Improved Chemical Synthesis of Avenanthramides Family and its Analogs by Mixed Anhydride Method

Abstract

Amides derived from common hydroxycinnamic acids—including 4-hydroxycinnamic acid, 3-methoxy-4-hydroxycinnamic acid, 3,4-dihydroxycinnamic acid, 3,4-dimethoxycinnamic acid, and 3,4,5-trimethoxycinnamic acid—along with various free aminobenzoic acids, such as 5-hydroxy-2-aminobenzoic acid, a key component of the avenanthramide family, have been rapidly synthesized using an innovative, environmentally friendly synthetic methodology. This approach, grounded in traditional chemistry, utilizes mixed anhydrides to simultaneously protect and activate hydroxycinnamic acids through the actions of triethylamine and isobutyl chloroformate while employing acetone as a green solvent. The resulting amides, formed from the coupling with free aromatic amino acids, are constructed as O-carbonate-protected derivatives with high yields and purity, isolated directly via crystallization, thus eliminating chromatographic or HPLC purifications. Furthermore, free phenols can be conveniently released on demand using morpholine in methanol. Under these conditions, C-protected aromatic amino acids remain unacylated. This synthetic strategy represents a significant advancement over conventional acyl chloride methodologies, which often rely on toxic reagents and solvents and entail time-consuming and complex procedures. It enhances the production of important phytochemicals such as avenanthramides and opens doors to various analogs, paving the way for potential pharmacological applications.