Phthalazines quaternization

Phthalazine forms monoquaternary salts with alkyl halides. 1-Substituted phthalazines are quaternized predominantly at position 3, and the site of quaternization of 1,4-disub-stituted phthalazines is determined by the steric hindrance of both substituents. 

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. 

Following the almost quantitative quaternization of phthalazine with chloromethyl trimethyl-silylmethyl sulfide, fluoride mediated desilylation liberates a carbanion which is trapped by intramolecular reaction (Scheme 17) to give a thiazolophthalazine derivative <8710C4423>. 

Note A-Alkylation of phthalazine can occur only by reduction of at least one C=N bond or by quaternization (exemplified later in this section). 

Some of these quaternary entities have been made by primary synthesis (see Chapter 8), but most of the more recently described examples have been obtained by quaternization of phthalazine (see Section 9.1.3). A few remaining preparative procedures are illustrated in the following examples. 

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