Pyridazines, reduced derivatives

The NMR spectra of pyrido[2,3-d]pyridazine Af-oxides reduced derivatives and quaternary salts have also been studied and alkaline deuterium exchange reactions investigated <77BSF919). 

The Diels-Alder reaction is a useful way of synthesizing six-membered carbocyclic rings. Since ADC compounds are usually better dienophiles than the corresponding C=C compounds, the Diels-Alder reaction provides a good general route to pyridazines, and their reduced derivatives. Although vast numbers of examples of Diels-Alder reaction involving ADC compounds have been reported, not many of these have been aimed specifically at heterocyclic synthesis. 

These compounds have been referred to as tetrazolo[l,5-c]pyrazines, and reduced derivatives have been named tetrazolo[l,5-a]piperazines. This ring system has attracted attention mainly in the study of tetrazolo azide tautomerism and has been used to generate nitrenopyrazine. Although tetrazolo derivatives of pyridazine and pyridine are stable in solution, tetrazolo[l,5-a]pyrazine isomerizes readily in chloroform or trifluoracetic acid. Although an earlier report indicated that no azide... 

Practically all pyridazine-carboxylic and -polycarboxylic acids undergo decarboxylation when heated above 200 °C. As the corresponding products are usually isolated in high yields, decarboxylation is frequently used as the best synthetic route for many pyridazine and pyridazinone derivatives. For example, pyridazine-3-carboxylic acid eliminates carbon dioxide when heated at reduced pressure to give pyridazine in almost quantitative yield, but pyridazine is obtained in poor yield from pyridazine-4-carboxylic acid. Decarboxylation is usually carried out in acid solution, or by heating dry silver salts, while organic bases such as aniline, dimethylaniline and quinoline are used as catalysts for monodecarboxylation of pyridazine-4,5-dicarboxylic acids. 

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). 

The 6- and 7-quaternary salts of pyrido[2,3-d]pyridazine are reduced by borohydride with subsequent air oxidation to 5,6- and 7,8-dihydro oxo derivatives respectively (77BSF919), whilst the [3,4-d] analogues give the corresponding 1,2- and 3,4-dihydro oxo compounds 72CR(C)(275)1383). ... 

As in the pyridopyrimidines, the MacFadyen-Stevens degradation of tosylhydrazino derivatives has been used to prepare the parent [2,3-tf] compound (63JCS6073), and 1,4-bishydrazinopyrido[3,4-tf] pyridazines are reduced to the 1,4-diamino derivatives by Raney nickel (68AJC1291). 

Reduced pyrido[4,3-c]pyridazines are obtained from piperidine derivatives such as (371) with hydra2dne e.g. 79AF1835), whilst another related synthesis coupled the enamine (372) with phenacyl bromide semicarbazone to give (373) (74JAP(K)7488897). 

The cyano group of l-(cyanomethyl)perhydropyrido[l,2-h]pyridazine was reduced with LAH to yield the l-(2-aminoethyl) derivative (66KGS91). The amino group was reacted with methyl isothiourea in boiling 50% aqueous ethanol to afford the l-(2-guanidinoethyl) derivative (66KGS91). 

Bromination of 1114 gave l-(3-bromo-2-oxopropyl)pyridazin-6-ones (1116) as a major product in addition to 1115 (91JHC385). Reaction of 1116 with sodium azide gave the corresponding l-(3-azido-2-oxopropyl)-pyridazin-6-ones 1117, which was reduced to 1118. 4,5-Dichloro-l-(2,3-dihydroxypropyl)pyridazin-6-one 1121 was also prepared from 1116 via 1119 and the corresponding 2,3-epoxypropyl derivative 1120 (91JHC1235). 

Antwerp (2004), and Strasbourg (2006) in the covered period of this chapter. Certainly there has been a lot of activity in the pyridazine and benzo derivative field in the 1996-2006 period. A search on the Web of Science revealed 1756 articles for the topic pyridazin , 574 for phthalazin and 168 for cinnolin . The same search on the Scifinder database revealed 5203, 1943 and 462 hits for the concepts pyridazin , phthalazin , and cinnolin , respectively. Patents have only been taken into account in Section 8.01.12. In this chapter emphasis has been put on new and adapted older methods, as well as new interesting examples of well established methods. Selections necessarily had to be made due to the large amount of material published within the considered timeframe. Fully conjugated pyridazines, phthalazines and cinnolines as well as (partly) reduced and oxo forms (both only in the 1,2-diazine ring) are covered in this work. 

Pyridazino[l,2-pyridazine derivatives are easily reduced with either hydrogen over a catalyst or with metal hydrides. Reaction of the pyridazino[l,2- ]pyridazine-l,4,6,9-tetrone (44) with hydrogen over platinum oxide gives the hydrogenated product (45) (66JOC1311). This product can be further reduced with lithium aluminum hydride to give the octahy-dropyridazino[l,2- ]pyridazine (24) (67JA4875). 

When a second nitrogen atom is introduced into the pyridine ring the basicity is reduced (pjRTa 5.23 for pyridine and 2.33 for pyridazine). The effect of the additional substituents on pKK depends on the position of the substituents (Table 3). An extensive set of pK values of pyridazine derivatives has been submitted to correlation analysis using the Hammett and the two Taft equations, which shows that the pKa values are most sensitive to the effect of a 2-substituent followed by the effects of 3- and 4-substituents. The interactions between nitrogen atom and 2-substituents represent over 70% of the inductive character. The composition of the effects of +M 4-substituents is significantly enriched in the resonance interactions, whereas -M 4-substituents interact with the nitrogen atom mainly by induction (77MI21201). 

The half-lives have been determined for deuteriation (in NaOD) of imidazo[l,2-6]pyridazine, 1,2,4-triazolo[4,3-b]pyridazine, and tetrazolo-[l,5-6]pyridazine and some of their derivatives (Scheme 8.13) (71M837). The results are much as expected The greater the number of nitrogens, the faster the rate rates are larger for quarternary ions than for the corresponding neutral species and the rate is reduced (in some cases quite markedly) by methyl substituents, presumably due to steric effects. Steric effects may also account for the unexpected and large deactivation by o-chlorine. 

Reduction of pyridazin-4-ones seems not to have been reported, f. Derivatives of Cinnoline. 3-Hydroxycinnoline (222)44 is reduced in a two-electron wave from pH 0 to 11. In strongly acid solution the main product is 1-aminooxindole (223), which is also obtained on reduction with zinc and sulfuric acid.232 Reduction in an emulsion of an aqueous phosphate buffer (pH 6.5) and n-butanol produced a nearly quantitative yield of 3-keto-l,2,3,4-tetrahydrocinnoline (224) this compound was easily reoxidized to 3-hydroxycinnoline. 

The saturated analogs, e.g., succinic anhydride or succinic esters, behave differently and only in few cases were pyridazines obtained. The reaction between succinic anhydride and various amounts of hydrazine hydrate has been studied under different reaction conditions, but always uncyclized products were formed. One of these is a polymeric hydrazide which, when treated with benzenesulfonyl chloride, yielded the monobenzenesulfonyl derivative of cyclic succinhydrazide (30, R = PhS02) along with a compound formulated as bicyclic disuccinhydrazide (152, Section IV,H, 4), but later shown to be 153. Authentic cyclic succinhydrazide (30, R = H) was obtained upon reducing maleic hydrazide with aluminum amalgam. Previous claims that 30 (R = H) may be obtained from succinic acid or A-aminosuccinimide proved to be incorrect. 

Pyridazines have been prepared from furans and their reduced analogs. One of the most investigated reactions was introduced by Clauson-Kaas. Furans are treated with bromine in methanolic solution to give derivatives of 2,5-dihydrofuran (39). These are then submitted to acid hydrolysis and the intermediate en-dione (40) (or the aldehydic analog) reacts with hydrazine to form the corresponding pyridazine (41). - The intermediate 40 should... 

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. ... 

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