Mechanistic aspects of the ligand-assisted nucleophilic addition reaction

Swiss, Kevin A.; Liotta, Dennis; Maryanoff, Cynthia A.

doi:10.1021/ja00181a051

Cited by 51 publications

(27 citation statements)

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“…Rapid assembly of the carbon scaffold was achieved by sequential addition of MeMgCl and 4-pentenylmagnesium bromide to oxonitrile 21 27. Key to this multiple bond-forming process is the alkylmagnesium alkoxide 22 28 which assists in preorganizing the stereoelectronically controlled axial29 conjugate addition 30. Axial addition of the pentenyl group occurs opposite the quaternary methyl leading initially to a diaxial cyclohexanecarbonitrile that subsequently equilibrates to the cyclic nitrile 23 in which both alkyl substituents are relaxed into the equatorial orientation.…”

Section: Resultsmentioning

confidence: 99%

“…Addition of i -PrMgCl to 17 leads to the isopropylmagnesium alkoxide33 25 (Scheme 6) in which the Grignard-type reagent is ideally anchored for the internal deprotonation en route to 26 and yet geometrically prevented from attack on the electrophilic nitrile group 34 . C -magnesiated nitriles35 analogous to 26 exhibit a preference for retentive alkylation with alkyl halides through a 3-centered, C-Mg – σ* orbital overlap 36.…”

Section: Resultsmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Metalated nitriles: stereodivergent cation-controlled cyclizations

et al. 2008

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“…Our attention then turned toward the possibility of using quinol 9 in a ligand-assisted nucleophilic addition (LANA) reaction. 26 We were delighted to find that the reaction of three equivalents of the Mg acetylide of trimethylsilylacetylene with quinol 9 produced cyclohexenone 10 as the only observed product (Scheme 6). Notably, neither conversion of 9 into the lithium alkoxide prior to acetylide addition nor the addition of HMPA was necessary in this case.…”

Section: Resultsmentioning

confidence: 99%

“…Notably, neither conversion of 9 into the lithium alkoxide prior to acetylide addition nor the addition of HMPA was necessary in this case. 26 Incomplete conversion was observed with two equivalents of the magnesium acetylide. A similar LANA reaction was attempted using allylmagnesium bromide, but only the 1,2-addition product was observed.…”

Section: Resultsmentioning

confidence: 99%

Torsional steering as friend and foe: development of a synthetic route to the briarane diterpenoid stereotetrad

Moon

Harned

2017

Org. Biomol. Chem.

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Two synthetic routes to the briarane stereotetrad have been investigated. The first route employed a boron aldol reaction to establish the stereogenic all-carbon quaternary carbon (C1). In this case, it was found that torsional steering in the transition state led to the formation of the undesired configuration at this position. The second route makes use of a highly diastereoselective acetylide conjugate addition/β-ketoester alkylation sequence to construct the vicinal C1 and C10 stereocenters with the correct relative configuration. Originally, it was proposed that torsional steering in the transition state for the ketoester alkylation step was the primary factor responsible for generating the major product. DFT calculations reveal that while torsional steering does play a role, larger conformational factors must also be considered. Tthese calculations also reveal that an unusual C–H•••π (alkyne) interaction may contribute to lowering the energy of one transition state that leads to the observed stereoisomer. Ultimately, this strategy leads to a concise synthesis (under 10 steps) of the stereotetrad core common to the briarane diterpenoids.

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“…5 % of the applied phenyl lithium); 2-4 (petroleum ether:benzene = 10:1. (2) 1757 (3) 44(1) C (6) 6638 (3) 4448 (2) 1859 (3) 46(1) C (7) 3804 (4) 2996 (2) 546(4) 62(1) C (8) 3213 (4) 3282 (3) 1408 (4) 92(2) C (9) 2832 (4) 3131 (2) -819(4) 88(2) C (10) 4006 (5) 2174 (2) 733 (6) 127(2) C (ll) 8123 (3) 2933 (2) 532 (3) 43(1) C ( 12) 8482 (4) 2352 (2) 1376 (3) 52(1) C (13) 9433 (4) 1869 (2) 1434 (4) 62(1) C ( 14) 10047 (4) 1964 (2) 664 (4) 64(1) C (15) 9683 (4) 2528 (2) -183(4) 61(1) C ( 16) 8734 (4) 3005 (2) -232 (3) 49(1) C ( 17) 8898 (4) 4334 (2) 1868 (3) 47(1) C (18) 10097 (4) 4044 (2) 2608(4) 59(1) C ( 19) 11219 …”

Section: 6-di-tert-butyl-4-hydroxy-4-methyl-3-( 4-tolyl )-unclassified

1,4-Addition of Lithium Organyls to para-Quinols / Structure Determination of 2,6-Di-tert-butyl-4-hydroxy-4,5-diphenylcyclohex-2-en-1-one

Henes

Rieker

Neumayer

et al. 1996

Zeitschrift Für Naturforschung B

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Addition of lithium organyls to sterically hindered para-quinols leads to 1,2-or 1,4-adducts. The 1,4-addition prevails, if the 4-substituents in the quinol and the organic group in the lithium organyl are large. Four 1,4-addition products (2-cyclohex-2-en-l-ones) are synthesized and their structures investigated by NMR spectroscopy. The aryl groups at C-4 and C-5 acquire equatorial positions, the alkyl group at C-6 is bisectional. These results are confirmed by Xray analysis of 2,6-di-terr-butyl-4-hydroxy-4,5-diphenylcyclohex-2-en-1 -one, revealing a twist boat conformation of the cyclohexene ring.

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Mechanistic aspects of the ligand-assisted nucleophilic addition reaction

Cited by 51 publications

References 0 publications

Metalated nitriles: stereodivergent cation-controlled cyclizations

Metalated nitriles: stereodivergent cation-controlled cyclizations

Torsional steering as friend and foe: development of a synthetic route to the briarane diterpenoid stereotetrad

1,4-Addition of Lithium Organyls to para-Quinols / Structure Determination of 2,6-Di-tert-butyl-4-hydroxy-4,5-diphenylcyclohex-2-en-1-one

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