Metalated Nitriles: Selective Formation and Alkylation


Wang Liu

Defense Date


Graduation Date

Spring 1-1-2008



Submission Type


Degree Name



Chemistry and Biochemistry

Committee Chair

Fraser F. Fleming

Committee Member

Bruce Beaver

Committee Member

Paul G. Johnson

Committee Member

Paul Sampson


Alkylation, Deprotonation, Internal induction, Metalated nitrile, Rearrangement, Stereoselectivity


Metalated nitriles are powerful nucleophiles for a diverse array of alkylations. Augmenting the classical deprotonation route to metalated nitriles is a new exchange of halonitriles with alkyllithium, organomagnesium, and lithium dimethylcuprate which generates reactive, metalated nitriles. The halogen-metal exchange with alkyllithium and Grignard reagents allows selective exchange in the presence of reactive carbonyl electrophiles, including aldehydes, providing a high yielding alkylation protocol.

The tolorence of nitriles to Grinnard reagents allows metalated nitriles to be generated by conjugate addition to alkenenitriles. Alkenenitriles bearing an adjacent hydroxyl group react with Gringards to afford E-alkenenitriles with transmissive relocation of the C=C bond. Mechanistically the transmissive olefination is consistent with rearrangement through a cyclic 6-membered transition structure in which the formal displacement of hydroxide is favored by formation of magnesium oxide.

Selective alkylation of acyclic nitriles is particularly challenging. Alkenenitriles containing vicinal dimethyl groups and an adjacent trisubstituted alkene alkylate with exceptionally diastereoselectivity through formal 1,2 - asymmetric induction. Probing the alkylation stereoselectivity with a series of C- and N-metalated nitriles implicates a reactive conformation in which an alkyl group projects over the plane of the metalated nitrile to avoid allylic strain. Steric screening thereby directs the electrophilic attack from the face of the metalated nitrile opposite the projecting alkyl group. Excellent stereoselectively is maintained in a diverse range of alkylations that efficiently install quaternary centers, even with isopropyliodide in which contiguous array of tertiary-quaternary-tertiary stereocenters is created!

1, 3 - induction asymmetric induction with acyclic, conformationally mobile nitriles are extremely challenging. Varying the substituent size in a series of pentanenitriles reveal the fundamental requirements for 1,3-internal asymmetric induction and provides a predictive model that accounts for preferential attack on the more stable diamond lattice conformation. Metalated phenyl- and naphthyl-substituted pentanenitriles intercept a diverse range of electrophiles, efficiently installing new quaternary centers.





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