Simple primary amine catalyzed aerobic reductive ring-cleavage of isoxazole motif

Article abstract of DOI:10.1016/S1872-2067(14)60200-X

A clean and highly efficient catalytic aerobic reductive ring-cleavage of 3-methylanthra[1,2-c]isoxazole-6,11-dione to 1-amino-2-acetylanthraquinone was performed using simple organic amines as organocatalysts and water as a green reaction medium. This method provides a new clean transformation of isoxazole-containing compounds to the corresponding ortho-amino ketones. The catalytic performance of various organic amines was carefully screened, and simple organic primary amines were found to be promising practical catalysts with outstanding catalytic performance. Isopropylamine as the organocatalyst gave 97.2% conversion of 3-methylanthra[1,2-c]isoxazole-6,11-dione, with 97.2% selectivity to 1-amino-2-acetylanthraquinone, in the presence of oxygen only, using 1 equiv. of hydrazine hydrate at room temperature for 3 h. A possible mechanism is also proposed.

Full text of DOI:10.1016/S1872-2067(14)60200-X

Chinese Journal of Catalysis 36 (2015) 204–208
ava i l a b l e a t w w w. s c i e n c ed i r e c t . c o m
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e /c h n j c
Article
Simple primary amine catalyzed aerobic reductive ring‐cleavage of
isoxazole motif
Zhongkui Zhao*, Renzhi Li, Yu Li, Guiru Wang
State Key Laboratory of Fine Chemicals, Department of Catalysis Chemistry and Engineering, School of Chemical Engineering, Dalian University of
Technology, Dalian 116024, Liaoning, China
A R T I C L E I N F O
A B S T R A C T
A clean and highly efficient catalytic aerobic reductive ring‐cleavage of 3‐methylan‐
Article history:
Received 25 June 2014
Accepted 18 July 2014
Published 20 February 2015
thra[1,2‐c]isoxazole‐6,11‐dione to 1‐amino‐2‐acetylanthraquinone was performed using simple
organic amines as organocatalysts and water as a green reaction medium. This method provides a
new clean transformation of isoxazole‐containing compounds to the corresponding ortho‐amino
ketones. The catalytic performance of various organic amines was carefully screened, and simple
organic primary amines were found to be promising practical catalysts with outstanding catalytic
performance. Isopropylamine as the organocatalyst gave 97.2% conversion of 3‐methylan‐
thra[1,2‐c]isoxazole‐6,11‐dione, with 97.2% selectivity to 1‐amino‐2‐acetylanthraquinone, in the
presence of oxygen only, using 1 equiv. of hydrazine hydrate at room temperature for 3 h. A possi‐
ble mechanism is also proposed.
Keywords:
Organocatalysis
Simple primary amine
Aerobic reductive ring cleavage
1‐Amino‐2‐acetyl anthraquinone
Green chemistry
© 2015, Dalian Institute of Chemical Physics, Chinese Academy of Sciences.
Published by Elsevier B.V. All rights reserved.
1. Introduction
mands of green chemistry. The search for a clean and efficient
method for reductive cleavage under mild reaction conditions
ortho‐Amino ketones, a series of important organic inter‐
mediates, are widely used in the dye, pigment, medical, and
petrochemical fields [1–3]. Recently, the preparation of or‐
tho‐amino ketones has attracted much attention. The synthesis
of this type of amino ketone via ring cleavage of an isoxazole
motif is an efficient strategy, e.g., for the synthesis of
1‐amino‐2‐acetylanthraquinone for Vat blue 66 [4].
Stoichiometric reduction processes have generally been
used in the synthesis of ortho‐amino ketones, with ferrous sul‐
fate [5], sodium hydrosulfite [6], Mo(CO)6 [7], CuI [8],
EtMgBr/Ti(Oi‐Pr) [9], or sodium [10] as reducing agents.
However, large amounts of chemical reagents are required, and
large amounts of wastes are produced. The heavy pollution
caused by this process is inconsistent with the increasing de‐
is therefore important. Electron‐transfer reactions by AlI3 [11],
iron dichloride [12–14], TiCl3 [15], SmI2 [16,17] or iodotrime‐
thylsilane [18,19] are feasible alternative strategies for isoxa‐
zole cleavage, but stringent anhydrous conditions are essential,
and heavy pollution cannot be avoided. The development of
clean methods for synthesizing ortho‐amino ketones such as
1‐amino‐2‐acetylanthraquinone, an important dye intermedi‐
ate, is therefore desirable.
To overcome the above issues, catalytic hydrogenation,
which is a clean method, has been used in the ring‐cleavage of
isoxazole motifs for the production of ortho‐amino ketone de‐
rivatives. Precious metals such as palladium or platinum
[20–23] and non‐precious metals such as Raney nickel effi‐
ciently catalyze the production of various isoxazole motifs [24].
* Corresponding author. Fax: +86‐411‐84986354; E‐mail: zkzhao@dlut.edu.cn
This work was supported by the Chinese Ministry of Education via the Program for New Century Excellent Talents in University (NCET‐12‐0079) and
the Fundamental Research Funds for the Central Universities (DUT12LK51).
DOI: 10.1016/S1872‐2067(14)60200‐X | http://www.sciencedirect.com/science/journal/18722067 | Chin. J. Catal., Vol. 36, No. 2, February 2015

Zhongkui Zhao et al. / Chinese Journal of Catalysis 36 (2015) 204–208
205
The high costs and poor availability of precious metals limit
their extensive use, and careful handling and finely controlled
reaction conditions are required if Raney nickel is used. We
previously demonstrated that copper can efficiently catalyze
this reaction for the clean synthesis of ortho‐amino ketones,
including 1‐amino‐2‐acetylanthraquinone [25]. However, the
problem of pollution by residual transition metals still needs to
be resolved. The search for metal‐free highly efficient catalysts
for catalytic hydrogenation reactions for ortho‐amino ketone
production is therefore important.
aqueous hydrazine as the reducing reagent; we therefore
thought that oxygen in the air could be used in the amine‐cata‐
lyzed reductive ring‐cleavage of 3‐methylanthra[1,2‐c] isoxa‐
zole‐6,11‐dione. A possible mechanism for the highly efficient
amine‐catalyzed transformation in the presence of air is also
proposed. The organic‐amine‐catalyzed aerobic reductive
ring‐cleavage of 3‐methylanthra[1,2‐c]isoxazole‐6,11‐dione can
be extended to other isoxazole‐containing compounds to pro‐
duce the corresponding ortho‐amino ketones.
Organocatalysis, or the use of small organic molecules to
catalyze organic transformations, is a relatively new and popu‐
lar research field. Although chemical transformations that use
organocatalysts have been documented sporadically over the
past century, it was not until the late 1990s that the field of
organocatalysis was born, based on a small number of articles
that inspired an explosion of research. Between 1998 and
2008, the field of organocatalysis grew rapidly, and at least
1500 papers describing the use of organocatalysts in more than
130 discrete reaction types were published [25,26]. Organocat‐
alytic methods have also been used in hydrogenations [27–29]
and ring‐opening reactions [30]. In our previous research [31],
dimethyl formamide (DMF)‐promoted ring‐opening reactions
of 3‐methylanthra[1,2‐c]isoxazole‐6,11‐dione to 1‐amino2‐
2. Experimental
2.1. Materials and instruments
All reagents were purchased from Aladdin and were used
without further purification. 1H nuclear magnetic resonance
(NMR) spectroscopy was performed using a Bruker Avance
400M instrument at room temperature, with tetramethylsilane
as the internal standard; coupling constants (J) were measured
in hertz; mass spectrometry (MS) was performed using an
HP1100LC/MSD instrument.
2.2. Catalytic performance measurement
acetylanthraquinone were established. However,
a
large
In
a
typical experimental procedure, 3‐methylan‐
25 mL
amount of DMF, which is poisonous, and excess hydrazine are
required to obtain a good catalytic performance. The develop‐
ment of more efficient organocatalysts, with water as a clean
solvent, is an increasingly important goal for chemists, for both
economic and environmental reasons. Simple and complex
organic amines are popular organocatalysts, and have been
extensively used in many transformations, with excellent re‐
sults [32–34]. However, the catalytic performance of organic
amines in ring cleavage of isoxazole‐containing compounds to
produce the corresponding ortho‐amino ketones has not been
investigated.
In this study, using the ring cleavage of 3‐methylan‐
thra[1,2‐c]isoxazole‐6,11‐dione to produce 1‐amino‐2‐acety‐
lanthraquinone as a model reaction (Scheme 1), we explored
the possibility of using simple amines as organocatalysts for the
ring cleavage of isoxazole motifs to produce the corresponding
ortho‐amino ketones. The aim of the present work is to con‐
struct a clean and efficient strategy for the synthesis of
1‐amino‐2‐acetylanthraquinone via a ring‐opening route, by
the reduction of 3‐methylanthra[1,2‐c]isoxazole‐6,11‐dione in
the presence of organocatalysts. An excellent catalytic perfor‐
mance was achieved using isopropylamine as the catalyst, and
97.2% 3‐methylanthra[1,2‐c]isoxazole‐6,11‐dione conversion,
with 97.2% 1‐amino‐2‐acetylanthraquinone selectivity, was
achieved. It has been shown [27] that oxygen is important in
guanidine‐catalyzed selective hydrogenation of olefins using
thra[1,2‐c]isoxazole‐6,11‐dione was placed in
a
one‐necked round‐bottomed flask, and deionized water (3.0
mL, a green reaction medium) and an appropriate amount of
isopropylamine were introduced. The reaction mixture was
stirred at room temperature for 30 min to obtain good disper‐
sion, and the desired amount of hydrazine hydrate was then
added, with continuous stirring. The mixture was continuously
stirred for the desired reaction time. The product was insoluble
in water, and was easily separated by filtration. After the reac‐
tion, the mixture was filtered, and the solid product was
washed with deionized water and dried at 105 °C overnight.
The product was quantitatively analyzed using high‐perfor‐
mance liquid chromatography (HPLC). The conversion was
calculated, based on the HPLC results, as the ratio of the con‐
sumed amount to the total amount of 3‐methylan‐
thra[1,2‐c]isoxazole‐6,11‐dione, expressed as a percentage. The
1
product was characterized using H NMR and MS spectrosco‐
pies. Characterization results: red powder, mp 222–226 °C; 1H
NMR (CDCl3): δ 2.68 (3H, s, CH3), 7.55 (1H, d), 7.72–7.83 (2H, t),
8.16 (1H, d), 8.23–8.32 (2H, d), 9.51, and 9.92 (2H, s, NH2); MS
(APCI, m/z) for 1‐amino‐2‐acetylanthraquinone [M +1] = 266.
3. Results and discussion
3.1. Effect of type of organic amine
The molecular structure of the product obtained via organ‐
O
O
N
NH2
O
O
ic‐amine‐catalyzed ring‐cleavage of 3‐methylanthra[1,2‐c]
Organoamine
O2, Hydrazine
1
isoxazole‐6,11‐dione was determined using H NMR and MS
N
H O
2
+
+
2
spectroscopies. The results confirm that the molecular struc‐
ture is 1‐amino‐2‐acetylanthraquinone, i.e., the desired product
was successfully obtained using organic‐amine‐catalyzed
O
O
Scheme 1. Synthesis of 1‐amino‐2‐acetylanthraquinone.

206
Zhongkui Zhao et al. / Chinese Journal of Catalysis 36 (2015) 204–208
Table 1
Table 2
Catalytic reduction of 3‐methylanthra[1,2‐c]isoxazole‐6,11‐dione.
Optimization of reaction conditions.
Entry
1
2
3
4
5
6
7
Catalyst
iso‐C3H7NH2
CH3CH2NH2
CH3NH2
(CH3)2NH
(iso‐C3H7)2NH
(CH3)3N
Pyridine
NH3·H2O
—
Conversion (%) Selectivity (%)
Hydrazine hy‐ iso‐C3H7NH2 Time Conversion Selectivity
Entry
drate (equiv.)
(mol)
0.01
0.01
0.01
0.01
0.02
0.02
(h)
1
1
3
3
(%)
95.4
65.2
94.0
63.0
97.7
97.2
(%)
98.5
96.6
98.1
97.3
98.3
97.2
95.4
95.3
91.8
81.9
48.5
43.7
21.2
26.1
9.6
98.5
98.1
97.7
97.6
95.7
94.7
86.5
91.2
67.9
1
2
3
4
5
6
8
4
4
2
2
1
3
3
8
9*
Reaction conditions: room temperature (25 °C), total water volume 3.0
mL.
Reaction conditions: hydrazine hydrate 8 equiv., room temperature (25
°C), reaction time 1 h (* 3 h), total water volume 3.0 mL, catalyst dosage
10 mmol (organic amine).
The reaction conditions for the isopropylamine‐catalyzed
ring‐cleavage reaction were optimized; the results are summa‐
rized in Table 2. The data in Table 2 show that the results of the
catalytic ring‐cleavage reaction are strongly dependent on the
reaction conditions; 97.2% conversion and 97.2% selectivity
for 1‐amino‐2‐acetylanthraquinone were obtained using
iso‐propylamine (0.02 mol) and hydrazine hydrate (1 equiv.) at
room temperature for 3 h, with water as the clean reaction
medium.
ring‐cleavage of 3‐methylanthra[1,2‐c]isoxazole‐6,11‐dione.
Various organic amines were tested as organocatalysts in the
reaction. The results are summarized in Table 1.
The data in Table 1 show that the best catalyst was isoprop‐
ylamine, giving 95.4% 3‐methylanthra[1,2‐c]isoxazole‐6,11‐
dione conversion and 98.5% selectivity for 1‐amino‐2‐acety‐
lanthraquinone (Table 1, entry 1). To confirm that the added
organic amine catalyzed the reaction, a blank experiment was
performed; only 9.6% conversion (Table 1, entry 9) was
achieved under the same conditions in the absence of an or‐
ganic amine, clearly confirming the catalytic effect. The catalytic
performance of various simple organic amines in the ring
cleavage of 3‐methylanthra[1,2‐c]isoxazole‐6,11‐dione was
explored; pyridine and aqueous ammonia were included for
comparison. The data in Table 1 show that primary amines
exhibited excellent catalytic efficiency, and the conversions
reached 95.4%, 95.3%, and 91.8% using isopropylamine,
CH3CH2NH2, CH3NH2, respectively, as catalysts (Table 1, entries
1–3). However, except for (CH3)2NH (Table 1, entry 4), second‐
ary and tertiary amines had poor catalytic activity; this may be
because steric hindrance inhibits attack of the isoxazole by the
amine‐hydrazine complex. This conclusion is supported by a
comparison of the catalytic activity of CH3NH2, (CH3)2NH, and
(CH3)3N (91.8%, 81.9%, and 43.7%, respectively). We consider
that the electron‐donating group influences the electron cloud
density of the lone pair of electrons on the nitrogen atom, re‐
sulting in different activation degrees of hydrazine hydrate.
Pyridine was also used as the catalyst, but its catalytic activity
was significantly lower than those of other organic amines,
possibly because the electron cloud density of the nitrogen lone
pair electrons is lower. NH3·H2O also had low activity, which
shows that the catalytic effect of organic amines arises from the
lone pair of electrons on the nitrogen atom, rather than the
alkalinity.
3.3. Plausible catalytic reaction mechanism with organic
amines
We explored the mechanism of the simple organ‐
ic‐amine‐catalyzed ring‐cleavage of 3‐methylanthra[1,2‐c]
isoxazole‐6,11‐dione via reduction using hydrazine hydrate as
the reducing reagent. The data in Table 1 show that primary
amines are highly efficient catalysts for isoxazole cleavage. In
aqueous solution, the order of the alkalinity of amines is sec‐
ondary amine > primary amine > tertiary amine, but in isoxa‐
zole cleavage, the catalytic efficiency order is primary amine >
secondary amine > tertiary amine > ammonia solution (Table
1). The reducing ability of hydrazine hydrate is generally high
under alkaline conditions, but in our work, the activity was not
directly related to the alkalinity; this further confirms that the
catalytic effect of the organic amine comes from hydrazine hy‐
drate activation by the lone pair of electrons on the nitrogen
atom rather than enhancement of its reducing power by the
alkalinity of the reaction medium. The steric hindrance of
branched amines may prevent the amine‐hydrazine complex
attacking the substrate, and, as a result, the primary amine
exhibits high catalytic activity. We therefore conjecture that the
catalytic effect of simple organic amines arises from the for‐
mation of an amine‐hydrazine complex by hydrogen‐bond
formation, followed by attack on the substrate by the complex.
A plausible reaction mechanism for the developed approach is
shown in Scheme 2.
Although the catalytic efficiency of CH3CH2NH2 is close to
that of isopropylamine, its toxicity is twice that of isopropyla‐
mine (820 and 400 mg/kg of LD50 for isopropylamine and
CH3CH2NH2, respectively). These results show that isopropyl‐
amine is clean and highly efficient, and is the best organocata‐
lyst for the reductive ring‐cleavage of 3‐methylanthra[1,2‐c]
isoxazole‐6,11‐dione to 1‐amino‐2‐acetylanthraquinone.
N
O
O
O
R
R
H
NH2
H
O
O
N
H
N
H
Oxygen
H NNH
+
RNH2
2
2
N2
H2O
N=N
O
H
H
Scheme 2. Plausible mechanism for reductive cleavage of 3‐methylan‐
thra[1,2‐c]isoxazole‐6,11‐dione to 1‐amino‐2‐acetylanthraquinone in
the presence of organic amine catalysts.
3.2. Optimization of reaction conditions

Zhongkui Zhao et al. / Chinese Journal of Catalysis 36 (2015) 204–208
207
Graphical Abstract
Chin. J. Catal., 2015, 36: 204–208 doi: 10.1016/S1872‐2067(14)60200‐X
Simple primary amine catalyzed aerobic reductive
ring‐cleavage of isoxazole motif
Zhongkui Zhao*, Renzhi Li, Yu Li, Guiru Wang
Dalian University of Technology
NH2
O
O
O
O
N
O
O
O
O
A simple organic‐primary‐amine‐catalyzed aerobic reductive
isoxazole ring‐cleavage strategy for clean and highly efficient
1‐amino‐2‐acetylanthraquinone production was described.
OXYGEN
HYDRAZINE HYDRATE
DLUT
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Technol, 2011, 45: 4793
Simple primary amines are highly efficient organocatalysts
for ring‐opening reactions of isoxazoles via catalytic aerobic
reduction with hydrazine hydrate as the reducing reagent and
water as the green reaction medium. The primary‐amine‐cata‐
lyzed ring‐cleavage of 3‐methylanthra[1,2‐c]isoxazole‐6,11‐
dione can be used for the clean and efficient synthesis of
1‐amino‐2‐acetylanthraquinone, a useful dye intermediate.
Primary amines are promising catalysts, with excellent catalytic
performance; 97.2% conversion and 97.2% selectivity were
obtained in the presence of isopropylamine (0.02 mol) using of
(hydrazine hydrate 1 equiv.) at room temperature for 3 h. This
method could be extended to other isoxazole‐containing com‐
pounds to produce the corresponding ortho‐amino ketones,
including, but not limited to, 1‐amino‐2‐acetylanthraquinone.
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