Cyclization Research Articles

Microwave-assisted safe and efficient synthesis of α-ketothioesters from acetylenic sulfones and DMSO

ABSTRACT α-Ketothioesters are safely and efficiently synthesized from arylacetylenic sulfones and dimethyl sulfoxide (DMSO) in the presence of equivalent of water and catalytic amount of 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) under microwave irradiation. Arylacetylenic sulfones and dimethyl sulfoxide first form arenecarbonyl sulfonyl dimethylsulfonium methylides via nucleophilic addition, ring closure, and 4e ring opening. The methylides undergo a radical process to generate α-methylthio-α-sulfonylacetophenones, which further convert to α-ketothioesters through the Pummerer oxidation. Compared to the previous methods, the current method is safer and more efficient.

Radical Redox Annulations: A General Light-Driven Method for the Synthesis of Saturated Heterocycles.

We introduce here a two-component annulation strategy that provides access to a diverse collection of five- and six-membered saturated heterocycles from aryl alkenes and a family of redox-active radical precursors bearing tethered nucleophiles. This transformation is mediated by a combination of an Ir(III) photocatalyst and a Brønsted acid under visible-light irradiation. A reductive proton-coupled electron transfer generates a reactive radical which undergoes addition to an alkene. Then, an oxidative radical-polar crossover step leading to carbocation formation is followed by ring closure through cyclization of the tethered nucleophile. A wide range of heterocycles are easily accessible, including pyrrolidines, piperidines, tetrahydrofurans, morpholines, δ-valerolactones, and dioxanones. We demonstrate the scope of this approach through broad structural variation of both reaction components. This method is amenable to gram-scale preparation and to complex fragment coupling.

Ring closure outcome for laparoscopic ventral hernia repair (IPOM plus) in medium and large defects. Long-term follow-up.

Despite advances in laparoscopic ventral hernia repair (LVHR) with the Intra-peritoneal onlay mesh technique (IPOM), recurrence continues to be a frequent postoperative complication. The aim of this study is to analyze the long-term recurrence rate in two series, by incorporating in IPOM technique the laparoscopic closure of the defect (IPOM plus). We also want to determine the ring size cut-off point from which the recurrence risk increases in IPOM technique and determine if the cut-off point is modified with IPOM plus technique. A comparative retrospective study was conducted analyzing patients who underwent LVHR. They were divided into 2 groups according to the surgical technique used: IPOM or IPOM plus. We determined in each group the cut-off point where the ring size presents a greater recurrence risk by calculating the better point of sensitivity/specificity relationship of the ROC curve. Between 2007 and 2018, 286 patients underwent LVHR. The ROC curve for IPOM technique has shown a cut-off point of higher recurrence risk for rings larger than 63 cm2. While the ROC curve in IPOM plus group showed an increase in the cut-off point, with a higher recurrence risk in rings > 168cm2. Overall median ring size was 30 cm2 (range 4-225; IQR 16-61). However, when comparing the ring size between techniques we found a relatively larger size in IPOM plus (p: 0.013). The recurrence rate in the IPOM group was 19.51% while in the IPOM plus group was 3.57% (p: 0.005). For standard LVHR with IPOM technique, the greatest recurrence risk occurs in rings larger than 63cm2. The addition of ring closure (IPOM plus) was associated with a recurrence risk reduction, which occurs in rings larger than 168cm2. These findings would allow expanding the indication for LVHR, using the IPOM plus technique.

Ammonium Ferrate‐Catalyzed Cycloaddition of CO2 to Aziridines for the Synthesis of 1,3‐Oxazolidin‐2‐ones

AbstractSimple ammonium ferrates are competent catalysts for the CO2 coupling with aziridines to yield 5‐substituted 1,3‐oxazolidin‐2‐ones. Good yields with remarkable selectivity are obtained under mild reaction conditions, room temperature, and atmospheric CO2 pressure, especially for non‐hindered N‐alkyl, N‐benzyl and N‐allyl aziridines, without the need of any co‐catalyst. To shed light on the reaction mechanism, an extensive set of theoretical calculations has been carried out. A viable reaction mechanism involving just one ferrate molecule and where the rate determining step is the 1,3‐oxazolidin‐2‐one ring closure has been found, and the corresponding barrier is compatible with the experimental conditions tested in this study.

Synthesis and Antimicrobial activity of 1-(3-amino-5-chloro-2, 3-dihydro-1-benzofuran-2-yl) ethan-1-one [2, 1-b]-furan and their derivatives

The current study is focused on the conversion of 2- chlorosalicylaldehyde into its oxime which was then converted into 5-chloro-2-hydroxy-benzonitrile 1, a key starting material for the present synthetic work. The nitrile 1 on reaction with chloroacetone/phenacyl bromide/4-chlorophenacyl bromide in anhydrous acetone and potassium carbonate gave 2-acyl-3- amino-5-chlorobenzofuran (2a-c). Acetylation of compounds 2a-c furnishes 2-acyl-3acetamido-5- chlorobenzofuran (3a-c). Compounds 3a-c on further treatment with hydrazine hydrate undergo ring closure producing 3-amino-8- chloro-2, 4-dimethyl-3, 4-dihydro [1] benzofuran [3, 2- d] pyrimidin-4-ol (4a-c). The synthesised compounds were characterised by spectral and analytical data and screened for antibacterial and antifungal activity.

Lignin-based benzoxazines: A tunable key-precursor for the design of hydrophobic coatings, fire resistant materials and catalyst-free vitrimers

The meaningful concept of circular economy has prompted the scientific community to re-think the design of materials. In this work, lignin-based benzoxazines (LBZs) thermosets with tuneable properties were synthesized in agreement with the principles of Green Chemistry, following a straightforward two-step synthetic route. The reactivity of a soda lignin was enhanced by its esterification with phloretic acid, a naturally occurring phenolic acid. Thereafter, the resulting structure enriched in phenolic rings with no ortho substituents, was used to prepare LBZs precursors with a bio-based primary amine via a Mannich-like ring-closure reaction. The structure and properties of each LBZ precursor were confirmed by multiple NMR techniques, Fourier transform infrared spectroscopy, elemental analysis, gel permeation chromatography, differential scanning calorimetry, rheology, and solubility assays. Lignin-based polybenzoxazine with high lignin mass fraction (between 46 and 66 wt.%) were obtained following curing via a vacuum compression molding manufacture process. Lignin-based thermosets exhibit a single-phase confirmed by X-ray computed tomography analysis, a Tg ranging from 136 to 197 °C, and storage moduli from 0.5 to 3.1 GPa. The features of each lignin-based precursor were tuned depending on the structure of the bio-based primary amine used to close the oxazine ring. Stearylamine confers good processability and yields hydrophobic coatings with a water contact angle reaching 91°. Furfurylamine-based LBZs generate high-Tg (197 °C) and fire-resistant materials with a peak of heat release rate of no>47 W.g−1. Finally, ethanolamine produces lignin-based thermosets capable of internally catalysed bond exchange via transesterification, providing vitrimeric properties such as fast stress relaxation (τ*200 °C = 233 s) and a complete circularity.

The Dark Side of Cannabidiol: The Unanticipated Social and Clinical Implications of Synthetic Δ8-THC.

Introduction: The explosive growth of the cannabis industry in the United States over the past decade has spurred a multitude of products derived from phytocannabinoids produced by Cannabis sativa L. Decades of cannabis prohibition coupled with the more recent 2018 Farm Bill have lead to several unanticipated consequences and the widespread availability of synthetic cannabinoids derived from hemp CBD, including Δ8-THC, Δ10-THC and HHC. Methods: Herein, we review the available literature of the complexity of the chemistry of its current manufacture, namely, the acid-catalyzed ring closure of cannabidiol (ACRCC), the myriad of issues involving the unsolved technical problems with quality control of ACRCC-Δ8-THC and the multitude of isomerized byproducts, and the lack of consistent regulation regarding consumer safety and labeling. Results: We provide what we believe is the first comprehensive listing of all the documented ACRCC-Δ8-THC byproducts. Perhaps, most importantly, we highlight the growing concern that, other than Δ8-THC itself, the compounds in ACRCC-Δ8-THC product mixtures have not been subjected to any human toxicological evaluation. This is especially troubling as ACRCC-Δ8-THC products relate to vaping, and their contribution to a growing and lethal epidemic of electronic cigarette, or vaping, product use-associated lung injury (EVALI). Conclusions: Quality control is totally inadequate in the newly emerging Δ8-THC industry. American consumers are ingesting products that are mislabeled with many compounds that have never received any toxicological testing. EVALI cases continue to be reported with a fatality rate approaching 2% (in California).

Domino Aza-Michael-SNAr-Heteroaromatization Route to C5-Substituted 1-Alkyl-1H-Indole-3-Carboxylic Esters.

A new synthesis of C5-substituted 1-alkyl-1H-indole-3-carboxylic esters is reported. A series of methyl 2-arylacrylate aza-Michael acceptors were prepared with aromatic substitution to activate them towards SNAr reaction. Subsequent reaction with a series of primary amines generated the title compounds. Initially, the sequence was expected to produce indoline products, but oxidative heteroaromatization intervened to generate the indoles. The reaction proceeded under anhydrous conditions in DMF at 23–90 °C using equimolar quantities of the acrylate and the amine with 2 equiv. of K2CO3 to give 61–92% of the indole products. The reaction involves an aza-Michael addition, followed by SNAr ring closure and heteroaromatization. Since the reactions were run under nitrogen, the final oxidation to the indole likely results from reaction with dissolved oxygen in the DMF. Substrates incorporating a 2-arylacrylonitrile proved too reactive to prepare using our protocol. The synthesis of the reaction substrates, their relative reactivities, and mechanistic details of the conversion are discussed.

Synthesis of Dehydromuscone by an Alkene Metathesis Macrocyclization Reaction at 0.2 M Concentration

AbstractThe industrial fragrance compound dehydromuscone was synthesized in five linear steps and 19% overall yield. The synthesis features a highly efficient nondiluted ring-closing metathesis macrocyclization reaction as a key step that proceeds at a 0.2 M concentration in the presence of 0.1 mol% Nitro-Grela catalyst. The synthesis employs commercially available linear starting materials and is shorter by at least two steps than the current industrial synthesis route.

Model for ring closure in ER tubular network dynamics

Tubular networks of the endoplasmic reticulum (ER) are dynamic structures whose steady-state conformations are maintained by a balance between the persistent generation and vanishing of the network elements. While factors producing the ER tubules and intertubular junctions have been investigated, the mechanisms behind their elimination remained unknown. Here, we addressed the ER ring closure, the process resulting in the tubule and junction removal through constriction of the network unit cells into junctional knots followed by the knot remodeling into regular junctions. We considered the ring closure to be driven by the tension existing in ER membranes. We based our consideration on the notion of Gibbs’ thermodynamic tension and reviewed its relationship to other tension definitions used in the literature. We modeled, computationally, the structures of the junctional knots containing internal nanopores and analyzed their tension dependence. We analyzed the process of the pore sealing through membrane fission resulting in the formation of regular junctions. Considering the hemi-fission as the rate-limiting stage of the fission reaction, we evaluated the membrane tensions guaranteeing the spontaneous character of the pore sealing. We concluded that feasible membrane tensions explain all stages of the ER ring closure.

Synthesis ofC2‐Formamide(thiophene)pyrazolyl‐C4’‐carbaldehyde and their Transformation to Schiff's Bases and Stereoselectivetrans‐β‐Lactams: Mechanistic and Theoretical Insights

AbstractHerein, we describe synthesis of functionalized thiophenyl acetyl‐hydrazones using acetyl‐thiophene derivative as precursor which further underwent Vilsmeier‐Haack reaction in an unexpected manner, providing three‐carbon atoms to the molecular framework. The mechanistic view explained formation ofC2‐formamide(thiophene)pyrazolyl‐C4’‐carbaldehyde by three consecutive actions in single‐pot: 1) nucleophilic amino toC2‐iminium ion generation, 2) cyclization to pyrazole ring and 3) nucleophilic attack by pyrazole toC4’‐iminium ion which finally leads to dual formylation in the system. This product burst to primary amines to synthesize highly substitutedC2‐formamide(thiophene)pyrazolyl‐C4’‐Schiff's bases. Further, the reactivity of synthesized Schiff's bases underwent metal‐free ring closure with diverse heteroatomic ketene sources which exposed the emergence of stereoselectivetrans‐β‐lactams. The broad functional groups encircled monocyclic β‐lactams were achieved in moderate to excellent yields under gentle conditions. Additionally, theoretical calculations on B3LYP/6‐31G(d,p) level of some representative compounds are also investigated to support mechanistic explanation with their stabilized structures and physical properties.

Theoretical study on the mechanism and kinetics of the oxidation of allyl radical with atomic and molecular oxygen

The C3H5O and C3H5O2 potential energy surfaces accessed by the oxidation reactions of allyl radical with atomic and molecular oxygen have been mapped out at the CCSD(T)-F12b/cc-pVTZ-F12//ωB97XD/6-311G(d,p) level of electronic structure theory to unravel the reaction mechanism. Temperature- and pressure-dependent reaction rate constants have been evaluated using variable reaction coordinate transition state and RRKM-Master Equation theoretical kinetics methods. The C3H5 + O reaction is found to be fast in the 300-2500 K temperature interval, with the total rate constant of 1.8-1.0 × 10−10 cm3 molecules s−1 independent of pressure in the considered 30 Torr – 100 atm range. Acrolein + H formed by a simple O addition/H elimination mechanism via the CH2CHCH2O association complex are predicted to be the major reaction products with the branching ratio decreasing from 61% at 300 K to 44% at 2500 K. Other substantial bimolecular products include C2H3 + formaldehyde (32%-26%) formed through the C-C bond β-scission in CH2CHCH2O and two minor products C2H4 + formyl radical HCO and allene + OH, where the latter, formed via direct H abstraction by O from the central carbon atom of allyl, becomes significant only at high temperatures above ∼1500 K. The C3H5 + O2 reaction studied in the 200-2500 K temperature range shows a peculiar kinetic behavior characteristic for a bimolecular reaction with a low entrance barrier, shallow association well, and high ensuing isomerization and decomposition barriers to bimolecular products. This behavior is described in terms of three distinct temperature regimes: the low-temperature one with slightly negative dependence of the rate constant, the intermediate one where the rate constant sharply drops, and the high-temperature regime with an Arrhenius-like rate constant. The rate constant is relatively high (10−13-10−12 cm3 molecule−1 s−1) in the low-temperature regime when the reaction produces the peroxy association complex CH2CHCH2OO, but slow at higher temperatures when it leads to bimolecular products. Under combustion relevant conditions, the C3H5 + O2 rate constant is by 5 to 3 orders of magnitude lower than that for C3H5 + O, but since O2 concentrations in flames could be as much as 3 orders of magnitude larger than O concentrations, C3H5 + O2 cannot be ruled out as a significant allyl radical sink. Above 1500 K, the C3H5 + O2 reaction can form vinoxy radical + formaldehyde (40%-15%) via the five- or four-membered ring closure and opening mechanism starting from the initial peroxy intermediate, acrolein + OH (41%-49%) via the H shift from the attacked carbon to the terminal oxygen followed by the immediate O-O bond cleavage, and allene + OH (18-25%) via the H migration from the central CH group to the terminal O atom accompanied or followed by the C-O bond rupture. Modified Arrhenius expressions fitting the computed rate constants for both reactions have been generated and proposed for kinetic models.

Design, Synthesis, and Characterization of Stapled Oligosaccharides.

Stapling short peptides to lock specific conformations and thereby obtain superior pharmacological properties is well established. However, similar concepts have not been applied to oligosaccharides. Here, we describe the design, synthesis, and characterization of the first stapled oligosaccharides. Automated assembly of β-(1,6)-glucans equipped with two alkenyl side chains was followed by on-resin Grubbs metathesis for efficient ring closure with a variety of cross-linkers of different sizes. Oligosaccharide stapling increases enzymatic stability and cell penetration, therefore opening new opportunities for the use of glycans in medicinal chemistry.

Ruthenium-Locked Helical Chirality: A Barrier of Inversion and Formation of an Asymmetric Macrocycle.

Upon coordination to metal centers, tetradentate ligands based on the 6,6′-bis(2″-aminopyridyl)-2,2′-bipyridine (bapbpy) structure form helical chiral complexes due to the steric clash between the terminal pyridines of the ligand. For octahedral ruthenium(II) complexes, the two additional axial ligands bound to the metal center, when different, generate diastereotopic aromatic protons that can be distinguished by NMR. Based on these geometrical features, the inversion barrier of helical [RuII(L)(RR′SO)Cl]+ complexes, where L is a sterically hindered bapbpy derivative and RR′SO is a chiral or achiral sulfoxide ligand, was studied by variable-temperature 1H NMR. The coalescence energies for the inversion of the helical chirality of [Ru(bapbpy)(DMSO)(Cl)]Cl and [Ru(bapbpy)(MTSO)(Cl)]Cl (where MTSO is (R)-methyl p-tolylsulfoxide) were found to be 43 and 44 kJ/mol, respectively. By contrast, in [Ru(biqbpy)(DMSO)(Cl)]Cl (biqbpy = 6,6′-bis(aminoquinolyl)-2,2′-bipyridine), increased strain caused by the larger terminal quinoline groups resulted in a coalescence temperature higher than 376 K, which pointed to an absence of helical chirality inversion at room temperature. Further increasing the steric strain by introducing methoxy groups ortho to the nitrogen atoms of the terminal pyridyl groups in bapbpy resulted in the serendipitous discovery of a ring-closing reaction that took place upon trying to make [Ru(OMe-bapbpy)(DMSO)Cl]+ (OMe-bapbpy = 6,6′-bis(6-methoxy-aminopyridyl)-2,2′-bipyridine). This reaction generated, in excellent yields, a chiral complex [Ru(L″)(DMSO)Cl]Cl, where L″ is an asymmetric tetrapyridyl macrocycle. This unexpected transformation appears to be specific to ruthenium(II) as macrocyclization did not occur upon coordination of the same ligand to palladium(II) or rhodium(III).

Toward Homogeneous Brønsted-Acid-Catalyzed Intramolecular Carbonyl-Olefin Metathesis Reactions.

The carbonyl-olefin metathesis (COM) reaction is an attractive approach for the formation of a new carbon-carbon double bond from a carbonyl precursor. In principle, this reaction can be promoted by the activation of the carbonyl group with a Brønsted acid catalyst; however, it is often complicated as a result of unwanted side reactions under acidic conditions. Thus, there have been only a very few examples of Brønsted-acid-catalyzed COM reactions, all of which required specially designed setups. Herein, we report a new practical homogeneous Brønsted-acid-catalyzed protocol using nitromethane, a readily available solvent, to promote intramolecular ring-closing COM reactions.

Structural and Electronic Effects on Phosphine Chalcogenide Stabilized Silicon Centers in Four-Membered Heterocyclic Cations.

Understanding the interplay of structural and electronic parameters in the stabilization of Lewis acidic silicon centers is crucial for stereochemical questions and applications in bond activation and catalytic transformations. Phosphine chalcogenide functionalized (Ch = O, S, and Se) hydrosilanes having tert-butyl and 2,4,6-trimethoxyphenyl (TMP) substituents on the silicon atom were synthesized, and the ring-closing reactions to afford the heterocyclic four-membered CPChSi cations were investigated. Synthetic access was only achieved for the sulfur- and selenium-based cations. A thorough study by means of single-crystal X-ray structure determination, NMR spectroscopic data, and density functional theory (DFT) calculations provided insight into important electronic and structural parameters affecting the stability of the intramolecularly stabilized cations. Detailed structural considerations were made on the contributions to the ring strain (angular strain and steric repulsion). Thermochemical investigations showed that the substituents on the silicon and phosphorus atoms play an important role for the stability of the cationic heterocycles. In the absence of large steric repulsions through bulky substituents (methyl groups on silicon and tert-butyl groups on phosphorus), an intrinsic stability sequence of the intramolecular Ch-Si coordination depending on the chalcogen atom in the direction Se ≤ S < O can be observed. However, the order is reversed (O < S < Se) in the case of strong repulsions between sterically demanding substituents (tert-butyl groups on both silicon and phosphorus atoms). Natural bond orbital (NBO) analysis supported the explanations for the observed deshielding trends in 31P NMR spectroscopy and revealed that the O-Si bond is more ionic in nature compared to the S-Si and Se-Si bonds, with the latter exhibiting higher covalent character due to a more efficient charge transfer through a σ-type nCh → pSi interaction.

Effect of Molecular Structure of Photoswitchable Surfactant on Light-Responsive Shape Transition of Block Copolymer Particles

Photoactive shape-changing particles offer a promising platform for smart materials with tunable properties at high spatiotemporal resolutions. Herein, a series of spiropyran-based surfactants with different alkyl spacer lengths are developed to achieve photoactive, shape-changing particles through confined self-assembly of polystyrene-block-poly(4-vinylpyridine) (PS-b-P4VP) within an evaporative emulsion. The length of the alkyl chain spacer between the spiropyran headgroup and ionic chain-end is modulated from hexyl to ethyl decanoate to provide surfactants with tunable amphiphilicity. Under UV light, the hydrophilic ring-opened merocyanine surfactants produce onion-like microspheres with a P4VP surface. Conversely, by exposure to visible light, the ring-closure reaction of the spiropyran moieties shifts their hydrophobicity and yields striped ellipsoids with axially stacked PS and P4VP blocks. This sphere-to-ellipsoid transition is observed only for surfactants that contain spacers longer than or equal to octyl. The effects of photoswitchable surfactants on their interfacial properties and corresponding morphological evolution of the particles are investigated to elucidate the mechanism of the shape transition of the photoactive particles.

Synthesis of 7-Arylpurines from Substituted Pyrimidines

AbstractA simple three-step approach for the synthesis of substituted N7-arylpurines with an overall yield of the whole sequence from 40% to 71% is described. N7-Arylpurines were constructed by de novo synthesis from commercially available substituted 4-chloropyrimidine-5-amines. Different substituents at purine C2 and C6 were obtained by changing the corresponding substituents of the starting pyrimidine. Further, heteroaromatic, electron-deficient, and electron-rich aromatic groups were attached to the exocyclic amino group by iodane reagents under copper catalysis. This moiety is prepared to become purine N7 position after the ring closure. Finally, purine C8 substitution was varied during the last step of the developed sequence by employing different reagents for the purine ring closing reactions or post functionalization.

Structures and Chemical Rearrangements of Benzoate Derivatives Following Gas Phase Decarboxylation.

Decarboxylation of carboxylate ions in the gas phase provides a useful window into the chemistry displayed by these reactive carbanion intermediates. Here, we explore the species generated by decarboxylation of two benzoate derivatives: 2-formylbenzoate (2FBA) and 2-benzoylbenzoate (2BBA). The nascent product anions are transferred to a cryogenic ion trap where they are cooled to ∼15 K and analyzed by their pattern of vibrational bands obtained with IR photodissociation spectroscopy of weakly bound H2 molecules. The structures of the quenched species are then determined by comparison of these spectra with those predicted by electronic structure calculations for local minima on the potential energy surface. The 2-phenide carbanion generated by decarboxylation of 2FBA occurs in two isomeric forms that differ in the orientation of the formyl group, both of which yield a very large (∼110 cm-1) redshift in the stretching frequency of the H2 molecule attached to the anionic carbon center. Although calculated to be a local minimum, the analogous 2-phenide species could not be isolated upon decarboxylation of 2BBA. Rather, the anionic product adopts a ring-closed structure, indicating efficient nucleophilic attack on the pendant phenyl group by the nascent phenide. The barrier for ring closing is evaluated with electronic structure calculations.

Stereoselective Synthesis and Application of Gibberellic Acid-Derived Aminodiols.

A series of gibberellic acid-based aminodiols was designed and synthesized from commercially available gibberellic acid. Exposure of gibberellic acid to hydrochloric acid under reflux conditions resulted in aromatization followed by rearrangement to form allo-gibberic acid. The key intermediate, ethyl allo-gibberate, was prepared according to literature methods. Epoxidation of key intermediate and subsequent ring-opening of the corresponding epoxide with different nucleophiles resulted in N-substituted aminodiols. The regioselective ring closure of N-benzyl-substituted aminodiol with formaldehyde was also investigated. All aminodiol derivatives were well characterized using modern spectroscopic techniques and evaluated for their antiproliferative activity against a panel of human cancer cell lines. In addition, structure–activity relationships were examined by assessing substituent effects on the aminodiol systems. The results indicated that aminodiols containing aromatic rings on their nitrogen substituents displayed significant cytotoxic effects. Among these agents, N-naphthylmethyl-substituted aminodiols were found to be the most potent candidates in this series. One of these molecules exhibited a modest cancer selectivity determined by non-cancerous fibroblast cells. A docking study was also made to exploit the observed results.