A Catalytic Tethering Strategy: Simple Aldehydes Catalyze Intermolecular Alkene Hydroaminations

Melissa J. MacDonald, Derek J. Schipper, Peter J. Ng, Joseph Moran and Andre M. Beauchemin J. Am. Chem. Soc.

Broadly speaking, synthetic catalysis operates by activating a reacting partner by lowering the LUMO in electrophiles or (less commonly) raising the HOMO in nucleophiles in order to reduce the energy of activation required for reaction. Recent advances in catalysis have developed systems for activating both reaction partners.

However, as well as substrate activation, catalysts often perform another crucial role in reaction pathways: substrate preorganisation. Asymmetric catalysis relies heavily on the ability of the catalyst to organise at least one of the reacting partners into a specific conformation. And proximity effects allow for highly chemoselective transformations, used heavily in C-H activation techniques.

While it is common for a catalyst system to carry out substrate activation without any degree of substrate preorganisation, there are hardly any reported systems where a catalyst brings substrates together without activating either species for reaction.

Beauchemin reports conditions for carrying out hydroaminations with hydroxy amines (reverse Cope elimination) using an aldehyde as catalyst to bring the two reaction partners together temporarily. The technique relies on the reversible formation of a mixed aminal intermediate where hydroamination can take place in an intramolecular fashion.

Their studies found that benzyloxyacetaldehyde works efficiently as catalyst in 20 mol% loading, and a series of diamines were prepared. The authors also show that chiral aldehydes can induce asymmetry in the reaction.

The concept of temporary intramolecularity may be applicable to other reactions, but a complex balance of kinetics involving the equilibria between iminiums, all possible aminals and the relative rates of reaction, both inter- and intramolecularly, needs to be achieved in any prospective system.

DOI: 10.1021/ja208867g


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