Quinazolines oxidation

Reduction of quinazoline oxides to quinazolines, catalytically (Raney nickel, palladium on charcoal) or with iron and ferrous sulfate in 85% alcohol can be extended to the preparation of benz-substituted quinazolines. ... 

It has been proposed that the ring-expansion reaction is initiated by attack of the base at position 2 of the quinazoline oxide, which is rendered electron deficient by the inductive effect of the (V-oxide group. In fact, 2-(Chloromethyl)quinazolines, compounds that lack this feature, react with amines to give only simple substitution products.1133... 

In a similar fashion, 1-acetylisatin, when reacted with hydroxylamine hydrochloride furnishes quinazoline-3-oxide through cyclization of the intermediate hydroxamic acid234. This intermediate hydroxamic acid can be isolated by treatment of the quinazoline oxide with alkali235 (Scheme 54). 

Rademaker M (1994) Allergic contact dermatitis from lavender fragrance in Difrlam gel. Contact Dermatitis 31 58-59 Rebandel P, Rudzki E (1986a) Dermatitis from quinazoline oxide. Contact Dermatitis 15 63-5... 

In the reaction of DMAD with the quinazoline oxide (103), the major products are the stilbene derivative (104) and the benzodiazepine (105). The skeletal rearrangement in Scheme 4 was suggested to account for their formation. ... 

The use of oximes as nucleophiles can be quite perplexing in view of the fact that nitrogen or oxygen may react. Alkylation of hydroxylamines can therefore be a very complex process which is largely dependent on the steric factors associated with the educts. Reproducible and predictable results are obtained in intramolecular reactions between oximes and electrophilic carbon atoms. Amides, halides, nitriles, and ketones have been used as electrophiles, and various heterocycles such as quinazoline N-oxide, benzodiayepines, and isoxazoles have been obtained in excellent yields under appropriate reaction conditions. 

There is a scattered body of data in the literature on ordinary photochemical reactions in the pyrimidine and quinazoline series in most cases the mechanisms are unclear. For example, UV irradiation of 4-aminopyrimidine-5-carbonitrile (109 R=H) in methanolic hydrogen chloride gives the 2,6-dimethyl derivative (109 R = Me) in good yield the 5-aminomethyl analogue is made similarly (68T5861). Another random example is the irradiation of 4,6-diphenylpyrimidine 1-oxide in methanol to give 2-methoxy-4,6-diphenyl-pyrimidine, probably by addition of methanol to an intermediate oxaziridine (110) followed by dehydration (76JCS(P1)1202). 

The oxidation of quinazoline with alkaline permanganate is still the preferred route to pyrimidine-4,5-dicarboxylic acid (04CB3643). 

Quinazoline, 2,4-bis(/3-diethylaminoethoxy)-Hilbert-Johnson reaction, 3, 93 Quinazoline, 2-chloro-4-(p-chlorophenylthio)-synthesis, 3, 137 Quinazoline, 6,8-dichloro-chlorosulfonation, 3, 76 Quinazoline, dihydrosynthesis, 3, 108, 124 Quinazoline, 2,4-dimethyl-Mannich reactions, 3, 78 Quinazoline, 4-ethoxy-1-oxide... 

They also state that analytical studies of the oxidation products of dichroine-a indicate that the dichroines are quinazoline derivatives, as already indicated by Koepfli et al. for their alkaloids. With the probable exception of dichroine-a, these bases are active against malaria in chicks in the descending order dichroine-y (1), dichroine- (4) dichroidine quinazolone (40) the figures in brackets are effective doses (mgm./kilo.). There are also two neutral substances present, umbelliferone (dichrin-A) and dichrin-B, m.p. 179-181°. 

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 sole known example of electrophilic substitution in quinazoline is nitration. Quinazoline gives 6-nitroquinazoline with fuming nitric acid in concentrated sulfuric acid. No oxidation of the heterocyclic ring can occur under these conditions because the hydrated cation (see Section IIA>4) is not present. This substitution is in agreement with theoretical calculation [see (2) and reference 36]. 

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... 

Unsubstituted quinazoline 3-oxide was prepared in an attempt to react quinazoline with hydroxylamine. This reaction gave a product of variable composition, but when an acetone solution was heated in a sealed tube it gave quinazoline 3-oxide. The oxide is more conveniently prepared, in excellent yield, from o-aminobenzaldehyde oxime and ethyl orthoformate. This method appears to be of general use and has been used for the preparation of 4-methylquinazoline... 

S-oxide. The reaction of quinazoline with hydroxylamine is not hindered by the presence of a 4-substituent since 4-methyl-quinazoline also gives 4-methylquinazoline 3-oxide with hydroxyl-... 

Quinazoline 3-oxide reacts further with hydroxylamine to give 2-aminoquinazoline 3-oxide (see 2c). 

---