Pyridazine substitution

E. Pyridazines Substituted with Another Heterocyclic Ring. 187... 

A substantial number of pyridazines, substituted with another heterocyclic ring, have been prepared since the late 1980s. It was therefore decided to summarize their preparation in a special section. 

A simple approach to pyridazine-substituted pyrimidine nucleosides (52) in the reaction of alkyne derivatives (51) with tetrazine diester (48) was reported by Maggiora and Mertes (Equation (2)) <86JOC950> use of the 1,2,4-triazine triester as diene yields the corresponding pyridine derivatives. A new route to the novel C-nucleosides (55) with substituted pyridazines as aglycones by the reaction of tetrazines (48) and (53) with the sugar alkyne (54) has been described (Equation (3)) <94AP(327)365>. 

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). 

The H NMR spectrum of pyridazine shows two symmetrical quartets of an A2X2 or A2B2 type dependent on the solvent and concentration. The satellites have been used to obtain all coupling constants. Spectra of C-substituted pyridazines, methylthio- and methylsulfonyl-pyridazines, both as neutral molecules and as cations, N-1 and N-2 quater-nized species, pyridazinones, hydroxypyridazinones, A-oxides and 1,2-dioxides have been reviewed (b-73NMR88> and are summarized in Tables 6, 7 and 8. 

Transformation of pyridazine 1-oxides and their methyl derivatives into cyclopropyl ketones and/or substituted furans can also occur (Scheme 14). 

IV-Methylation of polysubstituted pyridazinones is frequently accompanied by some side reactions, mainly substitutions. For example, methylation of 4-nitro-5,6-diphenyl-pyridazin-3(2//)-one with methyl iodide in the presence of sodium methoxide affords... 

Quatemization of various pyridazinethiones and pyridazinyl sulfides is dependent on the substituents attached to the pyridazine ring. For example, 3-methylthiopyridazine and 6-methyl-3-methylthiopyridazine react with methyl iodide to form the corresponding 1-methyl-3-methylthio and l,6-dimethyl-3-methylthio derivatives (85). On the other hand, if a larger group, such as methoxy or phenyl, is attached at the 6-position, quaterniza-tion takes place at position 2 to give 6-substituted 2-methyl-3-methylthiopyridazines (86 Scheme 24). 

AIkyI-substituted pyridazine-3(2//)-thiones undergo reaction with methyl iodide at the sulfur atom. Methylation of 4,5-diaminopyridazine-3(2ff)-thione with excess methyl iodide produces 4,5-diamino-l-methyIthiopyridazinium iodide (81JOC2467). 

The 3-, 4-, 5- and 6-positions in the pyridazine nucleus are electron deficient due to the negative mesomeric effect of the nitrogen atoms. Therefore, electrophilic substitution in pyridazines is difficult even in the presence of one or two electron-donating groups. The first reported example is nitration of 4-amino-3,6-dimethoxypyridazine to yield the corresponding 5-nitro derivative. Nitration of 3-methoxy-5-methylpyridazine gives the 6-nitro-,... 

Pyridazine 1-oxides substituted at position 3 or positions 3 and 6 afford the corresponding 5-nitro derivatives. A methyl group at position 6 (a with respect to the iV-oxide group) is frequently converted into the cyano group, and a methoxy group at position 6 is demethy-lated by benzoyl chloride/silver nitrate. For example, 3-substituted 6-methylpyridazine 1-oxides give the 5-nitro derivatives (96) and the 6-cyano-5-nitro derivatives (97), whereas... 

Mannich reaction with pyridazinone 1-oxides takes place at the a- or y-positions relative to the iV-oxide group, in contrast to the reaction in the pyridazinone series, where N-substituted products are formed. Pyridazin-3(2FT)-one 1-oxide gives first the corresponding 6-substituted derivative with excess of the reagents, 4,6-disubstituted products are obtained. When position 6 is blocked the corresponding 4-dialkylaminomethyl derivatives are obtained. 

Phenyllithium in ether adds to pyridazine and 6-substituted pyridazines at position 3. By using TMEDA, addition at position 4 is strongly promoted (78RTC116). 

Nucleophilic substitution in the pyridazine 1-oxide series takes place either according to pathway (a) or pathway (b) (Scheme 31). Pathway (a) operates when position 6 is unsubstituted. 

Treatment of pyridazine 1-oxides with phosphorus oxychloride results in a-chlorination with respect to the N-oxide group, with simultaneous deoxygenation. When the a-position is blocked, substitution occurs at the y-position. 3-Methoxypyridazine 1-oxide, for example, is converted into 6-chloro-3-methoxypyridazine and 3,6-dimethylpyridazine 1-oxide into 4-chloro-3,6-dimethylpyridazine. 

Chloro-4-methyl- and 6-methoxy-4-methyl-pyridazine 1-oxides give the corresponding 4-acetoxymethyl derivatives, while the corresponding 6-substituted 5-methylpyridazine 1-oxides do not react at the methyl group. 

A substituted acyl amino group can be introduced by reaction of pyridazine 1-oxide with A-phenylbenzonitrilium hexachloroantimonate 3-A-benzoylanilinopyridazine is formed (75JOC41). 

Alkylthio- and arylthio-pyridazines can be prepared from the corresponding halo-substituted pyridazines by using appropriate alkyl and aryl thiolates. 

The reactivity of halogens in pyridazine N- oxides towards nucleophilic substitution is in the order 5 > 3 > 6 > 4. This is supported by kinetic studies of the reaction between the corresponding chloropyridazine 1-oxides and piperidine. In general, the chlorine atoms in pyridazine A-oxides undergo replacement with alkoxy, aryloxy, piperidino, hydrazino, azido, hydroxylamino, mercapto, alkylmercapto, methylsulfonyl and other groups. 

The second most important nucleophilic substitution in pyridazine A-oxides is the replacement of a nitro group. Nitro groups at the 3-, 4-, 5- and 6-position are easily substituted thermally with a chlorine or bromine atom, using acetyl chloride or hydrobromic acid respectively. Phosphorus oxychloride and benzoyl chloride are used less frequently for this purpose. Nitro groups in nitropyridazine A-oxides are easily replaced by alkoxide. The... 

There are several examples of replacement of methoxy and ethoxy groups in substituted pyridazine N- oxides, with ammonia or hydrazine producing the corresponding amino and hydrazino compounds. 

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). 

Pyridazine carboxylates and dicarboxylates undergo cycloaddition reactions with unsaturated compounds with inverse electron demand to afford substituted pyridines and benzenes respectively (Scheme 45). 

Substituents on benzene or benzenoid rings in fused pyridazines, i.e. in cinnolines and phthalazines, usually exhibit reactivity which is similar to that found in the correspondingly substituted fused aromatic compounds, such as naphthalene, and is therefore not discussed here. 

Since the pyridazine ring is generally more stable to oxidation than a benzene ring, oxidation of alkyl and aryl substituted cinnolines and phthalazines can be used for the preparation of pyridazinedicarboxylic acids. For example, oxidation of 4-phenylcinnoline with potassium permanganate yields 5-phenylpyridazine-3,4-dicarboxylic acid, while alkyl substituted phthalazines give pyridazine-4,5-dicarboxylic acids under essentially the same reaction conditions. 

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