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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
  • 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
complex induced proximity effect cipe the concept
Complex-Induced Proximity Effect (CIPE): The Concept
  • 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
  • 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 α’-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
slide17
CIPE: Analysis of Intra- and Intermolecular Kinetic Isotope Effects in Directed Aryl and Benzylic Lithiations

Possible reaction pathways:

slide18
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

slide19
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

slide20
CIPE: Analysis of Intra- and Intermolecular Kinetic Isotope Effects in Directed Aryl and Benzylic Lithiations
slide21
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
slide22
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
slide23
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

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

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

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

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

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

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

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

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 o-Carbamate DMG

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

n cumyl arylsulfonamide dom chemistry
N-Cumyl Arylsulfonamide DoM Chemistry

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

n cumyl arylsulfonamide dom chemistry1
N-Cumyl Arylsulfonamide DoM Chemistry

Merck carbapenem-type

antibacterial agents

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

arylsulfonamide dom chemistry
Arylsulfonamide DoM Chemistry

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

arylsulfonamide dom chemistry1
Arylsulfonamide DoM Chemistry
  • 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
  • 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
  • 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
  • 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

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

enantioselective functionalization of ferrocenes via dom
Enantioselective Functionalization of Ferrocenes Via DoM

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

enantioselective functionalization of ferrocenes via dom1
Enantioselective Functionalization of Ferrocenes Via DoM
  • 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

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

enantioselective functionalization of ferrocenes via dom3
Enantioselective Functionalization of Ferrocenes Via DoM

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

enantioselective functionalization of ferrocenes via dom4
Enantioselective Functionalization of Ferrocenes Via DoM

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

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

enantioselective functionalization of ferrocenes via dom6
Enantioselective Functionalization of Ferrocenes Via DoM

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

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

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

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

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

enantioselective functionalization of ferrocenes via dom11
Enantioselective Functionalization of Ferrocenes Via DoM

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

conclusion
Conclusion
  • 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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