Pyridazine reaction with enolates

The coupling of enals and glyoxals was realized by hydrogen-mediated reaction with the cationic Rh complex and PI13P [35]. The intermediate aldehyde enolates derived via Rh-catalyzed hydrogenation were trapped with glyoxals to form (l-hydroxy-y-kclo-aldchydes, which were treated sequentially with hydrazine to give pyridazines in a one-pot transformation to provide, for example, a 62% yield of 72 (Scheme 21). 

Conversion of other heterocyclic systems into pyridazines has also been used, for example the reaction of 3-aminopyrone 9 with hydrazine, followed by oxidative aromatisation <06T9718> and the more unusual utilisation of a 1,2,4-triazole 10 as the source of the N-N unit <06T8966>. In this latter transformation, the intermediate quaternary salt 11 was isolable. An even more unusual example was the reaction of the diazetidine 12 with enolates <06S2885>. 

Pyridazines can be activated to addition in a similar fashion in a reaction with silyl enol ethers 295, attack in the (296) and (297) positions occurred <1997H(46)83>. 

Cyclic enol ethers give first the intermediate bicyclic dihydro-pyridazine adducts that isomerize by ring cleavage to pyridazines with hydroxyalkyl or alkoxyalkyl substituents. Several other alkenes were also used in the reaction with tetrazines to give pyridazines. ... 

Di- and trihalohydrazones react with enol ethers or enamines in the presence of base to give pyridazines via the intermediacy of an azadiene. The final pyridazine may be formed directly in the reaction mixture or with intermediate di- or tetrahydro-intermediate isolated and further treated with base. ... 

The enolate ions of aliphatic ketones can react in the dark with iodobenzene and its derivatives in DMS07> The occurrence of these spontaneous initiations is facilitated by the electron affinity of the substrates and the 55°C increment in temperature with respect to liquid ammonia in which no dark reaction takes place. Other substrates that can react in the dark with enolate ions of ketones are halo-substituted pyrimidines, " pyrazines, " pyridazines, " and quinoxalines." Although some reactions occur in the dark, photostimulation is recommended to achieve higher yields of substitution in shorter reaction times. 

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

Other syntheses involve the preparation from the monoacetate of the enolic form of nitrosuccindialdehyde/ or the dibenzoyldioxime of maleic aldehyde/ or by dehydrogenation of l-tosyl-l,4-dihydro-pyridazine. From 2,5-diacetoxy- or 2,5-dimethoxy-2,5-dihydro-furan pyridazine can be obtained in high yield. Maleic aldehyde has been obtained also when decomposing the adduct obtained in the Diels-Alder reaction between furan and diethyl azodicarboxylate and straightforward condensation with hydrazine afforded pyridazine in 55% yield.Another direct reaction involving maleic aldehyde... 

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... 

Pyridazine and its derivatives were substituted with nucleophilic radicals. They react either with 1-formylpyrrolidine or with A/-acetylproline in the presence of radical generators to give 5-substituted pyridazines (78TL619 86MI6). Also, reactions of 3-chloro-6-methoxypyridazine with ketone enolates in liquid ammonia show typical characteristics of a radical chain (SrnI) mechanism, and ketones 105 are obtained (81JOC294). 

---