Direct N-Alkylation of Amines with Alcohols

In recent years there have been a number of groups publish on the direct alkylation of amines using alcohols using a range of transition metal catalysts (eg Ru, Cu, Ir).  The mechanism for these reactions is generally that of the ‘borrowing hydrogen’ type wherein the alcohol is oxidised, there is imine formation and the supposedly generated metal hydride delivers the hydrogen back to reduce the imine.  Undoubtedly this is a powerful tool for the synthetic chemist, but there are some functional group incompatibilities (eg alkenes may undergo competitive reduction).  Sato et al have published an iron (III) mediated reaction wherein the mechanism does not involve these redox steps and therefore should have wider applicability (Angew Chem Int Ed, 2011, 50, (13), 3006).

The group report 28 examples using various anilines with a range of alcohols (benzylic, allylic, primary alkyl, secondary alkyl) giving yields in the range of 64-92% for the isolated products.  An example is presented below.

The group conducted some studies using deuterated substrates and concluded the mechanism does not involve redox cycles (no deuterium exchange was observed) but involves an SN2 mechanism.

The paper also reports that selective mono- or dialkylation can be achieved using appropriate ratios of reactants.