Synthesis of 2-aroylfuran and novel 3,5-diaroyl-4-arylisoxazole derivatives by ring contraction of pyrylium salts

Article abstract of DOI:10.1007/s11164-015-2202-3

Ring contraction of 2,4,6-triarylpyrylium perchlorates by use of sodium nitrite mediated by ionic liquid has been used as a new, direct, and environmentally benign method for synthesis of bioactive 2-aroylfuran and novel 3,5-diaroyl-4-arylisoxazole deriva

Full text of DOI:10.1007/s11164-015-2202-3

Res Chem Intermed
DOI 10.1007/s11164-015-2202-3
Synthesis of 2-aroylfuran and novel 3,5-diaroyl-4-
arylisoxazole derivatives by ring contraction
of pyrylium salts
Arash Mouradzadegun1 Fatemeh Abadast1
•
•
Somayeh Elahi1 Neda Askarikia1
•
Received: 16 May 2015 / Accepted: 29 July 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract Ring contraction of 2,4,6-triarylpyrylium perchlorates by use of sodium
nitrite mediated by ionic liquid has been used as a new, direct, and environmentally
benign method for synthesis of bioactive 2-aroylfuran and novel 3,5-diaroyl-4-
arylisoxazole derivatives in excellent yields. The versatility of the approach enables
rapid and simple access to these pharmaceutically important compounds. The products
were readily isolated from the reaction mixture by simple filtration.
Graphical Abstract
Y
O
Y
X
X
N
O
O
+
NaNO2
X
Y
Br -
O
-
X
ClO4
X : H, OMe
Y : H, Me, OMe, Cl, NO2
X
N
N
O
O
X
Electronic supplementary material The online version of this article (doi:10.1007/s11164-015-2202-3)
contains supplementary material, which is available to authorized users.
&
Arash Mouradzadegun
arash_m@scu.ac.ir
1
Department of Chemistry, Faculty of Science, Shahid Chamran University, Ahvaz, Iran
123

A. Mouradzadegun et al.
Keywords 2-Aroylfuran Á 3,5-Diaroyl-4-arylisoxazole Á Pyrylium salts Á
Heterocyclic compounds Á Green synthesis Á Ionic liquid
Introduction
Heterocyclic compounds have always attracted much attention because of their
numerous uses in the design of biologically active molecules with pharmaceutical
applications [1, 2]. Hence, practical methods for preparation of such compounds is
of great interest in synthetic organic chemistry.
Isoxazole derivatives are important heterocycles which are widely used in
pharmaceuticals and therapeutics, for example as potent and selective antagonists of
the NMDA receptor and because of their anti-HIV activity [3, 4]. They have
antihyperglycemic [5], antitumor [6], inflammatory [7], antifungal [8], antibacterial
[9, 10] and immunosuppressive activity [11]. They have also been used as versatile
building blocks in organic synthesis [12]. Several methods have been developed for
synthesis of substituted isoxazoles. Commonly used methods include addition of
nitrile oxides to supported alkynes [13], condensation [14], anchoring of a nitrile
oxide precursor to a solid phase [15], intermolecular cycloadditions [16],
intramolecular cyclization of amino acids [17], and condensation of 1,3-dicarbonyl
compounds with hydroxylamine [18]. However, many of these procedures are not
environmentally benign and have been associated with other disadvantages
including use of toxic, expensive, and unrecyclable catalysts, multi step reactions,
low product yields, difficult work-up procedures, and use of organic solvents. It is,
therefore, still a major challenge to find simple ways to synthesize novel isoxazole
derivatives from inexpensive and readily available starting materials by use of mild
reaction conditions.
Substituted furans, because of their unique chemical and structural properties,
have received much attention over the past decade and found wide application in
medicinal chemistry [19–25]. In this context, organic and medicinal chemists
continually seek new approaches for synthesis of furan derivatives.
Because readily available pyrylium salts can function as intermediates in a very
wide variety of syntheses, because of their high reactivity toward nucleophiles, their
use as simple and available precursors has attracted much interest [26–28].
Ionic liquids are widely used as green reaction media to replace conventional
harmful organic solvents in both academic and industrial research [29–35]. The
possibility of recycling and their low vapor pressure ensure their utility in
environmentally friendly technology. They have been used as solvents for many
organic transformations [36].
Because of the importance of both the isoxazole and furan structures, and in
continuation of our efforts to develop new synthetic methods for promising
molecules [26–28, 37–42], we report, for the first time, a new, highly practical, and
eco-friendly approach for synthesis of novel 3,5-diaroyl-4-arylisoxazole 2 and
2-aroylfuran 3 derivatives by novel ring contraction of readily available
triarylpyrylium salts 1 with sodium nitrite in the presence of 1-n-butyl-3-
123

A conceptually new shortcut to 2-aroylfuran and novel…
methylimidazolium bromide, [bmim]Br, as promoter and efficient reaction medium
(Scheme 1).
Experimental
Chemicals were purchased from Fluka, Merck, and Aldrich. Reactions were monitored
by TLC. IR spectra were acquired with a Bomem MB:102 FTIR spectrophotometer. 1H
NMR and 13C NMR spectra were acquired with a Bruker spectrometer at 400 and
100 MHz, respectively, in CDCl3 as solvent with tetramethylsilane as internal standard.
Mass spectra were acquired with a Finnigan MAT TSQ 70 mass spectrophotometer.
General procedure for synthesis of triarylpyrylium perchlorates
All triarylpyrylium perchlorates were synthesized from the corresponding aldehydes
and ketones by the method described elsewhere [43, 44]. Briefly, the corresponding
benzaldehyde (0.1 mol) and acetophenone (0.2 mol) were stirred at room temper-
ature, and sulfuric acid (6 mL) was added dropwise during 30 min. The mixture was
stirred at 100 °C for 60 min, then ethanol (200 mL) and perchloric acid 70 %
(10 mL) were added. The mixture was left 24 h and the precipitate formed was
recrystallized from acetic acid.
General procedure for synthesis of [bmim]Br
A mixture of 1-methylimidazole (4.1 g, 0.05 mol) and 1-bromobutane (6.85 g,
0.05 mol) in the absence of solvent was heated with stirring at 80 °C for 12 h. The
product was washed with diethyl ether and dried in vacuum to afford [bmim]Br.
Y
O
X
X
Y
N
O
N
N
O
2
+
NaNO2
X
O
Y
-
X
ClO4
X
1
X : H, OMe
O
O
Y : H, Me, OMe, Cl, NO2
X
3
Scheme 1 Synthesis of novel 3,5-diaroyl-4-arylisoxazole 2 and 2-aroylfuran 3 derivatives by reaction of
triarylpyrylium perchlorates 1 with NaNO2 in the presence of [bmim]Br
123

A. Mouradzadegun et al.
General procedure for synthesis of 3,5-diaroyl-4-arylisoxazole (2) and 2-
aroylfuran (3) derivatives
Reactions were typically performed by addition of triarylpyrylium perchlorates
(0.1 mmol) to sodium nitrite (0.3 mmol) in [bmim]Br (1 g) as solvent (this ratio
was optimized under our experimental conditions) and heated to 110 °C. After
completion of the reaction, as indicated by TLC (n-hexane–ether, 4:1), the reaction
mixtures were quenched with H2O and the insoluble products were isolated by
filtration. The products were adsorbed on silica, transferred to a silica column, and
eluted with a 4:1 mixture of n-hexane–ether. The first and second fractions
contained the 3,5-diaroyl-4-arylisoxazole and 2-aroylfuran derivatives, respectively.
Results and discussion
In continuation of our systematic research on the reactions of pyrylium and
thiopyrylium salts [26–28, 37–42], reactions between triarylpyrylium perchlorates
and sodium nitrite were investigated.
Nucleophilic reaction of triarylpyrylium salts with sodium nitrite in the presence
of a variety of organic solvents, for example ethanol, acetonitrile, dichloromethane,
and toluene, among others, resulted in mixtures of compounds in poor yields, in
agreement with previously reported research [45].
To enhance the selectivity of the reaction, and because of the importance of ionic
liquids (IL) in green synthesis of heterocyclic compounds, in our next attempt we
investigated this reaction in the presence of [bmim]Br as a green and efficient
medium.
Initially, [bmim]Br was prepared in accordance with a literature procedure, from
1-bromobutane and 1-methylimidazole. Preliminary tests were then conducted to
determine the best conditions for reaction of triarylpyrylium perchlorates and
sodium nitrite. Triphenylpyrylium perchlorate (1a) was chosen as model compound.
In a typical reaction, when 1a was treated with sodium nitrite in [bmim]Br we
obtained 2a and 3a in excellent yield and short reaction time. No byproducts were
formed. In classical organic solvents the same reaction gave poor yields (15–5 % for
2a and 3a respectively) even under reflux conditions for long reaction times
(approx. 20–24 h).
This green method is of substantial interest because it was an atom-efficient and
straightforward route for synthesis of valuable 2-aroylfurans and novel 3,5-diaroyl-
4-arylisoxazole derivatives, which are present in many biologically active
molecules.
We believe the high polarity of IL and their ability to dissolve both inorganic and
organic compounds can result in enhanced rates of chemical reactions and higher
selectivity compared with conventional solvents.
After completion of the reaction and quenching with water, the insoluble
products 2a and 3a were isolated by filtration of the reaction mixture, without
laborious aqueous workup.
123

A conceptually new shortcut to 2-aroylfuran and novel…
Further experiments were designed to survey other optimization conditions. The
model reaction was investigated in the presence of different amounts of sodium
nitrite. As is apparent from Table 1, the reaction is favored by increasing
nucleophile-to-substrate ratio, as shown by the substantial decrease in the reaction
time. Bearing in mind that the reaction proceeds via addition then ring contraction,
an increase in the concentration of the nucleophile favors the first reaction step and,
on the whole, product formation. The best results were obtained when 3 mmol
nucleophile and 1 mmol substrate were used (Table 1).
To evaluate the effect of reaction temperature, the reaction was performed at
different temperatures under similar experimental conditions and monitored by
TLC. The reaction occurred at r.t., but only slowly. After 2 h, the reaction was still
incomplete. To improve the reaction time and yield, higher temperatures were used
(Table 2). Higher temperatures resulted not only in better yields but also in much
shorter reaction times. As shown in Table 2, when the reaction was conducted at
110 °C it was complete in 30 min and the total yield was as high as 97 %. It should
be noted that temperatures [110 °C did not result in significant improvements.
To further examine the efficacy of the reaction it was repeated with a variety of
triarylpyrylium perchlorates containing electron-donating and withdrawing groups
in the para position of substituted phenyl rings, again with sodium nitrite in the
presence of [bmim]Br (Table 3).
The results in Table 3 clearly show that aromatic aldehydes and acetophenones
bearing either electron-donating or electron-withdrawing functional groups partic-
ipate in the reaction smoothly and produce 2 and 3 in good yields. The results also
show that electron-donating groups cause the reactions to become slow (e.g., entries
B–D). This may be rationalized by considering that these groups reduce the positive
charge on the a-position of the heterocyclic ring. In contrast electron-withdrawing
groups (e.g., entries E and F) accelerate the reaction.
Table 1 Trend of the model reaction with different amounts of NaNO2 in [bmim]Br solution
Entry
[Nu]/[Sub]
Time (min)
Yield % (2/3)
1
2
3
2/1
3/1
4/1
45
30
30
93 (73/20)
97 (75/22)
97 (75/22)
Nu, nucleophile, Sub, substrate
Table 2 Trend of the model
reaction with different
temperature
Entry
T (°C)
Time (min)
Yield % (2/3)
1
2
3
4
5
6
r.t.
120
95
65
50
30
30
Reaction not completed
90 (70/20)
80
100
105
110
120
90 (70/20)
90 (70/20)
97 (75/22)
97 (75/22)
123

A. Mouradzadegun et al.
Table 3 Conversion of different triarylpyrylium salts 1 into the corresponding 3,5-diaroyl-4-arylisoxa-
zole 2 and 2-aroylfuran 3 derivatives in [bmim]Br under the optimized conditions
Ar2
O
Ar2
NaNO2
[bmim]Br
Ar2
O
Ar1
Ar1
Ar1
N
Ar1
+
O
°
110 C
O
Ar1
O
Ar1
O
1
2
3
ClO4
Entry
A
Substrate (1)
Product (2)
Product (3)
Yield %
Time (h)
0.5
(2/3)
O
97 (75/22)
N
O
O
O
O
O
OCH3
H3CO
H3CO
O
B
C
69 (50/19)
67 (52/15)
1.3
6
N
O
O
O
O
O
CH3
H3
C
H3C
O
H3CO
H3CO
OCH3
N
O
O
O
O
O
OCH3
OCH3
H3CO
O
H3CO
H3CO
96 (63/33)
16
OCH3
O
N
D
E
O
O
O
OCH3
O
H3CO
OCH3
Cl
Cl
Cl
O
95 (80/15)
32 (20/12)
0.5
0.4
N
O
O
O
O
O
O
O
O2
N
O2N
NO2
O
F
N
O
O
O
1
The structures of the products were determined from their physical and IR, H
NMR, 13C NMR and mass spectrometric data.
A conceivable mechanism for the synthesis of 3,5-diaroyl-4-arylisoxazole 2 and
2-aroylfuran 3 derivatives via nucleophilic attack of nitrite is outlined in Scheme 2.
The isoxazole 2 is assumed to be formed by initial attack of nitrite on 1 to give
intermediate 4 which in turn rearranges to oxime 5. Subsequently, nucleophilic
attack by the hydroxyl group of 5 gives product 2 by nucleophilic ring closure and
oxidative aromatization (path I). 2-Aroylfuran 3 was formed by thermal elimination
of NO? from compound 4 followed by nucleophilic ring closure of pseudobase 6
and oxidative aromatization (path II).
This procedure results in a substantial decrease in reaction time and improved
yield compared with conventional conditions. Furthermore, the procedure gives the
123

A conceptually new shortcut to 2-aroylfuran and novel…
Ar2
O
Ar2
O
Ar2
(I)
O
(II)
O
N
N
O
O
O
Ar1
O
N
Ar1
Ar1
O
Ar1
Ar1
Ar1
4
4
1
Ar1: C6H5, C6H4(p-OMe)
Ar2
O
Ar2
O
Ar2: C6H5, C6H4(p-Me), C6H4(p-OMe), C6H4(p-Cl), C6H4(p-NO2)
O
N
Ar1
Ar1
Ar1
Ar1
O
O
6
Ar2
Ar2
O
OH
Ar1
N
Ar1
O
O
Ar1
Ar1
O
[O]
5
Ar2
O
O
Ar2
[O]
Ar1
Ar2
Ar1
Ar1
Ar1
O
N
Ar1
N
Ar1
O
O
O
O
O
3
2
Scheme 2 Plausible mechanism for the formation of 3,5-diaroyl-4-arylisoxazole 2 and 2-aroylfuran 3
derivatives
desired 2-aroylfuran and novel 3,5-diaroyl-4-arylisoxazole derivatives exclusively
with no byproducts. In addition, [bmim]Br is much less hazardous to use than
organic solvents. This is, therefore, an atom-efficient process that produces less
waste than would otherwise have arisen from use of excess reagents.
Conclusion
In summary, we have described a clean and atom-efficient process for synthesis of
valuable 2-aroylfuran and novel 3,5-dibenzoyl-4-arylisoxazole derivatives by novel
ring-contraction of pyrylium salts. Readily available and easily varied tri-
arylpyrylium salts react with sodium nitrite mediated by the ionic liquid. The
approach is environmentally benign, and more straightforward than established
methods. We believe this method is a useful alternative to existing methods for
synthesis of these pharmaceutically important compounds.
123

A. Mouradzadegun et al.
Acknowledgments This work was supported by the Research Council at the University of Shahid
Chamran.
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