Discovery of Pd2(DBA)3

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It is hypothesized that selective muscarinic M1 subtype activation could be a strategy to provide cognitive benefits to schizophrenia and Alzheimer’s disease patients while minimizing the cholinergic side effects observed with nonselective muscarinic orthosteric agonists. Selective activation of M1 with a positive allosteric modulator (PAM) has emerged as a new approach to achieve selective M1 activation. This manuscript describes the development of a series of M1-selective pyridone and pyridine amides and their key pharmacophores. Compound 38 (PF-06767832) is a high quality M1 selective PAM that has well-aligned physicochemical properties, good brain penetration and pharmacokinetic properties. Extensive safety profiling suggested that despite being devoid of mAChR M2/M3 subtype activity, compound 38 still carries gastrointestinal and cardiovascular side effects. These data provide strong evidence that M1 activation contributes to the cholinergic liabilities that were previously attributed to activation of the M2 and M3 receptors.

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Reference:
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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An intermolecular Pd-catalyzed allylic dearomatization reaction of polycyclic indoles with substituted allylic carbonates was realized in the presence of a newly synthesized chiral phosphoramidite ligand. Various polycyclic indoline and indolenine derivatives were successfully synthesized in excellent yields (up to 99%) with excellent enantioselectivity (up to 98% ee). The obtained products could undergo versatile transformations, increasing the application potential of the method in organic synthesis.

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Reference:
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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The title compound, 5,6-dihydrocyclohepta[b]indol-6-one (1), was synthesized from 2-chlorotropone (7) by a two-step sequence involving Pd-catalyzed amination with 2-bromoaniline (15) and subsequent Pd-catalyzed intramolecular Heck reaction. Besides its synthetic detail, some physical properties of 1, such as acidity, basicity and spectroscopic behavior, were also reported. Compound 1 was transformed into 6-(1H-pyrazol-1-yl)- and 6-(1H-1,2,3-triazol-1-yl)-5-azabenz[b]azulenes (13 and 14) as a potential ligand.

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Reference:
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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The pyridoxal 5?-phosphate (PLP)-dependent transaminase BioA catalyzes the second step in the biosynthesis of biotin in Mycobacterium tuberculosis (Mtb) and is an essential enzyme for bacterial survival and persistence in vivo. A promising BioA inhibitor 6 containing an N-aryl, N?-benzoylpiperazine scaffold was previously identified by target-based whole-cell screening. Here, we explore the structure-activity relationships (SAR) through the design, synthesis, and biological evaluation of a systematic series of analogues of the original hit using a structure-based drug design strategy, which was enabled by cocrystallization of several analogues with BioA. To confirm target engagement and discern analogues with off-target activity, each compound was evaluated against wild-type (WT) Mtb in biotin-free and -containing medium as well as BioA under- and overexpressing Mtb strains. Conformationally constrained derivative 36 emerged as the most potent analogue with a KD of 76 nM against BioA and a minimum inhibitory concentration of 1.7 muM (0.6 mug/mL) against Mtb in biotin-free medium.

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Reference:
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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Phosphinic acids, RfP(O)(OH)H (Rf=CF3, C2F5, C6F5), turned out to be excellent preligands for the coordination of phosphonous acids, RfP(OH)2. Addition of C2F5P(O)(OH)H to solid PtCl2 under different reaction conditions allows the isolation and full characterization of the mononuclear complexes [ClPt{P(C2F5)(OH)O}{P(C2F5)(OH)2}2] and [Pt{P(C2F5)(OH)O}2{P(C2F5)(OH)2}] containing hydrogen-bridged [RfP(OH)O]- and RfP(OH)2 units. Further deprotonation of [Pt{P(C2F5)(OH)O}2{P(C2F5)(OH)2}2] leads to the formation of the dianionic platinate, [Pt{P(C2F5)(OH)O}4]2-, revealing four intramolecular hydrogen bridges. With PdCl2 the dinuclear complex [Pd2(mu-Cl)2{[P(C2F5)(OH)O]2H}2] was isolated and characterized. The Cl- free complex [Pd{P(C2F5)(OH)O}2{P(C2F5)(OH)2}2] was also prepared and deprotonated to the dianionic palladate, [Pd{P(C2F5)(OH)O}4]2-. Both compounds were characterized by NMR spectroscopy, IR spectroscopy, and X-ray analyses. In addition, the C6F5 derivatives [ClPt{P(C6F5)(OH)O}{P(C6F5)(OH)2}2] and [Pd2(mu-Cl)2{[P(C6F5)(OH)O]2H}2] as well as the CF3 derivative [Pd2(mu-Cl)2{[P(CF3)(OH)O]2H}2] were synthesized and fully characterized. Phosphonous acid complexes are inert towards air and moisture and can be stored for several months without decomposition. The catalytic activity of the palladium complexes in the Suzuki cross-coupling reaction between 1-bromo-3-fluorobenzene and phenyl boronic acid was demonstrated. A tautomeric equilibrium between phosphinic, RP(O)(OH)H, and phosphonous acids, RP(OH)2, is evidenced by this work (see figure). The coordination properties of phosphonous acids with electron-withdrawing CF3, C2F5, and C6F5 groups is also described.

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Reference:
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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Kinetic, spectroscopic, crystallographic, and computational studies probing a Pd-catalyzed C-H arylation reaction reveal that mono-oxidation of the bis-phosphine ligand is critical for the formation of the active catalyst. The bis-phosphine mono-oxide is shown to be a hemilabile, bidentate ligand for palladium. Isolation of the oxidative addition adduct, with structural elucidation by X-ray analysis, showed that the mono-oxide was catalytically competent, giving the same reaction rate in the productive reaction as the Pd(II)/xantphos precursor. A dual role for the carboxylate base in both catalyst activation and reaction turnover was demonstrated, along with the inhibiting effect of excess phosphine ligand. The generality of the role of phosphine mono-oxide complexes in Pd-catalyzed coupling processes is discussed.

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Reference:
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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The first C2-selective alkynylation of indoles using the hypervalent iodine reagent triisopropylsilylethynyl-1,2-benziodoxol-3(1H)-one (TIPS-EBX) with Pd(II) as a catalyst is described. This convenient and robust method gives a single-step access to substituted alkynyl indoles with very high C2 selectivity. The reaction is orthogonal to classical Pd(0) cross-coupling reactions, as it is tolerant to bromide and iodide substituents. The used silyl protecting group can be easily removed to give terminal acetylenes.

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Reference:
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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A new tandem palladium-catalyzed reaction involving a Suzuki-Miyaura coupling, a desulfenylative coupling, and a hydrothiolation of a triple bond is reported. Notably, the desulfenylative coupling occurs without copper(I) assistance and the hydrothiolation is totally regioselective and stereoselective. The overall process results in the double incorporation of the boronic acid and the reincorporation of the sulfenyl moiety into the product structure. Starting from 2-(bromobenzylsulfenyl)-1-propargyl benzimidazoles, the transformation led to variously substituted benzimidazoles bearing a stereodefined alkenyl sulfide.

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Reference:
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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Bipolar hosts derived from dibenzothiophene and indolocarbazole were developed for usage in blue phosphorescent organic light-emitting diodes (PhOLEDs). The 4 position of dibenzothiophene and the 2 position of indolocarbazole were used to couple the dibenzothiophene and indolocarbazole. Two hosts, with and without a pi linker, were synthesized, characterized, and explored as hosts for a blue phosphorescent emitter. The blue PhOLEDs fabricated using the new hosts demonstrate high external quantum efficiency over 18%.

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Reference:
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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Linear meta-polyaniline (m-PAni) has been synthesized and proton-conducting polymer membranes have been prepared through solution casting of acid-doped m-PAni. The obtained membranes show good proton conductivities at temperatures above 100 C, achieving 10-2.7 S/cm at 120 C under extremely low-humidity conditions. The effect of doping acids, doping levels and humidity, on the conductivity is discussed.

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Reference:
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method