Microwave-assisted H/D exchange reactions

This thesis describes a new microwave-assisted method for the synthesis of poly-deuterated anilines and pyridines. The microwave mediated deuteration of aniline derivatives both with and without a platinum catalyst has been studied. Selectivity and yields are compared, showing the well established electronic selectivity of deuteration in the absence of a platinum catalyst, and a selectivity governed by steric factors for the platinum catalysed exchange. Differences in percentage yield can be explained for each method but vary greatly with changes in substrate. The ability for platinum catalysed exchange to deuterate aliphatic positions has also been observed and a tentative mechanism is proposed for the exchange of protons on substituents. Following investigation into the two different catalysts, the yield for the microwave assisted procedure is good, and high levels of deuterium incorporation are observed with only a single cycl

Synthesis and properties of pyridine containing drugs and heterocycles

Chapter 1 provides an overview on the chemistry of pyridines and aminopyridines, their biological activities and their synthesis using Bohlmann-Rahtz, Hantzsch and Chichibabin methodology. It discusses the application of modern alternative reaction platforms, such as microwave-assisted synthesis and flow chemistry, of relevance to the synthesis and reactions of pyridine derivatrives. Chapter 2 discusses Lewis acid catalysis in the Bohlmann-Rahtz pyridine synthesis and describes new one-pot, two- and three-component methodologies that have been developed for the synthesis of natural products containing the pyridine motif. These methods have been compared and contrasted and applied to the use of tetranuclear coordination clusters as Lewis acid mixed metal catalysts for Bohlmann-Rahtz cyclodehydration and pyridine synthesis. Chapter 3 discusses the use of the Bohlman–Rahtz pyridine synthesis for the preparation of a range of fused heterocycles containing the pyridine moiety in high yield, including 1,3,7-trimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, 1,3-dimethyl-7-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, 1,7-dimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)dione and 1-methyl-7-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. Chapter 4 describes new substrate scope for the Bohlmann-Rahtz pyridine synthesis by incorporating an amino group at the 2-position of the products. The synthesis of a range of 2,3,6-trisubstituted and 2,3,4,6-tetrasubstituted pyridines was accomplished with total regiocontrol using this new method under microwave-assisted conditions. Chapter 5 describes a new microwave-assisted method for the synthesis of poly-deuterated pyridines. The microwave mediated deuteration of aminopyridine derivatives both with and without the presence of DCl has been studied. The regioselectivity and yields for these processes were compared. Following discovery of a new method for single cycle H/D exchange at multiple positions, high yield and high levels of deuterium incorporation have been found for a range of substrates

Rapid protium-deuterium exchange of 4-aminopyridines in neutral D2O under microwave irradiation

4-Aminopyridines undergo surprisingly rapid and highly-selective H/D exchange at C-2 and C-6 in neutral D2O upon microwave irradiation at only 190 °C for 2 h in a sealed vessel. This method contrasts and complements acid-mediated H/D exchange, requires no catalyst and is appropriate for the synthesis of deuterium isotop-ologues of N- and C-substituted 4-aminopyridines and a ben-zofused (quinoline) analogue

Microwave-assisted Bohlmann–Rahtz synthesis of highly-substituted 2-aminonicotinates

Microwave irradiation of 2-carbethoxyacetamidine and an ethynyl ketone under acidic or basic conditions in ethanol at 150 °C for 1.5 h facilitated Bohlmann-Rahtz pyridine synthesis to give highly-substituted ethyl 2 aminonicotinates with total regiocontrol and in reasonable to excellent yield, following purification by immobiliza tion upon an acidic resin