Site-Selective Carbonylative Cyclization with Two Allylic C-H Bonds Enabled by Radical Differentiation.

Controlling the site-selectivity of C-H functionalization is of significant importance and a formidable undertaking in synthetic organic chemistry, motivating the continuing development of efficient and sustainable technologies for activating C-H bonds. However, methods that control the site-selectivity for double C-H functionalization are rare. We herein report a conceptually new method to achieve highly site-selective C-H functionalization by implementing a radical single-out strategy. Leveraging the steric hindrance-sensitive CO-insertion as the radical differentiation process, a site-selective and stereoselective carbonylative formal [2 + 2] cycloaddition of imines and alkenes by sequential double allylic C-H bond activation was established without special and complicated HAT-reagents. This reaction was compatible with a wide range of alkenes and imines with diverse skeletons to deliver allylic ß-lactams that are of synthetic and medicinal interest.

Fluoroalkylative Ketonization of Malononitrile-Tethered Alkenes via Nickel Electron-Shuttle and Lewis Acid Catalysis.

A binary Ni/Eu catalytic system has been developed, which enables an efficient reductive dicarbofunctionalization of unactivated alkenes with alkyl halides and malononitriles. The combination of Ni electron-shuttle catalysis with Eu(OTf)3, a non-redox-type Lewis acid, effectively activates the iminyl radicals, enabling the direct formation of the C(sp3)-C(sp3) bond and ß-ketonitrile functionality across a variety of C═C double bonds. This reaction allows for the expedient synthesis of densely functionalized cyclic ß-ketonitriles bearing all-carbon quaternary centers.

Enantioselective Ring-Closing Aminomethylamination of Allylic Aminodienes with Aminals Triggered by C-N Bond Metathesis.

A conceptually novel strategy utilizing a cyclopalladated complex as an electrophile to activate the C-N bond for the C-N bond metathesis between allylamines and aminals is developed, which enables an efficient ring-closing aminomethylamination of allylic aminodienes and aminals. The reaction proceeds under mild reaction conditions and displays a remarkable scope. Utilizing a modified Trost-type diphosphine as the ligand, this method enables the efficient synthesis of 5-10-membered aminoallylated chiral N-heterocycles in good yields with high enantiomeric excess values.

Construction of Bidentate Phosphines Enabled by Photoinduced Reductive Diphosphination of Alkenes.

The diphosphination of alkenes through a radical pathway offers a promising approach for the rapid construction of aryl bisphosphines. However, such a synthetic strategy has not been successfully applied to the preparation of alkyl bisphosphines, partially due to the difficulties in the generation of phosphorus-centered radicals from common alkyl phosphine compounds. We herein demonstrate that this challenge can be overcome by hiring Janus-faced chlorophosphine as the phosphine source that can act as not only a radical precursor to generate phosphine-centered radicals but also a radicalphile to capture alkyl radicals. With this novel strategy, a photocatalyzed reductive diphosphination reaction has been established, allowing for a straightforward synthesis of both aryl and alkyl 1,2-bisphosphines from readily accessible alkenes and chlorophosphines.

Iron-catalyzed fluoroalkylative alkylsulfonylation of alkenes via radical-anion relay.

Transition metal-catalyzed reductive difunctionalization of alkenes with alkyl halides is a powerful method for upgrading commodity chemicals into densely functionalized molecules. However, super stoichiometric amounts of metal reductant and the requirement of installing a directing group into alkenes to suppress the inherent ß-H elimination bring great limitations to this type of reaction. We demonstrate herein that the difunctionalization of alkenes with two different alkyl halides is accessible via a radical-anion relay with Na2S2O4 as both reductant and sulfone-source. The Na2S2O4 together with the electron-shuttle catalyst is crucial to divert the mechanistic pathway toward the formation of alkyl sulfone anion instead of the previously reported alkylmetal intermediates. Mechanistic studies allow the identification of carbon-centered alkyl radical and sulfur-centered alkyl sulfone radical, which are in equilibrium via capture or extrusion of SO2 and could be converted to alkyl sulfone anion accelerated by iron electron-shuttle catalysis, leading to the observed high chemoselectivity.

Intramolecular Carboamination of Aminodienes to N-Heterocycles via C-N Bond Activation.

The catalytic transformation of ubiquitous but inert C-N bonds is highly appealing in synthetic chemistry, but the efficient cleaving inert C-N bond and simultaneous incorporation of both the cleaved C-moiety and N-moiety into the desired products has been a long-standing formidable challenge so far. Here, we developed a radical-addition triggered cyclization and C-N bond cleavage process enabled by the unique I2 /Ni or benzyl halide/Ni-catalytic system, allowing the formal insertion of diene into the inert C-N bond. This reaction features high atom economy and enables an expedient annulative carboamination of aminodienes to diverse pyrrolidines, piperidines, and tetrahydroisoquinolines. Mechanistic studies have revealed that the reaction is initiated via the generation of a benzyl radical and the formation of quaternary ammonium salt is key for the C-N bond cleavage.

Palladium-Catalyzed Aminoalkylative Cyclization Enables Modular Synthesis of Exocyclic 1,3-Dienes.

A novel and efficient palladium-catalyzed regioselective and stereodivergent ring-closing reaction of aminoenynes with aldehydes and boronic acids or hydrosilane is developed. This three-component reaction allows for the modular synthesis of a series of exocyclic 1,3-dienes bearing 5- to 8-membered saturated N-heterocycles. The reactions utilize a simple Pd-catalyst and work with broad range of aminoenynes, aldehydes and organometallic reagents under mild reaction conditions. The products represent useful intermediates for chemical synthesis due to the versatility of the conjugated diene. Preliminary mechanistic details of the method are also revealed.

Photocatalyzed Aminomethylation of Alkyl Halides Enabled by Sterically Hindered N-Substituents.

The catalytic C(sp3 )-C(sp3 ) coupling of alkyl halides and tertiary amines offers a promising tool for the rapid decoration of amine skeletons. However, this approach has not been well established, partially due to the challenges in precisely distinguishing and controlling the reactivity of amine-coupling partners and their product homologues. Herein, we developed a metal-free photocatalytic system for the aminomethylation of alkyl halides through radical-involved C(sp3 )-C(sp3 ) bond formation, allowing for the synthesis of sterically congested tertiary amines that are of interest in organic synthesis but not easily prepared by other methods. Mechanistic studies disclosed that sterically hindered N-substituents are key to activate the amine coupling partners by tuning their redox potentials to drive the reaction forward.

NEP010, a novel compound with minor structural modification from afatinib, exhibited significantly improved antitumor activity.

Non-small cell lung cancer (NSCLC) is classified into many subclasses according to the specific kinase mutations. The most common mutation is epidermal growth factor receptor (EGFR) somatic mutation, which has promoted the development of several novel drugs (Tyrosine kinase inhibitors, TKIs). Although various TKIs are recommended as targeted therapy for NSCLC with EGFR mutations in NCCN guidelines, not all patients respond equally to the recommended TKIs, which lead to series of novel compound under development to satisfy actual clinical needs. Based on the structure of afatinib, a marketed drug recommended as the first-line therapy for patients with EGFR mutation, NEP010 was synthesized with structural modification. The antitumor efficacy of NEP010 on mouse tumor xenograft models with different EGFR mutations was determined. Results showed that with minor structural modifications on afatinib, the inhibitory effect of NEP010 on EGFR mutant tumors was significantly improved. Pharmacokinetics test was adopted, and compared with afatinib, the increased tissue exposure of NEP010 may be the potential factor responsible for the increased efficacy. Furthermore, tissue distribution test showed a high concentration of NEP010 in the lung which happens to be the target organ of NEP010 in clinical practice. In conclusion, data obtained suggested that NEP010 has an increased anti-tumor effect via improving pharmacokinetics, and may provide a potent therapeutic option for the patients with EGFR mutation of NSCLC in the future.

Palladium-Catalyzed Hydrocarbonylative Spirolactonization for Expedite Construction of Oxaspirolactones.

A novel palladium-catalyzed cascade hydrocarbonylation of the alkene moiety followed by intramolecular spirolactonization of 2-vinylaryl hydroxyalkyl ketones has been developed, which offers efficient and expedited access to furnishing oxaspirolactones in high yields with high chemoselectivities. This new method is compatible with an array of functional groups and proceeds under mild reaction conditions with commercially available catalyst components.

Carbonylative Formal Cycloaddition between Alkylarenes and Aldimines Enabled by Palladium-Catalyzed Double C-H Bond Activation.

Double C-H bond activation can enable an expeditious reaction pathway to cyclic compounds, offering an efficient tool to synthesize valuable molecules. However, cyclization reaction enabled by double C-H bond activation at one carbon atom is nearly unknown. Herein, we report a carbonylative formal cycloaddition of alkylarenes with imines via double benzylic C-H bond activation at one carbon atom, allowing a straightforward synthesis of ß-lactams from readily accessible alkylarenes and imines, which paves the way for developing an annulation reaction through double C-H bond activation at one carbon atom.

Palladium-Catalyzed Ring-Closing Aminoalkylative Amination of Unactivated Aminoenynes.

An efficient strategy for preventing the ß-hydride elimination of alkylpalladium species by ligation of the palladium with adjacent amino-group was developed, which enabled a novel palladium-catalyzed ring-closing aminoalkylative amination of unactivated aminoenynes. The reaction is amenable to aminals, as well as aliphatic aldehydes with secondary amines, which provides straightforward access to structurally diverse exocyclic allenic amines bearing 5 to 12-membered N-heterocycles. With chiral phosphoramidite-ligated palladium complex as the catalyst, an enantioselective variant was achieved with up to 93 % ee. Simultaneously, synthetic transformations of the chiral products were also conducted to afford structurally unique spirodiamines including one pharmaceutically active molecule via axial-to-central chirality transfer.

Palladium-Catalyzed Chemodivergent Carbonylation of ortho-Bromoarylimine to Biisoindolinones and Spiroisoindolinones.

We herein report a palladium-catalyzed carbonylative cyclization reaction of ortho-bromoarylimines that allows for the chemodivergent synthesis of functionalized biisoindolinones and spirocyclic isoindolinones. Either product could be selectively obtained by switching the reaction temperatures and ligands, and the biisoindolinone products could be afforded facilely with catalyst loadings as low as 0.05 mol %. Further transformation of the biisoindolinone product is also described, which represents a novel and concise approach to the biisoindoline diamine ligand.

Copper-Catalyzed Claisen Rearrangement with AIBN and Allylic Alcohols.

A novel and succinct method for the synthesis of N-cyanomethyl amides from allylic alcohols with AIBN as the nitrile source is developed. Owing to the coordination effect with the copper catalyst, a ketenimine intermediate is formed via couplings of isobutyronitrile radicals. The copper-activated ketenimine could subsequently be intercepted by allylic alcohols and undergo Claisen rearrangement to furnish N-cyanomethyl amides. Further functional group transformations of the N-cyanomethyl amide products are also described.

Nickel-Catalyzed Oxidative Carbonylation of Alkylarenes to Arylacetic Acids.

A catalytic system combined with NiBr2 and diphenylphosphine oxide that enabled direct access to the valuable arylacetic acids from inexpensive alkylarenes and H2O via oxidative carbonylation was developed. Alkylarenes with primary and secondary benzylic C-H bonds were compatible with this method. Remarkably, the marketed drugs ibuprofen and diclofenac could be easily obtained by this procedure straightforwardly.

A universal strategy for the fabrication of single-photon and multiphoton NIR nanoparticles by loading organic dyes into water-soluble polymer nanosponges.

The development of optical organic nanoparticles (NPs) is desirable and widely studied. However, most organic dyes are water-insoluble such that the derivatization and modification of these dyes are difficult. Herein, we demonstrated a simple platform for the fabrication of organic NPs designed with emissive properties by loading ten different organic dyes (molar masses of 479.1-1081.7 g/mol) into water-soluble polymer nanosponges composed of poly(styrene-alt-maleic acid) (PSMA). The result showed a substantial improvement over the loading of commercial dyes (3.7-50% loading) while preventing their spontaneous aggregation in aqueous solutions. This packaging strategy includes our newly synthesized organic dyes (> 85% loading) designed for OPVs (242), DSSCs (YI-1, YI-3, YI-8), and OLEDs (ADF-1-3, and DTDPTID) applications. These low-cytotoxicity organic NPs exhibited tunable fluorescence from visible to near-infrared (NIR) emission for cellular imaging and biological tracking in vivo. Moreover, PSMA NPs loaded with designed NIR-dyes were fabricated, and photodynamic therapy with these dye-loaded PSMA NPs for the photolysis of cancer cells was achieved when coupled with 808 nm laser excitation. Indeed, our work demonstrates a facile approach for increasing the biocompatibility and stability of organic dyes by loading them into water-soluble polymer-based carriers, providing a new perspective of organic optoelectronic materials in biomedical theranostic applications.

Pd-Catalyzed carbonylative lactonization of 2-halidearomatic aldehydes with H2O as a nucleophile.

A palladium-catalyzed carbonylative cyclization reaction of 2-halidebenzaldehydes with H2O is described, which provides a strategy for the synthesis of diversely substituted 3,3'-oxyphthalides. Notably, the obtained 3,3'-oxyphthalide could be easily transformed into 3-aryl and alkyl phthalides with excellent efficiency using organozinc reagents under mild reaction conditions.

Silver-catalyzed chemodivergent assembly of aminomethylated isochromenes and naphthols.

A silver-catalyzed chemodivergent cyclization of alkyne-tethered aldehydes with aminals to aminomethylated 1H-isochromenes and naphthols is described by tuning the reaction conditions. The reaction exhibits broad substrate generality and functional group compatibility. Mechanistic studies have disclosed that the aminomethylated naphthols are generated from the resulting N,O-aminal containing isochromenes via a silver-catalyzed unusual rearrangement process.

Unlocking a self-catalytic cycle in a copper-catalyzed aerobic oxidative coupling/cyclization reaction.

Presented here is a copper-catalyzed, aerobic oxidative C-H/C-H cyclization reaction, which occurs by cleaving the C-H and N-H bonds of 3-phenylindoles. A broad range of 3-phenylindoles can be well tolerated to produce the indole-containing polycyclic aromatic hydrocarbons (PAH) in good to excellent yields. An evaluation of the reaction mechanism is enabled by the isolation of the di- and tri-indole intermediates, highlighting the role of the substrate for this catalytic reaction. The results of these controlled experiments and kinetic studies provide solid experimental support for a self-catalysis reaction, which has rarely been observed in oxidative C-H activation reactions. Additional mechanistic studies indicate that the substrate for this reaction accelerates by the following mechanism: The substrate combines with the Cu catalyst to transform the less active di-indole intermediate into a tri-indole intermediate. This intermediate is quickly converted into the desired product along with regeneration of the substrate copper complex.

Highly regioselective and diastereodivergent aminomethylative annulation of dienyl alcohols enabled by a hydrogen-bonding assisting effect.

A ligand-controlled palladium-catalyzed highly regioselective and diastereodivergent aminomethylative annulation of dienyl alcohols with aminals has been established, which allows for producing either cis- or trans-disubstituted isochromans in good yields with complete regioselectivity and good to excellent diastereoselectivity. Moreover, the chiral cis-products were also obtained in good yields with up to 94% ee by using a chiral phosphinamide as the ligand. Mechanistic studies revealed that the hydroxyl group plays a key role in facilitating the Pd-catalyzed Heck insertion regioselectively taking place across the internal C[double bond, length as m-dash]C bond of conjugated dienes.