Simple Amides Research Articles

Chemists add carbons one at a time

Chemists have increased their power to make a variety of compounds by figuring out how to add a single carbon to simple amides, creating four new C bonds in a single step. Mamoru Tobisu and coworkers at Osaka University used an N-heterocyclic carbene, a stable compound with two unpaired electrons at the C, to make a variety of cyclic amides called lactams, with a variety of side groups ( Science 2023, DOI: 10.1126/science.ade5110 ). In the past, single carbon atoms have been too unstable to be useful in organic synthesis. In this method, the researchers gamed the system by using the carbene as a stable precursor to an atomic carbon, creating a more practical way to add just one C atom at a time. The group was initially working on a reaction that used the carbene as a catalyst but were surprised to find products that had an extra C,

One carbon-four new bonds.

Stable carbenes deliver a carbon atom to simple amides, producing a range of cyclic compounds.

Practical synthesis of allylic amines via nickel-catalysed multicomponent coupling of alkenes, aldehydes, and amides.

Molecules with an allylic amine motif provide access to important building blocks and versatile applications of biologically relevant chemical space. The need for diverse allylic amines requires the development of increasingly general and modular multicomponent reactions for allylic amine synthesis. Herein, we report an efficient catalytic multicomponent coupling reaction of simple alkenes, aldehydes, and amides by combining nickel catalysis and Lewis acid catalysis, thus providing a practical, environmentally friendly, and modular protocol to build architecturally complex and functionally diverse allylic amines in a single step. The method is remarkably simple, shows broad functional-group tolerance, and facilitates the synthesis of drug-like allylic amines that are not readily accessible by other methods. The utilization of accessible starting materials and inexpensive Ni(ii) salt as the alternative precatalyst offers a significant practical advantage. In addition, the practicality of the process was also demonstrated in an efficient, gram-scale preparation of the prostaglandin agonist.

Silica Immobilised Chloro- and Amido-Derivatives of Eremomycine as Chiral Stationary Phases for the Enantioseparation of Amino Acids by Reversed-Phase Liquid Chromatography.

Macrocyclic glycopeptide antibiotics immobilized on silica are one of the effective classes of stationary phases for chiral recognition and HPLC separation of a wide range of optically active compounds. Enantioselectivity primarily depends on the chemical structure of the chiral ligand, immobilization chemistry, and separation conditions. In the present work, three new chiral stationary phases (CSPs) based on macrocyclic antibiotic eremomycin were prepared and investigated for enantioseparation of amino acids. Two eremomycin derivatives, including simple non-substituted amide and bulky adamantyl amide, provided important information on the role of the carboxylic group in the eremomycin structure in the chiral recognition mechanism concerning amino acid optical isomers. One more CSP having a chlorine atom in the same position elucidates the role of the first aromatic ring in the eremomycin structure as a crucial point for chiral recognition. CSP with immobilized chloreremomycin was the most successful among the phases prepared in this work. It was additionally investigated under various separation conditions, including the type and content of the organic solvent in the eluent, the effects of different additives, and the concentration and pH of the buffer. Importantly, an efficient enantioselective separation of amino acids was achieved with pure water as the eluent.

Catalytic Efficiency of Primary α-Amino Amides as Multifunctional Organocatalysts in Recent Asymmetric Organic Transformations

Chiral primary α-amino amides, consisting of an adjacent enamine bonding site (Bronsted base site), a hydrogen bonding site (Bronsted acid site), and flexible bulky substituent groups to modify the steric factor, are proving to be extremely valuable bifunctional organocatalysts for a wide range of asymmetric organic transformations. Primary α-amino amides are less expensive alternatives to other primary amino organocatalysts, such as chiral diamines and cinchona-alkaloid-derived primary amines, as they are easy to synthesize, air-stable, and allow for the incorporation of a variety of functional groups. In recent years, we have demonstrated the catalytic use of simple primary α-amino amides and their derivatives as organocatalysts for the aldol reaction, Strecker reaction, Michael tandem reaction, allylation of aldehydes, reduction of N-Aryl mines, opening of epoxides, hydrosilylation, asymmetric hydrogen transfer, and N-specific nitrosobenzene reaction with aldehydes.

Photoinduced Pd-Catalyzed Csp2-H/Csp3-H Dehydrocoupling Reaction Employing Polyhaloaromatics as the Dehydrogenating Agent.

A mild strategy for intermolecular cross-dehydrocoupling of Csp2-H bonds and Csp3-H bonds has been developed with the aid of photoinduced Pd catalysis. Polyhalogenated arenes can be used as the efficient dehydrogenating agent, which enables multifold transfer of carbon radical to avoid the production of stoichiometric or excess wasted arenes. In this strategy, substituted styrenes and N-arylacrylamides with simple ethers or amides as the coupling partners gives the corresponding internal alkenes and benzolactams with moderate to good yield.

Access to α-Hydroxy Amides via a Practical Metal-Free "One-Pot" Tandem Reaction Involving Aerobic C(sp3)-H Hydroxylation and C(sp2)-C(sp3) Cleavage.

A flexible metal-free cascade reaction involving aerobic C(sp3)-H hydroxylation and decarbonylation with high regioselectivity and functional group tolerance has been established. Moreover, this indirect hydroxylation approach of N-aryl amides could enable the construction of a wide range of valuable secondary alcohols at α-position of N-aryl amides. It provides a supplementary strategy for direct α-hydroxylation of simple amides.

Native Amide-Directed C(sp3 )-H Amidation Enabled by Electron-Deficient RhIII Catalyst and Electron-Deficient 2-Pyridone Ligand.

Trivalent group-9 metal catalysts with a cyclopentadienyl-type ligand (CpMIII ; M=Co, Rh, Ir, Cp=cyclopentadienyl) have been widely used for directed C-H functionalizations, albeit that their application to challenging C(sp3 )-H functionalizations suffers from the limitations of the available directing groups. In this report, we describe directed C(sp3 )-H amidation reactions of simple amide substrates with a variety of substituents. The combination of an electron-deficient CpE Rh catalyst (CpE =1,3-bis(ethoxycarbonyl)-substituted Cp) and an electron-deficient 2-pyridone ligand is essential for high reactivity.

Native Amide‐Directed C(sp3)−H Amidation Enabled by Electron‐Deficient RhIII Catalyst and Electron‐Deficient 2‐Pyridone Ligand

AbstractTrivalent group‐9 metal catalysts with a cyclopentadienyl‐type ligand (CpMIII; M=Co, Rh, Ir, Cp=cyclopentadienyl) have been widely used for directed C−H functionalizations, albeit that their application to challenging C(sp3)−H functionalizations suffers from the limitations of the available directing groups. In this report, we describe directed C(sp3)−H amidation reactions of simple amide substrates with a variety of substituents. The combination of an electron‐deficient CpERh catalyst (CpE=1,3‐bis(ethoxycarbonyl)‐substituted Cp) and an electron‐deficient 2‐pyridone ligand is essential for high reactivity.

Cesium Amide-Catalyzed Selective Deuteration of Benzylic C-H Bonds with D2 and Application for Tritiation of Pharmaceuticals.

Hydrogen isotope exchange (HIE) represents one of the most attractive labeling methods to synthesize deuterium- and tritium-labeled compounds. Catalytic HIE methods that enable site-selective C-H bond activation and exchange labeling with gaseous isotopes D2 and T2 are of vital importance, in particular for high-specific-activity tritiation of pharmaceuticals. As part of our interest in exploring s-block metals for catalytic transformations, we found CsN(SiMe3 )2 to be an efficient catalyst for selective HIE of benzylic C-H bonds with D2 gas. The reaction proceeds through a kinetic deprotonative equilibrium that establishes an exchange pathway between C-H bonds and D2 gas. By virtue of multiple C-H bonds activation and high activity (isotope enrichment up to 99 %), the simple cesium amide catalyst provided a very powerful and practically convenient labeling protocol for synthesis of highly deuterated compounds and high-specific-activity tritiation of pharmaceuticals.

Cesium Amide‐Catalyzed Selective Deuteration of Benzylic C‐H Bonds with D2 and Application for Tritiation of Pharmaceuticals

AbstractHydrogen isotope exchange (HIE) represents one of the most attractive labeling methods to synthesize deuterium‐ and tritium‐labeled compounds. Catalytic HIE methods that enable site‐selective C−H bond activation and exchange labeling with gaseous isotopes D2 and T2 are of vital importance, in particular for high‐specific‐activity tritiation of pharmaceuticals. As part of our interest in exploring s‐block metals for catalytic transformations, we found CsN(SiMe3)2 to be an efficient catalyst for selective HIE of benzylic C−H bonds with D2 gas. The reaction proceeds through a kinetic deprotonative equilibrium that establishes an exchange pathway between C−H bonds and D2 gas. By virtue of multiple C−H bonds activation and high activity (isotope enrichment up to 99 %), the simple cesium amide catalyst provided a very powerful and practically convenient labeling protocol for synthesis of highly deuterated compounds and high‐specific‐activity tritiation of pharmaceuticals.

Illuminating the dark metabolome of Pseudo-nitzschia-microbiome associations.

The exchange of metabolites mediates algal and bacterial interactions that maintain ecosystem function. Yet, while thousands of metabolites are produced, only a few molecules have been identified in these associations. Using the ubiquitous microalgae Pseudo-nitzschia sp., as a model, we employed an untargeted metabolomics strategy to assign structural characteristics to the metabolites that distinguished specific diatom-microbiome associations. We cultured five species of Pseudo-nitzschia, including two species that produced the toxin domoic acid, and examined their microbiomes and metabolomes. A total of 4826 molecular features were detected by tandem mass spectrometry. Only 229 of these could be annotated using available mass spectral libraries, but by applying new in silico annotation tools, characterization was expanded to 2710 features. The metabolomes of the Pseudo-nitzschia-microbiome associations were distinct and distinguished by structurally diverse nitrogen compounds, ranging from simple amines and amides to cyclic compounds such as imidazoles, pyrrolidines and lactams. By illuminating the dark metabolomes, this study expands our capacity to discover new chemical targets that facilitate microbial partnerships and uncovers the chemical diversity that underpins algae-bacteria interactions.

Perdeuteration of Arenes via Hydrogen Isotope Exchange Catalyzed by the Superbasic Sodium Amide Donor Species NaTMP·PMDETA.

Hydrogen isotope exchange (HIE) has become one of the most studied methods to prepare deuterated molecules, with the primary focus recently on metal-catalyzed C-H activation with transition metals. Here we report the use of a simple sodium amide, NaTMP (TMP = 2,2,6,6-tetramethylpiperidide), combined with tridentate Lewis donor PMDETA (N,N,N',N″,N″-pentamethyldiethylenetriamine), which is able to catalytically promote the HIE of a series nonactivated arenes under mild reaction conditions using C6D6 as the deuterium source. Establishing the potential of NaTMP for the deuteration of aromatic molecules, several nonactivated substrates such as naphthalene, diphenylacetylene, and stilbene could be deuterated under mild reaction conditions without the need of transition metals. Combining NMR studies with the isolation of key organometallic intermediates, we demonstrate that the ability of NaTMP/PMEDTA to partially metalate C6D6, with concomitant generation of TMP(D), is key to enable the catalytic deuteration.

Supramolecular Architecture of an Amphiphilic Amino Alcohol as a Versatile Chiral Environment for Stereocontrolled Photoreaction of Various Anthracenes.

The photocyclodimerization of 2-anthracenecarboxylic acid has been extensively studied as a model reaction of asymmetric photochemistry. So far, numerous chiral environments have been employed to control this photoreaction, while the scope of photoreactants has been limited only to 2-anthracenecarboxylic acid and its simple esters and amides. Here, we developed a systematic series of photoreactants (2 a-d) by introducing various substituents to 2-anthracenecarboxylic acid, which showed different reactivities and selectivities depending on the substituents. By using the photoreactants 2 a-d, we evaluated the performance of a chiral environment composed of an amphiphilic amino alcohol (1), where the photocyclodimerization of 2 a-d generally proceeded in excellent regio- and enantioselectivities (71-98 % regio ratio, 76-86 % ee). Furthermore, by reacting 2 a and 2 b together in the chiral environment of 1, we succeeded in the first stereocontrolled cross-photocyclodimerization between two prochiral anthracenes (58 % chemo ratio, 83 % regio ratio, 90 % ee).

Highly Ordered Supramolecular Assembled Networks Tailored by Bioinspired H-Bonding Confinement for Recyclable Ion-Transport Materials

Highly Ordered Supramolecular Assembled Networks Tailored by Bioinspired H-Bonding Confinement for Recyclable Ion-Transport Materials

Sub-field of view surface thermal modeling of Cassini CIRS observations of Rhea during south polar winter

Rhea's exosphere is thought to originate from sources of carbon, water ice and other volatiles that arrived at Rhea by bombardment. Its seasonal variability is directly driven by polar surface temperatures allowing surface adsorption, and the persistence of source volatiles require that seasonal temperatures remain sufficiently cold to retain them. Cassini CIRS detected temperatures in Rhea's winter polar region of 23 K, amongst the coldest measured in the Solar System, but with a relatively large footprint we seek to add value to these observations by modeling sub field-of-view (FOV) temperature distribution and examining how the coldest scenes evolve on a seasonal basis.A simple, rough surface 1-dimensional thermal model is developed using a digital elevation map as input to a thermal model. We compared averaged rough and flat modeled FOVs to CIRS temperatures for a set of case study observations in the south polar region in winter darkness and found they both agree within expected CIRS error in all cases. We develop an asymmetric estimate of CIRS FOV temperature uncertainty, which is particularly important for very cold spectra to accurately represent the sensitivity of the instrument. This approach provides a conservative upper temperature limit to spectral fits whilst highlighting there is often little information to constrain the lower bound of temperature uncertainty in these cases.The distribution of modeled sub-FOV facet temperatures is explored for the full range of azimuth angles and slope gradients. More extensive and cooler temperatures were found in the rough model, complemented by fewer but warmer areas than the flat model. We find temperature contrasts of individual model facets of up to 15 K warmer and 11 K colder within some CIRS FOV when the rough model was compared flat, in a case study of scenes in winter darkness. This is due to the persistence of the seasonal thermal wave beneath the surface. We tested model sensitivity to thermal input parameters (thermal inertia and bolometric Bond albedo). These values are challenging to constrain due to limited observations and measurement noise and are expected to vary with subtle changes in surface characteristics. We found that within 20° of the pole, temperatures do not rise significantly above 80 K all year, implying that a variety of simple organic molecules, linear amides and other carbon-containing compounds would remain stable on a quasi-permanent basis, potentially until photolytic or radiolytic mechanisms liberate by-products which provide a source for exospheric constituents. The simple rough model indicates that some facets experience very different summer/winter season lengths than a flat model can represent, which is important in terms of the exospheric sequestration process.We use threshold temperatures of 55 K for CO2 and 30 K for O2 ice as proxies for their relative stability at the surface. The surface coverage of these temperatures with time was compared to modeled exospheric abundance by Teolis and Waite (2016). They are anti-correlated which is expected, but with slight differences in timings of minima and the equinoctial maxima. We find that the rough model suggests larger areas able to adsorb these species than the flat model, and that the cumulative influence of topography would have a direct relationship on the timing and abundance of the exosphere.We place Rhea's polar environment in context with other icy moons in the Saturnian system using the flat model. The satellites Tethys, Dione and Enceladus experience similar polar thermal regimes to Rhea (with exceptionally cold winters) and would potentially benefit from the consideration of topography in relation to exospheric modeling.

Profiling sirtuin activity using Copper-free click chemistry

The mammalian sirtuins are a group of posttranslational modification enzymes that remove acyl modifications from lysine residues in an NAD+-dependent manner. Although initially proposed as histone deacetylases (HDACs), they are now known to target other cellular enzymes and proteins as well. Sirtuin-catalyzed simple amide hydrolysis has profound biological consequences including suppression of gene expression, promotion of DNA damage repair, and regulation of glucose and lipid metabolism. Human sirtuins have been intensively pursued by both academia and industry as potential therapeutic targets for the treatment of diseases such as cancer and neurodegeneration. To gain a better understanding of their roles in various cellular events, innovative chemical probes are highly sought after. This current study focuses on the development of activity-based chemical probes (ABPs) for the profiling of sirtuin activity in biological samples. Cyclooctyne-containing and azido-containing probes were synthesized to enable the subsequent copper-free “click” conjugation to either a fluorophore or biotin. The two groups of structurally related ABPs demonstrated different labeling efficiency and selectivity: the cyclooctyne-containing probes failed to label recombinant sirtuins to any appreciable level, while the azido-containing ABPs showed good isoform selectivity. The azido-containing ABPs were further analyzed for their ability to label an individual sirtuin isoform in protein mixtures and cell lysates. These biocompatible ABPs allow the study of dynamic cellular protein activity change to become possible.

Selective Extraction of Platinum(IV) from the Simulated Secondary Resources Using Simple Secondary Amide and Urea Extractants

The recycling of rare metals such as platinum (Pt) from secondary resources, such as waste electronic and electrical equipment and automotive catalysts, is an urgent global issue. In this study, simple secondary amides and urea, N-(2-ethylhexyl)acetamide, N-(2-ethylhexyl)octanamide, and 1-butyl-3-(2-ethylhexyl)urea, which selectively extract Pt(IV) from a simulated effluent containing numerous metal ions, such as in an actual hydrometallurgical process, were synthesized and achieved efficient Pt(IV) stripping using only water. Comparison of Pt(IV) extraction behavior with a tertiary amide without N–H moieties suggests that the secondary amides and urea extractants effectively use hydrogen bonding to the hexachloroplatinate anion by N–H moieties. Examining the conditions for the third phase formation revealed that the secondary amide extractant with the longest alkyl chain can be used in the extraction process for a long time without forming any third phase, despite its lower Pt(IV) extraction capacity. The practical trial with simple compounds developed in this study should contribute to the development of Pt separation and purification processes.

Synthesis of Aminopropyltriethoxysilyl-Substituted Imines and Amides

A series of small molecules containing aminopropyltriethoxysilyl-substituted imines and amides were synthesized so that they could potentially be incorporated into self-assembled monolayers (SAMs) on metal oxide surfaces. Simple one-step imine preparations and two-step amide preparations are reported here.

Allenone-Mediated Racemization/Epimerization-Free Peptide Bond Formation and Its Application in Peptide Synthesis.

Allenone has been identified as a highly effective peptide coupling reagent for the first time. The peptide bond was formed with an α-carbonyl vinyl ester as the key intermediate, the formation and subsequent aminolysis of which proceed spontaneously in a racemization-/epimerization-free manner. The allenone coupling reagent not only is effective for the synthesis of simple amides and dipeptides but is also amenable to peptide fragment condensation and solid-phase peptide synthesis (SPPS). The robustness of the allenone-mediated peptide bond formation was showcased incisively by the synthesis of carfilzomib, which involved a rare racemization-/epimerization-free N to C peptide elongation strategy. Furthermore, the successful synthesis of the model difficult peptide ACP (65-74) on a solid support suggested that this method was compatible with SPPS. This method combines the advantages of conventional active esters and coupling reagents, while overcoming the disadvantages of both strategies. Thus, this allenone-mediated peptide bond formation strategy represents a disruptive innovation in peptide synthesis.