Multi-component synthesis of methylene bis isoxazolo[4,5-b]-pyridine-N- oxides

Article abstract of DOI:10.1016/j.cclet.2010.03.014

A three component one-pot protocol was investigated for the synthesis of methylene bis isoxazolo[4,5-b]-pyridine-N-oxides from commercially available materials.

Full text of DOI:10.1016/j.cclet.2010.03.014

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 927–930
www.elsevier.com/locate/cclet
Multi-component synthesis of methylene bis
isoxazolo[4,5-b]-pyridine-N-oxides
*
E. Rajanarendar , M. Nagi Reddy, K. Rama Murthy
Department of Chemistry, Kakatiya University, Warangal 506009, A.P., India
Received 17 December 2009
Abstract
A three component one-pot protocol was investigated for the synthesis of methylene bis isoxazolo[4,5-b]-pyridine-N-oxides
from commercially available materials.
# 2010 E. Rajanarendar. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Multi-component synthesis; Knoevenagel condensation; Michael addition; New methodology
Multi-component reactions (MCRs) have proved to be remarkably successful in generating products in a single
synthetic operation [1] and are important owing to their synthetic efficiency [2]. In times, where a premium is put on
speed, diversity and efficiency in the drug discovery process [3], MCR strategies offer significant advantages over
conventional linear-type syntheses. MCRs contribute to the requirements of an environmentally friendly process by
reducing the number of synthetic steps, energy consumption and waste production. Various biological applications
have been reported for isoxazoles such as antitumor [4], CNS-active [5], analgesic [6], antimicrobial [7] and
chemotherapy [8]. Isoxazoles display a wide range of organic reactivities and could be used as an effective means of
preparing new molecular scaffolds [9]. Several pyridine-N-oxide derivatives were shown to exhibit anti-HIV activity
and they are unusual anti-HIV compounds with multiple mechanism of antiviral action [10–12]. Pyridine-N-oxides are
usually synthesized by the oxidation of pyridine derivatives [13–15] or by ring transformation of isoxazole [16,17].
These reactions require the usage of variety oxidants, drastic conditions, and moreover results in poor yields. Hence,
we thought of constructing the pyridine-N-oxide ring by interaction of 3,5-dimethyl-4-nitroisoxazole 1 with
compounds possessing a methyl ketone or b-diketone moiety in piperidine [18–20]. We could able to achieve the
target, because our method produced good yields under mild conditions compared to the existing known methods. In
continuation of our earlier work, now, we proposed the synthesis of title compounds.
3,5-Dimethyl-4-nitroisoxazole 1 represents a versatile building block bearing a number of different functionalities
which can be selectively reacted to generate molecularly diverse products and we reported many reactions by
describing the reactivity of isoxazole 1 [21–24]. Our approach to the development of multi-component one-pot
synthesis is based on the creation of building blocks containing several reactive centres which can be selectively
* Corresponding author.
E-mail address: rajanarendareligeti@gmail.com (E. Rajanarendar).
1001-8417/$ – see front matter # 2010 E. Rajanarendar. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.03.014

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E. Rajanarendar et al. / Chinese Chemical Letters 21 (2010) 927–930
reacted. Owing to the potential activity of pyridine-N-oxides and isoxazoles, we are interested in development of
hybrid molecules and in the design of new drugs to accommodate bis-pyridine-N-oxide and isoxazole moieties in a
single molecular frame work for enhancing biological activity. Inspired by these findings and to develop new synthetic
strategies, we could able to perform a multi-component one-pot synthesis on 3,5-dimethyl-4-nitroisoxazole 1 to
synthesize the title compounds. As a part of our endeavour to develop diversity-oriented synthesis using poly
functional scaffold such as 3,5-dimethyl-4-nitroisoxazole 1, we now report a new one-pot three-component procedure
(actually involving 5 components, MCR-5) which allows the synthesis of title compounds, which may probably
possess potential pharmacological activity, from commercially available starting materials.
Considering that, tandem synthesis involving Knoevenagel and Michael reaction in a sequential order have been
extensively reported [25], we anticipated that methylene bis isoxazolo[4,5-b]pyridine-N-oxides could be prepared
through a multi-component procedure in which 6 was generated first from 1 and 5 by Knoevenagel condensation and
these reacted in situ with 7 through Michael addition and subsequently it undergoes further in situ cyclocondensation
with 2 moles of 1 to give the title compounds 4.
1. Experimental
All the melting points were determined on a Cintex melting point apparatus and are uncorrected. Analytical TLC
was performed on Merck precoated 60 F254 silica gel plates. Visualization was done by exposing to iodine vapour. IR
spectra (KBr pellet) were recorded on a PerkinElmer BX series FT-IR spectrometer. 1H NMR spectra were recorded on
a Varian Gemini 300 MHz spectrometer. Chemical shift (d) is given with tetramethyl silane as an internal standard.
Mass spectral measurements were carried out by EI method on a Jeol JMC-300 spectrometer at 70 eV. Elemental
analyses were performed on a Carlo Erba 106 and PerkinElmer model 240 analyzers.
To a stirred solution of 1 (1 mmol) in ethanol (10 mL) were added piperidine (0.1 mmol) and an aromatic aldehyde
2 (1 mmol). The reaction mixture was refluxed at 80 8C for 1 h, and acetyl acetone 3 (1 mmol) was added later to the
reaction mixture, heating continued at 80 8C for 2 h, and then 1 (2 mmol) was further added to it and heating continued
further for 3 h. After completion of the reaction (monitored by TLC) the solid product 4 separated on cooling was
filtered and recrystallized from methanol.
To a solution of Michael adduct 8 (1 mmol) in ethanol (10 mL), catalytic amount of piperidine (0.01 mmol) and 2
equivalents of nitro isoxazole 1 (2 mmol) were added and the contents are refluxed for 3 h. The product separated on
cooling was filtered and recrystallized from methanol. The compound 4 obtained in this method was found to be
1
similar to that of a multi-component one-pot synthesis by mps, H NMR and mass spectral data.
2. Results and discussion
In a typical experiment, equimolar amounts (1 equivalent) of 3,5-dimethyl-4-nitroisoxazole 1, aromatic aldehyde 2,
were reacted in the presence of piperidine in ethanol (1 h at 80 8C), and acetyl acetone (1 equiv) was added and the
refluxing continued for another 2 h at 80 8C, finally 2 equivalents of 1 was added and the reaction was carried out for
another 3 h at 80 8C. The solid that separated on cooling, was filtered and purified by recrystallization from ethanol.
Compounds 4a–j, were isolated in good yields (Scheme 1).
In order to establish the evidence for the formation of 4a–j, we carried out a step-wise synthesis of compounds 4a–j,
starting from the building block 1. We reacted 3,5-dimethyl-4-nitroisoxazole 1 (1 mmol) with different aromatic
aldehydes (1 mmol) in alcohol under refluxing condition on a hot-water bath for 1 h in presence of catalytic amount of
piperidine (0.01 mmol) which led to the formation nitrostyryl isoxazole 6 by Knoevenagel condensation in good yields
[26]. Only the 5-methyl group of isoxazole is activated by the nitro group, hence it alone takes part in this
regioselective reaction [27]. Compound 6 was later reacted with acetyl acetone 7 in ethanol containing catalytic
amount of piperidine for 2 h at 80 8C. This reaction led to the formation of Michael adducts 8 in moderate yields [28].
Finally compound 8 containing two acetyl groups was reacted with 2 equivalents of 1 in ethanol containing catalytic
amount of piperidine for 3 h at 80 8C, which resulted in the formation of title compounds 4a–j (Scheme 2).
The compounds 4a–j, obtained in a one-pot multi-component synthesis and by a step-wise synthesis were found to
1
be similar by mps, H NMR and mass spectra. The structure of newly synthesized methylene bis isoxazolo[4,5-
1
b]pyridine-N-oxides 4a–j were established on the basis of IR, H NMR and MS spectra and by elemental analyses
[29]. The yields in multi-component synthesis are more (80–85%), compared to that of step-wise synthesis (65–75%).

E. Rajanarendar et al. / Chinese Chemical Letters 21 (2010) 927–930
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Scheme 1. Reagents and conditions: i) ethanol–piperidine, reflux, 6 h.
Scheme 2. Reagents and conditions: i) ethanol–piperidine, reflux, 1 h. ii) Ethanol–piperidine, reflux, 2 h. iii) Ethanol–piperidine, reflux, 3 h.
The different substituents present on benzene ring of aromatic aldehydes did not affect much on the yields of the
products 4a–j.
In conclusion, we reported the multi-component (MCR-5) synthesis of methylene bis isoxazolo[4,5-b]-pyridine-N-
oxides with potential biological activity using inexpensive and commercially available materials in a one-pot reaction.
This synthesis benefits from a simple method of purification, which does not require chromatography. This ease of
purification compliments the one-pot synthesis, making the technology practical, easy to perform and facile.
Moreover, pyridine-N-oxides are recently proved to be anti-HIV agents, this study may activate the researchers
concerned in this field to explore the pharmacological activity of the compounds.
Acknowledgments
The authors are thankful to the Head, Department of Chemistry, Kakatiya University, Warangal for the facilities and
1
to the Director, Indian Institute of Chemical Technology, Hyderabad for recording H NMR and Mass Spectra.
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(c) Analytical data for compound 8a: Colourless solid, yield 65%, mp 170 8C, IR (KBr): cmÀ1; 1705 (C O), 1600 (C N), 1520 (NO2), 1H
NMR (300 MHz, CDCl3): d 1.8(s, 3H, CH3), 2.2 (s, 3H, CH3), 2.3 (s, 3H, CH3), 3.6 (m, 2H), 4.1(m, 1H, benzylic-H), 4.3(d, 1H, J = 12 Hz),
6.8–7.2 (m, 5H, Ar–H); MS (EI): m/z 330 [M+]. Anal. Calcd. for C27H18N5O2; C, 61.81; H, 5.45; N, 8.48; Found: C, 61.76; H, 5.41; N, 8.45. 8b:
Colourless solid, yield 60%, mp 146 8C, IR (KBr): cmÀ1; 1709 (C O), 1600 (C N), 1575 (NO2), 1H NMR (300 MHz, CDCl3): d 1.7(s, 3H,
CH3), 2.1 (s, 3H, CH3), 2.3 (s, 3H, CH3), 3.8 (s, 3H, OCH3), 4.1 (m, 1H, benzylic-H), 4.5(d, 1H, J = 12 Hz), 7.1 (d, 2H, Ar–H, J = 7.3 Hz), 7.4
(d, 2H, Ar–H, J = 7.3 Hz); MS (EI): m/z 360 [M+]. Anal. Calcd. for C18H20N2O6; C, 60.00; H, 5.55; N, 7.77; Found: C, 60.03; H, 5.49; N, 7.75.
[29] Aanalytical data for compounds: 4a: pale red crystalline solid, yield 85%, mp 240 8C, IR (KBr): cmÀ1; 1385 ( N+–OÀ), 1648 (C N), 1H
NMR (300 MHz, CDCl3): d 2.2 (s, 6H, 2CH3), 2.5 (s, 3H, CH3), 3.8 (m, 2H), 4.2 (m, 1H, benzylic-H), 4.9 (d, 1H, J = 12 Hz), 6.6 (s, 2H,
pyridine-H), 6.8–7.2 (m, 5H, Ar–H), 7.5 (s, 2H, pyridine-H); MS (EI): m/z 542 [M+]. Anal. Calcd. for C27H22N6O7; C, 59.77; H, 4.05; N, 15.49;
Found: C, 59.81; H, 4.02; N, 15.50. 4b: pale red crystalline solid, yield 82%, mp 221 8C, IR (KBr): cmÀ1; 1325 ( N+–OÀ), 1659 (C N), 1H
NMR (300 MHz, CDCl3): d 2.2 (s, 6H, 2CH3), 2.5 (s, 3H, CH3), 3.6 (s, 3H, OCH3), 3.8 (m, 2H), 4.2 (m, 1H, benzylic-H), 4.8 (d, 1H, J = 12 Hz),
6.6 (s, 2H, pyridine-H), 6.8 (d, 2H, Ar–H, J = 7.5 Hz), 7.2 (d, 2H, Ar–H, J = 7.5 Hz), 7.6 (s, 2H, pyridine-H); MS (EI): m/z 572 [M+]. Anal.
Calcd. for C28H24N6O8; C, 58.74; H, 4.19; N, 14.68; Found: C, 58.77; H, 4.22; N, 14.66. 4c: pale red crystalline solid, yield 81%, mp 211 8C.
4d: pale red crystalline solid, yield 82%, mp 202 8C. 4e: orange crystalline solid, yield 82%, mp 198 8C. 4f: orange crystalline solid, yield 81%,
mp 190 8C. 4 g: pale red crystalline solid, yield 83%, mp 188 8C. 4 h: pale red crystalline solid, yield 80%, mp 217 8C. 4i: pale red crystalline
solid, yield 82%, mp 223 8C. 4j: orange crystalline solid, yield 81%, mp 232 8C.