Acta Scientific Pharmacology

Research Article Volume 2 Issue 6

Synthesis of Some New Oxazine Compounds Derived from Phenols and Schiff Bases

Asmaa Saad Al-Tayar and Mohammad S Al-Ajely*

Chemistry Department, College of Education for Girls, Mosul University, Mosul, Iraq

*Corresponding Author: Asmaa Saad Al-Tayar and Mohammad S Al-Ajely, Chemistry Department, College of Education for Girls, Mosul University, Mosul, Iraq.

Received: April 23, 2021; Published: May 06, 2021

Abstract

  The implication of heterocyclic compounds in most of the drugs used in the market and the timely need for changing drugs due to the drug resistance encourage researchers to synthesis new heterocyclic compounds especially those with oxygen and nitrogen heteroatoms which according to recent FDA reports. They form of 90 percent as anti-tumor agent and about 75 percent of the other diseases. Accordingly in the present research new oxazine compounds have been synthesized from two routes. The first one by grinding technique using formaldehyde, aromatic amines and methanolic ammonia to the synthesis of compounds (A1-5) as a one pot three components reaction system. The second route including the condensation of some aryl aldehydes with antharanilic acid (A6) then the resulting Schiff bases (A7-11) were cyclized using acetic anhydride into the corresponding oxazine compounds (A12-16) This type of reaction including the loss of a molecule of acetic acid molecules from (the solvent)anhydride. The anhydride containing the evolved acetic acid was used several times for some more reaction samples keeping its efficiency during the cyclization process. All the synthesized oxazines were studied using IR,1 HNMR methods and are discussed.

Keywords: Synthesis; Oxazine Compounds; Phenols and Schiff Bases

Introduction

  As it was mentioned above concerning the importance of hetero cyclic compounds as drug or co-drug compounds. Researchers always provides the market with new drug discovery research leading into new drug product. Oxazine compounds have proved to be used as drug according the works of many researchers. The synthesis of this type of heterocyclic compounds were achieved from different precursors, Either from antharanilic acid and its derivatives by ring closure either by acetic anhydride [1,2] or by chloro acetyl chloride [3] or succinic anhydride [3] or by alkyl chloro acetate [4] and ethyl ester derivatives [5] for example cyano ethyl ester. There were another methods for the synthesizing of oxazine compounds from other than antharanilic acid [6-11] among these precursors are the amido salicylate [12,13] cyclized by different reagents [14-17] some were cyclized using Vilsmeier-Haack reaction. The cyanate derivative were also cyclized into oxazine [18-21]. It was reported in the literature that cyanate derivatives of antharanilic acid when allowed to react with amino acid esters afforded the quinazoline derivatives and these compounds showed a biological effects in which the water solution of these compounds had HLE and human sputum elastase activities [22,23]. The above work encourage many researchers to develop new synthetic pathways in synthesizing this type of heterocyclic compounds. So Anilkumar. R. has published the synthesis of some oxazine compounds from antharanilic acid. These compounds have showed anti-inflammatory activities [24]. Osman and his co-workers have synthesized oxazine compounds from antharanilic acid containing sulfonic ester moiety, These compounds have been tested against Bacillus Thuringenesis and Klebseilla Pneumonia and showed remarkable activity against these micro organisms [25]. James D. Patronea and his co-workers have prepared 4-Bromo-2-(3-(N-(3,4-dichlorophenyl) sulfamoyl)-4-methyl benzamido) benzoic which is a derivative of antharanilic acid. This compound was found to be active toward inhibition the Replication of Protein A (RPA) which is specific in distribution of proten-proten interaction that make them as therapeutic cancer target [26]. Guhufran has synthesized aroyloxy oxazines from antharanilic acid. She tested these compounds against Gram +ve and Gram -ve bacteria and got excellent screening effects [27,28]. Among the studied oxazines derived from phenols are the work of Zuhal et-al. whom they prepared oxazines and studied their medical applications [29]. In 2014 Mathew and co-workers have prepared cromino oxazine from hydroxyl cromine and 7-hydroxy 4-methyl-2- thio coumarin and screening these compounds against some micro organism in vivo and in vitro studies [30]. Fadia and here co -workers have synthesized some coumarin compounds from resorcinol and ethyl aceto acetate using pole styrene sulfonic acidAmberlyst-15) as catalyst via Pechmann condensations [31]. Monar and co-workers have synthesized some coumarin derivatives and studied Antioxidant Activity Using ABTS Inhibition, their protective activity against DNA damage induced by the bleomycin-iron complex [32].

  Pradeep K., et al. have synthesized some 1,3-oxazine compounds, These compounds were used in the synthesis of Cephalandole A an anti -cancer indole type compounds with 80% yield [33]. Dhafer., et al. recently have published a review on the synthesis and biological applications of oxazine compounds [34]. Çigdem Özen and co-workers have studied the action of some 1,4-oxazines as DNA strand repairing agent [35]. 84.             S. Ondrej and H. Richard have studied poly(oxazine)s of phenolic precursors and the found that this polymer can be used as drug carrier an alternative PEG and poly (N-hydroxypropylmethacrylamide) usually used in the market nowadays [36] in our study we used two different methodologies in the synthesis of oxazine compounds aiming to study there biological effects in our drug discovery program.

Experimental

  All melting points were uncorrected using electro thermal type SMP30 UK melting point apparatus. IR spectra were measured using Alpha (ATR) instrument. 1HNMR spectra were recorded using Varian Agilent Type 499.53MHZ, DMSO as internal solvent. All chemical were supplied by Sigma- Aldrich and Fluka chemical companies. 7-hydroxy-4-methylcoumarin-8-carbaldehyde was prepared according to the well-known procedure [37]. 2-Chloro-3-formyl quinolone was also prepared according to the well-established procedure [38].

Synthesis of oxazine compounds(A1-5) General procedure

  Following the same published procedure [39] Formaldehyd (0.2 ml), ZrOCl2. 8H2O, (0.2 mol., 5.8g), Aromatic amine (0.1mol) and Euginol or 1-Naphtol (0.1 mol) were mixed together in ceramic mortar and pistil. The mixture were grinded for30 minutes, dichloromethane about 25 mil. was then added. The organic layer was then separated, washed with brine then with water twice and dried over MgSO4 anhydrous. Evaporation of the solvent affords the crude products of the titled compounds. Crystallization from ethanol gave pure product. The physical properties were listed in figure 1.

Figure 1: Physical properties of compounds(A1-5).

Synthesis of 2-carboxy aryldine aniline(A7-11) General procedure:

  These compounds were synthesized following an elsewhere published procedure [40] with some modification on the method. So Aromatic aldehyde (0.01 mol.), antharanilic acid (0.01 mol.) were mixed together after that methanol (15 ml.) was then added and two drops of glacial acetic acid. The final mixture was refluxed for one hour. And monitored by TLC, solvent was evaporated under reduced pressure. The resulted final product was recrystallized. The physical properties were shown in figure 2.

Figure 2: Physical properties of compounds(A7-11).

Synthesis of compounds (A12-16)

  The products of the previous method was dissolved in acetic anhydride, then it was refluxed for 3hours. The solvent was removed under reduced pressure and re used again for the rest of compounds. The final product was recrystallized from methanol. The physical properties of the final compounds were shown in figure 3.

Figure 3: Physical properties of compounds(A12-16).

Results and Discussion

Using grinding technique compounds (A1-5) were prepared Scheme1 and were characterized by the combination of IR and1H NMR methods as follows:

Figure a

N-4-Nitro phenyl-6- [(1-propenyl)-7-methoxy] [3,-e] benzoxazine A1

  IR cm-1: 1600,1529 for C=C Aromatic, 1262, 1142 C-O-C, 1498, 1230 for asym and sym. stretch for NO2, 1HNMR(ppm); 3.3(d,2H) for eugenol aliphatic protons, 4.7,5 (d,t2H) alkene protons, 3.78 (s,3H) OCH3, 4.9, 6(d of d 4H) AB aromatic., 6.79(s,2H) aromatic, 8.02-8.1(d,2H) AB pro tons near NO2 group.

N-2-Nitrophenyl-6- [(1-prppylenyl)-7 methoxy [3,1-e] benzoxazine A2

  IR cm-1: 1611,1590,1505 for C=C Aromatic,1136, 1197 f or C-O-C, 1440, 1277 for aSym and sym. stretch forNO2, 1HNMR(ppm); 3.3(d,2H) of eugenol,3.7(s,3H) of OCH3, 4.6(s,2H) for CH2N of Oxazine 4.7(2H) of CH2 euginol, 6.7(s,2H) for OCH2N of oxazine, 7.1-7.7(m,4H), 7.73(s,d2H) aromatic protons and ortho protons to the NO2 group respectively.

N-2-Bromophenyl-6- [91-propenyl-7-mothoxy] [3,1-e]benzoxazine A3

  IR cm-1: 3011 for C-H, 1617 for C=C, 16051 C=C, 1507 for C=C Aromatic, 1HNMR(ppm); 3.32 (d,2H) CH2 of eugenol aliphatic protons, 3.3 (s,3H) OCH3, 4.9(t,1H) olefinic proton, 4.7 5and5 (t,2H) for olefinic CH2 protons.

N-4-Chlorophenyl-6-(3-methyl) [3,1-e] Cumarinyl oxazine A4

  IR cm-1:3080 forC-H,1792 for C=O lactone, 1662 for C=C, 1596, 1541 for C=C Aromatic, 1451, 1260 for asym and sym. NO2, 1388, 1260 for C-O-C, 1213 for C-N, 1HNMR(ppm); 2.3 (s,3H) CH3, 2.6(s,2H) C5 of coumarin ring, 4.8(s,2H) C4 oxazine ring, 6.13(s,2H)C2 oxazine, 7.13,7.12 (d,2H) A protons Of AB system, 6.8, 7.0(d,2H) of B type protons.

N—Thiazolyl [3,1-e [naphthaoxazine] A5

  IR cm-1: 3022 for C-H, 1647, 1635 for C=N, 1596, 1577 for C=C aromatic,1318 for C-N, 752 for C-S, 1HNMR(ppm); 3.35(s,2H) –CH2N, 4.92(s,2H) for- OCH2, 6.5, 6.8(d,2H) thiazole, 6.88-7-8(m,6H) aromatic.

Schiff bases compoundsA7-11, Scheme 2. were characterized by the mainIR absorption peaks at1605cm-1for aromatic, C=C aromatic and at 1330 cm-1 for C-O.

Figure b

Figure c

Compounds A 12-16 as shown above in scheme2.were characterized as follows :

N-acetyl-2- [5-methyl-7-acetoxy cumarin-8-yl] [3,1benzoxazine-2-one A12]

  • IR cm-1: 2926 for C-H, 1792for C=O lactone, 1746,1716 for ester, 1696 for C=O amide, 1600, 1540 Aromatic, 1HNMR(ppm);
  • 9(s,3H) CH3CON, 2.3(s,3H)for - CH3, 2.4(s,3H) forCH3 COO, 6.43(d1H) C3 of coumarin proton, 7.1(d,1H) for C4, 7.4-8 (m,6H) Aromatic.

N-Acetyl-2-(2-fury) [3,1]benzoxazine-4-one A13

  IR cm-1: 2927 for C-H, 1771f or C=O lactone, 1665 for C=O amide, 1490, 1608 for C=C Aromatic, 1339, 1145 for C-O-C, 1HNMR; 2.2(s,3H) CH3CO, 6.6,6.9 (d,2H) furan protons, 7.54(d,1H) furan proton, 7.64-7.9 (m,4H) aromatic, 8.0(s,1H0 for oxazine protons.

N-Acetyl-2-(2-Chloro quinolin-2-yl) [3,1-e] benzoxazine-4-one A14

  3056 for C-H, 1733 for ester, 1668 for C=O amide, 1637 for C=N, 1606, 1507 for C=C aromatic, 788 f or C-Cl, 1HNMR(ppm); 2.1(s,3H) for CH3CO, 7.1-8 (m9H) aromatic, 8.47 (s,1H) for C2 oxazine ring.

N-Acetyl-2-(methoxy phenyl-2-yl) [3,1]benzoxazine -4-oneA15

  IR cm-1: 3056 for C-H, 1685 for C=O lactone, 1653 for C=O amide, 1606, 1540 for C=C aromatic, 1143 for C-O,1HNMR(ppm); 2.1(s,3H) for CH3CON, 2.3(s,3H), 3.17(s,3H) for OCH3, 7.1-7.9(m,7H) aromatic, 8.4 (s,1H) C2 of oxazine ring proton.

N-Acetyl-2-(2-methoxy phenyl) [3,1-e] benzoxazine-4-one A16

  IR cm-1: 1771, C=O lactone 1684 for C=O Amide, 1646 for C=O amide, 1600, 1541 for C=C Aromatic,776 for C-Cl, 1HNMR(ppm); 2.1 (s,3H) for CH3CO, 2.3(s,3H) for CH3COO, 3.8(s,3H) for OCH3, 6.9, 7.13, 7.4(d and singlet) 3H of vanilin residue protons, 7.6,7.9 and 7.99(m,4H) aromatic protons of benzoxazine ring. It is with to note that this work is extension to our previous work [44-46]. So adding new moiety for oxazine ring which is vanillin and nitrogenous residue will might increase the biological effects. We know that vanillin itself known to have antioxidant properties and oxazines also known to have versatile biological applications so making a combination of both may cause to improve the therapeutic impact of this type of compounds.

Conclusions

  In conclusion to the above work it is clear that using one pot three component system and two steps cyclization reaction of antharanilic acid with some aromatic aldehydes resulted into the formation of new oxazine derivatives. The IR and 1HNMR studies of the above studied compounds revealed it formation through their structures confirmations. The other step of study will be their biological study which is our next goal.

Acknowledgement

  The authors would like to thanks the Ministry of higher and research, university of Mosul and dean of our college for providing the facilities to do this work which is part of Asmaa thesis.

References

  1. R Arora., et al. “Synthesis of substituted 2‐ethyl‐3‐ (4‐hydrazinocarbonylphenyl)‐4‐quinazo‐lones and 2‐ethyl‐3‐ (4‐hydrazinocarbonylmethylphenyl)‐4‐quinazolones”. Journal of Heterocyclic Chemistry 15 (1978): 869.
  2. S Bahadur., et al. “Synthesis and antimicrobial evaluation of some new n-substituted benzylidene-6,8-substituted-2-ethyl-quinazolin-4-oxyacetic acid hydrazides”. Current Science 52 (1983): 910.
  3. A Krantz and J Young. U.S. Patent 4873232 112 (1989): 157888. 1989.
  4. A Essawy., et al. Indian Journal of Chemistry 21B (1982): 593.
  5. R Srivastava. Journal of the Indian Chemical Society 60 (1983): 610.
  6. J Mayer., et al. “Solid phase synthesis of quinazolinones”. Tetrahedron Letter 38 (1997): 8445-8448.
  7. T Vandana., et al. “Novel oxazine skeletons as potential anti plasmodial 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 Chemistry4 (2011): 569-578.
  8. G Chaitra and RM Rohini. “Synthesis of 1,3-Oxazine derivative from Chalcone and Screening for their Anti-Oxidant and Anti-Inflammatory activity”. International Research Journal of Pharmaceutical and Biosciences 6 (2018): 19-27.
  9. J Gilmore., et al. Bioorganic and Medicinal Chemistry Letters 6 (1996): 679.
  10. M Kerdawy., et al. Egyptian Pharmaceutical Journal 1-6 (1994): 1.
  11. H Istvan., et al. Journal of Heterocyclic Chemistry 30 (1993): 1413.
  12. G Fenton., et al. Journal of Medicinal Chemistry 32 (1989): 265.
  13. D Catarzi., et al. Journal of Medicinal Chemistry 38 (1995): 1330.
  14. V Balsubr Tang., et al. “Synthesis and Fungicidal Activity of Novel 2,3-Disubstituted-1,3-benzoxazines”. Molecules 17 (2012): 8174-8185.
  15. T Belz., et al. “Synthesis Characterization and Antibacterial, Antifungal Activity of N- (Benzyl Carbamoyl or Carbamothioyl)-2-hydroxy Substituted Benzamide and 2-Benzyl Amino-Substituted Benzoxazines”. International Journal of Medicinal Chemistry (2013): 1-20.
  16. D Rahul Kamble., et al. “Green synthesis and in silico investigation of dihydro-2H-benzo [1,3]oxazine derivatives as inhibitors of Mycobacterium tuberculosis”. Medicinal Chemistry Research 24 (2014): 1077-1088.
  17. R Mazurkiewicz. “Synthesis and rearrangement of 4-imino-4H-3,1-benzoxazines”. Organische Chemie Und Biochemie 120 (1989): 973-980.
  18. MS Al-Jelly. “Synthesis and Atiplatelet of 2- (ethyl amino acid esters), Amino pyridyl”. Journal of Advances in Chemistry2 (2013): 92-97.
  19. Y Uejima., et al. “Inhibition of human sputum elastase by 7-substituted 5-methyl-2-isopropylamino-4H-3,1-benzoxazin-4-ones”. Biochemistry and Pharmacology2 (1994): 426-428.
  20. R Vaid., et al. Indian Journal of Chemistry B 26 (1987): 376.
  21. R Anilkumar. Synthesis, characterization and biological activity of 1,3-benzoxazine derivatives. Msc. pharmacy thesis, Rajiv Gandhi University of health science. Karnataka. Bangalore. India (2011).
  22. A Mohamed Abd-Elhakeem and M Ahmed Elsayed. “Synthesis and antimicrobial activity of some new 2,3-disubstituted quinazoline-4 (3H)-ones derivatives”. Journal of Chemical and Pharmaceutical Research 5 (2013): 275-279.
  23. A Mohamed Abd-Elhakeem and M Ahmed Elsayed. “Synthesis and antimicrobial activity of some new 2,3-disubstituted quinazoline-4 (3H)-ones derivatives”. Journal of Chemical and Pharmaceutical Research5 (2013): 275-279.
  24. JD Patrone., et al. “Identification and Optimization of Anthranilic Acid -Based Inhibitors of Replication Protein A”. ChemMedChem8 (2016): 893-899. 2016.
  25. R Anilkumar. Synthesis, characterization and biological activity of 1,3-benzoxazine derivatives. Msc. pharmacy thesis, Rajiv Gandhi University of health science. Karnataka. Bangalore. India (2011).
  26. M Osman O., et al. “Studies on Some Benzoxazine-4-one Derivatives with Potential Biological Activity”. American Journal of Organic Chemistry3 (2012): 45-51.
  27. JD Patrone., et al. “Identification and Optimization of Anthranilic Acid -Based Inhibitors of Replication Protein A”. ChemMedChem8 (2016): 893-899.
  28. G Sadeek., et al. “New Approach for the Synthesis of Aryloxy 1,3-Oxazines”. Journal of Material Sciences and Manufacturing Research2 (2020): 1-5.
  29. G Sadeek. Synthesis of some heterocyclic compounds ( oxazines) and the study of their biological activities, PhD. Thesis, Mosul university Mosul-Iraq (2021).
  30. T Zuhal., et al. “Synthesis of New 1,3-Disubstituted-2,3-dihydro-1H-naphth- [1,2e] [1,3]oxazines”. Molecules 12 (2010): 345-352.
  31. P Bijoy Mathew., et al. “Synthesis and anti-bacterial activity of novel dihydrochromeno [8, 7-e] [1, 3] oxazine-2 (8H)-thiones”. Journal of Sulfur Chemistry 35 (2014): 31-41.
  32. H Fadia., et al. “Synthesis and Nitration of 7-Hydroxy-4-Methyl Coumarin via Pechmann Condensation Using Eco-Friendly Medias”. International Letters of Chemistry, Physics and Astronomy 69 (2016): 66-73.
  33. A Mounir., et al. “Synthesis and Characterization of Some New Coumarins with In Vitro Antitumor and Antioxidant”. Molecules 21 (2016): 249.
  34. K Pradeep Jaiswal., et al. “On water” ultrasound-assisted one pot efficient synthesis of functionalized 2-oxo-benzo [1,4]oxazines: First application to the synthesis of anticancer indole alkaloid, Cephalandole A”. Tetrahedron Letter (2017).
  35. S Dhafer., et al. “Medicinal chemistry of oxazines as promising agents in drug discovery”. Chemical Biology and Drug Design (2019): 1-32.
  36. E Foto and Ç Özen. “Benzoxazines as new human topoisomerase I inhibitors and potential poisons. DARU”. Journal of Pharmaceutical Science 28 (2019): 65-73.
  37. S Ondrej and H Richard. “Drug delivery systems based on poly (2-oxazoline)s and p (2-oxazine)s”. Advanced Therapeutics1 (2020).
  38. S Jamal., et al. “Synthesis and characterization of new coumarin derivatives containing various moieties with antibacterial activities”. International Journal of Pharmacy and Pharmaceutical Sciences8 (2015): 70-74.
  39. R Aju nandha Kumar., et al. “Isolation of 2-chloro-3-formyl-2- (2-hydroxyethene-1-yl) quinolines by Vilsmeier Haack reaction on quinaldines: Construction of diazepino quinoline heterocycles and their antimicrobial and cytogenetic studies”. Acta Pharmaceutica 53 (2003): 1-14.
  40. Al-Ajely Mohammad S and A M Noori. “An Efficient and Solvent Free Synthesis of N-Aryl 2,3-Dihydro-4H naphtho- [2,1-e] 1,3-oxazines”. Journal of Biomedical Science3 (2020).
  41. F Nikpour., et al. “A Facile and Convenient Synthesis of N-acetyl-2-aryl-1,2-dihydro- (4H)-3,1-benzoxazine-4-ones from the Reaction of Anthranilic Acid Derivatives with Aryl Aldehydes”. Chemistry Letters 8 (2007).
  42. Al-Ajely and H Noori. “Synthesis of New Oxazin Compounds derived from Furfural, Chalcons and Schiff Bases”. Journal of Pharmacology and Clinical Research3 (2019): 66-71.
  43. Al-Ajely and H Norri. “An Efficient and Solvent Free Synthesis of N-Aryl 2,3-Dihydro-4H naphtho- [2,1-e] 1,3-oxazines”. Bio Medical Journal of Scientific and Technical Research3 (2020): 22510-22516.
  44. ST Ghufran., et al. “New Approach for the Synthesis of Aryloxy 1,3-Oxazines”. Journal of Material Sciences and Manufacturing Research2 (2020): 1-5.
  45. ST Ghufran., et al. “Synthesis of Some Oxazine Compounds Derived from TDI and Schiff Bases”. Acta Scientific Medical Sciences 9 (2020): 20-28.
  46. ST Ghufran., et al. “Synthesis of some oxazine compounds derived from phenols and 8-hydroxy quinolone”. Solid State Technology5 (2020): 3179-3190.

Citation

Citation: Asmaa Saad Al-Tayar and Mohammad S Al-Ajely. “Synthesis of Some New Oxazine Compounds Derived from Phenols and Schiff Bases".Acta Scientific Pharmacology 2.6 (2020): 04-09.

Copyright

Copyright: © 2021 Asmaa Saad Al-Tayar and Mohammad S Al-Ajely. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.




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