Metalated Nitriles:  Internal 1,2-Asymmetric Induction

Abstract

Alkylations of conformationally constrained acyclic nitriles containing vicinal dimethyl groups and an adjacent phenyl group or trisubstituted alkene are exceptionally diastereoselective. Probing the alkylation stereoselectivity with a series of C- and N-metalated nitriles implicates a reactive conformation in which an sp2-hybridized substituent projects over the metalated nitrile to avoid allylic strain. Steric screening thereby directs the electrophilic attack to the face of the metalated nitrile opposite the projecting substituent. Excellent stereoselectively is maintained in a diverse range of alkylations that efficiently install quaternary centers, even with isopropyliodide in which a contiguous array of tertiary-quaternary-tertiary stereocenters is created! Screening the conformational requirements with a series of acyclic nitriles and esters reveals the key structural requirements for high selectivity while providing a robust, predictive model that accounts for comparable ester alkylations affording the opposite diastereomer! The intensive survey of metalated nitrile alkylations identifies the key structural features required for high 1,2-asymmetric induction, addresses the long-standing challenge of asymmetric alkylations with acylic metalated nitriles, and provides a versatile method for installing hindered quaternary centers with excellent stereocontrol.

Template Catalysis by Metal–Ligand Cooperation. C–C Bond Formation via Conjugate Addition of Non-activated Nitriles under Mild, Base-free Conditions Catalyzed by a Manganese Pincer Complex

“…5−10 Fleming and co-workers discussed the stereochemical aspects of αlithiation and α-magnesation of nitriles with strong bases. 6,11 In an early report Rappoport and co-workers described the utilization of a large excess of tetraethylammonium fluoride to generate cyanmethide carbanions from acetonitrile and use them in Michael addition reactions. 12 An example making use of the bifunctional reactivity of Ru-and Ir-based amido complexes to activate α-substituted α-cyano acetates was reported by Ikariya and co-workers.…”

“…The same applies for previously reported transition-metal-catalyzed Michael addition reactions, therefore significantly limiting the substrate scope. The reaction usually involves C–H activation at the α-carbon at the metal center to generate the Michael donor moieties (i.e., metal stabilized carbanions). − Fleming and co-workers discussed the stereochemical aspects of α-lithiation and α-magnesation of nitriles with strong bases. , In an early report Rappoport and co-workers described the utilization of a large excess of tetraethylammonium fluoride to generate cyanmethide carbanions from acetonitrile and use them in Michael addition reactions . An example making use of the bifunctional reactivity of Ru- and Ir-based amido complexes to activate α-substituted α-cyano acetates was reported by Ikariya and co-workers …”

Stereodivergent Quaternization of 2‐Alkyl‐2‐p‐tolylsulfinylacetonitriles: NMR Spectroscopic Evidence of Planar and Pyramidal Benzylic Carbanions

“…To verify the viability of such a proposal, we decided to study the alkylation of 2-alkyl-2-[(2-p-tolylsulfinyl)phenyl]acetonitriles 3 (Scheme 1) under different conditions, which would provide a ready access to the a,a-dialkylphenylacetonitrile fragment, present in biologically active molecules, in either of its two possible configurations. Compounds 3, with intermediate structures between those of 1 and 2, were chosen for this study because marked conformational constrains of differently metalated nitriles have been reported recently as responsible for their stereodivergent evolution in intramolecular [13] and intermolecular [14] alkylation processes. Results obtained in this study are herein reported.…”

Enantioselective synthesis of all-carbon quaternary stereogenic centers in acyclic systems

“…69 Embedding vicinal methyl groups in an alkyl chain containing a trisubstituted alkene, or a benzene ring, creates a strong bias for the stereoselective installation of quaternary stereogenic centers (Scheme 52). 70…”