Transmetalation Step Research Articles

DFT Mechanistic Study on Palladium‐Catalyzed Redox‐Neutral Hydroarylation of Unactivated Alkenes with Arylboronic Acids

AbstractDensity functional calculations were carried out on the mechanism of a palladium‐catalyzed hydroarylation reaction of β,γ‐unsaturated carbonyl compounds with arylboronic acids reported by Engle's group. The proposed reaction pathway consists of several key mechanistic steps, including the chelation of substrate 1 a, transmetalation of organoboron 2 a, migratory insertion, protodepalladation, and dechelation of product 3 a, among which the transmetalation step is rate‐determining with a free‐energy barrier of 27.0 kcal/mol. Experimental researchers proposed that the chelation of Daugulis's 8‐aminoquinoline (AQ) directing group facilitated the desired hydroarylation in a γ‐selective manner. However, the present study revealed that the chelation of AQ indeed retarded the delivery of the aryl group to the double bond and the regioselectivity was not necessarily the result of this group. Indeed, it could effectively prevent the homocoupling of 2 a, because the homocoupling was predicted to be easier than the desired hydroarylation in the absence of AQ. Additionally, some reductive coupling pathways between 1 a and 2 a were designed, and the competition of them was discussed in great detail. Lastly, the extension of this synthetic strategy to other types of alkenes was predicted.

The site-selectivity and mechanism of Pd-catalyzed C(sp2)-H arylation of simple arenes.

Control over site-selectivity is a critical challenge for practical application of catalytic C–H functionalization reactions in organic synthesis. Despite the seminal breakthrough of the Pd-catalyzed C(sp2)–H arylation of simple arenes via a concerted metalation–deprotonation (CMD) pathway in 2006, understanding the site-selectivity of the reaction still remains elusive. Here, we have comprehensively investigated the scope, site-selectivity, and mechanism of the Pd-catalyzed direct C–H arylation reaction of simple arenes. Counterintuitively, electron-rich arenes preferably undergo meta-arylation without the need for a specifically designed directing group, whereas electron-deficient arenes bearing fluoro or cyano groups exhibit high ortho-selectivity and electron-deficient arenes bearing bulky electron-withdrawing groups favor the meta-product. Comprehensive mechanistic investigations through a combination of kinetic measurements and stoichiometric experiments using arylpalladium complexes have revealed that the Pd-based catalytic system works via a cooperative bimetallic mechanism, not the originally proposed monometallic CMD mechanism, regardless of the presence of a strongly coordinating L-type ligand. Notably, the transmetalation step, which is influenced by a potassium cation, is suggested as the selectivity-determining step.

Experimental and Computational Studies towards Chemoselective C−F over C−Cl Functionalisation: Reversible Oxidative Addition is the Key

AbstractCatalytic cross‐coupling is a valuable tool for forming new carbon‐carbon and carbon‐heteroatom bonds, allowing access to a variety of structurally diverse compounds. However, for this methodology to reach its full potential, precise control over all competing cross‐coupling sites in poly‐functionalised building blocks is required. Carbon‐fluorine bonds are one of the most stable bonds in organic chemistry, with oxidative addition at C−F being much more difficult than at other C‐halide bonds. As such, the development of methods to chemoselectively functionalise the C−F position in poly‐halogenated arenes would be very challenging if selectivity was to be induced at the oxidative addition step. However, metal‐halide complexes exhibit different trends in reactivity to the parent haloarenes, with metal‐fluoride complexes known to be very reactive towards transmetalation. In this current work we sought to exploit the divergent reactivity of Ni−Cl and Ni−F intermediates to develop a chemoselective C−F functionalisation protocol, where selectivity is controlled by the transmetalation step. Our experimental studies highlight that such an approach is feasible, with a number of nickel catalysts shown to facilitate Hiyama cross‐coupling of 1‐fluoronapthalene under base free conditions, while no cross‐coupling with 1‐chloronapthalene occurred. Computational and experimental studies revealed the importance of reversible C−Cl oxidative addition for the development of selective C−F functionalisation, with ligand effects on the potential for reversibility also presented.

Anchoring Positively Charged Pd Single Atoms in Ordered Porous Ceria to Boost Catalytic Activity and Stability in Suzuki Coupling Reactions.

Single-atom (SA) catalysis bridging homogeneous and heterogeneous catalysis offers new opportunities for organic synthesis, but developing SA catalysts with high activity and stability is still a great challenge. Herein, a heterogeneous catalyst of Pd SAs anchored in 3D ordered macroporous ceria (Pd-SAs/3DOM-CeO2 ) is developed through a facile template-assisted pyrolysis method. The high specific surface area of 3DOM CeO2 facilitates the heavily anchoring of Pd SAs, while the introduction of Pd atoms induces the generation of surface oxygen vacancies and prevents the grain growth of CeO2 support. The Pd-SAs/3DOM-CeO2 catalyst exhibits excellent activity toward Suzuki coupling reactions for a broad scope of substrates under ambient conditions, and the Pd SAs can be stabilized in CeO2 in long-term catalytic cycles without leaching or aggregating. Theoretical calculations indicate that the CeO2 supported Pd SAs can remarkably reduce the energy barriers of both transmetalation and reductive elimination steps for Suzuki coupling reactions. The strong metal-support interaction contributes to modulating the electronic state and maintaining the stability of Pd SA sites. This work demonstrates an effective strategy to design and synthesize stable single-atom catalysts as well as sheds new light on the origin for enhanced catalysis based on the strong metal-support interactions.

Dynamic PdII /CuI Multimetallic Assemblies as Molecular Models to Study Metal-Metal Cooperation in Sonogashira Coupling.

Cooperation between two different metals plays a crucial role in many synergistic catalytic reactions, such as the Sonogashira C-C cross-coupling reaction, where an interaction between the Pd and Cu centers is proposed in the transmetalation step. Although several heterobimetallic Pd/Cu complexes were proposed as structural models of the active species in Sonogashira coupling, the detailed understanding of the metal-metal cooperation in transmetalation is still lacking in current systems. In this work, we report a stepwise and systematic approach to building heteromultimetallic Pd/Cu assemblies as a tool to study metal-metal cooperativity. We obtained fully characterized Pd/Cu multimetallic assemblies that show reactivity in alkyne activation, formation of catalytically relevant aryl/acetylide species, and C-C elimination, serving as functional models for Sonogashira reaction intermediates. The combined experimental and DFT studies highlight the importance of ligand-controlled coordination geometry, metal-metal distances and dynamics of the multimetallic assembly for transmetalation step.

Palladium-Catalyzed Regioselective and Stereospecific Ring-Opening Cross-Coupling of Aziridines: Experimental and Computational Studies.

Aziridines, i.e., the smallest saturated N-heterocycles, serve as useful building blocks in synthetic organic chemistry. Because of the release of the large ring strain energy accommodated in the small ring, (ca. 27 kcal/mol), aziridines undergo ring-opening reactions with a variety of nucleophiles. Therefore, among the synthetic reactions utilizing aziridines, regioselective ring-opening substitutions of aziridines with nucleophiles, such as heteroatomic nucleophiles (e.g., amines, alcohols, and thiols) and carbonaceous nucleophiles (e.g., carbanions, organometallic reagents, and electron-rich arenes), constitute a useful synthetic methodology to synthesize biologically relevant β-functionalized alkylamines. However, the regioselection in such traditional ring-opening substitutions of aziridines is highly dependent on the substrate combination, and stereochemical control is challenging to achieve, especially in the case of Lewis acid-promoted variants. Therefore, the development of robust catalytic ring-opening functionalization methods that enable precise prediction of regioselectivity and stereochemistry is desirable. In this direction, our group focused on the highly regioselective and stereospecific nature of the stoichiometric oxidative addition elementary step of 2-substituted aziridines into Pd(0) complexes in an SN2 fashion. In conjunction with the recent advancements in transition-metal-catalyzed cross-coupling reactions of alkyl pseudohalides containing a C(sp3)-Q (Q = O, N, S, etc.) bond, aziridines can be used as nonclassical alkyl pseudohalides in regioselective and stereospecific cross-couplings.In this Account, starting from the background of transition-metal-catalyzed ring-opening functionalization of aziridines, our contributions to the palladium-catalyzed regioselective and stereoinvertive cross-couplings of aziridines with organoboron reagents to form C(sp3)-C, C(sp3)-B, and C(sp3)-Si bonds have been compiled. The developed methods allow the syntheses of medicinally important amine compounds, e.g., enantioenriched β-phenethylamines, β-amino acids, and their boron and silyl surrogates, from readily available enantiopure aziridine substrates. Notably, the regioselectivity of the ring opening can be switched by appropriate selection of the catalyst (i.e., Pd/NHC vs Pd/PR3 systems). Computational studies rationalized the detailed mechanisms of the full catalytic cycle and the regioselectivity and stereospecificity of the reactions. The computational results suggested that the interactions operating between the Pd catalyst and aziridine substrate play important roles in determining the regioselection of the aziridine ring-opening event (i.e., oxidative addition). Also, the computational results rationalized the role of water molecules in promoting the transmetalation step through the formation of a Pd-hydroxide active intermediate. This Account evidences the benefits of synergistic collaborations between experimental and computational methods in developing novel transition-metal-catalyzed cross-coupling reactions.

Ni-Catalyzed Enantioconvergent Coupling of Epoxides with Alkenylboronic Acids: Construction of Oxindoles Bearing Quaternary Carbons

We have developed a nickel- nickel/bisphosphine-catalyzed stereoconvergent cross-coupling reaction of epoxides with alkenylboronic acids. Racemic spiroepoxyoxindoles were converted to chiral homoal...

Palladium-Catalyzed Homocoupling of Highly Fluorinated Arylboronates: Studies of the Influence of Strongly vs Weakly Coordinating Solvents on the Reductive Elimination Process.

C-C reductive elimination from [PdL2(C6F5)2] to form polyfluorinated biaryls has been a challenge for over 50 years. Thus, palladium-catalyzed homocoupling of arylboronates (ArF-Bpin) containing two ortho-fluorine substituents is very difficult, as the reaction typically stops at the [PdL2(ArF)2] stage after two transmetalation steps. The transmetalated complexes cis-[Pd(MeCN)2(C6F5)2] (3a), cis-[Pd(MeCN)2(2,4,6-C6F3H2)2] (3b), and cis-[Pd(MeCN)2(2,6-C6F2H3)2] (3e) have been isolated from the reaction of ArF-Bpin with Pd(OAc)2 in acetonitrile solvent, with no homocoupling observed. However, catalytic homocoupling proceeds smoothly in a "weakly coordinating" arene solvent as long as no ancillary ligands or coordinating solvents are present. DFT computations reveal that the active catalyst formed by arene solvent coordination leads to an overall reduced barrier for the reductive elimination step compared to the formation of stable [PdL2(ArF)2] complexes in the presence of a donor ligand or solvent L.

Rational Design of an Iron‐Based Catalyst for Suzuki–Miyaura Cross‐Couplings Involving Heteroaromatic Boronic Esters and Tertiary Alkyl Electrophiles

AbstractSuzuki–Miyaura cross‐coupling reactions between a variety of alkyl halides and unactivated aryl boronic esters using a rationally designed iron‐based catalyst supported by β‐diketiminate ligands are described. High catalyst activity resulted in a broad substrate scope that included tertiary alkyl halides and heteroaromatic boronic esters. Mechanistic experiments revealed that the iron‐based catalyst benefited from the propensity for β‐diketiminate ligands to support low‐coordinate and highly reducing iron amide intermediates, which are very efficient for effecting the transmetalation step required for the Suzuki–Miyaura cross‐coupling reaction.

Cross-Coupling of Aryl Trifluoromethyl Sulfones with Arylboronates by Cooperative Palladium/Rhodium Catalysis.

The Suzuki-Miyaura arylation of aryl trifluoromethyl sulfones via C-SO2 bond cleavage has been developed by means of cooperative palladium/rhodium catalysis. A series of aryl trifluoromethyl sulfones and arylboronic acid neopentylglycol esters are converted to the corresponding biaryls. Mechanistic investigations suggest that (1) the rhodium catalyst mediates the transfer of the aryl ring from arylboronate to palladium, resulting in the acceleration of the transmetalation step, and (2) the C-C bond-forming reductive elimination step is the turnover-limiting step.

Free Energy Profile of a Model Palladium Catalyzed Fluorination of Aryl Bromide with Cesium Fluoride.

Addition of fluorine to aromatic rings has increased in importance in the past decade in view of the increased role of organofluorine compounds in the design of new pharmaceuticals. Palladium catalyzed nucleophilic fluorination of unactivated aryl halides using salts such as cesium fluoride was achieved with the use of bulky biaryl monophosphine ligand. Simple monophosphine palladium complexes were not able to promote this reaction, which is attributed to the difficult reductive elimination step and the formation of dimers of the PdL(Ph)(F) intermediate. The use of theoretical methods for reliable design of new ligands requires the knowledge of the complete free energy profile of the catalyzed reaction. Otherwise, predictions may not be observed. In this work, a complete free energy profile of a model palladium catalyzed fluorination (trimethyl phosphine ligand), including the precatalyst decomposition mechanism (allylpalladium chloride), was investigated using a reliable theoretical method, the mPW2-PLYP double-hybrid functional, which was compared with the DLPNO-CCSD(T) benchmark method. The results suggest that palladium(π-cinnamyl) chloride is not a good precatalyst, while the monophosphine palladium complex bonded to an alkene should work better. The transmetalation step raises the overall barrier for the reductive elimination by 4.3 kcal mol-1 in the case of monophosphine catalyst, making the reaction difficult (ΔG⧧ = 34.1 kcal mol-1), even in the case of no dimerization of the monophosphine palladium fluoride complex. Thus, success of a ligand to promote palladium catalysis requires not only a monophosphine ligand that avoids dimerization but also a strong repulsion to both phenyl and fluorine bonded to the palladium in the PdL(Ph)(F) complex.

The Hiyama Cross-Coupling Reaction at Parts Per Million Levels of Pd: In Situ Formation of Highly Active Spirosilicates in Glycol Solvents.

A palladium NNC-pincer complex at a 5 mol ppm loading efficiently catalyzed the Hiyama coupling reaction of aryl bromides with aryl(trialkoxy)silanes in propylene glycol to give the corresponding biaryls in excellent yields. This method was applied to the syntheses of adapalene and a biaryl-type liquid-crystalline compound, as well as to the derivatization of dextromethorphan and norfloxacin. ESI-MS and NMR analyses of the reaction mixture suggested the formation of pentacoordinate spirosilicate intermediates in situ. Preliminary theoretical studies revealed that the glycol-derived silicate intermediates formed in situ are quite reactive silicon reagents in the transmetalation step.

The kinetics and mechanism of polymer‐based NHC‐Pd‐pyridine catalyzed heterogeneous Suzuki reaction in aqueous media

AbstractOne of the most important challenges of the Suzuki reaction is a green synthesis of reaction products. In terms of economy and ecology, the Suzuki reaction details must be characterized for the industrial‐scale Suzuki reaction processes. In this paper, for the first time, a kinetic and mechanistic study on the Suzuki reaction catalyzed with hydrogel‐supported PEPPSI (pyridine‐enhanced precatalyst preparation stabilization (and) initiation) type NHC‐Pd‐pyridine composite has been investigated. To determine the rate‐limiting step, the effects of reactants and experimental conditions on the heterogeneous Suzuki reaction have been experimentally defined. The experimental results demonstrated that it is possible to reach 100% yield under the optimum reaction conditions, which were found as 75 × 10−3 mol/L of phenylboronic acid (FBA), 50 × 10−3 mol/L of bromoacetophenone (Brac), 125 × 10−3 mol/L of K2CO3, 1 g/L of catalyst, 80°C of reaction temperature, 400 rpm of mixing rate, and 3 h of reaction time. The transmetalation step in the cycle was defined as the rate‐limiting step. On the basis of kinetic results, a mathematical reaction rate expression was presented assuming the steady‐state approach to steps of the catalytic cycle. The activation energy (Ea) of the reaction was estimated to be 34.88 kJ/mol.

Off-Cycle Processes in Pd-Catalyzed Cross-Coupling of Carboranes.

Off-cycle processes in catalytic reactions can dramatically influence the outcome of the chemical transformation and affect its yield, selectivity, rate, and product distribution. While the generation of off-cycle intermediates can complicate reaction coordinate analyses or hamper catalytic efficiency, the generation of such species may also open new routes to unique chemical products. Recently, we reported the Pd-mediated functionalization of carboranes with a range of O-, N-, and C-based nucleophiles. By utilizing a Pd-based catalytic system supported by a biaryl phosphine ligand developed by Buchwald and co-workers, we discovered an off-cycle isomerization process ("cage-walking") that generates four regioisomeric products from a single halogenated boron cluster isomer. Here we describe how several off-cycle processes affect the regioisomer yield and distribution during Pd-catalyzed tandem cage-walking/cross-coupling. In particular, tuning the transmetallation step in the catalytic cycle allowed us to incorporate the cage-walking process into Pd-catalyzed cross-coupling of sterically unencumbered substrates, including cyanide. This work demonstrates the feasibility of using tandem cage-walking/cross-coupling as a unique low-temperature method for producing regioisomers of mono-substituted carboranes.

Overcoming Halide Inhibition of Suzuki–Miyaura Couplings with Biaryl Monophosphine-Based Catalysts

The Suzuki–Miyaura reaction is one of the most widely employed transformations in synthetic chemistry. Despite extensive investigation, questions remain about the mechanistic nature of the transmetalation step when catalysts based on advanced ligands such as biaryl monophosphines are used, impeding the development of improved catalysts. Here we demonstrate that the often overlooked halide salt (KX) generated as a byproduct of cross-coupling renders the transmetalation step reversible with SPhos-based catalysts, leading to severe reaction inhibition with (hetero)aryl iodides. Stoichiometric and kinetic studies reveal that halide inhibition likely originates from disfavoring the formation of a highly reactive Pd–OH intermediate. We demonstrate that changing the organic solvent in the biphasic reaction mixture from tetrahydrofuran to toluene is sufficient to minimize this inhibition and enable the general Suzuki–Miyaura coupling of (hetero)aryl iodides. Our studies suggest that halide inhibition may be a mor...

Unexpected formation of 2-alkynylpyridines from iodo-selenopyridines by selective activation of C[sbnd]Se over C[sbnd]I bonds

The synthesis of bicyclic 2-alkynylpyridines is performed in the presence of iodo-selenopyridines and terminal alkynes, using a palladium(II) catalyst, a copper(I) co-catalyst, and triethylamine as a base. This facile cross-coupling reaction leads to a wide variety of 2-alkynylpyridines in good yields. Mechanistic investigations provided by DFT calculations reveal that the reaction should involve a key selective activation of the CSe bond of the 2-selenopyridyl moiety by the in situ generated Pd(0) catalyst, preferentially to the CI bond activation. A transmetalation step with copper acetylide, followed by a reductive elimination, affords the 2-alkynylpyridine product.

Facilitating the transmetalation step with aryl-zincates in nickel-catalyzed enantioselective arylation of secondary benzylic halides

Nickel-catalyzed asymmetric cross-coupling of secondary alkyl electrophiles with different nucleophiles represents a powerful strategy for the construction of chiral tertiary carbon centers. Yet, the use of aryl Grignard reagents or aryl zinc halides in many reactions typically resulted in low enantioselectivity, mainly due to their slow transmetalation step in the catalytical cycle and consequently the requirement of relatively high temperature. Here we report that the use of lithium aryl zincate [Ph2ZnBr]Li facilitates the transmetalation step of the nickel-catalyzed cross-coupling reaction. Based on this discovery, a highly enantioselective construction of fluoroalkyl-substituted stereogenic center by a nickel-catalyzed asymmetric Suzuki-Miyaura coupling of α-bromobenzyl trifluoro-/difluoro-/mono- fluoromethanes with a variety of lithium aryl zincates [Ph2ZnBr]Li that were in situ generated from the reaction of lithium organoboronate with 1.0 equivalent of ZnBr2 was described.

Rh-catalyzed 1,4-addition reactions of arylboronic acids accelerated by co-immobilized tertiary amine in silica mesopores

Mesoporous silica-supported Rh complex catalysts were prepared by simple silane-coupling, followed by complexation, and characterized by FT-IR, SEM, Rh K-edge XAFS, and elemental analysis. Local structures of the Rh complexes in each sample were almost similar to those of a nonporous silica-supported diaminorhodium complex. Co-immobilization of a tertiary amine on the same silica surface induced slight changes to the Rh complex structure in the case of the support with smaller pores. The prepared catalysts showed high activity for the 1,4-addition reaction of phenylboronic acids. Co-immobilization of the tertiary amine increased the reaction rate by more than 7-fold, with turnover number of nearly 8500. The catalytic performance achieved with this novel system is with much higher than that reported previously with a nonporous silica-supported catalyst. The mesoporous silica-supported Rh complex-tertiary amine showed a wide substrate scope, including unsaturated ketones and nitriles. This co-immobilized tertiary amine may activate phenylboronic acid to enhance its reactivity in the transmetalation step with Rh-OH species.

Nickel-catalyzed Suzuki\u2013Miyaura cross-couplings of aldehydes

Transition-metal-catalyzed cross-couplings have been extensively used in the pharmaceutical and agrochemical industries for the construction of diverse C–C bonds. Conventional cross-coupling reactions require reactive electrophilic coupling partners, such as organohalides or sulfonates, which are not environmentally friendly and not naturally abundant. Another disadvantage associated with these transformations is the need for an exogenous base to facilitate the key transmetalation step, and this reagent inevitably induces side reactions and limits the substrate scope. Here, we report an unconventional Suzuki-type approach to the synthesis of biaryls, through nickel-catalyzed deformylative cross coupling of aldehydes with organoboron reagents under base-free conditions. The transformation tolerates structurally diverse (hetero)aryl substituents on both coupling partners and shows high reactivity and excellent functional group tolerance. Furthermore, the protocol was carried out on gram scale and successfully applied to the functionalization of complex biologically active molecules. Mechanistic investigations support a catalytic cycle involving the oxidative addition of the nickel into the aldehyde C(acyl)–H bond with subsequent hydride transfer, transmetalation, decarbonylation and reductive elimination processes.

2‐Adamantyl Complexes of Platinum

The first adamantyl platinum complexes were isolated and characterized, namely [(COD)Pt(2‐Ad)Cl], [(dppe)Pt(2‐Ad)Cl], [(COD)Pt(2‐Ad)Me] and, [(dppe)Pt(2‐Ad)Me] {COD = 1,5‐ cyclooctadiene, dppe = 1,2‐bis(diphenylphosphino)ethane, Ad = adamantyl}. These complexes show considerable stability, including resistance to heating to 125° C in solution for several days. It is therefore concluded that previously existing road blocks to synthesizing platinum adamantyls were due to complications in the transmetallation step, and not due to intrinsic instability of the final product. Counterintuitively, the key to successful transmetallation from ZnII onto PtII is imposing slow reaction progress via use of a solvent in which both the platinum chloride precursor and adamantyl anion precursor are poorly soluble.