Synthesis and Characterization of Novel Pyridazinone derivatives with 5-Mercapto Tetrazole

 

Kumaran Kubendiran ¹*, Jaisankar Raguraman¹, S. Raja Mohamed Kamil¹ and S. Syed Shafi²

¹Department of Chemistry, Islamiah College, Vaniyambadi - 635 751, Tamil Nadu, India.

² Department of Chemistry, Thiruvalluvar University, Vellore, Tamil Nadu, India.

*Corresponding Author E-mail: kumaranchem@yahoo.co.in.

ABSTRACT:

A simple and efficient experimental procedure for the synthesis of novel pyridazinone derivatives containing 5-mercaptoTetrazole moiety was developed in the presence of several Aryl/alkyl halides and sodium hydride using Dry tetrahydrofuran (as a solvent). The structures of the newly synthesized compounds were characterized by ¹HNMR, IR, LCMS data, elemental analysis and melting point.

 

 

 

INTRODUCTION:

The development of the chemistry of tetrazoles^1-9 during the last decade has been largely associated with the wide-scale employment of these compounds in drugs or drug candidates with antihypertensive, anti allergic and antibiotic activity ^10-12.  Also used in agriculture as plant growth regulators, herbicides and fungicides¹³ or in photography and photo imaging as stabilizers¹⁴  Tetrazole derivatives have been explored as explosives, propellant components for missiles and as gas generators for air bags in automobile industry¹⁵.

 

Syntheses of 5- substituted tetrazoles have been developed during these years and the existing methods ^16-25 have been significantly improved. Also very few literature reports describing the pyridazinone derivatives^26-35, for that we combined to developed the novel derivatives, these compounds containing the N-N bond and thiol group; exhibit a wide range of pharmacological activities^36-40.  The data on methods of synthesis, chemical/physical properties and practical   applications of tetrazoles are discussed below.

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EXPERIMENTAL:

General procedure to synthesize Int-1:

The mixture of benzyl isothiocyanate (1gm, 1eq) and sodium azide (1gm, 2eq) in water was heated to 90^oC for 4hrs. It was then quenched with ice water and acidified with Con. HCl followed by dilution with water. The white color precipitate obtained was, filtered and then washed up with water up to neutral stage. The solid was dried under high vacuum and confirmed by spectral studies.

 

General procedure to synthesize Int-2 and Int-3:

The mixture of hydrazine hydrate and Con. HCl was heated to 110⁰ C reflux and then added with 3, 4-dimethylfuran-2, 5-dione drop wise for the 5-10min. It was continued for 5-6 hrs at the same temperature. Then this organic mixture was cooled to room temperature and then to 0⁰C, allowed for 30min.  The solid was filtered and washed with excess water and dried over vacuum. Then crude INT-2 was added with POCl₃ and heated to 90⁰C for 6-7hrs. The reaction mass was concentrated up to residue stage under high vacuum, then crude residue was poured to ice water, and stirred for 15min, and filtered. This intermediate INT-3 was dried. The white solid was confirmed by LCMS, ¹H NMR and IR spectral studies.

 

 

The mechanism for the formation of 5-mercapto tetrazole

 

Scheme-3 Synthesis route to the title compound and melting point of derivatives

 

 

Experimental Section:

In order to prepare a variety of derivatives of 6-(1-benzyl-1H-tetrazol-5-ylthio)-4, 5-dimethylpyridazine 3(2H)-one (6) was prepared as a precursor. Preparation of 6-(1-benzyl-1H-tetrazol-5-ylthio) - 4, 5-dimethylpyridazine 3 (2H)-one was accomplished as given in scheme 3. As depicted in scheme 3, reaction between the isolated compound INT-1 was treated with 2, 5 dichloro3, 4 dimethyl pyridazine (INT-3) in THF in the presence of sodium hydride to give anINT-4.Then hydrolysis was carried out using acetic acid and the mixture of 1, 4 dioxane: water (2:1), to provide compound (5) which was treated with corresponding alkyl halides to get N-alkylated product (6a-i). The completion of reaction was monitored by TLC and the products were isolated by column chromatography.

1-benzyl-1H-tetrazole-5-thiol (Int-1):

The yield of the product INT 1 was 95%. Mol. Wt. 192.24, ¹HNMR (400MHz, DMSO-d6) (δ ppm) 5.40 (s, 2H), 7.27 (m, 5H); LCMS: M⁺+1 (192.8); Anal Calcd. For C₈H₈N₄S: C, 49.98%; H, 4.19%; N, 29.14%; S, 16.68% , Found: C, 50.10%; H, 4.57%; N, 29.54%, S, 15.43%.

 

4, 5-dimethylpyridazine-3, 6-diol (Int-2):

The yield of the product INT 2 was 80%. Mol. Wt. 140.14, ¹HNMR (400MHz, DMSO-d6) (δ ppm) 1.99 (s, 6H), 10.79 (b, 1H), 11.69 (b, 1H); LCMS: M⁺+1 (141.2); Anal Calcd. For C₆H₈N₂O₂: C, 51.42%; H, 5.75%; N, 19.99%; O, 22.83% Found: C, 51.14%; H, 5.12%; N, 19.52%.

 

 

 

3, 6-dichloro-4, 5-dimethyl-pyridazine (Int-3):

The yield of the product INT 3 was 90%. Mol. Wt. 177.03, ¹HNMR (400MHz, DMSO-d6) (δ ppm) 2.40 (s, 6H), LCMS: M⁺+1 (178.0); Anal Calcd. For C₆H₆Cl₂N₂: C, 40.71%; H, 3.42%; Cl,40.05%; N, 15.82%. Found: C, 41.14%; H, 4.12%; N, 15.52%.

 

3-(1-benzyl-1H-tetrazol-5-ylthio)-6-chloro-4, 5-dimethyl-pyridazine (Int-4):  The yield of the product INT 4 was 85%. Mol. Wt. 332.81, ¹HNMR (300MHz, DMSO-d6) (δ ppm)  2.34  (d, 3H) , 2.49 (d, 3H) , 5.63 (s,2H),7.24 ( d, 2H), 7.28(m, 5H);  LCMS : M⁺+1 (333.0), MS/MS(m/z):305.1; Anal Calcd. For C₁₄H₁₃ClN₆S: C, 50.52%; H, 3.94%; Cl,10.65%; N, 25.25%; S, 9.63%. Found: C, 51.14%; H, 4.12%; N, 25.52%; S, 8.95%.

 

6-(1-benzyl-1H-tetrazol-5ylthio)-4, 5-dimethylpyridazin-3(2H)-one (INT-5):  The yield of the product INT 5 was 90%. Mol. Wt. 314.37, ¹HNMR (300MHz,DMSO-d6) (δ ppm)  2.00  (s, 3H) , 2.11 (s,3H) , 5.66 (s,2H),7.33 ( m, 5H), 12.92(s, 1H);  IR  (KBr) cm^-1 ;   735 (C-S-), 1298 (C-N) 3118 ( Ar- C-H ), 1495 (N=N); LCMS : M⁺+1 (315.0), MS/MS(m/z) : 287.0; Anal Calcd. For C₁₄H₁₄N₆OS: C, 50.52%; H, 3.94%; Cl,10.65%; N, 25.25%; S, 9.63%. Found: C, 51.14%; H, 4.12%; N, 25.52%; S, 8.95%.

 

General procedure to synthesize N-alkylated 6 - (1-benzyl-1H-tetrazol-5-ylthio) - 4, 5 - dimethylpyridazin-3(2H)-one (for 6a-i): To the solution of INT-5 (100mg) in Dry THF, sodium hydride was added in portion wise at 0⁰C then stirred for 15-20minutes in the same temperature. Then slowly added alkyl halides (a-i) at 0⁰C and stirred at Room temperature for 2hrs.  Reaction was monitored by TLC, and the reaction mixture was quenched with saturated NH₄Cl solution and extracted with ethyl acetate (2x15ml), the combined organic layer was washed with water (2x10ml), dried over Na₂SO₄ and evaporated to dryness.  Crude compound was purified by column chromatography (10-15% ethyl acetate in Pet. Ether) to get good required product.

 

6-(1-benzyl-1H-tetrazol-5ylthio)-2-isopropyl-4, 5-dimethylpyridazin-3(2H)-one (6a): The yield of the product 6a was 55%. Mol. Wt. 356.45, ¹HNMR (400MHz,DMSO-d6) (δ ppm)  1.27  (S, 6H) , 2.25 (S, 6H) , 3.89 (m,1H),5.64 (s, 2H),7.24 ( d, 2H), 7.21(d, 2H), 7.15 (m,1H);  IR  (KBr) cm^-1 ; 1635 (C=O),  735 (C-S-), 1298 (C-N) 3118 ( Ar- C-H ), 1495 (N=N); LCMS : M⁺+1 (357.1), MS/MS(m/z) : 329.1, 314.12, 224.2; Anal Calcd. For C₁₇H₂₀N₆OS: C, 57.28%; H, 5.66%; N, 23.58%; O, 4.49%; S, 9.00%. Found: C. 57.14%; H. 5.68%; N. 23.52%; S. 8.9%.

 

6-(1-benzyl-1H-tetrazol-5-ylthio)-2- (4-(trifluoromethyl) benzyl)-4, 5-dimethylpyridazin-3(2H)-one (6b): The yield of the product 6b was 50%. Mol. Wt. 472.49, ¹HNMR (400MHz, DMSO-d6) (δ ppm)  2.35  (S, 6H) , 4.5 ( s, 2H), 5.32 (s, 2H), 7.34 ( m, 5H), 7.4 (m, 4H) ;  IR  (KBr) cm^-1 ; 1642 (C=O),  715 (C-S-), 1295 (C-N) 3108 ( Ar- C-H ); LCMS : M⁺+1 (475.16), MS/MS(m/z) : 444.5, 404.2; Anal Calcd. For C₂₂H₁₉F₃N₆OS: C, 55.92% ; H, 4.05%; F, 12.06%; N, 17.79%; O, 3.39%; S, 6.79%. Found: C, 55.82%; H, 4.21%; N, 17.81%; S, 7.01%.

 

6-(1-benzyl-1H-tetrazol-5ylthio)-2- (3 - (trifluromethoxy) benzyl)-4, 5-dimethylpyridazin-3(2H)-one (6c): The yield of the product 6c was 53%. Mol. Wt. 488.49, ¹HNMR (300MHz, DMSO-d6) (δ ppm)  2.39  (S, 6H) ,  5.23 (S, 2H) , 5.55 ( s, 2H),7.24 ( m, 5H), 7.32(m, 4H);  IR  (KBr) cm^-1 ; 1605 (C=O),  755 (C-S-), 1290 (C-N); LCMS : M⁺+1 (489.19), MS/MS(m/z) : 462.10; Anal Calcd. For C₂₂H₁₉F₃N₆O₂S: C, 54.09%; H, 3.92%; F, 11.67%; N, 17.20%; O, 6.55%; S, 6.56%. Found: C, 53.82%; H, 4.11%; N, 19.81%; S, 6.95%.

 

6-(1-benzyl-1H-tetrazol-5-ylthio)-2-(3, 4, 5-trifluorobenzyl)-4, 5-dimethylpyridazin-3(2H)-one (6d): The yield of the product 6d was 46%. Mol. Wt. 458.46, ¹HNMR (300MHz, DMSO-d6) (δ ppm)  2.55  (s, 6H) , 5.31 ( s, 2H), 5.55 (s, 2H),  6.5   (d, 2H), 7.4 (m, 5H) ;  IR  (KBr) cm^-1 ; 1650 (C=O),  1275 (C-N) ; LCMS : M⁺+1 (459.1), MS/MS(m/z) : 431.08; Anal Calcd. For C₂₁H₁₇F₃N₆OS:    C, 55.02% ; H, 3.74%; F, 12.43%; N, 18.33%; O, 3.49%; S, 6.99%. Found: C, 55.04%; H, 3.84%; N, 19.81%; S, 8.01%.

 

6-(1-benzyl-1H-tetrazol-5ylthio)-2-ethyl-4, 5-dimethylpyridazin-3(2H)-one (6e): The yield of the product 6e was 50%. Mol. Wt. 342.42, ¹HNMR (400MHz, DMSO-d6) (δ ppm)  1.22  (q, 2H) , 2.2 (s,6H), 3.52 (t, 3H) , 5.89 ( s,2H),7.15 (m,5H);  IR  (KBr) cm^-1 ; 1605 (C=O),  755 (C-S-), 1290 (C-N); LCMS : M⁺+1 (343.1), MS/MS(m/z) : 315.09; Anal Calcd. For C₁₆H₁₈N₆OS: C, 56.12% ; H, 5.30%; N, 24.54%; O, 4.67%; S, 9.36%. Found: C, 57.45%; H, 6.11%; N, 20.81%; S, 9.55%.

.

6-(1-benzyl-1H-tetrazol-5ylthio)-4, 5-dimethyl -2-propylpyridazin-3(2H)-one (6f): The yield of the product 6f was 55%. Mol. Wt. 356.45, ¹HNMR (300MHz, DMSO-d6) (δ ppm)  1.95  (t, 3H) , 2.21 ( m, 2H),2.83 (s, 6H) 2.12 (t, 2H), 5.75 (s, 2H), 7.24 (m, 5H);  IR  (KBr) cm^-1 ; 1612 (C=O),  742 (C-S-), 1310 (C-N) ; LCMS : M⁺+1 (357.1), MS/MS(m/z) : 329.12, 314.37; Anal Calcd. For C₁₇H₂₀F₃N₆OS: C, 57.28% ; H, 5.66%; N, 23.58%; O, 4.49%; S, 9.00%. Found: C, 59.14%; H, 4.84%; N, 24.81%; S, 8.91%.

 

3-((3-(1-benzyl-1H-tetrazol-5-ylthio)-4, 5-dimethyl-6oxopyridazin-1 (6H) -yl) methyl) benzonitrile (6g): The yield of the product 6g was 40%. Mol. Wt. 429.50, ¹HNMR (300MHz, DMSO-d6) (δ ppm) 1.55  (s, 6H) , 5.45 (s, 2H), 4.89 (s, 2H),7.15 (m, 5H), 7.25 (m, 4H); IR (KBr) cm^-1 ; 1622 (C=O), 2270 () 745 (C-S-), 1290 (C-N); LCMS : M⁺+1 (430.14), MS/MS(m/z) : 402.11; Anal Calcd. For C₂₂H₁₉N₇OS: C, 61.52% ; H, 4.46%; N, 22.83%; O, 3.73%; S, 7.47%. Found: C, 62.15%; H, 4.54%; N, 22.81%; S, 7.11%.

 

6-(1-benzyl-1H-tetrazol-5ylthio)-2-(cyclopropylmethyl) -4, 5-dimethylpyridazin-3(2H)-one (6h): The yield of the product 6h was 45%. Mol. Wt. 368.46, ¹HNMR (300MHz, DMSO-d6) (δ ppm)  0.6  (m, 5H) , 2.25 (s, 6H), 2.52 (d, 2H), 5.23 (s, 2H), 7.24 ( m, 5H),;  IR  (KBr) cm^-1 ; 1612 (C=O), 1310 (C-N) ; LCMS : M⁺+1 (369.15), MS/MS(m/z) : 341.1; Anal Calcd. For C₁₈H₂₀N₆OS: C, 58.68% ; H, 5.47%; N, 22.81%; O, 4.34%; S, 8.70%. Found: C, 57.98%; H, 6.15%; N, 22.91%; S, 8.11%.

 

6-(1-benzyl-1H-tetrazol-5ylthio)-2- (2, 4-dichlorobenzyl) - 4, 5-dimethylpyridazin-3(2H)-one (6i): The yield of the product 6i was 40%. Mol. Wt. 473.38, ¹HNMR (300MHz, DMSO-d6) (δ ppm)  2.15 (s, 6H), 5.52 (s, 2H), 5.11 (s, 2H), 7.02 ( m, 5H), 7.07(m, 3H);  IR  (KBr) cm^-1 ; 1685 (C=O), 1350 (C-N) ; LCMS : M⁺+1 (474.01), MS/MS(m/z) :445.01; Anal Calcd. For C₂₁H₁₈Cl₂N₆OS: C, 53.28% ; H, 3.83%; Cl, 14.98% N, 17.75%; O, 3.38%; S, 6.77%. Found: C, 57.98%; H, 6.15%; N, 22.91%; S, 8.11%.

 

All reagents were purchased from Aldrich and used as received.  Dry THF, Ethanol, Acetic acid were supplied by Spectrochem. All chemistry was performed under a nitrogen atmosphere using standard techniques.  All the NMR spectra were measured using either Bruker AMX 400 or Bruker DPX 300 instrument with 5mm PABBO BB-1H tubes. 1H NMR spectra were measured for approximately 0.03M solutions in d6-DMSO at 300MHZ or 400MHZ with TMS as internal reference. The IR spectra were measured as potassium bromide pellets using a Perkin-Elmer 1600 series FTIR spectrometer. LCMS were obtained using Agilent 1200 series LC and Micromass zQ spectrometer, Column chromatography was performed using a slilica gel (230-400mesh). Combustion analysis was performed on a Costech Elementel, Combution System CHNS elemental analyzer. The melting point of the 5-mercapto tetrazole with pyradizine derivatives was found using an open micro- capillary melting point apparatus with a thermometer nearby (error+ 1⁰C).

 

CONCLUSION:

We synthesized a series of novel pyridazine derivatives with 5-mercapto tetrazole in high yields. The advantages are the usage of low cost starting chemicals and simple experimental procedure. These pyridazine derivatives are also having anti-microbioal activity with thiol compounds.

 

ACKNOWLEDGEMENT:

The authors express their profound gratitude to the VME Society, Islamiah College, Vaniyambadi for the laboratory facilities provided to carry out the research work. They also acknowledge the help rendered by    Dr. K. Subramani, Department of Chemistry, Islamiah College, Vaniyambadi.

 

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Received on 25.10.2011        Modified on 11.11.2011

Accepted on 20.11.2011        © AJRC All right reserved