Preparation and Characterization of Novel disubstituted 1,3- Oxazepine-tetra-one from Schiff bases reaction with 3-methylfuran-2,5-dione and 3-Phenyldihydrofuran-2,5-dione

 

Abdul Kareem Hamad Ayfan¹, Rasim Farraj Muslim²*, Noor Sabah Noori³

¹Pharmacy College, University Of Anbar, Anbar, Iraq

²Department of Ecology, College of Applied Sciences-Hit, University Of Anbar, Anbar, Iraq

³Department of Chemistry, College of Science, University Of Anbar, Anbar, Iraq

 

ABSTRACT:

This research includes synthesis of new heterocyclic derivatives of novel disubstituted 1,3- oxazepine-tetra-one from Schiff bases reaction with 3-methylfuran-2,5-dione and 3-phenyldihydrofuran-2,5-dione. Schiff bases [A₁-A₅] were synthesized by the reaction of aromatic aldehydes with primary aromatic amines, in the presence of glacial acetic acid as catalyst in absolute ethanol. The novel derivatives[A₆-A₁₀] were obtained from treatment of Schiff bases with anhydrides. The synthesized compounds were identified by TLC and via spectral methods, their (FT-IR, ¹H-NMR and ¹³C-NMR) and measurements of some of its physical properties.

 

 

 

INTRODUCTION:

Schiff basesare class of the compounds which contain the group (-HC=N-) (Scheme 1), Schiff bases are synthesizing by the reaction between primary aromatic amine with aromatic aldehyde^1-3. These compoundswere classified as a class of organic compounds and these compounds contain a group known as imine(azomethine) of the formula (R-C=N),^2-6 see (scheme 1).

 

 

 

Scheme 1. Structure of Schiff bases

 

 

The compound 5-aminosalicylic acid was dissolved in methanol with 2-hydroxy-3-methoxybenzaldehyde the two refluxed to prepared the 2-hydroxy-5-((2-hydroxy-3-methoxybenzylidene) amino) benzoic acid^7,8, see (Scheme 2).

 

 

Scheme 2. Uses of methanolin Schiff base formation:

 

Oxazepine is unsaturated seven membered heterocycle containing oxygen in position 1 and nitrogenin position 3 in addition to the five carbon atoms. It is prepared by the pericycliccyclo addition of schiff bases with maleic, phthalic, nitrophthalic and succinic anhydrides^9,10. The reaction of 3-(dimethylamino)-6-((Z)-((4-hydroxyphenyl) imino) methyl)-2-((4-methoxy phenyl) diazenyl) phenol with Phthalic anhydride (Scheme 3) produces the following oxazepine derivative¹¹.

Scheme 3. Using dry benzene to prepare the oxazepine derivative

 

MATERIALS AND METHODS:

General procedure for synthesis of Schiff bases^12-14:

Equimolar mixtures 0.01mole aromatic amines and 0.01 mole aromatic aldehydes presence trace of glacial acetic acid dissolved in 25 ml absolute ethanol was placed in a 100-ml round-bottom flask equipped with condenser and stirrer bar. The mixture was allowed to react at reflux temperature for 4hours, then allowed to cool down to the room temperature, the progress of the reaction and the purity of the compounds were monitored with TLC technique, whereby a crystalline solid was separated out. The solid product was recrystallized twice from ethanol. The structural formulae, names, melting points, colors, and percentage of yields for the synthesized Schiff bases are recorded in table1.

 

General procedure for synthesis of disubstituted 1,3-oxazepine-tetra-one derivatives^15-17:

A mixture of synthesized Schiff base 0.001 mole with 0.002 mole of anhydride respectively in 25 ml of dry benzene, was refluxed for 3 hours, the progress of the reaction and the purity of the compounds were monitored with TLC technique^18,19, then, recrystallization was done with absolute ethanol. Table 2 shows the physical properties of the prepared compounds.

 

RESULTS AND DISCUSSION:

Tables 1 and 2 exhibited structural formula, nomenclature, the percentage of yield, melting point and the color of all prepared compounds. The best yield of the synthesized Schiff bases was for compound A₁85%, while the lower yield was for compound A₃ 73% and the best yield of the synthesized disubstituted1,3- oxazepine-tetra-one derivatives was for A₇90% while the lower yield was for A₁₀75%. The higher melting point for azomethine compounds was for compound A₁ (220-222^OC), the lower melting point was for compound A₃ (99-100^OC), while the higher melting point of the synthesized disubstituted 1,3- oxazepine-tetra-one derivatives was for compound A₇ (205-207 ^OC), the lower melting point was for compound A₉ (79-80 ^OC). The different colors, melting points and the number with distance of spots in the TLC technique to the products comparisonwith the raw material are initial evidence of interaction.

 

Table 1. Structural formulae, nomenclature, melting points, colors and percentages of yield of synthesized Schiff bases

Comp. Code	Structural formula	Nomenclature	Yield %	m. p.a °C	Color
A1		4,4'-(((thiobis(4,1-phenylene) bis (azanylylidene) bis (methanylylidene) bis (N,N-dimethylaniline)	85	220-222	Dark Yellow
A2		2,2'-((1Z,1'Z)-((methylenebis(2-chloro-4,1-phenyl ene))bis (azanylylidene)) bis(methanylylidene))diphenol	78	200-202	Yellow
A3		N,N'-(thiobis(4,1-phenyle ne))bis(1-(3-chlorophenyl) methanimine)	73	99-100	Pale green
A4		(1Z,1'Z)-N, N'-(methylene bis(2-chloro-4,1-phenyle ne))bis(1-(3-chlorophenyl) methanimine)	77	110-112	Dark Yellow
A5		N,N'-(thiobis(4,1-phenyle ne))bis(1-(4-fluorophenyl) methanimine)	82	186-188	Silver

^aMelting point (Celsius).

 

Table 2. Structural formulae, nomenclature, melting points, colors and percentages of yield of disubstituted 1,3- oxazepine-tetra-one derivatives

Comp. Code	Structural formula	Nomenclature	Yield %	m. p.a °C	Color
A6		3,3'-(thiobis(4,1-phenylene))bis(2-(4-(dimethylamino)phenyl)-5-phenyl-1,3-oxazepane-4,7-dione)	85	120-122	Yellow
A7		3,3'-(methylenebis(2-chloro-4,1-phenylene))bis(2-(2-hydroxyphenyl)-5-phenyl-1,3-oxazepane-4,7-dione)	90	205-207	Light Yellow
A8		3,3'-(thiobis(4,1-phenylene))bis(2-(3-chlorophenyl)-6-methyl-2,3-dihydro-1,3-oxazepine-4,7-dione)	88	132-133	Orange
A9		3,3'-(methylenebis(2-chloro-4,1-phenylene))bis(2-(3-chlorophenyl)-6-methyl-2,3-dihydro-1,3-oxazepine-4,7-dione)	80	79-80	Off White
A10		3,3'-(thiobis(4,1-phenylene))bis(2-(4-fluorophenyl)-6-methyl-2,3-dihydro-1,3-oxazepine-4,7-dione)	75	143-145	White

^aMelting point (Celsius)

 

Synthesized Schiff bases:

Schiff bases were synthesized from commercially available aromatic aldehydes and primary aromatic amines. Thin layer chromatography were used to follow the chemical reaction²⁰, the synthesized azomethine identified by their melting points and Fourer transfer infra red spectra FT-IR.

 

The FT-IR spectra showed the appearance of the stretching absorption bands of azomethine group C=N at (1697-1664)cm^-1 indicative of the formation of the resulting azomethine compounds and the stretching absorption bands of C-N group at(1193-1160) cm^-1, C-S group at (700-680) cm^-1, C-Cl group at (700-680cm^-1 beside the characteristic bands of the residual groups in the structure²¹, See table 3, figure 1 and figure 2.

 

Scheme 4. Structure of the synthesized Schiff bases

 

Table 3. FT-IR of synthesized Schiff bases

^aFourer Transform - Infra Red.^bThe wavenumber (centimeter unit)^-1. Dash means no stretching; N.A.: Not applicable.

 

 

Figure 1. FT-IR spectra of A₁

 

 

Figure 2. FT-IR spectra ofA₂

The mechanism of Schiff bases formation was established by literature as given by scheme 6, the reaction involves a nucleophile attack of the double-electronic of the amino group (NH₂) of aromatic amine on the carbonyl group (C=O) of aromatic aldehydes to form a hemiaminal N-substituted medium that loses a water molecule to give the stable compound (Schiff base). The reaction is believed to occur in the following mechanism²², see scheme 5.

 

 

Scheme 5. Mechanism of Schiff bases formation

Synthesized disubstituted 1,3-oxazepine-tetra-one derivatives:

The FT-IR spectra of disubstituted 1,3-oxazepine-tetra-one derivatives showed the disappearance of the stretching absorption bands of the group (C=N) of the azomethine compounds and the stretching absorption bands of two anhydride compounds and showed the appearance of the stretching absorption bands at (1683-1627) cm^-1 indicative of C=O lactam bonds, stretching absorption bands at (1712-1619) cm^-1 indicative of C=O lacton bonds, stretching absorption bands at (1398-1284) cm^-1 indicative of C-O bonds, stretching absorption bands at (1193-1160) cm^-1 indicative of C-N bonds, stretching absorption bands at (664-588) cm^-1 indicative of C-S bonds, beside the characteristic bands of the residual groups in the structure^21,23, see the table 4 and example figures 3 and 4.

 

 

 

Table 4. FT-IR of disubstituted 1,3- oxazepine-tetra-one derivatives

^aFourer Transform - Infra Red. ^bThe wavenumber (centimeter unit)^-1.

Dash means no stretching; N.A.: Not applicable.

 

 

Figure 3. FT-IR spectra of A₉

 

Figure 4. FT-IR spectra of A₁₀

 

The ¹H-NMR spectrum of compound A₆ in DMSO solvent (figure 5) showed chemical shifts, δ(ppm), Singlet in 1.43 for (12H, 4 N-CH₃), doublet in 3.09 for (4H, CH₂-CH), triplet in 3.57 for (2H, CH₂-CH), singlet in 9.74 for (2H, 2 N-CH), multiplet in 6.70-7.75 for (26H, aromatic protons).. Spectrum of compound A₁₀ (figure 6) showed chemical shifts, δ(ppm) at: Singlet in 2.21 for (6H, 2 =C-CH₃), singlet in 5.53 for (2H, 2 =CH), singlet in 9.98 for (2H, 2 N-CH), multiplet in 6.49-7.93 for (16H, aromatic protons)²⁴. Other chemical shifts of A₇, A₈ and A₉, δ(ppm) are presented in table 5.

 

Table 5. The ¹H-NMR Spectra of disubstituted 1,3- oxazepine-tetra-one derivatives in DMSO

Comp. Code	Chemical Shift δ ppma
A6	Singlet in 1.43(12H, 4 N-CH3), doublet in3.09 (4H, CH2-CH), triplet in 3.57 (2H, CH2-CH), singlet in 9.74 (2H, 2 N-CH), multiplet in 6.70-7.75 (26H, aromatic protons).
A7	Doublet in 3.50 (4H, CH2-CH), triplet in 3.99 (2H, CH2-CH), singlet in 4.10 (2H, Ph-CH2-Ph), singlet in 8.64 (2H, 2 N-CH), singlet in 13.22 (2H, 2 -OH), multiplet in 6.94-7.42 (24H, aromatic protons),
A8	Singlet in 1.87 (6H, 2=C-CH3), singlet in 6.50(2H, 2 =CH), singlet in 9.99 (2H, 2 N-CH), multiplet in 7.16-7.87 (16H, aromatic protons).
A9	Singlet in 2.20 (6H, 2 =C-CH3), 3.49 (2H, Ph-CH2-Ph), singlet in 6.51 (2H, 2 =CH), singlet in 9.98 (2H, 2 N-CH), multiplet in 6.72-7.87 (14H, aromatic protons).
A10	Singlet in 2.21 (6H, 2 =C-CH3), singlet in 5.53 (2H, 2 =CH), singlet in 9.98 (2H, 2 N-CH), multiplet in 6.49-7.93 (16H, aromatic protons).

^a The references point (the chemical shift of tetramethylsilane (CH₃)₄Si)

 

Figure 5.¹H-NMR Spectra of A₆

 

Figure 6.¹H-NMR Spectra ofA₁₀

 

The ¹³C-NMR spectrum of compound A₇ in DMSO solvent (figure 7) showed chemical shifts, δ(ppm), 38.98 for (Ph-CH₂-Ph), 70.10 for (CH₂-CH), 116.17 for (CH₂-CH), 142.65 for (2 N-CH), 180.03 for (2 N-C=O), 164.14 for (2 O-C=O), 119-129 for (aromatic carbon).. While spectrum of compound A₉ (figure 8) exhibited chemical shifts, δ(ppm), 40.63 for (Ph-CH₂-Ph), 77.28 for (2 =C-CH₃), 116.05 for (2 =CH), 119.17 for (2 =C-CH₃), 141.03 for (2 N-CH), 149.23 for (2 N-C=O), 193.83 for (2 O-C=O), 128-137 for (aromatic carbon)²⁵.Other chemical Shifts of A₆, A₈, A₁₀, δ(ppm) are displayed in table 6.

 

 

Table 6. The ¹³C-NMR spectra of disubstituted 1,3- oxazepine-tetra-one derivatives in DMSO

Comp. code	Chemical Shift δ ppm
A6	40.43 (4 N-CH3), 70.98 (CH2-CH), 112.80 (CH2-CH), 145.02 (2 N-CH),172.34 (2 N-C=O), 174.46 (2 O-C=O),115.16-127.53 (aromatic carbon).
A7	38.98 (Ph-CH2-Ph), 70.10 (CH2-CH), 116.17 (CH2-CH), 142.65 for (2 N-CH),180.03 (2 N-C=O), 164.14 (2 O-C=O), 119-129 (aromatic carbon).
A8	79.11 (2 =C-CH3), 113.67(2 =CH), 115.49 (2 =C-CH3), 131.08 (2 N-CH), 169.05 (2 N-C=O), 173.22 (2 O-C=O), 118-126 (aromatic carbon).
A9	40.63 (Ph-CH2-Ph), 77.28 (2 =C-CH3), 116.05 (2 =CH), 119.17 (2 =C-CH3), 141.03 (2 N-CH), 149.23 (2 N-C=O), 193.83 (2 O-C=O), 128-137 (aromatic carbon).
A10	77.31 (2 =C-CH3), 116.26(2 =CH), 116.47 (2 =C-CH3), 132.29 (2 N-CH), 160.03 (2 N-C=O), 190.51 (2 O-C=O), 126-131 (aromatic carbon).

^a The references point (the chemical shift of tetramethylsilane (CH₃)₄Si).

 

 

Figure 7.¹³C-NMR Spectra ofA₇

 

Figure 8.¹³C-NMR Spectra ofA₉

 

 

 

Scheme 7. Structure of the synthesized disubstituted 1,3- oxazepine-tetra-one derivatives from two types of anhydrides

 

 

 

Scheme 8. Mechanism of disubstituted 1,3- oxazepine-tetra-one derivatives formation for two types of anhydrides

 

The both reactions of the synthesized Schiff bases with two anhydridesare given by the following equation^26,27, see scheme 7.

 

It may be concluded that the both reactions takes places via interaction between HOMO orbital of anhydrides with LUMO orbital of (C=N) group by concerted dipolar cycloaddition mechanism²⁸ as represented in the flowing reaction²⁹, see scheme 8.

The mechanism involves the addition of one σ-carbonyl to π-bond (N=C) to give 4- membered cyclic and 5-membered cyclic ring of anhydride in the same transition state [T.S.], which opens into 3-methylfuran-2,5-dione and 3-phenyldihydrofuran-2,5-dione anhydrides to give 7- membered cyclic ring disubstituted 1,3-oxazepine-tetra-one derivatives^30,31-33.

 

 

CONCLUSION:

It was possible to prepare derivatives of disubstituted 1,3- oxazepine-tetra-one derivatives. The results of FT-IR, ¹³C-NMR and ¹H-NMR showed that the seven-ringed compounds were the least obstructed in all preparation processes. Because of the complete clarity in infrared beams and clear signals separated from each another by the resonance spectrum nuclear magnetic of hydrogen and carbon, this is the basis of organic preparation processes.

 

ACKNOWLEDGMENT:

Special thanks to Anbar University's President Professor Dr. Khalid Battal Najim for his continuous support to publishing the research in a Certified International Journals. Also, grateful is for Dr. Abdullah Hussein Kshash, Department of Chemistry, College of Education for Pure Sciences, University of Anbar for helping to measurement the FT-IR spectra.

 

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

REFERENCES:

1.     Qin W. Long S. Panunzio M. Biondi S. Schiff Bases: A Short Survey on an Evergreen Chemistry Tool. Molecules.2013; 18: 12264-12289.

2.     Schiff H. Communications from the University laboratory in Pisa: a new range of organic bases. Annal Chem. 1864; 131(1): 118-119.

3.     El-ajaily M. Maihub A. Mahanta U. Badhei G. Mohapatra R. Das P. Mixed ligand complexes containing schiff bases and their biological activities: a short review. Rasayan J. Chem.2018; 11(1): 166-174.

4.     Patil S. Jadhav S. Deshmukh M. Patil U. Natural Acid Catalyzed Synthesis of Schiff under Solvent-Free Condition: As a Green Approach. International Journal of Organic Chemistry.2012; 2 (2):166-171.

5.     Anwar U. Bokhari T. Rizvi S. Mehdi M. Tariq S. Synthesis, Characterization and Antimicrobial Investigation of Transition Metal Complexes by using Schiff Base Containing N-, O- Donor Atoms. Clinical Biotechnology and Microbiology.2018; 2(4): 382-391.

6.     Sallal Z. Ghanem H. Synthesis and Identification of New Oxazepine Derivatives bearing Azo group in their structures. Iraqi Journal of Science.2018; 59(1A): 1-8.

7.     Abid O. Tawfeeq H. Muslim R. Synthesis and Characterization of Novel 1,3-oxazepin-5(1H)-one Derivatives via Reaction of Imine Compounds with Isobenzofuran-1(3H)-one. Acta Pharm. Sci.2017; 55(4): 43-55.

8.     Hanoon H. Synthesis and characterization of new seven-membered heterocyclic compounds from reaction of new Schiff bases with maleic and phthalic anhydrides. National Journal of Chemistry.2011; 41:77-89.

9.     Sunil D. Ranjitha C. Rama M. Pai K. Oxazepine Derivative as an Antitumor Agentand Snail1 Inhibitor against Human Colorectal Adenocarcinoma. IJIRSET. 2014; 3(8):15357-15363.

10.   Murhekar M. Khadsan R. Synthesis of Schiff bases by organic free solvent method. J. Chem. Pharm. Res. 2011; 3: 846-849.

11.   Sabah H. Synthesis, spectroscopic characterization of schiff bases derived from 4,4'- methylen di aniline. Der PharmaChemica.2014; 6: 38-41.

12.   Muslim R. Tawfeeq H. Owaid M. Abid O. Synthesis, characterization and evaluation of antifungal activity of seven-membered heterocycles. Acta Pharm. Sci.2018; 56(2): 39-57.

13.   Yousif S. Synthesis of substituted (oxazepine, Diazepine, tetrazde) via Schiff Bases for 2- Aminobenzo Thaizole Derivatives. J. Baghdad for Sci.2013; 10(3): 637-648.

14.   Hussein F. Mahmoud M. and Tawfig M. Synthesis of substituted 1,3-oxazepine-4,7-diones via Schiff bases (Part 1).Al–Mustansirya J. Sci.2006; 17(1):43-48.

15.   Silverstein R. Webster F. and Kiemle D. Spectrometric identification of organic compounds, John Wiley and sons, Inc. 2005; 7th edition: 72-126.

16.   Simek J. Organic Chemistry, Pearson education, Inc.2013; 8th edition: 412-414.

17.   Silverstein R. Webster F. and Kiemle D. Spectrometric identification of organic compounds, John Wiley and sons, Inc.2005; 7th edition: 127-202.

18.   Mistry B.A Handbook of spectroscopic Data chemistry, Oxford book company Jaipor India, Mehra Offset Printers, Delhi.2009; edition 2009: 99-127.

19.   Abid O. Muslim R. Mohammed K. Synthesis and Characterization of Novel 1,3-oxazepin-4-ones derivatives via Schiff Bases Reactions with Phthalide. J. of University of Anbar for pure science. 2016; 10(2): 1-9.

20.   O. Abid, R. Muslim and K. Mohammed, Synthesis and Characterization of Novel 1,3,4,9a-Tetrahydrobenzo [e] [1,3] oxazepin-5(5aH)-one Derivatives via Cycloaddition Reactions of Schiff Bases. J. of University of Al-Anbar for pure science.2016; 10(3):8-18.

21.   Al-Bayati R. Al-Amiery A. Al-Majedy Y. Design, Synthesis and Bioassay of Novel Coumarins. African Journal of Pure and Applied Chemistry.2010; 4: 74-86.

22.   Samir A. Rumez R. Fadhil H. Synthesis and characterization of some New Oxazepine Compounds Containing 1,3,4-Thiadiazole Ring Derived from D-Erythroascorbic Acid. International Journal of Applied Chemistry.2017; 13: 393-407.

23.   Puttaraj C. Bhalgat C. Chitale S. Ramesh B. Synthesis and Biological Activities of Some Novel Heterocyclic Compounds Containing Thiazolidinone Derivatives. Research Journal of Pharmacy and Technology.2011; 4: 972-975.

24.   Thorat B. Mustapha M. Lele K. Kamat S. Sawant S. Jadhav R. Shelke D. Kolekar S. Atram R. Yamgar R. Synthesis and Fluorescence Properties of Schiff Bases of 2-chloro-3-formylquinoline.Research Journal of Pharmacy and Technology.2012; 5: 369-375.

25.   Bhavnani V. Deshpande P. Gandhi S. Pawar P. Gaikwad A. High Performance Thin Layer Chromatographic Determination of Metoprolol Succinate and Olmesartan in Combined Capsule Dosage Form. Research Journal of Pharmacy and Technology.2012; 5: 1461-1464.

26.   Aljamali N. Alfatlawi I. Synthesis of Sulfur Heterocyclic Compounds and Study of Expected Biological Activity. Research Journal of Pharmacy and Technology.2015; 8: 1225-1242.

27.   Al-Zubiady S. Al-Khafaji Z. Mohamed I. Synthesis, Characterization of New1,3,4-thiadiazole Derivatives with Studying their Biological Activity. Research Journal of Pharmacy and Technology.2018; 11:0974-3618.

28.   Solomon W. Kumar R. Anand P. Venkatnarayanan R. Derivatized HPTLC Method for Simultaneous Estimation of Glucosamine, Vitamin C and Vitamin E in Tablets. Asian Journal of Research in Chemistry.2010; 3: 0974-4169.

29.   Valli G. Ramu K. Mareeswari P. Salicylaldehyde Schiff bases Bioactivity Prediction by Insilico Approach. Asian Journal of Research in Chemistry.2012; 5: 0974-4169.

30.   Valli G. Ramu K. Mareeswari P. Thanga A. Synthesis, Characterization and CNS Activity of 1,3-bis(2-hydroxybenzylidene) thiourea and 2-(2- hydroxyl benzylidene amino) Acetic acid Schiff bases, Asian Journal of Research in Chemistry, Vol. 5, 0974-4169(2012).

31.   Raj M., Patel H., Raj L., Patel N. Novel Heterocyclic Compounds: Synthesis, Characterization and Biological Evaluation. Asian Journal of Research in Chemistry.2013; 6: 0974-4169.

32.   Dighe V. Pujari R. Synthesis of some Sulphur and Nitrogen containing Heterocyclic Compounds. Asian Journal of Pharmaceutical Research.2017; 7: 2231-5683.

33.   Patil C. Mrunmayee C. Manisha M. Studies on Synthesis of Aromatic Schiff Bases. Part-V. Evaluation of Antifungal Potential of Ketimines from 5-Chloro-2-hydroxy-4-methyl-acetophenone. Research Journal of Science and Technology. 2018; 10(2): 1-8.

 

 

 

 

 

 

Received on 25.10.2018         Modified on 19.11.2018

Accepted on 29.12.2018      © RJPT All right reserved