Annulation Process Research Articles

Radical-Initiated Dearomative Annulation of Tryptamine-Derived Isocyanides: Selective Synthesis of CF3-Substituted β-Aza-spiroindolines and β-Carbolines.

A mild approach for synthesizing CF3-substituted β-aza-spiroindolines and β-carbolines from tryptamine-derived isocyanides via site-selective radical annulations has been reported. The crucial role of C2 substituents in the selective annulation process has been clarified. The approach shows good generality and practical applicability, highlighting its effectiveness and versatility.

Electrochemical Synthesis of Quinolines

AbstractThis report outlines an intramolecular oxidative annulation process involving N-substituted o-amino phenylacetylene, performed under electrochemical conditions, which yields substituted quinoline in an undivided cell at room temperature. The reaction features mild conditions, requiring neither external oxidants nor metals, and achieves yields that range from good to excellent. Moreover, the synthetic potential of quinoline has been demonstrated resulting in the synthesis of substituted polycyclic isoindolinone and (aza-)isoindolinone compounds.

Photocatalytic PPh3-Mediated Synthesis of C3-Functionalized Indoles via Radical Annulation of Nitroarenes and Alkenes.

Oxidatively generated phosphine radical cations are reactive intermediates that can be used for the generation of carbon and heteroatom centered radicals via deoxygenation processes. Such P-radical cations can readily be generated via single electron transfer oxidation using a redox catalyst. Cheap and commercially available nitroarenes are ideal nitrogen sources for the construction of organic amines and N-containing heterocycles. Activation of nitroarenes with phosphines has been achieved in the ionic mode, which requires specially designed P-nucleophiles and high temperatures. Herein, we report an alternative mode of nitro activation that proceeds via a radical process. The radical strategy leads to open shell intermediates that show interesting unexplored reactivity. This is documented by the development of an economic and highly efficient synthesis of valuable indole derivatives through photocatalytic PPh3-mediated annulation of nitroarenes with alkenes showing large functional group tolerance. The method allows room-temperature activation of nitroarenes and a double C-H bond functionalization of alkenes is achieved to provide rapid access to C3-functionalized indoles, which are key structural components of diverse natural and drug molecules. Experimental mechanistic studies that are further supported by DFT calculations indicate that a nitrosoarene radical cation plays a key role in the annulation process.

Synthesis, Characterization and Biological Evaluation of 3‐Oxo‐Pyrimido[1,2‐b]indazoles

AbstractThe synthesis of substituted 3‐oxo‐pyrimido[1,2‐b]indazoles from 3‐aminoindazoles and ketones has been established. It involves one molecule of 3‐aminoindazoles and two molecules of ketones via a [3+2+1] three‐component annulation process. 3‐Oxo‐pyrimido[1,2‐b]indazoles exhibit strong yellow fluorescence in various solvents. A wide range of products have anti‐oxidant activities. Cytotoxicity studies indicate that compounds 3 a, 3 aa and 3 ab have obvious effects on both HCT116 and A549 cancer cell lines.

Stable and Reusable Pd/Cu Bimetallic Nanoparticle Catalysts for the Synthesis of Hydroxy Isoindolones by Domino C−H Activation and Annulation

AbstractA domino C−H activation and annulation process catalyzed by stable and reusable bimetallic nanoparticles (Pd/Cu‐binapthyl nanoparticles) was developed for the synthesis of 3‐hydroxyisoindolin‐1‐ones/thiones. The scope of the reaction was examined utilizing a variety of N‐alkoxy benzamide/benzothioamide derivatives and benzaldehydes, which yielded moderate to good yields of 3‐hydroxyisoindolin‐1‐ones/thiones, one of which was used to synthesize a BRD4 inhibitor. A gram‐scale synthesis is also reported. The Pd/Cu‐binapthyl nanocatalyst has been recovered and reused up to four times without any major change in particle size and reactivity.

Formal High-Order Cycloadditions of Donor-Acceptor Cyclopropanes with Cycloheptatrienes.

The design of various cycloaddition/annulation processes is one of the most intriguing challenges in the development of donor-acceptor (D-A) cyclopropane chemistry. In this work, a new class of formal high-order [6+n]-cycloaddition and annulation processes of D-A cyclopropanes with cycloheptatriene systems has been designed and reported, to fill a significant gap in the chemistry of D-A cyclopropanes. The reactivity of methylated cycloheptatrienes from Me1 to Me5 as well as unsubstituted cycloheptatriene was studied in detail under GaCl3 activation conditions, which makes it possible to efficiently generate gallium 1,2-zwitterionic complexes or 1,3-zwitterionic intermediates starting from D-A cyclopropanes, while other Lewis acids are ineffective and non-selective. New examples of formal [6+2]-, [6+3]-, [6+4]-, [6+1]-, and [4+2]-cycloaddition and annulation reactions with cycloheptatrienes along with more complex processes were discovered. Cycloheptatriene itself can also successfully act as a hydride anion donor, which allows the ionic hydrogenation of D-A cyclopropanes to be performed under mild conditions. As a result, a number of efficient and highly diastereoselective protocols for the synthesis of seven-membered carbocycles has been developed.

Iodine-Catalyzed [5 + 1] Carbonylation of 2-Alkenyl/Pyrrolylanilines with CS2 as the Carbonylating Reagent.

Novel metal-free iodine (I2)-catalyzed [5 + 1] carbonylation of 2-alkenyl/pyrrolylanilines with carbon disulfide (CS2) as the carbonylating reagent has been developed. This innovative method allows for the synthesis of valuable derivatives such as 4-aryl-2-quinolinones and pyrrolyl-fused quinoxalinones. Notably, this work represents the first instance where CS2 has been utilized as a carbonylating reagent source. The protocol demonstrates the utilization of various substrates, leading to diverse reactions that afford excellent yields under mild conditions. The method also shows good compatibility with functional groups present in the substrates, further enhancing its synthetic utility. Importantly, the developed reaction exhibits scalability, enabling gram-scale synthesis, and shows promise for the synthesis of druglike molecules. In this catalytic system, CS2 serves as the carbonyl source, while dimethyl sulfoxide plays multiple roles, including acting as an oxidant and a solvent. Mechanistic studies have been conducted to elucidate the underlying processes, with the formation of quinolone-2-thiones identified as crucial intermediates, facilitating the carbonylation annulation process.

Dehydrogenation Coupling and [3 + 2] Cycloaddition of Indolizines with Allenes in the Presence of Piezoelectric Materials under Ball Milling Conditions.

A wide range of indolizines with allenes proceeded smoothly under mechanochemical-induced conditions via [3 + 2] annulation process, affording various substituted pyrrolo[2,1,5-cd]indolizines with good yield. The reaction efficiency was greatly improved by using a piezoelectric material as the charge transfer catalyst. The photophysical properties of the resulting pyrrolo[2,1,5-cd]indolizine was characterized.

Formal High‐Order Cycloadditions of Donor‐Acceptor Cyclopropanes with Cycloheptatrienes

Design of various cycloaddition / annulation processes is one of the most intriguing challenges during all time in the development of the donor‐acceptor (D–A) cyclopropanes chemistry. In this work, a new missing class of formal high‐order [6+n]‐cycloaddition and annulation processes of D–A cyclopropanes with cycloheptatriene systems has been designed and reported, to fill a significant gap in the chemistry of D–A cyclopropanes. The reactivity of methylated cycloheptatrienes from Me1 to Me5 as well as unsubstituted cycloheptatriene was study in detail under GaCl3 activation conditions, which makes it possible to efficiently generate gallium 1,2‐zwitterionic complexes or 1,3‐zwitterionic intermediates from starting D–A cyclopropanes, when other Lewis acids are ineffective and non‐selective. New important examples of formal [6+2]‐, [6+3]‐, [6+4]‐, [6+1]‐, and [4+2]‐ cycloaddition and annulation reactions with cycloheptatrienes along with more complex processes were discovered. Cycloheptatriene itself also can successfully act as a hydride anion donor which allows ionic hydrogenation of D–A cyclopropanes to be performed under mild conditions. As a result, a number of efficient and highly diastereoselective protocols for the synthesis of seven‐membered‐based carbocycles has been developed.

Modular Assembly of Pyrrolo[3,4-c]isoquinolines through Rh-Catalyzed Cascade C-H Activation/Annulation of O-Methyl Aryloximes with Maleimides.

An efficient and practical strategy for the construction of pyrrolo[3,4-c]isoquinolines via Rh(III)-catalyzed cascade C-H activation and subsequential annulation process from easily available O-methyl aryloximes and maleimides has been disclosed. This facile protocol does not require any inert atmosphere protection with good efficiency in a low loading of catalyst and exhibits good functional group tolerance and broad substrate scope. Notably, the as-prepared products show potential photophysical properties.

Gold-Catalyzed Cascade Reaction of Yne-Enones with Iminooxindoles, Access to 3,2'-Pyrrolidinyl-Spirooxindole Derivatives.

Herein, a gold-catalyzed cascade reaction of yne-enones with iminooxindoles has been developed through a cascade cycloisomerization/(3 + 2) annulation process. This approach provides a straightforward and efficient route for the synthesis of functionalized 3,2'-pyrrolidinyl-spirooxindoles in high reactivity and broad substrate scope with excellent cis-selectivity. Moreover, the subsequent functionalization of furan units allows for the diverse synthesis of spirooxindole derivatives, which have demonstrated good antitumoral activity.

Photocatalytic Annulation of Enaminones with Thioureas for the Synthesis of 2-Aminothiazoles via Tandem C–S and C–N Bond Formation

AbstractVisible-light photocatalytic reactions between enaminones and thioureas leading to thiazole products have been achieved. The annulation process consists of tandem C–S and C–N bond formation by running reactions under air atmosphere at ambient temperature. Broad substrate tolerance of the sustainable protocol has been verified by the practical synthesis of divergent thiazoles with both monocyclic and fused cyclic structures.

Synthesis of β,β-Dithioketones by Merging C-C and C-S Bond Cleavage in [1 + 1 + 1 + 1 + 1 + 1] Annulation.

An unconventional [1 + 1 + 1 + 1 + 1 + 1] annulation process was developed for the construction of β,β-dithioketones by merging C-C and C-S bond cleavage. In this reaction, rongalite concurrently served as triple C1 units, dual sulfur(II) synthons, and a reductant for the first time. Mechanism investigation indicated that the reaction involved the self-mediated valence state change of rongalite. By performing this step-economical method, the challenging construction of C5-substituted 1,3-dithiane can be achieved under mild and simple conditions.

Merging of Palladium and Organocatalysis Enabled Asymmetric Decarboxylative (2+1) Cycloadditions toward Cyclopropanes.

A cascade reaction enabling enantio- and diastereoselective construction of strained cyclopropanes is described. This asymmetric (2+1) annulation process uses vinyl methylene carbonate and 2-cyanoacrylate as reaction partners in the presence of Pd(PPh3)4 as a precatalyst and an enantioenriched phosphoramidite ligand featuring a morpholine functionality. Mechanistic investigations unveil that the PPh3 derived from the Pd(PPh3)4 and the morpholine-containing phosphoramidite work as cooperative phosphorus and Brønsted base catalysts to promote the reaction.

Synthesis of Azepinoindoles and Oxepinoindoles through Brønsted-Acid-Catalyzed Cyclization of an In Situ Generated Dihydrospiroquinoline Intermediate.

We have developed a straightforward and efficient synthetic protocol to produce 5,6,7,12-tetrahydrobenzo[2,3]azepino[4,5-b]indole and 7,12-dihydro-6H-benzo[2,3]oxepino[4,5-b]indole derivatives under mild conditions. This annulation process involves the intramolecular cyclization of the in situ generated ketimine moiety via the formation of dihydrospiroindolequinoline, which serves as a key intermediate in the reaction pathway. Several control experiments and spectroscopic studies were performed to elucidate the underlying reaction mechanism.

Unlocking the Potential of Oxidative Asymmetric Catalysis with Continuous Flow Electrochemistry.

In the field of catalytic asymmetric synthesis, the less-treated path lies in oxidative catalytic asymmetric transformations. The hurdles of pinpointing the appropriate chemical oxidants and addressing their compatibility issues with catalysts and functionalities present significant challenges. Organic electrochemistry, employing traceless electrons for redox reactions, is underscored as a promising solution. However, the commonly used electrolysis in batch cells introduces its own set of challenges, hindering the advancement of electrochemical asymmetric catalysis. Here we introduce a microfluidic electrochemistry platform with single-pass continuous flow reactors that exhibits a wide-ranging applicability to various oxidative asymmetric catalytic transformations. This is exemplified through the sulfenylation of 1,3-dicarbonyls, dehydrogenative C-C coupling, and dehydrogenative alkene annulation processes. The unique properties of microfluidic electrochemical reactors not only eliminate the need for chemical oxidants but also enhance reaction efficiency and reduce the use of additives and electrolytes. These salient features of microfluidic electrochemistry expedite the discovery and development of oxidative asymmetric transformations. In addition, the continuous production facilitated by parallel single-pass reactors ensures straightforward reaction upscaling, removing the necessity for reoptimization across various scales, as evidenced by direct translation from milligram screening to hectogram asymmetric synthesis.

Selectivity in Catalytic Asymmetric Formal [3 + 3] Annulation of 2-Enoyl-pyridine N-Oxide with Benzyl Methyl Ketone

The asymmetric formal [3 + 3] annulation process of (E)-2-(3-phenylacryloyl)pyridine N-oxide with benzyl methyl ketone was investigated. The possibility of a stereoselective outcome was checked using salts of natural amino acids, as well as chiral bifunctional derivatives containing amino groups and thiourea or squaramide fragments as organocatalysts. Different types of organocatalysts applied led to opposite enantiomers of 2-(3-oxo-4,5-diphenyl-cyclohex-1-en-yl)pyridine 1-oxide (up to 60% ee). Spectroscopic analysis of the isolated product and analysis of the reaction course was carried out, taking into account the obtained regio- and stereoselectivity. In order to verify the postulated results, calculations of the energy of the intermediate reaction products and the final product using the Kohn–Sham Density Functional Theory (KS-DFT) were made.

Base-mediated [4 + 3] annulation of α-halogen hydroximate with o-QMs: Facile access to 1, 4-benzoxazepine scaffold

An efficient and facile approach to 1, 4-benzoxazepine was developed from α-halogen hydroximate and o-QMs. This protocol underwent formal [4 + 3] annulation process smoothly under mild reaction conditions to afford the desired products in moderate to excellent yields. A plausible mechanism was proposed.

Recent development in the synthesis of imidazo[1,5-a]indole derivatives: an in-depth overview.

In the realm of nitrogen-fused heterocycles, imidazo[1,5-a]indole and its derivatives are recognized as privileged structural patterns in various pharmaceutical drugs and biologically active natural products, emphasizing their significance. This review comprehensively explores the synthetic strategies for constructing imidazo[1,5-a]indole scaffolds, with a particular focus on transition metal-catalyzed methodologies. The primary highlighted method is [4 + 1] annulation, along with other notable approaches such as C-H activation/cyclization, enantioselective C-H annulation, intramolecular hydroamination, and double cyclization processes.

Dealing with Unsatisfactory Arbitral Awards: Observing the Grounds of Annulment of Arbitral Awards in Indonesia

Arbitration is often preferred because its award is final and binding. Nonetheless, this premise is not absolute. There are situations where the arbitral award can be set aside. In Indonesia, this procedure is locally known as annulment and requested to the District Court (or Pengadilan Negeri ‘PN’). Article 70 of Law No. 30 of 1999 on Arbitration and Alternative Dispute Resolution (‘AADR Law’) sets out three main grounds to request an annulment, i.e., forgery, concealment, and deception. However, the General Elucidation of the AADR Law suggests a non-exhaustive list of grounds by using the term ‘amongst others’. This vague phrase opens the grounds for interpretation by the Court, and parties seeking annulment can request grounds outside those expressly listed in the AADR Law. The most common examples include ultra petita, unfairness, and even Article 643 of the Reglement op de Rechtsvordering (RV), which have been previously invoked in annulment cases. The authors aim to scrutinize the prevailing laws and decisions regarding the annulment of the arbitral award and delve deeper into the grounds for arbitral award annulment requests in Indonesia from 2019-2022. Seventy cases were examined during this period. Out of seventy cases, twenty-nine cases were filed for an appeal to the Supreme Court, and two cases out of the twenty-nine cases sent for civil review. In total, fourteen cases were granted annulment, whereas twenty-two requests were held inadmissible (niet onvankelijke verklaard), and thirty-four requests were rejected. Arbitration, Grounds for Annulment, Grounds for Setting Aside, Arbitral Award, Award Annulment, Article 70 of Law Number 30 of 1999 on Arbitration and Alternative Dispute Resolution, Award Annulment in Indonesia, Award Annulment Process, Unsatisfactory Arbitral Award