Diazanaphthalenes

Quinazoline (1,3-diazanaphthalene) was prepared by Gabriel in 1903 although the first derivative tvas synthesized by Griess 34 years earlier. The name was proposed by Widdege. Other names such as phenmiazine, benzo-l,3-diazine, and 5,6-benzopyrimidine have occasionally been used. The numbering suggested by Paal and Busch (1) is still in use. ... 

Unlike the other diazanaphthalenes (i.e., naphthyridines/ cinno-line, phthalazinc/ and quinoxaline), quinazoline shows abnormal behavior when converted into its cation. This anomaly was first discovered by Albert et who noticed that 4-methylquinazoline was a w eaker base (tenfold) than quinazoline (see Table I). This was... 

An early claim by Gabriel and Neumann to have synthesized 1-methylisoindolenine (59) from the diazanaphthalene (60) has been shown to he in error, the actual product being 1-methylisoindoline (61). Several synthetic routes to 1,3,3-trisubstituted isoindolenines... 

The rate of amination and of alkoxylation increases 1.5-3-fold for a 10° rise in the temperature of reaction for naphthalenes (Table X, lines 1, 2, 7 and 8), quinolines, isoquinolines, l-halo-2-nitro-naphthalenes, and diazanaphthalenes. The relation of reactivity can vary or be reversed, depending on the temperature at which rates are mathematically or experimentally compared (cf. naphthalene discussion above and Section III,A, 1). For example, the rate ratio of piperidination of 4-chloroquinazoline to that of 1-chloroisoquino-line varies 100-fold over a relatively small temperature range 10 at 20°, and 10 at 100°. The ratio of rates of ethoxylation of 2-chloro-pyridine and 3-chloroisoquinoline is 9 at 140° and 180 at 20°. Comparison of 2-chloro-with 4-chloro-quinoline gives a ratio of 2.1 at 90° and 0.97 at 20° the ratio for 4-chloro-quinoline and -cinnoline is 3200 at 60° and 7300 at 20° and piperidination of 2-chloroquinoline vs. 1-chloroisoquinoline has a rate ratio of 1.0 at 110° and 1.7 at 20°. The change in the rate ratio with temperature will depend on the difference in the heats of activation of the two reactions (Section III,A,1). 

The reaction conditions of this modified indazole synthesis can also be applied to the preparation of 1,2-diazanaphthalenes, the so-called cinnolines, although in such syntheses no deprotonation prior to cyclization is likely to occur. Ruchardt and Hassmann (1980) obtained 4-phenylcinnoline (6.85) in 53% yield from 2-(a-methyl-ene-benzyl)aniline (Scheme 6-53). 

Molecular models indicate that cavitand (259) has a tall, vase-shaped architecture in which the four benzene rings and four nine-membered rings combine to form a concave cavity to which is attached the four diazanaphthalenes (Moran, Karbach Cram, 1982). The latter groups resemble flaps which may occupy either equatorial or axial positions. In the former arrangement, the inner surface area of the cavity is quite reduced and hence a considerable decrease in the inclusion ability of this form is expected. 

AO is also effective in metabolizing a wide range of nitrogen-containing heterocycles such as purines, pyrimidines, pteridines, quinolines, and diazanaphthalenes (95). For example, phthalazine is rapidly converted to 1-phthalazinone by AO and the prodrug, 5-ethynyl-2-(l//)-pyrimidone, is oxidized to the dihydropyrimidine dehydrogenase mechanism-based inhibitor, 5-ethynyluracil, by AO (Fig. 4.40) (96). 

Pyrimidine 1 is the lUPAC accepted name for 1,3-diazabenzene, while quinazoline 2 is the accepted name for benzo[r lpyrimidine or 1,3-diazanaphthalene. Perimidine 3 is the lUPAC accepted name for l//-benzo[r/ ]quinazoline or H -naphtho[l,8-r/i ]pyrimidine, while benzo. 4]perimidine 4 is also known as 1,3-diazapyrene. 

The naphthyridines consist of those diazanaphthalenes which have one nitrogen atom in each ring neither of which occupies a bridgehead position. Alternatively they can be named as pyridopyridines. The six possible isomers (1)—(6) are shown below. ... 

Pyridazine (1,2-diazine) (1) and its benzo analogs cinnoline (1,2-diazanaphthalene) or benzo[c]pyridazine (2) and phthalazine (benzo[rf]pyridazine) (3) have been known since the nineteenth century. Although the basic synthetic principles and reactivity were investigated in the early years, interest in these compounds was not very intense, compared with pyrimidines and their bicyclic analogs, as they were not found in nature. However, during the last three decades intensive research has been stimulated because many derivatives have found application as a result of their biological activity. 

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