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

Abstract

Metalated nitriles are exceptional nucleophiles capable of forging highly hindered stereocenters in cases where enolates are unreactive. The excellent nucleophilicity emanates from the powerful inductive stabilization of adjacent negative charge by the nitrile, which has a miniscule steric demand. Inductive stabilization is the key to understanding the reactivity of metalated nitriles because this permits a continuum of structures that range from N-metalated ketenimines to nitrile anions. Solution and solid-state analyses reveal two different metal coordination sites, the formally anionic carbon and the nitrile nitrogen, with the site of metalation depending intimately on the solvent, counterion, temperature, and ligands. The most commonly encountered structures, C- and N-metalated nitriles, have either sp or sp hybridization at the nucleophilic carbon, which essentially translates into two distinct organometallic species with similar but nonidentical stereoselectivity, regioselectivity, and reactivity preferences. The hybridization differences are particularly important in Si displacements of cyclic nitriles because the orbital orientations create very precise trajectories that control the cyclization selectivity. Harnessing the orbital differences between C- and N-metalated nitriles allows selective cyclization to afford nitrile-containing cis- or trans-hydrindanes, decalins, or bicyclo[5.4.0]undecanes. Similar orbital constraints favor preferential Si displacements with allylic electrophiles on sp centers over sp centers. The strategy permits stereoselective displacements on secondary centers to set contiguous tertiary and quaternary stereocenters or even contiguous vicinal quaternary centers. Stereoselective alkylations of acyclic nitriles are inherently more challenging because of the difficulty in creating steric differentiation in a dynamic system with rotatable bonds. However, judicious substituent placement of vicinal dimethyl groups and a trisubstituted alkene sufficiently constrains C- and N-metalated nitriles to install quaternary stereocenters with excellent 1,2-induction. The structural differences between C- and N-metalated nitriles permit a rare series of chemoselective alkylations with bifunctional electrophiles. C-Magnesiated nitriles preferentially react with carbonyl electrophiles, whereas N-lithiated nitriles favor S2 displacement of alkyl halides. The chemoselective alkylations potentially provide a strategy for late-stage alkylations of polyfunctional electrophiles en route to bioactive targets. In this Account, the bonding of metalated nitriles is summarized as a prelude to the different strategies for selectively preparing C- and N-metalated nitriles. With this background, the Account then transitions to applications in which C- or N-metalated nitriles allow complementary diastereoselectivity in alkylations and arylations, and regioselective alkylations and arylations, with acyclic and cyclic nitriles. In the latter sections, a series of regiodivergent cyclizations are described that prov...

Reductive C−C Coupling from α,β‐Unsaturated Nitriles by Intercepting Keteniminates

“…Nitrile anions are a diverse class of synthetic intermediates that provide access to highly functionalized products through nucleophilic addition and substitution reactions . Analogous to enolates, nitrile anions are ambident nucleophiles that can react either as carbanions to provide α‐functionalized cyano products,– or as keteniminates to provide neutral ketenimines . Each product class has further synthetic utility as building blocks for natural products and pharmaceuticals; while α‐cyano groups are easily derivatized, ketenimines further undergo nucleophilic, electrophilic, and/or cyclization reactions.…”

Isolation of the Metalated Ylides [Ph3P−C−CN]M (M=Li, Na, K): Influence of the Metal Ion on the Structure and Bonding Situation

“…Therefore, cation coordination in 1-M can either occur at the cyanido nitrogen or at the a-carbon [a] C. Schwarz, + L. T. Scharf, + T. Scherpf atom. These different coordination modes have been shown to influencet he reactivity of variousm etalated nitriles [11,12] and are expected to affect the bonding situation. Comparable to CDPs, the electronic structure in yldiides can be described by different bonding situations.I nt he past, the ylidic form 1A (Figure 2) was used to account for the two lone pairs at the central carbon atom and the high nucleophilicity, which have both been experimentally provenb yt he use in double-functionalization and cascadereactions or in the formation of digold complexes.…”

Asmic Isocyanide‐Nitrile Isomerization‐Alkylations

“…Subsequent reorientation with attack from the carbon of the cyanide ion on the carbene [5] would generate a lithiated nitrile whose alkylation would afford the corresponding quaternary nitrile. [6] The speculation led to screening several additives known to suppress carbene formation: [7] HMPA, 18-crown-6, LiCl, DMPU, DME, KOtBu and TMEDA. TMEDA proved optimal in suppressing the rearrangement, allowing for sulfanyl-lithium exchange-alkylations for a variety of electrophiles; [1] the exchange-stannylation of 2b to afford isocyanide 2d [8] is representative (Scheme 2).…”

“…The limited stability of metalated isocyanides suggested that the rearrangement might involve cyanide expulsion with formation of a carbene. Subsequent reorientation with attack from the carbon of the cyanide ion on the carbene would generate a lithiated nitrile whose alkylation would afford the corresponding quaternary nitrile . The speculation led to screening several additives known to suppress carbene formation: HMPA, 18‐crown‐6, LiCl, DMPU, DME, KO t Bu and TMEDA.…”