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Research Article
The Open Access Journal of Science and Technology
Vol. 2 (2014), Article ID 101056, 7 pages
doi:10.11131/2014/101056

Greener, Simple and Efficient Synthesis of Some Oxazine-2-amine Derivatives by Preheated Fly-Ash Catalyzed Cyclization of Aryl Chalcones under Solvent-Free Conditions

G. Thirunarayanan

Department of Chemistry, Annamalai University, Annamalai Nagar 608002, India

Received 3 December 2013; Accepted 15 March 2015

Academic Editor: Rafik Karaman

Copyright © 2014 G. Thirunarayanan. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

To synthesize some aryl oxazine amines including 4-(4-methoxy-1-naphthyl)-6-(substituted phenyl)-4H-5,6-dihydro-1,3-oxazine-2-amines by preheated fly-ash catalyzed solvent-free cyclization of aryl chalcones and urea under microwave irradiation, the yields of the oxazines were more than 50%. These oxazine imines were characterized by their physical constants and spectroscopic data.

1. Introduction

Compounds containing one oxygen and one nitrogen atom in the six membered heterocyclics are known as unsaturated 1,3-oxazine or generally oxazines [1,2]. These oxazine molecules include many isomeric structures such as 1,2 or 1,3 or 1,4 oxazine types [3] depending upon the relative position of these tow atoms and the double bond. These oxazines were medicinally important due to the presence of oxygen and nitrogen heteroatoms along with a double bonds in their structural moieties [4]. The important medicinal activities of these oxazine derivatives are anti-bacterial [4,5], anti-fungal [4,5,6], anti-plasmodial [7], anti-cancer [8], anti-depressants [9], cytotoxicity [10], anti-osteoplastic [11], anti-tumour [12], anti-oxidant [13], anti-tuberculosis [14], anti-neoplastic [15], antagonists [16], anti-inflammatory [17], anti-infectants [18], IKB kinase beta [19] and PTP-1B inhibition [20]. These oxazine derivatives were applied for improving the super resolution microscope [21], synthesis of eosinophils [22], and identification and separation of neutrophils [23]. Many oxazine derivatives were used as a dyes [24]. Numerous solvent assisted and solvent-free synthetic methods were available for synthesis of oxazine derivatives [25]. Nowadays scientists, organic chemists, are interested in solvent-free synthesis [6,26,27,28,29,30]. Some reactions such as hetero Diels-alder reaction [4], ring closure [31], Betti base induced condensation [32], Mannich type condensation-cyclization [6] and cyclization of chalcones[5] were used for synthesis of oxazine derivatives. Verma et al. [26] have synthesised some benzoxazine/oxazine fused isoquinolines and naphthyridines by solvent-free method. Elarfi and Al-Difar [5] have synthesised some 1,3-oxazine derivatives by solvent-assisted method from chalcones and urea. More than 75% yield of dihydro-2H-benzo- and naphtho-1,3-oxazine derivatives were prepared by [6] using eco-friendly method. Efficient synthesis of some 1,3-oxazine-4-thiones were synthesised by N-methyl imidazole promoted solvent-free conditions. Sapkal et al. have studied the role of ammonium acetate for solvent-free synthesis of 1,3-disubstituted-2,3-dihydro-1H-naphthyl oxazines[31]. Within the above view, there is no information available in the literature for the solvent-free synthesis of 4-methoxy-1-naphthyl based oxazine-2-amine derivatives. Therefore the author has taken effort to synthesize some 4-methoxy-1-naphthyl based oxazine amines characterized by their analytical and spectral data.

2. Materials and Methods

2.1. General

All chemicals used in this present study were purchased from Sigma-Aldrich and Merck Chemical companies. Mettler FP51 melting point apparatus was used for determining the melting point of all synthesized oxazines in open glass capillaries and uncorrected. The AVATAR-300 Fourier transform spectrophotometer was used for recording infrared spectra (KBr, 4000–400 cm−−1) of all oxazines in KBr disc. The Bruker AV400 series type NMR spectrometer was utilized for recording NMR spectra of all oxazines, operating at 400MHz for 1H and100 MHz for 13C spectra in CDCl3 solvent using TMS as internal standard. Mass spectra of all synthesised oxazines were recorded on SHIMADZU mass spectrometer using chemical ionization technique.

2.2. Preparation of preheated fly-ash [33]

The fly-ash was heated on hot air oven at 110C for 2h. During heating demoisturising takes place. This preheating helps avoiding colloidal formation during the reaction.

2.3. Synthesis of 4-(aryl)-5,6-dihydro-6-(substituted phenyl)-4H-1,3-oxazine-2-amines

Equimolar quantities of chalcones (2 mmol), urea (2mmol) and 0.4 g of preheated fly-ash were taken in a 50 mL beaker, closed with the lid. This mixture was subjected to microwave irradiation for 2–4 minutes at 650W (Scheme 1) (Samsung, Microwave Oven, 100–700W). After completion of the reaction, dichloromethane (20 mL) was added, followed by simple filtration. The solution was concentrated and purified by recrystallization. The synthesized oxazines were characterized by their physical constants, IR, 1H, and 13C NMR and Mass spectral data. Analytical and mass spectral data are presented in Table 1.

Sch1
Scheme 1: Synthesis of 4-aryl-5,6-dihydro-6-(substituted phenyl)-4H-1,3-oxazine-2-amines by preheated fly-ash catalyzed cyclization of aryl chalcones and urea under microwave irradiation.
T1

Table 1: Analytical, physical constants, yield and mass fragment of 4-aryl-5,6-dihydro-6-(substituted phenyl)-4H-1,3-oxazine-2-amines.

3. Results and Discussion

The author attempts to synthesize oxazine derivatives by cyclization of chalcones possessing electron withdrawing as well as electron donating group as substituents, urea and in the presence of acidic catalyst preheated fly-ash using microwave irradiation. Hence the author has synthesized some substituted 1,3-oxazine derivatives by the cyclization of 2 mmole of chalcone, 2 mmole of urea under microwave irradiation with 0.4g of preheated fly-ashcatalyst at 550W for 4-6 minutes (Samsung Grill, GW73BD Microwave oven, 230V A/c, 50Hz, 2450Hz, 100-750W (IEC-705), (Scheme 1)). During the course of this reaction preheated fly-ash catalyses cyclization between chalcones and urea followed by rearrangement gave the 1,3-oxazine amines. The yields of the oxazine in this reaction are more than 80%. The chalcone containing electron donating substituent (OCH3) gave higher yields than electron-withdrawing (halogens, NO2) substituents. Further we have investigated this cyclization reaction with equimolar quantities of the styryl 4-methoxy-1-naphthyl ketone (entry 11 ) and urea under the same condition as above. In this reaction the obtained yield was 60%. The effect of catalyst on this reaction was studied by varying the catalyst quantity from 0.1 g to 1 g. As the catalyst quantity is increased from 0.1 g to 1 g, the percentage of yield of product is increased from 52 to 60%. Considering further increase in the catalyst amount beyond 0.4 g, there is no significant increase in the percentage of the product. The effect of catalyst loading is shown in Figure 1. The optimum quantity of catalyst loading was found to be 0.4 g. The reusability of this catalyst was studied for the cyclization of styryl 4-methoxy-1-naphthyl ketone and urea (entry 11) is presented in Table 2. From Table 2, first two runs gave 60% product. The third, fourth and fifth runs of reactions gave, respectively, the yields 59.5%, 59.5% and 59% of oxazines. There was no appreciable loss in its effect of catalytic activity observed up to fifth run. The effect of solvents on the yield was also studied with methanol, ethanol, dichloromethane and tetrahydrofuran from each component of the catalyst (entry 11). Similarly the effect of microwave irradiation was studied on each component of the catalyst. The effect of solvents on the yield of oxazine derivatives was presented in Table 3. From the table highest yield of oxazine is obtained from the cyclization of chalcones and urea with the catalyst preheated fly-ash in microwave irradiation. The infrared and nmr spectroscopic data of these oxazine-2-amines are summarized in Table 4.

F1
Figure 1: The effect of catalyst loading.
T2

Table 2: Reusability of preheated fly-ash catalyst on cyclization of styryl 4-methoxy-1-naphthyl ketone (2 mmol) with urea (2 mmol) under microwave irradiation(entry 11).

T3

Table 3: The effect of solvents in conventional heating and without solvent in microwave irradiation on yield of oxazine amine (entry 11).

4. Conclusions

Some oxazine-2-amine derivatives including 4-(4-methoxy-1-naphthyl)-5,6-dihydro-6- (substituted phenyl)-4H-1,3-oxazine-2-amines have been synthesised by solvent-free cyclization of aryl chalcones and urea in presence of preheated fly-ash catalyst undermicrowave irradiation. This synthetic methodology offers solvent-free cyclization, nonhazardous, shorter reaction time, easy-workup procedure and better yields. The analytical and spectral data were supported for these oxazine derivatives.

T4

Table 4: Infrared and NMR spectroscopic data of 4-aryl-5,6-dihydro-6(substituted phenyl)-4H-1,3-oxazine-2-amines.

Acknowledgement

The author thank DST NMR facility, Department of Chemistry, Annamalai University, Annamalai Nagar 608 002, India, for recording NMR spectra of compounds.

References

  1. A. Banerjee, S. Ganguly, T. Chattopadhyay, K. S. Banu, A. Patra, S. Bhattacharya, E. Zangrando, and D. Das, Metal-assisted oxazolidine/oxazine ring formation in dinuclear Zinc(II) complexes: Synthesis, structural aspects, and bioactivity, Inorganic Chemistry, 48, no. 18, 8695–8702, (2009). Publisher Full Text | Google Scholar
  2. P. Jacob III, N. L. Benowitz, L. Yu, and A. T. Shulgin, Determination of nicotine N-oxide by gas chromatography following thermal conversion to 2-methyl-6-(3-pyridyl)tetrahydro-1,2-oxazine, Analytical Chemistry, 58, no. 11, 2218–2221, (1986).
  3. I. P. Yakovlev, A. V. Prep'yalov, and B. A. Ivin, Unsaturated 4H-1,3-oxazines (review), Chemistry of Heterocyclic Compounds, 30, no. 3, 255–271, (1994). Publisher Full Text | Google Scholar
  4. M. K. Manjula, K. M. L. Rai, S. L. Gaonkar, K. A. Raveesha, and S. Satish, Synthesis of new series of 5,6-dihydro-4H-1,2-oxazines via hetero Diels-Alder reaction and evaluation of antimicrobial activity, European Journal of Medicinal Chemistry, 44, no. 1, 280–288, (2009). Publisher Full Text | Google Scholar
  5. P. Jacob III, N. L. Benowitz, L. Yu, and A. T. Shulgin, Determination of nicotine N-oxide by gas chromatography following thermal conversion to 2-methyl-6-(3-pyridyl)tetrahydro-1,2-oxazine, Analytical Chemistry, 58, no. 11, 2218–2221, (1986).
  6. B. P. Mathew, A. Kumar, S. Sharma, P. K. Shukla, and M. Nath, An eco-friendly synthesis and antimicrobial activities of dihydro-2H-benzo- and naphtho-1,3-oxazine derivatives, European Journal of Medicinal Chemistry, 45, no. 4, 1502–1507, (2010). Publisher Full Text | Google Scholar
  7. V. Tiwari, J. Meshram, P. Ali, J. Sheikh, and U. Tripathi, Novel oxazine skeletons as potential antiplasmodial active ingredients: Synthesis, in vitro and in vivo biology of some oxazine entities produced via cyclization of novel chalcone intermediates, Journal of Enzyme Inhibition and Medicinal Chemistry, 26, no. 4, 569–578, (2011). Publisher Full Text | Google Scholar
  8. B. C. Das, A. V. Madhukumar, J. Anguiano, and S. Mani, Design, synthesis and biological evaluation of 2H-benzo[b][1,4] oxazine derivatives as hypoxia targeted compounds for cancer therapeutics, Bioorganic and Medicinal Chemistry Letters, 19, no. 15, 4204–4206, (2009). Publisher Full Text | Google Scholar
  9. D. Zhou, B. L. Harrison, U. Shah, T. H. Andree, G. A. Hornby, R. Scerni, L. E. Schechter, D. L. Smith, K. M. Sullivan, and R. E. Mewshaw, Studies toward the discovery of the next generation of antidepressants. Part 5: 3,4-Dihydro-2H-benzo[1,4]oxazine derivatives with dual 5-HT1A receptor and serotonin transporter affinity, Bioorganic and Medicinal Chemistry Letters, 16, no. 5, 1338–1341, (2006). Publisher Full Text | Google Scholar
  10. S. Wang, Y. Li, Y. Liu, A. Lu, and Q. You, Novel hexacyclic camptothecin derivatives. Part 1: Synthesis and cytotoxicity of camptothecins with an A-ring fused 1,3-oxazine ring, Bioorganic and Medicinal Chemistry Letters, 18, no. 14, 4095–4097, (2008). Publisher Full Text | Google Scholar
  11. Y. Ando, K. Ando, M. Yamaguchi, J. Kunitomo, M. Koida, R. Fukuyama, H. Nakamuta, M. Yamashita, S. Ohta, and Y. Ohishi, A novel oxazine ring closure reaction affording (Z)-((E)-2-styrylbenzo[b]furo[3,2-d][1,3]oxazin-4-ylideno)acetaldehydes and their anti-osteoclastic bone resorption activity, Bioorganic and Medicinal Chemistry Letters, 16, no. 22, 5849–5854, (2006). Publisher Full Text | Google Scholar
  12. L. Benameur, Z. Bouaziz, P. Nebois, M. Bartoli, M. Boitard, and H. Fillion, Synthesis of furonaphth[1,3]oxazine and furo[1,3]oxazinoquinoline derivatives as precursors for an o-quinonemethide structure and potential antitumor agents, Chemical and Pharmaceutical Bulletin, 44, no. 3, 605–608, (1996).
  13. K. Roy, I. Mitra, and A. Saha, Molecular shape analysis of antioxidant and squalene synthase inhibitory activities of aromatic tetrahydro-1,4-oxazine derivatives, Chemical Biology and Drug Design, 74, no. 5, 507–516, (2009). Publisher Full Text | Google Scholar
  14. A. Blaser, B. D. Palmer, H. S. Sutherland, I. Kmentova, S. G. Franzblau, B. Wan, Y. Wang, Z. Ma, A. M. Thompson, and W. A. Denny, Structure-activity relationships for amide-, carbamate-, and urea-linked analogues of the tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl] oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824), Journal of Medicinal Chemistry, 55, no. 1, 312–326, (2012). Publisher Full Text | Google Scholar
  15. L. Seal, D. Von Hoff, R. Lawrence, E. Izbicka, and R. M. Jamison, An in vitro assessment of the antineoplastic potential of 2H-1,3-Oxazine-2,6(3H)-dione (3-oxauracil), a novel pyrimidine, Investigational New Drugs, 15, no. 4, 289–293, (1997). Publisher Full Text | Google Scholar
  16. B. Brudeli, L. R. Moltzau, K. W. Andressen, K. A. Krobert, J. Klaveness, and F. O. Levy, Synthesis and pharmacological properties of novel hydrophilic 5-HT 4 receptor antagonists, Bioorganic and Medicinal Chemistry, 18, no. 24, 8600–8613, (2010). Publisher Full Text | Google Scholar
  17. M. Akhter, A. Husain, N. Akhter, and M. S. Y. Khan, Synthesis, antiinflammatory and antimicrobial activity of some new 1-(3-Phenyl-3,4-Dihydro-2H-1,3-Benzoxazin-6-yl)-ethanone derivatives, Indian Journal of Pharmaceutical Sciences, 73, no. 1, 101–104, (2011).
  18. D. Gothi and J. M. Joshi, Resistant TB: Newer drugs and community approach, Recent Patents on Anti-Infective Drug Discovery, 6, no. 1, 27–37, (2011). Publisher Full Text | Google Scholar
  19. K. Oh, S. Lee, J. K. Choi, and B. H. Lee, Identification of novel scaffolds for IκB kinase beta inhibitor via a high throughput screening TR-FRET assay, Combinatorial Chemistry and High Throughput Screening, 13, no. 9, 790–797, (2010). Publisher Full Text | Google Scholar
  20. S. Y. Cho, J. Y. Baek, S. S. Han, S. K. Kang, J. D. Ha, J. H. Ahn, J. D. Lee, K. R. Kim, H. G. Cheon, S. D. Rhee, S. D. Yang, G. H. Yon, C. S. Pak, and J. Choi, PTP-1B inhibitors: Cyclopenta[d][1,2]-oxazine derivatives, Bioorganic and Medicinal Chemistry Letters, 16, no. 3, 499–502, (2006). Publisher Full Text | Google Scholar
  21. S. F. Lee, Q. Vérolet, and A. Fürstenberg, Improved super-resolution microscopy with oxazine fluorophores in heavy water, Angewandte Chemie - International Edition, 52, no. 34, 8948–8951, (2013). Publisher Full Text | Google Scholar
  22. L. Kass, A selective stain for eosinophils using two oxazine dyes applied sequentially, Biotechnic and Histochemistry, 70, no. 1, 19–23, (1995).
  23. Kass, L.(1995). Identification of neutrophils with an oxazine dye. Biotech Histochem. 70(1), 29-33.
  24. C. Jung, B. K. Müller, D. C. Lamb, F. Nolde, K. Müllen, and C. Bräuchle, A new photostable terrylene diimide dye for applications in single molecule studies and membrane labeling, Journal of the American Chemical Society, 128, no. 15, 5283–5291, (2006). Publisher Full Text | Google Scholar
  25. MacMillan, J. H., & Washburne, S. S.: Detailed Synthetic Procedure for 4-(4-bromophenyl)-1,3(3H) Oxazine-2,6-Dione and related 4 and 5-aryl substituted -1,3(3H) Oxazine-2,6-Diones. Spectroscopic and analytical data are included. Temple University, http://www.archive.org. 2013.
  26. A. K. Verma, D. Choudhary, R. K. Saunthwal, V. Rustagi, M. Patel, and R. K. Tiwari, On water: Silver-catalyzed domino approach for the synthesis of benzoxazine/oxazine-fused isoquinolines and naphthyridines from o-alkynyl aldehydes, Journal of Organic Chemistry, 78, no. 13, 6657–6669, (2013). Publisher Full Text | Google Scholar
  27. M. A. Khalilzadeh, I. Yavari, Z. Hossaini, and H. Sadeghifar, N-Methylimidazole-promoted efficient synthesis of 1,3-oxazine-4-thiones under solvent-free conditions, Monatshefte fur Chemie, 140, no. 4, 467–471, (2009). Publisher Full Text | Google Scholar
  28. S. P. Sakthinathan, G. Vanangamudi, and G. Thirunarayanan, Synthesis, spectral studies and antimicrobial activities of some 2-naphthyl pyrazoline derivatives, Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 95, 693–700, (2012). Publisher Full Text | Google Scholar
  29. Sasikala, S., Thirumurthy, K., Mayavel, & P., Thirunarayanan, G.(2012). Eco-friendly synthesis and antimicrobial activities of some 1-phenyl-3-(5-bromothiophen-2-yl)-5-(substituted phenyl)-2-pyrazolines, Organic and Medicinal Chemistry Letters, doi:10.1186/2191-2858-2-20.
  30. G. Thirunarayanan, P. Mayavel, and K. Thirumurthy, Fly-ash:H2SO4 catalyzed solvent free efficient synthesis of some aryl chalcones under microwave irradiation, Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 91, 18–22, (2012). Publisher Full Text | Google Scholar
  31. S. B. Sapkal, K. F. Shelke, A. H. Kategaonkar, and M. S. Shingare, Dual role of ammonium acetate for solvent-free synthesis of 1,3-disubstituted-2,3-dihydro-1H-naphth-[1,2e] [1,3]-oxazine, Green Chemistry Letters and Reviews, 2, no. 2, 57–60, (2009). Publisher Full Text | Google Scholar
  32. Z. Turgut, E. Pelit, and A. Köycü, Synthesis of new 1,3-disubstituted-2,3-dihydro-1H-naphth-[1,2e][1,3] oxazines, Molecules, 12, no. 3, 345–352, (2007). Publisher Full Text | Google Scholar
  33. R. Arulkumaran, R. Sundararajan, S. Vijayakumar, S. P. Sakthinathan, R. Suresh, D. Kamalakkannan, K. Ranganathan, G. Vanangamudi, and G. Thirunarayanan, Solvent free synthesis, spectral correlation and antimicrobial activities of some 2E 4′-nitrochalcones, Journal of Saudi Chemical Society, (2012). Publisher Full Text | Google Scholar
Research Article
The Open Access Journal of Science and Technology
Vol. 2 (2014), Article ID 101056, 7 pages
doi:10.11131/2014/101056

Greener, Simple and Efficient Synthesis of Some Oxazine-2-amine Derivatives by Preheated Fly-Ash Catalyzed Cyclization of Aryl Chalcones under Solvent-Free Conditions

G. Thirunarayanan

Department of Chemistry, Annamalai University, Annamalai Nagar 608002, India

Received 3 December 2013; Accepted 15 March 2015

Academic Editor: Rafik Karaman

Copyright © 2014 G. Thirunarayanan. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

To synthesize some aryl oxazine amines including 4-(4-methoxy-1-naphthyl)-6-(substituted phenyl)-4H-5,6-dihydro-1,3-oxazine-2-amines by preheated fly-ash catalyzed solvent-free cyclization of aryl chalcones and urea under microwave irradiation, the yields of the oxazines were more than 50%. These oxazine imines were characterized by their physical constants and spectroscopic data.