ICl-Mediated Functional Group Interconversion from Methyl Homopropargyl Ether to α-Iodo-γ-chloroketone.

An ICl-mediated highly chemo- and regioselective functional group interconversion from methyl homopropargyl ether to α-iodo-γ-chloro-ketone is reported. Density functional theory (DFT)-calculated reaction coordinate and potential energy surface support the high chemo-selectivity observed for the formation of α-iodo-γ-chloroketone over furan. The five-membered oxonium ring formation-ring opening mechanism is a potential template for the preparation of polyfunctionalized carbonyl compounds.

Organometallic chemistry and application of palladacycles in asymmetric hydrophosphination reactions.

A number of palladacycles containing chiral chelating auxiliaries have been utilized as efficient catalysts for asymmetric hydrophosphination reactions. In all cases, the chiral auxiliaries remained coordinated to the palladium centres throughout the course of the reactions. Despite the presence of a large quantity of powerful tertiary phosphines, which are known to be strong metal ion sequesters, the expected catalyst poisoning was rarely observed in these palladacycle catalyzed processes. This review highlights the unique stereoelectronic features and the important organometallic chemistry of palladacycle catalysts which are essential to their synthetic operations.

Chelating Phosphine-N-Heterocyclic Carbene Platinum Complexes via Catalytic Asymmetric Hydrophosphination and Their Cytotoxicity Toward MKN74 and MCF7 Cancer Cell Lines.

A series of activated vinyl azoles was hydrophosphinated in the presence of a chiral palladacycle catalyst under mild conditions to give enantioenriched phosphine azoles with moderate enantioselectivities and yields. The racemic phosphine azoles were transformed into eleven novel chelating phosphine-N-heterocyclic carbene (NHC) platinum complexes. The drug efficacies of nine selected phosphine-NHC platinum(II) chlorides in two cancer cell lines (MKN74 and MCF7) were evaluated, and two were found to exhibit activities comparable to that of cisplatin.

Enantioselective C,P-Palladacycle-Catalyzed Arylation of Imines.

Chiral diarylmethylamines are of great interest because of their prevalence in biological and pharmaceutical sciences. Herein, we report a C,P-palladacycle-catalyzed enantioselective synthesis of chiral diarylmethylamines via asymmetric arylation of N-protected imines with arylboronic acids. The C,P-palladacycle showed high reactivity (up to 99% yield) and enantioselectivity (up to 99% ee) toward this arylation, enabling the tolerance of a wide range of functionalities, providing a convenient and efficient access to enantiomerically enriched diarylmethylamines. The absolute configuration of the product was well rationalized by the proposed stereochemical pathway and the catalytical cycle.

Catalytic Asymmetric Diarylphosphine Addition to α-Diazoesters for the Synthesis of P-Stereogenic Phosphinates via P*-N Bond Formation.

The asymmetric catalytic P-H addition of racemic secondary phosphines to electrophilic α-diazoesters via P*-N bond formation is disclosed for the first time. Interaction between the diazoester and the palladium catalyst resulted in the unusually enhanced electrophilic ability of the terminal nitrogen in the diazo functionality, as opposed to the commonly expected formation of a metal carbene by nitrogen elimination. Further derivatization of the generated phosphinic hydrazones provided access to enantioenriched P-stereogenic diarylphosphinates via a simple transformation.

Catalytic Approach toward Chiral P,N-Chelate Complexes Utilizing the Asymmetric Hydrophosphination Protocol.

A synthetic procedure for obtaining a chiral P,N ligand was developed by exploiting the versatility of the asymmetric hydrophosphination protocol catalyzed by a phosphapalladacycle complex. The addition of the synthesized ligand to various metal sources led to the generation of chiral and enantioenriched chelate complexes, which can be useful prototypes for catalyst design in the future. The resulting coordination compounds were comprehensively characterized by solid-state (X-ray crystallography) and solution-based (one- and two-dimensional NMR spectroscopy) techniques and natural bond orbital (density functional theory) analysis to determine their structural and key electronic features.

Iron-Catalyzed Transfer Hydrogenation in Aged N-Methyl-2-pyrrolidone: Reductive Ring-Opening of 3,5-Disubstituted Isoxazoles and Isoxazolines.

3,5-Disubstituted isoxazoles and isoxazolines undergo an iron-catalyzed reductive ring-opening in aged N-methyl-2-pyrrolidone (NMP). 5-Hydroxy-N-methyl-2-pyrrolidone generated in situ via a simple activation of commercial NMP acts as the hydrogen donor in the iron-catalyzed transfer hydrogenation reaction. It is the first example employing a combination of an iron catalyst and 5-hydroxy-N-methyl-2-pyrrolidone as reducing agents in a transfer hydrogenation reaction. The protocol is highly efficient for the synthesis of ß-enaminones and 1,3-diketones, providing a versatile route for the preparation of these 1,3-difunctional compounds bearing diversified substitution patterns.

Tandem double hydrophosphination of α,ß,γ,δ-unsaturated-1,3-indandiones: diphosphine synthesis, mechanistic investigations and coordination chemistry.

A metal-free tandem double hydrophosphination of extended conjugated indandiones has been established. Mechanistic investigations confirmed the consecutive manner of the nucleophilic addition reaction. Complexation of the generated keto-diphosphine resulted in the formation of an unexpected tridentate bridging ligand with an anionic P,O-bidentate and a neutral P-monodentate coordination mode on two palladium units. In the presence of an external chiral auxiliary, the coordinated diphosphines could be separated into their enantiomeric forms.

Catalytic and Mechanistic Developments of the Nickel(II) Pincer Complex-Catalyzed Hydroarsination Reaction.

Synthetic challenges have significantly slowed the development of the catalytic asymmetric hydroarsination reaction despite it being a highly attractive C-As bond formation methodology. In addition, there is a poor understanding of the main reaction steps in such reactions which limit further development in the field. Herein, key intermediates of the hydroarsination reaction catalyzed by a PCP NiII -Cl pincer complex are presented upon investigating the reaction with DFT calculations, conductivity measurements, NMR spectroscopy, and catalytic screening. The novel Ni-Cl-As interaction proposed was then contrasted against known NiII -catalyzed hydrophosphination reactions to highlight dissimilarities between them even though P and As share a close group relationship. Lastly, the asymmetric hydroarsination of nitroolefins was further developed to furnish a library of chiral organoarsines in up to 99 % yield and 80 % ee under mild conditions (-20 °C to RT) between 5 to 210 mins.

Investigating palladium pincer complexes in catalytic asymmetric hydrophosphination and hydroarsination.

Given the periodic relationship of phosphines and arsines, is remodeling the catalytic asymmetric hydrophosphination reaction an efficient manner to develop the corresponding hydroarsination reaction? Herein, a chiral PCP-Pd(ii) pincer complex adept at generating enantioenriched phosphines was examined in the asymmetric hydroarsination reaction. Under distinct conditions, tertiary phosphines and arsines were generated in excellent yields (P: 96%, As: 91%) and ees (P: 90%, As: 85%). While secondary arsine reagents were not direct substitutes for the analogous phosphines, important parameters were identified which increased yield and ee of the hydroarsination reaction. Unlike the PCP-PdOAc pincer complex commonly used for hydrophosphinations, hydroarsination reactions involved a PCP-PdCl catalyst with 10 equiv. of CsF for optimal performance. Notable differences between the two reactions and their workup procedures were highlighted to guide further developments in the field. Lastly, respective mechanisms were proposed and contrasted for the activation of HEPh2 (E = P, As).

Challenges in cyclometalation: steric effects leading to competing pathways and η1,η2-cyclometalated iridium(iii) complexes.

The iridation of (R)-N,N-dimethyl-1-(1-naphthyl)ethylamine in the presence of a base afforded an assortment of products ranging from organic molecules to coordinated systems and cyclometalated complexes. The transformation affirmed the postulation where steric effects within the coordination sphere favor a ß-hydride elimination-like decomposition pathway, competing alongside ortho-metalation, thus leading to iminium intermediates. The same procedure also generated an unprecedented carbocyclic η1,η2-cycloiridated species that could not be attained from the direct cyclometalation of its organic ligand.

Desymmetrization of Achiral Heterobicyclic Alkenes through Catalytic Asymmetric Hydrophosphination.

Asymmetric addition of diarylphosphines to oxa- and azabicyclic alkenes proceeded in the presence of a chiral phosphapalladacycle catalyst and a mild acid at room temperature to give exclusively the enantioenriched addition products in excellent yields and good selectivities. Three new chiral carbon centers were generated stereoselectively by the catalytic hydrophosphination reaction.

Nickel catalyzed enantioselective hydroarsination of nitrostyrene.

A catalytic asymmetric hydroarsination reaction of an activated alkene viz. (E)-nitrostyrene was developed using chiral PCP Pt-, Pd- and Ni-pincer complexes as catalysts. The corresponding chiral tertiary arsine adduct was obtained in ees of up to 80% under mild reaction conditions using the PCP Ni-Cl pincer catalyst. The arsine adduct was furnished with catalyst loadings of 1-5 mol% and the reaction duration ranging from <5 min to 180 min. The subsequent coordination of the hydroarsination product to gold(i) chloride allowed for the confirmation of the stereochemistry of the arsine adduct via crystallographic analysis.

Efficient access to a designed phosphapalladacycle catalyst via enantioselective catalytic asymmetric hydrophosphination.

A chiral phosphine auxiliary was generated with excellent ee via catalytic asymmetric hydrophosphination of 3-(naphthalen-1-ylmethylene)pentane-2,4-dione. The subsequent metal complexation of the monophosphine yielded two different coordination complexes depending on the reaction conditions. The ortho-palladation of both coordination complexes resulted in the formation of a single dimeric phosphapalladacycle complex that could be further converted to the monomeric bisacetonitrile derivative. Moreover, the palladium complex exhibits interesting oxophilicity as the stable bisaquo derivative could be isolated and characterized crystallographically. The catalytic potential of the phosphapalladacycle was also demonstrated.

Mechanistic insights into the role of PC- and PCP-type palladium catalysts in asymmetric hydrophosphination of activated alkenes incorporating potential coordinating heteroatoms.

The impact of the structural attributes of chiral PC- and PCP-palladium catalysts was investigated in the asymmetric hydrophosphination of various heterocycle-functionalized enone substrates. Due to the architecture of the catalysts, they are confronted with potential catalyst deactivation arising from the coordination of the electron-rich heteroatoms (P, O, N and S) to the metal center. A systematic variation of the location and identity of the heteroatoms demonstrated the impact of structural modifications on the substrates, which have a significant influence on both yields (16-99%) and enantioselectivities (0-99%). A detailed discussion on the distinct catalytic mechanisms (intra- vs. inter-molecular addition) provides important information to explain the results obtained.

The synthesis and efficient one-pot catalytic "self-breeding" of asymmetrical NC(sp(3))E-hybridised pincer complexes.

Cyclopalladation of the pyridyl-substituted chiral phosphine sulfide (N-P=S) and oxide (N-P=O) compounds afforded the asymmetric N-C(sp(3))*-S and N-C(sp(3))*-O pincer complexes. When applied as catalysts in asymmetric hydrophosphination, the newly developed aliphatic pincer catalyst could be recycled over three runs and obtained in large quantities via a one-pot "self-breeding" catalytic protocol.

Our Odyssey with Functionalized Chiral Phosphines: From Optical Resolution to Asymmetric Synthesis to Catalysis.

Our journey in organophosphorus research over the past 26 years is compiled in this Personal Account. Advances in palladacycle design have engendered a shift in our focus from template-mediated transformations to catalysis for the direct preparation of chiral phosphines containing a wide variety of functional groups. Novel approaches to access previously inaccessible phosphines and their applications in cancer research are summarized herein.

Computational and carbon-13 NMR studies of Pt-C bonds in P-C-P pincer complexes.

A (13)C{(1)H} NMR based investigation was conducted to examine the electronic properties of C(aryl)-M bonds and their trans influence in P-C(aryl)-P pincer complexes. A series of structurally related platinum pincer complexes were rationally designed and their corresponding (13)C-(195)Pt coupling constants were systematically examined. By methodical substitution of the ligand trans to the organometallic C(aryl)-Pt bond, this study revealed the significant influence of the ligands on the nature of the C(aryl)-M bonds. The single crystal X-ray analysis of the complexes and computational studies further confirmed the observations that the C-M bond exhibits significant π-character.

Palladacycle promoted base controlled regio- and enantioselective hydrophosphination of 2-pyridylacrylate/amide and the cytotoxicity of their gold complexes.

The regioselective asymmetric hydrophosphination of pyridine-functionalized alkenes can be achieved in the presence of stoichiometric amounts of the chiral palladium complex (R)-1. The presence or absence of base affords the respective ß- and α-adducts with excellent regiocontrol. Chiral gold-phosphine complexes incorporating the adducts exhibited good in vitro anticancer activity against the breast cancer cell line MDA-MB-231. Selectivity between the cancer cell line and normal cells was also observed.

Highly selective anti-cancer properties of ester functionalized enantiopure dinuclear gold(I)-diphosphine.

Two chiral (-)-diphosphine-digold(I) complexes containing mono- and di-methylester substituted diphosphine ligands have been prepared and structurally characterized. Both complexes are highly potent against breast cancer cell line MDA-MB-231 but showed much lower cytotoxicity against the normal human breast epithelial cells MCF10A. When compared with its mono-substituted analogue, the di-methylester substituted complex caused markedly lower and relatively insignificant damage to the normal breast cells. The analogous mono- and di-ethylester substituted complexes with the same stereochemistry exhibited similar anti-cancer properties but with noticeably higher cytotoxicity against the MCF10A cells. The enantiomeric complex (+)-diphosphine-digold(I) complexes containing the di-methylester substituted diphosphine ligand exhibited clearly different biological properties from its (-)-enantiomer. Furthermore, a structurally similar diphosphine-digold(I) complex but in the absence of an ester substituent, killed both the cancerous and the healthy cells indiscriminately. The current study thus revealed that the introduction of multi-esters, particularly methylesters, is an efficient approach to suppress the side-effects and to improve the efficiency of potential gold-based anti-cancer reagents. When combined with the biological observations, the chirality of gold complexes may serve as a sensitive probe for the future mechanistic studies.