Regioselective lithiation of chiral 3-acylamino-2-alkylquinazolin-4(3H)- ones: Application in synthesis

Abstract

Reaction of 3-amino-2-alkylquinazolin-4(3H)-ones with several chiral acid chlorides was found to be dependent on the molar proportions. When a 1:1 molar mixture was heated under reflux, the corresponding 3-(diacylamino)- derivatives were obtained in poor yields. However, when a 2:1 molar mixture was reacted in refluxing toluene, the 3-acylamino- derivatives were obtained in good yields based on the acid chloride. Lithiation of the 3-acylamino-2-alkyl-quinazolin- 4(3H)-ones was achieved by the use of lithium diisopropylamide (LDA) in anhydrous THF at -78°C and the reaction was regioselective at the carbon α to position 2 of the quinazolin-4(3H)-one moiety. The dilithio reagents thus obtained reacted with electrophiles to give the corresponding 2-substituted derivatives in very good yields. The NMR spectra of the products show the expected diastereotopism for all the CH2 groups and provide evidence for long-range asymmetric induction.