Excellent Yields Research Articles

Recent Progress for the Synthesis of Pyrrole Derivatives – An Update

Abstract: Pyrrole is a versatile heterocyclic moiety exhibiting a wide range of pharmacological actions with high therapeutic value. The importance of pyrrole in the pharmaceutical field lies in its versatility, selectivity, and biocompatibility, and these properties make it a valuable tool for drug design and development. The pyrrole moiety is a fundamental building block for many biologically active molecules and has gathered significant attention in the fields of medicinal and organic chemistry; hence, its synthesis has been a crucial area for research. There are various conventional as well as modern approaches to acquiring a series of pyrrole scaffolds, with a wide range of attractive features and drawbacks pertaining to each approach. An extensive amount of literature must be studied to compare the best synthetic routes. This article highlights the applications of pyrrole derivatives in various fields, such as drug discovery, material science, and catalysis, and provides an overview of modern synthetic pathways that include metals, nanomaterials, and complex heterogeneous catalysed methods for pyrrole derivatives. Special emphasis is given to the use of green chemistry principles like green solvent-based methods, microwave-aided methods, and solvent-free methods in the synthesis of pyrroles, with the recent developments and prospects in the synthetic and organic chemistry fields. Overall, this review article provides a comprehensive overview of the synthesis of pyrroles and complies with all the possible developments in the synthetic routes for pyrroles within 2015– 2022. Among all, the reactions catalysed by proline, copper oxides, and oxones have been shown to be the most effective synthetic route for pyrrole derivatives at mild reaction conditions and with excellent yields. This information will be helpful for researchers interested in the development of new pyrrole-based compounds. The categorization in this review provides an easy means for the reader to rationally select the best possible synthetic method for pyrrole derivatives.

An improved synthesis of alkyl AMP esters

Enzymes belonging to the Acyl-CoA/NRPS/Luciferase (ANL) superfamily of enzymes, are significant targets in drug development. One member of this superfamily is Acetyl-CoA Synthetase (ACS). This enzyme is an emerging target for the treatment of various infectious diseases and cancer. Alkyl AMP esters have emerged as potent inhibitors of ACS. Previous methods for synthesizing these esters often involved water-based reactions or necessitate purification through reverse phase prep-HPLC or ion-exchange chromatography. To address these challenges, we developed a new approach utilizing 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) to couple 5′-adenylic acid to the corresponding alcohol, utilizing triethylamine as the base. This method yielded primary, secondary, unsaturated, and cyclic alcohols in excellent yields. Importantly, we optimized the reaction conditions to achieve excellent yield and purity without the need for reverse phase prep-HPLC or ion exchange chromatography. Instead, purification was achieved through silica gel chromatography using Biotage ® Sfar spherical silica gel.

Three-Component Photochemical Cyclization/Dithiocarbamate Formation of gem-Difluoro Quinolin-2(1H)-ones.

Herein, a novel visible-light-induced 6-exo-trig difluoromethylation cyclization and subsequent carbo-thioesterification reaction is described. This protocol allows efficient access to valuable gem-difluoro quinolin-2(1H)-ones in moderate to excellent yields under mild conditions. Broad amino sources compatibility, including cyclic morpholine, thiazolidine, thiomorpholine, pyrrolidine, 1,4-oxazepane, 2,6-dimethylmorpholine, tert-butyl piperazine-1-carboxylate and noncyclic diethylamine, N-ethylpropan-1-amine, N-benzylethanamine, N-benzyl-trimethylsilanamine, dibenzylamine, and N-(4-methoxybenzyl)ethanamine, demonstrated the practicability of this strategy. A radical-radical crossover route was proposed on the basis of radical inhibition experiments, visible light irradiation on-off test, apparent quantum efficiency (AQE) calculation, and fluorescence quenching studies.

Solvent-Controlled Divergent Cyclization of 3-Ylideneoxindoles with Ethyl 2-Diazoacetate: Access to Spirocyclopropyl and Spiropyrazolines Oxindoles.

Herein a catalyst-free solvent-controlled method for the divergent synthesis of spirocyclopropyl and spiropyrazoline oxindoles from 3-ylideneoxindoles and ethyl diazoacetate was developed. With ClCH2CH2Cl as the solvent, spirocyclopropyl oxindoles were obtained in moderate to excellent yields, whereas the use of MeOH as solvent afforded spiropyrazoline oxindoles in moderate to good yields. The readily available substrates, simple operation and various product transformations further highlighted the utility of this method.

Design, synthesis, characterization, and theoretical calculations, along with in silico and in vitro antimicrobial proprieties of new isoxazole-amide conjugates

Abstract Functionalized isoxazoles provide valuable structural motifs, opening up a wide range of uses in the medicinal, pharmacological, and pharmaceutical fields. Within this scope, an efficient approach has been adopted to synthesize a novel series of functionalized isoxazole derivatives, starting from aza-aurone, providing reproducible access to the desired isoxazoles in excellent yields. All synthesized compounds were structurally elucidated through the use of various spectroscopic techniques and mass spectrometry. The derivatives generated were screened for their antimicrobial potential against the fungus Candida albicans as well as three bacterial strains. The results show that almost all of the tested isoxazole derivatives were found to be significantly potent against the fungus C. albicans. The functionalized isoxazoles were also computed using the Gaussian software package with the 6-31++G(d,p) basis set at B3LYP, HF, and M062X levels, and their chemical activities were compared. Moreover, the molecular docking studies of tested isoxazole compounds were performed against the C. albicans receptor. The results suggest that the newly synthesized compounds exhibit docking scores ranging from −10.29 to −15.08 kcal/mol, revealing a high affinity for the target enzyme (5V5Z). Lastly, drug similarity studies and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties assessments indicate that isoxazole derivatives have favorable absorption, distribution, and metabolism properties associated with a proven lack of toxicity.

One-pot Hydrogenolysis of Polyethylene Terephthalate (PET) to p-xylene over CuZn/Al2O3Catalyst.

Chemical upcycling of plastic wastes into valuable chemicals is a promising strategy for resolving plastic pollution, but economically viable methods currently are still lacking. Here, we report one-pot hydrogenolysis of PET plastic into p-xylene with an excellent yield (99.8 %) over a robust non-precious Cu-based catalyst, CuZn/Al2O3, in the absence of alcohol solvents. The presence of Zn species promotes the dispersion of Cu0 and increases the ratio of Cu+/Cu0, whereas the synergistic effect of Cu0 and Cu+ leads to a superior performance in the conversion of PET. The combination of GC-MS, 13C CP MAS NMR, 2D 1H-13C CP HETCOR NMR spectroscopy and kinetic studies for the first time demonstrates 4-methyl benzyl alcohol as an important reaction intermediate in the hydrogenolysis of PET. Mechanistic studies indicate that the conversion of PET mainly follows a hydrogenolysis process, involving the cleavage of ester bonds to alcohols and the C-O bond cleavage of alcohols to alkanes. This work not only brings new insight for understanding the upgrading pathway of PET, but also provides a guidance for the design of high-performance non-precious catalysts for the chemical upcycling of plastic wastes.

One‐Pot Synthesis of C‐Substituted bis‐Benzimidazoles and Benzobisimidazoles via Reductive Cyclization of o‐Nitroaniline Derivatives and Aldehydes using Sodium Metabisulfite in a Microwave Reactor

AbstractHerein, we report a simple and an economical method to synthesize C‐substituted bis‐benzimidazole and C‐substituted benzobisimidazole derivatives in moderate to excellent yields using sodium metabisulfite, under microwave irradiation conditions. The most attractive feature of the methodology is the three‐step yet one‐pot condensation of nitroarenes with various benzaldehyde derivatives to synthesize useful benzimidazoles, and an easy product isolation method by simple solvent trituration techniques. The methodology can be fine‐tuned to synthesize selectively the mono C‐substituted benzimidazoles, leaving a nitroaniline functionality intact for preparing a variety of unsymmetrical C‐substituted bis‐benzimidazoles.

Novel Polyphenolic Hybrids Modulate Quorum Sensing Regulated Virulence in Pseudomonas aeruginosa

AbstractNaturally occurring substituted benzoic acids, known for their exceptional biological activity against Pseudomonas aeruginosa, were reacted with various aldehydes, aniline, and tert‐butyl isocyanide at 25 °C to give the desired hybrids with good to excellent yield in the range of 60–85 % and well characterized by 1H NMR, 13C NMR, HRMS, IR, and HPLC analysis. Molecular docking and simulation studies of compounds were conducted which predicted a high affinity towards quorum‐sensing (QS) receptors of P. aeruginosa. The polyphenolic hybrids were first screened for anti‐QS activity using the Agrobacterium tumefaciens NTL4 biosensor strain, followed by examining the antivirulence potential of selected hybrids against P. aeruginosa PAO1 in vitro. The highest degree of AHL (acyl homoserine lactone) inhibition in PAO1 was observed with the compound having a maximum number of phenolic groups. The hybrids in this investigation were also found to be non‐cytotoxic (biocompatible) towards HEK cells and may be further tested for their therapeutic efficacy against P. aeruginosa infections in vivo. It has been observed that the anti‐QS activity is directly proportional to the number of hydroxyl groups on the aromatic ring and one of the major contributing factors can be their chelating capacity as depicted by CAS shuttle assay.

Recyclable Ag/g‐C3N4 Catalyzed Visible‐light Promoted Heterogeneous Synthesis of Unsymmetric Diaryl Chalcogenides

With Ag/g‐C3N4 semiconductor as the heterogeneous photocatalyst, the visible light promoted heterogeneous synthesis of unsymmetric diaryl chalcogenides could be achieved under additive‐free and mild conditions. A series of unsymmetric diaryl chalcogenides were generated in good to excellent yields with high functional group tolerance. The Ag/g‐C3N4 photocatalyst is easily recovered from the reaction mixture and reused at least 5 times, opening the way for larger‐scale industrial applications of this type of photocatalytic bond‐forming reactions.

Rapid and Environmentally-Friendly Synthesis of Thiazolidinone Analogues in Deep Eutectic Solvent Complemented with Computational Studies.

A greener, safer, and more efficient methodology for the synthesis of (Z)-5-benzylidene-2-thioxothiazolidin-4-ones (3 a-u) and (Z)-5-benzylidenethiazolidine-2,4-diones (4 a-i) has been developed. The deep eutectic solvent (DES) ZnCl2/urea used as a greener solvent as well as a catalyst in this study accelerated the condensation of rhodanine and thiazolidine-2,4-dione with different aldehydes to afford the target scaffolds in excellent yields (88-98 %). The reaction methodology adopted offered significant advantages such as mild reaction conditions, functional group tolerance, quick reaction time, column-free isolation, catalytic recyclability, and applicability to gram-scale production. Moreover, density function theory calculations were carried out to investigate the global reactivity and stability profiles of these compounds. Finally, the green metrics analysis supported the greener nature of the present methodology.

Ultralow-Power Circuit and Sensing Applications Based on Subthermionic Threshold Switching Transistors.

The most recent breakthrough in state-of-the-art electronics and optoelectronics involves the adoption of steep-slope field-effect transistors (FETs), promoting sub-60 mV/dec subthreshold swing (SS) at ambient temperature, effectively overcoming "Boltzmann limit" to minimize power consumption. Here, a series integration of nanoscale copper-based resistive-filamentary threshold switch (TS) with the IGZO channel-based FET is used to develop a TS-FET, in which the turn-on characteristics exhibit an abrupt transition over five decades, with an extremely low SS of 7 mV/dec, a high on/off ratio (>109), and ultralow leakage current (40-fold decrease), ensuring excellent repeatability and device yield. Unlike previous device-centric studies, this work highlights potential circuit applications (logic-inverter, pulse-sensor amplification, and photodetector) based on TS-FET. The sharp transition behavior of TS-FET enables the establishment of logic inverters with a high voltage gain of ≈800, with a circuit-level demonstration achieving a bias-independent record-high intrinsic gain (>1000). A wearable pulse sensor integrated with an amplifier circuit ensured the precise amplification of electrophysical signals by 450 times. In addition, the application of a TS-FET-based photodetector features high responsivity (1.08 × 104 mA/W) and detectivity (1.03 × 1020 Jones). The low-power strategy of TS-FETs is promising for the development of energy-efficient integrated circuits alongside sensor-interconnected biomedical applications in wearable technology.

Synthesis of 3-Benzazepines via Cobalt-Catalyzed C-H Bond Functionalization with CaC2 as the Acetylene Source.

Herein, we report a simple method for the synthesis of 3-benzazepine derivatives via a cobalt-catalyzed, picolinamide-directed α-amidoacrylate C(sp2)-H bond functionalization approach. The reactions utilize calcium carbide as an inexpensive, easy-to-handle, and solid acetylene source, and simple CoCl2 as the reaction catalyst. Excellent functional group tolerance is observed, yielding diverse substituted 3-benzazepine derivatives in good to excellent yields.

A Base Promoted [3+2] Cycloaddition of Benzothiazolium Salts with Isoindigos to Synthesis N, S‐polyheterocyclic 3, 3′ Bispirooxindoles

A base promoted [3+2] cycloaddition of benzothiazolium salts with isoindigos has been developed, and a series of nove N, S‐polyheterocyclic 3, 3′ bispirooxindoles with four contiguous cycles and two spiro quaternary stereocenters have been successfully and effectively prepared in good to excellent yields (up to 99%) under mild conditions.

Electron donor-acceptor complex enabled photocascade strategy for the synthesis of trans-dihydrofuro[3,2-c]chromen-4-one scaffolds via radical conjugate addition of pyridinium ylide.

A visible-light-induced photocascade strategy is disclosed for the synthesis of trans-dihydrofuro[3,2-c]chromen-4-one scaffolds. The photocascade consists of electron donor-acceptor (EDA) complex enabled formation of arylidene coumarinone, followed by 1,4-radical conjugate addition (1,4-RCA) of an in situ generated pyridinium ylide radical (PyYR) towards diastereoselective formation of the trans-dihydrofuro[3,2-c]chromen-4-one scaffold in good to excellent yield. Thorough mechanistic investigations comprising photophysical, spectroscopic, electrochemical and DFT studies provide further insights into the reaction mechanism.

Aligning fermentation conditions with non-canonical amino acid addition strategy is essential for Nε-((2-azidoethoxy)carbonyl)-L-lysine uptake and incorporation into the target protein

Protein engineering with non-canonical amino acids (ncAAs) holds great promises for diverse applications, however, there are still limitations in the implementation of this technology at manufacturing scale. The know-how to efficiently produce ncAA-incorporated proteins in a scalable manner is still very limited. In the present study, we incorporated the ncAA N6-[(2-azidoethoxy)carbonyl]-L-lysine (Azk) into an antigen binding fragment (Fab) in Escherichia coli. We used the orthogonal pyrrolysyl-tRNA synthetase/suppressor tRNACUAPyl pair from Methanosarcina mazei to incorporate Azk site-specifically. We characterized Azk uptake and Fab production at bench-scale under different fermentation conditions, varying timing and mode of Azk addition, Azk-to-cell ratio and induction time. Our results indicate that Azk uptake is comparatively efficient in the batch phase. We discovered that the time between Azk uptake and inducing its incorporation into the Fab must be kept short, which suggests that intracellular Azk is consumed and/or degraded. The results obtained in this study are an important step towards the development of efficient production methods for Azk-incorporated proteins in E. coli. The developed process is scalable and provides excellent yields of 2.95 mg functionalized Fab per g CDM, which corresponds to 80% of yield obtained with the wild type Fab. We also identified the cellular uptake of Azk being dependent on the physiological state of the cell as a potential bottleneck in production.

Design of Stable Chiral Aminosulfonium Ylides and Their Catalytic Asymmetric Synthesis

AbstractThe isolation and catalytic enantioselective synthesis of configurationally stable S‐stereogenic sulfonium ylides have been significant challenges in the field of asymmetric synthesis. These reactive intermediates are crucial for a variety of synthetic transformations, yet their inherent tendency towards rapid inversion at the sulfur stereocenter has hindered their practical utilization. Conventional approaches have focused on strategies that incorporate a C=S bond‐containing cyclic framework to help mitigate this stereochemical lability. In this work, we present an alternative tactic that leverages the stabilizing influence of an adjacent N‐atom and cyclic sulfide moiety. Exploiting a copper catalyzed enantioselective intermolecular carbene transfer reaction, structurally diverse S‐stereogenic aminosulfonium ylides have been achieved in excellent yields and enantioselectivities. Experimental results indicate that the careful selection of 2‐diazo‐1,3‐diketone precursors is crucial for achieving optimal stereoinduction in this transformation. The resulting highly enantioenriched aminosulfonium ylides allow for further stereospecific elaborations to furnish aminosulfonium ylide oxides and sulfinamide. This work expands the boundaries of chiral sulfonium ylide chemistry, providing access to a broad range of previously elusive S‐stereogenic aminosulfonium ylide scaffolds.

Direct Synthesis of Benzothiazoles and Benzoxazoles from Carboxylic Acids Utilizing (o-CF3PhO)3P as a Coupling Reagent.

A general and efficient method for the direct synthesis of benzothiazoles and benzoxazoles from carboxylic acids with 2-aminobenzenethiols or 2-aminophenols using (o-CF3PhO)3P as a simple coupling reagent has been developed. Diverse benzothiazoles and benzoxazoles were synthesized in moderate to excellent yields. And the gram-scale preparation of benzothiazole and benzoxazole also proceeded smoothly under the mild conditions. Moreover, a plausible reaction mechanism was discussed, with (o-CF3PhO)3P and its hydrolysis product (o-CF3PhO)2P(O)H contributing to the formation of the target products as an amide synthesis coupling agent and a cyclization reaction promoter, respectively.

A Synthetic Route Towards Spiro Indanone Fused Pyrano[2,3‐c]Chromene Derivatives via Oxa–Diels–Alder Reaction: Computational Investigation, Antibacterial Evaluation and Molecular Docking Studies as Potential DNA Gyrase Inhibitors

ABSTRACTA highly efficient method for the synthesis of 2′H‐spiro[indene‐2,3′‐pyrano[2,3‐c]chromene] derivatives 20(a–s) has been developed involving oxa–Diels–Alder reaction as the key step under conventional conditions in good to excellent yields. The compounds were all characterized using 1H, 13C NMR, HRMS, and X‐ray crystallography. The present study employs DFT to validate the reaction pathway. In vitro antibacterial assay of all the synthesized derivatives was evaluated against Gram‐negative Escherichia coli and Gram‐positive Staphylococcus aureus bacterial strains. Compound 20e was found to be the most potent molecule with ZI of 19 mm and MIC of 16 μg mL−1 in E. coli and ZI of 14 mm and MIC of 32 μg mL−1 in S. aureus. Additionally, 20e demonstrated a strong inhibition of DNA gyrase in silico, with a binding affinity of −9.3 and − 9.0 kcal/mol in E. coli and S. aureus respectively. Also, significant pharmacokinetic, physicochemical, and drug‐like properties of the spirocyclic compounds were further corroborated by ADME investigations. Hence, these new series of spiro indanone fused pyrano[2,3‐c]chromene derivatives may be potent druggable antibacterial agents in future.

DMAP Catalyzed Ring-Opening/Cycloaddition of Vinyl Oxiranes with Activated Ketone Compounds to Construct the 1,3-Dioxolane Skeletons.

The present work develops a DMAP-catalyzed [3 + 2] cycloaddition of vinyl oxiranes with activated ketone compounds, affording dioxolane derivatives with moderate to excellent yields. This approach represents the first Lewis base (LB)-catalyzed ring-opening reaction of vinyl epoxides, simultaneously providing a rare oxygen-containing active intermediate in this field. The gram-scale preparation and facile derivatization of the cycloadduct highlight the significant synthetic potential of this strategy.

N-heterocyclic silylene-Cu(I) Complexes as Efficient Catalysts for Three-Component Coupling Reactions.

We have explored NHSi-supported copper(I) complexes as active and highly efficient catalysts for A3 (aldehyde-alkyne-amine) and KA2 (ketone-alkyne-amine) three-component coupling reactions to synthesize propargyl amines in excellent yields with high TOF under solvent-and additive-free conditions.