Quinazoline Group

The cation of 4,4 -biquinazolinyl and its 2,2 -dimethyl derivative readily add water across the 3,4- and 3, 4 -double bonds, but the cation of 2,2 -biquinazolinyl is not hydrated. Hydration in the 4,4 -isomers has been attributed to restricted rotation about the 4,4 -bond, a steric effect which is relieved by hydration. The ultraviolet spectrum of 2,2 -biquinazolinyl (neutral species and cation) shows that there is considerable conjugation between the quinazoline groups. Covalent hydration is absent from the latter compound because it would otherwise destroy the extended conjugation present. 

A convenient synthesis of quinazolines has been reported, and has been applied to the synthesis of representative alkaloids of the quinazoline group (Scheme 5).27 The procedure depends on the formation of sulphinamide anhydrides (23) from the reaction of anthranilic acids with thionyl chloride and the generation in situ of the iminoketens (24). Addition of the latter to the imine (25) or to 2-piperidone, for example, afforded alkaloid (27). Arborine (26) was prepared similarly from N-methylanthranilic acid application of the method to the synthesis of rutecarpine is described in Chapter 11. 

There are several alkaloids in the structure of which are both quinazoline and indole nuclei. Evodiamine (1001 R = H) and rutaecarpine (1002) were both isolated from the seeds of Evodia rutaecarpa about 1916 and synthesized in 1927. They were found subsequently to occur also in Xanthoxylum rhetsa, which in addition yielded rhetsinine (1001 R = OH) (59T(7)257). The plant Hortia arborea afforded two more related alkaloids, hor-tiacine and hortiamine, each characterized by a methoxy group in the benzene ring of the indole portion (60JA5187). 

Under the heading Alkaloids of Undetermined Constitution, have been included bases about which a good deal of information is available, though they cannot yet be allocated to sturctural groups, either because sufficient, definite information is not available, or because such data are available only about one or two members of an extensive series found in one plant or one genus. The Diehroa bases are probably quinazolines. Of the Erythrophloeum alkaloids some might be placed in the group of... 

The stabilizing influence in the hydrated cation is the amidinium resonance. If a solution of the cation is neutralized, a short-lived hydrated neutral molecule (4) (half-life 9 sec at pH 10) is obtained with an ultraviolet spectrum similar to that of the hydrated cation but shifted to longer wavelengths (5 m/ ). Supporting evidence can be derived from the anhydrous nature of the cation of 4-nitroiso-quinoline (pK 1.35), in which the nitro group has a similar electronic influence to that of the ring nitrogen atom N-I in quinazoline and where amidinium resonance is not possible. 

The lactam-lactim tautomerism of hydroxyquinazolines is reflected in their chemical reactivity. Thus they are chlorinated to 4-chloro-quinazolines (see Section VI,A), and both 0- and A-methylation have been observed. When a substituent is already present on a nitrogen atom, as in 3-methyl-4(3i7)quinazolinone, chlorination gives 4-chloroquinazoline with loss of the methyl group (see la). 2-... 

Ether groups in the benzene ring of quinazoline behave as in ethers of homocyclic aromatic compounds, e.g., they can be demethylated with anhydrous aluminum chloride. Allyl ethers also undergo a Claisen rearrangement/ ... 

Chloroquinazoline can be isolated, at best in 40% yield, by boiling 2-hydroxyquinazoline with phosphorus pentachloride in phosphorus oxychloride for 45 min, and attempts to improve this yield have proved fruitless. The yields are much higher when an aryl group is in position 4 w hich suggests an attack of the 3,4-double bond in 2-hydroxy- and 2-chloro-quinazolines by the chlorinating agent. 

Fusion of 4-hydroxyquinazoIine with phosphorus pentasulfide yields 4-mercaptoquinazoline and, similarly, substituted 2,4-dimercapto-quinazolines have been obtained from the corresponding dihydroxy compounds. The greater reactivity of the 4-mercapto as compared with the 2-mercapto group has permitted the preparation of 4-amino-2-mercaptoquinazolines (see 7a). 

Alkaloids containing a quinazoline nucleus form a small but important group of natural products and have been isolated from a number of different families in the plant kingdom. The quinazoline alkaloids are of the four types (48), (49), (50), and (51). The structures of arborine, peganine, febrifugine, rutaecarpine, and evodi-amine have been elucidated by degradation and synthesis and are described in recent reviews on quinazoline alkaloids. ... 

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-... 

The physical properties of the pyridopyrimidines closely resemble those of their nearest A-heteroeyclie neighbors the quinazolines and the pteridines. Thus, in common with the pteridines, the presence of groups capable of hydrogen-bonding markedly raises the melting point and lowers the solubility. - The acid dissociation constants (pif a values) and ultraviolet absorption spectra of all four parent pyridopyrimidines have been determined by Armarego in a comprehensive study of covalent hydration in these heterocyclic systems. The importance of these techniques in the study of covalent hydration, and... 

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