Asymmetric Reductive Amination: Convenient Access to Enantioenriched Alkyl‐Alkyl or Aryl‐Alkyl Substituted α‐Chiral Primary Amines

Abstract

A two-step procedure for producing optically active, high value primary amines has been developed. The first and key step is the asymmetric reductive amination of a prochiral alkyl alkyl (acyclic or cyclic) or aryl alkyl (acyclic or cyclic) ketone with (R)-or (S)-a-methylbenzylamine (a-MBA). The normally stepwise excessive procedures of chiral auxiliary approaches are avoided by simultaneously incorporating the auxiliary and a new stereogenic center at the former carbonyl carbon of the ketone during step one. Specifically, step one is the hydrogenation (4-8 bar) of a prochiral ketone substrate in the presence of a-MBA, a Lewis acid 4 ], and a heterogeneous hydrogenation catalyst (Raney-Ni, Pt-C, Pd-C, Ru-C, or Rh-C), providing the amine diastereomers 2 in good to excellent yield and diastereoselectivity. Depending on the ketone examined (acyclic vs. cyclic, alkyl alkyl vs. aryl alkyl, sterically encumbered vs. unencumbered), the correct combination of heterogeneous hydrogenation catalyst, solvent, and temperature is crucial for allowing high yield and de with practical reaction times (generally 6-20 h). Performing the reaction in the absence of one of the indicated Lewis acids results in the formation of large amounts of alcohol by-product (> 25 %).Step two, hydrogenolysis, allows smooth removal of the chiral auxiliary providing a-chiral primary amines in good overall yield (5 examples 71-78 %, 1 example 64 %) and in 66-98 % enantiomeric excess. This two-step strategy is noteworthy because: 1) it is yield and stepwise efficient; 2) all the reagents are inexpensive and already used by the pharmaceutical industry; 3) a broad range of ketone substrates are suitable; 4) either enantiomeric form of the a-chiral amine product can be produced; 5) the reaction conditions are mild; and 6) the process is amenable to scale-up.

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

“…[17] Here we show that it is not only possible and generic in nature, but also grants access to chiral amine structures whose synthetic histories are punctuated by a lack of accomplishment.…”

“…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.…”

Selective Synthesis of Unnatural α‐, β‐ and γ‐Amino Esters

“…at 22°C, providing 72 % de. [17] In other polar (dichloromethane or EtOAc) or non-polar (hexane or toluene) aprotic solvents, 2-octanone provided similar results, but these aprotic solvents significantly slowed down the rate of reaction for γ-keto ester 1h.…”

“…Because of this, the carbonyl moiety would be expected to react like a non-functionalized ketone substrate, it was therefore not surprising that our previously established method for ketone reductive amination using Ti(OiPr) 4 and Raney-Ni was optimal. [17] With acetic acid, an undesirable mixture of the product (2h), the corresponding ring-closed lactam (3h), and larger quantities of the hydroxy ester were noted. Ti(OiPr) 4 reductive amination of γ-keto ester 1h was optimally performed in EtOH at a hydrogen pressure of 30 bar (22°C); these conditions allowed full consumption of 1h within 18 h with smooth formation of 2h in 74 % de.…”

“…Depending on the ketone substrate category, Raney-Ni, Pt-C, or Pd-C hydrogenation catalysts are required and provide good to excellent yield and diastereoselectivity for the amine products. [17] This prompted us to investigate the reductive amination of keto esters, and we chose to begin our studies with β-keto ester 1a (tert-butyl acetylacetonate). The reaction was performed in EtOH using a combination of Ti(OiPr) 4 , Raney-Ni, and α-MBA (1.5 equiv.)…”