Grignard reagents with pyridazines

Terminal enynes Reaction of aryl Grignard reagents with pyridazine 1-oxide leads exclusively to terminal (E)-enynes in 50-75% yield. Alkyl Grignard reagents lead to 1,3-dienes in rather low yield. 

In some instances a carbon-carbon bond can be formed with C-nucleophiles. For example, 3-carboxamido-6-methylpyridazine is produced from 3-iodo-6-methylpyridazine by treatment with potassium cyanide in aqueous ethanol and l,3-dimethyl-6-oxo-l,6-dihydro-pyridazine-4-carboxylic acid from 4-chloro-l,3-dimethylpyridazin-6-(lH)-one by reaction with a mixture of cuprous chloride and potassium cyanide. Chloro-substituted pyridazines react with Grignard reagents. For example, 3,4,6-trichloropyridazine reacts with f-butyl-magnesium chloride to give 4-t-butyl-3,5,6-trichloro-l,4-dihydropyridazine (120) and 4,5-di-t-butyl-3,6-dichloro-l,4-dihydropyridazine (121) and both are converted into 4-t-butyl-3,6-dichloropyridazine (122 Scheme 38). 

Reaction of pyridazine 1-oxide with phenylmagnesium bromide gives 1,4-diphenyl-butadiene as the main product and l-phenylbut-l-en-3-yne and 3,6-diphenylpyridazine as by-products, while alkyl Grignard reagents lead to the corresponding 1,3-dienes exclusively (79JCS(P1)2136>. 

The ring opening of pyridazine 1-oxide (770) by aryl Grignard reagents has been found to yield exclusively terminal ( )-enynes (773) (79JCS(P1)2136, 63CPB83). With more... 

The reaction of the diamino compound (107) under several different nitration conditions led to the formation of 5-nitroamino-8-aminopyrazino[2,3-d]pyridazine exclusively (68JHC53). 5,8-Dimorpholino substituted pyrazino[2,3-d]pyridazines are known to react with Grignard reagents to give 3-substituted 3,4-dihydro derivatives (75CPB1488). The dimorpholino heterocycles are also known to react photochemically with alcohols and cyclic ethers in the presence of photosensitizers to give 3-substituted 3,4-dihydro derivatives (Scheme 3) (75CPB1500). 

An entirely different method for effecting, overall, an jp - p -coupling of aryl Grignard reagents is by reaction of the latter with pyridazine A-oxide (Scheme 20). In the simple cases studied, yields of enynes were 52-77%. The possibility of applying this approach to more highly substituted substrates does not appear to have been examined. 

There are several examples of pyridazine ring opening under the action of nucleophiles. Pyridazine Al-oxide and its methyl analogs react with Grignard reagents or phenyllithium to give the vinylacetylene 241, the... 

There are some examples when A/-ami nopyrroles were transformed into pyridazines either in boiling toluene (94ZOR1433) or after treatment with a Grignard reagent [96ZN(B)1334 98S1627]. 

The reaction of 5,8-dimorpholino-2-phenylpyrimido[4,5-c/]pyridazine (1) with Grignard reagents proceeds with formation of various 4-substituted derivatives 262 which can be dehydrogenated to the corresponding fully conjugated pyrimido[4,5-r/]pyridazine systems (see Section 7.4.6.I.2.)61... 

Substituted 5,8-dimorpholino-3-phcnyl-l,2-dihydropyrazino[2,3-photochemical addition or by reaction with Grignard reagents (see Section 7.4.9.2), can be oxidized to the parent pyrazino[2,3-d]pyridazines with potassium hexacyanoferrate(in).6 ... 

Dimorpholino-2-phenylpyrazino[2,3-rf]pyridazine (3) reacts with Grignard reagents to form 2-substituted 5,8-dimorpholino-3-phenyl-l,2-dihydropyrazino[2,3-tf]pyridazines 4.62... 

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