Synthesis of Primary Amines by One-Pot Reductive Amination of Aldehydes

We report here a novel, one-pot, two-step reductive amination of aldehydes for the atom-economical synthesis of primary amines. The amination step has been carried out with hydroxylammonium chloride and does not require the use of a base. In the subsequent reduction step, a metal zinc/hydrochloride acid system has been used. This method is applicable to both aliphatic and aromatic aldehydes. The operational simplicity, the short reaction times, and the mild reaction conditions add to the value of this method as a practical alternative to the reductive amination of aldehydes.

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A One-Pot Selective Synthesis of N-Boc Protected Secondary Amines: Tandem Direct Reductive Amination/N-Boc Protection

A one-pot tandem direct reductive amination of aldehydes with primary amines resulting in N-Boc secondary amines using a (Boc)(2)O/sodium triacetoxyborohydride (STAB) system is reported. The tandem procedure is efficient, selective, and versatile, giving excellent yields of N-Boc protected secondary amines even in those cases where the products are prone to intramolecular lactamization.     

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.     

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 (NH₄CO₂H) type reaction as well as in the hydrogenative (H₂/NH₄AcO) 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 NH₄CO₂D or D₂ resulted in a high degree of deuterium incorporation into the primary amine α-position.     

Asymmetric Reductive Amination in Organocatalysis and Biocatalysis

This review summarizes the recent progress of organocatalytic and biocatalytic asymmetric reductive amination (ARA), a challenging but important topic for drug discovery and the pharmaceutical industry. At present, ARA can be divided into three categories: metal catalysis, organic catalysis, and biocatalysis. In the past decade, transition metal-catalysed ARA has been well established. Organocatalytic ARA has emerged as a powerful alternative to metal-catalysed ARA, the hydrogen sources used in organocatalytic ARA are usually Hantzsch esters, benzothiazolines, boranes, and hydrosilanes, which require Lewis base or phosphoric acid catalysts to activate them to give secondary chiral amines. It is worth mentioning that biocatalytic ARA has made remarkable progress in the last decade, amino acid dehydrogenases, amine dehydrogenases, opine dehydrogenases and imine reductases have been successfully used in ARA.     

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

A Ru‐catalyzed direct asymmetric reductive amination of ortho‐OH‐substituted diaryl and sterically hindered ketones with ammonium salts is reported. This method represents a straightforward route toward the synthesis of synthetically useful chiral primary diarylmethylamines and sterically hindered benzylamines (up to 97 % yield, 93–>99 % ee). Elaborations of the chiral amine products into bioactive compounds and a chiral ligand were demonstrated through manipulation of the removable and convertible ‐OH group.     

Reductive Amination of Carbonyl Compounds with Ammonia and Hydrogenation of Nitriles to Primary Amines with Heterogeneous Cobalt Catalysts

Reductive amination of aldehydes/ketones with aqueous NH3 and hydrogenation of nitriles to primary amines with Co catalysts were reported. Co@NC-700 exhibited remarkable activity and high selectivity for the reductive amination of aldehydes/ketones with aqueous NH3 and the hydrogenation of nitriles to primary amines. Several primary amines can be obtained with good to excellent yields via the reductive amination of aldehydes/ketones and the hydrogenation of nitriles. The nitrogen-doped carbon(C)-supported Co@NC-700 metal catalyst was prepared via the pyrolysis of bioMOF Co/adenine in activated C. Co@NC-700 can be reused five times without evident loss of activity.     

Primary Amines by Transfer Hydrogenative Reductive Amination of Ketones by Using Cyclometalated IrIII Catalysts

Cyclometalated iridium complexes are found to be versatile catalysts for the direct reductive amination (DRA) of carbonyls to give primary amines under transfer‐hydrogenation conditions with ammonium formate as both the nitrogen and hydrogen source. These complexes are easy to synthesise and their ligands can be easily tuned. The activity and chemoselectivity of the catalyst towards primary amines is excellent, with a substrate to catalyst ratio (S/C) of 1000 being feasible. Both aromatic and aliphatic primary amines were obtained in high yields. Moreover, a first example of homogeneously catalysed transfer‐hydrogenative DRA has been realised for β‐keto ethers, leading to the corresponding β‐amino ethers. In addition, non‐natural α‐amino acids could also be obtained in excellent yields with this method.     

Reductive Amination of Aldehydes and Ketones with Primary Amines by Using Lithium Amidoborane as Reducing Reagent

A variety of secondary amines were obtained in high isolated yields in the reductive amination of aldehydes and ketones by using lithium amidoborane as reducing agent. Compared to ammonia borane, lithium amidoborane has higher reducibility, and thus, exhibits faster reaction rate.     

General Reductive Amination of Aldehydes and Ketones with Amines and Nitroaromatics under H2 by Recyclable Iridium Catalysts

Heterogeneous iridium catalysts were prepared and applied for the reductive amination of aldehydes and ketones with nitroaromatics and amines using H₂ . The iridium catalysts were prepared by pyrolysis of ionic liquid 1‐methyl‐3‐cyanomethylimidazoulium chloride ([MCNI ]Cl) with iridium chloride (IrCl₃ ) in activated carbons. Iridium particles were well dispersed and stable in the N‐doped carbon materials from [MCNI ]Cl with activated carbon. The Ir@NC (600‐2h) catalyst was found to be highly active and selective for the reductive amination of aldehydes and ketones using H₂ and a variety of nitrobenzenes and amines were selectively converted into the corresponding secondary and tertiary amines. The Ir@NC (600‐2h) catalyst can be reusable several times without evident deactivation.     

Earth-abundant Metal-catalyzed Reductive Amination: Recent Advances and Prospect for Future Catalysis

Nitrogen-containing compounds, as an important class of chemicals, have been used widely in pharmaceuticals, materials synthesis. Transition metal-catalyzed reductive amination of an aldehyde or a ketone with ammonia or an amine has been proved to be an efficient and practical method for the preparation of nitrogen-containing compounds in academia and industry for a century. Given the above, several effective methods using transition metals have been developed in recent years. Noble transition metals like Pd, Pt, and Au-based catalysts have been predominately used in reductive amination. Because of their high prices, strict official regulations of residues in pharmaceuticals, and deleterious effects on the biological system, their industrial applications are severely hampered. With the increasing sustainable and environmental problems, the Earth-abundant transition metals including Ti, Fe, Co, Ni, and Zr have also been investigated for the reductive amination reaction and showed great potential to the advancement of sustainable and cost-effective reductive amination processes. This critical review will mainly summarize the work using Earth-abundant metals. The effects of different transition metals used in catalytic reduction amination were discussed and compared, and some suggestions were given. The last section highlights the catalytic activities of bi- and tri-metallic catalysts. Indeed, this latter family is very promising and simultaneously benefits from increased stability, and selectivity, compared to monometallic NPs, due to synergistic substrate activation. Few comprehensive reviews focusing on Earth-abundant transition metals catalyst has been published since 1948, although several authors reported some summaries dealing with one or the other part of this aspect. It is hoped that this critical review will inspire researchers to develop new efficient and selective earth-abundant metal catalysts for highly, environmentally sustainable reductive amination methods, as well as improve the pharmaceutical industry and related chemical synthesis company traditional method with the utilization of the green method widely.     

Catalytic One-Pot Reductive Amination of Carboxylic Acids

The broad applications of primary alkyl amines in various fields have spurred extensive interests in synthetic organic chemistry. Recently, the reductive amination of carboxylic acids has become an attractive and practical strategy for synthesizing primary alkyl amines, due to their wide availability and bench stability. However, the inherent stability and higher oxidation state of carboxylic acids render this new strategy with new challenges. This Concept provides a summary of the recent advancements in the reductive aminations of carboxylic acids, specifically focusing on the catalytic tactics, underlying mechanisms, and applications in the synthesis of valuable products.     

Raney Ni催化生物基糠醛还原胺化合成糠胺

生物质衍生物糠醛还原胺化是合成糠胺的一种有效方法。本文以糠醛为原料、氨水为氨源,使用商业Raney Ni催化糠醛还原胺化合成糠胺,考察了氢压、温度、n(糠醛)/n(氨水)、溶剂、催化剂用量等条件对反应的影响。实验结果表明：在1,4-二氧六环溶剂中,0.03 g Raney Ni、n(糠醛)/n(氨水)=1/2、130 ℃、2.0 MPa H₂条件下反应3 h,糠醛转化率100%,糠胺选择性96.3%。与传统方法相比,该工艺实现了非贵金属催化剂作用下高选择性反应,具有操作简单、低成本、收率高等优点。      

Reductive Amination Reaction for the Functionalization of Cellulose Nanocrystals

Cellulose nanocrystals (CNCs) represent intriguing biopolymeric nanocrystalline materials, that are biocompatible, sustainable and renewable, can be chemically functionalized and are endowed with exceptional mechanical properties. Recently, studies have been performed to prepare CNCs with extraordinary photophysical properties, also by means of their functionalization with organic light-emitting fluorophores. In this paper, we used the reductive amination reaction to chemically bind 4-(1-pyrenyl)butanamine selectively to the reducing termini of sulfated or neutral CNCs (S_CNC and N_CNC) obtained from sulfuric acid or hydrochloric acid hydrolysis. The functionalization reaction is simple and straightforward, and it induces the appearance of the typical pyrene emission profile in the functionalized materials. After a characterization of the new materials performed by ATR-FTIR and fluorescence spectroscopies, we demonstrate luminescence quenching of the decorated N_CNC by copper (II) sulfate, hypothesizing for these new functionalized materials an application in water purification technologies.     

Rapid Construction of Structurally Diverse Quinolizidines,Indolizidines, and Their Analogues via Ruthenium‐Catalyzed Asymmetric Cascade Hydrogenation/Reductive Amination

A rapid construction of enantioenriched benzo‐fused quinolizidines, indolizidines, and their analogues by ruthenium‐catalyzed asymmetric cascade hydrogenation/reductive amination of quinolinyl‐ and quinoxalinyl‐containing ketones has been developed. This reaction proceeds under mild reaction conditions, affording chiral benzo‐fused aliphatic N‐heterocyclic compounds with structural diversity in good yields (up to 95 %) with excellent diastereoselectivity (up to >20:1 dr) and enantioselectivity (up to >99 % ee). Furthermore, this catalytic protocol is applicable to the formal synthesis of (+)‐gephyrotoxin.     

Convenient Synthesis of 6-Bromo-1,2,3,4-tetrahydroisoquinoline and 3-Methoxy-1,2,3,4-tetrahydro-[2,7]-naphthyridine via Reductive Amination of Schiff's Bases

Synthesis of 7-bromo-1,2,3,4-tetrahydroisoquinoline and 6-methoxy-1,2,3,4-tetrahydro-[2,7]-naphthyridine via lithiation of 2-methylarylidene-tert-butylamines, followed by formylation, reductive amination in one-pot, and removal of the tert-butyl group from the nitrogen, is described.     

A Fast and Highly Efficient Protocol for Reductive Amination of Aromatic Aldehydes Using NaBH4 and Isoxazole Amines in an Ionic Liquid Medium

Reductive amination of aromatic aldehydes using NaBH₄ and isoxazole amines is carried out in a Brønsted acidic ionic liquid 1‐methylimidazolium tetrafluoroborate [(HMIm)BF₄]. The ionic liquid plays dual roles of solvent as well as catalyst for the efficient transformation of aromatic aldehydes to heterocyclic substituted amines in excellent yields without any undesired side product formation. The newly synthesized compounds ( 3 , 6 and 7 ) were characterized by IR, ¹H NMR and mass spectral techniques.