Alkylation of pyridazinones

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. 

Alkylations of pyridazinones have been performed in the usual way i.e., they were treated with an alkylhalide or dialkylsulfate in the presence of a base. Most frequently methylations were performed, but other alkylating agents such as a-haloacids (or esters), 497-499 alkylaminoalkylhalides, or even 2-bromopyridine ... 

Acylation or alkylation of 1-hydroxypyridazinones, as exemplified by benzoylation of l-hydroxy-3-methoxy-6(l.ff)-pyridazinone and its 4- or 5-substituted derivatives or methylation of 1-hydroxy-3,4-disubstituted-6(l.f )-pyridazinones, affords the corresponding 1-benzyloxy and 1-methoxy derivatives, respectively. 

Protonation and basicity studies are reported in Section IV,B. Alkylations, like methylation, which proceed in the case of pyridazinones as N- and/or O-methylation, are treated in Section III,C. Only N-alkylations are mentioned in this section. 

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. ... 

A-Alkylation or acylation of 3(2//)-pyridazinones by standard procedures afforded derivatives with unambiguous structure, whereas pyri-dazines can yield either Ar or (V2-substituted products. Pyridazine-4-carboxamide, when alkylated with 5-iodovaleric acid or related acids, yielded a mixture of both Nr and A -regioisomers in the ratio of 1 1.25 or 1 1. They were not separated (95AP307 96PHA76). Alkylation of 3-(2-pyrrolyl)pyridazine afforded the A -alkylated product, as evidenced from X-ray analysis [96AX(C)1002]. 

The quaternization of (benzo)pyridazines by alkyl halides (these systems are not readily susceptible to arylation) was reviewed in CHEC-I <84CHEC-l(3B)l>. Monoquaternization of pyridazines occurs more readily than other diazines but less readily than pyridine, reflecting the intermediate basicity/nucleophilicity of pyridazine. Diquaternization of pyridazine can only be achieved with oxonium salts, particularly Me30 BF4 . As with protonation and A-oxidation, mixtures of products are often obtained on quaternization of unsymmetrical pyridazines and have been the subject of theoretical studies. A number of 2-(ribofuranosyl)-3(2//)-pyridazinones have been prepared by stannic chloride catalyzed alkylation of 3-(trimethylsilyloxy)pyridazines with protected 1-0-ace-tylribofuranose <83JHC369>. The quaternization behavior of phthalazines is similar to that of pyridazines, but with cinnolines alkylation usually occurs at N-2, unless there is a particularly bulky substituent at C-3. 

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>. 

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). 

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]. 

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