Coaxing New Reactivity from Metalated Nitriles

This dissertation describes a unique series of reactions with metalated nitriles for selective carbon-carbon bond formation. A summary of reactions with metalated nitriles describes the general structural features of N and C-metalated nitriles and their reactivity preferences in a diverse variety of reactions. The third chapter describes the reactions of a novel amido cuprate, generated from CuCN and LDA (Lithium Diisopropylamide). The amido cuprate allows for the deconjugative [alpha]-alkylation of cyclic alkenenitriles, a process that was previously difficult owing to a polymerization side reaction. Deprotonating cyclic alkenenitriles with the novel amido cuprate effectively avoids polymerization of alkenenitriles, and generates metalated nitriles for alkylation with a variety of electrophiles. The strategy provides an effective synthesis of quaternary 5-, 6-, and 7-membered cycloalk-1-enecarbonitriles substituted on the nitrile-bearing quaternary carbon. Chapter 4 describes a general method for sulfone–metal exchange. Treating tetra-substituted 2-pyridylsulfonylacetonitriles with either BuLi or Bu3MgLi generates metalated nitriles, which efficiently alkylate with various electrophiles to generate quaternary nitriles. The 2-pyridylsulfone is essential, as the pyridine nitrogen anchors the organometallic and facilitates the exchange. Commercial 2-pyridinesulfonylacetonitrile is readly deprotonated with mild bases, either K2CO3 or DBU (1, 8-Diazabicyclo (5.4.0)undec-7-ene) allowing two sequential alkylations to rapidly assemble a tetrasubstituted nitrile. Thus, subsequent sulfone–metal exchange and alkylation efficiently assembles quaternary nitriles. The fifth chapter describes a preliminary approach to chiral nitrile alkylations. Sulfinyl-metal exchange where step is a chelation site allows the metal cation to anchor and prevents epimerization. A chiral sulfinate precursor has been prepared by separating a diastereomeric mixture of sulfinyl nitriles. Preliminary exchange-alkylations lay the foundation for exploring this potential chiral metalated nitrile alkylation strategy.Ph.D., Chemistry -- Drexel University, 201