Configurational stability of chiral lithiated cyclopropylnitriles: A density functional study

Carlier, Paul R.

doi:10.1002/chir.10222

Cited by 31 publications

(23 citation statements)

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“…Carlier reported that the calculated inversion barrier for lithioacetonitirile is 0.45 kcal/mol, [15,16] and X-ray analysis of lithiophenylacetonitrile indicated that the geometry is planar. [17] The formation of enantiomer- ically enriched products by change in the O-substituent of the cyanohydrin from TBS to carbamoyl seems to be consistent with a pathway that involves an α-nitrile carbanion.…”

Section: Resultsmentioning

confidence: 99%

Chirality Transfer from Epoxide to Carbanion: Base‐Induced Alkylation of O‐Carbamoyl Cyanohydrins of β‐Silyl‐α,β‐epoxy Aldehyde

et al. 2008

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Section: Resultsmentioning

confidence: 99%

Chirality Transfer from Epoxide to Carbanion: Base‐Induced Alkylation of O‐Carbamoyl Cyanohydrins of β‐Silyl‐α,β‐epoxy Aldehyde

et al. 2008

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“…17 Under kinetic conditions the deuteration of chiral cyclopropanecarbonitrile 8 proceeds with greater than 99.9% stereochemical retention, implying the intermediacy of the pyramidal anion 9 18. Subsequent quests to generate chiral nitrile anions19 have proved challenging because of the relatively low barrier for inversion of the pyramidal nitrile anion 20…”

Section: 1 Introductionmentioning

confidence: 99%

Metalated nitriles: stereodivergent cation-controlled cyclizations

et al. 2008

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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...

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“…Note that the depicted pyramidalization of the cyclopropyl anion in 6 is supported by calculations of the free anion;25 reduced angle strain is no doubt responsible for this preference 26. In addition we would like to point out that a “conducted tour” pathway25 to directly generate an ion‐pair like 7 would also be consistent with observed Δ S ≠ value and cannot be ruled out. Carbanion inversion of 7 and N → C migration would ultimately lead to enantiomerization of 2 .…”

Section: Methodsmentioning

confidence: 66%

Incremental Solvation Precedes Ion‐Pair Separation in Enantiomerization of a Cyano‐Stabilized Grignard Reagent

Gao

Carlier

2011

Chemistry A European J

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[a] Dedicated to Professor K. Barry Sharpless on the occasion of his 70th birthday Configurationally stable enantioenriched organolithium compounds are important in asymmetric synthesis.[1] Studies of the enantiomerization pathways of these compounds are useful for improving the stereochemical outcome of these reactions, and provide insight into the structure and dynamics of these compounds.[1a, f, 2] The composition of the organic fragment, [1a, f, 2a, d] the presence of additives, [2d, 3] and the identity of the solvent [2d, 4] are all known to affect configurational stability. In contrast, few such studies have been reported for enantioenriched organomagnesium compounds, perhaps reflecting the relative paucity of these reagents.[5] Herein we report Eyring analyses and reaction order studies of the racemization of enantioenriched Grignard reagent 2 in ethereal solvents. Enantiomerization rates increase in the order Et 2 O < 2-methylTHF < THF. A highly negative activation entropy for enantiomerization ((À49 AE 4) eu) is seen under conditions where reaction is zero-order in [Et 2 O] and first-order in [Mg]. These results are consistent with an ion-pair separation enantiomerization mechanism wherein association of solvent precedes rupture of the Mg À C bond. To our knowledge this is the first experimental determination of the timing of incremental solvation and ion-pair separation for a Group I or II organometallic reagent.We previously reported [5h] that enantioenriched cyano-stabilized Grignard reagent 2 could be prepared by Mg/Br exchange [6] of enantiopure a-bromonitrile (S)-1 with iPrMgCl (Scheme 1). The overall transformation of (S)-1 to [D 1 ]-3 was shown to favor retention, and measurements of the e.r. of [D 1 ]-3 with increasing delay time t demonstrated that 2 possessed a racemization half life (t 1/2 A C H T U N G T R E N N U N G (rac)) of 11.4 h in Et 2 O at 173 K. The extrapolated e.r. at t = 0 for 2 from these experiments was 91:9, suggesting that Mg/Br exchange was not perfectly retentive.To explore the role of solvent in the enantiomerization process, we reinvestigated this reaction in Et 2 O, 2-methyltetrahydrofuran (2-MeTHF), and THF, at several temperatures. A key feature of our reinvestigation was the use of a precooled CH 3 OD quench in place of room-temperature D 2 O.[7] Delay times t varied from 60 to 3600 s and > 95 % recovery of [D 1 ]-3 (> 98 % deuterium incorporation) was obtained after workup even at the shortest time points (60 s) at 175 K. First-order rate constants for enantiomerization of 2 (k enant ) derive from slopes (À2k enant ) of the plots of ln-versus delay time t (Figure 1).[8]

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Configurational stability of chiral lithiated cyclopropylnitriles: A density functional study

Cited by 31 publications

References 36 publications

Chirality Transfer from Epoxide to Carbanion: Base‐Induced Alkylation of O‐Carbamoyl Cyanohydrins of β‐Silyl‐α,β‐epoxy Aldehyde

Chirality Transfer from Epoxide to Carbanion: Base‐Induced Alkylation of O‐Carbamoyl Cyanohydrins of β‐Silyl‐α,β‐epoxy Aldehyde

Metalated nitriles: stereodivergent cation-controlled cyclizations

Incremental Solvation Precedes Ion‐Pair Separation in Enantiomerization of a Cyano‐Stabilized Grignard Reagent

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