Pyridazines, methyl-, acidity

In the last decade new reactions have been elaborated in which pyridazines can be transformed into a variety of other heterocycles. Esters of pyridazine-carboxylic acids and 1-diethylaminopropyne undergo cycloaddition reactions with inverse electron demand. The orientation of the two reactants depends on the position of the carboxylate group in the pyridazine ring. For example, from methyl pyridazine-4-carboxylate the pyridine derivative 245 was formed via the adduct 244 and subsequent elimination... 

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). 

Amino-6-chloro-4-methyl- and 3-amino-6-chloro-5-methyl-pyridazine and 3-amino-6-methylpyridazin-4(l//)-one are transformed with sodium nitrite in the presence of acid into the corresponding oxo compounds. If concentrated hydrochloric acid is used, in some instances the corresponding chloro derivatives are obtained as side products. On the other hand, 3-, 4-, 5- and 6-aminopyridazine 1-oxides and derivatives are transformed into stable diazonium salts, which can easily be converted into the corresponding halo derivatives. In this way 3-, 4-, 5- and 6-bromopyridazine 1-oxides, 5-chloropyridazine 1-oxide, 3,4,5-trichloropyridazine 1-oxide and 6-chloropyridazine 1-oxide can be obtained. 

Methyl groups in pyridopyrazines (64IMC240) and pyridopyrazinones (71TH21500) are oxidized to carboxylic acids with potassium permanganate. Aryl carbinol substituents are also very readily oxidized to benzoyl derivatives in alkaline conditions (76CPB238). Bromina-tion of 2,3-dimethylpyrido[3,4-f ]pyridazine gives the 2,3-bisbromomethyl derivative, whilst... 

On boiling the methiodide with 70% sulfuric acid an N-methyl-oxo derivative was obtained, and this in turn gave 3-amino-2-phenyl-quinoline, methylamine, and ammonia on fusion with soda lime. The bulk of the evidence therefore favors quaternization at N-2 (cf, 154), in which case the acid-hydrolysis product is 155. Quaternization at N-2 would be expected because of the steric influence of the 10-phenyl group and the influence of the 4-amino group (cf. 4-hydroxy-pyridazine ) in the pyridazine-type ring, although the partial double-bond character of that ring is probably different from that in pyridazine itself. 

Six-membered rings with two nitrogen atoms behave differently depending on the position of the nitrogen atoms. 1,2-Diazines (pyridazines) are very stable to catalytic hydrogenation [482]. 1,3-Diazine (pyrimidine) and its 2-methyl, 4-methyl and 5-methyl homologs were easily hydrogenated in aqueous hydrochloric acid over 10% palladium on charcoal to 1,4,5,6-tetrahydropy-rimidines in yields of 97-98% [483]. 

The values of perhydropyrido[l,2-f)]pyridazine and its 2-oxo derivative were found to be 2.80 0.04 and 7.32 0.03, respectively (72KGS220), whereas that of anhydro 4-hydroxy-2-methyl-5,6,7,8-tetrahydropyrido(l,2-6]pyridazinium hydroxide (16) was determined by spectrophotometry to be 2.77 (71CPB159). UV spectroscopic measurements in sulfuric acid gave a pKa value of -0.25 for pyrido[l,2-6]cinnoline derivative (17, R = H) (74JHC125). 

Another series of compounds which are easily accessible from levulinic acid are pyridazone and pyridazine derivatives. Levulinic acid and its esters condense almost quantitatively with hydrazine to ve 6-methyl-3-P3rridazinone (XLVI), which is readily dehydrogenated by means of bromine to give 6-methyl-3-pyridazone (XLVII). 

Nitration of 4-amino-6-methylpyridazin-3(2-ff)-one at C-5 was performed in two steps. Treatment with concentrated nitric acid affords 6-methyl-4-(nitroamino)pyridazin-3(2f/)-one whose rearrangement in concentrated sulfuric acid led to the formation of 4-amino-6-methyl-5-nitropyridazin-3(2/0-one <2001RJ01026>. 

The synthesis of pyrrolo[2,3- 7 pyridazines can be achieved by starting either with pyridazine, a tetrazine, or a pyrrole. Pyridazinone 80 reacts with bromomethyl derivatives to give poor yields of 81 <1996H(43)1863> (Equation 34), while 5-acetyl-2-methyl-4-nitro-6-phenyl-3(2//)-pyridazinone, after treatment with sarcosine ethyl ester for a brief time at room temperature, followed by acid hydrolysis afforded a good yield of 82 (70%) <1994S669>. 

Transformation of both the ester and nitrile derivatives 726 or 727 into pyrano[2,3-t7 pyridazines 728 or 729, respectively, by treatment with dilute HCl at room temperature involved nucleophilic displacement of the morpholine group by the hydroxyl group with an acidic hydrolysis followed by intramolecular iminolactonization and then hydrolysis of the formed imino group to a carbonyl group. Compounds 726 and 727 were prepared by Vilsmeier-Haack formylation of 2-methyl-5-morpholino-3(2/7)-pyridazinone 724 followed by condensation of the resulting product 725 with either ethyl a-cyanoacetate or malononitrile in EtOH (Scheme 34) <1994H(37)171>. 

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