Synthetic and mechanistic investigations of iridium-catalysed imine hydrogenation

Chiral amines occur as structural elements in many biologically active natural and unnatural products. In addition, they find applications as chiral auxiliaries, catalysts, and resolving agents. Consequently, the asymmetric hydrogenation of imines has received much attention as a direct, atom-economical route to optically active amines. The Pfaltz group has developed chiral iridium catalysts enabling the reduction of imines, bearing at least one aryl substituent, in excellent enantioselectivities (up to 96% ee). However, purely aliphatic imines gave only low conversions and enantioselectivities. Therefore, the development of an efficient protocol for the hydrogenation of purely aliphatic imines remained of great interest. The goal of this doctoral thesis was to continue the studies initiated by Dr. Fabiola Barrios to gain a better understanding of the reaction course in imine hydrogenation as well as to develop an efficient protocol for the iridium-catalysed asymmetric hydrogenation of aliphatic imines. The mechanistic studies on iridium catalysed imine hydrogenation commenced by Dr. Fabiola Barrios were continued towards the development of an efficient hydrogenation protocol for purely aliphatic imines. Chapter 2 summarizes the previous results where new iridium(III) complexes, formed under the reaction conditions, were observed and characterized. These iridacycles bear a cyclometalated imine and were used as catalysts, showing virtually identical enantioselectivity and similar conversion as the iridium(I) complexes initially used as catalysts for imine and olefin hydrogenation. Furthermore, these in situ formed iridacycles demonstrated superior reactivity in the hydrogenation of dialkyl imines compared to their corresponding iridium(I) complexes. In-depth understanding of the reaction course was obtained with extended mechanistic investigations outlined in chapter 3. Cyclometalation of a chiral imine to an achiral iridium complex generated a chiral catalyst was formed. The structure of the cyclometalated imine was demonstrated to influence the enantioselectivity of the catalyst as well as to be involved in the enantiodiscriminating step of the hydrogenation. Furthermore, the iridacycle remained stable throughout the reaction as no dissociation of the cyclometalated imine was observed. While acyclic chiral imines as cyclometalating ligands gave only low ee’s, cyclic ligand structures with a C-N double bond such as benzoxazines gave consistently higher ee’s. The iridacycles were investigated in further detail by two-dimensional NMR studies and their preparation was improved by counterion metathesis. Deuterium labelling experiments depicted addition of hydrogen along the C-N double bond. Nevertheless, multiple isomerisation and scrambling processes were detected as well. Imine-enamine tautomerism occurs under hydrogenation conditions but hydrogenation proceeding via the enamine tautomer was excluded with imine substrates preventing tautomerism. Chiral phosphoric acids were evaluated as additives but resulted in low reactivity as well as imine hydrolysis. Chapter 4 summarizes the synthetic efforts for the synthesis of the different ligands with a C-N double bond employed in cyclometalation. Three different ligand scaffolds were prepared. Chapter 5 presents the optimisation studies for an efficient asymmetric hydrogenation protocol for purely aliphatic imines. Identification of the optimal imine additive used as a cyclometalating ligand led to the sterically demanding 2,6-dimethyl aniline derived imine. Furthermore, hydrogenations could be conducted at -5 °C achieving full conversion and improving enantioselectivity up to 92%. Cyclic aliphatic imines could also be hydrogenated with these iridacycles, but required elevated reaction temperatures as well as hydrogen pressures to achieve turnover and displayed low conversions and enantioselectivities. These studies concluded that iridium-catalysed imine hydrogenation is commenced by cyclometalation of the imine substrate to form an active iridium(III) catalyst prior to hydrogenation. If the imine substrate subjected to hydrogenation cannot undergo cyclometalation, low conversions and enantioselectivities as well as competitive hydrolysis are observed, as other catalytically active complexes are formed in solution. Therefore, acetophenone-derived imines can be used as additives to improve both reactivity and enantioselectivity of iridium catalysts for the hydrogenation of dialkyl imines generating a superior catalyst in situ.