ramesh giri department of chemistry brandeis university waltham, ma 02454 02

3. Introduction 1.1. Cross-Coupling Reactions 1.2. Call for New Catalysts 1.3. Is Iron a Good Candidate?

4. 1.1. Cross-Coupling Reactions

5. 1.1. Cross-Coupling Reactions

6. 1.1. Cross-Coupling Reactions Cross-coupling reactions are catalytic. Typically 1-10 mol% catalyst. Cross-coupling reactions use readily available starting materials. Cross-coupling reactions tolerate a wide range of functional groups. Cross-coupling reactions give high yields of products. Cross-coupling reactions are chemo-, regio- and stereo-selective.

7. 1.2. Call for New Catalysts Pd catalysts are expensive: Pd(II) ~$160-260 per 5 g. Pd and Ni catalysts are toxic and not environmentally friendly. Pd- and Ni-catalyzed reactions need extended reaction times. Typically 2-40 h. Pd- and Ni-catalyzed reactions proceed at elevated temperatures. Typically 40 oC to 90 oC. Pd- and Ni-catalyzed reactions need ancillary ligands to render the catalysts sufficiently reactive.

8. 1.3. Is Iron a Good Candidate? Fe catalysts are inexpensive and readily available. Costs per gram Pd(OAc)2 $33 Pd(acac)2 $38 Fe(OAc)3 $4 Fe(acac)3 $0.4 (Fe catalysts are ~ 10-100 times cheaper than Pd-catalysts) Fe catalysts are non-toxic and environmentally friendly. Fe catalysts are air and moisture stable and easy to store for long periods under normal laboratory conditions. Iron can exist in very low and very high oxidation states: Fe(-II), Fe(0), Fe(I), Fe(II),Fe(III), Fe(IV), Fe(V) and Fe(VI).

9. Discovery and Development 2.1. Kochi’s Pioneering Work 2.2. Catalytic Cycle 2.3. Grignard Reagents as Coupling Partners 2.4. Other Organometallic Reagents as Coupling Partners

10. 2.1. Kochi’s Pioneering Work Cross-coupling of alkenyl halides with Grignard reagents

11. 2.2. Proposed Catalytic Cycle

12. 2.2. Proposed Catalytic Cycle

13. 2.2. Proposed Catalytic Cycle

14. 2.2. Proposed Catalytic Cycle

15. 2.2. Proposed Catalytic Cycle

16. 2.2. Proposed Catalytic Cycle Is Fe(I) or Fe(-II) the active catalytic species?

17. 2.3. Grignard Reagents as Coupling Partners 2.3.1. Alkenyl derivatives as substrate 2.3.2. Aryl derivatives as substrate 2.3.3. Alkyl derivatives as substrate 2.3.4. Acyl derivatives as substrate Discovery and Development

18. 2.3. Grignard Reagents as Coupling Partners 2.3.1. Alkenyl derivatives as substrate 2.3.2. Aryl derivatives as substrate 2.3.3. Alkyl derivatives as substrate 2.3.4. Acyl derivatives as substrate Discovery and Development

19. 2.3.1. Alkenyl Derivatives as Substrate Low initial temperature (-20 °C) is beneficial

20. 2.3.1. Alkenyl Derivatives as Substrate Less stable functionalized aryl Grignard reagents can be coupled at low temperature

21. 2.3.1. Alkenyl Derivatives as Substrate NMP as a cosolvent with THF is determinant to carry out the reaction in high yields and under mild conditions

22. 2.3.1. Alkenyl Derivatives as Substrate

23. 2.3.1. Alkenyl Derivatives as Substrate

24. 2.3.1. Alkenyl Derivatives as Substrate

25. Iron-catalyzed reactions can be carried out on solid phase supports 2.3.1. Alkenyl Derivatives as Substrate

26. Iron-catalyzed cross-coupling is sensitive to steric hindrance exerted by ortho-substituents 2.3.1. Alkenyl Derivatives as Substrate

27. 2.3. Grignard Reagents as Coupling Partners 2.3.1. Alkenyl derivatives as substrate 2.3.2. Aryl derivatives as substrate 2.3.3. Alkyl derivatives as substrate 2.3.4. Acyl derivatives as substrate Discovery and Development

28. Aryl chlorides, triflates and tosylates are better substrates than aryl bromides and iodides 2.3.2. Aryl Derivatives as Substrate

29. 2.3.2. Aryl Derivatives as Substrate

30. 2.3.2. Aryl Derivatives as Substrate

31. Dichloroarenes can be regioselectively monoalkylated 2.3.2. Aryl Derivatives as Substrate

32. Polysubstitution and one pot consecutive cross-coupling can be effected efficiently 2.3.2. Aryl Derivatives as Substrate

33. Various p-electron-deficient heterocycles can be coupled with aryl Grignard reagent 2.3.2. Aryl Derivatives as Substrate

34. 2.3. Grignard Reagents as Coupling Partners 2.3.1. Alkenyl derivatives as substrate 2.3.2. Aryl derivatives as substrate 2.3.3. Alkyl derivatives as substrate 2.3.4. Acyl derivatives as substrate Discovery and Development

35. ß-Hydride elimination and homocoupling are the major setback with the cross-coupling of 1o and 2o alkyl substrates with aryl Grignard reagents 2.3.3. Alkyl Derivatives as Substrate

36. 2.3.3. Alkyl Derivatives as Substrate TMEDA plays a crucial role to reduce ß-hydride elimination and homocoupling

37. 2.3.3. Alkyl Derivatives as Substrate

38. 2.3. Grignard Reagents as Coupling Partners 2.3.1. Alkenyl derivatives as substrate 2.3.2. Aryl derivatives as substrate 2.3.3. Alkyl derivatives as substrate 2.3.4. Acyl derivatives as substrate Discovery and Development

39. 2.3.4. Acyl Derivatives as Substrate

40. 2.3.4. Acyl Derivatives as Substrate Polymer supported Fe-complex can be used to perform heterogeneous catalysis

41. 2.4. Other Organometallic Reagents as Coupling Partners 2.4.1. Organocopper Reagents 2.4.2. Organomanganese Reagents 2.4.3. Organozinc Reagents Discovery and Development

42. 2.4.1. Organocopper Reagents

43. 2.4.1. Organocopper Reagents

44. 2.4.2. Organomanganese Reagents

45. 2.4.3. Organozinc Reagents

46. 3.1. Synthesis of Z-Jasmone and Dihydrojasmone 3.2. Synthesis of Latrunculin B 3.3. Synthesis of R-(+)-Muscopyridine and immuno- suppressive agent FTY720 Application to Target-Oriented Synthesis

47. 3.1. Synthesis of Z-Jasmone and Dihydrojasmone

48. 3.2. Synthesis of Latrunculin B

49. 3.3. Synthesis of R-(+)-Muscopyridine and immuno- suppressive agent FTY720

50. Summary Iron catalysts activate alkenyl, aryl, alkyl and acyl derivatives. Iron catalysts activate aryl chlorides, triflates and tosylates under ligand free conditions. 1o and 2o alkyl halides possessing ß-hydrogens are good substrates. Iron-catalyzed cross-coupling shows excellent functional group tolerance. Iron-catalyzed cross-coupling needs only short reaction (typically 5-30 min) time and are performed at low temperatures (typically -20 oC to 0 oC).

51. Thank you.