Reactions with pyridazines

Pyridazinium salts, 1-methoxy-reaction with pyridazines, 3, 23 Pyridazino[4,5-6]azepines synthesis, 7, 522 Pyridazino[4,5-d]azepines synthesis, 7, 522 Pyridazinofuroxans synthesis, 6, 425 Pyridazinoheteronins synthesis, 7, 729 Pyridazino[2,3-a]indole synthesis, 4, 297... 

In the course of probing the range of reactivity accessible to decamethyl-samarocene, substrates containing C=N double bonds as part of 6-membered heterocycles have been tested. In the reaction with pyridazine reductive carbon-carbon bond formation occurred (compare Sect. 3.2) [99], The coupled ligand bridges two Sm(III) centers via the four nitrogen positions. In the phenazine reaction one phenazine ligand is placed between the Sm(III) centers (Fig. 20 Table 16) [203]. 

A few years after this initial report, Acheson and Foxton5 reinvestigated some of Letsinger s work and showed that the dimethyl acetylenedicarboxylate reaction with pyridazine was very solvent dependent. In a... 

Didehydrotropone, prepared by oxidation of l-amino[4,5-d]-1,2,3-triazole with lead tetraacetate, undergoes cycloaddition reactions with pyridazine M-oxides <94H(38)957>. Loss of nitrogen by the cycloadduct results in the formation of tropono[4,5-b]oxepines (Scheme 10). The electron deficient nature of the tropolone ring precludes the formation of [4 + 2]jt cycloaddition products by the oxepine ring, in contrast to the reactivity of benz[l>]oxepines. 

AIkyI-substituted pyridazine-3(2//)-thiones undergo reaction with methyl iodide at the sulfur atom. Methylation of 4,5-diaminopyridazine-3(2ff)-thione with excess methyl iodide produces 4,5-diamino-l-methyIthiopyridazinium iodide (81JOC2467). 

Disubstituted pyridazine-3,6(l//,2//)-diones add halogens to the 4,5-double bond, followed by dehydrohalogenation to give 4-halo derivatives. 1,2-Disubstituted 5-bromopyridazine-3,6(l//,2F0 diones react with bromine to give the corresponding 4,5-dibromo derivative. The Mannich reaction with 2-arylpyridazin-3(2//)-one occurs at position 4. 

Mannich reaction with pyridazinone 1-oxides takes place at the a- or y-positions relative to the iV-oxide group, in contrast to the reaction in the pyridazinone series, where N-substituted products are formed. Pyridazin-3(2FT)-one 1-oxide gives first the corresponding 6-substituted derivative with excess of the reagents, 4,6-disubstituted products are obtained. When position 6 is blocked the corresponding 4-dialkylaminomethyl derivatives are obtained. 

A substituted acyl amino group can be introduced by reaction of pyridazine 1-oxide with A-phenylbenzonitrilium hexachloroantimonate 3-A-benzoylanilinopyridazine is formed (75JOC41). 

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>. 

Pyridazine carboxylates and dicarboxylates undergo cycloaddition reactions with unsaturated compounds with inverse electron demand to afford substituted pyridines and benzenes respectively (Scheme 45). 

Pyridazine, 4-amino-5-formyl-3,6-dimorpholino-synthesis, 3, 346 Pyridazine, 4-amino-3-halo-reaction with potassium amide, 3, 29 Pyridazine, aryl-synthesis, 3, 28 Pyridazine, arylthio-synthesis, 3, 27 Pyridazine, 3-azido-... 

Paal-Knorr synthesis, 4, 118, 329 Pariser-Parr-Pople approach, 4, 157 PE spectroscopy, 4, 24, 188-189 photoaddition reactions with aliphatic aldehydes and ketones, 4, 232 photochemical reactions, 4, 67, 201-205 with aliphatic carbonyl compounds, 4, 268 with dimethyl acetylenedicarboxylate, 4, 268 Piloty synthesis, 4, 345 Piloty-Robinson synthesis, 4, 110-111 polymers, 273-274, 295, 301, 302 applications, 4, 376 polymethylation, 4, 224 N-protected, 4, 238 palladation, 4, 83 protonation, 4, 46, 47, 206 pyridazine synthesis from, 3, 52 pyridine complexes NMR, 4, 165... 

These pyridazines are subject to direct deactivation of the leaving group. It would appear from the conditions used in its reactions with ammonia (115°) and methylamine (50°) that 4-chloro-2-ethylthiopyrimidine (225) is somewhat deactivated (indirect). In various aminations of pyrimidines, the effect of an alkylthio group seems to be very mildly deactivating, like that of methyl groups. However, these surmises from the conditions used are not as reliable as the direct qualitative comparison described above and the kinetic data. 

The reaction of pyridazine 1-oxide or 3- and/or 6-substituted pyridazine 1-oxides with benzyne gives 1 -benzoxepins 2 in variable yield. As byproducts, the respective 3-(2-hydroxyphenyl)pyrid-azines 3 can be isolated in 0-20% yield.88... 

A further example of an azo coupling reaction with an activated methylene compound (12.91), followed by ring closure to give a pyridazine derivative (12.92) in good yield (66%) was decribed by Gewald and Hain (1984). The reductive treatments of 12.92 give the pyrrole compounds 12.93 and 12.94 in 70% yield (Scheme 12-45). 

RATE COEFFICIENTS AND KINETIC PARAMETERS FOR REACTION FOR REACTION OF PYRIDAZINE DERIVATIVES WITH D2O-D2SO4.513... 

Mono- and dilithio derivatives of p-tosylmethyl isocyanide 297a were shown to display interesting reactions. Reaction of the monoanion with unsaturated esters was shown to give pyrrole derivatives . Dianion 297b was found to add to the carbon-nitrogen double bonds of isoquinoline, quinoline and quinoxaline affording compounds 298, 299 and 300, respectively. In the reactions with pyridine iV-oxide and pyridazine iV-oxide, unstable open-chain products 301 and 302 were obtained . 

The coupling of enals and glyoxals was realized by hydrogen-mediated reaction with the cationic Rh complex and PI13P [35]. The intermediate aldehyde enolates derived via Rh-catalyzed hydrogenation were trapped with glyoxals to form (l-hydroxy-y-kclo-aldchydes, which were treated sequentially with hydrazine to give pyridazines in a one-pot transformation to provide, for example, a 62% yield of 72 (Scheme 21). 

The pyridazine ring of 111 is formed from [4+2] atom fragments in the cyclization of 3-amino-2-chloromethyl-quinazolin-4-one with activated acrylthioamides. The saturated pyridazine ring of 111 aromatized spontaneously to give 112 (Equation 12). Reaction with io-nitrostyrene yielded the 3-nitro analogue of 112 <2003MOL401>. 

Corsaro and co-workers studied the reaction of pyridazine, pyrimidine, and pyrazine with benzonitrile oxide and utilized H NMR spectral analysis to determine the exact structure of all the cyclized products obtained from these reactions <1996T6421>, the results of which are outlined in Table 1. The structure of the bis-adduct product 21 of reaction of pyridazine with benzonitrile oxide was determined from the chemical shifts of the 4- and 5-isoxazolinic protons at 3.76 and 4.78 ppm and coupled with the azomethine H at 6.85 ppm and with the 5-oxadiazolinic H at 5.07 ppm, respectively. They determined that the bis-adduct possessed /(-stereochemistry as a result of the large vicinal coupling constant (9.1 Hz). Similarly, the relative stereochemistry of the bis-adducts of the pyrimidine products 22-25 and pyrazine products 26, 27 was determined from the vicinal coupling constants. 

A 1,2-diazetidine has been proposed as an intermediate in the reaction of pyridazine-3,6-dione (12) with styrene.87 The observed product was thought to arise from addition of water to the 1,2-diazetidine, although the alternative more likely explanation involving a dipolar intermediate (cf. Scheme 5) was apparently not considered. In the photochemical reaction of styrene with DEAZD, a 1,2-diazetidine structure was tentatively assigned to a minor product.88 Attempted photochemical [2 + 2] cycloaddition of DEAZD to other olefins failed to give any 1,2-diazetidines.88... 

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