Quinazolinones, halogenation

Dihydroquinazolines are normally stable compounds but they deteriorate on long standing. Some examples are known to oxidize to the corresponding 4(3H)quinazolinones. 3-Methyl-3,4-dihydroquin-azoline is converted to the 4-oxo compound after three recrystallizations from light petroleum. The most remarkable example is 3,4-dihydro-6-fluoro-3(p-fluorophenyl)quinazoline [(44), R = F] which oxidizes at its melting point (137°-I38°C), Other halogenated derivatives of (44) are more stable. ... 

Halogen-lithium exchange has also successfully been performed with 6-bromo-4(3//)-quinazolinone 327, by first using methyllithium to deprotonate the NH group, and then /, r7-butyllithium to give the dilithio species 328 <2004M323>. 

Apart from early reports on the bromination of quinazolinones which gave undefined products, reports dealing with the direct introduction of a halogen into a quinazoline nucleus via the electrophilic reaction are scarce, probably because these derivatives are more easily accessible by cyclization of appropriate halogen-substituted precursors (cf. Section 6.3.1.1.1.). Quinazolin-4(3//)-one can be brominated by bromine in aqueous potassium bromide solution... 

The 5,8-dihydroxy-4(3//)-quinazolinones possess three protons capable of dissociation in aqueous buffer, viz. N3—H and the protons of the 5- and 8-hydroxyl groups (Scheme 107). Initial acid dissociation of the N3 proton does not take place at low pH because electron-rich substituted quinazolin-4(3//)-ones possess pK values greater than 10. The first dissociation is from the 5-hydroxyl which affords an anion (697) which is stabilized by internal hydrogen bonding expressed by pK 7.3 (7.8). Cleavage of the halogen-carbon bond in the 2-substituent in (697) involves a rate-determining reaction of the hydroquinone monoanion and dianion species, since there is an approximate 100-fold difference in rate constants between the precursor 2-chloro (696 X = Cl) and... 

Table 4. SAR Protectant Activity of Halogen-substituted Quinazolinones against Wheat Powdery Mildew ...

The mechanism of quinazolinone formation follows the general pattern of isocyanide-based heterocyclization (cf p. 173) primary intermediate is the 2-lithioquinazolinone 38, which can be trapped with electrophilic reactands (e.g., by hydrolysis, alkylation, halogenation). 

Tani J, Yamada Y, Oine T, Ochiai T, Ishida R, Inoue I (1979) Studies on biologically active halogenated compounds. 1. Synthesis and central nervous system depressant activity of 2-(fluoromethyl)-3-aryl-4(3/f)-quinazolinone derivatives. J Med Chem 22 95-99... 

Our plan as outlined in Scheme 5 was to treat 2,6-dibromopyridine with butyllithium, to quench the mono-anion with DMF (dimethylformamide), and then to do a reductive amination with diethylamine to provide the diethylamine 5. This would be followed by a second metal-halogen exchange and the resultant anion would be trapped with DMF to provide the desired aldehyde 4. This aldehyde would then be condensed with die quinazolinone nucleus 2 under conditions analogous to those developed by our Discovery group. 

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