Metalated nitriles: stereodivergent cation-controlled cyclizations

Abstract

Stereodivergent cyclizations of γ-hydroxy cyclohexanecarbonitriles are controlled simply through judicious choice of cation in the alkylmetal base. Deprotonating a series of cyclic γ-hydroxy nitriles with i-PrMgBr generates C-magnesiated nitriles that cyclize under stereoelectronic control to cisfused hydrindanes, decalins, and bicyclo [5.4.0] undecanes. An analogous deprotonation with BuLi triggers cyclization to trans-fused hydrindanes, decalins, and bicyclo [5.4.0] undecanes consistent with a sterically controlled electrophilic attack on an equatorial nitrile anion. Using cations to control the geometry of metalated nitriles provides a versatile, stereodivergent cyclization to cis-and transhydrindanes, decalins, and [5. 4. 0] undecanes, and reveals the key geometric requirements for intramolecular S N 2 and S N 2′ displacements. IntroductionMetalated nitriles are nucleophilic chameleons, readily adapting to the local environment by adopting different structures. 2 X-ray crystallographic analyses of metalated nitriles 3 show two main structural classes: N-metalated nitriles in which the metal coordinates to the nitrile nitrogen, 4 and C-metalated nitriles 5 in which the metal is bound to the formally anionic carbon (Figure 1, 1 and 2, respectively). Crystallographically derived bond lengths for N-and Cmetalated nitriles reveal only a slight weakening of the C≡N triple bond (1.15-1.20 Å), relative to the C≡N bond length of neutral nitriles (1.14 Å), 6 indicative of a predominant inductive stabilization 7 of the negative electron density. Consistent with the inductive stabilization are short C-CN bonds 8 stemming from an electrostatic contraction between the formal anion and the powerful electron-withdrawing nitrile group. 9 Moderating the ligand or metal environment exerts a pronounced influence on the site of coordination in metalated nitriles. The solid-state N-and C-palladated nitriles 1 and 2 10 differ rather modestly in their structural features, essentially in the nature of the phosphine ligand, but exhibit completely different coordination modes to the same nitrile! 7 Li NMR reveals basically the same structural trends for metalated nitriles in solution; a preference for N-or C-metalation that depends intimately on ligand and solvent, 11 and minimal delocalization of the anion into the carbon-nitrogen triple bond. 9 Differences in the site of metal coordination relay into different reactivity modes for N-and C-metalated nitriles. For example, reductive elimination from the N-palladated nitrile 1 is ten Correspondence to: Fraser F. Fleming. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers th...

Cyclic Metalated Nitriles: Stereoselective Cyclizations to cis‐ and trans‐Hydrindanes, Decalins, and Bicyclo[4.3.0]undecanes

“…In the absence of chelation 33 cyclizes exclusively to the cis -hydrindane 35 (Scheme 8). Moving the lithium alkoxide one carbon further from the nitrile is thought to reduce the interaction because the dilithiated nitrile 53 [52] cyclizes only to the cis -hydrindane 54 (Scheme 12). Deprotonating the γ-hydroxynitrile 51 with BuLi is thought to proceed via an oxygen assisted deprotonation [53] of the alkoxide 52 because alkyllithiums are otherwise prone to attack nitriles.…”

“…[52] Addition of excess BuLi to 55 generates two cis -hydrindanes 57 and 58 that correlate with cyclization through internally coordinated C -lithiated nitriles 56 and 56′ , respectively. Forming the two cis -hydrindanes 57 and 58 in roughly equal amounts likely reflects similar energetics for the nucleophilic attack on the diastereotopic faces of the allylic chloride.…”

Metalated nitriles: SNi′ cyclizations with a propargylic electrophile

“…2 The structures are partitioned into two distinct types, N- and C- metalated nitriles (Figure 1), depending on whether the metal is coordinated to the nitrile nitrogen or the nucleophilic carbon, 1 and 2 , respectively. 3 …”

Intramolecular Enolate Alkylation: From Steroids through Cladiellins to Isolaurallene

“…51 Many of the extant applications of this INAA methodology have involved the stereoselective construction of a quaternary center by taking advantage of the relatively small size and powerful nucleophilicity of the nitrile functionality. However, the presence of an acidic proton in α-unsubstituted cases, such as the above, raises a concern regarding the potential loss of the stereochemical integrity during the cyclization.…”