Additive-Free Transfer Hydrogenative Direct Asymmetric Reductive Amination Using a Chiral Pyridine-Derived Half-Sandwich Catalyst

Chiral amines are broadly used compounds in pharmaceutical industry and organic synthesis, and reductive amination reactions have been the most appreciated methods for their syntheses. However, one-step transfer hydrogenative direct asymmetric reductive amination (THDARA) that could expand the scope, simplify the operation and eliminate the use of additives has been challenging. In this work, based on the Xiao's racemic transfer hydrogenative reductive amination in 2010 and our recent work in novel chiral pyridine ligands, chiral half-sandwich iridium catalysts were rationally designed and synthesized. Using the optimized catalyst and azeotropic mixture of formic acid and triethylamine as the hydrogen source, a broad range of α-chiral (hetero)aryl amines, including various polar functional groups and heterocycles, were prepared in generally high yield and enantioselectivity under mild and operationally simple conditions. Density functional theory (DFT) calculation of the catalytically active Ir−H species and the key hydride transfer step supported the chiral pyridine-induced stereospecific generation of the iridium center, and the enantioselection by taming the highly flexible key transition structure with multiple attractive non-covalent interactions. This work introduced a type of effective chiral catalysts for simplified approach to medicinally important chiral amines, as well as a rare example of robust enantioselective transition-metal catalysis.     

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.     

Metal-based Heterogeneous Catalysts for One-Pot Synthesis of Secondary Anilines from Nitroarenes and Aldehydes

Recently, N-substituted anilines have been the object of increasing research interest in the field of organic chemistry due to their role as key intermediates for the synthesis of important compounds such as polymers, dyes, drugs, agrochemicals and pharmaceutical products. Among the various methods reported in literature for the formation of C–N bonds to access secondary anilines, the one-pot reductive amination of aldehydes with nitroarenes is the most interesting procedure, because it allows to obtain diverse N-substituted aryl amines by simple reduction of nitro compounds followed by condensation with aldehydes and subsequent reduction of the imine intermediates. These kinds of tandem reactions are generally catalyzed by transition metal-based catalysts, mainly potentially reusable metal nanoparticles. The rapid growth in the last years in the field of metal-based heterogeneous catalysts for the one-pot reductive amination of aldehydes with nitroarenes demands for a review on the state of the art with a special emphasis on the different kinds of metals used as catalysts and their recyclability features.     

Enantioselective organocatalytic reductive amination

The first enantioselective organocatalytic reductive amination reaction has been accomplished. The development of a new chiral phosphoric acid catalyst has provided a convenient strategy for the enantioselective construction of protected primary amines and provided a highly stereoselective method for the reductive amination of heterocyclic amines. A diverse spectrum of ketone and amine substrates can be accommodated in high yield and excellent enantioselectivity. This new protocol realizes a key benefit of reductive amination versus imine reduction, in that ketimines derived from alkyl-alkyl ketones are unstable to isolation, a fundamental limitation that is comprehensively bypassed using this direct organocatalytic reductive amination.     

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.     

General and selective synthesis of primary amines using Ni-based homogeneous catalysts

The development of base metal catalysts for industrially relevant amination and hydrogenation reactions by applying abundant and atom economical reagents continues to be important for the cost-effective and sustainable synthesis of amines which represent highly essential chemicals. In particular, the synthesis of primary amines is of central importance because these compounds serve as key precursors and central intermediates to produce value-added fine and bulk chemicals as well as pharmaceuticals, agrochemicals and materials. Here we report a Ni-triphos complex as the first Ni-based homogeneous catalyst for both reductive amination of carbonyl compounds with ammonia and hydrogenation of nitroarenes to prepare all kinds of primary amines. Remarkably, this Ni-complex enabled the synthesis of functionalized and structurally diverse benzylic, heterocyclic and aliphatic linear and branched primary amines as well as aromatic primary amines starting from inexpensive and easily accessible carbonyl compounds (aldehydes and ketones) and nitroarenes using ammonia and molecular hydrogen. This Ni-catalyzed reductive amination methodology has been applied for the amination of more complex pharmaceuticals and steroid derivatives. Detailed DFT computations have been performed for the Ni-triphos based reductive amination reaction, and they revealed that the overall reaction has an inner-sphere mechanism with H₂ metathesis as the rate-determining step.

A Ni-triphos based homogeneous catalyst enabled the synthesis of all kinds of primary amines by reductive amination of carbonyl compounds with ammonia and hydrogenation of nitroarenes.     

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.     

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.     

氰基衍生化制备胺的研究进展

胺是有机分子中最常见且重要的结构之一,广泛存在于天然产物分子、药物、染料、塑料等的分子结构中,开发合成胺的有效方法在化学工业中具有很高的需求但仍充满挑战。在诸多已知有机胺的合成方法中,以氰基为前体还原衍生化制备胺被认为是一条原子经济且绿色可行的方案。然而,氰基中存在稳定的碳氮三重键,还原过程涉及较多中间体,而部分中间体活性比氰基更高,因此反应受还原剂、催化剂、反应条件的影响很大,由氰基选择性制备目标胺结构仍充满挑战。本文从氰基的基本电子结构与反应活性出发,综述了近年来以氰基为原料的官能团胺基化反应,对部分重要反应的催化剂和反应机理做了简要讨论,为设计氰基制胺催化剂和应用工艺提供了新的视角。     

Brevibacterium epidermidis催化酮不对称还原胺化合成(S)-手性胺

光学纯手性胺是一类非常重要的手性化学品,作为手性砌块和手性拆分剂广泛用于医药、农业化学品、精细化学品等产品的合成中.据统计,美国FDA近年来批准的约40％药物中都含有一个或多个手性胺结构单元.胺脱氢酶(AmDH)是由氨基酸脱氢酶改造而来的一类催化酮不对称还原胺化的新酶,其在手性胺的合成中展现出较强的潜力,已引起国内外学术界和工业界的广泛关注.这是因为该酶能够利用廉价的无机铵为胺供体,且具有催化效率高、原子经济性好和环境友好等优点.迄今为止已经有数个高效的胺脱氢酶被成功开发和报道,但是这些通过蛋白质工程改造的胺脱氢酶均为(R)-选择性,因此只能合成(R)-选择性的手性胺,遗憾的是还未见有(S)-选择性胺脱氢酶的报道.因此,本文主要目的是期望从自然环境中鉴定能够不对称还原胺化酮合成(S)-手性胺的微生物,进而从中分离得到能够以无机铵作为胺供体合成(S)-手性胺的(S)-选择性酶.本文首先利用苯乙胺作为唯一氮源,从土壤中筛选能够利用苯乙胺生长的菌株,进而利用苯乙酮作为初筛底物对得到的菌株进行胺化能力筛选,再利用(4-氟苯基)丙酮作为模式底物进行进一步的筛选.幸运的是,我们获得了能够利用无机铵作为胺供体催化(4-氟苯基)丙酮不对称还原胺化合成(S)-4-氟-α-甲基苯乙胺的菌株,经过16S RNA鉴定为表皮短杆菌,命名为B.epidermidis ECU1015.接下来,我们对B.epidermidis ECU1015催化的胺化反应中的关键参数如胺基供体及其最适浓度、反应温度、pH值和底物浓度等进行了优化,确定最佳反应条件:胺供体为NH4Cl(1.25 mol/L),反应温度为30°C,KPB缓冲液(200 mmol/L,pH 7.5),底物浓度10 mmol/L.最后,在最适的反应条件下,我们对B.epidermidis ECU1015催化的底物谱进行了研究.结果表明,该微生物不能催化大位阻芳香酮和链状酮的胺化,对位阻较小的苯乙酮及(4-氟苯基)丙酮具有较好的还原胺化能力,而且对苯环上带有吸电子取代基的酮化合物具有更好的转化效果.经手性分析,所有生成的手性胺均为(S)-构型,产品的光学纯度均>99％.B.epidermidis催化酮不对称胺化所形成的产物构型均为(S)-选择性,这不同于已报道的(R)-选择性胺脱氢酶.该菌株的发现为(S)-选择性胺脱氢酶的进一步鉴定奠定了一定的研究基础,相关蛋白的分离纯化工作正在进行.     

Fast Reductive Amination by Transfer Hydrogenation “on Water”

Reductive amination of various ketones and aldehydes by transfer hydrogenation under aqueous conditions has been developed, by using cyclometallated iridium complexes as catalysts and formate as hydrogen source. The pH value of the solution is shown to be critical for a high catalytic chemoselectivity and activity, with the best pH value being 4.8. In comparison with that in organic solvents, the reductive amination in an aqueous phase is faster, and the molar ratio of the substrate to the catalyst (S/C) can be set as high as 1×10⁵, the highest S/C value ever reported in reductive amination reactions. The catalyst is easy to access and the reaction is operationally simple, allowing a wide range of ketones and aldehydes to react with various amines in high yields. The protocol provides a practical and environmental friendly new method for the synthesis of amine compounds.     

Polymer-supported triacetoxyborohydride: a novel reagent of choice for reductive amination

A novel polymer-supported triacetoxyborohydride reagent for reductive amination of aldehydes and ketones is reported. The bound reagent was found to be shelf-stable and provided broad scope and reactivity in reductive amination reactions under mild reaction conditions. Streamlined protocols for its application in reductive amination reactions using both primary and secondary amines are described.     

Biomimetic reductive amination under the continuous-flow reaction conditions

This study present a full account of continuous-flow reaction conditions for biomimetic reductive amination of fluorinated carbonyl compounds to corresponding amines and amino acids of biomedical importance. We demonstrate that simple silica-adsorbed DBU can be used as efficient catalysts for on-column 1,3-proton shift reaction, a key transformation in the biomimetic reductive amination process. This new on-column process features operationally convenient conditions, higher chemical yields, enantioselectivity and purity of the corresponding products as compared with traditional in-flask reactions. Moreover the removal of base-catalyst, the most delicate problem of the in-flask reactions, is not an issue in the on-column process, as the silica-adsorbed DBU or polymer-bound guanidine remains on the column and can be reused. This feature renders the overall process substantially more economical and synthetically efficient, in particular, for large-scale synthesis of the corresponding fluorinated amines and amino acids target.     

Reusable Nickel Nanoparticles‐Catalyzed Reductive Amination for Selective Synthesis of Primary Amines

The preparation of nickel nanoparticles as efficient reductive amination catalysts by pyrolysis of in situ generated Ni‐tartaric acid complex on silica is presented. The resulting stable and reusable Ni‐nanocatalyst enables the synthesis of functionalized and structurally diverse primary benzylic, heterocyclic and aliphatic amines starting from inexpensive and readily available carbonyl compounds and ammonia in presence of molecular hydrogen. Applying this Ni‐based amination protocol, ‐NH₂ moiety can be introduced in structurally complex compounds, for example, steroid derivatives and pharmaceuticals.     

Direct reductive amination of carbonyl compounds with primary/secondary amines using recyclable water-soluble Fe/EDTA complex as catalyst

Direct reductive amination of aliphatic, aromatic and heterocyclic carbonyl compounds with primary/secondary amines is reported with water-soluble Fe^II/EDTA complex as a catalyst using low-pressure molecular hydrogen in a biphasic media. The catalyst is highly selective, recyclable and is an excellent replacement for expensive noble metal catalysts or stoichiometric reducing agents.     

Simple, efficient catalyst system for the palladium-catalyzed amination of aryl chlorides, bromides, and triflates

Palladium complexes supported by (o-biphenyl)P(t-Bu)(2) (3) or (o-biphenyl)PCy(2) (4) are efficient catalysts for the catalytic amination of a wide variety of aryl halides and triflates. Use of ligand 3 allows for the room-temperature catalytic amination of many aryl chloride, bromide, and triflate substrates, while ligand 4 is effective for the amination of functionalized substrates or reactions of acyclic secondary amines. The catalysts perform well for a large number of different substrate combinations at 80-110 degrees C, including chloropyridines and functionalized aryl halides and triflates using 0.5-1.0 mol % Pd; some reactions proceed efficiently at low catalyst levels (0.05 mol % Pd). These ligands are effective for almost all substrate combinations that have been previously reported with various other ligands, and they represent the most generally effective catalyst system reported to date. Ligands 3 and 4 are air-stable, crystalline solids that are commercially available. Their effectiveness is believed to be due to a combination of steric and electronic properties that promote oxidative addition, Pd-N bond formation, and reductive elimination.     

Lithium borohydride: a reagent of choice for the selective reductive amination of cyclohexanones

Traditional reductive amination of substituted cyclohexanones are either selective toward the formation of cis-products or show low selectivity. Herein we report a selective procedure for the reductive amination of substituted cyclohexanones with primary amines using lithium borohydride that is selective toward formation of trans-products.     

Inside Cover: General Reductive Amination of Aldehydes and Ketones with Amines and Nitroaromatics under H2 by Recyclable Iridium Catalysts (Chin. J. Chem. 9/2017)

The inside cover picture shows secondary and tertiary amines, which are important intermediates in organic synthesis for the preparation of natural products, pharmaceutical and agronomical compounds. The direct reductive amination of aldehydes and ketones represents a powerful tool for the preparation of secondary and tertiary amines. Here, direct and general reductive amination of aldehydes and ketones with amines and nitroaromatics was presented under H₂ using recyclable iridium catalysts, and lots of secondary and tertiary amines were produced in high yields. Moreover, the heterogeneous iridium catalysts Ir@NC(600‐2h) can be reused several times without evident deactivation. More details are discussed in the article by Huang et al. on page 1371–1377.

     

Ultra-small cobalt nanoparticles from molecularly-defined Co–salen complexes for catalytic synthesis of amines

We report the synthesis of in situ generated cobalt nanoparticles from molecularly defined complexes as efficient and selective catalysts for reductive amination reactions. In the presence of ammonia and hydrogen, cobalt–salen complexes such as cobalt(ii)–N,N′-bis(salicylidene)-1,2-phenylenediamine produce ultra-small (2–4 nm) cobalt-nanoparticles embedded in a carbon–nitrogen framework. The resulting materials constitute stable, reusable and magnetically separable catalysts, which enable the synthesis of linear and branched benzylic, heterocyclic and aliphatic primary amines from carbonyl compounds and ammonia. The isolated nanoparticles also represent excellent catalysts for the synthesis of primary, secondary as well as tertiary amines including biologically relevant N-methyl amines.

We report the synthesis of in situ generated cobalt nanoparticles from molecularly defined complexes as efficient and selective catalysts for reductive amination reactions.     

Isomerization of an imine intermediate in a reductive amination reaction over metal catalysts

The reductive amination reaction of acetone by cyclohexylamine over hydrogenation metal catalysts was investigated. The study is focused on the formation of side products in the reaction. It was verified that the formation of amines having unusual combinations of alkyls is caused by the metal-catalyzed rearrangement of the double bond around the nitrogen atom in an imine intermediate and consequent reactions of the isomeric imine. It was found that the isomerization reactions occur over virtually all of the hydrogenation catalysts studied, while their respective activities for the imine isomerization decreases in the order Ni = Co > Ru > Pt = Rh > Pd.