Regioselective one-pot , three component synthesis of ethyl 6-aryl-3-propylpyridazine-4-carboxylates in water

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Introduction
Chemical processes that allow assembly of several building blocks in a single operation are gaining increasing attention in the search for new efficient, diversity-oriented synthetic methodologies, and particularly those directed toward heterocyclic compounds.9][10] The chemistry and pharmacology of pyridazine derivatives have recently received considerable interest.2][13][14] The pyridazines and their derivatives exhibit a broad range of biological activity, such as analgesic, 15 antibacterial, 16 anti-inflammatory, 11 antihypertensive 17 or antihistaminic 18 properties.The derivatives of pyridazines could also find application as ligands in metallic complexes which possess catalytic properties. 19,20These compounds could also be used as semi-conductor materials and as materials with non-linear optical properties. 21hese pharmacological and technological properties of pyridazines encourage the development of methods for their synthesis and functionalization.In continuation of our interest in the synthesis of various pyridazine derivatives, [22][23][24][25][26] we decided to investigate the three-component reaction of arylglyoxals, ethyl butyrylacetate and hydrazine hydrate which is extended to the regioselective synthesis of ethyl 6-aryl-3-propylpyridazine-4-carboxylates as a new series of three substituted pyridazines.

Scheme 1: Synthesis of ethyl 6-aryl-3-propylpyridazine-4-carboxylates
All of the obtained products were listed at the Table 1.Formation of the 6-aryl substituted pyridazines as sole products proves this fact that the outlined strategy acts regioselectively and there is no evidence for production of 5-aryl substituted isomers.The mechanism of the regioselective synthesis of the products was shown in Scheme 2.
Owing to the high reactivity of the external carbonyl in comparison with internal carbonyl in an arylglyoxal system, the reaction was run through the nucleophilic attack of enol (15) to the aldehyde carbonyl of arylglyoxal (6) leading to form the intermediate (16) as a sole product.The subsequent condensation of hydrazine with the carbonyl groups of the intermediate (16) gives the final product (13).
Table 1.List of pyridazine products.

Conclusions
We have synthesized some new three substituted pyridazines via one-pot three component reaction of arylglyoxals, ethyl butyrylacetate and hydrazine hydrate in water at room temperature.The simple operation, the high regioselectivity and the convenient reaction condition of this procedure makes it a valuable route to prepare new substituted pyridazines.
Matt 311 spectrometer operating at nominal accelerating voltage of 70 eV.Thin layer chromatography (TLC) was run on silica percolated aluminium plates (Merck Kieselgel F254).Melting points were determined on a Kofler hot-stage apparatus.

Sample procedure for pyridazine synthesis.
To a mixture of ethyl butyrylacetate (1 mmol) and arylglyoxal 27 (1 mmol) in water (5 mL), was successively added hydrazine hydrate (5 mmol) at room temperature; the resultant mixture was stirred for 20-35 min during which time a precipitate was formed.The precipitate was then filtered and washed with excess water.The crude product was purified by recrystallization from ethanol.