Reductive Transamination of Pyridinium Salts to N-Aryl Piperidines.

Saturated N-heterocycles are found in numerous bioactive natural products and are prevalent in pharmaceuticals and agrochemicals. While there are many methods for their synthesis, each has its limitations, such as scope and functional group tolerance. Herein, we describe a rhodium-catalyzed transfer hydrogenation of pyridinium salts to access N-(hetero)aryl piperidines. The reaction proceeds via a reductive transamination process, involving the initial formation of a dihydropyridine intermediate via reduction of the pyridinium ion with HCOOH, which is intercepted by water and then hydrolyzed. Subsequent reductive amination with an exogenous (hetero)aryl amine affords an N-(hetero)aryl piperidine. This reductive transamination method thus allows for access of N-(hetero)aryl piperidines from readily available pyridine derivatives, expanding the toolbox of dearomatization and skeletal editing.

Hydrogenation of functionalised pyridines with a rhodium oxide catalyst under mild conditions.

Piperidines are one of the most widely used building blocks in the synthesis of pharmaceutical and agrochemical compounds. The hydrogenation of pyridines is a convenient method to synthesise such compounds as it only requires reactant, catalyst, and a hydrogen source. However, this reaction still remains difficult for the reduction of functionalised and multi-substituted pyridines. Here we report the use of a stable, commercially available rhodium compound, Rh2O3, for the reduction of various unprotected pyridines. The reaction only requires mild conditions, and the substrate scope is broad, making it practically useful.

Werner Salt as Nickel and Ammonia Source for Photochemical Synthesis of Primary Aryl Amines.

Cheap, stable and easy-to-handle Werner ammine salts have been known for more than a century; but they have been rarely used in organic synthesis. Herein, we report that the Werner hexammine complex [Ni(NH3 )6 ]Cl2 can be used as both a nitrogen and a catalytic nickel source that allow for the efficient amination of aryl chlorides in the presence of a catalytic amount of bipyridine ligand under the irradiation of 390-395 nm light without the need of any additional catalysts. More than 80 aryl chlorides, including more than 20 drug molecules, were aminated, demonstrating the practicality and generality of this method in synthetic chemistry. A slow NH3 release mechanism is in operation, obviating the problem of catalyst poisoning. Still interestingly, we show that the Werner salt can be easily recovered and reused, solving the problem of difficult recovery of transition metal nickel catalysts. The protocol thus provides an efficient new strategy for the synthesis of primary aryl amines.

Ni-Catalyzed Photochemical C-N Coupling of Amides with (Hetero)aryl Chlorides.

This paper reports a photochemical C-N coupling of abundant, but less reactive aryl chlorides, with structurally diverse primary and secondary amides by Ni-mediated without an external photocatalyst. Under the irradiation of light (390-395 nm) with a soluble organic amine as the base, the reaction allows for the successful transformation of (hetero)aryl chlorides to a wide range of N-aryl amides. More than 60 examples are shown, demonstrating the feasibility and applicability of this protocol in organic synthesis. Mechanic studies indicate that this amidation proceeds via a Ni(I)-Ni(III) catalytic cycle.

Soft, flexible pressure sensors for pressure monitoring under large hydrostatic pressure and harsh ocean environments.

Traditional rigid ocean pressure sensors typically require protection from bulky pressure chambers and complex seals to survive the large hydrostatic pressure and harsh ocean environment. Here, we introduce soft, flexible pressure sensors that can eliminate such a need and measure a wide range of hydrostatic pressures (0.1 MPa to 15 MPa) in environments that mimic the ocean, achieving small size, high flexibility, and potentially low power consumption. The sensors are fabricated from lithographically patterned gold thin films (100 nm thick) encapsulated with a soft Parylene C film and tested in a customized pressure vessel under well-controlled pressure and temperature conditions. Using a rectangular pressure sensor as an example, the resistance of the sensor is found to decrease linearly with the increase of the hydrostatic pressure from 0.1 MPa to 15 MPa. Finite element analysis (FEA) reveals the strain distributions in the pressure sensor under hydrostatic pressures of up to 15 MPa. The effect of geometry on sensor performance is also studied, and radially symmetric pressure sensors (like circular and spike-shaped) are shown to have more uniform strain distributions under large hydrostatic pressures and, therefore, have a potentially enhanced pressure measurement range. Pressure sensors of all geometries show high consistency and negligible hysteresis over 15 cyclic tests. In addition, the sensors exhibit excellent flexibility and operate reliably under a hydrostatic pressure of 10 MPa for up to 70 days. The developed soft pressure sensors are promising for integration with many platforms including animal tags, diver equipment, and soft underwater robotics.

ß-Arylation of Racemic Secondary Benzylic Alcohols to Access Enantioenriched ß-Arylated Alcohols.

The transformation of alcohols into value-added products is of great importance, as simple alcohols are widespread and can be easily derived from both fossil fuels and biomass. The selective functionalization of a sp3 C-H bond on the alkyl side chain of an alcohol over its hydroxyl group would offer an expedient route to expand the chemical space of alcohols but it remains a challenging task. Harnessing the borrowing hydrogen strategy, the ß-arylation of secondary alcohols with aryl bromides has been achieved in this study, which allows for the selective functionalization of a ß-Csp3 -H bond in an alcohol substrate. Under the catalysis of a Pd complex, secondary alcohols reacted with aryl bromides to afford 1,2-diaryl alcohols with broad substrate scope in the presence of a ketone additive. Furthermore, the enantioconvergent version of the reaction has also been realized, transforming racemic secondary alcohols into enantioenriched chiral 1,2-diaryl alcohols under the cooperative Pd and Ru catalysis. Mechanism studies indicate that the reactions are enabled by borrowing hydrogen catalysis.

Chemical Recycling of Polystyrene to Valuable Chemicals via Selective Acid-Catalyzed Aerobic Oxidation under Visible Light.

Chemical recycling is one of the most promising technologies that could contribute to circular economy targets by providing solutions to plastic waste; however, it is still at an early stage of development. In this work, we describe the first light-driven, acid-catalyzed protocol for chemical recycling of polystyrene waste to valuable chemicals under 1 bar of O2. Requiring no photosensitizers and only mild reaction conditions, the protocol is operationally simple and has also been demonstrated in a flow system. Electron paramagnetic resonance (EPR) investigations and density functional theory (DFT) calculations indicate that singlet oxygen is involved as the reactive oxygen species in this degradation process, which abstracts a hydrogen atom from a tertiary C-H bond, leading to hydroperoxidation and subsequent C-C bond cracking events via a radical process. Notably, our study indicates that an adduct of polystyrene and an acid catalyst might be formed in situ, which could act as a photosensitizer to initiate the formation of singlet oxygen. In addition, the oxidized polystyrene polymer may play a role in the production of singlet oxygen under light.

Fe-Catalyzed Amidation of Allylic Alcohols by Borrowing Hydrogen Catalysis.

Allylic amines are useful building blocks in organic synthesis, so the development of green and efficient methods for the preparation of allylic amines are of great importance. An Fe-catalyzed amidation of allylic alcohols with chiral tert-butylsulfinamide has been developed. With water as the only by-product, a range of synthetically useful chiral sulfinamide olefin derivatives (30 examples) were obtained under mild reaction conditions. The reaction can be performed on a gram-scale, and the products could serve as chiral ligands for asymmetric catalysis. Mechanistic studies suggest that the reaction proceeds by an Fe-catalyzed borrowing hydrogen process, which is different from most of the reported allylic amination reactions.

Asymmetric Hydrogenation of Racemic Allylic Alcohols via an Isomerization-Dynamic Kinetic Resolution Cascade.

Prochiral racemic allylic alcohols are converted to enantioenriched chiral alcohols bearing adjacent stereocenters catalyzed by a diamine diphosphine Ru complex in the presence of tBuOK. The protocol features a broad substrate scope (56 examples) and high diastereo- and enantioselectivities (up to >99:1 dr, >99% ee) and could be applied to the synthesis of enantioenriched chromane and indane compounds. Mechanistic studies suggest that the reaction proceeds via tBuOK-promoted allylic alcohol isomerization followed by Ru-catalyzed hydrogenative dynamic kinetic resolution.

General Method for the Amination of Aryl Halides with Primary and Secondary Alkyl Amines via Nickel Photocatalysis.

The Buchwald-Hartwig C-N coupling reaction has been ranked as one of the 20 most frequently used reactions in medicinal chemistry. Owing to its much lower cost and higher reactivity toward less reactive aryl chlorides than palladium, the C-N coupling reaction catalyzed by Ni-based catalysts has received a great deal of attention. However, there appear to be no universal, practical Ni catalytic systems so far that could enable the coupling of electron-rich and electron-poor aryl halides with both primary and secondary alkyl amines. In this study, it is reported that a Ni(II)-bipyridine complex catalyzes efficient C-N coupling of aryl chlorides and bromides with various primary and secondary alkyl amines under direct excitation with light. Intramolecular C-N coupling is also demonstrated. The feasibility and applicability of the protocol in organic synthesis is attested by more than 200 examples.

Recent developments in enantio- and diastereoselective hydrogenation of N-heteroaromatic compounds.

The enantioselective and diastereoselective hydrogenation of N-heteroaromatic compounds is an efficient strategy to access chirally enriched cyclic heterocycles, which often possess highly bio-active properties. This strategy, however, has only been established in recent times. This is in part due to the challenges of the high stability of the aromatic compounds and the presence of heteroatoms that have the potential to poison the chiral catalysts. Additionally, N-heteroaromatic compounds are a structurally diverse family of substrates, each group showing distinct reactivity in hydrogenation. Advances in recent years have allowed various N-heteroaromatic compounds, including pyridines, indoles, quinolines, isoquinolines, quinoxalines and imidazoles, to be hydrogenated with good to excellent enantioselectivity under appropriate reaction conditions. Transition-metal catalysis, utilising iridium, ruthenium, rhodium, and palladium complexes, has been found to play an important role in this field. More recently, organocatalysis has been shown to be efficient for the hydrogenation of certain N-heteroaromatic compounds. This review provides an analysis of the recent developments in the enantioselective and diastereoselective hydrogenation of N-heteroaromatic compounds. The importance of these molecules and their applications to drug discovery has been highlighted throughout the review.

Asymmetric Ruthenium-Catalyzed Hydroalkylation of Racemic Allylic Alcohols for the Synthesis of Chiral Amino Acid Derivatives.

The asymmetric hydroalkylation of racemic allylic alcohols has been developed for the synthesis of chiral amino acid derivatives with two remote chiral centers by borrowing hydrogen catalysis. The stereoselectivities are controlled by a single chiral Ru catalyst via a dynamic kinetic asymmetric transformation process and an interesting diastereoselectivity amplification process of the product. The method could be used for the synthesis of several types of biologically important molecules, including stereodivergent synthesis of chiral pyrrolidine derivatives.

Chemoselective Oxyfunctionalization of Functionalized Benzylic Compounds with a Manganese Catalyst.

Whilst allowing for easy access to synthetically versatile motifs and for modification of bioactive molecules, the chemoselective benzylic oxidation reactions of functionalized alkyl arenes remain challenging. Reported in this study is a new non-heme Mn catalyst stabilized by a bipiperidine-based tetradentate ligand, which enables methylene oxidation of benzylic compounds by H2 O2 , showing high activity and excellent chemoselectivity under mild conditions. The protocol tolerates an unprecedentedly wide range of functional groups, including carboxylic acid and derivatives, ketone, cyano, azide, acetate, sulfonate, alkyne, amino acid, and amine units, thus providing a low-cost, more sustainable and robust pathway for the facile synthesis of ketones, increase of complexity of organic molecules, and late-stage modification of drugs.

Oxidative Cleavage of Alkenes by O2 with a Non-Heme Manganese Catalyst.

The oxidative cleavage of C═C double bonds with molecular oxygen to produce carbonyl compounds is an important transformation in chemical and pharmaceutical synthesis. In nature, enzymes containing the first-row transition metals, particularly heme and non-heme iron-dependent enzymes, readily activate O2 and oxidatively cleave C═C bonds with exquisite precision under ambient conditions. The reaction remains challenging for synthetic chemists, however. There are only a small number of known synthetic metal catalysts that allow for the oxidative cleavage of alkenes at an atmospheric pressure of O2, with very few known to catalyze the cleavage of nonactivated alkenes. In this work, we describe a light-driven, Mn-catalyzed protocol for the selective oxidation of alkenes to carbonyls under 1 atm of O2. For the first time, aromatic as well as various nonactivated aliphatic alkenes could be oxidized to afford ketones and aldehydes under clean, mild conditions with a first row, biorelevant metal catalyst. Moreover, the protocol shows a very good functional group tolerance. Mechanistic investigation suggests that Mn-oxo species, including an asymmetric, mixed-valent bis(µ-oxo)-Mn(III,IV) complex, are involved in the oxidation, and the solvent methanol participates in O2 activation that leads to the formation of the oxo species.

Recent Development in the Synthesis and Catalytic Application of Iridacycles.

Cyclometallated complexes are well-known and have found many applications. This article provides a short review on the progress made in the synthesis and application to catalysis of cyclometallated half-sandwich Cp*Ir(III) complexes (Cp*: pentamethylcyclopentadienyl) since 2017. Covered in the review are iridacycles featuring conventional C,N chelates and less common metallocene and carbene-derived C,N and C,C ligands. This is followed by an overview of the studies of their applications in catalysis ranging from asymmetric hydrogenation, transfer hydrogenation, hydrosilylation to dehydrogenation.

Chiral cyclometalated iridium complexes for asymmetric reduction reactions.

A series of chiral cyclometalated iridium complexes have been synthesised by cyclometalating chiral 2-aryl-oxazoline and imidazoline ligands with [Cp*IrCl2]2. These iridacycles were studied for asymmetric transfer hydrogenation reactions with formic acid as the hydrogen source and were found to display various activities and enantioselectivities, with the most effective ones affording up to 63% ee in the asymmetric reductive amination of ketones and 77% ee in the reduction of pyridinium ions.

Chiral Arylated Amines via C-N Coupling of Chiral Amines with Aryl Bromides Promoted by Light.

The Buchwald-Hartwig C-N coupling reaction has found widespread applications in organic synthesis. Over the past two decades or so, many improved catalysts have been introduced, allowing various amines and aryl electrophiles to be readily used nowadays. However, there lacks a protocol that could be used to couple a wide range of chiral amines and aryl halides, without erosion of the enantiomeric excess (ee). Reported in this article is a method based on molecular Ni catalysis driven by light, which enables stereoretentive C-N coupling of optically active amines, amino alcohols, and amino acid esters with aryl bromides, with no need for any external photosensitizer. The method is effective for a wide variety of coupling partners, including those bearing functional groups sensitive to bases and nucleophiles, thus providing a viable alternative to accessing synthetically important chiral N-aryl amines, amino alcohols, and amino acids esters. Its viability is demonstrated by 92 examples with up to 99 % ee.

Sustainable Production of Benzylamines from Lignin.

Catalytic conversion of lignin into heteroatom functionalized chemicals is of great importance to bring the biorefinery concept into reality. Herein, a new strategy was designed for direct transformation of lignin ß-O-4 model compounds into benzylamines and phenols in moderate to excellent yields in the presence of organic amines. The transformation involves dehydrogenation of Cα -OH, hydrogenolysis of the Cß -O bond and reductive amination in the presence of Pd/C catalyst. Experimental data suggest that the dehydrogenation reaction proceeds over the other two reactions and secondary amines serve as both reducing agents and amine sources in the transformation. Moreover, the concept of "lignin to benzylamines" was demonstrated by a two-step process. This work represents a first example of synthesis of benzylamines from lignin, thus providing a new opportunity for the sustainable synthesis of benzylamines from renewable biomass, and expanding the products pool of biomass conversion to meet future biorefinery demands.

Light-Promoted C-N Coupling of Aryl Halides with Nitroarenes.

A photochemical C-N coupling of aryl halides with nitroarenes is demonstrated for the first time. Catalyzed by a NiII complex in the absence of any external photosensitizer, readily available nitroarenes undergo coupling with a variety of aryl halides, providing a step-economic extension to the widely used Buchwald-Hartwig C-N coupling reaction. The method tolerates coupling partners with steric-congestion and functional groups sensitive to bases and nucleophiles. Mechanistic studies suggest that the reaction proceeds via the addition of an aryl radical, generated from a NiI /NiIII cycle, to a nitrosoarene intermediate.

Rapidly-customizable, scalable 3D-printed wireless optogenetic probes for versatile applications in neuroscience.

Optogenetics is an advanced neuroscience technique that enables the dissection of neural circuitry with high spatiotemporal precision. Recent advances in materials and microfabrication techniques have enabled minimally invasive and biocompatible optical neural probes, thereby facilitating in vivo optogenetic research. However, conventional fabrication techniques rely on cleanroom facilities, which are not easily accessible and are expensive to use, making the overall manufacturing process inconvenient and costly. Moreover, the inherent time-consuming nature of current fabrication procedures impede the rapid customization of neural probes in between in vivo studies. Here, we introduce a new technique stemming from 3D printing technology for the low-cost, mass production of rapidly customizable optogenetic neural probes. We detail the 3D printing production process, on-the-fly design versatility, and biocompatibility of 3D printed optogenetic probes as well as their functional capabilities for wireless in vivo optogenetics. Successful in vivo studies with 3D printed devices highlight the reliability of this easily accessible and flexible manufacturing approach that, with advances in printing technology, can foreshadow its widespread applications in low-cost bioelectronics in the future.