Reduced Pyridazines

Large Rii Nitrogm Systems.—Most 1-benzazepine syntheses involve a ring expansion step, and the use of azides in azepine formation is well established. When 3-alkyl-l,2-dihydroquinolines (221 = alkyl) were heated with ethyl azido- 

Spiroquinol ethers e.g, (226) have been obtained in high yield by the oxidative coupling of 2,4-disubstituted phenols.Treatment of the ethers with amines led to l,3-dihydro-2i/-azepine-2-ones (227) by ring expansion, and oxidation to 

Exposure of l,l-dimethyl-2-vinylpiperidinium chloride (239) to sodamide gave a 94% yield of l-methylazacyclonon-4-ene (240) by a Sommelet-Hauser rearrangement. The catalytic co-oligomerization of ketazines and aldazines with butadienes 

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Similarly, reduced pyridazines have been prepared by pertungstate oxidation of the corresponding diamines, as shown in Scheme 60 (75JOC1395). 

A large number of pyridazines are synthetically available from [44-2] cycloaddition reactions. In one general method, azo or diazo compounds are used as dienophiles, and a second approach is based on the reaction between 1,2,4,5-tetrazines and various unsaturated compounds. The most useful azo dienophile is a dialkyl azodicarboxylate which reacts with appropriate dienes to give reduced pyridazines and cinnolines (Scheme 89). With highly substituted dienes the normal cycloaddition reaction is prevented, and, if the ethylenic group in styrenes is substituted with aryl groups, indoles are formed preferentially. The cycloadduct with 2,3-pentadienal acetal is a tetrahydropyridazine derivative which has been used for the preparation of 2,5-diamino-2,5-dideoxyribose (80LA1307). 

Structurally unique, potent, and selective oxytocin antagonistic agents characterized by a cyclic hexapeptide structure have recently been isolated from the broth filtrate of a novel Streptomyces silvensis strain [434,435]. As shown in formula (106), these compounds contain two hexahydro-3-pyrid-azinecarboxylic acid moieties. A study has been made of their structural modifications (including oxidation of the reduced pyridazine nuclei) [436]. 

Other reduced pyridazines and 1,2-oxazines can be also prepared by Diels-Alder-type reactions. Butadiene condenses with Et02CN = NC02Et and nitrosobenzene to yield (99) and (100), respectively. 

These reduced pyridazines (56) are easily oxidized to pyridazines... 

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. ... 

According to the number and position of hydrogen atoms in the pyridazine nucleus several reduced pyridazines are theoretically possible and existence of most of them has been registered. Frequently, the structures of reduced p3u-idazines are written as proposed by the authors, but a detailed study relating their structures is lacking. 

Dihydropyridazines have not been prepared by direct cycliza-tions reductions of pyridazines and oxidations of reduced pyridazines are known. 3,6-Diphenylp3n idazine is reduced with sodium and ethanol to the 1,2-dihydro derivative and the 1,2-dicarbethoxy analog is formed in a selenium dioxide oxidation of the corresponding 1,2,3,6-tetrahydro compound. 1-Carbethoxy- or 1,2-dicarbethoxy-1,2-dihydropyridazine was obtained similarly from an alkali treatment of 1,2-dicarbethoxyhexahydropyridazine. l,2-Dihydro-3,6-diphenylpyridazine is unstable and oxidizes to the parent pyridazine in the presence of air or on attempted acetylation. ... 

Dihydropyridazines are obtained from 1,4-dicarbonyl compounds and hydrazine (Section III,B) or from the reaction of sym-tetrazines and simple ethylenic compounds (Section III,H). There are also a few special reactions, such as that between a tetrahydrofuran and phenylhydrazine, or from a 1,4,5,6-tetrahydropyridazine derivative. The 1,4-dihydro structure has been found to be correct, rather than the 1,6-dihydro structure, postulated earlier for some of these reduced pyridazines (Section III,H). 1,4-Dihydropyridazines can be reduced or oxidized easily and acid treatment of l-tosyl-1,4-dihydropyridazine causes rearrangement to 1-tosylaminopyrrole. ... 

Like other reduced pyridazines, hexahydropyridazines can be oxidized to pyridazines and acylated, and they form thiourea derivatives with isothiocyanates. Hexahydropyridazine condenses with 1,4-dihalobutanes to give the diazadecalin with formaldehyde or benzaldehyde, 147 or its diphenyl analog have been obtained. ... 

A quantitative measure of electron distribution has been developed using C-NMR chemical shifts. These correlations also allow the prediction of C chemical shifts in substituted pyridazines (820MR192). C-NMR spectra of various pyridazines were recorded and analyzed. They were used to determine the most stable conformations of reduced pyridazines (87T2443) or the ring-chain isomerization of heterospiro compounds of type 122 (830MR42). Substituent effects of several 3(2//)-pyridazinones were correlated [83JCS(P1)1203], and nuclear relaxation rates of C and quadrupole relaxation of N have been measured for pyridazine (78MP997). 

Reduced pyridazines have also been irradiated. The dihydropyridazine 290 gives in high yield the open-chain product 291, whereas dimethyl... 

NMR spectroscopy has been widely used in particular to study the conformations and conformational interconversions of reduced pyridazines. The conformations of tetra- and hexahydropyridazines have been extensively studied by several groups in order to examine the influence of steric and electronic effects upon the geometry of the hydrazine part of the molecule. The temperature dependence of their NMR spectra was used to examine ring inversion and nitrogen inversion processes. 

Reduced pyridazines have also been irradiated. The dihydropyridazine 290 gives in high yield the open-chain product 291,582 whereas dimethyl l,2-dihydropyridazine-l,2-dicarboxylate gives two isomeric compounds, 292 and 293 (the minor product).493 It is postulated that the latter is formed by... 

An efficient synthesis of reduced pyridazines has been reported by Deshayes and Selin, who formed the appropriate hydrazone (327) in a Japp-Klingemann condensation with a substitued acetoacetate, and then caused it to cyclize. The overall yields ranged from 50% to 80%. 

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