Abstract
2-Aminoquinolin-4(1H)-one was reacted with various primary/secondary amines and paraformaldehyde under Mannich reaction conditions. In the case of secondary amines, the reaction in N,N-dimethylformamide yielded expected Mannich products accompanied with 3,3'-methylenebis(2-aminoquinolin-4(1H)-one). Except these main products, the pyrimido[4,5-b]quinolin-5-one derivative was also identified as co-product. The reaction with primary amines led to the formation of pyrimido[4,5-b]quinolin-5-ones. The Mannich reaction products were thermally unstable and afforded a mixture of bis-(2-aminoquinolin-4(1H)-one) and tris-(2-aminoquinolin-4(1H)-one) derivative, probably via reactive methylene species. This retro-Mannich reaction was tested in reaction with indole and thiophenole as nucleophilles, and appropriate conjugates were formed. The mechanism of above discussed reactions in which 2-aminoquinolinone displays the nucleophilicity on C3 carbon as well as N2 nitrogen is discussed.
Highlights
Due to the outstanding position of the quinolin-4(1H)-one scaffold in the field of medicinal chemistry, 2-aminoquinolin-4(1H)-ones have been widely studied as potential pharmacological agents in different areas
We report the results of the study of 2-aminoquinolin-4(1H)-one modification via the Mannich reaction to enlarge the portfolio of synthetic strategies applicable for the preparation of new biologically relevant compounds
The study of the Mannich reaction employing 2-aminoquinolin-4(1H)-one 1 was performed with use of selected primary amines (β-alanine, 1-phenylethanamine, propylamine) and secondary amines (Scheme 1)
Summary
Due to the outstanding position of the quinolin-4(1H)-one scaffold in the field of medicinal chemistry, 2-aminoquinolin-4(1H)-ones have been widely studied as potential pharmacological agents in different areas. The first paper in this field published in 1974 was devoted to the synthesis and evaluation of antimicrobial activity of selected 2-amino-4-alkoxyquinolines. [1] Recently, 3-acetyl-2-aminoquinolin-4(1H)-ones were reported as potent and selective calpain inhibitors. [2] 2-[2-Substituted-3-(3,4-dichlorobenzylamino)propylamino]qui-nolin-4-ones were found to possess antibacterial activity against various strains, mainly Staphylococcus aureus and Enterococci.[3] Derivatives of 2-aminoquinolin-4-ol have been identified as suitable structural motifs for the preparation of novel oligonucleotide conjugates to enhance binding affinities for complementary RNA targets.[4].
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