Some Conventional and Convenient Process for Functionalization of 6-Phenyl-4,5- Dihydropyridazinone Compounds

Nitrogen-containing heterocyclic plays an important role, not only for health science, but also in many other industrial fields related to special and fine chemistry. The interesting pharmacological activity displayed by pyridazine derivatives has been demonstrated in recent years not only by the growing number of papers and patents describing them, but also by the development of several pyridazine-based drugs and other pharmacological tools1–3. Pyridazines are important biologically active scaffolds, possessing antihypertensive and antiplatelets4,5, cardiotonic6–8, analgesic, antipyretics, anti-inflammatory9–12, central nervous system disorders13, antibacterial antifeedant, and herbicidal14–16, anticancer and anti-HIV17–19,and other anticipated activities, in particular, intermediates for drugs and agrochemicals20. Pyridazines further drew our attention because of their easy functionalization at various ring positions of pyridazine ring, which makes them attractive synthetic building blocks for designing and development of novel pyridazine based pharmacotherapeutic agents. The discovery of biological activity in a series of pyridazine derivatives stimulated the vigorous growth of investigations in this area.


Introduction
Nitrogen-containing heterocyclic plays an important role, not only for health science, but also in many other industrial fields related to special and fine chemistry. The interesting pharmacological activity displayed by pyridazine derivatives has been demonstrated in recent years not only by the growing number of papers and patents describing them, but also by the development of several pyridazine-based drugs and other pharmacological tools [1][2][3] . Pyridazines are important biologically active scaffolds, possessing antihypertensive and antiplatelets 4,5 , cardiotonic [6][7][8] , analgesic, antipyretics, anti-inflammatory 9-12 , central nervous system disorders 13 , antibacterial antifeedant, and herbicidal [14][15][16] , anticancer and anti-HIV [17][18][19] ,and other anticipated activities, in particular, intermediates for drugs and agrochemicals 20 . Pyridazines further drew our attention because of their easy functionalization at various ring positions of pyridazine ring, which makes them attractive synthetic building blocks for designing and development of novel pyridazine based pharmacotherapeutic agents. The discovery of biological activity in a series of pyridazine derivatives stimulated the vigorous growth of investigations in this area.

Chemistry of Pyridazine
Pyridazine is heterocyclic 1,2-diazine, formally derived from benzene by the replacement of two of the ring carbon atoms by nitrogen atoms. In pyridazine ( Fig.1a and 1b), two nitrogen atoms are presented adjacent to each other (Fig. 1). Pyridazine is assumed to be a planar six member ring structure and is represented as a resonance hybrid of two structures (Fig. 1a) and (Fig. 1b) with a greater contribution from the canonical structure (Fig. 1a). The 3-oxy derivatives of pyridazine are called pyridazinone. Pyridazinone compounds showed tautomeric structures (Fig. 2a) and (Fig. 2b) 21 .

Synthesis of Various 6-Arylsubstituted Pyridazinone Derivatives
Recently, a series of pyridazines have been studied, in the ongoing research program, these compounds will be subjected to further synthesis of newer pyridazinone compounds for pharmacological investigations. This study aimed at utilizing pyridazinone for the synthesis of substituted-arylpyridazinone derivatives for interesting biological activities by prompting us to synthesize a new substituted aryl pyridazinones. The compounds were characterized on the basis of spectral data (IR, 1H-NMR, mass and elemental analysis). Spectral data of the synthesized compoundswere in full agreement with the proposed structure [22][23][24] . To a solution of phenyl-4-oxobutanoic acid (0.01mol) in 20 ml ethanol, 1 ml of (80%) hydrazine hydrate was added. The reaction mixture was heated under reflux for 3 h. The solid product obtained after cooling was filtered off and crystallized from ethanol to give a compound 1 as a white crystals 25 .

Synthesis of 3-Hydrazino-6-Arylpyridazine or 6-Phenyl-Pyridazin-3yl-Hydrazine(3)
The ethanolic solution of compound 2 (0.01 mol), hydrazine hydrate (99%,10 mL), was added and the resulting reaction mixture was refluxed on a steam bath for 16 h. The mixture was concentrated, cooled and poured into crushed ice. The resulting solid compound 3was separated out and filtered, washed with water, dried and re-crystallized from ethanol 26 .

Synthesis of 6-Aryl-4,5-Dihydropyridazin-3(2H)Thione(4)
Compound 1 (0.1 mol) dissolved in xylene was refluxing with phosphorus pentasulphide(P 2 S 5 ) (0.1 mol) for 4 h at a temperature of 150°C. The contents were concentrated to a smaller volume, then crystals were obtained and collected, crystallized from ethanol and dried 27 or a solution of compound 1(0.01 mol), P 2 S 5 (0.03 mol) in dry xylene (50 mL) was boiled under reflux for 6 h. The reaction mixture was filtered while hot and the filtrate concentrated. The product 4 which separated on cooling was filtered off and recrystallized 26 .

Synthesis of 3-Imino-6-Arylpyridazine (5)
A mixture of compound 1 (0.04 mol) and ammonium acetate (12.3 g, 0.20 mol) was heated in an oil bath at 180°C for 4 h. Then the reaction mixture was poured into water and the solid separated was filtered and crystallized from ethanol 26 .

Synthesis of 2-Hydroxy-Methyl-6-Aryl-4,5-Dihydropyridazin-3(2H)-one (6)
To a solution of compound 1 (0.001 mol) in methanol (30 mL) was added formaldehyde (37-41% aqueous solution) (2.5 mL) and the mixture was refluxed for 6 h. After completion of the reaction, methanol was distilled off and the residue was poured into the crushed ice to separate out compound 6. The solid which separated was filtered and crystallized from methanol 28 , or a solution of compound 1(0.01 mol) in methanol (20 ml) was treated with formaldehyde (0.1 mol), and the reaction mixture was refluxed for 6 h. The colourless solid which precipitated after cooling, filtered off, dried and crystallized from a suitable solvent to afford compound 6, oramixture of compound1(0.01 mol), aqueous formaldehyde (10 ml, 35%) and 20 ml waterwere refluxed for 4h. The solid product obtained after cooling was filtered off and crystallized from ethanol to give 6 as white crystals.

Synthesis of 6-Aryl-2-Methyl Pyridazin-3(2H)-one (7)
The compound 1(1.2 g, 5 mmol) under solvent free condition was added potassium carbonate (0.692 g, 5 mmol), TBAB (0.3 g, 1 mmol) and methyl iodide (0.73 g, 5 mmol). The mixture was introduced into a microwave monomode reactor, fitted with a rotational system. At the end of the irradiation time (10 min, 90 W irradiation power), the mixture was cooled to ambient temperature. The precipitate formed was filtered and washed with water to give compound 7 29 .

Synthesis of 6-Phenyl-Pyridazin-3-yl-Methylamine (8)
The aliphatic or aromatic amine (1 mmol) was added to a mixture of 1 (1 mmol) in dry benzene (5 mL) and the reaction mixture was heated in an oil bath for 6 h. The solid that separated on cooling was recrystallized from benzene to give compounds 8, or Methylamine (1 mmol) was added to a mixture of compound 1(1 mmol) and the reaction mixture was heated for 4 h on an oil-bath at 140 °C then cooled and triturated with methanol. The solid that separated was recrystallized from methanol to give 8 as white crystals 22 .

Synthesis of 4-Arylidene-6-Aryl-4,5-Dihydro-Pyridazin-3(2H)-one (9)
Appropriate aliphatic or aromatic aldehyde(1 mmol) was added to a mixture of compound 1 (1 mmol), NaOH (10%) in ethanol (5 mL) and the reaction mixture was refluxed for 6 h. The solid that separated on cooling was re-crystallized from benzene to give a compound 9, orcondensation of compound 1 with appropriate aldehydeby a solution of sodium ethoxide (prepared from 0.23 g sodium and 30 ml absolute ethanol), compound 1 (0.01 mol) was added. The appropriate aldehyde (0.01 mol), was added with stirring. The reaction mixture was kept overnight the solid product obtained was filtered off and crystallized from the proper solvent, orcondensation of compound 1(0.01 mol)with appropriate aldehyde (0.01 mol) in glacial acetic acid (20 ml) and add sodium acetate (2 g.) was refluxed for 6-8 h (monitored by TLC) and cooled and poured onto ice. The solid compound was obtained and then recrystallized with ethanol, a mixture of the compound 1 (0.75 g, 0.0018 mol) and aromatic aldehydes (0.0019 mol) in ethanol (20 ml) was treated with 4% ethanolic sodium hydroxide solution (20 ml) and the whole mixture was refluxed for 3 h. The solid product which formed after cooling and acidification was filtered off and crystallized from a suitable solvent to furnish 13,30 .

Synthesis of 4-Benzylamino-2-Cyanoethyl-4,5-Dihydropyridazin-3one (10)
A mixture of compound 1(0.58 g, 0.0014 mol) and acrylonitrile (0.08 g, 0.0015 mol) in ethanol (25 ml) was treated with a few drops of 10% NaOH solution and the mixture was heated under reflux for 4 h. The colourless solid which formed after concentration and cooling were crystallized from a proper solvent to furnish 10 22 .

Synthesis of 2-(Amino-1-yl-Methyl)-6-Aryl-4,5-Dihydropyridazin-3(2H)-one (11)
A mixture of compound 1(0.001 mol), formaldehyde (0.02 mol) and secondary amines (0.002 mol) in ethanol (30 ml) was left overnight at room temperature and then heated under reflux for 3 h. The solid which formed after evaporation of most of the solvent was crystallized from a suitable solvent to obtain the compound 11, or The aliphatic or aromatic amine (1 mmol) was added to a mixture of compound 2(1 mmol) in dry benzene (5 mL) and the reaction mixture was heated in oil bath for 6 h. The solid that separated on cooling was recrystallized from benzene to give compound11, or a mixture of compound 1 (0.01mol), amine (0.02 mol), formaldehyde (2.5 ml) and methanol (50 ml) was refluxed for 5 h, then kept overnight at room temperature, then treated with H 2 O and the precipitated solid filtered and crystallized from ethanol to give compound 11 by Mannich reaction, oramixture of compound 6(0.5 g, 0.001 mol) and secondary amines Some Conventional and Convenient Process for Functionalization of 6-Phenyl-4,5-Dihydropyridazinone Compounds (0.1 g, 0.0012 mol) in ethanol (25 ml) was heated under reflux for 3 h. The solid that separated after concentration and cooling was crystallized from a proper solvent to yield a compound 11, or a mixture of compound 1(0.75 g, 0.0018 mol), formaldehyde (0.81 g, 0.027 mol) and secondary amines (0.17 g, 0.002 mol) in ethanol (30 ml) was left overnight at room temperature and then heated under reflux for 3 h. The solid which formed after removal of most of the solvent was crystallized from a suitable solvent to afford compound 11 as colourless crystal 22,31 .

Synthesis of 5-Bromo-6-Phenyl-3(2H)-Pyridazinone (12)
A stirred solution of compound 1(0.01 mol) in glacial acetic acid (20 mL) was treated dropwise with bromine (0.02 mol) at 60-70°C. The solution was further stirred for 2 hand then cooled in ice. The precipitated product was filtered off, washed with petroleum ether (40-60°C) and stirred with concentrated ammonium hydroxide for 50 min. The resulting solid product was filtered off and recrystallized to give 12, or a solution of compound 1 (0.01 mol) in glacial acetic acid (10ml) and bromine (0.01 mol) was stored at room temperature for 3 h. The solid product obtained was filtered off, washed with petroleum ether (40-60°C) and recrystallized from ethanol give compound 12.

Synthesis of 6-Phenyl-3-Hydrazinopyridazines (15)
To a solution of compound 2(0.01 mol) in absolute ethanol (50 mL), hydrazine derivatives (0.01 mol) was added and the reaction mixture was refluxed for 3 h. The solid that separated on cooling was recrystallized to give compound15 32 .

6-Phenyl-4,5-Dihydropyridazin3(2H)-Thione (16)
To a solution of compound 2(0.01 mol) in absolute ethanol (50 ml) and an equimolar amount of thiourea was added and the reaction mixture was refluxed for 4-10 h. (determined by TLC). The crude material obtained after concentration and cooling were filtered off and recrystallized from the suitable solvent to give a compound 16, thiourea (0.01 mol) was added to a solution of compound 1 (0.01 mol) in butanol (50 mL), and the reaction mixture refluxed for 5 h. The solid that separated on cooling was washed with water and recrystallized to give 16 22,33 .

Synthesis of 3-(4-Hydroxy-3-Iminnophenol)-6-Phenylpyridazinone Derivative (17)
To a solution of compound 2(0.01 mol) in absolute ethanol (50 ml) and equimolar amount of para-aminophenol was added and the reaction mixture was refluxed for 4-10 h. The crude material of compound 17 was obtained after concentration and cooling were filtered off and recrystallized from the suitable solvent to give compound 17.

Synthesis of 6-Phenyl-N-Pyridin-2-yl-Pyridazin-3-Amineor3-Iminnopyridine-6-Phenylpyridazinone Derivative (18)
To a solution of compound 2(0.01 mol) in absolute ethanol (50 ml) and equimolar amount of aminopyridine was added and the reaction mixture was refluxed for 4-10 h. The crude material 18 was obtained after concentration and cooling were filtered off and recrystallized from the suitable solvent to give compound 18.

Synthesis of 6-Phenyl-N-(Benzenesulfonyl-2-Amino-Pyrimidine)-Pyridazin-3-Amine (19)
To a solution of compound 2(0.01 mol) in absolute ethanol (50 ml) and equimolar amount of sulphadiazine was added and the reaction mixture was refluxed for 4-10 h. The crude material 19 was obtained after concentration and cooling was filtered off and recrystallized from the suitable solvent to give compound 19.

Synthesis of 6-Phenyl-N-(Benzenesulfonyl-2-Aminothiazol)-Pyridazin-3-Amine (20)
To a solution of compound 2(0.01 mol) in absolute ethanol (50 ml) and equimolar amount of sulphathiazole was added and the reaction mixture was refluxed for 4-10 h. The crude material 20 was obtained after concentration and cooling was filtered off and recrystallized from the suitable solvent to give compound 20.

Synthesis of 2-[Dialkylaminomethyl]-4,5-Dihydro-6-Phenyl-3(2H)-Pyridazinone (22)
An aqueous solution of formaldehyde(3 ml, 35%) was added to a mixture of compound 1(0.01 mol) and the appropriate secondary amine (0.02 mol) in ethanol, the reaction mixture was kept overnight at room temperature. The solid product obtained after dilution with water was filtered off and crystallized from the proper solvent to give compound 22.

Synthesis of 3-Benzylamino-6-Phenyl-Pyridazine (23)
A mixture of the compound 2 (1 mmol) and benzylamine (2 mmol) was heated inan oil bath for 6 h and the residue was triturated with diethyl ether, followed by crystallization from ethanol to give 23 as a buff powder.

Synthesis of 3-o-Carboethoxymethyl-4,5-Dihydropyridazine(24)
A mixture of compound 2 (1.8 g, 0.004 mol), anhydrous K 2 CO 3 (2.20 g, 0.016 mol), ethyl chloroacetate (1.96 g, 0.016 mol) and dry acetone (50 ml) was refluxed for 35 h. The excess acetone was removed by distillation and the reaction mixture then poured into water and the content was extracted with ether. After evaporation of the dried ethereal solution, the solid that separated was crystallized from a suitable solvent to afford the corresponding ester 24.

Synthesis of 6-Phenyl-Pyridazin-3-yl-Trimethylammonium Iodide(26)
Excess methyl iodide (5 mL) was added to a mixture of compound 2 (1 mmol) in methanol (10 mL) and the reaction mixture was refluxed for 8 h. After evaporation of all the solvent, the solid residue was recrystallized from methanol to give 26 as white crystals.

Synthesis of1,2,3,4-Tetrazolo[1,5-b]-7,8-Dihydropyridazine(30)
To a solution of compound 3(0.52 g, 0.0012 mol) dissolved in 10% aq. HCl (10 ml) was added a solution of sodium nitrite (0.1 g, 0.0014 mol) dissolved in water (2 ml) dropwise under cooling and the mixture was allowed to stand for 45 min. The mixture was basified with solid NaHCO 3 , extracted into CHCl 3 and the organic layer was dried (Na 2 SO 4 ). The solvent was removed in vacuo and the residue was crystallized from a proper solvent to give 30.

Synthesis of 4-Benzylamino-3o-(pht-or tos-amino acid)-4,5-Dihydropyridazine Derivatives(39a and 39b)
An N-phthalyl or N-tosylamino acids, namely, glycine and DL-alanine (0.001 mol) and compound2 (0.5 g,0.001 mol) were dissolved in tetrahydrofuran (50 ml). The reaction mixture was cooled to 0 °C , then dicyclohexylcarbodiimide (0.021 g) was added and the mixture stirred for 2 h at 0 °C , left for 24 h at 0 °C and for another 24 h at room temperature. The dicyclohexylurea was filtered off, the filtrate evaporated in vacuo and the residue recrystallized from a suitable solvent to furnish compound 39a and 39b respectively. The reaction of 6-aryl-4,5-dihydropyridazinone (1) with formaldehyde and secondary amines under goes Mannich reaction and/or ethylchloro acetate, benzenesulfonyl chloride in boiling ethanol in the presence of potassium carbonate (K 2 CO 3 ) afforded the substituted pyridazinone derivatives, respectively. Interestingly, the reaction of compound 1 with monochloroacetic acid in dry acetone/K 2 CO 3 yielded the 2-methyl pyridazinone derivativethrough nucleophilic substitution and decarboxylation. The 2-methyl pyridazinone (7)can be prepared through an alternative route, by reacting with compound 1 with methyl iodide in dry acetone/K 2 CO 3 to give the compound 7. Treatment of compound 1 with bromine-acetic acid mixture afforded compound 12. The formation of this compound can be explained on the basis that the first step is dehydrogenation followed by addition of bromine on the formed double bond and the elimination of hydrogen bromide. The behaviour of pyridazinone derivative 1towards electrophilic reagents like POCl 3 gave 3-chloro pyridazine derivative 2, by substitution of the enolic hydroxyl group with chlorine together with dehydrogenation. The compound 2 has been used as starting material for the preparation of a series of new compounds. Thus, reaction of compound 2 with hydrazine hydrate and/or phenylhydrazine gave the hydrazine derivatives 3, respectively. The reaction of compound 2 with thiourea in absolute ethanol gave the pyridazine-thione 4, while the reaction of compound 2 with sodium azide in DMF gave tetrazolopyridazine derivative. The behaviour of compounds 1towards carbon electrophiles, namely, ethyl chloroacetate, acrylonitrile, formaldehyde and secondary amines (Mannich reaction), aromatic aldehydes and carbon nucleophiles, namely, POCl 3 /PCl 5 and P 2 S 5 has been investigated. The compound 2 reacts with hydrazine hydrate to give the 3-hydrazino derivative (3).On treatment with ethyl acetoacetate and/or acetylacetone with the compound 3undergoes cyclization to afford pyrazolone derivative and 3-(3,5-dimethylpyrazol-1-yl)-pyridazine derivative, respectively. On reaction with acetylhydrazine in boiling butanol and/or sodium azide in DMF the compounds 2 affords the triazolo [4,3-b]pyridazine and the tetrazolo [1,5-b]pyridazine, respectively.Reactivity of pyridazinone, which bears bulky heteryl moieties at position 4 and 6 and the effects of steric hindrance of these groups has been studied with different carbon electrophiles and nitrogen nucleophiles. Thus, pyridazinone reacted with ethyl chloroacetate in boiling dry acetone and dry K 2 CO 3 to afford 3-o-carboethoxymethyl-4,5-dihydropyridazine. Thus, on treatment of 2 with acrylonitrile in boiling ethanol containing catalytic amounts of aqueous sodium hydroxide solution, a Michael-type addition occurred at the activated double bond and afforded the 2-cyanoethyl-4,5-dihydropyridazin-3-one (Wasfy 2002) 24 , On the other hand, 2-hydroxymethyl derivative 7 which on cyclocondensation with urea yielded 9-benzylamino-2,3,4,8,9-pentahydropyridazino[1,6-a]-1,3,5-triazin-2one (8). In continuation, we considered to synthesize novel congeners bearing pyridazine and amino acid moieties in a single molecular framework. Thus, compound 2 reacted with phthalyl and/or tosyl derivatives of the amino acids glycine and/or DL-alanine to furnish 3-o-(phtor tos-amino acid)-4,5-dihydropyridazine derivatives, respectively.
The pyridazinones have also been used as the key material for the synthesis of some new heterocyclic compounds. Thedifferent synthetic methods are used for the synthesis of 6-aryl-pyridazinone derivatives by using different reagents [34][35][36][37][38][39] . The reactions of pyridazinones with PCl 5 /POCl 3 , arylsulphonyl chloride derivatives, aliphatic/ aromatic aldehydes and towards reaction with hydrazine hydrate, carbohydrate hydrazones, aliphatic/aromatic amines, etc. Sometimes the incorporation of amino acid residues in various sulfur-and nitrogen-containing heterocycles enhances the biological profile much folds over that of its parent nucleus 40-44 .

Conclusion
Pyridazine belongs to an important group of heterocyclic compounds and lot of research work on has been done in the past. The pyridazine moiety possesses almost all types of pharmacological activities and also used as intermediates for drugs and agrochemicals agents. Recently, pyridazine derivatives have received considerable interest due to their wide range of applications. We encouraged by these reports, series of pyridazines containing a substitution of a different group at the different position hoping to improve the biological activities of these compounds in the future. Pyridazines further drew our attention because of their easy functionalization at various ring positions, which makes them attractive synthetic building blocks for designing and development of novel pyridazines [45][46][47][48][49][50] . The structures of all newly synthesized compounds were established from their spectral data and elemental analysis. By the present scenario, it can be concluded that pyridazinone have a great potential which remains to be disclosed till date.The discovery of biological activity in a series of pyridazine derivatives stimulated the vigorous growth of investigations in this area.