Synthesis and Biological Evaluation of Some Schiff’s Bases of 2-Substituted- 1, 3, 4-Oxadiazole

 

Kishore U. Kothule*, Prashant Kesharwani, Rakesh R. Somani and Prabhakar Y. Shirodkar

Department of Medicinal Chemistry, Bharati Vidyapeeth’s College of Pharmacy, C.B.D., Belapur, Navi Mumbai - 400 614 India

*Corresponding Author E-mail: kothule@rediffmail.com

ABSTRACT:

The present research work is oriented towards the synthesis of coupled heterocyclic system and its subsequent conversion into Schiff’s bases. Ethyl-5-N¢-(1,2,4-triazolyl)-acetate 1 was converted in to its hydrazide by heating with hydrazine hydrate. Hydrazide was further cyclised to 2-amino-5-(N¢-1,2,4-triazolomethyl)-1,3,4-oxadiazole 3, which upon further treatment with various aromatic aldehydes under acidic condition afforded corresponding Schiff’s bases 4a-4j. All compounds were screened for anticonvulsant activity by MES method.

Graphical abstract:

Hitherto unreported Schiff’s bases 4a-4j of 1,2,4-triazolo substituted 1,3,4-oxadiazole amine 3 are prepared under acidic conditions. The newly synthesized compounds are characterized by spectral analyses. All the compounds are screened for anticonvulsant activity using MES method. 4d exhibited promising anticonvulsant activity, whereas others have shown moderate activity.

 

 

INTRODUCTION:

Heterocyclic compounds have been proven to the backbone for the discovery of many bioactive compounds. Majority of these heterocycles consist of quinoline, triazoles, thiazoles, thiadiazoles, imidazoles and oxadiazoles. Oxadiazoles in particular, disubstituted-1, 3, 4-oxadiazoles^1-3 are among the various heterocycles that have received the most attention during last three decades as potential biomolecules. The majority of them have been exploited for anti-microbial, anti-convulsant, anti-tubercular, anti-cancer and anti-fungal activities.

Also the Schiff’s bases of 1, 3, 4-oxadiazoles have been found bioactive^4-7. In view of this and our interest in the synthesis of biologically active heterocyclic compounds, it was thought of interest to synthesize Schiff’s bases of 1, 3, 4-oxadiazoles and to evaluate them for anticonvulsant activity against the MES induced convulsions in male Swiss albino mice by literature method⁸.

 

RESULTS AND DISCUSSION:

This work aimed at synthesis of Ethyl-5-N¢-(1,2,4-triazolyl)-acetate 1 and subsequent conversion to its hydrazide using hydrazine hydrate. This was further cyclised to 2-amino-5-(N¢-1,2,4-triazolomethyl)-1,3,4-oxadiazole 3, which was allowed to treat with various aromatic aldehydes in presence of concentrated hydrochloric acid to yield corresponding Schiff’s bases 4a-4j (Scheme 1).

Scheme 1

Table 1- Various Substituents on titled compounds 4a-4j

Compd.	R
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j

The various substituents on titled compounds 4a-4j are described in Table 1 and physical and analytical data is described in Table 2.

 

Anticonvulsant activity:

The compounds were screened for their anticonvulsant activity against the MES induced convulsions in male Swiss albino mice by literature method¹⁰. The test compounds were suspended in 4% aqueous CMC suspension and were injected i.p. at dose of 300mg/kg. Phenytoin was used as a reference drug at the dose of 30mg/kg which was observed to protect 100% against the induced convulsions. Results are presented in Table 3.

 

Experimental section:

All the melting points were determined on ‘Veego’ VMP-D apparatus and are uncorrected. Silica gel G plates of 3x8 cm (Sigma-Aldrich) were used for TLC and spots were located by UV or in iodine chamber. The IR spectra were recorded in the 4000-400 cm^-1 range using KBr discs on FT-IR 8400 SHIMADZU spectrometer. ¹H NMR spectra were recorded on Varian Mercury (300MHz) spectrometer in CDCl₃ as solvent using TMS as an internal standard and values are expressed in δ ppm. The elemental analyses were performed for C, H, N and were within ±0.4% of theoretical values.

 

Synthesis of Ethyl-5-N¢-(1,2,4-triazolyl)-acetate 1. In a solution of 1,2,4-triazole (0.1mole, 6.9gm) in dry methanol, ethylbromoacetate (0.1mole, 16.7gm) was slowly added under constant stirring in the presence of 5 gm of anhydrous K₂CO₃. The resulting solution was then refluxed on a water bath for about 7-8 hours or till TLC (Chloroform: Methanol, 2:3) is correct. Then the reaction mixture was cooled and filtered. The filtrate was distilled to obtain a light yellow color liquid (Yield: 14.7g, 95 %) which was utilized in next reaction without further purification. IR (KBr): 3167 (NH), 1740 (CO), 1620 (C=N), 1547 (NH) cm^-1.

 

Synthesis of Ethyl-5-N¢-(1, 2, 4-triazolomethyl)-hydrazide 2. Ethyl-5-N¢-(1,2,4-triazolyl)-acetate 1 (0.1mole, 15.5gm) was dissolved in methanol and hydrazine hydrate (0.15mole, 7.65gm) was added to this solution slowly. The mixture was refluxed on a water bath for about 5-6 hours. The removal of excess of solvent afforded a dark red color liquid. (Yield: 13.25 gm, 94 %). IR (KBr): 3145 (NH), 1680 (CO), 1605 (C=N), 1511 (NH) cm^-1.

 

Synthesis of 2-amino-5-(N¢-1, 2, 4-triazolomethyl)-1, 3, 4-oxadiazole 3. A solution of Ethyl-5-N¢-(1, 2, 4-triazolomethyl)-hydrazide 2 (0.1mole, 14.1gm) and CNBr (0.11mole, 10.5gm) in about 50ml methanol was refluxed on a water bath for 2 hours. The excess of solvent was removed under reduced pressure and residue was poured in ice cold water and then neutralized with 10% sodium bicarbonate solution to remove unreacted CNBr. The solvent was evaporated off and the resultant semi-solid was again mixed with excess of methanol. A white solid thus separated was filtered off and the filtrate was concentrated on the water bath to obtain a reddish liquid (Yield: 14.9 gm, 90%). IR (KBr): 3235 (NH), 1605 (C=N), 1511 (NH), 1100, 1080 (C-O-C) cm^-1.

 

Table 2- Characterization data of the titled compounds 4a-4j

Compd.	Mole. Formula (Mole. Wt.)	Physical Constant (0C)(%Yield)	IR (KBr, cm-1 )
4a	C12H10N6O	m.p:167-169 (55)	3062(-NH), 1626(-C=N), 1596(-NH), 1166-1050
4b	C13H12N6O2 (254)	m.p:166-168 (60)	3062(-NH), 1626(-C=N), 1487 (-NH), 1105-1030 (C-O-C)
4c	C12H10N6O2 (270)	m.p:210-212 (45)	3068(-NH), 1596(-C=N), 1511 (-NH), 1115-1032 (C-O-C)
4d	C12H9N7O3 (299)	m.p:101-103 (48)	3086(-NH), 1615(-C=N), 1531 (-NH), 1085-1024 (C-O-C)
4e	C12H9N7O3 (299)	m.p:171-173 (53)	3085(-NH), 1606(-C=N), 1521(-NH), 1190-951 (C-O-C)
4f	C12H9N6OCl (288.5)	m.p:125-128 (61)	3066(-NH), 1614(-C=N), 1500 (-NH), 1047-959 (C-O-C)
4g	C13H12N6O3 (300)	m.p:115-118 (58)	3075(-NH), 1583(-C=N), 1500(-NH), 1122-1033 (C-O-C)
4h	C12H10N6O2 (270)	m.p:160-162 (68)	3168(-NH), 1595(-C=N), 1516 (-NH), 1111-1160 (C-O-C)
4i	C18H15N6O (294)	b.p:147-148 (67)	3100(-NH), 1604(-C=N), 1447 (-NH), 1121-1072 (C-O-C)
4j	C18H15N6O (331)	m.p:52-53 (71)	3114(-NH), 1594(-C=N), 1517 (-NH), 1112-1032 (C-O-C)

 

 

Table 3- Anticonvulsant activity of the compounds 4a-4j

Compd.	% Protection
4a	38.4
4b	63.8
4c	53.9
4d	94.3
4e	44.7
4f	55.7
4g	47.9
4h	54.4
4i	64.4
4j	46.8

 

General procedure for synthesis of Schiff’s bases 4a-4j. In a mixture of 2-amino-5-(N¢-1, 2, 4-triazolomethyl)-1, 3, 4-oxadiazole 3 (0.1mole) in 100ml dry benzene, was added appropriate aldehydes (0.1mole). The mixture was refluxed for about 6 hours, cooled and solvent was distilled off and solid thus obtained was dried in oven. All these compounds were recrystallized from chloroform and methanol (1:1).  IR (KBr): 3235 (NH), 1605 (C=N), 1511 (NH), 1080, 976(C-O-C) cm^-1.

 

The NMR data of some of the compounds is as follows:

4b:  NMR (δ ppm): 8.61 (s, 1H, N=CH), 7.8-6.98 (m, 6H, aromatic), 7.26 (s, 2H, N-CH₂), 3.93 (s, 3H, OCH₃); 4e:  NMR (δ ppm): 10.43 (s, 1H, N=CH), 8.11-7.67 (m, 6H, aromatic), 7.25 (s, 2H, N-CH₂), 9.11 (s, 2H, N=CH); 4f:  NMR (δ ppm): 9.10 (s, 1H, N=CH), 7.8-7.5 (m, 6H, aromatic), 7.25 (s, 2H, N-CH₂), 8.69 (s, 2H, N=CH); 4h:  NMR (δ ppm): 9.85 (s, 1H, N=CH), 7.98-6.97 (m, 6H, aromatic), 7.34 (s, 2H, N-CH₂), 8.69 (s, 2H, N=CH), 10.09 (s, 1H, OH).

 

CHN data of some of the compounds is as follows:

4a: Anal Calcd for C₁₂H₁₀N₆O: C, 56.69, H, 3.93; N, 33.07; Found: C, 56.69, H, 3.93; N, 33.07; 4d: Anal Calcd for C₁₂H₉N₇O₃: C, 48.16, H, 3.01; N, 32.77; Found: C, 48.16, H, 3.01; N, 32.77; C; H, ; N, 16.87%

 

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Received on 17.06.2010        Modified on 29.06.2010

Accepted on 08.07.2010        © AJRC All right reserved