Quinazoline methylation

In many pyrimidine ring syntheses, it is possible or even desirable to isolate an intermediate ripe for ring-closure by the formation of just one bond. For example, ethyl 3-aminocrotonate (502) reacts with methyl isocyanate to give the ureido ester (503) which may be isolated and subsequently converted into 3,6-dimethyluracil (504) by the completion of one bond. However, viewed pragmatically, the whole synthesis involves the formation of two bonds and therefore is so classified. On such criteria, only two pyrimidine/quinazoline syntheses involve the formation of only one bond. 

The 2- and 4-alkylthioquinazolines are formed by the second or third of the above methods as appropriate. For example, quinazoline-2(l//)-thione and methyl iodide/alkali give the thioether (883) and the 4-thioether is made similarly (62JCS3129) 2,4-dichloroquinazoline and sodium p-chlorothiophenate give 2-chloro-4-p-chlorophenylthio-(884 R = C1) or 2,4-bis-p-chlorophenylthio-quinazoline (884 R = SC6H4C1) according to conditions (48JCS1766). 

Pyrazolopyrimidinones C NMR, 5, 308 methylation, 5, 310 synthesis, 5, 329 Pyrazolopyrimidinones, thioxo-synthesis, 5, 324 Pyrazoloquinazolines synthesis, 5, 317, 322 Pyrazolo[ 1,5-n]quinazolines synthesis, 5, 273 Pyrazolo[ 1,5-c]quinazolines synthesis, 5, 324 Pyrazolo[2,3-n]quinazolines synthesis, 3, 378 Pyrazoloquinazolinones synthesis, 5, 342 Pyrazolo[4,3-/]quinazolinones synthesis, 5, 273 Pyrazolo[4,3-g]quinazolinones synthesis, 5, 273 Pyrazolo[3,4-/]quinolines synthesis, 5, 273 Pyrazolo[4,3-/]quinolines synthesis, 5, 273 Pyrazolo[l,5-n]quinoxalines synthesis, 5, 339 Pyrazolo[3,4-6]quinoxalines synthesis, 5, 272... 

Quinazolin-2( 1H) -one, 1 -hydro xy-4-methoxy-tautomerism, 3, 106 Quinazolin-2(lH)-one, 4-methyl-synthesis, 3, 109... 

The hydrochloride of (3) holds water rather tenaciously, and the infrared spectrum indicates that the water is covalently bound. Mild oxidation of the cation (3) gives 4-hydroxyquinazoline in high yield and ring-chain tautomerism is excluded on the grounds that quinazo-line does not give a positive aldehyde test in acid solution, 2-Methyl-quinazoline also has an anomalous cationic spectrum and a high basic strength (see Table I), but 2,4-dimethylquinazoline is normal in both these respects, which supports the view that abnormal cation formation entails attack on an unsubstituted 4-position. ... 

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-... 

The rearrangement of l-methyl-2-arainopyrimidine to 2-methyl-aminopyrimidine with alkali has been recently observed in amino-quinazolines. The following rearrangement proceeded in high yields when R was Me, Et, Pr , Ph, and p-MeOC6H4 ... 

Further methylation of 2-methylmercapto- and 2,4-dimethylmer-capto-quinazolines has not been studied. 

S-oxide. The reaction of quinazoline with hydroxylamine is not hindered by the presence of a 4-substituent since 4-methyl-quinazoline also gives 4-methylquinazoline 3-oxide with hydroxyl-... 

These compounds show the typical reactions of heterocyclic N-oxides and their structure was proved by methylation which takes place on N-1. Quinazoline 3-oxide is soluble in water and melts at 155°C. It has basic properties and its pKa value in water is 1.47. ... 

Dihydroquinazolines are normally stable compounds but they deteriorate on long standing. Some examples are known to oxidize to the corresponding 4(3H)quinazolinones. 3-Methyl-3,4-dihydroquin-azoline is converted to the 4-oxo compound after three recrystallizations from light petroleum. The most remarkable example is 3,4-dihydro-6-fluoro-3(p-fluorophenyl)quinazoline [(44), R = F] which oxidizes at its melting point (137°-I38°C), Other halogenated derivatives of (44) are more stable. ... 

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