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Ramesh Giri Department of Chemistry Brandeis University Waltham, MA 02454 02

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Ramesh Giri Department of Chemistry Brandeis University Waltham, MA 02454 02

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    2. Overview

    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.

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