Pyridazinones halogenation

Nitro derivatives of several halogenated pyridazin-3(2//)-ones have been prepared by treating the pyridazinones with a mixture of a nitrate salt and acetic anhydride or trifluoroacetic anhydride <2003JOC9113>. These compounds have been used for the synthesis of nitramines (see Section 8.01.8.3). 

The structure of the pyridazine-based antidepressant agent minaprine (34-6) departs markedly from both the older tricyclic drugs and the more recent selective serotonin re-uptake inhibitors. There is evidence that the compound acts via a dopa-mimetic route. Friedel-Crafts acylation of benzene with itaconic anhydride (34-1) leads to the keto-acid (34-2). Condensation with hydrazine leads to the formation of the hydrazine and hydrazide bonds the double bond shifts into the ring to give the fully unsaturated pyridazinone (34-3) this is then converted to the chloride (34-4) in the usual way. The displacement of halogen by the amine on 3-(A -morpho-lino)propylamine (34-5) affords (34-6) [36]. 

Quinolin-4-one forms a 3-bromo derivative, but coumarin gives the addition compound (116) which is easily re-aromatized (116 — 117). 4-Thiopyrones are halogenated in position 3. Pyridazinones and cinnolinones are also readily halogenated in the expected position. 

The palladium-catalyzed formation of diarylamines has been used in several contexts to form molecules of biological relevance. The ability to prepare haloarenes selectively by an ortfio-metalation-halogenation sequence allows the selective delivery of an amino group to a substituted aromatic structure. Snieckus has used directed metalation to form aryl halides that were subsequently allowed to react with anilines to form diarylamines (Eq. (34)) [209]. Frost and Mendonqa have reported an iterative strategy to prepare, by the palladium-catalyzed chemistry, amides and sulfonamides that may act as peptidomimetics. Diaryl-amine units were constructed using the DPPF-ligated palladium catalysts, and the products were then acylated or sulfonated with 4-bromobenzoyl or arylsulfonyl chlorides [210]. Le-miere has coupled primary arylamines with 4-chloro-3(2H)-pyridazinones to form compounds with possible analgesic and antiinflammatory properties. 

Halogenated pyridazinones have been thus prepared from muco-chloric acid (35) 286,312-316 mucobromic acid, or the related chlorobromo acid. Instead of hydrazine semicarbazide can be used and the intermediate semicarbazone cyclized in hot acetic acid, loss of the carbamide group taking place simultaneously. Acid hydrazides likewise form hydrazones first, which cyclize with the aid of phosphorus oxychloride. Tosylhydrazones are reported to cyclize easily. ... 

Since kinetic data are scarce, a comparison of relative reactivities of halogen atoms at different positions in the pyridazine or pyridazinone ring is difficult. The differences in reactivities which will be referred to are based on synthetic work. 

Pyridazines with hydroxyl groups (generally in the oxo form) at different positions in the ring can be prepared by several methods as outlined in Section III. Syntheses from open-chain compounds are particularly suitable for obtaining 3(2/I)-pyridazinones and their 6-hydroxy analogs. If more complex pyridazinones are available, such as halogenated pyridazinones, catalytic dehalogenation is one of the preferred methods. In this manner 3(2 I)-pyridazinone ... 

During aminolysis side reactions may occur, the most common being the solvolytic displacement of the halogen or methoxy group with the formation of pyridazinones or methoxypyridazines. ... 

Another widely used method involves hydrolysis of cyanopyrida-zines. These are usually obtained from cyclizations of open-chain cyano compounds (synthesis of 4-cyano-3(2/7)-pyridazinone and its methyl analogs ), since replacement of a halogen atom by cyano group proceeds with pyridazines in low yields or not at all. Many cyanopyridazines have been obtained by dehydration of amides, such as 3- or 4-cyanopyridazine, 3-chloro-6-cyanopyridazine or 6-cyano-2-methyl-3(2.ff)-pyridazinone, and 3-chloro-4-cyano-... 

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