Cyclic Metalated Nitriles: Alkylations and Cyclizations

Guoqing Wei

Defense Date

9-26-2007

Graduation Date

Fall 1-1-2007

Availability

Restricted

Submission Type

dissertation

Degree Name

PhD

Department

Chemistry and Biochemistry

Committee Chair

Jeffry Madura

Committee Member

Bruce Beaver

Committee Member

Paul Johnson

Committee Member

Xiaodong Michael Shi

Keywords

Metalated, Nitriles

Abstract

Cyclic metalated nitriles generated by 1,2-1,4-addition-conjugate addition of Grignard reagents to 3-oxocyclohex-1-ene-1-carbonitrile, alkylate electrophiles with unique reactivity and stereoselectivity. Alkylating cyclic 6-membered C-magnesiated nitriles with alkyl halides, sulfonates, and unstrained ketones occur with retention of the C-Mg configuration, whereas aldehyde and acyl cyanide acylations proceed with inversion of stereochemistry. Mechanistic probes indicate that the stereoselectivity is controlled by stereoelectronic effects for most electrophiles except allylic, benzylic, and cyclopropyl halides where single electron transfer processes intervene. Remarkably, pivaloyl chloride preferentially attacks the nitrogen of nitrile functionality rather than the carbanion of C-magnesiated nitriles. Sequential addition of three different Grignard reagents and pivaloyl chloride to 3-oxo-1cyclohexene-1-carbonitrile installs four new bonds to generate a diverse array of highly substituted cyclic enamides. Comparative alkylations of cyclic 5-7 membered magnesiated nitriles reveal that stereoelectronic effects control the alkylation selectivities of cyclic 6 and 7-membered magnesiated nitriles whereas alkylation preferences with cyclic 5-membered metalated nitriles are controlled by steric constraints. Reversing the alkylation selectivity of 6-membered C-magnesiated nitriles is achieved by conversion to an N-metalated nitrile in which steric, rathe rhtan electronic, effects direct the electrophile trajectory.

The stereoselective alkylation methodology was employed in the stereoselective synthesis of cis- and trans-abietanes. A series of intramolecular cyclizations with substituted hydroxynitriles reveal fundamental stereoselectivity trends in Friedel-Crafts cyclizations. Comparative Friedel-Crafts cyclizations of hydroxynitriles containing electron rich and electron poor aromatic nucleophiles and having diastereomeric ring substitution patterns, exhibit similar cyclization preferences. Optimizing the cyclizations for trans-abietanes has identified ZrCl4 as an exceptional Lewis acid which, for cyclizations of iminolactone, favors trans-abietanes as the only observable diastereomers.

Format

PDF

Language

English

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