Reaction of chloropyridazin-3 ( 2 H )-ones with iodide ion . Part II

The reactions of 5-chloro-6-phenyl-,4,5-dichloro-6-phenyland 5-chloro-6-(2,4-dichlorophenyl)2-methylpyridazin-3(2H)-ones with 57% aqueous hydrogen iodide or sodium iodide in dimethyl formamide, respectively, are described. Upon treatment of chloro compounds with 57% hydrogen iodide, besides nucleophilic substitution of chloroby iodo substituent, subsequent hydrodeiodination also occurred. Thus, e.g. 4,5-dichloro-2-methyl-6-phenylpyridazin-3(2H)-one gave first 5-chloro-4-iodo-2-methyl-6-phenylpyridazin-3(2H)-one and in the next step, 5-chloro2-methyl-6-phenylpyridazin-3(2H)-one. Similarly, treatment of 5-chloro-2-methyl-6phenylpyridazin-3(2H)-one led to the formation of 5-iodo-2-methyl-6-phenylpyridazin-3(2H)one and 2-methyl-6-phenylpyridazin-3(2H)-one. The structure of each new product was proved by H, C and partly by N NMR spectroscopy.


Introduction
2][3] Their simple and straightforward preparation is based on a nucleophilic halogen displacement reaction.This was carried out by the treatment of chloropyridazine have been treated with 57% hydrogen iodide, 4,5 hydrogen iodide with iodine monochloride 6 or hydrogen iodide with sodium iodide 7 as iodide source.
11b In a more recent paper, a detailed mechanistic study was also reported 11a .It was supposed that formation of 5-iodo-2-methylpyridazin-3(2H)-one might proceed via nucleophilic substitutions of both chlorine atoms in positions 4 and 5 by iodine once, followed by selective mono deiodination reaction.Our DFT calculations suggested that the 5-iodo substituent might preferably facilitate the formation of a more stable anionic intermediate in the 4hydrodeiodination reaction in comparison with the formation of the respective intermediate in the case of 5-hydrodeiodination.Fully in accord with this explanation, it was found that in case of the 6-nitro derivative, the regiochemistry of the reductive dehalogenation changed, resulting in the formation of a product with a different regioisomeric substitution pattern.
This rather interesting mechanism, and the high synthetic importance of monoiodopyridazinone derivatives prompted us to investigate these transformations further.In this paper, we report on the reactions of 6-phenyl-chloropyridazinones 1-3 with 57% hydrogen iodide or sodium iodide in dimethyl formamide (DMF), respectively, under various reaction conditions.The products (both in the crude reaction mixtures and after separation) were characterized by NMR spectroscopy and in pure form also by elemental analysis.
Upon heating 4,5-dichloro-2-methyl-6-phenylpyridazin-3(2H)-one 2 with 57% hydrogen iodide at different temperatures for various periods of time (Table 1) the reaction temperature was found to influence the composition of the product mixture to a larger extent than the reaction duration (Scheme 4).At a moderately high temperature (120 o C) and for a short reaction time (2h) the substitution of chlorine-by iodine atom in position 4 was predominant, the main product was 5-chloro-4-iodo-2-methyl-6-phenylpyridazin-3(2H)-one 9.It is noted that 5-chloro-4iodopyridazinones were prepared earlier by Stevenson et al. 18 and Haider et al. 19 starting from 3chloro-2-iodomalealdehydic acid. 20At a somewhat higher temperature (140 o C) a dramatic change occurred and the 4-deiodinated 5-chloro-2-methyl-6-phenylpyridazin-3(2H)-one 1 was the main product.A further increase of the temperature to 155 o C did not bring about substantial changes but prolonged heating resulted in a considerable increase in the amount of the substitution product 5-iodo-2-methyl-6-phenylpyridazin-3(2H)-one 7.This observation supports the idea, that the 5-chloro-4-iodo derivative 9 might be the first intermediate in the reaction pathway starting from 2. The higher temperatures and the longer reaction time are favourable for the deiodination of 9 although the main product remains the 5-chloro-2-methyl-6phenylpyridazin-3(2H)-one 1 even after heating at 155 o C for 25 hours.The experiments starting with 1 and 2 (Table 1) indicate that the iodine atom at position 4 exhibits an enhanced tendency toward reduction by hydrodeiodination.While the rate of substitution of the chlorine atom at position 5 in compound 1 is very low deiodination of 7 is faster.Scheme 3. Proposed pathway for the formation of 2-methyl-6-phenylpyridazin-3(2H)-one 8 from 5-halo-or 4,5-dihalo-derivatives.
The reaction sequence proposed for the transformations of chloro substituted phenylpyridazinones 1 and 2 is depicted in Scheme 3. Noticeably, that, in contrast with earlier assumptions, 4,5-diiodo-6-phenylpyridazin-3(2H)-one 10 could not be detected, which means that its formation is possible only as a reactive intermediate undergoing very fast conversion to 5-iodo-6-phenylpyridazin-3(2H)-one 7.
As another model compound 5-chloro-6-(2,4-dichlorophenyl)-2-methylpyridazin-3(2H)-one (3) was heated with hydrogen iodide at 150 °C.After 60 hours 6-(2,4-dichlorophenyl)-2-methylpyridazin-3(2H)-one 11 was obtained in a yield of 52% (Scheme 4), other congeners could not be detected in the crude reaction mixture.Thus, under these conditions 3 underwent nucleophilic substitution and subsequent dehalogenation affording 11 while, as expected, the chloro substituents on the phenyl ring did not take part in these reactions.In an alternative series of the displacement reactions sodium iodide was applied as iodine source.Thus, compounds 1-3 were heated with NaI in dimethyl formamide (DMF) at 150 °C for 60 hours.Under these conditions the 5-monochloro compounds 1 and 3, remained practically unchanged while 4,5-dichloro-6-methyl-2-phenylpyridazin-3(2H)-one 2 gave a multicomponent mixture.These results are consistent with our earlier obsevations 11 that, contrary to monochloropyridazinone derivatives, only 4,5-dichloropyridazinones are reactive enough to interact with sodium iodide.The situation with 57% hydrogen iodide is different because under strongly acidic conditions the pyridazinone derivatives are expected to be activated by protonation at the carbonyl oxygen.The preferred O-protonation of pyridazinones has been evidenced by experimental and theoretical studies 21 on compounds related to our present model compounds.The enhanced electron-deficiency of the cationic intermediates facilitates the attack of iodide ion making possible the substitution reactions of monochloropyridazinones, too.

Conclusions
By using hydrogen iodide, chloropyridazinones could be converted into iodo derivatives which underwent a reductive deiodination reaction.The regiochemistry of the substitution is independent of the 6-phenyl substituent.Eventual chloro substituents on the phenyl ring were not replaced by iodine.In the case of 4,5-dichloro-6-phenylpyridazinone, the first step is the displacement of the 4-chloro atom by iodine.Our results indicate that dichloropyridazinones could be transformed into monoiodopyridazinones with a predictable regiochemistry.Unfortunately, due to the presence of the phenyl ring, the substitution of the 5-chloro atom is rather slow, and the subsequent reductive deiodination reduction may proceed to completion.This is why the reaction mixtures can be more complex than in case of 6-hydrogen or 6-nitro pyridazinone derivatives studied earlier, and monoiodopyridazinones important from the synthetic aspects cannot be isolated in pure form.As main products halogen-free pyridazinone derivatives are formed.On the other hand, when using sodium iodide as an iodide ion source, reaction occurred only in the case of a 4,5-dichloropyridazinone but gave a very complex mixture.

Reactions with sodium iodide
The chloro substituted 2-methyl-6-phenyl-pyridazin-3(2H)-one 1, 2 or 3 (10.0mmol) was dissolved in DMF (20 mL), sodium iodide (3.0 g, 20.0 mmol) was added and the solution was heated under reflux for 1 hour.Sodium iodide (1.50 g, 10.0 mmol) was again added and the mixture was refluxed for 1 hour.After addition of another 1.50 g portion of sodium iodide the mixture was refluxed for a total of 60 hours.Then DMF was removed in vacuo, an aqueous solution (10%) of sodium thiosulfate was added to the residue until the colour of iodine disappeared.The solution was extracted with chloroform (4x30 mL), the combined organic layers were dried, filtered and the solvent was evaporated.The obtained crude product was analysed by 1 H NMR. 1 and 3 were found practically unchanged, yields of recovery: 80% and 85%, resp., while starting with 2 a multicomponent mixture was formed.

Table 1 .
Relative ratios of compounds 1