Intramolecular Oxidative Cyclization Research Articles

One-pot expeditious synthesis of pyrazoloindolones via base promoted electrocyclization, C-N coupling and intramolecular oxidative cyclization

Pyrazoloindolones are synthesized from N-tosylhydrazones in one-pot multistep process which include base promoted (i) electrocyclization reaction of N-tosylhydrazones derived from α,β-unsaturated aldehydes, (ii) aromatic nucleophilic substitution and (iii) a domino cyclization-oxidation process under aerobic conditions.

Synthesis of Spiro Polycyclic N-Heterocycles and Indolecarbazoles via Merging Oxidative Coupling and Cascade Palladium-Catalyzed Intramolecular Oxidative Cyclization.

We report a step-economic strategy for the direct synthesis of spiro polycyclic N-heterocycles and indolecarbazole-fused naphthoquinones by merging oxidative coupling and cascade palladium-catalyzed intramolecular oxidative cyclization. In the protocol, bi-indolylnaphthoquinones were first synthesized by oxidative coupling of indoles and naphthoquinones. Subsequent cascade palladium-catalyzed intramolecular oxidative cyclization of bi-indolylnaphthoquinones gave spiro polycyclic N-heterocycles and indolecarbazoles. The intramolecular oxidative cyclization approach could also be realized by the presence or absence of iron catalysts under standard conditions. This protocol is featured with moderate to excellent yields, a wide substrate scope, and divergent structures of products.

(Invited) Electrochemical Multi-Electron Oxidation of Thiophene-Derivatives Promoted by Coordination of Electrolytes

Supporting electrolyte is an essential component of the electrochemical systems, although its effect on the reactivity of electrochemically generated cation/anion species has been rarely discussed.[1][2] Our recent study on the electrochemical behavior of tellurium-containing π-conjugated molecule revealed that the coordination of anion species toward the electrochemically generated radical cation species determines the number of electrons, where 1e/2e oxidation were switched depending on the donor number of electrolyte-derived anion species as well as solvents.[3] In the present study, we expanded this idea to thiophene-derivatives to explore the synthetic applicability of electrolyte-coordination. As expected, electrolyte-dependent oxidation behavior of π-expanded thiophene derivatives was confirmed. Especially, the use of coordinating anion promoted multi-electron oxidation of thiophene derivatives, which enabled facile C-C coupling chemistry and oxidative intramolecular cyclization to give rare thiophenium motif in a single step. This study implies the importance of a rational design of the electrolyte to develop novel electrosynthetic reactions.[1] N. Shida, Electrochemistry, 2022, 90, 101004[2] S. Yoshinaga, M. Atobe, N. Shida, Electrochemistry, in press (DOI: 10.5796/electrochemistry.23-67013)[3] N. Shida, H. Nishiyama, F. Zheng, S. Ye, D. S. Seferos, I. Tomita, S. Inagi, Commun. Chem. 2019, 2, 124. Figure 1

On Water Synthesis of 3-Aryl-1,2,4-Triazolo[4,3-a]Pyridines Using Iodobenzene Diacetate (IBD)

Abstract: An iodobenzene diacetate (IBD)-mediated simple and green method was determined for the intramolecular oxidative cyclization of 3-aryl-2-pyridiylhydrazones of different aromatic aldehydes in an aqueous medium at room temperature. This efficient strategy provides a route to the synthesis of 3-aryl-1,2,4-triazolo[4,3-a]pyridines in water which eliminates the requirement to use costly and unsafe volatile organic solvents. All reactions were carried out by just stirring the reaction components in water at room temperature. This protocol provides a wide substrate scope and good functional group tolerance.

Cycloadditions and Cyclization Reactions via Post-Synthetic Modification and/or One-Pot Methodologies for the Stabilization of Imine-Based Covalent Organic Frameworks

Interest in covalent organic frameworks as high-value materials has grown steadily since their development in the 2000s. However, the great advantage that allows us to obtain these crystalline materials—the reversibility of the bonds that form the network—supposes a drawback in terms of thermal and chemical stability. Among the different strategies employed for the stabilization of imine-based Covalent Organic Frameworks (COFs), cycloaddition and other related cyclization reactions are especially significant to obtain highly stable networks with extended π-delocalization and new functionalities, expanding even further the potential application of these materials. Therefore, this entry gathered the most recent research strategies for obtaining stable COFs by means of cyclization reactions, including the Povarov reaction and intramolecular oxidative cyclization reactions as well as some other recent innovative approaches.

Synthesis of Chiral Spiro[4.5]decadienones via Chirality-Transferring Oxidative Intramolecular Cyclization of Allenylsilane-Tethered Phenols

AbstractReactions of phenols having a methylene-tethered chiral allenylsilane at the para position with a hypervalent iodine reagent result in chirality-transferring oxidative intramolecular cyclization accompanied by dearomatization of the phenol to stereoselectively give spiro[4.5]decadienones possessing a silylethynyl group.

Oxidative Cyclization at ortho-Position of Phenol: Improved Total Synthesis of 3-(Phenethylamino)demethyl(oxy)aaptamine.

A shorter synthesis of the demethyl(oxy)aaptamine skeleton was developed via oxidative intramolecular cyclization of 1-(2-azidoethyl)-6-methoxyisoquinolin-7-ol followed by dehydrogenation with a hypervalent iodine reagent. This is the first example of oxidative cyclization at the ortho-position of phenol that does not involve spiro-cyclization, resulting in the improved total synthesis of 3-(phenethylamino)demethyl(oxy)aaptamine, a potent anti-dormant mycobacterial agent.

Palladium-Catalyzed Oxidative Cyclization of α-Allenols in the Presence of TBN: Access to 3(2H)-Furanones

A new palladium-catalyzed oxidative cyclization of α-allenols is described. The readily accessible α-allenols participate in intra-molecular oxidative cyclization in the presence of TBN to grant access to multisubstituted 3(2H)-furanones, which are common motifs in several biologically important natural products and pharmaceuticals.

Transition-Metal-Free Dehydrogenative Cyclization via α-Csp3–H Activation of Ethers and Thioethers

AbstractWe report herein the tetraethylammonium bromide catalyzed intramolecular oxidative cyclization of O- or S-alkylated salicylic or thiosalicylic acid derivatives to access 4H-benzo[d][1,3]dioxin-4-ones or 4H-benzo[d][1,3]oxathiin-4-ones, respectively. The oxidative cyclization of salicylic acid derivatives proceeds through a radical pathway at 110 °C. In contrast, the cyclization of the thiosalicylic acids proceeds smoothly at room temperature via an ionic pathway. Notably, the overall reactions are fast, completed within short reaction times, furnishing the products in high yields and with smooth formation of quaternary carbon centers.

Molecular engineering of nitrogen-rich helicene based organic semiconductors for stable perovskite solar cells.

Polycyclic heteroaromatics play a pivotal role in advancing the field of high-performance organic semiconductors. In this study, we report the synthesis of a pyrrole-bridged double azahelicene through intramolecular oxidative cyclization. By incorporating bis(4-methoxyphenyl)amine (OMeDPA) and ethylenedioxythiophene-phenyl-OMeDPA (EP-OMeDPA) into the sp3-nitrogen rich double helicene framework, we have successfully constructed two organic semiconductors with ionization potentials suitable for application in perovskite solar cells. The amorphous films of both organic semiconductors exhibit hole density-dependent mobility and conductivity. Notably, the organic semiconductor utilizing EP-OMeDPA as the electron donor demonstrates superior hole mobility at a given hole density, which is attributed to reduced reorganization energy and increased centroid distance. Moreover, this organic semiconductor exhibits a remarkably elevated glass transition temperature of up to 230 °C and lower diffusivity for external small molecules and ions. When employed as the p-doped hole transport layer in perovskite solar cells, TMDAP-EP-OMeDPA achieves an improved average efficiency of 21.7%. Importantly, the solar cell with TMDAP-EP-OMeDPA also demonstrates enhanced long-term operational stability and storage stability at 85 °C. These findings provide valuable insights into the development of high-performance organic semiconductors, contributing to the practical application of perovskite solar cells.

One‐Pot Synthesis of Functionalized Isoindolinones and Their Bis(isoindolinone)ethane Derivatives

AbstractHighly efficient one‐pot synthesis of a series of substituted 3‐methylene‐isoindolinones (3 a–x), bis(isoindolinone)ethanes (4 a–d) and 3‐hydroxy‐isoindolinones (6 a–h) derivatives is portrayed from easily accessible starting materials such as 2‐cyanobenzaldehydes (1 a–h) and different aryl/heteroaryl methyl ketones (2 a–k). The structure of Z‐isomer of 3‐methylene‐isoindolinone 3 x was confirmed by single crystal X‐ray analysis. The reaction mechanism studies by control experiments and using O18‐labelled water revealed that the reaction was initiated by attack of a conjugate base of aryl/heteroaryl methyl ketones (2 a–k) to aldehyde group of 1 a–h followed by intramolecular oxidative cyclization involving nitrile functionality to furnish isoindolinone derivatives in good to excellent yields.

Synthesis of π-Extended Carbazole Dimers Via Oxidative Cyclization Using DDQ and Sulfonic Acid and Elucidation of the Reaction Mechanism.

This paper describes the synthesis of various π-extended carbazole dimers via intramolecular oxidative cyclization using a chain precursor consisting of two carbazole units bridged by a nitrogen atom. A careful selection of the reaction conditions using 2,3-dichloro-5,6-dicyano-p-benzoquinone/sulfonic acid enabled the selective synthesis of a π-extended analogue with an angular (L-shape) structure in moderate yield. The preferential positions for the bonding of the two carbazole units in this π-extended derivative were determined by performing density functional theory calculations.

Synthesis, Characterization and Preliminary Antimicrobial Evaluation of New Schiff bases and Aminothiadiazole Derivatives of N- Substituted Phthalimide

A new series of schiff base and aminothiadiazole derivatives of N- substituted phthalimide (I-VI) were synthesized. In this work, the intermediate 4-(1,3-dioxoisoindolin-2-yl)benzaldehyde compound (I), was formed by reaction of 4-amino benzaldehyde with phthalic anhydride in glacial acetic acid(GAA). A series of Schiff bases (IV-VI) was prepared by the reaction of benzidine with compound (I) in ethanol and presence of GAA as a catalyst to form compound (IV) which react with compound (I) and p-nitro benzyldehyde to give compound (V) and (VI) respectively. A new phthalimide thiosemi-carbazone derivative (ll) was prepared by reaction of compound (l) with thiosemi-carbazide HCl in the presence of equimolar amount of sodium acetate. Finally, a new phthalimide containing (1,3,4- thiadiazole ring) compound (III) was formed by bromine mediated “oxidative intramolecular cyclization” of compound (I) in the presence of sodium acetate. All of the final target compounds' structures were successfully synthesized and confirmed using analytical and spectroscopic data. These compounds were identified and confirmed by melting points, TLC, FT IR, and 1H NMR. While the antimicrobial effect of the new derivatives has been assessed in vitro against G-positive, G-negative bacteria and fungi activity. All screened compounds exhibited no activity against G-positive bacteria (Staph. Aureus, and Bacillus subtilis). Many of synthesized compounds displayed moderate effect against “G-negative bacteria Escherichia coli, and Klebsiella pneumonia and against Candida tropicalis”. While the best antifungal activity was obtained from compound I which has high activity against Candida tropicalis.

Tandem synthesis, cytotoxicity, and in silico study of new 1,3,4-oxadiazoles as potential thymidylate synthase inhibitors.

A new series of pyrrole-linked mono- and bis(1,3,4-oxadiazole) hybrids, attached to various arene units, was prepared using a two-step tandem protocol. Therefore, a benzohydrazide derivative was condensed with the appropriate aldehydes in ethanol at 80°C for 60-150 min to give the corresponding N-(benzoylhydrazones). Without isolation, the previous intermediates underwent intramolecular oxidative cyclization in dimethyl sulfoxide at 180°C for 90-200 min in the presence of chloramine trihydrate to afford the target hybrids. The cytotoxicity of all hybrids was examined in vitro against the MCF-7, HEPG2, and Caco2 cell lines. Arene-linked hybrids 4i and 4j, attached to p-nitro and p-acetoxy units, were the most potent ones, with IC50 values ranging from 5.47 to 8.80 and 12.75 to 21.22 μM, respectively, when tested on the above cell lines. At the tested concentrations of 5 and 7.5 μM, hybrid 4i inhibited thymidylate synthase (TS) with the best inhibition percentages of 72.3 and 91.3, whereas hybrid 4j displayed comparable inhibitory activity to the reference pemetrexed. Hybrid 4j had inhibition percentages of 62.7 and 82.6, whereas pemetrexed had inhibition percentages of 59.2 and 80.2, respectively. The capability of hybrids 4i and 4j as potential TS inhibitors is supported by molecular docking studies, while SwissADME predicts their efficacy as drug-like scaffolds.

KI-TBHP mediated cascade oxidative annulations of enaminones: A facile approach towards 2, 4, 5-Trisubstituted oxazoles

A practical and efficient method for the construction of poly substituted oxazoles has been developed using a catalytic amount of potassium iodide and TBHP as the green oxidant via amidation followed by intramolecular oxidative cyclization of enaminone derivatives under mild reaction conditions. The attracting feature is oxidation of benzylic C–H bond and dehydrogenation of enaminone occurred in one pot under base free conditions.

Sustainable Synthesis of Noroxymorphone via a Key Electrochemical N-Demethylation Step

Noroxymorphone is a pivotal intermediate in the synthesis of important opioid antagonists such as naloxone and naltrexone. The preparation of noroxymorphone from thebaine, a naturally occurring opioate isolated from poppy extract, is a multistep sequence in which oxycodone is first generated and then N- and O-demethylated. Both demethylations are problematic from the safety and sustainability viewpoint, as they involve harmful reagents such as alkyl chloroformates or boron tribromide. Herein, we present a green, safe, and efficient process for the N- and O-demethylation of oxycodone. The method is based on the anodic oxidative intramolecular cyclization of the N-methyl tertiary amine with the 14-hydroxyl group of the morphinan, followed by hydrolysis with hydrobromic acid, which releases the carbon from both heteroatoms. The electrolysis process has been transferred to a scalable flow electrolysis cell, significantly improving the reaction throughput and increasing the space-time yield over 300-fold with respect to batch. The sustainability of the new methodology has been assessed by means of green metrics and qualitative indicators. The sustainability assessment has demonstrated that the new methodology is far superior to the conventional chloroformate process.

Versatile Electrochemical Synthesis of Selenylbenzo[b]Furan Derivatives Through the Cyclization of 2-Alkynylphenols.

We report an electrochemical oxidative intramolecular cyclization reaction between 2-alkynylphenol derivatives and different diselenides species to generate a wide variety of substituted-benzo[b]furans. Driven by the galvanostatic electrolysis assembled in an undivided cell, it provided efficient transformation into oxidant-, base-, and metal-free conditions in an open system at room temperature. With satisfactory functional group compatibility, the products were obtained in good to excellent yields.

PIDA‐Mediated Intramolecular N‐N Bond Formation to Access 2‐Aminoindazoles and 2,2′‐Biindazoles**

AbstractA synthesis of 2‐aminoindazole and 2,2′‐biindazole derivatives from corresponding hydrazones using phenyliodine(III) diacetate (PIDA) as oxidant is reported at ambient temperature. This oxidative intramolecular cyclization reaction proceeds through the formation of the N−N bond. This protocol is metal‐free, operationally simple, has a short reaction time, and proceeds in ethyl acetate (preferred green solvent). Indazole core moieties are well established for their biological activity similarly 2‐aminoindazoles may also possess biological significance. A plausible reaction pathway has been reported based on a few control experiments.

Hypervalent iodine( III) mediated synthesis of 2-substituted benzoxazoles

2-Substituted benzoxazoles (6a-j, 7a-e, 7j-l) have been synthesized via the oxidative intramolecular cyclization of Schiff's bases (4a-j, 5a-e, 5j-l) using iodobenzene diacetate (IBD) as an oxidant in dry methanol. A one-pot procedure for the synthesis of 6a-j, 7a-e and 7j-l starting from o-aminophenol/p-chloro-o-aminophenol and aldehydes has also been developed.

PIFA-promoted intramolecular oxidative cyclization of pyrrolo- and indolo[1,2-a]quinoxalino-appended porphyrins: an efficient synthesis of meso,β-pyrrolo- and indolo[1,2-a]quinoxalino-fused porphyrins.

We have developed an efficient protocol for the synthesis of meso,β-pyrrolo- and indolo[1,2-a]quinoxalino-fused porphyrin systems 7-9 by PIFA-promoted intramolecular oxidative cyclization of easily accessible meso-pyrrolo- and indolo[1,2-a]quinoxalino-appended porphyrins 6a-j. The absorption spectra of meso,β-pyrrolo- and indolo[1,2-a]quinoxalino-fused porphyrins 7-9 displayed bathochromic shifted (100-150 nm) and broadened Soret bands and Q bands in addition to intense band near IR region. The indolo[1,2-a]quinoxalino-fused porphyrin 9bZn with lower fluorescence quantum yield (0.003) and reduced energy gap (∼1.3 eV) was found to sensitize singlet oxygen effectively.