C-H Activation: The New Generation

1. 5th Winter Conference on Medicinal and Bioorganic Chemistry (WCMBC)Steamboat Springs, ColoradoJanuary 26 – 31, 2003 C-H Activation: The New Generation Victor Snieckus, Christopher Jones, Bert Nolte and VS Group Queen’s University Kingston, ON Canada Email: snieckus@chem.queensu.ca

2. Victor Snieckus, Queen’s University, Session Chair C-H Activation: An Overview Professor Robert Bergman, University of California, Berkeley C-H Activation: the Last Generation Tries to Keep Up with the Next Generation Professor John Hartwig, Yale University Catalytic Regioselective Functionalization of Alkanes and Arenes with Borane Reagents Professor Howard Alper, University of Ottawa Metal Catalyzed Reactions of Pharmaceutical Value ? Professor Shinji Murai, Osaka University Manipulation of usually unreactive C-H bonds for organic synthesis

3. Holy Grails of Chemistry Grail (Holy): cup or platter used (according to legend) by Christ at the Last Supper, and in which Joseph of Arimathea received Christ’s blood at the Cross; this as object of prolonged quest (by medieval knights, or fig.) [ME, OF groal etc. f. med. L. gradalis dish, of unkn. orig.] The Concise Oxford Dictionary 7th Ed. Clarendon Press, 1987. Reference works define a Holy Grail (“usually capitalized”) as an “eminently desirable and ultimate object of extended effort”, a “knightly quest”. … Holy Grails are also said to be “achievable only by those chaste in thought, word, and deed”; we leave judgment in this regard to our readers. Bard, A.J., Whitesides, G.M.; Zare, R.N.; McLaffertv, F.W. Acct. Chem. Res. 1995, 28, 91.

4. Holy Grails of Chemistry One “Holy Grail” of C-H activation research, therefore, is not simply t o find new C-H activation reactions but to obtain an understanding of them that will allow the development of reagents capable of selective transformations of C-H bonds into more reactive functionalized molecules. Arndtsen, B.A.; Bergman, R.G.; Mobley, T.A.; and Peterson, T.H. Acc. Chem. Res. 1995, 28, 154.

5. Holy Grails of Chemistry I am pleased that you should write to me about the series of articles "Holy Grails." I do not have any interest in any of the Holy Grails mentioned in your letter. I have been interested in several efforts to find the Holy Grail, that is, to find the answer to some question that I had formulated. Linus Pauling,Acct. Chem. Res. 1995, 28, 93

6. Reaching for the Holy Grail: Activation of Traditionally Unreactive Bonds • Efficient, economic, clean (green) methods to bulk commodity chemicals • Synthesize new raw materials for industry, medicine, research • Overcome traditional dependence on C-X (X = heteroatom) SMs • C – H Activation: inexpensive, available sources of functionalized carbon from hydrocarbon feedstocks - oil, petroleum (50% methane), natural gas • C – X (X = Cl, F, OR) Activation: destruction of man-made environmental toxic compounds • C – C Activation: application in synthesis • Si – Si Activation: materials • N triple bond N Activation: discover an environmentally friendly Haber process – production of ammonia • Murai, S. Ed. Activation of Unreactive Bonds and Organic Synthesis, Springer: Berlin, 1999. (Book review: Snieckus, V. Advanced Synthesis & Catalysis, 2001, 3, 139) • Herrmann,W.A.; Cornils, B. Angew. Chem. Int. Ed. 1999, 36, 1048.

7. C-H Activation: The New Generation. Reviews • Jones, W.D. In Murai, S. Ed. Activation of Unreactive Bonds and Organic Synthesis, Springer: Berlin, 1999, p 9. See also Jones, W.D.et al Organometallics 2002, 21, 5320 (mechanism). • Kakiuchi, F.; Murai, S. In Murai, S. Ed. Activation of Unreactive Bonds and Organic Synthesis, Springer: Berlin, 1999, p 47. • Reviews: • Thermal Activation of Hydrocarbon C-H Bonds by Cp*M(NO) Complexes of Molybdenum and Tungsten, Pamplin, C.B.; Legzdins, P. Acc. Chem. Res. 2003, Web Release Date: 09-Jan-2003; (Article) DOI: 10.1021/ar0202215 • Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826. • Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731. • Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633. • Guari, Y.; Sabo-Etienne, S.; Chaudret, B. Eur. J. Inorg. Chem. 1999, 1047. • Dyker, G. Angew. Chem. Int. Ed. 1999, 38, 1699. • Stahl, S.S.; Labinger, J.A.;Bercaw, J.E. Angew. Chem. Int. Ed. 1998, 37, 2181. • Shilov, A.E.; Shul’pin, G.B. Chem. Rev. 1997, 97, 2879. • Arndtsen, B.A.; Bergman, R.G.; Mobley, T.A.; and Peterson, T.H. Acc. Chem. Res. 1995, 28, 154. • Crabtree, R.H. Chem. Rev. 1995, 95, 2599.

8. Direct C-H Activation. Consequences

9. Enantioselective Synthesis of β-Amino Acids Csp3-H C-C Bond

10. Immobilized di-Rh Complex for Asymmetric C-H Activation Csp3-H C-C Bond

11. Immobilized di-Rh Complex for Asymmetric C-H Activation Csp3-H C-C Bond

12. Catalytic Arylation, Alkenylation of Unactivated C-H Bonds Csp3-H C-C Bond

13. Ar, HetAr C-H Activation. Addition to Olefins Csp2-H C-C Bond

14. Ar, HetAr C-H Activation. Addition to Olefins Csp2-H C-C Bond

15. Ar-H Act C-CBond Form Competitive Heck Intramolecular C-H Activation Gallegher, T. 02 OL 3115; see also Larock, R.C. 02 JACS 14326 Review: Dyker, G. 99 ACIEE 1699; Fujiwara, Y. O1 ACR 633 (via s-complexes)

16. Cross Metathesis (CM) as Conceptual Equivalent for Vinyl Substitution and Allylic Oxidation Csp2-H C-C Bond

17. Activation. Hydroacylation of Olefins

18. Catalyzed Hydroacylation Reactions. Imines

19. Csp3-H C-N Bond Enantioselective Synthesis of Alkaloids

20. Activation of Traditionally Unreactive Bonds: Some Categories

21. α – OSiR3 Insertion: Phosphonocyclopentenones

22. α – OSiR3 Insertion: Phosphonocyclopentenones

23. Ar-H Act C-CBond Form Acidic C-H Activation. Addition to and Aldehydes

24. Enantioselective Synthesis of β-Amino Acids Csp3-H C-C Bond

25. Catalytic Arylation, Alkenylation of Unactivated C-H Bonds Csp3-H C-C Bond

26. Chelation-Assisted β-Alkylation of Unsaturated Ketones Csp2-H C-C Bond

27. Vinyl C-H Activation. Addition to Olefins

28. Ar C-H Activation. Coupling with Olefins. Addition to Acetylenes

29. Ar C – H Activation. Coupling with CO and Olefins

30. Catalyzed Hydroacylation Reactions. Aldehydes

32. How CanadiansSave on Toothpaste !

33. Robert Bergman and Group 2002 - Present Gerald E.K. Branch Distinguished Professor University of California, Berekeley 1977 Professor University of California, Berkeley 1969 Assistant Professor California Institute of Technology 1966 Ph.D. University of Wisconsin (Prof. Berson) 1963 B.A. Carleton College Selected Awards and Honours 2003 ACS James Flack Norris Award in Physical Organic Chemistry 1999 American Institute of Chemists Chemical Pioneer Award 1996 American Chemical Society Arthur C. Cope Award

34. Professor Robert BergmanUniversity of California, Berkeley C-H Activation: the Last Generation Tries to Keep Up with the Next Generation

35. John Hartwig and Group 1992-Present Professor Yale University 1982-1986 B.A. Princeton University 1986-1990 Ph.D. University of California, Berkeley (Prof. Robert Bergman) 1990-1992 Post Doctoral Fellow Massachusetts Institute of Technology (Prof. Stephen Lippard) Selected Awards and Honours: 1997 Camille Dreyfus Teacher-Scholar Award 1997 Arthur C. Cope Scholar 1996 Alfred P. Sloan Research Fellow

36. Professor John HartwigYale University Catalytic Regioselective Functionalization of Alkanes and Arenes with Borane Reagents

37. Howard Alper 1996 Associate Vice-Rector, Research University of Ottawa 1997-Present Vice-Rector, Research University of Ottawa 1971-1974 Associate Professor State University of New York at Binghamton 1975-1978 Associate Professor University of Ottawa 1978 Professor University of Ottawa 1963 B.Sc Sir George Williams University 1967 Ph.D. McGill University 1967-1968 Post Doctoral Princeton University 1968-1971 Assistant Professor State University of New York at Binghamton Selected Awards and Honours: 2000 Gerhard Herzberg Canada Gold Medal for Science and Engineering 1999 Officer of the Order of Canada, 1999 1986 Killam Research Fellow

38. Professor Howard AlperUniversity of Ottawa Metal Catalyzed Reactions of Pharmaceutical Value

39. Professor Murai and Group 1999-Present Dean, Faculty Of Engineering Osaka University 1973-1987 Associate Professor Osaka University 1987-1999 Professor Osaka University 1961-1963 M. Eng. Osaka University 1963-1966 D. Eng. Osaka University 1966-1973 Assistant Professor Osaka University Selected Awards and Honours: 1998 The Chemical Society of Japan Award 1985 Divisional Award of the Chemical Society of Japan (Organic Chemistry)

40. Professor Shinji MuraiOsaka University ? Manipulation of usually unreactive C-H bonds for organic synthesis