Addition of alkyllithiums to 3H-quinazoline-4-thione and various substituted quinazoline derivatives; application in synthesis

Abstract

Reaction of 3H-quinazoline-4-thione (1) with two mole equivalents of an alkyllithium (t-BuLi, n-BuLi or MeLi) at -78 C in dry THF gave the corresponding 2-alkyl-1,2-dihydro-3H-quinazoline-4-thione (4, 5 or 6) in high yield. Similarly, reactions of 4-(methylthio)quinazoline (7), 4-(ethylthio)quinazoline (8) and 4-methoxyquinazoline (9) with alkyllithiums (one mole equivalent) gave the corresponding 4-substitued 2-alkyl-1,2-dihydroquinazolines 11-18. On the other hand, blocking position 2 with a phenyl group in 4-(methylthio)-2-phenylquinazoline (20) and 4-methoxy-2-phenylquinazoline (21) resulted in reaction with two mole equivalents of alkyllithiums to give 4,4-dialkyl-2-phenyl-3,4-dihydroquinazolines 22-24.

Reactions of organolithium reagents with quinazoline derivatives

“…149 The authors suggested that the reason for this difference could be due to the thiolate anion in 344 being less effective at donating negative charge to the ring than its oxygen counterpart. The acquisition of negative charge by the ring would be expected to deactivate the ring towards nucleophilic attack by alkyllithiums.…”

“…149 Compound 358 was the very product that might have been expected from the reaction of 3H-quinazolin-4-one with t-BuLi, but, of course, this direct reaction of 3H-quinazolin-4-one with t-BuLi did not occur. 149 Compound 358 was obtained due to nucleophilic addition of t-BuLi at the 2-position of 105 followed by a C=O formation at the 4-position. Yield of isolated product after column chromatography.…”

“…149 Lithiation of 348 with LDA under similar reaction conditions was not successful. 149 Scheme 42. Addition of alkyllithiums to 4-substituted quinazolines 105 and 348.…”

“…The acquisition of negative charge by the ring would be expected to deactivate the ring towards nucleophilic attack by alkyllithiums. 149 …”

“…121,[149][150][151] For example, reactions of 4-substituted quinazolines 105 and 348 with 1.2 molar equivalents of alkyllithiums took place smoothly and cleanly at -78 C in anhydrous THF for 1 h. 149 The lithium reagent reagents 349 were presumably obtained as intermediates and after quenching with aqueous ammonium chloride solution gave the corresponding 4-substituted 2-alkyl-1,2-dihydroquinazolines 350-357 (Scheme 42) in high yields (Table 22). 149 Lithiation of 348 with LDA under similar reaction conditions was not successful. 149 Scheme 42.…”