Tf₂O-Promoted Intramolecular Schmidt Reaction Of The ?-Azido Carboxylic Acids

This dissertation mainly focuses on the preparation of 2-substituted pyrrolidine through the Schmidt reaction as the key strategy.It is composed by two parts:1.A brief review on the 2-substituted pyrrolidine,and 2.The Tf2O promoted intramolecular Schmidt reaction of the ? azido carboxylic acids.In the first chapter,a brief review on the application and synthesis of the 2-substituted pyrrolidines was summarized.The 2-substituted pyrrolidine motif were found widely in the nature products,and the important bioactivities were doucemented.The synthetic methods toward the 2-substituted pyrrolidines were also reviewed,and they were classified into six strategies according to the order of bond formation to furnish the ring.The strategies included as the following:1.1,2 C-N bond formation,2.2,3 C-C bond formation,3.1,5 C-N bond formation,4.Double N-alkylation of the 1,4-butanediol or its derivatives,5.Modification of the pyrrolidine ring,and 6.Other methods.In the second chapter,the Tf2O-promoted intramolecular Schmidt reaction of the ?-azido carboxylic acids was described.The in situ activaction of the carboxylic acid with Tf2O was designed,and the Schmidt reaction of alkyl azide with anhydride was demonstrated.Ten 2-substituted ?-azido carboxylic acids were successfully prepared according to the general synthetic methods.The Tf2O was used as an activation reagent for the carboxylic acid,and the ?-azido anhydride was in situ generated with releasing a molecular TfOH,acting as an acid promoter for the Schmidt process.A series of 2-substituted pyrrolidines were produced from the ?-azido carboxylic acids.The whole conversion could be regarded as a combined process of decarboxylation,denitrogenation,and annulation.The 2-substituted pyrrolidines were acetylated for better purification.To demonstrate the Schmidt reaction of alkyl azides being a stereospecific 1,2-migration process,an enantiomerically pure 2-substituted substrate was prepared and submitted for the rearrangement,and the results indicated that the stereochemistry of the migration group was maintained.According to the experimental results,a possible mechanism of this conversion was proposed.The formation of mixed anhydride from the ?-azido carboxylic acid and Tf2O with releasing a molecular TfOH was a necessary stage,and it initiated the Schmidt rearrangement.An intramolecular attack of the azido group upon the carbonyl group of the mixed anhydride resulted in forming the aminodiazonium ion intermediate.Then a subsequent TfOH-promoted 1,2-migration of the more substituted carbon to the nitrogen atom gave the isocyanate ion,which would be hydrolyzed to a carbamic acid.The unstable carbamic acid would smoothly decompose into the pyrrolidine with releasing a molecular carbon dioxide gas.The strategy was also efficient for conversion of a 4-substituted ?-azido carboxylic acid to the tricyclic lactam.Finally,the procedures for preparation of the substrates and the Tf2O-promoted intramolecular Schmidt reaction of the ?-azido carboxylic acids were provided in the experimental section,and all the new compounds were confirmed by NMR and HRMS.