Electrocatalytic Hydrogenation of Pyridines and Other Nitrogen-Containing Aromatic Compounds.

The production of cyclic amines, which are vital to the pharmaceutical industry, relies on energy-intensive thermochemical hydrogenation. Herein, we demonstrate the electrocatalytic hydrogenation of nitrogen-containing aromatic compounds, specifically pyridine, at ambient temperature and pressure via a membrane electrode assembly with an anion-exchange membrane. We synthesized piperidine using a carbon-supported rhodium catalyst, achieving a current density of 25 mA cm and a current efficiency of 99% under a circular flow until 5 F mol.

Electrocatalytic hydrogenation of cyanoarenes, nitroarenes, quinolines, and pyridines under mild conditions with a proton-exchange membrane reactor.

An electrocatalytic hydrogenation of cyanoarenes, nitroarenes, quinolines, and pyridines using a proton-exchange membrane (PEM) reactor was developed. Cyanoarenes were then reduced to the corresponding benzylamines at room temperature in the presence of ethyl phosphate. The reduction of nitroarenes proceeded at room temperature, and a variety of anilines were obtained.

α-Functionalisation of Cyclic Sulfides Enabled by Lithiation Trapping.

A general and straightforward procedure for the lithiation trapping of cyclic sulfides such as tetrahydrothiophene, tetrahydrothiopyran and a thiomorpholine is described. Trapping with a wide range of electrophiles is demonstrated, leading to more than 50 diverse α-substituted saturated sulfur heterocycles. The methodology provides access to a range of α-substituted cyclic sulfides that are not easily synthesised by the currently available methods.

Exploration of piperidine 3D fragment chemical space: synthesis and 3D shape analysis of fragments derived from 20 regio- and diastereoisomers of methyl substituted pipecolinates.

Fragment-based drug discovery is now widely adopted for lead generation in the pharmaceutical industry. However, fragment screening collections are often predominantly populated with flat, 2D molecules. Herein, we report the synthesis of piperidine-based 3D fragment building blocks - 20 regio- and diastereoisomers of methyl substituted pipecolinates using simple and general synthetic methods.

Periodic cycles of seizure clustering and suppression in children with epilepsy strongly suggest focal cortical dysplasia.

Aim: We investigated characteristic seizure patterns in epilepsy caused by focal cortical dysplasia (FCD), which differ from epilepsy by other aetiologies in surgical cases with lesions on magnetic resonance imaging (MRI), then examined if these features were applicable to patients with epilepsy without any lesions on MRI.

Method: We retrospectively studied clinicopathological features in 291 (143 females) children with epilepsy who had undergone resective surgery after comprehensive evaluation, including 277 cases with lesions on MRI (136 females, age at resection 0-17 years [mean 6 years 10 months, SD 5 years 7 months]) and 14 cases without any lesions on MRI (seven females, age 0-16 years [mean 7 years 8 months, SD 4 years 8 months]).

Results: Among 277 patients with lesions on MRI, 87 cases exhibited recurrent periodic cycles of seizure clustering (≥5 seizures/day for ≥1 week) and suppression (no seizures for ≥1 week); of these, 80 cases (92%) were pathologically diagnosed with FCD.

Synthesis of piperidine and pyrrolidine derivatives by electroreductive cyclization of imine with terminal dihaloalkanes in a flow microreactor.

We have successfully synthesized piperidine and pyrrolidine derivatives by electroreductive cyclization using readily available imine and terminal dihaloalkanes in a flow microreactor. Reduction of the substrate imine on the cathode proceeded efficiently due to the large specific surface area of the microreactor. This method provided target compounds in good yields compared to a conventional batch-type reaction.

Bayesian optimization with constraint on passed charge for multiparameter screening of electrochemical reductive carboxylation in a flow microreactor.

Multiparameter screening of reductive carboxylation in an electrochemical flow microreactor was performed using a Bayesian optimization (BO) strategy. The developed algorithm features a constraint on passed charge for the electrochemical reaction, which led to suitable conditions being instantaneously found for the desired reaction. Analysis of the BO-suggested conditions underscored the physicochemical validity.

Triple-Phase Boundary in Anion-Exchange Membrane Reactor Enables Selective Electrosynthesis of Aldehyde from Primary Alcohol.

Invited for this month's cover is the group of Prof. Mahito Atobe at Yokohama National University, Japan. The image shows an anion-exchange membrane (AEM) reactor enabling selective oxidation of a primary alcohol to a corresponding aldehyde by the electrochemical reaction at the triple-phase boundary.

Triple-phase Boundary in Anion-Exchange Membrane Reactor Enables Selective Electrosynthesis of Aldehyde from Primary Alcohol.

Oxidation of primary alcohol to the corresponding aldehyde remains a significant challenge, even with the state-of-the-art chemistry. Here, a novel electrochemical system was developed for the exclusive production of aldehyde from primary alcohol using an anion-exchange membrane (AEM) reactor. Oxidation proceeded on a gold catalyst under basic conditions, which largely enhanced the reaction rate.

Electrocatalytic hydrogenation of benzoic acids in a proton-exchange membrane reactor.

The highly efficient chemoselective electrocatalytic hydrogenation of benzoic acids (BAs) to cyclohexanecarboxylic acids (CCAs) was carried out in a proton-exchange membrane reactor under mild conditions without hydrogenation of the carboxyl group. Among the investigated catalysts, the PtRu alloy catalyst was found to be the most suitable for achieving high current efficiencies for production of CCAs. An electrochemical spillover mechanism on the PtRu alloy catalyst was also proposed.

Integrated Flow Synthesis of α-Amino Acids by Generation of Aldimines and Subsequent Electrochemical Carboxylation.

The synthesis of α-amino acids was carried out in a continuous flow system. In this system, aldimines were efficiently generated via the dehydration-condensation of aldehydes with anilines in a desiccant bed column filled with 4 Å molecular sieves desiccant, followed by reaction with CO in an electrochemical flow microreactor to afford the α-amino acids in high to moderate yields. The present system can provide α-amino acids without using stoichiometric amounts of metal reagents or highly toxic cyanide reagents.

Electrosynthesis in Laminar Flow Using a Flow Microreactor.

Electrosynthesis and microflow synthesis have become essential tools in their own rights in modern organic synthesis. In this personal account, we summarize our works on the integrated use of these techniques, i. e.

Discovery of 4,6- and 5,7-Disubstituted Isoquinoline Derivatives as a Novel Class of Protein Kinase C ζ Inhibitors with Fragment-Merging Strategy.

Two chemical series of novel protein kinase C ζ (PKCζ) inhibitors, 4,6-disubstituted and 5,7-disubstituted isoquinolines, were rapidly identified using our fragment merging strategy. This methodology involves biochemical screening of a high concentration of a monosubstituted isoquinoline fragment library, then merging hit isoquinoline fragments into a single compound. Our strategy can be applied to the discovery of other challenging kinase inhibitors without protein-ligand structural information.

Design and Synthesis of 56 Shape-Diverse 3D Fragments.

Fragment-based drug discovery is now widely adopted for lead generation in the pharmaceutical industry. However, fragment screening collections are often predominantly populated with flat, 2D molecules. Herein, we describe a workflow for the design and synthesis of 56 3D disubstituted pyrrolidine and piperidine fragments that occupy under-represented areas of fragment space (as demonstrated by a principal moments of inertia (PMI) analysis).

Electrochemical synthesis of microporous polyaniline films using foam templates prepared by ultrasonication.

We report a new soft template method for the synthesis of unique polyaniline (PANI) films with microporous structures. In this process, ultrasonication is used to foam an electrolyte solution containing a surfactant, which is subsequently employed as a soft template for PANI growth via the electrochemical polymerization of aniline. Analysis by scanning electron microscopy demonstrates that the resulting PANI films contain numerous micropores.

Activation of Transient Receptor Potential Vanilloid (TRPV) 4 as a Therapeutic Strategy in Osteoarthritis.

Transient receptor potential vanilloid (TRPV) 4 belongs to the TRPV subfamily of TRP ion channels. TRPV4 channels play a critical role in chondrocytes and thus TRPV4 is an attractive target of Disease-Modifying Osteoarthritis Drugs (DMOADs). Initial investigations of small molecules by Glaxo Smith Klein (GSK) as both agonists and antagonists via oral/intravenous administration have led to the use of existing agonists as lead compounds for biological studies.

Size-controlled synthesis of polymer hollow nanoparticles using emulsion templates prepared by tandem acoustic emulsification.

We have developed a new emulsion template method for the synthesis of poly(methylmethacrylate) (PMMA) hollow nanoparticles with different sizes. This synthetic method involves sequential ultrasonic irradiation (20 kHz → 500 kHz → 1.6 MHz → 2.

Discovery of Novel Transient Receptor Potential Vanilloid 4 (TRPV4) Agonists as Regulators of Chondrogenic Differentiation: Identification of Quinazolin-4(3 H)-ones and in Vivo Studies on a Surgically Induced Rat Model of Osteoarthritis.

Osteoarthritis (OA) is a degenerative disease characterized by joint destruction and loss of cartilage. There are many unmet needs in the treatment of OA and there are few promising candidates for disease-modifying OA drugs, particularly, anabolic agents. Here, we describe the identification of novel quinazolin-4(3 H)-one derivatives, which stimulate chondrocyte cartilage matrix production via TRPV4 and mitigate damaged articular cartilage.

Discovery of a novel 2-(1H-pyrazolo[3,4-b]pyridin-1-yl)thiazole derivative as an EP receptor antagonist and in vivo studies in a bone fracture model.

We describe a medicinal chemistry approach to the discovery of a novel EP antagonist exhibiting high potency and good pharmacokinetics. Our starting point is 1, an EP receptor antagonist that exhibits pharmacological efficacy in cystometry models following intravenous administration. Despite its good potency in vitro, the high lipophilicity of 1 is a concern in long-term in vivo studies.

Increase of enzyme activity through specific covalent modification with fragments.

Modulation of enzyme activity is a powerful means of probing cellular function and can be exploited for diverse applications. Here, we explore a method of enzyme activation where covalent tethering of a small molecule to an enzyme can increase catalytic activity (/) up to 35-fold. Using a bacterial glycoside hydrolase, BtGH84, we demonstrate how small molecule "fragments", identified as activators in free solution, can be covalently tethered to the protein using Michael-addition chemistry.

A series of novel indazole derivatives of Sirt 1 activator as osteogenic regulators.

A series of indazole derivatives were identified as Sirt 1 activators though high-throughput screening. Optimization of each substituent on the indazole ring led to the identification of compound 13. Compound 13 appeared to give the best Sirt 1 activity of the compounds tested and also showed osteogenesis activity in a cell assay.

Applications of Flow Microreactors in Electrosynthetic Processes.

The fundamental advantages and potential benefits of flow microreactor technology include extremely large surface-to-volume ratios, precise control over temperature and residence time, extremely fast molecular diffusion, and increased safety during reactive processes. These advantages and benefits can be applied to a wide range of electrosynthetic techniques, and so the integration of flow microreactors with electrosynthesis has received significant research interest from both academia and industry. This review presents an up-to-date overview of electrosynthetic processes in continuous-flow microreactors.