Tetrahydropyridazines, addition

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). 

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). 

The steric course of electrophilic additions of BrN3, IN3, and iV-bromosuccinimide (NBS) to the tetrahydropyridazine ring of benzo[g]pyridazino[l,2- ]phthalazine-6,13-dione system, for example, 130, has been studied and the results are shown in Scheme 12 <1997CJC348>. 

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. 

The course of electrophihc additions (NBS, BrN3 or IN3) to the tetrahydropyridazine moiety of (12) has been elucidated and shown to be controlled by conformational factors (Scheme 4).29... 

Tetrahydropyridazines with unsubstituted NH groups behave as secondary amines the double bond has been hydrogenated with lithium aluminum hydride and addition of hydrogen cyanide is known. Oxidation of 3,6-diphenyl-1,4,5,6-tetrahydro-pyridazine with lead dioxide results in aromatization. ... 

Upon heating a mixture of benzaldehyde and hydrazine salt in the presence of styrene (2 1 6 molar mixture), in addition to 1,5-diazabicyclo [3.3.0] octane, 3,5,6-triphenyl-l,4,5,6-tetrahydropyridazine was obtained as byproduct. The latter was the only product when a 2 1 2 ratio was used. The pyridazine formation is explained on the basis of cycloaddition of benzaldehyde azine to styrene, followed by tautomerization (87JOC2277). Similarly, other diazadienes add ethyl vinyl ether to give also 1,4,5,6-tetrahydropyridazines [83JCS(PI)1803j. 

Tetrahydropyridazines were shown to undergo radical addition of thioacetic acid to the 4,5-double-bond to yield the corresponding 4-thioacetoxy derivatives (80JHC1465). One electron oxidation of maleic... 

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. ... 

Eq. (14)].122 Similarly, the addition of phenyl Grignard to 6-oxo-3-phenyl-1,4,5,6-tetrahydropyridazine gives the aromatic 3,6-diphenylpyridazine, presumably through the intermediacy of the dihydropyridazine.123,124... 

Conformational studies using C NMR show that the 1,2-dihydropyridazine (24) is planar, while the 1,2,3,6-tetrahydropyridazines (25) and (26) have a half chair or boat conformation, respectively, as a consequence of the position of ring substituents. The hexahydropyridazine (27) probably exists as a mixture of three conformers due either to restricted rotation or inversion of the N-substituents with the bromines d -axial. In the absence of the 4,5-methyl groups the situation is made more complex by the additional presence of di-equatorial bromines <8772443). 

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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