Bisphosphine Ligands Research Articles

Mechanistic study of the Ni-catalyzed hydroalkylation of 1,3-dienes: The origins of regio- and enantioselectivities and a further rational design.

The development of the catalytic regio- and enantioselective hydrofunctionalization of 1,3-dienes remains a challenge and requires deep insight into the reaction mechanisms. We herein thoroughly studied the reaction mechanism of the Ni-catalyzed hydroalkylation of 1,3-dienes with ketones by density functional theory (DFT) calculations. It reveals that the reaction is initiated by stepwise oxidative addition of EtO-H followed by 1,3-diene migratory insertion to generate the alkylnickel(II) intermediate, rather than the experimentally proposed ligand-to-ligand hydrogen transfer (LLHT) mechanism. In addition, we rationalized the role of t BuOK in the subsequent addition of enolate of ketone and transmetalation process. Based on the whole catalysis, the CC reductive elimination step, turns out to be the rate- and enantioselectivity-determining step. Furthermore, we disclosed the origins of the regio- and enantioselectivity of the product, and found that the 1,2-selectivity lies in the combination effects of the ligand-substrate electrostatic interactions, orbital interactions and Pauli repulsions, while the enantioselectivity mainly arises from substrate-ligand steric repulsions. Based on mechanistic study, new biaryl bisphosphine ligands affording higher enantioselectivity were designed, which will help to improve current catalytic systems and develop new transition-metal-catalyzed hydroalkylations.

Copper-Catalyzed Regio- and Enantioselective Hydroboration of Difluoroalkyl-Substituted Internal Alkenes.

Catalytic asymmetric hydroboration of fluoroalkyl-substituted alkenes is a straightforward approach to access chiral small molecules possessing both fluorine and boron atoms. However, enantioselective hydroboration of fluoroalkyl-substituted alkenes without fluorine elimination has been a long-standing challenge in this field. Herein, a copper-catalyzed hydroboration of difluoroalkyl-substituted internal alkenes with high levels of regio- and enantioselectivities is reported. The native carbonyl directing group, copper hydride system, and bisphosphine ligand play crucial roles in suppressing the undesired fluoride elimination. This atom-economic protocol provides a practical synthetic platform to obtain a wide scope of enantioenriched secondary boronates bearing the difluoromethylene moieties under mild conditions. Synthetic applications including functionalization of biorelevant molecules, versatile functional group interconversions, and preparation of difluoroalkylated Terfenadine derivative are also demonstrated.

SciPROP-R: An Effective Bisphosphine Ligand for the Chemo-Selective Iron-Catalyzed Suzuki–Miyaura Coupling of Alkyl Chlorides

Abstract Novel 2-substituted 1,3-bis[bis(3′,5′-di-tert-butylphenyl)phosphino]propanes (SciPROP-R; 1-R), as well as their iron complexes FeCl2(SciPROP-R) 2-R, are synthesized. Single-crystal X-ray analysis and solution-phase Fe K- and L-edge XAS of 2-R reveals that these complexes maintain tetrahedral geometry and hence paramagnetic high-spin properties both in the solid state and in the solution phase. 31P NMR results demonstrate that the superior coordination ability of SciPROP-TB (1-TB) is due to the bulky tert-butyl group at position 2 of the propane-1,3-diyl linker of the ligand. These novel iron-complexes catalyze Suzuki–Miyaura-type cross coupling under mild conditions. Notably, iron(II) chloride–1-TB complex (2-TB) exhibits excellent catalytic activity owing to the high coordination ability and electron-donating nature of 1-TB, being effective for chemoselective cross coupling between various alkyl chlorides and arylboron compounds.

Synergistic effect between monophosphine species for regioselective hydroformylation of olefin with CO2

CO2 as a substitute for CO in hydroformylation is promising for alleviating greenhouse effect. Phosphine ligand has a significant impact on the regioselectivity of olefin hydroformylation with CO2. Compared with complex and expensive bisphosphine ligands, easily available and inexpensive monophosphine ligands are potential for widespread application especially in industrial hydroformylation. However, the regioselectivity of monophosphine ligand catalysts is still unsatisfactory. Herein, we proposed synergistic effect existing in two types of monophosphine species, which was copolymerized in a concise manner. The single-atom catalysts (Rh-POL-PPO&PPh3) obtained through such a strategy, are efficient for olefins/CO2 hydroformylation with high regioselectivity (l/b = 18.4) and conversion (94.9 %), which is comparable to diphosphine ligand. The characterization and DFT calculations reveal that high hydroformylation regioselectivity is attributed to the synergistic effect between two monophosphine species, which endows the catalyst with better configuration of active sites, and can promote the association of Rh with the terminal carbon of olefin.

Cobalt-Catalyzed Enantioselective Alkynylation of Oxabicyclic Alkenes

AbstractEfficient access to enantioenriched cyclic homopropargylic alcohols through an unprecedented cobalt-catalyzed asymmetric alkynylation of oxabicyclic alkenes has been developed. By using inexpensive cobalt salt/chiral bisphosphine ligand as the catalyst and easy-to-handle potassium alkynyltrifluoroborates as the nucleophile, synthetically valuable homopropargylic alcohols are obtained in moderate to good yields and high enantioselectivities.

A General Enantioselective C-H Arylation Using an Immobilized Recoverable Palladium Catalyst.

We herein report a general and efficient enantioselective C-H arylation of aryl bromides based on the use of BozPhos as the bisphosphine ligand and SP-NHC-PdII as recoverable heterogeneous catalyst. By exploiting the "release and catch" mechanism of action of the catalytic system, we used BozPhos as a broadly applicable chiral ligand, furnishing high enantioselectivities across all types of examined substrates containing methyl, cyclopropyl and aryl C-H bonds. For each reaction, the reaction scope was investigated, giving rise to 30 enantioenriched products, obtained with high yields and enantioselectivities, and minimal palladium leaching. The developed catalytic system provides a more sustainable solution compared to homogeneous systems for the synthesis of high added-value chiral products through recycling of the precious metal.

Data Science-Enabled Palladium-Catalyzed Enantioselective Aryl-Carbonylation of Sulfonimidamides.

New methods for the general asymmetric synthesis of sulfonimidamides are of great interest due to their applications in medicinal chemistry, agrochemical discovery, and academic research. We report a palladium-catalyzed cross-coupling method for the enantioselective aryl-carbonylation of sulfonimidamides. Using data science techniques, a virtual library of calculated bisphosphine ligand descriptors was used to guide reaction optimization by effectively sampling the catalyst chemical space. The optimized conditions identified using this approach provided the desired product in excellent yield and enantioselectivity. As the next step, a data science-driven strategy was also used to explore a diverse set of aryl and heteroaryl iodides, providing key information about the scope and limitations of the method. Furthermore, we tested a range of racemic sulfonimidamides for compatibility of this coupling partner. The developed method offers a general and efficient strategy for accessing enantioenriched sulfonimidamides, which should facilitate their application in industrial and academic settings.

Serum-Stable Gold(III) Bisphosphine Complex Induces Mild Mitochondrial Uncoupling and In Vivo Antitumor Potency in Triple Negative Breast Cancer.

The preparation of cyclometalated complexes offers a path to stable materials, catalysts, and therapeutic agents. Here, we explore the anticancer potential of novel biphenyl organogold(III) cationic complexes supported by diverse bisphosphine ligands, Au-1-Au-5, toward aggressive glioblastoma and triple negative breast cancer cells (TNBCs). The [C^C] gold(III) complex, Au-3, exhibits significant tumor growth inhibition in a metastatic TNBC mouse model. Remarkably, Au-3 displays promising blood serum stability over a relevant therapeutic window of 24 h and alteration in the presence of excess L-GSH. The mechanism-of-action studies show that Au-3 induces mitochondrial uncoupling, membrane depolarization, and G1 cell cycle arrest and prompts apoptosis. To the best of our knowledge, Au-3 is the first biphenyl gold-phosphine complex to uncouple mitochondria and inhibit TNBC growth in vivo.

Enantioselective Sulfonium-Claisen Rearrangement with Cinnamyl Thioethers.

Sulfonium-Claisen rearrangement leveraged by the gold-catalyzed formation of allyl sulfonium intermediates has enabled an exceptional level of regio- and enantiocontrol for the synthesis of skipped 1,4-dienes. However, the application of cinnamyl thioether derivatives to the sulfonium-Claisen rearrangement has been unsuccessful so far due to the extensive dissociation of the cinnamyl cation. By fine-tuning bisphosphine ligands, we were able to engage cinnamyl thioethers in the [3,3]-sigmatropic rearrangement, delivering the desired 1,4-dienes in a highly enantioselective manner and in good yields. The resulting products could be transformed into optically active 2-chromanones and 4H-chromenes having a vinyl moiety.

Ligand‐Dictated Regiodivergent Allylic Functionalizations via Palladium‐Catalyzed Remote Substitution

AbstractDifferent from classical allylic substitutions that require a vicinal leaving group, an olefin bearing a remote leaving group is scarcely viewed as a potential allylation substrate. Herein, we describe feasible protocols to achieve regiodivergent allylic C−H functionalizations via palladium‐catalyzed remote substitution, which provides a novel strategy for the seldomly studied migratory Tsuji–Trost reaction. Dictated by a suitable ligand, a process that involved 4,3‐hydrofunctionalization of the generated conjugated diene intermediate via metal walking is observed in generally >20 : 1 regioselectivity. Unexpectedly, a related 1,4‐hydrofunctionalization pathway is found to be a major route with a newly synthesized electron‐rich bisphosphine ligand, which challenges the conventional viewpoint on the potential regioselectivity of hydrofunctionalizations of linear internal conjugated dienes via η3‐substitution. A series of deuterium experiments and kinetic studies provide a preliminary insight into the potential catalytic cycle.

Ligand-Dictated Regiodivergent Allylic Functionalizations via Palladium-Catalyzed Remote Substitution.

Different from classical allylic substitutions requiring a vicinal leaving group, an olefin bearing a remote leaving group is scarcely viewed as a potential allylation substrate. Here we describe feasible protocols to achieve the regiodivergent allylic C-H functionalizations via palladium-catalyzed remote substitution, which provides a novel strategy for seldomly studied migratory Tsuji-Trost reaction. With the dictation of a suitable ligand, a processinvolved 4,3-hydrofunctionalization of the generated conjugated diene intermediate via metal walking is observed in generally >20:1 regioselectivity. Unexpectedly, related 1,4-hydrofunctionalization pathway is tuned to work as a major route with a newly synthesized electron-rich bisphosphine ligand, which breakouts the conventional viewpoint on the potential regioselectivity of hydrofunctionalizations of linear internal conjugated dienes via ƞ3-substitution. A series of deuterium experiments and kinetic studies provide preliminary insight into the potential catalytic cycle.

Synthesis and luminescence properties of the four-coordinate N-heterocyclic carbene (NHC) copper(I) complexes with different bisphosphine ligands

Synthesis and luminescence properties of the four-coordinate N-heterocyclic carbene (NHC) copper(I) complexes with different bisphosphine ligands

Ligand Control in Co-Catalyzed Regio- and Enantioselective Hydroboration: Homoallyl Secondary Boronates via Uncommon 4,3-Hydroboration of 1,3-Dienes.

Enantiopure homoallylic boronate esters are versatile intermediates because the C-B bond in these compounds can be stereospecifically transformed into C-C, C-O, and C-N bonds. Regio- and enantioselective synthesis of these precursors from 1,3-dienes has few precedents in the literature. We have identified reaction conditions and ligands for the synthesis of nearly enantiopure (er >97:3 to >99:1) homoallylic boronate esters via a rarely seen cobalt-catalyzed [4,3]-hydroboration of 1,3-dienes. Monosubstituted or 2,4-disubstituted linear dienes undergo highly efficient regio- and enantioselective hydroboration with HBPin catalyzed by [(L*)Co]+[BARF]-, where L* is typically a chiral bis-phosphine ligand with a narrow bite angle. Several such ligands (e.g., i-PrDuPhos, QuinoxP*, Duanphos, and BenzP*) that give high enantioselectivities for the [4,3]-hydroboration product have been identified. In addition, the equally challenging problem of regioselectivity is uniquely solved with a dibenzooxaphosphole ligand, (R,R)-MeO-BIBOP. A cationic cobalt(I) complex of this ligand is a very efficient (TON >960) catalyst while also providing excellent regioselectivities (rr >98:2) and enantioselectivities (er >98:2) for a broad range of substrates. A detailed computational investigation of the reactions using Co complexes from two widely different ligands (BenzP* and MeO-BIBOP) employing the B3LYP-D3 density functional theory provides key insights into the mechanism and the origins of selectivities. The computational results are in full agreement with the experiments. For the complexes we have examined thus far, the relative stabilities of the diastereomeric diene-bound complexes [(L*)Co(η4-diene)]+ lead to the initial diastereofacial selectivity, which in turn is retained in the subsequent steps, providing exceptional enantioselectivity for the reactions.

Neutral, Heteroleptic [Cu(I)(PPh3 )2 (4H-imidazolato)] Complexes: Ligand Exchange Reactivity, Redox Properties, Excited-State Dynamics.

Cu(I) 4H-imidazolate complexes are rare examples of Cu(I) complexes with chelating anionic ligands and are potent photosensitizers with unique absorption and photoredox properties. In this contribution, five novel heteroleptic Cu(I) complexes with monodentate triphenylphosphine co-ligands are investigated. As a consequence of the anionic 4H-imidazolate ligand and in contrast to comparable complexes with neutral ligands, these complexes are more stable than their homoleptic bis(4H-imidazolato)Cu(I) congeners. Here, the ligand exchange reactivity was studied by 31 P-,19 F-, and variable temperature NMR and the ground state structural and electronic properties by X-ray diffraction, absorption spectroscopy, and cyclic voltammetry. The excited-state dynamics were investigated by femto- and nanosecond transient absorption spectroscopy. The observed differences, with respect to chelating bisphosphine bearing congeners, are often due to the increased geometric flexibility of the triphenylphosphines. These observations render the investigated complexes interesting candidates for photo(redox)reactions not accessible with chelating bisphosphine ligands.

DFT Studies on Ligand Controlled Highly Selective Copper‐Catalyzed Borylations of Allenes

AbstractThe mechanism of the Cu‐catalyzed borylations of allenes with bis (pinacolato) diboron has been studied by DFT calculations. The possible pathways involve two key steps, borylcupration and γ‐protonolysis. Computed results show that the γ‐protonolysis step is not only the rate‐limiting step but also determines the regioselectivity. When employing monophosphine P(p‐MeOC6H4)3 as the ligand, the electronic and steric effects are both effective in the control of regio‐ and stereoselectivity; however, for sterically hindered bulky bisphosphine ligand BIPHEP, it is the steric hindrance that reverses the regioselectivity of the γ‐protonolysis process.

Catalyst Comparison for Additive-Free Acceptorless Dehydro­genation of Indoline Derivatives

AbstractA group of thirteen catalysts of type [Ru(Cp/Cp*)(P–P)(MeCN)]PF6, bearing cooperative or noncooperative bidentate phosphine ligands, were evaluated for the catalytic acceptorless dehydrogenation of indoline. The systematic comparison revealed that the optimal cooperative catalyst structure included a Cp ancillary ligand, and an N,N-disubstituted P,P-disubstituted 1,5-diaza-3,7-diphosphacyclooctane ligand, denoted as (PR 2NR′ 2). A cooperative complex bearing a PPh 2NPh 2 ligand exhibited about a twofold longer lifetime than a noncooperative analogue with (diphenylphosphino)ethane (dppe) as the supporting bisphosphine ligand. The cooperative catalyst effectively dehydrogenated a range of indoline substrates to give substituted indoles.

Theoretical Study on the Formation of 2-Pyrone Derivatives from the Reaction of Alkynes with Carbon Dioxide in the Presence of Nickel Catalyst

The formation of 2-pyrone derivatives by the reaction of CO2 with a model internal alkyne, 2-butyne, in the presence of (cod)2Ni and a bisphosphine ligand (dppb), was studied using the M06/6-311G(d,p) density functional theory method, which revealed that the reaction takes place in three stages. The first stage is the formation of the 2-butyne complex intermediate (dppb)Ni(η2-MeC≡CMe). There are several pathways for the formation of 2-pyrone complexes from it, and the more favorable two pathways were found among them. In the second stage, the coupling of (dppb)Ni(η2-MeC≡CMe) with 2-butyne or CO2 produces nickelacyclopentadiene or oxanickelacyclopentenone with the Ni–O bond, respectively. In the third stage, the reaction of CO2 with nickelacyclopentadiene or that of 2-butyne with oxanickelacyclopentenone produces 2-pyrone Ni complexes. The rate-limiting step is the second, in which nickelacyclopentadiene or oxanickelacyclopentenone is formed. The formation of oxanickelacyclopentenone with the Ni–O bond is kinetically more favorable, while the formation of nickelacyclopentadiene is thermodynamically more favorable. Thus, depending on the experimental conditions, the two pathways are in competition. This supports the mechanisms suggested by Inoue et al. and Hoberg et al., and we discuss the factors that make these mechanisms more favorable.

Chemodivergent, Regio- and Enantioselective Cycloaddition Reactions between 1,3-Dienes and Alkynes.

Alkynes and 1,3-dienes are among the most readily available precursors for organic synthesis. We report two distinctly different, catalyst-dependent, modes of regio- and enantioselective cycloaddition reactions between these classes of compounds providing rapid access to highly functionalized 1,4-cyclohexadienes or cyclobutenes from the same precursors. Complexes of an earth abundant metal, cobalt, with several commercially available chiral bisphosphine ligands with narrow bite angles catalyze [4+2]-cycloadditions between a 1,3-diene and an alkyne giving a cyclohexa-1,4-diene in excellent chemo-, regio- and enantioselectivities. In sharp contrast, complex of a finely tuned phosphino-oxazoline ligand promotes unique [2+2]-cycloaddition between the alkyne and the terminal double bond of the diene giving a highly functionalized cyclobutene in excellent regio- and enantioselectivities.

Chemodivergent, Regio‐ and Enantioselective Cycloaddition Reactions between 1,3‐Dienes and Alkynes

AbstractAlkynes and 1,3‐dienes are among the most readily available precursors for organic synthesis. We report two distinctly different, catalyst‐dependent, modes of regio‐ and enantioselective cycloaddition reactions between these classes of compounds providing rapid access to highly functionalized 1,4‐cyclohexadienes or cyclobutenes from the same precursors. Complexes of an earth abundant metal, cobalt, with several commercially available chiral bisphosphine ligands with narrow bite angles catalyze [4+2]‐cycloadditions between a 1,3‐diene and an alkyne giving a cyclohexa‐1,4‐diene in excellent chemo‐, regio‐ and enantioselectivities. In sharp contrast, complex of a finely tuned phosphino‐oxazoline ligand promotes unique [2+2]‐cycloaddition between the alkyne and the terminal double bond of the diene giving a highly functionalized cyclobutene in excellent regio‐ and enantioselectivities.

Weak Electrostatic Interactions with Bisphosphine Ligands Facilitate Reductive Elimination of PhCF3 from Pd(II) Complexes.

The origins of ligand effects on PhCF3 reductive elimination from PdII complexes were computationally investigated by using energy decomposition analysis. The results indicate weak electrostatic interactions between ligands and Ph-Pd-CF3 lead to small barriers of PhCF3 reductive elimination. Two major factors affecting the electrostatic interactions are identified.