Cycloisomerization Process Research Articles

Attempted synthesis of the central 2,2-disubstituted pseudoindoxyl core of Austamide via a [Au]-catalyzed nitroalkyne cycloisomerization and intramolecular [3 + 2]-cycloaddition

Herein, we describe an Au-catalyzed cycloisomerization process of a nitroalkyne that was projected to construct the central 2,2-disubstituted pseudoindoxyl core of the natural product Austamide. Our intended strategy for forging the pseudoindoxyl core is based on the nitroalkyne cycloisomerization followed by a subsequent intramolecular [3 + 2] cycloaddition. However, the [3 + 2] cycloaddition occurred in an undesired manner, ultimately leading to a complex hexacyclic scaffold.

Skeletal and Mechanistic Diversity in Ir‐Catalyzed Cycloisomerizations of Allene‐Tethered Pyrroles and Indoles

AbstractPyrroles and indoles bearing N‐allenyl tethers participate in a variety of iridium‐catalyzed cycloisomerization processes initiated by a C−H activation step, to deliver a diversity of synthetically relevant azaheterocyclic products. By appropriate selection of the ancillary ligand and the substitution pattern of the allene, the reactions can diverge from simple intramolecular hydrocarbonations to tandem processes involving intriguing mechanistic issues. Accordingly, a wide range of heterocyclic structures ranging from dihydro‐indolizines and pyridoindoles to tetrahydroindolizines, as well as cyclopropane‐fused tetrahydroindolizines can be obtained. Moreover, by using chiral ligands, these cascade processes can be carried out in an enantioselective manner. DFT studies provide insights into the underlying mechanisms and justify the observed chemo‐ regio‐ and stereoselectivities.

Skeletal and Mechanistic Diversity in Ir-Catalyzed Cycloisomerizations of Allene-Tethered Pyrroles and Indoles.

Pyrroles and indoles bearing N-allenyl tethers participate in a variety of iridium-catalyzed cycloisomerization processes initiated by a C-H activation step, to deliver a diversity of synthetically relevant azaheterocyclic products. By appropriate selection of the ancillary ligand and the substitution pattern of the allene, the reactions can diverge from simple intramolecular hydrocarbonations to tandem processes involving intriguing mechanistic issues. Accordingly, a wide range of heterocyclic structures ranging from dihydro-indolizines and pyridoindoles to tetrahydroindolizines, as well as cyclopropane-fused tetrahydroindolizines can be obtained. Moreover, by using chiral ligands, these cascade processes can be carried out in an enantioselective manner. DFT studies provide insights into the underlying mechanisms and justify the observed chemo- regio- and stereoselectivities.

Puzzling Structure of the Key Intermediates in Gold(I)-catalyzed Cyclization Reactions of Enynes and Allenenes.

We identify the dominant structures of the intermediates of gold(I)-catalyzed cyclizations of 1,5-enynes and 1,5-allenenes through computational analysis as gold(I) cyclopropylcarbenes, endocyclic vinylgold complexes and previously unreported non-classical carbocationic minima. In contrast to 1,6-enynes, the exocyclic carbocations are found to be less stable. Cyclopropylcarbene structures are consistently favoured as the most stable intermediates for all studied substitution patterns. We validate the computational methods used by using DLPNO-CCSD(T) energies as a benchmark, indicating that the B3LYP-D3 and M06-D3 functionals are most accurate for energy determination, while NPA charges are mostly insensitive to functional. The evolution of a 1,6-enyne in a single-cleavage or double-cleavage rearrangement is attributed to the barrierless evolution of a common cyclopropyl-gold(I) carbocation non-stationary geometry. Our findings provide insights into reaction pathways and substrate dependence of the cycloisomerization processes.

Palladium‐Catalyzed Cycloisomerization of 1,6‐Allene‐Ene via [1,8]‐Sigmatropic Hydrogen Shift of Allylic C−H

AbstractA ligand‐free palladium‐promoted [1,8]‐sigmatropic hydrogen shift reaction of 1,6‐allene‐ene was reported, which went through an intramolecular Ene cyclization using base as a hydrogen shuttle. Notably, the transformation could realize the HAT process via the hydrogen shift from an old allylic C−H bond to a new one in the presence of oxidant, between which have low BDE distinction. The mild reaction conditions, high atom economy and good chemo/regioselectivity proved the valuable of this strategy. The control experiments using acetone‐D6/D2O proved that neither solvent nor water were involved in the cycloisomerization process and HAT process was more convincible. The target products could achieve more valuable molecules via convenient synthetic transformation.

Furan Synthesis via a Tandem 1,2-Acyloxy Migration/[3 + 2] Cycloaddition/Aromatization of Enol Ether-Tethered Propargylic Esters

An effective method for the synthesis of furans is developed via a tandem 1,2-acyloxy migration/intramolecular [3 + 2] cycloaddition/aromatization of enol ether-tethered propargylic esters. The reaction exhibits excellent functional group tolerance, broad substrate scope, and excellent chemoselectivity. The isolation of dihydrofuran intermediates in some cases gives more insight into the [3 + 2] cycloisomerization process.

Nickel Phosphite-Catalyzed Tetradehydro-Diels-Alder Reactions of (E)-3-ene-1,8-diynes.

A nickel-catalyzed tetradehydro-Diels-Alder reaction of (E)-3-ene-1,8-diynes for the preparation of isoindolines, dihydroisobenzofurans, and tetrahydroisoquinolines has been developed. A series of air-stable nickel catalysts were used in this study, including the novel nickel(0)-phosphite catalysts, Ni[P(O-3,5-Me-Ph)3]4, Ni[P(O-1-naphthyl)3]4, and Ni[P(O-2-naphthyl)3]4. To help understand the type of intermediate in the initial cycloisomerization process, the trapping of nickellacycle intermediates with pinacolborane to yield vinyl boronates is also discussed.

Sequencing palladium-catalyzed cycloisomerization cascades in a synthesis of the gelsemine core.

Transition metal-catalyzed cycloisomerization is a powerful strategy for the construction of cyclic organic molecules, and the use of palladium catalysts can deliver a wide range of monocyclic and bicyclic products. However, applications of cycloisomerizations in complex target synthesis in which more than one cycloisomerization process is deployed in a cascade context are rare. Here we report investigations of the relative rates of two different types of ene-ynamide cycloisomerization that form fused and spirocyclic rings, and use of these results to design a sequence-controlled cascade cycloisomerization that prepares the tetracyclic core of gelsemine in a single step. Crucial to this work was an evaluation of the kinetics of each cycloisomerization in competition experiments, which revealed a key influence of the ynamide electron-withdrawing group on the cycloisomerization reaction.

Synthesis of Polycyclic 3,3'-Biindoles via AgOTf-Catalyzed Nucleophilic Addition and Cycloisomerization.

A method for the rapid synthesis of polycyclic 3,3'-biindole derivatives has been developed through AgOTf-catalyzed nucleophilic addition and cycloisomerization processes. The cascade reaction employs readily accessible indoles and their N-2-formylphenyl derivatives and provides functionalized polycyclic 3,3'-biindoles in moderate to good yields under mild conditions. This reaction is highly efficient and takes only several minutes (∼5 min). Notably, the method is also highlighted by a Selectfluor-mediated oxidation reaction that quickly generates the oxindole derivatives.

Cu(I)-Catalyzed Cross-Coupling Rearrangements of Terminal Alkynes with Tropylium Tetrafluoroborate: Facile Access to Barbaralyl-Substituted Allenyl Acid Esters and 7-Alkynyl Cycloheptatrienes.

Herein, we report a novel strategy for the formation of copper carbene via the cycloisomerization of the π-alkyne-Cu(I) complex from terminal alkynes and tropylium tetrafluoroborate. Mechanistic studies and DFT calculations indicate that the reaction undergoes the intramolecular cycloisomerization process from the π-alkyne-Cu(I) complex to afford the copper carbene intermediate, followed by migratory insertion with the second terminal alkyne to afford the barbaralyl-substituted allenyl acid esters. In addition, we develop a mild and highly efficient Cu(I)-catalyzed cross-coupling protocol to synthesize 7-alkynyl cycloheptatrienes that has a broad functional group tolerance and is applicable to the late-stage functionalization of natural products.

Merging radical-polar crossover/cycloisomerization processes: access to polyfunctional furans enabled by metallaphotoredox catalysis

Metallaphotoredox catalysis for furan synthesis: The cyclisation of yne-enones proceeds smoothly via consecutive reductive radical-polar crossover and cycloisomerization processes enabled by cooperative photoredox-neutral and copper catalysis.

Recent Achievement in the Synthesis of Benzo[b]furans.

Benzo[b]furan derivatives are oxygen-containing heterocyclic compounds consisting of fused benzene and furan rings and are present in a large number of natural and non-natural compounds. This class of compounds has a wide spectrum of biological activities, such as antiarrhythmic, anticancer, inflammatory, antioxidant, antimicrobial, and antiviral. Furthermore, benzo[b]furan derivatives have also been applied in various areas, such as organic electroluminescence device materials and organic dyes, photosensitizing material, organic synthesis as building blocks or intermediates. Because of a broad range of applicability, the synthesis of benzo[b]furan derivative has drawn great attention of chemists and many studies on the synthesis of this class of compounds have been reported recently. This review will give an overview of benzo[b]furan preparation based on studies dating back to the year 2012. In this review, recent development in the synthesis of benzo[b]furans are discussed. There has been increasingly new methodologies for the construction of benzo[b]furans skeleton to improve efficiency or develop environmentally friendly procedures. In some studies, reaction mechanisms were also outlined. Many methods for the synthesis of benzo[b]furans have been reported recently. Most of them involve cyclization or cycloisomerization processes. Unquestionably, more imaginative strategies for the construction of benzo[b]furan skeleton will be established in the near future. Application of known methods to natural products or drug synthesis, on industrial scale for the synthesis of economically or medicinally important benzo[ b]furans will probably be paid attention to.

Attempted synthesis of central furopyran core of Diocollettines A via a Gold-Catalyzed cascade 1,6-Diyne cycloisomerization process

Herein, we describe an Au-catalyzed cascade diyne cycloisomerization process that was projected to construct the central furopyran bicyclic core of Diocollettines A. Our intended strategy for the annulation of the third thf ring is based on epoxidation and subsequent intramolecular acetalization. However, the initial alkynol cyclization occurred in an undesired 5-exo-dig mode, ultimately leading to an undesired furopyran.

Cobalt-Catalyzed Cycloisomerization of N,N-Diallylanilines

Cobalt catalysts bearing 2-imino-1,10-phenanthroline ligands are quite efficient bench-stable catalysts for the oligomerization of ethylenes. Herein, their further application was developed in the catalytic transformation of N,N-diallylanilines to pyrrolidines through a cycloisomerization process. In this protocol, chlorobenzene is a vital additive to promote reaction efficiency.

Allenes and Derivatives in Gold(I)- and Platinum(II)-Catalyzed Formal Cycloadditions.

ConspectusCycloaddition reactions, by involving the formation of at least two bonds and one cycle in a single operation, represent one of the more practical ways to assemble carbo- and heterocyclic structures from simple acyclic precursors. Especially appealing are formal cycloadditions promoted by transition metals, owing to the ability of these reagents to open mechanisms that are not accessible using classical chemistry. Therefore, along the years, a great variety of annulations based on first-, and particularly second-row transition metals have been discovered. Most of these reactions involve inner sphere mechanisms, with the metal participating via standard oxidative addition or reductive elimination processes. Curiously, metals of the third row like platinum and, especially, gold remained largely unexplored, likely because of the belief that they were inert and expensive. However, from the beginning of this century, many groups realized that these metals can open very interesting mechanistic scenarios and promote novel types of transformations. In particular, the π-acidic, carbophilic behavior of gold(I) complexes, together with the possibility of tuning their reactivity using designed ligands, has triggered important activity in the field. Many gold-catalyzed transformations involved addition or cycloisomerization processes, but during recent years, there have been also important advances in the development of formal cycloaddition reactions. While many of these reactions rely on the activation of alkynes, there has been an increasing number of reports that exploit the peculiar reactivities of allenes and derivatives.In this Account, we present recent efforts on the development of platinum- and gold-catalyzed formal cycloadditions of allenes. For the sake of simplicity, we only include annulations initiated by a direct metal-promoted activation of the allene moiety. Thus, alternative Pt- or Au-catalyzed reactions wherein the allene does not interact with the metal catalyst are not covered. Upon activation by the metals, allenes generate allyl-cation alkenylmetal species that can behave as 1,2- or 1,3-carbon dipoles in cycloaddition processes. Especially relevant is the reactivity of allenamides. The presence of the amide substituent provides for the generation of gold intermediates with a good balance of reactivity and stability, which can therefore react with the corresponding partners in a controlled manner. Moreover, despite the difficulties associated with the transfer of stereochemical information from chiral linear gold(I) complexes, a variety of enantioselective gold-catalyzed annulations have been discovered.This Account is organized considering the number of atoms engaged in the annulation process, and when possible, we present the results in a chronological order.

Iron- or Palladium-Catalyzed Reaction Cascades Merging Cycloisomerization and Cross-Coupling Chemistry.

A conceptually novel reaction cascade is presented, which allows readily available enynes to be converted into functionalized 1,3-dienes comprising a stereodefined tetrasubstituted alkene unit; such compounds are difficult to make by conventional means. The overall transformation is thought to commence with formation of a metallacyclic intermediate that evolves via cleavage of an unstrained C-X bond in its backbone. This non-canonical cycloisomerization process is followed by a cross-coupling step, such that reductive C-C bond formation regenerates the necessary low-valent metal fragment and hence closes an intricate catalytic cycle. The cascade entails the formation of two new C-C bonds at the expense of the constitutional C-X entity of the substrate: importantly, the extruded group X must not be a heteroelement (X=O, NR), since activated β-C-C bonds can also be broken. This concern was reduced to practice in two largely complementary formats: one procedure relies on the use of alkyl-Grignard reagents in combination with catalytic amounts of Fe(acac)3, whereas the second method amalgamates cycloisomerization with Suzuki coupling by recourse to arylboronic acids and phosphine-ligated palladium catalysts.

Cationic Gold(I)-Catalyzed Cascade Bicyclizations for Divergent Synthesis of (Spiro)polyheterocycles

We herein report an expeditious synthetic strategy to access diverse (spiro)polyheterocycles from easily available starting materials in two operational steps including an Ugi four-component reaction and a cationic gold(I)-catalyzed cascade bicyclization. Divergent synthesis of these structurally complex pyrido[2,1-a]isoindol-4(6H)-ones and spiroisoquinoline-pyrrole-3,5′-diones via a cascade nucleophilic cyclization/intramolecular 1,3-migration/1,5-enyne cycloisomerization process and a tandem hydroamination/Michael addition sequence, respectively, was controlled by substituents, where the electronic effect on the migrating groups and steric effect of the secondary amide moieties play crucial roles.

Uncovering Subtle Ligand Effects of Phosphines Using Gold(I) Catalysis.

Herein, we report the integration of simple linear regressions with gold(I) catalysis to interrogate the influence of phosphine structure on metal-catalyzed organic transformations. We demonstrate that observed product ratios in [4 + 3]/[4 + 2] cycloisomerization processes are influenced by both steric and electronic properties of the phosphine, which can be represented by the Au-Cl distance. In contrast, the observed selectivity of a similar [2 + 3]/[2 + 2] cycloisomerization is governed by L/B1, a steric parameter. Using this correlation, we were able to accurately predict the selectivity of a previously untested, Buchwald-type ligand to enhance selectivity for the same transformation. This ligand found further utility in increasing the selectivity of a previously reported gold-catalyzed cycloisomerization/arylation of 1,6-enynes by ~1 kcal/mol.

Ring Expansion and Skeletal Rearrangement of Propargyl Alcohol Substituted Aziridines Induced by Ruthenium Complexes.

The ring expansion and skeletal rearrangement of two types of propargyl alcohol substituted aziridines with or without cycloalkane moieties was induced by a ruthenium cyclopentadienyl phosphine complex. In the simple aziridine system with no cycloalkane, the unique cycloisomerization process altered the absolute connectivity of the two-carbon unit in the three-membered ring to give organometallic products with substituted pyridine or dihydropyridine ligands. For the aziridine on a cyclohexyl ring, the cycloisomerization process was controlled by an interchange process between vinylidene and allenylidene species, thus creating a better relative configuration of the aziridinyl and the alkynyl units. This determines the stereochemistry of the metal carbene products of the octahydroindole derivatives. The structures of five products were determined by X-ray diffraction analysis.

Cyclization of 2‐Ethynylphenyl Vinyl Ether Catalyzed by a Ruthenium Complex: Mechanism of Catalytic Cyclization and Stoichiometric Cycloisomerization

AbstractCatalytic cyclization reactions and new stoichiometric skeletal rearrangement cycloisomerizations of 2‐ethynylphenyl vinyl ethers containing methyl substituents on the vinyl groups by using [Ru]Cl {[Ru]=Cp(PPh3)2Ru, Cp=η5‐cyclopentadienyl} were observed in MeOH and CH2Cl2, respectively. In MeOH, the catalytic cyclization of three different enynes gave the corresponding benzoxepine derivatives in high yields in each case. Interestingly, in the stoichiometric reactions of [Ru]Cl with enynes, two unprecedented rearrangements of enynes were observed in CH2Cl2. The presence of a methyl group in the vinyl unit plays a critical role in choosing one of the double bonds of the vinylidene ligand, that is, the Ru=Cα or the Cα=Cβ bond, for the [2+2] cycloaddition in the cycloisomerization processes. Structure determination by single‐crystal X‐ray diffraction analysis along with various isotope studies corroborated the proposed mechanisms.