Synthesis of Flufenamic Acid: An Organic Chemistry Lab Sequence Using Boronic Acids and Nitrosoarenes under Transition-Metal-Free Conditions

• Published in: Journal of chemical education Vol. 96; no. 8; pp. 1738 - 1744
• Main Authors: Roscales, Silvia, Csákÿ, Aurelio G
• Format: Journal Article
• Language: English
• Published: Easton American Chemical Society and Division of Chemical Education, Inc 13.08.2019; Division of Chemical Education, Inc; American Chemical Society
• Subjects: Acids; Amines; Amino acids; Chemical synthesis; Chemistry; Chromatography; Column chromatography; Columnar structure; Cooperative Learning; Coupling; Laboratory Experiments; Melting point; Melting points; Metals; NMR spectroscopy; Organic Chemistry; Oxidation; Percolation; Pharmacy; Potassium; Science Instruction; Spectrometry; Spectroscopy; Students; Thin layer chromatography; Transition metals; Undergraduate Students; Upper-Division Undergraduate; Collaborative/Cooperative Learning; Drugs/Pharmaceuticals; Nonmetals; Aromatic Compounds; Organic Chemistry
• ISSN: 0021-9584; 1938-1328
• DOI: 10.1021/acs.jchemed.8b00824

A method for the synthesis of flufenamic acid, a nonstereoidal anti-inflammatory drug (NSAID) of the anthranilate family (fenams), is described as an experiment for the upper-division undergraduate organic chemistry laboratory. The key step is the formation of the diarylamine moiety of flufenamic acid by a novel reaction consisting of the coupling of nitrosobenzenes with boronic acids under transition-metal-free conditions. On the one hand, students can compare the performance of two different methods for the preparation of nitrosobenzenes (oxidation of amines and ipso-SEAr reaction on potassium organotrifluoroborates). On the other hand, they compare the yields of two complementary examples for the coupling of nitrosobenzenes with boronic acids. The reactions are followed by thin layer chromatography, and the products are purified by percolation or by column chromatography. Students are also tasked with the confirmation of the structure of the products based on melting point, infrared, 1H NMR, 13C NMR, and 19F NMR spectroscopy, and MS spectrometry.