Atroposelectivity in the electrophilic substitution reactions of laterally lithiated and silylated tertiary amides

Clayden, Jonathan; Pink, Jennifer H.; Westlund, Neil; Frampton, Christopher S.

doi:10.1039/b200358a

Cited by 26 publications

(23 citation statements)

References 52 publications

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“…6 -H: N , N -Diisopropyl-2-propylbenzamide was prepared from N , N -diisopropylbenzamide using a modified literature method [25]. Yield 1.11 g (90%); 1 H NMR (500 MHz, [D 8 ]toluene, 300 K) δ 7.13–7.00 (m, 4H, Ar), 3.54 (sept, 3 J (H,H) = 7 Hz, 1H, NCH), 2.99 (sept, 3 J (H,H) = 7 Hz, 1H, NCH), 2.73–2.61 (m, 2H, ArC H 2 ), 1.92–1.80 (m, 1H, ArCH 2 C H 2 ), 1.70–1.58 (m, 1H, ArCH 2 C H 2 ), 1.66 (d, 3 J (H,H) = 7 Hz, 3H, NCMe), 1.64 (d, 3 J (H,H) = 7 Hz, 3H, NCMe), 1.00 (d, 3 J (H,H) = 7 Hz, 3H, ArCH 2 CH 2 Me ), 0.68 (d, 3 J (H,H) = 7 Hz, 6H, NCMe 2 ) ppm; { 1 H} 13 C NMR (500 MHz, [D 8 ]toluene, 300 K) δ 169.6 (C=O), 138.9 (C-Ar), 138.7 (C-Ar), 129.5 (CH-Ar), 127.9 (CH-Ar), 125.7 (CH-Ar), 125.0 (CH-Ar), 50.1 (NCH), 45.4 (NCH), 35.4 (Ar C H 2 ), 24.7 (ArCH 2 C H 2 ), 20.4 (NCMe), 20.2 (NCMe), 20.0 (NCMe 2 ), 14.4 (ArCH 2 CH 2 Me ) ppm.…”

Section: Methodsmentioning

confidence: 99%

On the control of secondary carbanion structure utilising ligand effects during directed metallation

Wheatley¹,

Clayden²,

Hillier³

et al. 2012

Beilstein J. Org. Chem.

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Summary N,N-Diisopropyl-2-propylbenzamide 6-H undergoes lateral deprotonation by t-BuLi in the presence of the Lewis base PMDTA (N,N,N′,N″,N″-pentamethyldiethylenetriamine) to give a benzyllithium 6-Lil·PMDTA that incorporates a trigonal planar secondary carbanion. In the solid state, the amide directing group and the PMDTA additive work together to abstract the metal ion from the deprotonated α-C of the propyl group (4.107(4) Å). A short distance of 1.376(3) Å is observed between the deprotonated carbon centre and a planar aromatic system that shows a pattern of bond lengths which contrasts with that reported for related tertiary carbanion systems. Analogous benzylic deprotonation is seen if 6-H is treated with t-BuLi in the presence of diglyme to give 6-Lil·DGME. X-ray crystallography now shows that the metal ion more closely approaches the tertiary carbanion (2.418(6) Å) but that the planarity of the deprotonated carbon centre and the bonding pattern in the organic anion seen in the PMDTA complex are retained. DFT analysis corroborates both the short distance between aromatic ring and carbanion centre and the unperturbed nature of aromaticity in 6-Lil·L (L = Lewis base). The observation of two structure-types for the carbanion in solution is explained theoretically and by NMR spectroscopy in terms of cis and trans isomerism imparted by partial double bond character in the arene–(α-C) bond.

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Section: Methodsmentioning

confidence: 99%

On the control of secondary carbanion structure utilising ligand effects during directed metallation

Wheatley¹,

Clayden²,

Hillier³

et al. 2012

Beilstein J. Org. Chem.

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“…Transformations of ortho ‐ and laterally lithiated tertiary amides have been investigated,9 with directing effects having been attributed to the rate‐determining deprotonation of a substrate–organolithium complex 10–12. However, it is only very recently that solid‐state structural evidence has been presented in support of the nature of lithiated intermediates in either reaction pathway.…”

Section: Methodsmentioning

confidence: 99%

Controlling Chemoselectivity in the Lithiation of Substituted Aromatic Tertiary Amides

et al. 2004

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Aromatic compounds can be elaborated by directed lithiation in a number of ways [1] and both ortho and lateral metallation have been employed as synthetic tools generally [2] and in a host of recent total syntheses specifically. [3,4] Whereas ortho metallation occurs both because the directing group can inductively raise the acidity of the ortho hydrogen atom and also because the incoming organometallic substrate closely approaches this position, lateral metallation results from the directing function coordinating an organometallic substrate whilst conjugatively withdrawing electrons from a benzylic group. Consequently, the processes are competitive and, as such, result from the presence of similar directing agents. Recently, ring substitution and lateral-group branching [5] have been employed, in addition to the use of a-silyl lateral groups, [6] as means of controlling the regioselectivity of deprotonation. The use of deuterium as a protecting group at kinetically acidic positions has been reported both for amides [7] and N-heterocyclic systems. [8] Overall, studies to date have clearly established that, for either class of reaction, amide-type groups are among the most useful directors of reaction.[2]Transformations of ortho-and laterally lithiated tertiary amides have been investigated, [9] with directing effects having been attributed to the rate-determining deprotonation of a substrate-organolithium complex. [10][11][12] However, it is only very recently that solid-state structural evidence has been presented in support of the nature of lithiated intermediates in either reaction pathway. For 1 and 2 ortho lithiation has led to the characterization of solid-state dimers, 3, and isostructural N,N-diisopropyl-2-lithionaphthamide-THF complex, 4, respectively. These are based on core C···Li interactions, support of the metals coming from (amide)OÀLi bonding with concomitant modulation of the sterically induced twist angle between the amide and the plane of the aromatic ring.[13] Contrastingly, the laterally deprotonated salt of 5 reveals a tris(thf) solvate, 6, in which the metal center is only coordinated by O atoms with no C···Li interaction, thus allowing the amide and aromatic planes to be near to perpendicular in the solid state.[14] These data suggest a link between the number of donor atoms per solvent molecule (solvent denticity) and reaction chemoselectivity and lead us to report here on the competitive deprotonation of 2-ethyl-N,N-diisopropyl-1-benzamide, 7.Treatment of 7 in THF/toluene at À78 8C with 1 equivalent of tBuLi gave a maroon solution from which, on storage at À30 8C, crystals were deposited. Surprisingly, in light of previous work, [2,12,15] these were identified as N,N-diisopropyl-2-ethyl-6-lithiobenzamide-THF, 8, by X-ray crystallography. [16] In accordance with our own recent studies, [13] 8 forms a solid-state dimer based on the stabilization of each metal component in a {(CLi) 2 } core (C2ÀLi1 = 2.345(5) , C2A À Li1 = 2.187(5) ] by an amide-O center (O1 À Li1 = 1.972(5) ) and one THF m...

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“…The THF-solvated and perilithiated derivative of 1-(dimethylamino)naphthalene has been probed by low-temperature 13 C NMR spectroscopy, with both the observed 1 J( 13 C, 7 Li) coupling constant of 20.5 Hz and the sevenfold multiplicity of the peri carbon resonance suggesting that 1-(dimethylamino)-8-naphthyllithium·THF (104) is dimeric in [D 8 ]THF at Ϫ90°C. [120] In light of formative MNDO studies, [121] the perimetallation of 1-naphthol in THF to give LiOC 10 H 6 Li-8·THF (105) has been studied both as a function of the nBuLi:1-naphthol ratio and (for reaction in a 4:1 ratio) as a function of temperature.…”

Section: Solution Studiesmentioning

confidence: 99%

“…The 13 C NMR spectrum of 2,4,6-tri-tert-butylphenyllithium (1) in THF has been studied in some detail, with electric quadrupole relaxation of 7 Li incurring the partial averaging of 1 J( 13 C, 7 Li) while metal-carbon bond exchange has been reported between 6 Li enriched isotopomeric monomers. [21] In a similar vein, mesityllithium has been probed as a PMDETA complex (2), with data suggesting an asymmetric structure in which the metal is chiral at low temperature.…”

Section: Solution Studiesmentioning

confidence: 99%

“…Stereochemical aspects of the formation and reaction of laterally lithiated amides have been investigated, [5] with enantio- [6] and atroposelective lateral lithiations [7] having been published. Less commonly employed as a synthetic tool, the perimetallation of arenes occurs not because of directing group acidification of this position (cf.…”

Section: Dr Andrew Wheatley Graduated From the University Of Kent Anmentioning

confidence: 99%

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The Directed Lithiation of Benzenoid Aromatic Systems

Wheatley

2003

Eur J Inorg Chem

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Directed metallation using organolithium bases is one of the best ways of regiospecifically elaborating aromatic systems and their substituents. For benzenoid arenes, deprotonation occurs at the ortho, lateral or peri positions. The reasons for each type of reaction will be considered in the context of the propensities of different directing groups for complex formation with the incoming organolithium base, acidification of the reactive site(s) and post‐reaction stabilisation of the metal ion(s). Discussion will concentrate on structural investigations, for the most part by single‐crystal X‐ray diffraction and/or by multinuclear NMR spectroscopy. Theoretical studies will also be incorporated. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

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Atroposelectivity in the electrophilic substitution reactions of laterally lithiated and silylated tertiary amides

Cited by 26 publications

References 52 publications

On the control of secondary carbanion structure utilising ligand effects during directed metallation

On the control of secondary carbanion structure utilising ligand effects during directed metallation

Controlling Chemoselectivity in the Lithiation of Substituted Aromatic Tertiary Amides

The Directed Lithiation of Benzenoid Aromatic Systems

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