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.

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.

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.

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 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.

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.

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 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.

Catalytic Reactions Directed by a Structurally Well-Defined Aminomethyl Cyclopalladated Complex.

The introduction of N-containing moieties into feedstock molecules to build nitrogenated functional molecules has always been widely studied by the organic chemistry community. Progress in this field paves new roads to the synthesis of N-containing molecules, which are of significant importance in biological activities and play vital roles in pharmaceuticals and functional materials. Remarkable progress has been achieved in the field of transition metal-catalyzed C-N bond-forming reactions, typified by alkene hydroamination and the aza-Wacker reaction. However, the poisoning effect of electron-donating amine substrates on late transition metal catalysts presents a key impediment to these reactions, thus limiting the scope of amine substrates to electron-deficient amide derivatives. To address this problem, our group developed a palladium-aminomethyl complex with a three-membered palladacycle structure that allowed for the incorporation of electron-rich amine building blocks via C-C bond instead of C-N bond construction. This Account details the discovery of the well-defined aminomethyl cyclopalladated complex and recapitulates its applications for the catalysis of a series of aminomethylation reactions. We highlight how the understanding of the fundamental structural properties of the defined complex guided us toward tuning the reactivity of nucleophiles to initiate aminomethylation in different modes. Moreover, principles of designing and establishing further cascade reactions are also described.Aminomethyl cyclopalladated complexes can be prepared via the oxidative addition of aminals or N,O-acetals to Pd0 species. Thorough structural investigations by single-crystal X-ray diffraction analysis of the cyclopalladated complex suggest the presence of both aminomethylene-PdII (3-membered-ring) and Pd0-iminium (π-ligated) resonance forms, which indicates that both the palladium center and the methylene site are electrophilic. This is further verified by analysis of charge distribution. Two general types of reactions can be established, differing by the selective affinity of the nucleophiles to the two electrophilic positions, which is relevant to the "hardness suitability" of the nucleophiles with each electrophilic site. Softer nucleophiles such as alkenes prefer to attack the palladium center to initiate the reaction, mainly via migratory insertion into the Pd-C bond on the 3-membered ring with high strain. Through tandem ß-hydride or reductive elimination, the Heck-type aminomethylation of styrenes, the aminomethylalkoxylation of electron-rich olefins, and even the aminomethylamination of allenes, dienes, enynes, and carbenoids with full atom-economy have been realized in line with this reaction mode. In contrast, harder nucleophiles tend to attack the harder electrophilic methylene site, leading to the aminomethylation of electron-deficient dienes. For secondary amines, a "C-N bond metathesis" process would be furnished through a reductive elimination, 1,3-proton transfer, and oxidative addition sequence. More intriguingly, when using appropriate "dinucleophile" substrates such as electron-rich amine-tethered dienes, sequential C-N bond metathesis and intramolecular insertion would occur to furnish Pd-catalyzed annulation reactions, which exhibits both the hard and soft nucleophile reactivities mentioned above. These transformations provide convenient methods for the preparation of N-containing molecules, such as amines, diamines, amino acetals, and multiple types of N-heterocycles.

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.

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.

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.

Asymmetric Aminomethylative Etherification of Conjugated Dienes with Aliphatic Alcohols Facilitated by Hydrogen Bonding.

The asymmetric construction of allylic C-O bonds with primary or secondary aliphatic alcohols remains a substantial challenge in Pd-catalyzed allylation chemistry. Here, we report the development of an additive-free, palladium-catalyzed asymmetric aminomethylative etherification of conjugated dienes that enables the efficient, asymmetric O-allylation of primary and secondary aliphatic alcohols as well as water. Mechanism studies revealed that the hydrogen-bonding interaction between the alcohol and the in situ introduced aminomethyl moiety is critical to facilitate the nucleophilic addition of the alcohol to the π-allylpalladium species, which opened up the possibility of using aliphatic alcohols and water as nucleophilic substrates. This reaction tolerates a broad range of functional groups and shows remarkable regioselectivities and uniformly high enantioselectivities, which provides a direct and rapid approach to optically pure allylic 1,3-amino ethers and 1,3-amino alcohols from simple starting materials.

Palladium-Catalyzed Ring-Closing Reaction for the Synthesis of Saturated N-Heterocycles with Aminodienes and N,O-Acetals.

An efficient palladium-catalyzed ring-closing reaction of aminodienes with N,O-acetals for the synthesis of saturated N-heterocycles is described. The reaction is consistently operated at room temperature and tolerates a wide range of functional groups with volatile MeOH as the sole byproduct. This method provides rapid and practical access to a broad range of saturated N-heterocycles with diverse structural backbones that are useful building blocks in natural product synthesis and drug discovery.

Palladium-catalyzed dearomative cyclocarbonylation of allyl alcohol for the synthesis of quinolizinones.

An approach for the synthesis of quinolizinone with potential bioactivity has been developed via palladium-catalytic dearomative cyclocarbonylation of allyl alcohol. Diverse quinolizinone compounds could be attained with good efficiencies. A feasible reaction pathway could be a successive procedure of allylation, dearomatization, CO insertion and the Heck reaction.

Transition-metal-catalyzed reactions involving reductive elimination between dative ligands and covalent ligands.

Reductive elimination is a crucial bond-forming elementary reaction in various transition-metal mediated reactions. Apart from the well-developed classic reductive elimination, the non-classic reductive elimination occurring between a covalent ligand and a dative ligand, which has been known for over 50 years, has gradually attracted much attention from the organic community. By avoiding pπ-dπ repulsion between the filled metal d-orbital and the filled ligand p-orbital and forming a cationic-type molecule, non-classic reductive elimination could facilitate many catalytic reactions that were difficult to be realized via classic reductive elimination. In this review, transition-metal catalyzed C-P, C-S, C-N, and C-C bond-forming reactions with non-classic reductive elimination as the key elementary step are summarized.

Palladium-Catalyzed Ring-Closing Reaction via C-N Bond Metathesis for Rapid Construction of Saturated N-Heterocycles.

The ring-closing reactions based on chemical bond metathesis enable the efficient construction of a wide variety of cyclic systems which receive broad interest from medicinal and organic communities. However, the analogous reaction with C-N bond metathesis as a strategic fundamental step remains an unanswered challenge. Herein, we report the design of a new fundamental metallic C-N bond metathesis reaction that enables the palladium-catalyzed ring-closing reaction of aminodienes with aminals. The reactions proceed efficiently under mild conditions and exhibit broad substrate generality and functional group compatibility, leading to a wide variety of 5- to 16-membered N-heterocycles bearing diverse frameworks and functional groups.

Nickel-Catalyzed Alkylarylation of Activated Alkenes with Benzyl-amines via C-N Bond Activation.

A nickel-catalyzed alkylarylation of active alkenes with tertiary benzylamines was achieved by charge-transfer-complex promoted C-N bond activation. The reaction proceeded through initial Ni-catalyzed C-N bond activation, followed by sequential radical addition, redox and proton abstraction with cleaved amine moiety in the absence of oxidant, and provides an efficient method to prepare various alkyl-substituted oxindoles and dihydroquinolinones in good yields.

Nickel-Catalyzed Benzylation of Aryl Alkenes with Benzylamines via C-N Bond Activation.

We have developed the first example of nickel-catalyzed Heck-type benzylation of aryl olefins with various benzylamines as benzyl electrophiles, and the benzylic C-N bond cleavage was efficiently promoted by the amine-I2 charge transfer complex (CT complex). The combination of low-cost NiCl2 and I2 has been found to facilitate Heck reaction of tertiary benzylamines and alkenes into various benzyl-substituted alkenes in good to excellent yields. This unconventional Heck reaction is proposed to go through initially the formation of a benzylic radical via oxidative addition of the C-N bond with Ni(0), then capturing by aryl alkene via radical addition, followed by single-electron transfer redox and proton abstraction without oxidant and external base.

Palladium-Catalyzed Regioselective Hydroaminocarbonylation of Alkynes to α,ß-Unsaturated Primary Amides with Ammonium Chloride.

α,ß-Unsaturated primary amides have found numerous applications in drug development, organic materials, and polymer sciences. However, the catalytic synthesis of α,ß-unsaturated primary amides via carbonylation of alkynes has long been an elusive endeavor. Here, we report a novel palladium-catalyzed hydroaminocarbonylation of alkynes with NH4Cl as the amine source, enabling the highly chemo- and regioselective synthesis of α,ß-unsaturated primary amides. A variety of alkynes, including aromatic alkynes, aliphatic alkynes, terminal alkynes, internal alkynes, as well as diynes with various functional groups, react well. The method turns the parasitic noncoordination ability of ammonium salts into a strategic advantage, enabling the gram-scale reaction to be performed in the presence of 0.05 mol % of catalyst with excellent selectivity.