Developing Modular Syntheses of Diverse Nitrogen Heterocycle-Based Compounds for Metal Complexes, Catalysis, and Therapeutics

The Larsen group develops new methods to synthesize nitrogen-containing molecules, focusing on accessing hindered and aromatic amines using green catalyst systems to convert inexpensive starting materials directly to high-value products. Amines and heteroaromatic compounds permeate the list of top-grossing pharmaceuticals. Developing novel methodologies for the formation of these drug-like molecules streamlines the discovery of treatments for cancer, HIV, malaria, and other maladies, while decreasing environmental impact. In addition to purely organic therapeutics, metal-based treatments to effectively treat ailments, and there continues to be special interest in their ligands, the organic molecules which enable metallic drug delivery. To this end, we have developed solvent- and chromatography-free, catalytic methods that provide a wide range of 2-(2’-pyridyl)quinolines, 2-(2’-pyridyl)triazoles, and 2-(2’-pyridyl)pyrazoles, heteroaromatic ligands that also offer their own intrinsic bioactivity. Our modular methods provide these heteroaromatic compounds with a variety of substituents simply by selecting the appropriate starting materials. Due to the facile construction of an electronically-diverse library, a series of each type of 2-(2’-pyridyl)quinoline (PyQuin), 2-(2’-pyridyl)triazole (PyTri), and 2-(2’-pyridyl)pyrazole (PyPyr) ligands were complexed to different transition metals, including gold, copper, palladium, and platinum. The effect of the ligands’ substituents on the metal complex were tracked by proton NMR spectroscopy and X-ray crystal structure analysis. Ready access to mixed LX-type PyPyr ligands resulted in the discovery of a thoroughly unique 5-coordinate, square-based pyramidal copper(II) complex. Catalytic activity was observed with both palladium(II) and gold(III) complexes of the PyTri ligands. In culmination, PyTri-gold(III) complexes were found to be essential for formation of an unprecedented 1,4-dihydroquinoline product from the hydroamination reaction of aniline and phenylacetylene