Quinazolinones. formation

The mechanism of quinazolinone formation follows the general pattern of isocyanide-based heterocyclization (cf p. 173) primary intermediate is the 2-lithioquinazolinone 38, which can be trapped with electrophilic reactands (e.g., by hydrolysis, alkylation, halogenation). 

Oxadiazole was obtained through the first excited singlet state. When the reaction was carried out in the presence of a triplet sensitizer, 99 was not detected but the quinazolinone 100 was obtained (Scheme 41) [91JCS(P2)187]. Compound 99 cannot be obtained via the Dewar isomer. The author supposed the formation... 

Ring-opening of diastereomerically pure vinylaziridine 131, prepared by azir-idination of butadiene with 3-acetoxyaminoquinazolinone 130 [52], yielded acetate 132 with inversion of configuration, together with amino alcohol 133 with retention (Scheme 2.34) [53]. The formation of 133 can be explained by assuming participation by the quinazolinone carbonyl oxygen, which produces an intramolecular reaction with the aziridine carbon with retention of configuration. 

In another approach, the 3-[3 (2 -spirothiazolidin-4 -one)]quinazolin-4-one derivative 186 in the presence of sodium hydroxide in ethanol undergoes intramolecular cyclocondensation with the formation of the spirothiazolopyrazolo-quinazolinone 187 in moderate yield (Equation 82) <2001PS1>. 

Chebanov et al. in [59] offered the key stages of all these three MCRs. According to their hypothesis at room temperature under ultrasonication, the reaction passed via kinetically controlled intermediate 56 with the formation of quinazolinones 54 (Scheme 25). The high-temperature protocol allowed the reaction following via thermodynamically preferable tricyclic intermediate 57. 

Formation of chloroquinazolines by amine diazotization can also been performed, but in the case of 4-amino-2-chloro-5-iodo-6,7-dimethoxyquinazoline 122, chlorination with isobutyl nitrite and cupric chloride to give 123 was accompanied by hydrolysis to the analogous quinazolinone 124 <2005TL983>. 

Benzoxazin-4-ones (39) react with amines to give quinazolinones (40) (77JOC656), but this typical reaction is replaced in 1,3-benzoxazine-2-thiones (41) by the formation of imino derivatives (42) since now the oxygen ring atom is joined directly to the aryl nucleus (76MI22700). 

Numerous solid-phase preparations of quinazolinones have been reported. The main synthetic strategies used are summarized in Figure 15.16. Quinazolin-2,4-diones can be prepared from anthranilic acid derived ureas or from N-(alkoxycarbonyl)-anthranilamides. These reactions have been performed on insoluble supports either in such a way that the cyclized product remains linked to the support, or such that it is simultaneously cleaved from the support upon ring formation. Quinazolin-4-ones can be prepared by cyclocondensation of anthranilamides with aldehydes, orthoesters [342], or other carboxylic acid derivatives [343]. The selection of examples listed in Table 15.29 illustrates the variety of substitution patterns accessible by means of these cyclizations. 

The enantiopure 3-amino-2-(l-hydroxyethyl)quinazolinone 258 upon alkylation with cinnamyl bromide afforded O-alkylated product 259 as minor and N,0-dialkylated product as major (Scheme 58). Further iV-acetoxylation of 259 led to the formation of 260, which underwent intramolecular aziridination to give the 1,4,5-oxadiazepine 261 as a single diastereomer <1995J(P2)205>. 

Bergnes (3) prepared quinazolinone derivatives, (III), that were effective in the treatment of cellular proliferative diseases by causing mitotic arrest and monopolar spindle formation. 

Naphtho[2, 3 3,4]-[l,2,5]triazocino[8,l+]quinazolinone 137 was obtained by refluxing of 2-substituted 3-amino-quizalin-4-one with 2,3-dichloro-l,4-naphthoquinone in DMF (Scheme 35 <2001MOL267>). Initial formation of 5,6-dihydrotriazocine derivative was followed by elimination of arylsulfinic acid and formation of ring system 137. 

Anilides 6 react with ethyl carbamate in the presence of phosphorus pentoxide in refluxing xylene to furnish 2-substituted quinazolin-4(3//)-ones 7 - . 94,395 formation of a quina-zolinone by condensation of an (acylamino)benzene with ethyl carbamate in the presence of phosphorus pentoxide involves first aminocarbonylation affording an 2-(acylamino)-benzamide, which subsequently cyclizes to give a quinazolinone (cf. p 13). 

Analogous intramolecular additions have also been described. The importance of the trifluoromethyl group in influencing the course of a photoreaction has again been demonstrated in the conversion of 3-(but-3-enyl)-2-trifluoromethyl-4(3H)-quinazolinone (100) into the intramolecular adduct (101) the corresponding 2-unsubstituted quinazolinone is reported to be photostable. Intramolecular azetidine formation has also been... 

The pyrido[2,l- )]quinazolinone 286 could be produced in about 20% yield by simply boiling a solution of benzisothiazolinone (296) in aqueous pyridine for 6 hr. Pyrido[2,l- ]quinazolinone (286) formation can be interpreted by a mechanism in which nucleophilic attack of the pyridine nitrogen atom occurs on the carbonyl group of benzisothiazolinone (296). 

Suschitzky and co-workers hydrogenated the lactam 305 over palladium on charcoal under pressure in the presence of 1 molar equivalent of hydrochloric acid in ethanol at room temperature and observed the formation of the azepino[2, l- )]quinazolinone 306 and its iV-oxide 307 in yields of 12 and 69%, respectively. 

Hattori, K., Kido, Y., Yamamoto, H. et al. Rational design of con-formationally restricted quinazolinone inhibitors of poly(ADP-ribose)polymerase. Bioorg. Med. Chem. Lett. 2007, 77, 5577—5581. 

Electrophilic substitution in quinazoline takes place in the benzene ring theoretical prediction of positional reactivity is 8 > 6 > 5 > 7 4. 4(3//)-Quinazolinone was converted into a mixture of 6-and 8-chloro, and 6,8-dichloro products <57JCS252I>. Initial bromination of 4(3/7)-quinazolinone and its 3-methyl derivative is in the 6-position with slow formation of the 6,8-dibromoquinazolinone. Below pH 2, when the former substrate and its A3-methyl derivative exist mainly as cations, the latter was brominated slightly faster. The pathway is believed to involve bromine attack on covalent hydrates <76JOC838, 93AHC(58)27I>. 

Oxidative desulfurization can be effected by ozonolysis (Scheme 74). 2-Thiol-4(3//)-quinazolinone on ozonolysis in dry dichloromethane yields the disulfide (448) which is resistant to further oxidation under the reaction conditions. In acetic acid, desulfurization results with hydrogen substitution (449). Rationalization of the reaction in acetic acid involves formation of an unstable sulfinic acid which loses SO2 with replacement by hydrogen. In dichloromethane containing ethanol, the 2-ethoxy product (450) formed, corresponding to nucleophilic substitution of the reactive sulfinic acid from the oxidation. Similarly, ozonolysis of pyrimidine-2-thione acid gave bis-2-pyrimidinyl disulfide in dry dichloromethane and 2-ethoxypyrimidine in the presence of ethanol <93TL1631>. 

Quinazolinones and 2/4-alkoxy- and aryloxyquinazolines are prepared by the same sort of reactions as described for pyrimidines. Oxy functions in the carbocyclic ring are best introduced via the substrate used for ring formation. Among alternatives are a diazotization reaction from the corresponding amine. 

Hydration of nitriles Formation of the quinazolinone system from o-amido benzonitriles in one step is shown. 

In work previously cited <01BMCL211>, Corbett and co-workers reported an annulation onto the quinazolinone ring system. Treatment of 102 with 3-pyridyl acetylide generated in situ led to formation of adduct 103, which was then heated in POCI3 to provide a mixture of imidoyl chlorides 104. Heating the crude chlorides in a solution of thiourea in ethanol gave a 5-exo-dig cyclized product 105. 

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