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

2. Outline 2 1.Background Information 2. 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 3.Directed Ortho Metallation: Seminal Work 4.Directed Ortho Metallation: Methodological Aspects Arylsulfonamide DoM Chemistry Enantioselective Functionalization of Ferrocenes Via DoM

3. Background Information 3

4. Complex-Induced Proximity Effect (CIPE): The Concept 4 Beak, P. et al. J.Am.Chem.Soc. 1986, 19, 356-363 The CIPE process requires kinetic removal of the β-proton in the presence of an α-proton which is ca. 10 pK a 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

5. Complex-Induced Proximity Effect (CIPE): The Concept 5 Beak, P. et al. J.Am.Chem.Soc. 1986, 19, 356-363 Metallation ConditionsRatio 2:3 LDA-THF-HMPA100:0 LDA-THF40:60 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

6. CIPE : Kinetic Evidence for the Role of Complexes in the α ’-Lithiations of Carboxamides 6 The kinetics of the α’-lithiations in cyclohexane were determined by stopped-flow infrared spectroscopy The interaction of ligands with s BuLi 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 7 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 nRE+ETime (h)Yield (cis:trans) 1 i PrMe 3 SnClSnMe 3 578: 0 1 i PrMe 2 SO 4 Me368:0 1 i PrPhMe 2 SiClSiMe 2 Ph4.543:0 2 t BuMe 2 SO 4 Me585:0 2 t BuPhMe 2 SiClSiMe 2 Ph550:10 8 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 nRE+ETime (h)Yield (cis:trans) 1 i PrMe 3 SnClSnMe 3 578: 0 1 i PrMe 2 SO 4 Me368:0 1 i PrPhMe 2 SiClSiMe 2 Ph4.543:0 2 t BuMe 2 SO 4 Me585:0 2 t BuPhMe 2 SiClSiMe 2 Ph550:10 9 Beak, P. et al. J.Am.Chem.Soc. 2001, 123, 315-321 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 Me 3 SnCl proceeds with retention of configuration, the proton that is nearly coplanar with the carbonyl group would be favored for removal

10. CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions 10 Beak, P. et al. J. Org. Chem. 1995, 60, 7092-7093 The observation of a large intermolecular isotope effect ( ˃ 30) between 1 and 1-d 4 suggests that the deprotonation is the rate-determinating step The large value for K c indicates that the equilibrium lies heavily on the side of the complex C

11. CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions 11 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 SubstratePseudo-1st Order Competitive Efficiency Second Order Competitive Efficiency Dihedral Angles (H A, H B )(º) Distance from carbonyl oxygen (H A, H B )(Å) 11 36, 148 20, 97 2.64, 3.88 2.41, 3.44 3420, 1272.48, 3.78 2356836, 702.57, 3.16 33092020, 1272.69, 3.96 705480010, 962.66, 3.72 fast1900028, 772.78, 3.70 12

13. CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions 13 Synthesis of the trans-organostannane Evaluation of the effect of restricting the position of the carbamate carbonyl group on the configurational stability of a dipole-stabilized organolithium

14. CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions StannaneDiamineTemp (ºC)Time (h)Yield (%)cis:trans cisTMEDA-78457>99:1 cisTMEDA-40144>99:1 cisnone-78669>99:1 cisnone-40521>99:1 transnone-78556<1:99 transnone-401242:1 transTMEDA-781441:1 transTMEDA-786.521>99:1 14

15. CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions 15 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 SolventTemp (ºC)Time (h)Yield (%)e.r. Et 2 O-7816589:11 Et 2 O-7825382:18 Et 2 O-7837680:20 Et 2 O-7853365:35 Et 2 O-786.55461:39 Et 2 O-7882055:45 Et 2 O/TMEDA-78106690:10 Et 2 O/TMEDA-4015046:54 16

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

18. CIPE: Analysis of Intra- and Intermolecular Kinetic Isotope Effects in Directed Aryl and Benzylic Lithiations 18 Beak, P. et al. J.Am.Chem.Soc, 1999, 121, 7553-7558 Possible reaction pathways: Intramolecular effectIntermolecular effect Kinetically enhanced metallation Complex-induced proximity effect

19. CIPE: Analysis of Intra- and Intermolecular Kinetic Isotope Effects in Directed Aryl and Benzylic Lithiations 19 Intramolecular isotope effect: k H /k D = [2-d 1 ]/[2] Intermolecular isotope effect: k’ H /k’ D = log([1]/[1] i ) log([1-d 2 ]/[1-d 2 ] i ) The relative concentrations of 1 and 1-d 2 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 Substrate k’ H /k’ D Intermolecular k H /k D Intramolecular 5-6>20 >30 >20 20

21. CIPE: Analysis of Intra- and Intermolecular Kinetic Isotope Effects in Directed Aryl and Benzylic Lithiations Substrate k’ H /k’ D Intermolecular k H /k D Intramolecular 5-6>20 >30 >20 21 Limitations Intramolecular isotope effect: k H /k D = [2-d 1 ]/[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 Substrate k’ H /k’ D Intermolecular k H /k D Intramolecular 5-6>20 >30 >20 22 Limitations Intramolecular isotope effect: k H /k D = [2-d 1 ]/[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-d 2 ]/[1-d 2 ] i ) High conversions of 1 and very low conversions of 1-d 2 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 Substrate k’ H /k’ D Intermolecular k H /k D Intramolecular 5-6>20 >30 >20 23 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 24 DMG = Directed Metallation Group Bebb, R.L. et al. J.Am.Chem.Soc. 1939, 61, 109-112 Seminal Discovery (1939) Mechanism

25. Directed Ortho Metallation: Directed Metallation Groups 25 Beak, P. et al. J.Org.Chem. 1979, 44, 24, 4464-4466 Beak, P. et al. J.Org.Chem. 1979, 44, 24, 4463-4464 Beak, P. et al. Angew.Chem.Int.Ed. 2004, 43, 2206-2225

26. Directed Ortho Metallation: Methodological Aspects 26 Snieckus, V. et al. J.Org.Chem. 1989, 54, 4372-4385 Iterative DoM Reactions: The "Walk-Along-The-Ring" Sequence

27. Directed Ortho Metallation: Methodological Aspects 27 Snieckus, V. et al. Org.Let. 2005, 7, 13, 2523-2526 Silyl Group Functionalization : ipso-Halodesilylation Reactions CompdHal+/solvent/tempXYield (%) 2ICl/CH 2 Cl 2 /rtCl86 2NCS/MeCN/refluxCl70 2Br 2 /CH 2 Cl 2 /0°C-rtBr92 3ICl/CH 2 Cl 2 /rtCl71 3NCS/MeCN/refluxCl65 3Br 2 /CH 2 Cl 2 /0°C-rtBr78 4ICl/CH 2 Cl 2 /rtCl66 4NCS/MeCN/refluxClNR 4Br 2 /CH 2 Cl 2 /0°C-rtBr77

28. Directed Ortho Metallation: Methodological Aspects 28 Snieckus, V. et al. Org.Let. 2005, 7, 13, 2523-2526 Silyl Group Functionalization : ipso-Borodesilylation Reactions DMGRYield (%) CONEt 2 H76 N-cumyl amideH95 OCONEt 2 H85 OCONEt 2 6-TMS89 SO 2 NHEtH90

29. Directed Ortho Metallation: Methodological Aspects 29 Snieckus, V. et al. Org.Let. 2005, 7, 13, 2523-2526 Silyl Group Functionalization : in situ ipso-Borodesilylation and Suzuki Cross-Coupling Reactions DMGArXYield (%) PhBr76 (80) 3-Br-Py83(58) PhBr76

30. Directed Ortho Metallation: Methodological Aspects 30 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 31 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 32 Snieckus, V. et al. Org.Let. 1999, 1, 8, 1183-1186

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

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

35. Arylsulfonamide DoM Chemistry 35 Snieckus, V. et al. Angew.Chem.Int.Ed. 2004, 43, 888-891 EntryRYield (%) 1H(74) 22-Me(74) 33-Me(94) 44-Me(56) 52-CONEt 2 60(64) 64-CONEt 2 58(67) 72-N(Me)Ph53 84-N(Me)Ph18 92-OMe(97) 102-OCH 2 Ph68 112-O i Pr59 123-OMe(91) 134-OMe(18) 142-TMS(48) 154-TMS(76) 162-(p-MeO-C 6 H 4 )90 174-(p-MeO-C 6 H 4 )85

36. Arylsulfonamide DoM Chemistry 36 Snieckus, V. et al. Angew.Chem.Int.Ed. 2004, 43, 888-891 EntryRYield (%) 1H(74) 22-Me(74) 33-Me(94) 44-Me(56) 52-CONEt 2 60(64) 64-CONEt 2 58(67) 72-N(Me)Ph53 84-N(Me)Ph18 92-OMe(97) 102-OCH 2 Ph68 112-O i Pr59 123-OMe(91) 134-OMe(18) 142-TMS(48) 154-TMS(76) 162-(p-MeO-C 6 H 4 )90 174-(p-MeO-C 6 H 4 )85 Large ortho substituents and para-substituted electron-donating groups promote lower yields

37. Arylsulfonamide DoM Chemistry 37 Snieckus, V. et al. Angew.Chem.Int.Ed. 2004, 43, 888-891 EntryRYield (%) 1H(74) 22-Me(74) 33-Me(94) 44-Me(56) 52-CONEt 2 60(64) 64-CONEt 2 58(67) 72-N(Me)Ph53 84-N(Me)Ph18 92-OMe(97) 102-OCH 2 Ph68 112-O i Pr59 123-OMe(91) 134-OMe(18) 142-TMS(48) 154-TMS(76) 162-(p-MeO-C 6 H 4 )90 174-(p-MeO-C 6 H 4 )85 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

38. Arylsulfonamide DoM Chemistry 38 Snieckus, V. et al. Angew.Chem.Int.Ed. 2004, 43, 888-891 En try RR’Yield (%) 12-OMeMe(60) 22-OMePh52 34-OMePh79 42-(p-MeO-C 6 H 4 )Ph65 54-(p-MeO-C 6 H 4 )Ph72 62-MePh(69) 74-MePh(80) 82-TMSPh(73) 94-TMSPh(84) Electronic effects seem to have little influence on the yields of products

39. Arylsulfonamide DoM Chemistry 39 Snieckus, V. et al. Angew.Chem.Int.Ed. 2004, 43, 888-891 The reduction of 6 by [D 7 ] i Pr 2 Mg 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

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

41. Enantioselective Functionalization of Ferrocenes Via DoM 41 Snieckus, V. et al. J.Am.Chem.Soc. 1996, 118, 685-686 EntryE+E+ EYield (%)ee (%) 1TMSClTMS9698 2MeIMe9194 3Et 2 COEt 2 C(OH)4599 4Ph 2 COPh 2 C(OH)9199 5ClCH 2 OCH 3 CH 2 OCH 3 6281 6I2I2 I8596 7(PhS) 2 PhS9098 8(PhSe) 2 PhSe9293 9Ph 2 PClPh 2 P8290 10B(OMe) 3 B(OH) 2 8985

42. Enantioselective Functionalization of Ferrocenes Via DoM 42 Snieckus, V. et al. J.Am.Chem.Soc. 1996, 118, 685-686 EntryE+E+ EYield (%)ee (%) 1TMSClTMS9698 2MeIMe9194 3Et 2 COEt 2 C(OH)4599 4Ph 2 COPh 2 C(OH)9199 5ClCH 2 OCH 3 CH 2 OCH 3 6281 6I2I2 I8596 7(PhS) 2 PhS9098 8(PhSe) 2 PhSe9293 9Ph 2 PClPh 2 P8290 10B(OMe) 3 B(OH) 2 8985 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 n BuLi using chiral HPLC

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

44. Enantioselective Functionalization of Ferrocenes Via DoM 44 Snieckus, V. et al. Org.Lett. 2000, 2, 5, 629-631 EntryE+E+ EYield (%)ee (%) 1Ph 2 COPh 2 C(OH)9294 2Et 2 COEt 2 C(OH)4591 3Bu 3 SnClBu 3 Sn5882 4Ph 2 PClPh 2 P5397 5(PhS) 2 PhS7189 6(PhSe) 2 PhSe8271 7I2I2 I7089 8MeIMe7192

45. Enantioselective Functionalization of Ferrocenes Via DoM 45 Snieckus, V. et al. Org.Lett. 2000, 2, 5, 629-631 Entryee 1 (%)RE+E+ EYield (%) dl : meso ee (%) 10TMSTMSClTMS8651:4972 2aTMSTMSClTMS7584:1691 397Ph 2 PPh 2 PClPh 2 P45>95:598 489PhS(PhS) 2 PhS6099:197 a CSP HPLC enantiomeric resolution was not feasible, [α] 23 578 +67.5 (c 0.54, CHCl 3 )

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

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

48. Enantioselective Functionalization of Ferrocenes Via DoM 48 Snieckus, V. et al. Org.Lett. 2000, 2, 5, 629-631 Asymmetric alkylation of benzaldehyde EntryRee of ligand SolventYield (%)ee (%) 1Ph 2 C(OH)96Hexane9861(S) 2Ph 2 C(OH)96PhMe9812(R) 3Ph 2 C(OLi)95PhMe7047(S) 4Et 2 C(OH)90Hexane3760(S) 52,4-di(MeO)Ph89PhMe4390(S)

49. Enantioselective Functionalization of Ferrocenes Via DoM 49 Snieckus, V. et al. Adv.Synth.Catal. 2003, 345, 370-382 EntryE+E+ EYield (%) 2 Yield (%) 3 ee (%) 3 1MeIMe879996(R) 2DMFCH 2 OCH 3 a 758095(R) 3TMSClTMS699995(R) 4Ph 2 PClPh 2 PN.D.61N.D. 5(MeS) 2 MeS899988(R) 6ICH 2 CH 2 II729996(R) b a Product aldehyde was reduced with NaBH 4 to give the corresponding alcohol, which was methylated using NaH/MeI b Absolute stereochemistry was established by single crystal X-ray analysis

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

51. Enantioselective Functionalization of Ferrocenes Via DoM 51 Snieckus, V. et al. Adv.Synth.Catal. 2003, 345, 370-382 EntryEYield (%)ee (%) 1Me50(92)96 2TMS49(92)93 3I26(94)96

52. Enantioselective Functionalization of Ferrocenes Via DoM 52 Snieckus, V. et al. Adv.Synth.Catal. 2003, 345, 370-382

53. Conclusion 53 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