Pyridazines with nucleophiles

The unusual formation of N,N-dimethylaminophenyl substituted pyrimido[4,5-c]-pyridazines (74) by the reaction of the oxo compound (73) with phosphorus oxychloride and iV,AT-dimethylaniline has been reported (71CPB1849). The chlorination of other oxo substituted pyrimido[4,5-c]pyridazines with phosphorus oxychloride has been reported to be unsuccessful. Chloro derivatives of this heterocyclic ring undergo nucleophilic displacement with amines and hydrazine to give the corresponding amino and hydrazino substituted products. The catalytic dechlorination of these chloro substituted heterocycles has also been reported (68JHC523). 

Pyrazino[2,3-d]pyridazines undergo nucleophilic displacements readily. Pyrazino-[2,3-d]pyridazine-5,8-dione can be chlorinated in a mixture of phosphorus oxychloride and phosphorus pentachloride to give 5,8-dichloropyrazino[2,3-d]pyridazine. The corresponding dibromo product is prepared by reaction of the starting dione with phosphorus oxy-bromide and bromine. However, all attempts to chlorinate pyrazino[2,3-d]pyridazin-5-one failed (69JHC93). 

The majority of pyrimido[4,5-c]pyridazines have been prepared from pyrimidine precursors. The chloropyrimidines (176) give the desired heterocyclic ring (177) on reaction with hydrazine (72BSF1483). Hydrazine also reacts with ethyl a-diazo-/3-oxo-5-(4-chloro-2-methylthiopyrimidine)propionate (178) to give the pyrimido[4,5-c]pyridazine-3-carboxamide (78). A mechanism for this interesting reaction has been proposed as shown, on the basis of the detection of hydrogen azide in the reaction mixture. There is no precedent for the reaction of the a-carbon of a-diazo-/3-oxopropionates with nucleophiles under basic conditions (76CPB2637). 

Oxidation of 5-phenylpyrido[2,3-d]pyridazine with MCPBA gave the respective 7-oxide, whose reactions with nucleophiles afforded the 8-substituted products <83YZ63i>. 

However, the presence of other groups in the pyridazine nucleus may exert additional influences and a selective exchange or competitive monosubstitution has been observed. In the case of 4-substituted 3,6-dichloropyridazines monosubstitution of the individual chlorine atoms with nucleophiles can give two isomeric compounds, 73a and 74a. 

Druey et have performed reactions of 4-methyl-3,6-dichloro-pyridazine with ammonia and other nucleophiles, but did not establish their structures. Later studies revealed that treatment of the mentioned pyridazine with anhydrous ammonia in methanol at 120° afforded a mixture of aminochloro-4-methylpyridazines in the ratio of about 1 10, the isomer 73a (X = NH2, R = Me) predominating. Also modified reaction conditions have led to a mixture of both isomers, where the isomer 73a was prevailing, and when di-methylamine has been used only isomer 73a (R=Me, X = NMe2) was isolated. From the reaction with hydrazine hydrate the isomer 74a (R=Me, X = NHNH2) is claimed to be the main product. 

Pyridazine and its derivatives were substituted with nucleophilic radicals. They react either with 1-formylpyrrolidine or with A/-acetylproline in the presence of radical generators to give 5-substituted pyridazines (78TL619 86MI6). Also, reactions of 3-chloro-6-methoxypyridazine with ketone enolates in liquid ammonia show typical characteristics of a radical chain (SrnI) mechanism, and ketones 105 are obtained (81JOC294). 

There are many examples of replacement of the halogen atom in 3-halo-pyridazines with various nucleophiles.With phenols aryloxypyrida-zines were prepared with a N-hydroxycarbamate the corresponding pyridazinyloxycarbamate was obtained leading to several new amino-or hydrazinopyridazines. 372-374... 

There are numerous investigations of the reactivity of di- and polyhalo-pyridazines, particularly polyfluoropyridazines. Aminolysis of l-phenyl-4,5-dichloropyridazin-6-one has been studied in detail. In this and other reactions with nucleophiles, the halogen atom at position 4 is substituted preferentially, although a mixture of 4-amino and 5-amino derivatives is formed in the reaction between 4,5-dihalopyridazin-6-ones and ammonia or amines. It has been now firmly established that displacement reactions on 3,6-dichloropyridazine 1-oxide with sulfur nucleophiles take place at position 6 in contrast to nitrogen or oxygen nucleophiles, where the 3-chlorine atom is replaced preferentially. In connection with the previously observed self-condensation of 3-chloro-6-methylpyridazine to a tricyclic product, the reaction between 3,6-dichloropyridazine and pyridine N-oxides was investigated. 3,6-Dichloropyridazine with 2-methylpyridine N-oxide at 100°-110°C affords three compounds (171, 172, and 173). With 2,6-dimethylpyridine N-oxide, an ether (174) is also formed. The isolation of... 

Due to their nature as ambident nucleophiles, methylation of hydroxy-substituted pyridazi-no[4,5-z/]pyridazines with diazomethane usually yields a mixture of O- and (V-methylated products (Tabic 6). 

The reaction of 5,8-dichloro(or dibromo)pyrazino[2,3-c/]pyridazine with various nucleophiles yields mono- or disubstituted products. 

The quaternization of (benzo)pyridazines by alkyl halides (these systems are not readily susceptible to arylation) was reviewed in CHEC-I <84CHEC-l(3B)l>. Monoquaternization of pyridazines occurs more readily than other diazines but less readily than pyridine, reflecting the intermediate basicity/nucleophilicity of pyridazine. Diquaternization of pyridazine can only be achieved with oxonium salts, particularly Me30 BF4 . As with protonation and A-oxidation, mixtures of products are often obtained on quaternization of unsymmetrical pyridazines and have been the subject of theoretical studies. A number of 2-(ribofuranosyl)-3(2//)-pyridazinones have been prepared by stannic chloride catalyzed alkylation of 3-(trimethylsilyloxy)pyridazines with protected 1-0-ace-tylribofuranose <83JHC369>. The quaternization behavior of phthalazines is similar to that of pyridazines, but with cinnolines alkylation usually occurs at N-2, unless there is a particularly bulky substituent at C-3. 

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