Dihydro-pyridazines and -pyridazinones

6-Aryl-4,5-dihydropyridazine-3(2//)-one undergoes ring opening when submitted to Wolff-Kishner reduction, while with lithium aluminum hydride the corresponding 2,3,4,5-tetrahydro product is obtained. 

Addition of bromine to 5-f-butyl-3,6-dimethoxy-4,5-dihydropyridazine produces 5-bromo-4-f-butyl-3-methoxy-4,5-dihydropyridazin-6(l//)-one. 

Pyridazine-3,6-diones (diazaquinones) are prepared from cyclic hydrazides by oxidation with lead tetraacetate or other oxidizing agents, such as r-butyl hypochlorite, chlorine or nickel peroxide. 

Benzo analogs, 1,4-phthalazinediones and derivatives, react in the same way, while the corresponding diazaorthoquinones, i.e. 3,4-diketocinnolines, are not known. 

6-Dihydropyridazines are known as labile intermediates, and lose nitrogen at -78 °C with a half-life of 30 seconds or less. On the other hand, the corresponding 2-oxides are stable compounds which lose N2O only at 300 °C or above (77JA8505). 

5 SATURATED AND PARTIALLY SATURATED RINGS 2.12.5.1 Dihydro-pyridazines and -pyridazinones 

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Saturated 1,4-dicarbonyl compounds give 1,4-dihydro-pyridazines or -pyridazinones, etc., which are easily oxidized. 1,2-Diketone monohydrazones and esters containing a reactive CH2 group give 3-pyridazinones (95 — 96) (54HCA1467). 

Saturated 1,4-dicarbonyl compounds give 1,4-dihydro-pyridazines or -pyridazinones, etc., which are easily oxidized. 1,2-Diketone monohydrazones 124 and esters 125 containing a reactive CH2 group give 3-pyridazinones 126 (Scheme 64) . A popular modification of this approach is the Ugi four-component condensation of diarylethane-l,2-dione monohydrazones 127 with isocyanides, aldehydes, and methylene active acids leading to the corresponding substituted pyridazin-3(2//)-ones 128 (Scheme 65) The intermediate Ugi condensation products have never been observed because of their tendency to cyclize <2003S691>. 

There has been a considerable expansion in the use of C NMR in theoretical and structural studies since the publication of CHEC-I in 1985, but in many instances C NMR data is recorded for the purposes of characterization without detailed assignment of the chemical shifts. Selected assigned data from the review period for pyridazines and pyridazinones is shown in Table 1. Compared with these aromatic systems, dihydropyridazinones show normal C shifts as shown by the methylene 25.9 and 23.8) and carbonyl 5 166.6) carbons of 6-benzyl-4,5-dihydro-3(2//)-pyridazinone in DMSO <89JHC1787>. Care should be taken in making comparisons involving potentially tautomeric systems like the pyridazinones note, for instance, the equivalence of 3,6- and... 

The patent literature covers many pyridazine derivatives claimed as blood platelet aggregation inhibitors and antithrombotic agents. The interest has been focused mainly on 6-aryl-4,5-dihydro-3(2//)-pyridazinones. In these compounds the aryl substituent has been varied within a wide range. Thus, dihydro-pyridazinones bearing a substituted or heterocycle-fused phenyl group at C-6 (60, R R2,R3 = H, alkyl Ar = substituted Ph) [34, 110-112,205-233] as well as various heteroaryl substituted congeners (61, R1, R2, R3 = H, alkyl Ar = pyridyl, thienyl, pyrrolyl, pyrazolyl) [234-241] have been prepared in search of novel antithrombotics. 

A combination EIMS and X-ray study of [l,2,4]triazolo[l,2-b]- and [l,3,4]thiadiazolo[3,4-i>]phthalazines was undertaken [95JHC283], and X-ray crystal structure determinations of 5-(2-chlorobenzyl)-6-methyl-3(2W)-pyridazinone [95AX(C)1834], and on 6-benzyloxy-7,8-dihydro-8-phenyl-3-trifluoromethyl-r-triazolo[4,3-i>]pyridazine and its 5,6-dihydro-6-one derivative [95AX(C)1829] have been performed. Structures of some pharmacologically-active pyridazines previously reported as arylidene-4,5-dihydropyridazines need to be revised to those of aromatic pyridazine tautomers 6-8 based on a combination H NMR nOe and X-ray study [95AJC1601],... 

In a similar way other pyridazines,159 e.g., 3-phenyl-6-methoxy-pyridazine and 3-methyl-6-chloropyridazine, are reduced, but the dihydropyridazines are in these cases rather unstable and may lose methanol or hydrogen chloride forming the corresponding 4,5-dihydro-pyridazinone. The reduction of pyridazinones will be discussed below. 

The reduction in acid solution of di- and tetrahydropyridazines and pyridazinones is often best understood when their resemblance to hydrazones is considered. The reduction of such compounds has been discussed (Chapter 11), and the primary step is a hydro-genolysis of the nitrogen-nitrogen bond. The reduction of 1,4-dihydro-1-methyl-5-r-butyl-3,6-diphenylpyridazine to pyrroles has been described [148, 149] at more negative potentials, pyrrolines and pyrrolidines may be obtained from pyridazines,... 

Propylpyridazine was deprotonated and added to 4-methoxybenzophenone (98MI2). 6-Arylmethyl-3(2//)-pyridazinones were reacted with mercuric acetate in acetic acid to give a monomercuri derivative, whereas from 4,5-dihydro-3(2//)-pyridazinone a bis-pyridazine mercuri compound was formed(89MI2). 4-Methylpyridazine reacted with ninhydrin to give the adduct 151, but the 3-methyl analog added initially two molecules of ninhydrin to give finally the spiro compound 152 (96H1665). 

Several other ketones were employed as starting material. Pyridazines were obtained from y-nitroketones and hydrazine. The initially formed 4,5-dihydro-3(2H)-pyridazinone oximes (4) are transformed with dilute acid into 5.58 The reaction is postulated to proceed via a nitrile oxide, generated from the nitromethyl group. 

The role of carbonyl compounds is dominant in the chemistry of dihydro derivatives of pyridazines. Dihydro-3 (2/ -pyridazinone derivatives are more stable than the corresponding simple dihydropyridazine derivatives and constitute the majority of dihydro compounds reported. The analogous derivatives are of course not possible in the phthalazine and cinnoline series, though 1,4-dihydro-3 (2/ -cinnolinones are known. 

The synthesis of pyridazine derivatives from hydrazones includes the thermal cyclization of 2-arylhydrazono-3-oxo-5-phenyl-4-pentenenitriles (readily obtained from ethyl cinnamate by condensation with acetonitrile followed by Japp-Klingemann type reactions) to l-aryl-3-cyano-6-phenyl-5,6-dihydro-4(l//)-pyridazinones (Scheme 85) <86JHC93>, and base-induced cyclization of a hydrazone of a 4-chloro-l-arylbutan-l-one to prepare a 2,3,4,5-tetrahydropyridazine (Scheme 85) <88JHC1543>. An earlier route to 6-carboxy-5-hydroxy-2-phenyl-3(2//)-pyridazinone via condensation of benzenediazonium chloride and dimethyl acetonedicarboxylate has been adapted to give a series of aryl derivatives either as esters (by thermal cyclization) or as acids (by cyclization with hydroxide). Both cyclizations proceed in high overall yield (Scheme 86) and decarboxylation of the acids also proceeds in high yield <89JHC169>. 

Many (benzo)pyridazines are made from 1,4-diketo compounds, and the industrial supply of, for example, maleic and phthalic anhydrides and mucohalic acids make them attractive and widely used starting materials, which can be used in conjunction with substituted hydrazines to give a range of A-substituted derivatives. Some other 1,4-diketo compounds are commercially available on a smaller scale, including, for example, certain 3-benzoylpropionic acids from which 6-aryl-4,5-dihydro-3(2//)-pyridazinones can be prepared. When such precursors are not commercially available then ease and scope of synthetic approaches to the starting materials must be considered, but for established routes, such as 6-aryl-4,5-dihydro-3(2//)-pyridazinones from 3-aroylpropionic acids, a variety of synthetic methods have been developed so that a wide range of (substituted)aroyl derivatives can be prepared. Synthetically useful preformed (benzo)pyridazine derivatives that are commercially available include 4,5-dichloro-3(2F/)-pyridazinone, 3,6-dichloropyridazine, and 1,4-dichlorophthalazine. 

Many new pyridazine, cinnoline, and phthalazine syntheses relied on the use of hydrazine-based precursors. 4,5-Dihydro-3(2//)-pyridazinones were obtained by cyclization of hydrazine with Meldrum s acids <97SC3513>, and six-membered cyclic hydrazides 3 were obtained in very high diastereoselectivities by the coupling of azide-substituted bisfenol silanes) <97JOC5680>. PhSeBr-promoted cyclization of alkenyl phenylhydrazones led to tetrahydro-pyridazines <97T7311>, condensation of furofuranones and hydrazines led to pyrrolo[2,3-... 

Cycloaddition reactions of nitrile oxides with 5-unsubstituted 1,4-dihydro-pyridine derivatives produced isoxazolo[5,4-Z>]pyridines in moderate to good yield. In each case examined, the reaction produced only a single isomer, the structure of which was assigned by NMR spectra and confirmed by X-ray diffraction analysis of 102 (270). A study of the cycloaddition behavior of substituted pyridazin-3-ones with aromatic nitrile oxides was carried out (271). Nitrile oxides undergo position and regioselective 1,3-dipolar cycloaddition to the 4,5-double bond of pyridazinone to afford 3a,7a-diliydroisoxazolo 4,5-<7]pyridazin-4-ones, for example, 103. 

The formation of pyridazines from 1,4-ketoacids (10) or their esters and unsubstituted or substituted hydrazines is one of the most widely used methods of synthesis. It is possible to conduct the reaction in a single step or via the intermediate hydrazones or semicarbazones. The resulting 4,5-dihydro-3(2.fif)-pyridazinones (11) are then converted into the corresponding 3(2fl )-pyridazinones (12) upon dehydrogenation. Bromine in glacial acetic acid is the commonest and most useful... 

Like other azines with a hydroxyl group a or y to a ring nitrogen atom, 3- and 4-hydroxypyridazines exist predominantly in the oxo form in the solid state and in aqueous solution. This has been established for 3(2/f)-pyridazinone and related compounds from correlations of ultraviolet spectra of unsubstituted compounds and their 0- and iV-methyl derivatives in neutral, acid, and alkaline solution, on the basis of infrared spectra (for a summary of this aspect of tauto-merism see Volume 1, Chapter VII, Section II, K) and from the determined crystal structure of 6-oxo-l,6-dihydro-3-pyridazine-carboxamide. Here, the bond lengths and positions of hydrogen atoms clearly indicate its structure as the oxo form. Similar conclusions were reached also for 4(lJ )-pyridazinones (75) and the predominant cationic structure is represented by... 

The most useful procedure utilises a 1,4-keto-ester giving a dihydro-pyridazinone, which can be easily dehydrogenated to the fully aromatic heterocycle, often by C-bromination then dehydrobromination alternatively, simple air oxidation can often suffice. 6-Aryl-pyridazin-3-ones have been produced by this route in a number of ways using an a-amino nitrile as a masked ketone in the four-carbon component, or by reaction of an acetophenone with glyoxylic acid and then hydrazine. Friedel-Crafts acylation using succinic anhydride is an alternative route to 1,4-keto-acids, reaction with hydrazine giving 6-aryl-pyridazinones. Alkylation of an enamine with a phenacyl bromide prodnces 1-aryl-l,4-diketones, allowing synthesis of 3-aryl-pyridazines. ... 

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