Catalytic Amount Research Articles

Discovering the Cholinesterase Inhibitory Potential of Thiosemicarbazone Derivatives through In vitro, Molecular Docking, Kinetics, and Dynamics Studies.

The current study explored the cholinesterase inhibitory activities of some thiosemicarbazone derivatives bearing 2,4-dichloro phenylacetic acid scaffold. This study aimed to screen the synthesized derivatives for their in vitro acetylcholine and butyrylcholinesterase inhibition. These compounds were synthesized by refluxing 2,4-dichloro phenylacetic acid with sulfuric acid in ethanol to get the ester, which was further refluxed with thiosemicarbazide in ethanol to get the desired compound (2). Different benzaldehydes were treated with compound (2) in ethanol having a catalytic amount of acetic acid to get thiosemicarbazones. In the series, seven compounds, including compounds 2c, 2a, 2b, 2d, 2g, 2e, and 2f, displayed excellent acetylcholinesterase inhibition activities in the range of IC50 values from 41.51 ± 3.88 to 95.48 ± 0.70 μM, surpassing than the standard galantamine (IC50 = 104.5 ± 1.20 μM). Also, compounds 2a, 2g, 2h, 2f, 2b, and 2d with IC50 values ranging from 64.47 ± 2.74 to 80.62 ± 0.73 μM exhibited potent inhibition against butyrylcholinesterase enzyme, being similar to the standard galantamine (IC50 = 156.8 ± 1.50 μM). The molecular docking investigation was performed to assess the binding affinity of the compounds with the active site of the enzyme. These compounds, along with the docked complexes, specifically AChE-compound 2a and BuChE-compound 2g, were chosen and subjected to 100-nanosecond molecular dynamics simulations. The simulations demonstrated strong stability of the ligands within the active pockets of AChE and BuChE enzymes. These derivatives exhibited superior acetylcholinesterase and butyrylcholinesterase inhibitory activities compared to galantamine, with molecular docking and dynamic simulations confirming their strong binding affinity with the active sites of the enzymes.

Direct Access to 3,4‐Fused Spirooxindoles Through Visible‐Light‐Driven Diasterioselective [4+2] Cyclization of 3‐Methylene Oxindoles

AbstractA visible light‐mediated strategy has been developed to synthesize diastereoselective 3,4‐fused spirooxindoles via formal [4+2] cycloaddition of 3‐methylene oxindoles without the need of pre‐functionalization. The 3‐methylene oxindoles, when exposed to visible light in the presence of catalytic amount of CeCl3 under alkaline conditions, afforded the complex 3,4‐fused spirooxindole framework with four contiguous chiral centers. The protocol proved to be highly chemo‐ and regio‐selective by affording 3,4‐fused spirooxindoles in moderatetogood yields. The protocol also works smoothly under the direct exposure of sunlight. It has been demonstrated that the method is also scalable on gram quantity.

Synthesis of Benzofuro[3,2-c]isoquinolines through Anionic Intramolecular Cyclization

AbstractBenzofuro[3,2-c]isoquinolines are among the typical tetraheterocycles. The synthesis of benzofuro[3,2-c]isoquinoline derivatives in the presence of a catalytic amount of KOH has been developed. A variety of substituents could be tolerated. The base (KOH) works as a catalyst. A gram-scale synthesis was performed. Control experiments confirmed that a cascade anionic annulation is involved rather than a radical cyclization.

1,3- and 1,2-Zwitterionic Complexes of Donor-Acceptor Cyclopropanes in Reactions with Arylallenes.

The reaction of 2-arylcyclopropane-1,1-dicarboxylates (ACDC) with GaCl3 and other Lewis acids in the presence of 3-arylbuta-1,2-dienes, which acts as a trapping agent for the 1,2- or 1,3-zwitterionic intermediates being generated, has been studied. The reaction of 1,2-zwitterionic gallium complexes at low temperature has been found to give products of annulation at the phenyl substituent in the allene, 2-aryl-1-(inden-2-yl)ethylmalonates, as the main products. Only in the case of naphthylcyclopropanedicarboxylate, the formation of a polycyclic frame by annulation at both aromatic moieties occurred upon an increase in temperature to 0°C. Trapping of 1,3-zwitterions, the primary intermediates of cyclopropane ring opening, by the indicated allene was most successful if catalytic amounts of GaCl3 were added directly to the reaction mixture. In this case, the reaction followed the pathway of the usual formal (3+2)-cycloaddition of 1,3-zwitterions at each of the double bonds of the allene to give the corresponding exo-methylenecyclopentane-1,1-dicarboxylates in up to 93% yields. This process occurred with the highest efficiency at the unsubstituted double bond of 3-arylbuta-1,2-diene.

Manganese‐Triazolylidene Catalysis for The Synthesis of 1,2,3,4‐Tetrahydroquinoxalines and Selective Alkylation of Diamines and Anilines with Alcohols and Diols

AbstractIn this study, we present manganese‐catalyzed borrowing hydrogen processes for the efficient synthesis of 1,2,3,4‐tetrahydroquinoxalines and the selective N,N´‐dialkylation of o‐phenylenediamines with alcohols. A Mn(I)‐catalyzed method for synthesizing 1,2,3,4‐tetrahydroquinoxalines via the direct reaction of o‐phenylenediamine with diols under mild conditions (80 °C) is described. The catalyst, [Mn(bis‐1,2,3‐triazolylidene)(CO)3Br], which features a bidentate triazolylidene ligand, is air‐stable, easy to prepare, and exhibits broad activity across a wide range of substrates. Additionally, this Mn‐triazolylidene complex efficiently catalyzes the N,N´‐dialkylation of a variety of o‐ and p‐phenylenediamines with a range of primary alcohols, such as benzyl alcohols, furfuryl alcohol, and 3‐pyridine methanol, using catalytic amount of base and mild conditions (100 °C, 6 h). Notably, this method enables the derivatization of the important drug molecule Dapson, showcasing its practical utility. The catalyst also allows both selective monoalkylation and dialkylation of a broad range of aniline derivatives using aliphatic diols as alkylating agents. This method provides the corresponding alkylated amines in excellentyields, typically between 81% to 99%, thereby underscoring its efficiency. The straighforward nature of the method, together with the use of readily available manganese catalyst, makes this strategy particularly appealing and suggests significant potential for wider use in the synthesis of parmaceutically relevant molecules.

One‐Pot Microwave‐Assisted Olefin Hydroaminomethylation Over Bifunctional Heterogeneous Rh Catalysts

AbstractCommercial Rh/C and lab‐made Rh/CNTs catalysts were compared in the one‐pot microwave‐assisted hydroaminomethylation of olefins to amines using EtOAc as the solvent. This reaction accounts for two steps: hydroformylation from the alkene, followed by aldehyde reductive amination. Acid sites exposed at the surface of the support promote the formation of a metal‐alkene coordination complex to preferentially form the linear aldehyde. Synthetic and natural olefins were converted with yields up to 99% under mild conditions (120 °C, 40 bar of syngas, 4 h). With the addition of catalytic amounts of acetic acid, the hydroformylation step proceeded with a 99% yield over both catalysts. The catalysts were recovered and reused, maintaining their activity for three reaction cycles (12 h). The hydroaminomethylation step again gave yields up to 99%, using 1‐hexene as substrate (120 °C, 4 h, 40 bar of N2/H2 1:1). Subsequent tests with different nitrogen sources resulted in amine yields ranging from 56% to 99%, even with ammonia. FESEM, XRD, and XPS were employed for an exhaustive surface characterization and structure‐to‐activity correlation of the catalysts.

Metallaphotoredox Deoxygenative Arylation of Alcohols: A Viable Strategy for the Synthesis of Tryptamine Derivatives

AbstractA metallaphotoredox deoxygenative arylation of alcohols strategy has been applied to prepare in a one pot procedure tryptamine derivatives. Starting from 3‐Br indoles and 2‐amino alcohols, in the presence of an Ir photocatalyst and catalytic amounts of NiBr2, 3‐(2‐aminoethyl)‐substituted indoles have been synthesized in up to 76% yield after 2 h under blue LED irradiation. Improved productivity and space time yield were observed when continuous flow technologies were employed (60% yield with 30 min residence time).

Catalytic Silylation of Alkynyl C(sp)–H Bonds with tert‐Butyl‐Substituted Silyldiazenes

AbstractThe deprotonative silylation of terminal alkynes constitutes one of the most privileged strategies to prepare alkynylsilanes owing to the relatively high acidity of C(sp)–H bonds. While the key deprotonation step is usually mediated by stoichiometric amounts of strong Brønsted bases (e.g., nBuLi) followed by the trapping of the corresponding acetylide with electrophilic silylating reagents, such a sequence can also be transposed to a catalytic regime through pro‐base strategies. We herein demonstrate that N‐tert‐butyl‐N’‐silyldiazenes (tBu–N = N–Si) widen the repertoire of silylated pro‐bases that can be used to promote the silylation of a range of terminal alkynes. These reactions are initiated with only catalytic amounts of inexpensive potassium hydroxide, proceed rapidly at room temperature, exhibit broad scope, and allow seamless one‐pot integration with downstream transformations of alkynylsilane products.

Tandem Synthesis of Pyrrolidine and Piperidine Derivatives from Propargylic Alcohols Under Multimetallic Catalysis

Herein we report on tandem synthesis of 2‐carbonylmethyl pyrrolidine/piperidine derivatives from propargylic alcohols under multimetallic catalysis. A Meyer–Schuster rearrangement of propargylic alcohols under cationic Au catalysis, followed by in situ olefin cross‐metathesis with appropriately protected amino olefins delivered a,b‐unsaturated ketones, which without isolation underwent an intramolecular aza‐Michael addition to afford a variety of pyrrolidine and piperidine derivatives. The scope of the present tandem reaction was investigated to show that common amine protecting groups, such as Ts, Ns, Cbz, and Bz, were well tolerated. Addition of a catalytic amount of bismuth(III) triflate was required for promoting the intramolecular aza‐Michael addition where the N‐protected amino group was less nucleophilic. The stereochemical consequence of the present tandem reaction was found to be dependent on the amine protecting group.

Platinum-Catalyzed Alkenylation of Acetals with Alkenylsilanes.

In the presence of catalytic amounts of PtCl2 and LiI, alkenylsilanes reacted with dimethyl acetals of aromatic aldehydes in acetonitrile to give allylic methyl ethers. This alkenylation reaction occurred not at the α-carbon bound to silicon but at the β-carbon of alkenylsilanes. Use of chlorotrimethylsilane as an additive was effective in promoting the alkenylation of certain acetals. The PtCl2-catalyzed hydrosilylation of terminal alkynes with triethylsilane and subsequent alkenylation of acetals enabled easy and rapid synthesis of allylic ethers.

Silica-Immobilized Pd-Amine Catalysts for Suzuki-Miyaura Coupling with Catalytic Amounts of Base.

Suzuki-Miyaura coupling is a robust method for constructing C-C bonds. Typically, stoichiometric amounts of a base are required. However, high pH conditions can lead to the protodeboronation of several substrates and generate stoichiometric waste salt from the additive base. Here, we present a Pd-amine co-immobilized catalyst enabling SMC with a catalytic amount of base; the amount of cross-coupling product was 18 times higher than that of co-immobilized amines. Furthermore, the use of a co-immobilized amine with a hydrophobic alkyl chain and a water-based solvent effectively removed acid byproducts from the Pd active species on the support surface, resulting in a high coupling product yield. The immobilized catalyst was characterized by elemental analysis, solid-state NMR, and X-ray absorption fine structure spectroscopy. Additionally, X-ray photoelectron spectroscopy, powder X-ray diffractometry, and transmission electron microscopy measurements revealed the in situ formation of Pd nanoparticles as the active species. Crucially, this system facilitates reactions even in the presence of aryl halides with acidic substituents.

Superfast Protein Desulfurization Triggered by Low‐Energy Visible Light

AbstractThe combination of transthioesterification‐based ligation of thiol‐derived amino acids and the post‐ligation desulfurization has greatly expanded the scope of modern chemical protein synthesis. Here, we report a new strategy of low‐energy visible light‐induced desulfurization (LEnVLD) that enables superfast and clean protein desulfurization (half life = 1.7 s) with improved reaction selectivity compared to the previous methods. The LEnVLD method can be easily carried out under very mild conditions using only a catalytic amount of fluorescent dye and household flashlight (ca. 5 W) irradiation, eliminating the need for any pyrophoric reagent, thiol additives, or excessive radical initiators, and its practicality was demonstrated by the fast and high‐yielding desulfurization of more than 30 peptide and protein substrates bearing a variety of sensitive functional groups (e.g., Thz, N‐alkylated maleimide, and thioester). Moreover, the convenience and robustness of LEnVLD enable its extension to versatile reaction scenarios (e.g., solid‐supported desulfurization and flow chemistry‐based desulfurization) that would enhance the practical capability of chemical protein synthesis.

Superfast Protein Desulfurization Triggered by Low-Energy Visible Light.

The combination of transthioesterification-based ligation of thiol-derived amino acids and the post-ligation desulfurization has greatly expanded the scope of modern chemical protein synthesis. Here, we report a new strategy of low-energy visible light-induced desulfurization (LEnVLD) that enables superfast and clean protein desulfurization (half life =1.7s) with improved reaction selectivity compared to the previous methods. The LEnVLD method can be easily carried out under very mild conditions using only a catalytic amount of fluorescent dye and household flashlight (ca. 5W) irradiation, eliminating the need for any pyrophoric reagent, thiol additives, or excessive radical initiators, and its practicality was demonstrated by the fast and high-yielding desulfurization of more than 30 peptide and protein substrates bearing a variety of sensitive functional groups (e.g., Thz, N-alkylated maleimide, and thioester). Moreover, the convenience and robustness of LEnVLD enable its extension to versatile reaction scenarios (e.g., solid-supported desulfurization and flow chemistry-based desulfurization) that would enhance the practical capability of chemical protein synthesis.

Mild and easy access to sapphyrins by electrochemical synthesis

Here we report the optimized synthesis of pentapyrroles. We succeeded in increasing the yield for pentapyrrole PPy 1a by heating at [Formula: see text] for 4.5 h. These conditions also allowed a greater increase in the yield for PPy 1c. In contrast, with PPy 1d and 1e possessing EDGs the formation of pentapyrroles was not observed. These pentapyrroles then allowed us to access sapphyrins (e.g. cyclic analogs of pentapyrroles) by electrosynthesis. The optimized conditions for obtaining the fluorinated sapphyrins 2aand 2binvolve the addition of 10 mol% TBAI (tetra-n-butylammoniom iodide), 2 eq. of TFA in CHCl3. In comparison with classical organic synthesis, the amount of TFA was considerably reduced from 100 to 2 eq. and the oxidizing agent, [Formula: see text].[Formula: see text]. iodine, was continuously electrogenerated from the catalytic amount of TBAI used as a redox mediator.

Pyridine(diimine) Chromium η,1η3-Metallacycles as Precatalysts for Alkene-Diene [2 + 2] Cycloaddition.

The synthesis, characterization, and catalytic cycloaddition reactivity of aryl-substituted pyridine(diimine) (PDI) chromium ether complexes and alkene-diene derived metallacycles are described. The reduction of either (PDI)CrCl2 or (PDI)CrCl3 with sodium and catalytic amounts of naphthalene furnished the corresponding chromium THF or diethyl ether complexes. Exposure of the reduced chromium compounds to a mixture of butadiene and ethylene induced rapid oxidative cyclization and yielded isolable, thermally stable chromium η,1η3 trans-metallacycles. In the presence of pure butadiene, oxidative cyclization was also observed, and a η,1η3 diene-diene chromacycloheptane with vinyl substitution was isolated and crystallographically characterized. Reductive C(sp3)-C(sp3) elimination of the resulting vinylcyclobutane products was promoted by either one-electron oxidation or irradiation with visible light in the presence of diene or coordinating solvents such as THF. Under thermal catalytic conditions, the chromacycles converted butadiene and ethylene to a mixture of vinylcyclobutane arising from [2 + 2] cycloaddition and cis-1,4-hexadiene resulting from competitive hydrovinylation. Visible light irradiation at ambient temperature enabled selective catalytic [2 + 2] cycloaddition. Isotopic labeling studies with 13C-labeled ethylene established that the alkene-diene chromacycle is thermodynamically preferred over the diene-diene alternative and that both oxidative cyclization and reductive coupling steps are reversible. Visible light accelerated the reductive coupling step, while subsequent product displacement from the metal center occurs in the presence of excess diene.

CAN-Mediated Synthesis of 2-Deoxy Sugars: Access to Chiral 2-Deoxy 3-Bisindolyl-C-glycosides.

The 2-deoxy sugars and bisindole moieties are ubiquitously found in natural products and play a crucial role in medicinal chemistry and chemical biology. Herein, we report a novel, quick, and highly effective technique that utilizes ceric ammonium nitrate (CAN) to synthesize 2-deoxy sugars from various protected glycals within 1-2 h. Additionally, we further explore the new process of transforming 2-deoxy sugars into chirally pure 2-deoxy-3-bisindolyl-C-glycosides molecular scaffolds using a catalytic amount of indium trichloride (InCl3) in good yields at room temperature. This method emphasizes inherited stereo diversity and a wide substrate scope, which enables the synthesis of various new 2-deoxy 3-bisindolyl-C-glycoside analogues, paving the way for further exploration of their application in medicinal chemistry and chemical biology.

Rh‐catalyzed Tandem Coupling of Sulfonamide with Isonitrile and Amine in Presence of Iodobenzene Diacetate: Direct Access to N‐Sulfonyl Guanidines

AbstractWe report herein a new synthetic pathway for the formation of N‐sulfonyl guanidine via multicomponent coupling of arylsulfonamide, isonitrile, and amine in the presence of a catalytic amount of Rh(COD)Cl]2 and iodobenzene diacetate as a promoter. The reaction is presumed to proceed via in situ formation of PhINTs due to the presence of the hypervalent iodine reagent PhI(OAc)2 in the reaction medium. The addition of PPh3 has been found to be beneficial in enhancing the catalytic performance of [Rh(COD)Cl]2. The formation of the key intermediate, carbodiimide resulted from the reaction between PhINTs and isonitrile which gets converted to the respective sulfonyl guanidine due to the nucleophilic attack of the amine.

Graphite-Catalysed Synthesis of phenolic Schiff’s Bases: Rapid, Efficient and Environmentally benign Synthetic Approach

Herein we report a rapid and straightforward approach for the synthesis of phenolic Schiff bases employing graphite, a versatile form of carbon, as an effective heterogeneous catalyst. The synthesis involved the reaction of differently substituted aromatic aldehydes with o-amino phenol in ethanol solvent under reflux conditions, utilizing a catalytic amount of readily available graphite powder. This environmentally benign procedure offers several notable advantages including high product yields, the accessibility of the catalyst, simplified workup processes, short reaction times and advantages of recycling. Exploring the use of graphite as a catalyst in organic synthesis reveals its potential as an efficient and sustainable alternative. The method's simplicity and efficiency make it a promising pathway for the preparation of phenolic Schiff bases, showcasing the versatility and applicability of graphite in catalytic processes.

Selective Native N(in)-H Bond Activation in Peptides with Metallaphotocatalysis.

The development of chemical methods enabling site-selective incorporation of noncanonical amino acids into peptide backbones with precise functional tailoring remains a critical challenge. Particularly compelling is the use of underexplored endogenous amino acid hotspots, such as the N (in) of tryptophan, as versatile anchors for diversification. Herein, we report a chemoselective N(sp2)-H bond activation strategy targeting native tryptophan residues within peptide frameworks, exemplified by GLP-1 (7-37), using nickel metallaphotocatalysis under postsynthetic solid-phase conditions. This selective N (in)-arylation reaction proceeds efficiently within 3 h of light irradiation in highly functionalized heterogeneous environments, employing minimal excesses of electrophile and base, alongside catalytic quantities of nickel, ligand, and photocatalyst. The method affords homogeneous peptide products with high chemoselectivity and operational simplicity. We envision that this strategy could contribute to advancing the design of the next-generation long-acting class II G protein-coupled receptor agonist therapeutics.

Catalytic allylation of native hexoses and pentoses in water with indium.

Carbohydrates are an abundant, inexpensive and renewable biomass feedstock that could be a cornerstone for sustainable chemical manufacturing, but scalable and environmentally friendly methods that leverage these feedstocks are lacking. For example, 1-allyl sorbitol is the foundational building block for the polypropylene clarifying agent Millad NX 8000, which is produced on themulti-metricton scale annually, but the manufacturing process at present requires superstoichiometric amounts of tin1,2. The NX 8000 additives dominate about 80% of the global clarified polypropylene market3 and are used in concentrations of 0.01-1% during polypropylene production to improve its transparency and resistance to high temperatures, translatingto 300-30,000 metrictons annually. The market volume of polypropylene in 2022 was approximately 79.01 million metric tons (MMT), with demand expected to rise by nearly 33% to 105 MMT by 2030 (ref. 4). The cost and sustainability benefits of clarified polypropylene are driving this demand, necessitating more clarifying agents5. Here we report a high-yielding allylation of unprotected carbohydrates in water using a catalytic amount of indium metal and either allylboronic acid or the pinacol ester (allylBpin) as donors. Aldohexoses, aminohexoses, ketohexoses and aldopentoses are all allylated in high yield under mild conditions and the indium metal is recoverable and reusable with no loss of catalytic activity. Leveraging these features, this process was translated to a scalable continuous synthesis of 1-allyl sorbitol in flow6 with high yield and productivity through Bayesian optimization of reaction parameters.