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One shortcoming of olefin metathesis has been that acyclic alkenyl halides could not be generated efficiently and stereoselectively; but now halo-substituted molybdenum alkylidene species are shown to be able to participate in high-yielding olefin metathesis reactions that afford acyclic 1,2-disubstituted Z -alkenyl halides. Olefin metathesis has had a large impact on modern organic chemistry, but important shortcomings remain: for example, the lack of efficient processes that can be used to generate acyclic alkenyl halides. Halo-substituted ruthenium carbene complexes decompose rapidly or deliver low activity and/or minimal stereoselectivity, and our understanding of the corresponding high-oxidation-state systems is limited. Here we show that previously unknown halo-substituted molybdenum alkylidene species are exceptionally reactive and are able to participate in high-yielding olefin metathesis reactions that afford acyclic 1,2-disubstituted Z -alkenyl halides. Transformations are promoted by small amounts of a catalyst that is generated in situ and used with unpurified, commercially available and easy-to-handle liquid 1,2-dihaloethene reagents, and proceed to high conversion at ambient temperature within four hours. We obtain many alkenyl chlorides, bromides and fluorides in up to 91 per cent yield and complete Z selectivity. This method can be used to synthesize biologically active compounds readily and to perform site- and stereoselective fluorination of complex organic molecules. Catalytic olefin metathesis Olefins with a halide substituent are a mainstay in synthetic chemistry. However, the scope for the efficient stereoselective synthesis of acyclic alkenyl halides — a class of compound common that includes many biologically active natural products — has been limited. Amir Hoveyda and colleagues show here that previously unknown halo-substituted molybdenum alkylidene species are exceptionally reactive and can participate in high-yielding olefin metathesis reactions that produce acyclic 1,2-disubstituted Z -alkenyl halides. Many alkenyl chlorides, bromides and fluorides can be obtained in up to 91% yield and complete Z selectivity.

A series of amide-based mono and dimeric pyridinium bromides were synthesized using conventional and microwave-assisted solvent-free methods. The quaternization reactions of m -xylene dibromide and 4-nitrobenzylbromide with amide-based substituted pyridine proceeded efficiently, whereas 1,6-dibromohexane required reflux conditions. A comparative analysis of the solvent-free microwave-assisted reactions revealed a significant reduction in reaction time (up to 20-fold) and increased yields, accompanied by simplified work-up procedures. Notably, these reactions exhibited 100% atom economy and generated no environmental waste. The cytotoxic effects of the synthesized compounds were assessed using the MTT assay, nuclear staining, and Real Time-Polymerase Chain Reaction (PCR) on the lung cancer cell line (A-549).Molecular docking studies were performed to investigate the interaction and binding of B-Raf kinase inhibitors with the amide-based mono and dimeric pyridinium bromides. Furthermore, the toxicity of the drug molecules was assessed using the BOILED-Egg plot at the central nervous system.

Metal-catalysed cross-couplings are a mainstay of organic synthesis and are widely used for the formation of C–C bonds, particularly in the production of unsaturated scaffolds 1 . However, alkyl cross-couplings using native sp 3 -hybridized functional groups such as alcohols remain relatively underdeveloped 2 . In particular, a robust and general method for the direct deoxygenative coupling of alcohols would have major implications for the field of organic synthesis. A general method for the direct deoxygenative cross-coupling of free alcohols must overcome several challenges, most notably the in situ cleavage of strong C–O bonds 3 , but would allow access to the vast collection of commercially available, structurally diverse alcohols as coupling partners 4 . We report herein a metallaphotoredox-based cross-coupling platform in which free alcohols are activated in situ by N-heterocyclic carbene salts for carbon–carbon bond formation with aryl halide coupling partners. This method is mild, robust, selective and most importantly, capable of accommodating a wide range of primary, secondary and tertiary alcohols as well as pharmaceutically relevant aryl and heteroaryl bromides and chlorides. The power of the transformation has been demonstrated in a number of complex settings, including the late-stage functionalization of Taxol and a modular synthesis of Januvia, an antidiabetic medication. This technology represents a general strategy for the merger of in situ alcohol activation with transition metal catalysis. A metallaphotoredox-based cross-coupling platform is capable of activating a wide range of free alcohols using N-heterocyclic carbene salts, cleaving C–O bonds to form free carbon radicals that are then used to form new C–C bonds.

Despite advances in carbon–carbon fragment couplings, the ability to forge carbon–oxygen bonds in a general fashion via nickel catalysis has been largely unsuccessful; here, visible-light-excited photoredox catalysts are shown to provide transient access to Ni( iii ) species that readily participate in reductive elimination, leading to carbon–oxygen coupling. C–heteroatom coupling via nickel catalysis Despite advances in carbon–carbon fragment couplings, the ability to create carbon–oxygen bonds via nickel catalysis has been largely unsuccessful. Here David MacMillan and colleagues show that visible-light-excited photoredox catalysts can provide transient access to Ni( III ) species that readily participate in reductive elimination. Using this synergistic merger of photoredox and nickel catalysis, the authors develop a highly efficient and general carbon–oxygen coupling reaction using alcohols and aryl bromides. Transition-metal-catalysed cross-coupling reactions have become one of the most used carbon – carbon and carbon – heteroatom bond-forming reactions in chemical synthesis. Recently, nickel catalysis has been shown to participate in a wide variety of C−C bond-forming reactions, most notably Negishi, Suzuki – Miyaura, Stille, Kumada and Hiyama couplings 1 , 2 . Despite the tremendous advances in C−C fragment couplings, the ability to forge C−O bonds in a general fashion via nickel catalysis has been largely unsuccessful. The challenge for nickel-mediated alcohol couplings has been the mechanistic requirement for the critical C–O bond-forming step (formally known as the reductive elimination step) to occur via a Ni( iii ) alkoxide intermediate. Here we demonstrate that visible-light-excited photoredox catalysts can modulate the preferred oxidation states of nickel alkoxides in an operative catalytic cycle, thereby providing transient access to Ni( iii ) species that readily participate in reductive elimination. Using this synergistic merger of photoredox and nickel catalysis, we have developed a highly efficient and general carbon – oxygen coupling reaction using abundant alcohols and aryl bromides. More notably, we have developed a general strategy to ‘switch on’ important yet elusive organometallic mechanisms via oxidation state modulations using only weak light and single-electron-transfer catalysts.

The asymmetric cross-coupling reaction is developed as a straightforward strategy toward 1,1-diaryl alkanes, which are a key skeleton in a series of natural products and bioactive molecules in recent years. Here we report an enantioselective benzylic C(sp 3 )−H bond arylation via photoredox/nickel dual catalysis. Sterically hindered chiral biimidazoline ligands are designed for this asymmetric cross-coupling reaction. Readily available alkyl benzenes and aryl bromides with various functional groups tolerance can be easily and directly transferred to useful chiral 1,1-diaryl alkanes including pharmaceutical intermediates and bioactive molecules. This reaction proceeds smoothly under mild conditions without the use of external redox reagents. Chiral 1,1-diaryl alkanes are important targets in pharmaceutical industry. Here, the authors report report a redox-neutral enantioselective benzylic C−H bond arylation via photoredox/nickel dual catalysis accessing chiral 1,1-diarylalkane compounds under mild conditions.

Epilepsy is one of the most common and disabling chronic neurological disorders. Antiseizure medications (ASMs), previously referred to as anticonvulsant or antiepileptic drugs, are the mainstay of symptomatic epilepsy treatment. Epilepsy is a multifaceted complex disease and so is its treatment. Currently, about 30 ASMs are available for epilepsy therapy. Furthermore, several ASMs are approved therapies in nonepileptic conditions, including neuropathic pain, migraine, bipolar disorder, and generalized anxiety disorder. Because of this wide spectrum of therapeutic activity, ASMs are among the most often prescribed centrally active agents. Most ASMs act by modulation of voltage-gated ion channels; by enhancement of gamma aminobutyric acid-mediated inhibition; through interactions with elements of the synaptic release machinery; by blockade of ionotropic glutamate receptors; or by combinations of these mechanisms. Because of differences in their mechanisms of action, most ASMs do not suppress all types of seizures, so appropriate treatment choices are important. The goal of epilepsy therapy is the complete elimination of seizures; however, this is not achievable in about one-third of patients. Both in vivo and in vitro models of seizures and epilepsy are used to discover ASMs that are more effective in patients with continued drug-resistant seizures. Furthermore, therapies that are specific to epilepsy etiology are being developed. Currently, ~ 30 new compounds with diverse antiseizure mechanisms are in the preclinical or clinical drug development pipeline. Moreover, therapies with potential antiepileptogenic or disease-modifying effects are in preclinical and clinical development. Overall, the world of epilepsy therapy development is changing and evolving in many exciting and important ways. However, while new epilepsy therapies are developed, knowledge of the pharmacokinetics, antiseizure efficacy and spectrum, and adverse effect profiles of currently used ASMs is an essential component of treating epilepsy successfully and maintaining a high quality of life for every patient, particularly those receiving polypharmacy for drug-resistant seizures.

Organophosphorus (OP) compounds represent a serious health hazard worldwide. The dominant mechanism of their action results from covalent inhibition of acetylcholinesterase (AChE). Standard therapy of acute OP poisoning is partially effective. However, prophylactic administration of reversible or pseudo-irreversible AChE inhibitors before OP exposure increases the efficiency of standard therapy. The purpose of the study was to test the duration of the protective effect of a slow-binding reversible AChE inhibitor (C547) in a mouse model against acute exposure to paraoxon (POX). It was shown that the rate of inhibition of AChE by POX in vitro after pre-inhibition with C547 was several times lower than without C547. Ex vivo pre-incubation of mouse diaphragm with C547 significantly prevented the POX-induced muscle weakness. Then it was shown that pre-treatment of mice with C547 at the dose of 0.01 mg/kg significantly increased survival after poisoning by 2xLD 50 POX. The duration of the pre-treatment was effective up to 96 h, whereas currently used drug for pre-exposure treatment, pyridostigmine at a dose of 0.15 mg/kg was effective less than 24 h. Thus, long-lasting slow-binding reversible AChE inhibitors can be considered as new potential drugs to increase the duration of pre-exposure treatment of OP poisoning.

Secondary batteries based on earth-abundant sodium metal anodes are desirable for both stationary and portable electrical energy storage. Room-temperature sodium metal batteries are impractical today because morphological instability during recharge drives rough, dendritic electrodeposition. Chemical instability of liquid electrolytes also leads to premature cell failure as a result of parasitic reactions with the anode. Here we use joint density-functional theoretical analysis to show that the surface diffusion barrier for sodium ion transport is a sensitive function of the chemistry of solid–electrolyte interphase. In particular, we find that a sodium bromide interphase presents an exceptionally low energy barrier to ion transport, comparable to that of metallic magnesium. We evaluate this prediction by means of electrochemical measurements and direct visualization studies. These experiments reveal an approximately three-fold reduction in activation energy for ion transport at a sodium bromide interphase. Direct visualization of sodium electrodeposition confirms large improvements in stability of sodium deposition at sodium bromide-rich interphases. The chemistry at the interface between electrolyte and electrode plays a critical role in determining battery performance. Here, the authors show that a NaBr enriched solid–electrolyte interphase can lower the surface diffusion barrier for sodium ions, enabling stable electrodeposition.

A new method for catalysing the cross-coupling of two different aryl electrophiles is described; the principle of this method, which involves cooperation between two metal catalysts that are selective towards different substrates, should be generally useful in catalysis. Multiple catalysts for carbon–carbon bond formation Transition-metal-catalysed strategies for the formation of new carbon–carbon bonds are used to synthesize a broad range of small molecules, including pharmaceutical agents. In cases where a single metal fails to promote a selective or efficient transformation, the synergistic cooperation of two distinct catalysts — multimetallic catalysis — can be used instead. The application of this strategy has mainly been limited to the use of metals with distinct reactivities. These authors demonstrate that cooperativity between a nickel catalyst and a palladium catalyst can be used to couple aryl bromides with aryl triflates directly, eliminating the need to use arylmetal reagents. Each catalyst forms less than 5% cross product in isolation, but with both catalysts present the yields can reach 94%. These results reveal a new, general method for the synthesis of biaryls, heteroaryls, and dienes, and should simplify the synthesis of pharmaceutical agents, many of which are currently made with pre-formed organometallic reagents. The advent of transition-metal catalysed strategies for forming new carbon-carbon bonds has revolutionized the field of organic chemistry, enabling the efficient synthesis of ligands, materials, and biologically active molecules 1 , 2 , 3 . In cases where a single metal fails to promote a selective or efficient transformation, the synergistic cooperation 4 of two distinct catalysts—multimetallic catalysis—can be used instead. Many important reactions rely on multimetallic catalysis 5 , 6 , 7 , 8 , 9 , 10 , such as the Wacker oxidation of olefins 6 , 7 , 8 and the Sonogashira coupling of alkynes with aryl halides 9 , 10 , but this approach has largely been limited to the use of metals with distinct reactivities, with only one metal catalyst undergoing oxidative addition 11 , 12 . Here, we demonstrate that cooperativity between two group 10 metal catalysts—(bipyridine)nickel and (1,3-bis(diphenylphosphino)propane)palladium—enables a general cross-Ullmann reaction (the cross-coupling of two different aryl electrophiles) 13 , 14 , 15 . Our method couples aryl bromides with aryl triflates directly, eliminating the use of arylmetal reagents and avoiding the challenge of differentiating between multiple carbon–hydrogen bonds that is required for direct arylation methods 16 , 17 . Selectivity can be achieved without an excess of either substrate and originates from the orthogonal reactivity of the two catalysts and the relative stability of the two arylmetal intermediates. While (1,3-bis(diphenylphosphino)propane)palladium reacts preferentially with aryl triflates to afford a persistent intermediate, (bipyridine)nickel reacts preferentially with aryl bromides to form a transient, reactive intermediate. Although each catalyst forms less than 5 per cent cross-coupled product in isolation, together they are able to achieve a yield of up to 94 per cent. Our results reveal a new method for the synthesis of biaryls, heteroaryls, and dienes, as well as a general mechanism for the selective transfer of ligands between two metal catalysts. We anticipate that this reaction will simplify the synthesis of pharmaceuticals, many of which are currently made with pre-formed organometallic reagents 1 , 2 , 3 , and lead to the discovery of new multimetallic reactions.

Oligosaccharides have myriad functions throughout biological processes 1 , 2 . Chemical synthesis of these structurally complex molecules facilitates investigation of their functions. With a dense concentration of stereocentres and hydroxyl groups, oligosaccharide assembly through O -glycosylation requires simultaneous control of site, stereo- and chemoselectivities 3 , 4 . Chemists have traditionally relied on protecting group manipulations for this purpose 5 – 8 , adding considerable synthetic work. Here we report a glycosylation platform that enables selective coupling between unprotected or minimally protected donor and acceptor sugars, producing 1,2- cis - O -glycosides in a catalyst-controlled, site-selective manner. Radical-based activation 9 of allyl glycosyl sulfones forms glycosyl bromides. A designed aminoboronic acid catalyst brings this reactive intermediate close to an acceptor through a network of non-covalent hydrogen bonding and reversible covalent B–O bonding interactions, allowing precise glycosyl transfer. The site of glycosylation can be switched with different aminoboronic acid catalysts by affecting their interaction modes with substrates. The method accommodates a wide range of sugar types, amenable to the preparation of naturally occurring sugar chains and pentasaccharides containing 11 free hydroxyls. Experimental and computational studies provide insights into the origin of selectivity outcomes. A glycosylation platform is demonstrated that enables selective coupling between a wide range of unprotected or minimally protected donor and acceptor sugars, producing 1,2- cis - O -glycosides in a catalyst-controlled, site-selective manner.