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.

Metal-free directed sp2-C-H borylation.

Organoboron reagents are important synthetic intermediates that have a key role in the construction of natural products, pharmaceuticals and organic materials1. The discovery of simpler, milder and more efficient approaches to organoborons can open additional routes to diverse substances2-5. Here we show a general method for the directed C-H borylation of arenes and heteroarenes without the use of metal catalysts. C7- and C4-borylated indoles are produced by a mild approach that is compatible with a broad range of functional groups. The mechanism, which is established by density functional theory calculations, involves BBr3 acting as both a reagent and a catalyst. The potential utility of this strategy is highlighted by the downstream transformation of the formed boron species into natural products and drug scaffolds.

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.

Asymmetric 2,3-Addition of Sulfinylamines with Arylboronic Acids Enabled by Nickel Catalysis.

Sulfinamides have been widely used in organic synthesis, with research on their preparation spanning more than a century. Despite advancements in catalytic methodologies, creating sulfur stereocenters within these molecules remains a significant challenge. In this study, we present an effective and versatile method for synthesizing a diverse range of S-chirogenic sulfinamides through catalytic asymmetric aryl addition to sulfinylamines. By utilizing a nickel complex as a catalyst, this process exhibits impressive enantioselectivity and can incorporate various arylboronic acids at the sulfur position. The resulting synthetic sulfinamides are stable and highly adaptable, allowing for their conversion to a variety of sulfur-containing compounds. Our study also incorporates detailed experimental and computational studies to elucidate the reaction mechanism and factors influencing enantioselectivity.

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.

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.

Hydrodeuteroalkylation of Unactivated Olefins Using Thianthrenium Salts.

Isotopically labeled alkanes play a crucial role in organic and pharmaceutical chemistry. While some deuterated methylating agents are readily available, the limited accessibility of other deuteroalkyl reagents has hindered the synthesis of corresponding products. In this study, we introduce a nickel-catalyzed system that facilitates the synthesis of various deuterium-labeled alkanes through the hydrodeuteroalkylation of d2-labeled alkyl TT salts with unactivated alkenes. Diverging from traditional deuterated alkyl reagents, alkyl thianthrenium (TT) salts can effectively and selectively introduce deuterium at α position of alkyl chains using D2O as the deuterium source via a single-step pH-dependent hydrogen isotope exchange (HIE). Our method allows for high deuterium incorporation, and offers precise control over the site of deuterium insertion within an alkyl chain. This technique proves to be invaluable for the synthesis of various deuterium-labeled compounds, especially those of pharmaceutical relevance.

Chromium- and Metal-Reductant-Free Asymmetric Nozaki-Hiyama-Kishi (NHK) Reaction Enabled by Metallaphotoredox Catalysis.

Chiral allylic alcohols are highly prized in synthetic chemistry due to their versatile reactivity stemming from both alkenyl and hydroxyl functionalities. While the Nozaki-Hiyama-Kishi (NHK) reaction is a widely used method for the synthesis of allylic alcohols, it suffers from drawbacks such as the use of toxic chromium salts, high amounts of metal reductants, and poor enantiocontrol. To address these limitations, we present a novel approach involving a metallaphotoredox-catalyzed asymmetric NHK reaction for the production of chiral allylic alcohols. This method marries alkenyl (pseudo)halides with aldehydes, leveraging a synergistic blend of a chiral nickel catalyst and a photocatalyst. This innovative technique enables both oxidative addition and insertion just using nickel, diverging significantly from the conventional NHK reaction pathway mediated by nickel and chromium salts. The adoption of this methodology holds immense promise for crafting a spectrum of intricate compounds, particularly those of significance in pharmaceuticals. Detailed experimental investigations have shed light on the metallaphotoredox process, further enhancing our understanding and enabling further advancements.

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.

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.

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.

From C4 to C7: Innovative Strategies for Site-Selective Functionalization of Indole C-H Bonds.

The widespread presence of hydrocarbons makes C-H functionalization an attractive alternative to traditional cross-coupling methods. As indole is an important heteroarene in a plethora of natural products and pharmaceuticals, C-H functionalization of indole moieties has emerged as one of the most important topics in this field. Due to the presence of multiple C-H bonds in indoles, site selectivity is a long-standing challenge. Much effort has been devoted to the C-H functionalization of indoles at the C3 or C2 position, while accessing the benzene core (from C4 to C7) is considerably more challenging.This Account summarizes our recent efforts toward site-selective C-H functionalization of indoles at the benzene core based on innovative strategies. A common method to solve the issue involves the development of directing groups (DGs). Our early studies establish that the installation of the N-P(O)tBu2 group at the N position can produce C7 and C6 arylation products using palladium and copper catalysts, respectively. The developed system can also be extended to direct arylation of indoles at the C5 and C4 positions by installing a pivaloyl group at the C3 position. Further investigation of indoles bearing N-PtBu2 groups shows a more diverse reactivity for C-H functionalizations at the C7 position, including arylation, olefination, acylation, alkylation, silylation, and carbonylation with different coupling partners. Compared to the P(V) DG, the P(III) group can be easily attached to the indole substrates and detached from the products. However, these attractive reactions rely mostly on precious metal catalysts with ligands; this requirement can be a significant limitation, particularly for large-scale syntheses and the necessity of removal of toxic trace metals in pharmaceutical products. We have also uncovered a general strategy for chelation-assisted aromatic C-H borylation just using simple BBr3 under mild conditions, in which the installation of pivaloyl groups at the N1 or C3 position of indoles can selectively deliver the boron species to the unfavorable C7 or C4 positions and allow subsequent C-H borylation without any metal. This transition-metal-free strategy can be extended to synthesize C7 and C4 hydroxylated indoles by boron-mediated directed C-H hydroxylation under mild reaction conditions and with broad functional group compatibility.In this Account, we describe our contributions to this topic since 2015. These studies provide efficient and attractive methods for the divergent synthesis of valuable substituted indoles and insights into the exploration of new strategies for the site-selective C-H functionalization and directives for other important heteroarenes.

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.

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.

Methodologies and Strategies for Selective Borylation of C-Het and C-C Bonds.

Organoborons have emerged as versatile building blocks in organic synthesis to achieve molecular diversity and as carboxylic acid bioisosteres with broad applicability in drug discovery. Traditionally, these compounds are prepared by the substitution of Grignard/lithium reagents with electrophilic boron species and Brown hydroboration. Recent developments have provided new routes for the efficient preparation of organoborons by applying reactions using chemical feedstocks with leaving groups. As compared to the previous methods that used organic halides (I, Br, and Cl), the direct borylation of less reactive C-Het and C-C bonds has become highly important to get efficiency and functional-group compatibility. This Review aims to provide a comprehensive overview of this topic, including (1) C-F bond borylation, (2) C-O bond borylation, (3) C-S bond borylation, (4) C-N bond borylation, and (5) C-C bond borylation. Considerable attention is given to the strategies and mechanisms involved. We expect that this Review will inspire chemists to discover more efficient transformations to expand this field.

Site-selective C-H functionalization to access the arene backbone of indoles and quinolines.

The site-selective C-H bond functionalization of heteroarenes can eventually provide chemists with great techniques for editing and building complex molecular scaffolds. During the past decade, benzo-fused N-heterocycles such as indoles and quinolines have been among the most widely investigated organic templates. Early developments have led to site-selective C-H bond functionalization on the pyrrole and pyridine cores of indoles and quinolines; however, C-H functionalization on the benzenoid ring has remained a great challenge in catalysis. In this review, we elaborate on recent developments in the highly challenging functionalization of C-H bonds on the less-reactive benzenoid core of indoles and quinolines. These findings are mainly described as selective directing group assisted strategies, remote C-H functionalization techniques and their reaction mechanisms. The underlying principle in each strategy is elucidated, which aims to facilitate the design of a more advanced structure of heterocycles based on bioactive molecules, synthetic drugs, and material aspects. Moreover, the challenges and perspectives for catalytic C-H functionalization to access the arene backbone of indoles and quinolines are also proposed in the conclusion section.

Metal-catalysed C-Het (F, O, S, N) and C-C bond arylation.

The formation of C-aryl bonds has been the focus of intensive research over the last decades for the construction of complex molecules from simple, readily available feedstocks. Traditionally, these strategies involve the coupling of organohalides (I, Br, Cl) with organometallic reagents (Mg, Zn, B, Si, Sn,…) such as Kumada-Corriu, Negishi, Suzuki-Miyaura, Hiyama and Sonogashira cross-couplings. More recently, alternative methods have provided access to these products by reactions with less reactive C-Het (F, O, S, N) and C-C bonds. Compared to traditional methods, the direct cleavage and arylation of these chemical bonds, the essential link in accessible feedstocks, has become increasingly important from the viewpoint of step-economy and functional-group compatibility. This comprehensive review aims to outline the development and advances of this topic, which was organized into (1) C-F bond arylation, (2) C-O bond arylation, (3) C-S bond arylation, (4) C-N bond arylation, and (5) C-C bond arylation. Substantial attention has been paid to the strategies and mechanistic investigations. We hope that this review can trigger chemists to discover more efficient methodologies to access arylation products by cleavage of these C-Het and C-C bonds.

Recent advances in asymmetric borylation by transition metal catalysis.

Chiral organoboronates have played a critical role in organic chemistry and in the development of materials science and pharmaceuticals. Much effort has been devoted to exploring synthetic methodologies for the preparation of these compounds during the past few decades. Among the known methods, asymmetric catalysis has emerged as a practical and highly efficient strategy for their straightforward preparation, and recent years have witnessed remarkable advances in this respect. Approaches such as asymmetric borylative addition, asymmetric allylic borylation and stereospecific cross-coupling borylation, have been extensively explored and well established employing transition-metal catalysis with a chiral ligand. This review provides a comprehensive overview of transition metal-catalysed asymmetric borylation processes to construct carbon-boron, carbon-carbon, and other carbon-heteroatom bonds. It summarises a range of recent achievements in this area of research, with considerable attention devoted to the reaction modes and the mechanisms involved.