Direct Synthesis of 8‐Fluorocaffeine and Its Transformation to 8‐Substituted Caffeine

Abstract

AbstractCaffeine is a naturally occurring central nervous system (CNS) stimulant found in many drinks and foods. Many interesting biological activities of caffeine, and some of its derivatives, have been reported. Therefore, this study aims to conduct chemical transformations of caffeine. The method used is direct fluorination of caffeine using Selectfluor® in acetonitrile at room temperature, followed by purification to obtain 8‐fluorocaffeine. This reaction can be done on a multigram scale. Subsequently, 8‐fluorocaffeine was further modified by a nucleophilic substitution reaction with amines and alcohols as the nucleophiles under reflux conditions in an appropriate solvent to form fifteen 8‐substituted caffeine derivatives, with yields ranging from moderate to high. Of these derivatives, four are novel compounds, which are 8‐(3‐chloro‐4‐fluorophenyl)aminocaffeine, 8‐(3‐aminophenyl)amino‐caffeine, 8‐(azetidin‐1‐yl)‐caffeine, and 8‐(tetrahydrofuran‐3‐yl)oxycaffeine.