Pyridazine, 3-bromo-6-methyl

Bromo-6-chloro-2-methyl-imidazo-( 1,2b)-pyridazine-bromine complex dichloromethane 20°C, 2 min. 75 % (40 %) (refs. 13,31)... 

Only one example of a derivative of this ring system has been reported. This compound, 2,6-dimethyl-3,4-dioxo-2,3,4,6,7,8-hexahydropyridazino[4,3-c]pyridazine 4-(p-bromo-phenylhydrazone) (149), was obtained in the reaction of the lactone (148) with methyl-hydrazine. A proposed mechanism for this unusual reaction is shown (80JHC617). 

Pyrazino[2,3-djpyridazine, 2-methyl- H NMR, 3, 337 (66JHC512) Pyrazino[2,3-d]pyridazin-8-one, 5-bromo-IR, 3, 337 (68JHC53)... 

Evidence that nucleophilic substitution of pyridazines may occur also via the hetaryne mechanism has been presented in the case of l-methyl-2-phenyl-4-chloro-(or bromo-)3,6-pyridazinedione which, when treated with piperidine, yielded the 4- and 5-piperidino isomers. Formation of the 5-methoxy isomer as the sole product from the above 4-chloro compound can be interpreted also in terms of an intermediate hetaryne formation. 

In the frame of a medicinal chemistry program at Merck Sharp Dohme Ltd, Collins and co-workers reported successful Negishi cross-coupling reaction of 3-aryl-7-bromo-6-[( 1 -methyl-1/7-1,2,4-triazol-5-yl)methoxy][ 1,2,4]triazolo[4,3-/ pyridazines (63) with aliphatic organozinc reagents [35]. 

The first example of an alkynylation of a bicyclic pyridazine derivative was published in 2000 [35]. Collins studied Sonogashira coupling of 7-bromo-6-[(1-methyl-l//-l,2,4-triazol-5-yl)methoxy]-3-phenyl[l,2,4]triazolo[4,3-Z ]pyridazine (165) with propargyl alcohol at 90°C in a sealed tube using Pd(PPh3)4 and Cul in triethylamine. Unfortunately, only a low yield of the reaction product (202) was obtained. 

Heek reaetion involving C—H aetivation of a pyridazin-3(2//)-one eore has been far less studied. Maes and Matyus published the first examples in 2004 [42]. Intramoleeular Heek-type eyelization of 5-(2-bromophenoxy)-2-methylpyridazin-3(2Tf)-one (234) and 5-[(2-bromophenyl)amino]-2-methylpyridazin-3(2Tf)-one (237), involving C-4 C—H aetivation of the pyridazin-3(2//)-one, yielded 2-methylbenzo[Z ]furo[2,3-6/]pyridazin-l(2//)-one (235) and 2-methyl-2,5-dihydro-l/7-pyridazino[4,5-Z ]indol-l-one (238), respeetively, in good yields. For the eon-struetion of 235, a reverse approaeh in whieh a bromo atom was present at the C-4 position of the pyridazin-3(2//)-one eore (236) was also tested but proved to be less effieient. 

Because 3-chloropyridazines were not found to be very reactive in palladium coupling reactions and the bromo and iodo analogues are not readily available, the preparation and use of triflate esters of pyridazines have been developed. The readily prepared triflates undergo coupling with terminal acetylenes in the presence of palladium and copper iodide (Equation (27)). Reactions are rapid, normally complete in 0.5 to 6 hours at room temperature, and yields are high. In a comparative experiment 3-chloro-4-methyl-6-phenylpyridazine with 3,3-dimethyl-3-hydroxy-l-propyne gave only a 33% yield of 3-(3,3-dimethyl-3-hydroxy-l-propynyl)-4-methyl-6-phenylpyridazine after 12... 

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