2.3- Disubstituted quinazolin-4 -ones

A series of 4,4-disubstituted quinazolin-2-ones derived from HTV nonnucleoside reverse transcriptase inhibitor leads have shown good in vitro potency and in vivo efficacy [28]. Using FLIPR assays on cell lines with different resting membrane potentials, TTA-Q3 (10) and TTA-Q6 (11)... 

Using ortho esters with a catalytic amount of p-toluenesulphonic acid instead of formic acid resulted in the formation of 2,3-disubstituted quinazolin-4(3//)-ones in 79-89% yield, Scheme 5.30. 

Quinazoline is oxidized rapidly by xanthine oxidase to quinazolin-4(3//)-one which subsequently is oxidized more slowly to quinazoline-2,4(l//,3//)-dione. Quinazoline is also oxidized to quinazolin-4(3//)-one by rabbit liver aldehyde oxidase but the reaction ceases within a short time it appears that quinazoline is able to inactivate the aldehyde oxida.se, Quinazolin-4(3//)-one is rapidly oxidized by aldehyde oxidase to quinazoline-2,4(l//,3//)-dione. Various 6-substituted and 6,7-disubstituted quinazolin-4(3//)-ones are quantitatively oxidized to the respective quinazoline-2,4(l//,3//)-diones by buttermilk xanthine o.xidase, ° Biotransformation of quinazoline by a mutant strain of the bacterium Pseudomonas putida gives quinazolin-4(3//)-one, c(s-5,6-dihydroquinazoline-5,6-diol, and cis-5,6,7,8-tetrahydroquinazoline-5,6-di-... 

Quinazolincs bearing chloro,622.basic conditions to the corresponding quinazolinoncs. 4-Substituted quinazolines are more reactive on hydrolysis than 2-substituted quinazolinesand in 2,4-disubstituted quinazolines the substituent at position 4 can be selectively hydrolyzed to 2-substituted quinazolin-4(3/f)-ones. 4-(Methylsulf-anyl)quinazolines are also converted to quinazolin-4(3f/)-ones by oxidation with hydrogen peroxide. ... 

Several examples are known of the ring-expansion reactions that transform isatins into quinazolines. iV-Carbamoyl isatins rearrange in the presence of amines into derivatives of 4-carboxy-4-hydroxy-3,4-dihydroquinazolin-2(lH)-ones, and iV-carbamoyl-3-(dicyano)methylene oxindoles provided 4-(dicyano)methylene-3,4-dihydroquinazolin-2(l//)-ones. The two isomeric A-oxides 102 and 103 underwent ring expansion on photolysis and produced the same 1,3-disubstituted quinazoline-2,4-diones (104) among other products, which include isatins. The ratio of products was sensitive... 

There is evidence that in the acid hydrolysis of the 2,3-dicycloalkyl-aminoquinoxalines to the corresponding substituted quinoxalinones, the ease of hydrolysis is in the order morpholino>piperidino>pyrrolidinyl. Thus 2-morpholino-3-pyrrolidinylquinoxaline (10) can be selectively hydrolyzed to 3-pyrrolidinylquinoxalin-2-one (11). The hydrolysis of 2,3-dicycloaminoquinoxalines proceeds much more readily than is the case with the corresponding 2,4-disubstituted quinazolines, presumably because of the steric hindrance in the quinoxaline derivatives. ... 

Quinazolin-4(3//)-ones 561 were efficiently prepared in 68-87% yields by irradiating a mixture of anthranilic acid 436, formic acid, and an amine in an MW oven for 6-9 min in the absence of solvent and any dehydrating agents. Alternatively, MWI of a mixture of 2-formamidobenzoic acid (560) and aniline gave 561 (R = Ph) in 71% yield (Scheme 111). Using orthoesters with a catalytic amount of PTSA instead of formic acid led to the formation of 2,3-disubstituted quinazolin-4(3//)-ones 562 in 79-89% yields (98JCR(S)702). 

Trialkylalanes have been employed in the production of a series biologically relevant 2,4-disubstituted quinazolines. In one example, reaction of 2,4-dichloroquinazoline with methylalane gave the corresponding 4-substituted product selectively in 76% yield. Treatment of the 4-substituted product with wo-butylalane under the same conditions gave the 2,4-disubstituted product in 61% yield over two steps. 

The mono- and disubstituted quinazolin-4(3/7)-one derivatives were firstly synthesized under solvent-free conditions by one-pot three-component reaction of isatoic anhydride, ortho ester, and anunonium acetate or an aliphatic and aromatic primary amine in the presence of SSA (Salehi et al., 2005) (Scheme 5.8). After completion of the reaction, the crude mass was diluted with hot ethanol and filtered. The filtrate was concentrated and products were purified by recrystallization from ethanol. Solvent-free... 

Salehi, R, Dabiri, M., Zolfigol, M.A. and Baghbanzadeh, M. 2005. A new approach to the facile synthesis of mono- and disubstituted quinazolin-4(3//)-ones under solvent-free conditions. Tetrahedron Lett. 46(41) 7051-7053. 

The synthesis of 1,4-dihydropyridines (45) by four-component condensation reaction of 1,3-dicarbonyls (43), aldehydes (1), and ammonium carbonate (44) in an aqueous medium was reported at 60°C within 1.5-2.5 h (Scheme 9.11) (Tamaddon and Moradi 2012). ZnO nanoparticles can be used as a heterogeneous catalyst (Yavari and Beheshti 2011) for the one-pot three-component condensation of isatoic anhydride (46), amines (47), and aldehydes (48) to afford the corresponding 2,3-disubstituted quinazolin-4(l//)-ones (49) (Scheme 9.12). A short reaction time (3 h), solvent-free conditions, and an atom-economic nature are the significant advantages of the present method. The catalyst showed good recyclability without much loss of its catalytic activity. 

Dandia A, Singh R, Sarawgi P (2005) Green chemical multi-component one-pot synthesis of fluorinated 2,3-disubstituted quinazolin-4(3H)-ones under solvent-free conditions and their anti-fungal activity. J Fluor Chem 126 307... 

Quinazolin-4(3H)-one, 3-phenyl-reduction, 3, 75 Quinazolinones polymers, 1, 298 reactions, 3, 89 structure, 3, 66-67 synthesis, 2, 96 3, 133 thiation, 3, 89 Quinazolin-4-oties 2,3-disubstituted Grimmel synthesis, 3, 109 mass spectra, 2, 22... 

Kumar, R.R. and Reddy, M.S., One-pot synthesis of 2,3-dihydro-2,3-disubstituted benzo[g]quinazolin-4(lH)-ones, Synth. Commuru, 1992, 22, 2499-2508. 

Treatment of 2-mercapto-4(3W)-quinazolinone (52) with hydrazonoyl halides affords 1,3-disubstituted l,2,4-triazolo[4,3-a]quinazolin-5-ones 53 [95H(41)1999]. Hydrazones derived from [(2-methyl-4-quinazolinyl)oxy]acetic acid hydrazide and aldehydes or ketones were shown to give 4-thiazolidinones and pyrazoles under cyclization conditions [95UC(B)537]. 

Scheme 19 Microwave-assisted one-pot synthesis of 2,3-disubstituted 3ff-quinazolin-4-ones...

Solid-phase syntheses of pyrimidines continue to appear at a rapid pace. Solid-phase syntheses of olomoucine from 4,6-dichloro-2-(methylthio)-5-nitropyrimidine <02TL8071> and of 2,6-disubstituted 4(3//)-quinazolinones from 2,4-dichloro-6-hydroxyquinazoline <02TL2971> have been developed. 2-(Arylamino)quinazolinones 83 were accessed by a traceless parallel solid-phase route from 2-nitrobenzamides 82 <02JOC5831>. A solid-phase synthesis of quinazolin-4(3W)-ones with 3-point diversity relied on the use of immobilized arylguanidines <02TL5579>. 

Cyclocondensation routes also provide access to pyrimidines. 2,3-Disubstituted pyrido[2,3-/i]-quinazolin-4(3//)-ones are obtained via cyclocondensation of 5-aminoquinoline-6-caiboxylic acid with acid chlorides <02SC235>. 5,6,8-Trialkyl-7-methoxy-2-aminoquinazolines are obtained from 1,3-dimethoxybenzenes via cyclocondensation of intermediate dihydrobenzenes with guanidine carbonate <02TL3295>. Diastereoselective intramolecular hetero Diels-Alder cyclization of a pyrazole carboxaldehyde condensed onto 1,3-dimethylbarbituric acid (101) gave polycyclic heterocycle 102 <02T531>. An efficient one-step synthesis of cyclobutene-annelated pyrimidinones 103 from methyl 2-chloro-2-cyclopropylideneacetate and amidines has been... 

Disubstituted-4-oxopentyl)quinazolin-4(3//)-ones 32 General Procedure ... 

N-Substituted isatoic anhydrides condensed with S-methylthioureas to form 1-substituted 2-amino-quinazolin-4-ones in good yields. When S-N,N -trimethylthiourea was used, l,3-disubstituted-2-methylimino-l,2-dihydro-quinazolin-4-one was formed. ... 

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). 

Rajan S G et al. [74] designed and S3mthesized a sequence of 2-(2,4-disubstituted-thiazole-5-yl)-3-aryl-3H-quinazoline-4-one 23 compounds. S3mthesized molecules were estimated for their inhibitory activity in the course of record factors, nuclear factor-kB (NF-kB) and activating factor (AP-1) interceded transcriptional activation in a cell line based in vitro assay as well as for their anti-inflammatory activity in vivo model of severe inflammation. 

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