1.6- Dihydropyridazine

Aryl-4,5-dihydropyridazine-3(2//)-one undergoes ring opening when submitted to Wolff-Kishner reduction, while with lithium aluminum hydride the corresponding 2,3,4,5-tetrahydro product is obtained. 

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). 

Aryl-4,5-dihydropyridazin-3(2//)-ones react with pyrrolylmagnesium bromide to give 6-aryl-3(l-pyrrolyl)pyridazines or, when 1 4 molar amounts of reagents are used, a mixture of 6-aryl-3(l-pyrrolyl)pyridazines and 3,4-di(l-pyrrolyl)-4,5-dihydropyridazines (Scheme 54 (79RRC453). 

Addition of bromine to 5-f-butyl-3,6-dimethoxy-4,5-dihydropyridazine produces 5-bromo-4-f-butyl-3-methoxy-4,5-dihydropyridazin-6(l//)-one. 

It is customary to perform the condensation of 1,4-dicarbonyl compounds with hydrazines in the presence of mineral acid to avoid the formation of A-aminopyrroles. Contrary to early claims that 4,5-dihydropyridazines are formed <07CB4598), these compounds are now regarded as 1,4-dihydro derivatives 81CB564). 

A Diels-Alder type [4+2] cycloadditions of 4,5-dihydropyridazine, prepared in situ from its trimer, with 2-methyl- and 2,3-dimethyl-1,3-butadienes (65, R = H, Me R = Me) afforded a complex reaction mixture, from which 6-methyl- and 6,7-dimethyl-3,4,4n,5-tetrahydro-8//-pyrido[l,2-ftjpyridazines (66, R = H, Me R =Me) could be isolated (97CEJ1588). With 1,3-butadiene (65, R = R =H) only a mixture of endo and exo isomers 67 and 68 (R = R =H) was obtained. 

Furans add to DEAZD to give Diels Alder adducts, although short reaction times are essential if the initial adduct is to be isolated. Attempts to convert the adduct into the bicyclic compound 116 failed. The only product isolated was a trimer of 4,5-dihydropyridazine, possibly formed as shown in Scheme 16.178 However, the furan adducts are readily converted... 

Several interesting 1,2,4-triazole fused-ring systems have been reported. A facile synthesis of 3,5-dihydro-677-imidazo[l,2-fc]-l,2,4-triazol-6-ones 162 was obtained by an iminophosphorane-mediated annulation <06EJ04170>. 8-Trifluoromethyl-l,2,4-triazolo[4,3- >]pyridazines 163 has been prepared from 4-trifluoromethyl-4,5-dihydropyridazin-3-one... 

For several pyridazine derivatives reported in the patent literature a muscle relaxant activity has been claimed. In this context, oxadiazolylpyridazines (35) [117] and 6-aryl-4,5-dihydropyridazine-3(2/f)-ones bearing various functionalized alkyl side-chains at N-2 [163, 174, 188, 189] are to be mentioned. Denpidazone (56) (CAS 42438-73-3), a l,2-diphenylpyridazine-3,6-dione derivative, is listed as a muscle relaxant [96]. 

The electroreductive hydrogenation of pyridazine-3-ones performed at the first wave, in acidic or basic medium, takes place at the 4,5-double bond. A further reduction of 4,5- dihydropyridazin-3-ones in basic media, affords the corresponding tetrahydro derivatives (Scheme 139) [252]. 

The cathodic reduction in acidic medium, of 4,5-dihydropyridazine-3-ones unsubstituted at the N-2 position gives 1-aminopyrrohdin-2-ones via the corresponding tetrahydropyridazine-3-ones. 

Dihydropyridazine-3-ones substituted at the N-2 position afford pyrolin-2-ones derivatives [252] (Scheme 161). 

A semiempirical AMI study of the inverse-electron-demand Diels-Alder reaction of 4-substituted 6-nitrobenzofurans with enol ethers and enamines favours a stepwise mechanism involving short-lived diradical intermediates. The inverse-electron-demand intermolecular Diels-Alder reactions of 3,6-bis(trifluoromethyl)-l,2,4,5-tetra-zine with acyclic and cyclic dienophiles followed by the elimination of N2 produce 4,5-dihydropyridazines, which cycloadd further to yield cage compounds. The preparation of jS-carbolines (90) via an intramolecular inverse-electron-demand Diels-Alder... 

On the basis of H NMR, nuclear Overhauser effect (NOE) experiments, and X-ray diffraction Guard and Steel showed that earlier reported benzylidene-4,5-dihydropyridazines should be represented as aromatic pyridazine... 

Chlorination of 6-(4-chloro-3-methylphenyl) -(3,5-dimethyl-l//-pyrazol-l-yl), 5-dihydropyridazin-3(2//)-one 116 with a mixture of phosphorus pentachloride and phosphorus oxychloride is followed by an elimination of 3,5-dimethyl-177-pyrazole giving the aromatized 3-chloro-6-(4-chloro-3-methylphenyl)pyridazine 117 (Scheme 25) <2005CJC251>. 

Ring transformation involving the intramolecular reaction of a hydrazone or in situ formed hydrazone also appeared. The transformation of 6-methyl-2//-pyran-2,3,4-trione 3-arylhydrazones 332 into l-aryl-6-methyl-4-oxo-l,4-dihydropyridazine-3-carboxylic acids 333 is an example of the former (Scheme 82). Compound 332 are formed via reaction of 4-hydroxy-6-methyl-27/-pyran-2-one 331 with substituted benzenediazonium chlorides. These are normally not isolated and immediately used further <2005EJM1325>. An example where a hydrazone is formed in situ is the reaction of 2-amino-5-aryldiazenyl-4-oxo-6-phenyl-4//-pyran-3-carbonitriles 334 with H2SO4 in glacial acetic acid, yielding 2-aryl-6-benzoyl-3-hydroxy-5-oxo-2,5-dihydropyridazine -carbonitriles 335 (Scheme 83) <2001T6787>. 

Tetrazines react with alkenes to give bicycles (403) which lose nitrogen to give the 4,5-dihydropyridazine (404). This can either tautomerize to a 1,4-dihydropyridazine, be oxidized to the aromatic pyridazine, or undergo a second Diels-Alder reaction to give (405). Many heterocycles can act as the dienophiles in such reactions for example thiophene gives (406). The reaction is also used to trap unstable compounds, for example, 2-phenylbenzazete (407) as compound (408). 

The first product of the reaction of 1,2,4,5-tetrazines (39) with alkenes (142) is the bicyclic compound (143), which has never been isolated since it loses nitrogen immediately by a retro-Diels-Alder reaction to give 4,5-dihydropyridazine (144). These compounds have been isolated in a few cases but usually a product is obtained which is formed from (144) in one of four different ways ... 

Further cycloaddition of the 4,5-dihydropyridazine (144) with excess of the alkene to yield the isolable 2,3-diazabicyclo[2.2.2]oct-2-ene (147 Scheme 8). 

A combination EIMS and X-ray study of [l,2,4]triazolo[l,2-b]- and [l,3,4]thiadiazolo[3,4-i>]phthalazines was undertaken [95JHC283], and X-ray crystal structure determinations of 5-(2-chlorobenzyl)-6-methyl-3(2W)-pyridazinone [95AX(C)1834], and on 6-benzyloxy-7,8-dihydro-8-phenyl-3-trifluoromethyl-r-triazolo[4,3-i>]pyridazine and its 5,6-dihydro-6-one derivative [95AX(C)1829] have been performed. Structures of some pharmacologically-active pyridazines previously reported as arylidene-4,5-dihydropyridazines need to be revised to those of aromatic pyridazine tautomers 6-8 based on a combination H NMR nOe and X-ray study [95AJC1601],... 

There is convincing NMR spectroscopic evidence for the intermediate 5-amino-4-nitro-2-5-dihydropyridazine. 

DielsAlder type [4 + 2] cycloadditions of 4,5-dihydropyridazine 137, prepared in situ from its trimer, with 2-methyl-and 2,3-dimethyl-l,3-butadienes afford the tetrahydropyrido[l,2-A]pyridazines 138 in relatively low yields (Scheme 83) C1997CEJ1588, CHEC-III(12.02.2.5.4)90>. 

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