Synthesis and Characterization New Heterocyclic Compounds derivatives from Vanillin

Hutham Abd Ali Abd Al Hussain¹, Sawsan Khudhair Abbas²

¹Department of Physiology and Pharmacology/College of Veterinary Medicine/University of Kerbala, Iraq

²Department of Chemistry, College of Sciences/University of Kerbala, Iraq

*Corresponding Author E-mail: huthamabd15@yahoo.com

ABSTRACT:

In this article, some new heterocyclic derivatives, for example pyrimidine and pyrazoles were synthesized by reaction vanillin with paracetamol utilizing KOH as a catalyst to synthase 3-(4-hydroxy-3-methoxyphenyl)-N-(4-hydroxyphenyl)acrylamide(1).The compound (1) on react with Sodium azide, hydrazine, urea, and thiourea in the existence of acetic acid or KOH and ethanol as a catalyst to give (2,3,4,5) compounds. The reaction monitors by TLC. All synthesized compounds have been distinguished by melting point, IR, 1H.NMR spectroscopy.

KEYWORDS: Vanillin, paracetamol, heterocyclic.

INTRODUCTION:

Vanillin (4-hydroxy-3-methoxybenzaldehyde) is aromatic compound with the molecular formula C₈H₈O₃.Its functional groups (phenol, aldehyde and ether ) Fig1 [1] Vanillin is used as flavoring in the food stuff, for example as flavor in the ice cream , candies ,chocolate and biscuit industries. As well as is used in soaps and cosmetics manufacture [2]. Furthermore, vanillin has been also used as intermediate for pharmaceutical products, for example: L-dopa, aldomet, and trimethophin [3] other applications as antifoaming agent ,antioxidant additive, agrochemicals industries and vulcanization inhibitor [4] Vanillin can be found on the vanilla plant from vanilla planfolia [5] Vanillin may also be obtained by chemical synthesis [6]

Fig 1 4–hydroxyl-3-methoxybenzaldehyde

EXPERIMENTAL SECTION:

Instruments and reagents:

Each the chemicals are commercially obtainable and utilized without moreover purification these included vanillin, acetic acid, Ethanol, hydrazine, urea, thiourea and potassium hydroxide supplied by Fluka AG, Paracetamol, Sodium azide supplied by sigma – Aldrich. All the melting points of prepared compounds were measured by open capillary tube method and are uncorrected. The FTIR spectra for prepared compounds were enrollment on shimadzu FTIR -8400S spectrophotometer utilizing KBr disc. The 1H-NMR spectra were enrollment on a Fourier transform varian spectrometer operating at 400 MHz in DMSO- d. The Thin Layer Chromatographic technique which were used to monitor the completions of the reaction using chloroform: n-hexane (2:1). The spots was detected by using iodide.

Synthesis:

Scheme 1: Preparation of Chalcone3-(4-hydroxy-3-methoxyphenyl)-N-(4-hydroxyphenyl) acrylamide (compound 1) [7]

A mixture of (0.01mol) vanillin and (0.01 mol) paracetamol was stirred in ethanol (15ml) and the solution alkalined with KOH (5ml, 40%). The mixture was refluxed for (24 h) at room temperature and then it was acidified with HCl and poured into crushed ice. The product was separated crystallized from the solvent.

Scheme 2: Synthesis of Chalcone derivatives:

1-Synthesis of 4-(3-(4-hydroxyphenylamino)-1H-pyrazol-5-yl)-2-methoxyphenol (compound 2) [8]

An ethanolic solution (15ml) of Chalcones (1) (0.02 moles) and hydrazine hydrate 99 % (0.02 mole) added few drops of glacial acetic acid. Refluxed for 10 hour at 70˚C on water bath and cool it. The precipitate was filtered and recrystallized from ethanol.

2-Synthesis of 4-(6-(4-hydroxyphenylamino)-1,2,3-triazin-4-yl)-2-methoxyphenol (compound 3) [9]

A mixture of (0.02mol) Chalcone (1), (0.02 mol) Sodium azide were dissolved in(10ml) ethanolic sodium hydroxide and reflux for 7h. The precipitate was filtered and recrystallized from ethanol.

3- Synthesis of4-(4-hydroxy-3-methoxyphenyl)-6-(4-hydroxyphenylamino) pyrimidin-2-ol (compound 4)

A mixture of (0.01mol) Chalcone (1), (0.01mol) urea were dissolved in (15ml) ethanol and added few drops of glacial acetic acid and reflux for 7h. The precipitate was filtered and recrystallized from ethanol.

4- Synthesis of 4-(6-(4-hydroxyphenylamino)-2-mercaptopyrimidin-4-yl)-2-methoxyphenol (compound 5)

A mixture of (0.02mol) Chalcone (1), (0.02 mol) thiourea were dissolved in (15ml) ethanolic sodium hydroxide was reflux 9h. The precipitate was filtered and recrystallized from ethanol.

RESULTS AND DISCUSSION:

The synthesis of chalcone, pyrimidine andpyrazole derivatives has been achieved following the procedures as shown in Scheme No.1andScheme No.2. In the first step, Treatment of vanillin with paracetamol in alcoholic potassium hydroxide solution at room temperature for 24 h, pure compounds as shown in (scheme 1) in (88)% yield obtain after purification by recrystallization from ethanol. Then treatment of chalcones (1) with hydrazine hydrate, Sodium azide, urea, thioureain boiling ethanol gave pyrazine (2), pyrmidine derivatives (3,4,5), as shown in (scheme 2) in (75-80)% yield. Several methods has been used for study the properties of compounds such as melting point, solublity and the purity of the compounds which determined via TLC. The structures of these compounds were deduced from FT-IR and ¹H NMR spectra.

Compound (1) 3-(4-hydroxy-3-methoxyphenyl)-N-(4-hydroxyphenyl) acrylamide

Yield (88%), m.p. (95-97)^oC, FT-IR spectra ν(cm-1) 1649 (CH=CH), 1674 (C=O), 2968–3150 Aromatic (CH), 3325 (OH),3163 ( N-H ); ¹H–NMR(DMSO-d6): 6.671H (CH=CH),8.521H (CH=CH), δ 5.2 (s, 2H,Ar-OH), 2.64 (s, 3H, CH₃O), 3.8 (N-H) ,6.69 (s, 2H, Ar), 7.38 (s, 2H Ar), 6.93-7.36 (s,3HAr).

Compound (2) 4-(3-(4-hydroxyphenylamino)-1H-pyrazol-5-yl)-2-methoxyphenol

Yield (78%), m.p. (163-165) FT-IR spectra ν(cm-1) 3340pyrazoline ring (NH stretching), 1597pyrazoline ring (C=N stretching),1551(C=C stretching) 2841aliphatic (C–H stretching), , 1282pyrazoline ring (C–N stretching), ¹H–NMR(DMSO-d6): 6.30(s, 2H, Ar), 6.46 (s, 2H, Ar), 7.10-7.40(s,3HAr), 4.15(s, N-H), δ, 5.02 (s, 2H, Ar-OH), 4.6 (s, 3H, CH₃O), 12.3(s,N-H), 6.7 (C-H) pyrazole.

Compound (3) 4-(6-(4-hydroxyphenylamino)-1,2,3-triazin-4-yl)-2-methoxyphenol Yield (75%), m.p. (183-185)^oC, FT-IR spectra ν(cm-1)1514 (C=C stretching) , 2820 aliphatic (C–H stretching), 1597 (C=N stretching ), 1280pyrmidine ring (C–N stretching), 3200 (N-H), 3275 (OH),¹H–NMR(DMSO-d6):2.51 (s, 3H, CH₃O), 5.45 (s, 2H,Ar-OH), 6.69 (s, 2H, Ar), 6.67 (s, 2H Ar), 6.83-6.84(C-H) pyrimidine , 7.18-7.34(s,3HAromatic), 3.78 (N-H).

Compound (4) 4-(4-hydroxy-3-methoxyphenyl)-6-(4-hydroxyphenylamino) pyrimidin-2-ol yield 80%, mp. 171-173ºC, IR (KBr): 3381 (OH), 3200 (N-H), 1618 (C=N ) pyrimidine; 1597(C=C stretching), 1311 (C–N stretching of pyrmidine ring), ¹H–NMR(DMSO-d6): 5.10 (s, 2H,Ar-OH), 6.8 (s, 2H, Ar), 7.19-7.24(C-H) pyrimidine, 6.9 (s, 2H Ar), 7.29-7.44(s,3HAromatic), 3.8 (N-H) , 5.1(s, 1H,OH),2.51(s, 3H, CH₃O).

Compound (5) 4-(6-(4-hydroxyphenylamino)-2-mercaptopyrimidin-4-yl)-2-methoxyphenol Yield (77%), m.p. (190-192)^oC, FT-IR spectra ν(cm-1) 2843aliphatic (C–H stretching), 1548 (C=C stretching) , 1608 (C=N stretching ), 1256pyrmidine ring (C–N stretching), 2310 (SH stretching), ¹H–NMR(DMSO-d6): 5.1 (s, H,Ar-OH), 6.12 (s, 2H, Ar),2.51 (s, 3H, CH₃O), 6.66 (s, 2H, Ar), 3.10 (s, SH), 7.09-7.34 (s,3HAr),4 (N-H), 6.68-6.92 (C-H) pyrimidine.

Figure 2: FTIR of comp. (1)

Figure 3: FTIR of comp. (2)

Figure 4: FTIR of comp. (3)

Figure 5: FTIR of comp. (4)

Figure 6: FTIR of comp. (5)

Figure 7: ¹HNMR of comp. (1)

Figure 8: ¹HNMR of comp. (3)

Figure 9: ¹HNMR of comp. (4)

Figure 10: ¹HNMR of comp. (5)

CONCLUSION:

The present study involve the synthesis of chalcone from vanillin (aldehyde) and paracetamol (ketone) undergo to the Claisen-Schmidt condensation. From synthesizedchalcone new heterocyclic compound (pyrazole, pyrimidine ) prepared.

REFERENCE:

1. Borges D., Zabkova M., Araojo J., Cateto C., Barreiro M., Belgacem M., Rodrigues A., 2009. An integrated process to produce vanillin and lignin-based polyurethanes from Kraft lignin, Chemical Engineering Research and Design 87:1276–1292.

2. SandraS., Budimir V., Jasmina M. ,2009.Synthesis and structure of vanillin azomethines, Chemical Industry and Chemical Engineering Quarterly 15 : 279−281.

3. AlirezaS., SepidehM., and Ali G., 2013. Oxidative Production of Vanillin from Industrial Lignin Using Oxygen and Nitrobenzene: A Comparative Study, International Journal of Farming and Allied Sciences 2: 1165-1171

4. RavendraK., PremS., 2012. A Review on the Vanillin derivatives showing various Biological activities, International Journal of PharmTech Research 4: 266-279.

5. Luisa S., Ivana L., Luigi M., 2016.Characterization of natural vanilla flavour in foodstuff by HS‐SPME and GC‐C‐IRMS, Flavour and Fragrance JournalVolume 32:85-91

6. ConvertiA., AliaB.kbarian, DomínguezJ., Bustos G. and Perego P., 2010.Microbial Production of BiovanillinBrazilian Journal ofMicrobiol. 2010 Jul-Sep; 41(3): 519–530.

7. Rathnakar K., Ravindra G., Anil G., Sridhar N. and Achaiah G., 2017. Synthesis and Cytotoxic Activity of New Chalcones and their Flavonol Derivatives, Journal of MedChem7:20-27

8. PrasannaR., Riyazulah M., Siva V., 2010. Synthesis and Biological Evaluation of some Chalcone Derivatives, International Journal of ChemTech Research 2:1998-2004

9. Abbas F., Afak A., Ali., 2012. Synthesis, Characterization and Computational Study of Some New Heterocyclic Derived from 1-(biphenyl-4-yl)-3-(furan-2-yl)prop-2-en-1-one, Journal of Materials and Environmental Science 3 : 1071-1078.