Synthesis, Characterization and Biological Evaluation of some Novel  

1,3 Oxazepine derivatives from Vanillin Schiff’s Bases

 

Khudhayer J. Kadem, Murad G. Munahi

Department of Chemistry, College of Science, University of Babylon, Iraq

 

ABSTRACT:

A series of Schiff’s bases and their novel derivatives (Oxazepines) have been synthesized , 4-hydroxy-3-methoxy benzaldehyde (vanillin) was condensed with different amines to produce the Schiff’s bases in the presence of glacial acetic acid as a catalyst or KOH , novel five 1,3-oxazepine derivatives have been synthesized through reaction of Schiff’s bases with succinic anhydride and maleic anhydride using acidic catalyst. The identification was performed using, FT-IR and¹H-NMRspectroscopies. The synthesized1,3-oxazepine derivatives were biologically screened against gram positive (Staphylococcus aureus) and gram negative bacteria (Escherichia coli) . The results was showed excellent to moderate anti-bacterial activity.

 

 

 

INTRODUCTION:

Schiff’s bases are importantintermediates for synthesis of some bioactive compounds [1]. Schiff’s bases has been gained importance due to their application in several pharmacological activities like antibacterial [2], antifungal [3], antitumor [4],[5]. Oxazepine is unsaturated non-homologous seven membered heterocycle containing oxygen in position 1 and nitrogen in position 3 in addition to the five carbon atoms [6]. Oxazepine compounds have medicaland biological important [7] and they have medicinal and pharmaceutical application [8]. Among the wide chemical derivatives are a heteropolymer which have activity and effectiveness against cancer [9]. Oxazepine derivatives was found to exhibit a vast variety of biological activities like antibacterial [10], antifungal [11], hypnotic muscle relaxant [12], antagonistic [13] and anti-inflammatory [14].

 

EXPERIMENTAL:

All chemicals that used are obtained from Merck, Fluka and Aldrich companies without applying further purification. The uncorrected melting points were measured by using an (Electro thermal) melting point apparatus. FT-IR spectra were measured with SHIMADZU FTIR-4800S Infrared spectrophotometer by using KBr disk.¹ H-NMRspectra were recorded by using300MHz JNM ECP-600spectrometer and CDCl₃ or DMSO-d6was the solvent and tetramethylsilane, (TMS) was the internalstandard.

 

Synthesis of Schiff’s base (M1-M3):

The compounds ( M1-M3) were synthesized and spectrally investigated according to a reported method [15].

 

Synthesis of Schiff’s base ( M4):

 Into a round bottom flask (250 ml) containing 0.01 mol, 1.31gm of L-Lucien and 0.01 mol, 0.56 gm of KOH, 30 mlabsolute ethanol was added and stirred for 15 min, 20 ml absolute ethanol containing vanillin (0.01 mol, 1.52 gm) was drop wise added, and the mixture was refluxed for 4 h, the solution was reduced to half and allowed to cool, precipitate was obtained , filtered off, washed with small portion of ethanol and diethyl ether. The product was dried by CaCl₂ desiccator, recrystallized from methanol. m.p 117-119°C , Yield 76 % ,MW.303, FT-IR (ν,cm^-1):3414 ( phenolic OH); 1643 (C=N); 1585 (aromatic C=C); 1508, 1342 (asymmetric and symmetric –COOK); 1022, ( C-O-C).

 

Synthesis of Schiff’s base ( M5):

To a 250 ml round bottom flask containing 0.01 mol (1.52 gm) of vanillin dissolved in 25 ml absolute ethanol a 0.01 mol of diamino benzidinedissolved in 50 ml absolute ethanol (hot) was added, a few drops of glacial acetic acid was used as a catalyst and the reaction mixture was refluxed at 75 ⁰Cwith stirring for 3 h . After cooling at room temperature precipitate was formed, filtered off , washed with ethanol and diethyl ether , air dried and recrystallized from THF . m.p 260-262 °C, Yield 79 %, MW 750, FT-IR (ν, cm^-1): 3307(OH, phenolic); 1650( C=N); 1593 (C=C, aromatic); 1026 (C-O-C ).

 

General procedure for the Synthesis of 1,3-Oxazepine derivatives( M6-M10 )

 

A mixture of Schiff’s base (M6-M10) , ( 0.001 mol ) and equimolar amount of succinct anhydrideor maleic anhydridein 20 ml DMF ,( few drops of glacial acetic acid ) was heated at 70 ^oC for ( 8-10 h ) the solution was reduced by the rotary evaporator and allowed to cool at RT , the product was obtained by decantation, washed three times with small portions of DMF and diethyl ether , air dried and was recrystallized from a suitable solvents,

 

Compound M6:

m.p 181-183 ^oC; Yield 60% ; MW 422; FT-IR (ν, cm^-1): 3425 (OH, phenolic); 1735 (C=O, lactone); 1674 (C=O, lactam); 1598 (C=N, pyridine); 1558 (C=C, aromatic), ¹H-NMR ( DMSO-d6): δ(s, 9.4, 1H, phenolic OH), (m, 7.1-7.5, 8H, aromatic protons), (t,4.9, 1H, CH₂-CON-)  (t, 4.4, 1H, CH₂-COO-), (s, 3.6, 3H, -OCH₃).

 

Compound M7:

 m.p 270-272 ^oC; Yield 72% ; MW 468; FT-IR (ν, cm^-1): 3381(OH, phenolic );1733( C=O, ester); 1700(C=O, lactone); 1673(C=O, lactam); 1651(C=C, cyclic); 1556(C=C, aromatic ), ¹H-NMR ( DMSO-d6 ):δ( s, 9.6, 1H, phenolic OH), (m, 7.2 – 7.6, 7H, aromatic protons), (d, 6.7, 1H, = CH-CON- ), (d, 6.2, 1H, =CHCOO-), (t, 4.8, 2H, -OCH_2-) , ( s, 3.4, 3H, -OCH₃ ), (t, 2.9, 2H, -CH₂N ), (q , 2.2, 2H, -NCH₂-), (t, 1.1, 3H, -CH₃).

 

Compound M8:

m.p Dec > 300 ^oC; Yield 67%; MW 602; FT-IR (ν, cm^-1): 3331 (OH, phenolic); 1733(C=O lactone); 1672(C=O, lactam); 1597 (C=C, aromatic); 1541 and 1406( COO-, asymmetric and symmetric), ¹H-NMR (DMSO-d6): δ(s, 9.6, 1H, phenolic OH), (m, 6.5 – 7.9 13H, aromatic protons), (s, 5.6, 1H, C=NH) (t, 4.7, 1H, CH₂-CON-), (t, 4.3, 1H, CH₂-COO-), (s, 3.4, 3H, -OCH₃).

 

Compound M9:

m.p 323-325 ^oC; Yield 74%; MW 403; FT-IR (ν, cm^-1 ): 3422 (OH, phenolic); 1715(C=O, lactone); 1671( C=O, lactam); 1603(C=C, aromatic); 1535 and 1400 (COO-, asymmetric and symmetric), ¹H-NMR (DMSO-d6):δ(s, 9.6, 1H, phenolic OH), (m, 7.2-7.5, 3H, aromatic protons), (d, 6.6, 1H, = CH-CON-), (d, 6.5, 1H, = CHCOO-), (s, 3.4, 3H, -OCH₃), (t, 2.4-2.6, 1H, -CH-COOK), (m, 1.8-2.1, 1H, -CH-(CH₃ )₂ ), (t, 1.2-1.3, 2H, -CH₂-), (d, 0.9, 6H, -CH₃ ).

 

Compound M10:

m.p 202-204^oC; Yield 58% ; MW 1143; FT-IR(ν, cm^-1): 3387 (OH, phenolic); 1721(C=O, lactone); 1667 (C=O, lactam); 1631(C=C, cyclic); 1593(C=C, aromatic).

 

Anti-bacterial activity:

Thedisk diffusion method was used to screen the anti-bacterial activity for the synthesized heterocyclic compounds against gram positive (Staphylococcus aureus) and gram negative bacteria (Escherichia coli),the agar and Petri -dishes was sterilized by autoclave at 121^oC for 15 min , then the agar was poured to the disks and allowed to be solidify, then 5 holes (6 mm) are made, 0.1 ml solution of the synthesized compounds (1 mg in 1 ml DMSO) was added into each hole, These plates were incubated at (37^oC) for (24hours) [16].

 

RESULT AND DISCUSSION:

Vanillin as an aldehydic compound was used to prepare a series of Schiff’s basesthrough the condensation reaction with deferent amines, Schiff’s bases M3 and M4 were prepared using KOH to obtain free primary amino group then the produced Schiff’s bases were reacted with succinic anhydride and maleic anhydride to synthesize 1,3-Oxazepine derivatives according to the cycloaddition reaction.The mechanism of preparation of 1,3-Oxazepine derivatives via reaction of an imine compound with maleic anhydride was investigated as ( 5+ 2 ) cycloaddition involved simultaneous breaking and formation of bonds hence the reaction proceeds with a single transition state and the intermediate has no chance for formationas shown in (scheme 1) [17]. The synthesis of compounds (M1-M10) are shown in (scheme 2) .

 

 

 

FT-IR Spectra:

The FT-IR spectra of the prepared compounds (M1-M5) were not showed the band attributed to the υ (C=O) of vanillin at 1700 cm^-1 while a strong band attributed to υ(C=N) at (1632-1650 cm^-1) was appeared which conform the formation of Schiff’s bases , a broad band of hydrogen bonded phenolic hydroxyl group υ(bonding O-H) was appeared at (3319- 3414 cm^-1), A medium band attributed to υ(C-O phenolic ) was appeared at (1109- 1192 cm^-1 ). for compound M2 medium band at (1732 cm^-1) was attributed to υ (C=O) of ester. For compound M3 a weak band at 1560 cm^-1 was attributed for( νC=NH ).For compound M4 two bands at 1508 and 1332 cm^-1 was attributed to asymmetric and symmetric (COO-) respectively. The FT-IR spectra of the synthesized compounds (M6-M10) were showed absence of the band that belong to azomethine group on the other hand the bands belong to lactone and lactam were appeared at (1681-1706 cm^-1) respectively which confirm the synthesis of 1,3-oxazepine.

 

¹H-NMR Spectra:

The¹H-NMR spectra were recorded forthe synthesized 1,3-oxazepine derivatives ( M6-M9 ) , the results were showed disappearance of the signal which belong to the azomethine proton , on the other hand the signals that attributed for the Oxazepine ring-protons were appeared at δ( 4.3-4.9 ) for -CH₂-CH₂- and δ( 6.2-6.7 ) for –CH=CH- , this is a good evidence for the synthesis of the 1,3-oxazepine derivatives.

 

Anti-bacterial activity:

Through using disk diffusion method the anti-bacterial activity was screened against gram positive bacteria (Staphylococcus aureus) and gram negative (Escherichia coli ), the results are shown in Table 1

 

Table1: The inhibition zone of the prepared 1,3-oxazepines (mm)

Com. No	Staphylococcus aureus	Escherichia coli
1	21	25
2	14	15
3	15	24
4	18	16
5	16	13

 

CONCLUSION:

The synthesized Schiff’s bases have been used as a starting materials for the synthesis of some 1,3-oxazepine derivatives through the cycloaddition reaction using acid as a catalyst , the results were showed a good anti-bacterial activity .

 

ACKNOWLEDGE:

The authors would like to thank the Chemistry Department (College of Science) in the University of Babylon for the facilities during doing this work .

 

REFERENCES:

1.     Z. Amer, S. Hasan, and T. Ghanem, “Synthesis of New 1 , 3-Oxazepine Derivatives Containing Azo Group,” no. 2. pp. 11–23, 2011.

2.     S. Chigurupati, “Designing New Vanillin Schiff Bases and their Antibacterial Studies,” vol. 4, no. 5. pp. 363–366, 2015.

3.     M. B. Fugu, N. P. Ndahi, and B. B. Paul, “Antimicrobial studies of,” Screening, vol. 5, no. 5, pp. 2467–2468, 2012.

4.     C. Liang, J. Xia, D. Lei, X. Li, Q. Yao, and J. Gao, “Synthesis, in vitro and in vivo antitumor activity of symmetrical bis-Schiff base derivatives of isatin,” Eur. J. Med. Chem., vol. 74, pp. 742–750, 2014.

5.     W. Al Zoubi, “Biological Activities of Schiff Bases and Their Complexes: A Review of Recent Works,” Int. J. Org. Chem., vol. 3, no. 3, pp. 73–95, 2013.

6.     D. Sunil, C. Ranjitha, M. Rama, and K. S. R. Pai, “Oxazepine Derivative as an Antitumor Agent and Snail1 Inhibitor against Human Colorectal Adenocarcinoma,” vol. 3, no. 8, pp. 15357–15363, 2014.

7.     A. F. Kareem and H. T. Ghanim, “Synthesis aand identification some of 1,3-oxazepines derivatives containing azo group ,” vol. 1, no. 1, pp. 45–56, 2015.

8.     H. M. Sadiq, “Synthesis and Characterization of Novel 1,3-Oxazepine Derivatives From Aminopyrazine,” World J. Pharm. Pharm. Sci., vol. 6, no. 5, pp. 186–198, 2017.

9.     H. Kf and E. Hh, “Synthesis , Characterization , Biological Evaluation and Anti Corrosion Activity of Some Heterocyclic Compounds Oxazepine Derivatives from Schiff Bases,” vol. 2, no. 3, 2013.

10.   H. Agirbas, B. Kemal, and F. Budak, “Synthesis and structure-antibacterial activity relationship studies of 4-substituted phenyl-4,5-dihydrobenzo[f][1,4]oxazepin-3(2H)-thiones,” Med. Chem. Res., vol. 20, no. 8, pp. 1170–1180, 2011.

11.   M. H. Serrano-Wu et al., “Sordarin oxazepine derivatives as potent antifungal agents,” Bioorganic Med. Chem. Lett., vol. 12, no. 19, pp. 2757–2760, 2002.

12.   A. A. Abdel-Hafez and B. A. Abdel-Wahab, “5-(4-Chlorophenyl)-5,6-dihydro-1,3-oxazepin-7(4H)-one derivatives as lipophilic cyclic analogues of baclofen: Design, synthesis, and neuropharmacological evaluation,” Bioorganic Med. Chem., vol. 16, no. 17, pp. 7983–7991, 2008.

13.   E. A. Hallinan et al., “Aminoacetyl moiety as a potential surrogate for diacylhydrazine group of SC-51089, a potent PGE2 antagonist, and its analogs,” J. Med. Chem., vol. 39, no. 2, pp. 609–613, 1996.

14.   K. Kubota, H. Kurebayashi, H. Miyachi, M. Tobe, M. Onishi, and Y. Isobe, “Synthesis and structure-activity relationship of tricyclic carboxylic acids as novel anti-histamines,” Bioorganic Med. Chem., vol. 19, no. 9, pp. 3005–3021, 2011.

15.   K. J. Kadhim and M. G. Munahi, “Synthesis ,characterization and biological evaluation of some novel Schiff’s bases derived from vanillin,”J.Glob.Pharma.Tech,vol. 9, no. 8, , 2017.

16.   V. S. V Satyanarayana, P. Sreevani, A. Sivakumar, and V. Vijayakumar, “Synthesis and antimicrobial activity of new Schiff bases containing coumarin moiety and their spectral characterization,”no. xvii, pp. 221–233, 2008.

17.   H. I. Ibrahim, “Synthesis and study the biological activity of Schiff base derivatives of1 , 3-Oxazepines.” no .62 , pp . 9-14 , 2010 .

 

 

 

Accepted on 15.06.2018          © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(9): 4047-4050.