One-pot Protocol Research Articles

Visible-Light-Mediated Three-Component Decarboxylative Coupling Reactions for the Synthesis of 4-Alkylpyridines.

4-Alkylation of pyridines has been achieved by a photocatalyzed three-component reaction of an olefin, an aryloxyacetic acid, and cyanopyridine using Ir[dF(CF3)ppy]2(dtbbpy)PF6 as a photocatalyst. In this way, a new type of 4-alkylpyridines bearing aryl and aryloxy substituents on the phenyl was accessed with potential pharmaceutical value. In addition to mild reaction conditions, the method has several other advantages, including a multicomponent one-pot protocol, good functional group tolerance, and easy amplification of the reaction scale. The reaction mechanism has been clarified by control experiments and computation of the reaction energy profile.

Escape from Flatland: Stereoselective Synthesis of Hexa-aryl Borazines and their sp²-Based 3D Architectures.

Borazine and its derivatives can be considered critical doping units for engineering hybrid C(sp2)-based molecules with tailored optoelectronic properties. Herein, we report the first synthesis ofhexaarylborazines that, bearingortho-substituted aryl moieties, extend three-dimensionally.Using a one-pot protocol, we first form an electrophilic chloroborazole and then react it with an aryl lithium (ArLi). By selecting the appropriateortho-substituent, we can guide the ArLi to add to the BN-core in a specific way, ultimately controlling the stereochemical outcome of the three-substitution reaction. Rationalization of the stereochemical model through computational analysis allowed us to show thatwhen aryl lithium nucleophiles bearing rigid long-rangeortho-substituentsare used,i.e.,stiff substituents. Theortho-substituent shields its side of the electrophilic B3N3core, biasing the incoming ArLi to addantiat each addition step, forming the final tri-aryl borazine exclusively ascc-isomer.Leveraging this stereoselective approach, prototypical multichromophoric borazine derivatives were prepared, and we showcased how the stereochemical arrangement of these chromophores distinctly influences their redox behavior.This methodology paves the way for previously inaccessible borazines to serve asprivileged precursorsto transcend the conventional bidimensionality associated with graphenoid systems and pioneer the construction of new forms of three-dimensional C(sp2)-based architectures.

One Pot Synthesis of New Powerful Building Blocks in 1,8-Naphthalimide Chemistry

This communication reports a reliable one-pot synthetic protocol for preparation on a multigram scale of 3-bromo- and 3,4-dibromo-6-nitro-1,8-naphthalic anhydride from commercially available and economical 1,8-naphthalic anhydride. The synthetic steps used were nitration and selective bromination in sulfuric acid at room temperature. The reaction takes place under mild conditions and is completely controllable depending on the equivalents of the brominating reagent used. Both anhydrides are powerful building blocks in naphthalimide chemistry. In addition, their imides and esters were also synthesized.

Asymmetric Organocatalysed Synthesis of (R)-Mandelic Acid Esters and α-Alkoxy Derivatives from Commercial Sources.

Optically active mandelic acid esters represent a highly valuable class of building blocks in organic synthesis and recurrent motifs embedded in bioactive compounds and drugs. Herein, we provide an enantioselective one-pot synthesis based on Knoevenagel condensation/asymmetric epoxidation/domino ring-opening hydrolysis (DROH) sequence to the crude mandelic acids, which underwent a final esterification step to (R)-methyl mandelates. These products have been obtained in good to high overall yield and enantioselectivity, using commercially and widely available reagents and catalyst including aldehydes, phenylsulfonyl acetonitrile, cumyl hydroperoxide, water and an epi-quinine-derived urea as the organocatalyst. Moreover, the versatility of the process has been demonstrated to prepare the corresponding α-alkoxy esters in highly enantioselective manner, when using primary alcohols in a domino ring-opening esterification (DROE) step. This system is a first example of non-enzymatic catalytic one-pot protocol which allows a straightforward asymmetric synthesis of highly valuable mandelic acid derivatives from aldehyde feedstocks.

Diastereoselective Access to Ester-Substituted cis-Phenanthridinones via Hydrogen Atom Transfer-Involved 1,7-Enyne Bicyclization.

An organophotoredox-catalyzed 1,7-enyne bicyclization for the cis-diastereoselective synthesis of ester-substituted phenanthridinones has been achieved through radical cascade cyclization involving 1,6-hydrogen atom transfer. This transition-metal- and oxidant-free one-pot protocol generates three distinct C-C bonds and two quaternary carbon centers.

Synthesis and immunological study of tetrasaccharide repeating units of capsular polysaccharide of Group B Streptococcus serotype VIII and their protein conjugates

This study reports the efficient synthesis of three tetrasaccharide derivatives of Group B Streptococcus (GBS) serotype VIII capsular polysaccharide with alternative glycan sequences and spacer chains through a convergent chemical glycosylation manner or a one-pot three-enzyme assembly protocol. Using bifunctional glutarate ester as the linker, these synthesized oligosaccharides were efficiently conjugated with recombinant ScpA193 protein, generating the resultant oligosaccharide-ScpA193 conjugates with desirable carbohydrate loading. ELISA analysis of the antisera obtained from mice inoculated with the synthetic glycoconjugates showed the elicitation of strong oligosaccharide-specific immunoglobulin G (IgG) antibodies, suggesting the potential of the synthesized oligosaccharides for use in the development of GBS vaccines.

In Situ-Generated Formamidine as a Carbon/Nitrogen Source for Enaminone Formation: One-Pot Synthesis of Functionalized 4-Acyl-1,2,3-triazoles.

N,N-Dimethylformamide was reacted with hexamethyldisilazane to generate an N,N-dimethylformimidamide intermediate; thereafter, a reaction with acetophenones/β-diketones was induced to form enaminones. The one-pot synthetic protocol described in this paper can be applied to synthesize 1,4-disubstituted 1,2,3-triazoles and 1,4,5-trisubstituted 1,2,3-triazoles, in which organic azides are used as substrates under optimized conditions. Furthermore, this protocol uses readily available materials, is nearly free of solvent, can be applied to gram-scale operations, and leads to the formation of structurally diverse products with favorable yields.

Synthesis and application of triptycene based oligomers for the stereoselective aldol reaction of isatin and ketones

Novel triptycene derived oligomers (TOL1, TOL2 and TOL3) with multiple metal-coordinating sites have been synthesized in high yields using a three-component one-pot synthetic protocol and were characterized by various analytical tools such as FT-IR, solid state 13C NMR, GPC and FESEM. The GPC analysis revealed TOLs as oligomers with 8-10 repeating units. The catalytic applications of these oligomers were investigated for the stereoselective synthesis of 3-hydroxy-2-oxindoles via aldol reaction of isatin with ketones by the in-situ complexation of the oligomers with Cobalt metal. All the tested reactions worked well to generate the corresponding products in excellent yields with good diastereo-selectivities.

Hypervalent-Iodine-Mediated Base-Free Oxidative Olefination of Benzylic Amines to Access α,β-Unsaturated Ketones

AbstractWe report a one-pot base-free protocol for the oxidative olefination of benzylic amines promoted by a hypervalent iodine reagent for the synthesis of α,β-unsaturated ketones. Mechanistically, (diacetoxyiodo)benzene oxidizes the benzylic amine to the corresponding imine, which, on reaction with a phenacyl(triphenyl)phosphonium bromide salt and an in situ generated acetoxy anion leads to an α,β-unsaturated ketone. A wide range of α,β-unsaturated ketones were easily accessed through direct oxidative olefination of substituted benzylic amines in good to excellent yields and with high E-selectivity.

Elucidating the Synergistic Promotional Mechanism of Water and Oxygen in the Aerobic C-C Homocoupling Reaction Catalyzed by Visible-Light-Derived Core-Shell Pd@A-CQDs Nanostructures.

Rational design and precise synthesis of biogenic noble-metal-based catalysts possessing distinctive structure and composition play a crucial role in the chemical industry, enabling sustainable construction of an inclusive range of chemical resources. In this study, we have effectively fabricated Pd@A-CQDs through a straightforward one-pot aqueous protocol assisted by visible light employing renewable biomass-derived amine-rich carbon quantum dots (A-CQDs). The remarkable visible light harnessing capability (bandgap, ca. 2.81 eV), high density (35.7 × 1018 cm-3), and long lifetime (25 ps) of photocharge carriers and amine-rich surface in A-CQDs make them ideal candidates as both reducing and stabilizing agents, thereby facilitating the in situ construction of metallic Pd(0) nanoparticles. Comprehensive physicochemical characterizations have provided compelling evidence for the spherical morphology of Pd@A-CQDs core-shell nanostructures, with ultrathin A-CQDs shells of ca. 1.9 nm and an average diameter of 14 ± 1 nm. The effectiveness of the synthesized Pd@A-CQDs catalysts was assessed in the ligand- and base-free homocoupling reaction of arylboronic acids in water at ambient temperature. The catalytic tests demonstrated the selective production of the homocoupled compound over protodeboronation products with excellent yield and high catalyst recyclability under ambient conditions. The protocol employed exhibited a high TOF (1.05 × 10-2 mol g-1 min-1) and a low E-factor, with a remarkably low palladium loading. XPS analysis confirmed the retention of the metallic nature of the palladium core within the catalysts during the reaction. The catalytic function of the palladium core in conjunction with the A-CQDs shell, along with the promotional effects provided by water and oxygen for the formation of nucleophilic tetravalent boron, was conclusively recognized by 11B NMR and O2-TPD measurements. The obtained experimental results deliver valuable insights into the probable reaction pathway for the homocoupling reaction catalyzed by the Pd@A-CQDs catalysts. Through a comprehensive and sustainable evaluation, the current methodology exhibits superior performance compared to previously documented techniques in relation to estimated circularity and adherence to good manufacturing practices (GMP).

2,3-Difunctionalization of quinones: a gold-catalyzed cascade approach for trifluoromethyl-amination or sulfoximination.

A one-pot domino protocol employing gold(I) catalysis has been developed for the cascade trifluoromethyl-amination/sulfoximination of quinones. Togni I serves as the trifluoromethyl installing precursor, while amine or sulfoximine serves as the aminating source. Preliminary investigations suggest a mutual activation of Togni I and the amine precursor, facilitating the facile difunctionalization of quinones with excellent regioselectivity. Extensive substrate scope exploration demonstrates moderate to good yields of difunctionalized products. Application to the natural product Juglone highlights its potential for late-stage modifications in medicinal chemistry and drug discovery.

One-Pot Electrosynthesis of Gamma-Butyrolactone (GBL) from Biomass-Derived Furoic Acid

An efficient catalytic method to transform biomass into value-added products is critical to promoting a sustainable future. Ideally, such a transformation should be carried out efficiently in mild conditions. Herein, we developed a mild one-pot electrochemical protocol for converting furoic acid (FA), a common biomass-derived feedstock, into a versatile platform chemical, gamma-butyrolactone (GBL). All involved species participate in the desired redox pathway with high selectivity: FA was electrochemically oxidized with 84.2% selectivity to 2(5H)-furanone, the olefin of which was then hydrogenated to yield GBL with 98.5% selectivity. We identified that a specific temperature is an essential factor in enabling the one-pot reaction as it promotes thermal desorption of the key intermediate. The reaction was scalable to gram-scale, producing high-purity GBL isolated through a simple solvent extraction from a 500-mL electrolysis scale reaction.

Solid Phase Synthesis, DFT Calculations, Molecular Docking, and Biological Studies of Symmetrical N 2,N 4,N 6-Trisubstituted-1,3,5-triazines.

A diversity-oriented, multicomponent convergent synthesis of symmetrical triazines through a one-pot protocol is presented in this research project. The assembly of trisubstituted triazines was initially carried out using easily available reagents through three different protocols, i.e., conventional, MW-assisted synthesis, and solid-supported MW-assisted synthesis using organic and inorganic support to carry out a comparative analysis as to which procedure best corresponds to a greener synthesis protocol. The compounds formed were characterized for structure elucidation and subjected to in vitro anticancer and antibacterial screening. Additionally, computational studies, such as DFT calculations and molecular docking analyses, were conducted.

Triflic Acid-Promoted 1,2-Amino Migration Reactions in α-Arylaminoacrylamides: Access to Substituted β-Aminoamides.

A straightforward synthesis of substituted β-aminoamides from α-arylamino-β-hydroxyacrylamides, α-arylamino-β-oxoamides, or their tautomeric mixture has been described. The (E)-enol triflate intermediates are readily generated in situ from these substrates in the presence of triflic anhydride (Tf2O) and triethylamine (Et3N) in a chemoselective manner and undergo triflic acid (TfOH)-promoted cyclization and ring-opening reactions with alcohols to deliver the desired products. The one-pot two-step synthetic protocol features the use of readily available starting materials, mild reaction conditions, high chemoselectivity, operational simplicity, and a wide range of synthetic potential of the products.

Sustainable Synthesis of the Active Pharmaceutical Ingredient Atenolol in Deep Eutectic Solvents.

Atenolol, one of the top five best-selling drugs in the world today used to treat angina and hypertension, and to reduce the risk of death after a heart attack, faces challenges in current synthetic methods to address inefficiencies and environmental concerns. The traditional synthesis of this drug involves a process that generates a large amount of waste and other by-products that need disposal. This study presents a one-pot DES-based sustainable protocol for synthesizing atenolol. The use of the DES allowed the entire process to be conducted with no need for additional bases or catalysts, in short reaction times, under mild conditions, and avoiding chromatographic purification. The overall yield of atenolol was 95%. The scalability of the process to gram-scale production was successfully demonstrated, emphasizing its potential in industrial applications. Finally, the 'greenness' evaluation, performed using the First Pass CHEM21 Metrics Toolkit, highlighted the superiority in terms of the atom economy, the reaction mass efficiency, and the overall process mass intensity of the DES-based synthesis compared with the already existing methods.

Wet-Chemical Synthesis of Concave Hexoctahedral Pd and Pd@Pt Nanocrystals for Methanol Electrooxidation.

Nanocrystals (NCs) exposed with high-index facets usually show enhanced electrocatalytic performances. However, it is a great challenge to persevere with high-index facets against their high surface energy during the synthesis. Herein, we successfully synthesize concave hexoctahedral (c-HOH) Pd NCs exposed with 48 high-index {741} facets using a facile one-pot wet-chemical protocol. Control experiments illustrate that l-ascorbic acid plays a critical role in the formation of the c-HOH morphology, acting as both reducing and capping agents. Moreover, we can extend the synthesis for fabricating c-HOH Pd@Pt core-shell NCs by simply introducing a Pt precursor into the reaction solution, attaining remarkably boosted electrocatalysis for methanol electrooxidation reaction (MOR). Integrating the merits of {741} facets, concave structure, and ligand and strain effect of the core-shell structure, c-HOH Pd4@Pt1 core-shell NCs showed an excellent MOR mass activity of 1.18 A mgPGM-1 or 3.60 A mgPt-1, which is 3.80 or 11.61 times higher than that of commercial Pt/C, respectively.

Synthesis of Bisindole Alkaloids and Their Mode of Action against Methicillin-Resistant Staphylococcus Aureus.

About 100,000 deaths are attributed annually to infections with methicillin-resistant Staphylococcus aureus (MRSA) despite concerted efforts toward vaccine development and clinical trials involving several preclinically efficacious drug candidates. This necessitates the development of alternative therapeutic options against this drug-resistant bacterial pathogen. Using the Masuda borylation-Suzuki coupling (MBSC) sequence, we previously synthesized and modified naturally occurring bisindole alkaloids, alocasin A, hyrtinadine A and scalaradine A, resulting in derivatives showing potent in vitro and in vivo antibacterial efficacy. Here, we report on a modified one-pot MBSC protocol for the synthesis of previously reported and several undescribed N-tosyl-protected bisindoles with anti-MRSA activities and moderate cytotoxicity against human monocytic and kidney cell lines. In continuation of the mode of action investigation of the previously synthesized membrane-permeabilizing hit compounds, mechanistic studies reveal that bisindoles impact the cytoplasmic membrane of Gram-positive bacteria by promiscuously interacting with lipid II and membrane phospholipids while rapidly dissipating membrane potential. The bactericidal and lipid II-interacting lead compounds 5c and 5f might be interesting starting points for drug development in the fight against MRSA.

Photochemical Skeletal Editing of Pyridines to Bicyclic Pyrazolines and Pyrazoles.

We present an efficient one-pot photochemical skeletal editing protocol for the transformation of pyridines into diverse bicyclic pyrazolines and pyrazoles under mild conditions. The method requires no metals, photocatalysts, or additives and allows for the selective removal of specific carbon atoms from pyridines, allowing for unprecedented versatility. Our approach offers a convenient and efficient means for the late-stage modification of complex drug molecules by replacing the core pyridine skeleton. Moreover, we have successfully scaled up this procedure in stop-flow and flow-chemistry systems, showcasing its applicability to intricate transformations such as the Diels-Alder reaction, hydrogenation, [3 + 2] cycloaddition, and Heck reaction. Through control experiments and DFT calculations, we provide insights into the mechanistic underpinnings of this skeletal editing protocol.

One-Pot Synthesis of Functionalized Benzotropones via a Phthalide Ring-Opening/Intramolecular Aldol Condensation Cascade.

A one-pot protocol was developed for the synthesis of functionalized benzotropone derivatives via a nucleophilic phthalide ring opening by a 5-lithiated dioxinone derivative, followed by an intramolecular aldol condensation. The method demonstrates exceptional versatility with diverse substrates, yielding a variety of functionalized benzotropones. Subsequent transformations of the obtained benzotropone derivatives were explored for their potential applications.

Concise synthesis of 2,4-bis(fluoroalkyl)quinoline derivatives from arylamines

Quinolines and their derivatives bearing fluorine-containing substituents are essential structural motifs found in numerous bioactive compounds and advanced functional materials. Therefore, there is an urgent need to develop new synthetic methods for fluoroalkylated quinoline derivatives. In this study, we present a facile and efficient approach to access fluoroalkylated quinoline derivatives by using Eaton's reagent as a cost-effective, and commercially available reagent. This Combes cyclization reaction demonstrated compatibility with various arylamines bearing diverse functional groups, resulting in the synthesis of 2,4-bis(trifluoromethyl)quinolines and 2,4-bis(difluoromethyl)quinolines in moderate to high yields. Furthermore, this reaction can be conveniently carried out in a solvent-free one-pot protocol.