3-Pyridazinone reduction

Reaction of the 2-acetoxy-3(2//)-furanones (526) with monosubstituted hydrazines gives good yields of the pyridazinium-5-olates (527) together with varying amounts of isomeric products. Alkyl derivatives (527 R = alkyl) have also been prepared by base-catalyzed alkylation (Mel, Me2SO4, PhCH2Cl) of 3-methyl-6-phenyl-5-ethoxycarbonyl-4( 1 //)-pyridazinone. Reduction of the diphenyl compound 527 (R = Ar = Ph) by zinc and hydrochloric acid gives 3-ethoxycarbonyl-5-hydroxy-5-methyl-l,2-diphenyl-2-pyrrolin-4-one (528 R = Ar = Ph) (Scheme 21... 

In a similar way other pyridazines,159 e.g., 3-phenyl-6-methoxy-pyridazine and 3-methyl-6-chloropyridazine, are reduced, but the dihydropyridazines are in these cases rather unstable and may lose methanol or hydrogen chloride forming the corresponding 4,5-dihydro-pyridazinone. The reduction of pyridazinones will be discussed below. 

Chloro-6-methylpyridazine is reduced in a two-electron reaction the isolated product is 4,5-dihydro-6-methyl-3-pyridazinone. This indicates that the reduction takes place in the ring and the chlorine is then lost by hydrolysis.159... 

Synthesis of 1,2-disubstituted perhydro-3,6-pyridazinediones and 6-(S-carboxybutyl)-4,5-dihydro-3(2Zf)-pyridazinone is reported. Tetrahydropyridazines were also synthesized from 3 2H)-pyridazinones by reduction with LiAlH4. ... 

The reduction of cyclic acylated hydrazones like pyridazinones [59] and phthalazi-nones [81] is discussed in Chapter 18. 

The reduction in acid solution of di- and tetrahydropyridazines and pyridazinones is often best understood when their resemblance to hydrazones is considered. The reduction of such compounds has been discussed (Chapter 11), and the primary step is a hydro-genolysis of the nitrogen-nitrogen bond. The reduction of 1,4-dihydro-1-methyl-5-r-butyl-3,6-diphenylpyridazine to pyrroles has been described [148, 149] at more negative potentials, pyrrolines and pyrrolidines may be obtained from pyridazines,... 

Direct amination of 3(2//)-pyridazinones occurs when they are heated with hydrazine hydrate and this is a convenient route to many 4-amino-6-substituted-3(2//)-pyridazinones (Scheme 11). The reaction generally gives high yields and amination is regiospecific when the 6-position is occupied by an aromatic or heteroaromatic ring, but the parent 3(2/ -pyridazinone gives a mixture of the 4- and 5-amino-3(2//)-pyridazinones. The reaction tolerates jV-methyl substitution of the pyridazinone, but is sensitive to steric factors the presence of a 5-substituent causes a marked reduction in reaction rate, and amination does not occur with 4-phenyl-3(2//)-pyridazinone. With maleic hydrazide 4-hydrazination occurs, possibly by displacement of an intermediate amino compound or by oxidation of an intermediate 4,5-dihydro-4-hydrazino adduct both 4-hydrazino- and... 

The orientation of reaction of aminopyridazines with electrophiles, and further reaction of the intermediates is illustrated by a study with 4-amino-5-aroylpyridazines. Acylation and sulfonylation occurs on the amino nitrogen, while alkylation occurs, as expected, at N-1 the acylamino derivatives are relatively unstable, but the toluenesulfonamide is quite stable to acid and to base. Methylation of the toluenesulfonamide gives a mixture of ring and amino alkylated products with the latter predominating. Hydrolysis of the ring A-alkylated compounds gives 4(l//)-pyridazinones (Scheme 57). Selective amino-alkylation of the 4-amino-5-aroylpyridazines is achieved via the imidate by reduction and subsequent oxidation of the alcohol <85H(23)265l>. 

The benzyloxymethyl group has been used for the protection of the pyridazinone NH group. It is unaffected by a variety of acidic, basic, and reductive conditions and while removal by hydro-genolysis was erratic, the use of boron trichloride in DCM at — 78°C is effective <84JHC48l>. Ethyl (3-oxo-2,3-dihydropyridazin-2-yl)acetates react normally with ammonia and hydrazine to give the amides and hydrazides respectively <90CPB3009>. 

The reactivity of a 2-(2-oxopropyl) substituent in 4,5-dichloro- and 4,5-dichloro-6-nitro-3(2//)-pyridazinones, especially towards bromination, has been investigated. In the presence of sodium acetate/acetic acid in chloroform, bromination can be controlled to give mainly mono- or di-bromination of the methylene group, while in the absence of the buffer monobromination of the methyl group is favoured. The dibromomethylene derivative is readily hydrolyzed under mild basic conditions to regenerate the Y-unsubstituted pyridazinone <91JHC385>. Reactions of the monobromomethyl derivative (112) include displacement of bromine with azide, reduction to... 

Another synthon to 4-oxocarboxylic acids has been recently described and utilized for the synthesis of pyridazinones of potential antihypertensive activity. Thus, arylmethylene Meldrum acid derivatives 97 (prepared by reacting Meldrum acid 96 with aldehydes and subsequent reduction of the formed arylidene derivative using triethylammonium formate, TEAF) could be alkylated with 4-bromophenacyl bromide 98 to yield 99 that then reacted with hydrazine hydrate to yield 100 (2004SC783 Scheme 17). 

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