PEPPSI Complexes Research Articles

Synthesis and cytotoxic activity of PEPPSI complexes based on 2-R-5,6-dihydro[1,2,4]triazolo[3,4-a]isoquinolin-2-ium salts

Synthesis and cytotoxic activity of PEPPSI complexes based on 2-R-5,6-dihydro[1,2,4]triazolo[3,4-a]isoquinolin-2-ium salts

Mercaptopyridine-Functionalized MIC-Pd(II)-PEPPSI Complexes: Synthesis and Hemilability Effect in Catalytic Applications

Mercaptopyridine-Functionalized MIC-Pd(II)-PEPPSI Complexes: Synthesis and Hemilability Effect in Catalytic Applications

Synthesis, characterization, and catalytic evaluation of palladium PEPPSI complexes bearing unsymmetrical NHC ligands in Suzuki–Miyaura reactions

Seven unsymmetrical imidazolium chlorides featuring a mesityl (Mes) or 2,6-diisopropylphenyl substituent (Dip) on one of their nitrogen atoms and a cycloalkyl group of variable size (cyclopentyl, cyclohexyl, 1-adamantanyl, cycloheptyl, cyclooctyl, or cyclododecyl) on the other one served to prepare a small library of novel palladium PEPPSI complexes with the generic formula [PdCl2(NHC)(Py)]. Three symmetrical compounds featuring the bulky yet flexible 1,3-dicyclododecylimidazol-2-ylidene and the archetypical IMes and IDip ligands were also synthesized. All the products were isolated in modest to satisfactory yields (15–85%) and fully characterized using 1H and 13C NMR spectroscopies. The molecular structures of five of them were determined using single crystal X-ray diffraction analysis, which revealed that, in most cases, the conformational freedom of the N-cycloalkyl moieties subsisted in the crystal phase. Topographic maps and %VBur parameters were computed to quantify the steric requirements of the uNHC ligands. The catalytic activity of the ten complexes was assessed in the Suzuki–Miyaura cross-coupling of phenylboronic acid and aryl halides. The reactions required only a low catalyst loading (0.05–0.25 mol%) and were carried out under mild aerobic conditions in a green, water-based solvent mixture. High yields of biphenyl derivatives were achieved with all the aryl bromides tested, irrespective of the presence of electron-donating or withdrawing substituents on their aromatic ring. When 4-chloro-acetophenone, a representative electron-poor aryl chloride served as substrate, all the complexes featuring cycloalkyl substituents on their NHC ligand became mostly inactive, whereas the IMes and IDip-based catalyst precursors maintained a high activity.

Synthesis, characterization, and reactivity of [Pd(phosphine)(py)Cl2] (PEPPSI) and [Pd(phosphine)Cl2]2 complexes.

The synthesis of novel phosphine palladium PEPPSI and dimer complexes bearing RuPhos, SPhos and XPhos phosphines is reported. The crystal structures of XPhos Pd PEPPSI with pyridine, SPhos Pd PEPPSI with 3-chloropyridine as throw-away ligands and the RuPhos palladium dimer were obtained and compared with previously reported congeners. The catalytic activity of these novel complexes was examined via a C-N coupling reaction involving 4-chloroanisole and morpholine. RuPhos complex 2b proved most active, leading to 97% yield with a low (0.2 mol%) catalyst loading, while phosphine palladium dimers showed significantly lower catalytic activity. However, the addition of 3-pentanone as an activator/stabilizer significantly improved the yields of phosphine dimers and PEPPSI complexes when the reactions were performed in THF.

Novel PEPPSI-Type NHC Pd(II) Metallosurfactants on the Base of 1H-Imidazole-4,5-dicarboxylic Acid: Synthesis and Catalysis in Water-Organic Media.

Carrying out organic reactions in water has attracted much attention. Catalytic reactions in water with metallosurfactants, which have both a metallocenter and the surface activity necessary for solubilizing hydrophobic reagents, are of great demand. Herein we proposed new approach to the synthesis of NHC PEPPSI metallosurfactants based on the sequential functionalization of imidazole 4,5-dicarboxylic acid with hydrophilic oligoethylene glycol and lipophilic alkyl fragments. Complexes of different lipophilicity were obtained, and their catalytic activity was studied in model reduction and Suzuki-Miyaura reactions. A comparison was made with the commercial PEPPSI-type catalytic systems designed by Organ. It was found that the reduction reaction in an aqueous solution of the metallosurfactant with the tetradecyl lipophilic fragment was three times more active than the commercially available PEPPSI complexes, which was associated with the formation of stable monodisperse aggregates detected by DLS and TEM.

Glucopyranoside-Functionalized NHCs-Pd(II)-PEPPSI Complexes: Anomeric Isomerism Controlled and Catalytic Activity in Aqueous Suzuki Reaction

Glucopyranoside-Functionalized NHCs-Pd(II)-PEPPSI Complexes: Anomeric Isomerism Controlled and Catalytic Activity in Aqueous Suzuki Reaction

Quaternary 2-R-5,6-dihydro-1,2,4-triazolo[3,4-a]isoquinolin-2-ium salts and PEPPSI complexes based thereof

Alkylation of substituted 5,6-dihydro-1,2,4-triazolo[3,4-a]isoquinolines with iodomethane, 2-iodopropane, or substituted benzyl halides (R—Hal) afforded quaternary 2-R-5,6-dihydro-1,2,4-triazolo[3,4-a]isoquinolinium salts, for which a possibility of the formation of carbene PEPPSI complexes with palladium(ɪɪ) and pyridine, as well as 2-, 3-, and 4-picolines, was demonstrated.

N-Heterocyclic carbene-palladium-PEPPSI complexes and their catalytic activity in the direct C–H bond activation of heteroarene derivatives with aryl bromides: synthesis, and antimicrobial and antioxidant activities

The Pd–NHC–PEPPSI complexes were used as catalysts in the direct C5-arylation of 2-acetyl furan, 2-acetylthiophene, and 2n-propylthiazole with different aryl bromides and were evaluated for their potential antibacterial and antioxidant properties.

Synthesis, characterization, crystal structure and bioactivity properties of the benzimidazole-functionalized PEPPSI type of Pd(II)NHC complexes

Herein, six new benzimidazole-functionalized Pd-based complexes bearing N-propylphthalimide group were synthesized. These new PEPPSI type of Pd(II)NHC complexes (PEPPSI: Pyridine Enhanced Precatalyst Preparation, Stabilization and Initiation) were prepared from the N-propylphthalimide substituted benzimidazolium salts, palladium chloride (PdCl2) and 3-chloropyridine. The structures of all (NHC)PdX2(3-chloropyridine) complexes have been clearly characterized by using NMR (1H and 13C), FTIR spectroscopic method, and elemental analysis techniques. Also, the structures of three of the (NHC)PdX2(3-chloropyridine) complexes were confirmed by single-crystal X-ray diffraction. Also, novel N-propylphthalimide-substituted (NHC)PdX2(3-chloropyridine) complexes effectively inhibited acetylcholinesterase (AChE), with Ki values in the range of 0.54 ± 0.10 to 3.01 ± 0.63 µM. For butyrylcholinesterase (BChE) was obtained with Ki values in the range of 0.82 ± 0.11 to 5.03 ± 0.86 µM. For α-glycosidase (α-Gly) the most effective Ki values of 1c, 1d, and 1b were with Ki values of 23.83 ± 5.98, 26.04 ± 7.11, and 30.61 ± 3.85 µM, respectively. All novel N-propylphthalimide-substituted PEPPSI complexes and control compounds had almost similar inhibition profiles.

Synthesis, catalytic activity and medium fluorous recycle of fluorous analogues of PEPPSI catalysts

PEPPSI complexes are air and moisture stable Pd catalysts, which can be used conveniently in many coupling reactions. With the aim to obtain Pd catalysts recyclable by fluorous separation methods, we modified the structure of commercial PEPPSI complexes by per- or polyfluoroalkylation in various positions. The modifications included the use of a linear polyfluoroalkyl group instead of one aryl group on the NHC ligand, perfluoroalkylation of pyridine ligand, and substitution of chloride ligands on Pd for perfluoroalkanoates or perfluoropolyoxaalkanoates. Comparison of catalytic activity of commercial catalysts with the modified ones in Suzuki-Miyaura cross-coupling reactions showed that the fluorous modifications mostly resulted in the increase of catalytic activity. Moreover, polyfluoroalkylation enabled efficient medium fluorous recycle of the modified catalysts using a two phase aqueous DMF/HFE 7500 ether system.

Novel 2-aminopyridine liganded Pd(II) N-heterocyclic carbene complexes: Synthesis, characterization, crystal structure and bioactivity properties

In this work, the synthesis, crystal structure, characterization, and enzyme inhibition effects of the novel a series of 2-aminopyridine liganded Pd(II) N-heterocyclic carbene (NHC) complexes were examined. These complexes of the Pd-based were synthesized from PEPPSI complexes and 2-aminopyridine. The novel complexes were characterized by using 13C NMR, 1H NMR, elemental analysis, and FTIR spectroscopy techniques. Also, crystal structures of the two compounds were recorded by using single-crystal X-ray diffraction assay. Also, these complexes were tested toward some metabolic enzymes like α-glycosidase, aldose reductase, butyrylcholinesterase, acetylcholinesterase enzymes, and carbonic anhydrase I, and II isoforms. The novel 2-aminopyridine liganded (NHC)PdI2(2-aminopyridine) complexes (1a-i) showed Ki values of in range of 5.78 ± 0.33–22.51 ± 8.59 nM against hCA I, 13.77 ± 2.21–30.81 ± 4.87 nM against hCA II, 0.44 ± 0.08–1.87 ± 0.11 nM against AChE and 3.25 ± 0.34–12.89 ± 4.77 nM against BChE. Additionally, we studied the inhibition effect of these derivatives on aldose reductase and α-glycosidase enzymes. For these compounds, compound 1d showed maximum inhibition effect against AR with a Ki value of 360.37 ± 55.82 nM. Finally, all compounds were tested for the inhibition of α-glycosidase enzyme, which recorded efficient inhibition profiles with Ki values in the range of 4.44 ± 0.65–12.67 ± 2.50 nM against α-glycosidase.

Hydroxyl-functionalized triazolylidene-based PEPPSI complexes: metallacycle formation effect on the Suzuki coupling reaction.

We report the preparation and full characterization of a series of hydroxyl functionalized 1,2,3-triazolylidene-based PEPPSI complexes 2a-c and their catalytic application in the Suzuki cross coupling reaction of aryl chlorides/amides with boronic acids. Under basic reaction conditions, complexes 2a-c show a notable increase in their catalytic efficiency compared with two ether-wingtip functionalized PEPPSI analogues (3 and 4) and a commercially available NHC-Pd complex (5). The catalytic results suggest that deprotonation of the hydroxyl group in complexes 2a-c plays an important role in the overall process. Deprotonation of the alcohol moiety of complexes 2a-b with sodium tert-butoxide allows for the isolation of metallacycles 6a-b, which are proposed as the active species of cross coupling reactions.

Palladium complexes of N-heterocyclic carbenes displaying an unsymmetrical N-alkylfluorenyl/N'-aryl substitution pattern and their behaviour in Suzuki-Miyaura cross coupling.

A series of new Pd-PEPPSI complexes containing imidazolylidene ligands with a mixed 9-alkyl-9-fluorenyl/aryl N,N'-substitution pattern have been synthesised. Single crystal X-ray diffraction studies were carried out for four complexes, which revealed that the N-heterocyclic carbene ligands display a semi-open, unsymmetrical space occupancy about the metal. Despite their particular unsymmetrical shape, the new complexes were found to perform as well in Suzuki-Miyaura cross coupling (dioxane, 80 °C) as previously reported, highly active analogues bearing two sterically protecting 9-alkylfluorenyl substituents. They were further found to be considerably more active than the standard Pd-PEPPSI complexes [PdCl2IMes(pyridine)] and [PdCl2IPr(pyridine)]. Surprisingly, unlike the latter, the unsymmetrical complexes of this study were practically inactive in isopropanol at 80 °C. Under these conditions the complexes appear to decompose with formation of non-stabilised nanoparticles.

Palladium PEPPSI complexes: Synthesis and catalytic activity on the Suzuki-Miyaura coupling reactions for aryl bromides at room temperature in aqueous media

Abstract A new series of palladium N-heterocyclic carbene complexes having methoxyethyl on the side chain (3a–d, 4a–e) have been synthesized and fully characterized by NMR, HRMS and IR. Next, the palladium-NHC-PEPPSI complexes 3a-e and 4a-e were used as catalyst in Suzuki-Miyaura coupling reactions were investigated for aryl bromides at room temperature in aqueous media. 3a-d and 4a-e complexes showed good catalytic activity for electron-donating or electron-drawing aryl bromides with arylboronic acid. Complex 4b exhibited higher activity compared to other analogues due to bearing more electronically donating NHC ligands.

The Highly Efficient Suzuki–Miyaura Cross‐Coupling of (Hetero)aryl Chlorides and (Hetero)arylboronic Acids Catalyzed by “Bulky‐yet‐Flexible” Palladium–PEPPSI Complexes in Air

AbstractA series of Pd–PEPPSI complexes were designed and synthesized. The relationship between catalyst structure and properties was systematically investigated. It was revealed that “bulky‐yet‐flexible” C3 bearing ancenaphthyl backbone was a highly efficient precatalyst and could be successfully employed in Suzuki–Miyaura reactions of (hetero)aryl chlorides with (hetero)arylboronic acids at a low palladium loading in the presence of a weak inorganic base in air.

New Pd-NHC PEPPSI complexes from benzimidazolium salts with a phenacyl group attached to N3

New benzimidazole-2-ylidene palladium(II) complexes of PEPPSI type, having pyridine as a throw-away ligand were obtained in one step from phenacyl benzimidazolium bromides and PdCl2. Although the presence of phenacyl groups attached to the N3 could lead in basic medium either to the N-heterocyclic carbenes or to the corresponding N-ylides, 6 new complexes were obtained without need of supplementary reactions steps or carbene transfer agents. X-ray diffraction analysis revealed that the expected chlorine atoms in the complexes were replaced by bromine atoms.

Structural diversity of phenoxy functionalized triazol-5-ylidene palladium(II) complexes and their application in C–N bond formation

The preparation and isolation of a variety of mono-, bis-, and heteroleptic mesoionic triazol-5-ylidene palladium(II) complexes is reported. Treatment of phenoxy functionalized triazolium salts [Bn-MIC(H)]+I− (1) and [Mes-MIC(H)]+I− (2) with half equivalent of palladium acetate, produced complexes 3 and 4 with a general structure of [(MIC)2Pd(I)2] as isomeric cis/trans mixtures. When the reaction of palladium acetate and the cationic precursors was carried out with equimolar amounts in presence of sodium iodide, the μ2-I2 bridged complexes 5 and 6 of the type [(MIC)PdI2]2 were obtained as unique products. Additionally, the preparation of the heteroleptic PEPPSI-type complexes ([Py(PdI2)MIC]) 7 and 8 was readily achieved by the thermal treatment of the triazolium precursors with PdCl2, K2CO3, and sodium iodide in pyridine. All complexes have been fully characterized by 1H and 13C NMR, FT-IR, elemental analysis, and in the case of 2, 3trans, 6, and 7 single crystal X-ray diffraction. Preliminary catalytic results with the palladium series established the enhanced performance of PEPPSI complexes 7 and 8 in the Buchwald-Hartwing catalyzed formation of C–N bonds between aryl halides and primary/secondary amines under mild reaction conditions.

ChemInform Abstract: Synthesis, Characterization and the Suzuki—Miyaura Coupling Reactions of N‐Heterocyclic Carbene—Pd(II)—Pyridine (PEPPSI) Complexes.

AbstractA series of new air and moisture‐stable PEPPSI complexes are developed and evaluated for their catalytic performance in Suzuki cross‐coupling reactions.

Letter to the Editor concerning: “Carbon–Heteroatom Coupling Using Pd–PEPPSI Complexes” by Valente et al.

To the Editor: We write regarding a review, by Organ and co-workers, (DOI: 10.1021/op400278d) that was published on the 11th December 2013 in Organic Process Research & Development as a ‘Just Accepted’ manuscript, and more recently in its final form as an ASAP article.(1) The manuscript in question details work conducted on catalytic C–N and C–S bond formation using palladium precatalysts of the form [PdCl2(NHC)(py)] (where NHC = N-heterocyclic carbene and py = pyridine or a substituted variant thereof), predominantly conducted by the group of Professor Michael Organ (the corresponding author on the manuscript).

Chiral PEPPSI Complexes: Synthesis, Characterization, and Application in Asymmetric Suzuki–Miyaura Coupling Reactions

PEPPSI complexes incorporating chiral N-heterocyclic carbene (NHC) ligands based on 2,2-dimethyl-1-(o-substituted aryl)propan-1-amines were synthesized. Two complexes, with one saturated and one unsaturated NHC ligand, were structurally characterized. The chiral PEPPSI complexes were used in asymmetric Suzuki–Miyaura reactions, giving atropisomeric biaryl products in modest to good enantiomeric ratios.