Pyridazine analogs

The most active pyridazine of the group was the 3-methoxy analog, AC 247,909. Like most of the active pyridazine analogs, preemergence application of AC 247,909 caused bleaching. As the most active postemergence pyridazine herbicide, AC 247,909 caused rapid necrosis, suggesting a potential use as a contact-type herbicide. As in the 3-amino series, an extension of the alkyl chain resulted in the loss of activity. Besides methyl, other substituents introduced at the 3-position included alkylsulfonyl, cyano, carboxy, and amido. These pyridazines were inactive at 1 kg/ha and in some cases at 8 kg/ha. 

In 2002, Wonnacott published the synthesis and biological evaluation of a pyridazine analog (62) of nicotinic acetylcholine receptor agonist UB-165 [45]. This aza-UB-165 analog (62) was synthesized via Negishi cross-coupling reaction on triflate 60 with pyridazin-3-ylzinc halide (59). Compound 59 could be obtained from 3-bromopyridazine (58) via lithiation and subsequent transmetalation with zinc chloride. 

Since the antidepressant minaprine has been launched, several pyridazine analogs were proposed and synthesized. 

From 3-hydrazino-6(l//)-pyridazinone and protected /3-D-ribofuranose the nucleoside 142 (R=Bz) was prepared and after deprotection with sodium methoxide 142 (R=H) was obtained (89MI6).The pyridazine analog of 2 -deoxycitidine was synthesized from 3-methoxy-6-chloropyridazine by intramolecular glycosylation of 143. Compound 143 was treated with Me2S(SMe)BF4 and the oxonium intermediate was hydrolyzed to give the 2 -deoxynucleoside 144 (95MI4). 

There are various photochemical transformations of pyridazines, their corresponding benzo analogs, N-oxides and N-imides. Gas-phase photolysis of pyridazine affords nitrogen and vinylacetylene as the main products. Perfluoropyridazine gives first perfluoropyrazine, which isomerizes slowly into perfluoropyrimidine. 

With the saturated analogs, i.e. succinic anhydride and its derivatives, pyridazines are formed in only a few cases. The reaction has been applied to the preparation of perhydro-pyridazines and their 3,6-diones (68MI21200, 70JOC1468). For the synthesis of 4,5-dihalopyridazinones, /3-formylacrylic acids, for example mucochloric acid, are useful syn-thons (Scheme 80). 

Pyridazines are formed from pyrones or their thioxo analogs or from appropriate pyridones. Pyrones or pyridones react with diazonium salts to give the corresponding hydrazones (187) and (188) which are rearranged under the influence of acid or base into pyridazinones as shown in Scheme 107. On the other hand, kojic acid is transformed with hydrazine into a 1,4-dihydropyridazine and a pyrazole derivative. 4H-Pyran-4-thiones... 

Direct deactivation by a methoxy group makes 3-chloro-6-methoxy-pyridazine unreactive toward sulfanilamide anion in contrast to its 6-chloro, 6-methyl, and 6-hydrogen analogs. Both direct and indirect deactivation of the two chlorines in 3,6-dichloro-4-methoxy-pyridazine (160) are possible the greater reactivity at the... 

The ease of reaction of halopyridazines is indicated by the exothermic nature of the reaction of 3,6-dichloropyridazine with sodium methoxide at room temperature to yield 3-chloro-6-methoxy-pyridazine. Displacement of the deactivated chloro group in the latter required heating (66°, < 8 hr) the reaction mixture. Competitive methoxy-dechlorination (20°, 12 hr) of 3,4,6-trichloropyridazine shows the superior reactivity of the 4-position the 3,6-dichloro-4-methoxy analog (296) was isolated in high yield. The greater reactivity of the... 

Even though data for a quantitative comparison are lacking, the effect of the position of benzo-fusion onto pyridazines is analogous to that with pyridines in producing the very poorly reactive 3-chloro-cinnoline (396) and highly reactive 1-chlorophthalazine (Table XV, lines 8 and 9). 

The intramolecular cyclization of 2-alkynylaryldiazonium salts (Richter reaction) leads not only to 4-hydroxy- but also to 4-bromo- and 4-chlorocinnolines. The behavior of alkynylpyrazolediazonium chlorides differs from that of their benzene analogs. The Richter reaction of the series of alkynylaminopyrazoles gives only 4-halo derivatives of l//-pyrazolo[3,4-c]pyridazines and l//-pyrazolo[4,3-c] pyridazines, and mainly hydroxy derivatives of 2//-pyrazolo[3,4-c]pyridazines. 

In this work the possibility of the existence of 1,2-dihydro isomer with the core structure 42 was not considered. Recently, however, it was shown that 1,2-dihydropyridazines could be prepared by careful electroreduction of the corresponding pyridazines, and that their stability depends significantly on the ring substitutions. Thus, dimethyl l,2-dihydropyridazine-3,6-dicarboxylate 43a (R = H) is reasonably stable and rearranges into the 1,4-dihydro tautomer 43b only at a more negative potential, while the tautomerization in its tetrasubstituted analog 43a (R = COOMe) occurs more readily (Scheme 14) [00TL647]. 

The final chapter by Istvan Hermecz (Chinoin, Ltd., Budapest, Hungary) deals with bicyclic systems containing one ring junction nitrogen and one heteroatom and their benzologs, i.e. pyrido-oxazines, pyrido-thiazines, pyrido-pyridazines, pyrido-pyrazines, pyrido-pyrimidines and their analogs. Much of this material has not been reviewed for forty years, during which time immense advances have occurred. 

Compound 248 treated with (EtOhP in refluxing xylene provides an 89% yield of 19 (Equation 37) <2005AGE7089>. Similarly, [l,2,3]triazolo[4,5- /]pyridazine 249 provided a 68% yield of the corresponding mesomeric betaine 250 (Equation 38). However, reductive cyclizations of the analogous 3-(2-nitrophenyl)-377-[l,2,3]triazolo[4,5-//Jpyrimidine, 3-(3-nitropyridin-2-yl)-3//-[l,2,3]triazolo[4,5-. 

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