γ-Hydroxy-α,β-alkenenitriles:  Chelation-Controlled Conjugate Additions<sup>1</sup>

Fleming, Fraser F.; Wang, Qunzhao; Zhang, Zhe; Steward, Omar W.

doi:10.1021/jo0258150

Cited by 22 publications

(14 citation statements)

References 29 publications

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“…After 24 h, saturated, aqueous, NH 4 Cl (5 mL) was added, the mixture was extracted with EtOAc and the combined organic extracts were then washed with brine, dried (Na 2 SO 4 ), and concentrated. Purification of the resulting crude product by radial chromatography (10:90, EtOAc/hexanes) afforded 218.6 mg (24%) of 33 as an oil and 118.4 (13 %) of 34 spectrally identical to material previously isolated 64. For 33 : IR (film) 3482.2, 2236.0 cm -1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 1.24 (s, 3H), 1.38-1.82 (m, 15H), 2.07-2.08 (m, 1H), 2.69 (td, J = 11.7, 3.4 Hz, 1H), 3.53 (t, J = 6.6 Hz, 2H); 13 C NMR (125 MHz, CDCl 3 ) δ 20.1, 27.2, 29.0, 29.0, 29.5, 30.4, 31.4, 32.2, 39.7, 45.0, 47.7, 70.8, 122.9.; HRMS (ESI) m/z calculated for (M+Na) + (C 14 H 22 ClNONa + ): 278.1288, found 278.1278.…”

Section: Methodsmentioning

confidence: 71%

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: Methodsmentioning

confidence: 71%

Metalated nitriles: stereodivergent cation-controlled cyclizations

et al. 2008

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“…The stereochemical assignment is based on a 1 H NMR coupling constant analysis and by analogy to the conformational preferences of closely related nitriles 9a…”

Section: Referencesmentioning

confidence: 99%

“…The challenge stems from the paucity of anionic conjugate additions to unsaturated nitriles which, despite being highly polarized, are recalcitrant Michael acceptors that react poorly with many conventional nucleophiles . A particularly effective method for promoting conjugate additions to alkenenitriles 8 is to temporarily chelate Grignard reagents to γ-hydroxy unsaturated nitriles, effectively harnessing the inherent entropic advantages 10 of intramolecular reactions in promoting a formal intermolecular conjugate addition (Scheme ). Mechanistically, sequential deprotonation of hydroxyalkenenitriles 1 followed by alkyl exchange from a modest excess of a second Grignard reagent generates the alkylmagnesium alkoxide 2 that triggers a stereoselective conjugate addition.…”

Section: Introductionmentioning

confidence: 99%

Cyclic Alkenenitriles: Synthesis, Conjugate Addition, and Stereoselective Annulation

et al. 2003

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O-Alkylation of unsaturated silyl cyanohydrins with DMSO-Ac2O triggers a rearrangement to methylthiomethyl-protected hydroxyalkenenitriles that are easily hydrolyzed for subsequent annulations with omega-chloroalkyl Grignard reagents. Deprotonating the gamma-hydroxyalkenenitriles with t-BuMgCl followed by addition of omega-chloroalkyl Grignard reagents triggers a conjugate addition-alkylation sequence leading exclusively to cis-octalins, hydrindanes, and decalins. Stereoelectronic control favors an axial conjugate addition leading to a particularly reactive conformer that rapidly cyclizes to cis-fused bicyclic nitriles, whereas generating the ring-flipped conformer, through a stepwise sequence, allows access to the diastereomeric trans-decalin. Collectively, the rearrangement-annulation sequence represents the first general annulation of alkenenitriles to assemble diverse bicyclic nitriles with complete control over the two newly installed stereocenters.

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“…Conjugate addition is dramatically enhanced by temporarily chelating reactive Grignard 8 and organolithium 9 derived nucleophiles directly adjacent to the β-carbon of alkenenitriles (Scheme ). Transient formation of the alkylmagnesium alkoxide 2 , by sequential deprotonation and halogen−alkyl exchange, promotes the otherwise difficult conjugate addition that does not occur in the absence of an adjacent hydroxyl group . Alkylative interception of the intermediate nitrile anion 4 installs an additional C−C bond, with modest stereoselectivity, in an efficient intermolecular conjugate addition−alkylation 8b…”

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confidence: 99%

“…Curiously, the homologous Grignard 6c successfully annulates the six-membered nitrile 1b (Table , entry 4) but not the five-membered nitrile 1c (Table , entry 7). Suspecting formation of chelate 2g (Scheme ), where alkyl transfer is geometrically retarded, Grignard 6c was prepared by i -PrMgCl exchange followed by addition of tert -butyllithium to the chelate to stimulate conjugate addition from the more nucleophilic ate complex 9g …”

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confidence: 99%