Properties of Substituted Quinazolines

Adachi, Yakugaku Zasshi 77, 507 (1957) (English Summary) Chem. Abstr. 51, 14744 (1957). 

Methylation of 2- or 4-methylquinazoline is reported to proceed with difficultyj but 4-methylquinazoline has been quaternized with methyl iodide. The product was very hygroscopic and, although not purified, was shown to consist mostly of 1,4-dimethylquinazolinium iodide, since it gave the same cyanine dye (11) with 2-methylthio-benzthiazole metho-toluene-p-sulfonate as did l-methyl-4-methyl-thioquinazolinium iodide (of unambiguous structure) with 2-methyl-benzthiazole methiodide.  

2-Alkylquinazolines are catalytically reduced to the corresponding 3,4-dihydro derivatives/ The only example of a 4-substituted quin-azoline which was reduced to its 3,4-dihydro derivative is 2-chloro-4-phenylquinazoline which gave 4-phenyl-3,4-dihydroquinazoline/ 4-Methylquinazolines are susceptible to oxidation, as is shown by the attempted nitration of 2,4-diraethylquinazoline which causes the removal of the methyl group with formation of 4-hydroxy-2-methyl-6-nitroquinazoline/ When the 4-substituent is —C(Et) (C02Et)2 recrystallization of the picrate from ethanol is sufficient to convert it to 4-hydroxyquinazoline/ Similar hydrolyses occur in acid solution and the mechanism undoubtedly involves a hydrated intermediate/ 

The lactam-lactim tautomerism of hydroxyquinazolines is reflected in their chemical reactivity. Thus they are chlorinated to 4-chloro-quinazolines (see Section VI,A), and both 0- and A-methylation have been observed. When a substituent is already present on a nitrogen atom, as in 3-methyl-4(3i7)quinazolinone, chlorination gives 4-chloroquinazoline with loss of the methyl group (see la). 2- 

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The pK of quinazoline, as commonly measured, is 3.51 this represents mainly the equilibrium between the two most stable species, namely, the hydrated cation and the anhydrous neutral species. The true anhydrous pKa (i.e., for the instantaneous equilibrium between anhydrous cation and anhydrous neutral species) was obtained25 for quinazoline, twelve substituted quinazolines, and triazanaphthalenes in the rapid-reaction apparatus just described. The true anhydrous pKa of quinazoline turned out to be 1.95. The true hydrated pKa of quinazoline has already been reported26 as 7.77, the slower rate of hydration permitting its determination in the usual rapid-reaction apparatus. Thus, in general, three pKa values exist for each hydrating base, and the equilibrium between the totally hydrated species furnishes the strongest basic properties. 

Alkylation of 2-substituted quinazolin-4(3//)-ones by reaction with sodium hydride in dimethylformamide followed by alkylation provided O-and N-alkyl derivatives. The extent of alkylation at the different sites was reasonably explained in terms of steric properties of the 2-substituents. The silver salt of quinazolin-4(3H)-one and tetra-0-acetyl-) -D-glucopyrano-syl bromide gave a 40% yield of the 0-glycosyl derivative in contrast with the mercury salt, which gave mainly the iV-3-glycosyl derivative. As in the alkylation of mercapto compounds, quinazoline-4(3H)-thione gave the S-glycosyl derivative. If sodium hydroxide was used as base a 56% yield of the... 

A wide spectrum of other biological properties for these types of alkaloids has been discovered. It is proposed in this chapter to present the latest developments in the 2-substituted quinolin/ones, quinazolines, and acridones alkaloids biological activities as well as a overview of all members of these classes of compounds. 

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