Microwave-Assistanted Fluorous Synthesis Of 1,4-Benzodiazepine-2,5-dione Library

1,4-benzodiazepine-2,5-dione have a broad range of biological utilities, we applied fluorous synthesis and microwave heating method to Ugi four components reactions to synthesize a 1,4-benzodiazepine-2,5-dione library. We introduced two different methods for the synthesis process in order to verify that the method would be fit for synthesis of various of such libraries.Combinatorial chemistry is a new technology which related to organic chemistry, pharmaceutical chemistry, molecular biology and so on. Combinatorial chemistry has developed quickly in recent 30 years and extended to many aspects of the scientific research, such as nano technology, materials science, bioscience. Solution phase combinatorial chemistry which was developed from Ugi reactions takes advantage of traditional organic synthesis, and is suitable for synthesis of many compounds. But there are some limitation such as the reaction is time-consuming, and the products are difficult to purification. Fluorous chemistry and microwave chemistry developed quickly recently and had been widely used in combinatorial chemistry to conquer the bottleneck of the solution phase combinatorial chemistry.Fluorous synthesis is a complementary type of liquid-phase synthesis that is similar to solid-phase synthesis in concept but very different in practice. The fluorous separation technique is the most important aspect of fluorous chemistry. The fluorous separation is any methodology that separates fluorous or fluorous-tagged molecules from other types of molecules, or separates different fluorous molecules from each other, based on primarily on the structure of the fluorous domain of the molecules. Fluorous separation techniques are based on the interactions between a fluorous medium and a fluorous portion of a molecule, and include liquid-liquid extraction with organic and chromatography with fluorous solid phases. Molecules with longer fluorine chains have longer retention times on the FluoroFlash silica gel. The fluorous separation techniques are used in the solution phase combinatorial chemistry to simplify the purification of the products. Microwave-assistanted reactions have many advantages, such as reducing the reaction time, improving the efficiency. The microwave was used in our experiment to remove fluorous-tag by Suzuki reaction and to introduce some new aryl groups simultaneously, the reaction time was decreased obviously. Ugi four-component reactions were based on isocyanide, carboxylic acid, aldehyde (or ketone), primary (secondary) amine as raw materials and to produce analogs of a-amido amide in one pot reactions. Ugi four-component reactions are appropriate for the design of library because the four components of the reactions can introduce large diversity of building blocks in one pot reaction. But the numerous reactants hamper the purification the products, we introduce fluorous chemistry in this thesis to solve the problem skillfully.Finally we successfully synthesized a 1,4-benzodiazepine-2,5-dione library, including 36 kinds of compounds.4-Hydroxybenzaldehydes were modified by fluorous tag to achieve fluorous benzaldehydes which were prepared by coupling of perfluorooctanesulfonyl fluoride with corresponding 4-hydroxybenzaldehydes. Fluorous benzaldehydes as the fluorous component, were used to conduct Ugi four-component reactions with benzoic acid, amino acid esters and cyclohexyl isocyanide in one pot through the two kinds of reaction route. In the first method, we used Boc protected amino acid as the carboxylic acid component, used potassium hydroxide to accelerate the conversion of the reaction. When the fluorous benzaldehydes were converted completely, the products were purified by F-SPE, and then the Ugi products carried on de-Boc/cyclization reaction to get fluorous 1,4-benzodiazepine-2,5-diones; In the second method, we used 2-nitro-benzoic acids as the carboxylic acid component in Ugi four-component reaction, the Ugi products were purified by F-SPE and then to carry on nitryl reduction/cyclization reaction to get fluorous 1,4-benzodiazepine-2,5-dione compounds. The fluorous 1,4-benzodiazepine-2,5-dione compounds which were synthesized by the above two methods were purified by F-SPE. Suzuki reactions were used for F-linker cleavage and introduction of aryl functionality to 1,4-benzodiazepine-2,5-dione at the same time. We didn't carry out all the reactions between the building blocks of the whole library,40 compounds were selected randomly to be synthesized, and 36 ones with high purity were got. The method can be applied to the synthesis of large libraries. The 36 kinds of final 1,4-benzodiazepine-2,5-dione compounds existed as a mixture of diastereomers without further purification. All compounds were characterized by HPLC-MS, the diastereomers and selected compounds were further characterized by HRMS and 1H and 13C NMR. Thirty-six 1,4-benzodiazepine-2,5-diones derivatives were synthesized by a combinatorial approach involving MCRs, fluorous linkers, and microwave heating. Ugi four-component reactions and sequential cyclizations quickly assemble the BDZ core bearing four diversity points. F-SPE simplified the intermediate purification process. Microwave-assisted Suzuki reactions cleaved the F-linker and introduced the aryl group to the 1,4-benzodiazepine-2,5-dione core simultaneously.