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BACKGROUND: Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are chronic inflammatory diseases in which innate and adaptive responses of the immune system are induced. RA and PsA have complex signaling pathways. Despite the differences in their clinical presentation, there is a great demand for fast and accurate diagnosis of diseases to implement treatment and plan an individual therapeutic strategy quickly. In this report, we present the results of differential diagnosis of patients with RA and PsA and healthy subjects (C, control group), allowing for reliable differentiation of groups of rheumatoid patients based on biochemical parameters, attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectra, and combined data sets. MATERIALS AND METHODS: Biochemical analyses, ELISA (enzyme-linked immunosorbent assays), and multiplex assays were conducted for blood sera from patients with RA (n = 32), patients with PsA (n = 28), and the control group (n = 18). ATR-FTIR spectra were collected for lyophilized sera. RESULTS: The combination of six biochemical parameters (WBC, ESR, RF, CRP, HCC-4/CCL16, and HMGB1/HMGB) allowed the development of the partial least squares discriminant analysis (PLS-DA) model with an overall accuracy (OA) of 80% for test samples. The best separation between RA, PsA, and the control group was obtained utilizing spectral data. Using the interval PLS algorithm (iPLS) specific spectral ranges were selected and a classifier characterized by OA value for test set equal to 88% was obtained. This parameter, for the hybrid PLS-DA model constructed using selected biochemical parameters and a significantly reduced number of spectral variables, reached the level of 84%. CONCLUSIONS: PLS-DA models developed on the basis of spectral data enable effective differentiation of patients with RA, patients with PsA, and healthy subjects. They appeared to be insensitive to existing inflammation processes which opens interesting perspectives for new diagnostic tests and algorithms for identification of patients with RA and PsA.
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Artritis Psoriásica , Artritis Reumatoide , Biomarcadores , Humanos , Artritis Psoriásica/diagnóstico , Artritis Psoriásica/sangre , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Artritis Reumatoide/sangre , Artritis Reumatoide/diagnóstico , Diagnóstico Diferencial , Persona de Mediana Edad , Biomarcadores/sangre , Proyectos Piloto , Masculino , Femenino , Adulto , Análisis de los Mínimos Cuadrados , Análisis Discriminante , Anciano , Estudios de Casos y ControlesRESUMEN
Sterically-hindered N-heterocyclic carbenes (NHCs) with functionalized N-wingtips are a pivotal class of ligands in organic synthesis. Herein, we report the first class of sterically-hindered N-heterocyclic carbenes based on the indazole framework. These ligands combine the strong σ-donation of the carbene center due to the carbene placement at the C3-indazole position with the sterically-hindered and flexible N-substitution with the versatile 2,6-bis(diphenylmethyl)aryl moiety that extends beyond the metal centre for the first time in non-classical N-heterocyclic carbenes. The ligands are readily accessible by the rare Cadogan indazole synthesis of sterically-hindered N-aryl-1-(2-nitrophenyl)methanimines. Steric and electronic characterization as well as catalytic studies in the synthesis of oxazolines are described. Considering the unique properties of indazole-derived carbenes, we anticipate that this class of compounds will find broad application in organic synthesis and catalysis.
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BACKGROUND: Determination of composition and physicochemical parameters of natural products requires dedicated, often laborious and expensive, analytical protocols. Different spectroscopic techniques, in conjunction with chemometrics, seem to have a considerable potential in direct analysis of raw plant material and foods, without any chemical treatment. RESULTS: Fluorescence spectroscopy and three vibrational spectroscopy techniques were applied to determine total polyphenol content, antioxidant activity and macronutrient levels in red- and purple-fleshed potato varieties. Excitation-emission matrix fluorescence, Fourier transform Raman, attenuated total reflection Fourier transform infrared and near-infrared spectra were recorded for the freeze-dried samples. Combining spectral data and the results of reference analyses, partial least squares regression models were constructed for each parameter studied. For polyphenols and antioxidant activity, quantification errors found for validation samples amounted to 3.74-5.04% and 4.75-6.35%, respectively, whereas macronutrient analysis gave errors in the 3.45-4.55%, 3.09-5.30% and 5.10-8.58% ranges for starch, protein and sugar determinations, respectively. CONCLUSION: The obtained results demonstrate that different spectroscopic techniques in combination with multivariate modeling allow simultaneous determination of various parameters of plant samples based on a single sample spectrum. They can effectively replace commonly used protocols of food product analysis requiring sample dissolving and extraction of the compounds of interest. © 2023 Society of Chemical Industry.
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Solanum tuberosum , Solanum tuberosum/química , Espectrometría de Fluorescencia , Antioxidantes , Polifenoles/análisis , Análisis de los Mínimos Cuadrados , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
IMes (IMes=1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene) and IPr (IPr=1,3- bis(2,6-diisopropylphenyl)imidazol-2-ylidene) represent by far the most frequently used N-heterocyclic carbene ligands in homogeneous catalysis, however, despite numerous advantages, these ligands are limited by the lack of steric flexibility of catalytic pockets. We report a new class of unique unsymmetrical N-heterocyclic carbene ligands that are characterized by freely-rotatable N-aromatic wingtips in the imidazol-2-ylidene architecture. The combination of rotatable N-CH2 Ar bond with conformationally-fixed N-Ar linkage results in a highly modular ligand topology, entering the range of geometries inaccessible to IMes and IPr. These ligands are highly reactive in Cu(I)-catalyzed ß-hydroboration, an archetypal borylcupration process that has had a transformative impact on the synthesis of boron-containing compounds. The most reactive Cu(I)-NHC in this class has been commercialized in collaboration with MilliporeSigma to enable broad access of the synthetic chemistry community. The ligands gradually cover %Vbur geometries ranging from 37.3 % to 52.7 %, with the latter representing the largest %Vbur described for an IPr analogue, while retaining full flexibility of N-wingtip. Considering the modular access to novel geometrical space in N-heterocyclic carbene catalysis, we anticipate that this concept will enable new opportunities in organic synthesis, drug discovery and stabilization of reactive metal centers.
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N-heterocyclic carbenes (NHCs) have emerged as a major direction in ancillary ligand development for stabilization of reactive metal centers in inorganic and organometallic chemistry. In particular, wingtip-flexible NHCs have attracted significant attention due to their unique ability to provide a sterically-demanding environment for transition metals in various oxidation states. Herein, we report a new class of sterically-hindered, wingtip-flexible NHC ligands that feature N,C-chelating oxazole donors. These ligands are readily accessible through a modular arylation of oxazole derivatives. We report their synthesis and complete structural and electronic characterization. The evaluation of steric, electron-donating and π-accepting properties and coordination chemistry to Ag(I), Pd(II) and Rh(I) is described. Preliminary studies of catalytic activity in Ag, Pd and Rh-catalyzed coupling and hydrosilylation reactions are presented. This study establishes the fluxional behavior of a freely-rotatable oxazole unit, wherein the oxazolyl ring adjusts to the steric and electronic environment of the metal center. Considering the tremendous impact of sterically-hindered NHCs and their potential to stabilize reactive metals by N-chelation, we expect that this class of NHC ligands will be of broad interest in inorganic and organometallic chemistry.
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In this Special Issue, "Featured Papers in Organometallic Chemistry", we report on the synthesis and characterization of [IPr#-PEPPSI], a new, well-defined, highly hindered Pd(II)-NHC precatalyst for cross-coupling reactions. This catalyst was commercialized in collaboration with MilliporeSigma, Burlington, ON, Canada (no. 925489) to provide academic and industrial researchers with broad access to reaction screening and optimization. The broad activity of [IPr#-PEPPSI] in cross-coupling reactions in a range of bond activations with C-N, C-O, C-Cl, C-Br, C-S and C-H cleavage is presented. A comprehensive evaluation of the steric and electronic properties is provided. Easy access to the [IPr#-PEPPSI] class of precatalysts based on modular pyridine ligands, together with the steric impact of the IPr# peralkylation framework, will facilitate the implementation of well-defined, air- and moisture-stable Pd(II)-NHC precatalysts in chemistry research.
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ItBu (ItBu = 1,3-di-tert-butylimidazol-2-ylidene) represents the most important and most versatile N-alkyl N-heterocyclic carbene available in organic synthesis and catalysis. Herein, we report the synthesis, structural characterization and catalytic activity of ItOct (ItOctyl), C2-symmetric, higher homologues of ItBu. The new ligand class, including saturated imidazolin-2-ylidene analogues has been commercialized in collaboration with MilliporeSigma: ItOct, 929 298; SItOct, 929 492 to enable broad access of the academic and industrial researchers within the field of organic and inorganic synthesis. We demonstrate that replacement of the t-Bu side chain with t-Oct results in the highest steric volume of N-alkyl N-heterocyclic carbenes reported to date, while retaining the electronic properties inherent to N-aliphatic ligands, such as extremely strong σ-donation crucial to the reactivity of N-alkyl N-heterocyclic carbenes. An efficient large-scale synthesis of imidazolium ItOct and imidazolinium SItOct carbene precursors is presented. Coordination chemistry to Au(i), Cu(i), Ag(i) and Pd(ii) as well as beneficial effects on catalysis using Au(i), Cu(i), Ag(i) and Pd(ii) complexes are described. Considering the tremendous importance of ItBu in catalysis, synthesis and metal stabilization, we anticipate that the new class of ItOct ligands will find wide application in pushing the boundaries of new and existing approaches in organic and inorganic synthesis.
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In the last decade, major advances have been made in homogeneous gold catalysis. However, AuI /AuIII catalytic cycle remains much less explored due to the reluctance of AuI to undergo oxidative addition and the stability of the AuIII intermediate. Herein, we report activation of aryl halides at gold(I) enabled by NHC (NHC=N-heterocyclic carbene) ligands through the development of a new class of L-shaped heterobidentate ImPy (ImPy=imidazo[1,5-a]pyridin-3-ylidene) N,C ligands that feature hemilabile character of the amino group in combination with strong σ-donation of the carbene center in a rigid conformation, imposed by the ligand architecture. Detailed characterization and control studies reveal key ligand features for AuI /AuIII redox cycle, wherein the hemilabile nitrogen is placed at the coordinating position of a rigid framework. Given the tremendous significance of homogeneous gold catalysis, we anticipate that this ligand platform will find widespread application.
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Cationic Au(I)âNHC (NHC = N-heterocyclic carbene) complexes have become an important class of catalysts for alkyne π-activation reactions in organic synthesis. In particular, these complexes are characterized by high stability of catalytic species engendered by strong σ-donation and metal backbonding. Herein, we report the synthesis and characterization of well-defined [Au(NHC)Cl] complexes featuring recently discovered IPr# family of ligands that hinge upon modular peralkylation of aniline. These ligands have been commercialized in collaboration with MilliporeSigma (IPr#: 915653; Np#: 915912; BIAN-IPr#: 916420). Evaluation of the [Au(NHC)Cl] complexes in a series of Au(I)âNHC-catalyzed π-functionalizations of alkynes, such as hydrocarboxylation, hydroamination and hydration, resulted in the identification of wingtip-flexible [Au(Np#)Cl] as a highly reactive and broadly applicable catalyst with the re-activity outperforming the classical [Au(IPr)Cl] and [Au(IPr*)Cl] complexes. The utility of this catalyst has been demonstrated in the direct late-stage derivatization of complex pharmaceuticals. Structural and computational studies were conducted to determine steric effects, frontier molecular orbitals and bond orders of this class of catalysts. Considering the attractive features of well-defined Au(I)âNHC complexes, we anticipate that this class of bulky and wingtip-flexible Au(I)âNHCs based on the modular peralkylated naphthylamine scaffold will find broad application in π-functionalization of alkynes in various areas of organic synthesis and catalysis.
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Diosmin is widely used in the treatment of chronic venous diseases and hemorrhoids. Based on Raman and infrared reflection spectra of powdered tablets in the mid- and near-infrared regions and results of reference high-performance liquid chromatographic analysis, partial least squares models that enable fast and reliable quantification of the studied active ingredient in tablets, without the need for extraction, were elaborated. Eight commercial preparations containing diosmin in the 66-92% (w/w) range were analyzed. In order to assess and compare the quality of the developed chemometric models, the relative standard errors of prediction for calibration and validation sets were calculated. We found these errors to be in the 1.0-2.4% range for the three spectroscopic techniques used. Diosmin content in the analyzed preparations was obtained with recoveries in the 99.5-100.5% range.
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Diosmina , Espectrometría Raman , Espectrometría Raman/métodos , Comprimidos/química , Análisis de los Mínimos Cuadrados , CalibraciónRESUMEN
IPr* (IPr* = 1,3-bis(2,6-bis(diphenylmethyl)-4-methylphenyl)imidazol-2-ylidene) has emerged as a powerful highly hindered and sterically-flexible ligand platform for transition-metal catalysis. CAACs (CAAC = cyclic (al-kyl)(amino)carbenes) have gained major attention as strongly electron-rich carbon analogues of NHCs (NHC = N-heterocyclic carbene) with broad applications in both industry and academia. Herein, we report a merger of CAAC ligands with highly-hindered IPr*. The efficient synthesis, electronic characterization and application in model Cu-catalyzed hydroboration of alkynes is described. The ligands are strongly electron-rich, bulky and flexible around the N-Ar wingtip. The availability of various IPr* and CAAC templates offers a significant potential to expand the existing arsenal of NHC ligands to electron-rich bulky architectures with critical applications in metal stabilization and catalysis.
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Xanthines, such as caffeine and theophylline, are abundant natural products that are often present in foods. Leveraging renewable and benign resources for ligand design in organometallic chemistry and catalysis is one of the major missions of green and sustainable chemistry. In this Special Issue on Sustainable Organometallic Chemistry, we report the first nickel-N-heterocyclic carbene complexes derived from Xanthines. Well-defined, air- and moisture-stable, half-sandwich, cyclopentadienyl [CpNi(NHC)I] nickel-NHC complexes are prepared from the natural products caffeine and theophylline. The model complex has been characterized by x-ray crystallography. The evaluation of steric, electron-donating and π-accepting properties is presented. High activity in the model Suzuki-Miyaura cross-coupling is demonstrated. The data show that nickel-N-heterocyclic carbenes derived from both Earth abundant 3d transition metal and renewable natural products represent a sustainable alternative to the classical imidazol-2-ylidenes.
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We report the Sonogashira cross-coupling of aryl ammonium salts catalyzed by air- and moisture-stable [Pd(NHC)(3-CF3-An)Cl2] (An = aniline). This highly active Pd(II)-NHC complex features broad scope and excellent C-N activation selectivity in the challenging alkynylative cross-coupling of aryl ammonium salts. Full structural characterization and computational studies demonstrate the effect of pyridine to aniline replacement as highly effective stabilizing ancillary ligand in well-defined Pd(II)-NHCs. Considering the high reactivity and the recent commercialization of [Pd(NHC)(3-CF3-An)Cl2] (Millipore Sigma, no. 915165), this catalyst represents an attractive approach to the activation of C-N bonds of broad synthetic interest.
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Amide bond replacement with planar isosteric chalcogen analogues has an important implication for the properties of the N-C(X) linkage in structural chemistry, biochemistry and organic synthesis. Herein, we report the first higher chalcogen derivatives of non-planar twisted amides. The synthesis of twisted thioamide in a versatile system has been accomplished by direct thionation without cleavage of the σ N-C bond. The synthesis of twisted selenoamide has been accomplished by selenation with Woollins' reagent. The structures of higher chalcogen analogues of non-planar amides were unambiguously confirmed by X-ray crystallography. Reactivity studies were conducted to determine the effect of isologous N-C(O) to N-C(X) replacement on the properties of the amide linkage. Computational studies were employed to evaluate structural and energetic parameters of amide bond alteration in higher chalcogen amides. The study provides the first experimental evidence on the effect of chalcogen isologues on the structural and electronic properties of the non-planar amide N-C(X) linkage.
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Amidas , Calcógenos , Amidas/química , Calcógenos/química , Cristalografía por Rayos X , Tioamidas/químicaRESUMEN
Endometriosis is one of the most common gynecological diseases among young women of reproductive age. Thus far, it has not been possible to define a parameter that is sensitive and specific enough to be a recognized biomarker for diagnosing this disease. Nonspecific symptoms of endometriosis and delayed diagnosis are impulses for researching noninvasive methods of differentiating endometriosis from other gynecological disorders. We compared three groups of individuals in our research: women with endometriosis (E), patients suffering from other gynecological disorders (nonendometriosis, NE), and healthy women from the control group (C). Partial least squares discriminant analysis (PLS-DA) models were developed based on selected serum biochemical parameters, specific regions of the serum's infrared attenuated total reflectance (FTIR ATR) spectra, and combined data. Incorporating the spectral data into the models significantly improved differentiation among the three groups, with an overall accuracy of 87.5%, 97.3%, and 98.5%, respectively. This study shows that infrared spectroscopy and discriminant analysis can be used to differentiate serum samples among women with advanced endometriosis, women without this disease, i.e., healthy women, and, most importantly, also women with other benign gynecological disorders.
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Endometriosis , Espectroscopía Infrarroja por Transformada de Fourier , Biomarcadores , Análisis Discriminante , Endometriosis/diagnóstico , Femenino , Humanos , Análisis de los Mínimos Cuadrados , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Análisis EspectralRESUMEN
Poplar bark and leaves can be an attractive source of salicylates and other biologically active compounds used in medicine. However, the biochemical variability of poplar material requires a standardization prior to processing. The official analytical protocols used in the pharmaceutical industry rely on the extraction of active compounds, which makes their determination long and costly. An analysis of plant materials in their native state can be performed using vibrational spectroscopy. This paper presents for the first time a comparison of diffuse reflectance in the near- and mid-infrared regions, attenuated total reflection, and Raman spectroscopy used for the simultaneous determination of salicylates and flavonoids in poplar bark and leaves. Based on 185 spectra of various poplar species and hybrid powdered samples, partial least squares regression models, characterized by the relative standard errors of prediction in the 4.5-9.9% range for both calibration and validation sets, were developed. These models allow for fast and precise quantification of the studied active compounds in poplar bark and leaves without any chemical sample treatment.
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Flavonoides , Salicilatos , Calibración , Análisis de los Mínimos Cuadrados , Corteza de la Planta , Hojas de la PlantaRESUMEN
Over the last 20 years, N-heterocyclic carbenes (NHCs) have emerged as a dominant direction in ligand development in transition metal catalysis. In particular, strong σ-donation in combination with tunable steric environment make NHCs to be among the most common ligands used for C-C and C-heteroatom bond formation. Herein, we report the study on steric and electronic properties of thiazol-2-ylidenes. We demonstrate that the thiazole heterocycle and enhanced π-electrophilicity result in a class of highly active carbene ligands for electrophilic cyclization reactions to form valuable oxazoline heterocycles. The evaluation of steric, electron-donating and π-accepting properties as well as structural characterization and coordination chemistry is presented. This mode of catalysis can be applied to late-stage drug functionalization to furnish attractive building blocks for medicinal chemistry. Considering the key role of N-heterocyclic ligands, we anticipate that N-aryl thiazol-2-ylidenes will be of broad interest as ligands in modern chemical synthesis.
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Ni-NHCs (NHC = N-heterocyclic carbene) have become an increasingly important class of complexes in catalysis and organometallic chemistry owing to the beneficial features of nickel as an abundant 3d metal. However, the development of well-defined and air-stable Ni-NHC complexes for cross-coupling has been more challenging than with Pd-NHC catalysis because of less defined reactivity trends of NHC ancillary ligands coordinated to Ni. Herein, we report the synthesis and catalytic activity of well-defined [Ni(NHC)(η5-Cp)Cl] complexes bearing recently commercialized IPr# family of ligands (Sigma Aldrich) and versatile cyclopentadienyl throw-away ligand. The NHC ligands, IPr#, Np# and BIAN-IPr#, are prepared by robust and modular peralkylation of anilines. Most crucially, we identified [Ni(Np#)(η5-Cp)Cl] as a highly reactive [Ni(NHC)(η5-Cp)Cl] complex, with the reactivity outperforming the classical [Ni(IPr)(η5-Cp)Cl] (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene). These [Ni(NHC)(η5-Cp)Cl] precatalysts were employed in the Suzuki and Kumada cross-coupling of aryl chlorides and aryl bromides. Computational studies were conducted to determine steric effect and bond order analysis. Considering the attractive features of well-defined Ni-NHCs, we anticipate that this class of bulky and flexible Ni-NHC catalysts will find broad application in organic synthesis and catalysis.
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The first synthesis of Pd-PEPPSI N-heterocyclic carbene complexes derived from the abundant and renewable natural product caffeine is reported. The catalysts bearing 3-chloro-pyridine, pyridine and N-methylimidazole ancillary ligands were readily prepared from the corresponding N9-Me caffeine imidazolium salt by direct deprotonation and coordination to PdX2 in the presence of N-heterocycles or by ligand displacement of PdX2(Het)2. The model Pd-PEPPSI-caffeine complex has been characterized by x-ray crystallography. The complexes were successfully employed in the Suzuki cross-coupling of aryl bromides, Suzuki cross-coupling of amides, Heck cross-coupling and Sonogashira cross-coupling. Computational studies were employed to determine frontier molecular orbitals and bond order analysis of caffeine derived Pd-PEPPSI complexes. This class of catalysts offers an entry to utilize benign and sustainable biomass-derived Xanthine NHC ligands in the popular Pd-PEPPSI systems in organic synthesis and catalysis.
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We describe the development of [(NHC)Pd(cinnamyl)Cl] complexes of ImPy (ImPy = imidazo[1,5-a]pyridin-3-ylidene) as a versatile class of precatalysts for cross-coupling reactions. These precatalysts feature fast activation to monoligated Pd(0) with 1:1 Pd to ligand ratio in a rigid imidazo[1,5-a]pyridin-3-ylidene template. Steric matching of the C5-substituent and N2-wingtip in the catalytic pocket of the catalyst framework led to the discovery of ImPyMesDipp as a highly reactive imidazo[1,5-a]pyridin-3-ylidene ligand for Pd-catalyzed cross-coupling of nitroarenes by challenging C-NO2 activation. Kinetic studies demonstrate fast activation and high reactivity of this class of well-defined ImPy-Pd catalysts. Structural studies provide full characteristics of this new class of imidazo[1,5-a]pyridin-3-ylidene ligands. Computational studies establish electronic properties of sterically-restricted imidazo[1,5-a]pyridin-3-ylidene ligands. Finally, a scalable synthesis of C5-substituted imidazo[1,5-a]pyridin-3-ylidene ligands through Ni-catalyzed Kumada cross-coupling is disclosed. The method obviates chromatographic purification at any of the steps, resulting in a facile and modular access to ImPy ligands. We anticipate that well-defined [Pd-ImPy] complexes will find broad utility in organic synthesis and catalysis for activation of unreactive bonds.