Protein arginine methyltransferase 5 (PRMT5), a SAM-dependent type II methyltransferase implicated in chromatin regulation and cancer, is a highly sought-after target for small-molecule inhibitors. We report an (R,S)-selective vinylogous Mukaiyama aldol reaction enabled by a squaramide organocatalyst identified through HTE, delivering the product with good diastereoselectivity and excellent enantioselectivity. The reaction was translated to multigram scale and integrated into a convergent synthesis of a potent PRMT5 inhibitor, streamlining access to the active isomer and supporting biological and medicinal-chemistry studies.
A de novo synthesis of the imidazolyl quinolone core of the marine sponge-derived alkaloid ceratinadin B was developed from 1,4-dimethoxybenzene. An acid mediated Friedel-Crafts reaction of a γ-aminobutyric acid derivative provided an aryl ketone which after bromination gave rise to the 2-aminoimidazole via a Hantzsch reaction. Nitration and subsequent reduction delivered the corresponding aniline from which the quinolone was constructed via a Gould-Jacobs reaction. This short and efficient sequence sets the stage for an assault on ceratinadin B.
A photo-induced reductive amination of nitroarenes with aldehydes is achieved using B2(OH)4 and Et3N·BH3 under 360 nm LED irradiation. The metal- and photocatalyst-free protocol affords N-benzylanilines in up to an 88% isolated yield (23 examples) and is scalable to the gram level (82% yield). Mechanistic studies reveal a phenylhydroxylamine pathway.
Thiacalixarenes, a class of sulfur-containing macrocyclic compounds, have attracted considerable attention owing to their unique structural flexibility, conformational diversity, and remarkable molecular recognition abilities in host–guest systems. Herein, we report the successful synthesis of novel trisubstituted thiacalix[4]arene derivatives bearing ester and amide functionalities via selective lower-rim modification of p-tert-butylthiacalix[4]arene derivatives. The synthetic approach involved the preparation of mono-p-tosyl thiacalix[4]arene intermediate, followed by nucleophilic substitution reactions with ester- and amide-containing alkylating agents under appropriate reaction conditions. The target compounds were obtained in good yields and fully characterized by FT-IR, NMR spectroscopy, and elemental analysis. The spectroscopic data confirmed the successful incorporation of the desired functional groups while preserving the thiacalix[4]arene framework and its characteristic conformations, particularly the cone and 1,3-alternate conformers.
The 8-aminoquinoline (AQ) auxiliary occupies a privileged position among bidentate N,N-directing groups in transition metal catalysis, yet the structural basis of its catalytic performance has been rarely examined. Combining a crystallographic survey of free (non-metalated) reaction products with density functional theory (DFT) analysis of model compounds, we show that AQ is conformationally pre-organized and avoids the energetic penalty of reorganization required for binding. In every free-product structure, AQ is locked in a planar, chelation-ready geometry, whereas auxiliaries containing C(sp3)-based spacers—including 2-pyridylmethylamine (PM) and its gem-dimethyl (PIP) and gem-diethyl (PDE) congeners—mostly rest in an anti conformation and must reorganize to bind. This pre-organization is a concrete, measurable structural property that distinguishes AQ from flexible C(sp3)-linked auxiliaries and is a contributing factor that governs which one a shared Pd(II) catalyst preferentially engages under competition, highlighting a design principle for removable bidentate directing groups.
Readily accessible fused pyrrole scaffolds were further functionalized through a two-step sequence. In the first step, Vilsmeier–Haack formylation afforded the corresponding pyrrole aldehydes in good yields. Subsequently, these intermediates underwent annulation with a bromoallyl reagent under microwave irradiation to furnish indolizine derivatives.
This paper explores the synthesis of scaffolds based on pyrrole-fused dibenzoxazepines and dibenzothiazepine derivatives through a multi-step, one-pot, three-component, isocyanide-mediated reaction strategy (3CI-MR). In this protocol, a dibenzoxazepine or dibenzothiazepine imine is reacted with acyl chloride, a dialkyl acetylenedicarboxylate, and an isocyanide, using K2CO3 as a base to synthesize the desired products. The isocyanide enters the reaction at an early stage and emerges at the end as an isocyanate. It functions both as a key intermediate and as the principal driving force of the transformation. In this process, the isocyanide facilitates the formation of an oxazolone-ion intermediate, which subsequently undergoes the hetero-Diels-Alder reaction with dialkyl acetylenedicarboxylate. Elimination of the isocyanate group then affords the pyrrole-fused dibenzothiazepine or dibenzoxazepine products.
A selective aerobic oxidation of cumene and its derivatives to tertiary alcohols under solvent-free conditions based on Mn-based hybrid (BA-Ni2Mg2Mn) catalyst has been reported. The heterogeneous catalytic system exhibits excellent compatibility with a wide range of cumene derivatives, delivering satisfactory conversion and product selectivity. Under the optimized conditions, the aerobic oxidation of cumene reached 78.5% conversion with 64.0% selectivity toward 2-phenyl-2-propanol. The superior catalytic performance of the hybrid relative to its layered double hydroxide precursor (Ni₂Mg₂Mn-LDH) under solvent-free conditions is probably attributed to enhanced surface lipophilicity. Mechanistic investigations confirm that the selective transformation proceeds predominantly via a hydrogen atom transfer (HAT) pathway. The catalyst also shows robust stability and good recyclability.
In this study, we synthesized disaccharide oxazolines 3 and 4 bearing a tetrazine moiety. These compounds are recognized as substrates by Endo-S2 and efficiently undergo one-pot glycan remodeling reactions. Furthermore, combining two orthogonal click chemistry achieved, site-specific dual functionalization into a single antibody.
The facile and efficient synthesis of extended ladder-type benzo[k]tetraphene-derived (BTp) oligomers and polymers without defects has long been a challenge. In this paper, we combine Suzuki coupling and Knoevenagel condensation reactions to prepare BTp-based oligomers and a polymer. In this process, the Suzuki coupling and Knoevenagel condensation proceed sequentially under standard Suzuki coupling conditions. Notably, the Knoevenagel condensation does not occur prior to the Suzuki coupling. To demonstrate the applicability of the domino reaction, a series of ribbon-shaped conjugated oligomers were synthesized and fully characterized by 1H NMR, 13C NMR, and HRMS. The facile reaction process and high yields demonstrate that the domino reaction is an efficient method for synthesizing conjugated ladder-type polymers.
1,2-Disubstituted diazenes are versatile intermediates with applications ranging from materials science to radical-mediated bond construction, yet their synthesis often relies on highly reactive precursors and methods that are largely restricted to symmetrical substitution patterns. Herein, we report the scope and limitations of a practical and modular strategy for the synthesis of 1,2-disubstituted diazenes from readily available amine feedstocks under mild oxidative conditions. Leveraging Sulfur(VI) Fluoride Exchange (SuFEx) click chemistry, a variety of N,N′-disubstituted sulfamides were prepared and used to optimize mild and practical conditions for their oxidation to the corresponding diazenes via the aza-Ramberg–Bäcklund (aza-RB) reaction. Owing to the modularity of SuFEx, this sequence was applied to a large array of sulfamides including unsymmetrical derivatives. Importantly, this method was shown to effectively deliver mixed aryl–alkyl diazenes, an underexplored class of compounds, as well as electron-deficient azo-benzenes. This protocol is readily scalable and tolerant of functional groups, and is applicable to structurally diverse amines. Unlike prior conditions, it does not require the use of an excess of the oxidant. This study also provides insights into the dual role of the base in the aza-RB mechanism, evaluates a one-pot protocol, and investigates the stability of diazenes. Beyond expanding diazene scope, this work aims to provide practical guidelines for their synthesis from amines and subsequent handling.
Acridine derivatives, particularly 9-aminoacridines, are important nitrogen-containing heterocycles with broad pharmaceutical relevance. Herein, we report a metal-free and efficient strategy for the synthesis of 9-aminoacridines via a Kobayashi aryne-enabled annulation of 2-aminobenzonitriles. This transformation proceeds through a formal [4 + 2] annulation pathway, in which 2-aminobenzonitriles act as bifunctional synthons, enabling sequential nucleophilic addition and intramolecular cyclization. The reaction features readily accessible starting materials, operational simplicity, and broad substrate scope, affording a variety of substituted 9-aminoacridines in moderate to good yields. This method provides a straightforward and practical route to the biologically important 9-aminoacridine scaffold and further demonstrates the synthetic utility of aryne chemistry in nitrogen heterocycle construction.
