Multi-Component Copper Catalyzed Methods to Access Highly-Substituted Amine-Bearing Carbon Centers from Simple Starting Materials
- Author(s): Pierce, Conor John
- Advisor(s): Larsen, Catharine H.
- et al.
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.