Ketene Dithioacetals Research Articles

Design, Synthesis and Computational Insight of Isolated and Thiophene fused 2H‐Pyran‐2‐ones as PPAR‐γ Agonist

AbstractPeroxisome proliferator‐activated receptor gamma (PPAR‐γ) is a well‐known member of the PPAR family and a potential target for the treatment of various disorders. Herein, we present the design and synthesis of various 6‐aryl‐4‐sec.amino‐2‐oxo‐2H‐pyran‐3‐carbonitrile derivatives and functionalized thieno[3,2‐c]pyran‐2‐ones, derived from ketene dithioacetal. Then all the synthesized compounds were docked for their activity as PPAR‐γ to predict the binding mechanism and affinities regarding rosiglitazone and muraglitazar. Our studies revealed that three compounds 10 e, 10 f, and 10 h showed significant binding affinities, with energy ranges comparable to standard drugs rosiglitazone and muraglitazar. The docking conformation studies revealed that the selected compounds nicely interact with PPAR‐γ in the ligand binding domain with positive predictive values. We also performed molecular dynamics of the most potent compounds to validate the result. Our results indicate that these novel compounds are potential PPAR‐γ ligands, offering new possibilities for therapeutic applications. This study underscores the potential of these synthesized compounds in the development of novel PPAR‐γ agonists.

Role of Cyclic Ketene Dithioacetals in Free Radical Polymerization of Vinyl Chloride

AbstractThe role of the sulfur analog of cyclic ketene acetals in the synthesis of polyvinyl chloride is examined in this study. In this context, whether 2‐methylene‐1,3‐dithiolane (S‐CKA5), 2‐methylene‐1,3‐dithione (S‐CKA6), and 2‐methylene‐1,3‐dithiepane (S‐CKA7) monomers are involved in the radical polymerization of vinyl chloride through the ring opening reaction is examined by quantum chemical methods. In light of calculations at the M06‐2X/6‐31+G(d) level, it is concluded that, in general, S‐CKAs undergo little or no ring‐opening and form block copolymers, mainly with the homopolymerization of S‐CKAs and their ring‐retaining step. It is determined that S‐CKA7 is the most prone to ring‐opening reaction and inserting dithioate links to the polymer backbone. However, the radical ring‐opening of S‐CKA7 is strongly reversible, as in other S‐CKAs.

Transition-Metal-Free Approach for the Synthesis of N-Arylated Piperidones and their Ketals from Ketene Dithioacetals

AbstractN-Arylated piperidones are present as pharmacophores in many pharmaceuticals and serve as useful precursors for the construction of important new molecules. We have developed a transition-metal-free, cost-effective, and mild approach for the synthesis of N-(hetero)arylated piperidones and their ketals by using ketals of piperidones and 2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles as precursors. The desired products were obtained in two steps: amination of the 2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitrile from piperidone, followed by ring transformation using a suitable nucleophile source. We have successfully tethered functionalized dihydrophenanthrenes, hydrobenzo[c]phenanthrenes, and benzoquinolines to piperidinone moieties under transition-metal-free conditions.

Ultrasound promoted synthesis of 2-methylthio-3H-1,5-benzodiazepines using CaFe2O4 NPs as heterogeneous catalyst and their in-vitro experimental and theoretical studies as antifungal agents

In the current study, we have developed an efficient and simple ultrasound-promoted protocol for synthesizing 2-methylthio-3H-1,5-benzodiazepine derivatives from α-oxo ketene dithioacetals using reusable CaFe2O4 nanoparticles as heterogeneous catalysts. The use of CaFe2O4 nanoparticles as catalyst under ultrasonic irradiation gave better yields in shorter reaction times in comparison to our previous synthetic strategy which used basic alumina as a solid support. The nanocatalyst was found to be applicable to diverse aromatic/heteroaromatic and cyclic ketones. In addition, the quantum mechanical calculations (DFT studies) of all the derivatives were carried out using Spartan software to determine the geometry and physiochemical properties of the derivatives and the molecular docking studies of all the optimized derivatives using Autodock Vina and Discovery Studio software to check their efficacy as antifungal agents. Based on the best docking results, In-vitro experimental studies of BDZ-13 and BDZ-19 were carried out to test their efficacy as antifungal agents.

Synthesis of Functionalized Furans: Three‐Component Reactions Involving Ketene Dithioacetals, Acetylenes, and Phosphines to Generate Phosphorus Ylides or N‐Acyliminophosphoranes

AbstractSynthesis of new polysubstituted furans incorporating reactive phosphorus ylides or N‐acyliminophosphoranes was achieved by the heterocyclization of flexible α‐acyl ketene dithioacetals. This one‐pot tandem reaction was initiated by acyl‐directed desulfurative Sonogashira coupling, followed by 1,6‐addition of phosphine to the in situ‐generated enynone and subsequent 5‐exo‐dig cyclization, as well as phosphoranation. The selectivity toward the two products, i. e. α‐phosphorus ylides vs. α‐N‐acyliminophosphoranes‐substituted furans, was determined by both electron‐deficient acetylenes and copper salts.

Synthesis and cytotoxic evaluation of heterocyclic compounds by vinylic substitution of ketene dithioacetals.

N-heterocyclic compounds are important molecular scaffolds in the search for new drugs, since most drugs contain heterocyclic moieties in their molecular structure, and some of these classes of heterocycles are able to provide ligands for two or more biological targets. Ketene dithioacetals are important building blocks in organic synthesis and are widely used in the synthesis of N-heterocyclic compounds. In this work, we used double vinylic substitution reactions on ketene dithioacetals to synthesize a small library of heterocyclic derivatives and evaluated their cytotoxic activity in breast and ovarian cancer cells, identifying two benzoxazoles with good potency and selectivity. In silico predictions indicate that the two most active derivatives exhibit physicochemical properties within the range of drug-like compounds and showed potential to interact with HDAC8 and ERK1 cancer-related targets.

Electrochemical Oxidative Cross-Coupling Reactions of Ketene Dithioacetals and Dichalcogenides to Construct C−Se/C−S Bonds

A green protocol for construction of C−Se bonds from ketene dithioacetals and diselenides through direct electrochemical oxidative cross-coupling has been developed. This reaction was carried out in an undivided cell system with NaBF4 as the electrolyte and CH3CN as the solvent through galvanostatic electrolysis. A series of substituted ketene dithioacetals and diselenides were tolerant and the desired tetrasubstituted alkenyl selenides were obtained in moderate to excellent yields. In addition, construction of C−S bond from ketene dithioacetals and disulfides through electrochemical method in the presence of KI was also successfully realized. It exhibited high efficiency and broad functional group tolerance.

In the pursuit of novel therapeutic agents: synthesis, anticancer evaluation, and physicochemical insights of novel pyrimidine-based 2-aminobenzothiazole derivatives.

Cancer remains a worldwide healthcare undertaking, demanding continual innovation in anticancer drug development due to frequent drug resistance and adverse effects associated with existing therapies. The benzothiazole compounds, particularly 2-aminobenzothiazole derivatives, have attracted interest for their versatility in generating novel anticancer agents. This study explores the synthesis, and anticancer evaluation of new pyrimidine-based 2-aminobenzothiazole derivatives. A range of synthetic methods have been developed based on the reaction of 2-benzothaizolyl guanidine with various reagents such as α,β-unsaturated carbonyl, 2-cyano-three-(dimethylamino)-N-acrylamide, β-diketones, β-keto esters, and S,S ketene dithioacetals. Human tumour cell lines such as HepG2, HCT116, and MCF7 were used in in vitro cytotoxicity studies, and the results showed that several of the synthesized compounds were more potent than the standard drug, 5-fluorouracil, in terms of cell viability% with low IC50. Furthermore, the computed drug likeness and ADMET properties of the most potent synthesized compounds suggest their potential as promising candidates for further development, with favorable bioavailability and pharmacokinetic profiles.

Photoinduced regioselective trifluoroalkylation of ketene dithioacetals with CF3SO2Na

A regioselective hydro trifluoromethylation of ketene dithioacetals with CF3SO2Na was achieved via a visible-light promoted radical-polar process under mild and operationally simple conditions, using an inexpensive organic photocatalyst.

Visible-Light-Promoted Regioselective Hydroborylation of Ketene Dithioacetals with NHC-Boranes.

NHC-boranes have been treated as a reliable source of boryl radicals. In this study, regioselective hydroborylation of ketene dithioacetals with NHC-borane was achieved under mild conditions via a visible-light-promoted radical chain process using thiophenol as a proton donor and hydrogen atom transfer. This protocol features a low-cost catalyst, good functional group tolerance, a relatively broad range of substrate scope, and good to excellent yields. Moreover, mechanism of this hydroborylation reaction was preliminarily studied.

One‐Pot Synthesis of β‐Ketoesters from Aryl Methyl Ketone via Ketene Dithioacetal

AbstractWe have discovered base‐mediated conversion of 3,3‐bis(methylthio)‐1‐arylprop‐2‐en‐1‐ones to versatile active methylene compounds (β‐keto esters). A series of products were isolated and characterized as a mixture of keto‐enol form. We have modified the method and synthesized the active methylene compounds (β‐keto esters) directly from aryl methyl ketone via ketene dithioacetal intermediate (not isolated) by stepwise reactions in one pot. Most of the one‐pot reactions also provided excellent yields. In addition to aryl methyl ketones, we also tested cyclopropyl methyl ketone as a source of an aliphatic ketone, and under similar reaction conditions, ethyl 3‐cyclopropyl‐3‐oxopropanoate was afforded.

Acyl-Ethynylbenziodoxolone (acyl-EBX): Access to Ketene Dithioarylacetals.

We report the synthesis of ketene dithioarylacetals in 40-97% yield using thiophenols and acyl-EBXs (ethynylbenziodoxolones) generated in situ from a common hypervalent iodine precursor and alkynyl trifluoroborate salts. The products could be further modified to afford functionalized ketene dithioacetals and various S-substituted heterocycles.

Synthesis of Furfural Sulfides and 4‐Alkylthiopyridines via Heterocyclization of α‐Acyl Ketene Dithioacetals

AbstractHerein, we devised a synthetic approach for skeletally diversified furfuryl sulfides and 4‐alkylthiopyridines involving the heterocyclization of flexible α‐acyl ketene dithioacetals, enabled by cooperative Pd/Cu catalysis. The overall transformation was initiated by acyl‐directed desulfurative Sonogashira coupling, which was proposed as the key step in surmounting the competitive carbothiolation pathway. This step was followed by 1,6‐addition of either a S‐ or N‐nucleophile and intramolecular cyclization. Notably, the two different annulation reactions featured readily accessible starting materials, selective cleavage and reassembly of multiple chemical bonds, broad functional group tolerance, pharmacologically significant heterocyclic products with high regio‐ and chemoselectivities, and high atom economy.

Michael Addition and Oxidative Cross‐Coupling Reaction of α‐Oxo Ketene Dithioacetals and Maleimides: Switchable Synthesis of 3‐Alkenyl Succinimides and Maleimides

AbstractSwitchable synthesis of 3‐alkenyl succinimides and maleimides has been achieved via Michael addition and oxidative cross‐coupling reaction of α‐oxo ketene dithioacetals and maleimides by switching different reaction conditions. In the presence of 30 mol% of CH3SO3H in DCE at 120 °C, Michael addition reaction of α‐oxo ketene dithioacetals and maleimides occurred to afford 3‐alkenyl succinimides in 40–90% yields, whereas in the presence of 30 mol% of Pd(OAc)2 in DMF at 20 °C, 3‐alkenyl maleimides were obtained in 40–80% yields from the oxidative cross‐coupling reaction of α‐oxo ketene dithioacetals with maleimides. The presupposition of directing groups onto the substrates is not required in the Michael addition reaction. The method can be extended to gram scale.

Synthesis of 3,6-substituted 2-methylthio-4-pyrones by acylation of ketene dithioacetals via soft enolization

The tandem acylation-heterocyclization of ketene dithioacetals was performed via soft enolization in MgBr2·OEt2/NEt3 system. A series of 3,6-substituted 2-methylthio-4-pyrones were obtained with a wide functional group tolerance. The reaction showed a good scalability, and the isolation of the products was performed by crystallization without the use of chromatography. Some transformations of the obtained 2-methylthio-4-pyrones, including substitution of the SMe group with N-nucleophiles, have been demonstrated for the preparation of functionalized 4-pyrones as analogs of several bioactive molecules.

Zinc(II)-Catalyzed [2+2+1] Annulation of Internal Alkenes, Diazooxindoles, and Isocyanates to Access Spirooxindoles

Zinc(II)-catalyzed [2+2+1] annulation of internal alkenes, diazooxindoles, and isocyanates was successfully developed for the construction of multisubstituted spirooxindoles. This multicomponent transformation involves in situ generation of a sulfur-containing spirocyclic intermediate from the [4+1] annulation of diazooxindole to sulfonyl isocyanate, which subsequently reacts as a 1,3-dipole with the internal alkene, that is, α-oxo ketene dithioacetal, to furnish a formal [2+2+1] annulation in a one-pot manner. This synthetic protocol features a low-toxicity main group metal catalyst, readily available reagents, and ≤96% yields, offering an efficient route to multisubstituted spirooxindole derivatives.

Borane‐Catalyzed, HFIP‐Assisted Carbene Insertion into Internal Alkenyl C−H Bonds under Metal‐Free Conditions

AbstractCarbene insertion into the C(sp2)−H bonds of internal alkenes was enabled in air by HFIP (1,1,1,3,3,3‐hexafluoro‐2‐propanol) as both the mediator and solvent through its cooperation with borane B(C6F5)3 as the catalyst. 3‐Diazooxindoles and 3‐diazoindolin‐2‐imines were amenable to work as the carbene precursors, and α‐oxo ketene dithioacetals acted as the internal alkenes at ambient temperature. The present synthetic protocol features metal‐free conditions, diverse substituent tolerance, and 47–84% yields, offering an efficient route to 3‐vinylated oxindole and indole derivatives.magnified image

New Ketene Dithioacetals Generated from 2‐Nitroperchlorobutadiene and Investigation of Their Antibacterial, Antifungal, Anticonvulsant and Antidepressant Activities

The ketene dithioacetal 3 generated from 2-nitroperchlorobutadiene 1 reacted with various heterocyclic amines and aliphatic, aromatic and heterocyclic thiols to produce functionalized new ketene-N,S,S-acetals and S,S,S-acetals 4a-f, 5a-h as heterocyclic dithiolanes. They were separated/purified by chromatographic methods and their exact structure characterization were made clear by spectroscopic methods. These compounds synthesized could act as effective drugs for versatile activity. Evaluation of the antimicrobial effect of the obtained substances determined derivatives 4e and 5h, which have MIC=15.6 μg/mL for the test culture of Mycobacterium luteum bacteria closing to the control drug Vancomycin. The obtained compounds can be proposed as a promising synthetic objects for future molecular design to enhance the antimicrobial action. Ketene dithioacetals 3, 4a, 4b, 4e, 5g (50 mg/kg) exhibited antiseizure effect comparable with reference drug (valproic acid) on the model of pentylenetetrazole-induced convulsions after single oral administration both at 3 h and 24 h. Furthermore, tested dithioacetals possessed prolonged antidepressant activity in forced swim test (FST) considerable decreasing the duration of immobility time compared to reference drug amitriptyline. This is the first study of the investigation of anticonvulsant and antidepressant activities of ketene dithioacetals.

A Green and Base‐Free Arylation of Thiomethylated 2‐pyranones and Ketene Dithioacetals via Liebeskind‐Srogl Coupling in Water

AbstractA green and base‐free desulfitative coupling of different thioethers with aryl boronic acids in water. Various thiomethylated 2H‐pyran‐2‐ones, 2‐oxobenzo[h[chromones and α‐aroyl ketene‐dithioacetals were used as substrate to obtained arylated product in very good to excellent yield. Further utility of reaction was carried out by a one‐pot arylation followed by amination of α‐aroyl ketene dithioacetals for the synthesis of 3‐amino chalcones and diarylazoles. The structure of isolated product 4 a and 6 c were ascertained by spectroscopic and single crystal X‐ray diffraction analyses.

Tandem [3+1+1+1] Heterocyclization of α‐Acyl Ketene Dithioacetals with Ammonia and Methanol: Rapid Assembly of Polysubstituted Pyrimidines

AbstractA straightforward copper‐catalyzed aerobic cyclocondensation reaction of α‐acyl ketene dithioacetals with ammonium acetate and methanol was developed for synthesizing highly functionalized pyrimidines. This domino conversion relied on the dual activities of CuCl2, namely Lewis acid and dehydrogenation, which began with single C−S ammonolysis directed by an in situ generated imine, followed by cyclocondensation with aldehyde produced from alcohol and concomitant oxidative dehydrogenation under an oxygen atmosphere. Notably, readily accessible and flexible substrates, common chemical feedstock nitrogen and C1 sources, good functional group tolerance and procedural simplicity exhibit the efficiency and potential application of the new method.