High Throughput Experimentation as a Tool to Guide the Microwave Assisted Catalytic Amidation of Aryl Amines with Aryl Acids

Abstract

The formation of amides is one of the most essential transformations in the pharmaceutical industry, but most synthetic procedures include the use of stoichiometric poor atom economy reagents. These limitations are often compounded when condensing aryl amines with aryl acids due to their inherently low reactivity. To overcome such hurdles, we utilized high throughput experimentation to screen 640 different reaction conditions to find a suitable catalyst and solvent for benzamide formation. Based on those initial findings, we developed an efficient catalytic transformation of aryl amines with aryl acids into N-arylbenzamides using a 15 mol % loading of 2,4-bis(trifluoromethyl) phenyl boronic acid and trimethylamine N-oxide in 2-MeTHF under microwave conditions for 1 h in the presence of 3 Å molecular sieves. Our method shows that even sterically hindered amines and carboxylic acids can be converted to the corresponding N-arylbenzamides, including previously reported unreactive aromatic and secondary amines, in good to excellent yields. This approach follows the principles of green chemistry through use of[1] catalysis to improve atom economy,[2] a biorenewable solvent (2-MeTHF),[3] high substrate loadings (0.5 M), and[4] energy efficient microwave heating.