A multicomponent reaction for modular assembly of indole-fused heterocycles.

Indoles are privileged chemical entities in natural products and drug discovery. Indole-fused heterocycles, particularly seven-membered ones, have received increasing attention due to their distinctive chemical characteristics and wide spectrum of bioactivities. However, the synthetic access to these compounds is highly limited. Herein, we report a unique multicomponent reaction (MCR) for modular assembly of indole-fused seven-membered heterocycles. In this process, indole, formaldehyde and amino hydrochloride could assemble rapidly to yield indole-fused oxadiazepines, and another addition of sodium thiosulphate would furnish indole-fused thiadiazepines. The biological evaluation disclosed the promising anticancer activity of these compounds. Furthermore, this MCR could be applicable in the late-stage and selective modifications of peptides. Therefore, this work provides a powerful strategy for indole functionalization and valuable tool for construction of seven-membered heterocycles.

Site-selective peptide functionalisation mediated via vinyl-triazine linchpins.

Herein we introduce 3-vinyl-1,2,4-triazines derivatives as dual-reactive linkers that exhibit selectivity towards cysteine and specific strained alkynes, enabling conjugate addition and inverse electron-demand Diels-Alder (IEDDA) reactions. This approach facilitates site-selective bioconjugation of biologically relevant peptides, followed by rapid and highly selective reactions with bicyclononyne (BCN) reagents.

Modular assembly of indole alkaloids enabled by multicomponent reaction.

Indole alkaloids are one of the largest alkaloid classes, proving valuable structural moiety in pharmaceuticals. Although methods for the synthesis of indole alkaloids are constantly explored, the direct single-step synthesis of these chemical entities with broad structural diversity remains a formidable challenge. Herein, we report a modular assembly of tetrahydrocarboline type of indole alkaloids from simple building blocks in a single step while showing broad compatibility with medicinally relevant functionality. In this protocol, the 2-alkylated or 3-alkylated indoles, formaldehyde, and amine hydrochlorides could undergo a one-pot reaction to deliver γ-tetrahydrocarbolines or ß-tetrahydrocarbolines directly. A wide scope of these readily available starting materials is applicable in this process, and numerous structural divergent tetrahydrocarbolines could be achieved rapidly. The control reaction and deuterium-labelling reaction are conducted to probe the mechanism. And mechanistically, this multicomponent reaction relies on a multiple alkylamination cascade wherein an unusual C(sp3)-C(sp3) connection was involved in this process. This method could render rapid access to pharmaceutically interesting compounds, greatly enlarge the indole alkaloid library and accelerate the lead compound optimization thus facilitating drug discovery.

Multicomponent Reactions for Expeditious Construction of ß-Indole Carboxamide Amino Amides.

A multicomponent reaction of N-indole carboxylic acids, aldehydes, amines, and C2 building blocks can be transformed to structurally diverse ß-indole carboxamide amino amides. In this multicomponent reaction, the ynamides and triazenyl alkynes act as the C2 building block, and this protocol features readily available starting materials, high atom economy, and mild reaction conditions. Besides, the acyl triazene group in the product can be easily transformed to differential groups to expand the structural diversity.

Thallium release from biochar-amended soil to runoff in laboratory experiments.

Biochar has been widely used for trace metal(loid) (TM) immobilisation in contaminated soils. However, studies on the physicochemical mobility of TMs related to biochar application are highly limited, hampering the evaluation of the immobilisation efficiency of biochar. Therefore, after confirming the ability of biochar to decrease soil Tl bioavailability, this study examined the release of Tl in dissolved and particulate forms in surface runoff and leachate from soil mixed with biochar at different dosages and grain sizes under artificially simulated rainfall and irrigation experiments. The rainfall experimental results showed that the dissolved Tl in the surface runoff decreased from 1.30 µg in the control group to 0.75 µg and 0.54 µg in the groups with 3% and 5% biochar application, respectively. With the same dosages (5%), the finer the biochar applied, the higher the immobilisation ability achieved in surface runoff and the lower the Tl amounts in the leachate, indicating that the grain size of biochar can impact Tl mobility in dissolved forms. Comparisons between rainfall and irrigation experiments indicated that raindrops disturb the soil-water surface and enhance Tl diffusion. The mass in particulate form accounted for more than 95% of lateral released Tl in surface runoff. However, biochar application did not decrease the enrichment ratio of Tl in the eroded sediments. Notably, the finest biochar group produced less mass of eroded Tl owing to the low flux of soil erosion, indicating that grain size would indirectly impact sediment-bound Tl lateral mobility. Colloidal particles should be highlighted as they carried a maximum TI of up to 38% in the rainfall leachate. Focusing on the effect of biochar application on Tl chemical- and physical mobility from the soil matrix to runoff, this study contributes the comprehensive understanding of the role of biochar in TM remediation.

Construction of Axial Chirality via Click Chemistry: Rh-Catalyzed Enantioselective Synthesis of 1-Triazolyl-2-Naphthylamines.

A modular and practical click chemistry for atroposelective synthesis of 1-triazolyl-2-naphthylamines is developed. In this protocol, a variety of aromatic or aliphatic azides, and 1-alkynyl-2-naphthylamines could be assembled into valuable 1-triazlyl-2-naphthylamine scaffolds via a [3 + 2] cycloaddition under Rh-catalysis. This asymmetric click technology features easily accessible starting materials, mild reaction conditions, facile scalability, and good enantioselectivity. The good thermostability of products showcases great applicable potential, and the synthetic transformations further expand the molecular diversity of atropisomers.

Removal of Arsenic from Wastewater by Using Nano Fe3O4/Zinc Organic Frameworks.

Efficient removal of arsenic in wastewater is of fundamental importance due to the increasingly severe arsenic pollution. In this study, a new composite adsorbent (Fe3O4@ZIF-8) for As(V) removal from wastewater was synthesized by encapsulating magnetic Fe3O4 nanoparticles into metal organic frameworks. In order to evaluate the feasibility of Fe3O4@ZIF-8 as an adsorbent for As(V) removal, the adsorption properties of Fe3O4@ZIF-8 were systematically explored by studying the effects of dosage, pH, adsorption isotherm, kinetics, and thermodynamics. Additionally, the characterization of Fe3O4@ZIF-8 before and after adsorption was analyzed thoroughly using various tests including SEM-EDS, XPS, BET, XRD, TG, FTIR, and the properties and arsenic removal mechanism of the Fe3O4@ZIF-8 were further studied. The results showed that the Fe3O4@ZIF-8 has a specific surface area of 316 m2/g and has excellent adsorption performance. At 25 °C, the initial concentration of arsenic was 46.916 mg/L, and pH 3 was the optimum condition for the Fe3O4@ZIF-8 to adsorb arsenic. When the dosage of the Fe3O4@ZIF-8 was 0.60 g/L, the adsorption of arsenic by the Fe3O4@ZIF-8 can reach 76 mg/g, and the removal rate can reach 97.20%. The adsorption process of arsenic to the Fe3O4@ZIF-8 can be well described by the Langmuir isotherm model and the second-order kinetic equation. At pH 3 and temperature 298 K, the maximum adsorption capacity of arsenic by the Fe3O4@ZIF-8 was 116.114 mg/g. Through the analysis of thermodynamic parameters, it is proved that the adsorption process of arsenic by the Fe3O4@ZIF-8 is a spontaneous endothermic reaction. The Fe3O4@ZIF-8 has broad prospects for removing As(V) pollution in wastewater, because of its strong adsorption capacity, good water stability, and easy preparation.

Discovery of triazenyl triazoles as Nav1.1 channel blockers for treatment of epilepsy.

The voltage-gated sodium (Nav) channel is one of most important targets for treatment of epilepsy, and rufinamide is an approved third-generation anti-seizure drug as Nav1.1 channel blocker. Herein, by triazenylation of rufinamide, we reported the triazenyl triazoles as new Nav1.1 channel blocker for treatment of epilepsy. Through the electrophysiological activity assay, compound 6a and 6e were found to modulate the inactivation voltage of Nav 1.1 channel with shift of -10.07 mv and -11.28 mV, respectively. In the pentylenetetrazole (PTZ) mouse model, 6a and 6e reduced the seizure level, prolonged seizure latency and improved the survival rate of epileptic mice at an intragastric administration of 50 mg/kg dosage. In addition, 6a also exhibited promising effectiveness in the maximal electroshock (MES) mouse model and possessed moderate pharmacokinetic profiles. These results demonstrated that 6a was a novel Nav1.1 channel blocker for treatment of epilepsy.

Rhodium-Catalyzed Atroposelective Click Cycloaddition of Azides and Alkynes.

The cycloaddition of azides and alkynes is the leading click chemistry technology and has been widely used in drug discovery, biology and material sciences. However, the development of a modular and scalable enantioselective click cycloaddition remains a long-standing challenge. Herein, we report a rhodium-catalyzed enantioselective click cycloaddition of azides and alkynes for rapid and modular access to atropisomeric triazoles in excellent yields and enantioselectivities. The process is mild, efficient and scalable, and features broad substrate scope.

An Integrated Building Block for Cascade Diels-Alder and Hetero-Diels-Alder Reactions.

The Diels-Alder (DA) reaction and hetero-Diels-Alder (HDA) reaction are among the most powerful methods for the construction of carbocycles and heterocycles. Herein, an integrated building block of DA and HDA reactions is described. The triazenyl dienes could undergo a DA reaction, while the newly released alkene moiety and the triazene were able to engage in a HDA reaction. In these processes, the triazene group could facilitate the electron-demand DA reaction and also act as a fragment of diazadiene.

Multicomponent double Mannich alkylamination involving C(sp2)-H and benzylic C(sp3)-H bonds.

Alkylamines are ubiquitous in pharmaceuticals, materials and agrochemicals. The Mannich reaction is a well-known three-component reaction for preparing alkylamines and has been widely used in academic research and industry. However, the nucleophilic components in this process rely on C(sp2)-H and activated C(sp3)-H bonds while the unactivated C(sp3)-H bonds involved Mannich alkylamination is a long-standing challenge. Here, we report an unprecedented multicomponent double Mannich alkylamination for both C(sp2)-H and unactivated benzylic C(sp3)-H bonds. In this process, various 3-alkylbenzofurans, formaldehyde and alkylamine hydrochlorides assemble efficiently to furnish benzofuran-fused piperidines. Mechanistic studies and density functional theory (DFT) calculations revealed a distinctive pathway that a multiple Mannich reaction and retro-Mannich reaction of benzofuran and dehydrogenation of benzylic C(sp3)-H bonds were key steps to constitute the alkylamination. This protocol furnishes a Mannich alkylamine synthesis from unusual C-H inputs to access benzofuran-fused piperidines with exceptional structural diversity, molecular complexity and drug-likeness. Therefore, this work opens a distinctive vision for the alkylamination of unactivated C(sp3)-H bonds, and provides a powerful tool in diversity-oriented synthesis (DOS) and drug discovery.

Facile Synthesis of γ-Butenolides and Maleic Anhydrides via Annulation of α-Keto Acids and Triazenyl Alkynes.

A facile synthesis of γ-butenolides and maleic anhydrides via annulation of α-keto acids and triazenyl alkynes is described. In this process, α-keto acids and triazenyl alkynes could undergo a self-catalyzed annulation at room temperature to deliver γ-butenolides efficiently, while the further addition of BF3-Et2O furnished maleic anhydrides. Overall, these processes have mild reaction conditions, broad scope, and high efficiency.

Photo-induced synthesis of ß-sulfonyl imides from carboxylic acids.

A photo-induced imidation process of carboxylic acids is described. Numerous carboxylic acids could convert to ß-sulfonyl imides in the presence of N-sulfonyl ynamides under visible light irradiation. Control experiments and mechanistic studies demonstrate that this imidation process involves a hydroacyloxylation/radical rearrangement cascade. This protocol represents a direct imidation method from carboxylic acids under mild conditions, with broad scope and high atom-economy.

An Efficient Regioselective Synthesis of 8-Formylhomoisoflavonoids with Neuroprotective Activity by Enhancing Autophagy.

6-Formylisoophiopogonone B (7a) and 8-formylophiopogonone B (7b), two natural products isolated from Ophiopogon japonicus, represent a subgroup of rare 6/8-formyl/methyl-homoisoflavonoid skeletons. Herein we report an efficient method for the synthesis of these formyl/methyl-homoisoflavonoids. The synthesized compounds were evaluated for their neuroprotective effects on the MPP+-induced SH-SY5Y cell injury model and showed marked activity. Exploration of the neuroprotective mechanisms of compound 7b led to an increased expression of autophagy marker LC3-II and down-regulation of autophagy substrate p62/SQSTM1. Molecular docking studies showed that 7b may prevent the inhibition of the classic PI3K-AKT-mTOR signaling pathway by interfering with the human HSP90AA1.

Skeletal reorganization divergence of N-sulfonyl ynamides.

Skeletal reorganization is a type of intriguing processes because of their interesting mechanism, high atom-economy and synthetic versatility. Herein, we describe an unusual, divergent skeletal reorganization of N-sulfonyl ynamides. Upon treatment with lithium diisopropylamine (LDA), N-sulfonyl ynamides undergo a skeletal reorganization to deliver thiete sulfones, while the additional use of 1,3-dimethyl-tetrahydropyrimidin-2(1H)-one (DMPU) shifts the process to furnish propargyl sulfonamides. This skeletal reorganization divergence features broad substrate scope and scalability. Mechanistically, experimental and computational studies reveal that these processes may initiate from a lithiation/4-exo-dig cyclization cascade, and the following ligand-dependent 1,3-sulfonyl migration or ß-elimination would control the chemodivergence. This protocol additionally provides a facile access to a variety of privileged molecules from easily accessible ynamides.

Directing-Group-Enabled Cycloaddition of Azides and Alkynes toward Functionalized Triazoles.

Herein, we report a directing-group-enabled Huisgen cycloaddition of azides and alkynes for the synthesis of functionalized triazoles in which the triazene group could act as a directing group to enable this regioselective [3 + 2] cycloaddition and further replacement by diverse groups, including amino, amide, halogen, and heterocycle substituents. This method represents a general and practical synthesis of triazoles under mild reaction conditions and broad substrate scope.

Indole-N-Carboxylic Acids and Indole-N-Carboxamides in Organic Synthesis.

Indoles are ubiquitous structures that are found in natural products and biologically active molecules. The synthesis of indoles and indole-involved synthetic methodologies in organic chemistry have been receiving considerable attention. Indole-N-carboxylic acids and derived indole-N-carboxamides are intriguing compounds, which have been widely used in organic synthesis, especially in multicomponent reactions and C-H functionalization of indoles. This Minireview summarizes the advances of reactions involving indole-N-carboxylic acids and indole-N-carboxamides in organic chemistry, and discusses the synthetic potential and perspective of this field.

Iridium(i)-catalyzed hydration/esterification of 2-alkynylphenols and carboxylic acids.

An iridium(i)-catalyzed hydration/esterification of 2-alkynylphenols and carboxylic acids is described. Various 2-alkynylphenols and carboxylic acids could be used in this process to furnish aromatic ortho-acyloxyketones via a regio- and stereo-selective addition reaction followed by intramolecular rearrangement. This protocol features mild reaction conditions and broad substrate scope. Further transformations were conducted to demonstrate the synthetic application.

One-Pot Reaction of Carboxylic Acids, Ynol Ethers, and m-CPBA for Synthesis of α-Carbonyloxy Esters.

A novel one-pot reaction of carboxylic acids, ynol ethers, and m-CPBA for the synthesis of α-carbonyloxy esters in the presence of Ag2O is described. This process provides a direct approach to α-carbonyloxy esters with the achievement of formation of three C-O bonds. The protocol is featured with readily available starting materials and broad substrate scope. Control reactions and isotope-labeling reactions were conducted to elucidate a plausible mechanism.