Quinazoline-3-oxides, rearrangement

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. ... 

Another dihydro derivative has been described in connection with medicinal chemical studies. Thus, reaction of 2-(chloromethyl)quinazoline-3-oxide (3) with hydrazine gives hydr-oxytriazocinamine 4 (and not a diazepine derivative as originally assigned), vigorous acetylation of which results in a rearrangement to give oxazolotriazocine 5.10... 

Treatment of quinazoline 3-oxide with amines gives the rearrangement product, 1,4-benzodiazepine. 

The photoisomerizations of quinoxaline 1-oxides (533) give the 3,1,5-benzoxadiazepines (534) (67TL1873,68ACS877). The photoisomerization of quinazoline 3-oxides (535 R = H or Me) leads, by the rearrangement shown, to the isolable 1,3,5-benzoxadiazepines (536). 

Some oxidations of heterocyclcs with two heteroatoms proceed very readily. Thus, fluorinated quinazoline is oxidized to quinazol-4-one on fusing for only 2 minutes (Table 16).264 On the other hand, more vigorous oxidation of 5-fluoro-l,3-dimethyluracil by 3-chloroperoxybenzoic acid leads to the formation of unstable intermediate radicals that tend to rearrange to 4-hy-droxy-l,3-dimethylimidazoledione 3-chlorobenzoate (Table 16), similar177 to the chemical behavior of trifluoromethylated phenol.265... 

Although the reaction of 2-chloromethyl-4-phenylquinazoline-3-oxides with primary amines led to a rearrangement to diazepines, the reaction with secondary amines has been reported to give only the normal quinazoline product.204 It has now been observed, however,... 

Whereas the reaction of small primary amines with 2-(chloromethyl)quinazoline 3-oxides 1 leads to ring-enlarging rearrangement to 1,4-benzodiazepines (cf. p 159), weak primary amines.secondary amines, hydroxylamine, thiolates, " thiocyanate. cyanide, and the carbanions of nitroethane and nitropropane lead only to products 2 derived from substitution of the halogen. In a few cases, also in the reaction of 2-(chloro-methyl)quinazoline 3-oxides with methylamine, the unrearranged 2-[(methylamino)methyl]-quinazoline 3-oxide products are isolated. " ... 

Sternbach and coworkers pointed out that the reactions of the 6-chloro-2-chloromethyl-l,2-dihydro-4-phenylquinazoline 3-oxides 11 with a base gives either the 1,3-dihydro-2//-azirino[ 1,2-fl]quinazoline 4-oxides 13 or the 3H-1,4-benzodiazepine 4-oxide 15. In the first step of the reaction the anion 12 is formed by abstraction of a proton from the 1-nitrogen. The intermediate anion 12 can rearrange to the ring-chain tautomer 14. The relative stabilities of the two anions 12 and 14 are assumed to determine whether product 13 or 15 is formed. Thus when R is hydrogen or chloromethyl, the anion 12 is relatively sufficiently stable to allow the formation of the azirino-quinazoline 13. If, however, R is the electron-releasing methyl group, the anion 12 is destabilized and is converted to anion 14, which leads to benzodiazepine 15. The solvent polarity also influences the stability of the anions 12 and 14. In a nonpolar solvent (ether), the 5//-benzodiazepine 16 (R = Me) was obtained, which can be derived from anion 12 (R = Me) via the azirinoquinazoline 13 (R = Me). In a polar solvent (aqueous ethanol), however, the 3H-benzodiazepine 15 derived from anion 14 (R = Me) was the major product. As bases, potassium /er/-butoxide and sodium hydride were used. ... 

For molecular rearrangements involving quinazoline iV-oxide, see Section VII. 

Several examples are known of the ring-expansion reactions that transform isatins into quinazolines. iV-Carbamoyl isatins rearrange in the presence of amines into derivatives of 4-carboxy-4-hydroxy-3,4-dihydroquinazolin-2(lH)-ones, and iV-carbamoyl-3-(dicyano)methylene oxindoles provided 4-(dicyano)methylene-3,4-dihydroquinazolin-2(l//)-ones. The two isomeric A-oxides 102 and 103 underwent ring expansion on photolysis and produced the same 1,3-disubstituted quinazoline-2,4-diones (104) among other products, which include isatins. The ratio of products was sensitive... 

The oximes of aminoaldehydes yield the N-3 oxides of (fused) pyrimidines. Thus, several methoxy derivatives of trans-2-aminobenzaldoximes, heated at 140°C in triethyl orthoformate, gave good yields of the corresponding methoxy derivatives of quinazoline 3-oxide (88). Ultraviolet light rearranged these products to quinazolin-4-ones. (The cis forms of these aldehydes produced only benzoxadiazepines.) The same aldehydes, heated in decalin with... 

The base-induced rearrangement of the 1,3-dipolar cycloadducts of 2,5-di-f-butyl-/ -benzoquinone with 2,6-dichlorobenzonitrile oxide has been shown to afford isoxazole-fused / -quinol derivatives (250) by way of the pathway outlined in Scheme 64. Reduction of 2,4-dihydro-l//-pyrazino[2,l-fc]quinazoline-3,6-diones (251) with sodium borohydride has been reported to yield 11,1 la-dihydro derivatives... 

Compounds in which other heterocyclic rings (pyrazoles, isoxazoles, imidazoles ) are fused to thiopyrans have been described. The interesting thiazolium salts (56) were prepared by allowing the betaines (55) to react with 4-thioxothiazolidin-2-ones. Application of the Fischer indole synthesis and the Friedlander reaction to tetrahydrothiopyran-3-one led to the exported indolo-and quinolino-derivatives. Ring closure of (57) under acidic conditions afforded the rearranged product (58). Syntheses of benzothiopyrano[4,3,2-flfe]-quinazolines (59) from 1-amino-thioxanthones and of their S- and 7V-oxides have been described. ... 

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