Expeditious Synthesis Research Articles

Single‐Step Expeditious Synthesis of Diblock Copolymers with Different Morphologies by Lewis Pair Polymerization‐Induced Self‐Assembly

Lewis pair polymerization has demonstrated its unique advantages and powerful capability in polymer synthesis. Here we employ strong nucleophilic N-heterocyclic olefin (NHO) and bulky organoaluminum to construct a frustrated Lewis pair, which can realize the compounded sequence control (CSC) copolymerization and self-assembly the mixture of dimethylaminoethyl acrylate and fluoride-functionalized methacrylate into diblock copolymers (di-BCPs) nano-assemblies through polymerization-induced self-assembly in one-pot, single-step manner within minutes. These di-BCPs were characterized by 1 H and 13 C NMR, GPC, DSC, and TEM. By utilizing appropriate solvophilic block and solvophobic block, such Lewis pair polymerization-induced self-assembly strategy enables the expeditious, room-temperature synthesis of di-BCP nanoparticles with different morphologies, including spheres, worms, vesicles, and even fibers, thus suggesting the great application potential of such method in the future.

Desymmetric Partial Reduction of Malonic Esters

Desymmetrization of easily available disubstituted malonic esters is a rewarding strategy to access structurally diverse quaternary stereocenters. Particularly, asymmetric reduction of malonic esters would generate a functional group with a lower oxidation state than the remaining ester, thus allowing for more chemoselective derivatization. Here, we report a new set of conditions for the zinc-catalyzed desymmetric hydrosilylation of malonic esters that afford aldehydes as the major product. Compared with alcohol-selective desymmetrization, the partial reduction uses a higher concentration of silanes and new pipecolinol-derived tetradentate ligands, proposedly to switch the pathway of zinc hemiacetal intermediates from elimination to silylation. As a result, high aldehyde-to-alcohol ratios and enantioselectivity of aldehydes are obtained from malonic esters with a large collection of substituents. Together with the abundant reactivity of aldehydes, the partial reduction has enabled an expeditious synthesis of bioactive compounds and natural metabolites containing a quaternary stereocenter.

Expeditious and Cost-effective Synthesis of α-Amino Nitriles Using ZnCl2/hydrotalcite as a Recyclable Heterogeneous Catalyst

Expeditious and Cost-effective Synthesis of α-Amino Nitriles Using ZnCl2/hydrotalcite as a Recyclable Heterogeneous Catalyst

Direct and Catalytic C-Glycosylation of Arenes: Expeditious Synthesis of the Remdesivir Nucleoside.

Since early 2020, scientists have strived to find an effective solution to fight SARS‐CoV‐2, in particular by developing reliable vaccines that inhibit the spread of the disease and repurposing drugs for combatting its effects on the human body. The antiviral prodrug Remdesivir is still the most widely used therapeutic during the early stages of the infection. However, the current synthetic routes rely on the use of protecting groups, air‐sensitive reagents, and cryogenic conditions, thus impeding a cost‐efficient supply to patients. We have, therefore, focused on the development of a straightforward, direct addition of (hetero)arenes to unprotected sugars. Here we report a silylium‐catalyzed and completely stereoselective C‐glycosylation that initially yields the open‐chain polyols, which can be selectively cyclized to provide either the kinetic α‐furanose or the thermodynamically favored β‐anomer. The method significantly expedites the synthesis of Remdesivir precursor GS‐441524 after a subsequent Mn‐catalyzed C−H oxidation and deoxycyanation.

Direkte Katalytische C‐Glykosylierung von Arenen: beschleunigte Synthese des Remdesivir‐Nucleosids**

AbstractSeit Beginn des Jahres 2020 wird nach einer effektiven Lösung im Kampf gegen SARS‐CoV‐2 gesucht, vor allem durch Entwicklung verlässlicher Impfstoffe, welche die Verbreitung des Virus verhindern, und durch die Untersuchung bereits für andere Indikationen zugelassener Wirkstoffe. Diesbezüglich ist die Anwendung der antiviralen Prodrug Remdesivir immer noch am weitesten verbreitet, allerdings beschränkt sich die Synthese auf Schutzgruppen, sauerstoffsensitive Reagenzien und kryogene Temperaturen, weshalb eine kosteneffiziente Herstellung nicht immer gewährleistet werden kann. Um zur Lösung dieses Problems beizutragen, konzentrierten wir uns auf die Entwicklung einer direkten Addition von (Hetero)arenen an ungeschützte Zucker. Hier berichten wir von einer silyliumkatalysierten und vollkommen stereoselektiven C‐Glykosylierung, die zunächst offenkettige Polyole liefert, welche schließlich durch Cyclisierung unter kinetischer oder thermodynamischer Kontrolle zur α‐ oder β‐Furanose umgesetzt werden. Die Methode ermöglicht raschen Zugang zu Remdesivir‐Intermediat GS‐441524 nach anschließender Mn‐katalysierter C−H‐Oxidation sowie Deoxycyanierung.

Expeditious synthesis of highly substituted 3(2H)-furanone and quinoline by microwave assisted reaction between aldonitrones and dibenzoylacetylene

A rapid, catalyst-free, GREEN protocol for the synthesis of highly substituted 3(2H)-furanone and quinoline.

Pyromellitic diamide-diacid bridged mesoporous organosilica nanospheres with controllable morphologies: a novel PMO for the facile and expeditious synthesis of imidazole derivatives.

In this work, novel pyromellitic diamide–diacid bridged mesoporous organosilica (PMAMOS) nanospheres with controllable morphologies and Brønsted acid catalytic centers were designed and prepared through a convenient method by altering the addition sequence of precursors, solvent, and aging time. The obtained PMAMOSs demonstrate high surface areas and uniform pore sizes. FESEM, HRTEM, BET, EDX, XRD, FTIR and TGA analyses were performed to characterize and examine the effective factors for the preparation of PMAMOS nanospheres. Due to the appropriate physicochemical properties including Brønsted acid centers, suitable surface area and thermal stability of the PMAMOS nanosphere material, it was explored in the three-component reaction of benzyl or benzoin, ammonium acetate, and different aldehyde derivatives as a case study of multicomponent reactions. Corresponding imidazole derivatives were obtained in EtOH under reflux conditions in high to quantitative yields and short reaction times. It was also shown that the heterogeneous solid acid can be reused at least five times with negligible loss of its catalytic activity, indicating the appropriate stability and high activity of the newly introduced mesoporous organosilica.

Metal-free sulfonylation of arenes with N-fluorobenzenesulfonimide via cleavage of S-N bonds: expeditious synthesis of diarylsulfones.

A novel metal-free sulfonylation of arenes with N-fluorobenzenesulfonimide (NFSI) toward the synthesis of diarylsulfones has been developed. The reaction represents a rare example of sulfonylation reaction using NFSI as an efficient sulfonyl donor and the first example of acid-mediated sulfonylation of unactivated arenes with NFSI via selective cleavage of S-N bonds. This protocol provides a concise approach for the construction of pharmaceutically and biologically important diarylsulfones. Applications in the functionalization of natural products (e.g., β-estradiol) and in the synthesis of a key intermediate to an inhibitor of farnesyl-protein transferase, as well as in the gram-scale synthesis of the EPAC2 antagonist, are demonstrated.

Mild and Expeditious Synthesis of Sulfenyl Enaminones of l-α-Amino Esters and Aryl/Alkyl Amines through NCS-Mediated Sulfenylation.

Sulfenylation or selenylation of enaminones of l-α-amino esters requires mild reaction conditions due to the presence of a racemization-prone chiral center and reactive side chains. An N-chlorosuccinimide (NCS)-mediated methodology has been developed for rapid sulfenylation of enaminones of l-α-amino esters and aryl/alkyl amines at room temperature in open air under metal-free conditions. Enaminones of l-α-amino esters bearing aliphatic, aromatic, and heterocyclic side chains react efficiently with diverse aryl/alkyl/heteroaryl thiols (R1SH) in the presence of NCS to afford a library of biologically important sulfenyl enaminones in good-to-excellent yields (71–90%). Under similar reaction conditions, the enaminones also react with benzeneselenol to produce selenyl enaminones in good yield (73–83%). The NCS-mediated pathway generates sulfenyl chloride (R1SCl) as an intermediate which leads to rapid sulfenylation of enaminones through cross-dehydrogenative coupling (CDC) under mild reaction conditions.

A new expeditious synthesis of the core scaffold of salvianolic acid F trough a one-pot sequential Heck coupling catalyzed by palladium nanoparticles in ionic liquids

A new expeditious synthesis of tetramethyl salvianolic acid F is presented. Starting from the naturally occurring veratrole, the target molecule is easily obtained in a one-pot mode via a sequential double Heck coupling catalyzed by palladium nanoparticles dispersed in ionic liquids. The present method involves the chemoselective displacement of two different halogen atoms present on the veratrole ring and limits the need for tedious experimental procedures. A 66% of overall yield can be achieved, that represents, as far as we know, one of the best results present in the literature, until now. This protocol can also open the way for the synthesis of unnatural salvianolic-like compounds with potential bioactivity.

Copper-Catalyzed (4+1) Cascade Annulation of Terminal Alkynes with 2-(Tosylmethyl)anilines: Synthesis of 2,3-Disubstituted Indoles.

A novel strategy based on Cu-catalyzed (4+1) cascade annulation of terminal alkynes as one-carbon synthons with 2-(tosylmethyl)anilines has been developed for the expeditious synthesis of 2,3-disubstituted indoles, in which in situ generations of aza-o-quinone methides and alkynyl-copper(I) species are involved. This annulation provides an effective method for the assembly of synthetically and structurally interesting 2,3-disubstituted indoles.

Dinucleophilic Reactivity of Isocyanoacetate: Base-Catalyzed One-Pot Access to 4-Azafluorenes and 4-Azafluorenones.

A base-catalyzed double annulation of isocyanoacetates with various enynones has been developed for the expeditious synthesis of 4-azafluorene and 4-azafluorenone derivatives. Against the well-known 1,3-dipolar reactivities, the active methylene and isocyano groups of isocyanoacetate serve as nucleophiles in this domino transformation.

Dinuclear Copper(I) Thiodiacetate Complex-Mediated Expeditious Synthesis of the Chlorine-Containing Cyclen-Cored 36-Glucose-Coated Glycodendrimer

High-sugar-tethered glycodendrimers are a remarkable tool in glycobiology for the investigation of carbohydrate-protein interaction using its multivalency property. An enthralling double-stage convergent synthetic approach was selected to build a novel class of chlorine-containing glucose-coated dendrimers using an efficient click catalyst ‘dinuclear copper(I) thiodiacetate complex.’ In this context, cyclen core was developed through a divergent approach, while the glucodendron was developed via a convergent approach independently. Both azide-alkyne partners were coupled through a modular copper azide-alkyne cycloaddition (CuAAC) strategy to afford a high yield of the desired 36-glucose-coated glycodendrimer. The synthesized glycodendrimer has been elucidated by NMR, gel permeation chromatography (GPC), and IR spectral analysis.

Expeditious Asymmetric Synthesis of Polypropionates Relying on Sulfur Dioxide-Induced C–C Bond Forming Reactions

For a long time, the organic chemistry of sulfur dioxide (SO2) consisted of sulfinates that react with carbon electrophiles to generate sulfones. With alkenes and other unsaturated compounds, SO2 generates polymeric materials such as polysulfones. More recently, H-ene, sila-ene and hetero-Diels–Alder reactions of SO2 have been realized under conditions that avoid polymer formation. Sultines resulting from the hetero-Diels–Alder reactions of conjugated dienes and SO2 are formed more rapidly than the corresponding more stable sulfolenes resulting from the cheletropic additions. In the presence of a protic or Lewis acid catalyst, the sultines derived from 1-alkoxydienes are ionized into zwitterionic intermediates bearing 1-alkoxyallylic cation moieties which react with electro-rich alkenes such as enol silyl ethers and allylsilanes with high stereoselectivity. (C–C-bond formation through Umpolung induced by SO2). This produces silyl sulfinates that react with carbon electrophiles to give sulfones (one-pot four component asymmetric synthesis of sulfones), or with Cl2, generating the corresponding sulfonamides that can be reacted in situ with primary and secondary amines (one-pot four component asymmetric synthesis of sulfonamides). Alternatively, Pd-catalyzed desulfinylation generates enantiomerically pure polypropionate stereotriads in one-pot operations. The chirons so obtained are flanked by an ethyl ketone moiety on one side and by a prop-1-en-1-yl carboxylate group on the other. They are ready for two-directional chain elongations, realizing expeditious synthesis of long-chain polypropionates and polyketides. The stereotriads have also been converted into simpler polypropionates such as the cyclohexanone moiety of baconipyrone A and B, Kishi’s stereoheptad unit of rifamycin S, Nicolaou’s C1–C11-fragment and Koert’s C16–CI fragment of apoptolidin A. This has also permitted the first total synthesis of (-)-dolabriferol.

Rational design and expeditious synthesis of aromatic cyanodienone derivatives assisted by cyanide-halide exchange

1-n-Butyl-3-methylimidazolium cyanide ([bmim]CN), in the presence of [bmim]Br has been prepared and used for the first time as the medium as well as reagent for the synthesis of aromatic cyanodienones from the corresponding triarylpyrylium perchlorates by cyanide-halide exchange. The [bmim]CN having a reactive anion, is an accelerated reaction technique without external solvent and renders the whole synthesis into a truly eco-friendly protocol. The products can be isolated without aqueous work-up in high purity and excellent yield.

Mild and highly efficient deacetylation of acetamido and acetoxy coumarins: A convenient and expeditious synthesis of substituted 3-aminocoumarins

A convenient protocol for efficient and cost-effective method for synthesis of substituted 3-aminocoumarins has been developed. The synthetic route involves expeditious and fast quantitative deacetylation of readily available acetamido derivative under anhydrous acidic conditions, employing thionyl chloride in methanol, without formation of undesired substituted 3-hydroxycoumarins. The method is suitable for derivatives bearing electron-donating as well as electron-withdrawing groups at position 7 of the coumarin scaffold. Under these conditions, a series of acetoxy substituted 3-dialkylaminocoumarins has been also successfully deacetylated to afford easily isolable corresponding hydroxy derivatives in high yields.

Urea hydrogen peroxide-initiated synthesis of pyranopyrazoles through oxidative coupling under base- and metal-free conditions by physical grinding method.

A novel multicomponent one-pot expeditious synthesis of highly functionalized and pharmaceutically fascinated pyranopyrazoles has been developed. This reaction occurs via tandem Knoevenagel condensation reaction of methyl aryl derivatives, 3-methyl pyrazolone and malononitrile in the presence of urea hydrogen peroxide under the physical grinding method. The present methodology offers several benefits such as available green and cheap starting materials, solvent-free, mild reaction conditions, high atom economy, eco-friendly standards, excellent yields and easy isolation of the products without column chromatographic separation.

Dual-initiating and living frustrated Lewis pairs: expeditious synthesis of biobased thermoplastic elastomers

Biobased poly(γ-methyl-α-methylene-γ-butyrolactone) (PMMBL), an acrylic polymer bearing a cyclic lactone ring, has attracted increasing interest because it not only is biorenewable but also exhibits superior properties to petroleum-based linear analog poly(methyl methacrylate) (PMMA). However, such property enhancement has been limited to resistance to heat and solvent, and mechanically both types of polymers are equally brittle. Here we report the expeditious synthesis of well-defined PMMBL-based ABA tri-block copolymers (tri-BCPs)—enabled by dual-initiating and living frustrated Lewis pairs (FLPs)—which are thermoplastic elastomers showing much superior mechanical properties, especially at high working temperatures (80–130 °C), to those of PMMA-based tri-BCPs. The FLPs consist of a bulky organoaluminum Lewis acid and a series of newly designed bis(imino)phosphine superbases bridged by an alkyl linker, which promote living polymerization of MMBL. Uniquely, such bisphosphine superbases initiate the chain growth from both P-sites concurrently, enabling the accelerated synthesis of tri-BCPs in a one-pot, two-step procedure. The results from mechanistic studies, including the single crystal structure of the dually initiated active species, detailed polymerizations, and kinetic studies confirm the livingness of the polymerization and support the proposed polymerization mechanism featuring the dual initiation and subsequent chain growth from both P-sites of the superbase di-initiator.

Microwave prompted solvent-free synthesis of new series of heterocyclic tagged 7-arylidene indanone hybrids and their computational, antifungal, antioxidant, and cytotoxicity study

In this study, we report the expeditious synthesis of ten new antifungal and antioxidant agents containing heterocyclic linked 7-arylidene indanone moiety. The solvent-free microwave technique, ample substrate scope, superfast synthesis, and very simple operation are noteworthy features of this protocol. Antifungal activities of the newly synthesized compounds were evaluated against four fungal strains namely Rhizophus oryzae, Mucor mucido, Aspergillus niger, and Candida albicans. Most of the compounds were shown strong inhibition of the investigated fungal agents. In vitro, antioxidant potential against DPPH and OH radicals affirmed that the synthesized compounds are good to excellent radicals scavenging agents. The cytotoxicity data of the synthesized compounds towards HL-60 cells uncovered that the synthesized compounds display very low to negligible cytotoxicity. The structural and quantum chemical parameters of the synthesized compounds were explored by employing density functional theory (DFT) at B3LYP functional using 6-311G(d,p) basis set. The compound 3a is discussed in detail for the theoretical and experimental correlation. Time-dependent density functional theory (TD-DFT) at CAM-B3LYP functional with 6-311G(d,p) basis set was used for the electronic absorption study in the gas phase and indichloromethane and benzene solvents. The UV–Visible absorption peaks and fundamental vibrational wavenumbers were computed and a good agreement between observed and theoretical results has been achieved. From the DFT and antifungal activity correlation, it has been found that the 7-heteroarylidene indanones with more stabilized LUMO energy levels display good antifungal potential.

Rational design and expeditious synthesis of aromatic cyanodienone derivatives assisted by cyanide-halide exchange

1-n-Butyl-3-methylimidazolium cyanide ([bmim]CN), in the presence of [bmim]Br has been prepared and used for the first time as the medium as well as reagent for the synthesis of aromatic cyanodienones from the corresponding triarylpyrylium perchlorates by cyanide-halide exchange. The [bmim]CN having a reactive anion, accelerated reaction technique without external solvent renders the whole synthesis into a truly ecofriendly protocol. The products is isolated without aqueous work-up in high purity and excellent yield.