A mild and convenient one-pot synthesis of 4,6-diaryl- 3-aminoisoxazolo[3, 4-b]pyridines

Article abstract of DOI:10.3987/COM-13-12802

We have developed a convenient method for the synthesis of a series of new 4,6-diaryl-3-aminoisoxazolo[3,4-b]pyridines through one-pot reaction starting from the easily available chalcones, malononitrile, and hydroxylamine. This class of compounds might h

Full text of DOI:10.3987/COM-13-12802

HETEROCYCLES, Vol. 87, No. 12, 2013
2599
HETEROCYCLES, Vol. 87, No. 12, 2013, pp. 2599 - 2605. © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 6th August, 2013, Accepted, 21st October, 2013, Published online, 31st October, 2013
DOI: 10.3987/COM-13-12802
A MILD AND CONVENIENT ONE-POT SYNTHESIS OF 4,6-DIARYL-
3-AMINOISOXAZOLO[3,4-b]PYRIDINES
Chun-Bao Miao,* Yan-Hong Wang, Chun-Ping Dong, Hai-Tao Yang, Qi
Meng, and Xiao-Qiang Sun*
School of Petrochemical Engineering, Changzhou University, Changzhou 213164,
PR China
E-mail: estally@yahoo.com
Abstract - We have developed a convenient method for the synthesis of a series
of new 4,6-diaryl-3-aminoisoxazolo[3,4-b]pyridines through one-pot reaction
starting from the easily available chalcones, malononitrile, and hydroxylamine.
This class of compounds might have potential pharmacological activities in
medicinal chemistry.
Isoxazole-fused pyridine is one of the important heterocyclic units, which has been widely used as a key
building block for pharmaceutical agents.1-4 However, research on the construction of such skeletons with
an isoxazole ring fusing to pyridine is seldom reported. Isoxazolopyridine is commonly constructed from
either a pyridine5-7 or an isoxazole precursor.8,9 Sometimes, isoxazolopyridine can also be obtained by the
flash vacuum pyrolysis of 8-acetyltetrazolo[1,5-a]pyridine10 or from the reaction of potassium
cyanoacetohydroxamate with 2-arylhydrazono-3-oxobutyrates.11 Despite several reports on the
preparation of isoxazole-pyridines appeared recently,12-14 there is a continuous demand for the
exploitation of new methods to prepare novel isoxazolopyridines. The development of simple routes
toward preparing useful organic compounds from readily available reagents and compounds is one of the
major tasks in organic synthesis. One-pot operation has proved to be remarkably effective in organic
synthesis, while at the same time cutting out several purification steps, minimizing chemical waste
generation, and saving time.15,16 As a continuation of our interest in constructing heterocycles,17-19 herein,
we reported the one-pot synthesis of new isoxazole-fused pyridine derivatives from easily available
chalcones, malononitrile, and hydroxylamine hydrochloride.

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HETEROCYCLES, Vol. 87, No. 12, 2013
R1
R1
O
O
O
O
o
O
1)
2)
10 mol % NaOH, EtOH, 0 C
O
OR2
+
OR2
O
o
5 equiv NH2OH in EtOH, 0 C
N
O
previous work
OH
Ph
Ph
NH2
O
NC
NC
CN
O
NH2OH•HCl

NH2OH•HCl
base, solvent
Ph
H2N
N
Ph
N
Ph
N
Ph
base
OH
A
2a
1a
this work
Scheme 1
Most recently, we reported a one-pot strategy to synthesize the N-OH-Hantzsch esters through a tandem
Michael addition-condensation process (Scheme 1).19 In order to broaden the N-OH-1,4-dihydropyridines
family with different substituents, we attempted to synthesize compound A starting from 1a and
hydroxylamine hydrochloride (Table 1). At the onset, the reaction of 1a with hydroxylamine
hydrochloride was performed in the presence of various bases (2 equiv) in EtOH at room temperature
(Table 1, entries 1-5). To our disappointment, no desired product A was formed. Instead, bicyclic
compound 2a was obtained as the main product and KOH was the relatively efficient base. Up to now,
there was rare report on the construction of this kind of isoxazole-fused pyridine structure. So we
continued to investigate the reaction in detail. To optimize the reaction, we investigated the influence of
different solvents. EtOH was proved to be the most effective solvent, and using other solvents such as
THF, DMF, MeCN, acetone or CH2Cl2 led to noticeable decrease in the yield of 2a (Table 1, entries 6-10).
Next, the influence of molar ratio of reactants was studied (Table 2, entries 11-15). Changing the molar
ratio of NH2OH·HCl:KOH from 1:2 to 1:1 resulted in no generation of product, which indicated the
cyclization needed a strong base (Table 1, entry 11). Further investigation showed that optimal molar
ratio of 1a:NH2OH·HCl:KOH for the formation of 2a was 1:1.3:2.5 (Table 1, entry 15). The yield of 2a is
not high due to the incomplete conversion and formation of some byproducts. When we modulated the
feeding order by adding dropwise a solution of KOH (1.25 mmol) in 10 mL of EtOH to the mixture of 1a
(0.5 mmol) and hydroxylamine hydrochloride in 10 mL of EtOH within 1 h and then continue stirring for
another 43 h at room temperature, the yield of 2a was increased to 50% (Table 1, entry 16). Although
50% yield of 2a is acceptable, the reaction needed too long time (43 h). Raising the reaction temperature
to reflux resulted in a slightly higher yield (58%) within short reaction time (7 h) (Table 1, entry 17).

HETEROCYCLES, Vol. 87, No. 12, 2013
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Table 1. Screening of the reaction conditionsa
yield of
2a (%)c
entry
solvent
base
ratiob
temperature
time (h)
1
2
EtOH
EtOH
EtOH
EtOH
EtOH
THF
KOH
K2CO3
Et3N
1:1:2
1:1:2
rt
43
43
31
trace
0
rt
3
1:1:2
rt
43
4
piperidine
DBU
1:1:2
rt
43
trace
23
trace
5
5
1:1:2
rt
43
6
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
1:1:2
rt
43
7
DMF
1:1:2
rt
43
8
MeCN
acetone
CH2Cl2
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
1:1:2
rt
43
8
9
1:1:2
rt
43
10
9
10
11
12
13
14
15
16d
17e
1:1:2
rt
43
1:1:1
rt
43
0
1:1:1.5
1:1:2.5
1:1:3
rt
43
11
33
34
40
50
58
rt
43
rt
43
1:1.3:2.5
1:1.3:2.5
1:1.3:2.5
rt
rt
43
1+43
1+1+6
rt→reflux
a
A mixture of 1a (0.5 mmol), hydroxylamine hydrochloride, and base was stirred in 20 mL of solvent at room
b
c
d
temperature. 1a: hydroxylamine hydrochloride:base. Isolated yield. The solution of KOH (1.25 mmol) in 10
mL of EtOH was added dropwise into the mixture of 1a (0.5 mmol) and hydroxylamine hydrochloride in 10 mL of
EtOH with 1 h and then the solution was stirred for additional 43 h at room temperature. The same operation as
e
entry 16 except that after addition of the base, the mixture was further stirred for 1 h at room temperature and then
refluxed for another 6 h.
In an attempt to make this approach more efficient, a one-pot reaction to prepare 2a was tested (Table 2).
A mixture of chalcone 3a (0.5 mmol), malononitrile (0.55 mmol) and KOH (0.05 mmol) was stirred
in 10 mL of EtOH at room temperature for 1 h. After quantitative conversion to 1a (detected by TLC),
hydroxylamine hydrochloride (46 mg, 0.65 mmol) was added. Subsequently, an ethanol solution of
KOH (1.25 mmol, 10 mL) was added dropwise into the reaction mixture within 1 h under stirring.
The mixture was continually stirred for 1 h at room temperature and then refluxed for additional 6 h.
After purification, the desired 4,6-diphenyl-3-aminoisoxazolo[3,4-b]pyridine 2a was obtained as a white

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HETEROCYCLES, Vol. 87, No. 12, 2013
solid in 54% yield. Under the optimized conditions, the reaction scope was evaluated by using various
chalcones 1 (Table 2). The results showed that 3-aminoisoxazolo[3,4-b]pyridines 2 with different
substituent groups could be generated in moderate yields (40-60%). The electronic effect of the
substituent group on the phenyl ring in R1 had no significant impact on the reaction. However, the
electronic effect of substituent group on the phenyl ring in R2 had great influence on the reaction. When a
strong electron-withdrawing group (NO2) was linked with the phenyl ring in R2, no product was isolated.
Fortunately, heterocycle-substituted bicyclic compounds 2i and 2j could also be formed. All the products
were characterized by their NMR, IR and MS spectra. The structure of the product 2d was further
established by the X-ray determination (Figure 1, recrystallization from EtOH).
Table 2. One-pot reaction for the preparation of 4,6-diaryl-3-aminoisoxazolo[3,4-b]pyridines 2
R1
NC CN
NH2
O
(1)
(1.1 equiv)
O
KOH (0.1 equiv)
R1
R2
R2
N
(2) NH2OH•HCl (1.3 equiv)
(3) KOH (2.5 equiv)
N
2
3
entry
substrate
R1
R2
time (h)a
product
yield (%)
1
2
3a
3b
3c
3d
3e
3f
Ph
Ph
Ph
Ph
Ph
Ph
6
6
6
6
5
6
6
6
8
8
2a
2b
2c
2d
2e
2f
54
52
53
48
60
50
48
51
49
25
4-MeOC6H5
4-MeC6H5
4-ClC6H5
4-NO2C6H5
Ph
3
4
5
6
4-MeOC6H5
4-MeC6H5
4-ClC6H5
4-MeC6H5
2-pyridyl
7
3g
3h
3i
Ph
2g
2h
2i
8
Ph
9
2-furyl
10
3j
4-MeOC6H5
2j
a It refers to the reflux time of the last step.

HETEROCYCLES, Vol. 87, No. 12, 2013
2603
Figure 1. X-Ray crystal structure of 2d20
A mechanism for the formation of 2a-2j is outlined in Scheme 2. The nucleophilic addition reaction of
hydroxylamine with Michael adduct 1 gives the intermediate 5.21 Isomerization of 5 to 6, followed by
sequential intramolecular cyclization, and subsequent oxidative dehydrogenation afford compounds 2.
R1
HOHN
HO
H2N OH
R1
N
N
HON
NH2
O
NH
NH2
O
NH
O
N
H
NH2
O
C
N
C
C
C
NC
R1
-H2O
NC
O
NC
R1
NH
R2
-2H
R2
N
R2
R2
R2
N
H
R1
R2
R1
5
6
1
7
8
2
Scheme 2
In summary, we have developed a facile and convenient method for the synthesis of a series of
4,6-diaryl-3-aminoisoxazolo[3,4-b]pyridines. The key factor is to control the third-step cyclization
reaction by adding the solution of KOH in dropwise. Particularly, the method shows several attractive
characteristics, namely, one-pot, convenient, simple work-up procedure. This kind of skeleton may has
potential use in medicinal fields.
EXPERIMENTAL
General Procedure for the Three-Component Reaction of Chalcones 3, Malononitrile and
Hydroxylamine Hydrochloride: A mixture of chalcones 3 (0.5 mmol), malononitrile (36.3 mg, 0.55
mmol), and KOH (2.8 mg, 0.05 mmol) was stirred in 10 mL of EtOH at room temperature. Upon
completion of the Michael addition reaction (detected by TLC, about 1 h), hydroxylamine
hydrochloride (46 mg, 0.65 mmol) was added. Afterwards, a solution of KOH (70.0 mg, 1.25 mmol)

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HETEROCYCLES, Vol. 87, No. 12, 2013
in 10 mL of EtOH was added dropwise into the reaction mixture within 1 h under stirring. The
mixture was allowed to stir for 1 h at room temperature and then was refluxed for additional 5-8 h.
After completion of the reaction detected by TLC, the mixture was poured into 100 mL of ice-cold water.
The precipitate was filtered to give the crude product, which was then dried and purified by column
chromatography on silica gel (EtOAc/petroleum ether) to provide the products 2.
ACKNOWLEDGMENT
The authors are grateful for financial support from the National Natural Science Foundation of China
(Nos. 21202011, 20902039) and the Priority Academic Program Development of Jiangsu Higher
Education Institutions.
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