Kinetic studies of organic reactions in aqueous media and the applications of multicomponent reactions in organic syntheses

Reactions with negative activation volume can be accelerated under high pressure. Lubineau hypothesized that the reactions using hydrophobic reactants that can be accelerated under high pressure should also be accelerated in water because the source of acceleration in each case is negative activation volume. The kinetic studies of several reactions including ene reactions and Passerini reactions were conducted in both aqueous media and in organic solvents. These reactions are faster in water than in organic solvents. The reaction rates in water are different when different mixing methods are used because the reactions are heterogeneous.;Multicomponent reactions including Ugi and Passerini reactions are widely used in organic syntheses. The Ugi reaction of cyclobutanone was conducted to afford the corresponding Ugi product in high yield. The Passerini reactions of tetramethyl-1,3cyclobutanedione with different carboxylic acids and tert-butyl isocyanide were conducted in both water and organic solvent. The Passerini reactions in the organic solvent, methanol, are very slow and can be accelerated in water when hydrophobic carboxylic acids are used. A side product was formed when the Passerini reactions were conducted in water. The formation of the side product can be suppressed by using more hydrophobic carboxylic acids.;An efficient synthesis of a dipeptide including a cyclobutane amino acid, L-aspartyl-alpha-amino-cyclobutane-carboxylic acid methyl ester, was established using Ugi reaction as the key step. 1-Isocyanocyclohexene was synthesized by a new, more efficient route and used as the convertible isocyanide in the synthesis.;Three new convertible isocyanides including a fluorinated isocyanide were synthesized from oxazole. The reaction conditions for the preparation of the fluorinated isocyanide were optimized to synthesize mainly one isomer. Stille, Suzuki and Sonogashira coupling reactions of the Ugi product from the fluorinated isocyanide were conducted and the corresponding products were obtained in moderate yield.;The Passerini-Smiles reaction is a recently reported multicomponent reaction. Ambrisentan, a newly developed vasodilator drug, was synthesized using the Passerini-Smiles reaction as the key step.