1. 1 Iron-Catalyzed Cross Coupling – The Work of Alois Fürstner Literature meeting January 27 th, 2009 Brice Stenne

2. A Short Portrait of the Man Biography: Alois Fürstner (1962) studied chemistry at the Technical University of Graz, Austria, where he got his Ph.D. in 1987 (Prof. H. Weidmann). After postdoctoral studies with the late Prof. W. Oppolzer in Geneva, he finished his Habilitation in Graz (1992) before joining the Max-Planck- Institut für Kohlenforschung, Mülheim, Germany, in 1993 as a group leader. Since 1998, he is Director at that Institute and is also affiliated with the University of Dortmund. His research interests focus on organometallic chemistry and homogeneous catalysis, with particular emphasis on the application of catalytic tools to the synthesis of bioactive target molecules. Awards: In recognition of his accomplishments, he has received several awards, including the Leibniz award of the German Science Foundation (1999), the Thieme-IUPAC prize (2000), an Arthur C. Cope Scholar Award of the ACS (2002), the Otto-Bayer-Prize (2006), and the Janssen Pharmaceutica Prize for Creativity in Organic Synthesis (2008).

3. 3 Advantages of Using Fe in Cross- Coupling  toxicologically benign  commercially available  cheap  “ligand free”, they don’t need the use of special designed ligands (which can be sensitive to oxygen and moisture) as Pd and Ni.  Need mild reaction condition (r.t or bellow 0 o C)  Really effective ! Iron salts are:

4. 4 Some Applications in Total Synthesis FTY720 Seidel, G. Laurich, D. Fürstner, A. J. Org. Chem., 2004, 69, 3950-3952 (-)-cubebene Fürstner, A.; Hannen, P. Chem. Eur. J. 2006, 12, 3006–3019. Hamajima, A.; Isobe, M. Org. Lett. 2006, 8, 1205–1208. Ciguatoxin (right part)

5. 5 An Overview of Some Pioneering Work Kochi: Require 3 to 5 eq. of alkyl/alkenyl halide Yield vary with the source of iron Tamura, M. Kochi, J. J. Am. Chem. Soc. 1971, 93, 1487- 1489.

6. 6 Mechanism proposed: Propagating iron species still elusive! Is it a Fe 0, Fe I species or a “super-ate” complexes of Fe II. Smith, R.S. M. Kochi, J. J. Org. Chem, 1975, 41, 1976. An Overview of Some Pioneering Work

7. 7 Cahiez, G., Marquais, S. Pure. Appl. Chem.1996, 69, 53- 60. Cahiez, G., Avedissian, H. Synthesys.1998, 1199. Cahiez : Nature of the iron salt is no longer essential Still stereospecific Tolerate FGs (alkyl/aryl bromide, amides, esters and ketones) Need 1 eq. of alkenyl halide. THF: 40% THF-NMP (2 eq.): 87% THF: 5% THF-NMP (9 eq.): 85% An Overview of Some Pioneering Work All this work is limited to alkenyl halides, phosphates and sulfones!

8. 8 Cross- Coupling Reactions With Aryl Halides Bogdanovic, B. Schwickardi, M. Angew. Chem. Int. Ed. 2000, 39, 4610 - 4612. Fürstner A., Martin, R. Seidel, G. Goddard, R. Lehmann, C.W. J. Am. Chem. Soc. 2008, 130, 8773-8787. Black/brown solution There is a way to form a more nucleophilic Fe -II center!

9. 9 Catalytic cycle proposed: Cross- Coupling Reaction With Aryl Halides Black/brown solution Bogdanovic, B. Schwickardi, M. Angew. Chem. Int. Ed. 2000, 39, 4610-4612. Fürstner A., Leitner, A. Angew. Chem. Int. Ed. 2002, 41, 609. Fürstner A., Leitner, A. Mendez M. J. Am. Chem. Soc. 2002, 124, 13856-13863.

10. 10 Cross- Coupling Reactions With Aryl Halides and Grignard Reagents Fürstner A., Leitner, A. Angew. Chem. Int. Ed. 2002, 41, 609. [Fe(Salen)Cl]

11. 11 Fürstner A., Leitner, A. Angew. Chem. Int. Ed. 2002, 41, 609. Cross- Coupling Reactions With Aryl Halides and Alkyl Grignard Reagents

12. 12 Cross- Coupling Reaction With Aryl Halides Bogdanovic, B. Schwickardi, M. Angew. Chem. Int. Ed. 2000, 39, 4610 -4612. Fürstner A., Leitner, A. Angew. Chem. Int. Ed. 2002, 41, 609. Fürstner A., Leitner, A. Mendez M. J. Am. Chem. Soc. 2002, 124, 13856-13863. A Simple Proof Of Concept Is it really happening??? Control experiment:

13. 13 Cross- Coupling Reactions With Heteroaryl Halides and Alkyl Grignard Reagents Fürstner A., Leitner, A. Mendez M. J. Am. Chem. Soc. 2002, 124, 13856-13863.

14. 14 Fürstner A., Leitner, A. Mendez M. J. Am. Chem. Soc. 2002, 124, 13856-13863. Cross- Coupling Reactions With Aryl Halides and Aryl Grignard Reagents

15. 15 Cross-Coupling Reaction With Enol Triflates and Grignard Reagents Scheiper, B. Bonnekessel, M. Krause, H., Fürstner A. J. Org. Chem. 2004, 69, 3943-3949. Even MeMgBr, MeLi and Me 3 SiCH 2 MgBr have successfully been cross coupled!

16. 16 Is There Another Mechanism? Fürstner A., Leitner, A. Mendez M. J. Am. Chem. Soc. 2002, 124, 13856-13863. Fürstner A., Krause, H., Lehmann, C.W. Ang. Int. Ed. 2006, 45, 440-444. Black/brown solution Formation of Fe -II center: Formation of ate-complex : Pyrophoric, unstable above 0 o C, Yellow in solution (excess) Methyl case:

17. 17 Is There Another Mechanism? Fürstner A., Krause, H., Lehmann, C.W. Ang. Int. Ed. 2006, 45, 440-444. [(Me 4 Fe)(MeLi)][Li(OEt 2 )] 2

18. 18 Iron-catalyzed reaction can occur via "iron-ate" complexes in the case of a methyl donor and via highly reduced metal clusters such [Fe(MgX) 2 ] in the case of Grignard reagent that can do β-H elimination. Fürstner A., Krause, H., Lehmann, C.W. Ang. Int. Ed. 2006, 45, 440-444. Control 1: Control 2: Is There Another Mechanism? < 20%

19. 19 Phenyl case: Fürstner A., Krause, H., Lehmann, C.W. Ang. Int. Ed. 2006, 45, 440-444. Black/brown solution Formation of Fe -II center: Pyrophoric, unstable above 0 o C, Yellow in solution Formation of ate-complexe : (excess) Is There Another Mechanism? Iron-catalyzed reaction can occur via "iron-ate" complexes in the case of phenylmagnesium bromide and via highly reduced metal clusters such [Fe(MgX) 2 ] in the case of Grignard reagent that can do β-H elimination.

20. 20 Fürstner A., Krause, H., Lehmann, C.W. Ang. Int. Ed. 2006, 45, 440-444. Is There Another Mechanism? [(Ph 4 Fe)][Li(OEt 2 ) 2 ][Li(1,4-dioxane)]

21. 21 Summary for "in Situ" Conditions Fürstner A., Martin, R. Seidel, G. Goddard, R. Lehmann, C.W. J. Am. Chem. Soc. 2008, 130, 8773-8787.

22. 22 Cross-Coupling Reactions With Acid Chlorides and Grignard Reagents Scheiper, B. Bonnekessel, M. Krause, H., Fürstner A. J. Org. Chem. 2004, 69, 3943-3949.

23. 23 A Mechanistic Study for Fe -II Ruben, M. Fürstner, A., Leitner, A. Angew. Chem. Int. Ed. 2004, 43, 3955-3957.

24. 24 Cross- Coupling Reaction With Alkyl Halides and Aryl Grignard Reagents Ruben, M. Fürstner, A., Leitner, A. Angew. Chem. Int. Ed. 2004, 43, 3955-3957.

25. 25 Single Electron Transfer May Intervene Ruben, M. Fürstner, A., Leitner, A. Angew. Chem. Int. Ed. 2004, 43, 3955-3957. Fürstner A., Krause, H., Lehmann, C.W. Ang. Int. Ed. 2006, 45, 440-444.

26. 26 Interconnected Catalytic Redox Cycles Fürstner A., Martin, R. Seidel, G. Goddard, R. Lehmann, C.W. J. Am. Chem. Soc. 2008, 130, 8773- 8787. R 2 = allyl, alkenyl, enol triflate, etc...

27. 27 Jonas Type Catalyst Fürstner A., Martin, R. Seidel, G. Goddard, R. Lehmann, C.W. J. Am. Chem. Soc. 2008, 130, 8773- 8787. [Fe(cod) 2 ] [Li(dme)] 2 Cp 2 Fe -II L = TMEDA

28. 28 Interconnected Catalytic Redox Cycles Fürstner A., Martin, R. Seidel, G. Goddard, R. Lehmann, C.W. J. Am. Chem. Soc. 2008, 130, 8773- 8787. Is it possible? R 2 = allyl, alkenyl, enol triflate, etc...

29. 29 Mechanistic Studies Fürstner A., Martin, R. Seidel, G. Goddard, R. Lehmann, C.W. J. Am. Chem. Soc. 2008, 130, 8773- 8787. Oxidative addition or radical process? The formation of this complex is instantaneous and show that this ferrate can deliver up to four electrons with suitable organic partners!

30. 30 Interconnected Catalytic Redox Cycles Fürstner A., Martin, R. Seidel, G. Goddard, R. Lehmann, C.W. J. Am. Chem. Soc. 2008, 130, 8773- 8787. Is it possible? R 2 = allyl, alkenyl, enol triflate, etc...

31. 31 Mechanistic Studies Fürstner A., Martin, R. Seidel, G. Goddard, R. Lehmann, C.W. J. Am. Chem. Soc. 2008, 130, 8773- 8787. Oxidative addition or radical process? These iron complexes are capable of inserting into allylic substrates.

32. 32 Interconnected Catalytic Redox Cycles Fürstner A., Martin, R. Seidel, G. Goddard, R. Lehmann, C.W. J. Am. Chem. Soc. 2008, 130, 8773- 8787. Is it possible? R 2 = allyl, alkenyl, enol triflate, etc...

33. 33 Mechanistic Studies Fürstner A., Martin, R. Seidel, G. Goddard, R. Lehmann, C.W. J. Am. Chem. Soc. 2008, 130, 8773- 8787. This implies that radical processes (as manifested in the exo cyclizations) can intervene during the initial reaction of an organic halide with lithium ferrate complex or can be triggered after the formation of an organoiron complex. III Is a Fe I /Fe III process possible?

34. 34 Mechanistic Studies Fürstner A., Martin, R. Seidel, G. Goddard, R. Lehmann, C.W. J. Am. Chem. Soc. 2008, 130, 8773- 8787. III 20 h 2 h

35. 35 Interconnected Catalytic Redox Cycles R 2 = allyl, alkenyl, enol triflate, etc...

36. 36 Interconnected Catalytic Redox Cycles Fürstner A., Martin, R. Seidel, G. Goddard, R. Lehmann, C.W. J. Am. Chem. Soc. 2008, 130, 8773- 8787.

37. 37 You Against Me! Let’s Fight! Fürstner A., Leitner, A. Mendez M. J. Am. Chem. Soc. 2002, 124, 13856-13863 1.22$/g (2.15 $ 10 mmol scale) !!! 16.8$/g (45.50 $ 10 mmol scale) !!!

38. 38 You Against Me! Let’s Fight! 1.22$/g61.0$/g Scheiper, B. Bonnekessel, M. Krause, H., Fürstner A. J. Org. Chem. 2004, 69, 3943- 3949. Katayama, T.; Umeno, M. Chem. Lett. 1991, 2073. (222 $ 10 mmol scale) !!! (2.15 $ 10 mmol scale) !!!

39. 39 Conclusion  Iron catalyzed cross coupling can efficiently couple Csp2– Csp3 centers using catalysts that are non-toxic and of low cost.  Grignard reagents that are prone to β-H elimination are believed to pass through a Fe -II/ Fe 0 catalytic cycle.  Grignard reagents that cannot undergo β-H elimination are believed to occur via organoferrate species.  For other work in this field see Nakamura & Cossy.