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.     

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.     

Asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases

Chiral primary amines are important intermediates in the synthesis of pharmaceutical compounds. Fungal reductive aminases (RedAms) are NADPH-dependent dehydrogenases that catalyse reductive amination of a range of ketones with short-chain primary amines supplied in an equimolar ratio to give corresponding secondary amines. Herein we describe structural and biochemical characterisation as well as synthetic applications of two RedAms from Neosartorya spp. (NfRedAm and NfisRedAm) that display a distinctive activity amongst fungal RedAms, namely a superior ability to use ammonia as the amine partner. Using these enzymes, we demonstrate the synthesis of a broad range of primary amines, with conversions up to >97% and excellent enantiomeric excess. Temperature dependent studies showed that these homologues also possess greater thermal stability compared to other enzymes within this family. Their synthetic applicability is further demonstrated by the production of several primary and secondary amines with turnover numbers (TN) up to 14 000 as well as continous flow reactions, obtaining chiral amines such as (R)-2-aminohexane in space time yields up to 8.1 g L⁻¹ h⁻¹. The remarkable features of NfRedAm and NfisRedAm highlight their potential for wider synthetic application as well as expanding the biocatalytic toolbox available for chiral amine synthesis.

Fungal reductive aminases as effective biocatalysts for the preparation of chiral primary amines.     

High performance of nitrogen-doped carbon-supported cobalt catalyst for the mild and selective synthesis of primary amines

A nitrogen-doped carbon-supported Co catalyst (Co/N-C-800) was discovered to be highly active for the reductive amination of carbonyl compounds with NH₃ and the hydrogenation of nitriles into primary amines using H₂ as the hydrogen source. Structurally diverse carbonyl compounds were selectively transformed into primary amines with good to excellent yields (82.8–99.6%) under mild conditions. The Co/N-C-800 catalyst showed comparable or better catalytic performance than the reported noble metal catalysts. The Co/N-C-800 catalyst also showed high activity for the hydrogenation of nitriles, affording the corresponding primary amines with high yields (81.7–99.0%). An overall reaction mechanism is proposed for the reductive amination of benzaldehyde and the hydrogenation of benzonitrile, which involves the same intermediates of phenylmethanimine and N-benzylidenebenzylamine.     

硝基芳烃与醇还原胺化:催化剂和催化机制

胺类化合物由于其化学结构和性质上的特点,在合成药物、染料和精细化学品等方面有着重要的应用。胺类化合物的合成方法很多,其中硝基芳烃与醇还原胺化反应由于可以“一锅”法将性质稳定、来源广泛的硝基芳烃、醇转化为各类胺类化合物,且无需提供额外的氢源,从而成为研究的热点。本文即以硝基芳烃与醇还原胺化反应路径为主线,从催化剂及其催化机制两方面对硝基芳烃与醇还原胺化反应的研究进展进行综述,分别对已开发的贵金属催化剂、光催化剂及一些其他类型催化剂作了介绍,重点阐述了催化剂的催化性能、底物适用范围和催化机制。尽管目前各类催化体系都已取得较大的进展,但在一定程度上依然存在着催化剂成本高,底物适应性窄,需要大量使用碱性助剂、溶剂、供氢试剂等问题。基于以上问题,本文指出硝基芳烃与醇还原胺化应重点发展绿色高效、廉价、普适性好、通用性强的催化体系;同时,还要系统地对各种催化剂的催化机制进行深入的研究,为催化体系的开发提供指导。     

Effects of ruthenium hydride species on primary amine synthesis by direct amination of alcohols over a heterogeneous Ru catalyst

Heterogeneously catalysed synthesis of primary amines by direct amination of alcohols with ammonia has long been an elusive goal. In contrast to reported Ru-based catalytic systems, we report that Ru–MgO/TiO₂ acts as an effective heterogeneous catalyst for the direct amination of a variety of alcohols to primary amines at low temperatures of ca. 100 °C without the introduction of H₂ gas. The present system could be applied to a variety of alcohols and provides an efficient synthetic route for 2,5-bis(aminomethyl)furan (BAMF), an attention-getting biomonomer. The high catalytic performance can be rationalized by the reactivity tuning of Ru–H species using MgO. Spectroscopic measurements suggest that MgO enhances the reactivity of hydride species by electron donation from MgO to Ru.

Ru–MgO/TiO₂ exhibited high catalytic performance for direct amination of alcohols based on the acceleration effects of MgO.     

Synthesis of hindered tertiary amines by a mild reductive amination procedure

An efficient metal-free procedure for the synthesis of tertiary amines by the reductive amination of carbonyl compounds is reported, which allows a convergent access to sterically hindered amines of the general formulas NR(R′)₂ and NRR′R″. The mild and operationally simple protocol uses the Hantzsch ester for transfer hydrogenation and catalytic amounts of thiourea for imine activation.     

Ruthenium-Catalyzed Direct Reductive Amination of Carbonyl Compounds for the Synthesis of Amines: An Overview

Reductive amination is a valuable method for amine synthesis that has been the topic of a century‘s worth of in-depth study in both academia and industry. Amines and their derivatives serve as incredibly adaptable building blocks for a broad array of organic substrates and are significant precursors for a myriad of advanced chemicals, physiologically active compounds, agrochemicals, biomolecules, pharmaceuticals, and polymers. The creation of innovative catalytic processes for the long-term and selective synthesis of amines from readily accessible and environmentally benign reagents remains a top priority in chemical research. Both heterogeneous and homogeneous catalysts have been designed with success to enable these reactions to explore new amines. Ruthenium catalysts are employed in reductive amination owing to their stability, selectivity, versatility, low toxicity, and high efficiency. This review comprehensively overviews the Ru-catalyzed reductive amination processes and includes the literature from 2009 to 2022.     

Synthesis of primary amines: first homogeneously catalyzed reductive amination with ammonia

[reaction: see text] The synthesis of primary amines via reductive amination of the corresponding carbonyl compounds with aqueous ammonia is achieved for the first time with soluble transition metal complexes. Up to an 86% yield and a 97% selectivity for benzylamines were obtained in the case of various benzaldehydes by using a Rh-catalyst together with water-soluble phosphine and ammonium acetate. In the case of aliphatic aldehydes, a bimetallic catalyst based on Rh/Ir gave improved results.     

Production of Primary Amines by Reductive Amination of Biomass‐Derived Aldehydes/Ketones

Transformation of biomass into valuable nitrogen‐containing compounds is highly desired, yet limited success has been achieved. Here we report an efficient catalyst system, partially reduced Ru/ZrO₂, which could catalyze the reductive amination of a variety of biomass‐derived aldehydes/ketones in aqueous ammonia. With this approach, a spectrum of renewable primary amines was produced in good to excellent yields. Moreover, we have demonstrated a two‐step approach for production of ethanolamine, a large‐market nitrogen‐containing chemical, from lignocellulose in an overall yield of 10 %. Extensive characterizations showed that Ru/ZrO₂‐containing multivalence Ru association species worked as a bifunctional catalyst, with RuO₂ as acidic promoter to facilitate the activation of carbonyl groups and Ru as active sites for the subsequent imine hydrogenation.     

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.     

Synthesis of oxalamides by acceptorless dehydrogenative coupling of ethylene glycol and amines and the reverse hydrogenation catalyzed by ruthenium

A sustainable, new synthesis of oxalamides, by acceptorless dehydrogenative coupling of ethylene glycol with amines, generating H₂, homogeneously catalyzed by a ruthenium pincer complex, is presented. The reverse hydrogenation reaction is also accomplished using the same catalyst. A plausible reaction mechanism is proposed based on stoichiometric reactions, NMR studies, X-ray crystallography as well as observation of plausible intermediates.

Ruthenium catalyzed acceptorless dehydrogenative coupling of ethylene glycol and amines to oxalamides is reported. The reverse hydrogenation reaction is also accomplished.     

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.     

Catalytic Reductive N‐Alkylations Using CO2 and Carboxylic Acid Derivatives: Recent Progress and Developments

N‐Alkylamines are key intermediates in the synthesis of fine chemicals, dyes, and natural products, and hence are highly valuable building blocks in organic chemistry. Consequently, the development of greener and more efficient procedures for their production continues to attract the interest of both academic and industrial chemists. Reductive procedures such as reductive amination or N‐alkylation through hydrogen autotransfer by employing carbonyl compounds or alcohols as alkylating agents have prevailed for the synthesis of amines. In the last few years, carboxylic/carbonic acid derivatives and CO₂ have been introduced as alternative and convenient alkylating sources. The safety, easy accessibility, and high stability of these reagents makes the development of new reductive transformations with them as N‐alkylating agents a useful alternative to existing procedures. In this Review, we summarize reported examples of one‐pot reductive N‐alkylation methods that use carboxylic/carbonic acid derivatives or CO₂ as alkylating agents.     

A practical catalytic reductive amination of carboxylic acids

We report reductive alkylation reactions of amines using carboxylic acids as nominal electrophiles. The two-step reaction exploits the dual reactivity of phenylsilane and involves a silane-mediated amidation followed by a Zn(OAc)₂-catalyzed amide reduction. The reaction is applicable to a wide range of amines and carboxylic acids and has been demonstrated on a large scale (305 mmol of amine). The rate differential between the reduction of tertiary and secondary amide intermediates is exemplified in a convergent synthesis of the antiretroviral medicine maraviroc. Mechanistic studies demonstrate that a residual 0.5 equivalents of carboxylic acid from the amidation step is responsible for the generation of silane reductants with augmented reactivity, which allow secondary amides, previously unreactive in zinc/phenylsilane systems, to be reduced.

We report reductive alkylation reactions of amines using carboxylic acids as nominal electrophiles.     

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.     

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.     

Photoredox-enabled 1,2-dialkylation of α-substituted acrylates via Ireland–Claisen rearrangement

Herein, we report the 1,2-dialkylation of simple feedstock acrylates for the synthesis of valuable tertiary carboxylic acids by merging Giese-type radical addition with an Ireland–Claisen rearrangement. Key to success is the utilization of the reductive radical-polar crossover concept under photocatalytic reaction conditions to force the [3,3]-sigmatropic rearrangement after alkyl radical addition to allyl acrylates. Using readily available alkyl boronic acids as radical progenitors, this redox-neutral, transition-metal-free protocol allows the mild formation of two C(sp³)–C(sp³) bonds, thus providing rapid access to complex tertiary carboxylic acids in a single step. Moreover, this strategy enables the efficient synthesis of highly attractive α,α-dialkylated γ-amino butyric acids (GABAs) when α-silyl amines are used as radical precursors – a structural motif that was still inaccessible in related transformations. Depending on the nature of the radical precursors and their inherent oxidation potentials, either a photoredox-induced radical chain or a solely photoredox mechanism is proposed to be operative.

A photocatalytic 1,2-dialkylation of α-substituted acrylates is enabled by a reaction cascade combining reductive radical-polar crossover with the established Ireland–Claisen rearrangement for the synthesis of valuable tertiary carboxylic acids.     

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.     

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.