Addition Cyclization Research Articles

Innovative Ultrasound‐Assisted Synthesis of Isoxazolo[5,4‐b]Pyridines from Aryl Glyoxal, 5‐Aminoisoxazoles, and Malononitrile in Acetic Acid as a Solvent and Catalyst

AbstractIn this work, a novel strategy for the straightforward synthesis of isoxazolo[5,4‐b]pyridines from a one‐pot reaction of aryl glyoxal, 5‐aminoisoxazoles, and malononitrile under ultrasound (US) irradiation is described. In the reaction, acetic acid has a dual role as solvent and catalyst. The advantages of this reaction include easy purification of products, raw materials with easy access, short reaction time, high efficiency, and green conditions by utilizing ultrasound irradiation as an energy source and using acetic acid as solvent and Lewis acid. The synthesis achieved high yields of isoxazolo[5,4‐b]pyridines with a broad substrate scope, successfully producing twelve diverse derivatives. The methodology capitalizes on the benefits of sonochemistry, which accelerates reaction rates and improves selectivity while minimizing waste. The proposed mechanism involves a series of reactions including Knoevenagel condensation, Michael addition, and subsequent cyclization processes. This approach not only streamlines the synthesis of complex heterocycles but also aligns with environmentally friendly practices.

Regio-, Enantio-Controlled Cascade Oxa-Michael Addition of Hydroxyl Amine: Synthesis of Dihydro-1,2-Oxazines.

Herein, we disclose a cinchona-alkaloid-based squaramide-catalyzed intermolecular oxa-Michael cascade addition cyclization of N-protected hydroxyl amine to formyl-tethered Michael acceptors toward the synthesis of enantioenriched 1,2-oxazine scaffolds. Generally, good yield (up to 78%), good to excellent enantiomeric ratio (up to 98:2 er), and excellent regioselectivity (>19:1) were observed. Furthermore, the scalability of this methodology and a successful demonstration of postsynthetic transformations have been accomplished.

Ratiometric detection of lethal oxalyl and thionyl chloride by a thiophene-appended phenanthridine sensor

As fatal and potentially accessible reagents, oxalyl and thionyl chloride have become severe concerns for public safety. Therefore, it is essential to develop effective methods to discriminate them. Herein, a new fluorescent sensor, 2-(7,8,13,14-tetrahydrodibenzo[a, i]phenanthridin-5-yl)-4,6-di(thiophen-2-yl)aniline (TPTA) has been designed with the incorporation of classical phenanthridine fluorophore and o-aniline functionality to explore the versatile sensing capabilities. Due to the electrophilic character of chlorocarbonyls, the detection process occurs between TPTA and SOCl2, (COCl)2 via nucleophilic addition and subsequent cyclization, which produces new, green emissive cyclic adducts. An inhibited excited-state intramolecular proton transfer (ESIPT) followed by the ICT process endows sensitive ratiometric detection of oxalyl and thionyl chloride with a low limit of detection (4.15 and 2.93 nM). The limit of quantification (LOQ) was calculated to be (9.81 and 13.8 nM for SOCl2 and (COCl)2, which is far lower than the LD50 values. Because of its reaction-based sensing mechanism, robust selectivity with rapid response time has been achieved towards SOCl2 and (COCl)2 (<5 sec) with good stability. The anti-interference properties reveal that the sensor TPTA can efficiently detect SOCl2 and (COCl)2 even in the presence of other analytes. Further, the detection mechanism of the TPTA induced by oxychlorides was studied and well supported by NMR, HRMS, and DFT theoretical calculations. Remarkably, smartphone-assisted concentration-dependent test kit experiments enhance the practical utility of TPTA and facilitate the real-time detection of oxychlorides. Hence, TPTA has proven to be an inevitable and promising tool for the sensitive recognition oxychloride species.

Photocatalyst‐Free Synthesis of Oxindoles and Isoquinolinediones via the Radical Reaction of N‐Arylacrylamides with Monoalkyl Cesium Oxalate Salts by Visible Light Catalysis

AbstractA photocatalyst‐free cascade reaction of N‐alkyl‐N‐arylmethacrylamides with monoalkyl cesium oxalate salts is described. In the presence of visible light and (NH4)2S2O8, monoalkyl cesium oxalate salts undergo single‐electron oxidation/CO2 extrusion to generate alkyl radicals, followed by the addition and subsequent cyclization to give alkylated oxindoles. In addition, N‐alkyl‐N‐methacryloylbenzamides could be applied for the cascade reaction, providing a series of alkylated isoquinolinediones, which are completely different from the products obtained with monoalkyl oxalates as substrates.

Sequential Synthesis of Alkenylated Quinazolines Through sp3 C−H Functionalization and Their Photophysical Properties

AbstractQuinazolines are biologically potent heterocyclic compounds; however, their synthesis poses high challenges. In this present study, we have developed an inexpensive cobalt metal‐catalyzed acceptorless dehydrogenative pathway for the sequential synthesis of alkenylated quinazolines from benzhydrol via dehydrogenation, cyclization, and subsequent dehydrogenative sp3 C−H functionalization. This transformation holds potential owing to its commercially available key starting materials, good functional tolerance, moderate reaction conditions, environmental friendliness, and applicability for gram‐scale synthesis. Furthermore, the synthetic utility of the synthesized derivatives has been explored through various reactions, including reduction, halogenation, methoxylation, Michael addition, and spiro cyclization. Additionally, the photophysical properties indicate that the nitrogen atom of the synthesized derivatives readily undergoes a reversible protonation, leading to significant changes in colour. This characteristic presents an opportunity for the creation of pH sensors with colourimetric capabilities.

Electrochemically Induced Desulfurization of Thioureas for the Synthesis of Substituted 5‐Aminotetrazoles

AbstractA one‐pot method has been developed for synthesizing diverse substituted 5‐aminotetrazoles via the electrochemically induced desulfurizative addition–cyclization of thioureas with azidotrimethylsilane. This methodology enables the construction of C−N and N−N bonds under mild reaction conditions without transition metal catalysts or external oxidizing agents. The applicability of this approach is demonstrated by its broad substrate scope, compatibility with various functional groups, scalability to gram‐scale synthesis, and practicality evidenced by the synthesis of an antibacterial agent.

New Thiazole Derivatives: Carbonic Anhydrase I–II and Cholinesterase Inhibition Profiles, Molecular Docking Studies

AbstractThiosemicarbazone derivative was obtained by the addition of thiosemicarbazide to 5‐nitro‐thiophene‐2‐carbaldehyde. The addition–cyclization of the 2‐bromoacetophenone derivative to thiosemicarbazone derivative gave the new thiazole derivatives (2 a‐k). Acetylcholinesterase (AChE), butyrylcholinesterase (BChE), antioxidant, and human carbonic anhydrase (hCA) I and II isoform inhibitory activities of the thiazole derivatives 2 a‐k were investigated. The effects of thiazole derivatives on carbonic anhydrase I and II (hCA I–II) isoenzymes were examined in vitro using the esterase method. IC50 values for enzyme inhibition were found to be 2.661–22.712 μM for hCA I and 5.372–26.813 μM for hCA II. All derivatives reduced the activities of carbonic anhydrase I and II isoenzymes and were new potential inhibitor molecule candidates. These compounds were found to have minimal effects on AChE and BChE. The antioxidant properties of the target compounds were determined using DPPH and ferric ion‐chelating assays. In particular, compounds 2 k and 2 h had the highest antioxidant effect in the series with IC50 values of 30.11±0.008 μM and 30.21±0.006 μM, respectively. ADMET properties of the compounds found to be effective were evaluated and their interactions with the enzyme were determined by molecular docking.

Isocyanoalkene Addition–Cyclization–Decarboxylation Cascades

AbstractA rare conjugate addition to isocyanoalkenes with ethyl cyanoacetate triggers an efficient addition–cyclization–decarboxylation cascade. Using finely dispersed NaOH in THF as a base and nucleophile, is critical in facilitating the proton transfers, the ester hydrolysis, and the subsequent decarboxylation. The strategy provides an efficient route to valuable nitrile-substituted 2,3-dihydro-1H-pyrroles while providing fundamental insight into conjugate additions to isocyanoalkenes.

Synthesis of Oxadihydrophenanthroquinolizidinones by Photoinduced Rearrangement of 3‐Biphenyl‐1‐hydroxypropyl‐pyridin‐2(1H)‐ones

Synthesis of Oxadihydrophenanthroquinolizidinones by Photoinduced Rearrangement of 3‐Biphenyl‐1‐hydroxypropyl‐pyridin‐2(1H)‐ones

Synthesis and Ring‐Closing Reactions of Aminocyclohexane Derivatives Bearing Unsaturated Side Chains at C2: Stereocontrolled Approaches to cis‐ and trans‐Fused Perhydro‐indoles and ‐Quinolines

AbstractTwo epimeric pairs of N‐Ts‐protected cyclohexylamines that incorporate an unsaturated side‐chain at the C2 position have been prepared. Contrary to expectations, none of these underwent clean, photochemically‐induced intramolecular hydroamination reactions to give the corresponding perhydro‐indole or ‐quinolines. However, they did participate in efficient olefin cross metathesis (OCM) reactions with methyl crotonate. Three of the four acrylates so‐formed engaged in base‐promoted and completely diastereoselective, intramolecular aza‐Michael addition (cyclization) reactions to give the isomeric and C2‐substituted perhydro‐indoles or ‐quinolines with the structures of these being confirmed by single‐crystal X‐ray analyses. DFT calculations generated results consistent with the observed diastereoselectivities and the proposed transition states. Manipulation of the ester groups associated with the cyclization products allowed for their conversion, inter alia, into the corresponding n‐propyl residues and thus providing novel analogues of neurotoxic alkaloids such as pumiliotoxin C.

Construction of a mitochondria-targeted probe to monitor cysteine levels in cancer cells and zebrafish.

Cysteine (Cys) plays an indispensable role as an antioxidant in the maintenance of bioredox homeostasis. We have constructed an efficient fluorescent probe Mito-Cys based on the binding of indole and naphthol. The acrylic ester group serves as a recognition switch for specific detection of Cys, which undergoes Michael addition and intramolecular cyclization reactions, thereby ensuring the chemical kinetics priority of Cys compared to other biothiols. The probe has good water solubility, large Stokes shift (137nm), with a detection limit of 21.81nM. In addition, cell imaging experiments have shown that the probe has excellent mitochondrial targeting ability (R = 0.902). The probe can distinguish between Cys, homocysteine (Hcy) and glutathione (GSH), and can detect Cys specifically and quickly (100s) to ensure accurate quantitative analysis of Cys changes in cells. More importantly, the probe confirms that ferroptosis inducing factors trigger thiol starvation in mitochondria, which helps to gain a deeper understanding of the physiological and pathological functions related to Cys and ferroptosis.

Nickel-catalyzed defluorinative asymmetric cyclization of Trifluoromethyl-substituted 1,6-Enynes: Insights from DFT calculations on the reaction mechanism and selectivity

Density functional theory (DFT) calculations were employed to elucidate the mechanism and selectivity of nickel-catalyzed defluorinative asymmetric cyclization reactions of trifluoromethyl-substituted 1,6-enynes. The results indicate that the product is formed via a stepwise addition cyclization mechanism, including sequential steps of ligand coordination, transmetalation, ligand exchange, alkyne insertion, olefin insertion, β-F elimination, another transmetalation, and a final ligand exchange. The regioselectivity is primarily governed by the alkyne insertion step, where electrostatic interactions strongly favor 1,2-insertion of the carbon-carbon triple bond over 2,1-insertion. The enantioselectivity is largely determined during the insertion step of the olefin insertion step, with the (S)-product forming preferentially over the (R)-product due to stronger non-covalent interactions between the ligand and the substrate, minimal catalyst conformational distortion, and enhanced electronic interactions between the catalyst and the substrate.

Thermal and Photoinduced Radical Cascade Annulation using Aryl Isonitriles: An Approach to Quinoline-Derived Benzophosphole Oxides.

Herein, we present a radical cascade addition cyclization sequence to access quinoline-based benzophosphole oxides from ortho-alkynylated aromatic phosphine oxides using various aryl isonitriles as radical acceptors and inexpensive tert-butyl-hydroperoxide (TBHP) as a terminal oxidant in the presence of a catalytic amount of silver acetate. Alternatively, the same cascade can be realized through a sustainable photochemical approach utilizing 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) as an organic photocatalyst at room temperature. The introduced modular approach shows broad functional group tolerance and offers straightforward access to complex P,N-containing polyheterocyclic arenes. These novel π-extended benzophosphole oxides exhibit interesting photophysical and electrochemical properties such as absorption in the visible region, emission and reversible reduction at low potentials, which makes them promising for potential materials science applications. The photophysical properties can further be tuned by the addition of external Lewis and Brønsted acids.

Thermische und photoinduzierte Anellierungen über radikalische Kaskaden mit Arylisonitrilen: Ein Zugang zu Chinolin‐abgeleiteten Benzophospholoxiden

AbstractIn diesem Artikel stellen wir eine Kaskade bestehend aus einer radikalischen Addition und Zyklisierung vor, um Chinolin‐basierte Benzophospholoxide aus ortho‐alkinylierten aromatischen Phosphanoxiden zu erhalten. Dabei werden verschiedene Arylisonitrile als Radikalakzeptoren und kostengünstiges tert‐Butylhydroperoxid (TBHP) als terminales Oxidationsmittel in Gegenwart einer katalytischen Menge Silberacetat verwendet. Alternativ kann die Kaskade auch über einen nachhaltigen photochemischen Ansatz unter Verwendung von 1,2,3,5‐Tetrakis(carbazol‐9‐yl)‐4,6‐dicyanobenzol (4CzIPN) als organischem Photokatalysator bei Raumtemperatur realisiert werden. Der vorgestellte modulare Ansatz zeigt eine breite Toleranz gegenüber funktionellen Gruppen und bietet einen einfachen Zugang zu komplexen P,N‐haltigen polyheterozyklischen Arenen. Diese neuartigen π‐erweiterten Benzophospholoxide besitzen interessante photophysikalische und elektrochemische Eigenschaften wie Absorption im sichtbaren Bereich, Emission und eine reversible Reduktion bei niedrigen Potentialen, weswegen sie vielversprechend für potenzielle materialwissenschaftliche Anwendungen sind. Die photophysikalischen Eigenschaften können weiterhin durch Zugabe externer Lewis‐ und Brønsted‐Säuren beeinflusst werden.

TCS/ZnCl2 as a controlled reagent for the Michael addition and heterocyclic cyclization based on the phenyl pyrazolone scaffold with docking validation as a Covid-19 protease inhibitor

TCS/ZnCl2 is presented as a new catalyst for achieving the Michael addition adduct 5a-g by the reaction of phenyl pyrazolone 4 as the Michael donor and arylidene derivatives 3a-g as the Michael acceptor. The one-pot multi-component reaction of the same fragments' scaffolds as aldehydes 1a-g, malononitrile (2), and phenyl pyrazolone 4 with the same catalyst gives pyrano[2,3-c]pyrazole derivatives 6a-g as final products. The prepared compounds undergo docking validation as COVID-19 protease inhibitors and are compared with hydroxychloroquine as a reference drug. KEY WORDS: Pyranopyrazole, multi-component reactions, TCS/ZnCl2 catalyst, COVID-19, the energy score, hydroxychloroquine Bull. Chem. Soc. Ethiop. 2024, 38(4), 1119-1127. DOI: https://dx.doi.org/10.4314/bcse.v38i4.24

Sensing Mechanism of Cysteine Specific Fluorescence Probes and Their Application of Cysteine Recognition.

Due to the biological importance of cysteine (Cys), the development of organic fluorescence probes for Cys has been a wide, potent, and outstanding research field in most recent years. It has been used as a biomarker in treating various diseases; therefore, developing a sensing mechanism for detecting Cys is very important. In this Review, we focus on and summarize the specific results of recent exciting literature regarding the sensing mechanism of Cys-specific fluorescence probes and their applications in Cys recognition. Moreover, a design strategy of the sensing mechanism of Cys can be classified into seven reaction mechanisms, including the aromatic substitution rearrangement reaction, cyclization of aldehyde, Michael addition reaction, Se-N or S-S or bond cleavage reaction, addition cyclization of acrylate, metal complex reaction, and nucleophilic substitution reaction. In all sections, discussions have corresponded to Cys-specific sensing mechanisms, which consist of emission, color changes, and detection limits and deal with the application and recognition sites of molecules. Future directions and challenges have been proposed for the preparation of Cys-specific probes.

Ceric ammonium nitrate catalyzed one-pot three-component microwave-assisted synthesis of indole-substituted fused pyrimidine and pyridine derivatives

The study investigates the synthesis of fused pyridine and pyrimidine derivatives known for their diverse biological activities and structural versatility which serve as pivotal building blocks in organic synthesis. A series of indole-substituted cyanamide derivatives were synthesized by one-pot three-component cyclo-condensation between Indole-3-carboxaldehyde, malononitrile, and electron-rich aromatic and heterocyclic amines by employing several methods such as grinding, microwave irradiation and conventional reflux in the presence of ceric ammonium nitrate and DMF. The nuclei differ concerning the heterocyclic amines such as pyridine, pyrimidine, pyrazine, thiazole, and tetrazole. The newly synthesized compounds were characterized by IR, 1H NMR, 13C NMR, and Mass spectra. The reaction proceeds via Knoevenagel condensation, Michael addition, and intramolecular cyclization. The employed methodology offers the convenient advantages of cascade one-pot condensation, easy isolation, short reaction time, and excellent yield (83–95%).

Synthesis of Selenocyanated Indoles via PhICl2‐Induced Electrophilic Intramolecular Cyclization of 2‐Alkynylanilines or 2‐Alkenylanilines

AbstractThe 3‐selenocyanato‐substituted indoles were readily synthesized via (dichloroiodo)benzene (PhICl2)‐induced reaction of 2‐alkynylanilines or 2‐alkenylanilines with KSeCN in MeCN under metal‐free conditions. The reaction sequence was postulated to encompass the formation of a reactive selenocyanogen chloride species, generated in situ from the reaction of PhICl2 and KseCN, followed by electrophilic addition and intramolecular cyclization steps.

Photocatalytic intermolecular bromonitroalkylation of styrenes: synthesis of cyclopropylamine derivatives and their evaluation as LSD1 inhibitors.

A mild and efficient method for photoredox-catalyzed bromonitroalkylation of alkenes is described herein. In this reaction, bromonitromethane serves as a source of both nitroalkyl and bromine for direct and regioselective formation of C-Br and C-C bonds from alkenes, and additional cyclization provides C-C bonds to the cyclopropylamine core as an LSD1 inhibitor.

Serine 85 functions as a catalytic acid in the reprotonation process during EvAS-catalyzed astellifadiene biosynthesis.

The deprotonation-reprotonation sequence introduces additional cyclization branches in terpene biosynthesis. However, the underlying mechanism remains poorly understood. In this study, we employed a combined approach of molecular dynamics (MD) simulations and site-directed mutagenesis on astellifadiene synthase EvAS from Emericella variecolor to investigate the role of a protonated S85 residue. This residue acts as a catalytic acid, previously unreported, that facilitates the reprotonation step in astellifadiene biosynthesis. Mutating S85 led to the production of a new tricyclic sesterterpene.