Site-specific allylic C-H bond functionalization with a copper-bound N-centred radical.

Methods for selective C-H bond functionalization have provided chemists with versatile and powerful toolboxes for synthesis, such as the late-stage modification of a lead compound without the need for lengthy de novo synthesis1-5. Cleavage of an sp3 C-H bond via hydrogen atom transfer (HAT) is particularly useful, given the large number of available HAT acceptors and the diversity of reaction pathways available to the resulting radical intermediate6-17. Site-selectivity, however, remains a formidable challenge, especially among sp3 C-H bonds with comparable properties. If the intermediate radical could be further trapped enantioselectively, this should enable highly site- and enantioselective functionalization of C-H bonds. Here we report a copper (Cu)-catalysed site- and enantioselective allylic C-H cyanation of complex alkenes, in which a Cu(II)-bound nitrogen (N)-centred radical plays the key role in achieving precise site-specific HAT. This method is shown to be effective for a diverse collection of alkene-containing molecules, including sterically demanding structures and complex natural products and pharmaceuticals.

Copper-Catalyzed sp2 C-H Arylation and Alkynylation of Allenes via Hydrogen Atom Abstraction.

Development of methods for the sp2 C-H transformations of allenes has received much attention, and it presents a powerful tool for the synthesis of complicated allene-containing bioactive molecules. With a copper-catalyzed radical relay, sp2 allenic C-H arylation and alkynylation were established herein, using various aryl boronic acids and trimethoxysilyl-substituted alkynes as carbon nucleophiles and using electrophilic N-F reagents as nitrogen-centered radical precursors. These methods featured excellent site selectivity to deliver fully substituted allenes efficiently. Moreover, with silyl-substituted allenes as substrates, a subsequent dual sp2 C-H functionalization process was established as well, which allowed for the divergent synthesis of multifunctionalized allenes, significantly expanding their chemical spaces.

Palladium-Catalyzed Remote Hydrosulfonamidation of Alkenes: Access to Primary N-Alkyl Sulfamides by the SuFEx Reaction.

Herein, we establish a remote hydrosulfonamidation (HSA) of alkenes using palladium catalysis, where N-fluoro-N-(fluoro-sulfonyl)-carbamate with a sulfur(VI) fluoride moiety is demonstrated as a good amidation reagent. The anti-Markovnikov HSA reaction of terminal alkenes and the remote HSA of internal alkenes are achieved to efficiently yield primary N-alkyl-N-(fluorosulfonyl)-carbamates. In addition, this protocol enables the high-value utilization of alkane by combining the dehydrogenation process. The generated N-alkyl products exhibit a unique reactivity of sulfur(VI) fluorides, which can be directly transferred to N-alkyl sulfamides or amines via the sulfur(VI) fluoride exchange reaction, thereby streamlining their synthesis. Moreover, a (pyridyl) benzazole-type ligand proved to be vital for the excellent chemo- and regioselectivities.

Improved Mobility-Stretchability Properties of Diketopyrrolopyrrole-Based Conjugated Polymers with Diastereomeric Conjugation Break Spacers.

Stretchable conjugated polymers with conjugation break spacers (CBSs) synthesized via random terpolymerization have gained considerable attention because of their efficacy in modulating mobility and stretchability. This study incorporates a series of dianhydrohexitol diastereomers of isosorbide (ISB) and isomannide (IMN) units into the diketopyrrolopyrrole-based backbone as CBSs. It is found that the distorted CBS (IMN) improves the mobility-stretchability properties of the polymer with a highly coplanar backbone, whereas the extended CBS (ISB) enhances those of the polymer with a noncoplanar backbone. Additionally, the different configurations of ISB and IMN sufficiently affect the solid-state packing, aggregation capabilities, crystallographic parameters, and mobility-stretchability properties of the polymer. The IMN-based polymers exhibit the highest mobility of 1.69 cm2 V-1 s-1 and crystallinity retentions of (85.7, 78.6)% under 20% and 60% strains, outperforming their ISB-based or unmodified counterparts. The improvement is correlated with a robust aggregation capability. Furthermore, the CBS content affects aggregation behavior, notably affecting mobility. This result indicates that incorporating CBSs into the polymer can enhance backbone flexibility via movement and rotation of the CBS without affecting the crystalline regions.

Asymmetric 1,n-Remote Aminoacetoxylation of Unactivated Internal Alkenes Enabled by Palladium Catalysis.

A palladium-catalyzed asymmetric 1,n-remote aminoacetoxylation of cis-alkenes has been developed using PhI(OAc)2 as an oxidant, providing the acetoxylated lactams with excellent enantioselectivities under mild reaction conditions. The sterically hindered pyridine-oxazoline (Pyox) L3 with a tert-butyl group in oxazoline ring and propyl group in C6 position of pyridinyl is vital for the reaction, where the former is good for asymmetric aminopalladation step and the latter for the chain walking process. The enantioenriched lactam products were proven to be good building blocks for the synthesis of azabicycles.

Copper-Catalyzed Asymmetric Functionalization of Vinyl Radicals for the Access to Vinylarene Atropisomers.

A novel asymmetric radical strategy for the straightforward synthesis of atropisomerically chiral vinyl arenes has been established herein, proceeding through copper-catalyzed atroposelective cyanation/azidation of aryl-substituted vinyl radicals. Critical to the success of the radical relay process is the atroposelective capture of the highly reactive vinyl radicals with chiral L*Cu(II) cyanide or azide species. Moreover, these axially chiral vinylarene products can be easily transformed into atropisomerically enriched amides and amines, enantiomerically enriched benzyl nitriles via an axis-to-center chirality transfer process, and an atropisomerically pure organocatalyst for the chemo-, diastereo-, and enantioselective (4 + 2) cyclization reaction.

Site-Selective sp2 C-H Cyanation of Allenes via Copper-Catalyzed Radical Relay.

Compared with the extensively reported hydrogen atom transfer (HAT) at sp3 C-H, abstraction of hydrogen atoms at the sp2 carbon is extremely rare. Here, we communicate the site-selective cyanation of the sp2 C-H bond of allenes using the strategy of copper-catalyzed radical relay. The reactions afford various allenyl nitriles directly from simple allenes with a broad substrate scope and a remarkable functional group compatibility under mild conditions. These reactions exhibit excellent site-selectivity toward sp2 C-H, which can be attributed to the unique pocket created by the Cu-bound nitrogen-centered radical. The favorable HAT on sp2 C-H is due to crucial hydrogen bonding between the fluoride bonded to the Cu(II) center and the hydrogen atom at the allylic position. These features enable the late-stage functionalization of druglike bioactive molecules containing an allene motif.

Dissociable brainstem functional connectivity changes correlate with objective and subjective vigilance decline after total sleep deprivation in healthy male subjects.

The maintenance of vigilance relies on the activation of the cerebral cortex by the arousal system centered on the brainstem. Previous studies have suggested that both objective and subjective vigilance are susceptible to sleep deprivation. This study aims to explore the alterations in brainstem arousal system functional connectivity (FC) and its involvement in these two types of vigilance decline following total sleep deprivation (TSD). Thirty-seven healthy male subjects underwent two counterbalanced resting-state fMRI scans, once in rested wakefulness (RW) and once after 36 h of TSD. The pontine tegmental area and caudal midbrain (PTA-cMidbrain), the core regions of the brainstem arousal system, were chosen as the seeds for FC analysis. The difference in PTA-cMidbrain FC between RW and TSD conditions was then investigated, as well as its associations with objective vigilance measured by psychomotor vigilance task (PVT) and subjective vigilance measured by Stanford Sleepiness Scale. The sleep-deprived subjects showed increased PTA-cMidbrain FC with the thalamus and cerebellum and decreased PTA-cMidbrain FC with the occipital, parietal, and sensorimotor regions. TSD-induced increases in PVT reaction time were negatively correlated with altered PTA-cMidbrain FC in the dorsolateral prefrontal cortex, extrastriate visual cortex, and precuneus. TSD-induced increases in subjective sleepiness were positively correlated with altered PTA-cMidbrain FC in default mode regions including the medial prefrontal cortex and precuneus. Our results suggest that different brainstem FC patterns underlie the objective and subjective vigilance declines induced by TSD.

Copper-catalyzed radical relay in C(sp3)-H functionalization.

Radical-involved transition metal (TM) catalysis has greatly enabled new reactivities in recent decades. Copper-catalyzed radical relay offers enormous potential in C(sp3)-H functionalization which combines the unique regioselectivity of hydrogen atom transfer (HAT) and the versatility of copper-catalyzed cross-coupling. More importantly, significant progress has been achieved in asymmetric C-H functionalization through judicious ligand design. This tutorial review will highlight the recent advances in this rapidly growing area, and we hope this survey will inspire future strategic developments for selective C(sp3)-H functionalization.

Palladium(II)-Catalyzed Enantioselective Hydrooxygenation of Unactivated Terminal Alkenes.

A novel Pd(II)-catalyzed enantioselective Markovnikov hydrooxygenation of unactivated terminal alkenes using a substituted pyridinyl oxazoline (Pyox) ligand has been developed. Herein it was discovered that the (EtO)2MeSiH/BQ redox system is vital for the highly selective and efficient hydrooxygenation, where the alkylpalladium(II) species generated from enantioselective oxypalladation step is reduced by silane. This method provides efficient access to optically pure alcohol esters from easily available alkenes with excellent enantioselectivities and features a broad substrate scope.

Enantioselective Radical Trifluoromethylation of Benzylic C-H Bonds via Cooperative Photoredox and Copper Catalysis.

The first enantioselective radical trifluoromethylation of benzylic C-H bonds has been established by a cooperative photoredox and copper catalysis system, providing straightforward access to structurally diverse benzylic trifluoromethylation products in good yields with excellent enantioselectivities under mild conditions. Our method features a broad substrate scope and excellent functional group compatibility. Merging the cooperative photoredox catalysis with copper catalysis is essential for the reaction, where the photoredox catalysis is used for the generation of benzylic radicals from alkyl arenes through a hydrogen atom transfer process and the copper catalysis is used for the enantioselective trifluoromethylation of the benzylic radicals.

Palladium-Catalyzed Remote Hydro-Oxygenation of Internal Alkenes: An Efficient Access to Primary Alcohols.

As a general method for the synthesis of alcohols, the direct oxygenation of alkenes is difficult to afford linear alcohols. Herein, we communicate the remote hydro-oxygenation of alkenes under palladium catalysis, in which both terminal and internal alkenes are suitable to yield the corresponding linear alcohols efficiently. A compatible SelectFluor/silane redox system plays an essential role for the excellent chemo- and regioselectivities. The reaction features a broad substrate scope and excellent functional group compatibility.

Electrophotocatalytic Decoupled Radical Relay Enables Highly Efficient and Enantioselective Benzylic C-H Functionalization.

Asymmetric sp3 C-H functionalization has been demonstrated to substantially expedite target molecule synthesis, spanning from feedstocks upgradation to late-stage modification of complex molecules. Herein, we report a highly efficient and sustainable method for enantioselective benzylic C-H cyanation by merging electrophoto- and copper catalysis. A novel catalytic system allows one to independently regulate the hydrogen atom transfer step for benzylic radical formation and speciation of Cu(II)/Cu(I) to effectively capture the transient radical intermediate, through tuning the electronic property of anthraquinone-type photocatalyst and simply modulating the applied current, respectively. Such decoupled radical relay catalysis enables a unified approach for enantioselective benzylic C-H cyanation of diverse alkylarenes, many of which are much less reactive or even unreactive using the existing method relying on coupled radical relay. Moreover, the current protocol is also amenable to late-stage functionalization of bioactive molecules, including natural products and drugs.

Electrospun nanofibrous membrane with antibacterial and antiviral properties decorated with Myoporum bontioides extract and silver-doped carbon nitride nanoparticles for medical masks application.

Public health safety issues have been plaguing the world since the pandemic outbreak of coronavirus disease (COVID-19). However, most personal protective equipments (PPE) do not have antibacterial and anti- toxicity effects. In this work, we designed and prepared a reusable, antibacterial and anti-toxicity Polyacrylonitrile (PAN) based nanofibrous membrane cooperated with Ag/g-C3N4 (Ag-CN), Myoporum.bontioides (M. bontioides) plant extracts and Ag nanoparticles (NPs) by an electrospinning-process. The SEM and TEM characterization revealed the formation of raised, creased or wrinkled areas on the fiber surface caused by the Ag nanoparticles, the rough surface prevented the aerosol particles on the fiber surface from sliding and stagnating, thus providing excellent filtration performance. The PAN/M. bontioides/Ag-CN/Ag nanofibrous membrane could be employed as a photocatalytic bactericidal material, which not only degraded 96.37% of methylene blue within 150 min, but also exhibited the superior bactericidal effect of 98.65 ± 1.49% and 97.8 ± 1.27% against E. coli and S. aureus, respectively, under 3 hs of light exposure. After 3 cycles of sterilization experiments, the PAN/M. bontioides/Ag-CN/Ag nanofibrous membrane maintained an efficient sterilization effect. Molecular docking revealed that the compounds in M. bontioides extracts interacted with neo-coronavirus targets mainly on Mpro and RdRp proteins, and these compounds had the strongest docking energy with Mpro protein, the shortest docking radius, and more binding sites for key amino acids around the viral protein targets, which influenced the replication and transcription process of neo-coronavirus. The PAN/M.bontioides/Ag-CN/Ag nanofibrous membrane also performed significant inhibition of influenza A virus H3N2. The novel nanofiber membrane is expected to be applied to medical masks, which will improve human isolation and protection against viruses.

Enantioselective Copper-Catalyzed Radical Cyanation of Propargylic C-H Bonds: Easy Access to Chiral Allenyl Nitriles.

The first enantioselective copper-catalyzed cyanation of propargylic C-H bonds via radical relay was established using novel BoxOTMS ligands, providing an efficient and straightforward tool for the construction of structurally diverse chiral allenyl nitriles in good yields with excellent enantioselectivities. This reaction features high functional group tolerance and mild conditions. In addition, the chiral allene products can be readily converted to other chiral compounds via axis-to-center chirality transfer.

Asymmetric Palladium-Catalyzed Oxycarbonylation of Terminal Alkenes: Efficient Access to ß-Hydroxy Alkylcarboxylic Acids.

A novel PdII -catalyzed enantioselective oxycarbonylation of alkenes has been established. The ligand with an ethyl group at the C-6 position of Pyox plays a significant role in the intermolecular oxypalladation process, leading to high reactivity and excellent enantioselective control. Compared to the conventional methods, the reaction itself features alkenes as easily prepared starting materials, mild and operationally simple reaction conditions, and insensitivities to air and water. Moreover, this method allows for broad alkene substrate scope, excellent regio- and enantioselectivities, scalabilities and a wide array of applications, and provides a useful route for the convenient and straightforward synthesis of chiral ß-hydroxy alkylcarboxylic acids/esters.

Anionic Bisoxazoline Ligands Enable Copper-Catalyzed Asymmetric Radical Azidation of Acrylamides.

Asymmetric radical azidation for the synthesis of chiral alkylazides remains a tremendous challenge in organic synthesis. We report here an unprecedented highly enantioselective radical azidation of acrylamides catalyzed by 1 mol % of a copper catalyst. The substrates were converted to the corresponding alkylazides in high yield with good-to-excellent enantioselectivity. Notably, employing an anionic cyano-bisoxazoline (CN-Box) ligand is crucial to generate a monomeric CuII azide species, rather than a dimeric CuII azide intermediate, for this highly enantioselective radical azidation.

Enantioselective Copper-Catalyzed Alkynylation of Benzylic C-H Bonds via Radical Relay.

The first enantioselective alkynylation of benzylic C-H bonds via copper-catalyzed radical relay has been established herein, which provides an easy access to structurally diverse benzylic alkynes in good yields with excellent enantioselectivities. A key step for the asymmetric copper-catalyzed radical relay process is the enantioselective capture of a benzylic radical with chiral (Box)CuII-alkynyl species. In addition, the reaction displays good functional group tolerance, broad substrate scope, and mild conditions. The enantioenriched alkynylation products can be readily transformed into highly valuable synthons, such as chiral terminal alkynes, allenes, alkenes, and carboxylic acids. More importantly, our methodology can be applied to the synthesis of bioactive molecule AMG 837.

Enantioselective Palladium(II)-Catalyzed Oxidative Aminofluorination of Unactivated Alkenes with Et4 NF⋠3 HF as a Fluoride Source.

The first asymmetric PdII -catalyzed aminofluorination of unactivated alkenes using chiral quinoline-oxazolines (Quox) as ligands has been developed. This reaction provides easy access to a wide array of enantiomerically enriched ß-fluoropiperidines in good yields and with excellent enantioselectivity. Notably, Et4 NF⋅3 HF as a readily accessible nucleophilic fluoride source was found to play an essential role in the enantioselective control, and CsOCF3 also acts a key additive to improve the excellent ee value of products.

Palladium(II)-Catalyzed Enantioselective Azidation of Unactivated Alkenes.

The first Pd-catalyzed enantioselective azidation of unactivated alkenes has been established by using readily accessible 1-azido-1,2-benziodoxol-3(1H)-one (ABX) as an azidating reagent, which affords a wide variety of structurally diverse 3-N3 -substituted piperidines in good yields with excellent enantioselectivity. The reaction features good functional-group compatibility and mild reaction conditions. Notably, both an electrophilic azidating reagent and the sterically bulky chiral pyridinyl-oxazoline (Pyox) ligand are crucial to the successful reaction.