A fast and highly efficient protocol for synthesis of pyrrolo[2,3-d] isoxazoles and a new series of novel benzyl bis-pyrrolo[2,3-d]isoxazoles using task-specific ionic liquids as catalyst and green solvent

Article abstract of DOI:10.1248/cpb.58.833

We report a mild, fast, highly efficient and eco-friendly protocol for the green synthesis of pyrrolo[2,3-d]isoxazoles and a new series of novel benzyl bis-pyrrolo[2,3-d]isoxazoles from nitro styrylisoxazoles in SnCl ₂-ionic liquid by reductive

Full text of DOI:10.1248/cpb.58.833

June 2010
Regular Article
Chem. Pharm. Bull. 58(6) 833—839 (2010)
833
A Fast and Highly Efficient Protocol for Synthesis of Pyrrolo[2,3-
d]isoxazoles and a New Series of Novel Benzyl Bis-pyrrolo[2,3-d]isoxazoles
Using Task-Specific Ionic Liquids as Catalyst and Green Solvent
Eligeti RAJANARENDAR,* Samala RAJU, Atthunuri SIVA RAMI REDDY, Kundur GOVARDHAN REDDY, and
Modugu NAGI REDDY
Department of Chemistry, Kakatiya University; Warangal, A.P. 506 009, India.
Received February 16, 2010; accepted March 26, 2010; published online March 29, 2010
We report a mild, fast, highly efficient and eco-friendly protocol for the green synthesis of pyrrolo[2,3-
d]isoxazoles and a new series of novel benzyl bis-pyrrolo[2,3-d]isoxazoles from nitro styrylisoxazoles in SnCl2-
ionic liquid by reductive cyclization. These reactions were performed at ambient temperature which resulted in
good yields in short reaction time, without requiring any organic solvent and catalyst.
Key words task-specific ionic liquid; reductive cyclization; pyrrolo[2,3-d]isoxazole
Significant progress in green chemistry is being made in several approaches have been investigated. One method for
several key research areas, such as catalysis,1) the design of pyrrole ring formation is by de-oxygenative cyclization of
safer chemicals, environmentally benign solvents2) and the nitro styryl compounds using triethyl phosphite (TEP).20—22)
development of renewable feed stocks. Chemists are trained As the reaction requires heating of the nitro styrylisoxazole
to design products and processes with an increased aware- (3) in TEP at high temperature under N2 atmosphere, the
ness of environmental impact. Outreach activities within the reaction results in cleavage of the isoxazole ring, which is
green chemistry community highlight the potential for chem- unstable at higher temperature.23) To overcome this problem,
istry to solve many of the global environmental challenges. another method developed by Angelo Carotti24) is employed,
In the recent years, ionic liquids have emerged as green sol- which involves the reductive cyclization of a nitro styryl
vents with desirable properties such as good solvating ability, compound using SnCl2-N,N-dimethylformamide (DMF).
wide liquidous range, tunable polarity, high thermal stability, However, we could not achieve the synthesis of the target
negligible vapour pressure and ease of recyclability. These compounds using this procedure, even though the reaction
are referred to as designer solvents since they exhibit proper- was performed with SnCl2 in different solvents i.e., DMF,
ties like hydrophilicity, hydrophobicity, Lewis acidity, viscos- dimethyl sulphoxide (DMSO), dioxane and tetrahydrofuran
ity and density. These can be altered by the fine tuning of (THF) under a variety of reaction conditions. Thus, we decided
parameters such as the choice of organic cation and the to construct the pyrrolo[2,3-d]isoxazoles (4) by utilizing
length of alkyl chain attached to an organic cation. These amino styrylisoxazoles rather than nitro styrylisoxazoles.
structural variations offer flexibility to the chemists to devise Sharpless epoxidation of amino styrylisoxazoles resulted in
the most idealized solvent catering to the needs of any partic- title compounds in a one-pot synthesis.25) However, this
ular process. Due to the stabilization of charged intermedi- method requires ButOOH, chiral (ꢀ) diethyl tartarate and
ates by ionic liquids, they can promote unprecedented selec- Ti(OR)4. The approach is not widely applicable due to the
tivities and enhanced reaction rates. Consequently, ionic requirement of specific reagents and catalysts, which are not
liquids are being used as recyclable solvents for the immobi- environmentally benign and is costlier. Hence, we thought of
lization of transition metal-based catalysts, Lewis acids and constructing the title compounds by adopting a greener
enzymes. During the past few years, a variety of room tem- approach utilizing ionic liquids. To our surprise, we could
perature ionic liquids have been demonstrated as efficient synthesize title compounds by reductive cyclization of nitro
and practical alternatives to organic solvents for many impor- styrylisoxazoles (3) with SnCl2·2H2O in Bronsted acidic ionic
tant organic transformations.3—9) Particularly, the use of liquid 1-methyl imidazolium tetrafluoroborate [(HMIm)BF4]
[bmIm]OH as a novel and a recyclable reaction medium, as as a green solvent and catalyst, in which we initially failed by
well as an efficient catalyst for Knoevenagel and Michael using SnCl2-organic solvents. We report in this article, the
reactions has been reported in literature.10—12) Similarly, application of task-specific ionic liquids [bmIm]OH and
1-methyl imidazolium tetrafluoroborates has been exploited [HMIm]BF4 as efficient catalysts as well as reaction media
as an efficient Bronsted acid promoter ionic liquid in various for the green synthesis of pyrrolo[2,3-d]isoxazoles and a new
organic transformations.13—15) As a part of our study on envi- series of novel benzyl bis-pyrrolo[2,3-d]isoxazoles from
ronmentally friendly organic synthesis with isoxazoles,16—19) readily available nitro styrylisoxazoles.
avoiding organic solvent and toxic catalyst in reactions, we
demonstrated the use of room temperature ionic liquids as Results and Discussion
efficient catalysts as well as reaction media for Knoevenagel
and Michael reactions and also for conducting reductive zole (1) with substituted benzaldehydes (2) in the presence of
cyclization. basic ionic liquid, 1-methyl-3-butylimidazolium hydroxide,
Knoevenagel condensation of 3,5-dimethyl-4-nitroisoxa-
Looking for a valuable procedure for the conversion of [bmIm]OH, without any organic solvent and organic base at
nitro styrylisoxazoles (3) to pyrrolo[2,3-d]isoxazoles (4), room temperature results in the rapid formation of 5-
© 2010 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: eligeti_rajan@yahoo.co.in

834
Vol. 58, No. 6
styrylisoxazoles (3) in 10—15 min with excellent yields catalyzed the subsequent cyclization (Chart 1).
(85—92%). The condensation of aromatic aldehydes with
In a typical experiment, 3-methyl-4-nitro-5-styrylisoxazole
3,5-dimethyl-4-nitroisoxazole (1), which is easily achieved (3) (1 mmol) and SnCl2·2H2O (2 mmol) were taken in IL
by [bmIm]OH, did not proceed under the catalysis of other [(HMIm)BF4] (5 ml). The reaction mixture was stirred at
ionic liquids such as [bmIm]BF4 and [bmIm]Br. This shows room temperature for 15 min. After the completion of the
that [bmIm]OH is a task-specific ionic liquid in this transfor- reaction (monitored by TLC), the reaction mixture was
mation and the reaction is influenced by hydroxyl ion of the extracted with ethyl acetate. The evaporation of the solvent
ionic liquid. The results revealed that ionic liquid [bmIm]OH gave a crude product, which was purified by colum chro-
plays the dual role of solvent as well as catalyst in this reac- matography. The ionic liquid, left over in the reaction after
tion. The ionic liquid, which was remaining in the reaction being dried under vacuum was re-used for subsequent reac-
flask after being washed with ethyl acetate and dried at 80 °C tions. The product was identified as 3-methyl-5-phenyl-4H-
under vacuum for 3—4 h was recycled in subsequent runs pyrrolo[2,3-d]isoxazole 4 on the basis of spectral and analyti-
(four to five times). The structure of the products 3 were con- cal data. The reaction did not proceed in the absence of ionic
firmed on the basis of IR, 1H-NMR, 13C-NMR and MS spec- liquid [HMIm]BF4 as well as in the presence of [bmIm]Br
troscopy and finally by comparing with the authentic sam- and [bmIm]OH. This may be due to Bronsted acidic charac-
ples.26) This reaction, when performed in the presence of ter of [HMIm]BF4.
ethanol in piperidine base as reported in literature,26) requires
The applicability of this new procedure was assessed by
2—3 h refluxing and the yields are moderate (Entry 1—12, subjecting substituted nitro styrylisoxazoles (3) to reductive
Table 1). The reaction of 3-methyl-4-nitro-5-styrylisoxazoles cyclization under optimized conditions which afforded the
(3) with SnCl2·2H2O in the presence of a Bronsted acidic corresponding pyrrolo[2,3-d]isoxazoles (4) (Arꢁ4-CH3C6H4,
ionic liquid [HMIm]BF4 at room temperature afforded the 4-CH3OC6H4, 4-ClC6H4, 2-ClC6H4, 2,4-Cl2C6H3, 3,4-(O–
corresponding pyrrolo[2,3-d]isoxazoles (4) in excellent CH2–O)C6H3, 2-CH3C6H4, 4-N(CH3)2C6H4, 2,6-Cl2C6H3, 2-
yields within 15 min (Entry 1—12, Table 2). SnCl2·2H2O– OHC6H4 and 3-CH3O, 4-OHC6H3) in excellent yields (Entry
[HMIm]BF4 not only reduced the nitro group but efficiently 1—12, Table 2). The structure of the products 4 were estab-
Table 1. Ionic-Liquid Mediated Synthesis of 3-Methyl-4-nitro-5-styrylisoxazoles (3)
Reaction period
Yield (%)
mp
lit mp21)
(°C)
Entry
Ar
In presence
of ionic liquid
[bmIm]OH (min)
In presence
of solvent
and base (h)
In presence
of ionic liquid
[bmIm]OH
In presence
of solvent
and base
(°C)
1
2
3
4
5
6
7
8
9
C6H5
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
2-ClC6H4
2,4-Cl2C6H3
3,4-(OCH2O)C6H3
2-CH3C6H4
4-N(CH3)2C6H4
2,6-Cl2C6H3
2-OHC6H4
10
12
12
15
15
10
12
10
10
12
15
10
2
3
2
2
3
2
2
2
2
2
2
2
85
90
92
85
90
90
85
90
95
90
85
85
50
54
52
55
55
50
55
50
50
55
50
52
151
155
148
162
177
199
138
144
122
185
230
171
153
156
150
166
180
200
140
142
124
187
228
173
10
11
12
3-CH3O, 4-OHC6H3
Table 2. Synthesis of 3-Methyl-5-aryl-4H-pyrrolo[2,3-d]isoxazoles (4) in Ionic Liquid [HMIm]BF4
Reaction period
Yield (%)
Green
approach
method (min)
[HMIm]BF4
Green
approach
method (min)
[HMIm]BF4
mp
lit mp20)
(°C)
Entry
Ar
Sharpless
epoxidation
method (h)
Sharpless
epoxidation
method (h)
(°C)
1
2
3
4
5
6
7
8
9
C6H5
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
2-ClC6H4
2,4-Cl2C6H3
3,4-(OCH2O)C6H3
2-CH3C6H4
4-N(CH3)2C6H4
2,6-Cl2C6H3
2-OHC6H4
15
15
15
15
15
15
15
15
15
15
15
15
28
26
26
28
26
28
28
26
28
28
26
26
95
95
95
96
95
98
95
95
98
98
98
95
90
90
90
90
90
90
90
90
90
90
90
90
155—157
144—146
130—131
165—166
160—162
170—172
178—180
168—171
180—182
195—197
200—202
150—152
156—158
143—145
128—131
166—168
159—162
171—175
178—181
167—170
180—184
196—199
202—204
151—153
10
11
12
3-CH3O, 4-OHC6H3

June 2010
835
Chart 1. Reductive Cyclization of Nitro Styrylisoxazoles (3) to Pyrrolo[2,3-d]isoxazoles (4)
Chart 2. Retrosynthetic Analysis of Target Compound Benzyl Bis-pyrrolo[2,3-d]isoxazole (5)
Table 3. Synthesis of 3-Methyl-5-[3-(3-methyl-4-nitro-5-isoxazolyl)-2-
phenylpropyl]-4-nitroisoxazoles (7) in Ionic Liquid [bmIm]OH
lished by analytical and spectroscopic data and finally by
comparing with authentic samples.25)
Contrary to our earlier method,25) the reaction time was
effectively reduced from hours (26—28) to minutes (15) in
the present approach. The product yield was improved from
90 to 98%. Moreover, the new process does not involve
costly reagents, and is carried out under very mild experi-
mental conditions. Further, the method is environmentally
benign.
Having obtained favourable results with SnCl2-ionic liquid
for reductive cyclization, we then examined the synthesis of
novel benzyl bis-pyrrolo[2,3-d]isoxazoles under similar con-
mp
(°C)
Yield
(%)
Entry
Ar
1
2
3
4
5
6
C6H5
134
140
167
103
190
114
85
90
92
88
91
95
4-CH3C6H4
3-CH3O, 4-OHC6H3
4-N(CH3)2C6H4
2-OHC6H4
3,4-(OCH2O)C6H3
ditions, once again with the same starting material i.e. nitro scaffold which holds great potential for the generation of di-
styrylisoxazole (3). Considering that, it is possible to run the versity. For example, in compound 7 two active methylene
Knoevenagel condensation and Michael addition in a domino centers are available that can each be reacted independently
fashion, we envisaged the possibility of building libraries either with aromatic aldehydes to give bis-nitrostyryl deriva-
of potentially pharmacologically active novel benzyl bis- tives, which then subjected to reductive cyclization to afford
pyrrolo[2,3-d]isoxazoles (5) from the commercially available benzyl bis-pyrrolo[2,3-d]isoxazoles or with aromatic ketones
materials 1 and 2.
to give benzyl bis-isoxazolo[4,5-b]pyridine-N-oxides, or with
We proposed the following retro-synthetic analysis for the chalcones to give Michael adducts which can be subse-
target compounds (Chart 2). This disconnection looked par- quently subjected to reductive cyclization to afford benzyl
ticularly attractive due to the commercial availability of 3,5- bis-isoxazolo[4,5-b]azepines. Compound 7 could easily be
dimethyl-4-nitroisoxazole (1) and aromatic aldehydes (2) on generated from commercially available marterials 3,5-
the market. We reasoned that compound 5, could be obtained dimethyl-4-nitroisoxazole (1) and an aromatic aldehyde (2)
from 6 by reductive cyclization. Significantly, compound 6, by Knoevenagel–Michael reaction either by domino fashion
precursor of 5, could be achieved from 7 and 8 by Knoeve- or by stepwise process. The synthetic approach for building
nagel condensation. 7 could arise from 1 and 3 in a Michael the title compounds is as follows: 3-Methyl-4-nitro-5-
type reaction, finally compound 3 could be obtained from styrylisoxazole (3) was reacted with 3,5-dimethyl-4-ni-
commercially available materials 1 and 2 by a Knoevenagel troisoxazole (1) in the presence of basic ionic liquid [bmIm]
condensation.
OH without any solvent and catalyst at room temperature for
Our approach to the development of diversity-oriented 15—30 min to afford Michael type adducts 7 in excellent
synthesis of benzyl bis pyrrolo[2,3-d]isoxazoles (5) is based yields (85—95%) (Entry 1—6, Table 3). This Michael type
on the generation of building blocks that contain multiple reaction, which is easily achieved by [bmIm]OH, did not pro-
functionalities which could be selectively reacted. In this ceed at all under the influence of other ionic liquids
context, compound 7 represents a class of poly functional [bmIm]BF4 or [bmIm]Br. This reaction once again demon-

836
Vol. 58, No. 6
Table 5. Synthesis of Novel 3-Methyl-[6-[(3-methyl-5-phenyl-4H-
pyrrolo[2,3-d]isoxazole-6-yl)(phenyl)methyl]-5-phenyl-4H-pyrrolo[2,3-
d]isoxazoles (5) in Ionic Liquid [HMIm]BF4
Table 4. Synthesis of 3-Methyl-5-{(Z)-3-(3-methyl-4-nitro-5-isoxazolyl)-
2,4-diphenyl-1-[(Z)-1-phenylmethylidene]-3-butenyl}-4-nitroisoxazoles (6)
in Ionic Liquid [bmIm]OH
mp
(°C)
Yield
(%)
mp
(°C)
Yield
(%)
Entry
Ar
Arꢂ
C6H5
4-CH3C6H4
4-CH3OC6H4
2,4-Cl2C6H3
4-ClC6H4
2-ClC6H4
2-CH3C6H4
C6H5
Entry
Ar
Arꢂ
C6H5
4-CH3C6H4
4-CH3OC6H4
2,4-Cl2C6H3
4-ClC6H4
2-ClC6H4
2-CH3C6H4
C6H5
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
160
165
170
231
178
191
195
146
87
92
90
90
89
91
88
90
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
166
170
182
242
190
210
198
154
90
88
85
92
91
90
88
90
2-OHC6H4
4-CH3C6H4
3-CH3O, 4-OHC6H3
4-(NCH3)2C6H4
3,4-(OCH2O)C6H3
2-OHC6H4
4-CH3C6H4
3-CH3O, 4-OHC6H3
4-(NCH3)2C6H4
3,4-(OCH2O)C6H3
strates the specific role of the hydroxyl ion of this task- 5-phenyl-4H-pyrrolo[2,3-d]isoxazol-6-yl)phenylmethyl]-5-
specific ionic liquid in this Michael reaction. The residual phenyl-4H-pyrrolo[2,3-d]isoxazole (5) on the basis of spec-
ionic liquid after being dried under vacuum was reused to tral and analytical data.
subsequent runs. This Michael reaction, when conducted on
In order to study the scope of this methodology, several
nitro styrylisoxazoles (3) in the presence of either triethyl benzyl bis-nitro styrylisoxazoles (6) were tested under the
amine or piperidine base in ethanol resulted in approximately similar conditions. We could succeed with reductive cycliza-
50% product formation and reaction required nearly 2—4 h tion of these compounds with SnCl2·2H2O–[HMIm]BF4.
refluxing,27) and the reaction resulted in formation of by The method has a general applicability and it is compatible
products.28) Hence, ionic liquid mediated Michael addition with the reactivity of different functional groups. The prod-
has a clear advantage over the conventional base catalyzed ucts were obtained in excellent yields (80—90%) (Entry 1—
reaction with regard to reduction in reaction time, increasing 8, Table 5). The structure of all the new products 5—7 were
1
the yields, without forming undesired side-products. More- elucidated by spectroscopic (IR, H-NMR, 13C-NMR and
over, the process is environmentally benign. The present pro- MS) and micro analytical data.
cedure catalyzed by ionic liquid provides an efficient and
convenient protocol, without requirement of a conventional Conclusion
catalyst and organic solvent. Compounds 7 were subjected to
The present procedure that uses task-specific basic ionic
Knoevenagel condensation reaction with various kinds of liquid [bmIm]OH provides a fast and highly efficient
aromatic aldehydes in the presence of task-specific basic methodology for Knoevenagel condensation for the forma-
ionic liquid [bmIm]OH to afford the condensation products tion of compounds 3 and 6 and also for Michael type adducts
viz.; 3-methyl-5-{(Z)-3-(3-methyl-4-nitro-5-isoxazolyl)-2, 7. The specificites and catalytic activity of [bmIm]OH for
4-diphenyl-1-[(Z)-1-phenylmethylidene]-3-butenyl}-4- these reactions is established by the observation that the reac-
nitroisoxazoles (6). The reaction was carried out at room tem
-
tion did not proceed in the presence of other ionic liquids
perature for 15 min without any solvent and catalyst. The [bmIm]BF4 and [bmIm]Br. This reaction catalyzed by task-
products 6 were obtained in excellent yields (80—90%) specific basic ionic liquid [bmIm]OH, which is also acting as
without any undesired side products (Entry 1—8, Table 4). a solvent, provides an efficient and general methodology for
Similarly, this condensation did not proceed under the influ- Knoevenagel condensation and Michael addition. The signif-
ence of other ionic liquids [bmIm]BF4, or [bmIm]Br, indicat- icant improvements noticed in these reactions are: that a)
ing the specific role of [bmIm]OH as a catalyst and solvent. they are fast, b) they are carried out under mild conditions, c)
Finally, benzyl bis-nitro styrylisoxazoles (6) were converted they produce high yields and d) they avoids hazardous or-
to benzyl bis-pyrrolo[2,3-d]isoxazoles (5) by reductive ganic solvents. We have developed a new protocol for syn-
cyclization on treatment with SnCl2·2H2O–[HMIm]BF4· thesis of pyrrolo[2,3-d]isoxazoles and a new series of novel
SnCl2·2H2O–[(HMIm)]BF4 not only reduced the nitro group benzyl bis-pyrrolo[2,3-d]isoxazoles in SnCl2·2H2O–[HMIm]
but efficiently catalyzed the subsequent cyclization. The BF4 by reductive cyclization. This reaction did not proceed
reaction did not proceed in the absence of ionic liquid with other ionic liquids [bmIm]Br and [bmIm]OH. [HMIm]
[HMIm]BF4 as well as in presence of [bmIm]Br and [bmIm] BF4 which is a Bronsted acidic ionic liquid is task-specific in
OH (Chart 3).
these reactions. These reactions were clean, and no by-prod-
In a typical experiment, benzyl bis-3-methyl-4-nitro-5- ucts were detected under these conditions. There are several
styrylisoxazole (6) (1 mmol) and SnCl2·2H2O (5 mmol) were advantages in the use of ionic liquid for this transformation,
taken in IL [(HMIm)BF4] (5 ml). The reaction mixture was which includes high conversion, short reaction time, avoid-
stirred at room temperature for 15 min. After the completion ance of expensive reagents, and non-requirement of any
of the reaction (monitored by TLC), the reaction mixture was additives or stringent reaction conditions. The reported pro-
extracted with ethyl acetate. The evaporation of the solvent cedure is mild, efficient, simple, user and environmentally
gave a crude product, which was purified by column chro- friendly. To the best of our knowledge, this happens to be the
matography. The ionic liquid left over in the reaction after first report to construct pyrrole ring by reductive cyclization
being dried under vacuum was re-used for subsequent reac- of nitro styryl compounds with SnCl2·2H2O–[HMIm]BF4, in
tions. The product was identified as 3-methyl-6-[(3-methyl- which the ionic liquid is playing the dual role of solvent as

June 2010
837
Chart 3. Synthesis of Benzyl Bis-pyrrolo[2,3-d]isoxazoles (5)
the completion of the reaction, the reaction mixture was extracted with ethyl
acetate (3ꢃ10 ml). Evaporation of ethyl acetate gave crude product, which
was purified by silicagel column chromatography by eluting with
benzene–ethyl acetate. The ionic liquid left over in the reaction was washed
well as catalyst. Moreover, this work clearly demonstrates the
potential of room temperature ionic liquids [bmIm]OH and
[(HMIm)]BF4 to act as an efficient and recyclable catalyst
and green solvent and shows much promise for further appli- with ethyl acetate and dried at 80 °C under vacuum and was recycled for
four consecutive runs. This procedure was followed for all the reaction listed
in Table 2.
cations.
Experimental
Compound 4 (Entry 1, Table 2): Brown solid; IR (KBr): 3250 (s), 1600,
General The ionic liquids [bmIm]OH and [(HMIm)]BF4 were prepared 980 cmꢀ1; 1H-NMR (300 MHz, CDCl3) d: 2.52 (s, 3H, CH3), 7.40—7.62 (m,
following the reported procedures.29,30) All the melting points were deter- 5H, Ar-H), 7.76 (s, 1H, C6-H), 7.85 (s, 1H, NH, D2O exchangeable). MS
mined on a Cintex melting point apparatus and are uncorrected. Analytical
TLC was performed on Merck precoated 60 F254 silica gel plates. Visual-
(EI) m/z: 198 [M]ꢄ. 13C-NMR (75 MHz) d: 12.5 (C-7), 100.2 (C-3ꢂ), 110.4
(C-6), 128.5 (Ar-C), 129.4 (C-5), 130.2 (Ar-C), 132.8 (Ar-C), 136.3 (Ar-C),
ization was done by exposing to iodine vapour. Column chromatography 143.2 (C-3), 152.4 (C-6ꢂ).
was conducted by using silica gel with benzene–ethyl acetate solvent sys-
Compound 4 (Entry 2, Table 2): Brown solid; IR (KBr): 3300 (s), 1610,
1
tems as elute. IR spectra (KBr pellet) were recorded on a PerkinElmer BX 975 cmꢀ1; H-NMR (300 MHz, CDCl3) d: 2.42 (s, 3H, CH3), 2.80 (s, 3H,
series FT-IR spectrometer. 1H-NMR spectra were recorded on a Varian Gem- CH3), 7.29 (d, 2H, ArH, Jꢁ8 Hz), 7.50 (d, 2H, ArH, Jꢁ8 Hz), 7.81 (s, 1H,
ini 300 MHz spectrometer. Chemical shift values are given in ppm (d) with
tetramethyl silane as an internal standard. Mass spectral measurements were NMR (75 MHz) d: 11.3 (C-7), 21.1 (Ar-CH3), 100.1 (C-3ꢂ), 112.6 (C-6),
carried out by EI method on a Jeol JMC-300 spectrometer at 70 eV. Elemen-
127.3 (Ar-C), 128.5 (C-5), 130.0 (Ar-C), 133.1 (Ar-C), 137.8 (Ar-C), 145.5
tal analyses were performed on a Carlo Erba 106 and Perkin Elmer model (C-3), 156.0 (C-6ꢂ).
C6-H), 7.93 (s, 1H, NH, D2O exchangeable); MS (EI) m/z: 212 [M]ꢄ. 13C-
240 analyzers.
General Procedure for Synthesis of 3-Methyl-5-[3-(3-methyl-4-nitro-
Typical Procedure. Ionic-Liquid Catalyzed Fast and Efficient Synthe- 5-isoxazolyl)-2-phenyl propyl]-4-nitroisoxazoles (7) in Ionic Liquid
sis of 3-Methyl-4-nitro-5-styrylisoxazoles (3) 3,5-Dimethyl-4-nitroisoxa- (Entry 1, Table 3) 3-Methyl-4-nitro-5-styrylisoxazole 3 (Entry 1, Table 1)
zole 1 (1 mmol) and aromatic aldehyde 2 (1 mmol) were taken in IL [bmIm] (1 mmol) and 3,5-dimethyl-4-nitroisoxazole 1 (1 mmol), were taken in a
OH (5 ml) and the reaction mixture was stirred at room temperature for 10— conical flask containing 5 ml [bmIm]OH and the mixture was shaken at am-
15 min. The reaction was monitored by TLC. After the completion of the re- bient temperature for 15 min. The reaction mixture was extracted from the
action, the reaction mixture was extracted with ethyl acetate (3ꢃ10 ml). ionic liquid phase with ethyl acetate (3ꢃ10 ml). The organic layer was dried
Evaporation of ethyl acetate gave crude product, which was purified by re- over anhydrous sodium sulphate and evaporated under reduced pressure. The
crystallization from ethyl alcohol. The ionic liquid left over in the reaction residue was purified by petroleum ether to obtain the corresponding Michael
was washed with ethyl acetate and dried at 80 °C under vacuum and was re- adduct 7. The ionic liquid left in the conical flask was further washed with
used for conducting subsequent reactions (five times). This procedure was ether, dried under vacuum at 90 °C for 2 h. To eliminate any water trapped
followed for all the reactions listed in Table 1.
from moisture and reused for subsequent reactions. After five runs, about
Compound 3 (Entry 1, Table 1): Pale yellow solid; IR (KBr): 970 (s) 50% fresh ionic liquid was added to maintain consistent activity. This proce-
1
cmꢀ1; H-NMR (300 MHz, CDCl3) d: 2.2 (s, 3H, CH3), 6.8 (d, 1H, CHꢁ dure was followed for all the reactions listed in Table 3. White solid; IR
1
CH, Jꢁ15 Hz), 7.0 (d, 1H, CHꢁCH, Jꢁ15 Hz), 7.3—7.9 (m, 5H, Ar-H); (KBr): 1575 (ꢁNꢄ–Oꢀ), 1610 (CꢁN), cmꢀ1; H-NMR (300 MHz, CDCl3)
13C-NMR (75 MHz) d: 11.41 (C-6), 109.27 (C-4), 109.87 (C-7), 115.20 (C-
d: 2.4 (s, 6H, 2CH3), 3.5 (dd, 2H, Jꢁ14, 8 Hz, CH2CH), 3.7 (dd, 2H, Jꢁ14,
8), 127.35 (Ar-C), 127.81 (Ar-C), 128.52 (Ar-C), 129.01 (Ar-C), 129.09 8 Hz, CH2CH), 4.0 (quintet, 1H, Jꢁ8 Hz, CH Ar), 6.7—7.2 (m, 5H, Ar-H).
(Ar-C), 130.65 (Ar-C), 156.28 (C-5), 158.85 (C-3). MS (EI) m/z: 230 [M]ꢄ.
13C-NMR (75 MHz) d: 11.10 (C-6), 33.37 (C-7), 41.05 (C-8), 109.87 (C-4),
Compound 3 (Entry 2, Table 1): Pale yellow solid; IR (KBr): 989 (s) 125.10 (Ar-C), 126.87 (Ar-C), 127.35 (Ar-C), 127.81 (Ar-C), 130.05 (Ar-
cmꢀ1; 1H-NMR (300 MHz CDCl3) d: 2.4 (s, 3H, CH3), 2.6 (s, 3H, CH3), 6.9 C), 130.88 (Ar-C), 155.20 (C-3), 156.80 (C-5). MS (EI) m/z: 372 [M]ꢄ.
(d, 1H, CHꢁCH, Jꢁ15 Hz), 7.1 (d, 1H, CHꢁCH, Jꢁ15 Hz), 7.6 (d, 2H, Anal. Calcd for C17H16N4O6: C, 54.83; H, 4.30; N, 15.05. Found: C, 54.85;
ArH, Jꢁ8.5 Hz), 7.8 (d, 2H, ArH, Jꢁ8.5 Hz); 13C-NMR (75 MHz) d: 11.50 H, 4.35; N, 15.00%.
(C-6), 21.40 (Ar-CH3), 109.20 (C-4), 109.90 (C-7), 115.55 (C-8), 127.30
3-Methyl-5-[3-(3-methyl-4-nitro-5-isoxazolyl)-2-(4-methyl
(Ar-C), 127.99 (Ar-C), 128.05 (Ar-C), 128.52 (Ar-C), 129.15 (Ar-C), phenyl)propyl]-4-nitroisoxazole (Entry 2, Table 3) White solid; IR
130.00 (Ar-C), 156.65 (C-5), 158.90 (C-3). MS (EI) m/z: 244 [M]ꢄ.
(KBr): 1570 (ꢁNꢄ–Oꢀ), 1625 (CꢁN), cmꢀ1; H-NMR (300 MHz, CDCl3)
1
Typical Procedure. Green Chemistry Approach to a Fast and Highly d: 2.4 (s, 6H, 2CH3), 2.5 (s, 3H, CH3), 3.5 (dd, 2H, Jꢁ14, 8 Hz, CH2CH),
Efficient Synthesis of 3-Methyl-5-aryl-4H-pyrrolo[2,3-d]isoxazoles (4) 3.7 (dd, 2H, Jꢁ14, 8 Hz, CH2CH), 4.2 (quintet, 1H, Jꢁ8 Hz, CH Ar), 6.9—
3-Methyl-4-nitro-5-styrylisoxazole 3 (1 mmol) and SnCl2·2H2O (2 mmol)
were taken in IL [(HMim)BF4] (5 ml), and the reaction mixture was stirred 33.50 (C-7), 41.55 (C-8), 110.05 (C-4), 126.10 (Ar-C), 127.00 (Ar-C),
at room temperature for 15 min. The reaction was monitored by TLC. After 127.55 (Ar-C), 128.00 (Ar-C), 131.77 (Ar-C), 133.50 (Ar-C), 156.05 (C-3),
7.4 (m, 4H, Ar-H). 13C-NMR (75 MHz) d: 11.55 (C-6), 21.48 (Ar-CH3),

838
Vol. 58, No. 6
158.02 (C-5). MS (EI) m/z: 386 [M]ꢄ. Anal. Calcd for C18H18N4O6: C,
55.95; H, 4.66; N, 14.50. Found: C, 55.99; H, 4.62; N, 14.52%.
2-[(Z)-3-(2,4-Dichlorophenyl)-1-[(Z)-2-(2,4-dichlorophenyl)-1-(3-
methyl-4-nitro-5-isoxazolyl)-1-ethenyl]-2-(3-methyl-4-nitro-5-isoxazolyl)-
2-propenyl]phenol (Entry 4, Table 4) IR ( KBr): 980 (CꢁC),1575
(ꢁNꢄ–Oꢀ), 1630 (CꢁN), cmꢀ1; 1H-NMR (300 MHz, CDCl3) d: 2.2 (s, 6H,
2CH3), 4.3 (s, 1H, benzylic H), 6.2 (s, 2H, 2ꢁCH), 6.8—7.5 (m, 10H, ArH),
9.5 (br s, 1H, OH, D2O exchangeable). MS (EI) m/z: 700 [M]ꢄ. Anal. Calcd
for C31H20N4O7Cl4: C, 53.14; H, 2.85; N, 8.00. Found: C, 53.10; H, 2.88; N,
8.05%.
5-[(Z)-4-(4-Chlorophenyl)-1-[(Z)-1-(4-chlorophenyl)methylidene]-3-(3-
methyl-4-nitro-5-isoxazolyl)-2-(4-methylphenyl)3-butenyl]-3methyl-4-
nitro-isoxazole (Entry 5, Table 4) IR (KBr): 975 (CꢁC), 1560 (ꢁNꢄ–
Oꢀ), 1615 (CꢁN), cmꢀ1; 1H-NMR (300 MHz, CDCl3) d: 2.3 (s, 6H, 2CH3),
2.5 (s, 3H, CH3), 4.1 (s, 1H, benzylic H), 6.2 (s, 2H, 2CH), 6.9—7.6 (m,
12H, ArH). MS (EI) m/z: 630 [M]. Anal. Calcd for C32H24N4O6Cl2: C,
60.95; H, 3.80; N, 8.88. Found: C, 60.99; H, 3.81; N, 8.85%.
2-Methoxy-4-{2-(3-methyl-4-nitro-5-isoxazolyl)-1-[(3-methyl-4-nitro-
5-isoxazolyl)methyl]ethyl}phenol (Entry 3, Table 3) White solid; IR
1
(KBr): 1572 (ꢁNꢄ–Oꢀ), 1620 (CꢁN), cmꢀ1; H-NMR (300 MHz, CDCl3)
d: 2.3 (s, 6H, 2CH3), 3.5 (dd, 2H, Jꢁ14, 8 Hz, CH2CH), 3.7 (dd, 2H, Jꢁ14,
8 Hz, CH2CH), 3.9 (s, 3H, OCH3), 4.1 (quintet, 1H, Jꢁ8 Hz, CH Ar), 6.9—
7.5 (m, 3H, Ar-H), 8.5 (br s, 1H, D2O exchangeable) MS (EI) m/z: 418
[M]ꢄ. Anal. Calcd for C18H18N4O8: C, 51.67; H, 4.30; N, 13.39. Found: C,
51.71; H, 4.26; N, 13.43%.
N,N-Dimethyl-N-(4-{2-(3-methyl-4-nitro-5-isoxazolyl)-1-[(3-methyl-4-
nitro-5-isoxazolyl)methyl]ethyl}phenyl)amine (Entry 4, Table 3) White
solid; IR (KBr): 1575 (ꢁNꢄ–Oꢀ), 1615 (CꢁN), cmꢀ1; 1H-NMR (300 MHz,
CDCl3) d: 2.3 (s, 6H, 2CH3), 3.2 (s, 6H, 2NCH3), 3.6 (dd, 2H, Jꢁ14, 8 Hz,
CH2CH), 3.8 (dd, 2H, Jꢁ14, 8 Hz, CH2CH), 4.0 (quintet, 1H, Jꢁ8 Hz, CH
Ar), 6.8—7.4 (m, 4H, Ar-H). MS (EI) m/z: 415 [M]ꢄ. Anal. Calcd for
C19H21N5O6: C, 54.93; H, 5.06; N, 16.86. Found: C, 54.90; H, 5.01; N,
16.88%.
4-[(Z)-3-(2-(Chlorophenyl)-1-[(E)-2-(2-chlorophenyl)-1-(3-methyl-4-
nitro-5-isoxazolyl)-1-ethenyl]-2-(3-methyl-4-nitro-5-isoxazolyl)-2-
propenyl]-2-methoxyphenol (Entry 6, Table 4) IR (KBr): 975 (CꢁC),
1
1550 (ꢁNꢄ–Oꢀ), 1615 (CꢁN), cmꢀ1; H-NMR (300 MHz, CDCl3) d: 2.2
2-{2-(3-Methyl-4-nitro-5-isoxazolyl)-1-[(3-methyl-4-nitro-5-isoxa-
zolyl)methyl]ethyl}phenol (Entry 5, Table 3) White solid, mp; IR ( KBr):
(s, 6H, 2CH3), 3.8 (s, 3H, OCH3), 4.2 (s, 1H, benzylic H), 6.2 (s, 2H, 2ꢁ
CH), 6.8—7.5 (m, 11H, ArH), 9.0 (br s, 1H, OH, D2O exchangeable). MS
(EI) m/z: 662 [M]ꢄ. Anal. Calcd for C32H24N4O8Cl2: C, 58.00; H, 3.62; N,
8.45. Found: C, 58.04; H, 3.66; N, 8.41%.
1
1565 (ꢁNꢄ–Oꢀ), 1613 (CꢁN), cmꢀ1; H-NMR (300 MHz, CDCl3) d: 2.2
(s, 6H, 2CH3), 3.5 (dd, 2H, Jꢁ14, 8 Hz, CH2CH), 3.7 (dd, 2H, Jꢁ14, 8 Hz,
CH2CH), 4.0 (quintet, 1H, Jꢁ8 Hz, CH Ar), 7.0—7.5 (m, 4H, Ar-H), 9.5
(br s, 1H, OH, D2O exchangeable). MS (EI) m/z: 388 [M]ꢄ. Anal. Calcd for
C17H16N4O7: C, 52.57; H, 4.12; N, 14.43. Found: C, 52.61; H, 4.09; N,
14.45%.
N,N-Dimethyl-N-{4-[(Z)-2-(3-methyl-4-nitro-5-isoxazolyl)-1-[(Z)-1-(3-
methyl-4-nitro-5-isoxazolyl)-2-(2-methylphenyl)-1-ethenyl]-3-(2-
methylphenyl)-2-propenyl]phenyl}amine (Entry 7, Table 4) IR (KBr):
980 (CꢁC), 1575 (ꢁNꢄ–Oꢀ), 1630 (CꢁN), cmꢀ1 1H-NMR (300 MHz,
;
5-[2-(1,3-Benzodioxol-5-yl)-3-(3-methyl-4-nitro-5-isoxazolyl)propyl]-3-
methyl-4-nitroisoxazole (Entry 6, Table 3) White solid; IR (KBr): 1570
(ꢁNꢄ–Oꢀ), 1620 (CꢁN), cmꢀ1; 1H-NMR (300 MHz, CDCl3) d: 2.2 (s, 6H,
2CH3), 3.5 (dd, 2H, Jꢁ14, 8 Hz, CH2CH), 3.7 (dd, 2H, Jꢁ14, 8 Hz,
CH2CH), 4.1 (quintet, 1H, Jꢁ8 Hz, CH Ar), 5.0 (s, 2H, OCH2O), 6.9—7.3
(m, 3H, Ar-H). MS (EI) m/z: 416 [M]ꢄ. Anal. Calcd for C18H16N4O8: C,
51.92; H, 3.84; N, 13.46. Found: C, 51.90; H, 3.88; N, 13.50%.
CDCl3): d 2.3 (s, 6H, 2CH3), 2.5 (s, 6H, 2CH3), 3.2 (s, 6H, N(CH3)2), 4.0 (s,
1H, benzylic H), 6.2 (s, 2H, 2ꢁCH), 6.8—7.5 (m, 12H, ArH). MS (EI) m/z:
619 [M]ꢄ. Anal. Calcd for C35H33N5O6: C, 67.85; H, 5.33; N, 11.30. Found:
C, 67.88; H, 5.35; N, 11.27%.
5-{(Z)-2-(1,3-Benzodioxol-5-yl)-3(3-methyl-4-nitro-5-isoxazolyl)-4-
phenyl-1-[(Z)-1-phenylmethylidene]-3-butenyl}-3-methyl-4-nitro-isoxa-
zole (Entry 8, Table 4) IR (KBr): 970 (CꢁC), 1550 (ꢁNꢄ–Oꢀ), 1620
(CꢁN), cmꢀ1; 1H-NMR (300 MHz, CDCl3) d: 2.3 (s, 6H, 2CH3), 4.3 (s, 1H,
benzylic H), 5.0 (s, 2H, OCH2O), 6.1 (s, 2H, 2ꢁCH), 6.8—7.4 (m, 13H,
ArH). MS (EI) m/z: 592 [M]ꢄ. Anal. Calcd for C32H24N4O8: C, 64.86; H,
4.05; N, 9.45. Found: C, 64.85; H, 4.00; N, 9.40%.
General Procedure for Synthesis of 3-Methyl-5-{(Z)-3-(3-methyl-4-
nitro-5-isoxazolyl)-2,4-diphenyl-1-[(Z)-1-phenylmethylidene]-3-butenyl}-
4-nitroisoxazoles (6) in Ionic Liquid (Entry 1, Table 4) 3-Methyl-5-
[3-(3-methyl-4-nitro-5-isoxazolyl]-2-phenyl propyl]-4-nitroisoxazoles 7 (1
mmol) and aromatic aldehyde (2 mmol) were taken in IL, [bmIm]OH (5 ml)
and the reaction mixture was stirred at room temperature for 10—15 min.
The reaction was monitored by TLC. After the completion of the reaction,
the reaction mixture was extracted with ethyl acetate (3ꢃ10 ml). Evapora-
tion of ethyl acetate gave crude product, which was purified by recrystalliza-
tion from ethyl alcohol to give 6. The IL left over in the reaction was washed
with ethyl acetate and dried at 80 °C under vaccum and was further used for
conducting the reaction once again. It has been used for subsequent runs of
the reaction for five times. This procedure was followed for all the reactions
listed in Table 4. IR (KBr): 978 (CꢁC), 1550 (ꢁNꢄ–Oꢀ), 1630 (CꢁN),
General Procedure for Synthesis of 3-Methyl-6-[(3-methyl-5-phenyl-
4H-pyrrolo[2,3-d]isoxazol-6-yl)(phenyl)methyl]-5-phenyl-4H-
pyrrolo[2,3-d]isoxazoles (5) in Ionic Liquid (Entry 1, Table 5) A mix-
ture of benzyl bis-nitro styrylisoxazoles 6 (1 mmol) and SnCl2. 2H2O (5
mmol) were taken in IL [(HMIm)BF4] (5 ml), and the reaction mixture was
stirred at room temperature for 15—30 min. The termination of the reaction
was monitored by TLC. The product was extracted with ethyl acetate (2ꢃ
10 ml). Evaporation of ethyl acetate gave crude product, which was purified
by a short column chromatography over silica gel (benzene–ethyl acetate) to
provide the pure product, benzyl bis-pyrrolo[2,3-d]isoxazole as a pale yel-
low solid. The ionic liquid was dried under vacuum and reused for five reac-
tions by adding some more SnCl2·2H2O with out any loss of efficiency.
After five runs 50% of fresh IL and SnCl2·2H2O were added to it and this
was used again. This procedure was followed for all the reactions listed in
1
cmꢀ1; H-NMR (300 MHz, CDCl3) d: 2.3 (s, 6H, 2CH3), 4.2 (s, 1H, ben-
zylic H), 6.2 (s, 2H, 2ꢁCH), 6.9—7.5 (m, 15H, ArH). 13C-NMR (75 MHz)
d: 11.05 (C-6), 45.05 (C-9), 110.85 (C-4), 117.80 (C-7), 122.02 (C-8),
125.80 (Ar-C), 126.40 (Ar-C), 127.80 (Ar-C), 127.95 (Ar-C), 128.00 (Ar-
C), 128.70 (Ar-C), 129.10 (Ar-C), 129.22 (Ar-C), 130.00 (Ar-C), 131.07
(Ar-C), 137.06 (Ar-C), 137.50 (Ar-C), 155.45 (C-3), 158.90 (C-5). MS (EI)
m/z: 548 [M]ꢄ. Anal. Calcd for C31H24N4O6: C, 67.88; H, 4.37; N, 10.21.
Found: C, 67.85; H, 4.38; N, 10.20%.
Table 5. Pale color solid, IR (KBr): 3300 (S), 1600, 970 cmꢀ1 1H-NMR
;
(300 MHz, CDCl3) d: 2.3 (s, 6H, 2CH3), 4.6 (s, 1H, benzylic H), 7.2—7.8
(m, 15H, Ar-H), 8.1 (br s, 2H, pyrrole NH, D2O exchangeable). MS (EI)
m/z: 484 [M]ꢄ. 13C-NMR (75 MHz) d: 11.01 (C-7), 40.05 (C-8), 105.20 (C-
3ꢂ), 111.05 (C-6), 126.05 (Ar-C), 127.00 (Ar-C), 127.50 (Ar-C), 128.02 (Ar-
C), 128.75 (Ar-C), 128.99 (Ar-C), 130.02 (C-5), 131.75 (Ar-C), 133.50 (Ar-
C), 132.88 (Ar-C), 133.00 (Ar-C), 135.03 (Ar-C), 136.30 (Ar-C), 148.22 (C-
3), 155.40 (C-6ꢂ). Anal. Calcd for C31H24N4O2: C, 76.85; H, 4.95; N, 11.57.
Found: C, 76.88; H, 4.90; N, 11.58%.
3-Methyl-5-{(Z)-3-(3-methyl-4-nitro-5-isoxazolyl)-4-(4-
methylphenyl)1-[(Z)-1-(4-methylphenyl)methylidene]-2-phenyl-3-
butenyl}-4-nitroisoxazole (Entry 2, Table 4) IR (KBr): 980 (CꢁC),1570
1
(ꢁN–Oꢀ), 1625 (CꢁN), cmꢀ1; H-NMR (300 MHz, CDCl3) d: 2.3 (s, 6H,
2CH3), 2.5 (s, 6H, 2CH3), 4.2 (s, 1H, benzylic H), 6.1 (s, 2H, 2ꢁCH), 6.8—
7.4 (m, 13H, ArH). 13C-NMR (75 MHz) d: 11.40 (C-6), 21.75 (Ar-CH3),
45.13 (C-9), 111.25 (C-4), 118.50 (C-7), 125.05 (C-8), 126.05 (Ar-C),
126.80 (Ar-C), 127.95 (Ar-C), 128.03 (Ar-C), 128.75 (Ar-C), 129.00 (Ar-
C), 129.25 (Ar-C), 129.65 (Ar-C), 130.05 (Ar-C), 132.06 (Ar-C), 133.57
(Ar-C), 138.05 (Ar-C), 155.05 (C-3), 158.88 (C-5). MS (EI) m/z: 576 [M]ꢄ.
Anal. Calcd for C33H28N4O6: C, 68.75; H, 4.86; N, 9.72. Found: C, 68.77; H,
4.85; N, 9.70%.
3-Methyl-6-[(3-methyl-5-(4-methylphenyl)-4H-pyrrolo[2,3-d]isoxazol-
6-yl)(phenyl)methyl]-5-(4-methylphenyl)-4H-pyrrolo[2,3-d]isoxazole
(Entry 2, Table 5) Pale yellow solid, IR (KBr): 3250 (S), 1610, 980 cmꢀ1
;
1H-NMR (300 MHz, CDCl3) d: 2.2 (s, 6H, 2CH3), 2.5 (s, 6H, 2CH3), 4.8
(s, 1H, benzylic H), 6.8—7.6 (m, 13H, Ar-H), 8.5 (br s, 2H, pyrrole NH,
D2O exchangeable). 13C-NMR (75 MHz) d: 11.37 (C-7), 21.50 (Ar-CH3),
41.85 (C-8), 105.55 (C-3ꢂ), 111.85 (C-6), 125.85 (Ar-C), 126.85 (Ar-C),
127.05 (Ar-C), 127.95 (Ar-C), 128.33 (Ar-C), 128.87 (Ar-C), 130.08 (C-5),
131.21 (Ar-C), 131.95 (Ar-C), 132.05 (Ar-C), 133.08 (Ar-C), 135.00 (Ar-
C), 136.44 (Ar-C), 148.38 (C-3), 156.05 (C-6ꢂ). Anal. Calcd for
C31H24N4O2: C, 76.85; H, 4.95; N, 11.57. Found: C, 76.88; H, 4.90; N,
11.58%. MS (EI) m/z: 512 [M]ꢄ. Anal. Calcd for C33H28N4O2: C, 77.34; H,
5.46; N, 10.93. Found: C, 77.38; H, 5.40; N, 10.95%.
5-{(Z)-4-(4-Methoxyphenyl)1-[(Z)-1-(4-methoxyphenyl)methylidene]-
3-(3-methyl-4-nitro-5-isoxazolyl)-2-phenyl-3-butenyl}-4-nitroisoxazole
(Entry 3, Table 4) IR (KBr): 960 (CꢁC),1525 (ꢁNꢄ–Oꢀ), 1622 (CꢁN),
cmꢀ1 1H-NMR (300 MHz, CDCl3) d: 2.3 (s, 6H, 2CH3), 3.8 (s, 6H,
;
2OCH3), 4.1 (s, 1H, benzylic H), 6.2 (s, 2H, 2ꢁCH), 6.8—7.5 (m, 13H,
ArH). MS (EI) m/z: 608 [M]ꢄ. Anal. Calcd for C33H28N4O8: C, 65.13; H,
4.60; N, 9.21. Found: C, 65.10; H, 4.66; N, 9.25%.

June 2010
839
5-(4-Methoxyphenyl)-6-[(5-(4-methoxyphenyl)-3-methyl-4H- References
pyrrolo[2,3-d]isoxazol-6-yl)(phenyl)methyl]-3-methyl-4H-pyrrolo[2,3-
d]isoxazole (Entry 3, Table 5) Pale yellow solid, IR (KBr): 3300 (S),
1) Anastas P. T., Kirchhoff M. M., Williamson T. C., Appl. Catal. A:
Gen., 221, 3—13 (2001).
2) DeSimone J. M., Science, 297, 799—803 (2002).
3) Wasserscheid P., Keim W., Angew. Chem. Int. Ed., 39, 3773—3789
(2000).
4) Sheldon R., Chem. Commun., 2001, 2399—2407 (2001).
5) Wilkes J. S., Green Chem., 4, 73—80 (2002).
6) Yao Q., Org. Lett., 4, 2197—2199 (2002).
7) Sima T., Guo S., Shi F., Deng Y., Tetrahedron Lett., 43, 8145—8147
(2002).
1
1620, 975 cmꢀ1; H-NMR (300 MHz, CDCl3) d: 2.2 (s, 6H, 2CH3), 3.8 (s,
6H, 2OCH3), 4.0(s, 1H, benzylic H), 6.8—7.5 (m, 13H, Ar-H), 8.5 (br s, 2H,
pyrrole NH, D2O exchangeable). MS (EI) m/z: 544 [M]ꢄ. Anal. Calcd for
C33H28N4O4: C, 72.79; H, 5.14; N, 10.29. Found: C, 72.81; H, 5.15; N,
10.30%.
2-{Di-[5-(2,4-dichlorophenyl)-3-methyl-4H-pyrrolo[2,3-d]isoxazol-6-
yl)methyl}phenol (Entry 4, Table 5) Pale yellow solid, IR (KBr): 3300
(S), 1625, 970 cmꢀ1 1H-NMR (300 MHz, CDCl3) d: 2.3 (s, 6H, 2CH3),
;
4.6(s, 1H, benzylic H), 6.8—7.5 (m, 10H, Ar-H), 8.5 (br s, 2H, pyrrole NH,
D2O exchangeable), 9.5 (br s, 1H, D2O exchangeable) . MS (EI) m/z: 638
[M]ꢄ. Anal. Calcd for C31H20N4O3Cl4: C, 58.30; H, 3.13; N, 8.77. Found: C,
58.33; H, 3.10; N, 8.75%.
8) Zerth H. M., Leonard N. M., Mohan R. S., Org. Lett., 5, 55—57
(2003).
9) Su C., Chen Z. C., Zheng Q. G., Synthesis, 2003, 555—559 (2003).
10) Ranu B. C., Jana R., Eur. J. Org. Chem., 2006, 3767—3770 (2006).
5-(4-Chlorophenyl)-6-[(5-(4-chlorophenyl)-3-methyl-4H-pyrrolo[2,3- 11) Ranu B. C., Banerjee S., Jana R., Tetrahedron, 63, 776—782 (2007).
d]isoxazol-6-yl]-4-methyl phenyl)methyl]-3-methyl-4H-pyrrolo[2,3-d]isox
azole (Entry 5, Table 5) Pale yellow solid, IR (KBr): 3235 (S), 1620,
975 cmꢀ1
CH3), 4.7 (s, 1H, benzylic H), 6.8—7.3 (m, 12H, Ar-H), 8.6 (br s, 2H, pyr-
role NH, D2O exchangeable). MS (EI) m/z: 566 [M]ꢄ. Anal. Calcd for 14) Wang H., Cui P., Zou G., Yang F., Tang J., Tetrahedron, 62, 3985—
-
12) Xu J. M., Qian C., Liu B. K., Wu Q., Lin X. F., Tetrahedron, 63, 986—
990 (2007).
;
1H-NMR (300 MHz, CDCl3) d: 2.2 (s, 6H, 2CH3), 2.5 (s, 3H, 13) Wu H. H., Yang F., Cui P., Tang J., He M. Y., Tetrahedron Lett., 45,
4963—4967 (2004).
C32H24N4O2Cl2: C, 67.84; H, 4.24; N, 9.89. Found: C, 67.70; H, 4.20; N,
9.87%.
4-{Di[5-(2-Chlorophenyl)-3-methyl-4H-pyrrolo[2,3-d]isoxazol-6-
3990 (2006).
15) Reddy P. S., Kanjilal S., Sunitha S., Prasad R. B. N., Tetrahedron Lett.,
48, 8807—8810 (2007).
yl]methyl}-2-methoxyphenol (Entry 6, Table 5) Pale yellow solid, IR 16) Rajanarendar E., Ramesh P., Srinivas M., Mohan G., Ramu K., Synth.
(KBr): 3300 (S), 1625, 970 cmꢀ1; 1H-NMR (300 MHz, CDCl3) d: 2.2 (s, 6H,
2CH3), 3.8 (s, 3H, OCH3), 4.6 (s, 1H, benzylic H), 6.8—7.5 (m, 12H, Ar-H),
8.8 (br s, 2H, pyrrole NH, D2O exchangeable), 9.5 (br s, 1H, OH, D2O ex-
changeable). MS (EI) m/z: 598 [M]ꢄ. Anal. Calcd for C32H24N4O4Cl2: C,
64.21; H, 4.01; N, 9.36. Found: C, 64.25; H, 4.05; N, 9.32%.
Commun., 36, 665—671 (2006).
17) Rajanarendar E., Mohan G., Ramesh P., Srinivas M., J. Heterocyclic.
Chem., 44, 215—217 (2007).
18) Rajanarendar E., Ramesh P., Kalyan Rao E., Mohan G., Srinivas M.,
Arkivoc., xiv, 266—275 (2007).
N-(4-{Di-[3-methyl-5-(2-methylphenyl)-4H-pyrrolo[2,3-d]isoxazol-6- 19) Rajanarendar E., Ramesh P., Kalyan Rao E., Sivarami Reddy A., Phos-
yl]methyl}phenyl)-N,N-dimethylamine (Entry 7, Table 5) Pale yellow
phorous Sulfur and Silicone, 183, 2555—2564 (2008).
1
solid, IR (KBr): 3335 (S), 1630, 980 cmꢀ1; H-NMR (300 MHz, CDCl3) d: 20) Sudberg R., J. Org. Chem., 30, 3604—3610 (1965).
2.2 (s, 6H, 2CH3), 2.5 (s, 6H, 2CH3), 3.2 (s, 6H, N(CH3)2), 4.8 (s, 1H, ben- 21) Papa Rao C., Rao K. V., Sundaramurthy V., Synthesis, 3, 234—236
zylic H), 6.8—7.6 (m, 12H, Ar-H), 8.6 (br s, 2H, pyrrole NH, D2O
exchangeable). MS (EI) m/z: 555 [M]ꢄ. Anal. Calcd for C35H33N5O2: C,
75.67; H, 5.94; N, 12.61. Found: C, 75.65; H, 5.90; N, 12.65%.
(1981).
22) Mali R. S., Yadav V. J., Synthesis, 1984, 862—865 (1984).
23) Coda A. C., Desimoni G., Coda A., Heterocycles, 23, 1893—1896
(1985).
6-[1,3-Benzodioxol-5-yl-(3-methyl-5-phenyl-4H-pyrrolo[2,3-d]isoxa-
zol-6-yl)methyl]-3-methyl-5-phenyl-4H-pyrrolo[2,3-d]isoxazole (Entry 8, 24) Stefanachi A., Leonetti F., Cappa A., Carotti A., Tetrahedron Lett., 44,
Table 5) Pale yellow color solid, IR (KBr): 3300 (S), 1620, 975 cmꢀ1; 1H-
NMR (300 MHz, CDCl3) d: 2.3 (s, 6H, 2CH3), 4.6 (s, 1H, benzylic H), 5.0
(s, 2H, OCH2O), 6.8—7.3 (m, 13H, Ar-H), 8.5 (br s, 2H, pyrrole NH, D2O
exchangeable). MS (EI) m/z: 528 [M]ꢄ. Anal. Calcd for C32H24N4O4: C,
72.72; H, 4.54; N, 10.60. Found: C, 72.70; H, 4.55; N, 10.63%.
2121—2123 (2003).
25) Rajanarendar E., Mohan G., Ramesh P., Karunakar D., Tetrahedron
Lett., 47, 4957—4959 (2006).
26) Quilico A., Musantc C., Gazz. Chim. Ital., 72, 399—402 (1942).
27) Reddy K. M., Rao C. J., Murthy A. K., Indian J. Chem., 20B, 997—
998 (1981).
Acknowledgements The authors are thankful to the Head, Department
of Chemistry, Kakatiya University, Warangal for providing the facilities, the
28) Adamo M. F. A., Chimichi S., De Sio F., Donati D., Sarti-Fantoni P.,
Tetrahedron Lett., 43, 4157—4160 (2002).
Director, Indian Institute of Chemical Technology, Hyderabad for recording 29) Ranu B. C., Banerjee S., Org. Lett., 7, 3049—3052 (2005).
1H-NMR and Mass Spectra. Mr. K. Govardhan Reddy is thankful to CSIR, 30) Zhu H. P., Yang F., Tang J., He M. Y., Green Chem., 5, 38—40 (2003).
New Delhi for the award of fellowship (JRF).