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Amino acids are a class of compounds with wide‐ranging applications. The synthesis of amino acids from biomass‐derived α‐keto acids and ammonia is a sustainable way but the unstable primary imine intermediates (R−C=NH) easily form oligomers. Herein, targeting this problem, alkaline modified mesoporous silica was employed as a support for ruthenium (Ru/M‐MCM‐41), which could be used as a bifunctional catalyst in the reductive amination of α‐keto acids to synthesize α‐amino acids. The incorporation of Sr improved the dispersion of Ru nanoparticles and enhanced metal‐support interactions via electron transfer from Sr to Ru, and the active Ru sites could efficiently hydrogenate primary imine intermediates to α‐amino acids, thus prohibiting the formation of oligomers. Moreover, the Sr‐dopant introduces base sites that could catalyze the hydrolysis of oligomers back to primary imine intermediates and finally hydrogenated to α‐amino acids. As a result, >99 % yield of glycine was achieved from glyoxylic acid over Ru/Sr‐MCM‐41, which is nearly three times that achieved over Ru/MCM‐41 (32.2 %). [ABSTRACT FROM AUTHOR]

Producing biomass‐derived chemicals to substitute their petrochemical counterparts has long been an aspiration of the green chemistry research community. However, synthesizing secondary amines from biomass precursors presents several challenges related to catalyst nature and the mechanistic understanding of reaction systems. Here, we unravel the mechanistic and kinetic implications of the reductive amination of phenol with cyclohexylamine over Pd/C and Rh/C. A competitive Langmuir‐Hinshelwood reaction model well interpreted the kinetic data, suggesting that support‐metal interfaces serve as active sites for H2, ─NH2 and ═NH activation. The apparent activation energies for imine hydrogenation were 87.6 kJ mol−1 (Pd/C) and 34.5 kJ mol−1 (Rh/C), while ΔHads and ΔSads values confirmed the physicochemical consistency of the model. Moreover, the catalysts demonstrated their high stability to operate for several catalytic cycles, with minor activity losses due to metal leaching and partial sintering of Pd nanoparticles. Despite phenol reductive amination following similar mechanisms on Rh/C and Pd/C, they show differences in selectivity because the hydrogenation of imine is more efficient on Rh0 than on Pd0. This is the first mechanism‐oriented kinetic study for phenol reductive amination; thus, it provides valuable information for process design and scale‐up. [ABSTRACT FROM AUTHOR]

A convenient and concise base-promoted synthesis of 3,4-dihydro-2(1H)-quinazolinones and multi-membered cyclic ureas has been developed. In the presence of tBuOK, a variety of 3,4-dihydro-2(1H)-quinazolinones as well as the N-arylated five-, six- and nine-membered cyclic ureas were readily synthesized under mild conditions. This method offers an alternative synthesis toolkit towards cyclic ureas. [ABSTRACT FROM AUTHOR]

During the deamination and amination processes of meso -diaminopimelate dehydrogenase (meso -DAPDH) from Symbiobacterium thermophilum (StDAPDH), residue R71 was observed to display distinct functions. H154 has been proposed as a basic residue that facilitates water molecules to attack the D-chiral carbon of meso -DAP during deamination. Inspired by the phenomenon of R71, the effects of H154 during deamination and amination were investigated in this study with the goal of enhancing the amination activities of StDAPDH. Single site saturation mutagenesis indicated that almost all of the H154 mutants completely lost their deamination activity towards meso -DAP. However, some H154 variants showed enhanced k cat / K m values towards pyruvic acid and other bulky 2-keto acids, such as 2-oxovaleric acid, 4-methyl-2-oxopentanoic acid, 2-ketobutyric acid, and 3-methyl-2-oxobutanoic acid. When combined with the previously reported W121L/H227I mutant, triple mutants with significantly improved k cat / K m values (2.4-, 2.5-, 2.5-, and 4.0-fold) towards these 2-keto acids were obtained. Despite previous attempts, mutations at the H154 site did not yield the desired results. Moreover, this study not only recognizes the distinctive impact of H154 on both the deamination and amination reactions, but also provides guidance for further high-throughput screening in protein engineering and understanding the catalytic mechanism of StDAPDH. • H154 was first experimentally identified to be the fatal residue for deamination. • H154 mutation boosted the amination towards pyruvic acid and bulky 2-keto acids. • Coupling H154 variants with W121L/H227I resulted in enhanced amination activities. • The first report on the contrary effects of H154 during deamination and amination. • A reminder to update the high-throughput screening for DAPDH amination activity. [ABSTRACT FROM AUTHOR]

Earth abundant metal‐based heterogeneous catalysts with highly active and at the same time stable isolated metal sites constitute a key factor for the advancement of sustainable and cost‐effective chemical synthesis. In particular, the development of more practical, and durable iron‐based materials is of central interest for organic synthesis, especially for the preparation of chemical products related to life science applications. Here, we report the preparation of Fe‐single atom catalysts (Fe‐SACs) entrapped in N‐doped mesoporous carbon support with unprecedented potential in the preparation of different kinds of amines, which represent privileged class of organic compounds and find increasing application in daily life. The optimal Fe‐SACs allow for the reductive amination of a broad range of aldehydes and ketones with ammonia and amines to produce diverse primary, secondary, and tertiary amines including N‐methylated products as well as drugs, agrochemicals, and other biomolecules (amino acid esters and amides) utilizing green hydrogen. [ABSTRACT FROM AUTHOR]

The reductive amination of 1,6‐hexanediol with ammonia is one of the most promising green routes for synthesis of 1,6‐hexanediamine. Herein, we developed a phosphorous modified Ni catalyst of Ni−P/Al2O3. It presented satisfactory improved selectivity to 1,6‐hexanediamine in the reductive amination of 1,6‐hexanediol compared to the Ni/Al2O3 catalyst. The phosphorous tended to interact with Al2O3 to form AlPOx species, induced Ni nanoparticle to be flatter, and the decrease of strong acid sites, the new‐formed Ni−AlPOx−Al2O3 interface and the flatter Ni nanoparticle were the key to switch the dominating product from hexamethyleneimine to 1,6‐hexanediamine. This work develops an efficient catalyst for production of 1,6‐hexanediamine from the reductive amination of 1,6‐hexanediol, and provides a point of view about designing selective non‐noble metal catalysts for producing primary diamines via reductive amination of diols. [ABSTRACT FROM AUTHOR]

We report facile and versatile procedures for the synthesis of exo - and endo -isomeric spirocyclic hybrids of pharmacophoric (1 R ,5 S)-8-azabicyclo[3.2.1]octane (nortropane) and 1,3-oxazinan-2-one fragments. Our approach consists of the hydrocyanation of endo - and exo -isomeric N -Cbz-protected nortropane-3-spiroepoxides, the reduction of hydroxy nitriles into amino alcohols, the synthesis of N -alkylated amino alcohols via reductive amination, the spirocyclization of the amino alcohols, N -alkylation of the unsubstituted 1,3-oxazinan-2-one fragment in the spiro compounds, and removal of the Cbz protecting groups. [ABSTRACT FROM AUTHOR]

Integrating multi‐step reactions through tandem catalysis offers potential for efficient chemical engineering processes, but designing an efficient tandem catalyst is challenging. Herein, we report tailoring the d‐band centers of Ni through alloying with a second metal (M = Fe/Co/Cu/Ga), which enables it to be multifunctional site for tandem reductive amination. A linear correlation of d‐band center with yield of primary amine product was observed. Density functional theory and experiments revealed the upshifted d‐band center strengthened the adsorption of Schiff base intermediate in advantageous di(C&N) mode, also narrowed the adsorption energy gap between NH3 and H2. Furthermore, the multifunctional nanoparticles provide a confined space with short diffusion pathway for NH3* and H* to timely react with Schiff base. As a result, the NiFe/AlOx with a d‐band center nearest to the Fermi level exhibited the highest primary amine yield of 96.2% with five consecutive reusability under extremely low H2 pressure, which is superior to other reported precious‐metal‐based catalysts. [ABSTRACT FROM AUTHOR]

Abstract Catalytic transformation of renewable biomass into value-added chemicals is an appealing strategy to upgrade biomass resources. Due to the presence of abundant oxygen-containing groups such as hydroxyl and aldehyde, biomass and its derived platform molecules have been served as ideal starting feedstock to synthesize valuable N-containing chemicals through reductive amination. In this mini review, we overviewed the recent advances in the reductive amination of several key bio-platform molecules including hydroxyl carboxylic acids, furfural, 5-hydroxylmethyl furfural and levulinic acid, with a focus on the production of amino acids, furan amines and pyrrolidones using thermocatalysis, electrocatalysis or photocatalysis. Moreover, the functions of active sites and the reaction mechanisms in different catalytic systems are discussed to get insights into the key factors in the reductive amination of biomass resources.

Catalytic transformation of renewable biomass into value-added chemicals is an appealing strategy to upgrade biomass resources. Due to the presence of abundant oxygen-containing groups such as hydroxyl and aldehyde, biomass and its derived platform molecules have been served as ideal starting feedstock to synthesize valuable N-containing chemicals through reductive amination. In this mini review, we overviewed the recent advances in the reductive amination of several key bio-platform molecules including hydroxyl carboxylic acids, furfural, 5-hydroxylmethyl furfural and levulinic acid, with a focus on the production of amino acids, furan amines and pyrrolidones using thermocatalysis, electrocatalysis or photocatalysis. Moreover, the functions of active sites and the reaction mechanisms in different catalytic systems are discussed to get insights into the key factors in the reductive amination of biomass resources. [ABSTRACT FROM AUTHOR]

A seven-step ex-chiral-pool synthesis of optically active 4-alkylidenetetrahydroisoquinolines was developed. Starting from 6-bromopiperonal and (S)-serine esters, N -benzylation via reductive amination gave enantiopure N -piperonyl serine esters. Subsequent NH and OH protection delivered defined (S)-serine building blocks. The best results to achieve the conversion into the corresponding serinal were obtained via a two-step sequence of NaBH4 /LiCl reduction and subsequent TEMPO oxidation. Then, chain elongation using the Masamune–Roush variant of the Horner olefination afforded ethyl (E)-4-(N -6-bromopiperonyl)-substituted pentenoates in high yields. Intramolecular Heck cyclization employing the Herrmann–Beller catalyst enabled generation of enantiopure 4-(2-ethoxycarbonylmethylidene)tetrahydroisoquinoline building blocks in high Z -selectivity. Subsequent selected functional group transformations gave carbinols and lactones, which can be used as key intermediates in crinane alkaloid total syntheses. [ABSTRACT FROM AUTHOR]

Furfural is a well-recognized biomass platform. Hydrogenation and reductive amination of furfural are two principal routes in the valorization of this compound. In both reactions, the presence of reducible species (SMSI effect) and acid sites could favor the selectivity toward some interesting products. Both conditions could be obtained using metal particles supported on reducible mixed oxides. In this work, we investigate the use of Pt/Nb2O5-Al2O3 catalysts for the hydrogenation and reductive amination of furfural at distinct Nb2O5 contents. A decaniobate salt was used as a precursor of Nb2O5. The solids were reduced at 500 °C to assure the migration of reducible NbOx species. The solids were characterized by XRD, Raman spectroscopy, HR-TEM, N2-physisorption, NH3-TPD and Pyr-DRIFTS. The results showed that higher Nb2O5 loadings led to a lower distribution of Al2O3 and Pt, favoring the catalysts' acidity. This fact implies that large particle size and the presence of Nb2O5 islands favor the formation of furfuryl alcohol but have a detrimental effect on the amine formation in the reductive amination of furfural. [ABSTRACT FROM AUTHOR]

Nanogels are nanostructures with dimensions within the nanoscale, composed of crosslinked polymers through their functional groups. Nanogels can display sensitiveness to stimuli, such as pH or temperature. This characteristic has been used in the design of new platforms for the transport and release of active ingredients. Biopolymer‐based nanogels are of great interest due to their biodegradability, biocompatibility, nontoxicity, and among others. In this project, pH‐responsive nanogels are synthesized through a novel methodology, using two polysaccharides classified as safe, biocompatible, and easily accessible materials, i.e., chitosan (CS) and maltodextrin (MD). A reductive amination reaction between CS and partially oxidized MDs allows to synthesized MD/CS nanogels with sizes ranging from 90 ± 5 to 194 ± 40 nm and with a colloidal stability up to 7 weeks. It is found that the variation of nanogels size and charge depends on CS concentration, molecular weight, and pH, as well as on the % oxidation of the MD. As evidence of nanogels pH‐responsiveness, an increase of size and ζ‐potential is observed by decreasing the pH. This size increase is attributed to the swelling of the nanogels upon a change in pH. Finally, doxorubicin is encapsulated in MD/CS nanogels, with a loading capacity up to 57%. [ABSTRACT FROM AUTHOR]

A non-precious metal catalyst coated with carbon doped nitrogen supported cobalt by titanium oxide (Co/NC-TiO2-800) was prepared by hydrogen reduction at high temperature using poly (N-vinylimidazole), cobalt nitrate hexahydrate, and tetrabutyl titanate as the raw materials. The carbon network catalyst containing metal-nitrogen can effectively generate isolated active substances to catalyze the reduction amination reaction. Titanium oxide is introduced to stabilize cobalt nanoparticles on nitrogen-doped carbon, which enhances the stability of the catalyst. The samples were characterized by X-ray diffractometer (XRD), specific surface and aperture analyzer (BET), infrared spectrum analyzer (FT-IR), transmission electron microscope (TEM) and scanning electron microscope (SEM). The composition and structure of Co/NC-TiO2-800 were analyzed, and the active center and characteristics of Co/NC-TiO2-800 were revealed. The catalytic activity of Co/NC-TiO2-800 was tested using furfural reduction amination as the model reaction, and the reaction path was discussed. In addition, the effects of different nitrogen sources such as hydrazine hydrate, ammonia water and hydroxylamine hydrate on the reactivity were investigated. The results showed that the yield of furfuryl amine reached 99% at 100 °C and a H2 pressure of 2.0 MPa for 18 h with hydrazine hydrate as nitrogen source and hydrogen as hydrogen source. After 6 times of recycling, the catalytic activity is still high and has excellent stability. [ABSTRACT FROM AUTHOR]

Asymmetric reductive amination directly converts ketones and amines to alkylamines, which are important motifs in medicines. We report that cationic nickel complexes of chiral diphosphines promote enantioselective reductive amination of benzylic ketones with both arylamines and benzhydrazide. Isopropanol was used as a safe and cheap source of hydrogen instead of formic acid. The reaction can be readily applied to a concise synthesis of diarylethylamines, a class of neuroactive substances. [ABSTRACT FROM AUTHOR]

The reductive amination of levulinic and 2‐acetyl benzoic acids with hydrogen and various amines proceeds efficiently in the presence of a homogeneous Ni/triphos‐catalyst. The reaction rate of the overall process is significantly enhanced using 3,3,3‐trifluoroethanol (TFE) as solvent. The optimized synthetic protocol allows for a straightforward access of >20 examples of N‐functionalized pyrrolidinones in high yields (75 % and >99 %). Upscaling to 10 mmol‐scale is demonstrated and mechanistic in situ studies revealed the presence of alkoxy‐ and hydroxylactams as crucial intermediates. [ABSTRACT FROM AUTHOR]

This document provides information on the synthesis of the dopamine agonist Rotigotine, which is used to treat Parkinson's disease and restless leg syndrome. The authors discuss different synthetic approaches and successfully synthesized Rotigotine using reductive amination with a high yield. The document also includes information on the synthesis and characterization of three compounds related to Rotigotine, along with their spectral data. Additionally, it provides details on the synthesis and chiral separation of (±)-Rotigotine, including its chemical structure, physical properties, and analytical data. The authors acknowledge Chemveda Life Sciences for their assistance in the separation process. [Extracted from the article]

Reductive amination of biomass aldehydes is a vital process to synthesize chemical intermediates primary amine, but the selectivity is severely compromised by the self‐condensation of highly reactive imine intermediates. Herein, we proposed a solution by manipulating the adsorption configuration of secondary imine via defect engineering. Specifically, a gradient reduction strategy was used to adjust the driving force of NiCo alloy crystallization, thus motivating the formation of metal vacancy clusters. The primary amine selectivity was raised from 70.9% to 95.1% with defect concentration increased from 36.1% to 42.5% on catalysts. In situ fourier transform infrared spectroscopy (FTIR) and density functional theory demonstrated metal vacancy clusters induced remarkable NiCo electron transfer, which strengthened electronic coupling between secondary imine with catalyst, resulting in a flat configuration that was conducive to CN bond breakage to guarantee smooth conversion into primary amines. This catalyst exhibited potential real‐life application prospects for its low cost, universality in reductive amination of various aldehydes, and long‐life reusability. [ABSTRACT FROM AUTHOR]

Transaminase‐catalysed asymmetric amination is a valuable transformation for the synthesis of chiral amines. However, its use in synthetic chemistry has been curtailed by a narrow substrate scope and limited information on commercially available catalysts. In this work we have explored the substrate scope of selected commercially available transaminases, focusing on prochiral ketones bearing two bulky substituents and their application in both enzyme‐catalysed and enzyme‐triggered reactions. (R)‐ and/or (S)‐selective enzymes converted methyl‐, isopropyl‐, n‐butyl‐, and cyclohexyl‐phenone substrates to the corresponding amines in the range of 6–>99 % ee. In some cases, a stereochemical switch was detected, in which (R)‐enantioselectivity was observed with enzymes typically assigned as (S)‐selective. Upscaling of selected biotransformations provided chiral amines, in >99 % ee and up to 40 % isolated yield. Furthermore, transaminase‐triggered reactions, which were previously limited to methyl‐ and ethyl‐derivatives, were expanded to phenyl‐derivatives for the formation of a cis‐2,6‐disubstituted piperidine and 2,4‐diphenyl pyrroline, and isolated in up to 67 % yield. [ABSTRACT FROM AUTHOR]

Reductive amination with hydrogen is a green and atom‐efficient method to construct amines from accessible aldehydes and ketones. Flow reactors, with superior mass and heat transfer rate because of higher specific surface area, have emerged as a powerful tool to conduct reductive amination with high efficiency and selectivity. This article discusses the influence of catalysts, solvents, temperatures, additives, and substrate properties on reductive amination. Following this, a summary of research on reductive amination with hydrogen in flow reactors is provided. The investigations were classified based on distinct nitrogen sources, encompassing the use of ammonia, amines, and nitro compounds. Based on the influencing factors and reaction cases, the article analyzes the enhancement effects of temperature control, mass transfer intensification, and residence time distribution in flow reactors on the reductive amination. Finally, the article gives a conclusion by addressing challenges and prospects for further developments in this field. [ABSTRACT FROM AUTHOR]

Nitrogen‐containing molecules are used for the synthesis of polymers, surfactants, agrochemicals, and dyes. In the context of green chemistry, it is important to form such compounds from bioresource. Short‐chain primary amines are of interest for the polymer industry, like 2‐aminopropanol, 1‐aminopropan‐2‐ol, and 1,2‐diaminopropane. These amines can be formed through the amination of oxygenated substrates, preferably in aqueous phase. This is possible with heterogeneous catalysts, however, effective systems that allow reactions under mild conditions are lacking. We report an efficient catalyst Ru−Ni/AC for the reductive amination of hydroxyacetone into 2‐aminopropanol. The catalyst has been reused during 3 cycles demonstrating a good stability. As a prospective study, extension to the reactivity of (poly)carbohydrates has been realized. Despite a lesser efficiency, 2‐aminopropanol (9 % yield of amines) has been formed from fructose, the first example from a carbohydrate. This was possible using a 7.5 %Ru‐36 %WxC/AC catalyst, composition allowing a one‐pot retro‐aldol cleavage into hydroxyacetone and reductive amination. The transformation of cellulose through sequential reactions with a combination of 30 %W2C/AC and 7.5 %Ru‐36 %WxC/AC system gave 2 % of 2‐aminopropanol, corresponding to the first example of the formation of this amine from cellulose with heterogeneous catalysts. [ABSTRACT FROM AUTHOR]

In the light of recent progress in the development of SARS-CoV-2 main protease inhibitors, the synthesis of their key fragment, heterocyclic amino acids, is of great interest. Here, we report a method for the preparation of two new quisqualic acid analogs containing hydantoin and imidazolidinone moieties. The hydantoin analog was obtained using an amide ester cyclization, while the imidazolidinone unit was constructed by reductive amination and subsequent cyclization of a substituted ethylenediamine with carbonyldiimidazole. The presented approach provides the convergent synthesis of target analogs in 8 and 5 steps respectively. [ABSTRACT FROM AUTHOR]

N-aryl-substituted pyrrolidines are important moieties widely found in bioactive substances and drugs. Herein, we present a practical reductive amination of diketones with anilines for the synthesis of N-aryl-substituted pyrrolidines in good to excellent yields. In this process, the N-aryl-substituted pyrrolidines were furnished via successive reductive amination of diketones via iridium-catalyzed transfer hydrogenation. The scale-up performance, water as a solvent, simple operation, as well as derivation of drug molecules showcased the potential application in organic synthesis. [ABSTRACT FROM AUTHOR]

Indirect reductive amination of aromatic aldehydes was studied in this work; aqueous ammonia was used as a nitrogen source. The results showed that aromatic aldehydes' reaction with aqueous ammonia produced compounds known as hydrobenzamides (N,N´-(phenylmethylene)bis(1-phenylmethanimines), having good yield. The reaction of hydrobenzamides with sodium borohydride reduced both imine and aminal carbons and produced a primary and secondary benzylamine mixture. This article analyses such behaviour and proposes a possible mechanism for explaining such transformation. The reaction of aromatic aldehydes with aqueous ammonia produced compounds known as hydrobenzamides (N,N´-(phenylmethylene)bis(1-phenylmethanimines). The reaction of hydrobenzamides with sodium borohydride reduced both imine and aminal carbons and produced a primary and secondary benzylamine mixture. [ABSTRACT FROM AUTHOR]

Al2O3-supported monometallic Ni, Co, and bimetallic Ni–Co nanocatalysts originated from layered double hydroxide precursors were synthesized by co-precipitation method, and used for the synthesis of useful 5-amino-1-pentanol (5-AP) and 1,5-pentanediol (1,5-PD) by reductive amination (RA) or direct hydrogenation of biofurfural-derived 2-hydroxytetrahydropyran (2-HTHP), respectively. In both reactions, the yield of the target products decreased monotonously with the increasing amounts of Co in the NiCo/Al2O3 catalysts, owing probably to the replacement of highly reactive Ni by Co component with inferior hydrogenation activity at the low reaction temperature of 60 °C. However, the incorporation of Co could improve the reducibility of the NiCo/Al2O3 bimetallic catalysts and promote the reaction stability of the catalysts, especially for Ni2Co1/Al2O3, in both reactions with over 180 h time-on-stream. Characterization of the catalysts before and after the reaction showed that the incorporating Co could inhibit the sintering of metal particles and hinder the surface oxidation of the more reactive Ni0 species, thanks to the formation of Ni–Co alloy in the bimetallic catalysts. DFT-based modeling of the reaction mechanisms is also performed, supporting the reaction pathway proposed previously and also the much higher activity of Ni in the RA of 2-HTHP as compared with Co.

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. [ABSTRACT FROM AUTHOR]

A self-sufficient bifunctional enzyme integrating reductive amination and coenzyme regeneration activities was developed and successfully employed to synthesize (S)-cyclopropylglycine with an improved reaction rate 2.1-fold over the native enzymes and a short bioconversion period of 6 h at a high substrate concentration of 120 g·L−1 and space–time yield of (S)-cyclopropylglycine up to 377.3 g·L−1·d−1, higher than that of any previously reported data. Additionally, (S)-cyclopropylglycine could be continuously synthesized for 90 h with the enzymes packed in a dialysis tube, providing 634.6 g of (S)-cyclopropylglycine with >99.5% ee and over 95% conversion yield up to 12 changes. These results confirmed that the newly developed NADH-driven biocatalytic system could be utilized as a self-sufficient biocatalyst for industrial application in the synthesis of (S)-cyclopropylglycine, which provides a chiral center and cyclopropyl fragment for the frequent synthesis of preclinical/clinical drug molecules. [ABSTRACT FROM AUTHOR]

The present study focuses on enhancing the thermomechanical properties of poly(methyl methacrylate) (PMMA), a transparent and biocompatible polymer known for its high strength but limited toughness. The approach involves the development of PMMA/cellulose nanocrystals (CNCs) composites. To improve the interfacial compatibility between PMMA and CNCs, a two‐step process is employed. Initially, the CNCs undergo oxidation using sodium periodate, followed by the introduction of amino groups through reductive amination. The aminated CNCs are then covalently bonded to PMMA via an amidation reaction using the "grafting onto" approach. Subsequently, the grafted CNCs are incorporated into the PMMA matrix using the solvent casting method. The resulting composites are extruded into filaments. Elemental composition analysis confirms CNC modification, revealing the presence of 1.6% nitrogen. The modified CNCs exhibit a higher degradation temperature than unmodified CNCs, showing a 50°C increase. The composites' dynamic mechanical analysis (DMA) reveals a 20% improvement in storage modulus (E′) upon incorporating 1.5% of the grafted CNCs into the PMMA matrix. This enhancement is attributed to the formation of co‐continuous phases in the composite structure. [ABSTRACT FROM AUTHOR]

DNA‐encoded libraries (DELs) have become a leading technology for hit identification in drug discovery projects as large, diverse libraries can be generated. DELs are commonly synthesised via split‐and‐pool methodology; thus, chemical transformations utilised must be highly efficient, proceeding with high conversions. Reactions performed in DEL synthesis also require a broad substrate scope to produce diverse, drug‐like libraries. Many pharmaceutical compounds incorporate multiple C−N bonds, over a quarter of which are synthesised via reductive aminations. However, few on‐DNA reductive amination procedures have been developed. Herein is reported the application of the micelle‐forming surfactant, TPGS‐750‐M, to the on‐DNA reductive amination of DNA‐conjugated amines, yielding highly efficient conversions with a broad range of aldehydes, including medicinally relevant heterocyclic and aliphatic substrates. The procedure is compatible with DNA amplification and sequencing, demonstrating its applicability to DEL synthesis. [ABSTRACT FROM AUTHOR]

Sulfur-protected enantiomerically pure 1-phosphanorbornane aldehyde 5 is obtained in good yield via Swern oxidation of the previously reported 1-phosphanorbornane alcohol. The aldehyde is further used to prepare a novel sulfur-protected 1-phosphanorbornane enamine. [ABSTRACT FROM AUTHOR]

DNA encoded library (DEL) synthesis represents a convenient means to produce, annotate and store large collections of compounds in a small volume. While DELs are well suited for drug discovery campaigns, the chemistry used in their production must be compatible with the DNA tag, which can limit compound class accessibility. As a result, most DELs are heavily populated with peptidomimetic and sp2‐rich molecules. Herein, we show that sp3‐rich mono‐ and bicyclic heterocycles can be made on DNA from ketochlorohydrin aldol products through a reductive amination and cyclization process. The resulting hydroxypyrrolidines possess structural features that are desirable for DELs and target a distinct region of pharmaceutically relevant chemical space. [ABSTRACT FROM AUTHOR]

(R)-Homobenzylic amines are key structural motifs present in (R)-selegiline, a drug indicated for the treatment of early-stage Parkinson's disease. Herein, we report a new short chemoenzymatic approach (in 2 steps) towards the synthesis of (R)-selegiline via stereoselective biocatalytic reductive amination as the key step. The imine reductase IR36-M5 mutant showed high conversion (97%) and stereoselectivity (97%) toward the phenylacetone and propargyl amine substrates, offering valuable biocatalysts for synthesizing alkylated homobenzylic amines. [ABSTRACT FROM AUTHOR]

Al2O3-supported monometallic Ni, Co, and bimetallic Ni-Co nanocatalysts originated from layered double hydroxide precursors were synthesized by co-precipitation method, and used for the synthesis of useful 5-amino-1-pentanol (5-AP) and 1,5-pentanediol (1,5-PD) by reductive amination (RA) or direct hydrogenation of biofurfuralderived 2-hydroxytetrahydropyran (2-HTHP), respectively. In both reactions, the yield of the target products decreased monotonously with the increasing amounts of Co in the NiCo/Al2O3 catalysts, owing probably to the replacement of highly reactive Ni by Co component with inferior hydrogenation activity at the low reaction temperature of 60 °C. However, the incorporation of Co could improve the reducibility of the NiCo/Al2O3 bimetallic catalysts and promote the reaction stability of the catalysts, especially for Ni2Co1/Al2O3, in both reactions with over 180 h time-on-stream. Characterization of the catalysts before and after the reaction showed that the incorporating Co could inhibit the sintering of metal particles and hinder the surface oxidation of the more reactive Ni0 species, thanks to the formation of Ni-Co alloy in the bimetallic catalysts. DFT-based modeling of the reaction mechanisms is also performed, supporting the reaction pathway proposed previously and also the much higher activity of Ni in the RA of 2-HTHP as compared with Co. [ABSTRACT FROM AUTHOR]

1,4-Diazepane-6-amine (DAZA) can be alkylated with three 2-hydroxybenzyl pendant arms, resulting in hexadentate chelators suitable for coordination of radiometals like 68Ga. These chelators, N,1,4-tri(alkoxy-2-hydroxybenzyl)-DAZA, can be produced via a one-pot synthesis, with the first step being a carbonyl amine condensation of DAZA with two respective 4-alkoxy-2-hydroxybenzaldehydes, followed by reductive amination with sodium borohydride. While the first step of this reaction is predictable, the subsequent reductive amination can result in either mono-, di- or tri(alkoxy-hydroxybenzyl)-DAZA compounds. Seeking to identify dependencies that might allow a specific reaction control towards the formation of either of the three possible products, and particularly towards the favoured trialkylated DAZA compounds, a variety of synthesis trials were performed. Additionally, computational methods were employed to evaluate the underlying reaction mechanism. Synthesis trials verified that the trialkylated DAZA compounds are formed via direct reductive amination of the dialkylated DAZA compounds. Subsequently, a synthetic method was established, leading to an increase in the percentage of the trialkylated DAZA compounds, which allowed the successful isolation of those hexadentate chelators. Additionally, an alternative pathway proceeding via aminal C–N bond insertion of an attacking third carbonyl moiety was evaluated by means of quantum chemical calculations but so far remains entirely hypothetical.

Abstract Objectives Carbon-14 (14C) labeling is a standard technology for tracing molecules and providing their pharmacokinetic profiles. However, its primary focus has been on small molecules, with limited application to biomacromolecules. Particularly in the development of new biological entities (NBE), the utilization of microdosing with a 14C-labeled biomacromolecule proves beneficial in the early stages of drug development, contributing to significant time and cost savings. This study investigates the 14C-labeling of antibody and explores the stability of 14C-labeled antibody under various storage conditions. Methods and results In this study, the utilization of 14C-formaldehyde for labeling target antibodies at various molar ratios revealed a direct correlation between labeling efficiency and the quantity of 14C-formaldehyde applied: 1.5 mol/mol for 14C-labeled antibody with the use of 10 equivalents of 14C-formaldehyde, 3.8 mol/mol for 14C-labeled antibody with the use of 10 equivalents of 14C-formaldehyde, and 10.5 mol/mol for 14C-labeled antibody with the use of 60 equivalents of 14C-formaldehyde. All the reaction conditions exhibited no antibody degradation, as evidenced by the absence of a significant change in HPLC purity compared to the unlabeled antibody. Stability tests revealed that all groups maintained their purities over a 4-week period at both − 75 ± 10 °C and 5 ± 3 °C. Given safety concerns related to internal radiation exposure in potential human subjects during microdosing, this study established optimal conditions for employing 14C-labeled antibodies. Therefore, it is optimized that 10 equivalents of 14C-formaldehyde can be used for 14C-antibody labeling through reductive amination, storing the antibodies at 5 ± 3 °C, and assigning a storage period of 4 weeks. Conclusion The findings from this study offer valuable insights into the effective application of 14C-labeling in microdosing studies, especially for larger molecules such as antibodies.

Objectives: Carbon-14 (14C) labeling is a standard technology for tracing molecules and providing their pharmacokinetic profiles. However, its primary focus has been on small molecules, with limited application to biomacromolecules. Particularly in the development of new biological entities (NBE), the utilization of microdosing with a 14C-labeled biomacromolecule proves beneficial in the early stages of drug development, contributing to significant time and cost savings. This study investigates the 14C-labeling of antibody and explores the stability of 14C-labeled antibody under various storage conditions. Methods and results: In this study, the utilization of 14C-formaldehyde for labeling target antibodies at various molar ratios revealed a direct correlation between labeling efficiency and the quantity of 14C-formaldehyde applied: 1.5 mol/mol for 14C-labeled antibody with the use of 10 equivalents of 14C-formaldehyde, 3.8 mol/mol for 14C-labeled antibody with the use of 10 equivalents of 14C-formaldehyde, and 10.5 mol/mol for 14C-labeled antibody with the use of 60 equivalents of 14C-formaldehyde. All the reaction conditions exhibited no antibody degradation, as evidenced by the absence of a significant change in HPLC purity compared to the unlabeled antibody. Stability tests revealed that all groups maintained their purities over a 4-week period at both − 75 ± 10 °C and 5 ± 3 °C. Given safety concerns related to internal radiation exposure in potential human subjects during microdosing, this study established optimal conditions for employing 14C-labeled antibodies. Therefore, it is optimized that 10 equivalents of 14C-formaldehyde can be used for 14C-antibody labeling through reductive amination, storing the antibodies at 5 ± 3 °C, and assigning a storage period of 4 weeks. Conclusion: The findings from this study offer valuable insights into the effective application of 14C-labeling in microdosing studies, especially for larger molecules such as antibodies. [ABSTRACT FROM AUTHOR]

Catalytic hydrogenation of nitriles represents an efficient and sustainable one‐step synthesis of valuable bulk and fine chemicals. We report herein a molecular cobalt electrocatalyst for selective hydrogenative coupling of nitriles with amines using protons as the hydrogen source. The key to success for this reductive reaction is the use of an electrocatalytic approach for efficient cobalt‐hydride generation through a sequence of cathodic reduction and protonation. As only electrons (e−) and protons (H+) as the redox equivalent and hydrogen source, this general electrohydrogenation protocol is showcased by highly selective and straightforward synthesis of various functionalized and structurally diverse amines, as well as deuterium isotope labeling applications. Mechanistic studies reveal that the electrogenerated cobalt‐hydride transfer to nitrile process is the rate‐determining step. [ABSTRACT FROM AUTHOR]

Formamides are important feedstocks for the manufacture of many fine chemicals. State‐of‐the‐art synthesis of formamides relies on the use of an excess amount of reagents, giving copious waste and thus poor atom‐economy. Here, we report the first example of direct synthesis of N‐formamides by coupling two challenging reactions, namely reductive amination of carbonyl compounds, particularly biomass‐derived aldehydes and ketones, and fixation of CO2 in the presence of H2 over a metal‐organic framework supported ruthenium catalyst, Ru/MFM‐300(Cr). Highly selective production of N‐formamides has been observed for a wide range of carbonyl compounds. Synchrotron X‐ray powder diffraction reveals the presence of strong host‐guest binding interactions via hydrogen bonding and parallel‐displaced π⋅⋅⋅π interactions between the catalyst and adsorbed substrates facilitating the activation of substrates and promoting selectivity to formamides. The use of multifunctional porous catalysts to integrate CO2 utilisation in the synthesis of formamide products will have a significant impact in the sustainable synthesis of feedstock chemicals. [ABSTRACT FROM AUTHOR]

The efficient synthesis of useful primary amines via reductive amination of biomass-based aldehydes and ketones over earth-abundant base metal catalysts is an attractive biomass value-adding technology yet facing lots of challenges. Herein, natural attapulgite (ATP) was applied as support for the fabrication of active Ni catalysts with different Ni loadings (5-30 wt%) by the deposition-precipitation method. The Ni/ATP-550 catalyst with 10-15 wt % Ni loadings was found to present the highest catalytic performance for the synthesis of valuable 5-amino-1-pentanol (5-AP) via reductive amination of biofurfural-derived 2-hydroxytetrahydropyran among a variety of commonly used oxide supports loaded Ni catalysts, as well as ATP supported nickel catalysts with other loadings, achieving 5-AP yield up to 94%. The intrinsic activity of the Ni/ATP catalysts was found to depend strongly on the Ni0 crystallite size and Ni0 fraction of the catalysts, which generally increased with increasing Ni0 crystallite size and fraction, owing probably to the hydrogenation of imine intermediate is a structure-sensitive reaction. The efficient 10Ni/ATP-550 catalyst also exhibited good activity and stability in the reductive amination of several other biomass-derived aldehydes and ketones to their corresponding primary amines with good to excellent yields (81%-99%). This work provided a clean and efficient natural ATP-supported non-noble metal nickel-based catalytic system for the reductive amination of aldehydes and ketones to synthesize high-value-added primary amines, which could be a promising candidate for the industrial production of amines. [ABSTRACT FROM AUTHOR]

Valorization of biomass‐derived polyols into high‐value‐added ethanolamines and ethylenediamines is highly attractive. Herein, we report a one‐step photocatalytic protocol to convert bio‐polyols into a 60 % yield of ethanolamines and ethylenediamines over a multifunctional Cu/TiO2 catalyst. This catalyst enables a tandem process of photocatalytic polyol C−C bond cleavage and reductive amination in one pot at room temperature, and also allows the selective conversion of various bio‐polyols and amines. Mechanistic studies revealed that photogenerated holes in TiO2 promote the retro‐aldol C−C bond cleavage or oxidative dehydrogenation of polyols, and photogenerated electrons accumulate on small‐sized Cu clusters, which facilitate the reductive amination via hydrogen transfer and prevent the H2 generation. This strategy provides new opportunities for the development of non‐noble metal photocatalysts and methods of biomass conversion under mild conditions. [ABSTRACT FROM AUTHOR]

Aldehydes represent valuable precursors for chemical compounds. However, the incorporation of aldehydes in whole‐cell‐based synthetic enzyme cascades is problematic. Due to their toxicity, they are metabolized to the corresponding alcohols or carboxylic acids by the host enzymatic background. Previous research has shown that these endogenous side reactions can be reversed by alcohol dehydrogenase (AlkJ, Pseudomonas putida) and carboxylic acid reductase (CARNi, Nocardia iowensis) in Escherichia coli. Thereby, the aldehyde is available for further enzymatic conversion to a product of choice. Three different enzymes were incorporated into the concept for the transformation of the aldehyde intermediate: A pyruvate decarboxylase (PDCApE469Q, Acetobacter pasteurianus), ω‐transaminase (ω‐TAVf, Vibrio fluvialis) and imine reductase (IREDCf, Cystobacter ferrugineus). (R)‐Phenylacetylcarbinol and a range of primary and secondary amines were obtained as final products. Either the alcohol, the carboxylic acid or a 50 : 50 mixture could be employed as starting material. [ABSTRACT FROM AUTHOR]

Enzymatic processes play an increasing role in synthetic organic chemistry which requires the access to a broad and diverse set of enzymes. Metagenome mining is a valuable and efficient way to discover novel enzymes with unique properties for biotechnological applications. Here, we report the discovery and biocatalytic characterization of six novel metagenomic opine dehydrogenases from a hot spring environment (mODHs) (EC 1.5.1.X). These enzymes catalyze the asymmetric reductive amination between an amino acid and a keto acid resulting in opines which have defined biochemical roles and represent promising building blocks for pharmaceutical applications. The newly identified enzymes exhibit unique substrate specificity and higher thermostability compared to known examples. The feature that they preferably utilize negatively charged polar amino acids is so far unprecedented for opine dehydrogenases. We have identified two spatially correlated positions in their active sites that govern this substrate specificity and demonstrated a switch of substrate preference by site-directed mutagenesis. While they still suffer from a relatively narrow substrate scope, their enhanced thermostability and the orthogonality of their substrate preference make them a valuable addition to the toolbox of enzymes for reductive aminations. Importantly, enzymatic reductive aminations with highly polar amines are very rare in the literature. Thus, the preparative-scale enzymatic production, purification, and characterization of three highly functionalized chiral secondary amines lend a special significance to our work in filling this gap. Key points: • Six new opine dehydrogenases have been discovered from a hot spring metagenome • The newly identified enzymes display a unique substrate scope • Substrate specificity is governed by two correlated active-site residues [ABSTRACT FROM AUTHOR]

The piperazine moiety is often found in drugs or in bioactive molecules. This widespread presence is due to different possible roles depending on the position in the molecule and on the therapeutic class, but it also depends on the chemical reactivity of piperazine-based synthons, which facilitate its insertion into the molecule. In this paper, we take into consideration the piperazine-containing drugs approved by the Food and Drug Administration between January 2011 and June 2023, and the synthetic methodologies used to prepare the compounds in the discovery and process chemistry are reviewed. [ABSTRACT FROM AUTHOR]

This work represents reductive amination of 5-hydroxymethyl-2-furaldehyde (HMF) to 5-hydroxymethyl-2-furfurylamine (HMFA) catalyzed by Ni-based bimetallic catalysts. It was found that hydroxyapatite (HAP) was the excellent support for the reaction and the bimetallic 3 wt%Ni–2 wt% Co-loaded HAP (Ni3Co2HAP) catalyst gave the highest activity of 60% at 2 mmol scale by a batch reactor. X-ray photoelectron spectroscopy (XPS) and transmission electron microscope (TEM) results suggested that the large metallic composition of both Ni and Co were the crucial factor for high activity on the CoNi-supported HAP catalyst for the synthesis of HMFA via reductive amination of HMF. [ABSTRACT FROM AUTHOR]

Amines are a very important class of compounds and the selective synthesis of differently substituted primary, secondary and tertiary alkyl amines is challenging. Here we present the synthesis of primary, secondary, and tertiary alkyl amines from ammonia and alcohols, aldehydes, ketones and hydrogen by combining borrowing hydrogen or hydrogen autotransfer and reductive amination with hydrogen. The key is a nanostructured, bimetallic Co/Sc catalyst able to mediate both reactions or concepts efficiently. We observe a broad product scope, a very good functional group tolerance, upscaling is easily accomplished and our catalyst is reusable. [ABSTRACT FROM AUTHOR]

Nowadays, the field of biomass conversion is gradually moving towards an encouraging stage. The preparation of nitrogen‐containing chemicals using various biomass resources instead of fossil resources do not only reduce carbon emissions, but also diversify the products of biomass conversion, thus increasing the economic competitiveness of biomass refining systems. Levulinic acid (LA) can be used as a promising intermediate in biomass conversion for further synthesis of pyrrolidone via reductive amination. However, there are still many critical issues to be solved. Particularly, the specific effects of catalysts on the performance of LA reductive amination have not been sufficiently revealed, and the potential impacts of key conditional factors have not been clearly elucidated. In view of this, this review attempts to provide theoretical insights through an in‐depth interpretation of the above key issues. The contribution of catalysts to the reductive amination of LA as well as the catalyst structural preferences for improving catalytic performance are discussed. In addition, the role of key conditional factors is discussed. The insights presented in this review will contribute to the design of catalyst nanostructures and the rational configuration of green reaction conditions, which may provide inspiration to facilitate the nitrogen‐related transformation of more biomass platform molecules. [ABSTRACT FROM AUTHOR]

Background: In recent years, the uses of in situ reaction monitoring have expanded. ReactIR is one of the in situ reaction monitoring techniques used to understand chemical reactions. The reductive amination of Schiff base formed in situ, by treating salicylaldehyde and diethylene triamine using sodium borohydride in methanol, was completed within 28 min and monitored by ReactIR. Materials and Methods: Zinc complexes of diethylene triamine, Schiff base, and their reductive amination products were synthesized using 1:1, 1:2, and 1:3 mole ratios of ligand–zinc chloride at room temperature. Results and conclusion: The formation of the product was confirmed using IR spectra. All these complexes showed photoluminescence in the blue region. [ABSTRACT FROM AUTHOR]

We present an optimized method for the stereoselective synthesis of five‐membered alicyclic and heterocyclic trans‐β‐amino acid derivatives. The process involves a reductive amination of β‐keto esters using chiral auxiliary amines, with formic acid acting as a facilitator for rapid, diastereoselective reductions under gentle conditions. Our approach notably enhances isolated yields and permits the scalable production of trans‐2‐aminocyclopentanecarboxylic acid (trans‐ACPC), 4‐aminopyrrolidine‐3‐carboxylic acid (trans‐APC), 4‐aminotetrahydrofuran‐3‐carboxylic acid (trans‐ATFC), and 4‐aminotetrahydrothiophene‐3‐carboxylic acid (trans‐ATTC) building blocks. [ABSTRACT FROM AUTHOR]

This study reveals that unexpected degradation of food oligosaccharides can occur during conventional glycomics workflows, including sample preparation and analysis by liquid chromatography-mass spectrometry (LC-MS). With the present investigation, we aim to alert the scientific community of the susceptibility of specific glycosidic linkages to degradation induced by heat and acid. Key standard oligosaccharides representing the major types found in foods (3'-sialyllactose and 6'-sialyl-N-acetyllactosamine for milk, raffinose and stachyose for legumes) were selected as model systems and underwent each of the following treatments independently: (1) labeled with the derivatizing agent 1-aminopyrene-3,6,8-trisulfonic (APTS) (followed by analysis with a capillary electrophoresis system coupled with a fluorescence detector), (2) dried from an acetonitrile-water mixture containing 0.1% trifluoroacetic acid, and (3) injected into an LC-MS system. We demonstrated that both raffinose and stachyose degraded during APTS-labeling by the acid in the labeling reagents. We also discovered that during centrifugal evaporation at 37 °C, all of the four nonderivatized oligosaccharides tested were partially degraded. Additionally, when the LC-MS eluent contained 0.1% formic acid, 3'-sialyllactose, raffinose, and stachyose underwent extensive in-source fragmentation during analysis. Lastly, we identified a simple strategy that can reduce the probability of incorrect oligosaccharide identification resulting from extensive in-source fragmentation.