benzimidazoylquinoxaline derivatives starting from diamine and glycerol
using Au/CeO2 as the catalyst.[a]
Entry Reactants
Product
Sel. to 3[b] Yield[b]
[mol%]
[mol%]
1
81
79
2
3
4
5
6
7
82
78
76
76
81
83
80[c]
75[c]
71[c]
72[c]
75[c]
77
Scope of the reaction
To study the scope of the reaction, different
4-substituted 1,2-phenylenediamines (1,2-
phenylenediamine (1a), 4-methylbenzene-
1,2-diamine (1b), 4-chlorobenzene-1,2-dia-
mine (1c), 4-nitrobenzene-1,2-diamine (1d),
3,4-diaminobenzonitrile (1e), 4-methoxy-
benzene-1,2-diamine (1 f), and naphthalene-
2,3-diamine (1g)) were used in the first and
second step of the reaction in the presence
of Au/CeO2 as the catalyst. As can be seen
in Table 3, very good yields of benzimida-
zoylquinoxaline derivatives were obtained
in all cases. This is even more remarkable if
we consider that this synthetic route al-
lowed us to synthesize benzimidazoylqui-
noxaline derivatives with different substitu-
ents in each aromatic ring. Furthermore, if
o-phenylenediamine with substituents was
used in the first stage of this synthetic
route, only one regioisomer of the target
product was obtained, unlike what occurred
for the synthetic route starting from glycer-
ol described above or the synthetic routes
8
9
24[d]
50[e]
10
11
50[f]
72[c,g]
[a] Reaction conditions: diamine (1.2 mmol), 2 (0.5 mmol), diglyme (1.5 mL), Au/CeO2 (2.33 wt%), 2/
Au molar ratio=100, at 1408C, 24 h; [b] Selectivity to 3 at 90% conversion. Yield values were de-
termined from Equations (1) and (3); [c] A mixture of regioisomers was obtained. [d] Yield from re-
action reported in Ref. [11], [e] Ref. [12], [f] Ref. [13], and [g] Ref. [15].
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Table 2. Synthesis of different intermediates in the synthesis of benz-
imidazoylquinoxaline derivatives.[a]
Synthetic Reactant
route
Product
Sel. to product[b]
[mol%]
I
62
82
95
II
III
[a] Reaction conditions route I and II: 1a (0.5 mmol), reactant (0.5 mmol),
diglyme (1.5 mL), Au/CeO2 (2.33 wt%), reactant/Au molar ratio=100, and
1408C. Reaction conditions route III: 1a (0.5 mmol), reactant (0.5 mmol),
H2O (2.0 mL), Au/CeO2 (2.33 wt%), reactant/Au mol ratio=100, PO2 =
3 bar, room temperature, 4 h; [b] Selectivity values to product at com-
plete conversion were determined from the equation: Sel. (%)=
(molproduct)t/[(mol1)0ꢀ(mol1)t]ꢂ100.
Figure 2. Kinetics plots of the different compounds detected in the second
stage of the benzimidazoylquinoxaline synthesis starting from glyceralde-
hyde (10) and using Au/CeO2. 5b (&), 3ba (~), 6b+6a+7a+8a+9ba
(X). Stage 1: diamine 1b first step (0.5 mmol), 10 (0.5 mmol), H2O (2.0 mL),
Au/CeO2 (2.33 wt%), 10/Au mol ratio=100, PO2 =3 bar, room temperature,
4 h. Stage 2: diamine 1a step 2 (0.6 mmol) and diglyme (1.5 mL) were
added to the reaction mixture, provided with a Dean Stark system, at atmos-
pheric pressure and 1408C.
starting from 3-hydroxyimino-2-butanone[11] or alkanoylquinox-
alin-2-ones (see Scheme 2 and 4).[14,15] Entries 1–6 reveal the in-
fluence on the selectivity to 3 of the substituent of the dia-
mine used in the second stage, which was responsible for the
substituent present in the quinoxaline ring of the benzimida-
zoylquinoxaline product. Entries 7–12 reveal the influence of
the diamine substituent in the first stage, which was responsi-
ble for the substituent present in the benzimidazole group.
The results demonstrate that there were no significant differ-
ences in selectivity if the substituent was changed in the dia-
mine of the second stage as occurs in the case of the oxidative
coupling with glycerol. However, if the substituent was
changed in the diamine of the first stage, more important dif-
ferences in selectivity were observed. If electron-donating sub-
stituents were present in intermediate 5 (see Scheme 7), the
selectivity to 3 decreased considerably (entries 7, 11, and 12;
however, the H3CO group in entry 11 is not really electron-do-
nating). These results show that electron-donating substituents
favored the competitive oxidative cleavage of the diol 5, which
is in good agreement with the results reported in the literature
for the reaction between diols and 1,2-phenylenediamine de-
rivatives.[23]
Scheme 7. Proposed benzimidazoylquinoxalines (3) synthesis mechanism from 1,2-phenylenediamine derivatives (1) and glyceraldehyde (10).
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Stability and reusability of Au/CeO2 catalyst
Catalyst recyclability was checked by performing successive
reuses of the catalyst under the same reaction conditions as
for benzimidazoylquinoxaline (3aa) synthesis by oxidative cou-
pling of glycerol with o-phenylenediamine (1a). For the reuse,
the recovered catalyst was used in a subsequent run as de-
scribed in the Experimental Section. According to our previous
results for the synthesis of quinoxalines,[18] no leached gold
species were detected in the reaction media, whereas the gold
content in the used catalyst, as measured by X-ray fluores-
cence, remained the same after each run. Nevertheless, some
catalyst deactivation was observed (Figure 3). This catalyst de-
Figure 4. Conversion of 1a (&) and selectivity to 3aa (&) with successive
reuses of Au/CeO2 as a catalyst in the oxidation–cyclization reaction of 2
with 1a, and with previous treatment of the catalyst under oxygen flow at
2508C during 2 h. Reaction conditions: 1a (1.2 mmol), 2 (0.5 mmol), diglyme
(1.5 mL), Au/CeO2 (2.33 wt%), 1a/Au molar ratio=100, at 1408C.
the oxidant. The reaction network has been established for
both syntheses. Oxidative cleavage was a competitive reaction
responsible for the formation of byproducts. Moreover, the in-
fluence of the substituent in position 4 of the diamine com-
pound was studied, and it was demonstrated that this sub-
stituent had a high importance on the selectivity as it was
present in the intermediate 5. Electron-withdrawing substitu-
ents improved the selectivity to the benzimidazoylquinoxaline
compound. Au/CeO2 could be easily recovered and reused
with a small loss of activity whereby maintaining high selectivi-
ties towards 2-(1H-benzo[d]imidazol-2-yl)quinoxaline.
Figure 3. Conversion kinetic plots of the oxidation–cyclization of glycerol
with o-phenylenediamine to 3aa under successive reuses of Au/CeO2:
^
1st use (X), 2nd use ( ), 3rd use (&). Reaction conditions: 1a (1.2 mmol), 2
(0.5 mmol), diglyme (1.5 mL), Au/CeO2 (2.33 wt%), 2/Au mol ratio=100, at
1408C.
activation should be mainly associated to deposition of organ-
ic material on the catalyst surface. Therefore, to burn off the
organic deposits, the Au/CeO2 catalyst was pretreated before
each reuse with oxygen flow at 2508C during 2 h. This pre-
treatment allowed us to regenerate a large fraction of the ini-
tial activity, as can be seen in Figure 4, whereby the selectivity
to benzimidazoylquinoxaline (3aa) was maintained.
Experimental Section
Preparation of supported gold nanoparticles on nano-
particulated ceria
Au/CeO2 was prepared by gold deposition on cerium oxide nano-
particles with a BET surface area of 180 m2 gꢀ1, by using the follow-
ing procedure. A solution of HAuCl4·3H2O (360 mg) in deionized
water (160 mL) was brought to pH 10 by addition of a solution of
0.2m NaOH. Once the pH value was stable, the solution was added
to a second solution containing colloidal CeO2 (4.01 g) in H2O
(50 mL). After adjusting again the pH with 0.2m NaOH, the slurry
was left under vigorous stirring at RT for 18 h. The Au/CeO2 solid
was then filtered and exhaustively washed with distilled water
until no traces of chlorides were detected by the AgNO3 test. The
catalyst was dried at RT under vacuum. After this, the supported
gold nanoparticles were reduced with 1-phenylethanol (10 mL), at
1608C, during 2 h under constant agitation. The total Au content
of the final catalyst was 2.33wt% as determined by chemical analy-
sis using X-ray fluorescence, comparing the response of the Au/
CeO2 with standards. With this procedure, gold nanoparticles with
an average size of 3-4 nm supported on CeO2 were obtained as
measured by high-angle annular dark field scanning transmission
electron microscopy (HAADF-STEM).
Conclusions
Au/CeO2 was an excellent catalyst for the synthesis of benzimi-
dazoylquinoxaline derivatives through the one-pot oxidative
coupling of glycerol with 1,2-phenylenediamine derivatives, or
from glyceraldehyde in a two-steps reaction. The last process
involved a cyclocondensation with 1,2-phenylenediamine de-
rivative to form the benzimidazole intermediate 5, followed by
oxidative coupling with a different 1,2-phenylenediamine de-
rivative, which allowed us to perform the synthesis of benzimi-
dazoylquinoxaline derivatives with different substituents in
each aromatic ring. Both approaches were performed under
base-free conditions, at mild temperature and by using air as
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Reagents
Table 3. Synthesis of benzimidazoylquinoxaline derivatives starting from diamine and glycer-
aldehyde using Au/CeO2 as the catalyst.[a]
All reagents were purchased from Sigma Aldrich
except 4-methoxybenzene-1,2-diamine, which was
synthesized from 4-methoxy-2-nitroaniline by hy-
drogenation of the nitro group over Au/CeO2 fol-
lowing Ref. [16]
Entry Diamine
step 1
Diamine
step 2
Product
Sel. to Yield
3[b]
[mol%] [mol%]
1
79
76
75
72
77
79
73
79
82
78
66
77[c]
74[c]
72[c]
68[c]
72[c]
75
Catalyst regeneration and reuse
For catalyst reuse, the catalyst was collected after
the reaction by vacuum filtration and then it was
repeatedly washed. First, it was washed with ethyl
acetate under stirring in ultrasounds to remove or-
ganic compounds, and subsequently it was
washed with NaOH (0.2 mollꢀ1) to remove any
acid byproducts that may poison the gold nano-
particles. Then water was used to remove traces of
NaOH on the catalyst, and at last the catalyst was
washed with diethyl ether again. Finally, the cata-
lyst was dried overnight, after which it was ready
for reuse.
2
3
4
Reaction procedure
5
Synthesis of benzimidazoylquinoxaline derivatives
with the same substituents in each aromatic ring:
A generic experiment was as follows. In a two-
neck round-bottom flask of 10 mL placed in a sili-
cone bath that contained a magnetic stirrer, a tem-
perature controller, 1,2-phenylenediamine deriva-
tive (1, 1.2 mmol), glycerol (2, 0.5 mmol), diethy-
lene glycol (1.5 mL), and dimethyl ether (diglyme)
as a solvent. Subsequently the reaction mixture
was heated at 1408C, under atmospheric pressure
and an amount of 42 mg of Au/CeO2 (2.33 wt%)
catalyst was added. The yield of the correspondent
benzimidazoylquinoxaline derivative (3), the con-
version of 1, and the selectivity into the desired
product 3 were calculated according to Equa-
tions (1–3).
6
7
68
8
76
9
79
n3t
n20
ð1Þ
ð2Þ
ð3Þ
Yield ð%Þ ¼
ꢁ 100
n10 ꢀ n1t
2 ꢁ n20
Conv: ð%Þ ¼
ꢁ 100
10
11
74
Yield
Conv: n10 ꢀ n1t
2 ꢁ n3t
Sel: ð%Þ ¼
¼
ꢁ 100
63
Synthesis of benzimidazoylquinoxaline with differ-
ent substituents in each aromatic ring: In a glass
reactor of 3.0 mL, 1,2-phenylenediamine derivative
(1, 0.5 mmol), glyceraldehyde (10, 0.5 mmol), water
(2.0 mL), and an amount of 42 mg of Au/CeO2
(2.33 wt%) were added. Subsequently the reactor
was pressurized at 3 bar of pure oxygen and the
reaction performed under continuous stirring at RT
during 4 h. After that, the system was depressur-
ized and then another 1,2-phenylenediamine deriv-
ative (1’, 0.6 mmol) and diglyme (1.5 mL) as a sol-
vent were added. Subsequently, the flask was con-
nected to a refrigerant attached with a Dean Stark
system to remove the water from the reaction mix-
12
69
65
[a] Reaction conditions: Stage 1: diamine first step (0.5 mmol), 10 (0.5 mmol), H2O (1.5 mL),
Au/CeO2 (2.33 wt%), 10/Au mol ratio=100, PO2 =3 bar, room temperature, 4 h. Stage 2: dia-
mine second step (0.6 mmol) and diglyme (1.5 mL) were added to the reaction mixture, pro-
vided with a Dean Stark system, atmospheric pressure and 1408C; [b] Selectivity to 3 at 90%
conversion and yield values were determined from Equations (4) and (6); [c] A mixture of re-
gioisomers was obtained.
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 2013, 5, 3866 – 3874 3873

CHEMCATCHEM
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The authors wish to acknowledge the Spanish Ministry of Educa-
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Received: May 31, 2013
Published online on September 9, 2013
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 2013, 5, 3866 – 3874 3874