2-substituted quinazolinone

Kim and co-workers showed that the nitrile group of 3-methyl-2-cyano-4(3//)quinazolinones could readily exchange with a number of thio-, amino- and oxo-based nucleophiles to produce the corresponding 2-substituted quinazolinones in good to excellent yields." For example, reaction of 3-methyl-2-cyano-4(3//)quinazolinone with sodium ethoxide in ethanol gave the desired 2-ethoxy substituted product in 96% yield. 

The Bischler synthesis, first described in 1893, involves the fusion of A-acylanthranilic acid and ammonia to generate the corresponding 2-substituted quinazolinone, which exists in equilibrium with the 4-hydroxy quinazoline tautomer. Bischler s original synthesis, shown below, involved direct conversion of ammonium-A-acetylanthranilate to the corresponding 2-alkyl-2,3,4-dihydro-4-quinazolinone under thermal conditions. 

Abdel-Jalil and co-workers used a novel copper(II)-catalyzed condensation reaction between anthranilamides and aryl, alkyl, and heteroalkyl aldehydes to generate the corresponding 4(3 -quinazolinones in excellent yields." In one example, treatment of anthranilamide with 2-furaldehyde gave the corresponding 2-substituted quinazolinone in 85% yield. The resulting compound could be used to readily access the antibiotic nitrofurquinazol in just a few short steps. 

Cul-catalyzed coupling of amidine hydrochloride salts 172 with 2-halobenzoic acid and subsequent condensative cychzation worked well to provide 2-substituted quinazolinones 173 at room temperature (Scheme 60) [102, 103]. The ortho-substituent effect directed by the carboxylic acid group should be the reason of... 

Scheme 60 Synthesis of 2-substituted quinazolinones and quinazolines via Cul-catalyzed N-arylation of amidines...

When the quinazolinones or thiones 251 (X = O, S R = H, Me, CHaPh) were reacted with 2,4- or 2,6-dimethylphenol, an addition took place, resulting in the 8a-(2-hydroxy-3,5-dimethylphenyl)- or the 8a-(4-hydroxy-3,5-dimethylphenyl)-substituted quinazolinone 252 (70M1745). The stereochemistry of 252 was not investigated. 

An example of the separation of electronic effects that contribute to observed tt values in substituted quinazolinones has been described (113). It was found that the observed hydrophobic constant, irn, obtained from substituted quinazolinones can be correlated with the tt constant obtained from the phenozyacetic acid system (23, 24) and the Hammett o ... 

Grignard reagents are known to add across the carbonyl groups of N-substituted quinazolinones but are not generally useful reactions because... 

Fabis and co-workers used a base-catalyzed ring contraction to generate 2-pyrryl substituted quinazolinones. Treatment of pyrrolo[2,l-c][l,4]benzodiazepine with hydrazine in ethanol at room temperature provided the desired quinazolinone in 60% yield. 

Table 4. SAR Protectant Activity of Halogen-substituted Quinazolinones against Wheat Powdery Mildew ...

Table 8. Field Activity of Substituted Quinazolinones Against Grape...

Field activity of substituted quinazolinones, which generally had good photostability, is summarized in Table 7. Unlike pyridopyrimidinones, quinazolinones maintained very high activity under field conditions giving outstanding mildew control at 50-125 g/ha. Iodine analogs had optimum... 

Zhou, Yin et al. disclosed an efficient CuCl-catalyzed synthesis of 2-hetarylquinazolin-4(3//)-ones through aerobic oxidative C(sp )-H amination of (2-azaaryl)methanes with 2-aminobenzamides using oxygen as the sole oxidant under mild conditions (Scheme 8.106). Three C(sp )-H and three N-H bonds are removed in one reaction to produce the highly valuable Af-heterocycles. This copper-catalyzed tandem oxidation-amination-cyclization transformation is easy to handle, and various prepared 2-hetaryl-substituted quinazolinones could be obtained in moderate to good yields [180]. 

Ding found that coupling of 2-iodobenzobenzamides and amidine hydrochloride salts 172 led to formation of 2,3-substituted quinazolinones (Scheme 62) [107]. 

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. ... 

Hydroxyquinazolines react with primary amines or hydrazines to form 3-substituted 4(3//)quinazolinones (15). > The mechanism was shown to involve ring opening because with secondary amines (where ring closure is not possible) A-disubstituted benzamides are formed. Grignard reagents do not always react in the normal way with... 

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

The 2-aminoquinazolines 259 were prepared in two independent ways. The 2-quinazolinone 258 was transformed to 2-aminoquinazoline 259 by treatment with phosphorus oxychloride and subsequently with sodium amide in liquid ammonia, or with phosphorus pentachloride under carefully controlled conditions [75JCS(P1)1471]. Attempts to prepare the N-substituted derivatives failed, but the reaction was successful with the unsubstituted cis cyclopentane-fused homolog [76JCS(P1)1415]. 

When the 6-position of the 4(377)-quinazolone is blocked, nitration occurs at the 5-position <1975JOC363>, but when the 7-position is also substituted, as with 6-bromo-7-chloro-4(3/7)-quinazolinone 44, the 8-substituted product 45 is obtained as the sole product <1996JME918>. 

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