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Synthesizing nitrogen (N)-containing molecules from biomass derivatives is a new strategy for production of this kind of chemicals. Herein, for the first time we present the synthesis of N-substituted aryl pyrroles via reductive amination/cyclization of levulinic acid (LA) with primary aromatic amines and hydrosilanes (e.g., PMHS) over CsF, and a series of N-substituted aryl pyrroles could be obtained in good to excellent yields at 120 °C. The mechanism investigation indicates that the reaction proceeds in two steps: the cyclization between amine and LA occurs first to form intermediate 5-methyl-N-alkyl-1,3-dihydro-2H-pyrrolones and their isomeride (B), and then the chemo- and region-selective reduction of intermediates take place to produce the final products. This approach for synthesis of N-substituted aryl pyrroles can be performed under mild and green conditions, which may have promising applications.

This study investigates reaction kinetics of high-pressure amination of polyalkylene glycol (PAG) to polyetheramine (PEA). The reductive amination of PAG was carried out depending on the NH3 amount, reaction temperature, reaction pressure, and H2O content in a batch reactor to understand the effect of these factors on activity and selectivity toward the primary amine. Contrary to the fact that the amination step is a zero-order reaction and dehydrogenation of alcohol to ketone is the rate-limiting step in the reductive amination of alcohol, the amount of NH3 significantly affected the reaction rate. The increased amount of NH3 enhanced the activity and selectivity for PEA, in contrast with the results reported in prior studies. A Langmuir-Hinshelwood kinetic model was established to reflect the effect of the NH3 amount, and kinetic parameters such as the rate constant and activation energy were obtained at a high pressure around 150 bar. It was also found that the absence of NH3 caused the reverse reaction of PEA to the secondary amine in the presence of H2. The fundamental kinetic analysis provides a competitive synthesis route for improving the activity and selectivity toward the primary amine.

Colloidal metal nanoparticles were examined for reductive amination of phenol by ammonia under mild reaction conditions. The results showed that Rh-PVP was the most active catalyst for reductive am...

We report an efficient and straightforward method to synthesize enantio-enriched N-unprotected α-amino acetals via ruthenium-catalyzed direct asymmetric reductive amination. The α-amino acetal products are versatile and valuable platform molecules that can be converted to the corresponding α-amino acids, amino alcohols, and other derivatives by convenient transformations.

Amines with functional groups are widely used in the manufacture of pharmaceuticals, agricultural chemicals, and polymers, but most of them are still prepared through the petrochemical routes. A sustainable production of amines from renewable resources, such as biomass, is thus necessary. For this reason, we developed an eco-friendly, simplified, and highly effective procedure for the preparation of non-toxic heterogeneous catalyst based on the earth-abundant metals, whose catalytic activity on the reductive amination of furfural or other derives (more than 24 examples) were proved to be broadly available. More surprisingly, the cobalt-supported catalyst was found to be magnetically recoverable and reusable up to eight times with an excellent catalytic activity; on another hand, the gram-scale tests catalyzed by the same catalyst exhibited the similar yield of target products in comparison to its smaller scale, which was comparable to the commercial noble-based catalysts. Further results from a series of analytic technologies involving XRD, XPS, TEM/Mapping and in-situ FTIR revealed that the structural features of catalyst are closely in relation to its catalytic mechanisms. In simple terms, the outer graphitic shell is activated by the electronic interaction as well as the induced charge redistribution, enabling easy substitution of –NH2 moiety toward functionalized and structurally diverse molecules, even under very mild industrially viable and scalable conditions. Overall, this newly developed catalyst introduce the synthesis of amines from biomass-derived platforms with satisfied selectivity and carbon balance, providing a cost-effective and sustainable access to the wide application of reductive amination

Heterogeneous noble metal-based catalysts with stable, precise structures and high catalytic performance are of great research interest for sustainable catalysis. Herein, we designed the novel sandwich-like metal-organic-framework composite nanocatalyst UiO-66-NH2@Pt@mSiO2 using UiO-66-NH2@Pt as the core, and mesoporous SiO2 as the shell. The obtained UiO-66-NH2@Pt@mSiO2 catalyst shows a well-defined structure and interface, and the protection of the mSiO2 shell can efficiently prevent Pt NPs from aggregating and leaching in the reaction process. In the one-pot cascade reaction of nitroarenes and aromatic aldehydes to secondary amines, UiO-66-NH2@Pt@mSiO2 shows excellent catalytic performance due to acid catalytic sites provided by UiO-66-NH2 and Pt hydrogenation catalytic sites. Furthermore, the porous structure of the UiO-66-NH2@Pt@mSiO2 catalyst also enhances reactant diffusion and improves the reaction efficiency. This work provides a new avenue to meticulously design well-defined nanocatalysts with superior catalytic performance and stability for challenging reactions.

Beta-zeolite supported ruthenium catalysts for reductive amination of 5-hydroxymethyl-2-furaldehyde (HMF) with an aqueous solution of ammonia (NH3 aq.) and molecular hydrogen (H2) are examined to synthesize the corresponding primary amine of 5-aminomethyl-2-furylmethanol (FAA). Various SiO2/Al2O3 (Si/2Al) ratios of the beta-zeolite support were used to prepare the Ru-based catalysts. It was observed that the Si/2Al ratio was contributed to the catalytic activity, and the Si/2Al = 150 of beta-zeolite was found to be the most active for Ru catalyzed reductive amination of HMF, affording ca. 70% yield. Characterization techniques were taken to analysis the factors that influence the reactivity of catalysts, and which revealed that not only the ruthenium nanoparticle size but also the ratio of RuO2 against metallic Ru species were crucial factors for the reactivity of reductive amination of HMF to FAA.

We report the rational design of aldehyde-functional sterically stabilized diblock copolymer nano-objects in aqueous solution via polymerization-induced self-assembly. More specifically, reversible addition-fragmentation chain transfer aqueous dispersion polymerization of 2-hydroxypropyl methacrylate is conducted using a water-soluble precursor block in which every methacrylic repeat unit contains a pendent oligo(ethylene glycol) side chain capped with a cis-diol unit. Systematic variation of the reaction conditions enables the construction of a pseudo-phase diagram, which ensures the reproducible targeting of pure spheres, worms, or vesicles. Selective oxidation of the pendent cis-diol groups using aqueous sodium periodate under mild conditions introduces geminal diols (i.e., the hydrated form of an aldehyde obtained in the presence of water) into the steric stabilizer chains without loss of colloidal stability. In the case of diblock copolymer vesicles, such derivatization leads to the formation of a worm population, indicating partial loss of the original morphology. However, this problem can be circumvented by cross-linking the membrane-forming block prior to periodate oxidation. Moreover, such covalently stabilized aldehyde-functionalized vesicles can be subsequently reacted with either glycine or histidine in aqueous solution, followed by reductive amination to prevent hydrolysis of the labile imine bond. ζ potential measurements confirm that this derivatization significantly affects the electrophoretic behavior of these vesicles. Similarly, the membrane-crosslinked aldehyde-functionalized vesicles can be reacted with a model globular protein, bovine serum albumin, to produce "stealthy" protein-decorated vesicles.

Asymmetric reductive amination (ARA) is one of the most promising methods for the synthesis of chiral amines. Herein we report our efforts on merging two ARA reactions into a single-step transformation. Catalyzed by a complex formed from iridium and a steric hindered phosphoramidite, readily available and inexpensive aromatic ketones initially undergo the first ARA with ammonium acetate to afford primary amines, which serve as the amine sources for the second ARA, and finally provide the enantiopure C2 -symmetric secondary amine products. The developed process competently enables the successive coupling of inorganic and organic nitrogen sources with ketones in the same reaction system. The Bronsted acid additive plays multiple roles in this procedure: it accelerates the formation of imine intermediates, minimizes the inhibitory effect of N-containing species on the iridium catalyst, and reduces the primary amine side products.

The current Account gives an insight into the synthesis of some N-heterocyclic β-amino acid derivatives and various functionalized saturated azaheterocycles accessed from substituted cycloalkenes via ring C=C bond oxidative cleavage followed by ring closing across double reductive amination. The ring-cleavage protocol has been accomplished according to two common approaches: a) Os-catalyzed dihydroxylation/NaIO4 vicinal diol oxidation and b) ozonolysis. A comparative study on these methodologies has been investigated. Due to the everincreasing relevance of organofluorine chemistry in drug research as well as of the high biological potential of β-amino acid derivatives several illustrative examples to the access of various fluorine-containing piperidine or azepane β-amino acid derivatives are also presented in the current Account.1 Introduction2 Olefin-Bond Transformation by Oxidative Ring Cleavage3 Synthesis of Saturated Azaheterocycles via Oxidative Ring-Opening/Ring-Closing Double Reductive Amination3.1 Importance of Fluorine-Containing Azaheterocycles in Pharmaceutical Research3.2 Synthesis of Azaheterocyclic Amino Acid Derivatives with a Piperidine or Azepane Framework through Oxidative Ring Opening/Reductive Amination3.2.1 Synthesis of Piperidine β-Amino Esters3.2.2 Synthesis of Azepane β-Amino Esters3.2.3 Synthesis of Fluorine-Containing Piperidine γ-Amino Esters3.3 Synthesis of Tetrahydroisoquinoline Derivatives through Oxidative Ring Opening/Reductive Amination Protocol3.4 Synthesis of Functionalized Benzazepines through Reductive Amination3.4.1 Synthesis of Benzo[c]azepines3.4.2 Synthesis of Benzo[d]azepines3.5 Synthesis of Various N-Heterocycles via Ozonolysis/Reductive Amination3.5.1 Synthesis of Compounds with an Azepane Ring3.5.2 Synthesis of Piperidine β-Amino Acids and Piperidine-Fused β-Lactams3.5.3 Synthesis of γ-Lactams with a Piperidine Ring3.5.4 Synthesis of other N-Heterocycles4 Summary and Outlook5 List of Abbreviations

Direct reductive amination of ketones by reductive aminases (RedAms) is a promising method for the synthesis of primary, secondary and tertiary amines. In this work, five naturally occurring RedAms possessing reductive amination activity were identified using a structure-guided genome mining (SGGM) approach, which was based on highly conserved substrate binding and catalysis motif alignment. This RedAm toolbox facilitated the reductive amination of cyclohexanone and 4-fluoropropiophenone with various amine nucleophiles. In a preparative biotransformation (100 ​mg) with low stoichiometric ammonia donor and low catalyst loading, and three types of N-alkylcyclohexylamine were efficiently synthesized with a space-time yield up to 64.2 ​g ​L−1 ​d−1, demonstrating the potential of the RedAm enzymes as a biocatalyst toolbox for the synthesis of primary and secondary amines. Additionally, through protein engineering, the W205F variant of KfRedAm from Kribbella flavida was obtained with a 2-fold increased catalytic efficiency (kcat/Km), and the general applicability of the variant was verified, providing useful guidance for further evolution of RedAms within this family.

New pyridyl-containing diarylamines were obtained via Cu-assisted reductive amination of the ortho-2-pyridylarylboronic acids. Comparative analysis of the spectral and electrochemical data obtained for new diarylamines and their pyridyl-free counterparts revealed the intramolecular H-bond (IMHB) formation which significantly influences the properties of the amino group. The electron density at the N atom of the amino group is increased due to partial weakening of the N–H bond, although the BDE and activation energy for the H-atom abstraction is increased due to the chelating effect of two N atoms. The ortho-pyridyl-containing diarylamines are more prone to be oxidized as compared to their pyridyl-free counterparts; the shift in the oxidation potential values correlates with the strength of the intramolecular H-bonding which can be tuned by inserting substituents in the pyridyl or phenyl rings. The IMHB is reserved even in polar solvents having a significant H-acceptor ability (such as DMSO) but can be destroyed in methanol, testifying in favor of the dynamic nature of the H-bonding.

Interstrand DNA cross-links are important in biology, medicinal chemistry, and materials science. Methods for the targeted installation of interstrand cross-links in DNA duplexes may be useful in diverse fields including studies of DNA repair, materials science, and structural biology. Here a simple procedure is reported for the preparation of DNA duplexes containing site-specific, chemically-defined interstrand cross-links. The approach involves sequential reductive amination reactions between diamine linkers and two abasic (apurinic/apyrimidinic, AP) sites on complementary oligodeoxynucleotides. Use of the symmetrical triamine, tris(2-aminoethyl)amine, in this reaction sequence enabled preparation of a cross-linked DNA duplex bearing a derivatizable aminoethyl group.

The selective reductive amination of levulinic acid (LA) into pyrrolidone derivatives is regarded as one of the most promising reactions in the fields of biomass conversion into high value-added chemicals. Herein, we report a one-pot synthesis of N-substituted-5-methyl-2-pyrrolidones by reductive amination of LA/ester with nitriles over several commercial catalysts. Among the catalysts texted, Pd/C was found to be the most efficient for the reductive amination of LA/ester with various nitriles to give high yields of pyrrolidones (up to 92%) under mild reaction conditions (80 °C, 1.6 MPa H2, tetrahydrofuran solvent). And the catalyst showed good reusability.

We present here a metal-free, visible-light- and triphenylphosphine-mediated intermolecular, reductive amination between nitroarenes and boronic acids at ambient temperature without any photocatalyst. Mechanistically, a slow reduction of nitroarenes to a nitroso and, finally, a nitrene intermediate occurs that leads to the amination product with concomitant 1,2-aryl/-alkyl migration from a boronate complex. A wide range of nitroarenes underwent C-N coupling with aryl-/alkylboronic acids providing high yields.

2-Aminotetralin and 3-aminochroman derivatives are key structural motifs present in a wide range of pharmaceutically important molecules. Herein, we report an effective biocatalytic approach towards these molecules through the enantioselective reductive coupling of 2-tetralones and 3-chromanones with a diverse range of primary amine partners. Metagenomic imine reductases (IREDs) were employed as the biocatalysts, obtaining high yields and enantiocomplementary selectivity for >15 examples at preparative scale, including the precursors to Ebalzotan, Robalzotan, Alnespirone and 5-OH-DPAT. We also present a convergent chemo-enzymatic total synthesis of the Parkinson's disease therapy Rotigotine in 63 % overall yield and 92 % ee.

The site selectivity for lysine conjugation on a native protein is difficult to control and characterize. Here, we applied mass spectrometry to examine the conjugation kinetics of Trastuzumab-IgG (Her-IgG) and α-lactalbumin under excess linker concentration ([L]0) based on the modified Michaelis–Menten equation, in which the initial rate constant per amine (kNH2 = Vmax/NH2/KM) was determined by the maximum reaction rate (Vmax/NH2) under saturated accessible sites and initial amine–linker affinity (1/KM). Reductive amination (RA) displayed 3–4 times greater Vmax/NH2 and a different panel of conjugation sites than that observed for N-hydroxysuccinimide ester (NHS) chemistry using the same length of polyethylene glycol (PEG) linkers. Moreover, faster conversion power rendered RA site selectivity among accessible amine groups and a greater tunable range of linker/protein ratio for aldehyde-linkers compared to those of the same length of NHS-linkers. Single conjugation with high yield or poly-conjugations with site homogeneity was demonstrated by controlling [L]0 or gradual addition to minimize the [L]0/KM ratio. Formaldehyde, the shortest aldehyde-linker with the greatest 1/KM, exhibited the highest selectivity and was shown to be a suitable probe to predict conjugation profile of aldehyde-linkers. Four linkers on the few probe-predicted hot spots were elucidated by kinetically controlled RA with conserved drug efficacy when conjugated with the payload. This study provides insights into controlling factors for homogenous and predictable amine bioconjugation.

A ring expansion of 2-benzoylpyrrolidines, which involves the formal fluorinative ring opening utilizing the [1,2]-phospha-Brook rearrangement under Brønsted base catalysis and a subsequent intramolecular reductive amination, was developed. The operationally simple three-step protocol provides an efficient access to 2-aryl-3-fluoropiperidines. The methodology was further applied to the syntheses of azepanes and tetrahydroquinolines.

Background: For the past several decades, the presence of tuberculosis (TB) is being remarked as the most common infectious disease leading to mortality. Objective: Hydrazone containing azometine group (-NHN=CH-) compounds have been reported for a broad range of bioactivities such as antiplatelet, analgesic, anti-inflammatory, anticonvulsant, antidepressant, antimalarial, vasodilator, antiviral, and antimicrobial, etc. Methods: For the synthesis of compounds (4a-4d) and (6a-6e), aromatic amines were treated with methyl terephthalaldehydate in methanol, giving Schiff’s bases, followed by reductive amination and further treatment with hydrazine hydrate gave acid hydrazides (4a-4d). These acid hydrazides were then treated with different aromatic aldehydes to yield hydrazones (6a-6d). All the synthesized compounds were subjected to FT-IR, NMR, and UV spectroscopic characterization. Results: Compounds (4a-4d) and (6a-6e) were found to have highly potent activity against Mycobacteria tuberculosis (Vaccine strain, H37 RV strains): ATCC No- 27294 (MIC:1.6-6.25 μg/mL) than standard anti-TB drugs. The compounds exhibited good radical scavenging potentials(0- 69.2%), as checked from DPPH protocol. All compounds also demonstrated good in-silico ADMET results. Conclusion: The current study revealed promising in vitro anti-tuberculosis and anti-oxidant profiles of hydrazide-hydrazone analogues.

As a kind of environmentally benign reagents, α-keto acids have been extensively employed as key starting materials in organic synthesis. Organic electrosynthesis has the advantages of reducing byproduct generation, improving the cost-efficiency of synthetic processes, and accessing reactive intermediates under mild conditions. Inspired by the merits of organic electrosynthesis, α-keto acids have shown many synthetic applications in electrochemical acylation, cyclization, and reductive amination reactions with improved efficiencies and selectivities. This review covers the recent breakthroughs achieved in the electrochemical transformations of α-keto acids, aimed at highlighting these electrochemical reactions’ features and mechanistic rationalisations. Meanwhile, the practicalities and limitations of these transformations are also presented where possible.

One-pot direct synthesis of imines via reductive amination of nitroarenes with aromatic aldehydes remains a great challenge due in part to its over-hydrogenation of imines to secondary amines. Herein, a novel Co3ZnC and ZnO supported on N-doped carbon nanosheet catalyst with the thickness of ca. 5.0 nm was fabricated through the direct pyrolysis of a Co/Zn bimetallic MOFs at 500 °C (named as Co3ZnC-ZnO/NC-500). Surprisingly, the developed Co3ZnC-ZnO/NC-500 catalyst delivers 99.9 % conversion of nitrobenzene and 98.5 % selectivity to N-benzylideneaniline in one-pot reductive amination of nitrobenzene with benzaldehyde. Various characterizations (including as SEM, XRD, TEM, AFM, XPS, Raman and N2 adsorption–desorption) have revealed that the generated small size of Co3ZnC alloy, abundant structural defects, larger specific surface area (105.5 m2·g−1) as well as more basic sites are responsible for the outstanding catalytic activity of Co3ZnC-ZnO/NC-500 catalyst for tandem reaction. Moreover, the Co3ZnC-ZnO/NC-500 catalyst exhibits high stability during the recycling experiments without the loss of its catalytic activity. Notably, the results of contrast experiments have demonstrated that the intentional introduction of ZnO in Co3ZnC-ZnO/NC-500 catalyst plays a key role in the selectivity to N-benzylideneaniline in the tandem reaction. This study provides a new guideline for designing tandem catalysts with high selectivity.

A novel and concise synthesis towards DP2 receptor antagonist Fevipiprant (NVS-QAW039) was developed. The initial research route was suffering from lengthy access to the functionalized 7-aza-indole core followed by a low selective N(1)-alkylation with the benzyl side chain. These limitations were overcome by introducing the side chain early via reductive amination between the functionalized aldehyde and 2-amino-3-bromopyridine. Sonogashira coupling with prop-2-yn-1-ol introduces the 3 missing carbon atoms to build the 7-aza-indole core and sets the stage for the innovative Johnson-Claisen key step. Reaction of the advanced propargylic alcohol derivative with trimethyl orthoacetate leads to a reactive allene intermediate that spontaneously and selectively cyclizes to the 7-aza-indole QAW039-methly ester. QAW039 is isolated after ester saponification. Selectivity, yield, and ecological footprint of the new synthesis were significantly improved, and scalability was demonstrated.

Catalytic conversion of lignin into heteroatom functionalized chemicals is of great importance to bring the biorefinery concept into reality. Herein, a new strategy was designed for direct transformation of lignin β-O-4 model compounds into benzylamines and phenols in moderate to excellent yields in the presence of organic amines. The transformation involves dehydrogenation of C α -OH, hydrogenolysis of the C β -O bond and reductive amination in the presence of Pd/C catalyst. Experimental data suggest that the dehydrogenation reaction proceeds over the other two reactions and that secondary amines serve as both reducing agents and amine sources in the transformation. Moreover, the concept of "lignin to benzylamines" was demonstrated by a two-step process. This work represents a first example of synthesis of benzylamines from lignin, thus providing a new opportunity for the sustainable synthesis of benzylamines from renewable biomass, and expanding the products pool of biomass conversion to meet future biorefinery demands.

Pyrrolidones has gained much attention because of extensive use in agrochemical, pharmaceutical, industrial materials and chemical production. In that context, we demonstrated a novel and highly competent protocol for the reductive amination of biomass-based levulinic acid into N-alkyl pyrrolidone. The protic ionic liquid (PIL) [HmPip][OTf] used in this study plays a dual role as a catalyst for reductive amination as well as for dehydrogenation of dimethylamine borane complex (DMAB). Metal-free construction of N-alkyl pyrrolidone and its derivatives in remarkable yields are obtained with operational comfort because of the milder reaction conditions. The PIL could be recycled up to five times without significant loss in its catalytic activity. The developed process is promising drop-in technology because of the reductive heterocyclisation of direct biomass derived LA to pyrrolidones.

Copyright: © 2021 by the authors. Rifamycins are an extremely important class of antibacterial agents whose action results from the inhibition of DNA-dependent RNA synthesis. A special arrangement of unsubstituted hydroxy groups at C21 and C23, with oxygen atoms at C1 and C8 is essential for activity. Moreover, it is known that the antibacterial action of rifamycin is lost if either of the two former hydroxy groups undergo substitution and are no longer free to act in enzyme inhibition. In the present work, we describe the successful use of an Alder-Ene reaction between Rifamycin O, 1 and diethyl azodicarboxylate, yielding 2, which was a targeted introduction of a relatively bulky group close to C21 to protect its hydroxy group. Many related azo diesters were found to react analogously, giving one predominant product in each case. To determine unambiguously the stereochemistry of the Alder-Ene addition process, a crystalline zwitterionic derivative 3 of the diethyl azodicarboxylate adduct 2 was prepared by reductive amination at its spirocyclic centre C4. The adduct, as a mono chloroform solvate, crystallized in the non-centrosymmetric Sohnke orthorhombic space group, P212121. The unique conformation and absolute stereochemistry of 3 revealed through X-ray crystal structure analysis is described. Malaysia HIR MOHE (Grant No.F000009-21001).

The catalytic properties of a platinum catalyst supported on γ-alumina in the hydrogenation of imines formed during the condensation of 5-hydroxymethylfurfural (HMF) with primary amines in methanol have been studied. The reaction has been run in a flow reactor at a hydrogen pressure of 5 bar and a temperature of 15–65oC. It has been found that the reductive amination of HMF with n-hexylamine; aniline; ortho-, meta-, and para-toluidines; and aniline derivatives containing F, Cl, Br, and I substituents at the para- or meta-positions leads to the formation of N-substituted 5-hydroxymethyl-2-furfuryl amines with high yields (90–99%). At the same time, the reaction of HMF with aromatic amines exhibiting weak nucleophilic properties (o-chloroaniline, p-aminoacetophenone) provides a target product yield that does not exceed 52%.

On the basis of the 1,2,3,4-tetrahydrofluorenyl ligand, a simple approach was developed to new effective rhodium catalysts for the construction of C-C and C-N bonds. The halide compounds [(η5 -tetrahydrofluorenyl)RhX2 ]2 (2 a: X=Br; 2 b: X=I) were synthesized by treatment of the bis(ethylene) derivative (η5 -tetrahydrofluorenyl)Rh(C2 H4 )2 (1 a) with halogens. An analogous reaction of the cyclooctadiene complex (η5 -tetrahydrofluorenyl)Rh(cod) (1 b) with I2 is complicated by the side formation of [(cod)RhI]2 . The reaction of 2 b with 2,2'-bipyridyl leads to cation [(η5 -tetrahydrofluorenyl)Rh(2,2'-bipyridyl)I]+ (3). The halide abstraction from 2 a,b with thallium or silver salts allowed us to prepare sandwich compounds with incoming cyclopentadienyl, dicarbollide and mesityleneligands [(η5 -tetrahydrofluorenyl)RhCp]+ (4), (η5 -tetrahydrofluorenyl)Rh(η-7,8-C2 B9 H11 ) (5), and [(η5 -tetrahydrofluorenyl)Rh(η-mesitylene)]2+ (6). The structures of 1 b, 2 b ⋅ 2I2 , 3PF6 , 4TlI4 , 5, and [(cod)RhI]2 were determined by X-ray diffraction. Compounds 2 a,b efficiently catalyze the oxidative coupling of benzoic acids with alkynes to selectively give isocoumarins or naphthalenes, depending on the reaction temperature. Moreover, they showed moderate catalytic activity in other annulations of alkynes with aromatic compounds (such as benzamide, acetanilide, etc.) which proceed through CH activation. Compound 2 b also effectively catalyzes the reductive amination of aldehydes and ketones in the presence of carbon monoxide and water via water-gas shift reaction, giving amines in high yields (67-99 %).

Nitrogen mustards are a widely used class of antitumor agents that exert their cytotoxic effects through the formation of DNA interstrand cross-links (ICLs). Despite being among the first antitumor agents used, the biological responses to NM ICLs remain only partially understood. We have previously reported the generation of NM ICL mimics by incorporation of ICL precursors into DNA using solid-phase synthesis at defined positions, followed by a double reductive amination reaction. However, the structure of these mimics deviated from the native NM ICLs. Using further development of our approach, we report a new class of NM ICL mimics that only differ from their native counterpart by substitution of dG with 7-deaza-dG at the ICL. Importantly, this approach allows for the synthesis of diverse NM ICLs, illustrated here with a mimic of the adduct formed by chlorambucil. We used the newly generated ICLs in reactions with replicative and translesion synthesis DNA polymerase to demonstrate their stability and utility for functional studies. These new NM ICLs will allow for the further characterization of the biological responses to this important class of antitumor agents.

Pavettamine, a plant toxin first isolated from Pavetta harborii in 1995, was previously identified as a polyamine with C2 symmetry and a 1,3-syn-diol moiety on a C10 carbon backbone – one of very few substituted polyamines to be isolated from nature. Its absolute configuration was later established by our first reported total synthesis in 2010. Herein we report the first total synthesis of the enantiomer of pavettamine, ent-pavettamine. The symmetrical structure of the molecule allows for the synthesis of a common C5 fragment that can be divergently transformed into two synthons for later convergent coupling to furnish the target carbon framework. Based on the success of the protocol we employed for the synthesis of the naturally occurring pavettamine, (S)-malic acid was again the starting material of choice for the synthesis of the two individual C5 fragments, with strategic differences in terminal-group manipulation allowing for the synthesis of ent-pavettamine rather than pavettamine. Chain extension and stereoselective ketone reduction were achieved using the (R)-methyl p-tolyl sulfoxide chiral auxiliary to give the desired 1,3-syn-diol C5 unit. A protecting-group strategy was also developed for the orthogonal protection of the alcohol and amine functional groups as they were unveiled. The functionalized C5 fragments were coupled via reductive amination revealing the C10 carbon backbone. Deprotection of the alcohol and amine functional groups successfully provided ent-pavettamine as a TFA salt.

The synthesis of an octa-armed 24-membered cyclic octaamine (1) is reported. When 4-benzyl-1,4,7,10-tetraazacyclododecane-2,6-dione (3a) was prepared by the reaction of diethylenetriamine with diethyl N-benzyliminodiacetate (2), a dimeric macrocycle (3b) was obtained as a byproduct in a 5% yield. An octa-armed 24-membered cyclic octaamine (1), named Cosmosen, was prepared via the reductive amination and reduction of 3b. The binding constants for the 1:1 and 2:1 (Ag+/1) complexation of 1 were estimated to be ca. 7.9 and 13.9, respectively, by titration experiments using UV-vis spectrometry in methanol and chloroform (v/v, 9:1) solutions at 298 K.

Amine dehydrogenases (AmDHs) are one of the key emerging enzymes used in the synthesis of various amines with the expense of only one ammonium ion as an amino donor, thereby, generates only water molecule as a by-product. Currently, most available AmDHs have been created through protein engineering using the existing natural L-amino acid dehydrogenase, and native AmDHs are rarely reported. In this study, a novel native AmDH from Laribacter hongkongensis (LhAmDH) was identified based on the GenBank database using a sequence-driven approach. LhAmDH showed a good activity towards various carbonyl compounds such as cyclohexanone (170 mU/mg) and isovaleraldehyde (214 mU/mg). The reductive amination of model substrate, cyclohexanone (up to 100 mM) into cyclohexylamine was successfully performed in LhAmDH and FDH system with > 99% conversion using Escherichia coli whole-cell as well as purified enzymes. Furthermore, three enzymes cascade (ω-transaminase, LhAmDH, and FDH) was designed to produce chiral amine from the corresponding ketone using inexpensive ammonium formate as sole sacrificial agent. The active site of LhAmDH residues were predicted using the protein structure homology model building program SWISS-MODEL server. In the docking analysis, cyclohexanone is well-orientated with −5.4 kcal/mol of binding energy and 3.16 A distance from side chain of E104, which is a key residue for interacting ammonia and substrate. This LhAmDH model can be used as a promising template to produce chiral amines through semi-rational design.

Reactions of the tetraene macrolide antibiotic tetramycin B with p-substituted aromatic aldehydes and sodium cyanoborohydride in the conditions of reaction of reductive amination resulted in formation of its N-benzyl derivatives. Physicochemical and medical and biological properties of obtained derivatives of tetramycin B were studied. Biological investigations showed that N-benzyl derivatives of tetramycin B were low toxic agents and possessed high antifungal activity. The pharmacological tests revealed that the acute toxicity (LD50) of obtained derivatives of tetramycin B was 7–8 times low as that of the starting antibiotic. The automated intellectual information system for optimal choice of the conditions for rational design, synthesis and using in medical practice of novel derivatives of polyene macrolide antibiotics was developed.

[Image: see text] To improve the metabolic stability profile of BMS-741672 (1a), we undertook a structure–activity relationship study in our trisubstituted cyclohexylamine series. This ultimately led to the identification of 2d (BMS-753426) as a potent and orally bioavailable antagonist of CCR2. Compared to previous clinical candidate 1a, the tert-butyl amine 2d showed significant improvements in pharmacokinetic properties, with lower clearance and higher oral bioavailability. Furthermore, compound 2d exhibited improved affinity for CCR5 and good activity in models of both monocyte migration and multiple sclerosis in the hCCR2 knock-in mouse. The synthesis of 2d was facilitated by the development of a simplified approach to key intermediate (4R)-9b that deployed a stereoselective reductive amination which may prove to be of general interest.

A key aim of biocatalysis is to mimic the ability of eukaryotic cells to carry out multistep cascades in a controlled and selective way. As biocatalytic cascades get more complex, reactions become unattainable under typical batch conditions. Here a number of continuous flow systems were used to overcome batch incompatibility, thus allowing for successful biocatalytic cascades. As proof‐of‐principle, reactive carbonyl intermediates were generated in situ using alcohol oxidases, then passed directly to a series of packed‐bed modules containing different aminating biocatalysts which accordingly produced a range of structurally distinct amines. The method was expanded to employ a batch incompatible sequential amination cascade via an oxidase/transaminase/imine reductase sequence, introducing different amine reagents at each step without cross‐reactivity. The combined approaches allowed for the biocatalytic synthesis of the natural product 4O‐methylnorbelladine., The use of continuous flow reactors enabled previously inaccessible enzyme combinations in multi‐enzyme cascade reactions. This included the combination of oxidases with aminating biocatalysts (transaminase/reductive aminase) and was extended to the continuous in situ biocatalytic generation of amino donors for the reductive aminase.

Protein N-glycosylation characterization is challenging due to structural micro- and macro-heterogeneity. Although various N-glycan preparation strategies, including purification and derivatization, have been previously developed prior to mass spectrometric analysis, systematic evaluation still needs to be performed. This study compared the different N-glycan purification strategies, including filter-aided sample preparation, de-N-glycosylated protein precipitation, and trypsin digestion followed by reversed phase-based solid-phase extraction, and derivatization approaches, such as solid-phase permethylation, reductive amination, and reduction. With the comparative analysis, an optimized solid-phase permethylation (OSPP) workflow was developed for mass spectrometric N-glycomics, showing simplified analysis for N-glycan compositions and high yields using etanercept. The N-glycan samples released from trastuzumab and adalimumab were utilized to test OSPP to obtain their N-glycan profiles using mass spectrometry. Based on different standard procedures across laboratories, this study provides the reference for analysts to select an appropriate N-glycan preparation method with their research purposes.

The development of metal phosphide catalysts for organic synthesis is still in its early stages. Herein, we report the successful synthesis of single-crystal cobalt phosphide nanorods (Co2P NRs) containing coordinatively unsaturated Co–Co active sites, which serve as a new class of air-stable, highly active, and reusable heterogeneous catalysts for the reductive amination of carbonyl compounds. The Co2P NR catalyst showed high activity for the transformation of a broad range of carbonyl compounds to their corresponding primary amines using an aqueous ammonia solution or ammonium acetate as a green amination reagent at 1 bar of H2 pressure; these conditions are far milder than previously reported. The air stability and high activity of the Co2P NRs is noteworthy, as conventional Co catalysts are air-sensitive (pyrophorous) and show no activity for this transformation under mild conditions. P-alloying is therefore of considerable importance for nanoengineering air-stable and highly active non-noble-metal catalysts for organic synthesis.

The incorporation of –SF5 group onto model amino acids has been achieved using commercially available synthons substituted with this group. This work investigates the influence of the –SF5 group on a variety of common synthetic transformations utilized in fields of bioconjugation and drug development, namely, amide coupling, reductive amination, diazo-coupling, and CuAAC “click” reactions. The influence of the novel substituent on the success of these common transformations is presented, and alternative approaches for those which proved unsatisfactory are proposed herein.

The development of a continuous-flow sequence for the synthesis of an important drug candidate precursor is reported. Abediterol is a β2-adrenoceptor agonist that has undergone phase IIa clinical t...

Half-sandwich iridium complexes bearing bidentate urea-phosphorus ligands were found to catalyze the direct reductive amination of aromatic and aliphatic ketones under mild conditions at 0.5 mol % loading with high selectivity towards primary amines. One of the complexes was found to be active in both the Leuckart-Wallach (NH4 CO2 H) type reaction as well as in the hydrogenative (H2 /NH4 AcO) reductive amination. The protocol with ammonium formate does not require an inert atmosphere, dry solvents, as well as additives and in contrast to previous reports takes place in hexafluoroisopropanol (HFIP) instead of methanol. Applying NH4 CO2 D or D2 resulted in a high degree of deuterium incorporation into the primary amine α-position.

For the catalytic reductive amination of carbonyl compounds, the kind of active metal used is the most important factor determining the catalytic selectivity in heterogeneous catalysis systems. However, a detailed understanding of the intrinsic mechanism is still lacking. In this work, by evaluating the reductive amination of butyraldehyde and the hydrogenation reaction of secondary imine on various metal catalysts, the competitive hydrogenation reactions of primary imine and secondary imine are proven to be the key factors determining primary amine selectivity. DFT calculations verify that Co, Ni, and Ru, rather than Fe, Rh, Pd, and Pt, tend to show high primary amine selectivity in terms of adsorption energy and activation energy. It should be noted that the different stable adsorption modes of secondary imine on metal surfaces (C&N adsorption mode on Fe, Co, Ni, Ru, and Rh, and N adsorption mode on Pd and Pt) are key factors affecting these reaction characteristics. Moreover, microkinetic simulation proves that the coadsorption of NH3 improves primary amine selectivity on Co, Ni, and Ru surfaces. Combining the theoretical and experimental results, it is clearly verified that the active metal determines the catalytic selectivity of the primary amine by affecting the competitive hydrogenation reactions of the primary imine and secondary imine.

An efficient method has been developed for the reductive amination of CO2 by using readily available and recyclable oxofluorovanadates as catalysts. Various amines are transformed into the desired N-formylated products in moderate to excellent yields at room temperature in the presence of phenylsilane. Mechanistic studies based on in situ infrared spectroscopy suggest a reaction pathway initiated through F-Si interactions. The activated phenylsilane allows for CO2 insertion to produce phenylsilyl formate, which undergoes attack by the amine to generate the target product.

Aryl-ether cleavage and benzylic quaternary ammonium (QA) group degradation are promoted by C═O groups in most commercial anion exchange membrane materials. Herein, a novel strategy of converting C═O groups to the electron-donating C-NH2 linkages in conventional poly(arylene ether ketone)s is proposed by reductive amination via Leuckart reaction. Density functional theory (DFT) calculations indicate that the model compound containing C-NH2 linkage exhibits much higher barrier heights for aryl-ether cleavage and QA group degradation by enhancing the electronic cloud density on both the ether-connected carbon and the benzylic carbon. The C-NH2 linkages also induce hydrogen bond networks in the membranes, which enhance intermolecular interaction and provide additional hydroxide transport sites. As a result, the C-NH2 linkage membranes exhibit excellent hydroxide conductivity (108.2 mS cm-1 at 80 °C) and tensile strength (48.4 MPa) with high elongation at break (50.8%). The C-NH2 linkage membranes also show outstanding alkaline stability with no detectable backbone degradation even in 4 M KOH at 80 °C for 400 h, which is at the top-level among the state-of-the-art main chain architecture AEMs. This study proposes a new strategy for the synthesis of highly stable AEMs based on electron-donating C-NH2 link backbone.

Direct asymmetric reductive amination represents an efficient means of converting ketones to α-chiral primary amines, but reported examples are very limited. We describe the development of two sets...

N-Aryl-1,2,3,4-tetrahydroisoquinolines are obtained via a convenient and short protocol with a broad range of substituents on both aromatic rings and high functional group tolerance. Starting from readily available ortho-brominated aromatic aldehydes and primary aromatic amines, condensation of these building blocks under reductive conditions gives N-aryl 2-bromobenzylamines. The C-3/C-4-unit of the tetrahydroisoquinoline is introduced using commercially available 2-ethoxyvinyl pinacolboronate under Suzuki conditions. Finally, the obtained crude ortho-ethoxyvinyl benzylamines are cyclized via an intramolecular reductive amination using the combination of triethylsilane/TFA to give the desired N-aryl-1,2,3,4-tetrahydroisoquinolines.

Reducing or eliminating organic solvent use in pharmaceutical manufacturing is perhaps the most effective way to reduce the environmental, health, and safety impacts of drug substance manufacturing. With this in mind, we have developed a process to manufacture an investigational 5-HT4 receptor agonist that is conducted almost entirely in water, including multiple controlled isolations. Key transformations carried out in aqueous media include a benzimidazole cyclization, amide bond formation, reductive amination, and a selective oxidation of an aliphatic alcohol. Compared to the first-generation manufacturing process using organic solvents, the aqueous process described here uses 77% less material inputs, 94% less organic solvent, and, surprisingly, 48% less water, while improving overall yield from 35% to 56%.

The main functions of σ1 receptors include the modulation of release and reuptake of neurotransmitters, the regulation of ion channels and the influence on intracellular signaling through modulation of calcium levels. Due to these properties, σ1 receptors are interesting drug targets for the treatment of various neurological disorders, pain and cancer. In order to modify the distance between the pharmacophoric elements (the benzene ring of 2-benzopyran and an amino moiety), a set of spiro[[2]benzopyran-1,1′-cyclohexan]-3′-amines was synthesized. The key step of the synthesis was a Parham cyclization of 1-bromo-2-(2-bromoethyl)benzene (6) with the mono ketal 7 of cyclohexane-1,3-dione, which led in a one-pot reaction to the spirocyclic framework 8. Reductive amination of ketone 9 stereoselectively provided secondary amines cis-4, which were methylated to afford tertiary amines cis-5. Whereas spirocyclic compounds cis-4a and cis-5a bearing a benzyl moiety at the exocyclic amino moiety showed rather low σ1 affinity, the corresponding cyclohexylmethyl derivatives cis-4b and cis-5b exhibited low nanomolar σ1 affinity. The secondary amine cis-4b displayed the highest σ1 receptor affinity (Ki = 5.4 nM) in this series. Methylation of the secondary amine cis-4b led to a slightly decreased σ1 receptor affinity of cis-5b (Ki = 15 nM).

Oxidoreductase-mediated biotransformation often requires consumption of a secondary sacrificial co-substrate and an additional auxiliary enzyme to drive the cofactor regeneration, which results in generation of unwanted by-product. Herein, we report a highly atom-economic self-sufficient hydride-shuttling cascade to concurrently obtain two pharmaceutically important building blocks (7,12-dioxo-lithocholic acid and L-tert-leucine) in which oxidation of cholic acid (CA) and reductive amination of trimethylpyruvic acid were integrated for redox self-recycling. In this cascade, the cofactor acts as a hydride shuttle that interconnects the two synthetically relevant reactions at the cost of only inorganic ammonium as the sacrificial agent and generates water as the greenest by-product. The preparative biotransformation using a whole-cell biocatalyst in the absence of any exogenous cofactor displayed a space–time yield of 768 g L−1 d−1 and a total turnover number (TTN) of 20 363 for NAD+ recycling. This represents the highest cofactor TTN reported to date for the bio-oxidation of CA, indicating the great potential of this cofactor and redox self-sufficient bioprocess for cost-effective and sustainable biomanufacturing of high-value-added products.