Facile Amidation of Non-Protected Hydroxycinnamic Acids for the Synthesis of Natural Phenol Amides

Abstract

Phenol amides are bioactive compounds naturally present in many plants. This class of compounds is known for antioxidant, anti-inflammatory, and anticancer activities. To better understand the reactivity and structure–bioactivity relationships of phenol amides, a large set of structurally diverse pure compounds are needed, however purification from plants is inefficient and laborious. Existing syntheses require multiple steps, including protection of functional groups and are generally overly complicated and only suitable for specific combinations of hydroxycinnamic acid and amine. Thus, to facilitate further studies on these promising compounds, we aimed to develop a facile general synthetic route to obtain phenol amides with a wide structural diversity. The result is a protocol for straightforward one-pot synthesis of phenol amides at room temperature within 25 h using equimolar amounts of N,N′-dicyclohexylcarbodiimide (DCC), amine, hydroxycinnamic acid, and sodium bicarbonate in aqueous acetone. Eight structurally diverse phenol amides were synthesized and fully chemically characterized. The facile synthetic route described in this work is suitable for a wide variety of biologically relevant phenol amides, consisting of different hydroxycinnamic acid subunits (coumaric acid, ferulic acid, and sinapic acid) and amine subunits (agmatine, anthranilic acid, putrescine, serotonin, tyramine, and tryptamine) with yields ranging between 14% and 24%.

Comment on “Three New Dimers and Two Monomers of Phenolic Amides from the Fruits of Lycium barbarum and Their Antioxidant Activities”

“…Additionally, the 2D NMR spectroscopic data contained correlations that are typical for the 4- O -8′-linkage and that are also reported for other neolignanamides with the same linkage type, e.g., 4- O -8′-linked feruloylagmatine, corydalisin A and B, and melongenamide C . Furthermore, all of the proton signals that would be expected for an unsubstituted FerTrm unit , were detected. This indicates that none of its carbon atoms are involved in the linkage for one of the FerTrm moieties, as this would have resulted in the loss of at least one proton signal.…”

Biomimetic Enzymatic Oxidative Coupling of Barley Phenolamides: Hydroxycinnamoylagmatines

“…p -Coumaroylagmatine (CouAgm), feruloylagmatine (FerAgm), and sinapoylagmatine (SinAgm) were synthesized according to the protocol described by van Zadelhoff et al In short, equimolar amounts of the individual hydroxycinnamic acids and N , N ′-dicyclohexylcarbodiimide­(DCC) in acetone were stirred for 1 h at room temperature in the dark. After 1 h, an equimolar amount of agmatine sulfate and sodium bicarbonate dissolved in water in a volume equal to the acetone was added.…”

Sustainable Chemical Derivatization of Hydroxycinnamic Acids

“…However, despite the long reaction times, the reported yields are relatively modest. [27] In additional experiments, sodium azide in water was added to the acetone solution containing the O-protected mixed anhydride 2. The corresponding acyl azide 5 a was obtained from ferulic acid in 79 % yield.…”