Synthesis of Cycloheptylcinnamamide by Shiina Esterification

Cinnamamide (3-phenylacrilamide or cinnamic acid amide) is a cinnamic acid derivative present in various natural products such as fagaramide, piperine, antiepilepsirine, cinromide, etc. Cinnamamide and its derivatives demonstrate a wide spectrum of biological activities i.e. anti-microbial, anti-fungal, anti-tubercular, anti-inflammatory, and anti-cancer, antimalarial, antiviral, anti-diabetic, anticonvulsant, antidepressant. Cinnamamides are generally generated from cinnamic acid and the corresponding amines in the presence of thionyl chloride, phosphoryl chloride, (1-ethyl-3(3-dimethylaminopropyl)carbodiimide (EDC) or N,N'-Dicyclohexylcarbodiimide (DCC). However, these chemicals are dangerous, toxic, explosive, and some of them are categorized as third-class chemicals in the chemical weapons conventions. In this study, the Shiina esterification by using 4-dimethylaminopyridine (DMAP) and 2-methyl-6-nitrobenzoate anhydrate (MNBA) was utilized for the synthesis of cycloheptylcinnamamide. The reaction of cinnamic acid with activated acyl carboxylate MNBA produced the corresponding mixed anhydride (MA). The reactivation of MA by nucleophilic catalyst followed by the attack of amino group in N-cycloheptylamine to the host molecule gave cycloheptylcinnamamide. The structure of the product was confirmed by spectroscopic analysis (IR, NMR, MS). The reaction was succeeded and cycloheptylcinnamamide was resulted in 92% yield as white solid.