Aryl Phosphine Research Articles

One‐Pot Synthesis of Ortho‐Halogen‐Substituted Aryl(Alkynyl)Phosphinates Via Aryne‐Phosphite‐Haloalkyne Coupling

AbstractThe one‐pot formation of two C−P bonds and one C−halogen bond was achieved through a mild three‐component coupling reaction utilizing arynes, phosphites, and haloalkynes. In this reaction, the aryl anion, generated from the nucleophilic addition of phosphite to aryne, directly attacked the halogen of the haloalkyne. The reaction proceeded smoothly with a wide substrate scope and good functional group tolerance. This operationally simple method enables direct access to ortho‐halogen‐substituted aryl(alkynyl)phosphinates. The synthetic utility of ortho‐halogen‐substituted aryl(alkynyl)phosphinates with prospective applications in natural product synthesis, medicinal chemistry, and materials chemistry has also been demonstrated.

Molecular Structure, Spectroscopic, Frontier Molecular Orbital Analysis, Molecular Docking Studies, and In Vitro DNA-Binding Studies of Osmium(II)-Cymene Complexes with Aryl Phosphine and Aryl Phosphonium Assemblies.

X-ray crystallography, spectroscopy, computational methods, molecular docking studies, and in vitro DNA-binding studies have been useful in the investigations of intermolecular and intramolecular interactions of osmium-cymene oxalato complexes with aryl phosphine and aryl phosphonium groups in both primary and secondary coordination spheres, respectively. Molecular structures of the novel complexes PPh4[Os(η6-p-cymene)Br(κ2-O,O'-C2O4)] (1) and [Os(η6-p-cymene) (κ2-O,O'-C2O4)PPh3] (2) were resolved by single-crystal X-ray diffraction (XRD). Primary and secondary coordination sphere contacts were investigated using Hirshfeld surface analysis which was supported by molecular docking (MD) studies. The MD data obtained predicted significant differences in binding energy across three receptors for the two osmium complexes. An in vitro DNA-binding study was accomplished using UV-Vis spectroscopy which showed that both 1 and 2 bond with DNA through an intercalation approach. The optimized molecular geometry, frontier molecular orbital (EHOMO and ELUMO) energies, global electrophilicity index (ω), chemical hardness (η), chemical potential (µ), and the energy band gap (EHOMO-ELUMO) were calculated utilizing density functional theory (DFT) methods. Computed structural parameters (bond lengths and angles) support the experimental single-crystal XRD data.

Solvent-Switchable Remote C-H Activation via 1,4-Palladium Migration Enables Site-Selective C-P Bond Formation: A Tool for the Synthesis of P-Chiral Phosphinyl Imidazoles.

Solvent-switchable and site-selective phosphorylation of imidazoles at the C2 or C5 position of the imidazole ring was achieved via 1,4-palladium migration. P-Chiral tert-butyl(aryl)phosphine oxides were cross-coupled to 1-(2-bromophenyl)-1H-imidazoles with high enantiospecificity, thereby leading to a novel class of chiral imidazole-based phosphine oxides. As proof of concept, reduction of an analogue yielded the corresponding P-chiral 2-phosphinyl imidazole ligand, which was shown to induce high enantioselectivity in the formation of axially chiral molecules synthesized via Pd-catalyzed Suzuki-Miyaura cross-coupling.

Reaction of 1,3,5-Triazinanes with Phosphoryl Diazomethanes: Access to 5-Phosphoryl-1,2,3,4-tetrahydropyrimidines.

Conversion of 1,3,5-triazinanes into 5-phosporyl-1,2,3,4-tetrahydropyrimidines is achieved efficiently through the microwave-assisted reaction with phosphoryl diazomethanes. Both trialkyl and triaryl 1,3,5-triazinanes were converted by diazomethyldiarylphosphine oxides, dialkyl diazomethylphosphonates, and alkyl diazomethyl(aryl)phosphinates and functionalized simultaneously in good to excellent yields. The reaction is a sequence of 1,3,5-triazinane fragmentation, tandem nucleophilic addition of the generated formaldimines and phosphoryl diazomethanes, and final N,N-acetalization.

Rational Design of Palladium(II) Indenyl and Allyl Complexes Bearing Phosphine and Isocyanide Ancillary Ligands with Promising Antitumor Activity.

A new class of palladium-indenyl complexes characterized by the presence of one bulky alkyl isocyanide and one aryl phosphine serving as ancillary ligands has been prepared, presenting high yields and selectivity. All the new products were completely characterized using spectroscopic and spectrometric techniques (NMR, FT-IR, and HRMS), and, for most of them, it was also possible to define their solid-state structures via X-ray diffractometry, revealing that the indenyl fragment always binds to the metal centre with a hapticity intermediate between ƞ3 and ƞ5. A reactivity study carried out using piperidine as a nucleophilic agent proved that the indenyl moiety is the eligible site of attack rather than the isocyanide ligand or the metal centre. All complexes were tested as potential anticancer agents against three ovarian cancer cell lines (A2780, A2780cis, and OVCAR-5) and one breast cancer cell line (MDA-MB-231), displaying comparable activity with respect to cisplatin, which was used as a positive control. Moreover, the similar cytotoxicity observed towards A2780 and A2780cis cells (cisplatin-sensitive and cisplatin-resistant, respectively) suggests that our palladium derivatives presumably act with a mechanism of action different than that of the clinically approved platinum drugs. For comparison, we also synthesized Pd-ƞ3-allyl derivatives, which generally showed a slightly higher activity towards ovarian cancer cells and lower activity towards breast cancer cells with respect to their Pd-indenyl congeners.

Aerobic self-photooxidation of arylphosphines studied by steady state and laser flash photolyses

Arylphosphines (ArP) undergo UV-photodecomposition with quantum yields of 2 in aerated acetonitrile to form the corresponding oxides (ArPO). Laser flash photolysis studies showed that triplet ArP was quenched by the dissolved oxygen. Based on these results, it was concluded that singlet oxygen produced by triplet energy transfer from triplet ArP is involved as the primary oxidant in the formation of ArPO upon photolysis of ArP. We discuss the mechanism for forming ArPO upon photolysis of ArP with the over-unity quantum yield by considering phosphadioxiranes of ArP as the secondary oxidant.

Fully Aqueous and Air-Compatible Cross-Coupling of Primary Alkyl Halides with Aryl Boronic Species: A Possible and Facile Method.

Aqueous transformations confer many advantages, including decreased environmental impact and increased opportunity for biomolecule modulation. Although several studies have been conducted to enable the cross-coupling of aryl halides in aqueous conditions, until now a process for the cross-coupling of primary alkyl halides in aqueous conditions was missing from the catalytic toolbox and considered impossible. Alkyl halide coupling in water suffers from severe problems. The reasons for this include the strong propensity for β-hydride elimination, the need for highly air- and water-sensitive catalysts and reagents, and the intolerance of many hydrophilic groups to cross-coupling conditions. Here, we report a broadly applicable and readily accessible process for the cross-coupling of water-soluble alkyl halides in water and air by using simple and commercially available bench-stable reagents. The trisulfonated aryl phosphine TXPTS in combination with a water-soluble palladium salt Na2PdCl4 allowed for the Suzuki-Miyaura coupling of water-soluble alkyl halides with aryl boronic acids, boronic esters, and borofluorate salts in mild, fully aqueous conditions. Multiple challenging functionalities, including unprotected amino acids, an unnatural halogenated amino acid within a peptide, and herbicides can be diversified in water. Structurally complex natural products were used as testbeds to showcase the late-stage tagging methodology of marine natural products to enable liquid chromatography-mass spectrometry (LC-MS) detection. This enabling methodology therefore provides a general method for the environmentally friendly and biocompatible derivatization of sp3 alkyl halide bonds.

Electrochemical oxidative intramolecular annulation of aryl phosphine compounds: an efficient approach for synthesizing π-conjugated phosphonium salts

A simple electrochemical oxidation cyclization strategy for the construction of polycyclic phosphonium salts skeletons from trivalent arylphosphines was established.

Controlled CO labilization of tungsten carbonyl precursors for the low-temperature synthesis of tungsten diselenide nanocrystals

We report a low-temperature colloidal synthesis of WSe2 nanocrystals from tungsten hexacarbonyl and diphenyl diselenide in trioctylphosphine oxide (TOPO). We identify TOPO-substituted intermediates, W(CO)5TOPO and cis-W(CO)4(TOPO)2 by infrared spectroscopy. To confirm these assignments, we synthesize aryl analogues of phosphine-oxide-substituted intermediates, W(CO)5TPPO (synthesized previously, TPPO = triphenylphosphine oxide) and cis-W(CO)4(TPPO)2 and fac-W(CO)3(TPPO)3 (new structures reported herein). Ligation of the tungsten carbonyl by either the alkyl or aryl phosphine oxides results in facile labilization of the remaining CO, enabling low-temperature decomposition to nucleate WSe2 nanocrystals. The reactivity in phosphine oxides is contrasted with syntheses containing phosphine ligands, where substitution results in decreased CO labilization and higher temperatures are required to induce nanocrystal nucleation.

Synthetic Strategy for Aryl(alkynyl)phosphinates by a Three-Component Coupling Reaction Involving Arynes, Phosphites, and Alkynes.

An efficient and straightforward method for the synthesis of aryl(alkynyl)phosphinates was developed via a three-component coupling reaction involving arynes, phosphites, and alkynes. An array of aryl(alkynyl)phosphinates were produced from both aryl and aliphatic group-substituted acetylenes. This operationally simple reaction is tolerant to many functional groups, affording various aryl(alkynyl)phosphinates in moderate to good yields. The synthetic utility of alkynyl phosphinates afforded by this method was demonstrated by the elaboration of the products into various phosphorus-containing compounds.

Ligand-Determined Single, Double, and Triple C–H Arylation of Aryl Phosphines at Will

Controllable ortho-C–H arylation of aryl phosphines would provide a foundation for the modular synthesis of electronically and sterically tunable biaryl phosphines. However, this central task is challenging owing to the unfavorable four-membered cyclometalation and high tendency to undergo further interannular arylation. Herein phenolic compounds have been found to be effective ligands to determine single, double, or triple C–H arylation at will, providing a streamlined and practical synthetic approach to access (diaryl)- and (dialkyl)-biarylphosphines. The phosphine ligand library has been proven to be effective in catalytic coupling reactions and even exhibits unique chemoselectivity in comparison with commercially available classic phosphine ligands.

Design, Synthesis, and Applications of ortho -Sulfur Substituted Arylphosphanes

Design, Synthesis, and Applications of <i>ortho</i> -Sulfur Substituted Arylphosphanes

Catalyst‐Free Visible Light Mediated Synthesis of Unsymmetrical Tertiary Arylphosphines

AbstractArylation of tertiary aryl and alkyl phosphines bearing 2‐cyanoethyl group with aryl(mesityl)iodonium triflates under blue light irradiation followed by retro‐Michael reaction of the in situ generated quaternary phosphonium salts initiated by DBU represent a novel efficient and general method for the preparation of distinctly substituted tertiary arylphosphines. An operationally simple, one‐pot protocol features mild, transition‐metal‐free conditions, high selectivity, broad functional group compatibility, as well as scalability and would be applied to substrates with different electronic and steric nature.magnified image

Discovery and preclinical evaluations of WX-0593, a novel ALK inhibitor targeting crizotinib-resistant mutations

ALK gene rearrangements are oncogenic drivers in approximately 5% of NSCLC. Crizotinib, a first generation ALK inhibitor, is widely prescribed for ALK-positive NSCLC in clinic. Resistance to crizotinib and other ALK inhibitors has been problematic. Addressing resistance, here we describe discovery and development of a novel, proprietary spirocyclic diamine-substituted aryl phosphine oxide series of inhibitors, which led to the identification of WX-0593 (16a) as a potent ALK inhibitor. WX-0593 inhibited the activity of both wild type and resistant mutants of ALK in vitro, showed strong antitumor activity in a crizotinib-resistant mouse PDX model. WX-0593 is currently under development in phase II/III clinical trials.

Catalytic Cleavage of Unactivated C(aryl)-P Bonds by Chromium.

We describe here the coupling to transform aryl phosphine derivatives by the cleavage of unactivated C(aryl)-P bonds with chromium catalysis, allowing us to achieve the reaction with alkyl bromides and arylmagnesium reagents under mild conditions. Mechanistic studies indicate that catalytic cleavage of unactivated C(aryl)-P bonds is due to the in situ formed reactive Cr, followed by transmetalation and coupling with alkyl bromides.

Synthesis of diphenyl-(2-thienyl)phosphine, its chalcogenide derivatives and a series of novel complexes of lanthanide nitrates and triflates.

A novel synthesis of diphenyl(2-thienyl)phosphine, along with its' oxide, sulfide and selenide derivatives, is reported here. These phosphines have been characterized by NMR, IR, MS and X-Ray crystallography. The phosphine oxide derivative was reacted with a selection of lanthanide(III) nitrates and triflates, LnX3, to give the resultant metal-ligand complexes. These complexes have also been characterized by NMR, IR, MS and X-Ray crystallography. Single crystal X-Ray diffraction data shows a difference in metal-ligand complex stoichiometry and stereochemistry depending on the counteranion (nitrate vs. triflate). The [Ln(Ar3PO)3(NO3)3] ligand-nitrate complexes are nine-coordinate to the metal in the solid state (bidentate nitrate), featuring a 1 : 3 lanthanide-ligand ratio and bear an overall octahedral arrangement of the six, coordinated ligands. Our [Ln(Ar3PO)3(NO3)3] ligand-nitrate complexes gave three examples of fac-stereochemistry, where mer-stereochemistry is almost universally observed in the literature of highly related [Ln(Ar3PO)3(NO3)3] complexes. For the Tb complexes, two different arrangements of the ligands around the metal were observed in the solid state for [Tb(Ar3PO)3(NO3)3] and [Tb(Ar3PO)4(OTf)2] [OTf]. [Tb(Ar3PO)3(NO3)3] is strictly nine-coordinate, ligand mer-stereochemistry in the solid state, and [Tb(Ar3PO)4(OTf)2] [OTf] is strictly octahedral, six-coordinate, with a square-planar stereochemical arrangement of the phosphine oxide ligands around the metal.

New Access Routes to Privileged and Chiral Ligands for Transition‐Metal Catalyzed Hydrogen Autotransfer (Borrowing Hydrogen), Dehydrogenative Condensation, and Alkene Isomerization Reactions

AbstractA group of transition‐metal catalyzed hydrogen moving reactions, encompassing hydrogen autotransfer (HAT; also called borrowing hydrogen, BH), dehydrogenative condensation (DHC) and alkene isomerization, displays high atom economy and relies on widely available starting materials. Such reactions have considerable potential for clean reaction design and application in sustainable synthesis. With the aim to develop and study synthetic applications of the title reactions, we have set up synthetic access routes to a toolbox of structurally varied ligands for and pincer complexes of some transition metals (cobalt, ruthenium, iridium) that are well established for the title reactions. Ligand target structures, for which often improved syntheses have been found, encompass 6,6’‐dihydroxy‐2,2’‐bipyridine, 2(3‐hydroxyphenyl)pyridines (as backbones for PCN pincers), 2(6‐methylpyridine‐2‐yl)pyridines (as backbones for PNN pincers) and 2(3‐tolyl)pyridines (as backbones for PCN pincers). To support research towards asymmetric versions of the title reactions, we have prepared asymmetrically modified versions of well‐established catalysts, including chiral, enantiopure versions of Milstein’s PNN‐ruthenium pincer, Kempe’s triazinyl‐diaminophosphanyl PNP‐iridium‐ or ‐cobalt pincers, Huang’s PCN‐iridium pincers, and Grotjahn’s alkene zipper complex. The strategy applied to ‘chiral switching’ relied on replacing symmetric dialkylphosphine donor‐groups by dimenthylphosphine or aryl(menthyl)phosphine donor units. The resulting ligands or complexes have been structurally characterized, and the catalytic potential of the catalysts has been established in exploratory model reactions (transfer hydrogenation; diol to lactone dehydrogenative condensation; alkene isomerization). Several model reactions have been designed which will allow to study asymmetric catalytic hydrogen moving reactions.

Cross-dehydrogenative Coupling of N-Aryl Tetrahydroisoquinolines Catalyzed by an Anthraquinone-containing Polymeric Photosensitizer.

This work reports the photocatalytic application of an anthraquinone-containing polymeric photosensitizer (AQ-PHEMA) in the visible light-induced cross-dehydrogenative-coupling of N-aryl tetrahydroisoquinolines with several nucleophiles, including nitromethane, 1-methyl-2-alkyl ketone and dialkyl (aryl) phosphine oxide. The results revealed that the reaction could be catalyzed by AQ-PHEMA efficiently to afford a series of 1-substituted-2-aryl-1,2,3,4-tetrahydroisoquinolines in good to excellent yields with nice substrate tolerance under aerobic conditions at room temperature. The practical application potential was also showcased by a gram-scale synthesis. More importantly, the utilization of AQ-PHEMA as a heterogeneous photosensitizer also showed nice recyclability and reusability of the catalyst, whereas AQ-PHEMA can be easily separated and reused for at least 8 times without significant loss of photocatalytic activity.

Palladium-Catalyzed C-P Bond-Forming Reactions of Aryl Nonaflates Accelerated by Iodide.

An iodide-accelerated, palladium-catalyzed C–P bond-forming reaction of aryl nonaflates is described. The protocol was optimized for the synthesis of aryl phosphine oxides and was found to be tolerant of a wide range of aryl nonaflates. The general nature of this transformation was established with coupling to other P(O)H compounds for the synthesis of aryl phosphonates and an aryl phosphinate. The straightforward synthesis of stable, isolable aryl nonaflates, in combination with the rapid C–P bond-forming reaction allows facile preparation of aryl phosphorus target compounds from readily available phenol starting materials. The synthetic utility of this general strategy was demonstrated with the efficient preparation of an organic light-emitting diode (OLED) material and a phosphonophenylalanine mimic.

Synthesis and biological evaluation of novel 2-alkoxycarbonylallylester phosphonium derivatives as potential anticancer agents

Several phosphonium derivatives have been synthesized from Baylis-Hillman (BH) reaction derived allyl bromides and aryl phosphines as mitochondria targeting anticancer agents. In vitro cell proliferation inhibition studies on various solid tumor cell lines indicate that most of the compounds exhibit IC50 values in µM concentrations. Further studies reveal that β-substituted BH bromide derived phosphonium derivatives enhance the biological activity to low µM IC50 values. In vitrometabolic studies show that the lead candidate compound 16 inhibits the production of mitochondrial ATP, increases the proton leak within the mitochondrial membrane and abolishes the spare respiratory capacity in a concentration dependent manner.