SYNTHESIS OF FLUORINATED PHARMACEUTICAL PRECURSORS VIA RADICAL PATHWAYS
Ramon Martinez1, Alyssa Hua1, Jerry Vue2, Ryan Baxter1.
1University of California, Merced, Merced, CA, 2Golden Valley High School, Merced, CA.
Research and development of pharmaceutical precursors have always been integral components in the advancement of organic synthesis, especially with direct α-alkylation of heterocyclic aromatic compounds via metal catalyzed C-H radical reactions which offer a controlled pathway to form these pharmaceutical precursors. Fluorinated natural compounds show outstanding properties including modulating basicity/acidity of parent molecule, lipophilicity, and modulation of metabolic stability. As a result, there has been an increase in the demand for procedures to synthesize these compounds. The process we use to form these compounds is direct α-alkylation through radical species which is carried out in a mechanism similar to Michael addition of nucleophiles and electrophiles where the radical species formed is the nucleophile and the electron deficient aromatic is the electrophile. These reactions are typically metal catalyzed and controlled in order to synthesize desired molecules, but most procedures used today are not viable in large-scale or even small-scale synthesis, because procedures call for inert atmospheric conditions, large molar quantities of substrates, or use of expensive catalysts. In this research, we investigated methods that will allow us to optimize a general procedure that is both viable, efficient, and most of all applicable to many combinations of heterocyclic aromatics and α-proton sources. Our research focuses on using silver nitrate as the catalytic source and on adjustment of reaction variables in order to achieve the optimized procedure. With this generalized α-alkylation procedure, we are synthesizing fluorinated precursors, which usually take multiple steps, in just one concise aqueous step.