Pyridazines 3- chloro-, nucleophilic displacement

H-Pyrimido[l, 2-6]pyridazin-2-one, chloro-nucleophilic displacement reactions, 3, 343 2H-Pyrimido[l,2-6]pyridazin-2-one, 7-chloro-synthesis, 3, 354... 

Chlorinated 2H- pyrimido[l, 2-6 ]pyridazin-2-ones are known to undergo a variety of nucleophilic displacement reactions. Displacement of the chlorine atom in both the 4- and 7-positions of these compounds with methylamine and sodium methanethiolate is facile. Displacement of the chlorine atom in the 3-position does not occur. Therefore, 3,4,7-trichloro-2//-pyrimido[l,2-6]pyridazin-2-one (34) reacts with methanethiol in sodium methoxide to give 3-chloro-4,7-bis(methylthio)-2//-pyrimido[l,2-6]pyridazin-2-one (70) (71JOC3506). 

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). 

O-Demethylation has been observed as well as, or instead of, nucleophilic displacement on reaction of 3,4,5-chloro/methoxy pyridazines and 4,5-chloro/methoxy-2-methyl-3(2//)-py-ridazinones with morpholine (e.g.. Scheme 63). Demethylation was observed at all ring positions, but usually adjacent to chlorine or a carbonyl group, and A -methylmorpholine was isolated, consistent with demethylation rather than hydrolysis. The demethylation can also occur with other primary and secondary amines such as diethylamine, butylamine, and piperidine, but not with pyrrolidine and aniline <87H(26)1 >. 3-Phenolic ethers of pyridazines are resistant to reductive cleavage of the aryl ether bond under the conditions of phase transfer catalytic hydrogenolysis <82T3775>. 

Imidazo[4,5-d]pyridazine, 1-benzyl-4,7-dichloro-nucleophilic displacement reactions, 5, 629 midazo[ 1,5-6]pyridazine-5,7(3 H,6H)-dione, 4-acetyl-2-phenyl-synthesis, 5, 651 Imidazo[l, 2-6]pyridazines reactions, 5, 628 synthesis, 5, 650 Imidazo[l,5-6]pyridazines synthesis, 5, 651 Imidazo[4,5-c]pyridazines reactions, 5, 628-629 synthesis, 5, 651 Imidazo[4,5-d]pyridazines reactions, 5, 629 synthesis, 5, 436, 468, 651-652 3H-Imidazo[l,2-6]pyridazin-2-one, 6-chloro-3-dichloromethylene-synthesis, 3, 355... 

In work on 6-methoxypyrimidines (130), the 4-methylsulfonyl group was found to be displaced by the sulfanilamide anion more readily than were 4-chloro or trimethylammonio groups. This reactivity may be partly due to the nature of the nucleophile (106, Section II, D, 1). However, high reactivity of alkyl- and aryl-sulfonyl heterocycles with other nucleophiles has been observed. A 2-methylsulfonyl group on pyridine was displaced by methoxide ion with alkaline but not acidic methanol. 3,6-Bis(p-tolylsulfonyl)-pyridazine reacts (100°, 5 hr) with sulfanilamide anion and even the... 

Two methods for the preparation of [l,2,3]triazolo[4,5-, pyridazine-4-thione 29 were reported by Bussolari et al. involving nucleophilic substitution of sulfur by displacement of the 4-chloro substituent from 28 and of the oxygen atom of 4-lactam derivative 30 using sodium thiosulfate and phosphorus pentasulfide, respectively (Scheme 18) <1996BMC1725>. 

Dimethylpyrimido[4,5-f]pyridazine-5,7-dione 23 and its derivatives undergo attack at both C-3 and C-4. Under conditions of kinetic control, addition occurs preferentially at the more electron-deficient C, whereas thermodynamic control conditions, or the use of bulkier nucleophiles, favor addition at the less hindered position 3. This duality is illustrated by the addition of Grignard and organolithium reagents to C of 3-chloro analogue 24 (Equation 9), whereas stabilized nucleophiles such as the anion of nitromethane add at C-3 (Scheme 10) <2000CHE975>. Displacement of the 3-chloride occurs also upon treatment of 24 with amines (Equation 10) <2000CHE1213>. 

Chloro substituted pyrazino[2,3 -d]pyridazines react readily with amine and alkoxide nucleophiles to give the corresponding amino and alkoxy substituted products (66JHC512). 5,8-Dichloropyrazino[2,3-d]pyridazine (102) can be hydrolyzed in 2% aqueous sodium hydroxide to yield 5-chloropyrazino[2,3-d]pyridazin-8-one (103). Displacement of only one halogen substituent is also observed in the basic hydrolysis of the 5,8-dibromo analog (68JHC53). 

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... 

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