Intramolecular Cyclization Products Research Articles

Ultrafast Flow Synthesis of o-Functionalized Benzenesulfonyl Fluorides and Subsequent SuFEx Connections via Lithiated Chemistry.

Herein we present a flow-based, rapid, and straightforward approach to synthesize diverse functionalized sulfonyl fluorides by harnessing an aryllithium intermediate. The aryllithium intermediate was fully utilized under optimized conditions (0.016 s, -18 °C) to afford various functionalized sulfonyl fluorides and also intramolecular SuFEx cyclization products in high yields (27-94%). Furthermore, the integrated synthesis incorporating subsequent SuFEx connections with even unstable organolithium nucleophiles facilitated one-flow molecular assembly in high yields (42-72%).

METABOLIC PROFILE OF 4F-MDMB-BICA IN HUMAN URINE

The purpose of the study is to study the metabolic profile of the cannabimimetic 4F-MDMB-BICA in the urine of consumers and to identify markers of 4F-MDMB-BICA use using gas chromatography with a mass spectrometric detector (GC-MS) and liquid chromatography with tandem mass spec-trometry (LC-MS/ MS) in the urine of consumers of psychoactive substances, for chemical-toxicological and forensic chemical analysis. Material and methods. The study of urine samples of 4F-MDMB-BICA cannabimimetic users using enzymatic hydrolysis in combination with solid-phase extraction and gas chromatography with mass spectrometric detection showed that the 4F-MDMB-BICA marker and, in some cases, its nor-metabolite are detected in the urine of consumers. The 4F-MDMB-BICA nor-metabolite is a common biotransformation product for the cannabimimetics 4F-MDMB-BICA and 5F-MDMB-PICA, resulting from the hydrolysis of the ester bond and N-dealkylation of the heterocyclic core. Results. 35 compounds were identified by liquid chromatography with tandem mass spectrometry, including the original parent 4F-MDMB-BICA, 31 metabolites of biotransformation phases I and II, and 3 metabolite artifacts; it was found that the latter are the product of intramolecular cyclization of 4F-MDMB-BICA metabolites. 16 previously undescribed compounds, including 15 metabolites and one artifact were identified. The putative structures, mass spectra and some characteristics of the identified compounds are given, including retention time, MRM transitions, and relative peak area of the substance. Conclusion. From the presented data, it can be seen that the main pathways of 4F-MDMB-BICA metabolism in the human body are hydrolysis of the ester group, hydroxylation of alkyl radicals and the heterocyclic core, oxidative defluorination, and N-dealkylation. The hydrolysis products of the ester bond and hydroxyl derivatives are subsequently conjugated with glucuronic acid.

Catalytic [2+2+2] Tandem Cyclization with Alkyl Substituted Methylene Malonate Enabling Concise Total Synthesis of Four Malagasy Alkaloids

Catalytic [2+2+2] Tandem Cyclization with Alkyl Substituted Methylene Malonate Enabling Concise Total Synthesis of Four Malagasy Alkaloids

Reactivity of alicyclic 1,5,9-triketones toward five-, six-, and seven-membered rings in acidic medium. Stereochemistry of intramolecular cyclization products

Reactivity of alicyclic 1,5,9-triketones toward five-, six-, and seven-membered rings in acidic medium. Stereochemistry of intramolecular cyclization products

Phenyl(triazolyl)carbene revisited: Unique role of triazolyl group on carbene chemistry

AbstractThe chemistry of (1,4‐diphenyl‐1H‐1,2,3‐triazol‐5‐yl)(phenyl)carbenes (1T), originally reported by Smith et al., was reinvestigated by using modern spectroscopic methods as well as density functional theory (DFT) calculations, and the results were compared with that observed for analogous diphenylcarbene (1H) to clarify the role of triazole group in diarylcarbene chemistry. Product analysis indicated that 1T gave two intramolecular cyclization products (2 and 3) formed as a result of a formal attack of carbene on the phenyl rings at 1‐ and 4‐positions of the triazole ring. The results were closely similar to that observed for 1H. The behaviors of triplet carbene 31T were directly monitored not only by electron spin resonance (ESR) and UV‐Vis spectroscopic methods in rigid matrix at low temperature but also by laser flash photolysis in solution at room temperature and compared with those observed for 31H. Whereas the lifetime of 31T was some 2 orders of magnitude longer than that of 31H, the reactivity of 31T toward typical triplet trapping reagents was greater than that of 31H. In order to elucidate these rather conflicting observations, geometries and relative energies of carbenes 1T and 1H as well as species involved in the reactions leading to the final products were calculated by the DFT method. The results are interpreted as indicating that 31H decays by participating in the reaction of upper‐lying 11H much more easily than 31T. The difference in the reactivity toward external trapping reagents is explicable by taking into account the difference in steric crowdedness around carbene center between the two.

Cannabidiol as the Substrate in Acid-Catalyzed Intramolecular Cyclization.

The chemical reactivity of cannabidiol is based on its ability to undergo intramolecular cyclization driven by the addition of a phenolic group to one of its two double bonds. The main products of this cyclization are Δ9-THC (trans-Δ-9-tetrahydrocannabinol) and Δ8-THC (trans-Δ-8-tetrahydrocannabinol). These two cannabinoids are isomers, and the first one is a frequently investigated psychoactive compound and pharmaceutical agent. The isomers Δ8-iso-THC (trans-Δ-8-iso-tetrahydrocannabinol) and Δ4(8)-iso-THC (trans-Δ-4,8-iso-tetrahydrocannabinol) have been identified as additional products of intramolecular cyclization. The use of Lewis and protic acids in different solvents has been studied to investigate the possible modulation of the reactivity of CBD (cannabidiol). The complete NMR spectroscopic characterizations of the four isomers are reported. High-performance liquid chromatography analysis and 1H NMR spectra of the reaction mixture were used to assess the percentage ratio of the compounds formed.

Mass Spectra of New Heterocycles: XX. Electron Impact and Chemical Ionization Mass Spectra of 5-(Prop-2-yn-1-ylsulfanyl)-1H-pyrrol-2-amines

Electron impact (70 eV) and chemical ionization (methane as reactant gas) mass spectra of 1-alkyl- and 1-[2-(vinyloxy)ethyl]-5-(prop-2-yn-1-ylsulfanyl)-1H-pyrrol-2-amines have been studied for the first time. The title compounds under electron impact form stable molecular ions which decompose mainly along pathways typical of the molecular ions derived from the corresponding intramolecular cyclization products, 7-alkyl- and 7-[2-(vinyloxy)ethyl]-2,7-dihydrothiopyrano[2,3-b]pyrrol-6-amines. In addition, fragment ions that could be formed only via decomposition of unrearranged molecular ion were detected. The main fragmentation pathway of their molecular ions involves cleavage of the N1-CAlk bond with the formation of stable [M − R3]+ ions (Irel 85–100%) {except for N,N-diethyl- and N,N-dipropyl-1-[2-(vinyloxy)emyl]-5-(prop-2-yn-1-ylsulfanyl)-1H-pyrrol-2-amines}. The results of quantum chemical calculations at the B3LYP/6-311+G(d,p) level of theory are consistent with the experimental data. In the chemical ionization mass spectra of 5-(prop-2-yn-1-ylsulfanyl)-1H-pyrrol-2-amines, the major peaks were those corresponding to M+· (Irel 65–100%) and [M + H]+ (Irel 75–100%). The title compounds have been found to undergo partial (5–10%) thermally induced isomerization to 5-(prop-1-yn-1-ylsulfanyl)-1H-pyrrol-2-amines under the chemical ionization conditions.

Intermolecular Dehydrative Coupling and Intramolecular Cyclization of Ruthenium Vinylidene Complexes Formed from Aromatic Propynes Containing Carbonyl Functionalities.

A remarkable intermolecular dehydrative coupling reaction with the formation of a C-C bond was found for the vinylidene complex 2 a, yielding the dinuclear bisvinylidene complex 4 a. Complex 2 a containing 1-hydroxyindan moiety was first formed from the reaction of o-propynyl benzaldehyde 1 a with [Ru]-Cl ([Ru]=Cp(PPh3 )2 Ru) by a cyclization process. For analogous aldehyde 1 b containing an additional 1,3-dioxolane group on the aryl ring, similar intermolecular coupling yields the dinuclear bisvinylidene complex 4 b. However, the fluoro group on the aryl ring in aldehyde 1 c inhibits the coupling reaction, giving only the vinylidene complex 2 c. For the reactions of [Ru]-Cl in MeOH with compounds 1 f, 1 g and 1 h, each with a ketone functionality, cyclization gives vinylidene complexes 2 f, 2 g and 2 h, respectively. However, no similar intermolecular coupling was observed, instead, the intramolecular dehydration yields 8 f, 8 g and 8 h, respectively. In CDCl3 , catalytic cyclization is observed for the o-propynylphenyl ketone 1 h with [Ru]-Cl at 50 °C giving the isochromene products 14 h. Furthermore, treatment of the o-propynylaryl α,β-unsaturated ketones 1 k-m and 1 n with [Ru]-Cl in MeOH affords the corresponding vinylidene complexes 10 k-m and 11 n each with 1-benzosuberone moiety in the presence of NH4 PF6 . These intramolecular cyclization products were formed by the addition of Cβ onto the terminal carbon of the alkene moiety. All these reaction products were characterized by spectroscopic methods. In addition, structures of complexes 4 a, and 10 l were confirmed by single crystal X-ray diffraction analysis.

A novel pathway for the photooxidation of catechin in relation to its prooxidative activity

In the present study, we evaluated the prooxidative mode of action of photoirradiated (+)-catechin at 400 nm in relation to reactive oxygen species generation and its possible application to disinfection. Photoirradiation of (+)-catechin at a concentration of 1 mg/mL yielded not only hydrogen peroxide (H2O2) but hydroxyl radical (·OH) in a total amount of approximately 20 μM in 10 min. As a result, photoirradiated catechin killed Staphylococcus aureus, and a > 5-log reduction in viable bacteria counts was observed within 20 min. Liquid chromatography-high-resolution-electrospray ionization-mass spectrometry showed that photoirradiation decreased the (+)-catechin peak (molecular formula C15H14O6) whilst it increased two peaks of a substance with the molecular formula C15H12O6 with increasing irradiation time. Nuclear magnetic resonance analysis revealed that the two C15H12O6 peaks were allocated to intramolecular cyclization products that are enantiomers of each other. These results suggest that photoirradiation induces oxidation of (+)-catechin resulting in the reduction of oxygen to generate H2O2. This H2O2 is then homolytically cleaved to ·OH, and alongside this process, (+)-catechin is finally converted to two intramolecular cyclization products that are different from the quinone structure of the B ring, as proposed previously for the autoxidation and enzymatic oxidation of catechins.

Reactions of N‐alkenyl Thioureas with p‐alkoxyphenyltellurium Trichlorides

N‐Аlkenyl thioureas, under the action of aryltellurium trichlorides, form the addition products N‐{2‐chloro‐3‐[dichloro(4‐alkoxyphenyl)‐tellanyl]propyl} thioureas or the intramolecular cyclization products 5‐{dichloro(4‐alkoxyphenyl)‐telluromethyl}‐2‐phenylamino‐4,5‐dihydro‐1,3‐thiazole hydrochlorides. The reaction route depends on the nature of the substituent in the thiourea. The Fukui function reactivity indexes identify the electrophilic/nucleophilic centers and explain the possible cyclization reaction in the case of phenyl substituted thioureas. In the case of other substituents, the calculated values of partial atomic charges clearly predict that the addition reaction is more possible.

Reaction between Pyrocatechol and N,N,N',N'-Tetraethylphenylphosphonous Diamide

The reaction between pyrocatechol and N,N,N',N'-tetraethylphenylphosphonous diamide was studied. It was found that the main reaction products are bisphosphorylated pyrocatehol and and the product of intramolecular cyclization, ester of pyrocatechol and phenylphosphonic acid.

Contrasting C- and O-Atom Reactivities of Neutral Ketone and Enolate Forms of 3-Sulfonyloxyimino-2-methyl-1-phenyl-1-butanones.

The mechanisms of intramolecular cyclization of 3-sulfonyloxyimino-2-methyl-1-phenyl-1-butanones (1) under basic (DABCO and t-BuOK) and acidic (AcOH and TFA) conditions were investigated by means of experimental and computational methods. The ketone, enol, and enolate forms of 1 can afford different intramolecular cyclization products (2, 3, 4), depending on the conditions. The results of the reaction of 1 under basic conditions suggest intermediacy of neutral enol (DABCO) and anionic enolate (t-BuOK), while the results under acidic conditions (AcOH and TFA) indicate involvement of neutral ketones, which exhibit reactivities arising from both the oxygen lone-pair electrons (O atom reactivity) and carbon σ-electrons (C atom reactivity). The neutral enol in DABCO afforded 2H-azirine 4. On the other hand, the products (isoxazole 2 and oxazole 3) generated from the ketone form and from the enolate form are the same, but the reaction mechanisms are apparently different. The results demonstrate ambident-like reactivity of neutral ketone in the 3-sulfonyloxyimino-2-methyl-1-phenyl-1-butanone system.

Hepatic metabolism of licochalcone A, a potential chemopreventive chalcone from licorice (Glycyrrhiza inflata), determined using liquid chromatography-tandem mass spectrometry.

The metabolism of the chemoprevention agent licochalcone A, which is a chemopreventive chalcone found in abundance in the licorice species Glycyrrhiza inflata, was investigated using human liver microsomes and human hepatocytes combined with analysis using high performance liquid chromatography-mass spectrometry (LC-MS). Five oxygenated phase I metabolites of licochalcone A were formed by human liver microsomes, including a catechol on the A-ring, two intramolecular cyclization products following epoxidation of the exocyclic alkene at position 5 of the B-ring, and two dioxygenated products. Nine phase II monoglucuronides of licochalcone A and its oxygenated phase I metabolites were formed during incubation with human hepatocytes. These included (E)-licochalcone A-4-glucuronide, (E)-licochalcone A-4'-glucuronide, (Z)-licochalcone A-4-glucuronide, glucuronic acid conjugates of all of the monooxygenated phase I metabolites, and glucuronides of the licochalcone catechol after methylation by catechol-O-methyl transferase. In addition, human hepatocytes formed one sulfate conjugate and one glutathione conjugate of licochalcone A. The structures of all major metabolites were determined using a combination of accurate mass measurement, LC-tandem mass spectrometry, LC-UV, nuclear magnetic resonance, and comparison with standards. The cytochrome P450 enzymes and UDP-glucuronosyltransferases responsible for the formation of the major metabolites were identified. Based on in vitro hepatic clearance calculations, licochalcone A is predicted to be metabolized primarily by phase II conjugation reactions. Graphical abstract Phase I and II metabolism of licochalcone A from the licorice species Glycyrrhiza inflata by human liver microsomes and hepatocytes determined using LC-MS/MS, LC-UV and NMR.

Electrochemical transformations and evaluation of antioxidant activity of some Schiff bases containing ferrocenyl and (thio‐)phenol, catechol fragments

Electrochemical transformations and antioxidant activity of some Schiff bases 1–5 containing ferrocenyl group and (thio‐)phenol, catechol fragments were investigated. Compounds under investigation are: 2‐(ferrocenylmethylene)amino)phenol (1), 2‐((ferrocenylmethylene)amino)‐4,6‐di‐tert‐butylphenol (2), 2‐((ferrocenylmethylene)amino)‐thiophenol (3), 3‐((ferrocenylmethylene)hydrazonomethyl)‐4,6‐di‐tert‐butylcatechol (4) and 2‐((3,5‐di‐tert‐butyl‐4‐hydroxybenzylidene)amino)thiophenol (5).In a case of compounds 1–3 it has shown that the sequence of electrochemical transformations leads to the products of intramolecular cyclization – 2‐ferrocenylbenzoxazole (benzothiazole). o‐Quinone formation occurs during the electrochemical oxidation of catechol‐ferrocene 4 at the first anode stage. Electrochemical oxidation of the redox‐active fragments in Schiff bases 1–4 can be achieved indirectly at a lower potential corresponding to the oxidation of ferrocenyl moiety, consequently these substances can reveal more pronounced antioxidant properties. The antioxidant activities of the compounds were evaluated using 2,2′‐diphenyl‐1‐picrylhydrazyl radical (DPPH) assay, the reaction of 2,2′‐azobis(2‐amidinopropane hydrochloride) (AAPH) induced glutathione depletion (GSH), the oxidative damage of the DNA, the process of lipid peroxidation of rat (Wistar) brain homogenates in vitro. The compounds 1–4 in the antioxidant assays show effectiveness comparable with standard antioxidants (vitamin E, Trolox) and in some parameters superior to them. In the reaction of AAPH with the glutathione compounds 2–5 have a more pronounced protective activity than Trolox. Compounds 1–5 inhibit AAPH induced oxidation damage of the DNA. The more effective inhibitors of the lipid peroxidation process in vitro are molecules containing the bulky tert‐butyl groups: 2 and 4 and Schiff base 3.

Synthesis of Pyridone Derivatives from 7‐Hydroxy‐7‐polyfluoroalkylhexahydroimidazo[1,2‐a]pyridin‐5‐ones

The synthesis of 1‐(2‐aminoethyl)‐6‐alkyl‐4‐polyfluoroalkylpyridin‐2‐ones based on the acidic cleavage of 7‐hydroxy‐7‐polyfluoroalkylhexahydroimidazo[1,2‐a]pyridin‐5‐ones is reported. Depending on the reaction conditions, the pyridones can be obtained as bases, salts, acetamides, or the products of intramolecular cyclization, dihydroimidazopyridines. High tuberculostatic activity was observed for some of the synthesized compounds.

Fusion of 2-(furan-2-yl)thiazole to 1-methyl-1H-benzimidazole

Methylation of 5(6)-nitro-1H-benzimidazole with methyl iodide in the presence of potassium hydroxide and N-methylpyrrolidin-2-one gave a mixture of isomeric 1-methyl-5-nitro- and 1-methyl-6-nitro-1H-benzimidazoles which were reduced with tin in concentrated aqueous HCl on heating. The resulting amines reacted with furan-2-carbonyl chloride in N-methylpyrrolidin-2-one to give furan-2-carboxamides which were treated with excess P2S5 in pyridine. Oxidation of isomeric furan-2-carbothioamides with K3[Fe(CN)6] in alkaline medium afforded a mixture of intramolecular cyclization products, 2-(furan-2-yl)-6-methyl-6H-imidazo[4,5-g][1,3]benzothiazole and 2-(furan-2-yl)-8-methyl-8H-imidazo[4,5-g][1,3]benzothiazole which were separated by column chromatography and identified.

Functionalization of the naturally occurring linalool and nerol by the palladium catalyzed oxidation of their trisubstituted olefinic bonds

Linalool and nerol, bio-renewable terpenic alkenyl alcohols found in many essential oils, were selectively oxidized by molecular oxygen in the presence of the chloride-free Pd(OAc)2/p-benzoquinone catalytic system. An efficient dioxygen-coupled catalytic turnover was achieved in the absence of auxiliary electron-transfer mediators under 5–10atm of oxygen pressure. In both substrates, only one of two olefinic bonds was involved in the interaction with palladium, whereas the other one remained intact. Primary allylic acetates were formed as major reaction products: 8-linalyl acetate and 8-neryl acetate from linalool and nerol, respectively. In the case of linalool, the intramolecular cyclization product (known as herboxide), also resulted from the oxidation of the internal double bond, was also formed in significant amounts. All monoterpenic compounds obtained in the present work are natural products found in exotic plants or grape wines and are potentially useful as fragrance ingredients due to their pleasant scents.

Synthesis and heterocyclization of 2-{[2-(4-bromophenyl)-2-oxoethyl]sulfanyl}pyrimidin-4(3h)-ones

Alkylation of sodium 4(5)-alkyl-6-oxo-1,6-dihydropyrimidine-2-thiolates with 2-bromo-1-(4-bromophenyl)ethan-1-one afforded 2-{[2-(4-bromophenyl)-2-oxoethyl]sulfanyl}pyrimidin-4(3H)-ones. Analogous reaction with sodium 4-trifluoromethyl-6-oxo-1,6-dihydropyrimidine-2-thiolate gave a mixture of 2-{[2-(4-bromophenyl)-2-oxoethyl]sulfanyl}-4-(trifluoromethyl)pyrimidin-4(3H)-one and its intramolecular cyclization product, 3-(4-bromophenyl)-3-hydroxy-7-trifluoromethyl-2,3-dihydro[1,3]thiazolo[3,2-a]-pyrimidin-5-one.

Electrochemical reduction of N-(2-nitro-4-R-phenyl)pyridinium salts using redox-mediators

Electrochemical reduction of N-(2-nitroaryl)pyridinium chlorides was accomplished in acidic aqueous alcoholic medium in the galvanostatic mode using tin, titanium, vanadium, and iron chlorides as redox-mediators. The use of SnCl2 as a mediator catalyst made it possible to shorten the electrosynthesis time as compared to the direct electroreduction on an electrode and prepare the intramolecular cyclization products, viz., substituted pyrido[1,2-a]benzimidazoles, in high yield. The influence of the mediator nature and its amount, current density, temperature, cathode material, medium acidity, and the substrate structure on the efficiency of reductive heterocyclization of N-(2-nitroaryl)pyridinium salts was studied.

Deoxyfluorination of α- N -phthaloyl cycloalkanones with bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor)

Abstract The deoxyfluorination of α- N -phthaloyl cyclobutanone with bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) produced a gem -difluoride product together with a vic -difluoride bearing a cyclopropane ring. In contrast, the deoxyfluorination of the corresponding α- N -phthaloyl cyclopentanone produced the gem -difluoride only. Furthermore, the deoxyfluorination of the corresponding α- N -phthaloyl cyclohexanone produced an intramolecular cyclization product with two fluorine atoms as the main product, which provided the starting material after workup. Cationic species formed through neighboring group participation are most likely the key intermediates in these reactions. Control experiments using N -benzoyl congeners produced oxazole or oxazoline derivatives, indicating that the presence or absence of a hydrogen atom on the protected amine moiety was critical to determining the reaction path.