Extracurricular laboratory:new discovery of 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex

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Palladium-Catalyzed Intramolecular Self-Alkylation of Polyfluoroarene via Heck and Decarboxylation Process

An efficient palladium-catalyzed cyclization and polyfluorophenylation of gamma,delta-unsaturated polyfluorobenzoyl oxime ester via iminopalladation/polyfluorobenzoyloxy decarboxylation cascade reaction is developed. The protocol provides a practical and atom-economical access to a broad scope of various polyfluorophenylated dihydropyrrole derivatives. The reaction effectively utilizes the polyfluorobenzoyloxy leaving group as polyfluorophenylated source for the first time, precluding the need of additional polyfluoroarene. This is the first example of the introduction of electron-deficient arenes in the further transformation of Narasaka-Heck-type reaction. Additionally, the reaction is conducted in a short time.

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

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Cleavage of homometallic and formation of heterometallic M-M bonds. Serendipitous syntheses of bimetallic MnPd(mu-PPh2)- (CO)4(eta2-P-P) (P-P = dppm, dppe, dppf) and polymetallic Mn2Pd2Ag(mu-Cl)(mu-PPh2)2(mu-d ppm)(CO)8

Condensation of [Mn2(CO)8(mu-PPh2)]- with Pd(II) assisted by Ag(I) leads to cluster disproportionation, viz. Mn2Pd2Ag(mu-Cl)(mu-PPh2)2(mu-d ppm)(CO)8 and MnPd(mu-PPh2)(CO)4(eta2-P-P) (P-P = dppm, dppe, dppf). The former shows a distorted bow-tie structure with two heterometallic triangles {AgPdMn} sharing an Ag center. The unexpected phosphide migration across different metals holds the key to the cleavage and formation of metal-metal bonds. The bimetallic complexes are stabilized by all common diphosphines whereas the polymetallic structure is isolated only when supported by dppm. The latter shows three different types of heterometal-metal bonds Ag-Mn (2.6938(4) A), Ag-Pd (2.7637(1) A) and Mn-Pd (2.8183(9) A) (average values).

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

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Localised to intraligand charge-transfer states in cyclometalated platinum complexes: An experimental and theoretical study into the influence of electron-rich pendants and modulation of excited states by ion binding

The neopentyl ester of 1,3-di(2-pyridyl)benzene-5-boronic acid (dpy-B) is a useful intermediate in the divergent synthesis of N^C^N-coordinating, 1,3-di(2-pyridyl)benzene ligands, HLn, that carry aryl substituents at the 5-position of the central ring. The platinum(ii) complexes, PtL nCl, of several such ligands have been prepared, incorporating pendant anisoles, arylamines, an oxacrown, and an azacrown, all of which are strongly luminescent in solution at 298 K. The emission of the complexes is partially quenched by oxygen, and all of the compounds are very efficient sensitisers of singlet oxygen. The quantum yields of 1O2 formation have been measured on the basis of the intensity of the O 21Deltag emission at 1270 nm, and are in the range 0.25-0.65. Density functional theory (DFT) calculations have been carried out that include the effect of the solvent, on the unsubstituted complex PtL1Cl and on the derivatives incorporating p-dimethylaminophenyl and phenyl-15-mono-N-azacrown-5 pendants (PtL9Cl and PtL12Cl respectively). Absorption spectra have been simulated on the basis of the calculated singlet excitations: they closely resemble the experimental spectra. In particular, the DFT successfully accounts for the appearance of low-energy absorption bands that accompany the introduction of the aryl pendants, indicating the participation of the aryl group in the HOMO but not significantly in the LUMO. The calculated lowest energy triplet excitation of PtL 1Cl is close to the observed 0-0 emission maximum of this complex in solution. Taking together data for this series of complexes and related compounds previously studied, the energies of the lowest-energy spin-allowed absorption bands are shown to correlate approximately linearly with the oxidation peak potential. The emission energies show a similar correlation in toluene, but in CH2Cl2 the value for PtL9Cl is anomalously low. The differing emission properties of this complex in the two solvents suggest a switch to a TICT-like state in CH2Cl2 (TICT = twisted intramolecular charge transfer), stabilised in the more polar environment. Transient DC photoconductivity measurements confirm that the dipole moment of the triplet excited state is larger in CH2Cl2 than in toluene. The azacrown PtL12Cl displays similar behaviour. Binding of metal ions such as Ca2+ to the azacrown unit of this complex leads to a pronounced blue shift in the emission, which can be readily understood in terms of the large increase in the TICT energy that will accompany the binding of the metal ion to the lone pair of the azacrown nitrogen atom.

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

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Kumada – Corriu coupling of Grignard reagents, probed with a chiral Grignard reagent

The Grignard reagent 2, in which the magnesium-bearing carbon atom is the sole stereogenic centre has been coupled with vinyl bromide under Pd(0) or Ni(0)-catalysis to give compound 3 with full retention of configuration. Coupling using Fe(acac)3 or Co(acac)2 as catalyst was accompanied by considerable racemisation. These findings are discussed with respect to a dichotomy between concerted polar and stepwise SET transmetallation pathways.

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

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Hit Optimization of 5-Substituted-N-(piperidin-4-ylmethyl)-1H-indazole-3-carboxamides: Potent Glycogen Synthase Kinase-3 (GSK-3) Inhibitors with in Vivo Activity in Model of Mood Disorders

Novel treatments for bipolar disorder with improved efficacy and broader spectrum of activity are urgently needed. Glycogen synthase kinase 3beta (GSK-3beta) has been suggested to be a key player in the pathophysiology of bipolar disorder. A series of novel GSK-3beta inhibitors having the common N-[(1-alkylpiperidin-4-yl)methyl]-1H-indazole-3-carboxamide scaffold were prepared taking advantage of an X-ray cocrystal structure of compound 5 with GSK-3beta. We probed different substitutions at the indazole 5-position and at the piperidine-nitrogen to obtain potent ATP-competitive GSK-3beta inhibitors with good cell activity. Among the compounds assessed in the in vivo PK experiments, 14i showed, after i.p. dosing, encouraging plasma PK profile and brain exposure, as well as efficacy in a mouse model of mania. Compound 14i was selected for further in vitro/in vivo pharmacological evaluation, in order to elucidate the use of ATP-competitive GSK-3beta inhibitors as new tools in the development of new treatments for mood disorders.

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

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Design, Synthesis, Structure-Activity Relationship Studies, and Three-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) Modeling of a Series of O-Biphenyl Carbamates as Dual Modulators of Dopamine D3 Receptor and Fatty Acid Amide Hydrolase

We recently reported molecules designed according to the multitarget-directed ligand paradigm to exert combined activity at human fatty acid amide hydrolase (FAAH) and dopamine receptor subtype D3 (D3R). Both targets are relevant for tackling several types of addiction (most notably nicotine addiction) and other compulsive behaviors. Here, we report an SAR exploration of a series of biphenyl-N-[4-[4-(2,3-substituted-phenyl)piperazine-1-yl]alkyl]carbamates, a novel class of molecules that had shown promising activities at the FAAH-D3R target combination in preliminary studies. We have rationalized the structural features conducive to activities at the main targets and investigated activities at two off-targets: dopamine receptor subtype D2 and endocannabinoid receptor CB1. To understand the unexpected affinity for the CB1 receptor, we devised a 3D-QSAR model, which we then prospectively validated. Compound 33 was selected for PK studies because it displayed balanced affinities for the main targets and clear selectivity over the two off-targets. 33 has good stability and oral bioavailability and can cross the blood-brain barrier.

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

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Competing reactions of hydrophenylation and phenylation in tetraphenylantimony chloride methyl acrylate palladium chloride system

A new catalytic reaction of the competing phenylation and hydrophenylation in air of methyl acrylate with tetraphenylantimony chloride in the presence of PdCl2 (0.04 mol per 1 mol of organometallic compound) in acetonitrile at 50C for 6 h was studied. The yields of methyl cynnamate and methyl hydrocynnamate were 0.73 and 0.27 mol mol-1 respectively. The products ratio obtained depends slightly on the process duration, the Ph 4SbCl and methyl acrylate ratio, and the structure of Pd salt [PdCl2, Pd(OAc)2, Li2PdCl4], but significantly on the nature of a solvent (MeCN > DMF > THF). The use of Ph4SbCl instead of Ph4SbBr leads to decrease in the yield of methyl hydrocynnamate to 0.04 mol mol-1. In the reactions of Ph4SbX (X = F, I, OAc, O2CEt) the product is not formed at all. Pleiades Publishing, Inc., 2006.

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

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Development of a Synthesis of Kinase Inhibitor AKN028

The novel tyrosine kinase inhibitor AKN028 has demonstrated promising results in preclinical trials. An expedient protocol for the synthesis of the compound at kilogram scale is described, including an SNAr reaction with high regioselectivity and a Suzuki coupling. Furthermore, an efficient method for purification and removal of residual palladium is described.

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

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Highly stereoselective synthesis of (1E)-2-melethyl-1,3-dienes by palladium-catalyzed trans-selective cross-coupling of 1,1-dibromo-1-alkenes with alkenylzine reagents

Ligand control: The use of Pd complexes containing tBu3P or nitrogen-heterocyclic carbene (NHC) ligands almost completely prevents stereoisomerization, thereby permitting an efficient and selective methylation and higher alkylation of (Z)-2-bromo-1,3-dienes (see scheme, dba = trans,trans-dibenzylideneacetone).

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

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Palladium-catalyzed cyanomethylation of aryl halides through domino Suzuki coupling-isoxazole fragmentation

A one-pot protocol for the cyanomethylation of aryl halides through a palladium-catalyzed reaction with isoxazole-4-boronic acid pinacol ester was developed. Mechanistically, the reaction proceeds through (1) Suzuki coupling, (2) base-induced fragmentation, and (3) deformylation as shown by characterization of all postulated intermediates. Under optimized conditions (PdCl2dppf, KF, DMSO/H2O, 130 C) a broad spectrum of aryl bromides could be converted into arylacetonitriles with up to 88% yield.

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