Complex induced proximity effect in directed ortho and remote metallation methodologies
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Complex-Induced Proximity Effect in Directed Ortho and Remote Metallation Methodologies. February 5 2008 Louis-Philippe Beaulieu. Outline. Background Information Complex-Induced Proximity Effect: The concept

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Complex induced proximity effect in directed ortho and remote metallation methodologies

Complex-Induced Proximity Effect in Directed Ortho and Remote Metallation Methodologies

February 5 2008

Louis-Philippe Beaulieu


Outline
Outline Remote Metallation Methodologies

  • Background Information

  • Complex-Induced Proximity Effect: The concept

    • Effect of Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions

    • Analysis of Intra- and Intermolecular Kinetic Isotope Effects in Directed Aryl and Benzylic Lithiations

  • Directed Ortho Metallation: Seminal Work

  • Directed Ortho Metallation: Methodological Aspects

    • Arylsulfonamide DoM Chemistry

    • Enantioselective Functionalization of Ferrocenes Via DoM


Background information
Background Information Remote Metallation Methodologies


Complex induced proximity effect cipe the concept
Complex-Induced Proximity Effect (CIPE): The Concept Remote Metallation Methodologies

  • The CIPE process requires kinetic removal of the β-proton in the

  • presence of an α-proton which is ca. 10 pKa units thermodynamically

  • more acidic

  • The organolithium base is delivered with proper geometry to allow overlap

  • between the HOMO of the β-C-H bond being broken and the LUMO of

  • the π* orbital of the double bond

Beak, P. et al. J.Am.Chem.Soc.1986, 19, 356-363


Complex induced proximity effect cipe the concept1
Complex-Induced Proximity Effect (CIPE): The Concept Remote Metallation Methodologies

  • HMPA efficiently solvate cations and thus disrupts

  • the oligomers of lithium base that constitute the

  • preequilibrium complex

  • In the case of the methoxy-substituted phenyloxazoline,

  • no metalation occurs since the lithium base is complexed

  • in a manner which holds the base away from the proton to

  • be removed

Beak, P. et al. J.Am.Chem.Soc.1986, 19, 356-363


Cipe kinetic evidence for the role of complexes in the lithiations of carboxamides
CIPE : Kinetic Evidence for the Role of Complexes in the Remote Metallation Methodologiesα’-Lithiations of Carboxamides

  • The kinetics of the α’-lithiations in cyclohexane were determined by stopped-flow infrared spectroscopy

  • The interaction of ligands with sBuLi was investigated by cryoscopic measurements

  • Based on these investigations the reactive complex illustrated above was determined to have optimal reactivity

Beak, P. et al. J.Am.Chem.Soc.1988, 110, 8145-8153


Cipe the effect of varying directing group orientation on carbamate directed lithiation reactions
CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions

  • An orthogonal relationship between the lithio carbanion and the pi system of the amide is favorable:

  • Allows for complexation of the lithium with the carbonyl oxygen

  • Relieves the possible repulsive interaction between the electron pairs of the carbanion and the pi system

Beak, P et al. Acc.Chem.Res.1996, 29, 552-560


Cipe the effect of varying directing group orientation on carbamate directed lithiation reactions1
CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions

Beak, P. et al. J.Am.Chem.Soc. 2001, 123, 315-321


Cipe the effect of varying directing group orientation on carbamate directed lithiation reactions2
CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions

  • The relative configuration of the stannane product was determined to be cis by X ray crystallography

  • In this structure, the carbonyl group is nearly coplanar to the C-Sn bond. Assuming the reaction with

  • Me3SnCl proceeds with retention of configuration, the proton that is nearly coplanar with the carbonyl

  • group would be favored for removal

Beak, P. et al. J.Am.Chem.Soc. 2001, 123, 315-321


Cipe the effect of varying directing group orientation on carbamate directed lithiation reactions3
CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions

  • The observation of a large intermolecular isotope

  • effect (˃30) between 1 and 1-d4 suggests that the

  • deprotonation is the rate-determinating step

  • The large value for Kc indicates that the equilibrium

  • lies heavily on the side of the complex C

Beak, P. et al. J. Org. Chem.1995, 60, 7092-7093


Cipe the effect of varying directing group orientation on carbamate directed lithiation reactions4
CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions

Competitive Efficiency in Carbamate-Directed Lithiations:

Comparison of Constrained Carbamates and Boc Amines

  • The magnitudes of both the equilibrium constants and the rate constants can

  • affect the competitive efficiencies of the reactions compared


Cipe the effect of varying directing group orientation on carbamate directed lithiation reactions5
CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions


Cipe the effect of varying directing group orientation on carbamate directed lithiation reactions6
CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions

Evaluation of the effect of restricting the position of the carbamate carbonyl

group on the configurational stability of a dipole-stabilized organolithium

Synthesis of the trans-organostannane


Cipe the effect of varying directing group orientation on carbamate directed lithiation reactions7
CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions


Cipe the effect of varying directing group orientation on carbamate directed lithiation reactions8
CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions

  • The cis organolithium is more thermodynamically stable given the better chelating

  • interaction between the carbonyl oxygen and the lithium than the trans configuration

  • Additional stabilization results from the orthogonal relationship between pi system and the,

  • anion which is more accessible in the cis configuration


Cipe the effect of varying directing group orientation on carbamate directed lithiation reactions9
CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions


CIPE: Analysis of Intra- and Intermolecular Kinetic Isotope Effects in Directed Aryl and Benzylic Lithiations

Possible reaction pathways:


CIPE: Analysis of Intra- and Intermolecular Kinetic Isotope Effects in Directed Aryl and Benzylic Lithiations

Intramolecular effect

Intermolecular effect

Possible reaction pathways:

Complex-induced proximity effect

Kinetically enhanced metallation

Beak, P. et al. J.Am.Chem.Soc, 1999, 121, 7553-7558


CIPE: Analysis of Intra- and Intermolecular Kinetic Isotope Effects in Directed Aryl and Benzylic Lithiations

Intramolecular isotope effect: kH/kD = [2-d1]/[2]

  • Intermolecular isotope effect: k’H/k’D = log([1]/[1]i)

  • log([1-d2]/[1-d2]i)

  • The relative concentrations of 1 and 1-d2 change as a function of time ,

  • and consequently so does the relative forward velocities

, assuming the reaction is first order in substrate


CIPE: Analysis of Intra- and Intermolecular Kinetic Isotope Effects in Directed Aryl and Benzylic Lithiations


CIPE: Analysis of Intra- and Intermolecular Kinetic Isotope Effects in Directed Aryl and Benzylic Lithiations

  • Limitations

  • Intramolecular isotope effect:

  • kH/kD = [2-d1]/[2]

  • Precise determination of the isotope effect is

  • complicated by the low occurrence of 2

  • A different value of intra- and intermolecular

  • kinetic isotope effect precludes a one-step mechanism

  • Reaction pathway b, d or f might best describe the

  • reaction profile


CIPE: Analysis of Intra- and Intermolecular Kinetic Isotope Effects in Directed Aryl and Benzylic Lithiations

  • Limitations

  • Intramolecular isotope effect:

  • kH/kD = [2-d1]/[2]

  • Precise determination of the isotope effect is

  • complicated by the low occurrence of 2

  • Intermolecular isotope effect:

  • k’H/k’D = log([1]/[1]i)

  • ([1-d2]/[1-d2]i)

  • High conversions of 1and very low conversions

  • of 1-d2 complicate the determination of the

  • isotope effect

  • However qualitatively k’H/k’D would be large in value


CIPE: Analysis of Intra- and Intermolecular Kinetic Isotope Effects in Directed Aryl and Benzylic Lithiations

  • Similar values of inter- and intramolecular kinetic

  • isotope effects does not allow to distingsh between

  • kinetically enhanced metallation and CIPE.

  • However, if the deprotonations of all three substrates

  • can be described similarly, then the two benzamide

  • substrates may follow reaction pathway e.


Directed ortho metallation seminal work
Directed Ortho Metallation: Seminal Work Effects in Directed Aryl and Benzylic Lithiations

Mechanism

DMG = Directed Metallation Group

Seminal Discovery (1939)

Bebb, R.L. et al. J.Am.Chem.Soc. 1939, 61, 109-112


Directed ortho metallation directed metallation groups
Directed Ortho Metallation: Directed Metallation Groups Effects in Directed Aryl and Benzylic Lithiations

Beak, P. et al. J.Org.Chem. 1979, 44, 24, 4463-4464

Beak, P. et al. Angew.Chem.Int.Ed. 2004, 43, 2206-2225

Beak, P. et al. J.Org.Chem. 1979, 44, 24, 4464-4466


Directed ortho metallation methodological aspects
Directed Ortho Metallation: Methodological Aspects Effects in Directed Aryl and Benzylic Lithiations

Iterative DoM Reactions: The "Walk-Along-The-Ring" Sequence

Snieckus, V. et al. J.Org.Chem. 1989, 54, 4372-4385


Directed ortho metallation methodological aspects1
Directed Ortho Metallation: Methodological Aspects Effects in Directed Aryl and Benzylic Lithiations

Silyl Group Functionalization : ipso-Halodesilylation Reactions

Snieckus, V. et al. Org.Let. 2005, 7, 13, 2523-2526


Directed ortho metallation methodological aspects2
Directed Ortho Metallation: Methodological Aspects Effects in Directed Aryl and Benzylic Lithiations

Silyl Group Functionalization : ipso-Borodesilylation Reactions

Snieckus, V. et al. Org.Let. 2005, 7, 13, 2523-2526


Directed ortho metallation methodological aspects3
Directed Ortho Metallation: Methodological Aspects Effects in Directed Aryl and Benzylic Lithiations

Silyl Group Functionalization : in situ ipso-Borodesilylation and Suzuki Cross-Coupling Reactions

Snieckus, V. et al. Org.Let. 2005, 7, 13, 2523-2526


Directed ortho metallation methodological aspects4
Directed Ortho Metallation: Methodological Aspects Effects in Directed Aryl and Benzylic Lithiations

Anionic Rearramgement

Snieckus, V. et al. J.Org.Chem.1983, 48, 1935-1937

Snieckus, V. et al. J.Am.Chem.Soc.1985, 107, 6312-6315


Directed ortho metallation methodological aspects5
Directed Ortho Metallation: Methodological Aspects Effects in Directed Aryl and Benzylic Lithiations

Remote Aromatic Metalation

  • X-ray crystal structure data for N,N-Diisopropyl 2-phenyl-6-(1’-naphtyl)benzamide shows an

  • approximately orthogonal amide carbonyl with respect to the central aromatic ring

Snieckus, V. et al. J.Org.Chem.1991, 56, 1683-1685


N cumyl benzamide sulfonamide and aryl o carbamate dmg
N-Cumyl Benzamide, Sulfonamide and Aryl Effects in Directed Aryl and Benzylic Lithiationso-Carbamate DMG

Snieckus, V. et al. Org.Let.1999, 1, 8, 1183-1186


N cumyl arylsulfonamide dom chemistry
N-Cumyl Arylsulfonamide DoM Chemistry Effects in Directed Aryl and Benzylic Lithiations

Snieckus, V. et al. J.Org.Chem. 2007, 72, 3199-3206


N cumyl arylsulfonamide dom chemistry1
N-Cumyl Arylsulfonamide DoM Chemistry Effects in Directed Aryl and Benzylic Lithiations

Merck carbapenem-type

antibacterial agents

Snieckus, V. et al. J.Org.Chem. 2007, 72, 3199-3206


Arylsulfonamide dom chemistry
Arylsulfonamide DoM Chemistry Effects in Directed Aryl and Benzylic Lithiations

Snieckus, V. et al. Angew.Chem.Int.Ed. 2004, 43, 888-891


Arylsulfonamide dom chemistry1
Arylsulfonamide DoM Chemistry Effects in Directed Aryl and Benzylic Lithiations

  • Large ortho substituents and para-substituted

  • electron-donating groups promote lower yields

Snieckus, V. et al. Angew.Chem.Int.Ed. 2004, 43, 888-891


Arylsulfonamide dom chemistry2
Arylsulfonamide DoM Chemistry Effects in Directed Aryl and Benzylic Lithiations

  • Large ortho substituents and para-substituted

  • electron-donating groups promote lower yields

  • Groups ortho to the sulfonamide that are capable of

  • metal coordination enhance the yield significantly

Snieckus, V. et al. Angew.Chem.Int.Ed. 2004, 43, 888-891


Arylsulfonamide dom chemistry3
Arylsulfonamide DoM Chemistry Effects in Directed Aryl and Benzylic Lithiations

  • Electronic effects seem to have little

  • influence on the yields of products

Snieckus, V. et al. Angew.Chem.Int.Ed. 2004, 43, 888-891


Arylsulfonamide dom chemistry4
Arylsulfonamide DoM Chemistry Effects in Directed Aryl and Benzylic Lithiations

  • The reduction of 6 by [D7]iPr2Mg and the regiospecific

  • cross-coupling of aryl sulfonamides with aryl Grignard

  • reagents suggest that the cross-coupling reaction

  • proceeds through the catalytic cycle of the Corriu-Kumada-

  • Tamao reaction

Snieckus, V. et al. Angew.Chem.Int.Ed. 2004, 43, 888-891


Arylsulfonamide dom chemistry5
Arylsulfonamide DoM Chemistry Effects in Directed Aryl and Benzylic Lithiations

Snieckus, V. et al. Synlett 2000, 9, 1294-1296


Enantioselective functionalization of ferrocenes via dom
Enantioselective Functionalization of Ferrocenes Via DoM Effects in Directed Aryl and Benzylic Lithiations

Snieckus, V. et al. J.Am.Chem.Soc. 1996, 118, 685-686


Enantioselective functionalization of ferrocenes via dom1
Enantioselective Functionalization of Ferrocenes Via DoM Effects in Directed Aryl and Benzylic Lithiations

  • The (S) absolute configuration was

  • established by single-crystal X-ray

  • crystallographic analysis

  • Since the sp2-hybridized ferrocenyl

  • carbanions are configurationally stable,

  • the enantioselective induction must

  • occur at the deprotonation and not the

  • electrophile substitution step

  • On this basis, the configurational

  • outcome of the other 1,2-disubstituted

  • ferrocenes was assigned to be S

  • The enantiomeric excess was

  • determined by comparison with racemic

  • products generated by deprotonation

  • with nBuLi using chiral HPLC

Snieckus, V. et al. J.Am.Chem.Soc. 1996, 118, 685-686


Enantioselective functionalization of ferrocenes via dom2
Enantioselective Functionalization of Ferrocenes Via DoM Effects in Directed Aryl and Benzylic Lithiations

Snieckus, V. et al. J.Am.Chem.Soc. 1996, 118, 685-686


Enantioselective functionalization of ferrocenes via dom3
Enantioselective Functionalization of Ferrocenes Via DoM Effects in Directed Aryl and Benzylic Lithiations

Snieckus, V. et al. Org.Lett. 2000, 2, 5, 629-631


Enantioselective functionalization of ferrocenes via dom4
Enantioselective Functionalization of Ferrocenes Via DoM Effects in Directed Aryl and Benzylic Lithiations

a CSP HPLC enantiomeric resolution was not feasible, [α]23578 +67.5 (c 0.54, CHCl3)

Snieckus, V. et al. Org.Lett. 2000, 2, 5, 629-631


Enantioselective functionalization of ferrocenes via dom5
Enantioselective Functionalization of Ferrocenes Via DoM Effects in Directed Aryl and Benzylic Lithiations

Snieckus, V. et al. Org.Lett. 2000, 2, 5, 629-631


Enantioselective functionalization of ferrocenes via dom6
Enantioselective Functionalization of Ferrocenes Via DoM Effects in Directed Aryl and Benzylic Lithiations

Applications in asymmetric synthesis

Tsuji-Trost allylation

Snieckus, V. et al. Org.Lett. 2000, 2, 5, 629-631


Enantioselective functionalization of ferrocenes via dom7
Enantioselective Functionalization of Ferrocenes Via DoM Effects in Directed Aryl and Benzylic Lithiations

Asymmetric alkylation of benzaldehyde

Snieckus, V. et al. Org.Lett. 2000, 2, 5, 629-631


Enantioselective functionalization of ferrocenes via dom8
Enantioselective Functionalization of Ferrocenes Via DoM Effects in Directed Aryl and Benzylic Lithiations

a Product aldehyde was reduced with NaBH4 to give the corresponding

alcohol, which was methylated using NaH/MeI

b Absolute stereochemistry was established by single crystal X-ray analysis

Snieckus, V. et al. Adv.Synth.Catal.2003, 345, 370-382


Enantioselective functionalization of ferrocenes via dom9
Enantioselective Functionalization of Ferrocenes Via DoM Effects in Directed Aryl and Benzylic Lithiations

Latent Silicon Protection Route

Snieckus, V. et al. Adv.Synth.Catal.2003, 345, 370-382


Enantioselective functionalization of ferrocenes via dom10
Enantioselective Functionalization of Ferrocenes Via DoM Effects in Directed Aryl and Benzylic Lithiations

Snieckus, V. et al. Adv.Synth.Catal.2003, 345, 370-382


Enantioselective functionalization of ferrocenes via dom11
Enantioselective Functionalization of Ferrocenes Via DoM Effects in Directed Aryl and Benzylic Lithiations

Snieckus, V. et al. Adv.Synth.Catal.2003, 345, 370-382


Conclusion
Conclusion Effects in Directed Aryl and Benzylic Lithiations

  • Thinking beyond thermodynamic acidity leads to new synthetic methodologies for remote functionalization

  • CIPE provides a heuristic model to discover new modes of C-H activation

  • The involvement of CIPE in directed ortho and remote metallation allows the synthesis

  • of complex aromatic systems with ease

  • Combination of several methodologies to DoM and DreM expands the versatility of this synthetic strategy


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