Efficient Synthesis of Novel Coumarin-3-carboxamides (=2-Oxo-2H-1-benzopyran-3-carboxamides) Containing Lipophilic Spacers

The novel coumarin-3-carboxamides (¼ 2-oxo-2H-1-benzopyran-3-carboxamides) 5a - 5g containing lipophilic spacers were synthesized through the Ugi-four-component reaction (Scheme 1). The reactions of aromatic aldehydes 1, 4,4'-oxybis(benzenamine) or 4,4'-methylenebis(benzenamine) as diamine 2, coumarin-3-carboxylic acid (¼ 2-oxo-2H-benzopyran-3-carboxylic acid; 3), and alkyl isocyanides 4 lead to the desired substituted coumarin-3-carboxamides 5a - 5g at room temperature with high bond-forming efficiency. These novel coumarin derivatives exhibit brilliant fluorescence at 544 nm in CHCl3. Introduction. - Coumarins (¼ 2H-1-benzopyran-2-ones), and their analogs have attracted considerable attention in organic and medicinal chemistry (1). They have wide applications in food, pharmaceutical, and optical chemistry (2 - 4). Natural coumarins and their synthetic structural analogs show broad biological activities (5), such as antimicrobial (6), antitumor (7), and antiviral activities (8). Meanwhile, some coumarin derivatives could affect human immunodeficiency virus integrase inhibitors (9). Some coumarins have inhibitory activity against some serine proteases and matrix metalloproteases (MMPs) (10), and also act as a selective antiproliferative agent (11 - 14). It was shown that the existence of the amide group in coumarin-3-carboxamides (¼ 2-oxo-2H-1-benzopyran-3-carboxamides) improve the biological activity of these compounds (15 - 18). The presence of some nonpolar spacers could affect their ability to penetrate the bloodbrain barrier (19) (20). These compounds showed anti- Helicobacter pylori activity and also inhibition of breast cancer growth. Recently, some novel coumarin-3-carboxamides with effective anticoagulant activity (21) and also inhibitory activity against human monoamine oxidase (MAO) were synthesized (22). In continuation of our research work (23) to design novel one-pot reactions, we wish herein to report an approach to the synthesis of some new amidated coumarins which contain a lipophilic moiety and several amide bonds via the Ugi-four-component reaction (Ugi-4CR). Recently, Che, Yang and co-workers reported sequential Ugi-4CR