Quinazoline 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. 

In many cases, addition or removal of water proceeds sufficiently slowly that some of the physical properties of unstable species (such as hydrated neutral quinazoline or anhydrous 2-hydroxypteridine) can be observed. In these cases, reaction kinetics can also be examined. Addition of water to pteridine is of special interest in relation to studies of the formation and hydrolysis of Schiflf bases. The reaction proceeds in two reversible stages, 3 4 5 ... 

Reaetion of l,3-benzoxazin-4-ones (43, 44) or trithioisatoie anhydride (45) with amidrazones (46, 47) or thiosemiearbazide (48) resulted in the formation of 3-(l-amidino)- (49-51) and 3-(l-thioureido)pyrimidines (52) respeetively. Compounds 49-52 underwent thermal intramoleeular ey-elization to the eorresponding l,2,4-triazolo[l,5-c]quinazolines (53-56) [68CB2106 76MI1 80PHA582 83MI1 85H(23)2357] (Seheme 18). 

CN/CC replacements were also observed when the pyrimidine ring is part of a bicyclic system. Reaction of quinazoline with active methylene compounds, containing the cyano group (malonitrile, ethyl cyanoacetate, phenylacetonitrile) gave 2-amino-3-R-quinoline (R = CN, C02Et, Ph) (72CPB1544) (Scheme 12). The reaction has to be carried out in the absence of a base. When base is used, no ring transformation was observed only dimer formation and SnH substitution at C-4 was found. 

Quinazolin-4(3/7)-one was converted into 4-chloroquinazoIine on heating with a mixture of phosphoryl chloride and phosphorus pentachlo-ride [80IJC(B)775], Phosphoryl chloride in the presence of triethylamine, however, transformed quinazolin-2,4(lf/,3//)-dione into 2-chloro-4-diethylaminoquinazoline. More bulky amines allowed formation of the 2,4-dichloro derivative (82CPB1947). 

Lemus, R. H. Skibo, E. B. Design of pyritnido[4.5-s quinazoline-based anthraquinone mimics, structure-activity relationship for quinone methide formation and the influence of internal hydrogen bonds on quinone methide fate. J. Org. Chem. 1992, 57, 5649-5660. 

A more highly oxidized derivative of quinazoline forms the heterocyclic moiety of a compound with CNS activity. Condensation of the aminopropylpiperazine 141 with isatoic anhydride gives the anthranilamide 142. Reaction of that amide with phosgene gives directly the heterocyclic ring. (The reaction may proceed by initial formation of the carbamoyl chloride ... 

C(l)-Acylation of the l,4-dihydro-277-pyrazino[2,TA]quinazoline-3,6-diones 57 (R4 = Me, Rz = Bn, CH2-C6H4-MeO-/>) by treatment with LHDMS at — 78 °C followed by addition of acyl chlorides resulted in the as- 1-acyl derivatives with de > 95% in good yield. Formation of the air-product was explained by equilibration through the anion formed by deprotonation at C-l. The 1-acyl compounds were unstable and easily retransformed into the starting 57 <1998TA249>. 

The linearly fused benzologues, pyrimido[2,l-A]quinazolines, are most frequently synthesized from a 2-amino- or 2-iminoquinazoline. Synthesis from [6+0] atom fragments by bond formation 7 to the ring junction nitrogen takes place when the 2-aminoquinazoline bearing a suitable substituent at N-3 is cyclized. The 2-iminoquinazoline-3-propionates 197 cyclized on treatment with alkali to give 198 (Scheme 31) <1997EPP0778258>. 

Dehydrohalogenation of the 314 proceeded in excellent yield under the action of morpholine or piperidine at rt, during double bond formation between the C-l and C-2 atoms <2003CHE640>. The active methylene group of 3,4-dihydro-1 ///>//-[ 1,4 oxazino[3,4- quinazolin-6-onc 315 readily condensed with aromatic aldehydes at 160 °C in a melt to give the 1-benzylidenes, and coupled with aryldiazonium chlorides to give the arylhydrazono derivatives <1996BMC547>. 

Another multistep protocol that initially involves the formation of fused pyrimidines (quinazolines) has been described by Besson and coworkers in the context of synthesizing 8f-/-quinazolino[4,3-b]quinazolin-8-ones via double Niementowski condensation reactions (Scheme 6.250) [437]. In the first step of the sequence, an anthranilic acid was condensed with formamide (5.0 equivalents) under open-vessel microwave conditions (Niementowski condensation). Subsequent chlorination with excess POCl3, again under open-vessel conditions, produced the anticipated 4-chloro-quinazoline derivatives, which were subsequently condensed with anthranilic acids in acetic acid to produce the tetracyclic 8H-quinazolino[4,3-b]quinazolin-8-one target structures. The final condensation reactions were completed within 20 min under open-vessel reflux conditions (ca. 105 °C), but not surprisingly could also be performed within 10 min by sealed-vessel heating at 130 °C. 

Scheme 6.250 Formation of 8H-quinazolino[4,3-b]quinazolin-8-ones through double Niementowski condensation.

The same research group has shown that the 5-fluorophenyl-l,2,4-oxadiazoles 73 (Scheme 6) form the triazoles 74 as the major products in the presence of amine nucleophiles, together with varying amounts of side products 75-77, with product 76, for example, being formed by the competitive addition of the methanol solvent to the N-O-cleaved photolytic product <2005H(65)387>. The formation of quinazolin-4-ones 75 has been studied separately, and has been optimized to allow good yields as shown by the example in Equation (6) <1999JOC7028>. 

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>. 

Finally, three ring-enlargement reactions should be referenced in this section. Gerecke et al. reported <1994H(39)693> that treatment of the 5-chloromethyl-substituted triazolo[4,3-c]quinazoline compound 141 with sodium hydroxide results in the formation of a seven-membered diazepine ring 142 in good yield. 

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