Fully conjugated indeno[2,1-c]fluorene, a fragment of fullerene-C60, is a structural isomer of the 20π indenofluorene family, which is viewed as the antiaromatic analogue of the aromatic acene(s). Compared to the linear indeno[1,2-b]fluorene isomer featuring a para-quinoidal s-indacene core, the helical [2,1-c]IF features a para-quinoidal as-indacene core. It received relatively less attention than [1,2-b]IF despite the high electron affinity, small HOMO-LUMO energy gap, diradical character, and red-shifted UV-vis absorption, which are potentially important properties for organic optoelectronics applications. The stable [2,1-c]IF scaffold was first reported in 2013; however, an unstable [2,1-c]IF-embedded polycyclic hydrocarbon was originally disclosed in 1998. Lately, [2,1-c]IF derivatives have received significant attention in physical organic and organic materials chemistry as novel synthetic approaches emerged. Herein, we outline these synthetic approaches to [2,1-c]IF and its π-extended derivatives featuring the C/U-shaped [2,1-c]IF unit, including heterocyclic counterparts, exhibiting tunable antiaromaticity, helicity, open-shell traits and semiconducting properties.
Abstract Cyclobutastellettolide B is a structurally unique C19 norterpenoid bearing a highly strained 6/5/4-fused tricyclic core with three contiguous quaternary stereocenters. We describe synthetic studies toward this target based on a thermal ene–ketene [2+2] cycloaddition strategy to forge the central cyclobutanone. Starting from (+)-sclareolide, we developed a concise, chromatography-free, three-step isomerization that delivers a key carboxylic acid on a multigram scale in 78% overall yield. Central to this sequence is an improved Lindgren oxidation in which ethyl vinyl ether serves as a more effective and less expensive hypochlorous acid scavenger than the commonly used 2-methyl-2-butene, thereby suppressing competitive halohydrin formation at the electron-rich tetrasubstituted alkene. Despite an extensive survey of ketene and keteneiminium cycloadditions, the tetrasubstituted olefin could not be engaged, which we attribute to steric encumbrance. These results indicate that polar cycloadditions are poorly suited to constructing this cyclobutanone and reinforce that a Norrish–Yang cyclization is likely part of the biosynthetic pathway.
Abstract We introduce an effective approach for both intermolecular and intramolecular Diels–Alder reactions between furans and aryne intermediates. By employing o-diiodoarene as a stable precursor combined with sodium hydride, this method enables the straightforward in situ formation of reactive aryne species. Key advantages include a straightforward experimental procedure, readily available and low-cost starting materials, and relatively mild reaction conditions with reduced environmental impact, providing a reliable synthetic route to access 1,4-dihydro-1,4-epoxynaphthalenes and structurally complex polycyclic frameworks. The obtained products are valuable synthetic intermediates with promising potential for further derivatization across multiple research areas.
Abstract We report an operationally simple and highly efficient protocol for the visible light-induced photocatalytic synthesis of alkynyl germanes from coupling between aryl sulfonyl alkynes and hydrogermanes. This study highlights the use of the simple sulfonamides as hydrogen atom catalyst and readily available 4CzIPN as photocatalyst for the activation of Ge–H bonds of hydrogermanes. This transition metal-free protocol demonstrates broader substrate scope and is suitable for the late-stage functionalization.
Abstract Waste valorization by biological funneling is a new strategy that has emerged for the upgrading of plastic waste. The concept involves converting plastics to microbial metabolic substrates chemically, and then upgrading these in a subsequent fermentation step. To date, several polymer materials have been exhibited as substrates, each undergoing conversion to carboxylic acid products. These various acids have been upcycled by both bacterial and fungal hosts, the former producing polyhydroxyalkanoic acid materials and the latter producing a host of medicinal entities, fine chemicals, and biologics. In this short review, we will summarize the emerging field of plastics valorization by biological funneling and make a case for the utility of fungal platforms as a funneling back end, emphasizing the upcycling of synthetic polymers to high-value fungal metabolites.
Abstract We herein report the reaction between α-oxodithioesters and methyl ketones in the presence of sodium hydride and methyl iodide in DMF for the synthesis of symmetrical α,β-bis(methylthio)-α,β-unsaturated-1,4-diketones, which are novel key compounds. We explored potential application of these intermediates by reacting with arylhydrazines in the presence of potassium hydroxide in isopropyl alcohol at 75 °C, which afforded 1,3-di(hetaryl/aryl)-4-methylthio-5-acyl-pyrazoles in high yields and short reaction times. Wide substrate scope and development of novel key intermediates and pyrazoles are the advantages of this protocol.
The direct synthesis of 1,2-vicinal diamines via alkene diamination remains a significant challenge, particularly when utilizing free amines as nitrogen sources due to their strong coordination ability and propensity for oxidation. Here, we have reported a ligand-accelerated cobalt-catalyzed aerobic diamination of 1,1-disubstituted alkenes with anilines. This transformation employs a widely available CoI2 precursor combined with a simple diamine ligand, offering a practical alternative to the previously required Cp*Co(III) pre-catalysts. For Cp*Co(III) catalysis, DFT calculations revealed that the first C-N bond formation proceeds via a unique spin center shift mechanism involving spin state crossover, followed by a radical substitution for the second C-N bond formation. In the CoI2/diamine catalytic system, computational results suggest that a Co(III) species acts as the active catalyst, where the first C-N bond is also formed via a "spin center shift" mechanism, while the second C-N bond formation undergoes a one-electron reductive elimination. This work provides an efficient method for accessing vicinal diamines and unveils the mechanism of C-N bond-forming in Co(III) catalysis.
Abstract Chiral carbonyl compounds featuring α-stereocenters represent a fundamental structural motif prevalent in natural products and pharmaceutically relevant molecules. While transition-metal-catalyzed asymmetric hydrofunctionalization of alkenes offers a direct route to these scaffolds, established protocols typically rely on precious metals and toxic carbon monoxide gas. To address these challenges, this review highlights recent advancements in earth-abundant-metal-catalyzed asymmetric hydrofunctionalizations of alkenes utilizing acid derivatives as stable electrophilic coupling partners. We specifically focus on copper- and nickel-catalyzed strategies that employ reagents such as acid anhydrides, chloroformates, and carbamoyl chlorides to achieve enantioselective hydroacylation, hydrocarboxylation, and hydrocarbamoylation. These emerging protocols not only operate under mild conditions but also offer complementary chemo- and regioselectivity, enabling the efficient synthesis of structurally diverse α-chiral ketones, esters, and amides.
Abstract Selenium, an essential biological micronutrient, has found broad applications in the design of bioactive molecules and functional materials and also functions as a distinct reactive site in chiral catalysts and ligands in synthetic chemistry. Among various strategies, the catalytic hydroselenation and selenofunctionalization of alkenes and alkynes represent one of the most direct and efficient routes for synthesizing chiral selenides. To achieve these transformations, diverse catalytic systems—including transition-metal catalysis and organocatalysis—have been developed. This review systematically summarizes recent advances in the asymmetric hydroselenation and selenofunctionalization of alkenes and alkynes. Mechanisms and substrate scopes of some representative reactions are also briefly described to illustrate current capabilities and limitations, offering readers a perspective on the progress and potential of this evolving area of selenium chemistry.
Abstract DNA-encoded library (DEL) technology serves as a cornerstone of modern drug discovery, providing a cost-effective platform for the rapid interrogation of therapeutic candidates. However, the prerequisite for DNA-compatible synthetic reactions under aqueous conditions has historically constrained DEL chemical diversity to planar, C(sp2)-rich architectures, resulting from a reliance on traditional two-electron polar transformations. This short review evaluates recent advances in radical-mediated transformations as a powerful means to increase the chemical space of DELs. By facilitating access to three-dimensional sp3-rich scaffolds, these radical methodologies have the potential to significantly broaden the structural diversity of modern DELs.
Azanorbornadiene (ZND) molecules are assembled by Diels-Alder reaction of N - acyl- or N - sulfonyl-pyrroles with electron-deficient alkynes. ZND electrophiles of varying structures were tested for reactivity with protic nucleophiles and subsequent retro-Diels-Alder (rDA) fragmentation to the starting pyrrole, a reaction sequence of interest for drug delivery and degradable materials applications. ZNDs were shown to take on thiols and amines (including heterocyclic and tertiary examples) with similar rates in the range of 10 (-2) -10 (-4) M (-1) s (-1) . rDA fragmentation was found in most cases to be decelerated in protic solvents relative to chloroform, in contrast to thiol adducts of analogous oxanorbornadienes (ONDs). Furthermore, the presence of a 2-hydroxymethyl group on the N-acylpyrrole moiety gave rise to the release of the free carboxyl fragment by virtue of acyl migration following rDA cleavage, providing a potential method of traceless release of a carboxylic acid cargo molecule. Facile amine reactivity stands in sharp contrast to the thiol-selective reactivity of OND electrophiles. Density functional theory calculations identified electrostatic polarization of the reactive ZND double bond as a potential source of this difference. The reaction patterns identified here mark ZNDs as more complex motifs than ONDs, but also with the potential of a greater variety of uses.
Selectfluor is an important reagent playing either the role of an oxidant or an electrophilic fluorine source for various organic transformations. Herein, we report a solvent-selective, C-H fluorination of pyrazolo[1,5-a]pyrimidines in MeCN using select-fluor (1 equiv) as the electrophilic fluorine source at room temperature for the synthesis of a wide variety of 3-fluoropyrazolo [1,5-a]pyrimidines in good yield. Interestingly, when the solvent was changed from MeCN to DMSO, pyrazolo[1,5-a]pyrimi-dines did not undergo C-H fluorination at room temperature; however, at high temperature, they underwent oxidative alkylative dimerization reaction, where selectfluor played the role of an oxidant and DMSO as the C-1 synthon to access bis(pyrazolo [1,5-a]pyrimidin-3-yl)methanes in good yield. Thus, by choosing an appropriate solvent, two different classes of valuable products could be synthesized from pyrazolo[1,5-a]pyrimidines by utilizing the different characteristics of selectfluor.
Abstract Catalytic hydrogenation of alkenes is a cornerstone transformation in both industrial chemistry and synthetic methodology. While noble-metal catalysts have historically dominated this field, the development of efficient hydrogenation catalysts based on earth-abundant transition metals has emerged as a major research direction. Phosphine ligands play a central role in enabling such systems by stabilizing reactive metal centers, tuning electronic and steric environments, and facilitating diverse modes of H2 activation. This review highlights recent advances in phosphine-supported earth-abundant metal catalysts for alkene hydrogenation, focusing on representative systems based on Fe, Co, Ni, and Mn, together with several emerging metal platforms. Particular attention is given to ligand design strategies, catalyst structures, and mechanistic paradigms governing hydrogen activation and transfer, including classical metal-hydride insertion pathways, metal–ligand cooperative processes, and cooperative multisite activation. Despite significant progress, challenges remain in improving catalyst robustness, expanding substrate scope-especially for sterically hindered internal alkenes and developing broadly applicable asymmetric variants. Continued advances in phosphine ligand engineering and cooperative catalyst design are expected to further advance sustainable hydrogenation catalysis using earth-abundant metals.
Abstract Starting from ortho-iodo anilines, ethyl propiolate, and amines 19 ethyl o-anilino-β-aminoenoates are formed in a consecutive three-component Sonogashira alkynylation-Michael addition reaction in moderate to excellent yields (33–86%). These compounds undergo lactamization to 4-aminoquinolin-2(1H)-ones, either in a separate transformation in moderate to excellent yield (13 examples, 27–99%) with AlCl3 as a Lewis acid, or en route in the sense of a Sonogashira alkynylation-Michael addition-lactamization reaction in moderate to good yield (11 examples, 27–68%) in the presence of SnCl4 as a Lewis acid.
Abstract Photochemical isomerization is an expansive strategy to regulate the position and geometry of a preexisting alkene. Despite the operational simplicity this method confers, application in synthetic chemistry has until recently remained limited by the reliance on styrenyl-based chromophores. The emergence of borylated alkenes has enabled this limitation to be circumnavigated and provides a traceless handle for further (stereospecific) manipulations. Incorporation of a boron substituent modulates alkene photochemistry, enabling conjugation, excited-state energetics, and relaxation pathways to be understood at the level of well-defined boron-centered orbital interactions. This review discusses how the inclusion of a boron substituent can be leveraged as an active control element rather than a passive functional handle. These developments include selective manipulation of alkene geometry and position through subtle alterations to conjugation across a range of molecular contexts. Both energy transfer catalysis and direct substrate excitation can be applied to access isomers that are difficult to obtain selectively by conventional ground-state methods. By elevating boron to an active stereoelectronic design element that orchestrates excited-state reactivity, the photochemical isomerization of short borylated π-systems has emerged as an expansive strategy for structural modulation.
Abstract Fluorinated nitrile imines, particularly trifluoromethyl and difluoromethyl derivatives, belong to the highly reactive propargylic-type 1,3-dipoles. Their cycloaddition reactions have emerged as a key strategy for efficiently constructing structurally diverse fluorinated nitrogen-heterocycles. This review provides a comprehensive review of recent advances in this field. The discussion focuses on diverse cycloaddition reactions between fluorinated nitrile imines and various dipolarophiles (such as alkenes, alkynes, thiones, imines, carbodiimides, quinones, etc.), demonstrating that these cycloaddition approaches offer significant advantages in controlling reaction selectivity, achieving functional group versatility, and synthesizing complex molecules.
Abstract Vigabatrin (4-amino-5-hexenoic acid) is a potent and clinically approved antiepileptic agent that functions as an irreversible inhibitor of γ-aminobutyric acid aminotransferase (GABA-T), the enzyme responsible for the catabolism of the inhibitory neurotransmitter GABA in the central nervous system. Of its two enantiomers, the (S)-form is pharmacologically active, making the development of efficient, stereoselective synthetic routes to (S)-Vigabatrin of considerable importance in medicinal chemistry. This review provides a comprehensive overview of all known synthetic strategies for accessing Vigabatrin, with a primary focus on enantioselective methods for preparing the (S)-enantiomer. The article critically evaluates racemic approaches, chiral-pool strategies using amino acids and carbohydrates, asymmetric catalytic methods, modern resolution techniques, and formal synthesis. In particular, recent advancements in organocatalysis, transition-metal catalysis, and crystallization-induced resolution are discussed in detail. Synthetic pathways are compared based on factors including step economy, stereoselectivity, scalability, and overall yield. This review serves as a valuable resource for researchers engaged in synthesizing GABA analogues and related neuroactive compounds, underscoring the ongoing need for improved methodologies in the asymmetric synthesis of pharmaceutical agents.
Abstract Arylazoformamide (AAF) ligands coordinate to Pd(II)Cl2 creating Pd(II)Cl2(AAF)2 complexes. When subjected to typical Heck conditions at 1 mol% of complex loading, a broad substrate scope revealed the need for high heat (150 °C) and an inorganic base (Na2CO3) to give good to excellent yields (60–99%). Not surprisingly, aryliodides outperformed arylbromides when coupling alkenes with electron-donating group (EDG) substituents yet showed very limited selectivity for alkenes with electron-withdrawing groups (EWGs). Mechanistically, it is believed that the complex behaves as a precatalyst and, under reaction conditions, reduces to a Pd(0) complex before proceeding through the catalytic cycle. The reactive species is suggested to be either a bis-AAF coordinated Pd(0) complex or as a formal azoenolate coordinated Pd(II) complex and both neutral and cationic mechanistic pathways were evaluated. Overall, this report provides a glimpse at exploring ligand properties as seen through a known reaction.
Tetrazines are nitrogen-rich heterocycles with broad applications in bioorthogonal chemistry, energy materials, catalysis, and biomedical research. This review highlights the stability of s-tetrazines, the energetic nature of v-tetrazines, and summarizes diverse synthetic methods, including organocatalysis, cross-coupling, cycloaddition, and one-pot strategies, alongside the applications of their functional derivatives. Tetrazine belongs to a heterocyclic group of compounds bearing four nitrogen atoms in the ring system, with wide applicability in analytical and optical fields, energy and catalysis, and also in biomedical research. s-Tetrazine is emerging as one of the bioorthogonal molecules among other compounds like 1,2,4-triazines, trans-cyclooctenes, and heterocycloheptynes. The unique arrangement of nitrogen atoms in s-tetrazine, having a planar structure, significantly enhances its stability, making it superior to the rest isomers. v-Tetrazines are highly unstable, energetic molecules, and hence, are ideal for high-energy-density materials. Herein, we reviewed various synthetic methods of 1,2,4,5-; 1,2,3,4-; and 1,2,3,5-tetrazine, involving organocatalytic approaches, various cross-coupling methods, Pinner-type reactions, one-pot methodologies, cycloadditions, nucleophilic substitutions, polymerization, and solid-phase methods. This work will give a peek into the formation methods of tetrazines from various substrates, which are substituted with different groups, ranging from electron-withdrawing to electron-donating substituents. Applications of the developed tetrazine derivatives are also highlighted.
Abstract Nitriles are fundamental functional groups in organic synthesis, serving as versatile precursors to amides, amines, acids, and heterocycles, and play a central role in pharmaceutical and materials chemistry. Among nitrile derivatives, α-olefinated nitriles are particularly valuable intermediates due to their high synthetic versatility and broad applicability. In recent years, acceptorless dehydrogenative coupling (ADC) of alcohols with nitriles has emerged as an attractive and sustainable strategy for accessing these compounds, enabling C–C bond formation with the generation of only H₂ and H₂O as by-products. Despite growing interest in this area, a comprehensive overview of α-olefinated nitrile synthesis via ADC pathways has been lacking. This review provides an up-to-date summary of recent advances in transition-metal-catalyzed, earth-abundant metal-based, and photochemical approaches to nitrile olefination, with particular emphasis on ADC processes. Key developments in catalyst design, mechanistic understanding, and reaction selectivity are discussed, along with current challenges and future perspectives. By exploring these catalytic pathways, this review aims to inspire the development of novel and sustainable methods for α-olefinated nitrile synthesis from readily available feedstocks.
