Search Results (426)

Tetrahydrofuran scaffolds have found promising applications in both pharmaceutical chemistry and organic synthesis but remain underexplored owing to the challenges associated with their preparation. Herein, we have developed a robust synthetic strategy for the palladium-catalyzed cascade annulation reaction of buta-1,3-dienes with alkynols for the assembly of diverse 3-methylenetetrahydrofurans with excellent functional group compatibility and good regioselectivity. More importantly, this protocol features broad substrate scope, good functional group tolerance, and good step- and atom-economy. A diverse array of functional groups such as halogen atoms, aldehyde, nitro, ester, and several aromatic heterocycles were also nicely tolerated and provided the corresponding products in moderate to good yields. It is noteworthy that the practicability is further verified by gram-scale experiments and synthetic transformation to access organic functional molecules. Full article

The similar properties of the nitrogen atoms in azole ring complicate the regioselective N-functionalization of pyrazoles. This work demonstrates the role of the hydrazone substituent in the control of the alkylation selectivity of (trifluoromethyl)pyrazoles. Reaction conditions for the synthesis of 3- and 5-(trifluoromethyl)pyrazoles were developed, and all types of regioisomers formed under the alkylation of bis-pyrazolyl NH-ketazine were isolated. The structures of the synthesized compounds were confirmed by NMR spectroscopy and XRD data. Full article

An effective method for synthesizing dihalogenated derivatives of condensed benzimidazole diones with a nodal nitrogen atom has been developed. As a result, five new heterocyclic quinones were obtained, which differed in the structure of the heterocycle annelated to imidazole, as well as the nature and arrangement of halogen atoms. A comprehensive analysis of the anticancer potential of new heterocyclic quinones revealed pronounced cytotoxic activity of the molecules against tumor cells. Using in silico methods for predicting activity spectra, it was found that the synthesized compounds are capable of interacting with a number of key targets that play an important role in oncogenesis, with the highest probability of binding to STAT3, the central regulator of cell growth, proliferation and metabolism. Experimental studies have shown that, despite the lack of pronounced ability to induce apoptosis, these substances effectively inhibit the activity of allosteric glycolytic enzymes, disrupting metabolic adaptation and energy balance of tumor cells. The obtained results expand the understanding of the molecular basis of the antitumor action of heterocyclic compounds and lay a solid foundation for their use as promising modulators of tumor cell metabolism. Full article

The regioselectivity of the Claisen rearrangement with different meta-substituted and meta- and para-substituted allyl phenyl ethers was investigated. The main results were that in meta-substituted Claisen rearrangements the regioselectivity depends roughly on the electronic nature of the substituent, with electron-donating groups favoring migration further from the meta-substituent while electron-withdrawing groups favor migration towards the meta-substituent. Different para-substituents were tested with two meta-substituents, Me, and Cl. Most of the para-substituent tested had a clear effect on the product ratio, in all but one case enhancing the proportion of the major product favored by the meta-substituent. Population analysis was performed with Mulliken, Löwdin, Hirshfeld, and natural population analysis to analyze the influence of the substituents on the atomic charges on the reaction sites. It was observed that the atomic charge on the carbon that forms the major isomer is of higher negativity than the atomic charge on the carbon that forms the minor isomer. Full article

The reactivity and stereoselectivity in the inverse-electron-demand Diels–Alder reaction between 4-methoxycarbonyl-N-(phenylsulfonyl)-1-aza-1,3-butadiene and methoxyethene was examined using density functional theory (DFT) calculations at the M06-2X level. The formation of the two bonds in this reaction was calculated to be asynchronous. The formation of the C−C bond occurs first and is driven by electron delocalization from the dienophile to the diene, a process which simultaneously governs the regioselectivity. Moreover, the endo selectivity of the reaction was found to arise from non-bonding-orbital interactions, electrostatic attractions, and dispersion interactions. The sulfonyl group attached to the diene influences the selectivity and the reactivity. In contrast, when a methoxycarbonyl group is attached to the diene, it affects the selectivity in a different way depending on the position where it is attached. Full article

The relative reactivity of the nitrovinyl molecular segment characterized by the “cis” orientation of nitro group and the aryl ring was evaluated based on the experimental and Density Functional Theory quantum chemical data. It was found that, on the contrary to E-R-nitroethenes, the Z-2-Ar-1-EWG-1-nitroethene molecular segment is not planar. This fact reduces the possibility of the conjugation of π-electron systems, and as a consequence, decreases the global reactivity. Due to these conditions, the reaction of the model ethyl 4,β-dinitrocinnamate and 2-methylenecyclopentane is realized as a very difficult process; however, with full regioselectivity, it leads to the expected (4 + 2) hetero Diels–Alder cycloadduct. Bonding Evolution Theory studies show that the first new C4-C5 single bond is formed in Phase VIII by merging two pseudoradical centers. In turn, the second C6-O1 single bond is formed in last phase of the reaction, by the depopulation of V(C6), V(O1) and V’(O1) monosynaptic basins. According to this, the title reaction was classified as a process carried out according to a “one-step two-stage” mechanism. Full article

Developing highly efficient and cost-effective immobilized biocatalysts is essential for optimizing diacylglycerol (DAG) production via biotransformation of natural oil. To address this, the 1,3-regiospecific MAS1-H108W lipase, derived from marine Streptomyces sp. strain W007, was produced through high-density fermentation (20 °C, pH 7.0, 132 h). This lipase was immobilized by XAD1180 resin adsorption, yielding an immobilized MAS1-H108W lipase with a lipase activity of 4943.5 U/g and a protein loading of 201.5 mg/g under selected conditions (lipase/support ratio 100 mg/g, initial buffer pH of 8.0). After immobilization, the lipase maintained its optimal temperature at 70 °C and shifted its optimal pH from 7.0 to 8.0, along with enhanced thermostability. The immobilized MAS1-H108W lipase demonstrated superior efficiency in DAG synthesis compared to non-regiospecific immobilized MAS1 lipase and commercial lipases (Novozym 435 and Lipozyme RM IM). Under the optimized reaction conditions (reaction temperature 60 °C, olive oil/glycerol molar ratio 1:2, adding amount of immobilized MAS1-H108W lipase 1.0 wt.%), a maximum DAG content of 49.3% was achieved within 4 h. The immobilized lipase also exhibited excellent operational stability, retaining 81.9% of its initial production capacity after 10 reuse cycles. Furthermore, in the glycerolysis of various vegetable oils (corn oil, rapeseed oil, peanut oil, sunflower oil, and soybean oil), the DAG content catalyzed by immobilized MAS1-H108W lipase consistently exceeded 48%. This work provides a highly efficient and economical immobilized biocatalyst for DAG production, and highlights the significant potential of regioselective lipases in promoting efficient DAG synthesis via glycerolysis. Full article

Although sulfonated acridines and acridones are valuable scaffolds in diagnostics and materials science, to our best knowledge, there is no comprehensive study that addresses how the degree of sulfonation depends on reaction parameters. To fill this gap, we investigated the sulfonation behavior of unsubstituted acridine and acridone under classical conditions, using sulfuric acid, oleum, and chlorosulfonic acid. A factorial experimental design was applied to systematically evaluate the influence of temperature and reagent excess on the extent of sulfonation, while keeping the reaction time constant. Products were analyzed by HPLC–MS/MS to determine the degree of sulfonation and its distribution. Regioselectivity and product isolation were not addressed in this study. Our results provide a foundational dataset for controlling sulfonation level for these heterocycles and can help future synthetic applications where defined sulfonation patterns are desired. Full article

Brønsted acid-catalyzed, regiodivergent hydroindolation of indoles with terminal aryl alkynes was developed, affording bis(indolyl)alkanes in good to excellent yields. Systematic investigations revealed that temperature variation plays a key role in determining the regioselectivity of anti-Markovnikov and Markovnikov addition reactions. The reaction proceeds efficiently under transition metal-free conditions in an environmentally benign water/alcohol solvent system, using readily available and inexpensive p-toluenesulfonic acid (TsOH) as the catalyst. Control experiments and mechanistic studies support distinct reaction pathways for each regioisomer. Full article

Strategic scaffolds in molecules increase the possibility of obtaining derivatives with potential uses in scientific and industrial areas. The regio- and stereoselective reactions can be considered to gain these tactical motifs. Natural diterpenes are key molecules for reaching such aims. Among this class of compounds, neo-clerodanes are highlighted by the presence of a furan moiety in their chemical structure. This work describes a regio- and stereoselective strategy to gain beta-lactone and oxirane derivatives from kerlinic acid (1) when the β,γ-unsaturated carboxylic acid system is oxidized, preserving the furan moiety. Oxidation of 1 yielded salviaolide (2), suggesting regio- and stereoselective means. A reaction mechanism was proposed when oxidation of the acetate (1a), benzoate (1b), and methyl ester (1c) derivatives from 1 were gained. The obtention of the epoxide derivative 3, kernolide (4), and kernolide epoxide (5) also supported the reaction mechanism. X-ray diffraction analysis of 3, Karplus-type analyses, and DFT calculations from hypothetical intermediates revealed conformational preferences that guide the regioselectivity. The stereoselectivity was attributed to the natural origin of 1. All compounds were characterized by their physical and spectroscopical data. These results suggest the feasibility of promoting regioselective oxidation on neo-clerodane compounds, preserving the furan moiety. Full article

Herein, we report a one-pot palladium- and ligand-free tandem Sonogashira coupling/regioselective 6-endo-dig oxacyclization reaction of 2,4-diiodo-1-methyl-imidazole-5-carboxylic acid with terminal alkynes mediated by Copper(I). This impressive approach offers a straightforward, practical, and efficient tandem procedure for accessing 2-alkynylated pyrano[4,3-d]imidazol-4-one in moderate to good yields with an exclusive 6-endo-dig oxacyclization. Notably, this cost-effective methodology demonstrates broad substrate compatibility with various commercially available aliphatic and (hetero)aromatic terminal alkynes. Furthermore, DFT studies were performed to elucidate the origin of this regioselective 6-endo-dig oxacyclization reaction. Full article

A synthesis of substituted 1,4-benzodiazepines has been developed via palladium-catalyzed cyclization of N-tosyl-disubstituted 2-aminobenzylamines with propargylic carbonates. The reaction proceeds through the formation of π-allylpalladium intermediates, which undergo intramolecular nucleophilic attack by the amide nitrogen to afford seven-membered benzodiazepine cores. In reactions involving unsymmetrical diaryl-substituted carbonates, regioselectivity was observed to favor nucleophilic attack at the alkyne terminus substituted with the more electron-rich aryl group, suggesting that electronic effects play a key role in determining product distribution. The versatility of this reaction was further demonstrated by constructing a benzodiazepine framework found in bioactive molecules, indicating its potential utility in medicinal chemistry. Mechanistic insights supported by stereochemical outcomes and X-ray crystallographic analysis of key intermediates reinforce the proposed reaction pathway. This palladium-catalyzed protocol thus offers an efficient and practical approach to access structurally diverse benzodiazepine derivatives. Full article

Hydroxymethyl 1,3-diol motifs are common structural motifs in natural products, particularly in polypropionates with important therapeutic potential. However, general and complementary methods for their regio- and diastereoselective synthesis remain limited. In this study, we expanded a second-generation epoxide-based methodology involving the regioselective cleavage of TIPS-monoprotected cis- and trans-2,3-epoxy alcohols using alkenyl Grignard reagents. Regioselective ring opening of cis-epoxides provided anti-1,3-diols, while trans-epoxides afforded the corresponding syn-1,3-diols. The use of cis-propenylmagnesium bromide and vinyl Grignard reagents enabled direct access to cis- and terminal homoallylic 1,3-diols, respectively, with moderate to good yields (46–88%) and excellent regioselectivities (95:5). In contrast, reactions with trans-propenyl Grignard reagent led to partial alkene isomerization, limiting their synthetic utility. To address this, a complementary two-step approach employing propynyl alanate addition followed by sodium/ammonia reduction was incorporated, providing access to trans-homoallylic 1,3-diols with high diastereoselectivity. All 1,3-diols were characterized by NMR spectroscopy, confirming regioselective epoxide opening. These combined strategies offer a practical and modular platform for the synthesis of syn- and anti-hydroxymethylated 1,3-diols and their application to the construction of polypropionate-type fragments, supporting future efforts in the total synthesis of polyketide natural products. Full article

The regioselectivity and the molecular mechanism of the Diels–Alder reactions between N-(2,2,2-trichloroethylidene)carboxamides and dicyclohexylcarbodiimide were explored based on the ωB97xd/6-311G(d) (PCM) calculations. It was found that the reaction course is determined by polar local interactions. It is interesting that the most favored reaction channel is realized not via classical single-step Diels–Alder mechanism, but according to the stepwise scheme with the intervention of the zwitterionic intermediate. The details of the electron density redistribution along the reaction coordinate were explained using the ELF technique. Full article

This study presents a theoretical investigation of the electronic properties of mono- and pentasubstituted cyclopentadiene analogs and variously substituted conjugated nitroalkenes bearing electron-donating and electron-withdrawing groups. Conceptual Density Functional Theory (CDFT) and Electron Localization Function (ELF) analyses were employed to characterize the global and local reactivity indices of the reactants. The obtained data provided insights into the nucleophilic and electrophilic nature of the investigated systems, allowing for the prediction of their reactivity patterns in Diels–Alder reactions. A reactivity model for conjugated alkenes toward cyclopentadienes was developed based on correlation analysis using Hammett substituent constants. This approach enabled the prediction of reaction polarity in (4+2) cycloaddition processes, providing insight into how the electronic effects of substituents influence the reaction course. These findings contribute to a deeper understanding of structure–reactivity relationships in Diels–Alder processes. Full article