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Tesi etd-01222018-141841

Thesis type
Tesi di laurea magistrale
Studies on asymmetric alpha amination of 2-oxindoles with bis(2,2,2-trichloroethyl) azodicarboxylate
Corso di studi
relatore Dott. Mandoli, Alessandro
controrelatore Dott. Angelici, Gaetano
Parole chiave
  • enantioselective synthesis
  • asymmetric catalysis
Data inizio appello
Riassunto analitico
The asymmetric α-amination of 3-substituted-2-oxindoles has attracted the interest of many
organic synthesis researchers due to the possibility to prepare, through this reaction, a number of biologically active molecules. A particularly effective approach in this respect is the electrophilic attack of an azodicarboxylate on a racemic oxindole catalyzed by a chiral base, generally a cinchona alkaloid derivative, providing a product that could be further elaborated to obtain the desired amino group.
However, when diethyl or diisopropyl azodicarboxylates are used, the conversions of the aminated product into the corresponding amine are generally low yielding due to the harsh cleavage conditions. Furthermore the catalytic hydrogenation step needed to break the N-N bond imposes strong limitations on the groups that could be present in the molecule. To overcome these problems we explored the use of bis-(2,2,2-trichloroethyl)-azodicarboxylate (BTCEAD) as an alternative aminating agent that simplifies the subsequent conversion of the addition amination product in the amine. The trasformation of bis-Troc-protected hydrazines into the corresponding amines have been reported by Leblanc and Fitzsimmons under mild reductive conditions in a single step.
First of all, we focused on the optimization of the enantioselectivity of the α-amination
reaction by testing different catalysts, solvents, and reaction conditions. With this screening we reached ees as good as 75% for 3-aryl-2-oxindoles, and ee up to 65% for 2-oxindoles bearing an alkyl chain at position 3. Both aminated products were subsequently converted into the
corresponding amines, with satisfactory yields and without affecting functional groups like C-C
double bonds.
In the second part of this work we investigated the application of the new N-N cleavage
conditions to hydrazines deriving from other azodicarboxylates. In fact we demonstrated that
the α-amination product derived from bis(p-methoxybenzyloxy) azodicarboxylate could be converted in the corresponding amine under Leblanc conditions. The resulting amine have been used to accomplish a formal synthesis of the biologically important molecule AG-041R by using a new optimized series of reactions that does not involve the use of heavy metals.