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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. Background Information Complex-Induced Proximity Effect: The concept

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

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  1. Complex-Induced Proximity Effect in Directed Ortho and Remote Metallation Methodologies February 5 2008 Louis-Philippe Beaulieu

  2. 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

  3. Background Information

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions

  13. 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

  14. CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions

  15. 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

  16. CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions

  17. CIPE: Analysis of Intra- and Intermolecular Kinetic Isotope Effects in Directed Aryl and Benzylic Lithiations Possible reaction pathways:

  18. 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

  19. 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

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

  21. 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

  22. 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

  23. 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.

  24. 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

  25. 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

  26. 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

  27. Directed Ortho Metallation: Methodological Aspects Silyl Group Functionalization : ipso-Halodesilylation Reactions Snieckus, V. et al. Org.Let. 2005, 7, 13, 2523-2526

  28. Directed Ortho Metallation: Methodological Aspects Silyl Group Functionalization : ipso-Borodesilylation Reactions Snieckus, V. et al. Org.Let. 2005, 7, 13, 2523-2526

  29. 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

  30. 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

  31. 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

  32. N-Cumyl Benzamide, Sulfonamide and Aryl o-Carbamate DMG Snieckus, V. et al. Org.Let.1999, 1, 8, 1183-1186

  33. N-Cumyl Arylsulfonamide DoM Chemistry Snieckus, V. et al. J.Org.Chem. 2007, 72, 3199-3206

  34. N-Cumyl Arylsulfonamide DoM Chemistry Merck carbapenem-type antibacterial agents Snieckus, V. et al. J.Org.Chem. 2007, 72, 3199-3206

  35. Arylsulfonamide DoM Chemistry Snieckus, V. et al. Angew.Chem.Int.Ed. 2004, 43, 888-891

  36. 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

  37. 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

  38. 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

  39. 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

  40. Arylsulfonamide DoM Chemistry Snieckus, V. et al. Synlett 2000, 9, 1294-1296

  41. Enantioselective Functionalization of Ferrocenes Via DoM Snieckus, V. et al. J.Am.Chem.Soc. 1996, 118, 685-686

  42. 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

  43. Enantioselective Functionalization of Ferrocenes Via DoM Snieckus, V. et al. J.Am.Chem.Soc. 1996, 118, 685-686

  44. Enantioselective Functionalization of Ferrocenes Via DoM Snieckus, V. et al. Org.Lett. 2000, 2, 5, 629-631

  45. 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

  46. Enantioselective Functionalization of Ferrocenes Via DoM Snieckus, V. et al. Org.Lett. 2000, 2, 5, 629-631

  47. Enantioselective Functionalization of Ferrocenes Via DoM Applications in asymmetric synthesis Tsuji-Trost allylation Snieckus, V. et al. Org.Lett. 2000, 2, 5, 629-631

  48. Enantioselective Functionalization of Ferrocenes Via DoM Asymmetric alkylation of benzaldehyde Snieckus, V. et al. Org.Lett. 2000, 2, 5, 629-631

  49. 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

  50. Enantioselective Functionalization of Ferrocenes Via DoM Latent Silicon Protection Route Snieckus, V. et al. Adv.Synth.Catal.2003, 345, 370-382

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