Quinazolines. fused

H2SO4, anhydrous dication), pK " with 3,4-hydrated species), pKl 12.1 (hydrated anion). Purify quinazoline by passage through an activated alumina column in C6H6 or pet ether (b 40-60"). Distil it undar reduced pressure, sublime it undo-vacuum and crystallise it from pet ether. The.picrate has m 188-189" (from MeOH). [Armarego J Appl Chem 11 70 1961, Armarego Quinazolines, Fused Pyrimidines Part I Brown Ed, Wiley-Interscience 1967, Brown Quinazolines Supplement 1 Taylor Ed, Wiley-Interscience 1996, ISBN 0-471-14565-3 for covalent hydration see Albert Armarego Adv Heterocycl Chem 4 1 1965, Beilstein 23 H 175, 23 II 177, 23 III/IV 1221.]... 

Quinazohnone derivatives attract widespread attention due to the diverse biological activities associated with them. Rutaecarpine (Fig. 13.7) and luotonine A [80] (Fig. 13.8) are the two natural quinazoline-fused compounds exhibiting very potent pharmacological values. 

When two fused six-membered rings (naphthalene analogues) are considered, possibilities become very numerous, partly on account of the reduced symmetry of naphthalene, compared with benzene, and also because of the larger number of positions available for substitution. Thus, there are two monoazanaphthalenes, quinoline (8) and isoquinoline (9), four benzodiazines [cinnoline (10), phthalazine (11), quinazoline (12) and quinoxaline(13)], with the two nitrogen atoms in the same ring, and six naphthyridines (e.g. (14), named and... 

Cyclization of 2-(4-hydroxypentyl)quinazolin-4(3//)-ones 422 under Mitsunobu s conditions afforded only linearly fused 6,7,8,9-tetrahydro-1 l/f-pyrido[2,l-6]quinazolin-l l-ones 423 without angularly fused 1,2,3,4-tetrahydro-6//-pyrido[l, 2-n]quinazolin-6-ones 424 (98CPB928). 

However, another representative of benzo-fused tetrahydropyrimidines, 3,4,5,6-tetrahydrobenzo[/i]quinazoline 61, was reported to exist exclusively as the tautomer shown, without any indication of the annular tautomeric equilibrium (91M209). 

Isolated and benzo-fused diazine rings are key structural elements in many natural and synthetic compounds of current interest. This contribution relates highlights from many of the studies on the diazines pyridazine, pyrimidine, pyrazine, and their benzo-fused derivatives cinnoline, phthalazine, quinazoline, quinoxaline, and phenazine published in English in the journal literature during 1996, as covered by Chem. Abstr. through volume 126, issue 5. 

The angularly fused pyridazino[l,6- ]quinazolines were prepared by tandem [6+0 (a), 6+0 (7)] cyclization of functionalized, diazotized anthranilic acid derivatives. Depending on the order of reacting ethyl benzoylacetate, malonitrile, and the diazotized anthranilonitrile, the pyridazino[l,6- ]quinazolines 103 or 105 were obtained by alkaline or thermal cyclizations, respectively (Scheme 11) <2001T1813>. 

The tetrahydropyrimido[l,2- ]quinazoline 195, a representative of the angularly fused benzologues, has been formed in the microwave-assisted reaction of aminopyrimidine, dimedone, and an aromatic aldehyde (Equation 20) <2002HC0299>. 

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>. 

Malayamycin A has been synthesised by a lengthy route, starting with the reaction of a protected ribonolactone with a lithiated pyrimidine <06T5201>. A much shorter synthesis of the fused quinazoline asperlicin D involved direct cyclisation of a diamide <06TL693>. 

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. 

There are 12 isomeric structures for this ring system, where the triazine ring is directly fused to the pyrimidine nucleus of the quinazoline ring one of the nitrogen atoms of the quinazoline ring is located at the bridgehead of the bicyclic ring. 

The linearly fused oxadiazoloquinazoline derivative 90 also underwent ring opening with nucleophiles treatment of a toluene solution of this compound with tetrahydropyridine (refluxing conditions for 15 min followed by storage overnight at room temperature) yielded the urea-substituted quinazoline compound 91 in almost quantitative yield <2000S2009>. 

The same methodology can be applied to the synthesis of pharmaceutically relevant quinazolines and quinazolinones containing a fused alicyclic ring [45,46]. 

The extensive examinations of aromatic heterocvcles, such as benzoxa-zines, benzothiazines, and quinazolines, and the corresponding oxo derivatives may also have been due to the fact that the starting materials of the syntheses of these hetero compounds, such as salicylic acid or anthranilic acid and their derivatives, have been industrial products since the end of the nineteenth century. In contrast, the starting materials for the stereospecific syntheses of the related cycloalkane-fused heterocycles can generally be prepared only with some difficulty and did not become available commercially until more recently [90MI1, 91MI1 92ACH(129)107]. 

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