One-pot Protocol Research Articles

A Scalable and Metal-Free Synthesis of Indazoles from 2-Aminophenones and In Situ Generated De-Boc-Protected O-Mesitylsulfonyl Hydroxylamine Derivatives.

A one-pot metal-free protocol to access indazoles from easily available 2-aminophenones and hydroxylamine derivatives has been achieved. The reaction is operationally simple, mild, and insensitive to air and moisture. A broad range of indazoles were prepared in good to excellent yield (up to 97% yield), and the reaction displayed a broad functional group tolerance. The reaction was performed at gram scale, and its synthetic application was exhibited through the rapid and efficient preparation of bioactive molecule YC-3 and FDA-approved drug axitinib.

Visible-Light-Induced C-3 Difluoroalkylation of Quinoxalin-2(1H)-ones with Difluoroiodane(III) Reagents under Catalyst-Free Conditions

AbstractA visible-light-induced radical difluoroalkylation of quinoxalin-2(1H)-ones by hypervalent-iodine-based reagents was developed. To facilitate the final oxidative step, [bis(trifluoroacetoxy)iodo]benzene (PIFA) was employed as an oxidant. Moreover, a one-pot protocol for this transformation was realized by generating the difluoroalkylation reagent in situ. The readily accessible reagents and the mild reaction conditions make this reaction an alternative and practical strategy for the synthesis of C(3)-difluoroalkylated quinoxalin-2(1H)-ones.

Facile and efficient synthesis of carboxylic terminated Ti3C2Tx nanosheets using citric acid

For the last decade, researchers have been reporting various approaches for the synthesis and surface modification of Ti3C2Tx MXenes nanosheets. However, the use of concentrated acids and alkalis, elevated reaction temperature, and the subsequent degradation of MXenes nanosheets are considered sore points of the trade. In this study, we formulated an original, efficient, and one-pot protocol for the synthesis of carboxylic terminated Ti3C2Tx nanosheets incorporating non-hazardous citric acid with NH4HF2. Three different etchants: (i) NH4HF2 (ii) NH4HF2 and citric acid (iii) NH4F and citric acid, were used to etch the Ti3AlC2 MAX phase. Thus, three types of Ti3C2Tx nanosheets were synthesized and comparatively analyzed using XRD, SEM, TEM, EDX, AFM, FTIR, XPS, NMR, BET, TGA and AAS techniques. Firstly, it was established that among Ti3C2Tx samples, the best-exfoliated few-layered carboxylic terminated nanosheets of 1.36 nm thickness were achieved using NH4HF2 and citric acid. Secondly, the nanosheets displayed extraordinary features owing to their superior morphology, microporous structure, improved surface chemistry, better thermal stability, prolonged dispersity and enhanced adsorption performance in an aqueous media. For instance, the Ti3C2Tx nanosheets showed a d-spacing of 1.25 nm and a specific surface area of 42.63 m2/g with numerous active sites in terms of (–COOH) terminations alongside (=O), (-F) and (–OH) terminal groups. In addition, the carboxylic terminated MXene exhibited excellent dispersity and stability in water for 40 days. The nanosheets also displayed adsorption capacities of 338 mg/g and 349 mg/g for Cr(VI) and Pb(II), respectively. The adsorption performance of the MXenes nanosheets was quite encouraging compared to previous studies. Moreover, the carboxylic terminated nanosheets were regenerated over six cycles of adsorption–desorption. Hence, these high-quality Ti3C2Tx nanosheets are a promising candidate for environmental application in general and removal of toxic heavy metals from wastewater in specific.

A green one-pot synthetic protocol of hexahydropyrimido[4,5-d]pyrimidin-4(1H)-one derivatives: molecular docking, ADMET, anticancer and antimicrobial studies.

Ten hexahydropyrimido[4,5-d]pyrimidine derivatives have been synthesized by using a green and time-efficient microwave method. The synthesized motifs were evaluated for their anticancer activity, antimicrobial activity, molecular docking, drug likeliness and ADMET studies. Comparatively, the hetero-aromatic pyrazole substituted compound 4a exhibited the highest anticancer activity [Mean growth percent: 35.57], while EDG [-N(CH3)2] substituted compound 4i indicated very good activity [Mean growth percent: 60.92] against various cell lines. From the computational studies, Compound 4a passed the drug-likeness and ADME properties, fewer toxic properties, and potent inhibitory potential against the RIPK2 with significant binding affinity. In-silico molecular docking revealed that the compound 4a has significant binding energy (-9.8kcal/mol) and dissociation constant (0.54µM) properties. Additionally, synthesized motifs were evaluated for antimicrobial activity by MIC referencing the standards. According to the SAR evaluations, the compounds 4f (4-NO2), 4g (3-NO2), and 4h (2-Cl) that include EWGs substituted aldehydes performed well as antimicrobials against selected bacterial and fungal strains. Thus, the synthesized pyrimido[4,5-d]pyrimidine with the heterocyclic and EWGs substituents could act as a potential candidate after further structural optimization for anticancer and antimicrobial drug discovery, respectively.

Efficient Synthesis of Hydrolytically Degradable Block Copolymer Nanoparticles via Reverse Sequence Polymerization-Induced Self-Assembly in Aqueous Media.

Hydrolytically degradable block copolymer nanoparticles are prepared via reverse sequence polymerization-induced self-assembly (PISA) in aqueous media. This efficient protocol involves the reversible addition-fragmentation chain transfer (RAFT) polymerization of N,N'-dimethylacrylamide (DMAC) using a monofunctional or bifunctional trithiocarbonate-capped poly(ϵ-caprolactone) (PCL) precursor. DMAC monomer is employed as a co-solvent to solubilize the hydrophobic PCL chains. At an intermediate DMAC conversion of 20-60 %, the reaction mixture is diluted with water to 10-25 % w/w solids. The growing amphiphilic block copolymer chains undergo nucleation to form sterically-stabilized PCL-core nanoparticles with PDMAC coronas. 1 H NMR studies confirm more than 99 % DMAC conversion while gel permeation chromatography (GPC) studies indicate well-controlled RAFT polymerizations (Mw /Mn ≤1.30). Transmission electron microscopy (TEM) and dynamic light scattering (DLS) indicate spheres of 20-120 nm diameter. As expected, hydrolytic degradation occurs within days at 37 °C in either acidic or alkaline solution. Degradation is also observed in phosphate-buffered saline (PBS) (pH 7.4) at 37 °C. However, no degradation is detected over a three-month period when these nanoparticles are stored at 20 °C in deionized water (pH 6.7). Finally, PDMAC30 -PCL16 -PDMAC30 nanoparticles are briefly evaluated as a dispersant for an agrochemical formulation based on a broad-spectrum fungicide (azoxystrobin).

Production of diacetates from propenylphenols: A one-pot two-step approach involving hydroformylation/hydrogenation/O-acylation

A one-pot two-step approach for the synthesis of diacetate esters from propenylphenols was developed. This protocol involves the functionalization of the propenylphenol in two remote sites, performing multiple consecutive and parallel reactions: hydroformylation of the C-C double bond, hydrogenation of the formed aldehyde, and the O-acylation of both phenolic and hydroxy groups of the resulting alcohol. For such a challenging transformation, specific catalytic systems had to be developed, involving Rh complexes and phosphorus(III) ligands for the tandem hydroformylation/hydrogenation, along with 4-dimethylaminopyridine (an organocatalyst) to promote the acylation step by Ac2O. As the presence of Ac2O before the hydrogenation step leaded to undesired side reactions, a one-pot two-step protocol was developed to enhance the selectivity. Eventually, the method allowed to obtain diacetate esters, which are potentially valuable as flavor and fragrance ingredients, from propenylphenols in good to excellent yields (82–96 %).

Oxetane-, Azetidine-, and Bicyclopentane-Bearing N-Heterocycles from Ynones: Scaffold Diversification via Ruthenium-Catalyzed Oxidative Alkynylation.

A process for 3-fold scaffold diversification is achieved via ruthenium-catalyzed oxidative alkynylation of commercially available oxetanols, azetidinols and bicyclopentanols to form α,β-acetylenic ketones (ynones), which are subsequently converted to oxetane-, azetidine- and bicyclopentane-bearing pyrazoles, isoxazoles and pyrimidines. A one-pot oxidative alkynylation-condensation protocol that directly converts azetidinols to azetidine-substituted pyrazoles or pyrimidines is demonstrated.

An Aldehyde-Driven, Fe(0)-Mediated, One-Pot Reductive Cyclization: Direct Access to 5,6-Dihydro-quinazolino[4,3-b]quinazolin-8-ones and Photophysical Study.

A short, proficient, and regioselective synthesis of biheterocyclic 5,6-dihydro-quinazolino[4,3-b]quinazolin-8-ones has been revealed via an Fe(0)-powder-mediated, one-pot reductive cyclization protocol. Mechanistic investigation proved that water acts as a source of hydrogen for the reduction of the nitro group and the reaction rate was accelerated by an aldehyde. The designed transformation works under aerobic conditions, providing a series of bio-inspired molecular scaffolds. In addition, the photophysical study showed blue fluorescence emission with a good fluorescence quantum yield.

One-pot protocol for the reductive amination of aldehydes using thiamine hydrochloride as a green catalyst under solvent-free condition

A novel, green, solvent-free, and efficient method has been developed for the one-pot reductive amination of carbonyl compounds using thiamin hydrochloride as a catalyst. This method has performed reductive amination on various functionalized amines and aldehydes, including aliphatic, aromatic, and heteroaromatic ones. The reductive amination of the carbonyl compounds occurred in a single step without any side reaction. The key benefits of this technique included its easiness, greener protocol, quick transformation, variety of substrates, outstanding yield, metal-free, and catalyst recyclability. This helps to make the procedure practical, affordable, and biodegradable.

One pot, scalable synthesis of hydroxide derived ferrite magnetic nanoparticles

Herein we describe a new, quite simple, highly scalable, one-pot protocol for the synthesis of ferrite nanoparticles, NPs. We immerse water insoluble iron boride, FeB, powders – in plastic bottles at temperatures between 50 °C and 80 °C and ambient pressures – for tens of hours in high pH aqueous solutions of potassium-, sodium-, tetramethylammonium-, or tetrabutylammonium-hydroxides. The resulting powder is comprised of iron oxide, Fe3O4, NPs with, in one case, a saturation magnetization of 75 Am2kg−1, that exhibit ferrimagnetic behavior, with a critical temperature of 820 K. The same protocol was used to convert water soluble iron sulphate, FeSO4, to the same NPs. The average size of the NPs depends on reaction time; after 24 h, they are in the 15 nm range; after 48 h, they are closer to 25 nm. While our approach may appear to be similar to the co-precipitation method for making such NPs, we make a strong case that our approach is significantly simpler, nonetheless reaching high magnetization of NPs.

Regioselective synthesis and antibacterial screening of new thiazol-2(3H)-imines linked to arene or chromene units

A one-pot protocol was developed to prepare new thiazol-2(3H)-imines in efficient yields. Therefore, the reaction of the appropriate aromatic amine, phenyl isothiocyanate and chloroacetone (ratio 1:1:1) was mediated using different solvents and bases. The optimized protocol was to conduct the reaction in ethanol at reflux in the presence of 1.2 equivalents of sodium acetate. The reaction produced the regioisomeric (Z)-N-aryl-3-phenylthiazol-2(3H)-imine, as detected by 1D and 2D NMR spectral data. Using a similar protocol, new arene- or chromene-linked thiazol-2(3H)-imines were prepared by the use of the respective α-bromoketones. The new products were screened against six different bacterial strains. In general, chromene-linked thiazol-2(3H)-imines displayed superior antibacterial activity over other products. Thiazol-2(3H)-imines linked to 6-methyl and 6-methoxy-2-oxo-2H-chromene units had the most effective antibacterial activity with MIC/MBC values of 2.0/4.0 and 1.9/3.9 µM, respectively, against Staphylococcus aureus, Streptococcus mutans, and Escherichia coli strains.

2 + 2] Cycloaddition/Retro-Electrocyclization/Decarboxylation Reaction Sequence: Access to 4-Aminopyridines from Methylideneisoxazolones and Ynamines.

4-(1-Aminoallylidene)isoxazol-5-ones were synthesized in good yields by the [2 + 2]cycloaddition-retro-electrocyclization reaction of 4-methylideneisoxazol-5(4H)-ones with ynamines. The reaction mechanism and the absence of hetero-Diels-Alder cycloadducts were investigated by DFT calculations. 4-(1-Aminoallylidene)isoxazol-5-ones were found to be convenient substrates for the preparation of 4-aminopyridines under thermal metal-free conditions. The process proceeds via decarboxylative isomerization with cyclic amino groups and accompanied by partial dealkylation of acyclic amino groups. 4-Aminopyridines can also be prepared directly from 4-methylideneisoxazol-5(4H)-ones and ynamines by the one-pot protocol.

Synthesis of N-aryl derived formamides using triflic anhydride

A facile and convenient one-pot protocol for the N-formylation of aryl amines has been furnished using Tf2O. This approach involves N-formylation of anilines and its derivatives employing formic acid as a formyl source and triflic anhydride (Tf2O) as an activator as the key step. This work highlights the ability of Tf2O as an activating agent, includes operational simplicity, easy applicability to gram-scale preparation and to afford the N-formyl aryl amines in moderate to good yields.

One-pot synthesis of novel pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines under microwave irradiation in a green solvent

A one-pot microwave-assisted method for the synthesis of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines from 5-aminopyrazolyl-4-carbonitriles, orthoesters, and hydrazides was developed. The method utilizes anisole as a geen media for the reaction and tolerates variations in the structure of each substrate, thus allowing the preparation of diverse pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines. The catalyst-free one-pot protocol, short reaction time, and convenient work-up are additional beneficial features of this method.

One-Pot Synthetic Approach to 3-Carboxyl- and 3-Ketopyridines in Aqueous Media.

We describe a one-pot strategy to access 3-carboxyl- and 3-ketopyridines from readily available alkynes and propargylamine via a hydroamination process. This one-pot protocol uses alkynes as starting materials, has a broad substrate scope, and operates in aqueous media and open-air conditions. A series of aryl- and alkyl-substituted pyridines were synthesized. This green methodology can be scaled to laboratory size and was used for the synthesis of the natural product core, 4-aza-fluorenone. Density-functional theory and control mechanistic studies support a domino hydroamination/pericyclic reaction, which includes the formation of the enaminone intermediate and its transformation through an aza-Claisen rearrangement to the desired pyridine product.

Digital Microfluidics and Magnetic Bead-Based Intact Proteoform Elution for Quantitative Top-down Nanoproteomics of Single C. elegans Nematodes.

While most nanoproteomics approaches for the analysis of low-input samples are based on bottom-up proteomics workflows, top-down approaches enabling proteoform characterization are still underrepresented. Using mammalian cell proteomes, we established a facile one-pot sample preparation protocol based on protein aggregation on magnetic beads and intact proteoform elution using 40 % formic acid. Performed on a digital microfluidics device, the workflow enabled sensitive analyses of single Caenorhabditis elegans nematodes, thereby increasing the number of proteoform identifications compared to in-tube sample preparation by 46 %. Label-free quantification of single nematodes grown under different conditions allowed to identify changes in the abundance of proteoforms not distinguishable by bottom-up proteomics. The presented workflow will facilitate proteoform-directed analysis on samples of limited availability.

Elution von intakten Proteoformen von magnetischen Partikeln kombiniert mit digitaler Mikrofluidik für die quantitative Top‐down‐Nanoproteomik von einzelnen C. elegans‐Nematoden

AbstractWährend die meisten Ansätze zur Analyse von geringen Probemengen durch Nanoproteomik auf der bottom‐up‐Strategie basieren, sind top‐down‐Ansätze zur Charakterisierung von Proteoformen nach wie vor unterrepräsentiert. An Proteomen von Säugerzellen haben wir eine einfache Probenvorbereitungsmethode etabliert, welche auf Proteinaggregation an magnetischen Partikeln und anschließender Elution intakter Proteoformen durch 40 %ige Ameisensäure basiert. Die Implementierung der Methode auf einer Plattform für digitale Mikrofluidik ermöglichte die sensitive Analyse von einzelnen Individuen des Nematoden Caenorhabditis elegans. Die Anzahl identifizierter Proteoformen konnte dabei im Vergleich zu herkömmlicher Probenvorbereitung in einem Reaktionsgefäß um 46 % erhöht werden. Ferner erlaubte die markierungsfreie (label‐free) Quantifizierung von Proteomen einzelner Nematoden, welche unter verschiedenen Bedingungen kultiviert wurden, Änderungen der Abundanz von Proteoformen zu erkennen, welche in bottom‐up‐Experimenten nicht festgestellt wurden. Die hier präsentierte Methode wird die Proteoform‐zentrische Analytik in Proben mit limitierter Verfügbarkeit vereinfachen.

Metal-free, an effective and one-pot protocol for the reductive amination of aldehydes using glycerol as a green solvent

Metal-free, an effective and one-pot protocol for the reductive amination of aldehydes using glycerol as a green solvent

Regio- and Stereoselective Organocatalyzed Relay Glycosylations To Synthesize 2-Amino-2-deoxy-1,3-dithioglycosides.

Herein, we describe a novel methodology for the regio- and stereoselective convergent synthesis of 2-amino-2-deoxy-dithioglycosides via one-pot relay glycosylation of 3-O-acetyl-2-nitroglucal donors. This unique organo-catalysis relay glycosylation features excellent site- and stereoselectivity, good to excellent yields, mild reaction conditions, and broad substrate scope. 2-Amino-2-deoxy-glucosides/mannosides bearing 1,3-dithio-linkages were efficiently obtained from 3-O-acetyl-2-nitroglucal donors in both stepwise and one-pot glycosylation protocols. The dithiolated O-antigen of E. coli serogroup 64 was successfully synthesized using this newly developed method.

Synthesis and Anti-Tubercular Screening of 8-Benzyloxy-5-[2-(Substituted-Phenyl)-Thiazol-4-yl]-1H-Quinolin-2-One Derivatives

Novel 8-Benzyloxy-5-[2-(substituted-phenyl)-thiazol-4-yl]-1H-quinolin-2-one derivatives are synthesized by the cyclocondensation of substituted thiobenzamide and in-situ generated 8-benzyloxy-5-(2-bromo-acetyl)-1H-quinolin-2-one in the ethanol using simple one-pot multicomponent protocol under catalyst-free reaction conditions. All the products were screened for anti-tuberculosis (TB) activity against Mycobacterium tuberculosis H37Rv stains using L. J. medium conventional method and Compound 4h show good and Compound 4a, 4c, 4e, 4g, 4i, and 4j are also showing significant activity against M. tuberculosis.