Intermolecular Annulation Research Articles

Recent Developments in Copper-Catalyzed Annulations for Synthesis of Spirooxindoles.

Spirooxindoles represent a special scaffold for pharmaceuticals and natural products, and significant advancements have been achieved in their synthesis in recent years. Among these, transition metal catalysis, particularly copper catalysis, has emerged as an efficient and reliable method for the synthesis of spirooxindoles. Based on different reaction types, two distinct substrate types have been summarized and classified by us for constructing spirooxindole scaffolds via intramolecular and intermolecular annulations. This review outlines the latest advancements in copper-catalyzed cyclization reactions for synthesizing spirooxindoles and provides detailed insights into the types of annulation reactions and their possible reaction mechanisms.

Ligand-Enabled Palladium-Catalyzed [3 + 2] Annulation of Aryl Iodides with Maleimides via C(sp3)-H Activation.

Palladium-catalyzed intermolecular [3 + 2] annulation reactions via C-H activation represent a powerful and charming tool for assembling cyclopentanes. Herein, we have developed a strategy for the palladium-catalyzed intermolecular alkene-relayed annulation reaction of aryl iodides and maleimides via C(sp3)-H activation for the construction of polycyclic structures. In contrast to directed-group-enabled intermolecular maleimide-relayed [3 + 2] annulation reactions, this protocol stands out for its utilization of aryl iodides as substrates. Notably, monoprotected amino acids played a crucial role as ligands in this reaction, which is rarely observed in C-H activation reactions initiated with organohalides.

Gold catalysis in quinoline synthesis.

Quinolines are biologically and pharmaceutically important N-heterocyclic aromatic compounds, which have broad applications in medicinal chemistry. Thus, their efficient synthesis has attracted extensive attention, and a broad range of synthetic strategies have been established. Of note, gold-catalyzed methodologies for the synthesis of quinolines have greatly advanced this field. Various gold-catalyzed intermolecular annulation reactions, such as annulations of aniline derivatives with carbonyl compounds or alkynes, annulations of anthranils with alkynes, and annulations based on A3-coupling reactions, as well as intramolecular cyclization reactions of azide-tethered alkynes, 1,2-diphenylethynes, and 2-ethynyl N-aryl indoles, have been developed. This review provides an overview of this exciting research area. Typical achievements in reaction methodologies and plausible reaction mechanisms are summarized.

Synthesis of 1,2′‐Spirobi[indene]‐1,3‐diones by Pd(II)‐Catalyzed C−H Activation and Alkynes Annulation Reaction

AbstractAn intermolecular annulation reaction of 2‐aryl‐1,3‐indandions with alkynes was reported using Pd(OAc)2 to access spirobi[indene]‐1,3‐diones. Under palladium catalysis, the substrates form a homocoupling dimer intermediate through a catalytic dehydrogenative cross‐coupling process. The palladium(II) species could come from dimer or 2‐aryl‐1,3‐indandion. Notably, this pathway is not typically observed in enol‐directed formal sp3 C−H functionalization/oxidative annulation palladium chemistry. This transformation provides a route to access a class of functionalized spiro carbocyclic indenes.

Pd-catalyzed asymmetric Larock reaction for the atroposelective synthesis of N─N chiral indoles.

Atropisomeric indoles defined by a N─N axis are an important class of heterocycles in synthetic and medicinal chemistry and material sciences. However, they remain heavily underexplored due to limited synthetic methods and challenging stereocontrol over the short N─N bonds. Here, we report highly atroposelective access to N─N axially chiral indoles via the asymmetric Larock reaction. This protocol leveraged the powerful role of chiral phosphoramidite ligand to attenuate the common ligand dissociation in the original Larock reaction, forming N─N chiral indoles with excellent functional group tolerance and high enantioselectivity via palladium-catalyzed intermolecular annulation between readily available o-iodoaniline and alkynes. The multifunctionality in the prepared chiral indoles allowed diverse post-coupling synthetic transformations, affording a broad array of functionalized chiral indoles. Experimental and computational studies have been conducted to explore the reaction mechanism, elucidating the enantio-determining and rate-limiting steps.

Brønsted Acid-Promoted Cyclodimerization of α,β-Unsaturated γ-Ketoesters: Construction of Fused Pyrano-ketal-lactones and γ-Ylidene-butenolides.

Unprecedented MsOH-promoted diastereoselective cascade dimerization and intramolecular lactonization of readily accessible α,β-unsaturated γ-ketoesters are presented. The results obtained in this work, control experiments, and density functional theory (DFT) calculations suggested that the initial enolization and E to Z isomerization/equilibration of olefin (C=C) of substrate α,β-unsaturated γ-ketoesters give a Z-isomer preferentially over an E-isomer. Subsequently, the Z-isomer undergoes intermolecular annulation with α,β-unsaturated γ-ketoesters via domino Michael addition/ketalization/lactonization steps to furnish fused tetracyclic pyrano-ketal-lactone. However, the Z-isomer prefers intramolecular trans-esterification in a competing pathway and gives bicyclic γ-ylidene-butenolide. The key features of this work include simple Brønsted acid catalysis, the formation of three bonds, two rings, and three contiguous stereogenic centers in a single step, DFT calculations, and the assignment of relative stereochemistry through X-ray diffraction (XRD) and two-dimensional (2D) nuclear magnetic resonance (NMR) analyses.

Selective synthesis of pyridazine-fused chromones and 3-pyridazinyl chromones through intermolecular chromone annulation of o-hydroxyphenylenaminones with aryldiazonium salts

A chemodivergent and skeleton-controllable annulation reactions of readily available o-HPEs and aryldiazonium salts was described for the synthesis of highly functionalized pyridazine-fused chromones with high antiviral activity and higher safety.

Synthesis of pyrazino[1,2-b]indazoles via cascade cyclization of indazole aldehydes with propargylic amines.

An efficient intermolecular annulation of indazole aldehydes with propargylic amines has been developed for the synthesis of pyrazinoindazoles under catalyst- and additive-free conditions. This straightforward methodology was found to feature a wide substrate scope, high atom economy and environmental advantages. The bioactivity results of these new pyrazino[1,2-b]indazoles showed that some of them exhibited significant antifungal activity.

CuBr2-mediated dehydrogenative [4+2] annulation of 1-naphthyl-1,3-indandiones and alkenes.

Intermolecular annulation reactions of 1-naphthyl-1,3-indandiones with alkenes proceed efficiently in the presence of a copper catalyst to generate spirocarbocycle compounds. Various spirocyclic molecules bearing an all-carbon quaternary center could be obtained by this novel method with good yields, excellent regioselectivity, and good functional group tolerance. A radical mechanism is proposed based on the HRMS analysis results of control experiments.

Pd-Catalyzed Vicinal Intermolecular Annulations of Iodoarenes, Indoles, and Carbazoles with Enynes.

Reaching the formidable C-H corners has been one of the top priorities of organic chemists in the recent past. This prompted us to disclose herein a vicinal annulation of 2-iodo benzoates, indoles, and carbazoles with N-embedded 1,6-enynes through 7-/8-membered palladacycles. The relay does not require the assistance of any directing group, leading to multicyclic scaffolds, which are readily diversified to an array of adducts (with new functional tethers and/or three contiguous stereocenters), in which we showcase a rare benzylic mono-oxygenation.

Transition-Metal-Catalyzed Dehydrogenative (3 + 2) Annulation of Aromatic Compounds: Synthesis of Indenes and Indanes via Dual Functionalization of Benzylic and ortho C-H Bonds.

Intermolecular (3 + 2) annulation emerges as a potent approach for constructing 5-membered carbocycles through the fusion of two distinct components. This synopsis encapsulates recent strides in the realm of transition-metal-catalyzed dehydrogenative (3 + 2) annulation of aromatic hydrocarbons, achieved through the dual functionalization of benzylic and ortho C-H bonds. Encompassing three pivotal strategies, namely, (i) C-H bond activation, (ii) benzylic oxidation, and (iii) π-coordination activation, this review offers an overview of the field's recent developments.

Palladium-Catalyzed Intermolecular Dearomatization Annulation Cascade Reaction of Furans for Stereoselective Access to 2,5-Dihydrofurans.

A novel palladium-catalyzed intermolecular dearomatization of furans with alkynes via a three-component formal [3 + 2] spiroannulation/allylic substitution cascade reaction has been successfully developed for the stereoselective assembly of spiro 2,5-dihydrofuran frameworks. High step economy and efficacy as well as excellent stereoselectivity were achieved for a broad substrate scope. Two new C-C bonds and one new C-O bond were generated sequentially in a one-pot manipulation. The yielded spiro 2,5-dihydrofuran skeleton bearing a tetrasubstituted carbon center constitutes the core structure for plenty of useful natural products or corresponding analogues. This work represents a significant advancement in the dearomatization strategy for furan heterocycles and provides a practical methodology for expedited access to complex spiro dihydrofuran scaffolds.

Versatile Tetrasilane for Time-Controlled Palladium-Catalyzed Divergent Synthesis of Silacycles via C-H Activation.

Transition-metal-catalyzed intermolecular annulation of silicon reagents with organic molecules is still underdeveloped due to the scarcity of silicon reagent types and their diverse reactivity. Herein, a readily accessible silicon reagent (octamethyl-1,4-dioxacyclohexasilane) has been developed for divergent synthesis of silacycles via time-controlled palladium-catalyzed cascade C-H silacyclization. This protocol enables the rapid and selective transformation of acrylamides into spirosilacycles with different ring sizes, including benzodioxatetrasilecines, benzooxadisilepines, and benzosiloles, in moderate to good yields through a time switch. Notably, the tetrasilane reagent can also be utilized for C-H silacyclization of 2-halo-N-methacryloylbenzamides and 2-iodobiphenyls, leading to diverse fused silacycles. Furthermore, several synthetic transformations of products are achieved. A series of mechanistic studies demonstrate the transformation relationships and possible pathways among ten-, seven-, and five-membered silacycles.

Rhodium(III)‐Catalyzed Divergent C−H Functionalization of N‐Aryl Amidines with Iodonium Ylides: Access to Carbazolones and Zwitterionic Salts

AbstractWe described an Rhodium(III)‐catalyzed divergent C−H bond functionalization of N‐aryl amidines with iodonium ylides. Carbazolones and zwitterionic salts were diversely constructed through intermolecular annulation and intramolecular proton transfer under the different reaction conditions. This protocol is operationally simple and tolerates a variety of functional groups. The efficient post‐modification of pharmaceutical molecules demonstrates its practicability.

Cooperative Asymmetric Dual Catalysis Involving a Chiral N-Heterocyclic Carbene Organocatalyst and Palladium in an Annulation Reaction: Mechanism and Origin of Stereoselectivity

The increasing number of examples on cooperative dual catalysis involving organocatalysts and transition metal catalysts indicate their wider acceptance and utility in synthetic applications. In such reactions, the concurrent activation of substrates is likely to present mechanistic complexities. In one of the studies, designed for intermolecular annulation aimed at making a biologically important class of benzazepines, chiral N-heterocyclic carbenes engage an enal in the form of a Breslow intermediate (nucleophilic partner) and Pd(0) activates rac-vinyl benzoxazinanone as a Pd-π-allyl intermediate (electrophile). Given the current importance and the lack of molecular insights on the origin of high enantio-/diastereoselectivities and cooperativity in such dual catalytic reactions, we have undertaken a detailed computational investigation using density functional theory. The kinetically most accessible Pd-π-allyl intermediate from the (S)- and (R)-vinyl benzoxazinanone is found to be Cre and Csi (where re and si denote the open prochiral faces through which the nucleophile can add), respectively. An energetically favorable change in configuration from Csi to Cre, via a PPh3-induced π–σ–π isomerization, suggests that an enantioconvergent mechanism was responsible for the enrichment of the desired Cre Pd-π-allyl species. Ready availability of Cre and the higher energy transition state (TS) for the alternative nucleophilic addition to the Csi is responsible for the high ee (computed >99%, experimental 99%). Improved shape complementarity between the chiral electrophile and nucleophile in the most preferred C–C bond formation TS as well as the noncovalent interactions (C–H··· π, π···π, and H-bonding) therein dictates the diastereoselectivity. An intramolecular C–N bond formation to the final annulated product is the turnover-determining TS. Molecular insights and energetic features, as obtained through our computations, are found to be in concert with several experimental observations, even beyond the sense and extent of stereoselectivities.

Ru-catalyzed C-H activation/cyclization of oximes with sulfoxonium ylides to access isoquinolines.

An external oxidant free Ru(II)-catalyzed C-H activation followed by an intermolecular annulation between oximes and sulfoxonium ylides has been developed. This transformation proceeds smoothly with a broad range of substrates, affording a series of isoquinoline derivatives in moderate to good yields. This protocol was successfully applied to the synthesis of moxaverine.

Selective Syntheses of Coumarin and Benzofuran Derivatives Using Phenols and α-Methoxy-β-ketoesters

AbstractSelective syntheses of coumarin and benzofuran derivatives were achieved via HClO4-mediated intermolecular annulation using phenols and α-methoxy-β-ketoesters. Coumarins are formed under dehydrated conditions, whereas benzofurans are formed in the presence of water. In the synthetic process of benzofurans, α-methoxy-β-ketoesters are converted into α-methoxyacetophenones, and the methoxy group is an important element in the intermolecular annulation.

Ru(II)-catalyzed synthesis of poly-substituted furans via intermolecular oxidative annulation reaction of ethyl 3-oxo-3-phenylpropanoates with aryl alkynes/heteroaryl alkynes.

The oxidative annulation reaction of ethyl 3-oxo-3-phenylpropanoates with internal alkynes proceeds efficiently in the presence of a Ru(II)-catalyst, a copper oxidant and an additive such as AgSbF6 to give poly-substituted furans, which offers a novel method for the selective construction of poly-substituted furans. The reaction has wider substrate scope with simple starting materials, and the desired tetrasubstituted furans were prepared in good to excellent yields.

Thiol-promoted intermolecular cyclization to synthesize 1,2,4-oxadiazoles including tioxazafen under transition metal-free conditions.

A simple and efficient one-pot intermolecular annulation reaction for the synthesis of 1,2,4-oxadiazoles from amidoximes and benzyl thiols has been developed, in which benzyl thiols act as not only reactants but also organo-catalysts. The control experiments proved that thiol substrates could facilitate the dehydroaromatization step. High yield, functional group diversity and transition metal-free, extra oxidant-free, and mild conditions are the important practical features. Moreover, this protocol provides an effective alternative method for the synthesis of a commercially available broad-spectrum nematicide, tioxazafen.

Direct Assembly of Polysubstituted Furans with Dimethyl Sulfoxide as a Multipurpose Precursor via β‐C(sp3)−H Functionalization of Saturated Ketones

AbstractAn I2/K2S2O8 mediated multiple β‐C(sp3)−H functionalization reaction for the construction of polysubstituted furans has been established from readily available ethyl ketones and dimethyl sulfoxide. This transformation features dimethyl sulfoxide as a multipurpose precursor, acting as the precursor of the oxygen, methyl, and sulfur methyl units. Six new chemical bonds, involving two C−C, two C−O, and one C−S bonds were formed sequentially during the intermolecular oxidative annulation process.magnified image