Quinazoline, structure

It was recently observed that a iplant, Adhatoda vasica, long used in Indian herbal medicine (the source of many therapeutic leads) for the relief of cough and respiratory tract congestion, did appear to reduce the quantity and viscosity of sputum. The plant was studied and its active alkaloid named vasicine. The tricyclic quinazoline structure (XXVIII) was then reduced to fragments and a series of derivatives prepared [350]. From these bromhexine (XXIX, Na 274, Bisolvon)... 

Assignments have been accomplished for four structural isomers and stereoisomers with pyrim-ido[l,6-c][l,3]benzoxazine and pyrimido[l,2-c][l,3]benzoxazine structures <75S802>. The [l,4]oxa-zino[3,4-Z ]quinazoline structure (216), rather than a possible seven-membered ring structure, was established for the cyclization product of (305 R = CH2C02Me, = H) (see Section 8.25.3.6.8)... 

Several natural products contain the quinazoline structure, e.g. the quinazoline alkaloids obtained from rutaceae (e.g. arborine 24). Tetrodotoxin 25 derived from decahydroquinazoline and found in the Japanese puffer fish is one of the strongest nonproteinogenic neurotoxins. 

Febrifugine is the first alkaloid to be isolated from a member of the Saxifragaceae, and it is the first known alkaloid outside the cinchona group to possess marked antimalarial activity. Its quinazoline structure is of particular interest in view of the recorded antimalarial activity of some synthetic quinazolines (49). A number of synthetic analogues of XXXII have been prepared and tested as antimalarials (51). 

Tryptoquivaline (104) and Nortryptoquivalone. A strain of the fungus, Aspergillus clavatus, isolated from mold-damaged rice, produces these two, highly toxic, tremorigenic metabolites 46). The quinazoline structures of... 

Quinazoline alkaloids are found in at least six botanical families of which the Rutaceae are the most important in this respect. Thus, arborine was isolated from Glycosmis arborea in 1952 and in the following year appeared its structure (990) and synthesis by thermal cyclization of the phenylacetyl derivative (989) of (V-methylanthranilamide (53JCS3337>. The same plant material yields three related alkaloids, glycosmicine (991), glycorine (992) and glycosminine (993) (63T1011>. 

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). 

Quinazoline-4(3 H) -thione, 2-methy 1-synlhesis, 3, 136 Quinazolinethiones structure, 3, 67 synthesis, 3, 136 Quinazoline-4-thiones aminolysis, 3, 94... 

Quinazolin-4(3H)-one, 3-phenyl-reduction, 3, 75 Quinazolinones polymers, 1, 298 reactions, 3, 89 structure, 3, 66-67 synthesis, 2, 96 3, 133 thiation, 3, 89 Quinazolin-4-oties 2,3-disubstituted Grimmel synthesis, 3, 109 mass spectra, 2, 22... 

The present review describes recent advances in quinazoline chemistry, some of which are but modem applications of earlier methods, whereas others strike out on new, and sometimes surprising, pathways. The structure of the cation of the parent substance, quinazoline, has only recently been made clear, and it has become evident that covalent hydration is a phenomenon widely distributed throughout the quinazoline series. With this fact in mind, it seems better to set forth the newly found properties of quinazolines before proceeding to an account of advances in synthesis. 

Quinazoline 3-oxides were first prepared by Awers and von Meyen-burg in 1891 by the dehydration of o-acylamino benzophenone oximes with acetic acid-acetic anhydride and were assigned the in-dazole structure (33). This was then modified by Bischler to the... 

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. ... 

The usual syntheses of quinazolines make use of an o-disubstituted benzene structure (46) from which the quinazoline skeleton is completed by adding C-2 and N-3 in various ways. Substituents could either be in (a) the pyrimidine ring or (b) the benzene ring or in both rings. The syntheses will be described in this order and the methods used for (a) apply equally well to quinazolines substituted in both rings. 

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-... 

Quinazolin-4-one and its 6-nitro derivative were both shown to exist predominantly in the o-quinonoid form (cf. 96) by ultraviolet spectral comparisons of the parent compound with the 0-methyl derivative and with the two A -methyl analogs, The existence of quinazolin-2- and -4-ones in an oxo-type structure was demonstrated in 1952 by using solid-state infrared data and later confirmed by... 

Quinazoline-2,4-dione (108) has been assigned the dioxo formulation on the basis of its infrared spectrum. A dioxo structure has also been demonstrated for the derivative 108a by ultraviolet spectral comparisons and infrared data. ... 

The present review covers the literature to the end of 1967 and all original sources have been consulted. Syntheses of each of the four ring systems are summarized separately, but physical, chemical, and biological properties are considered generally. Many pjTidopyri-midines were initially synthesized for a study of biological activity or physical properties because of the close structural relationship of these systems to the quinazolines (5) and pteridines (6). Recent reviews have discussed these related compounds. 

The pyridopyrimidines possess the same 7r-electron structure as naphthalene. The electronic transitions between the 77-orbitals would therefore be expected to give rise to similar ultraviolet spectra. As in the case of the quinazolines and the pteridines, this has proved to be so. 

The methiodide of quinazoline (63) was studied by Gabriel and Colman and shown to possess structure 64. Gabriel s evidence has been checked by later workers and the substitution in the... 

Heterocyclic structures analogous to the intermediate complex result from azinium derivatives and amines, hydroxide or alkoxides, or Grignard reagents from quinazoline and orgahometallics, cyanide, bisulfite, etc. from various heterocycles with amide ion, metal hydrides,or lithium alkyls from A-acylazinium compounds and cyanide ion (Reissert compounds) many other examples are known. Factors favorable to nucleophilic addition rather than substitution reactions have been discussed by Albert, who has studied examples of easy covalent hydration of heterocycles. 

A particularly interesting example of this method of synthesis is the cy-clrzation of the 4-amino-3-(2-aminophyenyl)-l,2,4-triazoloes 73 with cyanogen bromide. Primarily, this reaction was applied to synthesize the 6-amino-l,2,4-triazolo[4,3-d]benzodiazepine hydrobromides 74 the obtained products, however, were found to be the l,5-diamino-l,2,4-triazolo-[l,5-c]quinazolin-ium bromides 77. Structure elucidation of 77 was accomplished by direct... 

The structures of 5-ethyl-1 ]-methyl-9-oxo-5,l l-dihydro-9/7-pyrido[2,1-6]-quinazohne-8-carboxylic acid (00K669), the chromophore 4 of isopyoverdin siderophores (01T1019), and that of 5,5n,6,7,8,9-hexahydro-l l//-pyrido [2,]-6]quinazoline (99SL1383) were justified by X-ray analysis. 

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). ... 

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. 

---