Hydroxylamine-Mediated C(sp2)-H Trifluoromethylation of Terminal Alkenes.

Introduction of the trifluoromethyl (CF3) group into organic compounds has garnered substantial interest because of its significant role in pharmaceuticals and agrochemicals. Here, we report a hydroxylamine-mediated radical process for C(sp2)-H trifluoromethylation of terminal alkenes. The reaction shows good reactivity, impressive E/Z selectivity (up to >20 : 1), and broad functional group compatibility. Expansion of this approach to perfluoroalkylation and late-stage trifluoromethylation of bioactive molecules demonstrates its promising application potential. Mechanistic studies suggest that the reaction follows a radical addition and subsequent elimination pathway.

Phosphonium-Catalyzed Monoreduction of Bisphosphine Dioxides: Origin of Selectivity and Synthetic Applications.

Controlling product selectivity in successive reactions of the same type is challenging owing to the comparable thermodynamic and kinetic properties of the reactions involved. Here, the synergistic interaction of the two phosphoryl groups in bisphosphine dioxides (BPDOs) with a bromo-phosphonium cation was studied experimentally to provide a practical tool for substrate-catalyst recognition. As the eventual result, we have developed a phosphonium-catalyzed monoreduction of chiral BPDOs to access an array of synthetically useful bisphosphine monoxides (BPMOs) with axial, spiro, and planar chirality, which are otherwise challenging to synthesize before. The reaction features excellent selectivity and impressive reactivity. It proceeds under mild conditions, avoiding the use of superstoichiometric amounts of additives and metal catalysts to simplify the synthetic procedure. The accessibility and scalability of the reaction allowed for the rapid construction of a ligand library for optimization of asymmetric Heck-type cyclization, laying the foundation for a broad range of applications of chiral BPMOs in catalysis.

Deoxygenation of Phosphine Oxides by PIII/PV═O Redox Catalysis via Successive Isodesmic Reactions.

Deoxygenation of phosphine oxides is of great significance to synthesis of phosphorus ligands and relevant catalysts, as well as to the sustainability of phosphorus chemistry. However, the thermodynamic inertness of P═O bonds poses a severe challenge to their reduction. Previous approaches in this regard rely primarily on a type of P═O bond activation with either Lewis/Brønsted acids or stoichiometric halogenating reagents under harsh conditions. Here, we wish to report a novel catalytic strategy for facile and efficient deoxygenation of phosphine oxides via successive isodesmic reactions, whose thermodynamic driving force for breaking the strong P═O bond was compensated by a synchronous formation of another P═O bond. The reaction was enabled by PIII/P═O redox sequences with the cyclic organophosphorus catalyst and terminal reductant PhSiH3. This catalytic reaction avoids the use of the stoichiometric activator as in other cases and features a broad substrate scope, excellent reactivities, and mild reaction conditions. Preliminary thermodynamic and mechanistic investigations disclosed a dual synergistic role of the catalyst.

Prediction of Nucleophilicity and Electrophilicity Based on a Machine-Learning Approach.

Nucleophilicity and electrophilicity dictate the reactivity of polar organic reactions. In the past decades, Mayr et al. established a quantitative scale for nucleophilicity (N) and electrophilicity (E), which proved to be a useful tool for the rationalization of chemical reactivity. In this study, a holistic prediction model was developed through a machine-learning approach. rSPOC, an ensemble molecular representation with structural, physicochemical and solvent features, was developed for this purpose. With 1115 nucleophiles, 285 electrophiles, and 22 solvents, the dataset is currently the largest one for reactivity prediction. The rSPOC model trained with the Extra Trees algorithm showed high accuracy in predicting Mayr's N and E parameters with R2 of 0.92 and 0.93, MAE of 1.45 and 1.45, respectively. Furthermore, the practical applications of the model, for instance, nucleophilicity prediction of NADH, NADPH and a series of enamines showed potential in predicting molecules with unknown reactivity within seconds. An online prediction platform (http://isyn.luoszgroup.com/) was constructed based on the current model, which is available free to the scientific community.

Revisiting the Electrochemistry of TEMPOH Analogues in Acetonitrile.

Hydroxylamines, represented by 1-hydroxy-2,2,6,6-tetramethylpiperidine (TEMPOH), are widely involved as active species in various chemical and electrochemical oxidations. The electrochemical behavior of TEMPOH is crucial to understanding the mechanisms of TEMPO-mediated redox sequences. However, compared to abundant studies on TEMPOH electrochemistry in aqueous solutions, the sole value of its oxidation potential Eox(TEMPOH) in organic solutions was reported to be 0.7 V (vs Fc in acetonitrile), seemingly conflicting with experimentally observed facile oxidation of TEMPOH. Herein, the electrochemistry of TEMPOH derivatives in acetonitrile was revisited, featuring much smaller oxidation potentials (about 0 V) than literature ones. Acid/base effects and kinetic studies lent credibility to these new values. Such a 0.7 V energy discrepancy impelled us to review the thermodynamic properties and oxidation mechanisms of TEMPOH deduced from the old value.

Catalytic Vilsmeier-Haack Reactions for C1-Deuterated Formylation of Indoles.

The Vilsmeier-Haack reaction is a powerful tool to introduce formyl groups into electron-rich arenes, but its wide application is significantly restricted by stoichiometric employment of caustic POCl3. Herein, we reported a catalytic version of the Vilsmeier-Haack reaction enabled by a P(III)/P(V)═O cycle. This catalytic reaction provides a facile and efficient route for the direct construction of C1-deuterated indol-3-carboxaldehyde under mild conditions with stoichiometric DMF-d7 as the deuterium source. The products feature a remarkably higher deuteration level (>99%) than previously reported ones and are not contaminated by the likely unselective deuteration at other sites. The present transformation can also be used to transfer other carbonyl groups. Further downstream derivatizations of these deuterated products manifested their potential applications in the synthesis of deuterated bioactive molecules. Mechanistic insight was disclosed from studies of kinetics and intermediates.

Synthetic applications of NHPs: from the hydride pathway to a radical mechanism.

The unique heterocyclic skeletons of N-heterocyclic phosphines (NHPs) endow them with excellent hydridic reactivity, which has enabled NHPs to be applied in a great array of catalytic hydrogenations of unsaturated substrates in the past few decades. Recently, applications of NHPs in radical reductions, especially in a catalytic fashion, have emerged as a promising forefront area. This new reaction pattern, distinctive from but complementary to the well-established hydride pathway, can greatly expand the reaction scope to σ-bond scission. Herein, we briefly summarized some representative examples of synthetic applications of NHPs in both hydridic and radical reductions with an emphasis on their radical reactivity, including the structural and property studies of NHP radicals and their precursors as well as their applications in radical processes.

Diazaphospholene-Catalyzed Hydrodefluorination of Polyfluoroarenes with Phenylsilane via Concerted Nucleophilic Aromatic Substitution.

The metal-free catalytic C-F bond activation of polyfluoroarenes was achieved with diazaphospholene as the catalyst and phenylsilane as the terminal reductant. Density functional theory calculations suggested a concerted nucleophilic aromatic substitution mechanism.

Kinetic Resolution of Sulfinamides via Asymmetric N-Allylic Alkylation.

An efficient kinetic resolution of sulfinamides via an asymmetric N-allylic alkylation reaction was realized using hydroquinine as a catalyst under mild conditions. The kinetic resolution of a range of Morita-Baylis-Hillman adducts and N-aryl tert-butylsulfinamides was highly effective. In addition, the synthetic utility of the protocol was demonstrated by a scaled-up reaction. Density functional theory calculations provide convincing evidence for the interpretation of stereoselection.

Recent progress in reactivity study and synthetic application of N-heterocyclic phosphorus hydrides.

N-heterocyclic phosphines (NHPs) have recently emerged as a new group of promising catalysts for metal-free reductions, owing to their unique hydridic reactivity. The excellent hydricity of NHPs, which rivals or even exceeds those of many metal-based hydrides, is the result of hyperconjugative interactions between the lone-pair electrons on N atoms and the adjacent σ*(P-H) orbital. Compared with the conventional protic reactivity of phosphines, this umpolung P-H reactivity leads to hydridic selectivity in NHP-mediated reductions. This reactivity has therefore found many applications in the catalytic reduction of polar unsaturated bonds and in the hydroboration of pyridines. This review summarizes recent progress in studies of the reactivity and synthetic applications of these phosphorus-based hydrides, with the aim of providing practical information to enable exploitation of their synthetically useful chemistry.

Access to P-stereogenic compounds via desymmetrizing enantioselective bromination.

A novel and efficient desymmetrizing asymmetric ortho-selective mono-bromination of bisphenol phosphine oxides under chiral squaramide catalysis was reported. Using this asymmetric ortho-bromination strategy, a wide range of chiral bisphenol phosphine oxides and bisphenol phosphinates were obtained with good to excellent yields (up to 92%) and enantioselectivities (up to 98.5 : 1.5 e.r.). The reaction could be scaled up, and the synthetic utility of the desired P-stereogenic compounds was proved by transformations and application in an asymmetric reaction.

Access to Axially and Centrally Chiral Sulfinamides via Asymmetric Allylic Alkylation.

Herein, access to axially and centrally chiral sulfinamides via asymmetric allylic alkylation was reported. A series of sulfinamides were obtained with good outcomes (up to 99% yield, >19:1 dr, and 98:2 er). The synthetic utility of the reaction was demonstrated by scaled-up synthesis, product transformation, and application as a catalyst in asymmetric catalysis.

Catalytic Asymmetric Aza-Diels-Alder Reaction of Ketimines and Unactivated Dienes.

The enantioselective aza-Diels-Alder reaction is efficient for constructing chiral tetrahydropyridines, but the catalytic asymmetric aza-Diels-Alder reaction of ketimines with unactivated dienes is still a challenging topic. Herein, guided by computational screening, a highly enantioselective aza-Diels-Alder reaction of 2-aryl-3H-indol-3-ones with unactivated dienes was realized by using a B(C6 F5 )3 /chiral phosphoric acid catalyst system under mild conditions. The reaction has a broad scope with respect to both aza-Diels-Alder reaction partners and hence offers rapid access to an array of tetrahydropyridine derivatives with pretty outcomes (up to 99 % yield, >20:1 dr and 98:2 er). The reaction is very efficient: lowering catalyst loadings for the model reaction to 0.1 mol %, enantioselectivity is still maintained. The synthetic utility was confirmed by transformations of the products. DFT calculations provide convincing evidence for the interpretation of stereoselection.

Chemoselective catalytic hydrodefluorination of trifluoromethylalkenes towards mono-/gem-di-fluoroalkenes under metal-free conditions.

Fluorine-containing moieties show significant effects in improving the properties of functional molecules. Consequently, efficient methods for installing them into target compounds are in great demand, especially those enabled by metal-free catalysis. Here we show a diazaphospholene-catalyzed hydrodefluorination of trifluoromethylalkenes to chemoselectively construct gem-difluoroalkenes and terminal monofluoroalkenes by simple adjustment of the reactant stoichiometry. This metal-free hydrodefluorination features mild reaction conditions, good group compatibility, and almost quantitative yields for both product types. Stoichiometric experiments indicated a stepwise mechanism: hydridic addition to fluoroalkenes and subsequent ß-F elimination from hydrophosphination intermediates. Density functional theory calculations disclosed the origin of chemoselectivity, regioselectivity and stereoselectivity, suggesting an electron-donating effect of the alkene-terminal fluorine atom.

The Acidities of Nucleophilic Monofluoromethylation Reagents: An Anomalous α-Fluorine Effect.

Fluorine incorporation into organic molecules is expected to lower the pKa of neighboring functionality via its strong electron-withdrawing effect, and this strategy has been widely exploited in diverse disciplines. Herein, we report a striking anomalous α-fluorine substitution effect on the α-Csp3 -H acidity. We have experimentally measured the pKa values of a series of popular nucleophilic monofluoromethylating reagents α-fluoro(phenylsulfonyl)methane derivatives as well as their C-H analogues by Bordwell's overlapping indicator method in dimethyl sulfoxide solution. Contrary to expectations, we found that α-fluorine substituent does not generally enhance but rather weaken the α-Csp3 -H acidity of most (phenylsulfonyl)methane derivatives. DFT computations reproduce and provide insight into the anomalous α-fluorine effect. A correlation was identified between the C-H pKa of (phenylsulfonyl)methane derivatives and Mayr's nucleophilicity parameter (N) of the corresponding carbanions.

Brönsted Basicities and Nucleophilicities of N-Heterocyclic Olefins in Solution: N-Heterocyclic Carbene versus N-Heterocyclic Olefin. Which Is More Basic, and Which Is More Nucleophilic?

A Brönsted basicity scale comprising nine representative N-heterocyclic olefins (NHOs) was established by measuring the equilibrium acidities of their corresponding precursors in DMSO using an ultraviolet-visible spectroscopic method. The basicities (pKaHs) of the investigated NHOs cover a range from 14.7 to 24.1. The basicities of unsaturated NHOs are stronger than those of their N-heterocyclic carbene (NHC) analogues; however, the basicities for the saturated ones are much weaker than those of their NHC analogues, which is largely due to the aromatization effect that intrinsically influences the acidic dissociations of NHC and NHO precursors. The nucleophilicities of four NHOs were measured photometrically by monitoring the kinetics of reactions of these NHOs with common reference electrophiles for quantifying nucleophilic reactivities. In general, the nucleophilicity of the NHOs is much stronger than that of commonly used Lewis bases such as Ph3P or DMAP [4-(dimethylamino)pyridine] but weaker than that of their NHC analogues; however, caution should be taken when generalizing this conclusion to a wide range of electrophiles with distinctively electronic and structural properties.

Correction: Enantioselective and regioselective aza-Friedel-Crafts reaction of electron-rich phenols with isatin-derived ketimines.

Correction for 'Enantioselective and regioselective aza-Friedel-Crafts reaction of electron-rich phenols with isatin-derived ketimines' by Liu Cai et al., Chem. Commun., 2020, 56, 10361-10364, DOI: 10.1039/D0CC04966B.

Bonding Energetics of Palladium Amido/Aryloxide Complexes in DMSO: Implications for Palladium-Mediated Aniline Activation.

Thermodynamic knowledge of the metal-ligand (M-L) σ-bond strength is crucial to understanding metal-mediated transformations. Here, we developed a method for determining the Pd-X (X=OR and NHAr) bond heterolysis energies (ΔGhet (Pd-X)) in DMSO taking [(tmeda)PdArX] (tmeda=N,N,N',N'-tetramethylethylenediamine) as the model complexes. The ΔGhet (Pd-X) scales span a range of 2.6-9.0 kcal mol-1 for ΔGhet (Pd-O) values and of 14.5-19.5 kcal mol-1 for ΔGhet (Pd-N) values, respectively, implying a facile heterolytic detachment of the Pd ligands. Structure-reactivity analyses of a modeling Pd-mediated X-H bond activation reveal that the M-X bond metathesis is dominated by differences of the X-H and Pd-X bond strengths, the former being more influential. The ΔGhet (Pd-X) and pKa (X-H) parameters enable regulation of reaction thermodynamics and chemoselectivity and diagnosing the probability of aniline activation with Pd-X complexes.

miR-4295 promotes cell proliferation, migration and invasion of osteosarcoma through targeting interferon regulatory factor 1.

Osteosarcoma (OS) is the most common form of primary malignant bone tumor. Despite encouraging progress in the treatment of OS, the survival rate for patients with OS has remained unchanged over the past 40 years. It has been established that miRNA plays a crucial regulatory role in the progression and development of OS. To explore the potential association of miRNAs with OS, bioinformatics techniques were used to screen for differentially expressed miRNA genes in OS in the Gene Expression Omnibus database. In the GSE70367 database, it was revealed that miR-4295 expression was abnormally elevated in the expression of OS cells. To characterize the potential function of miR-4295 in OS, the expression levels of miR-4295 in 30 samples of OS and adjacent normal tissues was examined. The results revealed that the expression of miR-4295 was significantly increased in OS tissues compared with the paired normal tissues. Moreover, the expression levels of miR-4295 in OS cell lines (MG-63 and Saos-2) were significantly higher compared with those in the normal human mesenchymal stem cells. In addition, miR-4295 was associated with OS cell proliferation, migration and invasion. Furthermore, it was demonstrated that the expression of interferon regulatory factor (IRF)1, a tumor suppressor, was regulated by miR-4295 directly in OS cells. Taken together, the present results revealed that miR-4295 may act as a tumor activator by targeting IRF1 during the progression of OS. Investigating miR-4295 may provide novel insight into the mechanisms of OS metastasis, and inhibition and targeting miR-4295 may be a novel therapeutic strategy for the treatment of OS.

Bi(OAc)3/chiral phosphoric acid catalyzed enantioselective allylation of seven-membered cyclic imines, dibenzo[b,f][1,4]oxazepines.

An efficient asymmetric allylation reaction of allylboronates with seven-membered cyclic imines, dibenzo[b,f][1,4]oxazepines, is described. The reaction, which is catalyzed by a Bi(OAc)3/CPA system, gives a range of chiral nitrogen-containing heterocycle structures in high yields and with good enantioselectivities. The conversion of these products to nitrogen-containing heterocycles is also demonstrated.