Pyridazine radical substitution

Pyridazines, introduction of carbofunctional groups into heterocycle using radical substitution 87H(26)481. 

The phenylation of pyridazine and quinoxaline has been carried out using dibenzoyl peroxide, iV-nitrosoacetanilide, and benzenedia-zonium hydroxide as the sources of phenyl radical, the first two methods giving very much better yields than the third.63 The most reactive positions in these ring systems are the 4-position in pyridazine and the 2-position in quinoxaline. Phthalazine has been phenylated with iV-nitrosoacetanilide, giving a low yield of 5-phenylphthalazine, but the main product from cinnoline in this reaction was 4,4 -bicin-nolyl, although a small quantity of 4-phenylcinnoline was obtained.63 Pyrimidine has been arylated only with the 4-nitrophenyl radical, substitution occurring at the 2- and 4-positions.12... 

Free-radical substitution of pyridazine has been performed via attack with acyl (83AP5O8 85T1199), a-N-amido-2-(l,3,5-trioxanyl) (as a precursor to the formyl group), and methyl radicals (84H1395). 

Minisci, F., Galli, R., Cecere, M., Malatesta, V. and Caronna, T., Tetrahedron Lett, 1968, 5609 Substitutions by nucleophilic free radicals a new general reaction of heteroaromatic bases , Minisci, F, Fontana, F. and Vismara, E., /. Heterocycl. Chem., 1990, 27, 79 Minisci, F, Citterio, A., Vismara, E. and Giordano, C., Tetrahedron, 1985,41,4157 Advances in the synthesis of substituted pyridazines via introduction of carbon functional groups into the parent heterocycle , Heinisch, G., Heterocycles, 1987, 26, 481 Recent developments of free radical substitutions of heteroaromatic bases , Minisci, F, Vismara, E. and Fonatana, F, Heterocycles, 1989, 28, 489. 

Since pyridazines are known to undergo electrophilic substitution only with difficulty, direct halogenation is not expected to be a method of wide application. Therefore, bromine in acetic acid is widely used for dehydrogenation of reduced pyridazines. In some instances simultaneous dehydrogenation of the pyridazine nucleus and bromina-tion of the attached aryl radical has been observed. Dehydrogenation and replacement of hydroxyls with bromine atoms occurs if hexahydro-3,6-pyridazinedione is treated with excess POBrg, giving 3,6-dibromopyridazine. ... 

Pyridazine and its derivatives were substituted with nucleophilic radicals. They react either with 1-formylpyrrolidine or with A/-acetylproline in the presence of radical generators to give 5-substituted pyridazines (78TL619 86MI6). Also, reactions of 3-chloro-6-methoxypyridazine with ketone enolates in liquid ammonia show typical characteristics of a radical chain (SrnI) mechanism, and ketones 105 are obtained (81JOC294). 

Nncleophilic radicals add readily to diazines under Minisci conditions. Additions to pyrimidine often show little selectivity, C-2 versus C-A, but a selective Minisci reaction on 5-bromopyrimidine provided a convenient synthesis of the 4-benzoyl-derivative on a large scale. Similar reactions on pyridazines shows selectivity for C-4, even when C-3 is unsubstituted. Pyrazines can, of course, substitute in only one type of position. 

Isopropyl-4,5,6-fm-butylpyridazine, which exists in the twist conformation, is transformed upon photolysis into the corresponding 1,2-Dewar-pyridazine, which is stable (91AG1495). Irradiation of the ketone 179 with UV light produces about 10% of 180 (92JA1838). Photooxidative decomposition of 3,3,6,6-tetraalkyl-substituted perhydropyridazines was investigated and it was found that decomposition is stereospecific and that the 1,4-biradical determined the stereochemical outcome and not the 1,4-cation radical. Cyclobutane and 1-butene derivatives were products identified (93JA4925). 

The gas-phase fluorination of substituted pyrimidine 117 (Rf = CF(CF3)2) over C0F3 leads to the selective and high-yield formation of azadiene 118, however, unsubstituted F-pyrimidine under similar conditions forms the dimer 119. On the other hand, the reaction of isomeric F-pyridazine with C0F3 is straightforward leading to azadiene 120 (Fig. 9.36). Detailed discussion on the radical cation mechanism... 

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