Phthalimide-N-oxyl salts: Efficient organocatalysts for facile synthesis of (Z)-3-methyl-4-(arylmethylene)-isoxazole-5(4H)-one derivatives in water

Article abstract of DOI:10.1007/s00706-015-1565-x

Green and simple protocols have been developed for the synthesis of (Z)-3-methyl-4-(arylmethylene)isoxazole-5(4H)-one derivatives in the presence of tetrabutylammonium or potassium salts of phthalimide-N-oxyl, as transition metal-free catalysts, through t

Full text of DOI:10.1007/s00706-015-1565-x

Monatsh Chem
DOI 10.1007/s00706-015-1565-x
ORIGINAL PAPER
Phthalimide-N-oxyl salts: efficient organocatalysts for facile
synthesis of (Z)-3-methyl-4-(arylmethylene)-isoxazole-5(4H)-one
derivatives in water
1
1
Mohammad G. Dekamin
•
S. Zahra Peyman
Received: 12 July 2015 / Accepted: 23 August 2015
Ó Springer-Verlag Wien 2015
Abstract Green and simple protocols have been devel-
oped for the synthesis of (Z)-3-methyl-4-(arylmethylene)-
isoxazole-5(4H)-one derivatives in the presence of tetra-
butylammonium or potassium salts of phthalimide-N-oxyl,
as transition metal-free catalysts, through the multicom-
ponent reaction strategy in aqueous medium at ambient
temperature. These procedures offer many advantages
including clean reaction profiles, mild reaction conditions,
short reaction times, high to quantitative yields, and
straightforward work-up.
Keywords Phthalimide-N-oxyl salts Á Organocatalysis Á
Multicomponent reactions (MCRs) Á
3-Methyl-4-(arylmethylene)isoxazole-5(4H)-ones Á
In water synthesis Á Green chemistry
Introduction
Multicomponent reactions (MCRs) have recently emerged
as a powerful strategy for the synthesis of structurally diverse
chemical libraries of drug like compounds since the products
are formed in a single step as well as diversity can be
achieved by simply varying each component [1–8]. How-
ever, sometimes MCRs may produce alternative products by
altering one component and/or catalysts. In this context,
competition between formation of (Z)-4-arylidene-3-
methylisoxazole-5(4H)-one(A) and N-hydroxy derivative of
Hantzsch 1,4-dihydropyridine (B) scaffolds is illustrative
when hydroxylamine is used as nitrogen source (Fig. 1) [9].
Literature survey shows that Hantzsch pseudo-four-
component reaction has been intensively investigated and
reviewed for different nitrogen sources such as ammonia or
amines [9–14]. However, less attention has been paid to the
synthesis of alternative products containing 4-(aryl-
methylene)isoxazole-5(4H)-one scaffold in their structure.
Furthermore, only aldehydes containing electron-donating
substituents are involved in this alternative reaction path
despite of pseudo-four-component Hantzsch reaction [15].
Isoxazole scaffold represents a class of heterocyclic com-
pounds demonstrating pharmacological and biological
activities such as anti-HIV [16], antifungal [17], analgesic
Graphical abstract
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-015-1565-x) contains supplementary
material, which is available to authorized users.
&
Mohammad G. Dekamin
mdekamin@iust.ac.ir
[
18], antitumor [19], COX-2 inhibitor [20], activator of the
enzyme responsible for inflammation and pain, antiviral
21], antioxidant [22], antimicrobial [23], and androgen
antagonists [24]. Furthermore, the isoxazole-5(4H)-one
1
Pharmaceutical and Biologically-Active Compounds
Research Laboratory, Department of Chemistry, Iran
University of Science and Technology, Tehran 16846-13114,
Iran
[
123

M. G. Dekamin, S. Zahra Peyman
Fig. 1 Competition between
formation of (Z)-4-arylidene-3-
methylisoxazole-5(4H)-one
Ar
O
O
H
EtO
OEt
Ar
N
(
A) and N-hydroxy derivative of
Hantzsch 1,4-dihydropyridine
B) scaffolds
O
N
OH
O
(
(
Z)-4-arylidene-3-methyl isoxazol-
Hantzsch 1,4-Dihydropyridines (B)
5
(4H)-one derivatives (A)
Prefered pseudo-4-C product for
strong Lewis or Bronsted acid catalysts
Prefered 3-C product for Lewis base
or weak Bronsted acid catalysts
Fig. 2 Selected examples of
isoxazole-5(4H)-one derivatives
demonstrating pharmacological
and biological activity (I) or as
ingredient of merocyanine dyes
H
H
H
N
O
N
O
N
O
N
O
(
II)
N
O
O
H
A
B
C
Androgen antagonist
Antifungal agent
Merocyanine dye
I
II
scaffold can also be found as the central moiety of mero-
cyanine dyes which are used in optical recording and
nonlinear optical research [25] (Fig. 2).
reaction times, and low yields. Thus, obviation of these
limitations is necessary to develop more efficient and
green synthesis of 3-methyl-4-(arylmethylene)isoxazole-
5(4H)-one derivatives. To address these concerns, the use
of water-soluble organocatalysts is very promising [37–
40]. Recently, we have demonstrated the catalytic activity
of phthalimide-N-oxyl (PINO) salts (1), as effective, easy
to handle, and readily available Lewis bases, for the
synthesis of 2-amino-4H-chromene derivatives in water
[41] and cross-linked poly(urethane–isocyanurate) net-
works [42], cyanosilylation of carbonyl compounds [37,
43], cyclotrimerization of isocyanates [44, 45], and pro-
tection of alcohols and phenols with trimethylsilyl group
[46]. In continuation of our interest to develop the cat-
alytic scope of PINO salts, we decided to study a metal-
free method for the synthesis of 3-methyl-4-
Recent methodologies for the synthesis of isoxazole
scaffold comprise the use of H BO [15], sodium ben-
3
3
zoate [26], Na B O [27], Na S [28], sodium citrate [29],
2
4
7
2
Na SiO [30], sodium saccharin [31], and potassium
2
3
phthalimide [32]. Furthermore, techniques such as visible
light in the presence of NaOAc in aqueous EtOH [33],
solid-state heating or solid-state grinding [34], ultrasonic
irradiation in the presence of pyridine at ambient tem-
perature [35], and microwave irradiation [36] have also
been reported. However, most of reported methods for the
synthesis of these compounds suffer from disadvantages
including the use of toxic or odorous catalysts, tedious
work-up procedures, troublesome waste discarding, long
Scheme 1
O
N O M
H
O
Ar
O
O
O
1
0 mol%
+
NH OH.HCl +
2
CO Et
2
Ar
H
Water, rt
M = K; 1a
N
O
M = (Bu) N; 1b
4
1
23

Phthalimide-N-oxyl salts: Efficient organocatalysts for facile synthesis of…
Table 1 Optimization of the three-component reaction of hydroxylamine hydrochloride (2), ethyl acetoacetate (3) and vanillin (4a) in the
presence of phthalimide-N-oxyl salts 1a, 1b at ambient temperature
a
Yield /%
b
c -1
TOF /h
Entry
Catalyst
Catalyst loading/mol%
Solvent
Time/h
TON
5
a
6a
1
2
3
4
5
6
7
8
9
–
–
H
H
H
H
2
2
2
2
O
O
O
O
3.5
1
22
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
–
–
POPINO (1a)
POPINO (1a)
POPINO (1a)
POPINO (1a)
POPINO (1a)
POPINO (1a)
POPINO (1a)
TBAPINO (1b)
TBAPINO (1b)
TBAPINO (1b)
TBAPINO (1b)
TBAPINO (1b)
TBAPINO (1b)
TBAPINO (1b)
15
10
7
90
6
6
1
94
9.4
12.7
7
9.4
6.4
3.5
2.9
3.2
–
2
89
10
10
10
10
15
10
7
EtOH
2
70
EtOH/H
DMSO
2
O
2.5
2.5
4
72
7.2
8
80
Cyclohexane
Trace
93
–
H
2
H
2
H
2
O
O
O
0.75
0.75
1.25
1.5
2
6.2
9.7
12.9
7.5
8.2
9
8.3
12.9
10.3
5
10
11
12
13
14
15
97
90
10
10
10
10
EtOH
75
EtOH/H
DMSO
2
O
82
4.1
4.5
–
2
90
Cyclohexane
2.5
Trace
–
3
Reaction conditions: hydroxylamine hydrochloride (2, 1 mmol), ethyl acetoacetate (3, 1 mmol), vanillin (4a, 1 mmol), 2 cm water and required
amount of the catalysts
a
The yields refer to the isolated product
b
Turn over number
c
Turn over frequency
(
arylmethylene)isoxazole-5(4H)-ones in the presence of
was significantly improved when catalytic amount of
POPINO (1a) or TBAPINO (1b) was added to the reaction
mixture (entries 2-4 and 9-11). TBAPINO (1b) required
shorter reaction times to afford slightly higher yields of the
desired product 5a than POPINO (1a). This can be attributed
to lower interaction of the bulky tetrabutylammonium cation
in 1b (entries 9–11) with the phthalimide-N-oxyl (PINO)
anion which makes it more efficient for its catalytic activity
compared to potassium cation in 1a (entries 2–4). These
findings are entirely consistent with our earlier research [37,
43–45]. The effect of other solvents or their mixture on the
progress of the model reaction was further studied in the
presence of 10 mol% loading of 1a or 1b (entries 5–8 and
12–15). According to the obtained results, water was found to
be the solvent of choice in terms of the yield of product and
required time for completion of the model reaction in com-
parison with other solvents.
potassium phthalimide-N-oxyl (POPINO, 1a) or tetra-
butylammonium phthalimide-N-oxyl (TBAPINO, 1b) in
water at ambient temperature (Scheme 1).
Results and discussion
To optimize reaction conditions, the effect of different
loadings of POPINO (1a) or TBAPINO (1b) was studied
for the reaction of hydroxylamine hydrochloride (2), ethyl
acetoacetate (3), and vanillin (4a, Ar = 4-hydroxy-3-
methoxyphenyl) (molar ratio: 1:1:1), as the model reaction,
in water at ambient temperature. The results are summa-
rized in Table 1.
It is noteworthy that a poor yield of the desired product of
(Z)-4-(4-hydroxy-3-methoxybenzylidene)-3-methylisoxa-
zole-5(4H)-one (5a) was obtained in water in the absence of
any catalyst (entry 1). Interestingly, the yield of the adduct 5a
After optimizing the reaction conditions, different
derivatives of 3-methyl-4-(arylmethylene)isoxazole-5(4H)-
123

M. G. Dekamin, S. Zahra Peyman
Table 2 Synthesis of (Z)-3-methyl-4-(arylmethylene)isoxazole-5(4H)-ones 5a–5l catalyzed by POPINO (1a) or TBAPINO (1b) in water at
ambient temperature
a
Product (5)
b
Yield /%
-1
TOF/h
Entry
Aryl (4)
Time/h
1
a
1b
1a
1b
1a
1b
1
2
3
4
5
6
7
8
9
4-Hydroxy-3-methoxyphenyl (4a)
2,4-Dimethoxyphenyl (4b)
4-Methylphenyl (4c)
4-Methoxyphenyl (4d)
4-Hydroxyphenyl (4e)
3-Hydroxyphenyl (4f)
2-Hydroxyphenyl (4g)
4-Dimethylaminophenyl (4h)
Phenyl (4i)
5a
5b
5c
5d
5e
5f
1
0.75
1.1
1.5
1
94
97
9.4
5.9
6.3
8.2
7.4
8.2
4.4
9.3
8.4
7.1
7.2
6.5
–
12.9
8.2
6.5
9.3
7.6
9.3
4.6
12.8
9.5
9.4
9.3
8.2
–
1.5
1.5
1.1
1.25
1.1
2
89
90
94
97
90
93
1.25
1
93
95
90
93
5g
5h
5i
2
88
91
1
0.75
1
93
96
1.1
1.25
1.25
1.3
3
92
95
1
1
1
1
1
1
1
0
1
2
3
4
5
6
2-Thienyl (4j)
5j
1
89
94
2-Furanyl (4k)
5k
5l
1
90
93
(E)-2-Phenylethenyl (4l)
4-Chlorophenyl (4m)
4-Nitrophenyl (4n)
1.1
3
85
90
5m
5n
5o
5p
Trace
NR
NR
NR
Trace
NR
NR
NR
3
3
–
–
3-Nitrophenyl (4o)
3
3
–
–
4-Cyanophenyl (4p)
3
3
–
–
3
Reaction conditions: hydroxylamine hydrochloride (2, 1 mmol), ethyl acetoacetate (3, 1 mmol), aldehydes (4, 1 mmol), 2 cm water, r.t., and
POPINO (1a, 10 mol %) or TBAPINO (1b, 10 mol %)
NR no reaction
a
All compounds are known and their structures were established from their spectral data and melting points as compared with literature values
12, 15, 26, 28]
[
b
The yields refer to isolated products
ones (5a–5l) were prepared from the one-pot reaction of
hydroxylamine hydrochloride (2), ethyl acetoacetate (3),
and aryl or heterocyclic aldehydes (4) in the presence of
the corresponding isoxazole-5(4H)-one derivatives in rel-
atively longer times and lower yields probably due to the
steric hindrance effect (entries 2, 7). On the other hand, p-
excessive heterocyclic aldehydes such as 2-thiophenecar-
boxaldehyde (4j) and furfural (4k) or cinnamaldehyde (4l),
which are susceptible for polymerization under acidic
conditions, in treatment with hydroxylamine hydrochloride
(2) and ethyl acetoacetate (3) afforded excellent yields of
the corresponding products 5j–5l, respectively (entries
10–12).
1
0 mol % catalyst (1) in water at ambient temperature. The
results are shown in Table 2. It was found that aldehydes
containing electron donating groups afford high to quan-
titative yields of desired products (entries 1–12), while
aromatic aldehydes having the electron withdrawing
groups fail to afford the desired products under the same
reaction conditions (entries 13–16). Indeed, aldehydes
containing electron withdrawing groups (4m–4p) react
exclusively with hydroxylamine hydrochloride (2) rather
than ethyl acetoacetate (3) for oxime formation. Therefore,
only the corresponding oximes of the used aldehydes were
isolated from the reaction mixture in the later cases. Fur-
thermore, ortho-substituted aromatic aldehydes afforded
A comparison of the catalytic efficiency of POPINO
(1a) and TBAPINO (1b) with the selected previously
known catalysts for preparation of the product 5a is shown
in Table 3. Data in Table 3 clearly demonstrate that the
present protocol is indeed superior to most of the others in
terms of calculated TON and TOF values.
1
23

Phthalimide-N-oxyl salts: Efficient organocatalysts for facile synthesis of…
Table 3 Comparative synthesis of compound 5a using the reported methods versus the present method
-
1
Entry
Catalyst
Mol%
Solvent
Temp.
Time/h
Yield/ %
TON
TOF/h
References
1
2
3
4
5
6
7
8
9
Boric acid
10
10
5
H
2
O
O
rt
rt
rt
rt
rt
rt
rt
rt
rt
1.42
1.5
1.5
1
95
86
89
95
95
94
92
94
97
9.5
8.6
8.9
9.5
9.5
9.4
9.2
9.4
9.7
6.7
5.7
5.9
9.5
8.1
9.4
6.1
9.4
12.9
[15]
Sodium benzoate
Sodium sulfide
Sodium tetraborate
Potassium phthalimide
Sodium saccharin
Sodium citrate
POPINO
H
2
[26]
EtOH
[28]
10
10
10
10
10
10
H
2
H
2
H
2
H
2
H
2
H
2
O
O
O
O
O
O
[27]
1.17
1
[32]
[31]
1.5
1
[29]
This work
This work
TBAPINO
0.75
Conclusion
reaction (monitored by TLC), pure products were simply
isolated by filtration of the reaction mixture and washing
the solid with cold distilled water. The solid products were
recrystallized from EtOH if necessary.
In summary, we have developed highly efficient, green,
and one-pot three-component methods for the synthesis of
(
Z)-3-methyl-4-(arylmethylene)isoxazole-5(4H)-ones
Acknowledgments We are thankful for the financial support from
The Research Council of Iran University of Science and Technology
which are often encountered in biologically and pharma-
cologically actives compounds. The present procedures
have been accomplished by the use of phthalimide-N-oxyl
salts as metal-free, cost-effective, and mild organocata-
lysts. Further important advantages of these methods
include in water synthesis, affording high to excellent
yields, clean reaction profile, and simple work-up, and
avoidance of using organic solvents in most cases.
(
IUST), Tehran, Iran (Grant no. 160/354).
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