Amino-Induced CO2 Spillover to Boost the Electrochemical Reduction Activity of CdS for CO Production.

A considerable challenge in CO2 reduction reaction (CO2RR) to produce high-value-added chemicals comes from the adsorption and activation of CO2 to form intermediates. Herein, an amino-induced spillover strategy aimed at significantly enhancing the CO2 adsorption and activation capabilities of CdS supported on N-doped mesoporous hollow carbon sphere (NH2-CdS/NMHCS) for highly efficient CO2RR is presented. The prepared NH2-CdS/NMHCS exhibits a high CO Faradaic efficiency (FECO) exceeding 90% from -0.8 to -1.1 V versus reversible hydrogen electrode (RHE) with the highest FECO of 95% at -0.9 V versus RHE in H cell. Additional experimental and theoretical investigations demonstrate that the alkaline -NH2 group functions as a potent trapping site, effectively adsorbing the acidic CO2, and subsequently triggering CO2 spillover to CdS. The amino modification-induced CO2 spillover, combined with electron redistribution between CdS and NMHCS, not only readily achieves the spontaneous activation of CO2 to *COOH but also greatly reduces the energy required for the conversion of *COOH to *CO intermediate, thus endowing NH2-CdS/NMHCS with significantly improved reaction kinetics and reduced overpotential for CO2-to-CO conversion. It is believed that this research can provide valuable insights into the development of electrocatalysts with superior CO2 adsorption and activation capabilities for CO2RR application.

Interfacial Hydrogen-Bond Interactions Driven Assembly toward Polychromatic Copper Nanoclusters.

Constructing versatile metal nanoclusters (NCs) assemblies through noncovalent weak interactions between inter-ligands is a long-standing challenge in interfacial chemistry, while compelling interfacial hydrogen-bond-driven metal NCs assemblies remain unexplored so far. Here, the study reports an amination-ligand o-phenylenediamine-coordinated copper NCs (CuNCs), demonstrating the impact of interfacial hydrogen-bonds (IHBs) motifs on the luminescent behaviors of metal NCs as the alteration of protic solvent. Experimental results supported by theoretical calculation unveil that the flexibility of interfacial ligand and the distance of cuprophilic CuI···CuI interaction between intra-/inter-NCs can be tailored by manipulating the cooperation between the diverse IHBs motifs reconstruction, therewith the IHBs-modulated fundamental structure-property relationships are established. Importantly, by utilizing the IHBs-mediated optical polychromatism of aminated CuNCs, portable visualization of humidity sensing test-strips with fast response is successfully manufactured. This work not only provides further insights into exploring the interfacial chemistry of NCs based on inter-ligands hydrogen-bond interactions, but also offers a new opportunity to expand the practical application for optical sensing of metal NCs.

Copper-Mediated N-Trifluoromethylation of O-Benzoylhydroxylamines.

The use of trifluoromethyl containing compounds is well established within medicinal chemistry, with a range of approved drugs containing C-CF3 and O-CF3 moieties. However, the utilisation of the N-CF3 functional group remains relatively unexplored. This may be attributed to the challenging synthesis of this unit, with many current methods employing harsh conditions or less accessible reagents. A robust methodology for the N-trifluoromethylation of secondary amines has been developed, which employs an umpolung strategy in the form of a copper-catalysed electrophilic amination. The method is operationally simple, uses mild, inexpensive reagents, and has been used to synthesise a range of novel, structurally complex N-CF3 containing compounds.

Cu-Catalyzed Coupling of Aliphatic Amines with Alkylboronic Esters.

We report a Cu-catalyzed oxidative coupling of aliphatic amines with benzylic and aliphatic boronic esters to give high value alkyl amines, products found widely in applications from medicinal chemistry to materials science. This operationally simple reaction, which can be performed on gram scale, runs under mild conditions and exhibits broad functional group tolerance. The terminal oxidant of the reaction is O2 from the air, avoiding the need for additional chemical oxidants. Investigation into the reaction mechanism suggests that the boronic ester is activated by an aminyl radical, formed through oxidation of the amine by the Cu catalyst, to give a key alkyl radical intermediate. To demonstrate its utility and potential for late-stage functionalization, we showcase the method as the final step in the total synthesis of a TRPV1 antagonist.

Sterically Congested Protecting Group for a Boronyl Group in Iterative Aminations.

In this study, we found that the sterically bulky α-hydroxycarboxamide moiety is a suitable framework for protecting the boronyl group of boron reagents during aminations. Condensation of α-hydroxycarboxamide with ArB(OH)2 produced aryloxazaborolidinone (ArOxB). The reactivity of the C-B bond in ArOxB is easily controlled by the steric and weak electronic effects of the backbone. H2N-(or Br-)ArOxB underwent Chan-Evans-Lam (C-E-L) or Buchwald-Hartwig (B-H) amination with retaining the C-B bond. On the other hand, direct C-E-L amination of ArOxB was also possible in an oxidative atmosphere, in which the C-B bond was activated by CuII species. Our methodology is effective for the precise synthesis of two or more arylamino group substituted arenes.

One-pot Twostep Chemobiocatalytic Synthesis of a Furan Amino Acid from 5-Hydroxymethylfurfural.

Recently, catalytic valorization of biomass-derived furans has received growing interest. 5-Aminomethyl-2-furancarboxylic acid (AMFC), a furan amino acid, holds great promise in the aeras of polymer and pharmaceutical, but its synthesis remains limited. In this work, we report a chemobiocatalytic route toward AMFC by combining laccase-TEMPO system and recombinant Escherichia coli (named E. coli_TAF) harboring ω-transaminase (TA), L-alanine dehydrogenase (L-AlaDH) and formate dehydrogenase (FDH), starting from 5-hydroxymethylfurfural (HMF). In the cascade, HMF is oxidized into 5-formyl-2-furancarboxylic acid (FFCA) by laccase-TEMPO system, and then the resulting intermediate is converted into AMFC by E. coli_TAF via transamination with cheap ammonium formate instead of costly organic amine donors, theoretically generating H2O and CO2 as by-products. The tandem process was run in a one-pot twostep manner, affording AMFC with approximately 81 % yield, together with 10 % 2,5-furandicarboxylic acid (FDCA) as by-product. In addition, the scale-up production of AMFC was demonstrated, with 0.41 g/L h productivity and 8.6 g/L titer. This work may pave the way for green manufacturing of the furan-containing amino acid.

Direct Synthesis of N-formamides by Integrating Reductive Amination of Ketones and Aldehydes with CO2 Fixation in a Metal-Organic Framework.

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.

Dehydrogenative Electrochemical Synthesis of N-Aryl-3,4-Dihydroquinolin-2-ones by Iodine(III)-Mediated Coupling Reaction.

Electrochemically generated hypervalent iodine(III) species are powerful reagents for oxidative C-N coupling reactions, providing access to valuable N-heterocycles. A new electrocatalytic hypervalent iodine(III)-mediated in-cell synthesis of 1H-N-aryl-3,4-dihydroquinolin-2-ones by dehydrogenative C-N bond formation is presented. Catalytic amounts of the redox mediator, a low supporting electrolyte concentration and recycling of the solvent used make this method a sustainable alternative to electrochemical ex-cell or conventional approaches. Furthermore, inexpensive, readily available electrode materials and a simple galvanostatic set-up are applied. The broad functional group tolerance could be demonstrated by synthesizing 23 examples in yields up to 96 %, with one reaction being performed on a 10-fold higher scale. Based on the obtained results a sound reaction mechanism could be proposed.

Deciphering Iron-Catalyzed C-H Amination with Organic Azides: N2 Cleavage from a Stable Organoazide Complex.

Catalytic C-N bond formation by direct activation of C-H bonds offers wide synthetic potential. En route to C-H amination, complexes with organic azides are critical precursors towards the reactive nitrene intermediate. Despite their relevance, α-N coordinated organoazide complexes are scarce in general, and elusive with iron, although iron complexes are by far the most active catalysts for C-H amination with organoazides. Herein, we report the synthesis of a stable iron α-N coordinated organoazide complex from [Fe(N(SiMe3 )2 )2 ] and AdN3 (Ad=1-adamantyl) and its crystallographic, IR, NMR and zero-field 57 Fe Mössbauer spectroscopic characterization. These analyses revealed that the organoazide is in fast equilibrium between the free and coordinated state (Keq =62). Photo-crystallography experiments showed gradual dissociation of N2 , which imparted an Fe-N bond shortening and correspond to structural snapshots of the formation of an iron imido/nitrene complex. Reactivity of the organoazide complex in solution showed complete loss of N2 , and subsequent formation of a C-H aminated product via nitrene insertion into a C-H bond of the N(SiMe3 )2 ligand. Monitoring this reaction by 1 H NMR spectroscopy indicates the transient formation of the imido/nitrene intermediate, which was supported by Mössbauer spectroscopy in frozen solution.

Metal-Free, Hindered, Regioselective Access to Multifunctional Groups Diarylamines via SN Ar Substitution of P-Nitroso Aromatic Methyl Ether by Arylamines.

Multifunctional groups diarylamines, an innovative product, efficiently produced from arylamines and p-nitrosoanisole derivatives by intermolecular SN Ar under weak acid conditions. This SN Ar proceeds under mild reaction conditions, and more significantly, the substrates involved do not necessarily require strong electron-withdrawing groups. Moreover, this SN Ar is characterized by resistance to space crowding, tolerance to halogen and nitroso functional groups, and high regioselectivity. Mechanistic observations suggest that the SN Ar is the result of the transfer of the positive charge center of the protonated nitroso group to the p-methoxy group.

Amino- and Alkoxybenziodoxoles: Facile Preparation and Use as Arynophiles.

We report here on the facile synthesis of amino- and alkoxy-λ3-iodanes supported by a benziodoxole (BX) template and their use as arynophiles. The amino- and alkoxy-BX derivatives can be readily synthesized by reacting the respective amines or alcohols with chlorobenziodoxole in the presence of a suitable base. Unlike previously known nitrogen- and oxygen-bound iodane compounds, which have primarily been employed as electrophilic group transfer agents or oxidants, the present amino- and alkoxy-BX reagents manifest themselves as nucleophilic amino and alkoxy transfer agents toward arynes. This reactivity leads to the aryne insertion into the N-I(III) or O-I(III) bond to afford ortho-amino- and ortho-alkoxy-arylbenziodoxoles, iodane compounds nontrivial to procure by existing methods. The BX group in these insertion products exhibits excellent leaving group ability, enabling diverse downstream transformations.

Micelle-Promoted Reductive Amination of DNA-Conjugated Amines for DNA-Encoded Library Synthesis.

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.

Enantioselective Amination of 3-Substituted-2-benzofuranones via Non-covalent N-Heterocyclic Carbene Catalysis.

Herein, an efficient method for asymmetric α-amination of 2-benzofuranones with N-heterocyclic carbene (NHC) catalysis is reported. The process is based on non-covalent interaction of NHC with substrate, facilitating the formation of a chiral ion-pair that encompasses enolate and azolium salt. The activated enolate adds to an electrophilic amine source with sufficient facial control to furnish an enantioenriched product having an amine substituted quaternary stereocenter. The process displays a broad substrate scope. A preparative scale synthesis has been achieved. Preliminary mechanistic investigations based on experimental and DFT studies suggest a reaction pathway that involves non-covalent substrate/NHC interactions and essentially implicate the role of π-π interaction in diastereomeric transition states for stereo-chemical discrimination.

Atroposelective Chan-Evans-Lam Amination.

The synthetic control of atropoisomerism along C-N bonds is a major challenge, and methods that allow C-N atroposelective bond formation are rare. This is a problem because each atropoisomer can feature starkly differentiated biological properties. Yet, among the three most practical and applicable classical amination methods available: 1) the Cu-catalyzed Ullmann-Goldberg reaction, 2) the Pd-catalyzed Buchwald-Hartwig reaction, and 3) the Cu-catalyzed Chan-Evans-Lam reaction, none has truly been rendered atroposelective at the newly formed C-N bond. The first ever Chan-Evans-Lam atroposelective amination is herein described with a simple copper catalyst and newly designed PyrOx chiral ligand. This method should find important applications in asymmetric synthesis, in particular for medicinal chemistry.

An Electrochemical Oxo-amination of 2H-Indazoles: Synthesis of Symmetrical and Unsymmetrical Indazolylindazolones.

We have established a supporting-electrolyte free electrochemical method for the synthesis of indazolylindazolones through oxygen reduction reaction (eORR) induced 1,3-oxo-amination of 2H-indazoles where 2H-indazole is used as both aminating agent as well as the precursor of indazolone. Moreover, we have merged indazolone and indazole to get unsymmetrical indazolylindazolones through direct electrochemical cross-dehydrogenative coupling (CDC). This exogenous metal-, oxidant- and catalyst-free protocol delivered a number of multi-functionalized products with high tolerance of diverse functional groups.

Reductive amination of ω-conotoxin MVIIA: synthesis, determination of modification sites, and self-assembly.

Peptide drugs have disadvantages such as low stability, short half-life and side effects, which limit their widespread use in clinical practice. Therefore, peptide drugs can be modified to improve these disadvantages. Numerous studies have shown that alkyl-modified peptide drugs can self-assemble to prolong the duration of efficacy and/or reduce side effects. However, the commonly used solid-phase synthesis method for alkyl-modified peptides is time-consuming. To overcome this, a simple reductive amination reaction was employed, which can directly graft the alkyl chain to the peptide sequence and effectively avoid stepwise synthesis from C- to N-terminal with amino acids. In this study, ω-conotoxin MVIIA was used as the peptide drug, while myristic aldehyde was used as the alkylating agent. To obtain the maximum productivity of modified peptides, the molar ratio of peptide MVIIA to myristic aldehyde in the reductive amination reaction was optimized. Furthermore, the peptide modification sites in this reaction were confirmed by secondary mass spectrometry analysis. Besides, alkyl-modified peptide MVIIA was able to form micelles by self-assembly and improved stability in serum, which was related to our previous work where myristoylated peptide MVIIA micelles can improve the drug stability. Finally, this study was intended to provide a methodological basis for modifying the alkyl chain of peptide drugs.

Discovery and biocatalytic characterization of opine dehydrogenases by metagenome mining.

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.

Metal-free visible light mediated direct C-H amination of benzoxazole with secondary amines.

An efficient visible light mediated, eosin Y catalyzed direct C-H oxidative amination of benzoxazoles with secondary amines has been developed, which providing a straightforward, green, and environmentally benign access to a wide variety of substituted benzoxazole-2-amines under mild reaction conditions. The biological studies such as drug-likeness and molecular docking are also carried out on the molecule.

Synthesis of novel benzylamine antimycotics and evaluation of their antimycotic potency.

A series of 23 novel benzylamines was synthesized by reductive amination from halogen-substituted 3- and 4-benzyloxybenzaldehyde derivatives and 6-methylhept-2-yl amine or n-octylamine. The antimycotic activity of the resulting amines was evaluated in a microdilution assay against the apathogenic yeast Yarrowia lipolytica as test microorganism. Promising compounds were also tested against human pathogenic Candida species. The influence of halogen substituents at the benzyl ether side chain was studied in this screening, as well as the influence of the branched side chain of (±)-6-methylhept-2-yl amine in comparison with the n-octyl side chain.

Construction of N-Aryl-Substituted Pyrrolidines by Successive Reductive Amination of Diketones via Transfer Hydrogenation.

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.