Quinazoline basicity

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. ... 

These compounds show the typical reactions of heterocyclic N-oxides and their structure was proved by methylation which takes place on N-1. Quinazoline 3-oxide is soluble in water and melts at 155°C. It has basic properties and its pKa value in water is 1.47. ... 

Aminoquinazolines have been the subject of considerable investigation and a large number of derivatives have been prepared as potential antimalarials. The secondary and tertiary amino compounds can be prepared from the corresponding chloroquinazolines and the required primary or secondary amines. The reaction depends on the reactivity of the halogen atom, e.g, the 4-chloro atom reacts more readily than the 2-chloro atom in quinazolines and also on the basic strength of the amine used (see 6a). The reaction is... 

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-... 

Alkylthio, arylthio, and thioxo. The thioxo group in pyrimidine-2,4-dithione can be displaced by amines, ammonia, and amine acetates, and this amination is specific for the 4-position in pyrimidines and quinazolines. 2-Substitution fails even when a 5-substituent (cf. 134) sterically prevents reaction of a secondary amine at the 4-position. Acid hydrolysis of pyrimidine-2,4-dithione is selective at the 4-position. 2-Amination of 2-thiobarbituric acid and its /S-methyl derivative has been reported. Under more basic conditions, anionization of thioxo compounds decreases the reactivity 2-thiouracil is less reactive toward hot alkali than is the iS-methyl analog. Hydrazine has been reported to replace (95°, 6 hr, 65% 3deld) the 2-thioxo group in 5-hexyl-6-methyl-2-thiouracil. Ortho and para mercapto- or thio- azines are actually in the thione form. ... 

The original objective of the synthetic work was the preparation of basic derivatives of the 3,1,4-benzoxadiazepine system (2) for animal testing. The basic ring system had been reported previously in the literature as the dehydration products of 2-acylaminobenzophenone oximes (1). Repetition of the work quickly cast doubt on the earlier structural assignment. Both the chemistry of the products and their spectral data suggested that the products were in fact quinazoline-3-oxides (3). ... 

While the examples outlined in the previous section all pertain to attack by a basic N-atom, another possibility is intramolecular attack by an acidic N-atom, i.e., a deprotonated amide. For example, in AT-(2-carbamoylphe-nyljcarbamalcs of model phenols (8.135, X = H, Cl, or MeO, Fig. 8.11), the deprotonated carboxamido group attacks the carbamate carbonyl C-atom to form a quinazoline-2,4-dione with release of the phenol [173]. In acidic media, formation of the quinazoline-2,4-dione is decreased by competitive breakdown of the intermediate to an anthranilate and C02 in addition to the phenol (not shown). 

Amino-ll//-pyrido[2,l-b]quinazolin-ll-one (203) was obtained as a degradation product of 5,ll-dihydro-6//-pyrido[2,3-b][l,4]benzodiazepin-6-one (327, R = H) and pirenzepine (328) by basic and acidic hydrolysis... 

Support-bound quinazolin-2,4-diones can be N-alkylated, either with alkyl halides under basic conditions or with aliphatic alcohols by means of the Mitsunobu reaction (Entries 12-14, Table 15.29). The methyl group of a 2-methylquinazolin-4-one is sufficiently acidic to undergo aldol condensations with aldehydes [343]. Aminations of chloroquinazolines are discussed in Section 10.1.2. 

The pK of quinazoline, as commonly measured, is 3.51 this represents mainly the equilibrium between the two most stable species, namely, the hydrated cation and the anhydrous neutral species. The true anhydrous pKa (i.e., for the instantaneous equilibrium between anhydrous cation and anhydrous neutral species) was obtained25 for quinazoline, twelve substituted quinazolines, and triazanaphthalenes in the rapid-reaction apparatus just described. The true anhydrous pKa of quinazoline turned out to be 1.95. The true hydrated pKa of quinazoline has already been reported26 as 7.77, the slower rate of hydration permitting its determination in the usual rapid-reaction apparatus. Thus, in general, three pKa values exist for each hydrating base, and the equilibrium between the totally hydrated species furnishes the strongest basic properties. 

An acetoxy moiety, present in a side chain in the position 9 on 7-oxo-lH,3H,7H-pyrido[3,2,l-zy][3,l]benzoxazine skeleton, was hydrolyzed under basic condition to yield a hydroxy derivative (07WOP2007/ 054296). Phtalimido, and benzyloxycarbonylamino (07JP2007131577) and ferf-butoxycarbonylamino groups (06WOP2006/050940, 06WOP2006/ 050943), present in a side chain on pyrido[3,2,l-zy][3,l]benzoxazin-7-one and pyrido[3,2,l-zy]quinazolin-4-one skeletons, were converted to an... 

Ester and pivaloyloxy groups, present in a side chain of 1,2,3,5,6,7-hexahydropyrido [3,2,1-zy]quinazolin-l-ones, were hydrolyzed to carboxyl and hydroxyl groups, respectively under basic conditions (07JP2007131577). 

Chloro-7-bromo-l,2,3,5-tetrahydroimidazo[2,l-b]quinazolin-2-one was produced next way to a solution of 1.30 g (8 mmole) of anhydrous ferric chloride in 30 ml of nitromethane was added 1.30 g (5 mmole) of solid 6-chloro-l,2,3,5-tetrahydroimidazo[2,l-b]quinazolin-2-one and 0.80 g (5 mmole) of bromine. The system was stoppered, warmed to 50°C in an oil bath overnight, cooled to room temperature and the solvent removed in vacuo. The resulting solid was suspended in water (50 ml), the mixture was made basic (pH = 10) with sodium bicarbonate and stirred at home temperature for 20 min. The solid was filtered under suction, washed with water, then isopropyl alcohol and dried yielding 1.19 g of 6-chloro-7-bromo-l,2,3,5-tetrahydroimidazo[2,l-b]quinazolin-2-one (78% yield). Purification was effected by formation of the hydrochloride salt (mp 275°C) from acetonitrile. 

Azine approach. Most widely used are cyclization reactions of lV-amino-2-pyrimidinethiones and analogous structures, as in the preparation of the 7H-derivative (724) (78ZC66) and the quinazoline (725) (7oiJC7io). Basically, the same reaction conditions are used to prepare the 1,2,4-triazine (726) (76JHC117). 

Comparison of the UV spectra of 5-amino-2-(2-furyl)-l,2,4-triazolo[l,5-c]quinazolines (196) and its 5-methylamino derivative (197) in neutral, acidic, and basic media with the spectra of the two tautomerically locked derivatives—2- (2-fury 1) -5-dimethylamino-1,2,4-triazolo [ 1,5-c]quinazolines (198) (amino-locked tautomers) and the imino-locked tautomers 2-(2-furyl)-5-imino-6-methyl-1,2,4-triazolo[ 1,5-c]quinazolines (199)—indicated that compounds 196 and 197 are best represented as a mixture of their amino and imino tautomers (88JMC1014) (Scheme 75). 

Protonation of quinazoline in anhydrous medium probably gives the cation 7 since N3 is the basic center however, water addition at the 3,4-positions will afford the resonance-stabilized hydrated cation 8, irrespective of the site of protonation in the anhydrous species. Quinazolines with 0X0. thioxo, amino and, less frequently, with other substituents at position(s) 2 or/and 4 are capable of tautomerism. Quinazolin-2-ones, quinazolin-4-ones, and quina-zoIine-2,4-diones have been shown to exist as oxo tautomers in solution and in the solid state. In quinazolin-4-ones the 3//-tautomer 9a is present to a greater extent than the 1 //-tautomer 10a. Quiiiazolin-2-oiie prefers the 1//-tautomeric form 11a which is more stable than the 3//-quinoid structure na. Similarly, in quinazoline-2-thione and -4-thione as well as quinazoline-2,4-dithiones the 3//-, 1//-, and 1//,3//-tautomeric structures 9b, 11b, and 13b, respectively, are predominant. 2-Thioxo-2,3-dihydroquinazolin-4(l//)-one adopts the preferred tautomer 13a... 

The center of basicity in quinazoline itself is N3. Depending on the conditions, quinazoline can form a normal monocation, an abnormal monocation, and a dication. The normal cation 1 is formed in anhydrous solvents, e.g. in anhydrous diethyl ether where quinazoline can be converted into a hydrochloride which is very hygroscopic and readily forms a hydrate, or in... 

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. ... 

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