C-Metalated Nitriles:  Electrophile-Dependent Alkylations and Acylations

Abstract

Sequential carbonyl addition-conjugate addition of Grignard reagents to 3-oxocyclohex-1-ene-1-carbonitrile generates C-magnesiated nitriles whose alkylation stereoselectivities intimately depend on the nature of the electrophile. Alkylating these 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. Screening numerous alkylations of C-magnesiated nitriles with a diverse range of electrophiles reveals the reaction scope and delineates the fundamental stereoelectronic effects responsible for the highly unusual electrophile-dependent alkylations.

Metalated nitriles: stereodivergent cation-controlled cyclizations

“…Addition of i -PrMgCl to 17 leads to the isopropylmagnesium alkoxide33 25 (Scheme 6) in which the Grignard-type reagent is ideally anchored for the internal deprotonation en route to 26 and yet geometrically prevented from attack on the electrophilic nitrile group 34 . C -magnesiated nitriles35 analogous to 26 exhibit a preference for retentive alkylation with alkyl halides through a 3-centered, C-Mg – σ* orbital overlap 36. Although the side-on orbital overlap is far from optimal, the alternative co-linear approach of the chloromethylene carbon to the small σ lobe of the C-Mg bond is sterically prohibited.…”

Metalated Nitriles: Internal 1,2‐Asymmetric Induction

“…Although the N metalation inherent in this predictive model is almost always favored with lithium counterions, unusual structural features15 and ligand effects16 sporadically lead to C‐lithiated nitriles. C‐metalated nitriles, particularly C‐magnesiated nitriles, are capable of stereodivergent alkylations with alkyl halides (retention), methyl cyanoformate (inversion), and allylic halides (unselective), thus prompting alkylations of 2 with two additional test electrophiles 17. Intercepting the lithiated nitrile 2 with 4‐pentenyl bromide and cinnamyl bromide affords 3 b and 3 c , respectively, as single diastereomers18 (Scheme ) with asymmetric induction analogous to 3 a (Scheme ).…”

Biomimetic Assembly Lines Producing Natural Product Analogs: Strategies from a Versatile Manifold to Skeletally Diverse Scaffolds

“…Initial nucleophilic addition to the carbonyl group of manifold 7 would produce a hydroxylalkenenitrile. Chelation‐controlled conjugate additions of acetylides based on Fleming's protocol would install R 1 and R 2 groups in an anti‐ relationship . Subsequent alkylation of the resulting cyclic dianion would occur with retention of the configuration to afford product 8 bearing R 1 –R 3 substituents with an anti ‐ syn stereochemical relationship.…”