CaO-catalyzed aerobic oxidation of α-hydroxy ketones: Application to one-pot synthesis of quinoxaline derivatives

Article abstract of DOI:10.1246/cl.2012.488

The aerobic oxidation of α-hydroxy ketones into α-diketones catalyzed by CaO is compared with the same reaction catalyzed by other metal oxides. The catalytic activities of the various metal oxides were proportional to their surface basicities. The direct conversion of α-hydroxy ketones into quinoxalines via CaO-catalyzed aerobic oxidation followed by in situ reaction with 1,2-diaminoaromatics is also achieved. Various types of quinoxalines were synthesized in the presence of the CaO catalyst and molecular oxygen. It was also found that the CaO catalyst was reusable without any loss of its catalytic activity.

Full text of DOI:10.1246/cl.2012.488

doi:10.1246/cl.2012.488
4
88
Published on the web April 21, 2012
CaO-catalyzed Aerobic Oxidation of ¡-Hydroxy Ketones:
Application to One-pot Synthesis of Quinoxaline Derivatives
Takayoshi Hara, Yukihiro Takami, Nobuyuki Ichikuni, and Shogo Shimazu*
Graduate School of Engineering, Chiba University, 1-33 Yayoi, Inage-ku, Chiba 263-8522
(
Received January 31, 2012; CL-120081; E-mail: shimazu@faculty.chiba-u.jp)
The aerobic oxidation of ¡-hydroxy ketones into ¡-
diketones catalyzed by CaO is compared with the same reaction
catalyzed by other metal oxides. The catalytic activities of
the various metal oxides were proportional to their surface
basicities. The direct conversion of ¡-hydroxy ketones into
quinoxalines via CaO-catalyzed aerobic oxidation followed by
in situ reaction with 1,2-diaminoaromatics is also achieved.
Various types of quinoxalines were synthesized in the presence
of the CaO catalyst and molecular oxygen. It was also found that
the CaO catalyst was reusable without any loss of its catalytic
activity.
Currently, the development of sustainable protocols using
abundant and inexpensive catalysts is becoming progressively
more important. From this viewpoint, alkaline earth metals are
some of the most promising elements for use as catalysts. Among
the alkaline earth metals, calcium seems to be an ideal candidate
because it is essentially nontoxic, cheap, and abundant in the
1
2
earth’s crust. From the point of “the Element Strategy,”
Figure 1. The relationship between the electronegativity of
metal cations and conversion of 1a. Reaction conditions: 1a
proposed by the Japanese government, the use of ubiquitous
elements such as calcium instead of rare elements as catalytically
active species in organic transformations is strongly desired.
Calcium oxide (CaO) is well known as a versatile hetero-
geneous catalyst. Regarding the application of CaO, a wide
variety of base-catalyzed reactions, such as transesterifica-
(
1.5 mmol), catalyst (0.05 mmol), O2 (1 atm), 130 °C, 1 h.
catalysts for the oxidation of benzoin (1a) without solvent under
an atmospheric pressure of O2 at 130 °C (Figure 1). Tanaka and
Ozaki reported on the acid­base properties of metal oxides
according to the electronegativity of metal ion (»i), which is
obtained by the following equation: »i = (1 + 2Z)»0, where Z
and »0 are the charge of metal ion and the electronegativity of
3
a,3b
3c­3f
tion,
several carbon­carbon bond-forming reactions,
3g­3i
the isomerization or hydrogenation of dienes,
genation of ethylbenzene combined with CO2 shift reaction,
the dehydro-
3
j
3
k
and urea synthesis, have been developed. However, there are
no reports of aerobic alcohol oxidation into the corresponding
carbonyl compounds by CaO catalyst. Herein, we describe the
use of CaO in oxidative dehydrogenation of ¡-hydroxy ketones
into ¡-diketones in the presence of molecular oxygen.
9
neutral atom (Z = 0) given by Pauling, respectively. As a result
of the relationship between »i of each metal oxide catalyst and
its catalytic activity, the reaction rate was inversely proportional
to the catalyst’s » value, indicating the surface basic function
i
¡
-Diketones are useful building-block chemicals for the
plays a key role in the successful catalytic oxidation of 1a.
With the optimized reaction conditions in hand, different ¡-
4
synthesis of various pharmaceuticals and porphyrin rings.
Although various oxidizing reagents, for example, acetic
anhydride/DMSO,
1
0
hydroxy ketones were investigated (Table 1). CaO acted as an
effective catalyst for this oxidation, and 63% benzil (2a), 5%
benzaldehyde (3a), and 10% benzoic acid (4a) were obtained,
5
a
5b
5c
(NH4)2Ce(NO3)6,
Tl(NO3)3,
SbCl5/
DMSO, Zn(BiO3)2, CsOH, and NaH5g are generally
available to perform this direct dehydrogenation, these reagents
are often harmful and toxic, and considerable amounts are
required. The oxidation of ¡-hydroxy ketones with molecular
oxygen, performed with various transition-metal catalysts such
5
d
5e
5f
11
¹1
respectively (Entry 1). Under air flow (5 mL min ), the
reaction rate decreased substantially (Entry 2). A small amount
of 2a was formed under a N2 atmosphere without formation of
3a and 4a, presumably due to the acceptor-free dehydrogenation
6
a
6b
6c
6d
6e,6f
6g,6h
as Pd, Ru, Zn, Co, V,
and Mo
has also been
(Entry 3). Under 1 atm of CO , the dehydrogenation reaction did
2
reported. Because of environmental concerns, there is a strong
demand for a clean catalytic methodology for the conversion of
not proceed in the presence of CaO catalyst (Entry 4). Almost no
reaction was observed in the absence of CaO (Entry 11). After
the 1a oxidation, the spent CaO catalyst was easily separated by
simple centrifugation or filtration after the addition of toluene.
¡-hydroxy ketones to ¡-diketones.
Calcium oxide (99.9%) used in this study was purchased
from Wako Pure Chemicals Ind. Co., Ltd., and its surface area
estimated by BET method was 11 m g . To begin our study,
we assessed the ability of various metal oxides to serve as
In the XRD profile of the recovered CaO catalyst, the broad and
2
¹1 7
12
weak peaks assignable to Ca(OH) phase were observed. After
2
calcination under air at 700 °C for 1 h, high crystalline CaO was
Chem. Lett. 2012, 41, 488­490
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

4
89
Table 1. Aerobic oxidation of various ¡-hydroxy ketones
using CaO catalyst
Table 2. One-pot synthesis of quinoxalines 6 using CaO
catalyst
a
a
Yield/%b
Temp Time Convn.
Entry Substrate
b
/
°C
/h
/%
2
3
4
1
2
3
4
5
6
7
8
9
0
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
130
130
130
130
130
90
100
100
100
130
130
1
1
1
1
1
24
12
1
6
3
96
48
14
2
93
80
89
96
63
38
5
10
6
Yield
c
d
e
f
3
Temp Time
Entry ¡-Hydroxyketone Diamine
Product of 6
k
12 n.d. n.d.
2
60
71 n.d.
76 n.d.
/°C
/h
b
/
%
n.d. n.d.
3
1
2
3
4
5
6
7
8
9
0
1a
1b
1c
1d
1e
1f
1a
1a
1a
1a
5a
5a
5a
5a
5a
5a
5b
5c
5d
5e
130
100
100
80
1
3
3
6aa
6ba
6ca
6da
6ea
6fa
6ab
6ac
6ad
6ae
93
97
94
94
69
27
88
86
87
92
3
3
4
c
c
g
g
8
95 n.d. n.d.
g
h
100
100
130
130
130
130
3
24
2
3
3
90
60 n.d.
1
d
22i
20i
n.d.i
n.d. n.d.
n.d.i
1
1
j
1
1a
1
5
2
a
b
CaO catalyst (5 mol %), 1 (1 mmol), and O2 (1 atm). Deter-
mined by HPLC using an internal standard. Under air flow
5 mL min ). Under N2. Under 1 atm of CO2. Reuse
experiment. Ethylene glycol (3 mL) was used as a solvent.
Formation of brown caramel was observed. Determined by
GC analysis. Without catalyst. n.d.: not detected.
c
1
2
¹1
d
e
f
(
a
g
CaO catalyst (5 mol %), 1 (1 mmol), 5 (1.5 mmol), ethylene
b
h
i
glycol (3 mL), and O2 (1 atm). Determined by HPLC using an
internal standard technique. 5 (1 mmol). d48% of 2-ethyl-
benzimidazole (7fa) was formed.
c
j
k
reconstructed and could be reused without any loss of its high
activity and selectivity (Entry 5).13 Substituted benzoin deriva-
tives such as p-toluoin (1b) or p-anisoin (1c) were also oxidized
into the corresponding ¡-diketones with some degree of
formation of the cleavage product (Entries 6 and 7). Among
the reactions of ¡-hydroxy ketones, including heterocycles, the
selective dehydrogenation of ¡-pyridoin (1d) occurred, and an
almost quantitative yield of ¡-pyridil (2d) was obtained within
and o-phenylenediamines.15 Quinoxaline derivatives are well
known because of their functions as the heterocyclic core of
1
6a
16b
anticancer,
agents,
antibacterial,
due to the biological activities of these compounds.
and many pharmaceutical re-
1
6c­16e
There are many methods of preparing quinoxalines, however,
condensation between an ¡-diketone and a 1,2-diaminoaromatic
1
7
is regularly employed.
1
h (Entry 8). When ¡-furoin (1e) was used as a substrate, the
In view of the success of this CaO-catalyzed one-pot
synthesis of quinoxalines, the scope and limitations of this
production of a brown caramel-like substance was observed
accompanied by the formation of ¡-furil (2e) (Entry 9). An
aliphatic ¡-hydroxy ketone, propioin (1f), was transformed
into 3,4-hexanedione (2f) using the current catalytic system
1
8
reaction were explored (Table 2). First, substrate compatibility
was investigated by varying the ¡-hydroxy ketone used as the
starting material. Both aromatic and heterocyclic substrates react
successfully in the current one-pot reaction system (Entries 1­4).
When using 1e as the substrate, the formation of a caramel-like
substance could not be inhibited (Entry 5). Aliphatic ¡-hydroxy
ketone such as 1f were found to be less selective because of the
formation of 2-ethylbenzimidazole (7fa) with carboxylic acid as
a cleavage product (Entry 6). In the case of substituted 1,2-
diaminoaromatics, the one-pot reaction efficiently proceeded
to produce the corresponding quinoxalines with high yields
(Entries 7­10). Moreover, the one-pot quinoxaline synthesis
using ¡-hydroxy acetophenone, an asymmetric ¡-hydroxy
ketone, proceeded efficiently in the presence of the CaO catalyst,
as highlighted in eq 1. The facile trapping of ¡-diketone formed
in situ by a cascade cyclization with a 1,2-diaminoaromatic is a
key step in achieving the selective synthesis of quinoxaline
(Entry 10). Although the present catalytic system was effective
for the oxidation of ¡-hydroxy ketones, several limitations
regarding substrates were observed. For example, the CaO-
catalyzed oxidation of the ¡-hydroxy alcohol, dihydrobenzoin,
did not proceed at all. Furthermore, the oxidations of methyl
mandelate classified with ¡-hydroxy ester, and secondary
alcohols such as benzhydrol and 2-adamantanol with the CaO
catalyst were relatively slow. In the case of the oxidation of 1a
in the presence of 2a, it should be noted that the selectivity for
3
a and 4a increased with increasing amounts of the 2a; thus the
oxidative cleavage reaction might be enhanced by ¡-diketones
formed in situ.
To achieve the selective transformation of ¡-hydroxy
ketones, this CaO catalyst system was applied to the one-pot
synthesis of quinoxaline derivatives using ¡-hydroxy ketones
1
4
1
9
derivatives.
Chem. Lett. 2012, 41, 488­490
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

4
90
00 °C for 1 h was 18 m g¹1, and the CO2-TPD profiles of fresh
2
7
and recovered CaO catalysts were shown in Supporting Informa-
tion.8
ð1Þ
8
9
Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.html.
K.-I. Tanaka, A. Ozaki, J. Catal. 1967, 8, 1.
In conclusion, the CaO-catalyzed aerobic oxidation of
-hydroxy ketones and its application in one-pot quinoxaline
synthesis were demonstrated. The CaO catalyst could be reused
without any loss of its high catalytic activity and selectivity.
Further mechanistic studies and the development of other CaO-
catalyzed organic transformations are now in progress.
10 Typical procedure of CaO-catalyzed aerobic oxidation of 1a: Into
a Schlenk tube with a reflux condenser was placed 1a (1 mmol,
¡
0.212 g) and CaO catalyst (0.05 mmol, 0.0028 g). The resulting
mixture was stirred at 130 °C for 1 h under atmospheric pressure
of O2. 1a conversion and 2a yield were periodically determined
by HPLC analysis using biphenyl as an internal standard.
1
1 In 1982, P. M. Keehn, et al. reported that a stoichiometric amount
of Ca(OCl)2 promoted the oxidative cleavage of ¡-hydroxy
ketones into aldehydes and carboxylic acids, see: S. O. Nwaukwa,
P. M. Keehn, Tetrahedron Lett. 1982, 23, 3135. In our catalysis,
the oxidation of 3a with the CaO catalyst also proceeded
smoothly and 44% of 4a was formed after 1 h under the same
conditions.
This study was supported by the Association for the
Progress of New Chemistry. Y.T. expresses his special thanks
for a research fellowship from Venture Business Laboratory,
Chiba University.
1
2 The aerobic oxidation of 1a in the presence of a Ca(OH)2 catalyst
instead of CaO also proceeded under the same reaction
conditions. For the results of the catalytic reaction and the XRD
profiles of recovered catalyst, see SI.8
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8
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19 During this one-pot reaction, ¡-diketone intermediate was not
7
The BET surface area of the recovered CaO catalyst calcined at
detected by HPLC analysis, see SI.8
Chem. Lett. 2012, 41, 488­490
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/