Quinazoline nucleophilic substitution

The alteration of nucleophilic reactivity by the intervention of covalent hydration and analogous nucleophilic additions needs to be borne in mind for many polyazanaphthalenes. Covalent hydration has been observed in several bicyclic azines besides pteridine and quinazoline (Section IV, B) and is related to nucleophilic substitution in activation and in proceeding through the same first stage as 8 Ar2 reactions. The Bucherer interconversion of naphthols and naphthylamines involves exchange of oxygen and nitrogen substituents in a covalent adduct produced by bisulfite ion. ... 

The cyano group in position 4 of quinazolines behaves like a halogen towards nucleophilic reagents and can be displaced by a hydroxide anion, alkoxides, amines, hydrazines, and various carbon nucleophiles, o.g. ketones, a-keto esters, dialkyl malonates, nitroalkanes, Gri-gnard reagents, and enamines, to give 4-substituted quinazolines 1. The cyano group of quin-azoline-2-carbonitriles is less reactive for nucleophilic substitution but its displacement has not been intensively studied. Alkaline or acid hydrolysis of quinazoline-4-carbonitriles affords quinazolin-4(3// )-oncs. ... 

The 4-halogen atom in chloroquinazoline was displaced by aziridine, by amines (with derivatives of a-amino acids), and by fluorine (with KHF) more readily than a halogen atom at C-2. When a 4-fluorine atom was activated, as in hexafluoroquinazoline, it could be readily substituted by an amino or methoxy group. Nucleophilic substitution in the benzene ring of quinazoline was also possible. Hexachloroquinazoline gave hexafluoroquinazoline with anhydrous potassium fluoride, and the latter... 

Alkoxy derivatives in the electrophilic positions are readily available by nucleophilic substitution reactions as discussed for the oxo derivatives above. 2,4-Dialkoxyquinazolines can be prepared by boiling 2,4-dichloroquinazolines with two equivalents of alkali alkoxide in the appropriate alcohol. Mixed ethers (137) are possible because of the great difference in positional reactivity the first substitution is in the 4-position (136). 4-Chloro- and 2,4-dichloro-quinazoline very readily suffer alcoholysis in the 4-position with acid catalysis, presumably via 4-adduct formation as in the facile hydrolysis discussed above. 

Alkylthio derivatives are frequently made by -alkylation of the corresponding quinazoline-thiones. Arylthio, as well as alkylthio derivatives, can be prepared by nucleophilic substitution of halogenoquinazolines by the corresponding thiolates [Pg.133]

The methods most frequently used to synthesize these compounds are [6 + 0(a)] cyclizations. Ring closures may take place via intramolecular alkylation, condensation, or nucleophilic substitution. The starting materials for the cyclizations in the case of pyrazino-oxazines are always pyrazine derivatives. Only a few representatives of these systems have been prepared. Pyrimido-oxazines are the most explored group of compounds. In the bicyclic series, cyclizations have been carried out in most cases from pyrimidine intermediates and only rarely from morpholino intermediates. For the preparation of benzo-fused derivatives, both benzoxazine and quinazoline intermediates have been used. Pyrazino-oxazines represent a small group of compounds. For cyclizations, both pyrazino and oxazino intermediates have been used. There are many lactone structures among these compounds. For their preparation, the usual methods of lactone formation have been applied. 

Reactions of benzodiazines show no exceptional features compared with the simple diazines. Reactivity towards electrophiles is less than in quinoline and isoquinoline. If S Ar reactions take place, they lead to substitution of the benzene ring. As a rule, nucleophilic substitution of benzodiazines occur in the diazine ring, particularly if substituted by halogen. The quinazoline system displays C-4 regioselectivity, e.g. in the reactions of 2,4-dichloroquinazoline with amines or alcohols ... 

There are few general methods for the direct functionalization of quinazolines and quinazolinones because of their deactivated nature. TTierefore, these compounds are more commonly constructed from acyclic precursors. For those examples that do exist, SeAr reactions generally take place on the benzene ring, while nucleophilic substitution reactions generally occur on the diazine ring and are selective for the C4 position due to the electropositive nature of this position. Reactions can take place at the C2 position, but generally only if the C4 position is already occupied. 

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. 

In 2,4-disubstituted quinazolines, the 4-position reacts fastest with nucleophiles, generally even when the 4-substituent is a poorer leaving group. 2,4-Dichloroquinazoline undergoes mono-substitution at the 4-position with alcoholic alkoxides (25°, 2 hr, 80-98% yield), phenolic phenoxide (20°, 16 hr, 50% yield), aqueous hydroxide (30°, 3 hr), alcoholic methylmercaptide (20°, exothermically), alkylamines (20°, 10-60 min, 100%... 

El-Hiti reported an in-depth study of the regioselective Iithiation of numerous substituted quinazolines and subsequent trapping of these nucleophiles with an array of electrophiles <00H1839>. As a representative example, Iithiation of dichloroquinazoline 150 gave rise to further substituted quinazolines 151. 

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>. 

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