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Iron-Catalyzed Cross Coupling – The Work of Alois

Fürstner

Literature meetingJanuary 27th, 2009

Brice Stenne

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).

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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 oC)- Really effective !

Iron salts are:

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Some Applications in Total Synthesis

FTY720Seidel, G. Laurich, D. Fürstner, A. J. Org. Chem., 2004, 69, 3950-3952

(-)-cubebeneFürstner, A.; Hannen, P. Chem. Eur. J. 2006, 12, 3006–3019.

Hamajima, A.; Isobe, M. Org. Lett. 2006, 8, 1205–1208.

Ciguatoxin (right part)

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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.

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Mechanism proposed:

Propagating iron species still elusive! Is it a Fe0, FeI species or a “super-ate” complexes of FeII.

Smith, R.S. M. Kochi, J. J. Org. Chem, 1975, 41, 1976.

An Overview of Some Pioneering Work

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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!

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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!

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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.

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Cross- Coupling Reactions With Aryl Halides and Grignard

Reagents

Fürstner A., Leitner, A. Angew. Chem. Int. Ed. 2002, 41, 609.

[Fe(Salen)Cl]

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Fürstner A., Leitner, A. Angew. Chem. Int. Ed. 2002, 41, 609.

Cross- Coupling Reactions With Aryl Halides and Alkyl Grignard

Reagents

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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:

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Cross- Coupling Reactions With Heteroaryl Halides and Alkyl

Grignard Reagents

Fürstner A., Leitner, A. Mendez M. J. Am. Chem. Soc. 2002, 124, 13856-13863.

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Fürstner A., Leitner, A. Mendez M. J. Am. Chem. Soc. 2002, 124, 13856-13863.

Cross- Coupling Reactions With Aryl Halides and Aryl Grignard

Reagents

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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 Me3SiCH2MgBr have successfully been cross coupled!

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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 0oC,

Yellow in solution

(excess)

Methyl case:

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Is There Another Mechanism?

Fürstner A., Krause, H., Lehmann, C.W. Ang. Int. Ed. 2006, 45, 440-444.

[(Me4Fe)(MeLi)][Li(OEt2)]2

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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%

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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 0oC,

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.

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Fürstner A., Krause, H., Lehmann, C.W. Ang. Int. Ed. 2006, 45, 440-444.

Is There Another Mechanism?

[(Ph4Fe)][Li(OEt2)2][Li(1,4-dioxane)]

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Summary for "in Situ" Conditions

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

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Cross-Coupling Reactions With Acid Chlorides and Grignard

Reagents

Scheiper, B. Bonnekessel, M. Krause, H., Fürstner A. J. Org. Chem. 2004, 69, 3943-3949.

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A Mechanistic Study for Fe-II

Ruben, M. Fürstner, A., Leitner, A. Angew. Chem. Int. Ed. 2004, 43, 3955-3957.

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Cross- Coupling Reaction With Alkyl Halides and Aryl Grignard

Reagents

Ruben, M. Fürstner, A., Leitner, A. Angew. Chem. Int. Ed. 2004, 43, 3955-3957.

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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.

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Interconnected Catalytic Redox Cycles

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

R2 = allyl, alkenyl, enol triflate, etc...

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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

Cp2Fe

-II

L = TMEDA

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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?

R2 = allyl, alkenyl, enol triflate, etc...

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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!

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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?R2 = allyl, alkenyl,

enol triflate, etc...

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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.

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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?

R2 = allyl, alkenyl, enol triflate, etc...

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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 FeI/FeIII process possible?

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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

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Interconnected Catalytic Redox Cycles

R2 = allyl, alkenyl, enol triflate, etc...

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Interconnected Catalytic Redox Cycles

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

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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) !!!

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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) !!!

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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/Fe0 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.