ASAP (As Soon As Publishable)

A metal-free photocatalytic methodology for the synthesis of amides has been developed using eosin Y as a photocatalyst under ambient conditions. This approach provides a sustainable and efficient alternative for amide formation by eliminating the need for metal catalysts, and operates efficiently at room temperature. The use of eosin Y promotes high selectivity and reactivity, providing a green and cost-effective pathway for the synthesis of amides.

Polymerases are among the most powerful tools in the molecular biology toolbox; however, access to large quantities of chemically modified nucleoside triphosphates for diverse applications remains hindered by the need for purification by high-performance liquid chromatography (HPLC). Here, we describe a scalable approach to modified nucleoside triphosphates that proceeds through a P(III)–P(V) mixed anhydride intermediate obtained from the coupling of a P(III) nucleoside phosphoramidite and a P(V) pyrene pyrophosphate reagent. The synthetic strategy allows the coupling, oxidation, and deprotection steps to proceed as stepwise transformations in a single one-pot reaction. The fully protected nucleoside triphosphates are purified by silica gel chromatography and converted to their desired compounds on scales exceeding those achievable by conventional strategies. The power of this approach is demonstrated through the synthesis of several natural and modified nucleoside triphosphates using protocols that are efficient and straightforward to perform.

We disclosed an organophotoredox-catalyzed three-component oxidative radical-polar crossover strategy for constructing 1,2-alkylamination products. Cycloketone oxime derivatives were used as cyanoalkyl radical precursors and anilines were used as the nucleophiles. This facile protocol shows a good reaction yield and broad substrate scope.

Canonical thermal cycloaromatizations (Bergman, C¹–C⁶; Myers-Saito, C²–C⁷; Schmittel, C²–C⁶; Schreiner-Pascal, C¹–C⁵) are limited to the formation of five- or six-membered rings, while the formation of larger rings from enediyne (or enyne-allenes) has no precedent experimental exploration. Herein, we present a novel thermal cyclization of enediyne, leading to the formation of a stable seven-membered cyclization product. The structure of this product was elucidated by using NMR and single-crystal X-ray diffraction techniques. The presence of a maleic hydrazide moiety is postulated to facilitate the proton transfer, resulting in the rearrangement of enediyne to enyne-allene, culminating in ring closure through C^α–C⁶ cyclization. The reaction mechanism was further explored by using density functional theory (DFT), revealing a low activation barrier for the C^α–C⁶ cyclization at 19.6 kcal/mol. The newly formed seven-membered ring exhibits strong Möbius aromaticity, as confirmed by calculations of the nucleus-independent chemical shift (NICS) and anisotropy of the induced current density (ACID). In the subsequent reaction, the fusion of the oxazolidin-2-one ring and the elimination of the isobutene molecule release a significant amount of energy, further driving the formation of the final product.

A chemoselective double allylic substitution involving two different carbon nucleophiles is described. The reaction relies on a dual catalytic approach, with a Lewis acid promoting the first allylic substitution and Pd promoting the second step. Starting from simple allylic diols, a diversity of polycyclic structures can be obtained, including tetrahydroindole, tetrahydrocarbazole, and tetrahydronaphthalene.

The combination of sulfoxides with MOMCl has been found for the first time to mediate electrophilic cyclization and install a variety of sulfenyl groups onto isocoumarin skeletons via regioselective cleavage and reconfiguration of C–S bonds. Notably, MOMCl, a mild and readily available alkyl chloride, was indispensable and played a significant role as an activator under neutral conditions in this transformation, thus expanding the scope of acid-labile substrates.

Herein, we described the addition reactions of sulfur-containing reagents (sodium sulfinates, dithiosulfonates) with α-trifluoromethyl alkenes under visible light. A series of trifluoromethyl sulfonates were synthesized via the visible-light-induced radical addition reaction of sodium sulfinates and α-trifluoromethyl alkenes to obtain protons from the solvent. A series of dithiosulfonated derivatives were synthesized via visible-light-induced bifunctionalization reaction of α-trifluoromethyl alkenes with dithiosulfonates.This strategy has the advantages of mild reaction conditions, good substrate universality and high yield up to 99% yield.

A visible-light-driven intermolecular tandem α-amidotrifluoroethylation/cyclization of enaminones using a previously unreported N-trifluoroethylaminopyridinium salt was achieved in the absence of transition metal catalysts or bases. Notable features of this synthetic method include mild conditions, high selectivity, excellent functional group compatibility, and satisfactory yields. Preliminary mechanistic studies indicate that the reaction proceeds via a radical pathway, involving an in situ generated N-trifluoroethyl radical, followed by a 1,2-H shift.

Electron-withdrawing groups are traditionally considered meta-directing in aromatic substitution reactions. However, when the pre-existing substituent is a π-acceptor, both experiment and calculation indicate that substantial amounts of ortho as well as meta substitution occur, with very little para reactivity. A simple perturbative MO argument rationalizes this finding. It is therefore suggested that these substituents are best understood as ortho, meta-directors, with a preference for meta, just as electron-donating groups are considered ortho, para-directors, with a preference for para.

An unexpected electrochemical cascade reaction of 1,2,3-benzotriazinones with alkynes to assemble 3,4-dihydroisoquinolin-1(2H)-ones has been developed, which avoids the use of pressurized H₂, any metal catalysts, and stoichiometric redox agents. This route tolerates a wide range of functional groups in both reactants and can be performed under an air atmosphere. The process of continuous cathodic reduction was demonstrated by control experiments and cyclic voltammograms. Moreover, the gram-scale reaction confirmed the potential of this environmentally benign method for practical applications.

Substrate and reagent-controlled dimerization of vinyl para-quinone methides (VPQMs) is reported. When subjected to Brønsted acidic conditions, VPQM dimerization occurs via a formal 1,8-addition to provide griffipavixanthone (GPX)-type congeners. Under optimized Lewis acidic conditions, a change in regioselectivity affords limonene-containing dimers by a 1,6-addition/cyclization process. This divergent reactivity has been explored on several substrates of differing complexity, providing access to analogues of the natural product griffipavixanthone (GPX) as well as a range of novel, substituted limonene dimers.

An acid or hydrogen gas-free electrochemical protocol is established for the hydrogenation of strained rings (cyclopropane and cyclobutane) at room temperature and atmospheric pressure. The mechanistic study revealed that the reaction was initiated via the reduction of the carbonyl group. The methodology is highly specific toward strained rings such as cyclopropane and cyclobutane, which exhibit broad functional group tolerance.

We here describe a versatile, convenient, and efficient approach to synthesize cyclic nitrone compounds by diamination of alkene, which was catalyzed by simple copper salts under basic conditions with good chemoselectivity. The method utilized γ,δ-unsaturated ketoximes with O-benzoylhydroxylamines as an electrophilic nitrogen source to realize intra-/intermolecular 5-exo-trig cyclization of internal alkenes of unsaturated ketoximes without external oxidants required, and a series of substitution patterns, both donor and withdrawing substituted moieties, are well-tolerated, leading to target products in moderate to good yields.

We designed a new type of redox-active molecular triad in which two electron-donating dithiafulvene (DTF) groups are connected to a central ferrocene (Fc) hinge unit through phenylene linkers. Three structural isomers of the (DTF)₂–Fc system were synthesized through Suzuki–Miyaura cross-coupling followed by phosphite-promoted olefination reactions. The molecular structures and solid-state properties of these compounds were investigated by X-ray single-crystallographic analysis. Their electronic absorption and electrochemical properties in the solution phase were examined using UV–vis spectroscopy and cyclic voltammetry. Our studies showed that these compounds possess multistage redox activities due to the presence of electron-donating DTF and Fc groups, while detailed redox behaviors are dependent on the substitution patterns and steric crowdedness of each compound. To gain deeper insight, we performed density functional theory (DFT) and molecular dynamics (MD) simulations to examine the conformational and electronic properties of these compounds in neutral and different oxidation states. Furthermore, the para-substituted (DTF)₂–Fc was found to show intriguing supramolecular interactions with γ-cyclodextrin.

N-Heterocyclic carbene-carbodiimide (NHC-CDI) adducts are versatile compounds that can be used as ligands and (pre)catalysts, but their systematic structure–property relationships are underexplored. Herein, we investigated how structural electronic variations on both the NHC and CDI affect the inherent kinetic and thermodynamic properties of the adducts. Using in situ carbene trapping and variable-temperature NMR spectroscopy, we measured the rates of dissociation and the equilibrium constants and then used Eyring and van’t Hoff analyses to calculate ΔG^‡ and ΔG, respectively. Linear free-energy relationships indicate that changing the para position of the CDI substituents yields a similar effect to changing the NHC core. These CDI structural modifications affected the adducts’ thermodynamics (ΔG) more than the kinetics (ΔG^‡) and were found to be influenced more by inductive, rather than resonance, factors. Preliminary results suggest a steric threshold beyond which steric effects dominate electronic effects in governing the strength of the adduct bond. This systematic investigation provides valuable insight into the design of NHC-CDIs for current and future applications.

We report an optimized protocol for the solid-phase synthesis of backbone-N-aminated peptides. Electrophilic N-amination of amino acid zwitterions provides crude α-hydrazino acids that can be used directly in SPPS. In situ formation of Fmoc-protected amino acid chlorides with Ghosez’s reagent enables base-free couplings to α-hydrazino acids on an automated system. TFA-free cleavage and global deprotection affords poly-N-amino peptides in high crude purity and in a fraction of the time required by previously reported methods.

Aerobic oxidative cross-dehydrogenative couplings of 1,2,3,4-tetrahydroisoquinolines were developed using a Mn(acac)₃ and ethyl 2-(4-nitrophenyl)hydrazine-1-carboxylate cocatalytic system. Nucleophiles, including nitroalkanes, dialkyl malonates, acetophenones, indoles, phosphonates, and phosphine oxides, were successfully employed to produce α-functionalized 1,2,3,4-tetrahydroisoquinolines. Control experiments revealed that radical species are not involved in the mechanism. Additionally, ¹H NMR and HRMS analyses in the stoichiometric reaction identified an aminal structure as a crucial intermediate. Computational studies further support the plausibility of a hydride transfer process in the oxidation of 1,2,3,4-tetrahydroisoquinolines instead of the triazane pathway, which was predominantly proposed in the DEAD-mediated reaction.

A rhodium-catalyzed synthesis of isobenzofurans via donor- and donor-type metal carbenoids has been developed. Nosylhydrazones were used as carbene precursors, generating rhodium carbenoid species under basic conditions. These intermediates underwent intramolecular cyclization with ester groups to afford isobenzofurans, which subsequently participated in a highly endo-selective [4 + 2] cycloaddition with maleimides and other dienophiles. The reaction exhibited a broad substrate scope, accommodating various ester and aryl substituents while maintaining excellent regio- and stereoselectivity. Mechanistic studies, including control experiments, NMR analysis, and computational calculations, revealed that the reaction proceeds through a rhodium carbenoid intermediate, leading to the formation of isobenzofuran prior to cycloaddition. The endo-selectivity was found to originate from the difference in activation energies between the transition states, as supported by computational studies. Additionally, the isolation of the diazo intermediate and its direct conversion to isobenzofuran confirmed the stepwise nature of the transformation. This study expands the utility of donor- and donor-type carbenoids in organic synthesis, demonstrating their effectiveness in constructing highly reactive isobenzofurans under mild conditions.

A new approach for the enantioselective synthesis of various bicyclo[2.2.2]octadiene ligands has been developed, which features a chiral oxazaborolidinium-catalyzed asymmetric Diels–Alder reaction to construct the bicyclo[2.2.2]octane framework. The pivotal ketone 12 served as a common intermediate that was finally transformed into the desired C₁- and C₂-symmetric chiral dienes. This work provides an alternative method to the reported chiral diene synthesis and would be beneficial to exploration of the potentials of this type of versatile ligand in new asymmetric transformations.

A straightforward and efficient strategy for the synthesis of fully functionalized indolizines has been developed through a transition metal- and oxidant-free [3 + 2] cycloaddition reaction of zwitterionic ketenimines and pyridinium salts. This versatile method proceeds under mild conditions, affording functionalized indolizines in moderate to good yields. This efficient approach involves an intermolecular [3 + 2] cycloaddition, followed by enamine/imine tautomerization and aromatization. Notably, this method demonstrates broad functional group compatibility and allows for facile scalability, making it a valuable tool for the synthesis of indolizine-based frameworks in organic and medicinal chemistry.

A Pd-catalyzed protocol that provides efficient access to acyclic 1,2-dioxygenated dienes has been established. The installation of the bifunctional carbonate electrofuge to the diene cores enabled such dienes to undergo a regioselective decarboxylative Diels–Alder cycloaddition/aromatization reaction, affording diverse synthetic challenging multisubstituted phenols with ease.

β-Sulfido sulfonyl fluorides, incorporating a clickable sulfonyl fluoride and a thioether motif, are valuable intermediates in chemical biology, materials science, and drug discovery. Herein, we developed a rapid and additive-free synthesis of these compounds via N-methyl-2-pyrrolidinone (NMP)-promoted thia-Michael addition of thiols to ethene sulfonyl fluoride (ESF). The reaction proceeds smoothly under neutral conditions without the need for a base or catalyst, achieving high efficiency within 20 min. This method demonstrates a broad substrate scope, tolerating thiophenols, alkylthiols, thioglycosides, and cysteine-containing peptides. The resulting β-sulfido sulfonyl fluorides enable diverse transformations, such as sulfur(VI) fluoride exchange (SuFEx) reaction and thioether oxidation, facilitating applications in drug conjugates and materials, such as additives for lithium-ion battery electrolyte components.

The 1,2,3-triazole scaffolds are an important class of biologically privileged heterocyclic compounds with several key applications in chemistry, biology, medicine, agriculture, and material science. The “postclick” functionalization of 1,2,3-triazoles may emerge as a promising tactic for the construction of molecular architectures of therapeutics and is considered to be a growing area of investigation. This interest extends beyond the regioselective Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) method that involves the trapping of Cu(I)-triazole with suitable precursors. In this Perspective, we highlight the growing impact of postclick strategies in organic synthesis required for the late-stage functionalization of 1,2,3-triazoles with a hope that this emerging concept may provide ample opportunities in modern organic synthesis of notable applications in medicinal chemistry, biology, and materials science.

We present a new, straightforward, and versatile approach that utilizes regioselective brominated precursors to synthesize both asymmetric and symmetric S-zig-zag-fused BODIPYs (s-TFB and bis-TFB) in moderate yields (45% and 40%, respectively). X-ray structure analyses reveal that the planar rigidity of the BODIPY skeleton is progressively enhanced with an increasing number of thiopyran rings. The annulation of S-heteroaromatic rings at the zig-zag edge of the BODIPY core results in blue-shifted absorption and emission spectra, with bis-TFB exhibiting maxima at 530 and 539 nm and elevated LUMO energy levels. In contrast, oxidation of s-TFB and bis-TFB with m-CPBA demonstrates significant site selectivity, affording four oxidation products, namely s-s-SFB, s-bis-SFB, bis-s-SFB, and bis-bis-SFB, in yields ranging from 22% to 36%. These oxidated S-zig-zag-fused BODIPY derivatives display large red-shifted absorption and emission spectra (e.g., 648 and 735 nm for s-bis-SFB), along with more stable HOMO and LUMO energy levels and reduced HOMO–LUMO gaps. This S-zig-zag-fused cyclization/oxidation strategy enables precise tuning of the BODIPY optoelectronic properties, opening new avenues in dye design and application.

We report an efficient palladium-catalyzed ring-opening defluorinative Hiyama cross-coupling of gem-difluorocyclopropanes with structurally diverse (hetero)arylsilanes through C–C bond activation and C–F bond cleavage. This regioselective ring-opening defluorinative Hiyama cross-coupling features a broad substrate scope with excellent functional group compatibility, affording a diverse variety of linear 2-fluoroallylic scaffolds in good yields with high Z-selectivity.

The development of water-soluble multicharged macrocycles has opened promising pathways in biomedical applications, enabling selective molecular recognition for therapeutic and diagnostic uses. Yet, traditional polyanionic and polycationic receptors often face performance limitations under realistic operating conditions. A major drawback is the natural tendency of these polycharged hosts to experience increasing screening effects as concentration rises due to self-ion pairing phenomena, which can reduce binding efficiency by several orders of magnitude. These issues are further intensified when polyionic receptors are used in high-salinity environments, typically used to replicate physiological settings, where the abundance of ions introduces additional screening effects that diminish the supramolecular affinity for a wide range of guests. This study presents a new approach that leverages zwitterionic synthetic receptors with rationally engineered architectures to overcome these challenges. By incorporation of specific structural features, self-ion pairing is eliminated, effectively making host concentration no longer a controlling factor in the thermodynamics of the complexation process. Additionally, these dual-charged hosts achieve self-contained stabilization, naturally shielding recognition sites from external ion interference under high-salinity conditions. Furthermore, the ability of these supramolecular hosts to encapsulate zwitterionic guests, a challenging task due to the strong solvation of these molecules in aqueous solution, adds significant value to the functional versatility of these macrocycles. Altogether, these findings represent a significant advancement in the design of stable and adaptable receptor systems for complex environments.

Vinyl diazo carbonyl compounds have received great attention and are widely employed in the cycloadditions of in situ formed reactive intermediates. Metal carbenes are predominantly involved in cycloadditions, and transformations of vinyl diazo compounds that do not proceed via the metal carbene pathway have been seldom reported. Herein, scandium-catalyzed cycloadditions of vinyl diazo compounds and in situ formed 2-naphthoquinone-8-methides are achieved, and naphthalene-fused polycyclic products were obtained in up to 88% yield. In the transformation, the nucleophilic conjugate addition of vinyl diazo compounds to in situ formed 2-naphthoquinone-8-methides generates vinyl diazonium intermediates, which undergo an intramolecular Friedel–Crafts reaction and intramolecular transesterification to yield the final product.

Compared to smaller or larger rings, seven- and eight-membered carbo- and heterocycles are typically nonplanar and exhibit greater conformational rigidity. This property alone can impart chirality to certain 7- or 8-membered ring systems. Herein, we summarize recent achievements in the enantioselective synthesis of this class of inherently chiral medium rings, including both ring construction and ring modification, as well as the applications of chiral ligands and catalysts derived from these rigid cyclic scaffolds in asymmetric catalysis.

An innovative method was developed for the performance of aldol additions in an irreversible fashion by the use of calcium metal impregnated silica gel (Ca@SiO₂) as a remarkable reducing reagent. In this approach, Ca@SiO₂ drove the reaction forward, prevented reversibility, and ensured the formation of the desired products. Thus, in the presence of Ca@SiO₂ (3.0 equiv), aldehydes (1.0 equiv) condensed with ketones (1.0 equiv) in 2-MeTHF to yield α,β-unsaturated enones in 71–90% yields at 25 °C. Additionally, a domino reaction involving successive aldol addition, dehydration, and Michael addition was developed for the preparation of 1,5-diketones. Accordingly, when aldehydes (1.0 equiv) were allowed to react with ketones (2.2 equiv) and Ca@SiO₂(4.0 equiv), 1,5-diketones were produced in 67–88% yields. These reactions involved radical processes, where Ca@SiO₂ abstracted two α hydrogen atoms from ketones and the oxygen atom from aldehydes to form CaH₂@SiO₂ and CaO@SiO₂, respectively. These species were confirmed by powder X-ray diffraction analysis. The resultant impregnated silica gel species were solid and insoluble in the reaction mixtures, which made the addition reactions irreversible. This method represents a significant advancement in aldol condensation reactions and offers the advantages of both atom economy and atom efficiency.

Aromatic systems with bridged sulfur units in varying oxidation states have enabled photoresponsive materials for anticounterfeiting and supramolecular assembly. However, only a few sulfoxide-bridged chromophores exhibit photoinduced sulfur extrusion, leading to drastic photophysical changes that make them useful as stimuli-responsive materials. Here, we present nitrogen-substituted anthracene (aza-anthracene) with a sulfur bridge in different oxidation states. Overall, aza-anthracene produces red-shifted green-to-red chromophores with similar sulfoxide photoconversion behavior compared to the anthracene analog.

We describe a sustainable process to synthesize chiral sulfur-based organofluorine compounds by integrating electrosynthesis and biocatalysis within a single vessel while using water as a solvent. In this context, differently substituted 2-fluoro-3-mercaptopropionic acids have been synthesized in good isolated yields using thiophenols and fluorine-containing α,β-unsaturated alkenes. In addition, molecular docking and control experiments were carried out that suggest the formation of radical species during the electrolysis and participation of the lipase active site during the biocatalysis. The scalability and applicability of the developed protocol have been illustrated through the synthesis of a key intermediate of the MMP-3 inhibitor and by performing a gram-scale reaction. Further, the compatibility of the lipase enzyme with electricity highlights the promising potential of enzymatic electrosynthesis in advancing environmentally friendly organic transformations.

Here, we report a photoredox/palladium-catalyzed reduction alkylation of imines and ammonium salts via dual C–N cleavage. This reaction proceeds under mild, green, and operationally simple conditions, offering a broad scope of secondary amine compounds with alpha quaternary carbon. Mechanistic studies indicate that the α-amino carbanion, generated by a successive single-electron transfer process, is a key intermediate in photoredox/palladium catalysis.

Herein, we establish two highly efficient reductions of α,β-unsaturated ketones and aldehydes via Raney nickel-catalyzed hydrogenation with distinct chemoselectivity, which is controlled by the solvent. This methodology demonstrates a brilliant result when reducing α,β-unsaturated ketones and aldehydes to ketones or alcohols. High isolated yields were obtained for a series of benzalacetone- and cinnamaldehyde-derived substrates without additional column chromatographic purification. The practicability of the methodology was demonstrated by reducing the natural products and synthesizing the approved drug.

Biaryl sulfides are important scaffolds found in various natural products and pharmaceutically active compounds. One of the main approaches for the synthesis of this compound class involves the substitution of arenes using electrophilic thioaryl species. However, these methods generally require acidic activation of the electrophile, more forcing conditions, and long reaction times. Here, we describe the combination of the super Lewis acid iron(III) triflimide with saccharin-based thioarylation reagents for the rapid synthesis of unsymmetrical biaryl sulfides under mild conditions. This approach was effective with electron-deficient thioaryl species that performed poorly with previous methods, allowing the efficient functionalization of bioactive compounds.

Herein, we report a concise route to the [5-5-6]-fused tricyclic core of scabrolide A and our efforts toward the construction of the fourth cycloheptane ring of the molecule via a 7-endo-trig radical cyclization. The tricyclic cyclohexenone core was assembled by a ring-closing metathesis (RCM) reaction followed by oxidation and concomitant isomerization of the double bond. These promising results have potential implications in the synthesis of similar tricyclic cores of many other congeners within this family of furanobutenolide-derived polycyclic cembranoids and norcembranoids.

Application of new reagents in the Z-selective synthesis of trisubstituted alkenes via modified Horner–Wadsworth–Emmons carbonyl olefination is presented. The reagents tested are ethyl bis(1,1,1,3,3,3-hexafluoroisopropyl)phosphonoalkanoates, structurally similar to Still–Gennari type reagents. A set of various trisubstituted Z-alkenes was obtained in very high or quantitative yields with excellent Z-selectivity. Remarkably, the procedure was very successful for the synthesis of Z-2-aryl-substituted cinnamic acid esters, maintaining exclusive Z-selectivity even at an increased temperature.

A new family of ortho-hydroxy-substituted diaryliodonium salts was synthesized with 1-acetoxy-2-iodobenzenes, in which the acetyl group was cleaved in a one-pot synthesis. The ortho-hydroxyl-substituted diaryliodonium salts underwent further intramolecular aryl migration reaction, giving ortho-iodo diaryl ethers either with or without the presence of bases.

DNA-encoded libraries (DELs) have emerged as powerful tools in drug discovery. Protected amino acids serve as essential building blocks in the construction of DELs, resulting in the widespread presence of amino groups within these libraries. N-formylation of free amines not only enhances the activity of lead compounds but also functions as an effective amino-protecting strategy. In this study, we introduce trimethyl(bromodifluoromethyl)silane (TMSCF₂Br) as a novel N-formylation reagent for DEL synthesis. This approach demonstrates robustness in DEL-compatible synthesis and enables library diversification through functional group transformation (FGT). Additionally, we achieved efficient removal of formyl groups, enabling the formyl group to be strategically used for on-DNA amino protection orthogonal to Fmoc and Boc groups.

The Hauser–Kraus annulation of sulfonylphthalide with Morita–Baylis–Hillman (MBH) adducts of nitroalkenes provides access to phenanthrenes and naphthoquinone fused dihydrobenzoxepines. The H–K annulation results in naphthoquinones bearing a key alcohol group in protected form, which leads to naphthoquinone fused tetracyclic oxepines upon reaction with formaldehyde. These alcohols yield functionalized phenanthrenes via oxidation and [3 + 3] annulation with β-ketoesters.

Direct installation of a sulfonyl functional group into the C5-position of tetrahydropyridazine was achieved using N′-benzylidene-N-cinnamylacetohydrazide as a new building skeleton via the photocatalytic carbosulfonylation/annulation procedure. Various substituted C5-sulfonylated tetrahydropyridazines were obtained in good to excellent yields employing aryl- or alkylsulfonyl chlorides as the sulfonyl radical sources. This reaction was realized through the selective addition of sulfonyl radical to the C2 position of cinnamyl followed by the 6-endo-trig annulation to the hydrazone CH═N bond.

CF₃-substituted tertiary alcohols are valuable as biologically active compounds, but the synthesis of the corresponding cyclopentadiene derivatives remains challenging. The DABCO-catalyzed 1,2-addition reaction of trifluoropyruvates with 2,4-dihydrocyclopenta[b]indoles has been developed, affording CF₃-substituted tertiary alcohols in up to 90% yield and with up to >99:1 dr. The catalytic reaction is facilitated by hydrogen bonding (N–H···N) between the cyclic tertiary amine and the indole moiety. Additionally, Et₃N (1.0 equiv) can promote the retro-1,2-addition reaction of the CF₃-subsituted tertiary alcohols, yielding dihydrocyclopenta[b]indole 1 in up to 72% yield.

We report a novel and efficient strategy for constructing tetrasubstituted alkenes and α-iminonitriles from 3-aminoindolizines and 3-aminoimidazo[1,2-a]pyridines. This approach involves a dearomative ring-opening of N-fused heteroaromatic amines coupled to a DDQ-mediated oxidative process under mild, metal-free conditions. The methodology demonstrates broad substrate scope, excellent functional group tolerance, and scalability, offering a versatile platform for synthesizing complex alkenes and nitrile-containing frameworks.

Spirocyclic motifs are attracting increasing attention owing to their three-dimensional geometries that endow bioactive molecules with superior physical and biological properties. We developed an efficient method for constructing spirocyclic phthalans via the Ru-catalyzed [2 + 2 + 2] cycloaddition of cycloalkanone-derived 1,6-diynes with acetylene gas ex-situ-generated from calcium carbide and H₂O.

A synthesis of (−)-viriditin A and (−)-viriditin B has been completed sequentially using a Suzuki coupling and a Heck reaction of trans-1,2-dichloroethylene. The selectivity for monocoupling of trans-1,2-dichloroethylene is attributed to a lower-energy transition state for the oxidative addition step.

In this study, we report the synthesis and chiroptical properties of biscarbazole-embedded diaza[7]helicenes. Although the classical photocyclization pathway was unsuccessful, the strategic introduction of a bromo group successfully yielded the desired helical compounds. Interestingly, using methoxy groups instead of bromo groups led to the formation of an unusual degraded product during photocyclization. The synthesized molecules were resolved into their enantiomers, and their chiroptical properties were investigated by using steady-state absorption and emission spectroscopy. Additionally, the excited-state dynamics were examined through time-resolved fluorescence decay measurements. Quantum chemical calculations were performed to rationalize the observed optical properties.

We report herein a method of substrate-controlled pentafluorosulfanylation of activated alkenes containing the benzimidazole moiety with SF₅Cl, which provides a highly efficient way to access SF₅-containing benzo[4,5]imidazole[2,1-a]isoquinolin-6(5H)-ones, as well as SF₅-containing N-benzoyl benzimidazoles. Besides the pentafluorosulfanyl group (−SF₅), the current method can be applied to the tetrafluorosulfanyl group (−SF₄−) incorporation. A radical mechanism involving single electron transfer (SET) or the atom transfer radical addition (ATRA) process is proposed.

Tetrahydro-γ-carbolines are especially outstanding fused heterocyclic ring systems possessing significant biological activities in the central nervous system. Here, using commercially available NBE derivatives (NBEs), we report an efficient protocol for the one-pot modular synthesis of 4-substituted tetrahydro-γ-carbolines via Catellani/aza-Michael addition cascade from easily available 3-iodo-1-tosyl-1H-indole, aziridines and olefins. This approach exhibits a wide substrate scope, good yields, scalability, and potential extension toward the synthesis of Mebhydroline analogues.

Yoshihara, Hiroki, Yagi, and Itami utilized an unusual Friedel–Crafts-like alkylation in the synthesis of an adamantane-annulated arene. The precursor was a 3° carbocation, which they proposed undergoes a Wagner–Meerwein shift to a 2° carbocation, which subsequently alkylates a benzene ring. This mechanism was supported by their DFT calculations. However, their choice of the B3LYP functional often finds false transition structures. A more appropriate functional showed that the alkylation occurs via a concerted reaction.

Herein, we describe the photomediated radical cascade addition–cyclization of N-butenoyl tetrahydroquinolines to access various functionalized julolidine-5-one. The scope of the methodology was illustrated with several sulfonyl chlorides and tetrahydroquinolines. Other radical precursors, such as trifluoromethyl, bromoacetonitrile, bromoacetates, etc., also worked efficiently, demonstrating the broad utility of the method. Finally, large-scale synthesis of sulfonyl-substituted julolidine-5-one and downstream conversions of the synthesized julolidine derivatives were carried out to illustrate the synthetic utility of the methodology.

Naloxone is a nonselective opioid receptor antagonist used to reverse the effects of opiate-related overdose. Studies aimed toward identifying naloxone degradants present in a buprenorphine/naloxone combination drug product revealed several compounds whose structures could not be confirmed by comparison to authentic samples. We report herein the confirmation of the structural assignment of one of these compounds (so-called, “Degradant E”) by chemical synthesis starting from naloxone. Key features of the developed route include the conversion of the N-allyl group to the corresponding Boc carbamate as a means of facilitating the chemoselective oxidative cleavage of the C6–C7 bond. In addition, the use of a pivalate ester derivative of naloxone’s phenol group offered a convenient means of isolating Degradant E as the corresponding HCl salt using an acid-promoted global ester hydrolysis in the final step.

Azobenzenes are promising materials for energy storage due to their reversible photoisomerization and redox properties. Given the critical role of redox behavior in the latter application, an investigation of their redox processes is essential. We propose a classification of azobenzenes into two categories: benzenoid-type and quinoid-type, based on the mechanism of their oxidation. Benzenoid-type compounds have been extensively studied due to their reversible reduction. Quinoid-type compounds exhibit oxidative and reductive versatility, making them promising for further research in energy storage.

Pyrazolo[1,2-a]indazoles and pyrazolo[1,2-a]cinnolines can be constructed selectively via catalytic system-controlled C(sp²)-H activation/[4 + 1] cyclization and C(sp²)-H activation/[4 + 2] cyclization reaction, utilizing pyrazolidinones and diazo indandiones. Employing two different Rh(III) catalysts, we successfully synthesized two distinct types of nitrogen-containing heterocyclic compounds, pyrazolo[1,2-a]indazoles and pyrazolo[1,2-a]cinnolines, respectively. Moreover, an inexpensive Ru(II) catalyst could also effectively generate pyrazolo[1,2-a]cinnolines with moderate to good yields. Overall, these methodologies offer advantages such as regioselectivity, broad substrate scope, operational simplicity, and product availability.

DNA-encoded chemical library (DECL) technology is recognized as a robust screening platform for drug discovery. Developing new DNA-compatible reactions is crucial for expanding the chemical space of DECLs. Cyclization reactions, particularly those involving the formation of heterocycles, offer unique and efficient methods for accessing privileged scaffolds or lead-like small molecules. In this study, we introduce two new methods that utilize readily accessible aldehydes to create substituted isoxazolines and isoxazoles by the 1,3-dipolar cycloaddition reaction. These methods demonstrate high conversion efficiency and can be applied to a wide range of substrates. The reactions are DNA-compatible and do not cause significant DNA degradation.

Herein, we reported a DBU-catalyzed cascade and sequential [1 + 2 + 3] annulation of malononitrile with α,β-unsaturated ketones to access polyfunctionalized cyclohexanes with high yield and excellent diastereoselectivity (>93% yield, >19:1 dr). Intriguingly, this appears to be the new strategy for using α,β-unsaturated ketones either as 2C or 3C synthon to react with dinucleophile 1C synthon to construct six-membered carbocycles in one-pot manner. In addition, these synthesized compounds suppressed the growth of phytopathogenic fungi in vitro. Among them, compound 3l exhibited excellent and broad antifungal activity, which possesses potential as an agricultural antifungal agent.

A library of fluorescent molecules based on imidazopyridine linked with benzothiazole and benzimidazole was assessed for pH sensitivity and the effect of substituents thereon, also leading to dual-state emission. A broad range of pH (1–13) was evaluated, where the benzothiazole-based (BnTA) compounds responded in acidic pH, whereas the benzimidazole-based (BnIm) compounds behaved differently at different pH with recognizable color change on shifting from acidic to neutral and then to basic. NMR titrations revealed the effect of substituents on governing the site of protonation and deprotonation. Further, the mechanism of fluorescence was comprehended through theoretical calculations. On assessing the solid state fluorescence briefly, 2e showed mechanochromic behavior, showing green fluorescence in the solid state, which vanished upon grinding, and upon fuming with acetone, the fluorescence turned yellowish orange, which reverted to the initial fluorescence upon long-term exposure of acetone. The cellular uptake and fluorescence response of 2l in pH were also evaluated. The colocalization experiment suggested that 2l crossed the nuclear membrane and stained the nucleus, showing its possible in vitro application. The compound serves as a potential lead for other applications likewise, such as optoelectronics, data encryption, and pH sensors.

A palladium-catalyzed decarboxylative cross-coupling of zinc polyfluorobenzoates with aryl fluorosulfates, which proceeded efficiently via C–O bond cleavage to afford the corresponding polyfluorinated biaryls in moderate-to-good yields, was developed. The reactions exhibited both good substrate scope and broad functional group compatibility, and it could be scaled-up easily. The synthetic simplicity and practicability of the reaction was further demonstrated by one-pot manipulation by directly mixing polyfluorobenzoic acid and Zn(OH)₂ in the coexistence of aryl fluorosulfate and a palladium catalyst in one flask. Further studies showed that aryl fluorosulfate is more robust than other aryl halides and pseudohalides as a arylating reagent, and zinc polyfluorobenzoate is a more effective decarboxylative polyfluoroarylating agent than their magnesium and potassium counterparts.

Herein, we report an efficient and straightforward access to highly functionalized thiochroman-4-ol derivatives by the construction of S–C and C–C bonds in a domino fashion. The methodology is based on a (4 + 2) annulation reaction involving α-substituted allenyl sulfones and aromatic thiolates displaying an ortho α-ketoester group as substrates. The anionic sulfur species were generated in situ by reduction of the corresponding disulfides, using a Rongalite/K₂CO₃ system. The practicality of the strategy was further demonstrated by gram-scale synthesis, postmodifications, and compatibility with other types of electron-deficient allenes (allenoate and allenone).

Clostridium difficile causes serious nosocomial diarrhea in humans. In particular, C. difficile ribotype 027 strain, which is more virulent in nature, is associated with higher mortality rates. To prevent disease caused by C. difficile, capsular polysaccharides such as PSI, PSII, and PSIII from the outermost protective layer of C. difficile bacterium are good targets in the development of vaccine against C. difficile. In this study, we report for the first time an efficient synthesis of phosphorylated PSI oligosaccharide and its derivatives in various lengths. We have also developed a one-pot strategy for the synthesis of a pentasaccharide repeating unit and used this approach to successfully synthesize the protected pentasaccharides in the gram scale.

(R)-Phenylglycinol-derived perhydrooxazoloquinoline 2 provides stereoselective access to angularly substituted enantiopure decahydroquinolines (DHQs). Reaction of 2 with appropriate Grignard reagents leads to cis-DHQs bearing a C_8a aza-quaternary stereocenter, whereas reaction of 2 with Michael acceptors followed by reductive removal of the 2-phenylethanol of the chiral inductor gives rise to cis- or trans-DHQs bearing a C4a all-carbon quaternary stereocenter depending on the hydride used for the cleavage of the oxazolidine C–O bond. Theoretical studies have clarified the mechanistic intricacies of the reaction of 2 with Michael acceptors, providing arguments for a proper understanding of the observed stereoselectivity. Finally, the reaction of 2 with formaldehyde is reversible, allowing the regioselective formation of either the angularly substituted hydroxymethyl derivative 12 or the C₈-substituted derivative 13 depending on the reaction temperature. An expeditious synthesis of the Myrioneuron-type alkaloid (−)-myrioxazine A from 13 is reported.

A Lewis base-catalyzed [4 + 3] annulation between dinucleophilic indole-2-carboxamides and Morita–Baylis–Hillmann (MBH) carbonates was developed to access densely substituted indole-1,2-fused diazepanones. This reaction is initiated by a Lewis base-catalyzed N-allylic alkylation of the indole scaffold with MBH carbonates, followed by intramolecular Michael cyclization. Notably, the selectivity of this process is controlled by a removable o-methoxyphenyl (OMP) directing group attached to the indole-2-carboxamides. The wide scope of substrates, high regio- and stereoselectivity, and diverse transformations highlight the potential synthetic utility of this method in drug discovery.

The halogenophilic S_N2X reaction involving a nucleophilic attack on the X group from the front is less sensitive to backside steric hindrance. Herein, we report a mild and efficient S_N2X reaction for sulfinylation of activated tertiary alkyl halides, which could provide a novel method for accessing sulfoxides decorated with a congested carbon center. Preliminary mechanistic studies indicated that the generated sulfinyl bromides would be the key electrophilic intermediates in the reaction.

An NIS-promoted cascade of intramolecular C–N bond formation/aromatization with 3-(1H-indol-3-yl)-2-(pyridin-2-yl)propanoates is described for synthesizing a polycyclic indole skeleton, indolo[3,2-c]quinolizine, as well as 1,9-dihydropyrazolo[4’,3′:5,6]pyrido[2,3-b]indole. The advantages of this protocol include accessible starting materials, mild conditions, simple operation, and good yields. Indolo[3,2-c]quinolizines exhibited good fluorescence properties and effective staining for live cells, targeting lysosomes and mitochondria. Additionally, the products showed significant antiproliferative activity against tumor cells in the MTT assay.

An environmentally friendly and practical method for the synthesis of various vinyl sulfones was developed through the direct sulfonylation of alkenyl sulfonium salts with sulfinic acids. The reaction was effectively triggered by the combined actions of milling, sunlight, and photocatalysts under solvent-free conditions, offering advantages such as a short reaction time (5–10 min), room temperature, and a straightforward workup procedure. Preliminary mechanistic studies suggested that a sulfonyl radical may be involved in this mechanophotocatalytic transformation process.

A palladium-catalyzed new mode of cascade arylative cyclization of 1,6-diynes is disclosed using dibenzoxaborin as an arylating agent featuring transmetalation and selective migratory insertion as the key steps. This process enables the efficient construction of polysubstituted fused naphthalene skeletons via the formation of three new C–C bonds through dual regioselectivity in both arylation as well as C–H functionalization. Some control experiments and kinetic isotope effect (KIE) studies were conducted to elucidate the reaction mechanism, and some product diversifications were achieved to showcase the synthetic potential.

An efficient and attractive method for the synthesis of valuable benzofuran-3(2H)-one derivatives bearing a quaternary center in one step by employing dimethyl sulfoxide (DMSO) as a dual synthon under metal-free conditions has been developed. In this reaction, DMSO activated by cyanuric chloride (TCT) provides two different units (CH₃ and SMe) in the target molecules, and the construction of the quaternary carbon center in the benzofuran-3(2H)-ones can be controlled by the addition of water. Furthermore, the functional group compatibility and synthetic value were demonstrated by scope evaluation and gram-scale experiments. The mechanistic studies show that the reaction may proceed via a radical process.

We have developed an umpolung method utilizing the Tf₂O/DMSO-based system for C(sp²)–P bond or C(sp³)–P bond formation. This method employs both P(O)–H and P(O)–OH compounds as phosphorus sources and demonstrates excellent compatibility with a wide range of Grignard reagents. Without the requirement of precious transition metals or additives, this one-pot protocol provides a practical and efficient synthetic pathway to a variety of aryl and alkyl phosphine oxides. The broad substrate scope and diverse synthetic applications highlight the practical utility of this method.

A visible-light-promoted FeCl₃-catalyzed protocol for the generation of alkyl and silyl radicals from alkanes and silanes, respectively, is described. Employing a chlorine radical as a hydrogen atom transfer agent, alkyl, and silyl radicals were accessed and functionalized by addition to coumarins, ultimately resulting in a redox-neutral alkylation/silylation. The reaction occurs without an exogenous oxidant and under mild conditions, highlighting the potential of 3D-metal compounds in achieving challenging bond activations via photochemical excitation.

An efficient method for reductive deoxygenation of isatin derivatives using catalyst B(C₆F₅)₃ and methylphenylsilane is described. This reaction proceeds rapidly under mild conditions, and the protocol provides a broad substrate scope. Notably, while general synthetic methods utilizing a combination of B(C₆F₅)₃ and hydrosilanes smoothly reduce indoles to generate indolines, the present strategy represents the first reductive deoxygenation reaction for the formation of indoles without further reduction.

In this work, we studied the conjugated additions of bis-trimethylsilylacetalketene acetals (bis-TMSKA) to para-quinone methides (p-QMs), which are one of the most explored molecules for the study of conjugated additions and gained significant attention in organic chemistry due to their versatile reactivity, particularly in Michael addition reactions. In this study, trifluoromethanesulfonic anhydride (Tf₂O) was used as an activating agent for p-QMs, aiming to achieve 1,6-Michael addition products and the least reported 1,8-Michael addition with pyridine substituents. The reactivity of p-QMs derived from pyridine demonstrated distinct reaction pathways, leading to the formation of δ and γ lactones. The investigation also involved synthesizing a 1-indanone derived from the carboxylic acids obtained from the 1,6-addition.

The mechanochemical C–H activation of heterocycles presents a sustainable, solvent-free alternative to the traditional solution-phase synthesis. Heterocycles are fundamental molecular scaffolds in medicinal chemistry and drug discovery. This review highlights recent advances in mechanochemical methods for metal-catalyzed and metal-free C–H functionalization/derivatization, including arylation, alkenylation, acylation, borylation, trifluoromethylation, etc., applied across various heterocyclic compounds. Emphasizing green aspects, this synopsis provides a comprehensive overview of mechanochemical innovations, their unique features and advantages, transformative potential for ecofriendly synthesis, and future prospects of sustainability.