Annulation Strategy Research Articles

3 + 2] Annulation of Vinyl Azides with Aldehydes for the Synthesis of 3-Oxazolines via the [CO + CCN] Strategy.

Despite the widespread utilizable value of 3-oxazolines, mild and efficient access to such a class of unique structures still remains, to date, a challenge. Herein, we present a [3 + 2] annulation strategy, guided by the retrosynthetic principle of [CO + CCN], that utilizes vinyl azides as the CCN module and aldehydes as the CO module. This approach enables the efficient construction of the 3-oxazoline framework with remarkable features, including operational simplicity, environmental friendliness, and high efficiency. Notably, it solely requires the addition of inexpensive and readily available N-hydroxyphthalimide (NHPI) and air oxygen to obtain the desired product. It also provides a new way to generate the hydroxyl radical, which is produced by the homolysis of peroxycarboxylic acid. In addition, control experiments, X-ray crystallographic analysis, high-resolution mass spectrometry (HRMS), and density functional theory (DFT) calculations afford evidence for the key intermediates (hydroxyl radical, carboxyl radical, imine radical, hydroxyl substituted amide derivatives), further confirming the path for realization of 3-oxazolines.

A Photoinduced Annulation Strategy Towards a Novel Polycyclic Heteroaromatic Chromophore: Scope, Mechanism, Properties and Applications.

This article reports a detailed mechanistic and kinetic study of an unusual photoreaction leading to the (diazonia)tetrabenzonaphthacene skeleton. The photo‐triggered double intramolecular nucleophilic aromatic substitution (SNAr∗) has been investigated by varying the leaving groups. Photoreaction quantum yields have been determined and mechanistic insights have been supported by theoretical calculations using DFT and TD‐DFT methods. Additionally, we show that this light‐triggered formed diazonia constitutes a potent photosentitizer with a singlet oxygen generation quantum yield of 55 %, both in organic solvents and in water, which is an extremely relevant value in view of PDT applications or use as an oxidation photocatalyst in aqueous media. Once again, the experimental observations were supported by TD‐DFT calculations showing a large density of triplet states below the S1 excited state along with large spin‐orbit couplings. The reaction is not restricted to solutions but can also occur in solid PDMS matrices thus allowing for photochemical encoding of information that will progressively vanish upon prolonged UV‐exposure.

Practical Access to Fused Carbazoles via Oxidative Benzannulation and their Photophysical Properties.

An aryne annulation strategy for the synthesis of fused carbazoles is developed using indolyl β-ketonitrile in a cascade manner. The reaction sequence involves aryne-mediated [2 + 2] cycloaddition cleavage and intramolecular Michael addition, followed by oxidation under transition-metal-free reaction conditions. Subsequently, conversion of benzo[b]carbazole-6-carbonitrile to carbazole quinone is observed upon prolongation of the reaction time. Furthermore, these materials exhibit high quantum efficiency, which promotes the light-emitting diode applications.

Atroposelective Synthesis of N–N Axially Chiral Indoles and Pyrroles via NHC-Catalyzed Diastereoselective (3 + 3) Annulation Strategy

Atroposelective Synthesis of N–N Axially Chiral Indoles and Pyrroles via NHC-Catalyzed Diastereoselective (3 + 3) Annulation Strategy

Copper-Catalyzed Domino-Double Annulation of o-Aminobenzamides with 2-Iodoisothiocyanates for the Synthesis of 12H-Benzo[4,5]thiazolo[2,3-b]quinazolin-12-ones.

A facile and efficient copper-catalyzed domino-double annulation strategy was developed from easily accessible o-aminobenzamides and 2-iodoisothiocyanates, which affords a direct pathway for the synthesis of tetracyclic fused 12H-benzo[4,5]thiazolo[2,3-b]quinazolin-12-ones in moderate to good yields without the addition of ligands, bases, and external oxidants. The reaction involves a C-N bond cleavage and the formation of a C-N/C-S bond in one step with the advantages of using an inexpensive copper catalyst and easy operation. Mechanistic studies suggest that this transformation proceeds via intermolecular condensation of o-aminobenzamides with 2-iodoisothiocyanates, followed by an intramolecular Ullmann-type cross-coupling cyclization reaction.

Efficient and metal-free synthesis of 2-aroyl 7-azaindoles via thermally induced denitrogenative intramolecular annulation of 1,2,3,4-tetrazolopyridines.

A facile and metal-free intramolecular denitrogenative annulation strategy for the preparation of novel 2-aroyl 7-azaindoles has been developed from 3-(tetrazolo[1,5-a]pyridin-8-yl)prop-2-en-1-one in the presence of the deep eutectic solvent Dowtherm A. The valuable features of the protocol include a short reaction time, absence of any metal catalyst, utilization of a eutectic solvent, easy product isolation, and very good yields of novel 2-aroyl 7-azaindoles.

Regioselective [3+2]‐Spiroannulation and [4+n]‐Annulation Approaches through Activation of C−H Bond Facilitated by Ru(II) as Catalyst: Role of Solvent Selectivity

AbstractRu(II)‐catalyzed and solvent‐switched [3+2]‐spiroannulation and [4+n] (n=1, 2, 3) annulations of 2‐aryl quinazolinone or 2‐aryl‐2,3‐dihydrophthalazine‐1,4‐diones with ynones or alkynyl alcohol or 1,3‐diynes under mild reaction conditions have been analyzed. These reactions take place in the presence of the appropriate solvent and features a redox‐neutral pathway. Ynone serves as an ‘atypical one‐carbon unit’ in [4+1] annulation and generates a tetrasubstituted carbon center bearing diverse heterocycles through [3+2] and [4+1] annulation strategies. Post transformations of the synthesized spiro‐products augments the potential of the developed methodology.

A Palladium‐Catalyzed Regioselective [3+2] Annulation Strategy to 1,2,3‐Oxathiazolidine‐2‐oxides

AbstractA palladium‐catalyzed [3+2] annulation reaction of N‐sulfinylanilines with vinylethylene carbonates and vinyl epoxides is developed. It affords 1,2,3‐oxathiazolidine‐2‐oxides under mild reaction conditions through allylic palladium intermediates. The versatile synthetic utility of 1,2,3‐oxathiazolidine‐2‐oxides in preparing sulfoxides, β‐amino alcohols, and substituted amines has also been demonstrated.

A Pd-Catalyzed Annulation Strategy to Linearly Fused Functionalized N-Heterocycles.

Linearly fused polycyclic piperidines represent common substructures in natural products and biologically active small molecules. We have devised a Pd-catalyzed annulation strategy to these compounds that converts readily available 2-tetralones and indanones into these scaffolds with the potential for control of both enantio- and diastereoselectivity. Importantly, these compounds can be chemoselectively functionalized, providing an efficient and robust methodology to these important nitrogen-containing molecules.

Pd-Catalyzed [4 + 1] Annulation Strategy to Functionalized 4-Methyleneproline Derivatives.

A Pd-catalyzed formal [4 + 1] cycloaddition reaction of sulfur ylides and in situ-generated Pd-stabilized zwitterions offers a convenient route to a series of functionalized proline derivatives. The utility of this method is demonstrated by a gram-scale synthesis and chemoselective functionalization of a proline-based derivative.

Site-Selective Decarbonylative [4+2] Annulation of Carboxylic Acids with Terminal Alkynes by C–C/C–H Activation Strategy and Cluster Catalysis

Cycloaddition and annulation strategies are among the most powerful methods for creating molecular complexity in organic molecules. In this manuscript, we report a highly site-selective palladium-catalyzed decarbonylative [4+2] cyclization of...

Highly enantio- and diastereoselective construction of spirocyclic oxindoles via a palladium-catalyzed decarboxylative asymmetric [4 + 2] annulation strategy.

A palladium-catalyzed decarboxylative asymmetric [4 + 2] annulation of methyleneindolinones with a zwitterionic oxo-1,4-dipole intermediate was successfully developed to access spirocyclic oxindoles bearing two vicinal stereocenters in good yields with high diastereoselectivities and enantioselectivities. This strategy features a broad substrate scope (28 examples), allowing for efficient scale-up. Further selective transformation of the product and preliminary mechanistic studies were conducted.

Rh(iii)-catalyzed sequential spiroannulation/lactonization of 3-aryl N-sulfonyl ketimines with 4-hydroxy-2-alkynoates by C–H bond activation

A rhodium(iii)-catalyzed C–H annulation strategy has been developed for the synthesis of a highly rigid spirobenzosultam lactones in good yields with high regioselectivity from 3-aryl N-sulfonyl ketimines and 4-hydroxy-2-alkynoates.

Electrochemically chalcogenative annulation enabled construction of functionalized saturated N-heterocycles.

An efficient chalcogenative annulation strategy for constructing functionalized saturated N-heterocycles from unactivated alkenes with dichalcogenides under electrochemical conditions has been presented. This protocol is applicable to mono-, di- or tri-substituted alkenes, providing a straightforward pathway to aziridines, azetidines, pyrrolidines, and piperidines with high regioselectivity. Moreover, the strategy is qualified to realize the oxychalcogenation of alkenes as well.

A rhodium-catalyzed cascade C-H activation/annulation strategy for the expeditious assembly of pyrrolidinedione-fused 1,2-benzothiazines.

A cascade annulation strategy triggered by rhodium(III)-catalyzed C-H activation has been reported for the expeditious assembly of pyrrolidinedione-fused 1,2-benzothiazines from free NH-sulfoximines with maleimides under mild conditions. Without the need for inert atmosphere protection, a broad range of sulfoximines with maleimides were well tolerated, producing diverse fused-thiazine derivatives in moderate to good yields. Additionally, the late-stage transformation of the target product demonstrated the potential synthetic value of this protocol.

Annulation reactions of electrophilic benzannulated heterocycles towards heteroacenes.

The current review describes different annulation strategies reported with electrophilic benzannulated heterocycles for accessing heteroacenes. For the past two decades, the chemistry of electrophilic benzannulated heterocycles was extensively investigated, and several dipolar cycloadditions, metal and organo-catalyzed transformations were introduced for the generation of fused heterocycles. In this review, we have collected all the reports where the annulation of electrophilic benzannulated heterocycles results in a fully aromatic system, viz. heteroacenes with tri-, tetra-, and pentacyclic rings. We reviewed every paper on the synthesis of fused heterocycles that was accessible and categorized the review into several parts based on the electrophilic benzannulated heterocycle used in the heteroacene synthesis such as electrophilic indole, electrophilic benzothiophene, and so forth. The generality and mechanistic postulates of each methodology are highlighted. In addition, we have also tried to feature the advantages or shortcomings of each method and have mentioned the possible applications of these methodologies for accessing heteroacenes for material applications.

Recent advances in the transformation of maleimides via annulation.

Over the past five years, maleimide scaffolds have gained considerable attention in organic synthesis for their role in forming cyclized molecules through annulation and C-H activation. As versatile and reactive coupling agents, maleimides have enabled the efficient synthesis of various cyclized products, including annulation, benzannulation, cycloaddition, and spirocyclization, with applications in medicinal chemistry, drug discovery, and materials science. Despite the extensive study of maleimide chemistry, certain reactions-such as cycloaddition-based annulation, photoannulation, and electrochemical transformations-remain underexplored despite their promising potential in the pharmaceutical and chemical industries. Recent advancements, such as photocatalysis and electrochemical methods, have expanded the utility of maleimides, providing more sustainable and selective approaches for synthesizing complex molecules. This review compiles research published between 2019 and 2024, highlighting the substrate scope, reaction diversity, and industrial relevance of maleimide-based annulation strategies. Additionally, we discuss emerging trends and future directions in maleimide chemistry, exploring opportunities for novel reaction pathways and broader applications in synthetic biology and materials science.

Revisiting the 1,3-azadiene-succinic anhydride annulation reaction for the stereocontrolled synthesis of allylic 2-oxopyrrolidines bearing up to four contiguous stereocenters.

Polysubstituted 2-oxopyrrolidines bearing at least two contiguous stereocenters constitute the core of several pharmaceuticals, including clausenamide (antidementia). Here, we describe a flexible annulation strategy, which unites succinic anhydride and 1,3-azadienes to produce allylic 2-oxopyrrolidines bearing contiguous stereocenters. The approach is chemoselective, efficient, modular, scalable, and diastereoselective. The scalable nature of the reactions offers the opportunity for post-diversification, leading to incorporation of motifs with either known pharmaceutical value or that permit subsequent conversion to medicinally relevant entities.

Reversal of Regioselectivity in Asymmetric C-H Bond Annulation with Bromoalkynes under Cobalt Catalysis.

Metal-catalyzed asymmetric C-H bond annulation strategy offers a versatile platform, allowing the construction of complex P-chiral molecules through atom- and step-economical fashion. However, regioselective insertion of π-coupling partner between M-C bond with high enantio-induction remain elusive. Using commercially available Co(II) salt and chiral-Salox ligands, we demonstrate an unusual protocol for the regio-reversal, enantioselective C-H bond annulation of phosphinamide with bromoalkyne through desymmetrization. The reaction proceeds through ligand-assisted enantiodetermining cyclocobaltation followed by regioselective insertion of bromoalkyne between Co-C, subsequent reductive elimination, and halogen exchange with carboxylate resulted in P-stereogenic compounds in excellent ee (up to >99 %). The isolation of cobaltacycle involved in the catalytic cycle and the outcome of control experiments provide support for a plausible mechanism.

Reversal of Regioselectivity in Asymmetric C−H Bond Annulation with Bromoalkynes under Cobalt Catalysis**

AbstractMetal‐catalyzed asymmetric C−H bond annulation strategy offers a versatile platform, allowing the construction of complex P‐chiral molecules through atom‐ and step‐economical fashion. However, regioselective insertion of π‐coupling partner between M−C bond with high enantio‐induction remain elusive. Using commercially available Co(II) salt and chiral‐Salox ligands, we demonstrate an unusual protocol for the regio‐reversal, enantioselective C−H bond annulation of phosphinamide with bromoalkyne through desymmetrization. The reaction proceeds through ligand‐assisted enantiodetermining cyclocobaltation followed by regioselective insertion of bromoalkyne between Co−C, subsequent reductive elimination, and halogen exchange with carboxylate resulted in P‐stereogenic compounds in excellent ee (up to >99 %). The isolation of cobaltacycle involved in the catalytic cycle and the outcome of control experiments provide support for a plausible mechanism.