Themed collection FOCUS: Cycloaddition Chemistry

We summarize recent advances in nitro(hetero)arenes-enabled CADA, with a detailed discussion of diverse types of reactions, involving asymmetric cycloaddition, asymmetric Michael addition, and asymmetric interrupted Barton-Zard reaction.

Nitrosobenzenes are versatile intermediates in organic synthesis. Their NO group on an aromatic ring gives them both electrophilic and nucleophilic character, enabling diverse reactivity in both metal-catalyzed and metal-free transformations.

Azlactones are widely studied for their inherent reactivity, performing diverse chemical transformations. This review summarizes key advances, focusing on reaction mechanisms, reactivity, and some synthetic applications.

Katritzky's pioneering studies revealed the multifaceted cycloaddition reactivities of oxidopyridinium betaines. In this review, the follow-up research into oxidopyridinium cycloadditions and their applications are discussed.

This review outlines recent progress in the total synthesis of cyclopropane-containing natural products, with a particular focus on the application of novel synthetic methodologies and tactics for assembling naturally occurring three-membered rings.

This review primarily focuses on the latest developments in Lewis acid-catalyzed strain-release cycloaddition reactions of BCBs.

This review summarizes recent advances in alkynyl trifluoroborate chemistry, emphasizing their unique reactivity and stability in organic synthesis and biological applications under transition metal catalyst-free conditions.

This review has summarized the development of organocatalytic asymmetric [3 + 3] cycloadditions and given insights into the remaining challenges to promote the future development of this field.

A higher-order dearomative [10 + 2] cycloaddition of 2-nitrobenzofurans with in situ generated 1-hydroxyisobenzofulvene anions enables fused pentacyclic benzofurocyclopenta[b]indanones in high yields with excellent diastereoselectivity.

A catalyst-free, visible-light-induced annulation of 2H-azirines and hydrazonyl chlorides via EDA activation affords 1,3,5-triazines or imidazoles. The 2H-azirine substitution pattern controls reactivity, giving a practical route to N-heterocycles.

Cycloaddition of pyrazolium ylides with alkynes, followed by in situ oxidation, enabled access to 1H-pyrrolo[1,2-b]pyrazole derivatives, 5/5-fused 10π N-heteroarenes. The reaction pathways were elucidated by DFT calculations.

Blue light-promoted concerted [2 + 4] heteroatom Diels–Alder cycloaddition of N-acylimines and phosphenes generated from phosphoryl aryl(diazo)methanes, affording highly diastereoselective trans-3,4-dihydro-1,5,2-oxazaphosphinine 2-oxides.

The Pd-catalyzed tandem reactions provide efficient access to cycloheptatriene[b]indole, spiro-cyclopentene[b]indole and carbazole skeletons with high selectivity.

All-carbon π-allylpalladium species, generated in situ from α,α-diester-δ-vinylvalerolactones, were first used as 1,4-dipoles in [4 + 2] cycloaddition reactions for the construction of structurally diverse spirocyclohexanes.

A convenient (3 + 2) cycloaddition of di-tert-butyl azodicarboxylate with terminal alkynes has been developed. This protocol, which employs a readily available copper catalyst, provides direct access to unprecedented N-aminooxazol-2-ones.

The biomimetic synthesis of ten Securinega alkaloids is reported, using biosynthetically relevant starting materials and conditions.

An efficient, reliable and atom-economic strategy employing azomethine ylides with isatin-derived trifluoromethyl acrylates has been developed to afford spirooxindole-pyrrolidine products featuring vicinal quaternary carbon centers.

A strategy utilizing bifunctional hydrogen-bonding organocatalysts has been established for the synthesis of chiral ε-sultams through two distinct annulation pathways.

Cycloadditions between hydroxypyrones or isochroman-3,4-diones and allenoates or butynoates allow for the direct synthesis of various 1,2,3-substituted phenols and naphthols.

An Ag-catalyzed N-terminus/dehydroalanine [3 + 2] cycloaddition enables site-specific peptide–peptide conjugation. Chiral (S)- and (R)-DTBM-SEGPHOS ligands control pyrrolidine stereochemistry independently of the peptide backbone.

This work reports the structures, total synthesis via the Diels–Alder cascade reaction and cytotoxic activity of (±)-muyoquinone A, a pair of rare pentacyclic benzoquinone dimers isolated from the endophytic fungus Muyocopron laterale.

We developed an one-pot relay strategy that combines the Staudinger–aza-Wittig reaction with a Pd-catalyzed [3 + 2] cycloaddition for the modular synthesis of pyrrolidinones under phosgene-free conditions.

Inherently chiral calix[4]arenes, which have triazole and amine-based functional/receptor groups asymmetrically arranged at the wide rim of a cone macrocycle, can be readily prepared through desymmetrization of a calix[4]arene triamine.

DFT was used to investigate the possible mechanisms of NHC-catalyzed asymmetric cycloadditions between hydrazones and isatins, including [4 + 2] and [3 + 2] cycloadditions.

We report a visible-light photocatalyzed radical 1,3-dipolar cycloaddition between benzo[b]thiophene sulfones and tetrahydroisoquinolines, providing an approach for the concise synthesis of pseudo-natural inspired fused pentacyclic skeletons.

We report a chiral phosphoric acid-catalyzed polar [2σ + 2π] cycloaddition of BCBs with o-QMs. This method efficiently constructs spiro-BCHs bearing vicinal tertiary–quaternary stereocenters with excellent atom economy and high enantioselectivity.

A [3 + 2] cycloaddition reaction utilizing cyclic diaryl λ³-bromanes and α-diazo esters to deliver either N–H or N-Me indazoles in a controllable manner is reported. DFT calculations explain the regioselectivity and the mechanism.

Synthesis of chiral spiro-heterocyclic azides via asymmetric [4 + 2]-cycloaddition of conjugated vinyl azides with aurones and (E)-alkenyloxindoles mediated by chiral N,N′-dioxide/metal complexes.

A new method for the rapid construction of oxabicyclo[3.2.1]octane scaffolds via Pd-catalyzed [3 + 4] cycloaddition of VDCP-diesters with 2-trifluoroacetyl-substituted pyrroles/indoles along with the related hydroamination reaction.

A Lewis acid-promoted [2π + 2σ] cycloaddition strategy enables the construction of bicyclo[2.1.1]hexanes (BCHs) from enol ethers and bicyclo[1.1.0]butanes (BCBs), with excellent functional group tolerance observed for both reactants.

Mild iodine(III) catalysts unlock aziridine reactivity through halogen bonding, delivering diverse N-heterocycles from challenging substrates in excellent yields.

The construction of aza-3D frameworks has emerged as a pivotal strategy in drug discovery, owing to their ability to mimic heteroarene bioisosteres.

Cyclic chlorosilane transformations present a valuable opportunity for the divergent synthesis of silacarbocycles, but their low availability has hindered this potential.

We report novel class of pyridinium-fused 1,2,4-diselenazoles. Most compounds demonstrated high antifungal activity against a number of phytopathogenic fungi.

A Co(II)-based metalloradical-catalyzed cycloaddition of α-trifluoromethyl-α-diazoketones with isothiocyanates was developed to access 4-trifluoromethylated 2-imino-1,3-oxathioles.

Visible-light-driven [2 + 2] cycloadditions of cinnamates proceed under mild, metal-free conditions using indole-fused organoPCs, enabled by ground-state catalyst–substrate association.

A transition-metal-free [3 + 2] cycloaddition between arylazo sulfones and diazo compounds for synthesizing tetrazoles is reported.

This work reports a rare main chain [6]rotaxane constructed from hydrogen-bonded azo-aramide macrocycles, exhibiting multi-stimuli-responsive motions and programmable supramolecular assembly.

Bicyclo[1.1.0]butanes have been utilized in a divergent Lewis acid catalytic platform to access various polycyclic architectures.

A formal (4 + 1) cycloaddition of oxene with a heterodiene was discovered and applied for the one-pot modular synthesis of 3-oxazolines.

Cu(II)/chiral phosphoric acid-catalyzed asymmetric (3 + 2) cycloaddition of donor–acceptor aziridines with aldehydes to synthesize enantioenriched oxazolidines as potential antitumor agents.

We disclose a method for BF₃-enabled, unusual (3 + 2) cycloaddition between BCBs and aldimine esters, providing access to previously elusive 2-aza-BCH derivatives.

We report an efficient, metal- and base-free synthesis of spiro[pyrrolidine-3,3′-oxindoles] and spiro[indoline-3,3′-pyrazol]-2-ones via 3 + 2 cycloadditions of in situ generated nitrile ylides and nitrile imines with alkylidene oxindoles.

We developed a protocol for synthesis of PDIZs from CMQZs with isocyanides. The cycloaddition of [1,4]/[1,6]/[1,2] and skeletal rearrangement were performed by heating a mixture of 1–2 in DMSO, which was promoted by Cs₂CO₃ and catalyzed by Ag₂CO₃.

A protocol for synthesizing all-carbon bicyclo[3.1.1]heptanes (BCHeps) through palladium-catalyzed dipolar (3 + 3) cycloadditions of bicyclobutanes (BCBs) with vinylcyclopropanes has been developed.

A rhodium or copper catalyzed (5 + 1) cycloaddition of diazooxindoles with imidazolidines is reported, offering a series of structurally novel piperazine-spirooxindoles. The asymmetric version has also been realized under Cu(II)/SaBOX system.

A variety of pyrazoline-derived N-vinyl nitrones was prepared in moderate to good yields with high regioselectivity and diastereoselectivity through the base-promoted regioselective [3 + 2] cycloaddition of N-vinyl nitrones and hydrazonoyl chlorides.

An efficient and environmentally benign strategy for the synthesis of three-dimensional semi-saturated rings – cyclobutane-fused indolines via photocatalytic intermolecular [2 + 2] cycloaddition/dearomatization reaction.

A copper-catalyzed enantioselective cycloaddition/amination cascade of azomethine imines, terminal alkynes and O-benzoylhydroxylamines has been developed to construct chiral amino-substituted bicyclic pyrazolines with high enantioselectivities.

In this work, we transition the blue LED-induced intramolecular [3 + 2] cycloaddition of nitrile ylides, generated from singlet carbenes of diazo esters, towards an intermolecular [3 + 2] cycloaddition with substituted isocyanates.

Successive energy-transfer-mediated dearomative [2π + 2σ] cycloaddition/1,6-HAT cascade reaction of quinolines with bicyclo[1.1.0]butanes provides a facile synthesis of pyridine-fused 3D complicated molecules.

Leveraging the chemical knowledge acquired from the literature and reported mechanisms, a synthetic route and stereochemical model for chiral azomethine imines have been developed via intermolecular [4 + 2] cycloaddition catalyzed by CPAs.

The first asymmetric [4 + 3] cycloaddition of hydroxyphenyl indolinones has been reported to afford spirooxindole oxadiazepines in high yields with excellent stereoselectivities, which is a new class of seven-membered spirooxindole compounds.

A mild, efficient method for synthesizing functionalized pyridines using an air-stable Co(III)-precatalyst is disclosed. DFT studies reveal the basis for chemo- and regioselectivity, highlighting the role of triplet states and intersystem crossings.

A versatile synthesis of triazole-fused piperazin-2-one and [1,4]diazepin-4-one scaffolds via a cascade azide–alkyne cycloaddition/oxetane ring opening reaction is reported.

Herein, we report a transition metal-free, chemodiverse cycloaddition reaction of azadienes with allylamines for the synthesis of a series of spirobenzofurans, spirotetrandrines, and benzothiophene-diazepines with high diastereoselectivity.

A formal [2π + 2σ] cycloaddition of BCBs with p-QMs has been developed using HFIP (2 M) as the solvent without an additional catalyst to enable the rapid construction of spiro-BCHs.

A new chemical class of 6/6/6/5/6/6/6/6 spiro-octacyclic Diels–Alder [4 + 2] heterodimers (ent-kaurene and norabietane) was isolated and characterized from Amentotaxus yunnanensis. They exhibited in vitro anti-inflammatory and anticancer activities.

The application of pyrrolidines as key intermediates in the diastereoselective α,β-difunctionalization of electron-deficient alkenes with alkylaminomethyl and heteromethyl moieties.

A novel palladium-catalyzed intermolecular dearomative [4 + 2] cycloaddition of 1,4-enynes with CO and arylamines to access polycyclic γ-lactams is described.

Hypericumonates A–C, the first α-pyrone meroterpenoid dimers with two motifs (a 6/6/4-6/6 ring system) connected via C-8–C-9, were isolated from Hypericum monogynum. (+)-1 exhibited good anti-neuroinflammatory activity.

A rhodium-catalyzed three-component reaction of trifluoromethyl N-triftosylhydrazones, alkenes, and nitriles is reported, which provides diverse α-trifluoromethyl-1-pyrrolines bearing a quaternary carbon center via in situ generated nitrile ylides.

Aza-π-allylpalladium zwitterions, in situ generated from methylene cyclic carbamates, are used as nucleophilic triggers for enantioselective [4 + 2] cycloaddition with electron-deficient alkenes, affording structurally diverse chiral piperidines.

A base-promoted and precise [3 + 2] cycloaddition strategy has been established to access 2,3,5-trisubstituted 1H-pyrroles.

The [3 + 2] cycloaddition reaction between cyclic diaryl λ³-bromanes as aryne precursors and nitrones towards the formation of dihydrobenzisoxazoles is reported.

A Rh(I)-catalyzed method to prepare indoline-fused polycyclic tropanes from 1H-indole N-tethered o-alkynylphenyl nitrone cycloisomerization and their Ce(IV)-mediated dealkylative spirocyclization is described.

We report a visible light-mediated [1 + 2 + 2] cycloaddition reaction between nitroarenes and alkenes, conducted under mild conditions, to synthesize isoxazolidines.

A method for cooperative rhodium/Lewis acid-catalyzed cycloadditions of carbonyl ylides with donor–acceptor (D–A) strained carbocycles is described. It affords structurally diverse oxa-bridged carbocycles with high efficiency and stereoselectivity.

A gold-catalyzed asymmetric [8 + 4] cycloaddition was developed to afford highly functionalized furan/pyrrole-fused [5.5.0] polycyclic heterocycles with good diastereo- and enantioselectivity.

We presented Lewis acid catalyzed [2 + 1 + 1] cycloaddition reactions of various isocyanides with alkylidene malonates and 3-alkylideneindolinones.