UC Riverside

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.