Synthesis and characterization of new 3-(4,5-dihydro-5-aryl)isoxazol-3-yl)-4-hydroxyquinolin-2(1H)-ones and 3-(4-styryl)isoxazolo[4,5-c]quinolin-4(5H)-one derivatives

1 Introduction

The quinolones known for their anti-microbial activities, based on their improved activities have been classified into four generations (Hooper et al., 2000). First-generation agents, are used less often today, with moderate gram-negative activity and minimal systemic distribution. Second-generation quinolones have expanded gram-negative activity and atypical pathogen coverage, but limited gram-positive activity. These agents are most active against aerobic gram-negative bacilli. Ciprofloxacin remains the most active quinolone against Pseudomonas aeruginosa (Hooper, 2000). Third-generation quinolones retain expanded gram-negative and atypical intracellular activity but have improved gram-positive coverage. Finally, fourth-generation agents improve gram-positive coverage, maintain gram-negative coverage, and gain anaerobic coverage. Marginal susceptibility and acquired resistance limit the usefulness of second-generation quinolones in the treatment of staphylococcal, streptococcal, and enterococcal infections (Oliphant et al., 2002). Clinafloxacin an investigational fluoroquinolone has the most potent in vitro anaerobic activity (Oliphant Applebaum, 1999). Several isoxazoline derivatives reported to show anti-inflammatory activity and imidazolyl isoxazoline derivatives show (Basappa et al., 2004) inhibitory activity against venom PLA₂ and reduced oedema inducing activity in mice. Andronati et al., 2004) reported that isoxazoline derivatives exhibit high activity in vitro bioassays on inhibiting platelet aggregation and was a potent anti-platelet agent for intravenous injection (Olson et al., 1999; Batt et al., 2000; Stilz et al., 1996). Isoxazole derivatives were reported as an important class of bioactive molecules, which exhibit significant activities such as antifungal (Desai et al., 2008) Aβ precursor protein (Rajeshwar et al., 2008) protein tyrosine phosphatase 1B inhibitors (Sung et al., 2003), antiviral (Lee et al., 2009), antihelmintics (Hansen and Stronge, 1977), anti-inflammatory (Adhikari et al., 2009), anticonvulsant (Balalaie et al., 2000), insecticidal (Kai et al., 2000), antitubercular (Kachhadia et al., 2004), immunomodulatory (Marcin et al., 2005) and hypolipemics (Nagar and Shan, 2003). The methylene-bis-isoxazoles reported to show 100% efficiency against PMA stimulated neutrophils (Mazzei et al., 2003). A series of structural optimizations led to improved efficacy and excellent functional receptor selectivity for PPARδ (Srinivas et al., 2010). The isoxazoles represent a series of agonists which display a scaffold that lies outside the typical PPAR agonist motif (Epple et al., 2006). The 3-pyrazolyl-4,5-dicarbethoxy isoxazoles exhibited the maximum Antinociceptive activity (Karthikeyan et al., 2009). Based on the above literature’s importance here in we report some new quinolinyl isoxazoline and isoxazole derivatives (Scheme 1).

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Scheme 1

Synthesis of 3-(4,5-dihydro-5-aryl)isoxazol-3-yl)-4-hydroxyquinolin-2(1H)-ones and 3-(4-substituted styryl)isoxazolo[4,5-c]quinolin-4(5H)-ones.

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2 Experimental

All the melting points reported were recorded in open capillaries and uncorrected. IR spectra of all the compounds were recorded on AVATAR330 FT-IR Spectrometer. ¹H NMR spectra were recorded on Bruker AMX 300. Chemicals for the synthesis were from Sigma Aldrich Co, St Louis, USA, and SD fine chemicals Pvt. Ltd., Boisar, India.

3 Results and discussion

4-Hydroxy-3-(3-arylacryloyl)quinolin-2(1H)-ones (1a–f) were synthesized from 3-acetyl-4-hydroxy-quinolin-2(1H)-one by the literature method (Sarveswari and Raja, 2006). The 4-hydroxy-3-(3-arylacryloyl)quinolin-2(1H)-ones in turn were converted into 3-(4,5-dihydro-5-aryl)isoxazol-3-yl)-4-hydroxyquinolin-2(1H)-ones (2a–f) and 3-(4-substituted styryl) isoxazolo[4,5-c]quinolin-4(5H)-ones (3a–f). The initial attempt of conversion of 3-(4,5-dihydro-5-aryl)isoxazol-3-yl)-4-hydroxyquinolin-2(1H)-ones from (1a–f) by refluxing with hydroxylamine hydrochloride failed in methanol, ethanol or benzene solvent. Where as the same reaction in glacial acetic acid resulted in the formation of two products. The mixture was purified through column chromatography using 4:1 mixture of chloroform and methanol. The spectral characterisation of products revealed the formation of 2a–f and 3a–f. Since the isoxazole (3a–f) formation could not be controlled to get only isoxazolines (2a–f), we increased the reaction duration to 19–20 h. The increased reaction duration resulted in isoxazoles as the major products and the minor products could not be isolated. We observed that both the isoxazole and isoxazoline derivatives are not stable in water, so the aqueous work up results in decomposition of the products.

All the compounds were characterized through IR, ¹H NMR and mass spectral studies. The compound 2a has been taken as the representative example and its proton chemical shift assignment, IR and mass spectral interpretations are discussed. Three doublet of doublets in aliphatic region of spectrum at δ 2.83 ppm (1H, dd, J_AM = 16 Hz and J_AX = 11 Hz), δ 3.50 ppm (1H, dd, J_AM = 16 Hz and J_MX = 3.3 Hz), δ 5.52 ppm (1H, dd, J_MX = 3.3 Hz and J_AX = 11 Hz) confirm the formation of isoxazoline ring. H-7 and H-6 protons of quinolone ring appear as two triplets at δ 7.41 ppm (7.3 Hz), δ 7.17 ppm (7.3 Hz) and H-5 and H-8 appear as two doublets at δ 7.82 ppm (7.8 Hz) and δ 7.23 ppm (8.1 Hz) respectively. The summary of the above chemical shift assignments is given in Fig. 1 The molecular ion peak at 307.1 in ESI mass spectrum confirms the formation of the product.

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Figure 1

Summary of Proton chemical shift values (δ) in ppm of 3-(4,5-dihydro-5-phenyl) isoxazol-3-yl)-4-hydroxyquinolin-2(1H)-one (2a).

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The compound 3d has been taken as the representative example for isoxazole derivatives and its proton chemical shift assignment, IR and mass spectral interpretations are discussed. In proton NMR spectrum of compound 3d, the four quinolone ring protons appear as two triplets viz δ 7.35 ppm (J = 7.5 Hz) for H-6, δ 7.59 ppm (J = 7.3 Hz) for H-7 and two doublets viz δ 7.94 ppm (J = 7.7 Hz) for H-5 and 7.50 ppm (J = 7.9 Hz) for H-8 protons. The styryl protons give two characteristic doublets with coupling constant 16.5 Hz. A peak at δ 7.41 ppm is due to styryl proton attached with 4-chlorophenyl substituent and δ 7.84 ppm is due to styryl proton attached with isoxazolo quinoline ring system. The downfield shift of styryl proton at δ 7.84 ppm compared to δ 7.41 ppm is due to its attachment with the highly electron withdrawing isoxazolo quinoline ring system. The four protons of 4-chlorophenyl substituents appear as doublets at 7.85 ppm (J = 8.3 Hz) and 7.52 ppm (J = 8.3 Hz) each of two proton intensity. The summary of the above chemical shift assignment is given in Fig. 2. The proton chemical shift values of other compounds in these series have been assigned and given below.

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Figure 2

Summary of proton chemical shift values (δ) in ppm of 3-(4-chlorostyryl) isoxazolo[4,5-c]quinolin-4(5H)-one (3d).

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4 Conclusion

Synthesis of 3-(4,5-dihydro-5-aryl)isoxazol-3-yl)-4-hydroxyquinolin-2(1H)-ones and 3-(4-substituted styryl)isoxazolo[4,5-c]quinolin-4(5H)-ones were effected from the corresponding 4-hydroxy-3-(3-arylacryloyl) quinolin-2(1H)-ones (1a–f). The compounds 2a–f were found to form in lower yields since the reaction involves the formation of 3a–f also. The presence of electron releasing groups favours the formation of 2a–f in higher yields where as the presence of electron withdrawing groups favours the formation of 3d–f with the reaction conditions adapted in method A. But the method B results in 3-(4-styryl) isoxazolo[4,5-c] quinolin-4(5H)-ones as the major product, from the obtained yield we can conclude that the presence of electron withdrawing groups favours the formation of 3a–f, Since the styryl double bond is stabilized by the presence of electron withdrawing groups and is unavailable for cyclization.