Direct Reductive Amination Of Ketones Research Articles

Iridium-Catalyzed Direct Reductive Amination of Ketones and Secondary Amines: Breaking the Aliphatic Wall.

Invited for the cover of this issue are Matthieu Jouffroy from Discovery Process Research at Janssen Pharmaceutica N.V. and the group of Rafael Gramage-Doria at the University of Rennes. The image depicts an Ir-based catalytic system "fueled" by hydrogen for the direct reductive amination of ketones and secondary amines, allowing complex aliphatic tertiary amines to be prepared and, so, new chemical space to be reached. Read the full text of the article at 10.1002/chem.202201078.

Front Cover: Iridium‐Catalyzed Direct Reductive Amination of Ketones and Secondary Amines: Breaking the Aliphatic Wall (Chem. Eur. J. 36/2022)

An iridium-catalyzed methodology leads to fully aliphatic tertiary amines starting from readily available ketones and amines. This direct reductive amination transformation, fueled by hydrogen similar to a space rocket, enables access to an unprecedented chemical space with a functional group relevance compatible with active pharmaceutical ingredients. More information can be found in the Research Article by M. Jouffroy, R. Gramage-Doria et al. (DOI: 10.1002/chem.202201078).

Iridium-Catalyzed Direct Reductive Amination of Ketones and Secondary Amines: Breaking the Aliphatic Wall.

Direct reductive amination (DRA) is a ubiquitous reaction in organic chemistry. This transformation between a carbonyl group and an amine is most often achieved by using a super stoichiometric amount of hazardous hydride reagents, thus being incompatible with many sensitive functional groups. DRA could also be achieved by means of chemo- or biocatalysis, thereby attracting the interest of industry as well as academic laboratories due to the virtually perfect atom economy. Although DRAs are well-established for substrate pairs such as aldehydes with either 1° or 2° amines as well as ketones with 1° amines, the current methodologies are limited in the case of ketones with 2° amines. Herein, we present a general DRA protocol that overcomes this major limitation by means of iridium catalysis. The applicability of the methodology is demonstrated by accessing an unprecedented range of biologically relevant tertiary amines starting from both aliphatic ketones and aliphatic amines. The choice of a disphosphane ligand (Josiphos A or Xantphos) is essential for the success of the transformation.

Direct reductive amination of ketones with amines by reductive aminases

Direct reductive amination of ketones by reductive aminases (RedAms) is a promising method for the synthesis of primary, secondary and tertiary amines. In this work, five naturally occurring RedAms possessing reductive amination activity were identified using a structure-guided genome mining (SGGM) approach, which was based on highly conserved substrate binding and catalysis motif alignment. This RedAm toolbox facilitated the reductive amination of cyclohexanone and 4-fluoropropiophenone with various amine nucleophiles. In a preparative biotransformation (100 ​mg) with low stoichiometric ammonia donor and low catalyst loading, and three types of N-alkylcyclohexylamine were efficiently synthesized with a space-time yield up to 64.2 ​g ​L−1 ​d−1, demonstrating the potential of the RedAm enzymes as a biocatalyst toolbox for the synthesis of primary and secondary amines. Additionally, through protein engineering, the W205F variant of KfRedAm from Kribbella flavida was obtained with a 2-fold increased catalytic efficiency (kcat/Km), and the general applicability of the variant was verified, providing useful guidance for further evolution of RedAms within this family.

Air Stable Iridium Catalysts for Direct Reductive Amination of Ketones.

Half-sandwich iridium complexes bearing bidentate urea-phosphorus ligands were found to catalyze the direct reductive amination of aromatic and aliphatic ketones under mild conditions at 0.5 mol % loading with high selectivity towards primary amines. One of the complexes was found to be active in both the Leuckart-Wallach (NH4 CO2 H) type reaction as well as in the hydrogenative (H2 /NH4 AcO) reductive amination. The protocol with ammonium formate does not require an inert atmosphere, dry solvents, as well as additives and in contrast to previous reports takes place in hexafluoroisopropanol (HFIP) instead of methanol. Applying NH4 CO2 D or D2 resulted in a high degree of deuterium incorporation into the primary amine α-position.

Direct reductive amination of ketones with ammonium salt catalysed by Cp*Ir(III) complexes bearing an amidato ligand.

A series of half-sandwich Ir(III) complexes 1-6 bearing an amidato bidentate ligand were conveniently synthesized and applied to the catalytic Leuckart-Wallach reaction to produce racemic α-chiral primary amines. With 0.1 mol% of complex 1, a broad range of ketones, including aryl ketones, dialkyl ketones, cyclic ketones, α-keto acids, α-keto esters and diketones, could be transformed to their corresponding primary amines with moderate to excellent yields (40%-95%). Asymmetric transformation was also attempted with chiral Ir complexes 3-6, and 16% ee of the desired primary amine was obtained. Despite the unsatisfactory enantio-control achieved so far, the current exploration might stimulate more efforts towards the discovery of better chiral catalysts for this challenging but important transformation.

The synthesis of sterically hindered amines by a direct reductive amination of ketones

An atom-economical methodology for the synthesis of sterically hindered tertiary amines was developed, which is based on complementary Rh- and Ru-catalyzed direct reductive amination of ketones with primary and secondary amines using carbon monoxide as a deoxygenating agent.

Design of a novel redox biocatalyst to specification (363.3)

Recently, we obtained the first amine dehydrogenases, termed L‐AmDH and F‐AmDH, from leucine DH [1] and phenylalanine DH [2], respectively, allowing direct reductive amination of ketones to chiral amines.Starting from a scaffold devoid of such activity, a robust AmDH has been evolved with a single two‐site library allowing for the direct production of (R)‐1‐(4‐fluorophenyl)‐propyl‐2‐amine from para‐fluoro phenyl acetone with a kcat value of 6.85 s‐1 at 25oC. Only (R)‐amine was formed (> 99.8% e.e.), showing that perfect enantioselectivity of the template was conserved.Successful domain shuffling created a chimeric amine DH with enhanced substrate specificity that allows to accommodate sterically very demanding side chains, such as adamantly groups. We will elucidate the impact of restricted libraries in the evolution towards higher activity and broader specificity.Many interesting substrates feature low solubility in aqueous solution. We describe how utilizing a two‐phase system can also lead to pinpointing broadened substrate specificity, as substrate candidates that were previously missed, can register as hits in the search.

ChemInform Abstract: Stereoselective Direct Reductive Amination of Ketones with Electron‐Deficient Amines Using Re2O7/NaPF6 Catalyst.

AbstractThe first examples of direct reductive amination of ketones with amines bearing electron‐withdrawing substituents are described.

ChemInform Abstract: S‐Benzyl Isothiouronium Chloride as a Recoverable Organocatalyst for the Direct Reductive Amination of Ketones with Hantzsch Ester.

AbstractThe procedure is successful for various ketones and aromatic amines to afford the desired products in moderate to good yield.

S-Benzyl Isothiouronium Chloride as a Recoverable Organocatalyst for the Direct Reductive Amination of Ketones with Hantzsch Ester

The direct reductive amination of ketones using the Hantzsch ester in the presence of <i>S</i>-benzyl isothiouronium chloride as a recoverable organocatalyst is reported. A wide range of ketones as well as amines were found to give the expected products in moderate to excellent yields.

A Facile One-Pot Process for the Formation of Hindered Tertiary Amines

A simple and convenient method was developed for the preparation of hindered tertiary amines via direct reductive amination of ketones with secondary aryl amines, using trichlorosilane as reducing agent and tetramethylethylenediamine (TMEDA) as organic Lewis base activator. A broad range of ketones were reacted with N-methylaniline to afford the corresponding tertiary amine products in high yield. An open transition model was proposed for the reductive step.

Rapid Microwave-Assisted Reductive Amination of Ketones with Anilines

Using microwave technology, a new protocol has been developed that improves the reaction rate and overall efficiency of the direct reductive amination of ketones with anilines. When using sodium triacetoxyborohydride as the reducing agent, high product yields and increased reaction rates are achieved for a variety of electronically different anilines. Furthermore, we have found that this protocol can also be applied to aldehydes.

Hydrogen Bond Catalyzed Direct Reductive Amination of Ketones.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Hydrogen Bond Catalyzed Direct Reductive Amination of Ketones

[reaction: see text] A novel, biomimetic concept for the direct reductive amination of ketones is described that relies on selective imine activation by hydrogen bond formation. The mild, acid- and metal-free process requires only catalytic amounts of thiourea as hydrogen bond donor and utilizes the Hantzsch ester for transfer hydrogenation. The method allows the efficient synthesis of structurally diverse amines.