Quinazoline 2-methyl-, formation

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 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. ... 

The reactivity of the methyl group in 4-methylcinnoline ethiodide indicates that the structure of this compound is 5, and this evidence has also been interpreted to mean that N-1 is the basic group in cinnolines. However, evidence of this type is only indicative since the formation of quaternary salts is subject to kinetic control, whereas protonation yields predominantly the thermodynamically more stable cation. The quinazoline cation has been shown to exist in the hydrated, resonance-stabilized form 6 7 by ultraviolet spectro-... 

Quaternary salt formation in 4-quinazoline 3-oxide and its 4-amino and 4-methyl derivatives has been studied by Adachi. These N-oxides, prepared by reaction of the simple quinazoline with hydroxylamine, react with ethyl iodide at N-1, although only in the case of the 4-amino derivative could the ethiodide be purified. The salts are degraded by alkali yielding derivatives of ethylaniline [Eq. (4)]. 

Covalent hydration has been demonstrated in the following families of compounds 1,6-naphthyridines, quinazolines, quinazoline. 3-oxides, four families of l,3,x-triazanapththalenes, both l,4,x-triazanaphthalenes, pteridines and some other tetraazanaphthalenes, and 8-azapurines these compounds are discussed in that order. In general, for any particular compound (e.g. 6-hydroxypteridine) the highest ratio of the hydrated to the anhydrous species follows the order cation > neutral species > anion. In some cases, however, anion formation is possible only when the species are hydrated, e.g. pteridine cf. 21 and N-methyl-hydroxypteridines (Section III, E, 1, d). Table V in ref. 10 should be consulted for the extent of hydration in the substances discussed here. 

A photolytic study with a 5-azidotetrazole derivative also led to the formation of a tetrazolo[l,5-/z]quinazoline compound, although the yield was fairly low. Araki et al. published findings that irradiation of 110 in aqueous medium resulted in formation of the mesoionic enolate 112 in 8% yield <2000JHC1129> (Scheme 20). The authors concluded that the formation of the tricyclic structure can be rationalized by an intramolecular insertion of the triplet nitrene formed from 110 to a C-H bond of an ortho-methyl group to give at first intermediate 111, which was converted under the applied reaction conditions to produce 112. 

The products obtained in the reaction of A -cyclopropyl-4,5-difluoroanthranilic acid hydrazides 429 with triphosgene were dependent on the steric hindrance imposed by substituent R at position 3, and not the electronic effect of this group. While the unsubstituted compound 429 (R = H) gave exclusively the 4-hydrazono-3,l-benzoxazin-2-one-type product 430, the similar reactions of the chloro-, methyl-, and methoxy-substituted analogs 429 (R = Cl, Me, OMe) resulted in formation of the corresponding quinazoline-2,4-diones 431 as the sole products. For the fluoro-substituted compound 429 (R = F), a 20 80 mixture of the products 430 and 431 was obtained (Equation 46) <2005JHC669>. 

The title compounds were also synthesized from quinazoline precursors through the formation of their 1,4-oxazine rings. N-Methylisatoic anhydride was first condensed with ethanolamine to give N-(2-hydroxyethyl)-2-methylaminobenzamide (580). Cyclization of the latter with ethyl pyruvate gave quinazoline derivatives 581 which, upon hydrolysis and dehydrative cyclization with l-methyl-2-chloropyridinium iodide, afforded the l,4-oxazines[3,4- ]quinazoline (582) (8QJHC1163). 

The title compounds (662) were synthesized through the formation of their azepine rings by cycloaddition of two molar equivalents of dimethyl acetylenedicarboxylate to 2-methyl-3-(2-tolyl)quinazolin-4(3//)-one (404) (72JHC1227). 

Refluxing of dihydroazoloazines and a,(3-unsaturated ketones in a methanol solution of sodium methoxide proceeds in a Michael-type addition. For example, reaction of 2-methyl-5,7-diaryl-6,7-dihydropyrazolo[l,5- ]pyrimidine 387 and chalcone 5 under these conditions yields adduct 388 [297] (Scheme 3.102). Treatment of 2-methyl-substututed triazolopyrimidine 389 with ketone 5 leads to cyclization with formation of the triazolo[5,l-Z ]quinazoline moiety [324]. 

Phenacyl bromides react (86JHC43) with anhydro l-amino-5-aryI-2-mercapto-l,2,4-triazolo[3,2-c]quinazolin-4-ium hydroxides (53) through pyrimidine ring-opening and simultaneous formation of the 1,3,4-thiadiazine nucleus to give 54. Compound 514 was also obtained [86JAP(K)61260085] when 2-hydrazino-5-methyl-6/f-l,3,4-thiadiazine (513) was cyclized with aryloxyacetyl chlorides. 

The 3-azido-3/f-indoles 3 undergo thermal rearrangement, upon refluxing in dimethylformamide, giving variable yields and ratios of quinazolines 4 and quinoxalines 5, along with the formation of the parent indoles 6. Thus, heating of 3-azido-5-chloro-3-methyl-2-phenyl-3//-indolc for 16 hours in dimethylformamide affords 6-chloro-4-methyl-2-phenylquinazoline (30%), 6-chloro-3-methyl-2-phenylquinoxaline (20%), and a trace of 5-chloro-3-methyl-2-phenyl-l//-indole. ... 

Sternbach and coworkers pointed out that the reactions of the 6-chloro-2-chloromethyl-l,2-dihydro-4-phenylquinazoline 3-oxides 11 with a base gives either the 1,3-dihydro-2//-azirino[ 1,2-fl]quinazoline 4-oxides 13 or the 3H-1,4-benzodiazepine 4-oxide 15. In the first step of the reaction the anion 12 is formed by abstraction of a proton from the 1-nitrogen. The intermediate anion 12 can rearrange to the ring-chain tautomer 14. The relative stabilities of the two anions 12 and 14 are assumed to determine whether product 13 or 15 is formed. Thus when R is hydrogen or chloromethyl, the anion 12 is relatively sufficiently stable to allow the formation of the azirino-quinazoline 13. If, however, R is the electron-releasing methyl group, the anion 12 is destabilized and is converted to anion 14, which leads to benzodiazepine 15. The solvent polarity also influences the stability of the anions 12 and 14. In a nonpolar solvent (ether), the 5//-benzodiazepine 16 (R = Me) was obtained, which can be derived from anion 12 (R = Me) via the azirinoquinazoline 13 (R = Me). In a polar solvent (aqueous ethanol), however, the 3H-benzodiazepine 15 derived from anion 14 (R = Me) was the major product. As bases, potassium /er/-butoxide and sodium hydride were used. ... 

The reaction of the benzylidene derivative of 5-methyl-6-thioxo-5,6,ll,12-tetrahydrodibenzo[fe,/]azocin-12-one (63) with hydroxylamine has been found to initiate a novel rearrangement to yield the hydroximinoisothiochromene (64), while the mechanism shown in Scheme 24 has been invoked " to explain the formation of 2,3,4,4a-tetrahydropyrrolo[2,l-fc]quinazolin-9(l//)-one-l-carboxylic acids from the treatment of 1,10,11,11 a-tetrahydropyrrolo [2,1 -c] [ 1,4]benzodiazepin-5,11 -diones (65) with concentrated hydrochloric acid. De Lucca has discovered that hexahydro-... 

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>. 

When 2,4(1//,3//)-quinazolinedione reacts with phosphoryl chloride in the presence of excess of iV-alkyl cyclic amines, mixtures of 2,4-dichloroquinazolines, and 4-chloro-2-(A-alkyl-co-chloro-alkylamino)quinazolines (120) result. Bulky amines favor dichloride formation. Almost exclusive formation of 2-aminated product results from A-methyl pyrrolidine, indicating that either 4-oxo-... 

Ethyl chloroformate and methyl anthranilate, heated 15 hr at 100CC, were converted quantitatively to methyl 2-ethoxycarbonyl aminobenzoate (181), which was converted to quinazoline-2,4-dione in excellent yield by heating in ethanolamine for 40 min at 160°C.341 Urethane (ethyl amino-formate) and ethyl JV-phenylanthranilate, when heated at 220°C for 1 hr, gave an excellent yield of l-phenylquinazoline-2,4-dione.342... 

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