Quinazoline 3-oxide, 2-chloromethyl-, ring

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... 

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. ... 

Chlordiazepoxide is prepared by the reaction scheme shown in Figure 6. 6-chloro-2-chloromethyl-4-phenyl-quinazoline 3-oxide is reacted with methylamine which presumably attacks the quinazoline at the 2 position. The nucleophilic attack is followed by enlargement of the ring to yield the 7-chloro-2-(methylamino)-5-phenyl-3H-l,4-benzodiazepine 4-oxide13. A complete review of the chemistry of benzodiazepines presents alternative pathways14. 

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