Pyridine Enhanced Precatalyst Preparation Research Articles

Synthesis, crystal structure, and DFT studies of NHC mediated Pd-PEPPSI complex: Application for Suzuki reaction

A novel air and moisture resistant Pd-PEPPSI (pyridine-enhanced precatalyst preparation, stabilization, and initiation) complex was synthesized via the reaction of benzimidazolium salt, PdCl2, KBr, K2CO3, and pyridine. The structure was characterized by spectroscopic methods such as 1H and 13C NMR, FT-IR, UV–vis. and single X-ray diffraction techniques. In order to evaluate the synthesized Pd complex in a detailed manner in terms of structural, bonding, electronic, and thermodynamic characteristics, DFT-based calculations were carried out at the B3LYP/6-311++G (d, p)/LANL2TZ theory level. Natural bond orbital (NBO) analysis was implemented to provide more insights about the possible donor-acceptor interactions and types of hybridization. Also, TD-DFT calculations were performed to rationalize the nature of the observed electronic transitions. The complex showed high catalytic activity in the Suzuki–Miyaura cross coupling of aryl chlorides with phenylboronic acid. Aryl chlorides bearing either electron- donating or withdrawing substituents afforded a wide range of biaryl derivatives that were isolated in the range of 55–97 % yields (7 examples). The reactions were carried out at very low catalyst loading (0.25 mol%) in the presence of air using a green water-based solvent (ipr:H2O/ 1:3). The palladium complex was found to be efficient for the coupling of aryl chlorides with arylboronic acids under aerobic conditions, affording the corresponding biaryls in high yields.

Pd–PEPPSI-type expanded ring N-heterocyclic carbene complexes: synthesis, characterization, and catalytic activity in Suzuki–Miyaura cross coupling

ABSTRACT In this work, we synthesized a series of six unsymmetrical benzimidazolium salts 2 and their pyridine-enhanced precatalyst preparation stabilization and initiation (PEPPSI)-themed palladium N-heterocyclic carbene complexes [PdCl2(NHC)(Py)]. All the products were isolated in satisfactory yields (75-85%). The synthesis of these novel palladium PEPPSI complexes involved in reacting NHC precursors with PdCl2 in pyridine at 60°C in the presence of excess K2CO3. The structures of all compounds have been characterized by 1H NMR, 13C NMR, HRMS and IR spectroscopy, as well as elemental analysis techniques, which support the proposed structures. The catalytic activity of the six complexes was assessed in the Suzuki-Miyaura cross-coupling of phenylboronic acid and aryl halides. The reactions required only a low catalyst loading (0.1 mol%) and were carried out under mild aerobic conditions in a green, water-based solvent mixture.

Palladium(ii) complexes bearing mesoionic carbene ligands: catalytic application in domino Sonogashira coupling/cyclization reactions for one-pot synthesis of benzofuran and indole derivatives.

Bioactive heterocycles such as benzofuran and indole derivatives were synthesized from commercially available 2-iodoarenes and alkynes via domino Sonogashira coupling followed by cyclization reaction using well-defined palladium PEPPSI (Pyridine Enhanced Precatalyst Preparation Stabilization and Initiation) complexes (2a and 2b). These reactions tolerate a variety of 2-iodoarenes and diversely substituted terminal alkynes, resulting in the corresponding product in moderate to good yields in an open-air atmosphere. In particular, two palladium(ii) PEPPSI complexes 2a and 2b were synthesized in good yields from the reaction of corresponding 1,2,3-triazol-5-ylidene (MIC: mesoionic carbene), PdCl2, KI, and K2CO3 in pyridine at 110 °C and structurally characterized by various spectroscopic techniques including NMR spectroscopy, IR spectroscopy, HRMS and elemental analysis studies. Complex 2b is also characterized by X-ray crystallography.

Synthesis, Characterization, and Molecular Docking Analysis of A Novel NHC Salt and Its Palladium-PEPPSI Complex

PEPPSI type Pd complexes have wide applications in recent years. Serum albumin carries very important molecules such as oleic and linoleic acids, nitric oxide, vitamin B6, thyroid and so do many drugs. In this study, a novel NHC molecule and its Pd-PEPPSI complex were synthesized and characterized. Both the ligand and the complex were optimized by DFT-based calculation methods. The binding properties of the molecules with HSA were analyzed by molecular docking methods. Binding affinity of -8.04 kcal/mol and inhibition constant of 1.29 µM were determined for NHC salt while the binding affinity was calculated as -7.04 kcal/mol and the inhibition constant as 6.92 µM for Pd-PEPPSI complex.

Trinuclear PdII Complexes with a C3 -Symmetric Triethynylbenzene-Based Tris-NHC Ligand: Catalytic Benefits.

A new C3 -symmetric tris-imidazolium tribromide salt 3, featuring 1,3,5-substituted triethynylbenzene, was used for the preparation of a trinuclear PdII pyridine-enhanced precatalyst preparation stabilization and initiation-type (PEPPSI) complex by triple C2 deprotonation followed by the addition of PdCl2 . Trinuclear PdII complex possessing a combination of NHC and PPh3 ligands has also been synthesized. The corresponding mononuclear palladium(II) complexes have also been synthesized for the comparison purpose. All these complexes have been characterized by using NMR spectroscopy and ESI mass spectrometry. The molecular structure of the trinuclear palladium(II) complex bearing mixed carbene and pyridine donor ligands has been established by using single crystal XRD. All the palladium(II) complexes have been used as pre-catalysts, which gave good to excellent yields in intermolecular α-arylation of 1-methyl-2-oxindole and Sonogashira coupling reaction. Catalytic studies indicate an enhanced activity of the trinuclear PdII complex in comparison to the corresponding mononuclear PdII complex for both catalytic transformations. The better performance of the trinuclear complex has also been further supported by preliminary electrochemical measurements. A negative mercury poison test was observed for both the aforementioned catalyses and therefore, it is likely that these organic transformations proceed homogeneously.

Antioxidant activity, enzyme inhibition, electrochemical and theoretical evaluation of novel PEPPSI type N-heterocyclic carbene complexes

N-Heterocyclic carbenes have attracted attention due to their strong sigma-donor and weak pi-acceptor properties since they were first isolated. Pyridine is also found in many natural products and is included in the content of many pharmaceutical molecules. Palladium complexes containing two halogens, a pyridine and an N-heterocyclic carbene have been identified as PEPPSI (Pyridine-Enhanced Precatalyst Preparation Stabilization and Initiation). Although Alzheimer Disease is thought to be affected by environmental and genetic factors, it has not been fully elucidated. There are various mechanisms used to explain the pathogenesis of this disease which guide the design of new drugs. In Alzheimer Disease cases, acetylcholinesterase activity decreases while butyrylcholinesterase increases and disproportionate reactive oxygen species is also recorded. So, the drug used in Alzheimer Disease treatment must have more than one function, that is, the molecule is expected to be effective in both acetylcholinesterase/butyrylcholinesterase balance and antioxidant activity. In this study, PEPPSI type complexes were synthesized and characterized. The structural, electronic, and reactivity properties of the molecules were analyzed by DFT-based calculation methods and Koopman’s Theory. The inhibition activities against acetylcholinesterase, butyrylcholinesterase and tyrosinase were also analyzed, and the antioxidant activity of the molecules were investigated. The inhibition and the activity details of the molecules were also evaluated by molecular docking methods.

Synthesis of PdII Triazolylidene Complexes via an Unusual Csp2‐Csp2 Decoupling Reaction: Applications in α‐Arylation of Amide and Suzuki‐Miyaura Coupling Reactions

AbstractMononuclear PdII complexes bearing mixed MIC/Py/PPh3 donor set ligands are presented starting from a bis‐triazolium salt featuring 4,4’‐substitution pattern of central biphenyl ring. The mononuclear PEPPSI (pyridine enhanced precatalyst preparation, stabilization and initiation) type complexes bearing triazolylidene donor ligand have been synthesized via an unusual Csp2‐Csp2 decoupling reaction. The complexes have been characterized by 1H, 13C{1H} NMR spectroscopy and mass spectrometry. Two of the complexes have also been structurally characterized by single crystal XRD. All the complexes appeared as active precatalysts in α‐arylation of amide and Suzuki‐Miyaura coupling reactions. Catalytic outcomes clearly indicate the superior activities of the PdII complexes with mixed MIC/PPh3 donor set ligands compared to the corresponding PEPPSI type complexes in α‐arylation of oxindole.

Synthesis and characterization of novel PEPPSI type bicyclic (alkyl)(amino)carbene (BICAAC)-Pd complexes

A series of bicyclic alkylamino carbenes (BICAAC) (where N-aryl = dipp, mes, 2,6-dimethyl-4-(dimethylamino)phenyl, 5a–d) and their novel air- and moisture-resistant pyridine (pyridine, 4-dimethylaminopyridine) containing palladium Pd(II) complexes (6a–e) were synthetized and characterized. As novel examples of the PEPPSI (“pyridine enhanced precatalyst preparation stabilization and initiation”)-Pd compounds, the reported complexes have shown high activity in Mizoroki–Heck coupling reaction even at as low as 100 ppm loading (TON up to 10000). Kinetic studies revealed that reactions carried out in the presence of elemental mercury resulted decrease in activity. It indicates that the coupling reaction may have both molecular and Pd(0)-mediated catalytic paths.

1,3-Dioxane Functionalized Pd-PEPPSI Catalyst for Direct Arylation of Heteroaromatics

A series of benzimidazolium salts (1a-d) and their Pd-PEPPSI complexes (pyridine-enhanced precatalyst preparation, stabilization, and initiation) (2a-d) were prepared to catalyze the direct arylation of heteroaromatics (2-acetylthiophene and 2-furaldehyde) with various aryl bromides. The structures of all isolated compounds were elucidated based on spectroscopic methods (1H and 13C NMR, FT-IR and LC-MS spectroscopy). Under optimized reaction conditions, C5-arylated products were obtained in moderate to excellent yields in the direct arylation of heteroaromatics.

Benzimidazole-functionalized PEPPSI type Pd(II)NHC complexes bearing nitrophenylethyl and hidroxyphenylethyl group: Synthesis, characterization, crystal structure and it's catalytic activity on direct arylation reaction

This study contains synthesis, characterization, crystal structure, and catalytic activity of the new two series PEPPSI (Pyridine Enhanced Precatalyst Preparation, Stabilization and Initiation) type Pd(II)NHC complexes nitrophenylethyl and hidroxyphenylethyl groups. All complexes were prepared from the nitrophenylethyl and hidroxyphenylethyl substitute benzimidazolium salts, palladium chloride (PdCl2) and 3-chloropyridine. The structures of all PEPPSI type Pd(II)NHC complexes have been fully characterized by using NMR (1H and 13C), FTIR spectroscopic method, and elemental analysis techniques. Also, the single-crystals of four of these complexes were examined by utilizing by the X-ray diffraction method. Also, the catalytic activity of the nitrophenylethyl and hidroxyphenylethyl substituted benzimidazole-functionalized PEPPSI type Pd(II)NHC complexes on the direct arylation reaction were examined. It has been observed that among these complexes, those bearing electron-donor groups (hydroxyphenylethyl) are more active catalysts than those bearing electron-withdrawing groups (nitrophenylethyl) for direct arylation reactions.

A new PEPPSI type N-heterocyclic carbene palladium(II) complexes and its efficiency as a catalyst for Mizoroki-Heck cross-coupling reactions in water : Synthesis, Characterization and their antimicrobial and Cytotoxic activities

A series of novel benzimidazolium salts 2 and their new air and moisture stable PEPPSI type N-heterocyclic carbene palladium(II) complexes (PEPPSI: pyridine-enhanced pre-catalyst preparation, stabilisation, and initiation), were synthesized and characterized by means of 1H and 13C{1H} NMR, FTIR spectroscopic methods and elemental analysis was employed to catalyze the Mizoroki-Heck cross-coupling reactions of aryl bromides with styrene in water. To the best of our knowledge, this is the first report where a Pd-PEPPSI catalyst was successfully employed in aqueous-phase Mizoroki-Heck reaction. Good to excellent yields of cross-coupling products were obtained with a range of representative aryl bromides under relatively mild conditions. Moreever the antimicrobial activity of the PEPPSI type N-heterocyclic carbene palladium(II) complexes 3a-e varies with the nature of the ligands. Also, the IC50 values of both, complexes (3a-e) have been determined. In addition, the new PEPPSI type N-heterocyclic carbene palladium(II) complexes were screened for their cytotoxic activities. Complex 3b exhibited the highest antitumor effect with IC50 values 0.63 μg/mL and against MCF-7.

Synthesis of [PdBr2(benzimidazole-2-ylidene)(pyridine)] complexes and their catalytic activity in the direct C[sbnd]H bond activation of 2-substituted heterocycles

A series of unsymmetrical 1,3-disubstituted benzimidazolium chlorides, 2a-f, having two nitrogen atoms substituted by various alkyl groups were synthesized as N-heterocyclic carbene (NHC) precursors in high yields. The benzimidazolium salts are readily converted into the corresponding PEPPSI-type palladium–NHC complexes 3a-f (PEPPSI = pyridine-enhanced precatalyst preparation, stabilization and initiation). The structures of all the compounds have been characterized by 1H NMR, 13C NMR and IR spectroscopy, as well as the X-ray diffraction technique (3a, 3d and 3e), which support the proposed structures. Next, the palladium-NHC-PEPPSI complexes were used as catalysts in the direct C(5)-arylation of 2-acetyl furan and 2-acetylthiophene with various aryl bromides. These complexes exhibited moderate to high catalytic activities and gave CH activation selectively at the C(5)-position of 2-acetylfuran and 2-acetylthiophene.

PEPPSI type Pd(II)NHC complexes bearing chloro-/fluorobenzyl group: Synthesis, characterization, crystal structures, α-glycosidase and acetylcholinesterase inhibitory properties

This work reported the synthesis of a new PEPPSI (Pyridine Enhanced Precatalyst Preparation, Stabilization and Initiation) type Pd(II)N-heterocyclic carbene (NHC) complexes bearing halo-benzyl (4-florobenzyl and 2-chloro-4-florobenzyl) group. These new complexes were synthesized from the florobenzyl / chlorofluorobenzyl substituted benzimidazolium salts, PdCl2 and pyridine. Characterizations of all the synthesized complexes were done using elemental analysis, 1H NMR, 13C NMR and FT-IR spectroscopy techniques. The molecular and crystal structures of the new PEPPSI type Pd(II)NHC complexes were determined by single-crystal X-ray diffraction method. X-ray studies show that molecular structures of three complexes comprise a palladium(II) atom with a slightly distorted square-planar coordination environment. These synthesized salts were found to be effective inhibitors for the α-glycosidase, and acetylcholinesterase (AChE) enzyme with Ki values in the range of 27.36 ± 5.06–124.88 ± 18.05 µM for α-glycosidase, and 0.78 ± 0.11–4.34 ± 1.02 µM for AChE, respectively. The significant group of drugs currently utilized for the therapy of Alzheimer's disease (AD) is acetylcholinesterase/cholinesterase inhibitor compounds. The first cholinesterase inhibitor licensed for symptomatic therapy of AD was tacrine. Inhibition acts of α-glycosidase enzyme by inhibitors tend to slow the breakdown and release of sugar molecules into the bloodstream and can be utilized as therapeutic factors in the therapy of obesity and diabetes.

Palladium(II), silver(I), and gold(I) complexes of a new class of chiral bicyclic [1,2,3]-triazolooxazine derived N-heterocyclic carbenes (NHCs): Synthesis, structure and application studies

A new class of chiral bicyclic [1,2,3]-triazolooxazine derived N-heterocyclic carbene (NHC) ligands was synthesised in its enantiopure form from commercially available, cheap amino acid without undertaking any chiral resolution. In particular, the bicyclic N-heterocyclic carbene precursor, (S)-7-benzyl-6,6-(R1)2–2-R2-[1,2,3]-triazolooxazinium iodide [R1 = R2 = Me (1a); R1 = H, R2 = Me (2a); R1 = H, R2 = Et (3a)] salts were conveniently prepared by the N-alkylation reactions of the corresponding [1,2,3]- triazolooxazine derivatives with alkyl iodides in ca. 37–73% yields. The copper mediated [3 + 2] cycloaddition reaction of the PhCH2CH(N3)CR2OH (R = H, Me) azido alcohol compounds and propargyl bromide gave the desired [1,2,3]-triazolooxazines. These chiral bicyclic [1,2,3]- triazolooxazine derived N-heterocyclic carbene ligands were characterised in the form of its silver (NHC)AgCl (1–3)b, gold (NHC)AuCl (1–3)c, and the palladium (NHC)2PdCl2 (1–3)d and the PEPPSI type (NHC)PdI2(NC5H5) (1–3)e complexes (NHC = (S)-7-benzyl-6,6-(R1)2–2-R2-[1,2,3]-triazolooxazin-3-ylidene; R1 = H, Me and R2 = Me, Et; PEPPSI = Pyridine Enhanced Precatalyst Preparation Stabilisation and Initiation).

Biological Activities of NHC–Pd(II) Complexes Based on Benzimidazolylidene N-heterocyclic Carbene (NHC) Ligands Bearing Aryl Substituents

N-heterocyclic carbene (NHC) precursors (2a–i), their pyridine-enhanced precatalyst preparation stabilization and initiation (PEPPSI)-themed palladium N-heterocyclic carbene complexes (3a–i) and palladium N-heterocyclic triphenylphosphines complexes (4a–i) were synthesized and characterized by elemental analysis and 1H NMR, 13C NMR, IR, and LC–MS spectroscopic techniques. The (NHC)Pd(II) complexes 3–4 were tested against MCF7 and MDA-MB-231 cancer cells, Escherichia coli, methicillin-resistant Staphylococcus aureus (MRSA), Candida albicans microorganisms, Leishmania major promastigotes and amastigotes, Toxoplasma gondii parasites, and Vero cells in vitro. The biological assays indicated that all compounds are highly active against cancer cells, with an IC50 < 1.5 µg mL−1. Eight compounds proved antibacterial and antileishmanial activities, while only three compounds had strong antifungal activities against C. albicans. In our conclusion, compounds 3 (b, f, g, and h) and 4b are the most suitable drug candidates for anticancer, antimicrobial, and antiparasitical.

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, characterization and catalytic activity of PEPPSI-type palladium–NHC complexes

Eight benzimidazolium salts (2a–h) with two nitrogen atoms substituted by various alkyl groups have been synthesized in high yields. The benzimidazolium salts were readily converted into the corresponding PEPPSI-type palladium–NHC complexes (PEPPSI = pyridine-enhanced precatalyst preparation, stabilization, and initiation) (3a–h). The structures of all compounds were characterized by 1H NMR, 13C NMR, and IR spectroscopy as well as by elemental analysis techniques, which support the proposed structures. The catalytic activity of the PEPPSI-type palladium–NHC complexes was evaluated with respect to the direct C5-arylation of 2-substituted heteroaryl derivatives (thiophene, furan and thiazole) with various aryl bromides. This arylation occurs efficiently and selectively at the C5-position of the 2-substituted thiophene, furan and thiazole derivatives.

A new PEPPSI type N-heterocyclic carbene palladium(II) complex and its efficiency as a catalyst for Mizoroki-Heck cross-coupling reactions in water

A new air and moisture stable PEPPSI (PEPPSI: pyridine-enhanced pre-catalyst preparation, stabilisation, and initiation) themed palladium N-heterocyclic carbene (NHC) complex [Pd(L)Br2(Py)] (1) [L: 2-flurobenzyl)-1-(4-methoxyphenyl)-1H-imidazolline-2-ylidene] was synthesized and characterized. The structure of complex 1 was determined by X-ray single-crystal analysis. The palladium center in 1 adopted a square planar geometry with carbene and pyridine ligands occupying the mutual trans position. The complex 1 was employed to catalyze the Mizoroki-Heck cross-coupling reactions of aryl bromides/iodides with styrene in water. To the best of our knowledge, this is the first report where a Pd-PEPPSI catalyst was successfully employed in aqueous-phase Mizoroki-Heck reaction. Good to excellent yields of cross-coupling products were obtained with a range of representative aryl bromides/iodides under relatively mild conditions (100 °C, 1 mol% of 1). A new palladium PEPPSI complex was synthesized, characterized and evaluated as catalyst for the Mizoroki-Heck reaction in aqueous medium. Both electron-donating and electron-withdrawing aryl halides (bromides and iodides) reacted with styrene to give corresponding coupling products in moderate to excellent yields.

Hydrogel supported vinylimidazole based PEPPSI-Pd-NHC catalysts: The catalytic activities in Heck and Suzuki-Miyaura coupling reactions

Increasing environmental awareness and limited raw material resources have increased the importance of catalysts by leading to green technology. For this purpose, there is a need for efficient, new, selective, reusable, environmentally friendly catalysts and catalytic systems. In this study, PEPPSI (pyridine enhanced precatalyst preparation, stabilization, and initiation) type and vinylimidazole (VI) based palladium complexes of N-heterocyclic carbenes (PEPPSI-Pd-NHCs) which have catalytic activity in homogeneous Suzuki and Heck reactions were prepared. To obtain environmentally safe polymeric heterogeneous catalysts, this novel PEPPSI-Pd-NHC complexes were polymerized with Acrylamide (AAm) and 2-acrylamido-2-methylpropane sulfonic acid (AMPS) by free radical polymerization. Characterization of PEPPSI-Pd-NHC complexes and polymer supported catalysts were made by using various elemental and structural analyses techniques. The synthesized polymeric supported heterogeneous catalysts have high activity, stability and reusability for Suzuki and Heck reaction of aryl bromides in aqueous media.

The direct C4-arylation of 3,5-dimethylisoxazole with aryl bromides catalyzed by imidazolidin-2-ylidene based palladium-PEPPSI complexes

In this study, the synthesis and characterization of four new imidazolinium salts as carbene precursors and their corresponding four new PEPPSI-type (PEPPSI = Pyridine Enhanced Precatalyst Preparation Stabilization and Initiation) palladium complexes were reported. The structures of these new compounds were characterized by spectroscopic and analytical techniques. The catalytic activities of all palladium complexes were evaluated in the direct C4-arylation of 3,5-dimethylisoxazole with para-substituted aryl bromides, ortho-substituted aryl bromides and heteroaryl bromides. A range of functional groups such as methoxy, acetyl, formyl, fluoro, trifluoromethyl, nitrile or tert-butyl on the aryl bromide were succesfully tolerated, and good yields were generally obtained in presence of 1 mol% catalyst loading at 120 °C.