C-H Functionalization: Recent Applications

1. C-H Functionalization: Recent Applications Jean-Francois Vincent-Rocan Department of Chemistry University of Ottawa Organic and Biological Chemistry Graduate seminar April 12, 2012

2. Books and Reviews

3. C-H Functionalization in SciFinder -Constant growth in the past 30 years -Explosion in the last 5 years -Focus on recent applications (not a comprehensive review)

4. Activation vs Functionalization • C-H bond activation: Cleavage of C-H bond that leads to the formation of a metal-C bond either through oxidative addition to a low valent metal center or electrophilic substitution • C-H bond functionalization: Cleavage of C-H bond that is followed by new bond formation at the carbon center Shilov, A. E.; Shul'pin, G. B. Chem. Rev. 1997, 57, 2879-2932 Kaikuchi, F.; Chatani, N. Adv. Synth. Catal. 2003, 345, 1077-1101

5. Outline • Part 1: Factors of selectivity • Inductive effects • Hyperconjugation • Steric factors • Strain release • Directed oxidations • Part 2: Recent applications • Mimicking nature • Increasing molecular complexity • Cross-Coupling • Divergent functionalization in drug discovery

6. Part 1Factors of selectivity

7. C-H Oxidation Mechanism using Dioxiranes Curci Acc. Chem. Res. 2006, 39, 1

8. Bond Strengths -Stronger bonds are formed -Most electron rich C-H is the easiest to break

9. -The most electron rich position is oxidized for non-metal insertions -Typical reactivity trend is tertiary> secondary> primary Inductive Effects -Secondary positions are less sterically hindered Selectivity can be tuned by reagent selection (polyoxometalates) Asensio, G.; Castellano, G.; Mello,R.; Gonzalez-Nunez, M. E. J. Org. Chem. 1996, 61, 5564−5566 Kamata,K.; Yonehara,K.; Nakagawa, Y.; Uehara, K.; Mizuno, N. Nat. Chem. 2010, 2, 478 – 483

10. Hyperconjugation Effects -Cyclopropane act as activating group (oxidation on the vicinal carbon) -Orbital overlap is required Daccolti, L.; Dinoi,A.; Fusco, C.; Russo, A.; Curci, R. J. Org. Chem. 2003, 68,7806 – 7810 Banwell, M. G.; Haddad, N.; Huglin, J. A.; MacKay, M. F.; Reum, M. E.;Ryan, J. H.; Turner, K. A. J. Chem. Soc. Chem. Commun.1993, 954 – 957 Brinker, U.H.; Lin, G.; Xu, L.; Smith, W. B.; Mieusset, J.-L. J. Org. Chem. 2007, 72, 8434 – 8451.

11. HyperconjugationEnabled by Heteroatoms -Non-bonding electrons of a heteroatom available for hyperconjugation - Non-bonding electron MUST be available (Delocalization in the aromatic ring in this case) Davies, H. M. L.; Beckwith, R. E. J.; Antoulinakis, E. G.; Jin, Q. J. Org. Chem. 2003, 68, 6126 – 6132. Barton, D. H. R.; Boivin, J.; Gaudin, D.; Jankowski, K. Tetrahedron Lett. 1989,30, 1381 – 1382. Liang, C.; Fabien, C.; Fruit, C.; Mller, P.; Dodd, R. H.; Dauban, P.Angew. ChemInt. Ed. 2006,45, 4641 – 4644.

12. Steric Factors -Rate reduction for hindered C-H bonds -Hyperconjugation+ steric factors Tenaglia, A.; Terranova, E.; Waegell, B. Tetrahedron Lett. 1989, 30, 5271 – 5274 Davies, H. M. L.; Venkataramani, C. Angew. Chem. Int. Ed. 2002, 41, 2197 – 2199 Gomez, L.; Garcia-Bosch, I.; Company, A.; Benet-Buchholz, J.; Polo, A.; Sala, X.; Ribas, X.; Costas, M.Angew. Chem. Int. Ed. 2009, 48, 5720 – 5723. Davies, H. M. L.; Beckwith, R. E. J.; E. Antoulinakis, G.; Jin, Q. J. Org. Chem. 2003, 68, 6126 – 6132. .

13. Strain Release • Elimination of 1,3 syndiaxial interaction in the transition state promotes a faster oxidation and an increased site-selectivity (in the example below) • Schreiber and Eschenmoser proposed this idea for the oxidation of axial alcohols (1955) Chen, K.; Eschenmoser, A.; Baran, P.S. Angew. Chem. Int. Ed. 2009,48, 9705 – 9708. Schreiber, J.; Eschenmoser, A.Helv. Chim. Acta 1955, 38, 1529 –1536

14. Energy diagram

15. Directed Oxidations -Excellent in the presence of opposing steric and electronic influences -Directing group is overriding the substrate’s preferences Breslow, R.; Corcoran, R. J.; Snider, B. B.; Doll, R. J.; Khanna, P. L.;Kaleya, R. J. Am. Chem. Soc. 1977, 99, 905 – 915 Kasuya, S.; Kamijo, S. ; Inoue, M. Org. Lett. 2009, 11, 3630 – 3632.

16. How is it Selective ?

17. Directing Groups Override Substrate Preferences -Directing groups can be employed to reverse the inherent selectivity -Intramolecular delivery is more important than the steric effects of the substrate Chen, K.; Richter, J. M.; Baran, P. S. J. Am. Chem. Soc. 2008,130, 7247 – 7249 Hofmann, A. W.   Ber. Dtsch Chem. Ges. 1879, 12 (1): 984–990 Löffler, K.; Freytag, C. Ber. Dtsch Chem. Ges. 1909,42 (3): 3427–3431

18. Radical[1,6]-Hydrogen ShiftHLF reaction

19. Metal Promoted Directed Oxidation Espino, C. G.; When, P. M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc. 2001, 123, 6935 – 6936 Yu, J.-Q.; Giri, R.; Chen, X. Org. Biomol. Chem. 2006, 4, 4041 – 4047

20. Directed Pd C-H activation • Insertion via CIPE, to form the new C-Pd bond Chen, X.; Engle, K. M.; Yu, J.-Q. Angew. Chem. Int. Ed., 2009, 48, 5094-5115

21. Hydrogen Bonding -Competitive ketone formation on the second substrate -H-bonding with TFDO is impossible for the second example Asensio, G.; Gonzlez-Nfflez, M. L.; Bernardini, C. B.; Mello, R.; Adam, W. J. Am. Chem. Soc. 1993, 115, 7250 – 7253

22. First Part: Conclusion • Inductive effects, hyperconjugation, steric factors and strain release will modulate C-H selectivity • Directed oxidation can be use for selective oxidation of complicated system or to invert the selectivity

23. Part 2:Recent Applications

24. Late Stage Hydroxylation • C-H activation can be used to avoid PG-chemistry using late-stage hydroxylation Wender, P. A.; Hilinski, M. K.; Mayweg, A. V. W. Org. Lett.2005, 7, 79– 82 Seto, H.; Fujioka, S.; Koshino, H.; Yoshida, S. ; Tsubuki, M.; Honda, T. Tetrahedron 1999, 55, 8341 – 8352 Curci, R.; Detomaso, A.; Prencipe, T.; Carpenter, G. B.J. Am. Chem. Soc.1994, 116, 8112−8115

25. Mimicking Nature • Nature usually oxidizes the targeted compound at the end of its biosynthesis • An abundant number of natural products are synthesised in 2 phases : Cyclase phase and Oxidation phase Chen, K.; Baran, P. S.  Nature2009, 459, 824–828

26. Baran’s Retrosynthetic Analysis for the EudesmaneTerpenes Family Chen, K.; Baran, P. S.  Nature 2009, 459, 824–828

27. Eudesmanes Synthesis: Cyclase Phase Chen, K.; Baran, P. S.  Nature2009, 459, 824–828

28. Eudesmanes synthesis: Oxidation phase Chen, K.; Baran, P. S.  Nature2009, 459, 824–828 .

29. Eudesmanes synthesis: Oxidation phase Chen, K.; Baran, P. S.  Nature2009, 459, 824–828 .

30. C-H functionalization • Aliphatic C-H (inherent preference, Directed oxidation)

31. The White Group • Major player in the allylic C-H functionalization field • Known for her Palladium(II) \ sulfoxide catalyst system for allylic oxidation • π-allyl complex followed by functionaliztion Chen, M.S.; White, M.C. J. Am. Chem. Soc2004, 126, 1346-1347 Fraunhoffer, K.J.; White, M.C.J. Am. Chem. Soc2007, 129, 7274-7276 Reed, S. A.; Mazzotti, A. R.; White, M. C. J. Am. Chem.Soc. 2009, 131,11701-11706 Young, A. J.; White, M. C. Angew. Chem., Int. Ed. 2011, 50, 6824-6827

32. Increasing Molecular Complexity -Stang and White developed that method to take fairly simple S.M and converted it to reactive intermediate Stang, E. M.; White, M. C. J. Am. Chem. Soc.2011, 133, 14892-14895

33. Optimization Stang, E. M.; White, M. C. J. Am. Chem. Soc.2011, 133, 14892-14895

34. Reaction Scope Stang, E. M.; White, M. C. J. Am. Chem. Soc.2011, 133, 14892-14895

35. Application in synthesis Stang, E. M.; White, M. C. J. Am. Chem. Soc.2011, 133, 14892-14895

36. C-H functionalization • Aliphatic C-H (inherent preference, Directed oxidation) • Allylic C-H (Directed, allyl activation)

37. Cross-Coupling reactions • Reaction using organohalides and pseudohalides and other functional groups • The reactive intermediate is the corresponding aryl and alkyl palladium(II) species. • The quickest and easiest sequences to prepare such intermediates would certainly improve these reactions • Unlimited opportunities for the use of unactivated carbon–hydrogen (C-H) bond Chen, X.; Engle, K. M.; Yu, J.-Q. Angew. Chem. Int. Ed., 2009, 48, 5094-5115

38. Cross-Coupling Featuring C-H Functionalization Lafrance, M.; Fagnou, K. J. Am. Chem. Soc.2006, 128,16496-16497 Giry, R.; Maugel, N.; Li, J. J.; Wang, D. H.; Breazzano, S. P.; Saunders, L. B.; Yu, J. Q. J. Am. Chem. Soc.2007, 129, 3510– 3511 Satoh, T.; Kawamura, Y.; Miura, M.; Nomura , M. Angew. Chem. Int. Ed. Engl. 1997, 36, 1740 Kamer, P. C. J.; de Vries, J. G.;Van Leeuwen , P.W. N. M .J. Am. Chem. Soc. 2002, 124, 1586

39. Concerted MetalationDeprotonation Lafrance, M.; Fagnou, K. J. Am. Chem. Soc.2006, 128, 16496-16497

40. Oxidative Heck Cross-Coupling Beck, E. M.; Grimster, N. P.; Hatley, R. ; Gaunt, M. J. J. Am. Chem. Soc. 2006, 128, 2528

41. Application in Total Synthesis Beck, E. M.; Hatley, R.; Gaunt, M. J. Angew. Chem., Int. Ed. 2008, 47, 3004-3007

42. Late-Stage Functionalization • 9 membered ring • Late stage functionalization • Functional group ‘’tolerance’’ Bowie, A. L.; Hughes, C. C.; Trauner, D. Org. Lett.2005, 7, 5207-5209

43. Cross-coupling featuring C-H functionalization Lafrance, M.; Fagnou, K. J. Am. Chem. Soc.2006, 128,16496-16497 Giry, R.; Maugel, N.; Li, J. J.; Wang, D. H.; Breazzano, S. P.; Saunders, L. B.; Yu, J. Q. J. Am. Chem. Soc.2007, 129, 3510– 3511 Satoh, T.; Kawamura, Y.; Miura, M.; Nomura , M. Angew. Chem. Int. Ed. Engl. 1997, 36, 1740 Kamer, P. C. J.; de Vries, J. G.;Van Leeuwen , P.W. N. M .J. Am. Chem. Soc. 2002, 124, 1586

44. Directing group For a good review :Chen, X.; Engle, K. M.; Yu, J.-Q. Angew. Chem. Int. Ed., 2009, 48, 5094-5115

45. Drug Discovery • Sulfonamide is an organic moiety present in many drugs • Has been found to direct C-H functionalization Dai, H.-X.; Stepan, A. F.; Plummer, M. S.; Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem. Soc.2011, 133, 7222-7228

46. Divergent Functionalization Dai, H.-X.; Stepan, A. F.; Plummer, M. S.; Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem. Soc.2011, 133, 7222-7228

47. Drug Analogues Dai, H.-X.; Stepan, A. F.; Plummer, M. S.; Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem. Soc.2011, 133, 7222-7228

48. C-H functionalization • Aromatic C-H (inherent preference, protecting group orientation, directing group)

49. Conclusion • 4 factors have been identified to modulate C-H functionalization selectivity (inductive effects, hyperconjugation, steric factors, strain release) • Directed oxidations can overcome the substrate’s preferences • C-H functionalization can be used easily in total synthesis of complex and drug-like molecules

50. What Is Next ? Mendoza, A.; Ishihara, Y.; Baran, P.S. Nature Chem. 2012, 4, 21-25.