C- and N-Metalated Nitriles: The Relationship between Structure and Selectivity

Area of Science:

• Organometallic Chemistry
• Organic Synthesis
• Stereoselective Reactions

Background:

• Metalated nitriles exhibit exceptional nucleophilicity due to inductive stabilization by the nitrile group.
• Two primary forms, C- and N-metalated nitriles, possess distinct sp3 or sp2 hybridization at the nucleophilic carbon.
• These hybridization differences dictate unique stereoselectivity, regioselectivity, and reactivity profiles.

Purpose of the Study:

• To summarize the bonding and preparation strategies for C- and N-metalated nitriles.
• To explore their applications in stereoselective and regioselective alkylations and arylations.
• To highlight their utility in chemoselective transformations of polyfunctional molecules.

Main Methods:

• Analysis of metal coordination sites (carbon vs. nitrogen) based on reaction conditions.
• Exploitation of hybridization differences (sp3 vs. sp2) for controlled S_Ni displacements and cyclizations.
• Utilizing steric and electronic properties for selective alkylations and acylations with bifunctional electrophiles.

Main Results:

• Demonstrated selective cyclization to form cis- and trans-hydrindanes, decalins, and bicyclo[5.4.0]undecanes.
• Achieved stereoselective formation of contiguous tertiary and quaternary stereocenters, including vicinal quaternary centers.
• Showcased chemoselective reactions: C-magnesiated nitriles with carbonyls, N-lithiated nitriles with alkyl halides.

Conclusions:

• C- and N-metalated nitriles provide complementary diastereoselectivity and regioselectivity in alkylation and arylation reactions.
• Regiodivergent cyclizations offer access to important structural motifs found in natural products.
• Chemoselective functionalization enables late-stage modifications of bioactive molecules without protecting groups.