Ramesh Giri

1
Iron-Catalyzed Cross-Coupling Reactions
Ramesh Giri Department of Chemistry Brandeis
University Waltham, MA 02454 02/11/2005
2
Overview

• Introduction
• Discovery and Development
• Application in Target-Oriented Synthesis
• Summary

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

• General Scheme of Cross-Coupling Reactions

5
1.1. Cross-Coupling Reactions

• Summary of Cross-Coupling Reactions

• Kumada et. al. and Corriu et. al. in 1972
  independently described the first Ni-catalyzed
  cross-coupling of the Grignard reagents with
  alkenyl and aryl halides.

6
1.1. Cross-Coupling Reactions

• Importance of 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. Kochis Pioneering Work
• 2.2. Catalytic Cycle
• 2.3. Grignard Reagents as Coupling Partners
• 2.4. Other Organometallic Reagents as Coupling
  Partners

10
2.1. Kochis Pioneering Work

• Cross-coupling of alkenyl halides with Grignard
  reagents

Kochi, J. K. et. al. J. Am. Chem. Soc. 1971, 93,
1487. Kochi, J. K. et. al. Synthesis 1971, 303.
11
2.2. Proposed Catalytic Cycle

• Proposed Catalytic Cycle I Iron(I) as a
  catalytic species

Kochi, J. K. J. Organomet. Chem. 2002, 653,
11. Kochi, J. K. et. al. J. Org. Chem. 1976, 41,
502.
12
2.2. Proposed Catalytic Cycle

• Proposed Catalytic Cycle I Iron (I) as a
  catalytic species
• Evidences for iron(I)
• ESR spectrum of a solution obtained from the
  reduction of Fe(dba)3 with ethylmagnesium
  bromide, (g) 2.08, is similar to that of the
  paramagnetic hydrido complex, HFe(I)(dppe)2, (g)
  2.085.
• Careful measurement of the formation of methane
  and ethane during the reduction of Fe(acac)3 with
  methylmagnesium bromide suggested the value of n
  2 in the following stoichiometric relationship
• where, n X 2Y. Therefore, Fe(III) goes to
  Fe(I).

Kochi, J. K. J. Organomet. Chem. 2002, 653,
11. Kochi, J. K. et. al. J. Org. Chem. 1975, 40,
599.
13
2.2. Proposed Catalytic Cycle

• Proposed Catalytic Cycle II Iron(-II) as a
  catalytic species

Fürstner, A. et. al. J. Am. Chem. Soc. 2002, 124,
13856.
14
2.2. Proposed Catalytic Cycle

• Proposed Catalytic Cycle II Iron(-II) as a
  catalytic species
• Evidences for iron(-II)
• Structurally well-known Fe(-II) complex
  Na2Fe(CO)4 exists suggesting that iron can exist
  at very low oxidation state.
• FeCl2 reacts with 4 equivalent of RMgX to give a
  new species of the formal composition Fe(MgX)2
  an inorganic Grignard reagent which is
  readily soluble in THF.
• X-ray crystal structure of Cp(dppe)Fe(MgBr)3THF
  has a covalent bond character between the Fe and
  Mg centers suggesting that in Fe(MgX)2, Fe can
  remain covalently bonded to Mg.

Fürstner, A. et. al. J. Am. Chem. Soc. 2002, 124,
13856. Bogdanovic, B. et. al. Angew. Chem. Int.
Ed. Engl. 2000, 39, 4610.
15
2.2. Proposed Catalytic Cycle

• Proposed Catalytic Cycle II Iron(-II) as a
  catalytic species
• Evidences for iron(-II)
• Finely dispersed Fe(0) particles in THF
  dissolves slowly on treatment with an excess of
  n-C14H29MgBr and the resulting solution catalyzes
  the cross-coupling reaction.

Fürstner, A. et. al. J. Am. Chem. Soc., 2002,
124, 13856.
16
2.2. Proposed Catalytic Cycle

• Is Fe(I) or Fe(-II) the active catalytic species?

17
Discovery and Development

• 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

• Reaction Condition Optimization
• Substrate Scope
• Functional Group Tolerance

18
Discovery and Development

• 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

19
2.3.1. Alkenyl Derivatives as Substrate

• Low initial temperature (-20 C) is beneficial

Molander, G. A. et. al. Tetrahedron Lett. 1983,
24, 5449.
20
2.3.1. Alkenyl Derivatives as Substrate

• Low initial temperature (-20 C) is beneficial

• Less stable functionalized aryl Grignard reagents
  can be coupled at low temperature

Knochel, P. Synlett 2001, 1901.
21
2.3.1. Alkenyl Derivatives as Substrate

• NMP as a cosolvent is crucial

• NMP as a cosolvent with THF is determinant to
  carry out the reaction in high yields and under
  mild conditions

Cahiez, G. et. al. Synthesis, 1998, 1199.
22
2.3.1. Alkenyl Derivatives as Substrate

• NMP as a cosolvent is crucial

Cahiez, G. et. al. Synthesis 1998, 1199.
23
2.3.1. Alkenyl Derivatives as Substrate

• NMP as a cosolvent is crucial

Fürstner, A. et. al. J. Org. Chem. 2004, 69,
3943. Alami, M. at. al. Tetrahedron Lett. 2004,
45, 1881.
24
2.3.1. Alkenyl Derivatives as Substrate

• NMP as a cosolvent is crucial

Fürstner, A. et. al. J. Org. Chem. 2004, 69, 3943.
25
2.3.1. Alkenyl Derivatives as Substrate

• Fe-Catalyzed Cross-Coupling on Solid Phase

• Iron-catalyzed reactions can be carried out on
  solid phase supports

Knochel, P. et. al. Synlett 2001, 1901.
26
2.3.1. Alkenyl Derivatives as Substrate

• Reactivity of Fe-Catalyzed Cross-Coupling

• Iron-catalyzed cross-coupling is sensitive to
  steric hindrance exerted by ortho-substituents

Fürstner, A. et. al. J. Org. Chem. 2004, 69, 3943.
27
Discovery and Development

• 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

28
2.3.2. Aryl Derivatives as Substrate

• Aryl chlorides, triflates and tosylates are
  better substrates than aryl bromides and iodides

Fürstner, A. et. al. Angew. Chem. Int. Ed. Engl.
2002, 41, 609.
29
2.3.2. Aryl Derivatives as Substrate

• Triflate is necessary with electron-rich aryl
  substrates

Fürstner, A. et. al. Angew. Chem. Int. Ed. Engl.
2002, 41, 609.
30
2.3.2. Aryl Derivatives as Substrate

• Various heterocyclic aryl derivatives react with
  alkyl Grignard reagents

aOne extra equivalent of RMgX is needed.
Fürstner, A. et. al. J. Am. Chem. Soc. 2002, 124,
13856.
31
2.3.2. Aryl Derivatives as Substrate

• Dichloroarenes can be regioselectively
  monoalkylated

Hocek, M. et. al. J. Org. Chem. 2003, 68,
5773. Fürstner, A. et. al. J. Org. Chem. 2004,
69, 3943.
32
2.3.2. Aryl Derivatives as Substrate

• Polysubstitution and one pot consecutive
  cross-coupling can be effected efficiently

Hocek, M. et. al. J. Org. Chem. 2003, 68,
5773. Fürstner, A. et. al. J. Am. Chem. Soc.
2002, 124, 13856.
33
2.3.2. Aryl Derivatives as Substrate

• Various p-electron-deficient heterocycles can be
  coupled with aryl Grignard reagent

Fürstner, A. et. al. J. Am. Chem. Soc. 2002, 124,
13856. Figadère, B. et. al. Tetrahedron Lett.
2002, 43, 3547
34
Discovery and Development

• 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

35
2.3.3. Alkyl Derivatives as Substrate

• ß-Hydride elimination and homocoupling are the
  major setback with the cross-coupling of 1o and
  2o alkyl substrates with aryl Grignard reagents

Amount after 0.05 mmol (equivalent to catalyst)
subtracted.
Hayashi, T. et. al. Org. Lett. 2004, 6, 1297.
36
2.3.3. Alkyl Derivatives as Substrate

• TMEDA plays a crucial role to reduce ß-hydride
  elimination and homocoupling

aPhMgBr (1.2 equiv), additive (1.2 equiv), 30
min.
Nakamura, E. et. al. J. Am. Chem. Soc. 2004, 126,
3686.
37
2.3.3. Alkyl Derivatives as Substrate

• TMEDA plays a crucial role to reduce ß-hydride
  elimination and homocoupling

aFe(acac)3 (5 mmol). bEt2O, reflux, 30 min.
cTHF-TMEDA, 0 oC or 25 oC, 30 min.
Hayashi, T. et. al. Org. Lett. 2004, 6, 1297.
Nakamura, E. et. al. J. Am. Chem. Soc. 2004,
126, 3686.
38
Discovery and Development

• 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

39
2.3.4. Acyl Derivatives as Substrate
Fürstner, et. al. A. J. Org. Chem. 2004, 69,
3943. Marchese, G. et. al. J. Organomet. Chem.
1991, 405, 53. Marchese, G. et. al. Tetrahedron
Lett. 1987, 28, 2053.
40
2.3.4. Acyl Derivatives as Substrate

• Polymer supported Fe-complex can be used to
  perform heterogeneous catalysis

Marchese, G. et. al. J. Mol. Catal. A 2000, 161,
239.
41
Discovery and Development

• 2.4. Other Organometallic Reagents as Coupling
  Partners
• 2.4.1. Organocopper Reagents
• 2.4.2. Organomanganese Reagents
• 2.4.3. Organozinc Reagents

42
2.4.1. Organocopper Reagents

• Aryl-aryl cross-coupling can be achieved using
  organocopper reagents

Konchel, P. et. al. Angew. Chem. Int. Ed. Engl.
2004, 43, 2. Fürstner, A. et. al. Angew. Chem.
Int. Ed. Engl. 2002, 41, 609.
43
2.4.1. Organocopper Reagents

• Aryl-aryl cross-coupling can be achieved using
  organocopper reagents

Konchel, P. Angew. Chem. Int. Ed. Engl. 2004, 43,
2.
44
2.4.2. Organomanganese Reagents
Cahiez, G. et. al. Tetrahedron Lett. 1996, 37,
1773. Cahiez, G. et. al. Pure Appl. Chem. 1996,
68, 53. Fürstner, A. et. al. J. Am. Chem. Soc.
2002, 124, 13856.
45
2.4.3. Organozinc Reagents
Knochel, P. et. al. Angew. Chem. Int. Ed. Engl.
1996, 35, 1700. Fürstner, A. et. al. J. Am. Chem.
Soc. 2002, 124, 13856.
46
Application to Target-Oriented Synthesis

• 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

47

• 3.1. Synthesis of Z-Jasmone and Dihydrojasmone

Marchese, G. et. al. Tetrahedron Lett., 1988, 29,
3587.
48

• 3.2. Synthesis of Latrunculin B

Fürstner, A. et. al. Angew. Chem. Int. Ed. 2003,
42, 5358.
49

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

Fürstner, A. et. al. Angew. Chem. Int. Ed. 2003,
42, 308. Fürstner, A. et. al. J. Org.Chem. 2004,
69, 3950.
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).

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Thank you.