2-Methyl-3- quinazolin

Al-Thebeiti and El-Zohary [101] have reported an efficient synthesis of a new series of spiroazetidin-2-one derivatives incorporated with quinazoline (Scheme 30). 3-Amino-2-methyl-3//-quinazolin-4-one 117 was treated with cyclic ketones 118 to afford the corresponding cycloalkylidene-3-aminoquinazolinone derivatives 119 in good yields. The reaction of the compounds 119 with chloro-acetyl chloride in the presence of triethylamine as a catalyst yielded the spiroaz-etidin-2-ones 120. 

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. ... 

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-... 

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... 

Photolysis of the 2-methyl-quinazolin-3-yl thioimidate 19 in the presence of butylamine produced an intricate mixture of products from which the... 

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). 

Diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline Glucuronic acid... 

Whereas the reaction of small primary amines with 2-(chloromethyl)quinazoline 3-oxides 1 leads to ring-enlarging rearrangement to 1,4-benzodiazepines (cf. p 159), weak primary amines.secondary amines, hydroxylamine, thiolates, " thiocyanate. cyanide, and the carbanions of nitroethane and nitropropane lead only to products 2 derived from substitution of the halogen. In a few cases, also in the reaction of 2-(chloro-methyl)quinazoline 3-oxides with methylamine, the unrearranged 2-[(methylamino)methyl]-quinazoline 3-oxide products are isolated. " ... 

The kinetics of hydration and dehydration for quinazoline and 2-methyl-quinazoline were studied in great detail by Bunting and Perrin, and the pH-rate profiles between pH 0.5 and 12.0 were determined. The profiles for quinazoline are illustrated in Fig. 1. The rate of hydration was given by the expression in Eq. (2). 

Methyl-, 2,4-dimethyl-, 2-ethyl-4-methyl-, 2-hydroxymethyl-4-methyl-, and 2-carbamoyl-4-methyl-quinazoline were isolated from Pseudomonas aeruginosa. (S)-Tryptophan was shown to be the precursor of these quinazo-lines by using the 14C-labeled amino acid in a new pathway of tryptophan biosynthesis73 (see Section III,A). 

Methylbenz[3,l]oxazin-4-one (acetylanthranil) (177), set aside at 25°C with ammonia in benzene, was quantitatively converted to 2-methyl-quinazolin-4-one. Slow as this reaction was in dry, apolar solvents, it became immensely faster when the solvent was undried however, the product was then 2-acetamidobenzamide. Nevertheless, the reaction proceeded rapidly in pyridine, whether wet or dry, and the sole product was the quinazoline.331... 

Benzoxazines, such as acetylanthranil (177), are sometimes isolated as fleeting intermediates in the conversion of the o-disubstituted benzenes to annelated pyrimidines and hence serve to connect this section with preceding ones. The origin of acetylanthranil and its ready conversion to 2-methyl-quinazoline-2,4-dione have been dealt with in Section VIII,B,3. Related examples include the conversion of other types of benzoxazine to quinazo-lines (Sections VIII,A,6 and VIII,B,3 and of pyridooxazines to pyri-dopyrimidines (Section VIII,A,3), as well as of pyrazolothiazines to pyrazolopyrimidines (Sections VI,B,1 and 2). 

A small number of simple substituted quinazolines can be formed in the course of tryptophan degradation by microorganisms (131, 132). In Pseudomonas species, three pathways of tryptophan degradation are known the aromatic pathway in Ps. fluorescens, the quinoline pathway in Ps. acidovorans, and the quinazoline pathway in Ps. aeruginosa. Investigations with [P- C]-tryptophan have provided evidence for a new pathway from tryptophan through the intermediates, formylkynurenine and N-formylaminoacetophenone, forming 4-methylquinazoline with ammonia and free 2-aminoacetophenone. Reacylation of the product and cyclization with ammonia produces other derivatives of 4-methyl-quinazoline. 

A range of secondary A-alkylanilines undergo oxidative olefination with 2-alkyl-quinoline, 4-methylquinoline, 1-methylisoquinoline, 2-methylquinoxaline, 2-methyl-quinazoline, 2-methylbenzo[fiG-thiazole, acetophenone, and malononitrile in DMF to form structurally diverse polysubstituted alkenes in moderate to excellent yields with excellent E Z >99 1 selectivity with the use of 2,3-dichloro-5,6-dicyano-l,4-benzoquinone as the oxidant. Mechanistically, the oxidative olefination reaction proceeds through amine oxidation followed by imine olefination." ii... 

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). 

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