Cyclization Sequence Research Articles

Reply to Correspondence on “Unlocking the Chain‐Walking Process in Gold Catalysis”

AbstractWe recently reported the gold‐catalyzed Heck and chain‐walking reactions, which utilize migratory insertion, β‐hydride elimination steps in a catalytic fashion. Budzelaar et al. in their correspondence state that these reactions proceed through gold‐catalyzed alkene heteroarylation followed by acid‐mediated elimination and cyclization sequence. In response to this correspondence, we have conducted some experiments which convinced us that the product formation solely can not be rationalized based on hetero‐arylation of alkenes under ligand‐enabled Au(I)/Au(III) catalysis.

Photoinduced Ag-Mediated Azaspirocyclic Approach Involves Cyclization and Dearomatization.

A visible-light-promoted protocol for azaspirocyclic synthesis from N-benzylacrylamides and alkyl chlorooxoacetates has been established. This cascade reaction proceeds through sequential free radical addition, cyclization, and dearomatization, enabling the convenient construction of key azaspirocyclic derivatives and the introduction of valuable ester groups in a single step. In addition, this transformation demonstrates broad substrate compatibility and high tolerance toward different functional groups, showcasing remarkable efficiency in functional group insertion and bond formation.

Sequential Decarboxylation, Substitution, Cyclization and Oxidation with Iodine‐DMSO Catalytic System: A New Methodology for the Construction of Imidazoquinoxaline Motifs

AbstractA one‐pot synthetic protocol has been developed using aryl acetic acid as new and alternate surrogate for the synthesis of 4‐aryl imidazoquinoxalines with molecular iodine‐DMSO green catalytic system under classical heating at 100–110 °C. A variety of quinoxaline derivatives containing quinoline are prepared by using this methodology. This new protocol has a potential to tolerate broad substrates, that is, different amines and aryl acetic acids.

Photocatalyzed Arylthiolation/Cyclization of 3‐(2‐(Ethynyl)phenyl)Quinazolinones with Disulfides towards Arylthiolated Quinolino[2,1‐b]Quinazolinones

AbstractAn approach to the synthesis of arylthiolated quinolino[2,1‐b]quinazolinones has been developed using unactivated alkynes containing quinazolinones and diaryldisulfides under visible light irradiation. The procedure entails a sequential radical arylthiolation and cyclization reaction. A possible radical mechanism has been investigated and proven as a single electron transfer (SET) process.

Ligand-controlled regiodivergent arylation of aryl(alkyl)alkynes and asymmetric synthesis of axially chiral 9-alkylidene-9,10-dihydroanthracenes

Transition metal-catalyzed addition of organometallics to aryl(alkyl)alkynes has been well known to proceed with the regioselectivity in forming a carbon–carbon bond at the alkyl-substituted carbon (β-addition). Herein, the reverse regiochemistry with high selectivity in giving 1,1-diarylalkenes (α-addition) was realized in the reaction of arylboronic acids with aryl(alkyl)alkynes by use of a rhodium catalyst coordinated with a chiral diene ligand, whereas the arylation of the same alkynes proceeded with the usual regioselectivity (β-addition) in the presence of a rhodium/DM-BINAP catalyst. The regioselectivity can be switched by the choice of ligands on the rhodium catalysts. This reverse regioselectivity also enabled the catalytic asymmetric synthesis of phoenix-like axially chiral alkylidene dihydroanthracenes with high enantioselectivity through an α-addition/1,4-migration/cyclization sequence.

Intramolecular/Intermolecular Sequential Cyclization Accompanied by Double C-F Bond Cleavage: Access to Tricyclic Fluorine-Containing Pyrano[3,2-c]chromenes.

Defluorinative cyclization of CF3-alkenes has emerged as a reliable strategy for crafting intricate polycyclic frameworks. In this study, a facile defluorinative bicyclization approach was developed for the construction of 4H,5H-pyrano[3,2-c]chromenes under mild conditions involving a sequence of intramolecular cyclization and intermolecular defluoroheterocyclization. A variety of polysubstituted 4H,5H-pyrano[3,2-c]chromenes featuring C2-fluorine could be synthesized in good yields with excellent tolerance toward various functional groups. Moreover, the introduction of a C-F bond provides additional possibilities for further modification of this skeleton. The product features aggregation-induced emission (AIE) characteristics after simple modification, which is promising for chemical and biomedical imaging.

Synthesis of 2,3,5,6‐Tetrasubstituted Thieno[3,2‐b]furans through Formal [3+2] Cycloaddition Utilizing [1,2]‐Phospha‐Brook Rearrangement/Brønsted Base‐Mediated Cyclization Sequence

AbstractWe have developed a method for the synthesis of thieno[3,2‐b]furans on the basis of a strategy consisting of a formal [3+2] cycloaddition utilizing the [1,2]‐phospha‐Brook rearrangement and a subsequent Brønsted base‐mediated cyclization. The method streamlines access to a wide range of well‐organized 2,3,5,6‐tetrasubstituted thieno[3,2‐b]furans that are otherwise difficult to synthesize and is also applicable to the syntheses of 2,3,5,6‐tetrasubstituted seleno[3,2‐b]furans.

Pragmatic Access to Hybrid Quinoxaline Scaffold Mediated by Elemental Sulfur Enabling Actualization to π-Extended and Aza-Annulated Heterocyclic Units.

A metal-free approach for synthesizing hybrid quinoxaline derivatives from sulfoxonium ylide and a 1,5-bis-nucleophilic N-heterocycle mediated by elemental sulfur is presented to illuminate the [5+1] cascade cyclization sequence. Large-scale synthesis and postsynthetic functionalizations for the annulative π-extension and intramolecular aza-annulation reactions reveal the potential utility and actualize the fabricated approach.

Benzo[d]oxazoles from Anilides by N-Deprotonation-O-SNAr Cyclization.

A synthesis of benzo[d]oxazoles by an N-deprotonation-O-SNAr cyclization sequence from anilide precursors is reported. Anilides derived from 2-fluorobenzaldehydes, activated toward SNAr ring closure by C5 electron-withdrawing groups, were prepared and subjected to deprotonation-cyclization using 2 equiv. of K2CO3 in anhydrous DMF. Following deprotonation at nitrogen, the delocalized anion cyclized from the amide oxygen to give high yields of benzo[d]oxazoles. The temperature required for the cyclization of benzanilides correlated with the potency of the C5 activating group on the SNAr acceptor ring with nitro (most potent) reacting at 90 °C (1 h), cyano reacting at 115 °C (1 h), methoxycarbonyl reacting at 120 °C (2 h), and trifluoromethyl (least potent) reacting at 130 °C (3 h). Acetanilides were more difficult to cyclize but generally required 4-6 h at these same temperatures for completion. Product purification was accomplished by recrystallization or chromatography.

Lewis Acid‐Catalyzed Tandem Annulation of Propargylic Alcohols with 2‐Allylphenols and Their Anti‐tumor Activities

AbstractA novel bismuth(III) trifluoro‐methanesulfonate‐catalyzed and environmentally benign synthetic strategy for the construction of a wide range of structurally diverse, sophisticated [5,6,5]‐oxygen‐containing tricyclic frameworks with easy‐to handle propargylic alcohols and 2‐allylphenols as substrates in the presence of Bi(OTf)3 and AgOTf is described. This Lewis acid catalyzed [3+2] annulation protocol, which tolerates a great deal of functional groups, proceeds through a sequential Meyer‐Schuster rearrangement, nucleophilic substitution, 5‐exo‐trig cyclization, 5‐endo‐trig cyclization, and proton exchange sequences, affording a versatile approach for accessing oxygen‐containing tricyclic skeletons in moderate‐to‐excellent yields. In addition, most of the obtained compounds exhibited anti‐tumor activities against three types of human cancer cell lines in vitro, including Caco‐2 colon cancer cells, MCF‐7 breast cancer cells, and Hepg‐2 liver cancer cells.

Ligand‐Free Pd‐Catalyzed Synthesis of PAHs via Vinyl C−H Activation/Decarboxylative Cyclization Sequence

AbstractHerein, we describe a strategy for the synthesis of polycyclic aromatic hydrocarbons (PAHs) from readily available 2‐iodostyrenes and o‐halobenzoic acids through a ligand‐free palladium‐catalyzed cascade vinyl C−H activation/decarboxylative cyclization. A vinyl‐coordinated five‐membered palladacycle was proposed as the key intermediate for this sequential process. Furthermore, Heptagon‐embedded aromatic compounds can be smoothly synthesized by employing 8‐bromo‐1‐naphthoic acid as decarboxylative insertion unit.

Synthesis, characterization and bioactivity of new pyridine-2(H)-one, nicotinonitrile, and furo[2,3-b]pyridine derivatives.

Pyridone heterocycles, such as furo[2,3-b]pyridines, have emerged as prominent scaffolds in medicinal chemistry due to their versatile pharmacological properties, including significant anticancer activity. In this study, we successfully synthesized new pyridine-2(H)-one, nicotinonitrile, and furo[2,3-b]pyridine derivatives from chalcones bearing 4-(benzyloxy)phenyl and dichlorothiophenyl subunits to explore their therapeutic potential against breast cancer. By employing a synthetic strategy involving Claisen-Schmidt condensation followed by sequential cyclizations and functional modifications, we synthesized and characterized four compounds (MI-S0, MI-S1, MI-S2, and MI-S3) using various spectroscopic methods, including FT-IR, 1H-NMR, 13C-NMR, DEPT, H,H- and C,H-COSY, and HRMS. The in vitro cytotoxic activity of these compounds was evaluated against two breast cancer cell lines, MCF-7 and MDA-MB-231, and compared with a noncancerous breast cell line, MCF-10A. All compounds exhibited potent cytotoxic activities with minimal selectivity toward normal cells. Molecular docking studies targeting the serine/threonine kinase AKT1, estrogen receptor alpha (ERα), and human epidermal growth factor receptor 2 (HER2) revealed strong binding affinities, suggesting a mechanism involving the disruption of key cellular signaling pathways. These findings underscore the potential of furo[2,3-b]pyridine derivatives as promising candidates for further development into anticancer agents, laying the groundwork for future investigations into their selective therapeutic efficacy and molecular mechanisms of action.

Divergent and gram-scale syntheses of (–)-veratramine and (–)-cyclopamine

Veratramine and cyclopamine, two of the most representative members of the isosteroidal alkaloids, are valuable molecules in agricultural and medicinal chemistry. While plant extraction of these compounds suffers from uncertain supply, efficient chemical synthesis approaches are in high demand. Here, we present concise, divergent, and scalable syntheses of veratramine and cyclopamine with 11% and 6.2% overall yield, respectively, from inexpensive dehydro-epi-androsterone. Our synthesis readily provides gram quantities of both target natural products by utilizing a biomimetic rearrangement to form the C-nor-D-homo steroid core and a stereoselective reductive coupling/(bis-)cyclization sequence to establish the (E)/F-ring moiety.

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.

Total Syntheses of (±)-Acetoxymarsupellone and (±)-Marsupellins A, B, and D Enabled by a Reductive Cyclization and Semipinacol Rearrangement Strategy.

We report herein the total syntheses of three marsupellin-family sesquiterpenoids, (±)-acetoxymarsupellone and (±)-marsupellins B and D, in 14-19 steps from our known precursor, making marsupellin A also accessible from marsupellin B through a known procedure. The critical tricyclic framework bearing the challenging C7 bridgehead all-carbon quaternary center is strategically constructed through a Ti-mediated reductive cyclization and semipinacol rearrangement sequence. This study provides a general approach to the syntheses of (ent-)longipinane-type molecules.

Construction of Hydroindole Skeleton by Photocatalytic Oxidative Dearomatization and Cyclization Sequence, and a Concise Synthesis of Melodamide A and (±)-Toussaintine C.

A method of synthesizing hydroindole skeletons has been developed by using photocatalytic oxidative dearomatization and an aza-Michael addition sequence. Using this method, optically active hydroindoles, which are often used in natural product synthesis as chiral building blocks, can be easily prepared with >99% ee. Furthermore, the synthesis of melodamide A and (±)-toussaintine C was achieved using this method as a key step.

Palladium-Catalyzed Domino Heck/Cross-Coupling Cyclization Reaction: Diastereoselective Synthesis of Furan-Containing Indolines.

Herein, a palladium-catalyzed diastereoselective dearomatization/cross-coupling cyclization reaction between N-arylacyl indoles and (E)-β-chlorovinyl ketones is reported. Through this cyclization/cycloisomerization cascade, a series of furan-containing indolines were obtained in yields up to 95%. The reaction features readily accessible starting materials, benzyl Pd(II)-catalyzed cycloisomerization of (E)-β-chlorovinyl ketones, the sequential formation of three bonds and bis-heterocycles, and excellent diastereoselectivity. More importantly, the carbene-secondary benzyl migratory insertion is proven to be a critical process in the sequential cyclizations.

Synthesis of Chiral Polycyclic Indoles via Pd(II)-Catalyzed Sequential Cyclization and Carbonylation

Synthesis of Chiral Polycyclic Indoles via Pd(II)-Catalyzed Sequential Cyclization and Carbonylation

Short Formal Syntheses of Lycorine and Congeners Using a 5-Endo-Trig/6-Endo-Trig Radical Cyclization Sequence.

Here, we report a practical route to medicinally interesting lycorine congeners alongside formal syntheses of various lycorine-type natural products, including lycorine itself. The efficiency of our strategy derives from a back-to-back 5-endo-trig/6-endo-trig radical cyclization sequence, which we systematically studied both experimentally and computationally. The results of our work will facilitate future development of urgently needed antiviral therapeutics based on lycorine.