Abstract The reactivity of the 3,6-dibromocarbazolyl nitrenium ion was investigated to determine how antiaromatic destabilization influences nitrenium ion chemistry. Laser flash photolysis and kinetic isotope effect experiments were employed to investigate the reactivity of this nitrenium ion. These results indicate that the 3,6-dibromocarbazolyl nitrenium ion undergoes rapid electron transfer with phenols and under trap-free conditions. Strong nucleophiles such as halides and alcohols trap the nitrenium ion directly, while electron-donor quenching generates a neutral radical intermediate whose fate is governed by proton availability. In the absence of protonation, radical–radical coupling yields an N–N dimer, whereas protonation diverts the pathway toward formation of the parent amine. Product accounting demonstrates that the parent pyridinium ion functions as a transient redox mediator rather than a sacrificial electron donor, with excess redox equivalents accommodated by formation of short oligomeric dibromocarbazolyl species. Alkene trapping experiments further define the limits of covalent reactivity, showing that only substrates capable of intercepting radical intermediates form stable adducts. Computational evidence suggests antiaromatic character of the 3,6-dibromocarbazolyl nitrenium ion. These experimental results demonstrate that antiaromatic destabilization biases diaryl nitrenium ions toward redox pathways that relieve antiaromaticity without expanding the scope of electrophilic addition chemistry.
Abstract A new strategy for the rapid and efficient synthesis of N-sulfonyl formamidines has been developed through the activation of N,N-dimethylformamide (DMF), assisted by (Methyl)thianthrenium salt under ambient conditions. The protocol offers a metal and oxidant-free process, utilizing a bench-stable and recyclable thianthrenium salt as an activator, via a convenient procedure. The protocol exhibits broad substrate compatibility and scalability. The practical utility of the method has been further demonstrated through the late-stage functionalization of pharmaceutically relevant drug molecules.
Abstract A copper-catalyzed asymmetric 1,3-dipolar cycloaddition of α-N-(heteroaryl-methyl)imines with gem-difluoroalkenes is reported. Using a Cu(I)/Segphos complex, this protocol provides diverse chiral fluorinated 2-heterocyclic pyrrolidines in high yields (up to 99%) with excellent stereoselectivity (up to 98% ee, >20:1 dr). This method is compatible with various heteroaryl groups and complex natural products. Notably, these scaffolds exhibit potent antifungal activity against Magnaporthe oryzae, with the lead compound 4a outperforming the commercial fungicide isoprothiolane by 50% in EC50 values.
Abstract A visible-light-induced sodium fluorescein-catalyzed four-component cascade reaction of N-arylpropiolamides, aryl thianthrenium salts, DABSO, and H2O has been developed, providing efficient access to diverse 3-sulfonyl-azaspiro[4.5]trienones in moderate to good yields. The reaction accommodates a broad range of aryl thianthrenium salts and propiolamide substrates, tolerating various functional groups. Mechanistic investigations suggest a radical cascade pathway involving the formation of arylsulfonyl radicals, followed by sulfonylation, ipso-spirocyclization, and H2O trapping. The four-component, one-pot nature of this transformation, combined with its mild conditions and operational simplicity, offers a sustainable and step-economical strategy for constructing pharmaceutically relevant azaspiro scaffolds.
A highly selective synthesis of xanthones and indanediones via the addition of 3-sulfonyl phthalide to aurones and auronimines under temperature-controlled reaction conditions has been demonstrated. While the reaction of phthalide with aurone in the presence of Cs2CO3 in THF at 0 °C favors the formation of indanedione, the favored product is xanthone at reflux temperature. On the other hand, the phthalide reacts with auronimine in the presence of Cs2CO3 in THF at room temperature to afford the Michael adduct but provides indanedione in the presence of KOtBu in THF under reflux conditions. The plausible mechanism suggests that the spiro-naphthoquinone that emerges from the [4 + 2] cycloaddition. Hauser-Kraus annulation serves as the key intermediate in the formation of both xanthone and indanedione via a cascade of rearrangements. Furthermore, the smooth conversion of aurone-derived indanedione to xanthone under reflux conditions in THF suggested that the former is the kinetic product, whereas the latter is the thermodynamic product.
Herein, we disclose a continuous-flow protocol for the lithiation of thiazoles, followed by a halogen dance rearrangement and subsequent trapping with diverse electrophiles. The transformation proceeds rapidly, occurring in less than 1 min, and exhibits broad applicability across a range of substrates, including oxazole and imidazole derivatives. The implementation of continuous-flow conditions provides enhanced control over reaction parameters and enables facile scale-up, thereby offering significant advantages for the development of streamlined and scalable synthetic methodologies.
Abstract Enantiomerically enriched [2.2]paracyclophanes (PCPs), particularly those bearing two functional groups on distinct decks, constitute privileged scaffolds for circularly polarized luminescence (CPL) materials owing to their inherent stable planar chirality and unique optoelectronic properties. Nevertheless, the efficient and enantioselective construction of structurally diverse PCPs equipped with synthetically versatile handles suitable for solid-state applications persists as a formidable challenge. Herein, we disclose a modular asymmetric copper-catalyzed azide–alkyne cycloaddition (CuAAC) desymmetrization of prochiral dialkynyl PCPs. This methodology enables the concise assembly of a diverse array of highly functionalized disubstituted PCPs in high yields with excellent enantioselectivities (up to 93% yield and >99% ee) while incorporating optically active terminal alkyne and triazole moieties ideally poised for downstream diversification. Subsequent elaborations of these chiral mono-terminal alkyne substituted PCPs furnish complex difunctionalized derivatives with complete retention of enantiopurity. As a proof-of-concept application, a pyrene-functionalized PCP derivative 5a displays pronounced solid-state CPL activity, delivering an impressive dissymmetry factor (glum = −2.7 × 10–3) alongside a high fluorescence quantum yield (ΦF = 0.59). This strategy establishes a modular platform for accessing enantiopure disubstituted PCPs, furnishing promising candidates for advanced solid-state chiral emitters in photonic technologies.
Abstract A practical total synthesis of streptospherin A (1), a cancer stem cell inhibitor, is reported. The key intermediates are obtained stereoselectively in a concise synthesis by a combination of asymmetric allylation and hydroxy-directed stereoselective diboration. These intermediates were coupled via N-acetylcysteamine thioester-mediated Liebeskind–Srogl cross-coupling to achieve the total synthesis of 1.
Abstract In this work, we have disclosed that available trifluoromethyl-substituted hydrazones derived from conjugated ynones undergo cyclization, followed by carboxylation with CO2 in the presence of K2CO3. The reaction enables the synthesis of a variety of pyrazole-4-carboxylates bearing a trifluoromethyl group in good yields under ambient conditions without the use of transition-metal catalysts. Furthermore, it was found that CF2Br-substituted ynones react with hydrazine salts in alcohols to afford hydrazones containing an alkoxycarbonyl group; these intermediates can also undergo carboxylation, providing access to pyrazole-3,4-dicarboxylates in good yields.
Abstract We report a photoinduced nickel-catalyzed cyclization/cyanation of functionalized alkynes using 2-(diisopropylamino)acetonitrile as a practical cyanide surrogate. Under mild conditions with Cat. 1, KI, Zn, and 395 nm LED irradiation, the reaction affords diverse cyano-containing heterocycles, including indole-3-carbonitriles, benzofuran carbonitriles, benzo[b]thiophene carbonitriles, and isocoumarin/isochromene carbonitrile derivatives. The method avoids the direct use of highly toxic cyanide sources such as KCN, HCN, and TMSCN while providing synthetically useful nitrile-containing products for further derivatization. Control experiments support the requirement for the nickel catalyst, iodide, zinc, and light, and are consistent with a photoassisted, low-valent nickel pathway involving a nickel–cyanide species and iodide-assisted substrate activation. DFT calculations comparing competing oxygen-tethered cyclization pathways indicate that the benzofuran-forming pathway to 2-phenylbenzofuran-3-carbonitrile (3g) is favored over the isochromene-forming pathway to 1-oxo-3-phenyl-1H-isochromene-4-carbonitrile (3h). This work provides a mild and practical platform for accessing cyano-functionalized heterocycles and offers mechanistic insight into the regioselectivity of photoinduced nickel-catalyzed cyclization/cyanation.
Abstract An efficient synthesis of the 2,3-dihydropyrrolo[3,4-b]indol-1(4H)-ones has been developed via BF3OEt2-promoted formal [3 + 2] annulation of 2-vinylindoles with isocyanates. The reaction features mild conditions and a broad substrate scope, showing excellent functional group tolerance toward various substituents on both the 2-vinylindole and the isocyanate partners. This protocol provides a facile and practical approach, holding significant potential for the synthesis of bioactive heterocyclic compounds and related pharmaceutical intermediates.
Prenylated 2H-pyrans, accessed through a domino Knoevenagel/oxa-6π electrocyclization reaction between 1,3-cyclohexanediones and citral, undergo an electrophilic cascade promoted by N-iodosuccinimide. Iodo-substituted bridged-tricyclic systems are obtained as products of this domino reaction in moderate to good yields and regio- and diastereoselectively, providing a simple synthetic strategy for the construction of heterocyclic frameworks related to biologically active natural products.
Herein, we report a convenient and efficient method for the reductive multideuteration of 2-vinylquinolines and 2-methylquinolines utilizing a Mg/CH3OD system. By employing readily available CH3OD as a deuterium source, this method achieves 3-5 deuterium atoms incorporation into the target structures. Moreover, the Mg/CH3OH system smoothly reduced quinoline substrates to the corresponding tetrahydroquinoline products. This protocol offers a practical and mild approach for high-level deuterium incorporation using inexpensive reagents while avoiding complex catalysts and harsh conditions. This work opens up a new avenue for the use of Mg/CH3OD in deuterium labeling.
We herein report a facile and efficient base-promoted annulation approach to construct cyclopropyl carbocyclic purine nucleoside analogues. Using α-purine-substituted acetones/acetophenones as challenging dinucleophiles, this reaction undergoes selective C/C nucleophilic attack to achieve [2 + 1] annulation with alkenyl sulfonium salts (up to 92% yield, 24 examples). This reaction employs safer and more readily available starting materials, proceeds under transition-metal-free and mild conditions, and possesses broad functional group tolerance, thus showing great potential for practical applications in nucleoside chemistry.
Two-step telescopic synthesis of unsymmetrical diarylhydrazides formally derived from di- and trifluoroacetic acid is reported. The method comprises trapping of the in situ-generated 1,3-dipolar di- and trifluoroacetonitrile imine with phenolate, followed by the Smiles rearrangement of the initially formed hydrazonoyl ester. Mechanistic analysis of the second step using DFT calculations revealed a single-step aryl migration proceeding through a pseudocyclic transition state and exhibiting only a minor influence of the fluoromethyl substituent. The structures of selected CF3- and CHF2-functionalized products were confirmed by X-ray analysis.
We report the first ligand-free palladium(II)-catalyzed regioselective C(sp3)-H selenylation of 8-methylquinoline derivatives using aryl selenenyl chlorides as the selenating reagents. The reaction proceeds smoothly over a broad range of substrates with excellent regioselectivity, affording the corresponding selenium-containing quinoline derivatives in good to high yields. The protocol does not require external ligands, is amenable to scale-up, and tolerates a wide variety of functional groups. Preliminary synthetic applications demonstrate the potential utility of this method in medicinal chemistry.
An oxidative rearrangement of 3,3'-bisindolylmethanes has been developed for the direct synthesis of 2,2'-biindoles using PdCl2 and Cu(OAc)2·H2O. The transformation proceeds through an unusual sequence of intramolecular C-C bond formation followed by C-C bond cleavage. Cu(OAc)2 acts as a co-oxidant and likely contributes beyond simple reoxidation. The method exhibits broad functional-group tolerance and provides practical access to diverse 2,2'-biindole derivatives, revealing bisindolylmethanes as latent synthons for biindole construction.
A bifunctional thiourea featuring a pyridinium cation is employed as an asymmetric organocatalyst in the Mannich reactions of protected aromatic aldimines and various carbon nucleophiles. This charged catalyst is 20 times more active than a neutral analog under identical conditions, enabling reduced catalyst loadings and shortened reaction times. Excellent enantioselectivities are accompanied by high diastereoselectivities in several cases with prochiral β-ketoesters.
DNA-encoded library (DEL) synthesis necessitates robust on-DNA chemical transformations that remain dependable throughout multistep library construction, especially for elongated DNA constructs. This study assessed the efficiency of commonly used on-DNA nitro reduction reactions under conditions relevant to practical DEL synthesis to evaluate the impact of DNA tag elongation. Although iron(II)-, diboron-, palladium(II)-, and dithionite-mediated reductions showed high efficiency for short DNA constructs, their performances varied significantly with DNA tag elongation. The generality of these reduction conditions was further explored across a diverse set of nitro-containing substrates, and their chemoselectivities toward additional functional groups were assessed to reflect realistic DEL design considerations. These findings underscore the importance of evaluating on-DNA chemistry beyond minimal tag systems and offer practical guidance for selecting suitable nitro reduction conditions for reliable DEL construction.
We report the first total synthesis of the cembranoid diterpenes knightol, knightal, and knightol acetate isolated from the Caribbean Sea Whip, Eunicea knighti. Highlights of the synthesis include leveraging farnesol as a feedstock starting material, a late-stage Shi epoxidation, and a penultimate Horner-Wadsworth-Emmons macrocyclization. Biological studies reveal modest biofilm inhibitory activity against Staphylococcus aureus for the most active member, (-)-knightol.
