2,4-disubstituted quinazolines

In 2,4-disubstituted quinazolines, the 4-position reacts fastest with nucleophiles, generally even when the 4-substituent is a poorer leaving group. 2,4-Dichloroquinazoline undergoes mono-substitution at the 4-position with alcoholic alkoxides (25°, 2 hr, 80-98% yield), phenolic phenoxide (20°, 16 hr, 50% yield), aqueous hydroxide (30°, 3 hr), alcoholic methylmercaptide (20°, exothermically), alkylamines (20°, 10-60 min, 100%... 

The reaction of 2-(acylamino)bcnzonitriles 20 with Grignard reagents in diethyl ether constitutes a fast and convenient route to 2,4-disubstituted quinazolines 21 which are obtained in reasonable yields. Introduction of the second substituent to yield, for example, 3,4-dihy-droquinazolines is not an interfering side reaction. 

Acid- or base-catalyzed cyclization of 2-(1-amino-3-oxoalk-l-enyl)acetanilides 33 constitutes a relatively novel route to various 2,4-disubstituted quinazolines. Reaction of 33 with a base gives the quinazolines 34 directly, whereas treatment of 33 with acid affords quinazolines 35 which can be converted practically quantitatively into quinazolines 34 by treatment with base. 

Aminobenzonitriles 17 react with Grignard reagents to give the intermediate iminium salt 20, which can be readily trapped in situ by carbonyl compounds (e.g., acid chlorides, anhydrides, formates, carbonates, and oxalates) or phosgeniminium chlorides and cyclized to quinazolines. With this method various 2-unsubstituted quinazolines, 2,4-disubstituted quinazolines, and quinazolines with certain functional groups (e.g., COjEt, NMe ) in the 2-position are readily available. 

Anilines 6 react with A,iV-dimethyl-iV -(trichlorovinyl)forniiniidaniide or iV-(l-chlorovinyl)-benzimidoyl chlorides 7 to give 2,4-disubstituted quinazolines 8a ° and Sb. ... 

Manganese(IV) oxide in dichloromethane or potassium permanganate in chloroform oxidizes 2,4-disubstituted 1,2-dihydroquinazoline 3-oxides 6 to 2,4-substituted quinazoline 3-oxides 7. Potassium hexacyanoferrate(III) or iron(lll) chloride in alcohol can also be used for this oxidation, but the yields are lower. Oxidation of 2,4-disubstituted 1,2-dihydroquinazoline 3-oxidcs to 2,4-disubstituted quinazoline 3-oxides with lead(IV) acetate apparently proceeds via the corresponding nitroxides." ... 

To a vigorously stirred solution of the 2,4-disubstituted 1,2,3,4-tetrahydroquinazoline (1 mmol) in acetone (20 mL) was gradually added a solution of KMnO, (0.16 g, I mmol) in H O (10 mL). After a short time the color faded and the precipitated MnOj was filtered off. The product was precipitated w ith H O, extracted with F.t O and the ethereal solution dried (MgSOj). After removal of EtjO, the 2,4-disubstituted quinazolines were obtained yield 61-92%. 

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. ... 

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. ... 

Multiple halogenations are possible when excess chlorinating reagent is used. For example, 2,4-dichloroquinazolines, which are important starting materials for synthesizing 2,4-disubstituted quinazolines, can be prepared using excess POCb. ... 

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. 

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-... 

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... 

The trimethyluracil (193) reacts with DMFDMA to afford the enamine (194), which reacts with dienophiles to give 5,6-disubstituted quinazoline-2,4-diones (195), via [4 + 2] cycloaddition followed by elimination of dimethylamine, and oxidative aromatization, as shown in Scheme 45 (89CB1673). 

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). 

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... 

The usual syntheses of quinazolines make use of an o-disubstituted benzene structure (46) from which the quinazoline skeleton is completed by adding C-2 and N-3 in various ways. Substituents could either be in (a) the pyrimidine ring or (b) the benzene ring or in both rings. The syntheses will be described in this order and the methods used for (a) apply equally well to quinazolines substituted in both rings. 

The bicyclic system quinazoline undergoes intermolecular inverse cycloaddition reactions with enamines RRiNCR2=CHR3 (RRi=(CH2)3, R2 = Ph, R3 = H) yielding 2,3-disubstituted quinolines. 

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