Pyridazines with acetylenic esters

Since the report by Carboni and Lindsey in 1959 on the cycloaddition reaction of tetrazines to multiple bonded molecules as a route to pyridazines, such reactions have been extensively studied. In addition to acetylenes and ethylenes, enol ethers, ketene acetals, enol esters and enamines, and even aldehydes and ketones have been used as starting materials for pyridazines. A detailed investigation of various 1,2,4, 5-tetrazines in these syntheses revealed the following facts. In [4 + 2] cycloaddition reactions of 3,6-bis(methylthio)-l,2,4,5-tetrazine with dienophiles, which lead to pyridazines, the following order of reactivity was observed (in parenthesis the reaction temperature is given) ynamines (25°C) > enamines (25-60°C) > ketene acetals (45-100°C) > enamides (80-100°C) > trimethylsilyl or alkyl enol ethers (100-140°C) > enol... 

Addition of dimethyl acetylene dicarboxylate to the C-glycosyldiazo-methanes 279 formed the pyrazol-3-yl C-nucleoside 280. Annulation of a pyridazine ring to 280 was accomplished by cyclocondensation of their ester groups with hydrazine hydrate to produce 281 [70JCS(CC)313,70TL4611 72CCC2798] (Scheme 86). 

This process works best when the tetrazine has electron-withdrawing snbstitnents, but 1,2,4,5-tetrazine itself will react with a range of simple aUcynes, enamines and enol ethers, nnder quite moderate condi-tions. A wide range of substitnents can be incorporated via the acetylene, including nitro and trimethyl-silyl, affording the means to access other snbstitnted pyridazines. The preparation of a boronic ester is another example. 

Because 3-chloropyridazines were not found to be very reactive in palladium coupling reactions and the bromo and iodo analogues are not readily available, the preparation and use of triflate esters of pyridazines have been developed. The readily prepared triflates undergo coupling with terminal acetylenes in the presence of palladium and copper iodide (Equation (27)). Reactions are rapid, normally complete in 0.5 to 6 hours at room temperature, and yields are high. In a comparative experiment 3-chloro-4-methyl-6-phenylpyridazine with 3,3-dimethyl-3-hydroxy-l-propyne gave only a 33% yield of 3-(3,3-dimethyl-3-hydroxy-l-propynyl)-4-methyl-6-phenylpyridazine after 12... 

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