Not long ago one of my project teams was expanding substitution on a primary amine to develop the Structure-Property Relationships (SPR) of a molecular series.  For those folks just early enough in your medicinal chemistry education to have learned about acquiring potency data to develop Structure-Activity Relationships (SAR), think of SPR as the same thing where the data collected are measurements of the physical properties (solubility, lipophilicity, membrane permeability, etc.) and metabolic profiles (microsomal stability, plasma protein binding, inhibition of hERG, etc.) of molecules.

As amine-containing drug molecules are absorbed into the body and try to diffuse to the target tissues where they’re needed, the body also busily sets about destroying these xenobiotics (foreign substances) to clear them out.  In drug discovery we try to build molecules that balance these factors to keep the drug substance in circulation long enough to have its desired effect, but without accumulating to the point where it becomes toxic.  Often this means modulating the properties of molecules through synthesis-directed changes to functional groups (among other things) to decrease the rate of its destruction, typically through metabolic processes (among other things, which largely includes direct excretion).

Medicinal chemists know that amine atoms in a molecule are metabolic ‘hot spots’, because their physicochemical properties make them enticing to direct interaction, or influence interaction at sites nearby within a molecule.  Our favorite games to moderate metabolic consequences of any given amine group become substitution of the amine to raise/lower its basicity properties, or to play ‘hide the polarity’ of the nitrogen within the overall framework of the molecule.

For the former ploy, we’ve long ago figured out that the addition of fluorine to an alkyl substituent on an amine can have a major impact on its resulting pK_a, and therefore modify its rate of elimination by metabolism, and often without a major influence on the overall desired potency profile of the molecule.  Similarly, fluoroalkyl substitutions of amines to tune basicity properties are a favorite way to improve PK properties.  For fantastic leading articles on this concept, see William Hagermann’s perspective paper in the Journal of Medicinal Chemistry 2008, 51(15), 4359-4369, the multi-author review in ChemMedChem 2007, 2(8), 1100-1115 and the tutorial review by Gouverneur and coworkers in Chemical Society Reviews 2008, 37(2), 320-330.

The remarkable ‘β-effect’ of fluorination of an alkyl chain on the pK_a of an amine (fluorination of a position two carbon atoms away) can be seen in the measured values of dimethylethylamine, piperidine and propranolol.  As the number of fluorine atoms on the carbon two atoms away from the nitrogen are increased, the basicity of the nitrogen decreases.  In a related way, the lipophilicity of the molecule is also increased based on the values of cLogP (calculated LogP) or LogD (measured values, taken from Upthagrove and Nelson, Drug Metabolism and Disposition 2001, 29(11), 1377-1388).

When our research team decided to prepare a trifluoroethylamine version of our molecule series, I figured that we’d get there by a reductive amination between the amine and trifluoroacetaldehyde, but it turns out that’s not the way to go.  One of my teammates (Nick) pointed out that we’d be likely better off by preparing the trifluoroacetamide, and then using amide reduction chemistry to bring the oxidation state to our desired alkylamine.  Cool idea, and one that I hadn’t ever come across in my time as an organic synthesis chemist!

Since I became interested in this particular transformation, and because we needed to dredge up some literature procedures by way of realistic precedent, I collected a few useful citations generated through a SciFinder search.  The two most-used methods out there for the reduction of the amide to the amine use either lithium aluminum hydride or a borane reagent.  Here are two recent literature examples of the former reducing agent:

Here are a few a recent literature examples of using borane (or diborane, depending on the conditions):

Hopefully you’ll find this useful information—I always find it helpful to have little tricks like this for my medicinal chemist toolbox.  And by the way, if you couldn’t get access to any of these articles, please let me know.