Abstract Nitrogen-containing polycyclic structures are core motifs in a range of biologically active compounds and organic functional materials, but efficient access to these benzofused skeletons from simple starting materials remains a challenge for synthetic chemists. In this work, we develop a practical intermolecular Diels–Alder reaction between arynes generated in situ from o-diiodoarenes and sodium hydride, and various substituted pyrroles. The transformation proceeds under relatively mild conditions to construct polycyclic N-bridged frameworks efficiently, with broad substrate tolerance for both coupling partners. A gram-scale experiment confirmed the good scalability of this protocol, and the obtained cycloadduct can be readily derivatized to a useful naphthylamine derivative, demonstrating the high synthetic utility of this method.

The search for novel anti-OA agents that combine high efficacy with long-term safety remains a great challenge. Herein, we wish to disclose the distinct combined effect of TCM-derived lipophilic phillygenin and naturally-occurred hydrophilic glucosamine (GlcN) in OA treatment, which enables the subsequent design and syntheis of a series of twin drugs from these two OA therapeutic agents via the formation of glycosidic bond and further derivatization of amine group. Among them, twin drug 6 with an unsubstituted amine group and β-configuration exhibited the nost significant and dose-dependent in vivo anti-OA activity while no apparent toxicity was observed. In particular, it displayed comparable therapeutic efficacy and more favorable safety profiles compared to the clinically-used diacerein (DIA) and functions via multiple cellular mechanisms ranging from osteoclast differentiation inhibition and anti-inflammation/anti-oxidation to cartilage protection. Overall, our findings highlight 6 as a promising candidate for anti-OA drug discovery.

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.

In our previous study, KH was employed as a metal-halogen exchange reagent to generate aryl anions for initiating the anionic Fries rearrangement. Herein, we demonstrate that cost-effective NaH can similarly activate ortho-iodoaryl alpha-ketoamide substrates via Na-I exchange with the aryl iodide moiety. The resultant aryl anions undergo intramolecular cyclization, efficiently affording 3-hydroxy-2-oxindoles or their heterocyclic analogues. Notably, these products can be further converted into other types of nitrogen-containing heterocycles, thereby establishing a platform for constructing diverse biologically important heterocyclic compounds for drug discovery.

​We introduce an effective approach for both intermolecular and intramolecular Diels-Alder reactions between furans and benzyne intermediates generated in situ. By employing o-diiodobenzene as a stable precursor combined with sodium hydride, this method enables the straightforward in situ formation of reactive benzyne species. Key advantages include a straightforward procedure, readily available and economical starting materials, and environmentally sustainable reaction conditions, offering a robust strategy for synthesizing 1,4-dihydro-1,4-epoxynaphthalenes and complex polycyclic frameworks. These products hold promise for broad applicability across various fields.

Based on our previous explorations of o-diiodoarene/NaH as a novel aryne-generation system, herein we present an efficient route for the divergent synthesis of 1,3,5-trisubstituted benzenes. Since carboxylic acid could be converted into a lot of functional groups, in this protocol, the readily available and inexpensive 2,3,5-triiodobenzoic acid (TIBA) was employed as the starting material for the preparation of diverse aryne precursors. With this aryne-generation toolbox, a series of transformations were achieved between various nucleophiles and these aryne precursors, producing 5-iodo-1,3-disubstituted benzenes as valuable intermediates. The subsequent Ullmann reaction then gave hetero-1,3,5-trisubstituted benzenes.

In order to generate an aryl anion, metal-halogen exchanges initiated by alkyllithium, lithium amide, or Grignard reagent are frequently employed. However, carbonyl groups are not compatible with these reagents. Herein, we demonstrate that aryl iodide can undergo direct K-I exchange with KH to produce an aryl anion species. Due to the toleration of this process with ester and ketone groups, it is suitable for the anionic Fries rearrangement reaction of ortho-iodophenyl carboxylates to provide ortho-acylphenol or ortho-acylaniline products, which has long been a great challenge for traditional methods. Moreover, our protocol can be used for cascade reactions to prepare xanthone and acridone. Notably, although K-I exchange is the major reaction pathway of our process, it is accompanied by hydrodehalogenation (Pierre's process) as a side reaction, which has been validated by the identification of phenol in the final reaction mixture.

We present an efficient strategy for constructing polysubstituted naphthalenes through Diels-Alder cycloaddition between cyclopentadienone derivatives and benzynes. Utilizing o-diiodobenzene as a stable benzyne precursor in combination with sodium hydride (NaH) enables facile in situ generation of reactive benzyne intermediate. The method features operational simplicity, use of readily accessible and cost-effective raw materials and tolerance towards diverse functional groups, thereby establishing an environmentally benign platform for synthesizing polycyclic aromatic architectures with potential applications in materials science and pharmaceutical chemistry.

Herein we report a method for the synthesis of thioethers by forging C(aryl)-S bond via an aryne mechanism. The active aryne species can be generated from o-diiodoarenes and NaH in THF at room temperature, then lead to the arylations of a wide range of aryl thiols and thioureas. Different from transition metal-catalyzed cross-coupling reactions, no disubstituted byproduct is formed in our protocol. The o-iodoaryl thioether products are intermediates that could be transformed into pharmaceutically interesting molecules.

A simple and efficient method is described for the synthesis of o-iodoaryl thioethers by the reaction of thiols and aryne. The aryne is generated from inexpensive and readily available reagents o-diiodoarene and sodium hydride. Remarkably, no disulfide substituted byproduct was observed in the reactions which is different from transition metal-catalyzed process. This method features simple operation, mild reaction conditions, broad substrate scope, and high reaction yields for many cases.

An efficient method has been developed for the synthesis of deuterated benzoins from two molecules of aldehydes under the catalysis of N-heterocyclic carbene by using D2O as the deuterium source, providing the products with deuterium selectively incorporated at the alpha-position of ketone group. The method features simple operation and mild reaction conditions, and a variety of aromatic aldehyde substrates could afford products with high deuterium incorporation.

Here, we document the reinvention of aryne chemistry with "old"o-diiodoarenes as aryne progenitors. We have established a NaHmediated activation strategy for the generation of highly reactive aryne species in a controlled manner. The resulting arynes can efficiently participate in a C-C s-bond-insertion reaction with unactivated ketones, which is difficult to achieve by existing methods. Density functional theory (DFT) calculations reveal that the two adjacent iodines in o-diiodoarenes play critical roles in the formation of aryne. The nucleophilic attack of hydride to the electrophilic iodine requires that the adjacent iodine act as a directing group to accelerate this process, whereas mono-substituted iodobenzene lacking the neighboring-group participation makes it difficult. The in -situ formed enolates from ketones are proposed to adopt tetrameric aggregates to react with arynes, which accounts for the high regiochemistry for substrates with bulky substituents.

An efficient and convenient palladium-catalyzed reductive system by employing sodium hydride as the hydrogen donor and acetic anhydride as an activator has been developed for transfer hydrogenation and acetylation of a wide range of N-heteroarenes including quinoline, phthalazine, quinoxaline, phenazine, phenanthridine, and indole. Moreover, acridine substrates could be directly reduced without the use of acetic anhydride. This protocol provides a simple method for the preparation of various saturated N-heterocycles.

A very simple and practical method has been uncovered for N-arylation of many sets of secondary amides/amines. The reaction could be easily conducted in a vial without the use of strictly anhydrous reagents and/or an inert atmosphere. This transition metal-free coupling reaction was based on the use of our previously reported novel aryne generation system: a combination of o-diiodoarene and sodium hydride. In our protocol, sodium hydride acts as an iodophile by forming a neighboring-group-assisted transition state with o-diiodoarene, which greatly enhances the metal-halogen exchange process. o-Diiodoarene has two roles in the reaction: (i) as an aryne precursor to produce an aryne at near room temperature and (ii) as an electrophilic iodine donor to support the generation of the final o-iodoaryl product. The generality of the method is demonstrated by 99 examples containing almost all kinds of amides and amines.

An amine and bis(phenylsulfonyl)methane co-catalyzed hydrogen-deuterium exchange (HDE) method via a Michael-retro-Michael pathway for site-selective introduction of deuterium at the α-position of enals using D2O as a deuterium source has been achieved. The mild, operationally simple protocol allows for high yielding and high level deuterium incorporation (up to 99%) for structurally diverse aromatic-derived enals and dienals.

A simple and efficient protocol was developed for the preparation of challenging α-aryl primary amides. This metal-free coupling process was triggered by TfOH-promoted electrophilic activation of α-silyl nitrile to generate keteniminium ion species, followed by reaction with aryl sulfoxide through [3,3]-sigmatrophic rearrangement to provide the target product. To the best of our knowledge, α-silyl nitrile has been rarely used as a pro-electrophilic reagent. Computational investigations confirmed the transient existence of a highly electrophilic keteniminium intermediate.

For the first time, calcium hydride and palladium chloride were used to reduce a wide range of organic halides including aromatic bromides, aromatic chlorides, aromatic triflates, aliphatic bromides, aliphatic chlorides and trihalomethyl compounds.

Troponoid derivatives incorporating imidazolin-2-one moieties were efficiently constructed via a cascade process, under simple thermal conditions, which features a novel nitrogen source, is catalyst- and oxidant-free, and has high atom- and step-economy.

We have identified a switchable Prins cyclization process to form indoline-fused tetrahydrofurans and indole-fused oxepanes by applying different types of aldehydes under two sets of optimized conditions. Significantly, a novel Prins reaction mechanism involving an oxonium-mediated rearrangement in the formation of five-membered cyclic ethers is realized for the first time.