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Use of the branched N-heterocyclic carbene (NHC) ligand 1,3-bis(2,6-bis(3-methyl-1-(2-methylpropyl)butyl)phenyl)-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene (DiMeIHeptCl) facilitated the stabilization of several relevant intermediates for Pd(NHC)-catalyzed C-N cross-coupling reactions. Complexes [Pd(DiMeIHeptCl)]2(µ-N2), [Pd(DiMeIHeptCl)]2(µ-η2-1,2-η2-4,5-C6H6), and Pd(DiMeIHeptCl)(pyridine), representing zerovalent Pd(NHC) bearing labile ligands, were isolated and structurally characterized, along with divalent PdCl(Ph)(DiMeIHeptCl) and PdCl(Ph)(DiMeIHeptCl)(n-propylamine). The former is a 14-electron Pd complex, which is stable under air and chromatography on silica gel or neutral alumina. One possible reason for this exceptional stability is the numerous dispersion interactions between the NHC alkyl chains and the Pd-Ph group. Detailed investigations of catalyst activation and oxidative addition confirmed that "Pd(NHC)" is formed from many known Pd(II)(NHC) precatalysts and provided activation rates for these different precatalysts.
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NaBHT (sodium 2,6-di-tert-butyl-4-methylphenolate), a strong, but hindered and lipophilic base, has been effectively paired with similarly lipophilic, high-reactivity Pd-NHC (N-heterocyclic carbene) catalysts to produce an ideal combination for performing solvent-free (melt) cross-coupling amination. The mild nucleophilicity of NaBHT, coupled with the anti-oxidant properties of its conjugate acid byproduct, BHT means the process seems to have no functional group incompatibilities. Highly effective coupling of base-sensitive and redox-active functional groups was observed in all cases with only 0.1-0.2â mol percent catalyst. Comparisons using the standard base for this reaction, KOtBu, led to poor couplings or complete degradation in most applications - only NaBHT works.
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Hidroxitolueno Butilado , Sódio , Aminação , Catálise , SolventesRESUMO
Compressed tablets containing a mixture of a photocatalyst, a nickel catalyst, an inorganic base, and an inert excipient are employed as a fast, safe, and user-friendly chemical delivery system for two different metallophotoredox-catalyzed reactions. This delivery method simplifies the preparation of compound libraries using photoredox chemistry in a parallel setting. The reagent tablets were successfully applied to late-stage functionalization of drug-like intermediates. These tablets can be prepared with various reagents and catalysts in different sizes and be stored on the bench thanks to blister packaging.
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Indicadores e Reagentes , Catálise , Solubilidade , ComprimidosRESUMO
(DiMeIHeptCl)Pd, a hyper-branched N-aryl Pd NHC catalyst, has been shown to be efficient at performing amine arylation reactions in solvent-free ("melt") conditions. The highly lipophilic environment of the alkyl chains flanking the Pd center serves as lubricant to allow the complex to navigate through the paste-like environment of these mixtures. The protocol can be used on a multi-gram scale to make a variety of aniline derivatives, including substrates containing alcohol moieties.
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Commercially available hydroxypropyl methylcellulose capsules are employed as a fast, safe, and user-friendly chemical delivery system containing all reagents (catalyst, ligand, and base) for three important transition-metal-catalyzed reactions: Buchwald-Hartwig, Suzuki-Miyaura, and metallophotoredox C-N cross-coupling reactions. This encapsulation methodology simplifies the screening of reaction conditions and the preparation of compound libraries using parallel synthesis in organic solvents or aqueous media. These reagents-containing HPMC capsules are easy to prepare, come in different sizes, and can be stored on the bench under noninert conditions.
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A simple and environmentally benign technology for synthesizing ultrasmall CuI nanoparticles (NPs) on the surface of the food additive hydroxypropyl methylcellulose (HPMC) and their application in completely organic solvent-free tandem alkyne-azide cycloaddition reactions were reported. The NP catalyst was thoroughly characterized by high-angle annular dark-field scanning transmission electron microscopy, high-resolution transmission electron microscopy, energy-dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy analysis for its morphology, particle size distribution, chemical composition, and oxidation state analyses. The NP catalyst was highly efficient, affording products in 10-45â min. All products were obtained in high purity by simple filtration, obviating organic solvents from the reaction set-up to product isolation. The methodology is general and scalable as validated by a broad substrate scope.
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In the micelle of PS-750-M, the presence of 3° amides from the surfactant proline linker mimics dimethylformamide, dimethylacetamide, and N-methyl-2-pyrrolidone. The resultant micellar properties enable extremely fast amide couplings mediated by 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide (without hydroxybenzotriazole), rather than expensive and specialized coupling agents. Conditions have been developed wherein products precipitate, and isolation by filtration completely avoids the use of organic solvent. This methodology is scalable and avoids product epimerization.
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Invited for this month's cover is the research group of Sachin Handa at the University of Louisville and Wilfried Braje at AbbVie. The image shows how green chemistry in industry and micellar catalysis are contributing toward the environmental sustainability. The Minireview itself is available at 10.1002/cssc.202000317.
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In this Minireview, the importance and implementation of green chemistry practices in the pharmaceutical industry are illustrated. With notable examples, some of the most important industrial organic transformations are discussed along with their applications in the synthesis of drug molecules. A brief comparison between traditional unsustainable methods and modern green methods is made to shed light on the economic and environmental benefits of greener methods. Finally, green chemistry practices in the pharmaceutical industries of India and China are also discussed.
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Indústria Farmacêutica , Química Verde , Biocatálise , China , Índia , Natureza , Solventes/químicaRESUMO
In our efforts to further pursue one of the most selective dopamine D(3)-receptor antagonists reported to date, we now describe the synthesis and SAR of novel and highly selective dopamine D(3) antagonists based on a 1H-pyridin-2-one or on a urea scaffold. The most potent compounds exhibited K(i) values toward the D(3) receptor in the nano- to subnanomolar range and high selectivity versus the related D(2) dopamine receptor. Thus, 1H-pyridin-2-one 7b displays oral bioavailability (F=37%) as well as brain penetration (brain plasma ratio 3.7) in rat. Within the urea series, an excellent D(3) versus D(2) selectivity (>100-fold) could be achieved by removal of one NH group (compound 6), although bioavailability (rat) was suboptimal (F<10%). These data significantly enhance our understanding of the D(3) pharmacophore and are expected to lead to novel approaches for the treatment of schizophrenia.
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Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacologia , Pirimidinonas/química , Pirimidinonas/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Disponibilidade Biológica , Antagonistas de Dopamina/síntese química , Humanos , Microssomos Hepáticos/metabolismo , Pirimidinonas/síntese química , Relação Estrutura-AtividadeRESUMO
A new solid-phase synthesis for ET receptor antagonists suitable for automation is presented. A support bound 2-hydroxybutyric acid derivative was converted to the corresponding ether derivatives using 4-halo-2-methylsulfonylpyrimidines. Subsequent Suzuki coupling with various aryl boronic acids gave the desired antagonists in good yields and purities. Highly potent antagonists with excellent selectivity for ET(A) were obtained.