Chemical Studies on 3,6-Dichloropyridazine (Part 2)

Abstarct: 3,6-Dichloropyridazine (1) reacted with 2-aminophenol, phenylalanine, acetophenone hydrazone derivatives, acid hydrazide derivatives and amino-aromatic acids (anthranilic acid and 5-bromoanthranilic acid) and yield the compounds (2), (3), (4a,b), (5a,b) and (6a,b) respectively. Reaction of compounds (5a,b) with acid hydrazide gave (8a,b). Also, compounds (6a,b) reacted with aromatic amino acid and gave (7a-c).


Introduction
The present work is an extension to our studies on the preparation of some fused heterocyclic compounds using 3,6-dichloropyridazine as a starting material 1 . Many derivatives of pyridazine have been synthesized when compound (1) is allowed to react with oxygen 2,3 , sulfur 4 , nitroge 5,6 and halogen nucleophile [7][8][9] . It has been pointed out that they possess extremely excellent biological activity 10 .
2-Chloro-and 2,6-dichloropyridazine are mainly found as medical and agricultural drug intermediate and pyridazine derivatives have been extensive therapeutic potential 11 and other medical and technological applications 12 as antibodies and antihypertensive agents 13,14 .

Experimental
All melting points are uncorrected and were determined on Gallenkamp electric melting point apparatus. IR spectra (KBr disc) were recorded on a FT/IR-400 spectrophotometer (Perkin Elmer). 1 H NMR spectra were recorded on a varian-300 (DMS-d 6 ) solution. Chemicals shifts are reported as δ values relative to tetramethylsilane (TMS) as internal reference. The elemental analyses were carried out at micro analytical center, Cairo University.

Reaction of compound (1) with L-phenylalanine; formation of compound (3)
A mixture of compound (1) (0.01 mole) and L-phenylalanine (0.01 mole) or (0.02 mole) was heated in oil bath at 180-200 °C for 3 h. The reaction product was washed with water and crystallized from ethanol into (3) ( Table 2).

Reaction of compound (1) with acetophenonehydrazone derivatives; formation of compound (4a,b)
A mixture of compound (1) (0.01 mole) and acetophenonehydrazone derivative (0.01 mol), was heated in oil bath at 160-180 °C for 4 h. The solid formed after cooling was collected and recrystallzien from the proper solvent into compounds (4a,b) ( Table 2).

Reaction of compound (1) with acid hydrazides; formation of compound (5a,b)
A mixture of compound (1) (0.01 mole) and acid hydrazides, namely (benzoylhydrazine and 4-aminobenzoylhydrazine) (0.01 mole) in 20 mL n-butanol was heated under reflux for 8 h; the reaction mixture was left to cool, the solid produced was collected and recrystallized from the proper solvent into compounds (5a,b) ( Table 2).

Reaction of compound (1) with aromatic amino acids; formation of compounds (6a,b)
Heat under reflux in 20 mL n-butanol a mixture of compound (1) (0.01 mole) and aromatic amino acids namely (anthranilic acid and 5-bromoanthranilc acid) (0.01 mole) for 7 h. The solid produced after cooling was collected, dried and recrystallized from the proper solvent into compounds (6a,b) ( Table 2).

Results and Discussion
When compound (1) was allowed to react with orthoaminophenol in refluxing butanol it afforded the chlorobenzoimidazolopyridazine (2) (Scheme 1). The structure of compound (2) was confirmed from its correct analytical and spectral analysis (Table 1 and 2). Also, compound (1) reacted with phenylalanine by heating in oil bath at 160-180 °C it yield imidazolo pyridazine derivative (3) (Scheme 2). The chemical structure of compound (3) was elucidated from its correct analytical and spectral data ( Table 1 & 2).
Heating a mixture of compound (1) and acetophenone hydrazone derivatives in an oil bath at 180-200 °C afforded the triazolopyridazine derivatives (4a,b) (Scheme 1).The structure of compounds (4a,b) was proved from their correct elemental and spectroscopic analysis (Table 1&2).