2-Methyl-3- -quinazolinones

With 2-unsubstituted quinazolines 426 (X = O or S), organometallic addition occurs at the 2-position to give 2-alkyl-l,2-dihydroquinazolines 428 <2005JSF121, 2005S2951>, while with 2-alkoxyquinazolines addition of orga-nometallics occurs at the 4-position, as demonstrated by the addition of lithium phenylacetylide to the 2-methoxy-methyl quinazolinone 429 which gave a quantitative yield of a tautomeric mixture of the 3,4- and 1,4-dihydro derivatives 430 and 431 <2004JA5427>. 

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... 

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-... 

Methyl-4-hydroxyquinazoline reacts with organic halides, in the presence of sodium methoxide, to give 3-substituted 2-methyl-4(3i/)-quinazolinones. The 0-acetyl derivative of 4-hydroxyquinazoline has been prepared under anhydrous conditions and gives the hydroxy compound with water or with lithium aluminum hydride. The N-3 acetyl derivative, however, is more stable and gives 3-methyl-4(31/)-quinazolinone with lithium aluminum hydride. ... 

Methylation of hydroxyquinazolines invariably produces a mixture of 0- and A -methylated derivatives. The A -methyl derivatives are, therefore, best prepared by unequivocal syntheses. 1-Methyl-2(1H)-quinazolinone (16) is not known. When o-aminobenzaldehyde is treated with methylisocyanate, 3-methyl-2(3i7)quinazolinone (17) is obtained. If this is heated in ethanol it dissolves and an alcoholate, presumably (18), crystallizes out, and this can be converted back to (17) by vacuum sublimation. Methylation of l-methyl-4(lH)Quinaz-... 

The ethers (40) are hydrolyzed in high yields, by boiling water (4 hr), to 4-hydroxyquinazoline 1-oxide, and their structures were deduced by methylation followed by reduction to 3-methyl-4(3H)-quinazolinone (Scheme 6). These N-1 oxides show the typical reac-... 

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. ... 

Reduction of 3-methyl-4(3H)quinazolinone with lithium aluminum hydride is known to give 3-methyl-l,2,3,4-tetrahydroquinazoline. The most interesting tetrahydroquinazoline is Trbger s base ° since it has added to our knowledge of the stereochemistry of tri-... 

Substituted 2-mercapto-4(3i/)quinazolinones were prepared by condensing methyl anthranilate with isothiocyanates (see 7c). 

Of agricultural importance is the plant-growth regulating activity of 6,8-dichloro-2-methyl-3-carboxymethyl-4(3H) quinazolinone which was as potent as 2,4-dichlorophenoxyacetic acid in the Lepidium test. 4-Hydroxy-5,6,7,8-tetrahydroquinazoline has been patented with reference to fungicidal activity. 

The anomalous behavior of quinazoline was first discovered by Albert et who made the surprising observation that 4-methyl-quinazoline 2.5) was a weaker base than quinazoline (pA 3.5). Mason then observed that the ultraviolet spectrum of the quinazoline cation was abnormal but that the spectrum of 4-methylquin-azoline was normal (see Fig. 2). These anomalies led to the suggestion that water adds covalently to the cation of quinazoline to give 12 (R = H). The occurrence and position of hydration were confirmed by a detailed study of the ultraviolet and infrared spectra of the anhydrous and hydrated hydrochlorides and by mild oxidation of the cation to 4(3 )-quinazolinone. Using the rapid-reaction technique (the continuous-flow method), the spectrum of the unstable... 

The isomerization described in Scheme 44 could not be observed when the 5-methyl derivative 108 was used. The quinazolinone 109 was obtained in high yield, probably via 110 through the cleavage of the O—N bond in the triplet state (Scheme 45) [89H(29)737 89H(29)1301 91 JCS(P2)187]. The same behavior (but in low yield) was observed with 111 (Scheme 45) (90JHC861). 

Fluproquazone (97) contains a 2-quinazolinone nucleus and is found to be an analgetic agent useful in mild to moderate pain. One of the preparations involves reaetion of 2-isopropylamino-4-methyl-4 -fluoro-benzophenone (96) with potassium cyanate in hot acetic acid [27],... 

The phosgene can be replaced by methyl or ethyl chloroformate the resulting hydrazone derivatives 7 or 8 readily cyclize to benzotriazepinones (Method C). The products are often accompanied by a quinazolinone.354... 

Aminothiadiazole (88 R = CF3) condenses with 5-fluoro-2-methylbenzoxazin-4-one in refluxing pyridine to give 5-fluoro-2-methyl-3-(2-trifluoromethyl-l,3,4-thiadiazol-5-yl)-4(3//)-quinazolinone in about 60% yield (Equation (4)) <92JHC749>. 

The quinazolinone moiety (36-3) for the cardiotonic agent prindoxan (36-5) is formed by reaction of diamine (36-1) with carbonyl diimidazole (36-2). Friedel-Crafts acylation of the product with the half-acid chloride from methyl succinate gives the corresponding keto-ester (36-4). The pyridazinone (36-5) is then obtained by condensation of that product with hydrazine [38]. 

A reaction of particular interest is the photochemical rearrangement of compound 243 to 3-methyl-4(3//)-quinazolinone (246). This transformation (243 -> 246) (Scheme 10), which takes place in high yield in ethanol, has been applied to several other derivatives and is clearly analogous to the photorearrangement of pyridazinium-5-olates to 4-pyrimidones (Section in,A,6). The mechanism of the reaction is not clear. 

Performing a Vilsmeier-Haack reaction on 3-benzoyloxy-2-methyl-quinazolin-4-one (184) afforded the isoxazolo[3,2- ]quinazolinone (185) [86IJC(B)709]. This ring system (187) was also synthesized by cyclocondensation of anthranilic acids or isatoic anhydrides with the isoxazolin-3-ones (186) (77AF766 83MIP1), or by condensation of methyl anthrani-late with 3-chloropropanoyl chloride followed by cyclization with hydroxylamine hydrochloride (77AF766). 

In a detailed thermolytic study, 5-methyl-1,2,4-oxadiazolo[2,3-c]-quinazolin-2-one (349), has been found to give the isomeric 1,3,4-oxadiazolo[4,3-c]quinazolinone (358) on heating or on treatment with triethyl phosphite (85H623). 

Treatment of the 1,2,4-triazino[5,6-benzoxazepine derivatives (631) with an excess of methyl iodide affected methylation and intramolecular rearrangement to give the mesoionic l,2,4-triazolo[l,6-c] quinazolinone (632) (73MI1). 

The chemical name for methaqualone is 2-methyl-3-0-tolyl-4(3H)-quinazolinone (C16H14N20). It is a white, crystalline, odorless substance with a bitter taste. 

Analytical Properties Resolution of transA, 2-diphenyloxirane, 2-methyl-3-(2 -methylphenyl)-4(3H)-quinazolinone, and some aromatic hydrocarbons Reference 9... 

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