1.4- Dihydropyridazines

Pyridazines with a hydroxy group at an a- or y-position to a ring nitrogen atom, i.e. 3-and 4-hydroxypyridazines (4) and (5), exist predominantly in the oxo form. This conclusion is based on spectroscopic evidence from UV spectra of unsubstituted compounds and their A-methyl and O-methyl derivatives in alkaline, neutral and acidic solutions. In some instances, as for example for 6-oxo-l,6-dihydropyridazine-3-carboxamide, there is also evidence from X-ray analysis <54AX199, 63AX318). Maleic hydrazide and substituted maleic hydrazides exist in the monohydroxymonooxo form (6). 

N-protonation the absolute magnitude of the Ad values is larger than for Af-methylation <770MR(9)53>. Nuclear relaxation rates of and have been measured as a function of temperature for neat liquid pyridazine, and nuclear Overhauser enhancement has been used to separate the dipolar and spin rotational contributions to relaxation. Dipolar relaxation rates have been combined with quadrupole relaxation rates to determine rotational correlation times for motion about each principal molecular axis (78MI21200). NMR analysis has been used to determine the structure of phenyllithium-pyridazine adducts and of the corresponding dihydropyridazines obtained by hydrolysis of the adducts <78RTC116>. 

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). 

Alkylidene-2,3-dihydropyridazines (124) are synthesized by coupling of 3-thiomethyl-pyridazinium salts with active methylene compounds in the presence of potassium carbonate in DMF (Scheme 39) (79TL4837). 

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. 

Aryl-2-phenyl-4,5-dihydropyridazin-3(2//)-ones react either with phenylmagnesium bromide or with phenyllithium to give 6-aryl-2,6-diphenyl-l,4,5,6-tetrahydropyridazin-3(2//)-ones (135) (products of 1,2-addition to the azomethine bond), while 2-methyl-6-phenyl-4,5-dihydropyridazine-3(2//)-one reacts with two equivalents of phenylmagnesium bromide at the carbonyl and azomethine group to produce 2-methyl-3,3,6,6-tetraphenyl-hexahydropyridazine (136) (Scheme 53) (80JPR617). 

Aryl-4,5-dihydropyridazin-3(2//)-ones react with pyrrolylmagnesium bromide to give 6-aryl-3(l-pyrrolyl)pyridazines or, when 1 4 molar amounts of reagents are used, a mixture of 6-aryl-3(l-pyrrolyl)pyridazines and 3,4-di(l-pyrrolyl)-4,5-dihydropyridazines (Scheme 54 (79RRC453). 

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. 

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). 

It is customary to perform the condensation of 1,4-dicarbonyl compounds with hydrazines in the presence of mineral acid to avoid the formation of A-aminopyrroles. Contrary to early claims that 4,5-dihydropyridazines are formed <07CB4598), these compounds are now regarded as 1,4-dihydro derivatives 81CB564). 

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

Pyridazines are formed from pyrones or their thioxo analogs or from appropriate pyridones. Pyrones or pyridones react with diazonium salts to give the corresponding hydrazones (187) and (188) which are rearranged under the influence of acid or base into pyridazinones as shown in Scheme 107. On the other hand, kojic acid is transformed with hydrazine into a 1,4-dihydropyridazine and a pyrazole derivative. 4H-Pyran-4-thiones... 

Diazonium salt 185 (R = H) when coupled with different CH active compounds yielded 3-hydrazono derivatives (e.g. 186 and 187). Hydrazono derivatives 186 and 187 were cyclized into 3-(l,4-dihydropyridazin-l-yl) 188 and 3-(pyrrolin-l-yl) derivatives 189, respectively (00MI33). 

In this work the possibility of the existence of 1,2-dihydro isomer with the core structure 42 was not considered. Recently, however, it was shown that 1,2-dihydropyridazines could be prepared by careful electroreduction of the corresponding pyridazines, and that their stability depends significantly on the ring substitutions. Thus, dimethyl l,2-dihydropyridazine-3,6-dicarboxylate 43a (R = H) is reasonably stable and rearranges into the 1,4-dihydro tautomer 43b only at a more negative potential, while the tautomerization in its tetrasubstituted analog 43a (R = COOMe) occurs more readily (Scheme 14) [00TL647]. 

The differences in free energy, AG°, between 1,4-dihydro and 4,5-dihydro tautomers in CDCI3 solution for some dihydropyridazines were calculated and have been found to be 1.24 kcal/mol for 3,6-diphenyldihydropyridazine 39 (R = Ph) and only 0.73 kcal/mol for 3,6-di-tert-butyldihydropyridazine 39 (R = t-Bu) [85AHC(38)l,p.40]. 

A derivative of 5-(indol-2 -yl)dihydropyridazine 44 (R = H) exists in DMSO-iig solution exclusively as tautomer 44a (within the limits of 400-MHz H NMR detection). However, the introduction of methyl groups both into the indole ring and into the pyridazine ring favors a shift of the tautomeric equilibrium... 

A Diels-Alder type [4+2] cycloadditions of 4,5-dihydropyridazine, prepared in situ from its trimer, with 2-methyl- and 2,3-dimethyl-1,3-butadienes (65, R = H, Me R = Me) afforded a complex reaction mixture, from which 6-methyl- and 6,7-dimethyl-3,4,4n,5-tetrahydro-8//-pyrido[l,2-ftjpyridazines (66, R = H, Me R =Me) could be isolated (97CEJ1588). With 1,3-butadiene (65, R = R =H) only a mixture of endo and exo isomers 67 and 68 (R = R =H) was obtained. 

Chloro-2-hydrazinoquinoxaline (254) with mucochloric acid (255) gave 6-chloro-2-(4,5-dichloro-6-oxo-1,6-dihydropyridazin-1 -yl)quinoxaline (256) (AcOH, reflux, 5.5 h 87% analogs likewise). ... 

Furans add to DEAZD to give Diels Alder adducts, although short reaction times are essential if the initial adduct is to be isolated. Attempts to convert the adduct into the bicyclic compound 116 failed. The only product isolated was a trimer of 4,5-dihydropyridazine, possibly formed as shown in Scheme 16.178 However, the furan adducts are readily converted... 

Several interesting 1,2,4-triazole fused-ring systems have been reported. A facile synthesis of 3,5-dihydro-677-imidazo[l,2-fc]-l,2,4-triazol-6-ones 162 was obtained by an iminophosphorane-mediated annulation <06EJ04170>. 8-Trifluoromethyl-l,2,4-triazolo[4,3- >]pyridazines 163 has been prepared from 4-trifluoromethyl-4,5-dihydropyridazin-3-one... 

The DA reaction of tetrazines such as 3 was also studied by use of the GS/ MW process [26, 27]. The expected adduct, however, decomposed by nitrogen elimination followed by dehydrogenation, giving a pyridazine or a dihydropyrida-zine [23-25], With 2,3-dimethylbutadiene and cyclopentadiene as dienophiles, SMWI gave dihydropyridazines 8 and 9, as with classical heating [23] (Tab. 7.1, entries 6 and 7). 

Under classical conditions, the reaction between 3 and styrene required 50 h of heating at 110 °C, and gave the dihydropyridazine adduct 10a [24], After SMWI with 30 W incident power for 5 min (Tmax = 154 °C), the adduct 10a was not detected whereas the totally dehydrogenated product, pyridazine 10b, was isolated in almost quantitative yield (Tab. 7.1, entry 8). Ethyl vinyl ether and 3 gave the same product, pyridazine 11, under both classical heating [25] and MW irradiation conditions (Tab. 7.1, entry 9). In this instance the DA adduct lost nitrogen and ethanol. 

For several pyridazine derivatives reported in the patent literature a muscle relaxant activity has been claimed. In this context, oxadiazolylpyridazines (35) [117] and 6-aryl-4,5-dihydropyridazine-3(2/f)-ones bearing various functionalized alkyl side-chains at N-2 [163, 174, 188, 189] are to be mentioned. Denpidazone (56) (CAS 42438-73-3), a l,2-diphenylpyridazine-3,6-dione derivative, is listed as a muscle relaxant [96]. 

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