Primary Amides Research Articles

Broad-Scope Amination of Aryl Sulfamates Catalyzed by a Palladium Phosphine Complex.

Among phenol-derived electrophiles, aryl sulfamates are attractive substrates since they can be employed as directing groups for C-H functionalization prior to catalysis. However, their use in C-N coupling is limited only to Ni catalysis. Here, we describe a Pd-based catalyst with a broad scope for the amination of aryl sulfamates. We show that the N-methyl-2-aminobiphenyl palladacycle supported by the PCyp2ArXyl2 ligand (Cyp = cyclopentyl; ArXyl2 = 2,6-bis(2,6-dimethylphenyl)phenyl) efficiently catalyzes the C-N coupling of aryl sulfamates with a variety of nitrogen nucleophiles, including anilines, primary and secondary alkyl amines, heteroaryl amines, N-heterocycles, and primary amides. DFT calculations support that the oxidative addition of the aryl sulfamate is the rate-determining step. The C-N coupling takes place through a cationic pathway in the polar protic medium.

Cyanation and Hydrolysis Cascade of Aryl Bromides with Cuprous Cyanide to Access Primary Amides

AbstractA convenient and efficient approach for the cyanation and hydrolysis of aryl bromides to afford primary amides was developed, in which cuprous cyanide is used as a cyanide source and a catalyst. It has the advantages of excellent functional-group compatibility, medium to high yields, a one-pot procedure, and a non-noble-metal catalyst. The reaction could be performed on a gram scale to give N-allyl-N-methyl-5-nitroisophthalamide in a 73% yield.

Reduction of Amides to Amines Catalyzed by Ca(CH2C6H4NMe2‐o)2(THF)2/HBpin

AbstractReduction of amides to amines is an attractive subject in organic synthesis. Ca(CH2C6H4NMe2‐o)2(THF)2, an easily accessible main‐group complex, on combination with pinacolborane (HBpin) could serve as a highly active catalyst system in the reduction of primary, secondary and tertiary amides into the corresponding amines. This protocol showed good tolerance for functional groups and heteroatoms, and the aimed products could be obtained in a gram‐scale. The active species in this transformation was supposed to be a calcium hydride.

Galdieria sulphuraria: An Extremophilic Alga as a Source of Antiviral Bioactive Compounds.

In the last decades, the interest in bioactive compounds derived from natural sources including bacteria, fungi, plants, and algae has significantly increased. It is well-known that aquatic or terrestrial organisms can produce, in special conditions, secondary metabolites with a wide range of biological properties, such as anticancer, antioxidant, anti-inflammatory, and antimicrobial activities. In this study, we focused on the extremophilic microalga Galdieria sulphuraria as a possible producer of bioactive compounds with antiviral activity. The algal culture was subjected to organic extraction with acetone. The cytotoxicity effect of the extract was evaluated by the 2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The antiviral activity was assessed through a plaque assay against herpesviruses and coronaviruses as enveloped viruses and poliovirus as a naked one. The monolayer was treated with different concentrations of extract, ranging from 1 µg/mL to 200 µg/mL, and infected with viruses. The algal extract displayed strong antiviral activity at non-toxic concentrations against all tested enveloped viruses, in particular in the virus pre-treatment against HSV-2 and HCoV-229E, with IC50 values of 1.7 µg/mL and IC90 of 1.8 µg/mL, respectively. However, no activity against the non-enveloped poliovirus has been detected. The inhibitory effect of the algal extract was confirmed by the quantitative RT-PCR of viral genes. Preliminary chemical profiling of the extract was performed using ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS), revealing the enrichment in primary fatty acid amides (PFAA), such as oleamide, palmitamide, and pheophorbide A. These promising results pave the way for the further purification of the mixture to explore its potential role as an antiviral agent.

Surmounting Byproduct Inhibition in an Intermolecular Catalytic Asymmetric Alkene Bromoesterification Reaction as Revealed by Kinetic Profiling.

Kinetic profiling has shown that a (DHQD)2PHAL-catalyzed intermolecular asymmetric alkene bromoesterification reaction is inhibited by primary amides, imides, hydantoins, and secondary cyclic amides, which are byproducts of common stoichiometric bromenium ion sources. Two approaches to resolving the inhibition are presented, enabling the (DHQD)2PHAL loading to be dropped from 10 to 1 mol % while maintaining high bromoester conversions in 8 h or less. Iterative post-reaction recrystallizations enabled a homochiral bromonaphthoate ester to be synthesized using only 1 mol % (DHQD)2PHAL.

Chlorination of amides: Kinetics and mechanisms of formation of N-chloramides and their reactions with phenolic compounds

Amides are common constituents in natural organic matter and synthetic chemicals. In this study, we investigated kinetics and mechanisms of the reactions of chlorine with seven amides, including acetamide, N-methylformamide, N-methylacetamide, benzamide, N-methylbenzamide, N-propylbenzamide, and N-(benzoylglycyl)glycine amide. Apparent second-order rate constants for the reactions of the amides with chlorine at pH 8 are in the range of 5.8 × 10−3 – 1.8 M−1s−1 and activation energies in the range of 62-88 kJ/mol. The second-order rate constants for the reactions of chlorine with different amides decrease with increasing electron donor character of the substituents on the amide-N and N-carbonyl-C in the amide structures. Hypochlorite (‒OCl) dominates the reactions of chlorine with amides yielding N-chloramides with species-specific second-order rate constants in the range of 7.3 × 10−3 – 2.3 M−1s−1. Kinetic model simulations suggest that N-chlorinated primary amides further react with HOCl with second-order rate constants in the order of 10 M−1s−1. The chlorination products of amides, N-chloramides are reactive towards phenolic compounds, forming chlorinated phenols via electrophilic aromatic substitution (phenol and resorcinol) and quinone via electron transfer (hydroquinone). Meanwhile, N-chloramides were recycled to the parent amides. At neutral pH, apparent second-order rate constants for the reactions between phenols and N-chloramides are in the order of 10−4-0.1 M−1s−1, comparable to those with chloramine. The findings of this study improve the understanding of the fate of amides and chlorine during chlorination processes.

Structure-activity relationship of BMS906024 derivatives for Cryptosporidium parvum growth inhibition

BMS906024, a γ-secretase inhibitor that blocks Notch signaling, was previously shown to inhibit Cryptosporidium parvum growth in vitro. A structure–activity relationship (SAR) analysis of BMS906024 reported herein demonstrates the importance of the stereochemistry of the C-3 benzodiazepine and the succinyl β-substituent. However, concomitant removal of the succinyl α-substituent and switching the primary amide with secondary amides was tolerated. For example, 32 (SH287) inhibited C. parvum growth in HCT-8 host cells with an EC50 = 6.4 nM and an EC90 = 16 nM; however, blocking C. parvum growth with BMS906024 derivatives was correlative with inhibition of Notch signaling, highlighting that additional SAR analysis will be needed to separate these two activities.

Solid AIE fluorophore molecule with specific response of amide functional group to detect gaseous phosgene

A new solid Aggregation-induced Emission (AIE) fluorophore molecule (Ind-CONH2) for specific response of gaseous phosgene based on the dehydration of primary amide to nitrile was designed. Specially, visible AIE color changes of Ind-CONH2 with phosgene could be observed directly from bright blue to greenish blue on a portable solid-state test-strip under a 365 nm ultraviolet (UV) lamp, which showed inverse color changes from colorless to bright blue in homogeneous acetonitrile solution due to intramolecular charge transfer (ICT) effect. LOD of Ind-CONH2 for phosgene in acetonitrile was 1.52 nM and that for gaseous phosgene was 0.16 ppm (response time was less than 10 s in acetonitrile and 3 min for gas), which had a good development prospect in detecting phosgene. Additionally, Ind-CONH2 was successfully used as an erasable fluorescent anti-counterfeiting ink.

Ni-Catalyzed Photochemical C-N Coupling of Amides with (Hetero)aryl Chlorides.

This paper reports a photochemical C-N coupling of abundant, but less reactive aryl chlorides, with structurally diverse primary and secondary amides by Ni-mediated without an external photocatalyst. Under the irradiation of light (390-395 nm) with a soluble organic amine as the base, the reaction allows for the successful transformation of (hetero)aryl chlorides to a wide range of N-aryl amides. More than 60 examples are shown, demonstrating the feasibility and applicability of this protocol in organic synthesis. Mechanic studies indicate that this amidation proceeds via a Ni(I)-Ni(III) catalytic cycle.

Alleviating the trade-off by site-guided function switch of nitrilase to nitrile hydratase

Catalytic promiscuity makes nitrilase-mediated unnatural reactivity a promising pathway in the production of primary amides. However, during the functional switch of nitrilase, a trade-off between the newly developed hydration activity and relative activity hinders the application of nitrilase in the production of amides. Our previous study showed that the mutant F193N (Mut0) of nitrilase NIT6803 from Synechocystis sp. PCC6803 improved the hydration activity as the amide ratio increased to 73.4%, whereas the relative activity was only 50.1% of that of the wild-type (WT). In this study, we succeeded in alleviating the trade-off of Mut0 through an evolutionary combination of the key identified sites 101, 192, and 201. Inside the active pocket, the co-evolution of residue Q192 was identified by hotspot prediction to correlate with N193, and Q192H exhibited an improved amide ratio of 76.9% with a relative activity of up to 72%. Outside the active pocket, the flexible loop surface residue G101 and homodimer “A” interface residue I201 were identified using sequence alignment-based mutations. Further evolutionary combination of the three key sites yielded the best triple mutant G101K/Q192H/I201M, which had the highest amide ratio of 98.5% and considerably recovered relative activity of 82.6% while retaining only 1.5% of the carboxylic acid ratio. The transition-state analogue sheds light on the basis of the almost identical switch of the reaction pathways, and our results expand the toolbox of nitrilase-catalysed promiscuity for amide formation.

Synthesis of Acyl Hydrazides from Carboxamides and Hydrazine Hydrate Under Metal‐Free Conditions at Room Temperature

AbstractSynthesis of acyl hydrazides from amides has been achieved at room temperature through N‐activation reactions. A wide spectrum of functionalized primary and secondary amides was initially converted into N‐Boc, N‐nitroso and N‐tosyl amides and subjected to transamidation with hydrazine hydrate to obtain the desired acyl hydrazides in 76–94% yields. Broad substrate scope, shorter reaction time and mild reaction conditions are the merits of the developed methodology.

Condition-Controlled O-Acylation and N–O Bond Reduction of Hydroximic Acids with Thioacetic Acid

Condition-dependent transformations between hydroximic acids and thioacetic acid were achieved. Using NH4HCO3 in the ethanol solvent, efficient N-O bond cleavage of hydroxamic acids occurred to afford primary amides with high functional group compatibility. The reaction was switched to O-acylation when NEt3 and H2O were used as the base and solvent, respectively. These facile transformations could be scaled up to the gram level smoothly. Preliminary mechanistic studies suggested that the N-O bond cleavage involves a cascade process of acylation/reduction.

A Mn(II)-Catalyzed Tandem Oxidative Cleavage and Ammoxidation of Alcohols to Primary Amides

AbstractThe cleavage/functionalization of C–C bonds in alcohols has emerged as a robust tool for exploration of new conversion. Herein, a Mn(OAc)2-catalyzed oxidative cleavage/ammoxidation of a wide range of alcohols to amides has been developed. The practicality of this transformation was demonstrated by a scale-up experiment and an amidation of mixed alcohols in a one-pot fashion. Moreover, a plausible mechanism was proposed based on a series of control experiments.

Synthesis and characterization of biocompatible silver nanoparticles with increased anti-Diabetic and anti-Microbial effectiveness via the mediation of aquatic plant Hygrophila corymbosa

Using extracts from plants and seaweed to make metal nanoparticles is an interesting topic that has some advantages over more traditional physicochemical methods. Recent developments in nanoscience and nanobiotechnology have made it possible for these breakthroughs. Nevertheless, the production of nanoparticles via the use of aquatic plants and the applications of these particles are not very well recognized. This article described an ecologically friendly method of producing AgNPs by employing the aquatic plant Hygrophila corymbosa as the starting material. The examination of the zeta potential at −31.4 mV reveals that the AgNPs that were synthesized were stable for an extended period of time. The pictures produced by the HR-TEM indicated the presence of polydispersed, spherical-shaped nanoparticles with a size of less than 20 nm and distinct lattice fringes. The unmixed state of the AgNPs is represented by the peak in the EDX spectroscopy that was found at roughly 3 keV. XRD studies revealed that the AgNPs were found to be fcc in nature with miller indices of (111), (200), (220), and (311), and the average particle size was found to be 43 nm. The compounds having functional groups secondary amine, alkane, primary amide, and aldehyde in the plants in charge of the reduction of AgNO3 into AgNPs were listed using FT-IR analysis. Gram-positive bacteria B. subtilis, S. aureus, S. mutans, E. faecalis, andL. salivarius, and gram-negative bacteria P. mirabilis, P. vulgaris, K. pneumoniae, P. aeruginosa, andE. coli, as well as the fungal strains Candida albicans, Aspergillus flavus, and Aspergillus niger, were used to test the anti-microbial activity of the AgNPs produced. The outcome demonstrates the potential anti-microbial activity of the produced AgNPs. The anti-diabetic effect of the produced AgNPs was determined using alpha-amylase inhibition test, and they possess excellent efficacy (IC50 value of 47.72) compared with the standard used. These findings demonstrated that AgNPs synthesized using aquatic plants are highly stable and have a higher potential for biological activities.

Azide-Enolate Cycloaddition-Rearrangement Enables Direct α-Amination of Amides and Enelactam Synthesis from Esters.

Azide-enolate cycloaddition-rearrangements offer potential for rapid access to diverse molecular frameworks from simple precursors. We report here that investigations into the cycloadditions of ester or amide enolates with vinyl azides led to the identification of two reaction processes - direct α-amination of amides and lactams, and the synthesis of ene-γ-lactams from esters. The outcomes of these reactions depended on the fate of key vinyl triazoline intermediates generated in the initial cycloaddition step. Isolation of reaction intermediates in the ene-γ-lactam synthesis revealed the unexpected addition of two enolate equivalents, one of which is later eliminated. Computational studies further suggested an unusual reaction pathway involving direct addition of an enolate to the terminal carbon of the N-vinyl triazoline. In contrast, the α-amination of amides and lactams proceeded by rearrangement of the intermediate triazoline to give an imine, hydrolysis or reduction of which gave access to primary or secondary α-amino amides or lactams.

Selective Hydrolysis of Primary and Secondary Amides Enabled by Visible Light.

Amide hydrolysis is a fundamentally important transformation in organic chemistry. Developing hydrolysis procedures under mild conditions with a broad substrate scope is desirable. Herein, by leveraging a photoresponsive auxiliary o-nitroanilide, we established a mild two-step protocol for the hydrolysis of primary and secondary amides. This protocol is driven by visible light irradiation at room temperature under neutral conditions, which tolerates numerous acid- and base-sensitive functional groups. Various drugs, natural product-, and amino acid-derived amides can be selectively hydrolyzed.

Alcoholysis of Primary Amides in the Presence of CF3SO3H

Alcoholysis of Primary Amides in the Presence of CF3SO3H

Mo(VI)-catalyzed conversion of nitriles to amides with hydrogen peroxide in ethanol

A method for the preparation of primary amides from nitriles using hydrogen peroxide and a catalytic amount of sodium molybdate in ethanol is described. Using this method, nitriles including aromatic nitriles, aromatic heterocyclic nitriles and aliphatic nitriles were converted into the corresponding amides in moderate to high yields. Electronic and steric effects of substituent have a significant effect on the reactivity of nitrile, nitriles with electron-withdrawing group at the para or meta position show high reactivities and they can be converted into the corresponding amide in good to high yield at room temperature.

Dehydrogenative Imination of Low-Valent Sulfur Compounds-Fast and Scalable Synthesis of Sulfilimines, Sulfinamidines, and Sulfinimidate Esters.

Herein, we describe an electrochemical pathway for the synthesis of sulfilimines, sulfoximines, sulfinamidines, and sulfinimidate esters from readily available low-valent sulfur compounds and primary amides or their analogues. The combination of solvents and supporting electrolytes together act both as an electrolyte as well as a mediator, leading to efficient use of reactants. Both can be easily recovered, enabling an atom-efficient and sustainable process. A broad scope of sulfilimines, sulfinamidines, and sulfinimidate esters with N-EWGs is accessed in up to excellent yields with broad functional group tolerance. This fast synthesis can be easily scaled up to multigram quantities with high robustness for fluctuation of current densities of up to 3 orders of magnitude. The sulfilimines are converted into the corresponding sulfoximines in an ex-cell process in high to excellent yields using electro-generated peroxodicarbonate as a green oxidizer. Thereby, preparatively valuable NH sulfoximines are accessible.

Direct synthesis of amides through transamidation using dichloroimidazolinedione (DCID)

The C-N bond of carboxamides is extremely stable under most conditions. The present study reveals an unconventional approach to the transamidation of primary amides using DCID as C-N bond activator. DCID alone mediates the reactions and no additional metal catalyst is required. The method exhibits broad scope and secondary and tertiary amide synthesized in good yield. The chemical structures of the intermediate 3 and all-synthesized compounds were confirmed by comparison of melting point with literature and NMR spectra.