Synthesis of functionalized a-trifluoroethyl amine scaffolds via Grignard addition to N-aryl hemiaminal ethers†

The design of compounds suitable for drug development is a multi-dimensional process that requires the ne tuning of molecular properties beyond potency. For instance, physical– chemical properties that directly affect hydrolytic stability and bioavailability of the compound must be addressed to avoid side effects in vivo. Due to the excellent pharmacological prole of uorinated drugs, the strategic incorporation of uorine atoms has nowadays become routine in medicinal chemistry development programs. For instance, incorporation of a triuoromethyl substituent adjacent to an amine is a means to improve the metabolic stability and to attenuate the basicity of the compound by shiing its pKa value more towards those of amides. Furthermore the C–CF3 bond is substantially isopolar with the C]O bond and the triuoroethyl amine moiety has a structural similarity to the tetrahedral proteolytic transition state. As a consequence, triuoroethyl amines can be used as versatile hydrolysis-resistant bioisosteres of amides which retain the geometry of the amide bond and, in contrast to other mimetics, also preserve the donating properties of the N–H bond. An illustrative example for the successful replacement of the amide functionality by a triuoroethyl amine is given by Odanacatib, a highly potent drug candidate for the inhibition of Cathepsin K. Various methods for the synthesis of a-triuoromethylated amines have been described so far, including hydrogenation and aromatic substitution of activated imines, as well as base-