Synthesis of Some Novel Coumarin Containing Oxadiazole Derivatives at Room Temperature (Part-1)

 

U. C. Mashelkar*, V. J. Pandey, B. U. Mashelkar

Organic Research Laboratory, Patkar College of Arts and Science, S V Road, Goregoan (W), Mumbai - 400062. India.

*Corresponding Author E-mail: vibhadr@yahoo.co.in , vibhagreat2007@sify.com

 

New approach for the synthesis of Coumarin oxadiazole was employed to get novel heterocycles. Synthesis of some new oxadiazole derivatives was described. Coumarin aldehyde was condensed with Benzo[d]isoxazol-3-yl-acetic acid hydrazide,    the hydrazide hydrazone, on subsequent cyclisation results in the target molecule.

 

Graphical Abstract:  New approach for the synthesis Coumarin oxadiazole was employed to get novel heterocycle.

 

 

INTRODUCTION:

Recent review of literature shows that considerable efforts were made on the development of new molecules based upon the concept of combining two or more biologically active heterocycles for enhanced overall activity.^1-3

 

It is well established that the biological activity associated with the hydrazone compounds attributed to the presence of the active pharmacophore (-CONH-N=C-). Hence many hydrazone compounds containing this active moiety showed good anticancer bioactivities according to the literature⁴. Therefore we have used this pharmacophore      (-CONH-N=C-) to bridge the coumarin with various heterocycles.

 

During literature search, it was found that a lot much work has been done on the 3- position of coumarin but comparatively 4- position of coumarin was not explored exhaustively. In attempt to synthesize new molecule we thought of the 4- position of coumarin, as the site of heterocycle development. We have selectively oxidized methyl group of 4- methyl coumarin and coumarin 4-acetic acid to yield our starting aldehydes as per literature^6-8. Starting materials 4- methyl coumarin and coumarin 4-acetic acid were synthesized from phenols via Pechmann

condensation^9-13. To combine benzisoxazole group with chromene, we derivatised benzisoxazole 3- acetic acid. Hydrazinolysis of esters is the conventional method for preparing acyl hydrazides ^{14, 15} Benzisoxazole 3- acetic acid was converted to hydrazide (3) with hydrazine hydrate after esterification, which was condensed with coumarin aldehyde. Cyclisation^16-18 of the condensation product (4a-e) with POCl₃ results in the target moiety (5a-e), where chromene was attached with benzisoxazole via 1, 3, 4-oxadiazole linkage.

 

Benzimidazole was synthesized as per the literature procedure¹⁹. To introduce coumarin and oxadiazole moieties in the molecule, -NH- group of benzimidazole was utilized. As synthetic strategy 3-(1H-benzoimidazol-2-ylmethyl)-benzo[d] isoxazole (6) was alkylated ²⁰ with ethylchloro acetate using K₂CO₃ as base, yielding (2-Benzo[d]isoxazol-3-ylmethyl-benzoimidazol-1-yl)-acetic acid ethyl ester (7). Ester group of the above product is converted to hydrazide with hydrazine hydrate and subsequently condensed with coumarin aldehyde to get the hydrazone (8). Condensation product hydrazone (8) was cyclised using POCl₃ to yield the desired product.

 

Mechanism was thought to follow through chlorination of hydrazone.²¹ Catalytic amount of acid is necessary for the cyclisation , without which the reaction does not proceed satisfactorily, Indicating the involvement of acid in the process of cyclisation. Though the role of acid is not certain in cyclisation, by observing the reaction it is obvious that, the acidic medium facilitates the tautomerism in the process, which is a key step in the cyclisation of hydrazones.

 

Synthetic route is outlined below.

  

Scheme 1:

 

EXPERIMENTAL:

Benzo[d]isoxazol-3-yl-acetic acid hydrazide (3):

Benzoisoxazole-3-acetic acid 1.65g, 10mmol (10) was dissolved in ethanol 10ml. Thionyl chloride 0.5ml was added to above solution and was heated to reflux. After 3 hrs solution was cooled and was poured to cold water 50ml. After 30 minutes reaction mass was extracted with 3 X 20ml chloroform. Organic layer was washed with water 20ml X 2 and dried over sodium sulphate. Organic layer was concentrated to oil. Ethanol 10ml was added to above solution. Hydrazine hydrate 0.4 ml, 10 mmol and catalytic amount 0.1 ml of acetic acid was added to above ester solution. Reaction mixture was heated to reflux for 1 hour. After cooling product was filtered and washed thoroughly with cold ethanol. Ethanol washing and filtrate was decomposed with water to get second crop of hydrazide. Product crystallized from ethanol.  IR(KBr):-   1643 cm^-1 (carbonyl), 2866 cm^-1 , 3054 cm^-1, 3312 cm^-1 (CH₂, NH, NH₂).

 

Condensation of Benzo[d]isoxazol-3-yl-acetic acid hydrazide (3) with aldehydes

Benzo[d]isoxazol-3-yl -acetic acid (6-methyl-2-oxo-2H-chromen-4-ylmethylene)-hydrazide (4a): Compound (3) Benzo[d]isoxazol-3-yl-acetic acid hydrazide  (0.201g, 1.0 mmol) and 6-methyl-2-oxo-2H-chromen-4-carbaldehyde  (0.179g, 1.0mmol) was dissolved in ethanol and Catalytic amount 0.1 ml of acetic acid was added. Reaction was heated to reflux and monitored on Thin Layer chromatography. Reaction was complete in 4 hours. Reaction was cooled to room temperature; product filtered and was thoroughly washed with cold ethanol. Product was purified by crystallization in ethanol. IR(KBr):-3178cm^-1(NH), 1727cm^-1(lactone carbonyl), 1674 cm^-1 (amide carbonyl), ¹H-NMR (400 MHz CDCl₃):-δ 12.0 (s, 1H, NH),  δ 7.2-8.2 (m, 9H, 8 Ar & 1-CH=N-) δ 4.5 (s, 2H, -CH₂-), δ 2.4 (s, 3H, CH₃). Benzo[d]isoxazol-3-yl -acetic acid (7-methyl-2-oxo-2H-chromen-4-ylmethylene)-hydrazide (4b), Benzo[d]isoxazol-3-yl -acetic acid (2-oxo-2H-benzo[h]chromen-4-ylmethylene)-hydrazide (4c), Benzo[d]isoxazol-3-yl -acetic acid (3-oxo-3H-benzo[f]chromen-1-ylmethylene)-hydrazide (4d)

 

Preparation of [5-(2-Benzo[d]isoxazol-3-ylmethyl)-[1,3,4]oxadiazol-2-yl] derivatives (5a-d):

Compound (4a-d) was cyclized with POCl_3.  Compounds (4a-d), 10mmol were taken in 10ml of POCl₃ in a 50ml round bottom flask; catalytic amount 0.1ml of acetic acid was added. Reaction mixture was stirred for 3 hours. After completion of reaction, it was poured in ice-cold water. Reaction mixture was neutralized with sodium carbonate. Solid product was filtered and dried.  Product was crystallized with ethanol.

 

Preparation of 4-[5-(2-Benzo[d]isoxazol-3-ylmethyl)-[1,3,4] oxadiazol-2-yl]-6-methyl-chromen-2-one:

(5a) Above mentioned general procedure for cyclisation was followed to cyclise 4a yielding 5a. Elemental analysis for C₂₀ H₁₃ N₃ O_4. Composition (cal) = C(66.85%) H(3.65%) N(11.69%) Composition (obs) = C (67.33%) H (3.83%) N (10.78%) IR(KBr):-  1724 cm^-1 (Lactone carbonyl), (400 MHz CDCl₃):- δ 7.2-8.2 (m, 8H, 8 Ar) δ 4.5 (s, 2H, -CH₂-) δ 2.5 (s, 3H, CH₃),  Mass :- m/z 359 (M+1)⁺ base peak, ¹³C-NMR (200 MHz CDCl₃):-:- 166, 162, 153, 130, 123, 122, 121, 109, 40, 39, 38, 30  ,(5b) 4-[5-(2-Benzo[d]isoxazol-3-ylmethyl)-[1,3,4]oxadiazol-2-yl]-7-methyl-chromen-2-one,  (5c)4-[5-(Benzo [d] isoxazol -3-ylmethyl)-[1,3,4]oxadiazol-2-yl]-benzo[h]chromen-2-one,  (5d) 1-[5-Benzo[d]isoxazol -3-ylmethyl)-[1, 3, 4] oxadiazol-2-yl]-benzo[f] chromen-3-one.

 

Synthesis of 3-(1H-benzimidazol-2-ylmethyl)-benzo[d]isoxazole (6):

3-(1H-benzimidazol-2-ylmethyl)-benzo[d]isoxazole(6) was prepared from benzo[d]isoxazole 3- acetic acid(5) using Phillip’s ¹⁹ method for synthesis of benzimidazoles as per literature²⁰. M. p. 174⁰ C, Yield – 81.0 %. IR (KBr) 3400 cm^-1(broad imidazole –NH-). ¹H-NMR (400 MHz CDCl₃):- d 12.5 (s, 1H, -NH), d7.0 -7.8 (m, 8H, Ar), d 4.6 (s, 1H,-CH₂).

 

Preparation of (2-benzo[d]isoxazol-3-ylmethyl-benzoimidazol-1-yl)-acetic acid ethyl ester (7)

3-(1H-benzoimidazol-2-ylmethyl)-benzo[d]isoxazole (6) (1.77g, 10 mmol) was dissolved in 10ml of DMF, to the above mixture finely powdered anhydrous K₂CO₃ (15 mmol) was added. (1.36g, 12 mmol) of ethylchloroacetate was added drop-wise to above solution at room temperature. Reaction mixture was heated to reflux. Reaction was monitored on Thin Layer chromatography for completion of reaction and it was completed in 4 hours. After cooling reaction mixture was decomposed in water. Reaction mixture was neutralized with dil. HCl. Solid product was filtered and washed thoroughly with water. Product was crystallized with alcohol. M. P. 100-103⁰C, Yield - 67% IR (KBr):- 1742cm^-1 ester carbonyl, (3400 cm^-1-NH-broad band absent). Product was identified as (2-benzo[d]isoxazol-3-ylmethyl-benzoimidazol-1-yl) acetic acid ethyl ester.

 

Preparation of (2-benzo[d]isoxazol-3-ylmethyl-benzoimidazol-1-yl)-acetic acid hydrazide (8):

Hydrazine hydrate (0.4 ml, 10 mmol), ethanol 10 ml and catalytic amount 0.1 ml of acetic acid was added to ester (7) (2.05 g, 10mmol) solution. Reaction mixture was heated to reflux for 1 hour. After cooling product was filtered and washed thoroughly with cold ethanol. Product was crystallized from ethanol.  M. P. 220-221⁰C, Yield - 77 % IR(KBr):-3300 & 3322cm^-1(-NH-, -NH₂- band), 3052cm^-1(-CH₂-) 1662cm^-1, (-CO- hydrazide carbonyl) ¹H-NMR (400 MHz CDCl₃):-δ 9.6 (s, 1H, amidic NH), δ 7.1-7.7(m, 8H, 8 Ar ), δ4.9 (s, 2H, -CH₂- carbonyl adjacent), δ 4.7 (s, 2H, -CH₂- iso-oxazole ring adjacent), δ 4.3 (NH₂).

 

9(a) (2-Benzo[d]isoxazol-3-ylmethyl-benzoimidazol-1-yl)-acetic acid (6-methyl-2-oxo-2H-chromen-4-ylmethylene)-hydrazide :

Compound (8) 10 mmol and  coumarin aldehydes 12 mmol was dissolved in ethanol; Catalytic amount 0.1 ml of acetic acid was added. Reaction mixture was heated to reflux. Reaction was monitored on thin layer chromatography and it was complete in 4 hours. After completion of reaction, product filtered and washed thoroughly with cold ethanol. Product was purified by crystallization in ethanol. IR(KBr):-3433cm^-1(-NH-), 1728 cm^-1  (lactone  carbonyl), 1691cm^-1 (amide carbonyl). ¹HNMR(400 MHz DMSO d₆):- δ 12.2 (s, 1H, amidic NH), δ 7.1- 8.6 (m, 13H, 12 Ar & one -HC=N-), δ 5.7 (s, 2H, -CH₂- adjacent to carbonyl), δ 4.7 (s, 2H, -CH₂- adjacent to iso-oxazole ring), δ 2.5 (s, 3H, CH₃). (9b) (2-Benzo[d]isoxazol-3-ylmethyl-benzoimidazol-1-yl)-acetic acid (7-methyl-2-oxo-2H-chromen-4-ylmethylene)-hydrazide, (9c) (2-Benzo[d]isoxazol-3-ylmethyl-benzoimidazol-1-yl)-acetic acid (2-oxo-2H-benzo[h]chromen-4-ylmethylene)-hydrazide, (9d) (2-Benzo[d]isoxazol-3-ylmethyl-benzoimidazol-1-yl)-acetic acid (3-oxo-3H-benzo[f]chromen-1-ylmethylene)-hydrazide

 

4-[5-(2-Benzo[d]isoxazol-3-ylmethyl-benzoimidazol-1-yl)-[1,3,4]oxadiazol-2-yl] derivatives (10a-d):

Cyclization of (9a-d): Compound (9a-d) was cyclised with POCl_3. Compound (9a-d) (10mmol) was taken in 10ml of POCl₃ in a 50ml round bottom flask catalytic amount of acetic acid was added. Reaction mixture was stirred at room temperature for 3 hours. After completion of reaction, it was poured in ice cold water. Reaction mixture was neutralized with sodium carbonate. Solid product was filtered and dried. Crystallized from ethanol. (10a) 4-[5-(2-Benzo[d]isoxazol-3-ylmethyl-benzoimidazol-1-yl)-[1, 3, 4] oxadiazol-2-yl]-6-methyl-chromen-2-one, (10b) (4-[5-(2-Benzo[d]isoxazol-3-ylmethyl-benzoimidazol-1-yl)-[1, 3, 4] oxadiazol-2-yl]-7-methyl-chromen-2-one, (10c) 4-[5-(2-Benzo[d]isoxazol-3-ylmethyl-benzoimidazol-1-yl)-[1,3,4]oxadiazol-2-yl]-benzo[h]chromen-2-one, (10d) 1-[5-(2-Benzo [d]isoxazol-3-ylmethyl-benzoimidazol-1-yl)-[1,3,4]oxadiazol-2-yl]-benzo[f]chromen-3-one. Elemental analysis for C₃₁ H₁₉ N₅ O₄ Composition (cal) = C (70.85%) H (3.64%) N (13.33%), (obs) = C (71.34%) H (3.44%) N (12.91%),  IR (KBr):-1724 cm^-1 (lactone carbonyl), 1609cm^-1 (aromatic stretching), ¹H-NMR (400 MHz  DMSO d₆ ):- δ 7.0-8.7 (m, 14H, Ar), δ 5.9 (s, 1H, pyran ring proton), δ 4.8 (s, 2H, -CH₂- adjacent to oxadiazole), δ 2.5 (s, 2H, -CH₂- adjacent to iso-oxazole ring, Mass:- m/z 525 [M] ⁺ base-peak.

 

Table 1: Physical constants

Sr. no.	Compound	R	M.P.0C	%Yield
1	4a	6-CH3	56	260
2	4b	7-CH3	78	272(d)
3	4c	7,8-C6H4	69	125
4	4d	5,6-C6H4	70	242
5	5a	6-CH3	63	227
6	5b	7-CH3	67	241
7	5c	7,8-C6H4	77	152-155
8	5d	5,6-C6H4	64	250
9	9a	6-CH3	71	204-206
10	9b	7-CH3	72	138-140
11	9c	7,8-C6H4	81	162-163
12	9d	5,6-C6H4	65	158
13	10a	6-CH3	77	153-155
14	10b	7-CH3	76	117
15	10c	7,8-C6H4	48	197
16	10d	5,6-C6H4	54	145

 

RESULT AND DISCUSSION:

Cyclisation methods described in the literature for hydrazones generally are oxidative cyclisation, though acyl hydrazides are cyclised through POCl₃. We tried less drastic conditions i.e. without solvent and heating, against what was described in the literature. We achieved the cyclisation of hydrazones, which is a green way of synthesis, making it less toxic and economic, as oxadiazole are economically important molecules. We successfully synthesized molecules with coumarin, imidazole and oxadiazole, all biologically important moites in a single molecule. 

 

ACKNOWLEDGEMENT:

Authors thank Director, SAIF IIT, Mumbai, for providing important analysis. We are also thankful to micro-analytical laboratory, Dept. of Chemistry, University of Mumbai, for providing spectral analysis.

 

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Received on 24.05.2013          Modified on 16.06.2013

Accepted on 21.06.2013         © AJRC All right reserved