Synthesis of Potentially Biologically Active Novel Phenolic Derivatives of Unsymmetrical Ureas from Substituted Phenethylamines

Abstract

Unsymmetrical urea derivatives have been reported to play a significant role in plethora of biological pathways (e.g., neurotransmission, neuromodulation). Notably, urea-based scaffolds are increasingly employed in medicinal chemistry campaigns to engage key protein interactions owing to their tunable physicochemical and structural properties. In this study, we disclose the first examples of unsymmetrical phenethylamine based urea derivatives in aqueous conditions. The reactions involving in-situ generated imidazolide intermediate proceed to completion in the absence of base and under air at room temperature thus allowing access to sensitive functional groups. We also demonstrate a useful product functionalization (i.e., demethylation of 4-methoxyphenethylamine via BBr3) to access the corresponding tyramine analogues. All urea and phenolic derivatives were characterized with H-1 NMR, C-13 NMR, FT-IR, and elemental analysis. Graphic abstract