Convenient Synthesis of More Complex 2-Substituted 4(3H)-Quinazolinones via Lithiation of 2-Alkyl-4(3H)-quinazolinones

Abstract

2-Methylquinazolin-4(3H)-one has been doubly lithiated, at nitrogen and in the 2-methyl group, with n-butylithium. The lithium reagent thus obtained reacts with a variety of electrophiles (iodomethane, D 2 O, phenyl isocyanate, benzaldehyde, benzophenone, cyclopentanone, 2-butanone, carvone) to give the corresponding 2-substituted derivatives in very good yields. Reaction of the dilithio reagent with acetonitrile gives an α,β-unsaturated imine by tautomerization of the initial addition product. Double lithiation of 2-ethyl-and 2-propyl-4(3H)-quinazolinones can be achieved using lithium diisopropylamide and the lithiated reagents thus obtained react with similar electrophiles to give the corresponding products in very good yields. In the reaction of the dianion of the 2-ethyl-4(3H)-quinazolinone with iodine, an oxidatively dimerised product was obtained. Lithiation of 2-unsubstituted 4(3H)-quinazolinone does not take place on C-2 under similar conditions. The rapid expansion of the list of functionalities capable of directing metalation 1 has made this an important strategy for the synthesis of regiospecifically substituted benzenes and heterocycles, but there are relatively few reports concerning the metalation of pyrimidine compounds 2-13 . In a continuation of our own interests in heterocyclic chemistry 14 , particularly in the use of directed lithiation for heterocyclic synthesis 15 , we have recently shown the lithiation of 3-acylamino-, 3-amino-and 3-methylamino-2-alkyl-4(3H)-quinazolinones 16-18 . Lithiation of 3-unsubstituted

Reactions of organolithium reagents with quinazoline derivatives

“…[143][144][145] Reactions of 222 with various electrophiles gave the corresponding 2-substituted derivatives 223-252 (Scheme 28) in good yields (Tables 15 and 16). 143 Yield of isolated product after crystallization. Yield of isolated product after crystallization.…”

“…Instead of 2-iodo derivative being formed oxidative dimerization took place to give 2,2 -(2,3-butanediyl)bis-3H-quinazolin-4-one 254 in 60% yield (Scheme 30) after purification. 143 Scheme 30. Synthesis of 2,2 -(2,3-butanediyl)bis-3H-quinazolin-4-one 254.…”

“…[143][144][145] Lithiation was regioselective at the carbon to the 2-position of the 3H-quinazolin-4-one moiety to give the dilithium reagents 222 (Scheme 28). [143][144][145] Reactions of 222 with various electrophiles gave the corresponding 2-substituted derivatives 223-252 (Scheme 28) in good yields (Tables 15 and 16). 143 Yield of isolated product after crystallization.…”

Synthesis of Substituted Quinazolin-4(3H)-ones and Quinazolines via Directed Lithiation

“…32,33 As part of our containing interest in quinazolin-4(3H)-ones chemistry [34][35][36][37][38][39] and in lithiation chemistry, [40][41][42][43] we have shown that quinazolin-4(3H)-ones undergo double lithiation by use of n-BuLi or LDA in THF at -78 °C. [44][45][46][47] The organolithiums thus obtained in such lithiation reactions are very useful intermediates for the synthesis of more complex substituted quinazolin-4(3H)-ones. [44][45][46][47] In the last few years lithiation of quinazolin-4(3H)-ones becomes the topic for some researchers which provide a simple and efficient method for the production of substituted derivatives which might have high pharmacological activities and difficult to be prepared by other means.…”

“…[44][45][46][47] The organolithiums thus obtained in such lithiation reactions are very useful intermediates for the synthesis of more complex substituted quinazolin-4(3H)-ones. [44][45][46][47] In the last few years lithiation of quinazolin-4(3H)-ones becomes the topic for some researchers which provide a simple and efficient method for the production of substituted derivatives which might have high pharmacological activities and difficult to be prepared by other means. This review will concentrate on the work published in this area, particularly on directed lithiation of various quinazoline derivatives, quinazolin-4(3H)-ones, 3-arylquinazolin-4(3H)-ones, 3-acylaminoquinazolin-4(3H)-ones, 2-alkylquinazolin-4(3H)-ones, 3-substituted 2-methylquinazolin-4(3H)-ones, 2-alkyl-3-aminoquinazolin-4(3H)-ones, 2-alkyl-3-methylaminoquinazolin-4(3H)-ones as well as directed lithiation of 3-acylamino-2-alkylquinazolin-4(3H)-ones.…”