ASAP (As Soon As Publishable)

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).

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.

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.

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.

The Pummerer reaction represents a well-known transformation of sulfoxides. Mechanistically, this reaction is initiated by the generation of the thionium ion, whereas forming such intermediates typically requires the use of a stoichiometric amount of activating reagent. In this regard, we report the activator-free Pummerer-type transformation, a silver-catalyzed thio-Claisen rearrangement of aryl sulfoxides with AIBN. Facilitated by silver catalyst, AIBN is transformed into highly reactive ketenimine in situ, which directly captures the sulfoxides to generate thionium ion intermediates.

Optical detection of the HSO₄^– ion in pure aqueous medium is rare, owing to the very high Gibbs free energy of hydration and ambiguity to distinguish with the isostructural H₂PO₄^– ion. Herein, a pair of triphenylamine-based push–pull dyes with different numbers of terminal pyridine fragments, connected via an acetylenic linker, were synthesized by Sonogashira cross-coupling reaction. These two dyes displayed highly selective (LOD = 15.1/8.3 ppb), dual-mode color-changing responses toward the HSO₄^– ion in pure aqueous medium without any interference. Despite the halochromic behavior, both compounds exhibited very distinct optical responses with the HSO₄^– ion. The mechanistic investigation indicated that HSO₄^– was engaged in a bifurcated intermolecular hydrogen bonding interaction (leading to proton transfer) with pyridine nitrogen atoms that altered the extent of intramolecular charge transfer (ICT). The self-assembly of such protonated species was found to be prominent when sulfate was present as the counteranion. The extent of self-assembly was found to be more prominent for the trisubstituted, Y-shaped quadrupolar derivative than that observed for the linear, monosubstituted one. Furthermore, the present system was utilized for the detection of HSO₄^– ions in commercially available samples with satisfactory responses.

Highly efficient catalyst-free annulative functionalization approaches to a novel imidazole-pyrrolo[1,2-a]pyrazine hybrid structure were devised from the reaction of β-enaminone with propargylamine where regioselective conjugate substitution of β-enaminone with propargylamine followed by cycloisomerization proceeded smoothly in a domino fashion to construct two heterocyclic moieties (pyrazine and imidazole) via successive formation of three C–N bonds, leading to the target tricyclic skeleton.

We have developed a hemin-catalyzed biomimetic oxidative annulation of 2,3-dihydroxybenzoic acid with an array of cyclic enamines to form isochromanones in good to excellent yields and high regioselectivity. This formal [4+2] cycloaddition protocol showed high efficiency and remarkable functional group tolerance. Mechanistic studies indicate the involvement of a single-electron oxidation pathway. Preliminary biological investigations showed that isochromanones 3ag and 3ca exhibited antineoplastic activities against MCF-7 cell lines with IC₅₀ values of 25.21 and 29.09 μM, respectively.

A previously unknown class of fluorophores was discovered, which represents 14-membered bridgehead heterocycles, pyrrolyl-diazabicyclo[8.3.1]tetradecadienones, herein referred to as PY-14-ONEs. The new fluorophores are characterized by giant Stokes shifts of ∼8000–10,250 cm^–1 and virtually zero overlap of the absorption and emission bands. They exhibit fluorescence maxima in the blue-green region (454 ≤ λ_em ≤ 513 nm, MeCN), which shift to the red side when converted to their water-soluble salts by alkylation with MeI (478 ≤ λ_em ≤ 516 nm, water). PY-14-ONEs were obtained by an original synthesis from DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene, which reacts with acylethynylpyrroles without catalysts under mild conditions to afford PY-14-ONEs in a 34–58% yield. The reaction represents a ring expansion of DBU. Since acylethynylpyrroles are readily available, the discovered reaction opens promising possibilities for the development of new fluorophores. The results of our time-dependent DFT calculations indicate that the pyrrole ring in PY-14-ONEs plays an important role in the formation of the Stokes shifts, which can be further enhanced by attaching appropriate substituents to it, capable of creating in S₁ an extended conjugated system and causing a substantial alternation of the molecular structure via its planarization.

An auxiliary-based protocol is described for an asymmetric allenoate Claisen rearrangement. Silicated tosic acid (10 mol %) was used as an inexpensive, user-friendly catalyst. Stereochemical analysis revealed a preferential attack at the si face of prostereogenic olefin. The amine auxiliary was readily hydrolyzed and can be isolated from the reaction mixture (85–87% recovery). The resulting unsaturated β-keto esters were isolated in ≤99% yield and 98% ee. Diastereoselective examples provided a 96:4 syn:anti ratio of the resulting vicinal stereocenters.

A three-component synthesis of multiply functionalized 5,6-dehydroisoquinuclidines is described. After the formation of an N-alkylpyridinium salt, Grignard addition led to the formation of the corresponding 1,2-dihydropyridine bearing an alkyl, alkene, aryl, or alkynyl group. Subsequent Diels–Alder reaction with a dienophile provided functionalized dehydroisoquinuclidines in high yields (up to 93%) with endo selectivities (73:27 to >99:1). This reaction was applicable to the synthesis of an N-(4-methoxybenzyl)pyridinium salt, where the 4-methoxybenzyl group was switched to a benzyloxycarbonyl group after the formation of the dehydroisoquinuclidine.

We describe complementary methods for synthesizing acyclic vinylic ethers from two carbohydrate-derived synthons. We compare a nonstereoselective olefination approach with a stereoselective catalytic C–O cross-coupling method, preparing 1,2-disubstituted vinylic ethers with complexity on both sides of the ether linkage. Upon epoxidation/in situ oxacyclization of acyclic vinylic ethers, we synthesized disaccharides with α-d-galacto-, α-d-talo-, β-d-allo-, and α-d-altropyranoside stereochemistry, from d-lyxose and d-ribose precursors. Stereoselective CuI/CyDMEDA-catalyzed C–O cross-couplings offer considerable potential for broadly implementing this nontraditional strategy for glycoside synthesis.

An expedient approach to the synthesis of 4-azaspiro[2.3]hexane derivatives is described. The synthetic scheme consists of Tebbe olefination of N-Boc-protected 2-azetidinone (including the first use of the deuterated Petasis reagent Cp₂Ti(CD₃)₂ in the building block preparation) and cyclopropanation of the resulting intermediate. The developed protocols allowed for the preparation of target building blocks on a multigram scale (up to 52 g). To illustrate the potential of the obtained 4-azaspiro[2.3]hexane derivatives for isosteric replacements in drug discovery, their physicochemical and structural characterization was performed, i.e., basicity (pK_a) and lipophilicity (Log P) measurements, X-ray diffraction studies, and exit vector plot (EVP) analysis.

A novel fluorophore 2-(2′-hydroxy-5′-benzaldehyde phenyl) benzothiazole (HBBT) with excited state intramolecular proton transfer (ESIPT) characteristics, showing good selectivity for Cu⁺/Cu²⁺ ions had been synthesized experimentally (Molecules 2022, 27, 7678). However, its ESIPT mechanism and fluorescent performance related to atomic substituents have not been investigated systematically. In this work, two HBBT derivatives, 2-(2′-hydroxy-5′-benzaldehyde phenyl)benzoimidazole (HBBI) and 2-(2′-hydroxy-5′-benzaldehyde phenyl)benzopyrrole (HBBP), were obtained by respectively using −NH and −CH₂ groups in place of the sulfur atom in the thiazole ring. The absorption/emission spectra and ring aromaticity as well as ESIPT processes of HBBT and its derivatives were studied using density functional theory (DFT) and time-dependent DFT (TD-DFT). The simulated absorption and fluorescence wavelengths of HBBT agreed well with the corresponding values obtained in the experiment. According to the analyses of geometry structures, electron densities, and infrared vibration frequencies, the intramolecular hydrogen bond becomes stronger upon light excitation. The frontier molecular orbitals were analyzed via establishing potential energy curves, and the ESIPT behavior was described deeply. Obviously, the NH–substitution makes ring 4 more aromatic, while the CH₂–substitution changes ring 4 from aromatic to antiaromatic. The ESIPT process helps to alleviate the excited state antiaromaticity. The greater the antiaromaticity of the S₁ state normal form, the higher the barrier of ESIPT.

A microwave-based method for the acylation of alcohols, phenols, and thiols has been developed without the need of a catalyst or base additives. The reaction is far more rapid than previously reported acylation methods, tolerates a wide variety of functional groups, and provides easy isolation of products in excellent yields without the need for chromatography. Most products can be isolated directly via evaporation under reduced pressure or by pouring the reaction mixture into water and filtering.

Herein, the first example of self-catalyzed sono-photoinduced carbon–carbon bond formation was described. Combining the advantages of phototriggered self-catalysis and ultrasonic catalysis, a wide range of 3-arylquinoxalin-2(1H)-ones can be efficiently synthesized in good yields with high functional-group compatibility under mild and eco-friendly conditions.

Recently, metallaphotoredox-catalyzed alkene dicarbofunctionalization reactions have been extensively investigated. Most cases are related to alkyl-arylation processes by conjugate coupling of alkyl radical precursors and aryl electrophiles across alkenes. By contrast, reported examples of alkylvinylation by coupling of vinyl electrophiles are largely limited. Herein, we represent a three-component aminoalkyl-vinylation of alkenes enabled by photoredox/nickel catalysis. This redox-neutral protocol exhibits broad substrate scope and good chemo-, regio- and E/Z-stereoselectivity. A series of valuable α-vinyl γ-amino acid derivatives are conveniently synthesized by the assembly of readily available starting materials.

An electrochemical protocol for the alkylthiolation of aryl halides was developed. By using dialkyl disulfides as the alkylthio sources, Mg plate as the sacrificial anode and graphite felt (GF) as the cathode, a series of aryl sulfides were obtained in moderate to good yields. The approach was also suitable for the synthesis of aryl selenides. This method has the features such as simple reaction conditions and good functional group compatibility, which makes it have a good application prospect in organic synthesis and drug synthesis.

The first efficient Cu(I) catalyzed regioselective C3-(hetero)arylation of 6-(hetero)arylated 1,2,4-triazolo[4,3-b]pyridazines has been developed to streamline the synthesis of pharmaceutically important 3,6-diarylated 1,2,4-triazolo[4,3-b]pyridazines. This direct (hetero)arylation is compatible with a range of aryl iodides and tolerates a variety of functional groups (23 examples). A series of new 3,6-diarylated 1,2,4-triazolo[4,3-b]pyridazines were synthesized with good to excellent yields (up to 98%). The reactivity varied depending on the nature of the aryl iodide and the substituent in position 6 of the starting substrate. The procedure is experimentally simple, cost-effective, and free of additional ligands and cocatalysts.

A quantitative and predictive understanding of how attractive noncovalent interactions (NCIs) influence functional outcomes is a long-standing goal in mechanistic chemistry. In that context, better comprehension of how substituent effects influence NCI strengths, and the origin of those effects, is still needed. We sought to build a resource capable of elucidating fundamental origins of substituent effects in NCIs and diagnosing NCIs in chemical systems. To accomplish this, a library of 893 NCI energies was calculated encompassing cation−π, anion−π, CH−π, and π–π interactions across 60 different arenes and heteroarenes. The interaction energies (IEs) were calculated using symmetry-adapted perturbation theory (SAPT), which identifies electrostatic, inductive, exchange-repulsive, and dispersive contributions to total IE. This descriptor library provides a comprehensive platform for evaluating substituent effect trends beyond traditional molecular descriptors such as Hammett values, frontier molecular orbital energies, and electrostatic potential, thereby expanding the tools available to analyze modern chemical processes that involve NCIs. To demonstrate the application of this library, three case studies in asymmetric catalysis and supramolecular chemistry are presented. These case studies informed the development of an automated NCI analysis tool, which employs statistical analyses to diagnose a particular NCI in a chemical system of interest.

The Suzuki–Miyaura biaryl cross-coupling is the pivotal technology for carbon–carbon coupling in pharmaceutical, polymer, and agrochemical fields. A long-standing challenge has been the development of efficient precursors for the decarbonylative cross-coupling of amide bonds. Herein, we report a highly chemoselective palladium-catalyzed Suzuki–Miyaura cross-coupling of N-mesyl amides for the synthesis of biaryls by a tandem N–C(O)/C–C bond activation with high selectivity for decarbonylative cleavage. The results demonstrate the first example of a decarbonylative coupling (−CO) of amide bonds activated by an atom-economic, low-cost, and benign N-pyramidalized mesyl group (>30 examples). The reaction shows high generality and functional group tolerance and can be applied in late-stage functionalization of pharmaceuticals. Notably, N-mesyl amides are significantly more reactive than other classes of amides in the decarbonylative Suzuki cross-coupling manifold. Density functional theory (DFT) studies demonstrate considerably lower barrier for rate-limiting transmetalation using N-mesyl amides. The study establishes N-mesyl amides as versatile precursors for Suzuki–Miyaura cross-coupling to afford valuable biaryls and opens the door to deploy N-mesyl amides in challenging cross-couplings of amides by decarbonylation.

A novel approach to sulfinylated phenanthrenes has been developed by BF₃-promoted annulation of 2-alkynyl biaryls with arylsulfinic acids. This approach utilizes readily available arylsulfinic acids as a sulfinyl source and affords a variety of sulfinylated phenanthrenes in good to excellent yields under simple and mild reaction conditions.

A one-pot, three-component synthesis of indole-benzofuran bis-heterocycles from terminal alkynes, salicylaldehydes, and indoles has been developed via copper-catalyzed tandem annulation. This catalytic system utilizes readily available starting materials, enabling predictable synthesis of indole-benzofuran bis-heterocycles with broad substrate versatility, excellent regiocontrol, and gram-scale amenability. The reaction proceeds via a sequential pathway involving A3 coupling, 1,4-conjugate addition, and 5-exo-dig cyclization.

Optimization of chemical reactions requires a thorough analysis of reaction products and intermediates over a given time course. Chemical reactions are often analyzed by liquid chromatography-mass spectrometry (LC-MS), but generating LC-MS samples and data analysis is time-consuming and produces a significant amount of waste. We sought to remove the sample preparation and data analysis steps by implementing an iChemExplorer/Agilent LC-MS instrument as our reactor and analysis tool, coupled with an automated report generator of reaction progress over time. Herein, we show that our easy-to-use walk-up automated reaction profiling (WARP) system can sample chemical reactions multiple times to produce a data-rich report of reaction progress over time.

A photocatalytic decyanative C(sp³)–H pyridination of dihydroquinoxalin-2-ones with 4-cyanopyridines was developed by utilizing 4CzIPN as the photocatalyst. Mechanism studies show that this organophotocatalytic direct C(sp³)–H pyridination undergoes a radical–radical cross-coupling pathway promoted by consecutive photoinduced electron transfer.

An efficient and convenient method for the synthesis of C3-hydroxytrifluoroalkylated indoles and pyrroles was described in this paper. The copper-catalyst-free site-specific cross-dehydrogenative coupling reaction of various indoles and pyrroles with hexafluoroisopropanol proceeded smoothly by using MnO₂ as oxidant to furnish a hydroxytrifluoroalkylated electron-rich N-heterocycle in satisfactory to excellent yields. Various groups, including the synthetically useful functional groups Cl, NO₂, and CN, were tolerated well. The mechanistic study revealed that a radical pathway accommodated the formation of a hexafluoroacetone intermediate.

The asymmetric syntheses of naturally occurring biologically relevant abeo-abietane diterpenoids, (−)-taiwaniaquinone G (1a), and H (1b) have been reported via a chiral pool strategy starting from commercially available abietic acid. A ring contraction of the middle ring of the [6,6,6]-carbotricyclic abietane diterpenoid core was carried out under the Wolff rearrangement. Finally, the synthesis of (−)-taiwaniaquinone H (1b) was completed via a one-pot CAN-mediated oxidative decarboxylation.

A novel Cu/Pd-catalyzed domino radical cyclization and C–H carbonylation of α-bromocarbonyls has been developed, which enables the rapid incorporation of CO unit into polycyclic quinolin-2(1H)-one scaffolds. By using Mo(CO)₆ as the CO source, the reaction proceeded smoothly to furnish various polycyclic carbonyl-containing quinolin-2(1H)-one derivatives in high yields. Notably, this method could be used in the late-stage modification of biologically active molecules such as estrone.

Schwarzites are hypothetical carbon allotropes in the form of a continuous negatively curved surface with three-dimensional periodicity. These materials of the future attract interest because of their anticipated large surface area per volume, high porosity, tunable electric conductivity, and excellent mechanical strength combined with light weight. A three-decade-long history attempting schwarzite synthesis from gas-phase carbon atoms went without success. Design of schwarzites is both a digital art and the science of placing tiles of sp²-carbon polygons on mathematically defined triply periodic minimal surfaces. The knowledge of how to connect polygons in sequence using the rules of symmetry unlocks paths for the bottom-up synthesis of schwarzites by organic chemistry methods. Schwarzite tiling by heptagons is systematically analyzed and classified by symmetry and topology. For the first time, complete plans for the bottom-up synthesis of many schwarzites are demonstrated. A trimer of heptagons is suggested as the key building block for most synthetic schemes.

Skeletal editing is an important approach for the modification and diversification of biologically active molecules. The utilization of nitrogen deletion strategies in skeletal editing has recently emerged as a new method for compound modification. Here, we report an unexpected nitrogen deletion in isoindolines. Contrary to the anticipated outcome of cyclobutane formation via intramolecular radical couplings, the nitrogen deletion of isoindoline triggers a Diels–Alder cycloaddition facilitated by the in situ formation of ortho-xylylene to yield tetraline. Inspired by this reaction, we developed a new strategy for synthesizing substituted tetralins, employing isoindoline, nitrogen deletion reagent (anomeric amide), and dienophiles. This methodology demonstrates a new pathway for tetralin synthesis and the modification and diversification of isoindolines.

The synthesis of pyranocoumarin is reported from 4-hydroxycoumarin, styrene oxide, and DMSO in the presence of p-TSA·H₂O at 110 °C using a three-component reaction. Interestingly, a CH₂ moiety from DMSO gets inserted in this reaction to form the pyranocoumarin ring. The plausible mechanism for this interesting reaction was proposed and validated using quantum chemical methods. Interestingly, when the reactions were performed with 7-methoxy-4-hydroxycoumarin and styrene oxides, having an electron-withdrawing group, the reaction followed a two-component pathway, and furocoumarins were obtained in good yields. Switching the solvent from DMSO to CH₃CN for the same reactants results in the exclusive formation of the novel monomeric product 4-hydroxy-3-styryl-2H-chromen-2-one (5) instead of the expected furocoumarins. Interestingly, one of the novel monomeric products, 4-hydroxy-3-styryl-2H-chromen-2-one, directly undergoes unexpected cyclization to provide a more interesting and complex tricyclic product. The salient features of the present strategy are its easy handling, commercial availability of starting material, metal-free synthesis, inexpensive catalysts, environmentally benign, and high atom economy.

The first deoxygenative hydrosilylation of ketones promoted by samarium diiodide and samarium has been reported. In this approach, secondary alkyl silanes are synthesized from unactivated ketones and chlorosilanes in one step. The carbonyl group of ketones is activated by SmI₂-mediated single-electron transfer process, which follows a deoxygenative elimination of O=Sm. Broad substrate scope and excellent functional group tolerance has been demonstrated.

A visible-light-driven radical C–H methylation of N-heteroarenes that is efficient and additive- and catalyst-free and employs readily available N,N-dimethylethanolamine as the methyl source has been developed. The transformation offers the benefits of broad substrate scope, mild reaction conditions, and operational simplicity. A photoactive electron donor–acceptor (EDA) complex between N-heteroarenes and N,N-dimethylethanolamine is essential for this transformation, as revealed by mechanistic investigations.

Nucleoside analogs have proven highly successful in many pharmaceutical intervention strategies, and continued exploration of next generation structural motifs is required. Herein we discuss recent advances toward the chemical synthesis of heteroatom-modified nucleosides, where this is constituted by the chalcogens sulfur or selenium. Paying specific focus to the organic chemistry to incorporate these heteroatoms, we consider developments toward ribose ring oxygen and ring carbon replacements alongside chalcogen-modified heterobases.

β,β-Disubstituted enesulfinamides undergo stereoselective nucleophilic addition to the formaldehyde imines, in situ formed from tosylmethylcarbamates, affording α-aminomethylated ketimines bearing a challenging acyclic quaternary stereocenter substituted by two sterically and electronically similar groups (e.g., Me and Et). The defined geometry of the C═C bond in the enesulfinamides, combined with the strong chiral induction offered by their chiral sulfinyl group, ensures precise stereocontrol during the formation of the new C–C bond.

Six fundamental chemical transformations of aryl carbonyls are achieved by properly adjusting the stoichiometry of the borane-amine and titanium tetrachloride reagent system. This set of reagents acts collectively as a hydride donor, Lewis acid catalyst, and halogen source for the reduction of carbonyls to alcohols, reductive halogenation of carbonyls to halides, deoxygenation of carbonyls to alkanes, dehydroxyhalogenation of alcohols to halides, deoxygenation of alcohols to alkanes, and hydrodehalogenation of halides to alkanes. While the carbonyl reduction is broadly applicable to both aromatic and aliphatic substrates, the remaining reactions are dependent on the stability of the proposed carbocationic intermediates, enabling highly selective reactions at the substrates’ benzylic position. This unique selectivity allows benzylic dehalogenation in the presence of aryl and alkyl halides in addition to highly selective dehydroxyhalogenation of alcohols even for tertiary versus secondary aliphatic and secondary versus primary benzylic substrates using only titanium tetrachloride as the chlorinating agent.

A pyridinium ylide-alkylation strategy has been developed for selectively accessing N,N-disubstituted pyridinium salts from monosubstituted pyridinium salts possessing ambident nucleophiles. The method was shown to be tolerant toward an array of different pyridinium scaffolds and common electrophiles, enabling access to structurally diverse pyridinium salts. The potential versatility of the approach was demonstrated through the synthesis of chemically complex, heterotrifunctional pyridinium salts containing a pyridinium warhead, a click chemistry handle, and a third, high-value, payload.

The trinitromethyl group plays a crucial role in the energetic material industry due to its high oxygen balance and energetic properties. This study focuses on the synthesis of dinitrophenyl-substituted trinitromethyl-1,3,4-oxadiazole. The introduction of dinitrophenyl groups to trinitromethyl-1,3,4-oxadiazole aims to improve its stability against heat-induced decomposition, a critical factor in ensuring the safe and reliable performance of energetic materials. Consequently, 2-(3,5-dinitrophenyl)-5-(trinitromethyl)-1,3,4-oxadiazole (6) was designed and synthesized. Compound 6 exhibited a remarkable thermal decomposition temperature of 117 °C, surpassing that of all other 1,3,4-oxadiazoles bearing the trinitromethyl group. This research highlights the incorporation of the dinitrophenyl ring to elevate the thermal decomposition temperature of the trinitromethyl group attached to the 1,3,4-oxadiazole ring, thereby presenting novel strategies for enhancing the thermal stability of these compounds.

The Rh(III)-catalyzed indole C4–H bond addition to nitroalkenes is disclosed under mild and redox-neutral reaction conditions, offering straightforward access to various 4-(2-nitroalkyl)indoles (34 examples) with excellent chemo- and regioselectivity. Furthermore, late-stage diversifications and mechanistic studies were also performed.

Energetic coordination compounds (ECCs) have demonstrated unique advantages in regulating the physicochemical properties of energetic materials through the design of organic ligands. The fundamental approach involves altering the electron cloud density distribution of organic ligands to modify the characteristics of coordination sites and, thus, achieve new coordination configurations. In this study, Mulliken charge distribution and surface electrostatic potential analysis were used to elucidate the effects of pyridinic N, pyrrolic N, oxazolic O, and thiazolic S on the electron cloud density of carbohydrazide groups through the induction effect and conjugate effect. Furthermore, three AgClO₄-based ECCs were synthesized based on 1H-imidazole-4-carbohydrazide, oxazole-4-carbohydrazide, and thiazole-4-carbohydrazide. Single-crystal X-ray diffraction analysis revealed that [Ag(IZ-4-CA)ClO₄]_n has a one-dimensional (1D) chain structure, while Ag₂(OZCA)₂(ClO₄)₂ and Ag₂(SZCA)₂(ClO₄)₂ exhibit zero-dimensional structures. The 1D structure, with good planarity, results in [Ag(IZ-4-CA)ClO₄]_n having lower mechanical sensitivity (IS = 21 J, FS = 80 N). The introduction of oxazolic O enhances oxygen balance (OB), leading to a higher predicted detonation velocity and pressure for Ag₂(OZCA)₂(ClO₄)₂ (D = 6.4 km s^–1, P = 23.6 GPa). Although the introduction of thiazolic S is unfavorable for improving oxygen balance, Ag₂(SZCA)₂(ClO₄)₂ exhibits the highest initial decomposition temperature among the three, at 232 °C. Additionally, initiation tests demonstrated that three ECCs can successfully detonate cyclotrimethylenetrinitramine (RDX), indicating good initiation capabilities.

In the Au(PPh₃)Cl/AgOTf/TsOH/MeCN/N₂/25 °C system, diastereoselective synthesis of cis-3a,8a-dihydrofuro[2,3-b]benzofuran derivatives with a substituent at the 8a-position has been achieved by using 1-(2-hydroxyphenyl)-3-arylprop-2-yn-1-ols and β-oxoketones (amides, acid) as starting materials. The studies revealed that the acidity of methylene in substrates plays a key role in the differential reactions. A stronger acidity of the methylene is favorable in the desired conversion. The unique role of TsOH as an additive acid in the synthesis strategy has been rationalized. 2-Oxo-phosphonate, 2-oxo-sulfonate, and 3-oxobutanoate are suitable for the conversion.

We report herein a concise route for the total synthesis of rapicone. The key strategy to form the ynone intermediate involves an Fe(III)/TEMPO-catalyzed aerobic oxidation of a 1,3-dihydroisobenzofuran moiety. This ether oxidation for the simultaneous installation of the keto aldehyde allowed the effective formation of the required ynone intermediate. The concise total synthesis of rapicone is substantiated by the unique formal [4 + 2] cycloaddition of acyl ketene with alkynone and is completed in 7 steps with 9.4% overall yield.

Herein, a cobalt-catalyzed intramolecular enantioselective reductive Heck reaction is disclosed. Starting from N-ortho-iodoaryl-2-(trifluoromethyl)acrylamides, a plethora of chiral oxindoles bearing trifluoromethylated quaternary stereogenic centers at the C3-position are achieved in moderate to good yields (up to 88% yield) and good to excellent enantioselectivities (up to 94% ee) by employing zinc/silane as reducing agent. Other than the trifluoromethyl group, a number of chiral oxindoles bearing alkyl, aryl, and ester groups at C3-position were also obtained albeit in relatively lower enantioselectivities (68–78% ee).

The mechanism of the dirhodium-catalyzed combined C–H functionalization/Cope rearrangement (CH/Cope) reaction discovered by the Davies group has been investigated with density functional theory (DFT) calculations and quasi-classical molecular dynamics (MD) simulations. Computations from the Davies group previously showed that there is a post-transition state bifurcation leading to a direct CH reaction and also to the CH/Cope product. While this work was in preparation, the Tantillo group and the Ess group independently reported quantum mechanical and molecular dynamics studies on the dirhodium-tetracarboxylate-catalyzed diazoester CH/Cope and CH insertion reactions with 1,3-cyclohexadiene and 1,4-cyclohexadiene, respectively. The Tantillo group cited “dynamic mismatching” to explain the origins of the low yield of CH/Cope products in some experiments; the Ess group explained the origins of product selectivity from the perspective of TS vibrational modes and their synchronization that occurs at the entropic intermediates. We report quasi-classical trajectories for the reaction of the carbene with 1-methylcyclohexene that afford both the CH/Cope and C–H insertion products. After passing through the transition state that involves mostly hydrogen transfer, momentum drives the reaction trajectories toward the CH/Cope products.

This work investigates a simple synthetic method for producing fused dinitromethyl energetic compounds. Fused compound 2 has a high detonation velocity (9358 m s^–1) close to that of the well-known high-energy-density explosive CL-20 (9455 m s^–1), an extremely high density (1.97 cm^–1), and acceptable sensitivity (IS = 8 J). The good thermal stability of 2 (T_d = 181 °C) is rarely reported in the field of dinitromethyl-based high explosives. The results show that compound 2 is a promising candidate for high explosives and provide new insight into the synthesis of dinitromethyl compounds.

We developed a method for allowing cascade cyclization of 2-nitrochalcones with pyrazoles, imidazole, and indazole in the presence of CuI catalyst, DBU base, and THF solvent. The conditions were tolerant of an array of useful functionalities including ester, nitro, cyano, halogen groups. A mechanistic consideration was also provided, as H₂O₂ was presumably a byproduct. Our method appears to be a rare example to directly prepare C3-heterocyclic unprotected indoles.

The synthesis of 1′-azido C-nucleosides is described to expand the set of azide-functionalized nucleosides for bioorthogonal applications and as potential antiviral drugs. Lewis acid-promoted azidation of a nucleoside hemiketal resulted in the formation of a tetrazole through a Schmidt reaction manifold. Conformational control to prevent ring–chain tautomerism enabled efficient 1′-azidation with complete β-diastereoselectivity. The unique reactivity and further derivation of the 1′-azido C-nucleosides are also reported.

A two-step formal (4 + 1) annulation-dehydration reaction offers a convenient route to C2-arylated indoles and benzofurans. This reaction exploits the bifunctional reactivity of electron-deficient benzyl chlorides with N-sulfonyl-2-aminobenzaldehydes or salicylaldehyde derivatives. The reaction tolerates both electron-withdrawing and donating groups on the substituted aldehydes, as well as variation of electron-withdrawing groups at the para position of the benzyl chloride reagent. This work also identifies interesting byproducts resulting from the self-reaction of these benzyl chlorides under basic conditions.

An iron-catalyzed nitrene transfer reaction for the rapid synthesis of sulfinamidines from readily available sulfenamides is reported. This method features mild conditions, short reaction times, and a broad substrate scope, allowing the preparation of a variety of sulfinamidines in good to excellent yields. The synthetic utility of the sulfinamidine products was further demonstrated through their conversion to other valuable sulfur(VI) compounds, such as sulfondiimidoyl fluorides, sulfinamidiate esters, and sulfonimidamides. Preliminary efforts in the development of an asymmetric variant showed moderate enantioselectivity.

A simple cobalt-catalyzed, picolinamide-directed C8–H sulfoxamination of 1-naphthalamides with NH-sulfoximines has been developed. This cross-dehydrogenative C–H/N–H coupling reaction offers a facile route to N-arylated sulfoximines, exhibiting high yields, a broad substrate scope, and excellent functional group tolerance and scalability.

The di-π-methane (DPM) rearrangement is an important organic photorearrangement that converts 1,4-diene-containing compounds to vinyl cyclopropanes, often resulting in extensive, synthetically valuable restructuring of the substrate’s carbon framework. We investigated the influence of Lewis and Brønsted acids on the DPM rearrangement of dibenzobarrelenes. These studies have culminated in the identification of a dual chiral Brønsted acid–iridium photosensitizer system that enables the first highly enantioselective catalytic all-carbon DPM rearrangement.

A simple and effective strategy for the construction of disulfide-substituted oxazole derivatives from amides, ynals, and acetyl disulfides via a Lewis acid-promoted three-component reaction has been reported. In addition, this reaction possesses other unique advantages, such as transition-metal-free catalysis, the production of disulfides, good functional group tolerance, and good regioselectivity.

We herein report the chemoselective dehydrogenation and heteroarylation of amides through photoexcited triplet ketone catalysis. Under mild reaction conditions, the generated aryl radical through the halogen atom transfer (XAT) process further undergoes an intramolecular 1,5-HAT event to generate an α-amido alkyl radical, which then intercepted with either cobalt or a reduced cyano arene radical leads to dehydrogenated and heteroarylated products, respectively, in good yields.

A robust pyrrolidine-BzOH salt-catalyzed one-pot three-component reaction involving 4-unsubstituted pyrazolones, aryl/heteroarylaldehydes, and aryl methyl ketones is reported for the first time. This catalytic process fortifies an efficient method, allowing for the practical synthesis of a wide array of synthetically useful 1,3-diarylallylidene pyrazolones in good to high yields exclusively in their single geometrical isomer forms. Furthermore, this catalyst facilitates a sequential double condensation reaction under thermal conditions, thereby enabling two consecutive C═C bonds through displacement of aryl groups. Moreover, this organocatalytic technique achieves a 100% carbon atom economy, marking a significant step forward toward efficient and sustainable synthesis.

A nickel-catalyzed coupling between S-2-pyridyl thioesters and redox-active esters has been reported. Diludine was used as a reductant in this strategy. Our method rapidly achieves the target ketone products in moderate to good yield. The construction of nonanomeric C-acyl glycosides was realized through the approach as well.

An organocatalytic asymmetric vinylogous Michael/oxa-Michael tandem reaction between β,γ-unsaturated pyrazoleamides and isatin-derived β,γ-unsaturated ketoesters has been developed with excellent regio-, diastereo-, and enantioselectivities. The methodology provides an effective approach to construct enantiomerically pure 3,4′-pyranyl spirooxindole derivatives containing three contiguous chiral centers. Moreover, the transformations of the chiral products, including the removal and reduction of the pyrazole group, have been investigated.

Direct C(sp²)–H bond functionalization of the tropone skeleton constitutes an atom-economical strategy to access substituted tropones that exist in some bioactive compounds. Herein, we report a convenient method for the preparation of 2-hydrazinotropones via C(sp²)–H bond functionalization. A variety of tropones participated in the dehydrogenative hydrazination reaction with hydrazine, delivering structurally diverse 2-hydrazinotropones in moderate to good yields with extremely high regioselectivity. This method is featured by operational simplicity and metal-free reaction conditions, thereby tolerating various functional groups.

We present a streamlined methodology that integrates regioselective tetrahalogen-BODIPY and o-hydroxyphenylboronic acid in a one-pot process, leveraging S_NAr nucleophilic substitution in conjunction with Suzuki coupling to afford diarenofuran [b]-fused BODIPYs (DBFB1–9) with commendable yields (85–95%) and short reaction times (0.5–1.0 h). X-ray structure analyses of DBFB5,7–9 elucidate that these diarenofuran[b]-fused BODIPYs adopt a “butterfly” conformation, maintaining a highly rigid planarity. A comprehensive examination of the spectroscopic and electrochemical properties of these diarenofuran[b]-fused BODIPY derivatives, incorporating various substituents, reveals intriguing characteristics, including pronounced absorption and emission in the near-infrared region (NIR), elevated fluorescence quantum yields (Φ_F = 75–89% in dichloromethane), and tunable HOMO–LUMO levels. Remarkably, compared to DBFB1–8, DBFB9 possesses a large extended π-conjugated system, resulting in significant red shifts in its absorption and emission maxima, reaching 623 and 635 nm, respectively, and a reduced HOMO–LUMO gap. Despite this substantial structural expansion, DBFB9 maintains a surprisingly high fluorescence quantum yield (Φ_F = 80%), underscoring its exceptional photophysical performance and strong potential for applications requiring efficient NIR emission and robust fluorescence retention.

A simple protocol for the Buchwald–Hartwig cross-coupling of (hetero)aryl halides with unprotected aminoglutarimide to afford diverse cereblon binding motifs is disclosed. The development of this C–N cross-coupling method was enabled by high-throughput combinatory screening of solvents, bases, temperatures, and ligands. Scope studies revealed generality across various heteroaryl and aryl halides with the reaction proceeding under mild conditions. In comparison, this method demonstrated strategic superiority over previously reported approaches, as evidenced by a significant decrease in step count from known syntheses in the patent literature.

We report a copper-catalyzed one-pot, multicomponent strategy for the convenient synthesis of N²-aryl 1,2,3-triazole-1-oxides using arylhydrazines, β-ketoesters, and tert-butyl nitrite. This mild and simple reaction proceeds in an atom-economic manner with broad substrate scope, affording a variety of N²-aryl 1,2,3-triazole-1-oxide derivatives. Other salient features of the reaction are good functional group tolerance, scalability, and product diversification.

The first systematic, concise and target-directed gold(I)-catalyzed synthesis of a family of 2,2′-biindoles containing different substitution patterns is described. The developed protocol involves the synthesis of 1,3-diyne-anilines followed by a one-pot gold(I)-catalyzed double cycloisomerization, giving rise to an efficient, broad and general protocol to get different 2,2′-biindoles under mild reaction conditions. Due to the methodological restriction of present methods for accessing this class of compounds, herein we present our synthetic proposal which allowed the preparation of several examples of 2,2′-biindoles. Their functionalization-guided us to the discovery that the chemical stability, is substitution structure-dependent.

The synthesis of C1-functionalized β-carbolines from N-Boc norharman is described. Substitution is realized by employing the Knochel–Hauser base (TMPMgCl·LiCl) followed by transmetalation with ZnCl₂ and subsequent Negishi cross-coupling of the resulting organozinc species. A variety of aryl or heteroaryl bromides participated in this one-pot reaction sequence, allowing for rapid diversification of the β-carboline scaffold in moderate to excellent yields. The reaction protocol has been applied to the synthesis of natural alkaloids nitramarine, nitraridine, eudistomin U, and perlolyrine.

A solvent-controlled Rh(III)-catalyzed mono- and dual-C–H bond activation/carbene migratory insertion with diazo compounds as a single coupling partner was demonstrated. The reaction proceeded under mild conditions, yielding products in good to excellent yields. These results are significant for the development of the domino multiple functionalization of C(sp²)–H bonds via a carbenoid insertion approach.

A diastereoselective addition and rearrangement reaction has been developed for the synthesis of pyrrolidine-2-ylidenes from NH-isoxazolines and electron-deficient allenes. This method proceeds via the rearrangement of a proposed N-alkenylisoxazoline intermediate to generate densely functionalized pyrrolidine-2-ylidenes under simple catalyst-free conditions that tolerate ketone substituents and install relative stereochemistry at positions 3 and 4 of the heterocycle. Reaction optimization and the substrate scope are described in addition to studies evaluating the reactivity of the gem-dione and enaminone groups of the products.

4-Alkylation of pyridines has been achieved by a photocatalyzed three-component reaction of an olefin, an aryloxyacetic acid, and cyanopyridine using Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ as a photocatalyst. In this way, a new type of 4-alkylpyridines bearing aryl and aryloxy substituents on the phenyl was accessed with potential pharmaceutical value. In addition to mild reaction conditions, the method has several other advantages, including a multicomponent one-pot protocol, good functional group tolerance, and easy amplification of the reaction scale. The reaction mechanism has been clarified by control experiments and computation of the reaction energy profile.

By using weakly coordinating amines, we developed remote C–H alkynylation with precise control of reactivity and regioselectivity, enabling modification of complex drugs, natural products, and materials. The readily transformable alkyne-containing amine products would facilitate expedient delivery of molecular libraries of functionalized amines and medium N-heterocycles, which are previously elusive to access. Moreover, the introduced alkyne functionality could serve as a versatile handle to expand the diversity and synthetic application of this remote C–H functionalization.

Four unprecedented nortriterpenoids, masterpenoids A–D, were isolated and fully elucidated from the resin of the mastic tree (Pistacia lentiscus). Masterpenoids A–C are the first norterpenoids featuring an unprecedented 6/6/6/10 ring system, while masterpenoid D possesses a novel 6/6/6/7/5 ring system. The anti-inflammatory potential of the compounds was meticulously assessed through the establishment of an in vitro model of lipopolysaccharide-induced inflammation in RAW264.7 macrophage cells. Among them, Masterpenoids A and D showed potent inhibition of NO production, with IC₅₀ values of 10.6 ± 0.8 and 8.2 ± 0.9 μM, respectively, compared to positive control dexamethasone (IC₅₀ = 23.2 ± 1.2 μM).

Carbon monoxide (CO) is endogenously produced with a range of pharmacological activities. Sensitive and selective detection of CO is critical to studying its biology. Since the first report of a CO fluorescent probe in 2012, more than 100 papers on this topic have appeared. Noteworthy in such work is the widespread use of two commercially available ruthenium–carbonyl complexes (CORM-2 and CORM-3) as CO surrogates. Unfortunately, these two CORMs are chemically very reactive and preferentially release CO₂ but not CO, unless in the presence of a nucleophile. As a result, there are “two tales” of the reported CO probes: those that detect CO and those that detect only the CORM used but not CO. In addition, because of their lack of reliable CO production and fast degradation in an aqueous solution, there is the question of what “detecting CORM-2 or CORM-3” really means in the context of CO research. Additionally, for applying fluorescent CO probes in detecting low levels (often nanomolar) of CO in vivo, fast reaction kinetics is a prerequisite for meaningful results. In this Perspective, we discuss in detail these issues with the understanding of the evolutionary nature of scientific discoveries and the aim of preventing further confusion.

A selective ortho-olefination of primary amides yields valuable motifs for pharmaceuticals. Primary amide-directed ortho-olefination of benzamide using unactivated alkenes was successfully conducted with a ruthenium(II) catalyst. The established protocol demonstrates efficacy across various benzamides, achieving moderate to good yields with high functional group tolerance. Furthermore, the transformation of ortho-olefinated amides into five-membered lactams highlights their synthetic applicability in the pharmaceutical sector.

Herein, we disclose a simple one-pot method for an efficient regio- and stereoselective synthesis of 1,3,5-triaroylcyclohexanes from aryl vinyl ketones using potassium tert-butoxide. The developed protocol allows the construction of various symmetrically substituted cyclohexanes in good to excellent yields. The major product 2 also can be converted to the product 3 (all equatorial) conveniently by acid catalysis. This protocol features a good substrate scope and functional group compatibility.

The deaminative coupling of gramines with nucleophiles represents a versatile approach for structure diversification, but often involves non innocent conditions and/or reagents. Here a new acetylenic reagent 2 is developed for the C–N bond activation of gramines and their in situ coupling with C- and N-centered nucleophiles. Using the new acid/base- and redox-neutral ynone reagent 2 the coupling reactions proceed exceedingly as exemplified by the synthesis of several indol-3-ylmethyl derivatives, including new indole-benzodiazepine and indole-hydrazone conjugates.

A Regioselectivity-switchable Diels–Alder reaction of arynes and 4-alkenyloxazoles was explored. By regulating the reaction temperature and the polarity of the solvent, the reaction activity of aryne was controlled to selectively react with different favorable reaction sites of 4-alkenyloxazoles, providing naphtho[2,1-d]oxazoles and 1,4-epoxyisoquinolines. Density functional theory (DFT) calculations demonstrated that the Diels–Alder reaction on acyclic dienes site needs more energy than the reaction on cyclic dienes to overcome the potential reaction barrier.

A Ag-catalyzed [2 + 3] cycloaddition of alkylidene azlactones with trifluoromethylated imines has been documented, providing spiro[pyrrolidine-azlactones] bearing four adjacent stereogenic centers with good yields and excellent diastereoselectivities. Catalytic asymmetric cycloaddition has also been developed with good yields and excellent enantioselectivities. Further gram-scale preparation and synthetic transformation to pyrrolidine derivative showed the good practicality and applicability of this reaction.

Herein, we introduce an unprecedented cascade reaction for the assembly of pyrrole-fused 1,5-benzodiazepine frameworks. These diverse privileged scaffolds were controllably constructed by intramolecular cyclization of β-enamino diketone, followed by annulation with o-phenylenediamine. The protocol features efficient one-pot cascade cyclization/annulation, performed under simple and mild reaction conditions. The products are obtained in a metal-free manner, in good to excellent yields (65–91%), and represent a fused heterocyclic scaffold that is not yet found in nature.

A visible-light-promoted protocol for azaspirocyclic synthesis from N-benzylacrylamides and alkyl chlorooxoacetates has been established. This cascade reaction proceeds through sequential free radical addition, cyclization, and dearomatization, enabling the convenient construction of key azaspirocyclic derivatives and the introduction of valuable ester groups in a single step. In addition, this transformation demonstrates broad substrate compatibility and high tolerance toward different functional groups, showcasing remarkable efficiency in functional group insertion and bond formation.

The efficient synthesis of 4-hydroxy-3-arylindolin-2-ones via phosphoric acid-mediated annulation of various β-nitrostyrenes and 1,3-cyclohexanedione is described. This annulation reaction gives a practical method for affording a diverse set of oxindoles, having simple experimentation, readily available starting materials, and very good yields. Additionally, substituted 1,3-cyclohexanediones under the same conditions afforded tetrahydrobenzofuran oxime compounds.

α-Methoxytropone is a structural motif found in various natural products and other compounds of interest to the scientific community but remains a synthetic challenge. The present Note describes the synthesis of variously substituted α-methoxytropones and related compounds through an intermolecular 3-hydroxy-4-pyrone-based oxidopyrylium (5 + 2) cycloaddition followed by a samarium iodide-mediated reductive ring-opening. The strategy is highlighted in the synthesis of a novel AC-ring analogue of colchicine to compare it to existing methods.