Amide Products Research Articles

Synthesis of α-Quaternary Amides via Cp*Co(III)-Catalyzed Sequential C-H Bond Addition to 1,3-Dienes and Isocyanates.

The synthesis of sterically congested amides was accomplished via Cp*Co(III)-catalyzed sequential C-H bond addition to 1,3-dienes followed by aminocarbonylation with isocyanates, a coupling partner that had never been utilized in sequential C-H bond addition reactions. A variety of C-H bond reactants, internally substituted dienes, and aromatic isocyanates provided secondary amide products incorporating α-all-carbon quaternary centers. The conversion of the amide products to other useful compound classes was also demonstrated.

Direct C3-H Alkylation and Alkenylation of Quinolines with Enones.

Conversion of quinoline C-H bonds into C-C bonds is essential for obtaining the enormous array of derivatives required for pharmaceutical and agrochemical development. Despite over a century of synthetic efforts, direct alkylation and alkenylation at C3-H positions in a wide array of quinoline precursors remain predominantly challenging and elusive. This report outlines the first successful quinoline C3-H alkylation and alkenylation reactions, exhibiting exceptional regio- and stereoselectivity, all achieved under redox-neutral and transition-metal-free conditions. The method involves a three-step, one-pot or two-pot sequence, including 1,4-dearomative addition, functionalization at C3, and elimination or transalkylation to produce 3-alkylated/alkenylated quinolines. The presence of a carbonyl group in these products allows for further synthetic manipulations, enabling the production of cyanides, amides, amines, and simple alkyl derivatives.

Direct C3−H Alkylation and Alkenylation of Quinolines with Enones

AbstractConversion of quinoline C−H bonds into C−C bonds is essential for obtaining the enormous array of derivatives required for pharmaceutical and agrochemical development. Despite over a century of synthetic efforts, direct alkylation and alkenylation at C3−H positions in a wide array of quinoline precursors remain predominantly challenging and elusive. This report outlines the first successful quinoline C3−H alkylation and alkenylation reactions, exhibiting exceptional regio‐ and stereoselectivity, all achieved under redox‐neutral and transition‐metal‐free conditions. The method involves a three‐step, one‐pot or two‐pot sequence, including 1,4‐dearomative addition, functionalization at C3, and elimination or transalkylation to produce 3‐alkylated/alkenylated quinolines. The presence of a carbonyl group in these products allows for further synthetic manipulations, enabling the production of cyanides, amides, amines, and simple alkyl derivatives.

Development of the esterase PestE for amide bond synthesis under aqueous conditions: Enzyme cascades for converting waste PET into tamibarotene.

A growing number of hydrolase enzymes show promiscuous acyltransferase activity, even under aqueous conditions. Here we report, for the first time, the ability of Pyrobaculum calidifontis VA1 esterase (PestE) to catalyse the formation of a wide range of amides in buffer, where the acyl donor forms a significant structural component in the amide product. The reactions occur under mild conditions and can achieve conversions up to 97% in 6 h for formation of N-benzylfuranamide as the model reaction. We demonstrate PestE's potential in enzyme cascades to make amides from waste PET plastic and the conversion of the terephthalic acid product to tamibarotene, a drug with activity against acute leukemia. Rational mutagenesis led to identification of PestE variants F33L_F289A and F33L. F33L_F289A increased conversion of N-benzylfuranamide by 1.2-fold, and F33L gave a 4-fold increase in conversion to tamibarotene.

Development of the esterase PestE for amide bond synthesis under aqueous conditions: Enzyme cascades for converting waste PET into tamibarotene.

A growing number of hydrolase enzymes show promiscuous acyltransferase activity, even under aqueous conditions. Here we report, for the first time, the ability of Pyrobaculum calidifontis VA1 esterase (PestE) to catalyse the formation of a wide range of amides in buffer, where the acyl donor forms a significant structural component in the amide product. The reactions occur under mild conditions and can achieve conversions up to 97% in 6 h for formation of N‐benzylfuranamide as the model reaction. We demonstrate PestE’s potential in enzyme cascades to make amides from waste PET plastic and the conversion of the terephthalic acid product to tamibarotene, a drug with activity against acute leukemia. Rational mutagenesis led to identification of PestE variants F33L_F289A and F33L. F33L_F289A increased conversion of N‐benzylfuranamide by 1.2‐fold, and F33L gave a 4‐fold increase in conversion to tamibarotene.

Mystery of the Passerini Reaction for the Synthesis of the Antimicrobial Peptidomimetics against Nosocomial Pathogenic Bacteria.

The first example of applying salicylaldehyde derivatives, as well as coumarin with the formyl group at the C8 position in its structure, as carbonyl partners in a three-component Passerini reaction, is presented. As a result of research on the conditions of the Passerini reaction, the important role of the hydroxyl group in the salicylaldehyde used in the course of the multicomponent reaction was revealed. When an aldehyde with an unprotected hydroxyl group is used, only two-component α-hydroxy amide products are obtained. In contrast, the use of acylated aldehyde results in three-component α-acyloxy amide products with high efficiency. The developed protocol gives access to structurally diversified peptidomimetics with good yield. The compounds were also evaluated as antimicrobial agents against selected strains of nosocomial pathogenic bacteria. The structure-activity relationship revealed that inhibitory activity is strongly related to the presence of the trifluoromethyl group (CF3) or the methyl group at the C4 position in an unsaturated lactone ring of the coumarin scaffold. MIC and MBC studies were carried out on eight selected pathogenic bacteria strains (Gram-positive pathogenic Staphylococcus aureus strain (ATCC 23235), as well as on Gram-negative E. coli (K12 (ATCC 25404), R2 (ATCC 39544), R3 (ATCC 11775), and R4 (ATCC 39543)), Acinetobacter baumannii (ATCC 17978), Pseudomonas aeruginosa (ATCC 15442), and Enterobacter cloacae (ATCC 49141) have shown that the tested compounds show a strong bactericidal effect at low concentrations. Among all agents investigated, five exhibit higher antimicrobial activity than those observed for commonly used antibiotics. It should be noted that all the compounds tested showed very high activity against S. aureus, which is the main source of nosocomial infections that cause numerous fatalities. Additionally, the cytotoxicity of sixteen derivatives was measured with the use of the MTT test on BALB/c3T3 mouse fibroblast cell lines. The cytotoxicity studies revealed that the tested substances exert a similar or lower effect on cell proliferation than that observed for commonly used antibiotics within the range of therapeutic doses. A parallel MTT assay using ciprofloxacin, bleomycin, and cloxacillin showed that these antibiotics are more cytotoxic when tested in mammalian cells, and cell viability is in the range of 85.0-89.9%. Furthermore, we have shown that the studied coumarin-based peptidomimetics, depending on their structural characteristics, are nonselective and act efficiently against various Gram-positive and Gram-negative pathogens, which is of great importance for hospitalised patients.

LC-HRMS-based metabolomics and lipidomics analyses of a novel probiotic Akkermansia Muciniphila in response to different nutritional stimulations

The mucin-degrading gut commensal Akkermansia muciniphila (A. muciniphila) negatively correlates with various diseases, including metabolic disorders, neurodegenerative disorders, and cancers, through interacting with host receptors by diverse molecules. Still, their exact metabolic capability within the nutrient-rich environment (such as in the human gut) is not fully characterized. Therefore, in the present study, we investigated the comprehensive metabolome and lipidome of A. muciniphila after supplementation of four major gut microbial nutrients: mucin, inorganic salts, bile salts, and short-chain fatty acids (SCFAs). Our results showed that mucin is the predominant driver of the different lipidomic and metabolomic profiles of A. muciniphila, and it promotes the overall growth of this bacteria. While the addition of inorganic salts, bile salts, and SCFAs was found to inhibit the growth of A. muciniphila. Interestingly, inorganic salts affected the purine metabolism in A. muciniphila cultures, while adding bile salts significantly increased the production of other bile acids and N-acyl amides. Lastly, SCFAs were identified to alter the A. muciniphila energy utilization of triglycerides, fatty acyls, and phosphatidylethanolamines. To our knowledge, this is the first study to examine the comprehensive lipidome and metabolome of A. muciniphila, which highlights the importance of nutritional impacts on the lipidome and metabolome of A. muciniphila and hence providing foundational knowledge to unveil the potential effects of A. muciniphila on host health.

Synthesis and molecular docking analysis of MBH adducts' derived amides as potential β-lactamase inhibitors.

Humans suffer from various diseases that require more specific drugs to target them. Among the different potent agents, β-lactamases serve as good antibacterial agents; however, β-lactamases are resistant to such antibiotics. The present study was designed to prepare efficient β-lactamase inhibitor amides (12-15) from inexpensive, easily accessible, and bioactive precursors; Morita Baylis Hillman (MBH) adducts (5-8). The adducts (5-8) were primarily prepared by treating their respective aldehydes with the corresponding acrylate in the presence of an organic Lewis base at ambient temperature. The compounds were characterized using mass spectrometry, FTIR and NMR spectroscopy. Furthermore, in silico studies (using AutoDock Tools and AutoDock Vina programs) on the adduct and corresponding amide product revealed that all MBH adducts (5-8) and their product amides (12-15) are significant inhibitors of β-lactamase. Additionally, among the MBH adducts, adduct 7 showed the highest binding affinity with β-lactamase, whereas amide 15 was identified as a highly potent antibacterial based on its docking score (-8.6). In addition, the absorption, distribution, metabolism, and excretion (ADME) test of the synthesized compounds demonstrated that all compounds showed drug-likeness properties.

Selective Hydrofunctionalization of Alkenyl Fluorides Enabled by Nickel-Catalyzed Hydrogen Atoms and Group Transfer: Reaction Development and Mechanistic Study.

Due to the unique effect of fluorine atoms, the efficient construction of high-value alkyl fluorides has attracted significant interest in modern drug development. However, enantioselective catalytic strategies for the efficient assembly of highly functionalized chiral C(sp3)-F scaffolds from simple starting materials have been underutilized. Herein, we demonstrate a nickel-catalyzed radical transfer strategy for the efficient, modular, asymmetric hydrogenation and hydroalkylation of alkenyl fluorides with primary, secondary, and tertiary alkyl halides under mild conditions. The transformation provides facile access to various structurally complex secondary and tertiary α-fluoro amide products from readily available starting materials with excellent substrate compatibility and distinct selectivity. Furthermore, the utility of this method is demonstrated by late-stage modifications and product derivatizations. Detailed mechanistic studies and DFT calculations have been conducted, showing that the rate-determining step for asymmetric hydrogenation reaction is NiH-HAT toward alkenyl fluorides and the stereo-determining step is alcohol coordination to Ni-enolates followed by a barrierless protonation. The mechanism for the asymmetric hydroalkylation reaction is also delivered in this investigation.

General Approach to Amides through Decarboxylative Radical Cross-Coupling of Carboxylic Acids and Isocyanides.

Herein, we report a silver-catalyzed protocol for decarboxylative cross-coupling between carboxylic acids and isocyanides, leading to linear amide products through a free-radical mechanism. The disclosed approach provides a general entry to a variety of decorated amides, accommodating a diverse array of radical precursors, including aryl, heteroaryl, alkynyl, alkenyl, and alkyl carboxylic acids. Notably, the protocol proved to be efficient for decarboxylative late-stage functionalization of several elaborate pharmaceuticals, demonstrating its potential applications.

Mn3O4 photocatalyzed oxidative amidation of aldehyde and amines for clean synthesis of amides

Amides are widely used in various fields of chemical and pharmaceutical industries. Developing a green and universal amide synthesis method that meets the needs of sustainable chemistry has always been a challenge for amide synthesis. In this paper, a direct and highly selective method for the synthesis of amide was developed under visible light irradiation and room temperature using air as an oxidant. Thanks to the prolongation of the C-H bond (0.1115 nm) and O-H bond (0.1002 nm) during the adsorption of hemiaminal on the Mn3O4 catalyst, and the energy barrier for hemiaminal dehydrogenation (-3.07 eV) is much lower than the energy barrier for dehydration (4.84 eV), thus the formation of imines is suppressed, resulting in highly selective clean production of amides with H2O as byproduct. Therefore, this clean and effective method for obtaining amides is one of the ideal alternative solutions for currently known methods.

High-throughput reprogramming of an NRPS condensation domain

Engineered biosynthetic assembly lines could revolutionize the sustainable production of bioactive natural product analogs. Although yeast display is a proven, powerful tool for altering the substrate specificity of gatekeeper adenylation domains in nonribosomal peptide synthetases (NRPSs), comparable strategies for other components of these megaenzymes have not been described. Here we report a high-throughput approach for engineering condensation (C) domains responsible for peptide elongation. We show that a 120-kDa NRPS module, displayed in functional form on yeast, can productively interact with an upstream module, provided in solution, to produce amide products tethered to the yeast surface. Using this system to screen a large C-domain library, we reprogrammed a surfactin synthetase module to accept a fatty acid donor, increasing catalytic efficiency for this noncanonical substrate >40-fold. Because C domains can function as selectivity filters in NRPSs, this methodology should facilitate the precision engineering of these molecular assembly lines.

Enhancing the catalytic activity of enzymes through tunnel amino acid modifications: The case of nitrile hydratase, a biocatalyst with posttranslational modifications used in amide production

Enhancing the catalytic activity of enzymes through tunnel amino acid modifications: The case of nitrile hydratase, a biocatalyst with posttranslational modifications used in amide production

Radical-Mediated Decarboxylative C-C and C-S Couplings of Carboxylic Acids via Iron Photocatalysis.

Despite the significant success of decarboxylative radical reactions, the catalytic systems vary considerably upon different radical acceptors, requiring renewed case-by-case reaction optimization. Herein, we developed an iron catalytic condition that enables the highly efficient decarboxylation of various carboxylic acids for a range of radical transformations. This operationally simple protocol was amenable to a wide array of radical acceptors, delivering structurally diverse oxime ethers, alkenylation, alkynylation, thiolation, and amidation products in useful to excellent yields (>40 examples, up to 95% yield).

Study on the characteristics of gas phase products in coal mine conveyor belt fire

This study aimed to use the thermogravimetric infrared coupling (TG-FTIR) and cone calorimeter coupling techniques to analyse the Pyrolysis characteristics and fire hazard of conveyor belt during heating process based on different stages of the combustion process. The results demonstrate that the conveyor belt is melted and volatilized by heat in the first stage (200∼350 °C), and a cross-linking polymerization process ensues, with the primary gas-phase products being chlorine-containing compounds, aromatic acid esters, and HCl. In the second stage (350∼600 °C), the conveyor belt started to burn fiercely, redox reactions occurred, the primary gas-phase products added to hydrocarbons, Benzoic acids, aldehydes, amides, and a significant number of CO2, CO, H2O(g). The third stage (600∼700 °C) corresponds to the recession phase of combustion, when the concentration of most gas phase products decreases and the production of amides and ketones increases. As the intensity of thermal radiation increases, the mass loss, heat release rate, fire hazard, CO/CO2 generation rate and smoke also increase.

Исследование эффективности амидов жирных кислот в качестве ингибиторов атмосферной коррозии

The use of anticorrosive agents increases the service life, reliability and safety of agricultural machinery. The shortage of domestic inhibitors is caused by the lack of a scientifically sound concept for their production, as well as a lack of raw materials. The authors have developed a technology for the production of fatty acid amides (FAA) from triglycerides of vegetable, animal origin or fat-containing waste. The purpose of this study was to evaluate the effectiveness of fatty acid amide used as an inhibitor of atmospheric corrosion. A comparative assessment of the protective effectiveness of FAA was determined in accordance with GOST 9.054-75 at elevated values of relative humidity and air temperature, exposure to salt mist, with constant immersion in an electrolyte and exposure to the hydrobromic acid. The authors compared preservation compositions based on FAA 16%, Avtokon LS, Kormin 50%, Rosoil 700, Kormin 30%. The protective properties of the products were studied on samples with dimensions of 50 × 50 mm made of steel grade St3. After the tests, the appearance of the samples was evaluated before and after removing the lubricant. According to the results of each experiment, the protective properties of the preservation compounds were arranged in the decreasing order. According to the results of four experiments, each composition was assigned a score characterizing the total assessment of the protective ability of the compositions according to GOST 9.407-2015. As a result of the study, the relationship between the effectiveness of preservative oils and the composition and amount of the inhibitor has been established. The effectiveness of fatty acid amides used as an inhibitor of atmospheric corrosion has been proven. Preservation oil made using 16% FAA exceeds the protective effect of analogue products in 1.1 to 2.0 times.

Anthraquinone-based covalent organic framework as a recyclable direct hydrogen atom transfer photocatalyst for C-H functionalization.

Photocatalytic direct hydrogen atom transfer (d-HAT) is a synthetically important strategy to convert C-H bonds to useful C-X bonds. Herein we report the synthesis of an anthraquinone-based two-dimensional covalent organic framework, DAAQ-COF, as a recyclable d-HAT photocatalyst for C-H functionalization. Powder X-ray diffraction, N2 sorption isotherms, solid-state NMR spectra, infrared spectra, and thermogravimetric analysis characterized DAAQ-COF as a crystalline, porous COF with a stable ketoenamine linkage and strong absorption in the visible region. Under visible light irradiation, DAAQ-COF is photo-excited to cleave C(sp3)-H or C(sp2)-H bonds via HAT to generate reactive carbon radicals, which add to different radical acceptors to achieve C-N or C-C coupling reactions. DAAQ-COF is easily recovered from the reaction mixture via centrifugation or filtration and used in six consecutive reaction runs without any decrease in catalytic efficiency. The ease of catalyst separation allows sequential conversion of the C-N coupling intermediate to synthetically useful amide, ester, or thioester products. Photophysical and isotope labelling experiments support the d-HAT mechanism of DAAQ-COF-catalyzed C-H bond functionalization.

Исследование реакции амидирования карбоновых кислот и их производных

The presented work shows the results of research in the field of studying the amidation reaction of carboxylic acids and their functionally substituted derivatives with various amines. The main patterns of the above reaction are shown, the mechanisms of reactions involving carboxylic acids, as well as their derivatives (esters, anhydrides and acid chlorides) are presented. The main areas of application of the synthesized amide products are considered. It is reported that the reaction of direct amidation of carboxylic acids with amine components can occur in the presence of various catalysts or auxiliary reagents, among which dicyclohexylcarbodimide is most often used. Direct amidation has been shown to be accelerated in the presence of nucleophilic reagents containing a free electron pair. Some features of the amidation reaction involving acid derivatives, in particular esters and acid chlorides, are also shown. It is noted that one of the variants of such reactions is the Schotten-Bauman reaction. The paper also describes the results of the authors’ own research. It is noted that condensation reactions of acid chlorides of some aliphatic, naphthenic and aromatic acids with amines of various structures have been carried out, leading to the formation of mono- and dicarboxyamide derivatives of heterocyclic compounds, such as benzimidazole, benzoxazole and oxadiazepine. The practical properties of the synthesized compounds were studied and it was found that their potassium salts have high biological activity and can be used as a growth stimulator for wheat and pea plants. In addition, it was shown that the resulting amides are corrosion inhibitors and some of them have highly protective effects and can be used in technology as inhibitors.

Технология производства защитных антикоррозионных материалов из жиросодержащих отходов

The processing of fat-containing waste from meat-packing enterprises that cannot be landfilled is an urgent problem. The authors developed the technology of processing fat-containing waste in a chemical reactor in one step, without dividing the technology into two steps: triglyceride hydrolysis and fatty acid amide production. The technology for processing fat-containing waste was tested in a laboratory plant. The target product obtained was analyzed using IR spectroscopy. As a result, the structural formula was clarified, functional groups were determined, and chemical intermediates in the synthesis process were identified. The proportions of the reagents were determined: technical fat in the amount of 65.3‑72.4 wt%, monoethanolamine - 14.5‑17.0 wt% and boric acid - up to 100 wt% of the mixture. The reaction time was 1.5 h. The protective effect was selected as a quality control indicator of the surfactant obtained. Solvent selection was carried out for producing anticorrosive materials. I‑20 industrial oil, diesel fuel and SN‑150 oil were selected as solvents. Electrochemical studies carried out on the AVTOLAB PGSTAT302N potentiostat-galvanostat made it possible to determine the mechanism of action of the surfactant as a corrosion inhibitor. Its optimum concentration was found to be 15%, with a protective efficiency of 99.33%. To increase the protective anticorrosive efficiency of the surfactant, the tests were carried out in a humidity chamber for 60 days on St3 steel plates. The test results showed high efficiency of the surfactant used as a corrosion inhibitor, with the Z value of more than 90%.

Identification and evolution of non-traditional nitrilase from Spirosoma linguale DSM 74 with high hydration activity

Hydration, a secondary activity mediated by nitrilase, is a promising new pathway for amide production. However, low hydration activity of nitrilase or trade-off between hydration and catalytic activity hinders its application in the production of amides. Here, natural C-terminal-truncated wild-type nitrilase, mined from a public database, obtained a high-hydration activity nitrilase as a novel evolutionary starting point for further protein engineering. The nitrilase Nit-74 from Spirosoma linguale DSM 74 was successfully obtained and exhibited the highest hydration activity level, performing 50.7 % nicotinamide formation and 87.6 % conversion to 2 mM substrate 3-cyanopyridine. Steric hindrance of the catalytic activity center and the N-terminus of the catalytic cysteine residue helped us identify three key residues: I166, W168, and T191. Saturation mutations resulted in three single mutants that further improved the hydration activity of N-heterocyclic nitriles. Among them, the mutant T191S performed 72.7 % nicotinamide formation, which was much higher than the previously reported highest level of 18.7 %. Additionally, mutants I166N and W168Y exhibited a 97.5 % 2-picolinamide ratio and 97.7 % isonicotinamide ratio without any loss of catalytic activity, which did not indicate a trade-off effect. Our results expand the screening and evolution library of promiscuous nitrilases with high hydration activity for amide formation.