Yohan Park

Thiazoles are privileged N-heterocyclic scaffolds ubiquitous in FDA-approved drugs, yet their clinical utility can be compromised by oxidative metabolism at the heterobenzylic position. Inspired by the metabolic-blocking strategy used in dabrafenib development, herein we report an iron-catalyzed strategy for direct α-quaternization of (benzo)thiazoles using unactivated alkenes. Under the proposed pathway, alkene-derived carbon-centered radicals undergo regioselective C2 addition and oxidative rearomatization, providing α-quaternary products without heteroarene preactivation or stoichiometric Lewis acids, thereby enabling analogue diversification.

We report an unprecedented, highly general organic photocatalytic strategy for direct C(sp ² )–H amination of arenes using easily accessible saccharin as a nitrogen source. In sharp contrast to conventional radical amination protocols requiring transient arene radical cation intermediates, our system operates via an initial preferential single‐electron transfer (SET) oxidation of the in situ–generated saccharinate anion. This mechanistic pivot successfully bypasses longstanding electronic limitations, enabling an exceptionally broad substrate scope. The protocol tolerates a full spectrum of aromatic systems, including unactivated benzene (using only 2.0 equiv), haloarenes, polycyclic networks, highly electron‐deficient arenes bearing strong electron‐withdrawing groups (ester, nitrile, or trifluoromethyl substituents), and complex pharmaceutical frameworks, delivering the corresponding N ‐aryl saccharins in up to 99% yield (98% for benzene) with predictable regioselectivity. Density functional theory (DFT) calculations quantitatively corroborate the electrophilic radical kinetics (Δ G ^‡ = 2.3–14.4 kcal/mol for arene addition) and TEMPO‐mediated rearomatization cascade. Furthermore, the N ‐aryl saccharin adducts function as robust, programmable modified Gabriel reagents, smoothly delivering diverse primary and secondary aryl amine hydrochloride salts in up to 99% yield under remarkably mild conditions.

We report an unprecedented, highly general organic photocatalytic strategy for direct C(sp ² )–H amination of arenes using easily accessible saccharin as a nitrogen source. In sharp contrast to conventional radical amination protocols requiring transient arene radical cation intermediates, our system operates via an initial preferential single‐electron transfer (SET) oxidation of the in situ–generated saccharinate anion. This mechanistic pivot successfully bypasses longstanding electronic limitations, enabling an exceptionally broad substrate scope. The protocol tolerates a full spectrum of aromatic systems, including unactivated benzene (using only 2.0 equiv), haloarenes, polycyclic networks, highly electron‐deficient arenes bearing strong electron‐withdrawing groups (ester, nitrile, or trifluoromethyl substituents), and complex pharmaceutical frameworks, delivering the corresponding N ‐aryl saccharins in up to 99% yield (98% for benzene) with predictable regioselectivity. Density functional theory (DFT) calculations quantitatively corroborate the electrophilic radical kinetics (Δ G ^‡ = 2.3–14.4 kcal/mol for arene addition) and TEMPO‐mediated rearomatization cascade. Furthermore, the N ‐aryl saccharin adducts function as robust, programmable modified Gabriel reagents, smoothly delivering diverse primary and secondary aryl amine hydrochloride salts in up to 99% yield under remarkably mild conditions.

The replacement of the benzene ring with its bioisosteres is a powerful strategy in drug discovery, yet the development of ortho-disubstituted benzene bioisosteres, particularly fused-ring systems, remains underexplored. Herein, we report an electrooxidative protocol for the synthesis of carborane-fused lactones via C(sp³)-H lactonization. This protocol provides concise access to carborane-fused γ- and δ-lactone frameworks, which closely mimic the geometric features of benzofused lactones, thereby underscoring their potential as bioisosteres of benzofused lactones.

In this study, we present an electrochemical method for forming C(sp³)-N and C(sp³)-O bonds from 2-alkylbenzamides, leading to the synthesis of 3-hydroxyisoindolinones. This reaction demonstrates broad substrate compatibility and can efficiently transform 2-alkylbenzamides with primary and secondary C(sp³)-H bonds by using n-Bu₄NBr under open-air conditions. The proposed methodology provides a straightforward, efficient, and atom-economical route to access diverse 3-hydroxyisoindolinones (28 examples, up to 82% yield).

Herein, we report direct electrochemical C(sp³)-H lactonization of 2-alkylbenzoic acids toward phthalides. The reaction provides a wide substrate scope of 2-alkylbenzoic acids bearing primary to tertiary C(sp³)-H bonds by utilizing a graphite anode, dichloromethane (DCM) solvent, hexafluoroisopropanol (HFIP) cosolvent, and n-Bu₄NClO₄ electrolyte. Our synthetic approach offers a simple, intuitive, and atom-economical protocol to synthesize various phthalides (25 examples, up to 92% yield) and obtain other 5- and 6-membered lactones (10 examples, up to 83% yield).

Herein, we report a regioselective visible-light-induced organophotoredox catalytic difunctionalization method to prepare β-hydroxysulfides using aryl alkenes and aryl thiols as substrates. The reaction provides a wide substrate scope of aryl alkenes (from simple styrene to complex bioactive compounds) and aryl thiols (from diverse heteroaromatic thiols to nonheteroaromatic thiols) (total 45 examples, up to 88% yield). Based on the combined experimental and computational studies, we demonstrate that in situ generated hydroperoxyl radicals from O₂ in air react with benzylic radicals, which restrains the reaction between benzylic radicals and the acidic form of thiols in a classical thiol-ene radical reaction. We show that difunctionalization is possible due to the choice of bases, diluted substrate concentrations, increment in catalyst loading, and selection of suitable aryl thiols under aerobic conditions. Considering the biological importance of heteroaromatic thiols and the lack of methods to install them, our approach offers a platform to derive various β-hydroxysulfides that contain aromatic elements.

Hypoxia‐inducible factor‐1 (HIF‐1) plays an important role in cellular responses to hypoxia, including the transcriptional activation of several genes involved in tumor angiogenesis. Melatonin, also known as N‐acetyl‐5‐methopxytryptamine, is produced naturally by the pineal gland and has anti‐angiogenic effects in cancer through its ability to modulate HIF‐1α activity. However, the use of melatonin as a therapeutic is limited by its low oral bioavailability and short half‐life. Here, we synthesized melatonin‐like molecules with enhanced HIF‐1α targeting activity and less toxicity and investigated their effects on tumor growth and angiogenesis, as well as the underlying molecular mechanisms. Among melatonin derivatives, N‐butyryl‐5‐methoxytryptamine (NB‐5‐MT) showed the most potent HIF‐1α targeting activity. This molecule was able to (a) reduce the expression of HIF‐1α at the protein level, (b) reduce the transcription of HIF‐1α target genes, (c) reduce reactive oxygen species (ROS) generation, (d) decrease angiogenesis in vitro and in vivo, and (e) suppress tumor size and metastasis. In addition, NB‐5‐MT showed improved anti‐angiogenic activity compared with melatonin due to its enhanced cellular uptake. NB‐5‐MT is thus a promising lead for the future development of anticancer compounds with HIF‐1α targeting activity. Given that HIF‐1α is overexpressed in the majority of human cancers, the melatonin derivative NB‐5‐MT could represent a novel potent therapeutic agent for cancer.

A single-step approach is reported for the preparation of nitrones from benzyl halides and nitrosoarenes via pyridinium ylides, utilizing 4-dimethylaminopyridine (DMAP) catalyst and mild reaction conditions (Li₂CO₃, dimethylacetamide, and room temperature). The reaction provides both keto- and aldonitrones in high yields with a wide scope for benzyl halides and nitrosoarenes. In the same reaction system, 2-methyl-2-nitrosopropane, which does not have an aryl group, also affords the corresponding N-tert-butyl nitrones from primary benzyl bromides that have an electron-withdrawing group. As an application of the reaction, methyl 2-bromo-2-phenylacetate was used to prepare the corresponding isoxazolidine by a sequential one-pot synthesis.