Mild, Efficient and Selective Silver Carbonate Mediated O-Alkylation of 4-Hydroxy-2-quinolones: Synthesis of 2,4-Dialkoxyquinolines

Abstract

The reaction of 4-hydroxy-2-quinolones with alkyl iodides, benzyl bromides and allyl bromides in benzene at room temperature, in the presence of Ag 2 CO 3 , afforded 2,4-dialkoxyquinolines in moderate to excellent yields. The process is highly regioselective and constitutes a new and mild one-pot alternative for the preparation of this class of compounds.

Pd-Catalyzed Chemoselective O-Benzylation of Ambident 2-Quinolinone Nucleophiles

“…Ambident nucleophilicity is often encountered in heterocyclic chemistry. − In particular, chemoselective alkylations (O vs N) of ambident 2-pyridones and related heterocycles have been pursued for decades in an effort to incorporate these pharmacophores into biologically active small molecules. − While selective N-alkylations are relatively straightforward and are driven by thermodynamics, methods to kinetically control O-alkylations of these heterocycles remain limited (Scheme ). Most approaches rely on the silver salt method, derived originally from the century-old Koenigs–Knorr reaction to synthesize O-glycosides, developed by Tieckelmann over 50 years ago to selectively O-alkylate heterocyclic ambident heterocyclic anions using stoichiometric amounts of Ag 2 CO 3 .…”

“…Most approaches rely on the silver salt method, derived originally from the century-old Koenigs–Knorr reaction to synthesize O-glycosides, developed by Tieckelmann over 50 years ago to selectively O-alkylate heterocyclic ambident heterocyclic anions using stoichiometric amounts of Ag 2 CO 3 . Since that time, little progress has been made and only sparse reports of methods that obviate the need of Ag-salts for selective O-alkylation, albeit with very limited substrate scope, have appeared in the literature. ,,− More specifically, a general chemoselective O-alkylation of ambident 2-quinolinones without the use of Ag-salts, to the best of our knowledge, is unprecedented. We are aware of a recent report of a proposed Pd-catalyzed O-benzylation of 2-pyridones in the presence of stoichiometric Ag-salts .…”