Enantioselective reductive amination with ammonia and hydrogen

keywords: enantioselective catalysis, reductive amination, atom economy

This week's post describes the enantioselective synthesis of branched primary amines by reductive amination, without isolation of an imine intermediate.  Most of the reductive amination examples described in Chapter 14 of "Finding the Right Partner" (Vol. 1) involve pre-formed imines, requiring a separate step in the condensation of a primary amine with a ketone.  Moreover, the nitrogen reactant is simply ammonia, which offers the advantage of not requiring a deprotection step if the primary amine is desired.  The lead communication is authored by a collaboration led by Thomas Schaub "Direct Asymmetric Ruthenium-Catalyzed Reductive Amination of Alkyl-Aryl Ketones with Ammonia and Hydrogen" (Gallardo-Donaire et al. 2017 ASAP).  This development builds on earlier work on the atom-economical synthesis of primary amines by reductive amination (Gallardo-Donaire et al. 2016), under conditions that give high chemoselectivity for reduction of the imine intermediate and minimizing the background reduction of the ketone precursor.  
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The direct reductive amination of ketone without isolating an imine intermediate presents a challenge in chemoselectivity, avoiding background reduction of the ketone reactant.  Moreover, imines arising simply from ammonia and ketones are sensitive to hydrolysis relative to the corresponding oximes.   However, a ruthenium catalyst with bidentate diphosphine, hydride, and chloride ligands, provides the desired chemoselectivity, provided that a Lewis acid co-catalyst is used such as aluminum triflate (Figure 1, Gallardo-Donaire et al. 2016).  The workers have established that aluminum triflate does not play a significant role in catalyzing imine formation, but instead either activates the imine for hydrogenation, or activates the catalyst.  This method is limited to aryl alkyl ketones, with dialkyl ketones giving much lower yields.  

Figure 1.  Chemoselective reductive amination of aryl alkyl ketones with ammonia and hydrogen

The enantioselective variation requires a chiral diphosphine ligand, with the ferrocene-linked binaphane ligand giving the highest enantioselectivity, in the presence of NH4I as a co-catalytic additive (Figure 2, Gallardo-Donaire et al. 2017).  In this case, the role of the additive enhances chemoselectivity by activating the catalyst, introducing an iodide ligand onto ruthenium.  Chemoselectivity for the amine is diminished with lower atomic weight halides, with fluoride giving ca. 4 : 1 mixture  of alcohol : amine. 

Figure 2.  Chemo- and enantioselective reductive amination of aryl alkyl ketones with ammonia and hydrogen

Based on a combination of experimental observations and theoretical insights, the ruthenium catalyst is covalently bound to iodide, which electronically favors chemoselective coordination of the imine nitrogen, and also increases steric hindrance in the complex, enhancing enantioselectivity arising from the chiral bisphosphine ligand.  In the proposed catalytic cycle (Figure 3), the rate-determining step is the reductive elimination step, in which a proton transfers from ruthenium to nitrogen.  This suggests that the migratory insertion and the oxidative addition of hydrogen steps are readily reversible, but that one diastereomer of the Ru(IV) complex preferentially undergoes reductive elimination, whereas the other diastereomer preferentially isomerizes via reductive elimination of hydrogen and beta-hydride elimination to return to the coordinated imine intermediate.  

Figure 3.  Proposed catalytic cycle for enantioselective imine hydrogenation stage

References:

- Gallardo-Donaire, J.; Ernst, M.; Trapp, O.; Schaub, T. Adv. Synth. Catal. 2016, 358, 358.  

- Gallardo-Donaire, J.; Hemsen, M.; Wysocki, J.; Ernst, M.; Rominger, F.; Trapp, O.; Hashmi, A. S. K.; Schäfer, A.; Comba, P.; Schaub, T. J. Am. Chem. Soc. 2017 ASAP; DOI: 10.1021/jacs.7b10496