Pyridazinones alkylation

Like pyridones, oxy-diazines are readily deprotonated under mild conditions, to give ambident anions which can be alkylated conveniently by phase-transfer methods, alkylation usually occurring at nitrogen. " M-Arylations of uracils also proceed in this way with, for example, l-fluoro-4-nitrobenzene."" 3-Pyridazinones alkylate cleanly on N-2 under phase-transfer conditions," but the regiochemistry of uracil alkylation is sometimes difficult to control (see also below). Uracils are sufficiently acidic to take part in Mitsunobu reactions." ... 

The most useful procedure utilises a 1,4-keto-ester giving a dihydro-pyridazinone, which can be easily dehydrogenated to the fully aromatic heterocycle, often by C-bromination then dehydrobromination alternatively, simple air oxidation can often suffice. 6-Aryl-pyridazin-3-ones have been produced by this route in a number of ways using an a-amino nitrile as a masked ketone in the four-carbon component, or by reaction of an acetophenone with glyoxylic acid and then hydrazine. Friedel-Crafts acylation using succinic anhydride is an alternative route to 1,4-keto-acids, reaction with hydrazine giving 6-aryl-pyridazinones. Alkylation of an enamine with a phenacyl bromide prodnces 1-aryl-l,4-diketones, allowing synthesis of 3-aryl-pyridazines. ... 

IV-Methylated pyridazinones can be obtained from 3,6-dialkoxypyridazines by treatment with alkyl halides or dialkyl sulfates. Methyl iodide and dimethyl sulfate are most frequently used. According to the proposed mechanism, an intermediate quaternary pyridazinium salt is formed, followed by elimination of a group R from the alkoxy group. At higher temperature, l,2-dimethylpyridazine-3,6(l//,2//)-dione is formed with dimethyl sulfate. 

Compounds which are of interest in this context include 4-oxadiazolylpyrid-azines (35, R = cyclopropyl, Et) [117], 6-aryloxy-2-hydroxyalkyI-3(27/)-pyri-dazinones [118], 3-halo-6-hydrazinopyridazines of type (36, R = substituted amino) [119], Ar-2-isoxazolylmethyl-substituted 3-iminopyridazines (37) [ 120], carbamates derived from 3,6-bis(hydroxymethyl)-4-pyridazinones (38, R = alkyl, Ph) [121], and iminodihydropyridazine derivatives (39, R1 = acyl R2 = H,MeS R3 = aryl) [122, 123]. In Hungary, antidepressant activity has been observed with some 3,6-disubstituted pyridazines of type (40) [124]. 

The patent literature covers many pyridazine derivatives claimed as blood platelet aggregation inhibitors and antithrombotic agents. The interest has been focused mainly on 6-aryl-4,5-dihydro-3(2//)-pyridazinones. In these compounds the aryl substituent has been varied within a wide range. Thus, dihydro-pyridazinones bearing a substituted or heterocycle-fused phenyl group at C-6 (60, R R2,R3 = H, alkyl Ar = substituted Ph) [34, 110-112,205-233] as well as various heteroaryl substituted congeners (61, R1, R2, R3 = H, alkyl Ar = pyridyl, thienyl, pyrrolyl, pyrazolyl) [234-241] have been prepared in search of novel antithrombotics. 

In Poland, various 5-cycloaminornetbyl-6-(p-chlorophenyl)-4,5-dihydro-3(2//)-pyridazinones (89, R1 = pyrrolidino, piperidino, morpholino, etc. R2 = H, substituted alkyl, aryl) have been prepared in search of biologically active pyridazines some of these compounds have been reported to exhibit immunosuppressive activity [180, 284, 285]. 

Alkylation of pyridazinone 945 with 4-bromoacetoacelic acid 944 did not give the 2 -oxo-4 -carboxylic acid analogs, but gave 946 of type 4.1. The uracil derivatives were prepared similarly (90MI4). 

In CHEC-II(1996) only one example of N-alkylation of a cinnolin-4(l//)-one is given <1996CHEC-II(6)1>. Nowadays, N-alkylation of pyridazinones is a quite general reaction. In most cases alkylations are achieved by a nucleophilic substitution reaction of the deprotonated azinone on alkyl halides and exceptionally also on aryl halides. Reagents other than halides are also used. 

While 124 is alkylated to give 125 on treatment with 123, the pyridazinone 126 is converted into 127 upon treatment with the same reagent (Scheme 3) <1993BML1019>. 

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... 

Not only alkylations, but also Michael-type reactions, with weakly basic heterocyclic amines, can be accomplished by PTC. Yamada and Ohki158 have recently reported such a reaction with pyridazinones (99). 

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