Thioether Ligands Research Articles

One‐Step Synthesis of Chiral 9,10‐Dihydrophenanthrenes via Ligand‐Enabled Enantioselective Cascade β,γ‐Diarylation of Acids

AbstractPd(II)‐catalyzed enantioselective C−H activation has emerged as a versatile platform for constructing point, axial, and planar chirality. Herein, we present an unexpected discovery of a Pd‐catalyzed enantioselective cascade β,γ‐methylene C(sp3)−H diarylation of free carboxylic acids using bidentate chiral mono‐protected amino thioether ligands (MPAThio), enabling one‐step synthesis of a complex chiral 9,10‐dihydrophenanthrene scaffolds with high enantioselectivity. In this process, two methylene C(sp3)−H bonds and three C(sp2)−H bonds were activated, leading to the formation of four C−C bonds and three chiral centers in one pot. A plausible catalytic pathway starts with enantioselective β,γ‐dehydrogenation to form chiral β,γ‐cyclohexene. Intriguingly, this olefin serves as a norbornene‐type reagent (presumably assisted by the carboxyl directing effect), relaying two successive Catellani arylation reactions and a C−H arylation reaction to furnish chiral 9,10‐dihydrophenanthrenes along with meta‐selective homocoupling products of iodoarene.

One-Step Synthesis of Chiral 9,10-Dihydrophenanthrenes via Ligand-Enabled Enantioselective Cascade β,γ-Diarylation of Acids.

Pd(II)-catalyzed enantioselective C-H activation has emerged as a versatile platform for constructing point, axial, and planar chirality. Herein, we present an unexpected discovery of a Pd-catalyzed enantioselective cascade β,γ-methylene C(sp3)-H diarylation of free carboxylic acids using bidentate chiral mono-protected amino thioether ligands (MPAThio), enabling one-step synthesis of a complex chiral 9,10-dihydrophenanthrene scaffolds with high enantioselectivity. In this process, two methylene C(sp3)-H bonds and three C(sp2)-H bonds were activated, leading to the formation of four C-C bonds and three chiral centers in one pot. A plausible catalytic pathway starts with enantioselective β,γ-dehydrogenation to form chiral β,γ-cyclohexene. Intriguingly, this olefin serves as a norbornene-type reagent (presumably assisted by the carboxyl directing effect), relaying two successive Catellani arylation reactions and a C-H arylation reaction to furnish chiral 9,10-dihydrophenanthrenes along with meta-selective homocoupling products of iodoarene.

Palladium-Catalyzed Ligand-Enabled Cyclization of Substituted Aliphatic Carboxylic Acids with Allylic Electrophiles.

A palladium-catalyzed cyclization of the β-C(sp3)-H bond of aliphatic carboxylic acids with allylic electrophiles providing five-membered γ-lactones in good to excellent yields is demonstrated. An acetyl-protected aminoethyl phenyl thioether ligand is used to promote the C-H activation reaction. A diverse range of allylic electrophiles such as allyl alcohols, allyl acetates, allyl sulfones, allyl phosphonate, allyl amine, and allyl ester have been utilized for this reaction. A feasible reaction mechanism has been proposed to account for the present cyclization reaction.

Synthesis of chiral α-amino acids via Pd(ii)-catalyzed enantioselective C-H arylation of α-aminoisobutyric acid.

Non-natural chiral α,α-disubstituted α-amino acids (α,α-AAs) constitute an attractive α-aminoisobutyric acid (Aib) replacement for improving bioavailability of linear peptides as therapeutics due to the ability of these amino acids to induce the peptides to form helical structures. Enantioselective β-C(sp3)-H arylation of Aib could potentially provide a versatile one-step strategy for accessing diverse α,α-AAs, but the installation and removal of external directing groups was found in our previously reported work to reduce the efficiency of this approach. Herein we report a Pd(ii)-catalyzed enantioselective C-H arylation of N-phthalyl-protected Aib enabled by a N-2,6-difluorobenzoyl aminoethyl phenyl thioether (MPAThio) ligand, affording α,α-AAs with up to 72% yield and 98% ee. Use of this newly developed chiral catalyst has also significantly improved enantioselective C(sp3)-H arylation of cyclopropanecarboxylic acids by expanding the substrate scope to heterocyclic coupling partners and increasing enantioselectivity to 99% ee.

Polymeric CuX coordination compounds assembled from acetylenic thioether ligands RSCH2CCCH2R (R = C6H11, t-Bu): effect of the RS-group, halide and stoichiometry on the network architecture and the luminescence properties

The self-assembly of acetylenic dithioethers with CuX salts produces coordination polymers, some of them being halogenated across the triple bond.

Effect of Tethered Sulfur Ligands on the Association Constants of Dirhodium(II,II) Paddlewheel Complexes

AbstractHerein we report on the association constants (Ka) of dirhodium(II,II) complexes bearing tethered thioether or sulfoxide ligands in the presence of binding analytes. The effect of substituent and tether length modifications on Ka and the stability of the complexes were analyzed by UV‐vis using pyridine and cysteine as binding analytes of interest. When pyridine was the incoming exogenous species, dirhodium(II,II) complexes with tethered sulfur ligands reduced the axial coordination of pyridine by up to four‐fold when compared to dirhodium(II,II) complexes without tethered axial coordination. Tuning the tethered sulfur coordination through changes in tether length, substituent, and electronics resulted in Ka values that spanned 2.6×103 M−1 to 8.1×103 M−1. The differences in Ka were correlated with structural features of crystals obtained from single crystal X‐ray diffraction and results pointed to release of strain as a factor in the association constants. Interestingly, cysteine interactions were greater for complexes with tethered, axial ligands than those without, alluding to an alternate mode of coordination with cysteine. These results demonstrate the tunability of tethered, axial coordination on dirhodium(II,II) paddlewheel complexes and provide access to controlled binding of exogenous species.

Abstract A027: A photoactivatable microtubule-targeting rigidin prodrug

Abstract Analogues of marine alkaloid rigidins have been found to kill cancer cells at nanomolar concentrations by targeting the microtubule network. Here, a rigidin analogue containing a thioether group was “caged” by coordination of its thioether group to a photosensitive ruthenium polypyridyl complex. In the dark, the coordinated ruthenium fragment prevented the rigidin analogue from inhibiting tubulin polymerization and reduced its toxicity in 2D cancer cell lines monolayers, 3D lung cancer tumor spheroids (A549), and in a lung cancer tumor xenograft (A549) in nude mice. Photochemical activation of the prodrug upon green light irradiation led to the photosubstitution of the thioether ligand by water, thereby releasing the free rigidin analogue capable of inhibiting the polymerization of tubulin. In cancer cells, such photorelease was accompanied by a drastic reduction of cell growth, not only when the cells were grown in normoxia (21% O2) but also, remarkably, in hypoxic conditions (1% O2). In vivo, light activation of the compound in the tumor led to 30% tumor volume reduction, which represents the first demonstration of the efficacy of a ruthenium-based photocaged compounds in a tumor xenograft. In subsequent unpublished work, we fine-tuned the excited states in this complex by adding an amide functional group on the ruthenium cage. By doing so, a new caged complex was obtained that was activated by red light (instead of green light). We demonstrated the red light activation of this compound in solution and in vitro. This result demonstrates that functionalization of ruthenium cage with electron-withdrawing groups can radically enhance their photochemical properties, which is essential for this method development (red light penetrates better into tissues than green light). We will present our results of in vivo testing of this caged compound activated by tumor penetrable red light, where significant tumor reduction is seen in mice xenografted with subcutaneous human uveal melanoma liver metastatic cells. Citation Format: Alexander Kornienko, Sylvestre Bonnet. A photoactivatable microtubule-targeting rigidin prodrug [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A027.

Synthesis of Organosilicon‐Based Thioether Ligand Class Showing Defined S‐Stereogenic Coordination in Crystalline Palladium(II) Complexes

AbstractA synthesis route to aromatic organosilicon‐based thioether ligands could be established and utilised for three congeners 2. These ligands were suitable for complexation with palladium(II) chloride forming three new complexes 3. The single crystal X‐ray diffraction and temperature‐dependent 1H and 13C‐NMR analysis of 3 are presented. The elucidated solid‐state structures suggested that one pair of diastereomers is favoured in crystalline phase and is controllable by the aromatic substituent. However, at room temperature in solution, the conformation at the sulphur atoms can fluctuate with a coalescence temperature for 1H‐NMR around 24 °C. At −31 °C, two signal sets could be observed since the inversion is slower than the 1H‐NMR timescale at lower temperatures.

B-carboranyl methyl thioether ligands in coordination with the W(CO)5 fragment

Complexation of B-closo- and nido-carboranyl methyl thioethers with the pentacarbonyltungsten fragment was studied. An unusual instability of the nido-derivative is detected and rationalized by means of the quantum chemical calculations followed by the topological analysis of electron density and the Interacting Quantum Atoms analysis. The structure of {(CO)5W[9-MeS-1,2-C2B10H11-κ1-S(1)]} was determined by single crystal X-ray diffraction.

Electrophilic C3−H Alkenylation of 2,6‐Dialkoxypyridine Derivatives via Pd(II)/Tl(III) Reaction System

AbstractHerein, we report the reaction system based on Pd(II) catalyst and Tl(OCOCF3)3 for the electrophilic C3−H alkenylation of 2,6‐dialkokypyridines with alkenes. Synergistic action of the Pd/thioether ligand catalytic system and Tl(III) results in efficient C−H alkenylation of various nitrogen heteroaromatics with complete regioselectivity. Remarkably, the use of a sterically hindered thioether ligand and the Pd(II)/Tl(III) system enables mono‐selective C3(5)−H alkenylation of 2,6‐dialkoxypyridines, and subsequent introduction of a second, different alkene affords unsymmetrical, multi‐substituted pyridine derivatives. Mechanistic studies indicate that the reaction proceeds via electrophilic thallation of heteroarenes followed by Pd‐catalyzed Heck‐type reaction. The utility of this method is showcased by its application to the late‐stage functionalization of structurally complex bioactive molecules having 2,6‐dialkoxypyridine as a core structure.

Technetium Complexes with an Isocyano-alkyne Ligand and Its Reaction Products.

The attachment of an ethyne substituent in the para position of phenylisocyanide, CNPhpC≡CH, enables the isocyanide to replace carbonyl ligands in the coordination sphere of common technetium(I) starting materials such as (NBu4)[Tc2(μ-Cl)3(CO)6]. The ligand exchange proceeds under thermal conditions and finally forms the corresponding hexakis(isocyanide)technetium(I) complex. The product undergoes a copper-catalyzed cycloaddition ("Click" reaction), e.g., with benzyl azide, which gives the [Tc(CNPhazole)6]+ cation. The free, uncoordinated "Click" product is obtained from a reaction of the corresponding tetrakis(CNPhazole)copper(I) complex and NaCN. It readily reacts with mer-[Tc(CO)3(tht)(PPh3)2](BF4) (tht = tetrahydrothiophene) under exchange of the thioether ligand. Alternatively, [Cu(CNPhazole)4]+ can be used as a transmetalation reagent for the synthesis of the hexakis(isocyanide)technetium(I) complex, which is the preferable approach for the synthesis of the technetium complex with the short-lived nuclear isomer 99mTc, and a corresponding protocol for [99mTc(CNPhazole)6]+ is reported. The 99Tc and copper complexes have been studied by single-crystal X-ray diffraction and/or spectroscopic methods including IR and multinuclear NMR spectroscopy.

Crystal structure of trimeth-yl({tris-[(phenyl-sulfan-yl)meth-yl]sil-yl}meth-oxy)silane and Hirshfeld surface analysis of 3-bromo-2,2-bis-(bromo-meth-yl)propan-1-ol.

Trimeth-yl({tris-[(phenyl-sulfan-yl)meth-yl]sil-yl}meth-oxy)silane (3), C26H32OS3Si, is a new ligand for transition-metal coordination chemistry derived from 3-bromo-2,2-bis-(bromo-meth-yl)propan-1-ol (1), C5H9Br3O, through silylation and following exchange of bromine groups with NaSPh. Silylated thio-ether ligand 3 crystallizes in the centrosymmetric space group C2/c. Bromo-methyl-alcohol 1 crystallizes in the space group P in the triclinic crystal system with four mol-ecules in the asymmetric unit. Analysis of the Hirshfeld surface shows structure-defining inter-actions for bromo-methyl-alcohol 1, resulting in inter-molecular hydrogen bonds between the hydroxyl groups along the a-axis direction.

Synthesis and Full Characterization of One Organometallic Polyoxometalate-Based Copper(I)-Alkene Complex.

An alkene-bridged thioether ligand (L) was designed and used for its first study within a polyoxometalate (POM) hybrid system, and a POM-based copper(I)-alkene compound [(CuIL)2(PVMoVI12O40)]·(CuIL) (1) was isolated and characterized by X-ray crystallography. A unique alkene-coordinating N(η2-C═C)N mode of L is observed, and the Cu centers are captured by σ2,π-L in a pocket fashion, giving birth to discrete [CuIL]+ cations and [(CuIL)2(PVMoVI12)]- anions. The ionic crystal exhibits solubility in aprotic polar solvents, and the electrospray ionization mass spectrometry is used to explore the nature of species present in the solution. It is found that the whole cluster [PVMoVI12]3- is completely present, and all the main peaks can be assigned to different charged fragments of the same parent cluster.

Investigations on the Reactivity of Copper(I) Complexes with a N3S Thioether Ligand System

AbstractIn the active site of several copper monooxygenases, thioether residues are coordinated through the sulfur atom, e. g. dopamine‐β‐monooxygenase (DβM). The reaction of dioxygen with a series of copper(I) complexes with thioether groups in tripodal ligands based on either derivatives of tris(2‐pyridylmethyl)amine (TMPA) or a guanidine system were investigated by low‐temperature stopped‐flow measurements. The formation of labile intermediates, an end‐on superoxido complex, and μ‐1,2‐trans‐peroxido copper(II) complexes were spectroscopically detected and a kinetic analysis allowed the calculation of activation parameters for these reactions supporting the postulated mechanism. Most interesting was the finding that replacing the ethyl group in the tren‐guanidine derivative (TMGEt)2(SEtEt)N with a methyl group allowed a dramatic increase in the stability of the formed superoxido copper complex. Measurements with ozone were performed in order to find an alternative way to obtain and stabilize the labile intermediates.

Manipulating Excited State Properties of Iridium Phenylpyridine Complexes with "Push-Pull" Substituents.

We have prepared a series of complexes of the type [IrIII(ppy)2(L]n+ complexes (1-4), where ppy is a substituted 2-phenylpyridine and L is a chelating phosphine thioether ligand. The parent complex (1) comprises an unsubstituted phenylpyridine ligand, whereas complex 2 contains a nitro substituent on the pyridine ring, complex 3 features a diphenylamine group on the phenyl ring, and 4 has both nitro and diphenylamine groups. Crystallographic, 1H NMR, and elemental analysis data are consistent with each of the chemical formulae. DFT (density functional theory) computational results show a complicated electronic structure with contributions from Ir, ppy, and the PS ligand. Ultrafast pump-probe data show strong contributions from the phenylpyridine moieties as well as strong panchromatic excited state absorption transitions. The data show that nitro and/or diphenylamine substituents dominate the spectroscopy of this series of compounds.

Ligand-Enabled Sequential C(sp3)-H and C(sp2)-H Diolefination Reaction via Palladium Catalyst.

Palladium-catalyzed sequential C(sp3)-H and C(sp2)-H bond diolefination reaction of o-toluidine has been realized for the first time using acetyl-protected aminoethyl phenyl thioether ligands. This novel reaction allows for preparation of the conjugated diene structure via an immediate second olefination on the basis of the first C(sp3)-H olefination in one pot. Various triflyl-protected anilines and acrylates were used as coupling partners elegantly. Furthermore, the unpurified diolefination products can be easily converted to tetrahydroquinoline derivatives.

Synthesis of π‐Expanded Coumarins by Ligand‐Enabled Selective C−H Functionalization

AbstractHerein, we report the synthesis of a series of π‐expanded coumarin derivatives by the selective C−H alkenylation of β‐naphthol in the presence of a palladium catalyst. The use of an anionic thioether ligand is critical for ensuring the high reactivity of this reaction; it enables low catalyst loadings, mild reaction conditions, and the use of acetic acid as a green solvent. This chemistry is widely applicable to naphthol‐based aromatic substrates bearing either electron‐donating or ‐withdrawing functional groups.magnified image

Simple chiral sulfinyl imine–thioether ligands for Pd-catalyzed allylic alkylation

Simple chiral sulfinyl imine–thioether ligands for Pd-catalyzed allylic alkylation

Palladium(II) complexes with thioether based ONS donor ligand: Synthesis, characterization, X-ray structure, DFT study and anti-cancer activity

Synthesis of new palladium(II) complexes, [Pd(L)Cl] (C1) and [Pd(L)PPh3](ClO4) (C2), with ONS donor thioether ligand (HL) is reported. All the complexes were thoroughly characterized by using numerous spectroscopic techniques like FT-IR, NMR and UV–visible spectroscopy and so forth. Distorted square planar geometries of the complexes were confirmed unambiguously by means of single crystal X–ray diffraction analysis. Moreover, DFT and TDDFT calculations were performed to interpret the electronic structure, redox and spectral properties of the complexes. Cytotoxicity of the complexes was evaluated in vitro using MTT assay on human gastric cancer cell lines (AGS). The anti-cancer effects of HL and palladium(II) complexes (C1/C2) on AGS cell lines were determined by comparing the half maximal inhibitory concentration (IC50) values. The results revealed that synthesized palladium(II) complexes (C1/C2) showed higher anti-cancer activity (IC50 = 13.4 µM for C1 and 16.0 µM for C2) compare to HL against AGS cell lines (67.1 µM).

Syntheses and investigation of metal complexes with macrocyclic polythioether ligands.

Copper(I) complexes with the macrocyclic thioether ligands 1,4,8,11-tetrathiacyclotetradecane (tetrathiacyclam, 14-S4) and 1,8-dithia-4,11-diazacyclotetradecane (dithiacyclam, 14-N2S2) were synthesised and structurally characterised. While the copper(I) complexes showed no reactivity towards dioxygen, the formation of "dioxygen adduct complexes" could be spectroscopically detected with ozone using low temperature stopped-flow techniques. Furthermore, it was possible to synthesise and characterise iron(II) and cobalt(II) complexes with the tetrathiacyclam ligand. No "dioxygen adduct" intermediates were observed when these complexes were reacted with dioxygen or ozone. Depending on the reaction conditions, the coordination of the metal ions could be controlled (endo- vs. exo-coordination and cis- vs. trans-coordination) and in addition to mononuclear complexes, also coordination polymers were obtained.