Late-Stage Diversification of Phosphines by C-H Activation: A Robust Strategy for Ligand Design and Preparation.

ConspectusThe advent of the twenty-first century marked a golden era in the realm of synthetic chemistry, exemplified by groundbreaking advancements in the field of C-H activation, which is a concept that quickly transitioned from mere academic fascination to an essential element within the synthetic chemist's toolkit. This methodological breakthrough has given rise to a wealth of opportunities spanning a wide range of chemical disciplines. It has facilitated the late-stage diversification of elaborate organic frameworks, encompassing the spectrum from simple methane to complex polymers, thus refining the lead optimization process and easing the production of diverse molecular analogues. Among these strides forward, the development of phosphorus(III)-directed C-H activation stands out as an increasingly significant and inventive approach for the design and synthesis of ligands, substantially redefining the contours of synthetic methodology.Phosphines, renowned for their roles as ligands and organocatalysts, have become fundamentally important in modern organic chemistry. Their efficiency as ligands is significantly affected by coordination with transition metals, which is essential for their involvement in catalytic processes, influencing both the catalytic activity and the selectivity. Historically, the fabrication of phosphines predominantly relied on synthesis employing complex, multistep procedures. Addressing this limitation, our research has delved into ligand design and synthesis through innovative catalytic P(III)-directed C-H activation strategies. In this Account, we have explored a spectrum of procedures, including direct arylation using metal catalysis, and ventured further into domains such as C-H alkylation, alkenylation, aminocarbonylation, alkynylation, borylation, and silylation. These advances have enriched the field by providing efficient methods for the late-stage diversification of biaryl-type monophosphines as well as enabled the C-H activation of triphenylphosphine and its derivatives. Moreover, we have successfully constructed libraries of diverse axially chiral binaphthyl phosphine ligands, showcasing their potency in asymmetric catalysis. Through this Account, we aim to illuminate the exciting possibilities presented by P(III)-directed C-H activation in propelling the boundaries of organic synthesis. By highlighting our pioneering work, we hope to inspire further developments in this promising field of chemistry.

P(III)-Directed Asymmetric C-H Arylation toward Planar Chiral Ferrocenes by Palladium Catalysis.

Planar chiral ferrocenyl phosphines have been employed as highly valuable ligands in metal-catalyzed asymmetric reactions. However, their preparation remains a formidable challenge due to the requirement for intricate, multistep synthetic sequences. In addressing this issue, we have developed a groundbreaking enantioselective C-H activation strategy facilitated by P(III) directing groups, enabling the efficient construction of planar chiral ferrocenyl phosphines in a single step. Our innovative approach entails the combination of a palladium catalyst, a parent ferrocenyl phosphine, and a chiral phosphoramidite ligand, leading to exceptional reactivity and enantioselectivity. Remarkably, these novel ligands exhibit remarkable efficacy in silver-catalyzed asymmetric 1,3-dipolar cycloadditions. We carried out a combination of experimental and computational studies to obtain a more comprehensive understanding of the reaction pathway and the factors contributing to enantioselectivity.

Enantioselective Rhodium-Catalyzed C-H Arylation Enables Direct Synthesis of Atropisomeric Phosphines.

Atropisomeric phosphines hold considerable significance in asymmetric catalysis, yet their synthesis presents a formidable challenge owing to intricate multistep procedures. In this context, a groundbreaking methodology has been presented for their preparation. This innovative approach entails an atroposelective rhodium-catalyzed C-H activation employing aryl and heteroaryl halides, chelated by a P(III) center. The essence of this strategy lies in its ability to directly construct chiral phosphine ligands in a single step, thereby exhibiting exceptional efficiency in terms of atom and redox economy. Illustrative examples serve to demonstrate the immense potential of in situ-formed ligands in asymmetric catalysis. Mechanistic experiments have further provided invaluable insights into this transformation.

A Green Environmental Protection Photocatalytic Molecular Reactor for Aerobic Oxidation of Sulfide to Sulfoxide.

The design and synthesis of metal-organic frameworks (MOFs) as photocatalytic molecular reactors for varied reactions have drawn great attention. In this work, we designed a novel photoactive perylenediimides-based (PDI) carboxylate ligand N,N'-di(3',3",5',5"-tetrakis(4-carboxyphenyl))-1,2,6,7-tetrachloroperylene-3,4,9,10-tetracarboxylic acid diimide (Cl-PDI-TA) and use it to successfully synthesize a novel Zr(IV)-based MOF 1 constructed from [Zr6 O8 (H2 O)8 ]8+ clusters bridged by Cl-PDI-TA ligands. Structural analysis revealed that Zr-MOF 1 manifests a 3D framework with (4,8)-connected csq topology and possesses triangular channels of ~17 Šand mesoporous hexagonal channels of ~26 Šalong c-axis. Moreover, the synthesized Zr-MOF 1 exhibits visible-light absorption and efficient photoinduced free radical generation property, making it a promising photocatalytic molecular reactor. When Zr-MOF 1 was used as a photocatalyst for the aerobic oxidation of sulfides under irradiation of visible light, it could afford the corresponding sulfoxides with high yield and selectivity. Experimental results demonstrated that the substrate sulfides could be fixed in the pores of 1 and directly transformed to the products sulfoxides in the solid state. Furthermore, the mechanism for the photocatalytic transformation was also investigated and the results revealed that the singlet oxygen (1 O2 ) and superoxide radical (O2 ⋅- ) generated by the energy transfer and electron transfer from the photoexcited Zr-MOF to oxidants were the main active species for the catalytic reactions. This work offers a perceptive comprehension of the mechanism in PDI-based MOFs for further study on photocatalytic reactions.

Nickel-Catalyzed Asymmetric Propargyl-Aryl Cross-Electrophile Coupling.

Performing asymmetric cross-coupling reactions between propargylic electrophiles and aryl nucleophiles is a well-established method to build enantioenriched benzylic alkynes. Here, a catalytic enantioselective propargyl-aryl cross-coupling between two electrophiles was achieved for the first time in a stereoconvergent manner. Propargylic chlorides were treated with aryl iodides as well as heteroaryl iodides in the presence of a chiral nickel complex, and manganese metal was used as a stoichiometric reductant, allowing for the construction of a propargyl C-aryl bond under mild conditions. An alternative dual nickel/photoredox catalytic protocol was also developed for this cross-electrophile coupling in the absence of a metal reductant. The potential utility of this conversion is demonstrated in the facile construction of stereoenriched bioactive molecule derivatives and medicinal compounds based on the diversity of acetylenic chemistry. Detailed experimental studies have revealed the key mechanistic features of this transformation.

Atroposelective hydroarylation of biaryl phosphines directed by phosphorus centres.

Prized for their ability to generate chemical complexity rapidly, catalytic carbon-hydrogen (C-H) activation and functionalization reactions have enabled a paradigm shift in the standard logic of synthetic chemistry. Directing group strategies have been used extensively in C-H activation reactions to control regio- and enantioselectivity with transition metal catalysts. However, current methods rely heavily on coordination with nitrogen and/or oxygen atoms in molecules and have therefore been found to exhibit limited generality in asymmetric syntheses. Here, we report enantioselective C-H activation with unsaturated hydrocarbons directed by phosphorus centres to rapidly construct libraries of axially chiral phosphines through dynamic kinetic resolution. High reactivity and enantioselectivity are derived from modular assembly of an iridium catalyst with an endogenous phosphorus atom and an exogenous chiral phosphorus ligand, as confirmed by detailed experimental and computational studies. This reaction mode significantly expands the pool of enantiomerically enriched functional phosphines, some of which have shown excellent efficiency for asymmetric catalysis.

Merging Visible Light Photocatalysis and P(III)-Directed C-H Activation by a Single Catalyst: Modular Assembly of P-Alkyne Hybrid Ligands.

Metal-catalyzed C-H activation strategies provide an efficient approach for synthesis by minimizing atom, step, and redox economy. Developing milder, greener, and more effective protocols for these strategies is always highly desirable to the scientific community. In this study, the utilization of a single rhodium complex enabled the visible-light-induced late-stage C-H activation of biaryl-type phosphines with alkynyl bromides, employing inherent phosphorus atoms as directing groups. This chemistry combines P(III)-directed C-H activation with visible light photocatalysis, under exogenous photosensitizer-free conditions, offering a unique platform for ligand design and preparation. Furthermore, this study also explores the asymmetric catalysis and coordination chemistry of the resulting P-alkyne hybrid ligands with specific transition metals. Experimental results and density functional theory calculations demonstrate the mechanistic intricacies of this transformation.

Metal-Free Stereoconvergent C-H Borylation of Enamides.

Enamides, functional derivatives of enamines, play a significant role as synthetic targets. However, the stereoselective synthesis of these molecules has posed a longstanding challenge in organic chemistry, particularly for acyclic enamides that are less thermodynamically stable. In this study, we present a general strategy for constructing ß-borylenamides by C-H borylation, which provides a versatile platform for generating the stereodefined enamides. Our approach involves the utilization of metalloid borenium cation, generated through the reaction of BBr3 and enamides in the presence of two different additives, avoiding any exogenous catalyst. Importantly, the stereoconvergent nature of this methodology allows for the use of starting materials with mixed E/Z configurations, thus highlighting the unique advantage of this chemistry. Mechanistic investigations have shed light on the pivotal roles played by the two additives, the reactive boron species, and the phenomenon of stereoconvergence.

Tunably strained metallacycles enable modular differentiation of aza-arene C-H bonds.

The precise activation of C-H bonds will eventually provide chemists with transformative methods to access complex molecular architectures. Current approaches to selective C-H activation relying on directing groups are effective for the generation of five-membered, six-membered and even larger ring metallacycles but show narrow applicability to generate three- and four-membered rings bearing high ring strain. Furthermore, the identification of distinct small intermediates remains unsolved. Here, we developed a strategy to control the size of strained metallacycles in the rhodium-catalysed C-H activation of aza-arenes and applied this discovery to tunably incorporate the alkynes into their azine and benzene skeletons. By merging the rhodium catalyst with a bipyridine-type ligand, a three-membered metallacycle was obtained in the catalytic cycle, while utilizing an NHC ligand favours the generation of the four-membered metallacycle. The generality of this method was demonstrated with a range of aza-arenes, such as quinoline, benzo[f]quinolone, phenanthridine, 4,7-phenanthroline, 1,7-phenanthroline and acridine. Mechanistic studies revealed the origin of the ligand-controlled regiodivergence in the strained metallacycles.

Facile preparation of organosilanes from benzylboronates and gem-diborylalkanes mediated by KOtBu.

Methods to efficiently synthesize organosilanes are valuable in the fields of synthetic chemistry and materials science. During the past decades, boron conversion has become a generic and powerful approach for constructing carbon-carbon and other carbon-heteroatom bonds, but its potential application in forming carbon-silicon remains unexplored. Herein, we describe an alkoxide base-promoted deborylative silylation of benzylic organoboronates, geminal bis(boronates) or alkyltriboronates, allowing for straightforward access to synthetically valuable organosilanes. This selective deborylative methodology exhibits operational simplicity, broad substrate scope, excellent functional group compatibility and convenient scalability, providing an effective and complementary platform for the generation of diversified benzyl silanes and silylboronates. Detailed experimental results and calculated studies revealed an unusual mechanistic feature of this C-Si bond formation.

Enantioselective Reductive (Hetero)Arylation of Cyclic N-Sulfonyl Imines by Cobalt Catalysis.

Transition-metal-catalyzed enantioselective addition of aryl organometallic reagents to imines has emerged as one of the most powerful tools for the formation of optically active diarylmethylamines. Here, we report the first asymmetric reductive (hetero)arylations of imines using aryl and heteroaryl halides enabled by a chiral cobalt-bisphosphine catalyst. This approach shows good functional group compatibility and complements the reported strategy without use of organometallic reagents. Mechanistic investigations supported that aryl-cobalt, instead of an arylzinc reagent, was formed in situ in this reductive aryl-addition event.

Stereospecific nickel-catalyzed [4+2] heteroannulation of alkynes with aminophosphanes.

Enantioenriched phosphorus compounds play crucial roles in many fields ranging from catalyst to materials science to drug development. Despite advances in the construction of phosphacycles, incorporation of a P-chirogenic center into heterocycles remains challenging. Here, we report an effective method for the preparation of phosphacycles through nickel-catalyzed [4+2] heteroannulation of internal alkynes with aminophosphanes derived from o-haloanilines. Notably, chiral 2-λ5-phosphaquinolines can be prepared from P-stereogenic substrates via NH/PH tautomeric equilibrium without loss of stereochemical integrity. The strategy is found to exhibit a broad scope in terms of both reaction components, enabling modular construction of libraries of 2-λ5-phosphaquinolines with different steric and electronic properties for fine-tuning photophysical properties, where some of these compounds showed distinct fluorescence with high quantum yields. A series of mechanistic studies further shed light on the pathway of the heteroannulation and reasons for stereospecificity.

Ru3 (CO)12 -Catalyzed Modular Assembly of Hemilabile Ligands by C-H Activation of Phosphines with Isocyanates.

Hemilabile ligands have been applied extensively in transition metal catalysis, but preparations of these molecules typically require multistep synthesis. Here, modular assembly of diverse phosphine-amide ligands, including related axially chiral compounds, is first reported through ruthenium-catalyzed C-H activation of phosphines with isocyanate directed by phosphorus(III) atoms. High reactivity and regioselectivity can be obtained by using a Ru3 (CO)12 catalyst with a mono-N-protected amino acid ligand. This transformation significantly expands the pool of phosphine-amide ligands, some of which have shown excellent efficiency for asymmetric catalysis. More broadly, the discovery constitutes a proof of principle for facile construction of hemilabile ligands directly from the parent monodentate phosphines by C-H activation with ideal atom, step and redox economy. Several dinuclear ruthenium complexes were characterized by single-crystal X-ray diffraction analysis revealing the key mechanistic features of this transformation.

Orthogonal excitations of lanthanide nanoparticle up/down conversion emissions via switching NIR lights for in-vivo theranostics.

With multiple emissions ranging from NIR-IIb to visible lights, near-infrared light-excited lanthanide nanoparticle (LnNP) is an ideal in-vivo theranostic platform to achieve imaging guided phototherapy. However, current reported LnNPs typically demonstrate simultaneous up and downconversion emissions with fixed single excitation light, which impairs therapeutic efficiency and generates side effect during navigation. Here we develop a lanthanide-based conversion switching nanoparticle (CSNP) with independent activation of 1550 nm NIR-IIb downconversion emission under 808 nm excitation and 345/450 nm upconversion emission under 980 nm excitation. CSNP is modified with Cy-GSH to quench NIR-IIb emission and photosensitizer hypocrellin A. In vivo delivery of CSNP is traced via 808 nm irradiation, and Cy-GSH changes structure in response to glutathione to activate NIR-IIb imaging. This indicates the tumor position and timing to switch for 980 nm irradiation to activate hypocrellin A for photodynamic therapy. Orthogonal activation of CSNP up/down conversion emissions demonstrates high tumor-to-normal tissue ratio in vivo and good therapeutic result, would have promising potential as a theranostics platform.

S-(Methyl-d3) Arylsulfonothioates: A Family of Robust, Shelf-Stable, and Easily Scalable Reagents for Direct Trideuteromethylthiolation.

A family of electrophilic deuterated methylthiolating reagents, S-(methyl-d3) arylsulfonothioates, was developed in two or three steps from cheap d4-MeOH in high yields. S-(Methyl-d3) arylsulfonothioates represent a kind of powerful deuterated methylthiolating reagent and allow modular trideuteromethylthiolation with a variety of nucleophiles or electrophiles including aryl(hetero) iodides, boronic acids esters, terminal alkynes, diazonium salts, ß-ketoester, and oxindole under mild reaction conditions. A structure-reactivity research (SAR) study was conducted and provided a new avenue for the development of deuterated methylthiolating reagents and efficient methodology for trideuteromethylthiolation.

PIII -Directed Late-Stage Ligation and Macrocyclization of Peptides with Olefins by Rhodium Catalysis.

Transition metal-catalyzed C-H activation is a step-economical strategy for peptide functionalization. Herein, we report the method of late-stage peptide ligation and macrocyclization through rhodium-catalyzed alkylation of tryptophan residues at the C7 position. This method utilizes a N-Pt Bu2 directing group and tolerates various peptide and alkene substrates. Utilizing internal olefins, this study represents the first example of site-selective peptide C-H alkylation through deconjugative isomerization. Furthermore, our method provides access to peptide macrocycles with unique Trp(C7)-alkyl crosslinks and potent cytotoxicity towards cancer cells.

Rhodium-catalyzed selective direct arylation of phosphines with aryl bromides.

The widespread use of phosphine ligand libraries is frequently hampered by the challenges associated with their modular preparation. Here, we report a protocol that appends arenes to arylphosphines to access a series of biaryl monophosphines via rhodium-catalyzed P(III)-directed ortho C-H activation, enabling unprecedented one-fold, two-fold, and three-fold direct arylation. Our experimental and theoretical findings reveal a mechanism involving oxidative addition of aryl bromides to the Rh catalyst, further ortho C-H metalation via a four-membered cyclometalated ring. Given the ready availability of substrates, our approach opens the door to developing more general methods for the construction of phosphine ligands.

Nickel-Catalyzed Intermolecular Asymmetric Addition of Aryl Iodides across Aldehydes.

Enantioenriched alcohols comprise much of the framework of organic molecules. Here, we first report that chiral nickel complexes can catalyze the intermolecular enantioselective addition of aryl iodides across aldehydes to provide diverse optically active secondary alcohols using zinc metal as the reducing agent. This method shows a broad substrate scope under mild reaction conditions and precludes the traditional strategy through the pre-generation of organometallic reagents. Mechanistic studies indicate that an in situ formed arylnickel, instead of an arylzinc, adds efficiently to aldehydes, forming a new C-C bond and a chiral nickel alkoxide that may be turned over by zinc powder.

Photoinduced Etherification of Less-Strained Cycloketoxime Esters Enabled by C-C Bond Cleavage.

We report a general, scalable, and convenient photochemical process for diversities of distal oxygenated nitriles from corresponding less-strained ketoxime esters allowing one-step introductions of ether and cyano groups, which avoids the utilization of toxic cyanide reagents. A wide range of ketoxime esters involving five-membered to eight-membered cycloketoxime esters and linear ketoxime esters participate smoothly under operately simple and mild conditions, affording structurally variable ring-opening products.

BBr3 -Mediated P(III)-Directed C-H Borylation of Phosphines.

Transition-metal-catalyzed C-H borylation has been widely used in the preparation of organoboron compounds. Here, we developed a general protocol on metal-free P(III)-directed C-H borylation of phosphines mediated by BBr3 , resulting in the formation of products bearing both phosphorus and boron. The development of the metal-free strategy to mimic previous metallic processes has shown low cost, superior practicality, and environmental friendliness. Density functional theory (DFT) calculations demonstrate the preferred pathway for this metal-free directed C-H borylation process.