Analysis of the current top grossing pharmaceuticals finds that a vast number of them contain amines. As a result, the development of methodologies for the formation of amine-containing compounds is of high value and great importance. With the ability to treat: cancer, HIV, malaria, diabetes, and depression, as well as other ailments, increased efforts have been made to optimize the production of these compounds to increase yield while decreasing the environmental impact. This work is ongoing, and is a culmination of the fields of organic synthesis, catalysis, green chemistry, and biochemistry. The work in the Larsen group revolves largely around the use of copper-based catalysis to access hindered amine scaffolds through single-step, multicomponent reactions. Further functionalization of these compounds allows for the synthesis of previously unknown, biologically active, α-amino triazoles. Preparation and analysis of electronically diverse pyridyl triazoles allows for the development of new complexes with platinum and palladium. These pyridyl triazole palladium

complexes are highly reactive under mild aerobic conditions when used in Suzuki-Miyaura cross-coupling reactions. Pyridyl pyrazoles are another class of compounds that show promise in the field of catalysis. Utilization of electronically diverse ligands allows for fine-tuning of the resulting complex for both classes of ligands. With further investigation, this may allow for the discovery of new reactivity in organic transformations.

The Larsen group specializes in maximizing the potential of simple organic substrates through single-step, multicomponent reactions to yield complex compounds with potential therapeutic and synthetic applications. Combining a carbonyl, an amine, and a terminal alkyne under a variety of novel conditions provides a range of propargylamines.

Attempts towards the incorporation of labile protecting groups on propargylamines led to the discovery of the first catalytic three-component method able to incorporate electron-poor amines, specifically p-toluenesulfonamide. Mechanistic studies showed copper(II) triflate to be unique in its ability to catalyze both the condensation of p-toluenesulfonamide onto an aldehyde and sequential coupling with a terminal alkyne. This method also provided a rare example of a three-component coupling between cyclohexanone, benzylamine, and 1-octyne. Investigations into the synthesis of this cyclohexanone-derived propargylamine led to an efficient copper(II) chloride catalyzed reaction yielding fully-substituted centers on cyclohexane rings. Equimolar amounts of starting reagents, low-catalyst loading, and water as the sole by-product of this reaction leant to its efficacy. Inclusion of Lewis acidic titanium tetraethoxide provided a Cu/Ti catalyzed method of novel scope, allowing for the first coupling of acyclic ketones with amines and alkynes to give fully-substituted amine-bearing carbon centers in a single step.

An alternate route to these densely-functionalized substrates was discovered to be a unique tandem hydroamination/alkynylation reaction. Markovnikov addition of an amine across a terminal alkyne yields enamine which, upon tautamerization to ketimine, is coupled with a second equivalent of the same alkyne to form propargylamine.

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.

A variety of unique small molecule families were created through copper-catalyzed three-component couplings. Propargylamines, 1,3-disubstituted allenes, α,β-unsaturated ketones, and 2,4-disubstituted aryl and alkyl quinolines have been studied in the Larsen lab over the past five years.

Electron-rich and electron-poor N-propargylamines were synthesized from pre-formed imines and terminal alkynes utilizing 10 mol% copper(II) triflate in toluene over 2 to 7 days. Electron-poor alkyl aldehyde derived imines were found to tolerate alkynylation, while electron-rich imines resulting from both aryl and alkyl derived aldehydes were alkynylated in yields ranging from 51-83%. Expansion of this work resulted in a copper catalyzed three component reaction of an amine, aldehyde, and alkyne to produce propargylamines in high yields. A wide range of amine sources were used and the process tolerated aryl and alkyl substituted aldehydes without the addition of ligand or base.

Through the Larsen Group research in three component reactions, two secondary amine sources, pyrrolidine, and N-methylaniline were found to act as promoters for the formation of 1,3-disubstituted allenes and α,β-unsaturated ketones respectively.

A third new substrate discovered through the three component synthesis were the 2,4-disustituted quinolines, also catalyzed by a copper source. The Cu(OTf)2 three-component reaction to form 2,4-substituted quinolines from commercially available resources, utilized both aryl and alkyl aldehydes, terminal alkynes, and a variety of aniline sources. The hardy process proceeded under solvent-free conditions in air and gave rapid access to a wide variety of quinolines with therapeutic potential. An in vitro collaboration with UC Riverside Biomedical Sciences demonstrated the Larsen Group's simple 2-alkyl quinolines to have activity against lung cancer line A549, and glioma line GL26.

In addition to the three-component coupling work, the Larsen Group has also made progress in the synthesis of a chiral dipyrrin with potential as a complexing agent and/or ligand. The conjugate addition product of 2.0 equivalents of cinnamaldehyde and p-methoxy aryl dipyrro backbone using MacMillan's first generation amine catalyst was successfully protected with tert-butyl dimethylsilyl chloride then oxidized using p-chloranil resulting in formation of chiral dipyrrin.

The Larsen group focuses on accessing small molecules through one-step multi-component coupling reactions from inexpensive starting materials and a catalyst source. To this end, we have developed a solvent-free catalytic method to access various substituted 2-(2'-pyridyl)quinoline compounds in one step directly from inexpensive and commercially available materials. Purification is simple and is accomplished with the use of a short basic alumina plug and diethyl ether as the eluent. Current published methods to access these targets are plagued with lengthy multi-step reactions, hazardous reagents, and/or the wasteful use of solvents and other materials for purification purposes. In vitro studies of two substituted 2-(2'-pyridyl)quinoline compounds revealed cytotoxic activities in the A549 lung cancer cell line. In addition to the synthesis of various bidentate substituted 2-(2'-pyridyl)quinoline ligands, the neutral 5-coordinate gold(III) complexes of 6-phenyl-2-(2'-pyridyl)quinolines substituted at position 6 of the quinoline ring with fluorine, methyl, methoxy, and phenyl groups were also achieved. The x-ray crystallographic data revealed that the neutral complexes have distorted square pyramidal geometries. Furthermore, the cationic gold(III) complex of a 6-phenyl-2-(2'-pyridyl)quinoline with a methoxy moiety at position 6 of the quinoline ring was also synthesized with a tetrafluoroborate counter anion. The x-ray structure of this cationic complex revealed its distorted square planar geometry.

Alpha-tetrasubstituted amines are found in numerous natural products and drug therapies. Variants are typically accessed through multiple steps: synthesis and isolation of the appropriate ketimine followed by stoichiometric reaction with an organometallic reagent. The first direct three-component coupling of a ketone, amine, and allyl nucleophile proceeds efficiently under green, solvent-free conditions to provide the hindered amine building blocks in a single catalytic step.

The resultant alpha-tetrasubstituted homoallyl amines provide a streamlined synthetic platform for producing a wide variety of structurally complex small molecules, including spirocyclic ring systems. Conditions were developed to allow the terminal olefin of the homoallyl amines to undergo cross-metathesis in the presence of Grubbs’ catalysts. When the free amine of the product is protected via either allylation or acrylation, ring-closing metathesis provides either amine or amide ring systems while only requiring column chromatography for a single step in the sequence.