ASAP (As Soon As Publishable)

N-Dealkylation of amides is a general process in living organisms and organic synthetic chemistry, but an efficient chemical approach for this transformation has not been explored. Herein, we report an electrochemical method for the monodealkylation of a wide range of tertiary amides, including benzamides, alkyl amides, lactams, and sulfonamides. The reaction proceeds smoothly under mild conditions using TMSN₃ as the initiator and is not limited to deethylation or demethylation. This protocol enables the large synthesis, providing a valuable tool for synthetic organic chemistry.

The standard protocol for Alloc group removal during peptide synthesis still presents limitations, including low reaction yields, N-allylated byproducts, and the use of air-sensitive Pd(PPh₃)₄. We addressed these challenges by developing a novel protocol using the air-stable Pd(PPh₃)₂Cl₂ catalyst, Meldrum’s acid (MA), and triethylsilane (TES-H). This combination ensured high yields, eliminated N-allylated byproducts, and is compatible with automated synthesis. This cost-effective and efficient method shows promise for widespread use in peptide chemistry applications and beyond.

A refined synthesis of 1,4,2-diazaphospholidine-3,5-dione derivatives was achieved through a cyclization reaction involving Na(OCP) and isocyanates. Na(OCP) was demonstrated to be a relatively stable and safe source of phosphorus, enabling the production of diverse 1,4,2-diazaphospholidine-3,5-dione derivatives with high yields. The reaction proceeds efficiently under catalyst-free and mild conditions. Both experimental findings and density functional theory calculations have elucidated that the process involves a crucial step of carbon monoxide elimination, which provides deeper insight into the reaction mechanism.

Fused heterocyclic scaffolds, such as benzimidazoles or larger ring systems containing a benzimidazole fragment, are frequently encountered in pharmaceutical compounds and other biologically active molecules. While there are many examples of N9- and/or C3-substituted 9H-benzo[4,5]imidazo[2,1-c][1,2,4]triazoles, current examples of the regioselective preparation of N1-substituted 1H-benzo[4,5]imidazo[2,1-c][1,2,4]triazoles are limited to N1-aryl substituted compounds, which also contain a C3-substituent. Here, we report an iodine-promoted C–H bond amination reaction that allows the selective preparation of 1H-benzo[4,5]imidazo[2,1-c][1,2,4]triazoles with a variety of aryl and alkyl N1-substituents. Not only do these cyclization reactions allow access to a new substitution pattern on the benzo[4,5]imidazo[2,1-c][1,2,4]triazole scaffold, but they are also tolerant toward a wide range of functional groups, including esters, amides, alcohols, alkynes, and alkenes. Our findings expand the synthetic toolbox for the preparation of nitrogen containing fused heteroarenes.

A new access to substituted pyridines was developed from iodoenones. This two-step procedure involves a Sonogashira coupling with a free alkyne containing a nosylamide followed by a thiophenol treatment in basic conditions that triggers nosyl deprotection, a Michael–retro-Michael process, condensation, and isomerization in cascade to yield the heterocycle. This method enables the introduction of different substituents at several pyridine positions. This approach offers new synthetic opportunities to produce heterocycles present in many bioactive compounds.

The evolution of energetic materials science presents new challenging tasks associated with the creation of advanced technologies for sustainable development of the future. In this work, a set of new heat-resistant high-energy materials incorporating the polynitrophenyl-1,2,5-oxadiazole scaffold enriched with azo/azoxy moieties have been designed and synthesized. Due to a smart combination of explosophoric groups and 1,2,5-oxadiazole rings, the prepared high-energy substances have excellent thermal stability (up to 300 °C), good densities (up to 1.75 g cm^–3), high enthalpies of formation (340–538 kJ mol^–1), and high combined nitrogen–oxygen content (63–68%). In-depth structural analysis revealed the presence of strong intra- and intermolecular hydrogen bonds in aminodinitrophenyl derivatives, which in combination with the small deviation of electrostatic potential values explains the low mechanical sensitivity of these materials. At the same time, trinitrophenyl-1,2,5-oxadiazoles incorporating three adjacent non-coplanar nitro groups demonstrated higher sensitivity to impact, albeit retaining complete insensitivity to friction. The overall performance of the thus prepared high-energy substances exceeds that of the known heat-resistant explosive hexanitrostilbene. Therefore, the newly synthesized family of energetic polynitrophenyl-1,2,5-oxadiazoles provides a fruitful foundation for the creation of the advanced heat-resistant energetic materials of the future.

A series of porphyrin analogues with fused 1,10-phenanthroline units were synthesized. The proton NMR spectra for phenanthroline-fused heteroporphyrins showed significantly upfield shifted meso-proton resonances compared to related porphyrinoid systems and the peaks corresponding to alkyl substituents directly attached to these macrocycles were also observed further upfield. These results indicate that the presence of the phenanthroline unit leads to reduced diatropicity, but the internal NH resonance was also further upfield, a result that is inconsistent with this interpretation. A phenanthrene-fused carbaporphyrin gave an unexpectedly upfield singlet for the internal C–H at nearly −9 ppm, while the NH protons appeared at −6.8 ppm. These unusual chemical shifts again imply enhanced diatropicity but the reduced downfield shifts for the external protons indicates that the aromatic ring current has been significantly reduced. Similar results were obtained for phenanthroline-fused oxybenzi- and oxypyriporphyrins. Detailed analyses of the spectroscopic properties for these systems are reported and protonation studies were conducted. The conjugation pathways and aromatic properties were computationally analyzed using nucleus independent chemical shifts (NICS) and anisotropy of induced current density plots.

O-GalNAc glycans on glycoproteins with eight different core structures sharing a common α-glycosidic linkage (O-GalNAc-α-Ser/Thr) are critical in various physiological and pathological processes. Among the eight O-GalNAc glycan cores, core 2 characterized by a GlcNAcβ1–6(Galβ1–3)GalNAc structural motif plays a significant role in regulating diverse biological processes, such as immune response modulation, adhesive properties of selectins, and gastrointestinal tract protection. However, the large-quantity synthesis of core 2 containing glyco-amino acids for downstream solid-phase peptide synthesis is challenging. In this work, we successfully employed a silver oxide for coupling a 2-azido-galactosyl chloride donor with two acceptors, Fmoc-Ser/Thr-O^tBu, respectively, for the large-scale synthesis of the two important intermediates, α-GalN₃–Fmoc-Ser/Thr-O^tBu, which can be further utilized for the large-scale synthesis of core 2 containing glyco-amino acids. The two intermediates, α-GalN₃–Fmoc-Ser/Thr-O^tBu, were utilized for synthesizing core 2 containing Fmoc-Ser/Thr-COOH. The synthesis of core 2 containing Fmoc-Ser-COOH was achieved on a 1.95 g scale, while the synthesis of core 2 containing Fmoc-Thr-COOH was achieved on a 0.38 g scale. Additionally, the synthesis of the 2-azido-galactosyl chloride donor was optimized into a three-step process with only one column chromatography purification. Finally, core 2 containing Fmoc-Ser/Thr-COOH were applied for the synthesis of glycosylated CCR1 and CCR5 N-terminal peptides.

Herein, we introduce a mild and efficient method for synthesizing aniline biaryls and unsymmetrical phenol biaryls through iodine-catalyzed coupling of quinone imine ketals (QIKs)/quinonemonoacetals (QMAs) and β-naphthols. This approach allows for the unusual formation of ortho-substituted anilines and phenols, valuable in pharmaceuticals and advanced materials but typically difficult to produce. Our method achieves high ortho-selectivity without needing transition metals or external/internal templates. The process involves a [3,3] sigmatropic rearrangement of the in situ generated mixed acetal, which is the key intermediate. Notable features include scalability, broad functional group tolerance, and late-stage derivatization of natural products using a cost-effective, air-tolerant catalytic system, eliminating the need for hazardous catalysts.

Herein, the palladium-catalyzed autotandem reaction of cyclopropyl alcohols with gem-dibromoolefins is described. This reaction system involves two distinct mechanistic processes, both efficiently catalyzed by the same palladium catalyst. This approach accommodates a wide substrate scope using readily available starting materials, offering a new and efficient method for synthesizing a series of β-pyrrolo[1,2-a]quinolinyl ketones.

Two novel Pd-catalyzed protocols for the controllable synthesis of benzo[b]furo[2,3-d]azepines and furo[3,2-b]indoles have been developed by intermolecular oxidative annulation of 2-(furan-2-yl)anilines and propargyl carbonates versus intramolecular C–H amination reactions. These two protocols feature great scalability, functional group tolerance, and relatively mild reaction conditions. Notably, the robust methodologies could also provide valuable opportunities for assembling azepine-fused benzothiophene, indole-fused benzothiophene, and indole-fused benzimidazole, which may have potential applications in the synthesis of related pharmaceuticals or polymeric materials.

Conjugation of radiofluorinated prosthetic groups to primary amines of peptides in an aqueous medium is still considerably challenging. Herein, we report a one-pot cascade synthesis of 1-[¹⁸F]fluoro-4-isothiocyanatobenzene ([¹⁸F]2d), an isothiocyanate-functionalized prosthetic group for radiolabeling of various peptides in aqueous medium. The developed compound [¹⁸F]2d was synthesized in >99% radiochemical purity with 22.9 ± 3.8% (n = 12) decay-corrected yield having molar activity of 0.65 ± 0.19 (n = 12) GBq/μmol. Various clinically important peptides including prostate-specific membrane antigen vector, octreotide acetate, biotin analogue, Arg-Gly-Asp analogue, and bradykinin were successfully conjugated with [¹⁸F]2d in an aqueous medium in a good to moderate radiochemical yield. The overall synthesis of [¹⁸F]2d and its conjugation with a peptide take around 155 min, including purification.

1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD) was used for the synthesis of cyclic imides via an amidation–cyclization–elimination cascade. This organocatalytic transformation features both the traditional reactivity of TBD and its unprecedented C–C bond cleavage capability, allowing rapid and efficient access to cyclic imides. This method is compatible with the late-stage functionalization of complex molecules and the synthesis of bioactive molecules. Both experimental and computational approaches were employed to gain a better understanding of the reaction mechanism.

Environmentally stable novel flexible bisperylene resorcin[4]arene molecular switch cavitand B and the corresponding rigid cavitand A were synthesized and a single crystal was obtained. Spectroscopic analysis revealed the formation of an excimer of perylene within the cavitand. The presence of flexible chains in cavitand B confers a high degree of environmental stability, rendering its fluorescence unaffected by external factors such as pH and temperature variations. In contrast, the rigid cavitand A exhibits heightened sensitivity to changes in environmental conditions.

We reported a palladium/norbornene-catalyzed dual intermolecular C–H arylation/intramolecular cyclization reaction of iodoferrocenes with ortho-bromobenzamides, enabling the formation of arylated isoquinolone-fused ferrocenes in a straightforward and effective manner. This method has a broad substrate scope and good functional group compatibility, while the gram-scale reaction demonstrates the practicality of this method.

Ion triplets of the chloride salts of two commonly used weakly coordinating cations are reported (i.e., Cl^–·NMe₄⁺Cl^– (1^–) and Cl^–·PPh₄⁺Cl^– (2^–)). Negative ion photoelectron spectra at 20 K afford vertical and adiabatic detachment energies of 5.18 and 5.00 eV (1^–) and 5.03 and 4.70 eV (2^–), respectively. These results are well reproduced by coupled cluster calculations with single, double, and perturbative triple excitations (CCSD(T)) whereas M06-2X is systematically too small by ∼0.3 eV (i.e., 7 kcal mol^–1). The structures of both 1^– and 2^– have five or six C–H···Cl^– interactions that stabilize these cluster anions by 32 (1^–) and 27 (2^–) kcal mol^–1 as given by their chloride dissociation enthalpies. These values drop to 7.4 and 3.8 kcal mol^–1 in dichloromethane based up conductor-like polarizable continuum model calculations and suggest that X^–·M⁺X^– ion triplets with a weakly coordinating cation maybe the reactive form of salts under some conditions.

A catalyst-free reductive radical-polar crossover cyclization with alkenes and sodium dithionite to construct densely functionalized cyclic sultines was described. The key to the success of this practical protocol relies not only on a bifunctional role of sodium dithionite, that is, serving as radical initiator and SO₂ source, but also on the diversified conversions (RPCC/SO₂ insertion/S_N2 cyclization and RPCC/SO₂ insertion/1,4-addition cyclization processes), which enabled efficient construction of target compounds with the high efficiency and atom- and step-economy under mild conditions.

An asymmetric tandem esterification/Michael addition reaction of β-keto acylpyrazoles with o-hydroxychalcones has been established under the catalysis of a bifunctional squaramide-tertiary amine. A wide variety of biorelevant 3,4-dihydrocoumarin derivatives were generally obtained in high yields (up to 93%) with excellent diastereo- and enantioselectivities (>19:1 dr, up to 93% ee) under mild reaction conditions. This reaction represents the successful application of β-keto acylpyrazoles as 2C building blocks in catalytic asymmetric cyclizations.

The structure–activity relationship between the metal center and regio-selectivity is persistently a pivotal scientific issue. To address this, we select the 2-phenylpyridine sulfonylation reactions catalyzed by ruthenium and palladium as research subjects. An extensive theoretical study has been conducted on their reaction mechanisms, the sources of regio-selectivity, and the evolution of electronic structures. The distinct electronic structures lead to completely different catalytic mechanisms and electronic structure evolution processes for ruthenium and palladium. Ruthenium tends to form six-coordinate octahedral complexes, thus undergoing an inner-sphere redox active Ru(II)–Ru(III)–Ru(IV)–Ru(II) catalytic cycle. In contrast, palladium tends to form four-coordinate planar quadrilateral complexes, hence undergoing an outer-sphere redox neutral Pd(II) catalytic cycle. The distinct electronic structure evolution processes fundamentally differentiate the radical attack modes in the sulfonation process, thereby determining the regio-selectivity of the reaction. In the Ru-catalyzed system, the meta-selectivity arises mainly from a more stable Schrock carbene-type meta-intermediate. For the Pd-catalyzed system, the ortho-selectivity mainly comes from the stabilizing effect of the Pd(II) center on the single electron. This study provides novel insights into how the electronic structure of metal centers influences the reaction mechanism and selectivity, making a theoretical contribution to a deeper comprehension of the mechanism and regio-selectivity underlying aromatic functionalization reactions.

A series of novel spirocyclic α-proline building blocks with a spiro conjunction in position 3 of the pyrrolidine ring was prepared to employ two convenient and practical synthetic approaches. Both alternative routes utilize simple and readily available starting materials─cyclic ketones and esters─and comprise 6 and 7 steps, respectively. The methodologies feature distinct advantages, using routine organic chemistry transformations, and are suitable for producing multigram amounts of the target prolines. The approach also became valuable for spirocyclic pyroglutamic acids.

The increasing popularity of the dihydrouracil motif in cereblon (CRBN) recruiting proteolysis-targeting chimeras (PROTACs) has necessitated the development of a facile, cost-effective, and high-yielding method for its introduction into molecules. To that end, we disclose herein an N-1 selective Pd-catalyzed cross-coupling of dihydrouracil with aryl electrophiles to provide access to medicinally relevant scaffolds in a single step. This approach exhibits excellent functional group tolerance and broad applicability to an abundance of (hetero)aryl halides and phenol derivatives and utilizes readily available catalyst/ligand systems. Thus, our strategy should find broad utility in the arena of PROTAC research, as it obviates the drawbacks of previous methodologies that rely on multistep synthetic routes and protecting group strategies to achieve N-1 selectivity.

A novel strategy for the synthesis of various isochromeno[4,3-c]quinolines via palladium-catalyzed tandem cyclization of functional diarylalkynes with isocyanides has been developed. This approach features excellent chemo- and regioselectivities as well as good functional group tolerance. Notably, 6-phenylimino-6H-isochromeno[4,3-c]quinolin-11-amines and 11-amino-6H-isochromeno[4,3-c]quinolin-6-ones can be selectively constructed by employing different protecting groups of functional diarylalkynes. The gram-scale and late-stage modifications further demonstrate the synthetic value of this method.

A simple strategy for the synthesis of β-keto phosphorodithioates has been developed through the direct oxyphosphorodithiolation of vinyl azides with P₄S₁₀ and alcohols in the presence of water. The reaction is conducted at room temperature to provide a number of β-keto phosphorodithioates in moderate to good yields. This methodology has the advantages of simple operation, mild condition, broad substrate scope, and favorable group compatibility.

A highly stereoselective protocol for the (3 + 2)-annulation of biphenyl-bridged seven-membered cyclic N-sulfonylimines with γ-hydroxy-α,β-unsaturated ketones was developed. The reactions afforded a wide range of chiral [5.7]-fused ε-sultams bearing N-adjacent 1,3-stereocenters in excellent yields (93–98% yields) and high enantio/diastereoselectivities (up to >99% ee, >20:1 d.r.) and two other examples with alkoxyl groups were obtained in 52–61% yields, 95% ee, and >20:1 d.r. by utilizing organocatalysis with quinine-derived squaramides.

The construction of N-containing aromatic compounds from lignin is of great importance to expanding the boundary of the biorefinery and meeting the demand for value-added biorefinery. However, it remains a huge challenge due to the complex lignin structure and the incompatible catalysis for C–O/C–C bond cleavage and C–N formation. Herein, sustainable synthesis of cinnamonitrile derivatives from lignin β-O-4 model compounds in the presence of 2,2,6,6-tetramethylpiperidine oxide (TEMPO), (diacetoxyiodo)benzene (BAIB), and a strong base has been achieved in a one-pot, two-step fashion under transition-metal-free conditions. Mechanistic studies suggest that this transformation starts from selective oxidation of C_γ-OH of the β-O-4 model compound, followed by retro-aldol condensation, resulting in the cleavage of the C_α–C_β bond to afford veratraldehyde. Whereafter, the aldol condensation reaction allows coupling of veratraldehyde with nitriles to provide cinnamonitriles. With this protocol, 3,4-dimethoxycinnamonitrile and 3,4-dimethoxyphenyl-2-phenylacrylonitrile were synthesized from lignin β-O-4 model compounds and showed good antibacterial or antifungal activity, showcasing the application potential of lignin in pharmaceutical synthesis.

A Pd/C-catalyzed dehydrogenative [3 + 2] cycloaddition is described for the diastereoswitchable synthesis of hexahydropyrrolo[2,1-a]isoquinolines by altering solvents. The reaction proceeds through a sequential Pd/C-catalyzed dehydrogenative formation of azomethine ylides from tetrahydroisoquinoline acetates and 1,3-dipolar cycloaddition with 2-nitroethenylbenzenes. This method displayed tunable diastereoselectivity, a broad substrate scope and good functional group compatibility. Moreover, a gram-scale synthesis and selective reductive or oxidative transformations of the product further demonstrate the utility of this methodology.

A novel method is reported to synthesize various pyrazolones through transition-metal-free and redox-neutral 1°, 2°, or 3° C(sp³)–H carbonylative cyclization using 1 atm of CO₂ as a green carbonyl source, featuring good functional group tolerance, a broad substrate scope, facile scalability, and easy product transformation. The utility of this method could be demonstrated by the applications in preparing useful synthetic intermediates and bioactive compounds.

To date, a general approach for the direct α-acyloxylation of cyclic 1,3-dicarbonyls remains challenging. Herein, we report a Pd-catalyzed α-acyloxylation of cyclic 1,3-dicarbonyl-derived hypervalent iodine compounds with highly abundant carboxylic acids. Our approach utilizes a commercially available Pd(OAc)₂ catalyst, which exhibits mild reaction conditions, scalability, operational simplicity, and robustness against moisture and air. Importantly, our approach eliminates the need for excess carboxylic acids (only 1 equiv) and the use of explosive peroxides and is compatible with diverse complex substrates (e.g., glycyrrhetinic acid and celastrol). The power of this method is further demonstrated through significantly simplifying a previous synthesis.

A copper catalyzed enantioselective formal aza-Diels–Alder reaction of in situ formed 1,2-diaza-1,3-dienes from α-halohydrazones and vinyl diazo compounds was described. The protocol provides a variety of optically enriched diazo-containing tetrahydropyridazines in moderate yields and with up to excellent enantioselectivities. The present methodologies utilize chiral oxazolines as the chiral ligands for asymmetric catalysis and feature mild reaction conditions, readily available substrates, and broad substrate scope.

An unprecedented, transition metal-free S-alkylation of disulfides with alkyl halides is developed for the first time, providing an efficient and green synthesis of thioethers and even thioesters. Notably, this new method allows the full utilization of both sulfur atoms of disulfides under chemical reductant-free conditions and can be easily scaled up in gram scale, showing good practical value. Control experiments suggested that water, unprecedentedly, serves as the terminal reductant of the whole reaction. Moreover, controllable N-alkyl thiopyridones can be readily obtained at a much lower reaction temperature from the same starting materials, suggesting a kinetic control of N-alkylation vs a thermodynamic control of the S-alkylation process may be involved in the reaction. Interestingly, a halo anion-mediated alkyl group migration from N-alkyl thiopyridones to S-alkyl pyridyl thioethers was observed, suggesting that the reaction may undergo a new and novel reaction mechanism.

Reported herein is the C(sp³)–C(sp³) bond-forming at an unactivated C(sp³)–H bond via hydride transfer-initiated deoxygenative coupling reactions. Various polycyclic hydroquinolines were provided under metal-free conditions with excellent diastereoselectivity. Mechanistic study revealed that quinoline served as an intramolecular hydride shuttle to achieve the hydride abstraction and release in order. This methodology not only provides a practical strategy for direct deoxygenative coupling for the C(sp³)–C(sp³) bond-forming but also develops a new reaction type involving quinoline-enabled hydride transfer.

3-Substituted indoles are an important framework of many drugs, agricultural chemicals, functional materials, and bioactive compounds. Malononitrile-based three-component Yonemitsu reactions are attractive choices for the synthesis of 3-substituted indole derivatives but suffered from long reaction time and harsh conditions (e.g., elevated temperature and special catalysts/solvents) in conventional conversions. In this study, we developed a metal-free, efficient, mild, and wide microdroplet/thin-film method to construct 18 3-substituted indoles from various substituted aromatic aldehydes and indoles with good reaction yields (42–69%) and fantastic reaction acceleration (1.32 × 10³ rate acceleration factor relative to the bulk reaction). By spraying 0.8 mol L^–1 reactants at 300 μL min^–1, the rate of the microdroplet/thin film product was scaled up to 1.72 g h^–1. Overall, the microdroplet/thin-film method offered several advantages including high efficiency, mild conditions, wide scope, and gram-scale ability, making it attractive for synthesizing 3-substituted indoles under the requirements of sustainable chemistry.

The hydroformylation of 1,3-butadiene for the selective synthesis of adipic aldehyde (AA) has been a long-standing challenge due to its intricate reaction network, resulting in low reaction efficiency and poor chemo- and regioselectivity. Herein, we propose a dual ligand-relay catalysis strategy for the selective hydroformylation of 1,3-butadiene to an AA. This strategy entails a one-pot and two-step process, commencing with a Rh-catalyzed 1,3-butadiene hydroformylation, followed by Rh-catalyzed isomerizing hydroformylation. The reaction is facilitated by using two distinct biphosphites as auxiliary ligands, each with a specific individual role in the process. Remarkably, an unprecedented chemo- and regioselectivity of up to 65.9% toward AA was achieved with complete conversion of 1,3-butadiene, marking the highest value compared to the previous state-of-the-art catalyst systems thus far. Furthermore, the process also produced a 26.5% selectivity for n-valeraldehyde as the major byproduct, a key compound of industrial importance. This study therefore represents a significant advancement in the hydroformylation of 1,3-butadiene, showcasing the potential of this ligand-relay catalysis strategy for improving selectivity in the reaction.

Herein, we report the synthesis of novel dimeric urea-bridged BODIPY–carbohydrate conjugates, which display circularly polarized luminescence (CPL). The dimers are composed of diastereomerically pure, axially chiral (P or M) BODIPY monomers containing a pendant glucose (d- or l-) unit. The latter was intended to add chirality, biocompatibility, and enhanced water solubility and facilitate the chromatographic resolution of the intermediate atropisomers. The dimerization process was based on the ureation reaction of azidomethyl BODIPYs. The rigorous structural assignment was possible by X-ray diffraction analysis of one of the BODIPY atropisomers.

A cerium-catalyzed C–H alkylation of N-sulfonyl ketimines with low-cost and readily available alkanes as alkyl sources was developed. This transformation proceeded through the synergy of photoinitiated ligand-to-metal charge transfer (LMCT) using a chlorine radical as an HAT reagent and air as a green oxidant. A series of alkylated N-sulfonyl ketimines were synthesized with moderate to good yields in a highly atom-economic manner under chemical oxidant-free conditions.

The generation, interconversion, and reactivity of electrophilic species generated upon activation of nitroalkanes with protic acids (the Nef and Meyer reactions) were investigated by quantum-chemical calculations. N,N-Bis(hydroxy)iminium (R₂C═N⁺(OH)₂) and N-oxoiminium (R₂C═N⁺═O) cations were shown to be produced independently from aci-nitroalkanes, while N-hydroxynitrilium cations (RC≡N⁺–OH) were formed via nearly barrierless C–H bond cleavage in N-oxoiminium cations. The N-oxoiminium and N-hydroxynitrilium cations whose formation is favored under highly acidic anhydrous conditions are strong electrophiles capable of reacting even with nonactivated arenes under ambient conditions. The N-oxoiminium cations R₂C═N⁺═O are highly unusual ambident species containing three contiguous electrophilic centers (C, N, and O atoms). Nucleophilic addition at the oxygen atom is less preferred than the C- and N-attack yet possible in an intramolecular variant. These computational results shed light on some key aspects of the mechanisms of the Nef and Meyer reactions and predict the possibility of numerous interrupted versions of these reactions.

We report the intermolecular (4 + 3) cycloadditions of oxetanyl and azetidinyl enolsilanes with different dienes by silylium catalysis to generate bicyclic scaffolds. These enolsilanes were competent to react with furans, cyclopentadiene, and 1,3-cyclohexadiene to deliver cycloadducts in up to 96% yields.

The synthesis of coumarin– and flavonoid–chalcone hybrids via Pd-catalyzed Heck-type coupling of arene diazonium salts and 8-allylcoumarins and −flavonoids is reported. The β-hydride elimination step proceeds with high regioselectivity if an OMOM-substituent is present at the position C7, adjacent to the allyl group. A selective allylic oxidation of the coupling products was accomplished using DDQ in the presence of silica to furnish the chalcones.

The Cu(MeCN)₄PF₆-catalyzed reaction of 1-(2-hydroxyphenyl)-propargyl alcohols with aryl/alkyl mercaptan and subsequent treatment with K₂CO₃ only offered 3-(alkylthio)benzofurans, whereas the stoichiometric-exceeding CuI-mediated reaction and subsequent treatment with DIPEA furnished 2-(alkylthiomethyl)benzofurans with high selectivity. The amount of Cu(I) salts plays a key role in selective formation. This unique protocol for the selective construction of the two series of benzofurans containing alkylthio group proved to be suitable for broad substrates 1 and 2 except for aliphatic alkynyl alcohols.

Silyl-phenanthroline (NN′Si) ligand ancillary iridium-catalyzed C(sp³)–H borylation is investigated theoretically. Density functional theory calculations clearly disclose that the (NN′Si)Ir^V(H)(Bpin)₃ (NN′Si = 6-[(di-tert-butylsilyl)methyl]-1,10-phenanthroline) complex is a resting state, and the (NN′Si)Ir^III(Bpin)₂ complex serves as an active species in the catalytic cycle. The remarkably high activity of this type of a catalyst arises from the rapid reductive elimination of HBpin from (NN′Si)Ir^V(H)(Bpin)₃ to generate the active species (NN′Si)Ir^III(Bpin)₂. The silyl group plays a crucial role in accelerating the crucial hydride-migration elementary step, which allows the isomerization of the (NN′Si)Ir^V(R)(H)(Bpin)₂ intermediate to achieve the C(sp³)–B reductive elimination and afford the borylated product. Although C(sp³)–H borylation with HBpin is thermodynamically unfavorable, the Ir-dihydride intermediate (NN′Si)Ir^V(H)₂(Bpin)₂ generated after product formation is slightly more stable than resting-state (NN′Si)Ir^V(H)(Bpin)₃ in this catalytic cycle, which is an important driving force for the HBpin reaction. Such success was not attained by many other traditional bidentate ligands. The unique regioselectivity of n-butyl ethyl ether and 2-methylheptane, induced by the NN′Si-pincer ligand, is well reproduced and the underlying reason for the selectivity is clearly elucidated.

A 3-step modular procedure combining carboxylic acids with acyl hydrazines provides access to medicinally relevant [1,2,4]-fused triazoles. Good to excellent yields are achieved with tolerance of aliphatic and aryl substituents as well as 5-, 6-, and 7-membered rings for the fused ring. Conditions that can avoid column chromatography and be applicable for both small scale discovery efforts as well as large scale development processes are demonstrated within.

A series of sulfonamido-substituted oxime-ethers have been synthesized by the reaction of donor–acceptor aziridines with aldo- and keto-oximes through C–C bond cleavage. Nucleophilic attack by an oxime hydroxyl group on the in situ-generated azomethine ylide rather than the routine cycloaddition reaction draws the novelty of the developed methodology. Selective protection of the oxime hydroxyl group is observed in the presence of phenolic −OH, which made the protocol enriched. In terms of a synthetic point of view, the uniqueness had been drawn further as it occurred at room temperature and within 30 min. Participation of a wide range of aziridines with a series of aldo- and keto-oximes made the developed methodology generalized by creating a novel library of substituted oxime-ethers.

The synthesis of photocaged substrates of the biologically important enzyme HMG-CoA reductase is reported. HMG-CoA bearing a p-hydroxyphenacyl (pHP) photocage moiety was synthesized in an overall yield of 14% over seven steps in addition to caged forms of mevalonate and mevaldehyde. The absorption maximum and quantum yield for the decaging of the photocaged compounds are dependent on pH with a λ_max of 330 nm and a ϕ of 5%, respectively, at pH 9.1 but a λ_max of 290 nm and a ϕ of 16%, respectively, at pH 6.7.

A method to access highly substituted dihydrothiophenes and the corresponding thiophenes is reported. This strategy complements traditional stepwise synthesis by coupling readily accessible bicyclic 1,2,3 thiadiazoles with alkenes in a modular, Rh-catalyzed formal (3 + 2) cycloaddition. Application of this method to an array of novel thiadiazoles generates densely functionalized dihydrothiophenes that can be subsequently oxidized to the corresponding thiophene products.

We report, for the first time, a visible-light-promoted Markovnikov hydroalkoxylation of α-trifluoromethyl alkenes with 1,2-diketones. This transformation proceeded smoothly in the presence of a tertiary amine (Et₃N), providing a series of enol ethers containing the trifluoromethylated tetrasubstituted center in moderate to excellent yields. In this protocol, hydrogen atom transfer between this amine and 1,2-diketone substrate affords a ketyl radical and an α-aminoalkyl radical, which engages in the formation of a radical anion of the α-CF₃ alkene via a single electron transfer. Notably, this protocol features several advantages including metal- and external photocatalyst-free, mild conditions, easy operation, a broad substrate scope, and good functional group tolerance. Moreover, by applying this new method, a great number of important deuterium-labeled organofluorine compounds can be readily prepared using CD₃OD as a deuterium source.

Distinctive, green, innovative, and well-organized photoinduced (metal- or photocatalyst-free) regioselective decarbonylative and decarboxylative C–O bond functionalization protocols to access aryl 2-aminobenzoates and 2-substituted benzoxazinone derivatives in excellent yields have been devised. These are achieved through the chemoselective scission of isatoic anhydride with ketones, diaryliodonium triflate, nitroalkene, phthalazinone, and phenol derivatives, which, in turn, served as the representative “electrophilic and nucleophilic” coupling partners. Control experiments and DFT calculations reveal that electrophilic radical-bearing coupling partners specifically follow the decarbonylation pathway, while nucleophilic radical-bearing conjugates facilitate the decarboxylation process. Thus, the devised methods represent the chemoselective fragmentation of isatoic anhydride, which occurs due to the electronic nature of the coupling partners. Again, the regioselective C–O/O–C bond formation is also a novel outcome of this methodology. We have also devised a green method for synthesizing 2-aminobenzoate-subtituted paracetamol through a decarboxylation route. A fluorescence quenching study indicates that phenyl 2-aminobenzoate specifically detects Fe(II) ions, exhibiting no reactivity toward various other metal ions. Additionally, transition-metal-catalyzed C–H bond functionalization of 2-substituted benzoxazinone with phenyl vinyl sulfone was performed at ease with significant yields, which appreciated the strategy developed by us.

The development of novel directing groups is a valuable strategy to secure the advancement of catalytic C–H functionalization. To illustrate the feasibility of urazoles as heterocyclic directing groups, we herein present the ruthenium(II)-catalyzed annulation of N–H/C–H bonds on N-aryl urazoles with vinylene carbonate. This transformation provides the rapid construction of triazolocinnoline derivatives as hemiaminal and dehydrated forms. A series of mechanistic investigations and post-transformations highlighted the amenability of the developed method.

A comprehensive theoretical investigation into the gold-catalyzed synthesis of polysubstituted pyrazolines and dihydropyridines from imines and methyl phenylpropiolate was conducted in this study. Three imines with distinct substituents were selected as model reactants. The computational outcomes reveal that four-membered intermediates generated from aza-enyne metathesis significantly affect the reaction selectivity. For nitrogen-centered NHCO₂Me substituents (series A), an outward ring opening occurs during the metathesis of the aza-alkyne. This leads to the formation of Z-butadiene intermediates and ultimately to pyrazoline products. Conversely, with an aromatic substituent at the nitrogen site (series B and C), an inward ring opening takes place. This results in E-butadiene intermediates and the synthesis of dihydropyridine derivatives. The dihydropyridine product’s configuration is determined by the aromatic ring’s substituent. Electron-donating groups tend to directly form 1,4-dihydropyridine through a 6π electrocyclization (series B). In contrast, strong electron-withdrawing substituents initially undergo azayne metathesis, followed by 6π electrocyclization to produce 1,2-dihydropyridine products (series C). Furthermore, the distinctive selectivities were investigated in depth using global reactivity index and distortion/interaction methods. This research may contribute to the design of more effective and selective protocols to access pyrazolines, dihydropyridines, and related compounds.

Herein, an approach for synthesizing 2-amino-3-substituted quinoline-4(3H)-ones and N-phenylbenzamide derivatives was developed. A series of quinoline-4(3H)-ones were synthesized through Ullmann cross-coupling under air conditions using inexpensive, readily available cyanamide with 2-bromo-N-phenylbenzamide as the starting material, copper iodide as the catalyst, and potassium tert-butoxide as the base in dimethyl sulfoxide. Noteworthy aspects of this method include its cost-effectiveness, the accessibility of raw materials, wide substrate applicability, ligand-free, open-air conditions, and simple operating procedures. Furthermore, investigations under similar reaction conditions further show that substituting water, alcohols, phenols, amines, or mercaptans for cyanamide as the nucleophilic reagent can be used to prepare 2-functionalized N-phenylbenzamides.

A direct electrochemical sulfonylation between indoles, inorganic sulfites, and alcohols was developed, in which various indoyl sulfonate esters were prepared efficiently. In this transformation, the easy-handle and cost-effective inorganic sulfite was disclosed to engage in a Csp²–H sulfonylation as the SO₂ source in an undivided electrolysis cell under mild conditions. In addition, the unexpected paired electrosynthesis has been achieved, owing to the dual role of inorganic sulfites, and led to a sulfonylation/reduction sequence to rapidly deliver hydroxyl substituted indole sulfonate esters.

Efficient synthesis of highly functionalized cyclopentenols with an exocyclic Z double bond was investigated via a (3 + 2) annulation reaction of 2-aroyl-D–A (donor–acceptor) cyclopropanes with alkynoates in the presence of DABCO. This synthetic approach featured a wide range of readily available 2-aroyl-substituted D–A cyclopropanes with diverse functional groups, densely substituted cyclopentenols with two stereogenic centers and an exocyclic double bond in a highly stereocontrolled manner and had operationally simple and mild reaction conditions.

We successfully reported selective C–H alkynylation of 2-pyridones with bromoalkynes under the catalysis of Co(III) or Ru(II). The alkynylation reaction used easily accessible bromoalkynes instead of high-valent iodine alkynes. There is a broad substrate scope of 2-pyridones with good yields. In addition, 2-pyridone can be used as a weakly directing group for C–H alkynylation of the proximal aryl C–H bond. This method offers an efficient approach for synthesizing diverse 2-pyridone derivatives, yielding alkynylated products up to 95% yield (>40 examples).

The functionalization of pyrazole-based compounds with dinitromethyl and N-hydroxytetrazole groups resulted in enhanced energetic properties. Two key compounds, 5-(dinitromethyl)-3,4-dinitro-1H-pyrazole (5) and 5-(3,4-dinitro-1H-pyrazol-5-yl)-1H-tetrazol-1-ol (7), along with their salts, were synthesized and evaluated for their energetic properties. Notably, the bishydroxylammonium salts 5b (D_v: 8778 m·s^–1; P: 33.1 GPa) and 7b (D_v: 8988 m·s^–1; P: 34.6 GPa) demonstrated an optimal balance between high detonation performance, good thermal stability, and low sensitivity, outperforming RDX, and positioning them as promising candidates for advanced secondary energetic materials.

Herein, is the reported synthesis and utilization of redox-active arylazoformamide (AAF) ligands in palladium(II) precatalysts for the Suzuki–Miyaura cross-coupling reaction. Complexes were formed from 2 equiv of an AAF ligand with Pd(II)Cl₂ in an appropriate solvent to create the square planar (AAF)₂PdCl₂ precatalyst. A thorough investigation of aryl bromides and arylboronic acids found that 1.0 mol % precatalyst with cesium carbonate (Cs₂CO₃) as base, 1,4-dioxane as solvent at 90 °C for 24 h allowed for excellent conversions to the biphenyl products (over 20 examples). To highlight the AAF ligand class, a set of comparison reactions were performed with redox-active arylazothioformamide ligands, i.e., an (ATF)₂PdCl₂ complex, other commercial palladium(II) complexes, and a Ni(II)Cl₂ arylazoformamide coordination complex₂. The (AAF)₂PdCl₂ complexes outperformed all of others tested. Mechanistically, it is proposed that the AAF ligand singly reduces to antiferromagnetically couple to the palladium(I) complex as a transmetalation intermediate. Ni-based precatalysts were found to be inactive for the studied Suzuki–Miyaura reaction. Overall, these ligand systems offer a unique look into redox-active palladium cross-coupling reactions as well as being phosphine-free and high yielding.

l-Guluronic acid is integral to the structures of alginates and to the pathogenesis of Pseudomonas aeruginosa. The exploitation of this hexose in both existing and new contexts is, however, limited by its prohibitively high commercial cost. We report on a short and efficient synthetic route to an l-GulA building block from a simple d-mannose thioglycoside. In this synthesis, the fluorine-directing effect is exploited to achieve a stereoselective C-5 epimerization. DFT calculations illuminate the substituent effects, which operate to confer this selectivity.

This study presents the application of a novel Fe-iminopyridine catalyst for the regioselective synthesis of oxazolidinones from carbon dioxide and aziridines. Our findings demonstrate that the Fe-iminopyridine catalyst containing imidazole functional group offers promising efficiency and facilitates a sustainable approach to green chemical synthesis at 50 °C and 10 bar CO₂ pressure in a single-component Fe catalyst system. Various aziridines with carboxylic acid-derived substituents were transformed into 5-carbonyl substituted oxazolidinone products. The regioselective synthesis of oxazolidinones followed by the reduction enhances their utility for the pharmaceutically valuable compounds.

Rongalite-mediated one-pot aminomethylation of heteroarenes using secondary amines/anilines has been developed. This transition-metal-free and mild reaction offers an efficient way to synthesize aminomethylated heteroaromatic compounds with high yields and broad functional group tolerance. Here, Rongalite plays a key role in generating the C1 unit source in situ, which triggers the aminomethylation process. This approach provides a library of aminomethylated imidazo[1,2-a]pyridines and imidazo[2,1-b]thiazoles.

Here we report a strategy that eliminates the need for photocatalysts and external additives, which provides an operable and mild method for halogen radical-enabled dearomatization of N-arylpropiolamides under an oxygen atmosphere at room temperature. The method is applicable to a wide range of substrates, extending beyond the limited scope of p-methoxyl N-phenylpropynamides. Furthermore, several functional synthetic intermediates and anticancer bioactive molecules were successfully derived from 3-halogenated azaspiro[4.5]trienones.

A visible-light-induced cascade radical trifluoromethylation/cyclization/dearomatization reaction between isocyanide-containing indoles and CF₃Br has been developed to afford trifluoromethylated spiro[indole-3,3-quinoline] and spiro [indole-3,3-pyrrole] derivatives in good yields. The utility of the process is demonstrated by a scale-up experiment. The mechanism was proposed based on the control experiments. The protocol constitutes a novel and efficient route for the synthesis of trifluoromethylated 3-spiroindolenines with advantages of good generality and practical applicability, broad substrate scope, and green energy source.

In this study, 5-(2-bromoaryl)tetrazoles were reacted with 1,3-diketones in DMF in the presence of a catalytic amount of magnetic Cu-MOF-74 (Fe₃O₄@SiO₂@Cu-MOF-74) and a base under microwave irradiation to yield the corresponding 1-aminoisoquinolines. The Fe₃O₄@SiO₂@Cu-MOF-74 catalyst could be easily recovered from the reaction mixture and reused four times without any significant loss of catalytic activity. An initial copper-catalyzed C(sp²)–C(sp³) bond formation accompanied by retro-Claisen deacylative cyclocondensation (for acyclic 1,3-diketones) and direct cyclocondensation (for cyclohexane-1,3-diones) is proposed as a key reaction pathway for this process. Cyclohexanone-fused 1-aminoisoquinolines produced from the reaction between 5-(2-bromoaryl)tetrazoles and cyclohexane-1,3-diones could be aromatized into 6-aminophenanthridines via a one-pot sequential process involving reduction, dehydration, and oxidation.

Herein we report two processes facilitated by diisopropylethylamine (DIPEA) for the synthesis of novel bridged polycyclic molecule analogues to natural products. The use of 4-bromoisochroman-3-one initiated an autoxidation reaction, followed by a Diels–Alder cycloaddition in the presence of electron-deficient dienophiles. Mechanistic studies revealed isochromane-3,4-dione as a key intermediate, which undergoes in situ dienolization/dearomatization followed by a [4 + 2] cycloaddition. Subsequently, the synthesis and direct application of isochromane-3,4-diones in the Diels–Alder reaction enabled the development of an alternative method with an enhanced efficiency and improved atom economy. In addition to chalcones, other enones and common electron-poor alkenes, bearing ester, nitro and cyano electron-withdrawing groups (including both terminal, cis acyclic and cyclic alkenes), were successfully reacted. The mechanism was also investigated, and a subsequent reductive ring opening was successfully carried out.

A highly convergent and scalable second-generation synthesis of the fully functionalized HIJKLMN-ring segment of Caribbean ciguatoxin C-CTX-1, the primary toxin responsible for ciguatera fish poisoning in the Caribbean Sea and the Northeast Atlantic regions, has been accomplished. Key aspects of the synthetic approach include the efficient syntheses of the HI- and KLM-ring fragments on gram scales, a convergent fragment coupling toward the HIJKLM-ring skeleton based on the Suzuki–Miyaura coupling strategy, and optimized iron hydride-catalyzed hydrogen atom transfer-mediated olefin coupling conditions for constructing the N-ring.

The site-selective functionalization of aromatic compounds via C–H activation has emerged as a popular tool in organic synthesis. In this study, we report a regioselective coupling of maleimide to 2-arylbenzo[d]thiazoles in the presence of a rhodium(III) catalyst. Depending upon the nature of the substituent (R²-group) present in the maleimide substrate, either mono- or bis-1,4-addition products were observed in this methodology. In the case of R² = aryl, cyclohexyl, and tert-butyl, mono coupling was observed, whereas substituents, such as methyl, ethyl, benzyl, and methyl thiophene, provided bis coupling as the major products. Similar selectivity was also observed in the case of 2-arylbenzo[d]oxazoles.

We report an unexpected gold-catalyzed 5C reaction of type II diene-ynenes to synthesize dihydrosemibullvalenes, which are potential bioisosteres for drug discovery. This 5C reaction occurs through a sequence of elementary reactions of cyclopropanation/Cope rearrangement/carbon shift/cyclopropanation/C–H insertion (shortened here as the 5C reaction), supported by quantum chemistry calculations. Mechanistic studies have also been applied to answer why type-II diene-ynenes cannot access seven-membered carbocycles-embedded bridged molecules under the gold catalysis, finding that the chair-like Cope rearrangement transition state (not the traditional boat-like transition state) is the key to the change of regiochemistry.

A triazinyluronium-based dehydrative condensing reagent, 2-(4,6-dimethoxy-1,3,5-triazin-2-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (DMT-TU), has been developed. Unlike commonly used guanidinium- and uronium-based reagents, DMT-TU does not contain high-energy N–N and N–O bonds, reducing its explosivity, as suggested by differential scanning calorimetry. Using DMT-TU in the presence of ⁱPr₂EtN at room temperature, carboxylic acids and amines were effectively converted to their corresponding amides. Additionally, peptide bond formation with DMT-TU exhibited suppressed racemization ratios.

This study presents a greener approach to the visible-light-induced micellar-catalyzed diastereoselective iodosulfonylation of cyclopropenes in a water medium. Remarkably, this process operates without a photocatalyst. Instead, it utilizes an electron-donor–acceptor complex formed between sulfonyl chloride and sodium iodide. This method is highly efficient and broadly applicable for both aromatic and aliphatic sulfonyl chlorides. Furthermore, this protocol enables the transformation of iodosulfonated cyclopropanes into sulfonated cyclopropenes, highlighting its substantial value as a versatile and powerful tool in synthetic chemistry.

In anodic electrosynthesis, cation radicals are often key intermediates that can be highly susceptible to nucleophilic attack and/or deprotonation, with the selectivity of competing pathways dictating product yield. In this work, we computationally investigate the role of methanol in alcohol trapping of enol ether cation radicals for which substantial modulation of the reaction yield by the solvent environment was previously observed. Reaction free energies computed for intramolecular coupling unequivocally demonstrate that the key intramolecular alcohol attack on the oxidized enol ether group is catalyzed by methanol, proceeding through overall second-order kinetics. Methanol complexation with the formed oxonium ion group gives rise to a “Zundel-like”, shared proton conformation, providing a critical driving force for the intramolecular alcohol attack. Free energies computed for methanol solvent attack of enol ether cation radicals demonstrate an analogous mechanism and overall third-order kinetics, due to similar complexation from a secondary methanol molecule to form the “Zundel-like”, shared proton conformation. As catalyzed by methanol, both intramolecular alcohol attack and methanol attack on the oxidized enol ether group are barrierless or low-barrier reactions, with kinetic competition dictated by the conformational free energy profile of the cation radical substrate and the difference in reaction rate orders.

A practical nickel-catalyzed decarboxylative cross-coupling of N-hydroxyphthalimide esters with 1,4-diiodobenzene analogues has been developed. Under mild reaction conditions, a series of structurally interesting 1,4-dialkylbenzene analogues have been accessed with good functional group tolerance, which are versatile precursors for organic synthesis and a kind of important unit for bioactive molecules, polymers, and other materials. The synthetic application of this methodology was demonstrated by the synthesis of 3-6-dialkylcarbazole derivatives.

The umpolung of N-tosylhydrazones was reported for the first time. Synthesis of N-cyano tosylhydrazones was developed, and various N-cyano tosylhydrazones were prepared in good yields. An umpolung N-tosylhydrazones mechanism was proposed. Meanwhile, the [3,3]-sigmatropic rearrangement of N-cyano tosylhydrazones was examined, and the corresponding 2-aminoimidazoles were given.

By employing electrophilic TsSCF₃ as an efficient SCF₃ source, we reported Cu/SOP (chiral sulfoxide-phosphine ligand)-catalyzed enantioselective nucleophilic substitutions. Under this protocol, α-pyridyl-α-fluoro esters as latent carbon nucleophiles, compounds containing a C-SCF₃ stereocenter along with azacycles and fluorine atoms, were obtained in good yields and enantioselectivities under mild conditions (up to 68% yield, 92% ee).

An efficient method for the synthesis of heterodiarylmethanes through the coupling of imidazo[1,2-a]pyridines and heteroarenes using indoles employing rongalite as a methylenating reagent has been developed. This regioselective C–H functionalization provides a wide range of heterodiarylmethanes of imidazo[1,2-a]pyridines and imidazo[2,1-b]thiazole. Here, rongalite plays a crucial role in generating a C1 unit in situ, which triggers the heterodiarylmethylation process. The use of inexpensive rongalite (ca. $0.03/1 g), mild reaction conditions, and gram-scale synthesis are some of the key features of this methodology.

An innovative solution that overcomes the long-standing inherently low efficiency in N-heterocyclic carbene-catalyzed aerobic oxidation of aldehydes is reported. This solution included the design and synthesis of a novel polymerized catalyst and the utilization of a flow reactor. The unprecedentedly high efficiency achieved via this protocol makes it synthetically applicable. A total turnover number (TON) of 26,300 was achieved based on recycling experiments (runs). The highest TON in a single run could be up to 2475 with a turnover frequency (TOF) of 208 h^–1, far superior to its traditional counterpart, in which a typical TON ranges from 20 to 100 with a TOF of less than 10 h^–1. The catalyst has been recycled over 50 times and is still fully active. The success was attributed to the discovery of hidden reactivity, which was observed for the first time as an autoacceleration in the reaction rate during kinetic investigations. The research also provided concrete evidence supporting the conclusion that radical intermediates played crucial roles in the catalytic cycle by having a determinative impact on the overall reaction rate.

Visible light-promoted α-aminoalkyl radical-triggered α-aminoalkylation and α-diaminoalkylation of Morita-Baylis–Hillman acetates with N-methyl arylamines to synthesize N-containing alkyl acrylates and γ,γ-diaminobutyl esters was reported. Photoinduced α-aminoalkylation is carried out with Na₂-eosin Y as an organophotocatalyst at room temperature under metal- and oxidant-free conditions. In particular, the α-diaminoalkylation is performed via α-aminoalkyl radical addition/elimination followed by a catalyst-controlled selective α-aminoalkyl radical addition strategy in one step under the [Ir(dtbbpy)(bpy)₂)]PF₆/KF catalytic system. The reaction is highly atom- and step-economic, with high selectivity, furnishing N-containing alkyl acrylates and butyl esters in moderate to good yields with wide substrate scope.

The concise and efficient total synthesis of (±)-tetraponerine-2 (T2) and (±)-tetraponerine-4 (T4) was achieved in 9% and 14% overall yield, respectively. The key step included the diastereoselective gold(I)-catalyzed intramolecular dehydrative amination of an allylic alcohol-tethered sulfamide to produce the cis-1,3-diamine moiety. The resulting olefinic side chain was then elaborated by cross-metathesis and cyclized to a five-membered pyrrolidine or a six-membered piperidine ring by intramolecular Mitsunobu N-alkylation. The unique tricyclic core of the (±)-tetraponerines was completed through cyclic sulfamide cleavage followed by aminal formation using 4-bromobutanal. This flexible synthetic strategy allows for the variation of the ring size, C-5 alkyl side chain length, and stereochemistry, which enables the preparation of diverse tetraponerine analogs for biological study.

Chiral diphosphines with a biphenyl bridge and the chirality borne by the phosphorus atoms and not due to the atropoisomery of the biaryl backbone have been scarcely studied. Herein, we report the asymmetric synthesis of the (S,S)-2,2′-bis(ferrocenylphenylphosphino)biphenyl (BipheP_Fc*) ligand and its application in Rh-catalyzed hydrogenation. The synthesis was based on the enantioselective preparation of P-chirogenic ferrocenyl(o-bromophenyl)phenylphosphine by the reaction of sec-phosphine-borane with 1,2-dibromobenzene and its homocoupling into BipheP_Fc*. Hydrogenations catalyzed by the Rh/BipheP_Fc* complex led to enantioselectivities of ≤96%.

We report herein that three facile rearrangements of epoxy ketones can be employed for the efficient and practical synthesis of cephalotaxine, the parent member of the family of Cephalotaxus alkaloids. The Meinwald rearrangement of epoxy ketone (90%) was used for the preparation of the dense functional groups in the cyclopentane ring of cephalotaxine. A novel acid-catalyzed umpolung S_N2′ rearrangement and the Wharton transposition reaction of epoxy ketones were also developed to synthesize the Mori intermediate via the key azaspiro allylic alcohols in a stereodivergent manner.

A convenient and practical method has been developed for synthesizing various N-aryl pyrazoles from vinyl sulfoxonium ylides and diazonium salts. When using 1,3-disubstituted vinyl sulfoxonium ylides, the reaction selectively yields 1,3,5-trisubstituted pyrazoles. On the other hand, employing 2,3-disubstituted vinyl sulfoxonium ylides results in the formation of 1,3,4-trisubstituted pyrazoles. The reaction proceeds through the novel aryl diazene-derived vinyl sulfoxonium ylide. Furthermore, this method efficiently produces pyrazoles from aniline derivatives in a one-pot transformation. The reaction takes place under transition metal-free, mild conditions using easily accessible starting materials, making it a practical approach for generating pyrazoles in pharmaceutical chemistry.

Electrooxidative transformations frequently rely on proton reduction as the terminal electron sink. However, this cathodic counterreaction can be slow in organic solvents and can operate at reducing potentials that are incompatible with catalysts and reagents needed for oxidative reactions. We report aminoborate adducts as redox mediators for proton reduction that operate at mild reducing potentials. This reliable cathodic couple ultimately enables successful oxidative organic transformations, including chlorodeborylation, developed herein, and Cu-catalyzed Chan–Lam coupling, reported previously by our group. Pyridinium borate adducts formed during electrooxidative chlorination of aryl trifluoroborates serve as easily reduced complexes (−1.1 V vs Fc/Fc⁺) to catalyze proton reduction. Reactions that promote the formation of borate adducts result in high yields, operate at low cell potentials, suppress aryl trifluoroborate decomposition, and mitigate electrode passivation. These studies illustrate the utility of Lewis acid–base complexes in cathodic counterreactions and underscore the importance of developing both anodic and cathodic reactions in electrosynthesis.

The reversible modulation of acidity using molecular photoswitches enables the remote control of a variety of (bio)chemical processes with light. Herein we investigated the structural features that allow amplifying photoinduced pK_a variation in phenol-diarylethene conjugates, which toggle between low- and high-acidity states by switching the conjugation between the ionizable moiety and electron-withdrawing groups upon photoisomerization. By tuning the structure of these conjugates, high pK_a modulation amplitudes were accomplished that surpass those previously reported.

DFT calculations have been performed to gain insight into the mechanism of hydrocarbonylation of olefins and the origin of regio- and chemoselectivity. It is shown that the most feasible mechanism involves five steps: (i) decomposition of acetic formic anhydride, (ii) hydropalladation of olefins, (iii) CO migratory insertion, (iv) iodide-assisted acetate-formate exchange, and (v) formylation or carboxylation. Importantly, carboxylation proceeds via the decomposition of anhydride, followed by reductive elimination instead of direct hydrolysis of anhydride. For phosphine-ligated palladium catalysis, on one hand, the lower stability of the transition state leading to 1,2-hydropalladation could be attributed to H···H steric hindrance. On the other hand, the high chemoselectivity for the aldehyde is ascribed to increased π back-donation effect and ligand-substrate noncovalent interactions, which stabilize the transition state and hence reduce the energy barrier. For ferrocenyl phosphine-ligated palladium catalysis, significant C–H···π interaction between the substrate and proximal phenyl moiety of the phenylphosphine and π–π interaction between formate and phenyl moiety can facilitate the carboxylation process. This in-depth mechanistic insight can account for reactivity and selectivity at an atomistic level and have implications for designing new generations of palladium catalysts.

A synthetic method was developed for the generation of a quaternary carbon center in carbonyl compounds. This innovative process involved the reaction of α-thiolate lactones and cycloalkanones with two equivalents of arynes in acetonitrile to give α,α-diarylated products in 63–85% yields at 25 °C. The reaction unfolds through an unconventional domino process, encompassing sequential 1,2-elimination, 1,2-nucleophilic addition, 1,4-proton transfer, the second 1,2-nucleophilic addition, interrupted Pummerer rearrangement, intramolecular spirocyclization, and sulfonium ring-opening. The potential of this “single-flask” reaction was systematically investigated and found well-suited to generate diarylated carbonyl compounds, incorporating naphthalene, pyridine, quinoline, or isoquinoline rings adorned with various substituents.

A catalyst-free photoinduced deconstructive fluorosulfonylation cascade of spiro dihydroquinazolinones with DABSO and NFSI is reported. This protocol features mild reaction conditions, good yields and excellent functional group tolerance, providing a practical approach to the quinazolin-4(1H)-one-functionalized aliphatic sulfonyl fluorides. In addition, the ease of gram-scale synthesis and the versatility of the SuFEx exchange highlight the application potential of this protocol.

This study focuses on investigating the use of β-cyclodextrin (β-CyD) derivatives as additives in continuous flow peptide synthesis, with particular emphasis on challenging sequences such as the Jung-Redemann decapeptide and the 42-residue amyloid β polypeptide [Aβ(1–42)]. The efficacy of the OH-free β-CyD and two of its derivatives (Ac-β-CyD and HP-β-CyD) is compared with alternative, state-of-the-art synthetic methods, including the widely used and recently improved pseudoproline monomer technique, e.g., Ser(ΨPro). Our results show that the use of β-CyD as an additive results in a significant (8–19%) increase in the purity of the crude polypeptide compared to that determined by our reference method. The chromatograms determined by LC-MS were deconvoluted to estimate the more precise purity of the crude products, and we found that the improvement is greater when the free OH β-CyD is used and moderate when the acetyl-β-CyD or the 2-hydroxypropyl-β-CyD derivatives are used. We have found that the free CyD gives an improvement comparable to that achieved with the Ser(ΨPro) derivative.

The newly discovered cyclo[13]carbon, the first artificially synthesized odd-numbered carbon ring, is an intriguing carbon isomer that provides a valuable subject for studying low-symmetry carbon materials. In this work, we employed first-principles calculations to explore the geometric structure and electronic properties of cyclo[13]carbon through various techniques such as vibrational mode analysis, bond order analysis, spin density analysis, electron localization analysis, electrostatic potential and van der Waals potential analysis, visualization of weak interactions, and energy decomposition analysis. We investigated the interaction characteristics of cyclo[13]carbon with small molecules and examined its dimer formation mechanism and dynamics features using ab initio molecular dynamics. Our study reveals the unique physicochemical properties of this novel carbon ring system. The antiaromaticity of the low-symmetry cyclo[13]carbon sets it apart from previously synthesized even-numbered carbon rings, with van der Waals interactions playing a crucial role in its binding with small molecules and in the formation of C₁₃ dimers. This research provides theoretical insights that complement experimental observations and theoretical studies, aiding further investigation into the diverse properties of fresh carbon material isomers and promoting the synthesis and application of novel molecular materials in molecular electronics and nanotechnology.

Protein–protein interactions (PPIs) are pivotal in regulating cellular functions and life processes, making them promising therapeutic targets in modern medicine. Despite their potential, developing PPI inhibitors poses significant challenges due to their large and shallow interfaces that complicate ligand binding. This study focuses on mimicking peptide loops as a strategy for PPI inhibition, utilizing synthetic peptide loops for replicating critical binding regions. This work explores turn-inducing elements and highlights the importance of proline in promoting favorable conformations for lactamization, yielding high-purity cyclic peptides. Notably, our one-pot method offers enhanced versatility and represents a robust strategy for efficient and selective macrolactamization, expanding the scope of peptide synthesis methodologies. This approach, validated through the synthesis of AAV capsid-derived loops, offers a robust platform for developing peptide-based therapeutics and highlights the potential of peptide macrocycles in overcoming PPI drug discovery challenges and advancing the development of new therapeutics.

An electrochemical tandem cyclization of enaminones with amidines has been reported for the first time using dibromomethane as an initiating agent in an undivided cell. Following this protocol, a vast variety of polysubstituted 5-acylimidazoles were obtained in moderate to good yields without the use of external oxidants. Mechanistic studies indicate that the bromide anion, electroreductively generated from dibromomethane, acts as a redox mediator to complete the catalytic cycle.

In this report, a new imidazole- and amide-functionalized pincer-like Cu(II) complex (1) was synthesized and characterized. By employing 1 and 9-azabicyclo[3.3.1]nonane NH-Oxyl (ABNOH), a catalytic protocol for alcohol oxidation and the subsequent alcohol oxidation-triggered synthesis of quinolines and pyrazines were explored. Alcohols such as 2-aminoaryl alcohols were also oxidized efficiently. As carbonyls from 2-arylaminobenzyl alcohols and secondary alcohols are synthons for quinolines, we explored their synthesis directly from alcohols. The protocol was quite efficient and completed the reaction in only ∼5–10 h. Combinations such as (a) primary 2-arylaminobenzyl alcohols with secondary alcohols or their ketones and (b) secondary 2-arylaminobenzyl alcohols with secondary alcohols or their ketones were found to be very effective for the synthesis of quinolines. The protocol was also successful for the synthesis of various pyrazines from 1,2-diols and 1,2-diaminobenzenes in 10 h. Mechanistic investigations showed that the generated complex acted as an active catalyst: it activated O₂ and subsequently with the cooperation of 9-azabicyclo[3.3.1]nonane N-Oxyl (ABNO^•) activated the α-CH hydrogen of coordinated alkoxide. Then, Cu(II)/Cu(I) reduction led to the formation of carbonyl compounds, which via successive C–C/C–N coupling reactions resulted in heterocycles in the presence of KO^tBu and 1.

A novel iridium-catalyzed [3 + 2] annulation of naphthylamines and α-diazocarbonyl compounds was developed for the rapid assembly of densely functionalized indoles. This new catalytic process represents the first example of a cascade intramolecular nucleophilic cyclization by the N–H insertion of amines. Various naphthylamines and α-diazocarbonyl compounds could be obtained in high yields with excellent functional group tolerance. The reaction affords valuable indole derivatives, enabling expedient access to novel heterocyclic analogues not easily accessible by other methods.

This study presents a method for synthesizing functionalized hydrodibenzofuran derivatives. Using palladium catalysis, O-aryl cyclic vinylogous esters undergo dehydrogenative intramolecular arylation at the vinylic carbon. Preliminary kinetic isotope effect studies suggest that the C(aryl)–H bond cleavage may be the rate-determining step.

A new and practical approach for the synthesis of arylamines via copper-catalyzed radical cross-coupling amination of arylboronic acids has been developed. The key enabling advance in this protocol is the design of N-hydroxyphthalimides as precursors to generate nitrogen-based radical intermediates for cross-coupling with arylboronic acids, providing the corresponding arylamines of a high yield of up to 98%. In addition, the procedure successfully demonstrated remarkable efficiency across a wide range of functional group tolerances. Mechanistic investigations suggested that a nitrogen radical cross-coupling pathway is possible via phosphite-mediated N–O bond scission.

In this report, we have established a novel and efficient method for selectively synthesizing either vinyl sulfides or 2-methylbenzothiazoles from the reaction of CaC₂ and disulfides. The selective synthesis of these two distinct products can be controlled by simply adjusting the amount of K₂S. The underlying reaction mechanism has been thoroughly investigated through control experiments, HRMS, and FTIR, which collectively support the pivotal role of a trisulfur radical anion. This radical species, generated in situ from K₂S, is essential for the homolytic cleavage of the S–S bonds in a catalytic manner. Additionally, the trisulfur radical anion also acts as an effective mediator for activating the vinyl group of 2-aminophenyl vinyl sulfides, facilitating the crucial intramolecular cyclization required to produce 2-methylbenzothiazoles. Moreover, CaC₂ not only serves as an acetylene source but also creates the basic conditions essential for the selective formation of vinyl sulfides. This methodology demonstrates broad substrate compatibility and excellent functional group tolerance, significantly enhancing its practical utility in diverse synthetic applications.

A novel annulation reaction of amidines with sulfur ylides and nitrobenzenes has been developed, affording various novel 4-hydroxy-5-phenylaminoimidazoles in moderate to excellent yields. The 4-hydroxy-5-phenylaminoimidazoles have been further converted into α-ketoamide and imidazol-4-imine derivatives. Moreover, a plausible mechanism for this multicomponent reaction is proposed.

A cascade cyclization reaction comprising two halogenation reactions and a Michael addition was developed for the synthesis of chromeno[2,3-c]pyrrole-3-ones 4. Additionally, another cascade cyclization reaction, which involves a halogenation reaction followed by two intramolecular Michael additions, was established for the synthesis of chromeno[2,3-b]pyrrole-2-ones 5. Both types of compounds were synthesized from o-hydroxyphenyl enaminones and 2-halo-N-alkyloxyacetamides through a process that facilitated the intramolecular formation of C–C, C–O, and C–N bonds to effectively establish two fused rings in a single operation. This novel protocol is efficient, uses readily accessible starting materials, and operates under mild conditions, demonstrating tolerance for various functional groups while achieving good yields.

The selective oxidation of methylbenzene to value-added products is of indisputable importance in organic synthesis. Although photocatalytic oxidation reactions of toluene have achieved great success for the preparation of its oxidative products, such as carboxylic acids, benzaldehyde, and benzoate, there remains a lack of a unified photocatalytic system for the selective preparation of these oxidation products. Herein, we report a metal- and additive-free photocatalytic protocol enabled by aryl halides using O₂ as a green oxidant for the selective synthesis of the above-mentioned three oxidation products by adjusting the reaction solvent. This strategy features many advantages, including environmentally friendly and mild reaction conditions, broad substrate applicability and functional group tolerance, and potential practical application for the synthesis of aromatic carboxylic drugs and polymer materials and degradation of polystyrene waste. The continuous-flow system was utilized for the oxidation of toluene, which resulted in a reduced reaction time and increased production efficiency. Detailed mechanistic investigation revealed that the hydrogen atom transfer process was facilitated by the bromine radical from aryl halides for further oxidation, and an electron donor–acceptor complex of methylbenzene and aryl halides may exist.

A high-precision asymmetric synthetic route for cis-2-fluorocyclopropanecarboxylic acid with excellent stereoselectivity and regioselectivity was developed from commercially available starting materials, namely, fluoromethylphenylsulfone and chiral glycidyl derivatives, on a 100 g scale at the start. Despite the high overall yield, the synthetic route is remarkable for its brevity. This strategy forms the basis for further production of sitafloxacin on an industrial scale and provides an affordable and high-quality product.

Nucleophilic aromatic substitutions (S_NAr) of alkoxides on pentafluoroaryl ethers are explored as a first step in a synthesis sequence to generate all-cis 2,3,5,6-tetrafluorocyclohexyl-1,4-dialkyl ethers 1. The S_NAr reaction was explored both experimentally and theoretically to rationalize ortho/para/meta selectivities. tert-Butyl deprotection of products followed by phenol alkylations introduces versatility to the synthesis. The final Rh(CAAC) 3 catalyzed aryl hydrogenation step of intermediate tetrafluoroaryl-1,4-diethers generated cyclohexane products 1. This chemistry introduces a new class of Janus fluorocyclohexane derivatives with ether substituents placed 1,4- to each other.

The Goossen decarboxylative coupling reaction enables the union of thiazole-2-carboxylic acids with a 2-pyridyl triflate, leading to the formation of pyridine-thiazole clusters of the kind found in thiopeptide antibiotics. The method avoids problematic or technically challenging reaction sequences involving 2-thiazolyl organometallics, facilitating the investigation of the structure–activity relationship of the thiopeptides.