NOVEL SYNTHESIS OF OXADIAZOLE DERIVATIVES WITH PYRIMIDINE MOIETY

NOVEL SYNTHESIS OF OXADIAZOLE DERIVATIVES WITH PYRIMIDINE MOIETY

Shubhangi P. Waghamale and Pravina B. Piste*

P.G. Department of Chemistry, Yashavantrao Chavan Institute of Science, Satara- 415 001, Maharashtra, India

ABSTRACT: A series of  different  6-Methyl - 4- aryl -5 - (5-aryl -1,3,4-oxadiazole-2-yl ) -1,2,3,4-tetrahydro pyrimidin-2- (1H) - one / thione ( IIIa-g) have been synthesised fromEthyl - 6- methyl- 2- oxo / thioxo – 4-substituted phenyl-1,2,3,4-tetrahydro pyrimidine-5-carboxylate (Ia-g) followed by reaction with hydrazine hydrate in ethanol gave 6 - methyl-2-oxo / thioxo – 4 -substituted phenyl - 1,2,3,4-tetrahydro pyrimidine-5-carbo hydrazide  (IIa-g)  by means of Microwave irradiation for 2-4 mins and giving excellent yield in short reaction time, are notable advantages of this method. The structure elucidations of all the synthesised compounds have been accomplished by elemental analysis, IR, NMR and Mass spectroscopic method.

Pyrimidines,   Carbohydrazides, Oxadiazoles

INTRODUCTION:Five membered heterocycle having three heteroatoms like oxadiazole known to have different biological activities such as Antibacterial ¹, Anti-inflammatory ², Anti-convulsant ³, Analgesics ⁴ activity. These activities are due to the presence of the -N=C-O-linkage and hence oxadiazole and its derivatives have attracted wide attention of chemist for preparation of different biological active drug. There are four possible isomers of oxadiazole depending on the position of nitrogen atom in the ring namely 1, 2, 3-, 1, 2, 4-, 1, 2, 5- and 1, 3, 4-oxadiazoles.Out of these 1, 3, 4-oxadiazoles are found to be most potent biologically ^5-12 could become new drug for market in future. Similarly, pyrimidine derivatives are important class of heterocyclic compound due to their therapeutic and pharmacological properties and used as calcium channel blockers and alpha-1α-antogonists.

The biological and synthetic significance places this scaffold at a prestigious position in medicinal chemistry research so we have developed an operationally simple, inexpensive, efficient and environmental benign protocol for synthesis. In present work, we have developed rapid and operationally simple method for synthesis of different oxadiazoles with pyrimidine nucleus.

MATERIALS AND METHODS: All chemicals were of synthetic grade (S.D. Fine Chem. Ltd. Mumbai, India). Melting point was determined by open capillary method and is uncorrected. Products were recrystalised from ethanol as a solvent. The purity of compound checked by the TLC on silica gel G plates and was purified by column chromatography on silica gel (60-120 mesh). The microwave used for the synthesis is of the LG-Little Chef MS-192 W. The compounds were characterised by using IR, ¹H NMR and Mass spectral analysis. The IR spectra were recorded on Perkin-Elmer spectrum in form of KBr pellet .¹ H NMR was recorded in CDCl₃ on Perkin Elmer R-32 spectrum using TMS as internal standard. Mass spectrum was recorded on EI-shimadzu GC-MS spectrometer. All the compounds were analysed for C, H and N on Carlo-Erba elemental analyser.

EXPERIMENTAL SECTION:

Ethyl -6- methyl- 2- oxo/thioxo- 4- substituted phenyl- 1, 2, 3, 4-tetrahydropyrimidine-5- carboxylates:

I(a-g): A mixture of substituted aldehyde (0.01 mol) ethylacetoacetate (0.015 mol),urea /Thiourea (0.01 mol) and concentrated H₂SO₄ (1 – 5 drops) in absolute ethanol (10 ml) were taken in a borosil beaker (250ml) was zapped inside the microwave oven for a period of 3 -4 min (at 160w) the reaction mixture was then allowed to stand at room temperature, and then poured on ice . The product formed was filtered, washed with water, dried and recrystalized from ethanol (Table 1).

TABLE 1: PHYSICAL AND ELEMENTAL ANALYSIS OF THE SYNTHESIZED COMPOUNDS (I a-g)

6-methyl-2-oxo/thioxo-4-substituted phenyl-1, 2, 3, 4-tetrahydropyrimidine-5-carbo hydrazide:

II(a-g): The compound I (0.01 mol) in ethanol and hydrazine hydrate (0.99%, 0.015 mol) were taken in borosil beaker (250 ml) the reaction mixture zapped inside the microwave oven for a period of 2 -3 min. (at 160w). Then reaction mixture allowed to cool for a while after some time mixture was poured on ice. Product formed filtered, washed with water, dried   and recrystalized from ethanol (Table 2).

TABLE 2: PHYSICAL AND ELEMENTAL ANALYSIS OF THE SYNTHESIZED COMPOUND (IIa-g)

 6-methyl-4-aryl-5-(5-phenyl-1, 3, 4-oxadiazole -2-yl)-1, 2, 3, 4-tetrahydropyrimidine-2-(1H)-one / thione:

III(a-g): Carbohydrazides II (0.02 mol) and substituted aromatic acid (0.02 mol) in POCl₃ were taken in Round bottom flask. The reaction mixture refluxed for 8- 10 hrs. The reaction mixture was cooled and poured on crushed ice and neutralised with 20% NaHCO₃ solution gave solid   which was filtered, dried and recrystallized from methanol (Table 3).

TABLE 3: PHYSICAL AND ELEMENTAL ANALYSIS OF THE SYNTHESIZED COMPOUND (IIIa-g)

RESULTS AND DISCUSSION: In this present work, synthesis of some new Oxadiazole derivatives with pyrimidine moiety have been reported from corresponding different hydrazide derivatives (IIa-g, Table 2). Initially, substituted pyrimidine carboxylate I(a-g) were prepared by our earlier reported method i.e. Hantsch synthesis which were treated with hydrazine hydrate in ethanol  to furnish the corresponding substituted hydrazide derivatives by microwave irradiation (IIa-g) followed by reflux with aromatic acid in POCl₃ predicts 6-methyl- 4- aryl- 5- (5-phenyl- 1,  3,  4-oxadiazole -2 -yl)- 1,  2,  3,  4  -tetrahydropyrimidine-2- (1H)-one/thione: IIIa-g (Table 3, Scheme I)).

SCHEME 1

The newly synthesized compounds I(a-g), II(a-g) and III(a-g)were established on the basis of IR, ¹H NMR and MASS spectroscopic method. The IR spectra of the compounds (IIa-g) showed absorption band at 1664-1672 cm-¹ indicates presence of amide group and in IIIa-g, absence of absorption band at 1664-1672 cm-¹ and at 1270cm^-1 due topresence of C-O-C group and indicating the formation of product. In ¹H NMR spectra, a peak observed at 4.53 ppm due to presence of -NH₂ group in IIa-g.  While in oxadiazole derivatives, absence of peak at 4.53 due to –NH₂ proved the structure of the products, the mass spectra of the substituted oxadiazole with pyrimidine derivative were showed molecular ion peak corresponding to their molecular formula. The IIIf and IIIg compound shows [M+] and [M⁺ +2] peak at m/z 366.5(M⁺), 368.5(M⁺+2) and 382.5(M⁺), 384.5(M⁺+2) showing presence of halogen respectively and peak at 35.5 and 37.5 confirms presence of Chlorine in the ratio 1:3.

TABLE IV:  IR, NMR AND MASS SPECTRAL ANALYSIS (Ia-IIIg)

 CONCLUSION: Keeping in view green approach, we have developed an operationally simple, inexpensive, efficient and environmental benign protocol for synthesis of oxadiazoles with pyrimidine moiety.

Synthesis of pyrimidine carboxylate derivatives were carried out by Hanztsch method followed by hydrazine hydrate in ethanol obtained Carbohydrazides under Microwave irradiation for 2-4 min., followed by cyclisation in POCl₃ gave Oxadiazoles.

The merits of the current protocol are:

1. Yields are excellent.
2. Required short reaction time.
3. Easy workup synthesis and operable on large scale.

ACKNOWLEDGEMENT: We are very thankful to National chemical laboratory, Pune for spectral interpretation and to Department of Chemistry for providing research facilities.

  REFERENCES:

1. Arora PK, Mittal A, Kaur G, and Chauhan A: Synthesis of some novel oxadiazole based chalcone derivatives as antibacterial agents. International Journal of Pharmaceutical sciences and Research 2013;4(1): 419-424.
2. Kumar B, Raj V, Kumar A and Singh V: Anti-inflammatory activity of 1, 3, 4-Oxadiazole derivatives compound. International Journal of Current Pharmaceutical Research 2012; 4(3):9-14.
3. Gilani SJ, Alam O, Khan SA, Siddiqui N, Kumar H: Synthesis of some derived thiazolidin-4-one, azetidin-2-one and 1, 3, 4-oxadiazole ring system from isoninicotinic acid hydrazide:A novel class of potential anticonvulsant agent . Der Pharmacial Letter 2009; 1(2):1-8.
4. Ullas P, Dsouza, Revanasiddappa BC and Subrahmanyam EVS: Analgesic and Anti-inflammatory activity of 1,3,4-oxadiazoles Derivatives. International Journal of pharmaceutical, chemical And Biological Sciences 2012; 2(3):202-205.
5. Singh P, Sharma PK, Sharma JK, Upadhyay A and Kumar N: Synthesis and evaluation of substituted diphenyl -1,3,4-oxadiazole derivatives for central nervous system depressant activity. Organic and Medicinal chemistry Letters 2012; 2:8.
6. Bala S, Kamboj S and Kumar A: Heterocyclic 1,3,4-oxadiazole compounds with diverse biological activities :A comprehensive review. Journal of Pharmacy Research 2010; 3(12):2993-2997.

1. Singh P and Jagra PK: Oxadiazoles: A novel class of anti-convulsant agents.Jangra Der Chemica Sinica 2010; 1(3):118-123.
2. Singh AK, Vinay KR, Sahu,Yadav D:biological Activities of 2,5-disubstituted-1,3,4-oxadiazoles. International Journal of Pharma Sciences and Research 2011;2(6):135-147.
3. Nimavat B, Mohan S, Saravanan J, Deka S, Talukdar A, Sahariah BJ, Dey BK  and Sarma RK: Synthesis and characterisation of some novel oxadiazoles for in –vitro Anti-inflammatory activity. International Journal of Research in Pharmacy and Chemistry 2012; 2(3):594-602.
4. Mohamed AA, Mohammad S: Oxadiazole Mannich bases Synthesis and   antimycobacterial activity. Bioorganic and Medicinal Chemistry Letters 2007; 17: 3314-3316.
5. Yarshahar M, Siddiqui AA, Aliashraf M: Synthesis and Anti-Tuberculostatic activity of Novel 1, 3, 4-Oxadiazole Derivatives. Journal of the Chinese Chemical Society 2007; 54: 5-8.
6. Kumar H, Javed A, Khan A. Suroor: 1,3,4-Oxadiazole/thiadiazole and 1,2,4-triazole derivatives of biphenyl-4-yloxy acetic acid; Synthesis and preliminary evaluation of biological properties. European Journal of Medicinal Chemistry 2008; 2688-2698.
   

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   How to cite this article:

   Waghamale SP and Piste PB: Novel synthesis of Oxadiazole derivatives with Pyrimidine moiety. Int J Pharm Sci Res 2013; 4(11): 4416-21. doi: 10.13040/IJPSR. 0975-8232.4(11).4416-21

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