Ruthenium-Catalyzed Amine Alkylation with Alcohols Via the Borrowing Hydrogen Methodology: Scope, Mechanism, and Application

Abstract

Amine alkylation reactions for the formation of C-N bonds are important in the fields of organic and biochemistry. Typical alkylation reactions require the use of stoichiometric amounts of toxic alkyl halide compounds or the use of stoichiometric amounts of strong reducing agents through reductive amination. Transition metal-catalyzed alkylation using alcohols, via the borrowing hydrogen methodology, is an attractive alternative since water is the only byproduct of this reaction. No ruthenium catalyst, to the best of our knowledge has been used below 100°C.

The second chapter of this work involved the development of a ruthenium catalyst for amine alkylation reactions under mild conditions. Using simple amino amide ligands, and the alcohol as the solvent, the first ruthenium-catalyzed amine alkylation with alcohols at 65°C for anilines, 45°C for primary aliphatic amines and 55°C for secondary aliphatic amines was successfully developed. Alkylation of secondary amines was also done for the first time at room temperature with higher catalyst loading. Catalysis using stoichiometric amounts of alcohol at 110°C was also successful.

Typical heterogeneous metal-catalyzed reactions are carried out at high temperatures with the lowest reported heterogeneous ruthenium-catalyzed reaction being at 120°C. The third chapter involves immobilization of the homogeneous catalyst and its application towards amine alkylation with alcohols. Application of the solvent alcohol methodology proved successful for the alkylation of secondary aliphatic amines and this represented the first heterogeneous metal-catalyzed amine alkylation with alcohols at 55°C. Reactions using stoichiometric alcohol at 110°C were also successful, providing an improvement to current average reaction temperatures.

The third chapter shows the successful application of ESI-MS to elucidate the reaction mechanism and the true nature of the catalyst during reaction. For the solvent alcohol reactions, the dominant catalyst species remains the piano stool structure and the mechanism follows the typical outer sphere transfer hydrogenation oxidation of the alcohol, in-situ condensation of the amine and aldehyde followed by outer sphere reduction of imine.

Finally, the application of the reaction methodologies developed above towards the practical synthesis of relevant piperazine-based pharmaceuticals was shown. The successful synthesis of piribedil and cyclizine amongst others was achieved in high yields.