Synthesis of Diarylalkanes by Photoreductive 1,2-Diarylation of Alkenes with Aryl Halides and Cyanoaromatics.

We report a visible light-induced photoreductive strategy for three-component diarylation of alkenes with aryl halides and cyanoaromatics. Upon photoredox catalysis and with tertiary alkyl amines as the electron transfer agent, aryl halides selectively undergo halogen atom transfer to generate the aryl radicals and two C(sp2)-C(sp3) bonds between the cabron atoms are created in a radical addition and radical-radical coupling fashion to rapidly assemble diverse functionalized polyarylalkanes with high regio- and chemoselectivity. This method can be applied to broad feedstocks, including terminal alkenes, internal alkenes, aryl iodides, aryl bromides, aryl chlorides, electron-deficient benzonitriles, and isonicotinonitriles.

Photoreductive 1,4-Dicarbofunctionalization of 1,3-Enynes with Organoiodides and Cyanoarenes via Halogen-Atom Transfer.

A photoreductive halogen-atom transfer (XAT) strategy for 1,4-dicarbofunctionalization of 1,3-enynes with organoiodides and cyanoarenes is disclosed, enabling access to functionalized allenes in a highly regio-, chemo-, and stereoselective manner. Upon the photoredox catalysis and the activation of Et3N XAT agents, the mild conditions and high functional group tolerance of this protocol enable the formation of two C-C bonds, including a C(sp3)-C(sp3) bond and a C(sp2)-C(sp2) bond, in a single reaction step, and provides a general avenue to polysubstituted allenes and late-stage modification of bioactive compounds.

Electrochemical Dehydrogenative [3 + 2]/[5 + 2] Annulation of N-Arylacrylamides with γ,σ-Unsaturated Malonates via Direct C(sp3)-H/C(sp2)-H Functionalization.

Herein, we introduce an electrochemical dehydrogenative [3 + 2]/[5 + 2] annulation of easily available N-arylacrylamides with γ,σ-unsaturated malonates through C(sp3)-H/C(sp2)-H functionalization. The employment of inexpensive ferrocene as the redox catalyst allows access to diverse benzo[b]azepin-2-ones in moderate to excellent yields without stoichiometric oxidants. This protocol features broad substrate scope and excellent selectivity, and mechanistic studies indicated that the reaction proceeded through the oxidation of a C(sp3)-H bond to generate an alkyl radical, radical addition across the C═C bond, [3 + 2]/[5 + 2] annulations, and C(sp2)-H functionalization cascades.

Photo-/Electrocatalytic Difunctionalization of Alkenes Enabled by C-H Radical Functionalization.

The difunctionalization of alkenes represents a powerful tool to incorporate two functional groups into the alkene bones for increasing molecular complexity and has been widely utilizations in chemical synthesis. Upon the catalysis of the green, sustainable, mild photo-/electrochemistry technologies, much attentions have been attracted to the development of new tactics for the transformations of the important alkene and alkane feedstocks driven by C-H radical functionalization. Herein, we summarize recent advances in the photo-/electrocatalytic difunctionalization of alkenes enabled by C-H radical functionalization. We detailedly discuss the substrate scope and the mechanisms of the photo-/electrocatalytic alkene difunctionalization reactions by selecting impressive synthetic examples, which are divided into four sections based on the final terminated step, including oxidative radical-polar crossover coupling, reductive radical-polar crossover coupling, radical-radical coupling, and transition-metal-catalyzed coupling.

Theoretical Insights into the Mechanism and Origin of Solvent-Dependent Selectivity in the Cyclization of Propargyl Alcohols for the Divergent Synthesis of N-Heterocycles.

This study elucidates the mechanisms and principles governing chemoselectivity in synthesizing two distinct N-heterocycles, benzimidazole thiazine and benzothiazole imidazole, through BF3•OEt2-catalyzed cyclization reactions of propargyl alcohols with benzimidazole thiols. Employing density functional theory calculations, we highlight the crucial role of fluorine source in influencing chemoselectivity. In DCM, BF3, as the catalytic center, coordinates with propargyl alcohol's hydroxyl group to form a precursor. Conversely, in DMF, [BF2•DMF]+, formed from DMF and BF3•OEt2, acts as the catalytic center, activating the propargyl alcohol's hydroxyl group. The mechanisms in both solvents involve sequential steps: B-O bond formation, C-O bond cleavage, S-C bond formation, hydrogen atom transfer (HAT), cyclization, and deprotonation. A notable difference is the HAT process: in DCM, it follows a 1,5-HAT process, while in DMF, BF4- formation from DMF and BF3•OEt2 provides a fluorine source and introduces steric hindrance, favoring a 1,6-HAT process and leading to unique chemoselectivity. This pioneering research showcases the impact of DMF on cyclization reactions, offering valuable insights for comprehending and designing reactions driven by fluorine sources. Crucially, our results propose an innovative reaction mechanism featuring lower potential energy surfaces, enhancing our understanding of the intricate interplay among reactants, catalysts, and solvents.

Ru(II)-Catalyzed C-H Amination of 1,2,3-Benzotriazinones with Azide Compounds.

A Ru(II)-catalyzed directed C-H amination of 1,2,3-benzotriazinones with azide compounds has been reported. The reaction has a wide substrate scope of organic azides with good results and represents a useful pathway to the construction of versatile heterocyclic amino products. In addition, the method can be used for the phthalazinones, highlighting the synthetic practicability of the strategy.

Photochemical Divergent Ring-Closing Metathesis of 1,7-Enynes: Efficient Synthesis of Spirocyclic Quinolin-2-ones.

A photocatalytic method for the ring-closing 1,7-enyne metathesis using the α-amino radical as an alkene deconstruction auxiliary is present. Preliminary mechanistic studies suggest that intramolecular 1,5-hydrogen atom transfer is the key to the generation and ß-scission of the α-amino radical, while the dearomatization of arenes and ring opening of cyclopropanes are the key to construct spirocyclic quinolin-2-ones. This approach highlights the potential of ring-closing 1,7-enyne metathesis, providing a green, efficient, and step-economical way for the synthesis of spirocyclic quinolin-2-ones.

Photoredox Ring Opening 1,2-Alkylarylation of Alkenes with Sulfonium Salts Toward Thioether-Substituted Oxindoles.

A novel strategy for the difunctionalization of electron-deficient alkenes with aryl sulfonium salts to access remote sulfur-containing oxindole derivatives by using in situ-formed copper(I)-based complexes as a photoredox catalyst is presented. This method enables the generation of the C(sp3)-centered radicals through site selective cleavage of the C-S bond of aryl sulfonium salts under mild conditions. Moreover, the oxidation reactions of desired products provide a new strategy for the preparation of sulfoxide or sulfone-containing compounds. Importantly, this approach can be easily applied to late-stage modification of pharmaceuticals molecules.

Iodoarene-directed photoredox ß-C(sp3)-H arylation of 1-(o-iodoaryl)alkan-1-ones with cyanoarenes via halogen atom transfer and hydrogen atom transfer.

Site selective functionalization of inert remote C(sp3)-H bonds to increase molecular complexity offers vital potential for chemical synthesis and new drug development, thus it has been attracting ongoing research interest. In particular, typical ß-C(sp3)-H arylation methods using chelation-assisted metal catalysis or metal-catalyzed oxidative/photochemical in situ generated allyl C(sp3)-H bond processes have been well developed. However, radical-mediated direct ß-C(sp3)-H arylation of carbonyls remains elusive. Herein, we describe an iodoarene-directed photoredox ß-C(sp3)-H arylation of 1-(o-iodoaryl)alkan-1-ones with cyanoarenes via halogen atom transfer (XAT) and hydrogen atom transfer (HAT). The method involves diethylaminoethyl radical-mediated generation of an aryl radical intermediate via XAT, then directed 1,5-HAT to form the remote alkyl radical intermediate and radical-radical coupling with cyanoarenes, and is applicable to a broad scope of unactivated remote C(sp3)-H bonds like ß-C(sp3)-H bonds of o-iodoaryl-substituted alkanones and α-C(sp3)-H bonds of o-iodoarylamides. Experimental findings are supported by computational studies (DFT calculations), revealing that this method operates via a radical-relay stepwise mechanism involving multiple SET, XAT, 1,5-HAT and radical-radical coupling processes.

Photoredox-Catalyzed Alkylarylation of N-Aryl Bicyclobutyl Amides with α-Carbonyl Alkyl Bromides: Access to 3-Spirocyclobutyl Oxindoles.

A visible-light-induced radical alkylarylation of N-aryl bicyclobutyl amides with α-carbonyl alkyl bromides for the synthesis of functionalized 3-spirocyclobutyl oxindoles is described in which ß-selective radical addition of the alkyl radical to N-aryl bicyclobutyl amides forms a key radical intermediate followed by interception with intrinsic arene functional group. This approach can be applicable to a wide range of α-carbonyl alkyl bromides, including primary, secondary, and tertiary α-bromoalkyl esters, ketones, nitriles, and nitro compounds.

Electroreductive Remote Benzylic C(sp3)-H Arylation of Aliphatic Ethers Using Cyanoarenes for the Synthesis of α-(Hetero)aryl Ethers.

An iodoarene-driven electroreductive remote C(sp3)-H arylation of unsymmetrical 1-(o-iodoaryl)alkyl ethers with cyanoarenes for the site selective synthesis of α-(hetero)aryl ethers is developed. With the introduction of cyanoarenes as both aryl sources and electron transfer mediators, this method includes an iodoarene-driven strategy to enable the regiocontrollable formation of two new bonds, one C(sp2)-H bond, and one C(sp2)-C(sp3) bond, in a single reaction step through the sequence of halogen atom transfer (XAT), hydrogen atom transfer (HAT), radical-radical coupling, and decyanation.

Nickel-Catalyzed Reductive Cross-Coupling of Propargylic Acetates with Chloro(vinyl)silanes: Access to Silylallenes.

Because of their various reactivities, propargyl acetates are refined chemical intermediates that are extensively applied in pharmaceutical synthesis. Currently, reactions between propargyl acetates and chlorosilanes may be the most effective method for synthesizing silylallenes. Nevertheless, owing to the adaptability and selectivity of substrates, transition metal catalysis is difficult to achieve. Herein, nickel-catalyzed reductive cross-coupling reactions between propargyl acetates and substituted vinyl chlorosilanes for the synthesis of tetrasubstituted silylallenes are described. Therein, metallic zinc is a crucial reductant that effectively enables two electrophilic reagents to selectively construct C(sp2)-Si bonds. Additionally, a Ni-catalyzed reductive mechanism involving a radical process is proposed on the basis of deuteration-labeled experiments.

Cobalt-Promoted Photoredox 1,2-Amidoamination of Alkenes with N-Sulfonamidopyridin-1-ium Salts and Free Amines.

A cobalt-promoted photoredox 1,2-amidoamination of alkenes with N-sulfonamidopyridin-1-ium salts and free amines for the synthesis of unsymmetrical vicinal diamines has been developed. The reaction handles N-(sulfonamido)pyridin-1-ium salts as the sulfonamidyl radical precursors and free amines as the nucleophilic terminating reagents to enable the formation of two new C(sp3)-N bonds in a single reaction step and offers a route to selectively producing unsymmetrical vicinal diamines with an exquisite selectivity and a good compatibility of functional groups.

Aryldiazonium-Salt-Triggered Carboxylative Azotization of Pyrroles or Indoles with Polyhalomethanes via Halogen-Atom Transfer (XAT).

A halogen-atom-transfer (XAT)-based method for carbonylazotization of pyrroles or indoles with aryldiazonium salts and polyhalomethanes via dual C(sp2)-H bond functionalization is described. Using aryldiazonium salts realizes carbonylation/azotization of pyrroles or indoles via polyhalomethyl-radical-mediated and electrophilic substitution, thus providing a green, efficient, and step-economy approach for synthesis of multifunctional pyrroles or indoles from the easily available substrates. Notably, this strategy relies on the use of aryldiazonium salts to extend the well-established iodine atom transfer to bromine or chlorine atom transfer.

Palladium/Norbornene Cooperative Catalysis Bifunctionalization: Acylation/Cyanation of Aryl Iodides by Cleaving C-CN Bond of Aryl Acyl Nitrile.

A palladium/norbornene catalyzed two-component coupling process involving acylation/cyanation of aryl iodides is reported. In this work, aryl acyl nitrile compounds are cleverly selected to provide both nitrile and acyl sources by palladium-catalyzed cleavage of the C-CN bond as both an electrophilic reagent and a termination reagent. This is the first example of C-CN bond cleavage bifunctionalization of aryl iodides. After a series of important NBE derivatives are screened, the products resulting from the bifunctionalization of aryl iodides are smoothly obtained. This strategy has a wide range of substrates and good functional group compatibility. Moreover, this synthetic protocol demonstrated a good application for the synthesis of diverse O,N,C-substituted isoindolinones.

Divergent [2 + n] Heteroannulation of ß-CF3-1,3-enynes with Alkyl Azides via Hydrogen Atom Transfer and Radical Substitution.

A copper-promoted divergent intermolecular [2 + n] heteroannulation of ß-CF3-1,3-enynes with alkyl azides via alkyl radical-driven HAT and radical substitution (C-C bond formation) to form four- to ten-membered saturated N-heterocycles is developed. This method enables the aryl-induced or kinetically controlled site selective functionalization of the remote C(sp3)-H bonds at positions 2, 3, 4, 5, 6, 7, or 8 toward the nitrogen atom through triplet nitrene formation, radical addition across the C═C bond, HAT and radical substitution cascades, and features a broad substrate scope, excellent site selectivity, and facile late-stage derivatization of bioactive molecules. Initial deuterium-labeling and control experiments shed light on the reaction mechanism via nitrene formation and HAT.

Visible-Light-Induced Photoredox 1,2-Dialkylation of Styrenes with α-Carbonyl Alkyl Bromides and Pyridin-1-ium Salts.

A visible-light-driven photoredox dialkylation of styrenes with α-carbonyl alkyl bromides and pyridin-1-ium salts for the synthesis of polysubstituted 1,4-dihydropyridines is reported. This reaction enables the formation of two new C(sp3)-C(sp3) bonds in a single reaction step and provides a strategy that employs pyridin-1-ium salts as the functionalized alkylating reagents via dearomatization to directly trap the resulting alkyl radicals from radical addition of alkenes and then terminate the alkene dialkylation.

Orange-derived extracellular vesicles nanodrugs for efficient treatment of ovarian cancer assisted by transcytosis effect.

Extracellular vesicles (EVs) have recently received much attention about the application of drug carriers due to their desirable properties such as nano-size, biocompatibility, and high stability. Herein, we demonstrate orange-derived extracellular vesicles (OEV) nanodrugs (DN@OEV) by modifying cRGD-targeted doxorubicin (DOX) nanoparticles (DN) onto the surface of OEV, enabling significantly enhancing tumor accumulation and penetration, thereby efficiently inhibiting the growth of ovarian cancer. The obtained DN@OEV enabled to inducement of greater transcytosis capability in ovarian cancer cells, which presented the average above 10-fold transcytosis effect compared with individual DN. It was found that DN@OEV could trigger receptor-mediated endocytosis to promote early endosome/recycling endosomes pathway for exocytosis and simultaneously reduce degradation in the early endosomes-late endosomes-lysosome pathway, thereby inducing the enhanced transcytosis. In particular, the zombie mouse model bearing orthotopic ovarian cancer further validated DN@OEV presented high accumulation and penetration in tumor tissue by the transcytosis process. Our study indicated the strategy in enhancing transcytosis has significant implications for improving the therapeutic efficacy of the drug delivery system.

Electroreductive Carboxylation of Propargylic Acetates with CO2: Access to Tetrasubstituted 2,3-Allenoates.

An electroreductive carboxylation of propargylic alcohols with CO2 and then workup with TMSCHN2 to construct tetrasubstituted 2,3-allenoates is developed. This method allows the incorporation of an external ester group into the resulting allene system through electroreduction, carboxylation, and deacetoxylation cascades. Mechanistically, electricity on/off experiments and cyclic voltammetry analysis support the preferential generation of the CO2 radical anion or the 3-aryl propargylic acetate radical anion based on the electron nature of the aryl rings.

Palladium-Catalyzed ß-C(sp3)-H Arylation of Silyl Prop-1-en-1-ol Ethers with Aryl Halides: Entry to α,ß-Unsaturated Ketones.

A palladium(0)-catalyzed ß-C(sp3)-H arylation of silyl prop-1-en-1-ol ethers with aryl halides for the synthesis of α,ß-unsaturated ketones is presented. In contrast to the reported ß-C(sp3)-H arylation of ketones, the chemoselectivity of this current method relies on the Pd(0) catalytic systems and reaction temperatures: While using the Pd(dba)2/DavePhos/KF system at 80 °C resulted in ß-C(sp3)-H monoarylation to produce ß-monoarylated α,ß-unsaturated ketones, harnessing the Pd(OAc)2/t-Bu XPhos/K2HPO4 system at 110 °C induced ß-C(sp3)-H diarylation to afford ß,ß-diarylated α,ß-unsaturated ketones. The method provides a versatile route that uses readily available ketone-derivatized α-nonsubstituted silyl prop-1-en-1-ol ethers as the alkene sources and is characterized by a good functional group compatibility, a broad substrate scope, and an excellent selectivity.