Ytterbium Acetate Promoted Asymmetric Reductive Amination:  Significantly Enhanced Stereoselectivity

Abstract

Reductive amination of prochiral unhindered 2-alkanones 1 with (R)- or (S)-alpha-MBA in the presence of Yb(OAc)3 (50-110 mol %), Raney-Ni, and hydrogen (120 psi) results in increased diastereoselectivity for the amine products 2 (80-89% de) with good yield (80-87%). The increased de is based on comparison with the best previously reported de's when using (R)- or (S)-alpha-MBA, regardless of the strategy employed [stepwise (isolation of ketimines) or one-pot (reductive amination)], reducing agent examined, or achiral Lewis acid or Brønsted acid examined. An in situ cis- to trans-ketimine isomerization mechanism, promoted by Yb(OAc)3, has been proposed to account for the observed increase in diastereoselectivity and suggests a new entry into the control of ketimine geometry.

Sequential Reductive Amination‐Hydrogenolysis: A One‐Pot Synthesis of Challenging Chiral Primary Amines

“…We have previously synthesized enantioenriched primary amines via two-step processes originating from the corresponding ketones (Scheme 2) [7b, 17,18] or aldehydes (not shown), [19] but not from demanding ortho-substituted acetophenones and not in a one-pot process. To explore this possibility we first reductively aminated these sterically hindered ketones with (S)-phenylethylamine, (S)-PEA, in the presence of a heterogeneous hydrogenation catalyst under pressurized hydrogen, and isolated the secondary amine products (S,S)-2 (major) and (S,R)-2 (minor), Table 1.…”

Direct Synthesis of Primary Amines via Ruthenium‐Catalysed Amination of Ketones with Ammonia and Hydrogen

“…At that point we speculate that the role of aluminium triflate could be to activate the imine towards hydrogenation rather than assisting in imine formation. [19] In order to support this idea, acetophenone 1a was charged into a1 00-mL autoclave,p ressurised with NH 3 (4 bar) and stirred for 1h at 120 8 8C( Supporting Information, Scheme S1). [13] After analysis of the crude reactionm ixture,o nly 6% of imine was detected.…”

Asymmetric Reductive Amination

“…In stark contrast to these stereochemical trends, 2-alkanones without branching at the a-or b-carbons, for example, 2-octanone or benzylacetone (Table 7.2), can be reductively aminated with significantly higher diastereoselectivity when using stoichiometric quantities (80-110 mol%) of Yb(OAc) 3 [33]. Finally, some general observations were noted by Nugent regarding reductive amination with phenylethylamine that are likely to be general in nature.…”

“…The method, initially reported on in 2005 [31], relies on reductive amination with (R)-or (S)-PEA followed by hydrogenolysis, and has been optimized for a large variety of ketone substrate classes. The key innovation was identification of the most efficient Lewis acid/heterogeneous hydrogenation catalyst combination, which in turn allowed the reductive amination of previously unreactive, sterically hindered ketones in good to excellent yield [31,32] and led to significantly improved stereoselectivity for alkyl-methyl ketone substrates [33]. One way of organizing the findings of Nugent is regarding the optimal heterogeneous hydrogenation catalyst.…”