Recent advances in the production of γ-valerolactone from biomass-derived feedstocks via heterogeneous catalytic transfer hydrogenation

γ-valerolactone (GVL) is an important intermediate chemical with a wide range of applications as fuel, fuel additive and as a green solvent which has received a great deal of attentions from both academia and industry. This review aims to summarise the advances in conversion of renewable feedstocks into GVL through heterogeneous catalytic transfer hydrogenation (CTH) with a strong emphasis on discussing preparation, characterisation and performance of the catalysts in order to provide a better understanding of various catalytic systems and also to compare them in terms of catalytic performance

Palladium-Catalyzed Nucleophilic Substitution of Alcohols : Mechanistic Studies and Synthetic Applications

This thesis deals with the palladium-catalyzed nucleophilic substitution of π-activated alcohols in which the C–O bond of a non-manipulated hydroxyl group is cleaved. The thesis is divided in two chapters describing two different catalytic systems. Chapter 2 describes a heterogeneous palladium-catalyzed transfer hydrogenolysis of primary, secondary, and tertiary benzylic alcohols to generate the corresponding aromatic hydrocarbons using formic acid as the hydrogen donor. A detailed mechanistic investigation of this reaction has been conducted that establish the kinetic order of each reaction component and also the deuterium kinetic isotope effects. This data provide a mechanistic picture that the hydride transfer from formic acid to palladium, and not the C–O bond cleavage, is involved in the rate-determining step and that a catalytic amount of a base promotes the transfer hydrogenolysis. Chapter 3 describes the development, mechanistic studies and synthetic scope of a homogeneous palladium-catalyzed amination of allylic alcohols. Isolation of the catalyst precursor and equilibrium studies of the palladium and π-acidic triphenylphosphite ligand show unique properties of this catalytic system. Stereochemical, kinetic, and kinetic isotope studies have been performed to provide insight into the mechanism of C–O bond cleavage of allylic alcohol and C–N bond formation catalyzed by the palladium complex. Interestingly, both O–H and C–O bond cleavages are involved in rate-determining steps

Palladium-Catalyzed Nucleophilic Substitution of Alcohols : Mechanistic Studies and Synthetic Applications

This thesis deals with the palladium-catalyzed nucleophilic substitution of π-activated alcohols in which the C–O bond of a non-manipulated hydroxyl group is cleaved. The thesis is divided in two chapters describing two different catalytic systems. Chapter 2 describes a heterogeneous palladium-catalyzed transfer hydrogenolysis of primary, secondary, and tertiary benzylic alcohols to generate the corresponding aromatic hydrocarbons using formic acid as the hydrogen donor. A detailed mechanistic investigation of this reaction has been conducted that establish the kinetic order of each reaction component and also the deuterium kinetic isotope effects. This data provide a mechanistic picture that the hydride transfer from formic acid to palladium, and not the C–O bond cleavage, is involved in the rate-determining step and that a catalytic amount of a base promotes the transfer hydrogenolysis. Chapter 3 describes the development, mechanistic studies and synthetic scope of a homogeneous palladium-catalyzed amination of allylic alcohols. Isolation of the catalyst precursor and equilibrium studies of the palladium and π-acidic triphenylphosphite ligand show unique properties of this catalytic system. Stereochemical, kinetic, and kinetic isotope studies have been performed to provide insight into the mechanism of C–O bond cleavage of allylic alcohol and C–N bond formation catalyzed by the palladium complex. Interestingly, both O–H and C–O bond cleavages are involved in rate-determining steps

Palladium-Catalyzed Nucleophilic Substitution of Alcohols : Mechanistic Studies and Synthetic Applications

This thesis deals with the palladium-catalyzed nucleophilic substitution of π-activated alcohols in which the C–O bond of a non-manipulated hydroxyl group is cleaved. The thesis is divided in two chapters describing two different catalytic systems. Chapter 2 describes a heterogeneous palladium-catalyzed transfer hydrogenolysis of primary, secondary, and tertiary benzylic alcohols to generate the corresponding aromatic hydrocarbons using formic acid as the hydrogen donor. A detailed mechanistic investigation of this reaction has been conducted that establish the kinetic order of each reaction component and also the deuterium kinetic isotope effects. This data provide a mechanistic picture that the hydride transfer from formic acid to palladium, and not the C–O bond cleavage, is involved in the rate-determining step and that a catalytic amount of a base promotes the transfer hydrogenolysis. Chapter 3 describes the development, mechanistic studies and synthetic scope of a homogeneous palladium-catalyzed amination of allylic alcohols. Isolation of the catalyst precursor and equilibrium studies of the palladium and π-acidic triphenylphosphite ligand show unique properties of this catalytic system. Stereochemical, kinetic, and kinetic isotope studies have been performed to provide insight into the mechanism of C–O bond cleavage of allylic alcohol and C–N bond formation catalyzed by the palladium complex. Interestingly, both O–H and C–O bond cleavages are involved in rate-determining steps

Pd-Catalyzed Substitution of the OH Group of Nonderivatized Allylic Alcohols by Phenols

Nonactivated phenols have been employed as nucleophiles in the allylation of nonderivatized allylic alcohols to generate allylated phenolic ethers with water as the only byproduct. A Pd­[BiPhePhos] catalyst was found to be reactive to give the O-allylated phenols in good to excellent yields in the presence of molecular sieves. The reactions are chemoselective in which the kinetically favored O-allylated products are formed exclusively over the thermodynamically favored C-allylated products

Equilibrium Study of Pd(dba)₂ and P(OPh)₃ in the Pd-Catalyzed Allylation of Aniline by Allyl Alcohol

Reaction of Pd­(dba)₂ and P­(OPh)₃ shows a unique equilibrium where the Pd­[P­(OPh)₃]₃ complex is favored over both Pd­(dba)­[P­(OPh)₃]₂ and Pd­[P­(OPh)₃]₄ complexes at room temperature. At a lower temperature, Pd­[P­(OPh)₃]₄ becomes the most abundant complex in solution. X-ray studies of Pd­[P­(OPh)₃]₃ and Pd­(dba)­[P­(OPh)₃]₂ complexes show that both complexes have a trigonal geometry with a Pd–P distance of 2.25 Å due to the π-acidity of the phosphite ligand. In solution, pure Pd­(dba)­[P­(OPh)₃]₂ complex equilibrates to the favored Pd­[P­(OPh)₃]₃ complex, which is the most stable complex of those studied, and also forms the most active catalytic species. This catalyst precursor dissociates one ligand to give the reactive Pd­[P­(OPh)₃]₂, which performs an oxidative addition of nonmanipulated allyl alcohol to generate the π-allyl-Pd­[P­(OPh)₃]₂ intermediate according to ESI-MS studies

Synthesis and preclinical evaluation of the CRTH2 antagonist [11C]MK-7246 as a novel PET tracer and potential surrogate marker for pancreatic beta-cell mass

Introduction: MK-7246 is a potent and selective antagonist for chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). Within the pancreas CRTH2 is selectively expressed in pancreatic β-cells where it is believed to play a role in insulin release. Reduction in β-cell mass and insufficient insulin secretion in response to elevated blood glucose levels is a hallmark for type 1 and type 2 diabetes. Reported here is the synthesis of [11C]MK-7246 and initial preclinical evaluation towards CRTH2 imaging. The aim is to develop a method to quantify β-cell mass with PET and facilitate non-invasive studies of disease progression in individuals with type 2 diabetes. Methods: The precursor N-desmethyl-O-methyl MK-7246 was synthesized in seven steps and subjected to methylation with [11C]methyl iodide followed by hydrolysis to obtain [11C]MK-7246 labelled in the N-methyl position. Preclinical evaluation included in vitro radiography and immune-staining performed in human pancreatic biopsies. Biodistribution studies were performed in rat by PET-MRI and in pig by PET-CT imaging. The specific tracer uptake was examined in pig by scanning before and after administration of MK-7246 (1 mg/kg). Predicted dosimetry of [11C]MK-7246 in human males was estimated based on the biodistribution in rat. Results: [11C]MK-7246 was obtained with activities sufficient for the current investigations (270±120 MBq) and a radiochemical purity of 93±2%. The tracer displayed focal binding in areas with insulin positive islet of Langerhans in human pancreas sections. Baseline uptake in pig was significantly reduced in CRTH2-rich areas after administration of MK-7246; pancreas (66% reduction) and spleen (88% reduction). [11C]MK-7246 exhibited a safe human predicted dosimetry profile as extrapolated from the rat biodistribution data. Conclusions: Initial preclinical in vitro and in vivo evaluation of [11C]MK-7246 show binding and biodistribution properties suitable for PET imaging of CRTH2. Further studies are warranted to assess its potential in β-cell mass imaging and CRTH2 drug development