Asymmetric Synthesis of Chiral Primary Amines by Ruthenium-Catalyzed Direct Reductive Amination of Alkyl Aryl Ketones with Ammonium Salts and Molecular H₂

Abstract

A ruthenium/C-TunePhos catalytic system has been identified for highly efficient direct reductive amination of simple ketones. The strategy makes use of ammonium acetate as the amine source and H as the reductant and is a user-friendly and operatively simple access to industrially relevant primary amines. Excellent enantiocontrol (>90% ee for most cases) was achieved with a wide range of alkyl aryl ketones. The practicability of this methodology has been highlighted by scalable synthesis of key intermediates of three drug molecules. Moreover, an improved synthetic route to the optimal diphosphine ligand C-TunePhos is also presented.

Enantioselective synthesis of (R)‐Cinacalcet via cobalt‐catalysed asymmetric Negishi cross‐coupling

“…The gram‐scale synthesis of a reaction exhibits its potential of practical application . Although racemic 4‐methoxybenzyl 2‐bromopropanoate 3 could couple with 1‐naphthalenylzinc bromide 2 on a o.5 mmol scale in our previous research, it is noteworthy to scale this enantioselective cross‐coupling to gram scale.…”

“…The gram-scale synthesis of a reaction exhibits its potential of practical application. 23 Although racemic 4methoxybenzyl 2-bromopropanoate 3 could couple with 1-naphthalenylzinc bromide 2 on a o.5 mmol scale in our previous research, 20 it is noteworthy to scale this enantioselective cross-coupling to gram scale. To our pleasure, a gram-scale cobalt-catalysed cross-coupling of ester 3 with arylzinc reagent 2 was successfully developed without the erosion of yield and ee.…”

Ruthenium‐Catalyzed Direct Asymmetric Reductive Amination of Diaryl and Sterically Hindered Ketones with Ammonium Salts and H2

“…Ortho ‐Me‐substituted diphenyl ketone 1 was initially considered and subjected to our previously developed reaction conditions in the presence of 1 equiv of Ti(O i ‐Pr) 4 . As expected, the reaction was sluggish and only afforded a small amount of desired product 2 , with most starting material recovered.…”

Dynamic Kinetic Asymmetric Reductive Amination: Synthesis of Chiral Primary β‐Amino Lactams

“…An additional deprotection step is necessary to access more valuable primary amines.A sc ompared to well-established methodologies toward chiral secondary amines,reports on the direct construction of chiral primary amines by ARA are limited. [9] Despite these promising results,the ARA of racemic ketones with ammonium salts or ammonia to access compounds containing contiguous stereocenters and ap rimary amino fragment through dynamic kinetic resolution (DKR) has not been systematically explored and remains ag reat challenge. [6] Subsequently,m ore efficient hydrogenation processes capable of constructing chiral primary b-amino esters with ammonium salts were developed by scientists at Lanxess and Takasago, [7] and shortly after, this approach was applied to prepare the top-selling drugs sitagliptin and ezetimibe.…”

“…[2] Owing to competitive reduction between ketone and imine intermediates in the presence of transition-metal hydrides and product inhibition by amines at transition-metal catalysts,t his field has remained underdeveloped. [9] Despite these promising results,the ARA of racemic ketones with ammonium salts or ammonia to access compounds containing contiguous stereocenters and ap rimary amino fragment through dynamic kinetic resolution (DKR) has not been systematically explored and remains ag reat challenge. An additional deprotection step is necessary to access more valuable primary amines.A sc ompared to well-established methodologies toward chiral secondary amines,reports on the direct construction of chiral primary amines by ARA are limited.…”