Annulation Reaction Research Articles

Synthesis of Dibenzoazulene Derivatives via Pd‐Catalyzed (3+2) Alkyne Annulation of Dibenzosuberenone

AbstractNon‐benzenoid PAHs with pentagon/heptagon pairs have unique electronic structures and promising opto‐electronic properties. However, the construction of pentagon/heptagon pair units in these PAHs is challenging. Herein, we developed a Pd‐catalyzed (3+2) alkyne annulation reaction of heptagons, and constructed heptagon/pentagon pairs. The substrate scope is wide and the yield is good to moderate. A series of dibenzoauzlene derivatives were synthesized and their opto‐electronic properties were systematically studied by UV‐vis absorption and cyclic voltammetry. In addition, the dibenzoazulene derivative was further transformed to tropylium cation and tropyl radical, which showed bathochromic shifted absorption and switched aromaticity.

Selective Preparation of Pyrrolo[2,3‐c]tetrahydroquinolines and Indolo[3,2‐c]tetrahydroquinolines through N‐Arylation/Cycloaddition/Rearrangement Annulation Reactions of Alkynyl‐Tethered Oximes with Diaryliodonium Salts

We describe a selective preparation of a variety of functionalized pyrrolo[2,3‐c]tetrahydroquinolines and indolo[3,2‐c]tetrahydroquinolines in 40‐82% and 40‐80% yields from alkynyl‐tethered oximes with diaryliodonium triflates, respectively. The one‐pot reaction underwent N‐arylation, intramolecular [3+2] cycloaddition, selective [1.3] or [3,3]‐rearrangement of N‐O bond in total three steps. Experimental studies revealed that EtOAc solvent and copper(II)‐catalyst played crucial roles on the formation of these two tetrahydroquinoline scaffolds. Moreover, these two tetrahydroquinoline scaffolds could be converted into various tetrahydroquinoline building blocks by further transformations.

Regioselective Synthesis of Thiazole‐5‐thione Based on [2 + 3] Annulation Trapping of α‐Keto Sulfine with Thioamide

Aiming to develop novel annulation reactions using sulfine intermediates, we have established a regioselective formal [2 + 3] cyclization reaction of α‐keto sulfines generated from the elimination of arylacyl sulfoxides and thioamides. This new strategy allows for the synthesis of thiazole‐5‐thiones directly without catalysts or additives. The approach features a step‐economic, one‐pot characteristics via a tandem sequence of in situα‐keto sulfines generation, regiospecifically nucleophilic attack or [3 + 2] cyclizatoin, dithioate (S=C−S−) skeletons formation, and subsequent intramolecular nucleophilic cyclization. This reaction also represents a novel method for constructing dithioate (S=C−S−) skeletons.

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.

Nickel-Catalyzed Asymmetric (3 + 2) Annulations of Propargylic Carbonates and Vinylogous Donors via an Alkenylation Pathway.

The transition-metal-catalyzed alkenylation strategy of propargylic alcohol derivatives provides an efficient protocol to access multifunctional products in a double-nucleophilic attack pattern. While limited relevant asymmetric examples have been reported via palladium catalysis, here we first demonstrate that a nonprecious Ni(0)-based chiral complex can efficiently promote the tandem substitution process between propargylic carbonates and N-trifluoroethyl ketimines via consecutive aza-vinylogous activations, finally accomplishing a (3 + 2) annulation reaction to afford products embedding a 4-methylene-3,4-dihydro-2H-pyrrole framework with high regio-, diastereo-, and enantiocontrol. Their assemblies with a few all-carbon-based vinylogous precursors are also successful, and enantioenriched adducts containing a 3-methylenecyclopentene scaffold are furnished effectively. The substitution patterns for both types of substrates are substantial, and an array of synthetic elaborations is conducted to deliver more versatile architectures with high application potential. In addition, density functional theory calculations and control experiments have been conducted to rationalize the catalytic pathways and regio- and enantioselectivity control.

Mechanistic studies on phosphine-catalyzed [4 + 3] annulation of β′-acetoxy allenoate with 1C,3N-dinucleophile

The mechanism and role of catalyst on the PPh3-catalyzed [4 + 3] annulation reaction have been systematically investigated using density functional theory (DFT) method. Based on the calculations, the possible mechanism contains six steps: nucleophilic addition of PPh3 to allenoate to give Z-configured intermediate, cleavage of CO bond for forming phosphonium diene, nucleophilic addition of phosphonium diene with anionic 1C,3N-dinucleophile, intramolecular [1,5]-proton shift, ring-closure, and dissociation of catalyst. Non-covalent interaction (NCI) analysis shows that the O⋯P interaction would be the key for leading to the Z-configured pathway more favorable and electron localization function (ELF) analysis indicates that the implication of PPh3 can significantly lower the energy barrier involved in CO cleavage process, which mainly because the addition of PPh3 reduces the electron density of CO bond and thus facilities the cleavage of CO bond. This theoretical study would provide some clues for understanding the role of catalyst in a catalytic reaction.

Synthesis and Characterization of a Hercynite-Supported Copper(II) Complex Based on 1,10-Phenanthroline-5,6-dione and Acetylacetone Building Blocks and Its Catalytic Application in Annulation Reactions.

In the present work, a novel Cu(II) complex containing 10-phenanthroline-5,6-dione (phen-dione) and acetylacetone (acac) was prepared via solid-phase synthesis on silica-modified hercynite magnetic nanoparticles (MNPs). The resulting structure underwent thorough structural analysis using diverse instrumental techniques. The catalytic potential of the synthesized Cu(II) complex was successfully demonstrated in the synthesis of 2-amino-3-cyano-4H-chromenes. This was accomplished via a one-pot, three-component condensation reaction involving lawsone, malononitrile, and aromatic aldehydes in ethanol under reflux conditions, leading to remarkably high yields and product purity. Several advantages stem from this investigation. Notably, the use of ethanol as a sustainable and environmentally friendly solvent highlights the ecoconscious approach of this research. Moreover, the reaction conditions were mild and the separation process was straightforward, resulting in reduced byproducts as well as time and cost savings. Furthermore, the catalyst's stability and reusability were studied under optimal conditions, revealing excellent reversibility for up to five cycles without any significant loss of activity. This excellent performance underscores the potential of the Cu(II) complex for sustainable catalytic applications.

Base-Mediated Annulation of ortho-Iminophenols and ortho-Vinylphenols with MBH Carbonates of Isatins: Straightforward Access to Dihydrobenzofuran and Benzofuran Derivatives.

We have developed a convenient synthetic protocol for efficient construction of significant dihydrobenzofuran and benzofuran scaffolds by Lewis base-mediated annulation reaction ortho-iminophenols and ortho-vinylphenols with MBH carbonates of isatins under mild and metal-free conditions. The selective generation of different kinds of dihydrobenzofuran and benzofuran derivatives was successfully achieved by employing different substituted isatin-derived MBH carbonates with ortho-N-tosyliminophenols and ortho-vinylphenols. The features included broad substrate scopes, excellent functional group compatibility, high molecular diversity, and atomic economy.

Photoredox Catalyzed Tandem Denitrogenative [4 + 2] Annulation of 1,2,3-Benzotriazin-4(3H)-ones with Terminal Olefins.

The dihydroisoquinolones skeleton is ubiquitous in natural products and biological molecules. Reported strategies for constructing dihydroisoquinolones usually require noble metal catalysts or stoichiometric oxidants, which limit their wide applications. Herein, we developed a photoredox catalyzed tandem denitrogenative [4 + 2] annulation reaction of 1,2,3-benzotriazin-4(3H)-ones with terminal olefins. A variety of dihydroisoquinolones can be accessed in moderate to excellent yield. This protocol features high atom-economy, mild reaction conditions, and is external oxidant-free, enabling the synthesis of various substituted dihydroisoquinolones.

Palladium-Catalyzed Annulation Reaction of Bay-Diiodinated Arenes with o-Chloroaromatic Carboxylic Acids to Access Polycyclic Aromatic Compounds.

A palladium-catalyzed annulation reaction of bay-diiodinated arenes with o-chloroaromatic carboxylic acids was established. This approach enables the synthesis of a variety of polycyclic aromatic compounds, especially polyalkoxy-substituted polycyclic aromatic compounds, frequently found in discotic liquid-crystalline materials. The investigations indicate that the product 2,3,8,9,12,13-hexakis(hexyloxy)-5-azadibenzo[fg,op]tetracene demonstrates favorable room-temperature liquid-crystalline properties.

Application of Chlorosulfonyl Isocyanate (CSI) in the Synthesis of Fused Tetracyclic Ketone Ring Systems.

Chlorosulfonyl isocyanate (CSI) is a complex reagent capable of facilitating numerous synthetic transformations, including lactam/lactone formation, sulfonylation, Friedel-Crafts-type acylations, and cycloadditions. Annulation reactions to form nitrogen-, oxygen-, and sulfur-bearing heterocycles have been observed with CSI; however, the application of CSI toward the generation of fused cyclic ketone ring systems has not been previously reported. A serendipitous discovery of the pertinence of CSI occurred during a structure-activity relationship campaign around our established lead benzosuberene-based molecule that functions as a potent inhibitor of tubulin polymerization. The benzylic olefin within this molecule represents a promising moiety for further functionalization. CSI was initially investigated as a reagent to effect transformation of this olefin to its corresponding β-lactam functionality, but instead resulted in an unexpected tetracyclic fused ring system in high yield (88%). This finding led to an exploration of the reactivity of CSI with various arenes. Benzosuberene analogues with varying functionalizations were synthesized and treated with CSI, with all examples resulting in a fused ring system except those bearing electron-withdrawing groups. Notably, simplified arene structures with fewer substituents were also observed to undergo cyclization under these conditions. This strategy represents a promising approach for the synthesis of appropriately functionalized tetracyclic ring systems.

Heteroatom-Controlled Three-Component [4 + 3] or [3 + 2] Annulation of Isatin-Derived Azomethine Ylide with Azadiene: Selective Synthesis of Spirooxindole-diazepines and Density Functional Theory Studies.

A novel three-component [4 + 3] annulation reaction of isatin-derived azomethine ylides with azadienes was developed for the first time to efficiently synthesize spirooxindole-diazepines incorporating a benzothiophene moiety under catalyst-free conditions. Effects of the heteroatom of azadiene on the chemoselectivity was investigated. With the use of the azadiene bearing a benzofuran moiety as a substrate, the dominant reaction pathway was changed to an α-[3 + 2] annulation. When azadiene bearing an indenone moiety was used, a distinct γ-[3 + 2] annulation was observed. Density functional theory calculations revealed that a delicate balance between kinetic accessibility and the thermodynamic driving force controlled the competition of different annulation reactions.

Rhodium(III)-Catalyzed Atroposelective Indolization to Access Planar-Chiral Macrocycles.

Macrocycles incorporating conformationally defined indoles are widely found in bioactive natural products. However, the catalytic enantioselective synthesis of planar-chiral indoles via indolization involving macrocyclization remains elusive. Herein, we present the first rhodium(III)-catalyzed atroposelective macrocyclization, which involves the C-H activation of aniline, and a subsequent oxidation [3 + 2] annulation reaction with an intramolecular alkyne. This protocol achieves the construction of indoles, macrocyclization, and planar chirality control in a single step. Importantly, this strategy produces macrocyclic atropisomers bearing full-carbon ansa chains, which represent challenging targets in organic synthesis. Thermodynamic experiments revealed that the rotational barrier of the full-carbon ansa chain-linked macrocyclic atropisomer was lower than that of the atropisomer bearing an oxa-ansa chain. The reaction mechanism was elucidated by computational studies, which revealed that the C-H activation and intramolecular alkyne insertion steps collectively determined the enantioselectivity.

Phosphine-Promoted Synthesis of Naphthoquinones Fused with Cyclopentadienyl Moiety Via Ring Expansion: Synthesis, Reactivity, and Ring Contraction Via [1,5] Sigmatropic Rearrangement.

Phosphine-promoted unprecedented [3 + 2] annulation reactions via ring expansion by using 2-benzylidene-indane-1,3-diones and diynoates for the synthesis of biologically interesting novel naphthoquinones fused with a five-membered ring bearing a phosphorus ylide up to 78% yield are described. Further ring contraction through [1,5] sigmatropic rearrangement to the spiro indan-1,3-diones by mCPBA oxidation was revealed and inferred through oxidation, followed by protonation. The relevant structures were confirmed by single-crystal X-ray diffraction. Electrochemical studies show that the naphthoquinones and lactones with phosphorus ylides could be applied to redox colorimetric materials.

Catalytic N-Alkylation of (Hetero)Aromatic Amines and Tandem Annulation Reactions.

A general and practical approach for N-alkylation of heteroaromatic amines with heteroaromatic alcohols is always challenging and rarely reported. Here, we designed and synthesized phosphine-free, robust, and efficient N,N-bidentate-Co(II) complexes for a universal N-alkylation of amines strategy. This present catalytic methodology can be applied to a wide range of substrates by varying alcohols, including aryl, aliphatic, acyclic, and cyclic groups, with heteroaromatic amines such as aminopyridine, 2-aminopyrimidine, and aminoquinoline to provide diverse monoalkylated organonitrogen compounds in good to excellent yields (108 examples). In addition, the utility of the developed catalytic protocol was also extended successfully for the dehydrogenative synthesis of biologically important quinoline derivatives (11 examples). Particularly, 8-aminoquinoline reacted differently with tandem N-alkylated-transfer hydrogenative byproduct (N-benzyl-1,2,3,4-tetrahydroquinolin-8-amine) was obtained, revealing the catalytic activity of the complex I. The reaction proceeded under environmentally benign conditions, which liberates water as the sole byproduct. Notably, a concise synthesis of acetylcholinesterase inhibitors (AChEIs) scaffolds as potential cognition enhancers illustrated the utility of the present protocol. Interestingly, various control and deuterium-labeled experiments were performed, suggesting that the reaction proceeds via the borrowing hydrogen pathway.

Synergistic Dual Activation Catalysis by Saccharin‐Based Ionic Liquids for Diastereoselective Synthesis of Ferrocene‐Appended Furopyranones, Furochromenones, and Benzofuranones

ABSTRACTA practical and straightforward strategy for the synthesis of ferrocene appended furopyranone, furochromenone, and benzofuranone via a metal‐free annulation reaction of imidazolium ylide with enone mediated by saccharin‐based ionic liquid has been reported. The mechanistic studies show an approach through synergistic dual activation of enone and imidazolium ylide via cation and anion of ionic liquid, respectively. This operationally simple protocol offers an easy and rapid access to a library of ferrocene appended furopyranone, furochromenone, and benzofuranone in moderate to good yields through the involvement of a six‐membered transition state.

Rh(III)-Catalyzed Chemoselective [4 + 2] Annulations for the Synthesis of [1,3]Oxazinoindolones: A Combined Experimental and Computational Study.

The interaction of N-alkoxy-1H-indole-1-carboxamides with transition metals leads to indole-fused heterocyclic scaffolds through directing group leaving/migration, [3 + 2], N-C2 [4 + 1], and [4 + 2] annulations. However, the corresponding O-C2 [4 + 2] annulation reactions have never been reported. Herein, we report the chemoselective annulation of N-alkoxy-1H-indole-1-carboxamides catalyzed by Rh(III), affording [1,3]oxazinoindolones through a hitherto unknown reaction pathway. This unprecedented C2 oxygen cyclization, rather than the known C2 nitrogen cyclization to form oxazinoindolones via five key steps, has been explained using density functional theory.

Rh(III)- or Ru(II)-Catalyzed C-H Annulation with Vinylene Carbonate and an Unexpected Aerobic Oxidation/Deprotection Cascade to Yield Cinnolin-4(1H)-ones.

Transition metal-catalyzed C-H annulation reactions have been extensively utilized for the synthesis of cinnolines, especially the N-protected ones; however, none of them can yield cinnolin-4(1H)-ones, a significant class of bioactive skeletons. Herein, we disclose one-pot access to cinnolin-4(1H)-ones through Rh(III)- or Ru(II)-catalyzed C-H activation/annulation of N-aryl cyclic hydrazides with vinylene carbonate, followed by an O2/K2CO3-promoted aerobic oxidation/deprotection cascade. The π-conjugation of the directing groups plays a crucial role in facilitating this transformation. Notably, seven-membered enolic Rh species IMC is characterized via electrospray ionization mass spectroscopy for the first time, which, along with systematic control experiments, provides compelling evidence for the mechanistic pathway encompassing alkenyl insertion, β-oxygen elimination, protonation, and dehydration.

DABCO‐Mediated [4+1] Annulation of Cyclopropane‐1,1‐dicarbonitriles with Ethyl Glycinate to Access Ethyl (2‐Amino‐1H‐pyrrol‐1‐yl)acetates

AbstractAn effective DABCO‐promoted (4+1) annulation reaction for the synthesis of ethyl (2‐amino‐1H‐pyrrol‐1‐yl)acetate derivatives from 2‐aroyl‐3‐arylcyclopropane‐1,1‐dicarbonitriles and ethyl glycinate was developed. This strategy is characterized by the readily accessible starting materials, mild conditions, and simplicity of operation.

Accessing polyarene-fused ten-membered lactams via oxidative N-heterocyclic carbene (NHC)-catalyzed high-order [7 + 3] annulation

A new oxidative N-heterocyclic carbene (NHC)-catalyzed high-order [7 + 3] annulation reaction of γ-indolyl phenols as 1,7-dinucleophiles and α,β‐alkynals with the aid of Sc(OTf)3 is reported, enabling the highly regioselective access to unprecedented polyarene-fused ten-membered lactams bearing a bridged aryl-aryl-indole scaffold in moderate to good yields. This protocol demonstrates a broad substrate scope, good compatibility with substituents and complete regioselectivity, providing an organocatalytic modular synthetic strategy for creating medium-sized lactams.