Three-step Synthesis Research Articles

Mannich-Type Condensation and Domino Quinazolinone-Amidine Rearrangement Affords Ring-Fused Mackinazolinones with Anti-Amoebic Activity.

A three-step synthesis of anti-amoebic, ring-fused mackinazolinones has been developed. A Mannich-type reaction between quinazolin-4-ones and N-Cbz propanal in the presence of AgOTf afforded quinazolinones (19-94% isolated yield) bearing a newly formed heterocycle with an alkylamine appendage that, upon N-Cbz deprotection and basification, triggered a domino rearrangement to afford 45 separable, ring-fused products. Several compounds inhibited growth of Naegleria fowleri parasites that can cause a lethal human brain infection. Thus, the methodology provides immediate access to a promising anti-amoebic scaffold.

A novel method for the synthesis of acyclic ligands with combined chelating groups

The synthetic methodology developed in this work provides a simple route to the acyclic versatile ligands with combined chelating groups. The approach involves three-step synthesis: the preparation of amide macrocyclic derivatives containing one type of chelating substituents, hydrolysis of macrocyclic compounds giving the acyclic derivatives with unsubstituted terminal amino groups and final modification of terminal amines by another type of chelating substituents. The obtained complexons combine chelating substituents of different nature and can be used for further studies with medical metal cations for use in radiopharmaceuticals.

The Subtype Selectivity in Search of Potent Hypotensive Agents among 5,5-Dimethylhydantoin Derived α1-Adrenoceptors Antagonists

In order to find new hypotensive drugs possessing higher activity and better selectivity, a new series of fifteen 5,5-dimethylhydantoin derivatives (1–15) was designed. Three-step syntheses, consisting of N-alkylations using standard procedures as well as microwaves, were carried out. Crystal structures were determined for compounds 7–9. All of the synthesized 5,5-dimethylhydantoins were tested for their affinity to α1-adrenergic receptors (α1-AR) using both in vitro and in silico methods. Most of them displayed higher affinity (Ki < 127.9 nM) to α1-adrenoceptor than urapidil in radioligand binding assay. Docking to two subtypes of adrenergic receptors, α1A and α1B, was conducted. Selected compounds were tested for their activity towards two α1-AR subtypes. All of them showed intrinsic antagonistic activity. Moreover, for two compounds (1 and 5), which possess o-methoxyphenylpiperazine fragments, strong activity (IC50 < 100 nM) was observed. Some representatives (3 and 5), which contain alkyl linker, proved selectivity towards α1A-AR, while two compounds with 2-hydroxypropyl linker (11 and 13) to α1B-AR. Finally, hypotensive activity was examined in rats. The most active compound (5) proved not only a lower effective dose than urapidil but also a stronger effect than prazosin.

Synthesis of ZnO-Cdots nanoflower by hydrothermal method for antibacterial agent and dye photodegradation catalyst

Implementing nanosized materials (1–100 nm) are considered to be effective approaches in addressing the issue of liquid waste pollution. Herein, ZnO-carbon quantum dots (ZnO-Cdots) were conducted by three-steps hydrothermal synthesis and the structural characterization is confirmed by the physical properties measurement, while, photodegradation activity of ZnO-Cdots compared to the prepared ZnO nanoflower has been investigated using UV–visible absorbance spectroscopy and its effect on organic pollutant removal from aqueous. The obtained ZnO-Cdots composites showed a superior performance in photocatalytic degradation of methylene blue (MB) and specific antibacterial activity against Staphylococcus aureus (S.A) and Eschericia coli (E.coli) compared to the prepared ZnO nanoflower. The findings of this research of ZnO-Cdots show great potential in treating liquid waste pollution, and can be considered as a promising antibacterial agent for Staphylococcus aureus (S.A) and Eschericia coli (E.coli).

Short, Scalable Access to Pyrrovobasine.

A concise gram-scale synthesis of pyrrovobasine (1) is reported. Key transformations include a three-step decagram-scale synthesis of the tetracyclic compound, Mn-mediated direct radical cyclization, and the introduction of a naturally rare pyrraline structure. The synthesis is designed to be applicable to gram-scale synthesis using inexpensive and readily available reagents.

Colorimetric and fluorimetric detection of CN– ion using a highly selective and sensitive chemosensor derived from coumarin-hydrazone

Novel chemosensors, including coumarin hydrazide, were designed and synthesized by a three-step synthesis sequence starting from 7-(diethylamino)-2-oxo-2H-chromene-3-carbohydrazide. General spectroscopic methods (FT-IR, 1H/13C NMR, and HRMS) were used to characterize all produced chemosensors. These chemosensors demonstrate the ability to detect cyanide (CN–) anion by shifting absorption and fluorescence turn-off response in DMSO. The reaction mechanism between the synthesized chemosensors and the CN– anion involves deprotonation and addition processes; as determined by dipole-dipole interactions, reversibility, 1H NMR experiments, and theoretical studies. With limit of detection (LOD) values of 0.25 μM and 0.15 μM for 3a and 3b, respectively, these chemosensors exhibit exceptional detection ability and demonstrate the high effectiveness of their use for CN– anion determination.

Iodine catalyzed one-pot three-step synthesis of isoxazoles from primary alcohols and 3-O-propargyl flavones using DMSO as the oxidant

An effective, trivial, green and metal free iodine catalyzed approach for the production of isoxazoles from primary alcohols and 3-O-propargyl flavones in one-pot three-step manner using DMSO as the oxidant has been developed. The stated methodology was promising for an extensive variety of primary alcohols and 3-O-propargyl flavones, generates isoxazoles within 10 h.

Preparation of hollow nanorod CoxCu2−xSe/CF electrode assembled from nanoparticles and its urea-assisted hydrogen production performance

Urea-assisted water splitting is a promising method for the production of H2 with reduced energy consumption, which can also purify urea-rich wastewater. Nevertheless, the development of bifunctional electrocatalysts that exhibit exceptional efficiency and affordability for the urea oxidation reaction (UOR) and hydrogen evolution reaction (HER) remains a challenging task. In this work, a MOFs-derived bifunctional electrode of Co-doped Cu2−xSe with a hollow nanorod structure assembled from nanoparticles is prepared on a copper foam substrate (CoxCu2−xSe/CF) by a three-step synthesis process. As anticipated, the CoxCu2−xSe/CF self-supported electrode shows promising performance in terms of the UOR and HER. This can be attributed to the unique hollow nanorod structure assembled from nanoparticles and incorporation of Co dopants, which can expose more active sites, enhance the electrochemical surface area, and facilitate faster reaction kinetics. When CoxCu2−xSe/CF was employed as the self-supported electrode for H2 production in a coupled HER||UOR system, only 1.51 V was required to drive a current density of 10 mA cm−2, which is 120 mV lower than the traditional water electrolysis system. And it also displays an outstanding stability, the current density retention ratio is approximately 82.1 % after 70 h. Noteworthy, XRD, XPS and in-situ Raman analysis reveal that CoxCu2−xSe/CF can form highly active CuO and amorphous Cu(OH)2 as the active sites in UOR. This work proposes a strategy for H2 production and urea-containing wastewater treatment.

Green synthesis and anti-biofilm activities of 3,5-disubstituted isoxazoline/isoxazole-linked secondary sulfonamide derivatives on Pseudomonas aeruginosa

The search for new classes of antibiotics is a real concern of public health due to the emergence of multi-resistant bacteria strains. We report herein the synthesis and characterization of a new series of 13 molecules combining isoxazoline/isoxazole sulfonamides and hydrazides motives. These molecules were obtained according to a costless eco-friendly procedure, and a one-pot three-step cascade synthesis under ultrasonic cavitation. All the synthesized compounds were fully characterized by HRMS, 1H NMR, 13C NMR spectroscopy and HPLC analysis. These new molecules have been evaluated against the major human opportunistic pathogen Pseudomonas aeruginosa to determine their potential to affect its growth and biofilm formation or dispersion. Two derivatives (5a and 6a) demonstrated their ability to destabilize a mature biofilm by about 50 % within 24 h. This may pave the way to the development of a new class of compounds affecting biofilm, which are easy to synthesize according to green chemistry processes.

Short and Efficient Synthesis of the Antituberculosis Agent Pretomanid from (R)-Glycidol.

An efficient gram-scale synthesis of the antituberculosis agent pretomanid using straightforward chemistry, mild reaction conditions, and readily available starting materials is reported. Four different protecting groups on the glycidol moiety were investigated for their technical feasibility and ability to suppress side reactions. Starting from readily available protected (R)-glycidols and 2-bromo-4-nitro-1H-imidazole, pretomanid could be prepared in a linear three-step synthesis in up to 40% isolated yield. In contrast to most syntheses reported so far, deprotection and cyclization were performed in a one-pot fashion without any hazardous steps or starting materials.

Silicon- and Germanium-Functionalized Perylene Diimides: Synthesis, Optoelectronic Properties, and Their Application as Non-fullerene Acceptors in Organic Solar Cells.

Organic solar cells have been continuously studied and developed through the last decades. A major step in their development was the introduction of fused-ring non-fullerene electron acceptors. Yet, beside their high efficiency, they suffer from complex synthesis and stability issues. Perylene-based non-fullerene acceptors, in contrast, can be prepared in only a few steps and display good photochemical and thermal stability. Herein, we introduce four monomeric perylene diimide acceptors obtained in a three-step synthesis. In these molecules, the semimetals silicon and germanium were added in the bay position, on one or both sides of the molecules, resulting in asymmetric and symmetric compounds with a red-shifted absorption compared to unsubstituted perylene diimide. Introducing two germanium atoms improved the crystallinity and charge carrier mobility in the blend with the conjugated polymer PM6. In addition, charge carrier separation is significantly influenced by the high crystallinity of this blend, as shown by transient absorption spectroscopy. As a result, the solar cells reached a power conversion efficiency of 5.38 %, which is one of the highest efficiencies of monomeric perylene diimide-based solar cells recorded to date.

Concise, three-step enantioselective total synthesis of (4S,5S)-4-hydroxy-5-octylpyrrolidin-2-one, a colibactin pathway metabolite

Concise, three-step enantioselective total synthesis of (4S,5S)-4-hydroxy-5-octylpyrrolidin-2-one, a colibactin pathway metabolite

Multistep Synthesis of Paracetamol in Continuous Flow

p-Aminophenol (AP) is the key intermediate of the traditional synthesis of paracetamol. The method of obtaining AP included a selective reduction reaction of the generation of N-arylhydroxylamine (AHA) using nitrobenzene (NB) as the raw material, followed by a Bamberger rearrangement reaction to transfer AHA to the target product. The generation of AHA is a key step, but due to its structural instability and the incompatibility of the two reaction systems, one-pot synthesis of paracetamol faces great challenges. Considering that using flow reactors in series may avoid the problems faced by batch reactors, the article presents the strategy to obtain paracetamol via a continuous flow technology. In particular, we focus on condition screening in total synthesis experiments, including hydrogenation, Bamberger rearrangement, and amidation in flow. The continuous three-step synthesis process used NB as a raw material to generate AHA, which entered the downstream for timely conversion, achieving in situ on-demand preparation of the unstable intermediate AHA, avoiding cumbersome processing and storage processes. Moreover, each step of the reaction system exhibits excellent compatibility, and the work-up is simple.

Gold(I)-Mediated Cyclizations of Triene-Yne Systems: An Easy Access to Cyclopenta-Fused Anthracenes.

The direct synthesis of cyclopenta-fused anthracenes (CP-anthracenes) through a gold(I)-catalyzed cyclization reaction of easily available triene-yne systems bearing a benzofulvene substructure, is reported. The targets are of great interest due to the potential use as organic materials and the preparation of these compounds is gaining huge importance. The applied starting materials are readily available through a three-step synthesis, which further contributes to the advantages of this route. In addition, UV-Vis and fluorescent spectra of the obtained CP-anthracenes were recorded.

Innovative Bioplasticizers from Residual Cynara cardunculus L. Biomass-Derived Levulinic Acid and Their Environmental Impact Assessment by LCA Methodology.

This work is focused on the application of Life Cycle Assessment (LCA) methodology for the quantification of the potential environmental impacts associated with the obtainment of levulinic acid from residual Cynara cardunculus L. biomass and its subsequent valorization in innovative bioplasticizers for tuning the properties as well as the processability of biopolymers. This potentially allows the production of fully biobased and biodegradable bioplastic formulations, thus addressing the issues related to the fossil origin and nonbiodegradability of conventional additives, such as phthalates. Steam explosion pretreatment was applied to the epigean residue of C. cardunculus L. followed by a microwave-assisted acid-catalyzed hydrolysis. After purification, the as-obtained levulinic acid was used to synthesize different ketal-diester derivatives through a three-step selective synthesis. The levulinic acid-base additives demonstrated remarkable plasticizing efficiency when added to biobased plastics. The LCA results were used in conjunction with those from the experimental activities to find the optimal compromise between environmental impacts and mechanical and thermal properties, induced by the bioadditives in poly(3-hydroxybutyrate), PHB biopolymer.

Effective Synthesis of 4-Quinolones by Reductive Cyclization of 2'-Nitrochalcones Using Formic Acid as a CO Surrogate.

4-Quinolones are the structural elements of many pharmaceutically active compounds. Although several approaches are known for their synthesis, the introduction of an aryl ring in position 2 is problematic with most of them. The reductive cyclization of o-nitrochalcones by pressurized CO, catalyzed by ruthenium or palladium complexes, has been previously reported to be a viable synthetic strategy for this aim, but the need for pressurized CO lines and autoclaves has prevented its widespread use. In this paper, we describe the use of the formic acid/acetic anhydride mixture as a CO surrogate, which allows us to perform the reaction in a cheap and commercially available thick-walled glass tube without adding any gaseous reagent. The obtained yields are often high and compare favorably with those previously reported by the use of pressurized CO. The procedure was applied to a three-step synthesis from commercially available and cheap reagents of the alkaloid Graveoline.

Total Synthesis of Thiamyxins A-C and Thiamyxin E, a Potent Class of RNA-Virus-Inhibiting (Cyclo)depsipeptides.

We present the first total synthesis of the thiamyxins A-C and the now fully characterized thiamyxin E, an interesting class of thiazole- and thiazoline-rich depsipeptides with diverse antiviral activity. The synthesis features a parallel closing of two methyl thiazoline units, with low epimerization of the very labile adjacent stereocenter. It also includes the three-step synthesis of an uncommon hydroxy acid and the oxidation-free elimination of a phenylselenide to form a dehydroalanine moiety. The exploitation of the acid-labile stereocenter at the isoleucine moiety and the reopening of the macrolactones gave access to the four thiamyxins with good yields and diastereomeric purities from a single precursor. The modular total synthesis allows further testing of the biological activity and gives opportunities to explore the pharmacophore and antiviral target through derivatization.

Totalsynthese von Thiamyxin A–C und Thiamyxin E, potente RNA‐Virus inhibierende (Cyclo)depsipeptide

AbstractWir präsentieren die erste Totalsynthese der Thiamyxine A–C und des jetzt vollständig charakterisierten Thiamyxins E, einer interessanten Klasse thiazol‐ und thiazolinreicher Depsipeptide mit vielfältiger antiviraler Aktivität. Die Synthese zeichnet sich aus durch einen parallelen Ringschluss zu zwei Methylthiazolin‐Einheiten unter geringer Epimerisierung des sehr labilen benachbarten stereogenen Zentrums. Des Weiteren wird die dreistufige Synthese einer ungewöhnlichen Hydroxysäure sowie die oxidationsfreie Eliminierung eines Phenylselenids zum Dehydroalanin gezeigt. Die Ausnutzung des säurelabilen Stereozentrums am Isoleucin‐Rest und die erneute Öffnung der Makrolactone ermöglichen den Zugang zu den vier Thiamyxinen in guten Ausbeuten und Diastereomerenverhältnissen aus einem einzigen Vorläufer. Durch die modular gestaltete Totalsynthese sind weitere Bioaktivitätstests und die Erforschung eines Pharmakophors über die Synthese weiterer Derivate möglich.

Scalable Preparation of the Masked Acyl Cyanide TBS-MAC.

This paper describes the three-step synthesis of TBS-MAC, a masked acyl cyanide (MAC) and a versatile one-carbon oxidation state three synthon. We have developed a scalable and detailed synthesis that involves: (1) acetylation of malononitrile to form the sodium enolate, (2) protonation of the enolate to form acetylmalononitrile, and (3) epoxidation of the enol, rearrangement to an unstable alcohol, and TBS-protection to form the title compound. Both the sodium enolate and acetylmalononitrile are bench-stable precursors to the intermediate hydroxymalononitrile, which can be converted to other MAC reagents beyond TBS by varying the protecting group (Ac, MOM, EE, etc.).

Synthesis of Selenium-Based Small Molecules Inspired by CNS-Targeting Psychotropic Drugs and Mediators

Due to its endogenously high oxygen consumption, the central nervous system (CNS) is vulnerable to oxidative stress conditions. Notably, the activity of several CNS-targeting compounds, such as antidepressant and hypnotic drugs, or endogenous mediators, such as melatonin, is indeed linked to their ability of mitigating oxidative stress. In this work, we report the synthesis of two organoselenium compounds of which the structure was inspired by CNS-targeting psychotropic drugs (zolpidem and fluoxetine) and an endogenous mediator (melatonin). The molecules were designed with the aim of combining the ROS-scavenging properties, which were already assessed for the parent compounds, with a secondary antioxidant action, a glutathione peroxidase (GPx) mimic role empowered by the presence of selenium. The compounds were obtained through a facile three-step synthesis and were predicted by computational tools to passively permeate through the blood–brain barrier and to efficiently bind to the GABA A receptor, the macromolecular target of zolpidem. Of note, the designed synthetic pathway enables the production of several other derivatives through minor modifications of the scheme, paving the way for structure–activity relationship studies.