Endocyclic Double Bond Research Articles

Forging 1,1'-Bicyclopropenyls by Synergistic Au/Ag Dual-Catalyzed Cyclopropenyl Cross-Coupling.

1,1'-Bicyclopropenyl is a constitutional isomer of benzene comprising two coupled cyclopropene units with the endocyclic double bonds in conjugation. Due to the intrinsic high strain energy, it remains a long-standing challenge to prepare 1,1'-bicyclopropenyl derivatives, particularly multisubstituted, nonsymmetrical ones, in an efficient and modular manner. Herein a straightforward Au/Ag bimetallic-catalyzed cyclopropenyl cross-coupling has been developed, providing a robust and versatile strategy for the rapid assembly of symmetrical and unsymmetrical 1,1'-bicyclopropenyl derivatives from cyclopropenyl benziodoxoles (CpBXs) and terminal cyclopropenes. Advantages of this strategy include tolerance to a wide range of synthetically useful functional groups, mild reaction conditions, and a simple catalytic system. The obtained 1,1'-bicyclopropenyl derivatives were shown to be valuable synthetic intermediates through selective downstream manipulations.

Sulfonyl Radical-Induced Regioselective Cyclization of Enamide-Olefin To Form Sulfonylated 6-7-Membered Cyclic Enamines.

Remarkable progress has been made in the radical cascade cyclization of heteroaryl- or aryl-tethered alkenes to construct benzene-fused frameworks via the cracking of aryl C-H bonds. In contrast, the radical cascade cyclization of linear dienes through the cracking of vinyl C-H bonds to construct nonbenzene-fused ring frameworks with endocyclic double bonds has significantly lagged behind, and major advances have largely been restricted to the generation of 5-membered heterocycles, such as pyrrolinones. Herein, we report the silver-mediated regioselective sulfonylation-cyclization of linear dienes with sodium sulfinates to form sulfonylated 6- and 7-membered cyclic enamines.

Synthesis of Pyrazoline Derivatives and Their Pharmacological Activities: A Review of the Last Decade

AbstractPyrazolines are nitrogen–containing heterocyclic compounds that find widespread use as herbicides and are active pharmaceuticals in the agrochemical and pharmaceutical industries. Pyrazolines possess a five–membered ring with two nitrogen atoms and one endocyclic double bond. They are synthesized by conventional methods. However, Claisen–Schmidt condensation, a reaction of α, β‐unsaturated carbonyl (chalcones) compounds with hydrazine in the presence of acetic acid under refluxing conditions, is a popular conventional method. They have antibacterial, anti‐inflammatory, antifungal, antipyretic, anticancer, antidepressant, and analgesic properties. The present study summarizes the chemistry of various chalcone–based pyrazolines and their pharmacological activities with the available data till 2023.

Nitrate radical formation and reaction with limonene by TiO2 photocatalysis: A kinetic study

The oxidative cleavage and the epoxidation of the endocyclic double bond of limonene can be performed in irradiated suspensions of TiO2 because of the formation of nitrate radical species deriving from the hole-induced oxidation of nitrate ions. The reaction is boosted by electron acceptors such as silver ions or in the presence of silver nanoparticles at the surface of TiO2. A thorough kinetic analysis of the reaction performances under several experimental conditions provided a set of kinetic constants, which characterise the elementary steps of this complex reaction. In particular, for the first time an evaluation of the kinetics of the formation of nitrate radicals in heterogeneous photocatalysis has been provided. Moreover, the effect of silver ions in solution and of silver nanoparticles at the surface of TiO2 could be quantitatively estimated. The developed set of kinetic equations satisfactorily predict the experimental data under several experimental conditions and can be used as the starting point of reactor design activities, in view of a future scale-up of the process. Moreover, the successful fitting of the model corroborates the proposed reaction mechanism, and provides fundamental insights on the elementary reaction steps.

Copper Catalyst-Promoted Regioselective Multicomponent Cascade Cyclization of 3-Aza-1,5-enynes with Sulfur Dioxide and Cycloketone Oxime Esters to Access Cyanoalkylsulfonylated 1,2-Dihydropyridines.

Radical cascade cyclization via the cracking of alkenyl C-H has emerged as an attractive and remarkable tool for the rapid construction of ring frameworks with endocyclic double bonds. We developed a cascade reaction of 3-aza-1,5-enynes with sulfur dioxide and cycloketone oxime esters to access cyanoalkylsulfonylated 1,2-dihydropyridines, which can be easily converted to pyridine derivatives. This protocol involves radical addition to the C≡C bond and 6-endo cyclization and features high regioselectivity and a broad substrate scope.

Recent advances in the synthesis of pyrazoline derivatives from chalcones as potent pharmacological agents: A comprehensive review

The pyrazoline scaffold plays a vital role in heterocyclic chemistry as a fundamental building block in both organic and medicinal chemistry. A pyrazoline scaffold is composed of an endocyclic double bond, two nitrogen atoms, and five different types of bonds. It is a significant chemical fragment and exhibits various bioavailabilities, allowing the synthesis of a range of diverse compounds with promising biological potential. Over the past decade, extensive research efforts have been devoted to investigating the therapeutic potentials of pyrazoline scaffolds, encompassing their antibacterial, anti-inflammatory, analgesic, cytotoxic, and anti-tumor activities. Moreover, in the presence of a unique chemical structure, pyrazolines have made it easier to produce new substitutions with low toxicity as compared to their natural analogue. The current review focuses on the recent progress in the synthesis of pyrazoline scaffolds from chalcones, with an emphasis on their possible biological functions. The study identifies a diverse range of pyrazoline derivatives that exhibit promising biological properties and have been successfully reported in various studies. The primary objective is to determine the chemical groups and structural modifications that enhance their bioactivity, low toxicity, and handling. Furthermore, the review explores the bioavailability, synthetic challenges, and progress made in utilising pyrazoline derivatives in pharmaceutical and synthetic chemistry from 2017 to 2023. The different biological potentials of various substituted pyrazolines are reported here such as 1,4-dimethylpiperazine, 2-(2-methyl-1H-benzo[d]imidazol-1-yl)acetohydrazide, 1-methyl-4-phenylpiperazine, 4,5-dihydrooxazole, 2H-chromen-2-one, 2-(4-chlorophenyl)-5-methyl-4,5-dihydrooxazole, benzo[d]thiazole, ethoxybenzene, and 1-bromo-4N,N-dimethylaniline. The review also discusses the effects of different functional groups, such as OCH3, OH, NO2, CF3, and halogens, added to different positions of the pyrazoline scaffold.

Contrasting impacts of humidity on the ozonolysis of monoterpenes: insights into the multi-generation chemical mechanism

Abstract. Secondary organic aerosol (SOA) formed from the ozonolysis of biogenic monoterpenes is a major source of atmospheric organic aerosol. It has been previously found that relative humidity (RH) can influence the SOA formation from some monoterpenes, yet most studies only observed the increase or decrease in SOA yield without further explanations of molecular-level mechanisms. In this study, we chose two structurally different monoterpenes (limonene with an endocyclic double bond and an exocyclic double bond, Δ3-carene with only an endocyclic double bond) to investigate the effect of RH in a set of oxidation flow reactor experiments. We find contrasting impacts of RH on the SOA formation: limonene SOA yield increases by ∼100 % as RH increases, while there is a slight decrease in Δ3-carene SOA yield. Although the complex processes in the particle phase may play a role, we primarily attribute the results to the water-influenced reactions after ozone attack on the exocyclic double bond of limonene, which leads to the increment of lower volatile organic compounds under high-RH conditions. However, as Δ3-carene only has an endocyclic double bond, it cannot undergo such reactions. This hypothesis is further supported by the SOA yield enhancement of β-caryophyllene, a sesquiterpene that also has an exocyclic double bond. These results greatly improve our understanding of how water vapor influences the ozonolysis of biogenic organic compounds and subsequent SOA formation processes.

Aza-Wacker Cyclization Toward the Bridged Core of FR901483

AbstractA nine-step synthetic route to access the tricyclic core of FR901483 is reported, featuring a key aza-Wacker cyclization step to construct an α-tertiary amine (ATA) in the bridged structure. The aza-Wacker protocol can tolerate both exocyclic and endocyclic double bonds, providing viable access to various bridged bicyclic rings bearing an ATA (e.g., 6-azabicyclo[3.2.1]octane, 7-azabicyclo[3.3.1]nonane, and 7-azabicyclo[4.2.1]nonane) in good to excellent yields. The synthetic studies presented herein enable structural derivatization of FR901483 to further exploit its compelling biological activities.

Синтез и исследование свойств 5-R-2-пропаргилсульфанилбензимидазолов

Synthesis of new medicinal substances and biologically active compounds, in particular, heterocyclic ones, is an integral part of modern pharmacology development. This is one of the reasons for steady synthetic and biological interest in the chemistry of imidazoles and benzimi-dazoles. Synthesis of 2-propargylsulfanylbenzimidazole (2a) (yielding 85 %) and 5-methyl-2-propargylsulfanylbenzimidazole (2b) (yielding 56 %) has been carried out for the first time by alkylation of benzimidazole-2-thiol (1a) and 5-methylbenzimidazole-2-thiol (1b), respectively, with propargyl bromide in the KOH–DMF system. The structure of the synthesized compounds 2a,b has been studied by the ¹Н and ¹³С NMR spectroscopy, as well as GC–MS. It has been found that propargyl sulfides 2а,b undergo acetylene-allene rearrangement and subsequent chemical transformations during chromatography under the GC–MS analysis conditions due to the high temperature in the injector (> 200 °C). The literature data on the synthesis of halogen- and selenium derivatives of [1,3]thiazinobenzimidazole based on 2-propargylsulfanylbenzimidazoles exist. We synthesized tricyclic fused [1,3]thiazolo[3,2-a]benzimidazolium systems by heterocyclization of compounds 2a,b under conditions of acetylene-allene rearrangement (heating in the KOH–DMSO or MeONa–MeOH system). According to the 1H NMR data, the reactions of propargyl sulfides 2a,b with a twofold excess of iodine in chloroform proceeded to give 3-iodomethyleno-2,3-dihydro-9H-[1,3]thiazolo[2,3-b]benzimidazolium iodide (11) and 3-iodomethyleno-6-methyl-2,3-dihydro-9Н-[1,3]thiazolo[2,3-b]benzimidazolium polyiodide (10b), respectively. When the solvent was changed to a more polar one and the iodination of compound 2а in glacial acetic acid at the same ratio of starting reagents (1:2) was carried out, isomerization of the heterocyclization product having an exocyclic double bond into a heterocyclization product having an endocyclic double bond in the thiazolium ring was observed. As a result, an individual 3-iodomethyl-9H-[1,3]thiazolo[2,3-b]benzimidazolium polyiodide (12) was isolated, and its structure was studied by 1H NMR spectroscopy.

A sustainable and chemoselective continuous flow hydrogenation of functionalized 2-azetines to azetidines

The synthesis of functionalized azetidines from azetines is poorly explored. Here, we report the safe and sustainable continuous flow hydrogenation of 2-azetines using ethyl acetate and CPME as environmentally responsible solvents. The chemoselective saturation of the endocyclic double bond of 2-azetines bearing additional functional groups sensitive to hydrogenation has been additionally disclosed. Moreover, the protocol has been successfully combined with the continuous flow preparation of the substrates, accessing to a bio-relevant azetidine through a telescoped multistep approach.

Reductive Heck cyclization of cage containing compounds: Convenient access to adamantyl-substituted indolines and spiro-homoadamantane-oxindole

Sterically hindered cage substrates with exo- and endocyclic double bonds were first used as substrates in the intramolecular reductive Heck reaction. The Pd(II) complex with an available vicinal diamine based on (S)-phenylethylamine is an effective catalyst for this reaction. The proposed approach was used for the synthesis of 3-adamantyl-substituted indolines, 2,3-dihydrobenzofuran, and the spirocyclic derivative containing homoadamantane and oxindole motifs.

Peroxy Radical Autoxidation and Sequential Oxidation in Organic Nitrate Formation during Limonene Nighttime Oxidation.

Limonene is an abundant monoterpene released into the atmosphere via biogenic emissions and biomass burning. However, the atmospheric oxidation and secondary organic aerosol (SOA) formation mechanisms of limonene, especially during nighttime, remain largely understudied. In this work, limonene was oxidized synergistically by ozone (O3) and nitrate radicals (NO3) in a flow tube reactor and a continuous flow stirred tank reactor. Upon oxidation, many highly oxidized organic nitrates and nitrooxy peroxy radicals (RO2) were observed in the gas phase within 1 min. Combining quantum chemical calculations with kinetic simulations, we found that the primary nitrooxy RO2 (C10H16NO5) through NO3 addition at the more substituted endocyclic double bond and at the exocyclic double bond (previously considered as minor pathways) can undergo autoxidation with rate constants of around 0.02 and 20 s-1 at 298 K, respectively. These pathways could explain a major portion of the observed highly oxidized organic nitrates. In the SOA, highly oxidized mono- and dinitrates (e.g., C10H17NO7-8 and C10H16,18N2O8-10) make up a significant contribution, highlighting nitrooxy RO2 autoxidation and sequential NO3 oxidation of limonene. The same organic nitrates are also observed in ambient aerosol during biomass burning and nighttime in the southeastern United States. Therefore, the present work provides new insights into the nighttime oxidation of limonene and SOA formation in the atmosphere.

Synthesis of Tetrahydroazepines through Silyl Aza-Prins Cyclization Mediated by Iron(III) Salts

A new methodology for the synthesis of seven-membered unsaturated azacycles (tetrahydroazepines) was developed. It is based on the powerful aza-Prins cyclization in combination with the Peterson-type elimination reaction. In a single reaction step, a C–N, C–C bond and an endocyclic double bond are formed. Under mild reaction conditions and using iron(III) salts as sustainable catalysts, tetrahydroazepines with different degrees of substitution are obtained directly and efficiently. DFT calculations supported the proposed mechanism.

Metal-ligand cooperation in the catalytic oxidation of (R)-carvone by Ga(NO3)3/H2O2

In this work, the catalytic epoxidation of (R)-carvone by the Ga(NO3)3/H2O2 system was studied alongside the metal-ligand cooperation by exploring 17 different ligands. It was observed that the acidic ligands such as acetic acid mostly favor the epoxidation of the endocyclic double bond of (R)-carvone (22% yield, 1 h), while nitrogen heterocycles direct the epoxidation to the exocyclic double bond, especially the ones that are unsubstituted or have electron-donating groups, such as pyrazine (28% yield, 5 h), 4-dimethylaminopyridine (28% yield, 8 h), and 1-methyimidazole (43% yield, 8 h). Pyrazinecaboxylic acid favored the epoxidation of the exocyclic double bond (25%, 3 h). EPR analysis of both Ga(NO3)3/H2O2 and Ga(NO3)3/PCA/H2O2 systems indicates the presence of hydroxyl radicals in the reaction medium, although these do not determine the epoxidation rate that is likely regulated by the interaction of Ga-peroxo complexes with (R)-carvone. This study contributes to widening the application of the cooperating ligand concept in molecular catalysis toward further development of more selective and efficient epoxidation reactions catalyzed by non-transition metal centers.

Shortest Enantioselective Total Syntheses of (+)-Isolaurepinnacin and (+)-Neoisoprelaurefucin.

The shortest enantioselective total syntheses of (+)-isolaurepinnacin and (+)-neoisoprelaurefucin have been accomplished. These syntheses were based on a common parallel synthetic strategy using Prins–Peterson cyclization in their core construction. In only one step, a seven-membered ring oxacycle with the correct cis-stereochemistry ring closure and the Δ4 position of the endocyclic double bond in (+)-isolaurepinnacin was obtained. This unsaturation was also necessary to accede to the bromodioxabicycle on (+)-neoisoprelaurefucin.

A rationale for the unlike potency of avibactam and ETX2514 against OXA-24 β-lactamase

Diazabicyclooctanone inhibitors such as ETX2514 and avibactam have shown enhanced inhibitory performance to fight the antibiotic resistance developed by pathogens. However, avibactam is ineffective against Acinetobacter baumannii infections, unlike ETX2514. The molecular basis for this difference has not been tackled from a molecular approach, precluding the knowledge of relevant information. In this article, the mechanisms involved in the inhibition of OXA-24 by ETX2514 and avibactam are studied theoretically by hybrid QM/MM calculations. The results show that both inhibitors share the same inhibition mechanisms, comprising acylation a deacylation stages. The involved mechanisms include the same number of steps, transition states and intermediates; although they differ in the involved activation barriers. This difference accounts for the dissimilar inhibitory ability of both inhibitors. The molecular reason for this is the endocyclic double bond in the piperidine ring of ETX2514 increasing the ring strain and chemical reactivity on the N6 and C7 atoms, besides the methyl substituent, which enhance the hydrophobic character of the ring. Furthermore, Lys218 and the carboxylated Lys84 of ETX2514, play a crucial role in the mechanism by coordinating their protonation states in an on/off (protonated/deprotonated) manner, favoring the proton transference between the residues and the inhibitor.

Kinetics, SOA yields, and chemical composition of secondary organic aerosol from <i>β</i>-caryophyllene ozonolysis with and without nitrogen oxides between 213 and 313 K

Abstract. β-caryophyllene (BCP) is one of the most important sesquiterpenes (SQTs) in the atmosphere, with a large potential contribution to secondary organic aerosol (SOA) formation mainly from reactions with ozone (O3) and nitrate radicals (NO3). In this work, we study the temperature dependence of the kinetics of BCP ozonolysis, SOA yields, and SOA chemical composition in the dark and in the absence and presence of nitrogen oxides including nitrate radicals (NO3). We cover a temperature range of 213–313 K, representative of tropospheric conditions. The oxidized components in both gas and particle phases were characterized on a molecular level by a chemical ionization mass spectrometer equipped with a filter inlet for gases and aerosols using iodide as the reagent ion (FIGAERO-iodide-CIMS). The batch mode experiments were conducted in the 84.5 m3 aluminium simulation chamber AIDA at the Karlsruhe Institute of Technology (KIT). In the absence of nitrogen oxides, the temperature-dependent rate coefficient of the endocyclic double bond in BCP reacting with ozone between 243–313 K is negatively correlated with temperature, corresponding to the following Arrhenius equation: k= (1.6 ± 0.4) × 10−15 × exp((559 ± 97)/T). The SOA yields increase from 16 ± 5 % to 37 ± 11 %, with temperatures decreasing from 313 to 243 K at a total organic particle mass of 10 µg m−3. The variation in the ozonolysis temperature leads to a substantial impact on the abundance of individual organic molecules. In the absence of nitrogen oxides, monomers C14−15H22−24O3−7 (37.4 %), dimers C28−30H44−48O5−9 (53.7 %), and trimers C41−44H62−66O9−11 (8.6 %) are abundant in the particle phase at 213 K. At 313 K, we observed more oxidized monomers (mainly C14−15H22−24O6−9, 67.5 %) and dimers (mainly C27−29H42−44O9−11, 27.6 %), including highly oxidized molecules (HOMs; C14H22O7,9, C15H22O7,9C15H24O7,9), which can be formed via hydrogen shift mechanisms, but no significant trimers. In the presence of nitrogen oxides, the organonitrate fraction increased from 3 % at 213 K to 12 % and 49 % at 243 and 313 K, respectively. Most of the organonitrates were monomers with C15 skeletons and only one nitrate group. More highly oxygenated organonitrates were observed at higher temperatures, with their signal-weighted O:C atomic ratio increasing from 0.41 to 0.51 from 213 to 313 K. New dimeric and trimeric organic species without nitrogen atoms (C20, C35) were formed in the presence of nitrogen oxides at 298–313 K, indicating potential new reaction pathways. Overall, our results show that increasing temperatures lead to a relatively small decrease in the rate coefficient of the endocyclic double bond in BCP reacting with ozone but to a strong decrease in SOA yields. In contrast, the formation of HOMs and organonitrates increases significantly with temperature.

Rational Design, Synthesis, and Mechanism of (3S,4R)-3-Amino-4-(difluoromethyl)cyclopent-1-ene-1-carboxylic Acid: Employing a Second-Deprotonation Strategy for Selectivity of Human Ornithine Aminotransferase over GABA Aminotransferase.

Human ornithine aminotransferase (hOAT) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that contains a similar active site to that of γ-aminobutyric acid aminotransferase (GABA-AT). Recently, pharmacological inhibition of hOAT was recognized as a potential therapeutic approach for hepatocellular carcinoma. In this work, we first studied the inactivation mechanisms of hOAT by two well-known GABA-AT inactivators (CPP-115 and OV329). Inspired by the inactivation mechanistic difference between these two aminotransferases, a series of analogues were designed and synthesized, leading to the discovery of analogue 10b as a highly selective and potent hOAT inhibitor. Intact protein mass spectrometry, protein crystallography, and dialysis experiments indicated that 10b was converted to an irreversible tight-binding adduct (34) in the active site of hOAT, as was the unsaturated analogue (11). The comparison of kinetic studies between 10b and 11 suggested that the active intermediate (17b) was only generated in hOAT and not in GABA-AT. Molecular docking studies and pKa computational calculations highlighted the importance of chirality and the endocyclic double bond for inhibitory activity. The turnover mechanism of 10b was supported by mass spectrometric analysis of dissociable products and fluoride ion release experiments. Notably, the stopped-flow experiments were highly consistent with the proposed mechanism, suggesting a relatively slow hydrolysis rate for hOAT. The novel second-deprotonation mechanism of 10b contributes to its high potency and significantly enhanced selectivity for hOAT inhibition.

Synthesis, DFT study, molecular docking and drug-likeness analysis of the heteroaryl substituted new pregnenolone derivatives

The hybrid molecules having heterocyclic structures in the D-ring of steroids have significant biological activities. Pregnenolone was converted to the hetero-arylidene derivatives by the aldol condensation reaction with two different heteroaromatic aldehydes in the alkali medium. New N- thiocarbomyl and N-acetyl substituted non-fused pyrazoline derivatives were synthesized from the reaction of the resulting hetero-arylidene steroid derivatives with thiosemicarbazide and hydrazine hydrate, respectively, in different reaction conditions. Also, the endocyclic double bond of the 2-pyridinyl substituted hetero-arylidene molecule was converted with stereo- and regioselective dihydroxylation reaction to the new trans-diaxial diol derivative. The theoretical binding affinities of nine compounds with human microsomal cytochrome protein P450 (CYP17; PDB: 1RUK) were evaluated using molecular docking simulations with the AutoDockVina program, and the obtained scores were compared lengthily in the relevant section. Additionally, ADME and drug-likeness analysis were performed for newly synthesized steroids. Finally, using the theoretical MEP analysis over the optimized structures, electrophilic and nucleophilic attack sites of the steroids were clearly determined and evaluated.

Five new germacrane sesquiterpenes with anti-inflammatory activity from Salvia petrophila

• Five new germacrane sesquiterpene lactones were isolated from Salvia Petrophila . • These sesquiterpenes are unusual with an endocyclic double bond in the γ-lactone ring. • All new compounds exhibited moderate anti-inflammatory activities in vitro. Five new germacrane sesquiterpene lactones, petrophins A–E ( 1 – 5 ), were isolated from the whole herbs of Salvia petrophila . The structures were established using spectroscopic analysis (1D and 2D NMR, HR-ESI-MS) and compatible with values in the literature. These sesquiterpenes are unusual with an endocyclic double bond in the γ -lactone ring. All the isolated compounds were evaluated for their inhibitory effects on the LPS-induced nitric oxide production using murine macro-phage RAW264.7 cells.