Unravelling the underlying mechanism of the reduction of aldehydes/ketones with metal borohydride in an aprotic solvent.

The reduction mechanism of aldehyde/ketones with M(BH4)n is not fully understood, even though the hydroboration mechanism of weak Lewis base borane complexes is known to involve a four-membered ring transition state. Herein, the reduction mechanism of M(BH4)n in aprotic solvents has been elucidated for a six-membered ring, in which hydride transfer to the C atom from the B atom, formation of an L·BH3 adduct, and disproportionation of (BH3(OR)-) borane are involved. The metal cations and solvents participate in and significantly influence the reaction procedure. We believe that this mechanistic study would provide a further reference for the application of M(BH4)n in organic reactions.

Facile Friedel-Crafts alkylation of arenes under solvent-free conditions.

The Friedel-Crafts alkylation of arenes is an important part of electrophilic aromatic substitution reactions. However, the reactivity of arenes is weakened by electron-withdrawing substituents, leading to limited substrate scopes and applications. Herein, we developed an efficient HOTf-promoted Friedel-Crafts alkylation reaction of broad arenes with α-aryl-α-diazoesters under metal-free and solvent-free conditions.

9,9'-Bis-o-carboranes: synthesis and exploration of properties.

A highly efficient Pd-catalyzed B(9)-H/B(9)-H oxidative dehydrogenation coupling of carboranes to synthesize 9,9'-bis-o-carboranes has been developed. The properties and derivatization of 9,9'-bis-o-carborane were also examined, which provided diverse bis-o-carborane derivatives and bis-nido-carborane.

Trifluoromethanesulfonic Acid Promoted Controllable Electrophilic Aromatic Nitration.

In this work, we developed a facile and controllable electrophilic aromatic nitration method with commercially available 68% HNO3 as the nitrating reagent and trifluoromethanesulfonic acid (HOTf) as the catalyst in hexafluoroisopropanol or under solvent-free conditions. The electrophilic nitration products of different arenes can be obtained in almost quantitative yields by tuning the loading of HOTf. The strong acidity and water absorbing property of HOTf allowed this transformation to reach completion in a short time at room temperature.

B(9)-OH-o-Carboranes: Synthesis, Mechanism, and Property Exploration.

Herein, we present a chemically robust and efficient synthesis route for B(9)-OH-o-carboranes by the oxidation of o-carboranes with commercially available 68% HNO3 under the assistance of trifluoromethanesulfonic acid (HOTf) and hexafluoroisopropanol (HFIP). The reaction is highly efficient with a wide scope of carboranes, and the selectivity of B(9)/B(8) is up to 98:2. The success of this transformation relies on the strong electrophilicity and oxidizability of HNO3, promoted through hydrogen bonds of the Brønsted acid HOTf and the solvent HFIP. Mechanism studies reveal that the oxidation of o-carborane involves an initial electrophilic attack of HNO3 to the hydrogen atom at the most electronegative B(9) of o-carborane. In this transformation, the hydrogen atom of the B-H bond is the nucleophilic site, which is different from the electrophilic substitution reaction, where the boron atom is the nucleophilic site. Therefore, this is an oxidation-reduction reaction of o-carborane under mild conditions in which N(V) → N(III) and H(-I) → H(I). The derivatization of 9-OH-o-carborane was further examined, and the carboranyl group was successfully introduced to an amino acid, polyethylene glycol, biotin, deoxyuridine, and saccharide. Undoubtedly, this approach provides a selective way for the rapid incorporation of carborane moieties into small molecules for application in boron neutron capture therapy, which requires the targeted delivery of boron-rich groups.

A Method for Highly Selective Halogenation of o-Carboranes and m-Carboranes.

A facile halogenation method for highly selective synthesis of 9-X-o-carboranes, 9,12-X2-o-carboranes, 9-X-12-X'-o-carboranes, 9-X-m-carboranes, 9,10-X2-m-carboranes, and 9-X-10-X'-m-carboranes (X, X' = Cl, Br, I) has been developed on the basis of our previous work. The success of this transformation relies on the usage of trifluoromethanesulfonic acid (HOTf), the easily available strong Brønsted acid. The addition of HOTf greatly increases the electrophilicity of N-haloamides through hydrogen bonding interaction, resulting in the low loading of N-haloamides, short reaction time, and mild reaction conditions. Additionally, the solvent 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) is also essential to further increase the acidity of HOTf.

Palladium-Catalyzed Regioselective B(9)-Amination of o-Carboranes and m-Carboranes in HFIP with Broad Nitrogen Sources.

Amination of carboranes has a good application prospect in organic and pharmaceutical synthesis. However, the current methods used for this transformation suffer from limitations. Herein, we report a practical method for a highly regioselective formation of a B-N bond by Pd(II)-catalyzed B(9)-H amination of o- and m-carboranes in hexafluoroisopropanol (HFIP) with different nitrogen sources under air atmosphere. The silver salt and HFIP solvent play critical roles in the present protocol. The mechanistic study reveals that the silver salt acts as a Lewis acid to promote the electrophilic palladation step by forming a heterobimetallic active catalyst PdAg(OAc)3; the strong hydrogen-bond-donating ability and low nucleophilicity of HFIP enhance the electrophilic ability of Pd(II). It is believed that these N-containing carboranes are potentially of great importance in the synthesis of new pharmaceuticals.

Practical Synthesis of B(9)-Halogenated Carboranes with N-Haloamides in Hexafluoroisopropanol.

The B(9)-H halogenation of o-carborane and m-carborane was achieved with excellent selectivities in hexafluoroisopropanol (HFIP) under simple reaction conditions: single reagent [trichloroisocyanuric acid (TCCA), tribromoisocyanuric acid (TBCA) or N-iodosuccinimide (NIS)], catalyst-free, air-/moisture-tolerant, and convenient work-up. With this method, a variety of 9-halogenated o-carboranes and m-carboranes were obtained in good to excellent yields with broad tolerance of functional groups.

Synthesis of Six-Membered N-Heterocycle Frameworks Based on Intramolecular Metal-Free N-Centered Radical Chemistry.

The formation of intramolecular C-N bond represents a powerful strategy in organic transformation as the great importance of N-heterocycles in the fields of natural products and bioactive molecules. This personal account describes the synthesis of cyclic phosphinamidation, benzosultam, benzosulfoximine, phenanthridine and their halogenated compounds through transition-metal-free intramolecular oxidative C-N bond formation. Mechanism study reveals that N-X bond is initially formed under the effect of hypervalent halogen, which is very unstable and easily undergoes thermal or light homolytic cleavage to generate nitrogen radical. Then the nitrogen radical is trapped by the arene to give aryl radical. Rearomatization of aryl radical under the oxidant to provide corresponding N-heterocycle. Under suitable conditions, the N-heterocycles can be further transformed to halogenated N-heterocycles.

Combined apocyanin and aspirin treatment activates the PI3K/Nrf2/HO-1 signaling pathway and ameliorates preeclampsia symptoms in rats.

OBJECTIVE: Pre-eclampsia (PE) is a pregnancy-associated disease characterized by placental dysfunction and increased oxidative stress. Apocyanin is a potent antioxidant and anti-inflammatory which has shown beneficial effects on PE pathogenesis. Aspirin is recognized as the recommendable drug in PE prevention and therapy. Therefore, we aimed to investigate the effects of combining apocyanin and aspirin to treat PE on rat models induced by N-nitro-L-arginine methyl ester (L-NAME) from gestational day (GD) 6 to 16 and elucidate the potential mechanisms. METHODS: First, female pregnant rats were divided into five different groups: pregnant control, PE, PE + apocyanin, PE + aspirin, and PE + apocyanin + aspirin. Animals received apocyanin (16 mg/kg/day) orally or aspirin by gavage (1.5 mg/kg BM/day) from GD 4 to 16. Blood pressure and urine protein content were monitored every 4 days. RESULTS: In the PE rat model, elevated systolic blood pressure and proteinuria were ameliorated by the combination of apocyanin and aspirin. Meanwhile, compared with single-dose apocyanin or aspirin, the combined treatment significantly corrected abnormal pregnancy outcomes, decreased sFlt-1 and PlGF, and alleviated oxidative stress both in blood and placental tissues. Moreover, the combined treatment upregulated PI3K, Akt, Nrf2, and HO-1 protein levels in the placental tissues from PE rats. CONCLUSION: Overall, our results suggested that combined treatment of apocyanin and aspirin ameliorates the PE symptoms compared with single-dose apocyanin or aspirin in a PE rat model. Also, we demonstrated that activating the PI3K/Nrf2/HO-1 pathway can be a valuable therapeutic target to improve the pregnancy outcomes of PE.

KB3H8: an environment-friendly reagent for the selective reduction of aldehydes and ketones to alcohols.

Selective reduction of aldehydes and ketones to their corresponding alcohols with KB3H8, an air- and moisture-stable, nontoxic, and easy-to-handle reagent, in water and THF has been explored under an air atmosphere for the first time. Control experiments illustrated the good selectivity of KB3H8 over NaBH4 for the reduction of 4-acetylbenzaldehyde and aromatic keto esters.

Efficient synthesis of primary and secondary amides via reacting esters with alkali metal amidoboranes.

Amides are one of the most important organic compounds that are widely applied in medicine, biochemistry, and materials science. To find an efficient synthetic method of amides is a challenge for organic chemistry. We report here a facile synthesis method of primary and secondary amides through a direct amidation of esters with sodium amidoboranes (NaNHRBH3, R = H, Me), at room temperature without using catalysts and other reagents. This process is rapid and chemoselective, and features quantitative conversion and wide applicability for esters tolerating different functional groups. The experimental and theoretical studies reveal a reaction mechanism with nucleophilic addition followed by a swift proton transfer-induced elimination reaction.

Hydroboration Reaction and Mechanism of Carboxylic Acids using NaNH2(BH3)2, a Hydroboration Reagent with Reducing Capability between NaBH4 and LiAlH4.

Hydroboration reactions of carboxylic acids using sodium aminodiboranate (NaNH2[BH3]2, NaADBH) to form primary alcohols were systematically investigated, and the reduction mechanism was elucidated experimentally and computationally. The transfer of hydride ions from B atoms to C atoms, the key step in the mechanism, was theoretically illustrated and supported by experimental results. The intermediates of NH2B2H5, PhCH═CHCOOBH2NH2BH3-, PhCH═CHCH2OBO, and the byproducts of BH4-, NH2BH2, and NH2BH3- were identified and characterized by 11B and 1H NMR. The reducing capacity of NaADBH was found between that of NaBH4 and LiAlH4. We have thus found that NaADBH is a promising reducing agent for hydroboration because of its stability and easy handling. These reactions exhibit excellent yields and good selectivity, therefore providing alternative synthetic approaches for the conversion of carboxylic acids to primary alcohols with a wide range of functional group tolerance.

Synthesis of Phenanthridines through Iodine-Supported Intramolecular C-H Amination and Oxidation under Visible Light.

Herein, we report a metal-free and step-economic synthesis of phenanthridines from 2-biarylmethanamines under mild conditions. The reaction involves iodine-supported intramolecular C-H amination and oxidation of 5,6-dihydrophenanthridine under air and benign visible light. The mechanism study reveals that visible light plays a key role in both these steps.

Synthesis of remote fluoroalkylated alkenes by a palladium-catalyzed relay Heck-type reaction.

Herein, we report a palladium-catalyzed relay Heck-type reaction of fluoroalkyl bromide and terminal alkenes. The reaction involves fluoroalkylation of alkenes and migration of double bonds via a 1,5-hydrogen atom transfer strategy. Through this method, a series of remote fluoroalkylated alkenes was obtained under mild conditions.

Syntheses of Bromo-N-heterocycles through Dibromohydantoin-Promoted Tandem C-H Amination/Bromination.

Herein, we report a metal-free radical tandem C-H amination and bromination reaction with dibromohydantoin (DBH) as both the amination and bromination reagents and water as the main solvent. The reaction involves in intramolecular C-H amination and electrophilic bromination using cheap commercially available DBH. The products represent heterocyclic building blocks, readily modifiable by classical cross-coupling reactions.

Photoredox-Catalyzed Remote Difunctionalizations of Alkenes To Synthesize Fluoroalkyl Ketones with Dimethyl Sulfoxide as the Oxidant.

Visible light-mediated cascade remote oxyfluoroalkylation of alkenes under mild conditions is developed for the first time. The key point of this transformation is the incorporation of alkene fluoroalkylation-initiated remote benzyl C-H bond activation via a 1,5-H shift in a highly controlled site-selective manner and Kornblum reaction with dimethyl sulfoxide as the oxidant. With this method, a broad array of fluoroalkyl groups were introduced into a double bond to produce 1,6-fluoroalkylated ketones at room temperature.

Facial Syntheses of Bromobenzothiazines via Catalyst-Free Tandem C-H Amination/Bromination in Water.

A transition-metal-free and environmentally friendly synthesis method for bromobenzothiazines through tandem C-H amination/bromination was reported. This reaction contains both intramolecular C-H amination and site-selective electrophilic bromination of arenes with NaBr as the bromo source, PhI(OAc)2 or K2S2O8 as the oxidant, and H2O as the only solvent.

One-Pot Synthesis of Iodo-Dibenzothiazines from 2-Biaryl Sulfides.

Herein, we report a metal-free and step-economic synthesis of iodo-dibenzothiazines from 2-biaryl sulfides under mild reaction conditions. The reaction involves sulfoximination of sulfides, intramolecular C-H amination, and iodization using cheap commercially available reagents. The products represent heterocyclic building blocks, readily modifiable by classical cross-coupling reactions.

New Approaches for Biaryl-Based Phosphine Ligand Synthesis via P═O Directed C-H Functionalizations.

Given the important influence of phosphine ligands in transition metal-catalyzed reactions, chemists have searched for straightforward and efficient methodologies for the synthesis of diverse phosphine ligands. Although significant progress has been made in this aspect over the past decades, the development of new phosphorus-containing ligands with properties superior to their predecessors remains a central task for chemists. Recently, researchers have demonstrated that biphenyl monophosphine ligands function as highly efficient ligands for transition-metal-catalyzed organic transformations, especially for reactions where chelating bisphosphine ligands cannot be used. In 1998, Buchwald introduced a new class of air-stable phosphine ligands based on the dialkylbiaryl phosphine backbone. These ligands have been successfully used for a wide variety of palladium-catalyzed carbon-carbon, carbon-nitrogen, and carbon-oxygen construction processes as well as serving as supporting ligands for a number of other reactions. At the same time, the use of the biphenyl monophosphine ligands often allows reactions to proceed with short reaction times and low catalyst loadings and under mild reaction conditions. However, the synthesis of chiral biphenyl monophosphine ligands, especially those the chirality of which is due to biaryl axial chirality, is very limited. In this Account, we summarize our methodologies for the synthesis of this kind of biphenyl monophosphine ligands including the P═O directed C-H functionalization, P═O directed diastereoselective C-H functionalization, P═O directed enantioselective C-H functionalization, and metal-free diastereoselective radical oxidative C-H amination under mild reaction conditions. With these methods, a series of biphenyl phosphine ligand precursors containing achiral or axially chiral centers and precursors possessing both axial chirality and a chirogenic phosphorus center with different electronic properties and steric effect have been obtained under different reaction conditions. For the preparation of chiral biphenyl monophosphine ligands, which not only possess axial chirality but in many cases also possess chirality at phosphorus, the primary means of introducing chirality is through the use of the menthyl phenylphosphinate. As a chiral auxiliary group, the menthyl phenylphosphinate has some unique features: (i) it is easy to prepare; (ii) the products contain both axial chirality and central chirality on the phosphorus atom; (iii) the menthyl group could easily be transformed into other functional groups, which is crucial for the diversity of the corresponding biphenyl ligands. In our reaction, the P═O group not only acts as the directing group but also facilitates the construction of the phosphine ligands. In addition, the application of these products in asymmetric catalysis has also been studied with good results obtained in some reactions. The further application of these ligands, especially the chiral biphenyl monophosphine ligands in catalysis reactions is underway in our laboratory, and we hope different kinds of reactions will be achieved with these ligands.