Search Results (53)

Ferrocenium catalysis is a growing field of research. This study investigates the catalytic activity of different ferrocenium salts in propargylic substitution reactions to afford propargylic ethers. Four different ferrocenium catalysts were employed in the title reaction, which was monitored over time. The rate of the disappearance of the starting material can be fitted to a first order rate law and observed rate constants were determined. The catalyzed propargylic substitution reactions display a moderate but discernible dependence on the ferrocenium counterion. The lack of an induction period for the reaction indicates that the ferrocenium cation itself is catalytically active, and not just a decomposition product thereof, which would result in an induction period. The presence of a carboxylic acid substituent on one of the cyclopentadienyl rings enhances catalytic activity. The Meyer–Schuster rearrangement of the propargylic alcohol to the corresponding conjugated enone played only a minor role in the ferrocenium-catalyzed reactions. Catalyst decomposition moderately retards the reaction but does not suppress product formation, as demonstrated by experiments with aged FcBF₄. In contrast, the presence of TEMPO as a radical scavenger completely inhibits product formation, while not causing detectable catalyst decomposition at room temperature. In turn, FeCl₃ catalyzes both the propargylic substitution and the Meyer–Schuster rearrangement equally and decomposes the catalysis product over time. These findings reinforce the notion that strong Lewis acids readily promote the rearrangement of propargylic alcohols and that Lewis acidity plays a crucial role in finding a balance between the substitution reactions of propargylic alcohols and their rearrangement to unsaturated aldehydes. Full article

Background/Objectives: The herbicide resistance of blackgrass (Alopecurus myosuroides Huds.) is one of the most serious problems in the winter cereal monoculture in Europe. Recently, Greek farmers expressed complaints of reduced susceptibility of this weed to winter wheat herbicides. Keeping this in mind, this study focused on the investigation of blackgrass resistance to herbicides at both phenotypic and molecular levels. Methods: Whole-plant rate-response pot assays were conducted to study the possible evolution of resistance (cross- or multiple-resistance) in a blackgrass population to ACCase- and ALS-inhibiting herbicides. Analysis of the ACCase gene sequence, herbicide metabolism study and competition with winter wheat studies were also conducted. Results: High levels of cross-resistance mainly to the ACCase post-emergence clodinafop-propargyl, medium to fenoxaprop-P-ethyl, cycloxydim, pinoxaden, as well as lower levels of resistance to ALS-inhibitors (mesosulfuron-methyl + iodosulfuron-methyl-sodium and pyroxsulam) were confirmed. In addition, the pre-emergence soil-applied herbicides chlorotoluron + diflufenican and prosulfocarb provided excellent control of the S and R blackgrass populations. The analysis of the ACCase gene sequence revealed a point mutation at position 1781, resulting in an amino acid substitution from isoleucine (Ile) to leucine (Leu). Furthermore, the combined application of the herbicides with piperonyl butoxide (PBO, applied 2 h before herbicide application) indicated that there was herbicide metabolism, which may be mediated by cytochrome P450. The R blackgrass population, when grown in competitive interaction with winter wheat, produced more tillers and aboveground fresh weight compared to the S population and caused greater reduction in winter wheat. Conclusions: The results suggest that a blackgrass population has developed multiple resistance to ACCase- and ALS-inhibiting herbicides, due to ACCase gene mutation and herbicide metabolism. No fitness cost and no compromised competitive ability associated with the blackgrass resistance were observed. 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

Over the past two decades, the copper(I)-catalyzed azide–alkyne 1,3-dipolar cycloaddition (CuAAC), commonly known as click chemistry, and C–H bond activation have gained significant attention and have emerged as key synthetic methodologies. In our efforts to synthesize fused nitrogen-containing heterocycles, we developed a palladium-catalyzed protocol for the synthesis of functionalized 7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinolines and 5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a]indoles from suitable bromo-substituted N-propargyl-indoles. The reaction conditions demonstrate broad functional group compatibility including halogen, alkoxyl, cyano, ketone, and ester, affording the target compounds in good to high yields. Full article

Nitrogen-containing substitutes, such as 1,2,3-triazoles and Mannich bases, are major pharmacophore systems, among others. The presented review summarizes the recent advances (2019–2024) in the synthesis of 1,2,3-triazoles and Mannich bases conjugated with a triterpenic core. These structural modifications have proven to be effective strategies for modulating the biological activity of triterpenes, with particular emphasis on antitumor and antiviral properties. Recent efforts in expanding the structural diversity of triazoles through A-ring modifications and C28 (or C30) substitutions are discussed. Notably, the first examples of N-alkylation of indole triterpenoids by propargyl bromide are presented, along with the application of propargylamine in the synthesis of rare triterpenic aldimines. The review also covers an application of triterpene alkynes in Mannich base synthesis, focusing on functionalization at various positions, including C28 and C19 of the lupane platform, and incorporating of amino acid spacers. While significant progress has been made both in synthetic strategies and pharmacological applications, further research is needed to fully explore the antibacterial, anti-inflammatory, and antidiabetic potential. The review will be useful to researchers in the fields of organic synthesis, natural product and medicinal chemistry, and pharmacology. Full article

The cyclization of propargyl alcohols with CO₂ represents a highly significant method for the utilization of CO₂. The resulting cyclic carbonates possesses high chemical value and hold great potential for applications in battery electrolytes, polymer precursors, and pharmaceutical intermediates. However, most existing reports on this cyclization have been limited to simple propargyl alcohol substrates that are substituted with inert alkyl, cycloalkyl, and phenyl groups. For functionalized propargyl alcohols, such as alkyne-1,2-diols, only a single report has been documented thus far. In this study, we have developed an innovative catalytic system comprising cost-effective copper salts and environmentally friendly ionic liquids (CuCl/1-ethyl-3-methylimidazolium acetate) for the cyclization of alkyne-1,2-diols with CO₂. Compared to the previously reported AgF/bulky monophosphine ligand (BrettPhos) system, our system is free of traditional volatile solvents, phosphine ligands, and additives. Notably, this is the first reported Cu(I)-catalyzed system for this cyclization, offering significant advantages in terms of cost-effectiveness and reduced toxicity compared to silver salts. Moreover, the use of ionic liquids ensures considerable recyclability, further enhancing the sustainability and practicality of this approach. Full article

Sigma receptors (σRs) represent very attractive biological targets for the development of potential agents for the treatment of several neurological disorders. In the search for new small molecule drugs against neuropathic pain, we identified 2-{[2-(1-benzylpiperidin-4-yl)ethyl]amino}-6-[methyl(prop-2-yn-1-yl)amino]pyridine-3,5-dicarbonitrile (5) as a polyfunctionalized small pyridine with potent dual-target activities against acetylcholinesterase (AChE) (IC₅₀ = 13 nM) and butyrylcholinesterase (BuChE) (IC₅₀ = 3.1 µM), exhibiting high σ₁R affinity (K_i(hσ₁R) = 1.45 nM) and 290-fold selectivity over the σ₂R subtype. These results are in good agreement with those found in the molecular modeling of compound 5. This is possibly due to the preferred combination in this molecule of a linker n = 2 connecting the N-Bn-piperidine motif to the C2 pyridine, without a phenyl group at C4, and a N-Me-substituted propargyl amine in the chain located at C6. Full article

Background: Gibberellins (GAs) are a family of tetracyclic ent-kaurenoid diterpenes found widely in several commonly used plants. Besides agricultural applications, gibberellins play an important role in the synthesis of bioactive compounds, especially those with antiproliferative and antibacterial activity. Methods: A series of gibberellic acid-based 2,4-diaminopyrimidines was designed and synthesized from commercially available gibberellic acid. The antimicrobial activity of the prepared compounds was also explored in B. subtilis, S. aureus, E. coli, and P. aeruginosa bacteria, as well as in C. krusei and C. albicans fungi. Results: The treatment of gibberellic acid with hydrochloric acid under reflux conditions resulted in aromatization followed by rearrangement to form allo-gibberic acid. The key intermediate azido alcohol was prepared according to the literature methods. The second key intermediate azidotriol was synthesized by the stereoselective dihydroxylation of the allylic function by the osmium (VIII)-tetroxide/NMO system. Starting from azide intermediates, click reactions were also carried out with 4-monoamino- and 2,4-diaminopyrimidines functionalized with the N-propargyl group. The new chimeric compounds, coupled with gibberellins thus obtained, were characterized by 1D- and 2D-NMR techniques and HRMS measurements. While the 4-monoamino-substituted derivatives exhibited only weak antibacterial activity, they demonstrated significant antifungal effectiveness against C. krusei. In general, 5-chloro-substituted pyrimidine derivatives displayed more consistent biological activities compared to their 5-fluoro counterparts, with the exception of one derivative, which showed acceptable activity against both C. krusei and C. albicans. The two derivatives featuring 5-chloro and 2-((4-(trifluoromethyl)phenyl)amino substituents proved to be highly effective against P. aeruginosa, making them promising candidates for further research. Aiming to elucidate the molecular interactions between the active compounds and their potential targets, molecular docking studies were conducted using AutoDock Vina 1.1.2. involving the most active compounds against P. aeruginosa.Conclusions: The biological effects of 2-monoamino or 2,4-diamino substitution as well as the effect of chloro or fluoro substitution at position 5 of the pyrimidine ring combined with the allo-gibberic acid moiety were determined. Compounds with selective antibacterial activity against P. aeruginosa as well as selective antifungal activity against C. krusei and C. albicans fungi were identified. Full article

Numerous emerging chemotherapeutic agents incorporate N-heterocyclic fragments in their structures, with the quinoline skeleton being particularly significant. Our recent works have focused on glycoconjugates of 8-hydroxyquinoline (8-HQ), which demonstrated enhanced bioavailability and solubility compared to their parent compounds, although they fell short in selectivity. In this study, our objective was to improve the selectivity of glycoconjugates by replacing the oxygen atom with nitrogen by substituting the 8-HQ moiety with 8-aminoquinoline (8-AQ). The 8-AQ derivatives were functionalized through the amino group and linked to sugar derivatives (D-glucose or D-galactose) that were modified with an azide, alkylazide, or propargyl group at the anomeric position by copper(I)-catalyzed 1,3-dipolar azido-alkyne cycloaddition (CuAAC). The resulting glycoconjugates, as well as their potential metabolites, were evaluated for their ability to inhibit the proliferation of cancer cell lines (including HCT 116 and MCF-7) and a healthy cell line (NHDF-Neo). Two of the synthesized glycoconjugates (17 and 18) demonstrated higher cytotoxicity than their oxygen-containing counterparts and showed improved selectivity for cancer cells, thus enhancing their anticancer potential. Furthermore, it was found that glycoconjugates exhibited greater cytotoxicity in comparison to their potential metabolites. Full article

Gold-catalyzed propargylic substitution of propargylic alcohols 1 with 1,3-dicarbonyl compounds 2 followed by cycloisomerization in ionic liquid enables the environmentally friendly synthesis of polysubstituted furans 3 in good-to-high yields. The reaction proceeds via the hydrated propargylic substitution product 3″aa. The gold catalyst can be recycled at least three times. Full article

Marine organisms represent a potential source of secondary metabolites with various therapeutic properties. However, the pharmaceutical industry still needs to explore the algological resource. The species Caulerpa lamouroux Forssk presents confirmed biological activities associated with its major compound caulerpin, such as antinociceptive, spasmolytic, antiviral, antimicrobial, insecticidal, and cytotoxic. Considering that caulerpin is still limited, such as low solubility or chemical instability, it was subjected to a structural modifications test to establish which molecular regions could accept structural modification and to elucidate the cytotoxic bioactive structure in Vero cells (African green monkey kidney cells, Cercopithecus aethiops; ATCC, Manassas, VA, USA) and antiviral to Herpes simplex virus type 1. Substitution reactions in the N-indolic position with mono- and di-substituted alkyl, benzyl, allyl, propargyl, and ethyl acetate groups were performed, in addition to conversion to their acidic derivatives. The obtained analogs were submitted to cytotoxicity and antiviral activity screening against Herpes simplex virus type 1 by the tetrazolium microculture method. From the semi-synthesis, 14 analogs were obtained, and 12 are new. The cytotoxicity assay showed that caulerpin acid and N-ethyl-substituted acid presented cytotoxic concentrations referring to 50% of the maximum effect of 1035.0 µM and 1004.0 µM, respectively, values significantly higher than caulerpin. The antiviral screening of the analogs revealed that the N-substituted acids with methyl and ethyl groups inhibited Herpes simplex virus type 1-induced cytotoxicity by levels similar to the positive control acyclovir. Full article

The intriguing ability of C-phenyl-nitrilimine to co-exist as allenic and propargylic bond-shift isomers motivated us to investigate how substituents in the phenyl ring influence this behavior. Building on our previous work on the meta- and para-OH substitution, here we extended this investigation to explore the effect of the NH₂ substitution. For this purpose, C-(4-aminophenyl)- and C-(3-aminophenyl)-nitrilimines were photogenerated in an argon matrix at 15 K by narrowband UV-light irradiation (λ = 230 nm) of 5-(4-aminophenyl)- and 5-(3-aminophenyl)-tetrazole, respectively. The produced nitrilimines were further photoisomerized to carbodiimides via 1H-diazirines by irradiations at longer wavelengths (λ = 380 or 330 nm). Combining IR spectroscopic measurements and DFT calculations, it was found that the para-NH₂-substituted nitrilimine exists as a single isomeric structure with a predominant allenic character. In contrast, the meta-NH₂-substituted nitrilimine co-exists as two bond-shift isomers characterized by propargylic and allenic structures. To gain further understanding of the effects of phenyl substitution on the bond-shift isomerism of the nitrilimine fragment, we compared geometric and charge distribution data derived from theoretical calculations performed for C-phenyl-nitrilimine with those performed for the derivatives resulting from NH₂ (electron-donating group) and NO₂ (electron-withdrawing group) phenyl substitutions. Full article

An enhanced, sustainable, and efficient method for synthesizing tacrine, achieving a 98% yield, has been developed by replacing volatile organic compounds with more eco-friendly solvents such as deep eutectic solvent (DESs). The optimized protocol scales easily to 3 g of substrate without yield loss and extends successfully to tacrine derivatives with reduced hepatotoxicity. Particularly notable is the synthesis of novel triazole-based derivatives, yielding 90–95%, by integrating an in situ preparation of aryl azides in DESs with N-propargyl-substituted tacrine derivatives. Quantitative metrics validate the green aspects of the reported drug development processes. Full article