3- Aryl-1,4,5,6-tetrahydropyridazines

The addition of phenyllithium to 6-arylpyridazin-3(2Er)-one takes place at position 6 to give 6-aryl-3-oxo-6-phenyl-l,2,3,4-tetrahydropyridazine and the reaction of 6-aryl-2,4-diphenylpyridazin-3(2H)-one with phenyllithium or phenylmagnesium bromide affords 6-aryl-2,3,4,6-pentaphenyl-l,2,3,4-tetrahydropyridazine (80S457). 

In some instances, ring contraction is accompanied by cyclization to indole derivatives. For example, l-aryl-6-oxo-l,4,5,6-tetrahydropyridazines with a carboxyl or methyl group at position 3 give indoles when treated with an ethanolic solution saturated with hydrogen chloride or in the presence of BF3 etherate. 

Aryl-2-phenyl-4,5-dihydropyridazin-3(2//)-ones react either with phenylmagnesium bromide or with phenyllithium to give 6-aryl-2,6-diphenyl-l,4,5,6-tetrahydropyridazin-3(2//)-ones (135) (products of 1,2-addition to the azomethine bond), while 2-methyl-6-phenyl-4,5-dihydropyridazine-3(2//)-one reacts with two equivalents of phenylmagnesium bromide at the carbonyl and azomethine group to produce 2-methyl-3,3,6,6-tetraphenyl-hexahydropyridazine (136) (Scheme 53) (80JPR617). 

There are some recent examples of this type of synthesis of pyridazines, but this approach is more valuable for cinnolines. Alkyl and aryl ketazines can be transformed with lithium diisopropylamide into their dianions, which rearrange to tetrahydropyridazines, pyrroles or pyrazoles, depending on the nature of the ketazlne. It is postulated that the reaction course is mainly dependent on the electron density on the carbon termini bearing anionic charges (Scheme 65) (78JOC3370). 

A large number of pyridazines are synthetically available from [44-2] cycloaddition reactions. In one general method, azo or diazo compounds are used as dienophiles, and a second approach is based on the reaction between 1,2,4,5-tetrazines and various unsaturated compounds. The most useful azo dienophile is a dialkyl azodicarboxylate which reacts with appropriate dienes to give reduced pyridazines and cinnolines (Scheme 89). With highly substituted dienes the normal cycloaddition reaction is prevented, and, if the ethylenic group in styrenes is substituted with aryl groups, indoles are formed preferentially. The cycloadduct with 2,3-pentadienal acetal is a tetrahydropyridazine derivative which has been used for the preparation of 2,5-diamino-2,5-dideoxyribose (80LA1307). 

Reaction of l-aryl-3-carbethoxy-6-phenyl-l,4,5,6-tetrahydropyridazin-4-ones 718 with activated olefins such as benzalacetophenone, benzalacetone, 3-benzylideneacetylacetone, diethyl 2-benzylidenemalonate, and a-cyano-/3-phenylacrylic acid in the presence of an organic base like pyrrolidine, morpholine, piperidine, or triethylamine gave the corresponding 2,8-dihydro-l//-pyrano[2,3-t7 pyridazines 719-723, respectively. The 1-oxo- and 1-imino derivatives of the pyrano[2,3-r/ pyridazine ring system were also prepared from the respective 6-oxo or 6-imino derivative of the starting pyridazine 718 under the same conditions (Equation 60) <1989IJB733>. 

Pyridazines, particularly 1,2,3,6-tetrahydropyridazines (38), can be prepared via the Diels-Alder reaction. This is a good synthetic route for obtaining various alkyl- or aryl-substituted pyridazines. The most used dienophile for tetrahydropyridazine syntheses is a... 

For example, mixing 6-oxo-3-styryl-l,4,5,6-tetrahydropyridazine with a three- to fourfold molar excess of certain aryl and a-naphthylmagne-sium bromides has been reported to yield the 4,5-dihydropyridazine 68... 

The amino nitrogen of 2,3,4,5-tetrahydropyridazines behaves normally and reacts with methyl isothiocyanate to give the 2-(Af-methylthiocarbamoyl) derivative <84JHC889>. Similarly, both 1,2,3,6-tetrahydropyridazine and its 1 -ethoxycarbonyl derivative react with arylisocyanates (Scheme 43) to give high yields of aryl carbamoyl derivatives <93JHC45>. 

The synthesis of pyridazine derivatives from hydrazones includes the thermal cyclization of 2-arylhydrazono-3-oxo-5-phenyl-4-pentenenitriles (readily obtained from ethyl cinnamate by condensation with acetonitrile followed by Japp-Klingemann type reactions) to l-aryl-3-cyano-6-phenyl-5,6-dihydro-4(l//)-pyridazinones (Scheme 85) <86JHC93>, and base-induced cyclization of a hydrazone of a 4-chloro-l-arylbutan-l-one to prepare a 2,3,4,5-tetrahydropyridazine (Scheme 85) <88JHC1543>. An earlier route to 6-carboxy-5-hydroxy-2-phenyl-3(2//)-pyridazinone via condensation of benzenediazonium chloride and dimethyl acetonedicarboxylate has been adapted to give a series of aryl derivatives either as esters (by thermal cyclization) or as acids (by cyclization with hydroxide). Both cyclizations proceed in high overall yield (Scheme 86) and decarboxylation of the acids also proceeds in high yield <89JHC169>. 

This reaction has been modified to occur under solid-supported condition or under microwave irradiation. In addition, the base-promoted transformation from ketazine into pyrrole has also been established by the treatment of alkyl aryl ketazine with two equivalents of strong base, such as LDA. However, such reaction can lead to the formation of pyrrole, tetrahydropyridazine, or pyrazole, depending on the nature of ketazine. In general, the ketazine dianions with an electron-donating group at their carbon termini form pyrroles, whereas ketazine dianions without a substituent at the terminal carbon or with an electron-withdrawing group at the terminal carbon yield tetrahydropyridazines and pyrazoles. ... 

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