Abstract
3-Aminomethylation of salicylalkylamides afforded hybrids with a Mannich base. In addition, it triggered the rotation of the amide bond. The observed conformational switch is driven by strong intramolecular hydrogen bonding between the Mannich base and phenolic group. Crystal structure analysis reveals the stabilization of the hybrid molecules by double hydrogen bonding of the phenolic OH, which acts as an acceptor and donor simultaneously. The molecules contain an amide site and a Mannich base site in an orthogonal spatial arrangement. The intramolecular hydrogen bonds are persistent in a nonpolar solvent (e.g., chloroform). The conformational change can be reversed upon protection or protonation of the Mannich base nitrogen.
Highlights
Salicylic acid amides are privileged scaffolds in medicinal chemistry
Synthesis of hybrids composed of salicylamide and a Mannich base started with aminomethylation of 2-hydroxy-N-(3-methyl-butyl)-benzamide (1) (Scheme 1; the isopentyl residue was chosen to mimic an isoprene moiety)
Salicylalkylamides undergo a conformational switch from the α- to the β-form upon aminomethylation in the 3-position
Summary
Salicylic acid amides are privileged scaffolds in medicinal chemistry. Pharmacological activities have been reported for numerous N-aryl (anilides) and N-alkyl salicylamides in the fields of antimicrobials [1,2,3,4,5,6,7,8,9,10,11,12], antivirals [13,14,15,16,17], anthelmintics [18,19], antimalarials [20,21,22,23], antimycotics [24], molluscicides [25,26], as well as target-specific interactions [27,28,29,30,31,32,33]. The conformations of salicylamides in solution and in the solid state are controlled by inter- and intramolecular networks of different types of hydrogen bonding. Control over the conformations of the salicylamide scaffold is of great value in medicinal chemistry. In this contribution, we report triggering the conformation of salicylalkylamides by intramolecular competition for hydrogen bonding
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