Tetrahydropyridazines, addition reactions

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). 

Azo compounds are reactive dienophiles. Indeed, one of the very first Diels-Alder reactions was the addition of diethyl azodicarboxylate to cyclopentadiene (equation 134)128 129. Other early examples of the reaction are the formation of tetrahydropyridazines from indazolone 252 and phthalazinedione 253 (equations 135 and 136)130. 

Pyridazines and their partially saturated analogs have been prepared on insoluble supports by Diels-Alder reaction of electron-rich alkenes or alkynes with 1,2,4,5-tetrazines (Entries 1-3, Table 15.27). The mechanism of this reaction is outlined in Figure 15.15. An additional approach, also based on the Diels-Alder reaction, is the cycloaddition of azo compounds to 1,3-dienes (Entries 4 and 5, Table 15.27). The resulting tetrahydropyridazines (Entry 4) have been used as constrained 3-strand mimetics for the discovery of new protease inhibitors [323], An example of the N-alkylation of hexahydropyridazines on solid phase is given in Section 10.3. 

Relative rates have been determined for the competitive methylations and also acetylations of azines. Pyridazine reacts faster than pyridines in both reactions this is interpreted in terms of pair-pair electron repulsion and the a-effect. An additivity approach provides reasonable predictions of isomer ratios of quatemization products of pyridazine and other azines. Reinvestigation of the quatemization of various amino- and diamino-pyridazines with methyl iodide shows that both 1- and 2-methyl derivatives were usually formed. 3-Amino-6-chloropyridazine forms JV2-quateraary salts with a- and -halo esters and 1,4-dibromobutane, but with 1 -dibromo-ethane or 1,3-dibromopropane bicyclic products, are formed. Protonation and quatemization of l,4,S,6-tetrahydropyridazines takes place at position 1, this being the more basic nitrogen. ... 

Reaction of monosubstituted hydrazines with the readily available spirocyclic cyclo-propanedicarboxylates (163) gives 1-substituted l,4,5,6-tetrahydropyridazin-3(2/i)-ones (164) in a one-pot reaction (Scheme 123). Initial attack is thought to be a homo-Michael type of addition by the substituted hydrazine nitrogen decarboxylation occurs under the reaction conditions. The formation of the alternative pyridazinone (165) by attack of the unsubstituted hydrazino nitrogen was only observed (<5%) with (4-chloro-2-methylphenyl)hydrazine <93H(36)219>. 

Pyridazine derivatives are also obtained by [4+2] cycloadditions. For instance, the tetrahydropyridazines 15 are produced by a Diels-Alder reaction from 1,3-dienes with azodicarboxylic ester. The pyridazines 17 are produced by addition of alkynes to 1,2,4,5-tetrazines followed by a retro-DiELS-Alder reaction of the adducts 16 with N2 elimination ... 

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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