Nucleophilic Attack at Hydrogen

In pyridazine, base-catalyzed hydrogen-deuterium exchange takes place at positions 4 and 5 more easily than at positions 3 or 6. Deuteration of pyridazine 1-oxide in NaOD/DiO 

In pyridazin-3(2//)-one only the hydrogen at position 6 is replaced at 180 °C, while in 3-hydroxypyridazine 1-oxide the deuterium exchange takes place first at position 6 and then at position 4 at 140 °C. 5-Hydroxy- and 5-methoxy-pyridazine 1-oxide exchange only the hydrogen at position 6 at 150 °C. 

7 Reactions with Radicais and Electron-deficient Species 

It has already been mentioned that some radical reactions can occur as side reactions by irradiation of pyridazine derivatives, especially in hydroxylic solvents. 

Reactions of 3-chloro-6-methoxypyridazine with ketone enolates in liquid ammonia exhibit characteristics consistent with a radical chain mechanism for substitution (8UOC294). 

The importance of this group of reactions to the chemistry of isoxazoles is shown by the considerable amount of effort expended on this topic (63AHC(2)365,79AHC(25)147). The lability of the isoxazole nucleus towards nucleophiles and bases distinguishes this heterocycle from other azoles. The conditions which lead to ring cleavage are quite varied and depend on the position and the nature of the substituents. 

The importance of this ring-opening reaction is illustrated by the following. 5-Methyl-isoxazole (110) on treatment with ammonia was partly converted into cyanoacetoneimine (111), and when refluxed with phenylhydrazine it yielded the 5-aminopyrazole (113) through the intermediate cyanoacetone (112) (63AHC(2)365). 

The ring opening of 3-substituted isoxazoles proceeds differently, and the reaction can take various courses depending on the nature of the substituent. The reaction has been effected by sodium hydroxide and sodium ethoxide in alcoholic or aqueous media and by sodium amide and also n-butyllithium in inert solvents. 

If the substituent at the 3-position is a group that can be eliminated as an anion (such as Cr, CN and NJ), the reaction proceeds without the cleavage of the C(3)—C(4) bond in the isoxazole ring and involves the ejection of the 3-substituent as an anion. For example, 3-cyanoisoxazole (114) reacted with sodium ethoxide at room temperature to give ethyl cyanoacetate (115) via an intermediate cyanoketene (32G436). 

It should be noted that when 3-acylisoxazoles (116) are heated with a base such as sodium ethoxide, the acyl group is eliminated to give a carboxylate salt and a /3-ketonitrile (117). The reaction probably occurs via initial attack at the carbonyl group (46G206). 

3-Chloropyrazolo[3,4- ]quinoline, 3-chloropyrazolo[3,4- r]isoquinoline, l,2-dihydro-l,2-dimethylpyrazolo[3,4-c]qumolin-3-one, and l,2-dihydro-l,2-dimethylpyrazolo[3,4- r]isoquinolin-3-one were obtained by acid-induced nucleophilic aromatic substitution (SnH) of H-3 in A -hydroxypyrazolo[3,4- r]quinoline and iV-hydroxypyrazolo[3,4-r-]isoquinoline, representing the first cases of nucleophilic aromatic substitution of a fused pyrazole 2002JOC585 . 

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Nucleophilic Attack at Hydrogen Attached to Ring Carbon or Ring Nitrogen... 

Three or Four Heteroatoms including at least One Se or Te 4.21.5.6 Nucleophilic Attack at Hydrogen... 

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