Selective Amination Research Articles

Thermally-Stable Single-Site Pd on CeO2 Catalyst for Selective Amination of Phenols to Aromatic Amines without External Hydrogen.

Developing a new route to produce aromatic amines as key chemicals from renewable phenols is a benign alternative to current fossil-based routes like nitroaromatic hydrogenation, but is challenging because of the high dissociation energy of the Ar-OH bond and difficulty in controlling side reactions. Herein, an aerosolizing-pyrolysis strategy was developed to prepare high-density single-site cationic Pd species immobilized on CeO2 (Pd1/CeO2) with excellent sintering resistance. The obtained Pd1/CeO2 catalysts achieved remarkable selectivity of important aromatic amines (yield up to 76.2 %) in the phenols amination with amines without external hydrogen sources, while Pd nano-catalysts mainly afforded phenyl-ring-saturation products. The excellent catalytic properties of the Pd1/CeO2 are closely related to high-loading Pd single-site catalysts with abundant surface defect sites and suitable acid-base properties. This report provides a sustainable route for producing aromatic amines from renewable feedstocks.

Thermally‐Stable Single‐Site Pd on CeO2 Catalyst for Selective Amination of Phenols to Aromatic Amines without External Hydrogen

AbstractDeveloping a new route to produce aromatic amines as key chemicals from renewable phenols is a benign alternative to current fossil‐based routes like nitroaromatic hydrogenation, but is challenging because of the high dissociation energy of the Ar−OH bond and difficulty in controlling side reactions. Herein, an aerosolizing‐pyrolysis strategy was developed to prepare high‐density single‐site cationic Pd species immobilized on CeO2 (Pd1/CeO2) with excellent sintering resistance. The obtained Pd1/CeO2 catalysts achieved remarkable selectivity of important aromatic amines (yield up to 76.2 %) in the phenols amination with amines without external hydrogen sources, while Pd nano‐catalysts mainly afforded phenyl‐ring‐saturation products. The excellent catalytic properties of the Pd1/CeO2 are closely related to high‐loading Pd single‐site catalysts with abundant surface defect sites and suitable acid‐base properties. This report provides a sustainable route for producing aromatic amines from renewable feedstocks.

Shaping the mechanical properties of a gelatin hydrogel interface via amination.

Injuries to musculoskeletal interfaces, such as the tendon-to-bone insertion of the rotator cuff, present significant physiological and clinical challenges for repair due to complex gradients of structure, composition, and cellularity. Advances in interface tissue engineering require stratified biomaterials able to both provide local instructive signals to support multiple tissue phenotypes while also reducing the risk of strain concentrations and failure at the transition between dissimilar materials. Here, we describe adaptation of a thiolated gelatin (Gel-SH) hydrogel via selective amination of carboxylic acid subunits on the gelatin backbone. The magnitude and kinetics of HRP-mediated primary crosslinking and carbodiimide-mediated secondary crosslinking reactions can be tuned through amination and thiolation of carboxylic acid subunits on the gelatin backbone. We also show that a stratified biomaterial comprised of mineralized (bone-mimetic) and non-mineralized (tendon-mimetic) collagen scaffold compartments linked by an aminated Gel-SH hydrogel demonstrate improved mechanical performance and reduced strain concentrations. Together, these results highlight significant mechanical advantages that can be derived from modifying the gelatin macromer via controlled amination and thiolation and suggest an avenue for tuning the mechanical performance of hydrogel interfaces within stratified biomaterials.

Sustainable ammonia and amines from chitin

Efforts are underway to explore alternative methods to the Haber-Bosch process for sustainable ammonia production, while the potential for ammonia extraction from natural nitrogenous biomass is under-exploited. Here, a synergistic catalytic strategy involving acid and modified Ru-based catalysts is communicated for the direct production of amines and ammonia from chitin. Phosphoric acid promotes the cleavage of ether bonds in biomass polymers and also serves to protect amino groups from being removed. Selective hydrogenation, deoxygenation, and amination can be achieved by controllably adjusting the ratio of Ru0/Run+. The utilization of nitrogen atoms in chitin can reach up to 95 % (21 % amines, 74 % ammonium), and the catalytic process is applicable to waste shrimp shells. This study demonstrates the possibility of efficient production of nitrogen-containing compounds from abundant biopolymers.

Ethynylbenzaldehydes as novel reaction-based “turn-on” fluorescent probes for primary amine detection in solution, vapor, food, proteins, and live cells

Amine detection is of great importance as excess volatile amine exposure and increased concentration of biogenic amines in human body can cause adverse effects to human health. Thus, the development of easy-accessible and efficient fluorescent probes for amine detection is of great importance. In this study, we are the first to establish a cascade reaction sequence featuring imine formation followed by 6-endo-dig cyclization reaction for the development of sensitive and selective “turn-on” fluorescent probes toward primary amines by using the ortho-ethynylbenzaldehydes (EBAs) as the reaction site. The corresponding isoquinolinium products generated give a significant red-shifted absorbance change and highly intense “turn-on” fluorescence. Nine EBAs (EBA-1a-1e, EBA-2–5) were designed and synthesized to study the structure-photophysical property relationship (SPPR) for selective primary amine sensing. Our EBAs possessed a highly sensitive response toward primary amines in aqueous conditions within 30 min (LOD as low as 0.45 µM) with tunable absorption (338–430 nm) and emission (410–535 nm), large Stokes shift (up to 115 nm), and high fluorescence quantum yield (up to 0.86). EBA-loaded paper strips were prepared as a portable low cost tool for amine detection in solution, vapor, and food. Fluorogenic protein labelling and in-gel fluorescent imaging were efficiently achieved by using EBAs in which the fluorescence signal was obviously observed by naked eyes under 365 nm UV lamp. Moreover, the favorable membrane permeabilization, low to moderate cytotoxicity, and “turn-on” fluorescent response of EBA-1a-1e and EBA-4–5 allow wash-free live cell imaging. Interestingly, EBA-1a-1e and EBA-4 showed high selectivity to fluorescent imaging of mitochondria.

Iron‐catalyzed C‐7 Selective NH2 Amination of Indoles

Abstract7‐Aminoindoles are important synthetic intermediates to a broad range of bioactive molecules. Transition metal‐catalyzed directed C−H amination is among the most straightforward route for their synthesis, whereas methods that could directly incorporate an NH2 group in a highly selective manner remains elusive. Moreover, there is still high demand for the development of earth‐abundant metal catalysis for such attractive reactivity. We present here the first C‐7 selective NH2 amination of indoles through a directed homolytic aromatic substitution (HAS) with iron‐aminyl radical. The reaction exhibits broad substrate scope, tolerates variety of functional groups, and is readily scalable with catalyst loading down to 0.1 mol % and turnover number (TON) up to 4500.

Iron-catalyzed C-7 Selective NH2 Amination of Indoles.

7-Aminoindoles are important synthetic intermediates to a broad range of bioactive molecules. Transition metal-catalyzed directed C-H amination is among the most straightforward route for their synthesis, whereas methods that could directly incorporate an NH2 group in a highly selective manner remains elusive. Moreover, there is still high demand for the development of earth-abundant metal catalysis for such attractive reactivity. We present here the first C-7 selective NH2 amination of indoles through a directed homolytic aromatic substitution (HAS) with iron-aminyl radical. The reaction exhibits broad substrate scope, tolerates variety of functional groups, and is readily scalable with catalyst loading down to 0.1 mol % and turnover number (TON) up to 4500.

Pd-catalyzed Markovnikov selective oxidative amination of 4-pentenoic acid.

Pd-catalyzed regioselective amination of unactivated alkene remains a challenge and is of great interest. Herein, a palladium-catalyzed and ligand-controlled strategy for the Markovnikov selective oxidative amination of 4-pentenoic acid has been described. The protocol effectively reverses the carboxylic acid-directed anti-Markovnikov selectivity in oxidative amination of 4-pentenoic acid, successfully constructing γ-ketoamide derivatives.

NNO Pincer-Supported Pd(II)-Catalyzed Reductive N-Alkylation of Challenging Nitroarenes with Alcohols via Borrowing Hydrogen Strategy.

A sustainable catalytic synthesis of selective monoalkylated amines from nitroarenes and alcohols by new palladium(II)-NNO pincer-type complexes has been described. Herein, a series of Pd(II) complexes [Pd(NNO)PPh3] (1-3) are synthesized and characterized by analytical and spectroscopic (IR, NMR, and HR-MS) methods. The solid-state molecular structures of two complexes are established by X-ray single-crystal diffraction. Furthermore, the catalytic N-alkylation of challenging nitroarenes with primary and secondary alcohols has been performed by the well-defined palladium(II) complexes via borrowing hydrogen strategy. The current protocol offers a wide range of monoalkylated amines (26 examples) with a maximum yield of 87% utilizing 1 mol % of catalyst loading. Gratifyingly, the catalytic system works well under mild reaction conditions and atom economy with water is the only byproduct. Furthermore, control experiments confirm the formation of probable intermediates (aniline, aldehyde, and imine), and deuterium labeling authenticates the borrowing hydrogen mechanism. A gram-scale synthesis of an alkylated product clearly demonstrates the synthetic efficacy of the present catalytic methodology.

Two‐Step Biocatalytic Synthesis of (1S)‐Nor(pseudo)ephedrine Catalyzed by Immobilized Enzymes

AbstractNor(pseudo)ephedrines [N(P)Es] are naturally occurring compounds showing sympathomimetic activity that have many applications especially in the chemical industry and in the pharmaceutical field. Recently a two‐step biocatalytic cascade for the preparation of (1S)‐N(P)E was designed, consisting of a benzoin‐type condensation catalyzed by the (S)‐selective acetoin:dichlorophenolindophenol oxidoreductase (Ao : DCPIP OR) followed by a transamination mediated by either a (S)‐ or (R)‐selective amine transaminase (ATA). In this study, we successfully immobilized both Ao : DCPIP OR and two ATAs of opposite enantioselectivity and used them in the biosynthetic cascade to N(P)Es. Immobilization yield, activity recovery, and stability of the immobilized enzymes, both after use (enzyme recycling) and storage (shelf‐life), were assessed. Ao : DCPIP OR immobilized on glyoxyl‐agarose exhibited remarkable stability under storage conditions throughout the 30‐days monitoring period. Moreover, it was successfully reused in the synthesis of (S)‐phenylacetylcarbinol [(S)‐PAC] yielding high conversion (>94 %) and enantiomeric excess (>99 %). The (R)‐selective At‐ATA from Aspergillus terreus, immobilized on Eupergit® C, demonstrated a slightly higher storage stability when compared to the (S)‐selective Sbv333‐ATA from Streptomyces sp. Bv333 immobilized on the same carrier. Remarkably, both enzymes were effectively reused for ten reaction cycles in the synthesis of N(P)Es, starting from the enzymatically synthesized (S)‐PAC, achieving complete conversions and excellent diastereoselectivity (>99 %).

Tuning the Selectivity of Catalytic Nitrile Hydrogenation with Phase-Controlled Co Nanoparticles Prepared by Hydrosilane-Assisted Method.

Cobalt (Co) is a promising candidate to replace noble metals in the hydrogenation process, which is widely employed in the chemical industry. Although the catalytic performance for this reaction has been considered to be significantly dependent on the Co crystal phase, no satisfactory systematic studies have been conducted, because it is difficult to synthesize metal nanoparticles that have different crystalline structures with similar sizes. Here we report a new method for the synthesis of cobalt nanoparticles using hydrosilane as a reducing agent (hydrosilane-assisted method). This new method uses 1,3-butanediol and propylene glycol to successfully prepare fcc and hcp cobalt nanoparticles, respectively. These two types of Co nanoparticles have similar sizes and surface areas. The hcp Co nanoparticles exhibit higher catalytic performance than fcc nanoparticles for the hydrogenation of benzonitrile under mild conditions. The present hcp Co catalyst is also effective for highly selective benzyl amine production from benzonitrile without ammonia addition, whereas many catalytic systems require ammonia addition for selective benzyl amine production. Mechanistic studies revealed that the fast formation of the primary amine and the prevention of condensation and secondary amine hydrogenation promote selective benzonitrile hydrogenation for benzylamine over hcp Co nanoparticles.

Benign and Selective Amination of Lignins towards Aromatic Biobased Building Blocks with Primary Amines.

Lignin is a widely available second-generation biopolymer and the main potential source of renewable aromatic building blocks. Lignin-based polyamines offer great potential in applications based on chemical and materials sciences. However, common aminations techniques for lignin usually involve toxic chemicals and generate hindered and low reactivity amines. In this study, we developed two new, simple, and benign 2-step methodologies for the elaboration of lignin-based polyamines from different technical lignins (kraft, soda and organosolv) with a selectivity towards reactive primary amines. These methods involve grafting amide groups onto lignin followed by a hydrolysis step. Non-toxic heterocyclic compounds N-acetyl-2-oxazolidinone and 2-methyl-2-oxazoline were used as amidation agents. Hydrolysis was performed in acetone-water mixtures. Reactions were studied on model compounds and optimized on lignins. Aminated lignins were fully characterized and primary amines were quantified using quantitative 19F NMR. Our methods generated aminated lignins with low apparent molar masses and high solubility in water and solvents. Nitrogen contents of the products ranged between 2.0 and 3.5 mmol/g with reactive primary amines counts up to 1.7 mmol/g. These soluble and reactive lignin-based polyamines offer great potential as a replacement for fossil-based polyamines in e.g., the synthesis of aromatic polymer materials or as potential chelating, antibacterial agents.

Benign and Selective Amination of Lignins towards Aromatic Biobased Building Blocks with Primary Amines

Lignin is a widely available second‐generation biopolymer and the main potential source of renewable aromatic building blocks. Lignin‐based polyamines offer great potential in applications based on chemical and materials sciences. However, common aminations techniques for lignin usually involve toxic chemicals and generate hindered and low reactivity amines. In this study, we developed two new, simple, and benign 2‐step methodologies for the elaboration of lignin‐based polyamines from different technical lignins (kraft, soda and organosolv) with a selectivity towards reactive primary amines. These methods involve grafting amide groups onto lignin followed by a hydrolysis step. Non‐toxic heterocyclic compounds N‐acetyl‐2‐oxazolidinone and 2‐methyl‐2‐oxazoline were used as amidation agents. Hydrolysis was performed in acetone‐water mixtures. Reactions were studied on model compounds and optimized on lignins. Aminated lignins were fully characterized and primary amines were quantified using quantitative 19F NMR. Our methods generated aminated lignins with low apparent molar masses and high solubility in water and solvents. Nitrogen contents of the products ranged between 2.0 and 3.5 mmol/g with reactive primary amines counts up to 1.7 mmol/g. These soluble and reactive lignin‐based polyamines offer great potential as a replacement for fossil‐based polyamines in e.g., the synthesis of aromatic polymer materials or as potential chelating, antibacterial agents.

Selective Multifunctional Aliphatic Amine Synthesis: Unraveling Universal Control Strategies in Catalytic Reductive Amination of Biobased α-Hydroxy Carbonyl Oxygenates

Selective Multifunctional Aliphatic Amine Synthesis: Unraveling Universal Control Strategies in Catalytic Reductive Amination of Biobased α-Hydroxy Carbonyl Oxygenates

A refined picture of the native amine dehydrogenase family revealed by extensive biodiversity screening

Native amine dehydrogenases offer sustainable access to chiral amines, so the search for scaffolds capable of converting more diverse carbonyl compounds is required to reach the full potential of this alternative to conventional synthetic reductive aminations. Here we report a multidisciplinary strategy combining bioinformatics, chemoinformatics and biocatalysis to extensively screen billions of sequences in silico and to efficiently find native amine dehydrogenases features using computational approaches. In this way, we achieve a comprehensive overview of the initial native amine dehydrogenase family, extending it from 2,011 to 17,959 sequences, and identify native amine dehydrogenases with non-reported substrate spectra, including hindered carbonyls and ethyl ketones, and accepting methylamine and cyclopropylamine as amine donor. We also present preliminary model-based structural information to inform the design of potential (R)-selective amine dehydrogenases, as native amine dehydrogenases are mostly (S)-selective. This integrated strategy paves the way for expanding the resource of other enzyme families and in highlighting enzymes with original features.

Synthesis of Secondary Amines via Self-Limiting Alkylation.

N-centered nucleophilicity increases upon alkylation, and thus selective partial alkylation of ammonia and primary amines can be challenging: Poor selectivity and overalkylation are often observed. Here we introduce N-aminopyridinium salts as ammonia surrogates for the synthesis of secondary amines via self-limiting alkylation chemistry. Readily available N-aryl-N-aminopyridinium salts engage in N-alkylation and in situ depyridylation to afford secondary aryl-alkyl amines without any overalkylation products. The method overcomes classical challenges in selective amine alkylation by accomplishing alkylation via transient, highly nucleophilic pyridinium ylide intermediates and can be applied in the context of complex molecular scaffolds. These findings establish N-aminopyridinium salts as ammonia synthons in synthetic chemistry and a strategy to control the extent of amine alkylation.

Selective amination of furfuryl alcohol to furfurylamine over nickel catalysts promoted by alumina encapsulation

Direct amination of bio-based furfuryl alcohol over metal catalysts provides an alternative route to produce furfurylamine without consuming expensive reducing reagents. The harsh and reductive condition of furfuryl alcohol amination, however, requires high durability and excellent resistance to side furan-ring hydrogenation for efficient catalysts, which is still substantially challenging to non-noble metals. We show here that alumina-encapsulated Ni catalysts prepared via a sol–gel method exhibited an outstanding and stable performance in selective amination of furfuryl alcohol to furfurylamine under mild NH3 and H2 partial pressures. Structural characterization unveiled that the alumina framework with appropriate mesopores effectively restrained the agglomeration of Ni nanoparticles and the side furan-ring hydrogenation. A volcano-type dependance of the intrinsic activity of Ni nanoparticles on their sizes was established with the maximum attained at about 5 nm, which correlated well with the redox ability of surface Ni sites. Kinetic assessments further indicated the kinetic relevance of furfural formation from furfuryl alcohol dehydrogenation, evidenced by quasi-zero and negative reaction orders on NH3 and H2 pressures, respectively. Combined with infrared spectroscopy, furfuryl alcohol was identified as the predominant adsorbed species with a nearly saturated coverage under reaction condition, consistent with the high susceptibility of furan-ring hydrogenations to H2 pressure. As a consequence, a slight amount of inert Ag (0.05 wt%) was introduced onto the alumina-encapsulated Ni catalysts to weaken the adsorption of furfuryl alcohol and its derivatives, which suppressed the side over-hydrogenation reactions to an extremely low level without sacrificing catalytic activity significantly.

Transaminase-catalysis to produce trans-4-substituted cyclohexane-1-amines including a key intermediate towards cariprazine

Cariprazine—the only single antipsychotic drug in the market which can handle all symptoms of bipolar I disorder—involves trans-4-substituted cyclohexane-1-amine as a key structural element. In this work, production of trans-4-substituted cyclohexane-1-amines was investigated applying transaminases either in diastereotope selective amination starting from the corresponding ketone or in diastereomer selective deamination of their diasteromeric mixtures. Transaminases were identified enabling the conversion of the cis-diastereomer of four selected cis/trans-amines with different 4-substituents to the corresponding ketones. In the continuous-flow experiments aiming the cis diastereomer conversion to ketone, highly diastereopure trans-amine could be produced (de > 99%). The yield of pure trans-isomers exceeding their original amount in the starting mixture could be explained by dynamic isomerization through ketone intermediates. The single transaminase-catalyzed process—exploiting the cis-diastereomer selectivity of the deamination and thermodynamic control favoring the trans-amines due to reversibility of the steps—allows enhancement of the productivity of industrial cariprazine synthesis.

Electron-Rich Ru Supported on N-Doped Coffee Biochar for Selective Reductive Amination of Furfural to Furfurylamine.

Highly selective synthesis of primary amines from renewable biomass has attracted increasing attention, but it still faces great challenges in chemical industry applications. In this study, an electron-rich Ru catalyst was constructed by doping N into coffee biochar using a one-pot carbonization method (Ru/NCB-600). Ru/NCB-600 showed high catalytic activity and yield for the reductive amination of furfural with green and cheap NH3 and H2. The excellent catalytic performance of Ru/NCB-600 was closely correlated to the formation of electron-rich Ruδ- species (Ruδ--Nxδ+), which endowed Ru/NCB-600 with an enhanced H2 adsorption and activation ability. Ru/NCB-600 showed a high formation rate of 95.6 gfurfurylamine·gRu-1·h-1 and a high yield of furfurylamine (98.6%) at 50 °C. Ru/NCB-600 can also be used for the reductive amination of various carbonyl compounds in good to excellent yield (95.4-99%). This study thus provides a potential pathway for the highly selective reductive amination of carbonyl compounds by regulating the electron density of Ru.

Selected Electrosynthesis of 3-Aminopyrazoles from α,β-Alkynic Hydrazones and Secondary Amines.

An available and simple electromediated cyclization method for 3-amino-substituted pyrazoles by using α,β-alkynic hydrazone and secondary amine is described. The strategy utilizes KI as an electrolyte in an undivided cell with a constant current, generating the desired products in moderate-to-good yield. The method features selective amination at the 3-position of the pyrazole skeleton. The results indicate that α,β-alkynic hydrazones functionalized with aromatic groups and secondary amines functionalized with electron-rich groups were better tolerated in this transformation.