Amination Strategy Research Articles

Enantioselective Synthesis of Axially Chiral Benzimidazoles ­Bearing a C–N axis via Pd-Catalyzed Buchwald–Hartwig ­Amination

AbstractBenzimidazole atropisomers bearing a C–N axis are privileged structural frameworks in pharmaceutical and natural products, thus appealing an increasing interest for its asymmetric synthesis. Here, we briefly discuss recent advances in the asymmetric synthesis of benzimidazole atropisomers with a C–N axis, with particular attention to our recently developed palladium-catalyzed intramolecular Buchwald–Hartwig amination strategy.

Facile One-Pot Synthesis of Furan Double Schiff Base from 5-Hydroxymethylfurfural via an Amination–Oxidation–Amination Strategy in Water

Facile One-Pot Synthesis of Furan Double Schiff Base from 5-Hydroxymethylfurfural via an Amination–Oxidation–Amination Strategy in Water

Intramolecular dehydrogenative amination of alkenes via dual organic photoredox and cobalt catalysis without a hydrogen acceptor

A strategy for the dehydrogenative amination of alkenes has been developed without using any oxidants and noble metals and with H2 released as the only by-product.

Electrochemical Synthesis of Allylic Amines from Terminal Alkenes and Secondary Amines

Allylic amines are valuable synthetic targets en route to diverse biologically active amine products. Current allylic C-H amination strategies remain limited with respect to the viable N-substituents. Herein, we disclose a new electrochemical process to prepare aliphatic allylic amines by coupling two abundant starting materials: secondary amines and unactivated alkenes. This oxidative transformation proceeds via electrochemical generation of an electrophilic adduct between thianthrene and the alkene substrates. Treatment of these adducts with aliphatic amine nucleophiles and base provides allylic amine products in high yield. This synthetic strategy is also amenable to functionalization of feedstock gaseous alkenes at 1 atm. In the case of 1-butene, high Z-selective crotylation is observed. This strategy, however, is not limited to the synthesis of simple building blocks; complex biologically active molecules are suitable as both alkene and amine coupling partners. Preliminary mechanistic studies implicate vinylthianthrenium salts as key reactive intermediates.

C–H Amination Enabled [2+1+1+1] Annulation Reaction in Water: Access to Benzoxazoles

AbstractA novel and efficient four‐component reaction in water is reported, enabling the efficient synthesis of benzoxazoles from aldehydes, benzo‐1,2‐quinones, hydroxylamine hydrochloride, and water via a C−H amination strategy. Importantly, water is not only employed as the solvent but also used as the oxygen source of the benzoxazole skeletons, while inorganic hydroxylamine hydrochloride serves as the nitrogen source. Preliminary mechanistic studies prove that the aldoxime rather than the quinone oxime is the reaction intermediate.

Copper-catalysed amination of alkyl iodides enabled by halogen-atom transfer

Despite the fact that nucleophilic displacement (SN2) of alkyl halides with nitrogen nucleophiles is one of the first reactions introduced in organic chemistry teaching, its practical utilization is largely limited to unhindered (primary) or activated (α-carbonyl, benzylic) substrates. Here, we demonstrate an alternative amination strategy where alkyl iodides are used as radical precursors instead of electrophiles. Use of α-aminoalkyl radicals enables the efficient conversion of the iodides into the corresponding alkyl radical by halogen-atom transfer, while copper catalysis assembles the sp3 C–N bonds at room temperature. The process provides SN2-like programmability, and application in late-stage functionalization of several densely functionalized pharmaceuticals demonstrates its utility in the preparation of valuable N-alkylated drug analogues. The SN2 reaction is essential in organic chemistry, but its substrate scope is limited. Now, a strategy based on halogen-atom transfer using α-aminoalkyl radicals and copper catalysis enables coupling of secondary alkyl iodides with N-nucleophiles with SN2-like programmability.

Post-Transition State Bifurcation in Iron-Catalyzed Arene Aminations

Recently, an iron-catalyzed meta-selective arene amination strategy was reported to show excellent regiocontrol, operational simplicity, and high atom and cost efficiencies. In this work, density functional theory (DFT) calculations and quasiclassical molecular dynamics (MD) simulations were carried out to study the mechanism of this reaction. Our computations revealed an unreported ambimodal attack of arene by hydroxylamine-O-sulfate, which forms not only σ-complex via electrophilic addition but also an aziridinium intermediate through energetically concerted electrophilic–nucleophilic additions. Quasiclassical trajectories suggest the orientation of the attacking NH2+ group with respect to arene control: (a) site selectivity of the post-transition state nucleophilic attack and (b) σ-complex/aziridinium selectivity on the bifurcating surface. The final amination products can be favorably generated via the ring opening of aziridinium intermediates, rearrangement of σ-complexes, and deprotonation of the resultant carbocations. Overall, our study illustrates a novel pathway in which an ambimodal reaction is incorporated into the standard SEAr mechanism.

Photocatalyzed intermolecular amination for the synthesis of hydrazonamides

A photocatalyzed intermolecular amination strategy for the synthesis of hydrazonamides is reported by a multi-component reaction of β-ketonitriles with N,N-disubstituted hydrazines.

Amination strategy to boost the CO2 electroreduction current density of M–N/C single-atom catalysts to the industrial application level

Amino-modification, as an ingenious strategy, was proposed for boosting CO2 electroreduction current density of Ni–N/C single-atom catalyst to industrial level.

Microwave-assisted Amination Reactions: An Overview

C-N coupling reactions were found to be attractive among researchers owing to the importance of C-N bond formation in heterocyclic synthesis. Hence C-N bond formation via amination reaction with the assistance of microwave radiations gained significant attraction recently. Microwave-assisted reactions are greener, faster and generally efficient compared to the conventional thermal reactions offering better purity of the product with enhancement in the yield. It was surprisingly revealed that several new advancements in amination reactions were highly influenced by this greener technology. This first review on microwave-assisted amination reaction focuses on the novel amination strategies that emerged with the help of microwave methodology, and covers literature up to 2019.

Intramolecular C(sp₃)-H Bond Amination Strategies for the Synthesis of Saturated N-containing Heterocycles.

The selective functionalization of C(sp³)-H bonds via intramolecular amination reactions represents a very attractive strategy for the construction of saturated N-containing heterocycles (SNHets). Over the past de- cades, the chemical community has devoted its efforts towards expanding the synthetic toolbox with the aim of facilitating access to these key fragments in a controllable, reproducible and efficient manner. This review covers selected examples of the most recent advances in intramolecular C(sp³)-N bond-forming reactions by three main approaches: (1) the Hofmann-Löffler-Freytag (HLF) reaction; (2) transition-metal-catalyzed nitrene C(sp³)-H inser- tion; and (3) transition-metal-catalyzed ligand-assisted C(sp³)-N bond-forming reactions via a reductive elimination step. We will discuss reactivity, selectivity and the major mechanistic insights into these transformations.

A combine approach of chemical synthesis, biological evaluation and structural dynamics studies revealed thiazole substituted arylamine derivatives as potent FabH enzyme inhibitors

Bacterial FabH enzyme is a broad-spectrum antimicrobial target and can be used in the design of novel antibiotics. This study reports chemical synthesis of thiazole based amine compounds as FabH inhibitors, followed by biological evaluation, and computational drug designing analysis with ultimate objective to guide further biological optimization of the identified hits. The compounds were synthesized through Pd-PEPPSI catalyzed cross coupling strategy for the Buchwald-Hartwig amination of thiazole-substituted aryl bromide. Pd-PEPPSI pre-catalysts were utilized for the cross couple with the diverse range of functionalized electron-deficient and electron-rich anilines and aliphatic amines. The thiazole based heteroaryl bromide coupling was found to be challenging and only specialized Pd-PEPPSI-IPr and Pd-PEPPSI-IPent catalysts were found to be effective providing the coupling product yield in the range of 78% to 99%. Biological investigation depicted compound 3f to be effective against Bacillus subtilis, Staphylococcus aureus, Staphylococcus epidermis, and Escherichia coli with mean + standard deviation value of 9.6 ± 0.4, 11.6 ± 0.4, 15.6 ± 0.4, and 11.6 ± 0.4, respectively. This compound is also active against free radicals with EC90 value of 39.45 µg/ml. Comparative docking predictions unravel the 3f binding mode at FabH active tunnel as such to block complete access for the natural substrate and involved balanced hydrogen and hydrophobic interactions. FabH-3f complex dynamics in solution found the docked conformation between the protein and compound of higher stability with mean carbon alpha deviation of 1.87 Å and mean residual deviation of 0.88 Å. Intermolecular interactions analysis depicted Asn274 from FabH active pocket to be significant in compound holding and strengthening of interaction as the simulation progresses. This was supported further by radial distribution function (RDF) and axial frequency distribution (AFD) that demonstrated the high distribution of compound atoms in close proximity of Asn274 residue and decrease in interaction distance. Further, the docking and simulation findings were validated through MMPB/GBSA methods that complements the compound affinity for the said target. In a nutshell, the identified hit could be subjected to structure, biological and pharmacokinetic optimization for development of effective FabH inhibitors.

Comparison of polysaccharide glycoconjugates as candidate vaccines to combat Clostridiodes (Clostridium) difficile.

Two known Clostridiodes (Clostridium) difficile surface antigens, a lipoteichoic acid (LTA) and a polysaccharide (PS-II) were isolated and purified in order to prepare glycoconjugate vaccines to the carrier protein human serum albumin utilising a reductive amination strategy. Mice and rabbits were immunized with a prime and two boost strategy and the resulting sera were examined for their ability to recognise the purified homologous antigens and subsequently killed whole cells of C. difficile strains and other Clostridia species. Immunisation derived antisera from rabbits and mice, recognised all strains of C. difficile vegetative cells examined, with generally similar titers from animals that received the LTA or the PS-II conjugates. Sera raised to the LTA conjugates were able to recognise other Clostridia species C. butyricum, C. bifermentans and C. subterminale whereas sera raised to the PS-II conjugates were not. These LTA and PS-II sera recognised live cells in an immunofluorescence assay and were also able to recognise the spore form of the bacterium. This study has confirmed that the LTA and PS-II polysaccharides are both highly conserved surface polymers of C. difficile that are easily accessible to the immune system and as such may have potential as vaccine antigens or as targets for therapeutics to combat C. difficile infection.

Design, synthesis and in silico evaluation of benzoxazepino(7,6-b)quinolines as potential antidiabetic agents

The second-generation XPhos palladium preformed catalyst-based C–N cross-coupling through Buchwald–Hartwig amination with primary and secondary amines towards functionalized benzoxazepino(7,6-b)quinolines is accounted for. The microwave irradiation in dioxane provided the desired highly functionalized oxazepino quinolines, 5, in high yield and purity from the corresponding 2-chloro-3-formyl quinolines, 1, via intermediate, 4, in a sequential cyclization/Buchwald amination strategy. Besides, functional group tolerance, low catalyst loading, microwave assistance, and a wide scope of reactions are the advantages. Compounds 5a, 5b, 5c, 5d, 5e, and 6j showed 50% inhibition in antioxidant potency, whereas compounds 5f, 5g, 5m, 6h, 6j, and 6k showed potent activity alongside 70% inhibition of alpha-amylase and 50% inhibition of alpha-glucosidase, respectively. The results were supported by molecular docking studies of the active compounds with acarvostatin as a standard drug for antidiabetic activity.

Copper-Catalyzed Electrophilic Amination of Arylboronic Acids with Anthranils: An Access to N-Aryl-2-aminophenones.

An efficient copper-catalyzed electrophilic amination strategy has been established for the rapid synthesis of N-aryl-2-aminophenones from readily available arylboronic acids/esters and anthranils. This protocol features good functional group tolerance, broad substrate scope, and operational simplicity. Moreover, a tandem C-H borylation and C-N coupling protocol has also been developed to transform simple arenes to the valuable N-aryl-2-aminophenones in one pot. Additionally, the synthetic potential of this methodology is further demonstrated by the synthesis of various useful N-heterocycles and derivatives.

Amination of Graphene Oxide Leads to Increased Cytotoxicity in Hepatocellular Carcinoma Cells.

Clinically, there is an urgent need to identify new therapeutic strategies for selectively treating cancer cells. One of the directions in this research is the development of biocompatible therapeutics that selectively target cancer cells. Here, we show that novel aminated graphene oxide (haGO-NH2) nanoparticles demonstrate increased toxicity towards human hepatocellular cancer cells compared to pristine graphene oxide(GO). The applied novel strategy for amination leads to a decrease in the size of haGO-NH2 and their zeta potential, thus, assuring easier penetration through the cell membrane. After characterization of the biological activities of pristine and aminated GO, we have demonstrated strong cytotoxicity of haGO-NH2 toward hepatic cancer cells—HepG2 cell line, in a dose-dependent manner. We have presented evidence that the cytotoxic effects of haGO-NH2 on hepatic cancer cells were due to cell membrane damage, mitochondrial dysfunction and increased reactive oxygen species (ROS) production. Intrinsically, our current study provides new rationale for exploiting aminated graphene oxide as an anticancer therapeutic.

Iodine-Catalyzed Aerobic Diazenylation-Amination of Indole Derivatives.

A mild strategy for consecutive diazenylation and amination of indole moieties has been demonstrated. The functionalization occurs at C3 and C2 carbon atoms, respectively, at the indole scaffold in the presence of catalytic iodine and air at 40 °C in the 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) solvent. It is noteworthy that the aromatic amines are generated in situ by the reaction of aryl hydrazine with iodine. In general, bright red products are obtained in moderate to good yield. Control reactions are conducted to establish the reaction mechanism.

Salient features of the aza-Wacker cyclization reaction.

The intramolecular aza-Wacker reaction has unparalleled potential for the site-selective amination of olefins, but it is perhaps underappreciated relative to other alkene oxidations. The first part of this review makes the distinction between classical and tethered aza-Wacker cyclization reactions and summarizes examples of the latter. The second portion focuses on developments in asymmetric aza-Wacker cyclization technology. The final part of the review summarizes applications of all classes of aza-Wacker cyclization reactions to natural product assembly.

Cycloamination strategies for renewable N-heterocycles

Efficient amination strategies for synthesis of N-heterocycles from functional molecules (bottom-up) or from biomass (top-down) via sustainable C–N/C–X bond chemistry.

Regioselective Radical Alkene Amination Strategies by Using Phosphite-Mediated Deoxygenation

Nitrogen-containing compounds are an essential motif in all disciplines of chemistry and the efficient synthesis of these frameworks is a highly sought-after goal. Presented here is a summary of recent efforts conducted by our group to develop radical-mediated amination strategies for the formal synthesis of primary amines from alkenes with exclusive anti-Markovnikov regioselectivity. We have found that N-hydroxyphthalimide is an effective reagent capable of supplying both the N and H atoms for alkene hydroamination in a group transfer radical addition-type mechanism. Furthermore, allyl-oxyphthalimide derivatives are similarly capable of radical group transfers and allow for the aminoallylation of an external alkene.