One-Pot Synthesis of Chiral 1-Aryl-2-Aminoethanols via Ir-Catalyzed Asymmetric Hydrogenation.

A straightforward synthesis approach to chiral 1-aryl-2-aminoethanols via the one-pot asymmetric hydrogenation catalyzed by Ir catalyst was developed. This tandem process involves the in situ generation of α-amino ketones via the nucleophilic substitution of α-bromoketones with amines and the Ir-catalyzed asymmetric hydrogenation of ketone intermediates to provide diverse enantiomerically enriched ß-amino alcohols. The excellent yields and enantioselectivities (up to 96 % yield and up to >99 % ee) with a wide substrate scope in this one-pot strategy were obtained.

para-Selective, Direct C(sp2)-H Alkylation of Electron-Deficient Arenes by the Electroreduction Process.

Direct para-selective C(sp2)-H alkylation of electron-deficient arenes based on the electroreduction-enabled radical addition of alkyl bromides has been developed under mild conditions. In the absence of any metals and redox agents, the simple electrolysis system tolerates a variety of primary, secondary, and tertiary alkyl bromides and behaves as an important complement to the directed alkylation of the C(sp2)-H bond and the classic Friedel-Crafts alkylation. This electroreduction process provides a more straightforward, environmentally benign, and effective alkylation method for electron-deficient arenes.

Iridium-Catalyzed Asymmetric Hydrogenation of Simple Ketones with Tridentate PNN Ligands Bearing Unsymmetrical Vicinal Diamines.

An iridium catalytic system with a ferrocene-based phosphine ligand bearing a modular and tunable unsymmetrical vicinal diamine scaffold was developed for the asymmetric hydrogenation of aryl ketones. This approach provided a powerful tool for the enantioselective synthesis of diverse chiral alcohols with excellent reactivity and enantioselectivity (up to 99% yield, up to 99% ee, and up to 50,000 turnover number). The substituents and chirality of unsymmetrical diamines in ligands played an important role in the satisfactory results.

Synthesis of Phenols from Aryl Ammonium Salts under Mild Conditions.

A general method for the synthesis of phenols from electron-deficient aryl ammonium salts or heteroaryl ammonium salts under mild conditions was developed. Benzaldehyde oxime, acetohydroxamic acid, and hydroxylamine hydrochloride were investigated as hydroxide surrogates respectively. With these hydroxide surrogates, a series of phenols were prepared in yields of 20-98%.

Synthesis of triarylphosphines from arylammonium salts via one-pot transition-metal-free C-P coupling.

A nucleophilic aromatic substitution (SNAr) reaction that allowed transition-metal-free C-P bond construction via C-N bond cleavage was developed. The coupling between aryltrimethylammonium salts and secondary phosphines from the in situ reduction of diarylphosphine oxides led to the formation of diverse triarylphosphines with various functional groups. This one-pot process was not only a pertinent SNAr precedent but also a favorable transition-metal-free alternative for C-P coupling.

Primary amine catalyzed diastereo- and enantioselective Michael reaction of thiazolones and α,ß-unsaturated ketones.

The chiral primary amine catalyzed asymmetric Michael reaction of thiazolones and α,ß-unsaturated ketones was reported. Two different optimal catalytic systems were obtained corresponding to cyclic and linear α,ß-unsaturated ketones. By employing chiral primary amines as the catalysts and amino-acid derivatives as the additives, a variety of Michael adducts containing the scaffold of the thiazole ring were prepared in moderate to good yields and with excellent diastereo- and enantioselectivities (up to 95% yield, all up to >19/1 dr, up to 96% ee). The reaction was scaled up to obtain 1.73 grams of the Michael adduct with the maintenance of yield and stereoselectivity.

Direct Arylation of α-Amino C(sp3 )-H Bonds by Convergent Paired Electrolysis.

A metal-free convergent paired electrolysis strategy to synthesize benzylic amines through direct arylation of tertiary amines and benzonitrile derivatives at room temperature has been developed. This TEMPO-mediated electrocatalytic reaction makes full use of both anodic oxidation and cathodic reduction without metals or stoichiometric oxidants, thus showing great potential and advantages for practical synthesis. This convergent paired electrolysis method provides a straightforward and powerful means to activate C-H bonds and realize cross-coupling with cathodically generated species.

Electrochemical [4+2] Annulation-Rearrangement-Aromatization of Styrenes: Synthesis of Naphthalene Derivatives.

We report the first electrochemical strategy to synthesize functionalized naphthalene derivatives through [4+2] annulation-rearrangement-aromatization from styrenes under mild conditions. The electrolysis does not require metals, oxidants and high valence substrates, indicating the atom and step-economy ideals. The dehydrodimer produced through [4+2] cycloaddition of 4-methoxy α-methyl styrene is isolated and proved to be the key intermediate for the following oxydehydrogenation to form carbon cation, which undergoes rearrangement-aromatization to afford the final products. This reaction represents a powerful access to construct multi-substituted naphthalene blocks in a single step.

Tuning the Adsorption-Induced Phase Change in the Flexible Metal-Organic Framework Co(bdp).

Metal-organic frameworks that flex to undergo structural phase changes upon gas adsorption are promising materials for gas storage and separations, and achieving synthetic control over the pressure at which these changes occur is crucial to the design of such materials for specific applications. To this end, a new family of materials based on the flexible metal-organic framework Co(bdp) (bdp2- = 1,4-benzenedipyrazolate) has been prepared via the introduction of fluorine, deuterium, and methyl functional groups on the bdp2- ligand, namely, Co(F-bdp), Co(p-F2-bdp), Co(o-F2-bdp), Co(D4-bdp), and Co(p-Me2-bdp). These frameworks are isoreticular to the parent framework and exhibit similar structural flexibility, transitioning from a low-porosity, collapsed phase to high-porosity, expanded phases with increasing gas pressure. Powder X-ray diffraction studies reveal that fluorination of the aryl ring disrupts edge-to-face π-π interactions, which work to stabilize the collapsed phase at low gas pressures, while deuteration preserves these interactions and methylation strengthens them. In agreement with these observations, high-pressure CH4 adsorption isotherms show that the pressure of the CH4-induced framework expansion can be systematically controlled by ligand functionalization, as materials without edge-to-face interactions in the collapsed phase expand at lower CH4 pressures, while frameworks with strengthened edge-to-face interactions expand at higher pressures. Importantly, this work puts forth a general design strategy relevant to many other families of flexible metal-organic frameworks, which will be a powerful tool in optimizing these phase-change materials for industrial applications.

Brønsted acid cocatalysis in photocatalytic intramolecular coupling of tertiary amines: efficient synthesis of 2-arylindols.

We report herein a highly efficient intramolecular coupling reaction of tertiary amines and ketones (α,ß-unsaturated ketones) by using a Brønsted acid as a cocatalyst, affording 2-arylindols in good to excellent yields (up to 92%) under visible light irradiation at room temperature.

γ'-Selective Functionalization of Cyclic Enones: Construction of a Chiral Quaternary Carbon Center by [4+2] Cycloaddition/Retro-Mannich Reaction with 3-Substituted Maleimides.

The first example of organocatalyzed γ'-selective functionalization of cyclic enones with 3-substituted maleimides results in the stereoselective construction quaternary carbon center is presented. The reactions provided γ'-functionalized cyclic enones and ß-functionalized cyclopentenones in good to excellent yields with excellent diastereo- and enantioselectivities. DFT calculations indicated that the reaction might proceed as a [4+2] cycloaddition/retro-Mannich reaction which could explain the unexpected product with a chiral quaternary carbon center and the excellent stereoselectivity.

Remote Construction of Chiral Vicinal Tertiary and Quaternary Centers by Catalytic Asymmetric 1,6-Conjugate Addition of Prochiral Carbon Nucleophiles to Cyclic Dienones.

An unprecedented remote construction of chiral vicinal tertiary and quaternary centers by a catalytic asymmetric 1,6-conjugate addition of prochiral carbon nucleophiles to cyclic dienones has been developed. Both 5H-oxazol-4-ones and 2-oxindoles were found to be very efficient carbon nucleophiles in this reaction at a remote position, giving products with excellent enantio- and diastereoselectivities (up to 99% ee and >19:1 d.r. for 5H-oxazol-4-ones and up to 97% ee and >19:1 d.r. for 2-oxindoles).

Copper-Catalyzed Trifluoromethylazidation of Alkynes: Efficient Access to CF3-Substituted Azirines and Aziridines.

A novel method for convenient access to CF3-containing azirines has been developed, and involves a copper-catalyzed trifluoromethylazidation of alkynes and a photocatalyzed rearrangement. Both terminal and internal alkynes are compatible with the mild reaction conditions, thus delivering the CF3-containing azirines in moderate to good yields. The azirines can be converted into various CF3-substituted aziridines.

Direct Catalytic Asymmetric Doubly Vinylogous Michael Addition of α,ß-Unsaturated γ-Butyrolactams to Dienones.

An asymmetric doubly vinylogous Michael addition (DVMA) of α,ß-unsaturated γ-butyrolactams to sterically congested ß-substituted cyclic dienones with high site-, diastereo-, and enantioselectivity has been achieved. An unprecedented DVMA/vinylogous Michael addition/isomerization cascade reaction affords chiral fused tricyclic γ-lactams with four newly formed stereocenters.

A novel atrial fibrillation automatic detection algorithm based on ensemble learning and multi-feature discrimination.

Atrial fibrillation (AF) is a prevalent cardiac arrhythmia disorder that necessitates long-time electrocardiogram (ECG) data for clinical diagnosis, leading to low detection efficiency. Automatic detection of AF signals within short-time ECG recordings is challenging. To address these issues, this paper proposes a novel algorithm called Ensemble Learning and Multi-Feature Discrimination (ELMD) for the identification and detection of AF signals. Firstly, a robust classifier, BSK-Model, is constructed using ensemble learning. Subsequently, the ECG R-waves are detected, and the ECG signals are segmented into consecutive RR intervals. Time domain, frequency domain, and nonlinear features are extracted from these intervals. Finally, these features are fed into the BSK-Model to discriminate AF. The proposed methodology is evaluated using the MIT-BIH AF database. The results demonstrate that when RR intervals are employed as classification units, the specificity and accuracy of AF detection in long-time ECG data exceed 99%, showcasing a significant improvement over traditional single-model classification. Additionally, the sensitivity and accuracy achieved by testing cardiac segments are both above 96%. With a minimum requirement of only four cardiac segments, AF events can be accurately identified, thereby enabling rapid discrimination of short-time single-lead ECG AF events. Consequently, this approach is suitable for real-time and accurate AF detection using low-computational-power ECG diagnostic analysis devices, such as wearable devices.

Highly diastereo- and enantioselective cross-cascade reactions of different enones.

Cascading ketones! The first highly efficient asymmetric cross-cascade reaction of different α,ß-unsaturated ketones catalyzed by an easily prepared bulky primary amine salt has been developed. It affords the corresponding diverse products containing three to four contiguous stereocenters with excellent enantio- and diastereoselectivities (see scheme).

Direct electrochemical synthesis of quinones from simple aromatics and heteroaromatics.

We developed an electrochemical strategy for the synthesis of quinones through direct oxidation of widely accessible arenes and heteroarenes under mild conditions. A variety of quinones and hetero quinones were prepared with moderate to good yields, without the involvement of the pre-functionalized substrates. In addition, this atom economic method also exhibits wide functional group tolerance, including C(sp2)-I bond, ester, aldehyde, and OTf groups. This synthetic approach provides a straightforward and atom economic method for the transformation of C(sp2)-H bonds.

Rapid Synthesis of α-Chiral Piperidines via a Highly Diastereoselective Continuous Flow Protocol.

A practical continuous flow protocol has been developed using readily accessible N-(tert-butylsulfinyl)-bromoimine and Grignard reagents, providing various functionalized piperidines (34 examples) in superior results (typically >80% yield and with >90:10 dr) within minutes. The high-performance scale-up is smoothly carried out, and efficient synthesis of the drug precursor further showcases its utility. This flow process offers rapid and scalable access to enantioenriched α-substituted piperidines.

Iridium-catalyzed enantioselective synthesis of chiral γ-amino alcohols and intermediates of (S)-duloxetine, (R)-fluoxetine, and (R)-atomoxetine.

Chiral γ-amino alcohols are the prevalent structural motifs and building blocks in pharmaceuticals and bioactive molecules. Enantioselective hydrogenation of ß-amino ketones provides a straightforward and powerful tool for the synthesis of chiral γ-amino alcohols, but the asymmetric transformation is synthetically challenging. Here, a series of tridentate ferrocene-based phosphine ligands bearing modular and tunable unsymmetrical vicinal diamine scaffolds were designed, synthesized, and evaluated in the iridium-catalyzed asymmetric hydrogenation of ß-amino ketones. The system was greatly effective to substrates with flexible structure and functionality, and diverse ß-tertiary-amino ketones and ß-secondary-amino ketones were hydrogenated smoothly. The excellent reactivities and enantioselectivities were achieved in the asymmetric delivery of various chiral γ-amino alcohols with up to 99% yields, >99% ee values, and turnover number (TON) of 48,500. The gram-scale reactions with low catalyst loading showed the potential application in industrial synthesis of chiral drugs, such as (S)-duloxetine, (R)-fluoxetine, and (R)-atomoxetine.

Electricity-driven three-component reductive coupling reaction for the synthesis of diarylmethylamine.

A three-component reductive coupling reaction of aldehydes, amines and cyanopyridines under electrochemical conditions has been developed. The in situ generated imine and cyanopyridine simultaneously undergo single-electron reduction at the cathode, and afford diarylmethylamines through radical coupling without the participation of reducing agents. The one-pot electrolysis method can modularly obtain various secondary and tertiary amines and exhibits broad functional group compatibility. Mechanistic experiments verify the pivotal reduction step from imine to α-amino radical and reveal the key role of benzoic acid in reducing the reduction potential of imine and cyanopyridine.