Review: B. D. Sherry, A. Fürstner, Acc. Chem. Res. 2008, 41, 1500

vinyl sulfones (Julia, 1982), vinyl halides (Hanack, 1974; Molander, 1983), acid chlorides (Marchese,

1984), allyl phosphates and halides (H. Yamamoto, 1991; Szeimies, 1994),

vinyl halides & phosphates (Cahiez, 1998)

J. Kochi et al., J. Am. Chem. Soc. 1971, 93, 1487

M. S. Kharasch et al. JACS 1941, 63, 2316; G. Vavon et al., Hebd. Sceances Acad. Sci. 1945, 220, 850;

W. C. Percival et al., JACS 1953, 75, 3731

Fe-II: [Ar] 3d8 4s2

Pd0: [Kr] 3d10 4s0

Cu+I: [Kr] 3d10 4s0

Fe0: [Ar] 3d6 4s2

Ni0: [Ar] 3d8 4s2

Ru0: [Kr] 3d6 4s2

RhI: [Kr] 3d8 4s0

IrI: [Xe] 3d8 4s0

A CHEAP METAL FOR A NOBLE TASK ?

X Cross coupling Reduction

I 27% 46%

Br 38% 50%

Cl > 95% ---

OTf > 95% ---

OTs > 95% ---

A. Fürstner et al. Angew. Chem. Int. Ed. 2002, 41, 609; JACS 2002, 124, 13856

for a larger scale application see: A. F. with A. Leitner, G. Seidel, Org. Synth. 2004, 81, 33

A. F. with A. Leitner, M. Méndez, H. Krause, J. Am. Chem. Soc. 2002, 124, 13856

alkyl-MgX >> aryl-MgX (homocoupling)

the reaction is sensitive to steric hindrance

H29C14

SN(iPr)2

O

O

C14H29MeO

OMeO

C14H29

N

N C14H29

NN

H

O

OAcAcO

NAcO

N

NN

C14H29

N

N

R

R = Ph (73%)

R = 2-pyridyl (82%)

94% 90% 81% 93%

67% 72%

R = C14H29 (95%)

for advances in Fe-catalyzed Ar-Ar cross coupling, see: M. Nakamura et al., JACS 2007, 129, 9844

A. F. with B. Scheiper, F. Glorius, A. Leitner, Proc. Natl. Acad. Sci. USA 2004, 101, 11960

F. Glorius et al., ACIE 2004, 43, 2850

A. F. et al., Chem. Eur. J. 2001, 7, 4811

commercially available (Umicore, Evonik)

NCl Cl

NHO

O

BrMgOBn

NCl OBn N

O O

N OBn

N

H

OHN

N

H

N O

HNs

OH

NN

H

N O

HR

R = Ns

R = H

NN

H

N O

HH

Ph

Ru

PCy3

PCy3

Cl

Cl

ee = 94%

Fe(acac)3 cat.

83%

CuI cat.

90%

H2 (120 atm)

Pd(OH)2/C cat.

78%

K2CO3, NaI, 73%

1. Swern, 81%

2. Ph3P=CH2, 82%

HSCH2COOH

LiOH, 84%

then H2

76%

(-)-Isooncinotine

NBr

N O

HNs

MeOH/HOAc

A. F. with G. Seidel, D. Laurich, J. Org. Chem. 2004, 69, 3950

ALTERNATIVE ROUTE TO FTY720

OAc

HO

C8H17MgBr

Fe(acac)3 cat.

OAc

OH

HO

NaHSO4/SiO2

EtOAc/hexane

98% (14 g scale)94% (23 g scale)

O

OTfO

Tf2O, pyridine

84% (9 g scale)

NH2

HO

OH

FTY720

(immunomodulatory, phase III clinical trials)

V. Prelog et al., Helv. Chim. Acta 1946, 29, 1524

previous syntheses: G. Büchi (1957), M. Kumada (1975), H. Nozaki (1980), M. Hesse (1992), M. Ando (2000)

MUSCOPYRIDINE

N NM M

N XX

NCl OTf

Cl N

N

BrMg

[Fe] cat.+ +

N6-heptenyl-MgBr

[Fe] cat.

A. Fürstner, A. Leitner, Angew. Chem. Int. Ed. 2003, 42, 308

for the preparation of the ruthenium indenylidene catalyst see: A. Fürstner et al., Chem. Eur. J. 2001, 7, 4811

since 2005 commercially available: STREM (g-quantities), UMICORE, Hanau (kg-quantities)

N

N

PhPCy3

Ru

PCy3

Cl

Cl

HCl/Et2O

then

+

0.006 M N

H

Cl

H2 (50 atm)

then aq. NaHCO3

N

57% overall

0.13 M

ADMET

polymer

„INTEGRATED„ SYNTHESIS OF MUSCOPYRIDINE

ENOL TRIFLATES

N

C14H29

BOCO

O

Ph O C14H29MeO

C14H29

Me73% 68% 67% 64% 91%

A. F. with B. Scheiper, M. Bonnekessel, H. Krause, J. Org. Chem. 2004, 69, 3943

O O

MeO

84%O O

TfO

MgBr

MeO

Fe(acac)3 (5 mol%)

APPLICATION IN TOTAL SYNTHESIS

A. Fürstner, P. Hannen, Chem. Eur. J. 2006, 12, 3006;

HAcOH

HTfOH

HMeH

O

O

PtCl2 cat.

MeMgBr

Fe(acac)3 cat.

90%

-cubebene

O

toluene, 80°C

92%

A. Fürstner, A. Schlecker, Chem. Eur. J. 2008, 14, 9181

ACID CHLORIDES

OAc

Cl

O

O

O MgBr

Fe(acac)3 (3 mol%)

OAc

O

O

O

78%ee > 99%

O

Cl OMe

96%

MeO

O O

MeO

O O

BnO

88%65%

OOO

O

O

59%

A. F. with B. Scheiper, M. Bonnekessel, H. Krause, J. Org. Chem. 2004, 69, 3943

see also: P. Knochel et al., Angew. Chem. Int. Ed. 2004, 43, 2968 (acyl cyanides)

for the synthesis, biological evaluation and computational analysis of the latrunculins and analogues, see:

A. Fürstner et al., Proc. Natl. Acad. Sci. USA 2005, 102, 8103;

Chem. Eur. J. 2007, 13, 115 and 135

O

OEt

MgBr

OEt

TfO

O

S

RN

O

O

S

PMBN

O Cl

O

Fe(acac)3 cat.

97%

MeMgBr

Fe(acac)3 cat.

80%

O

PMBN

S

O

O

OMeH

O

O

PMBN

S

O

O

OMeH

O

ring closing

alkyne metathesis

O

O

O

HN

S

OH

H

O

Latrunculin B

review: A. Fürstner et al.

Chem. Commun. 2005, 2307

B. D. Sherry, A. Fürstner, Chem. Commun. 2009, 7116

A. Fürstner, M. Méndez, Angew. Chem. Int. Ed. 2003, 42, 5355

A. F. with E. Kattnig, O. Lepage J. Am. Chem. Soc. 2006, 128, 9194

synthesis and biological assessment of a library of analogues: Chem. Eur. J. 2009, 15, 4030

CROSS COUPLING OF ALKYL HALIDES

Br BrMg

X

+

X

94% (X = H)

95% (X = OMe)

93% (X = Ph)

67% (X = Cl)

88% (X = NTMS2)

iron catalyst

R. Martin, A. Fürstner, Angew. Chem. Int. Ed. 2004, 43, 3955

E. Nakamura et al., JACS 2004, 126, 3686

T. Hayashi et al., Org. Lett. 2004, 6, 1297

R. B. Bedford et al., Chem. Commun. 2004, 2822

CHEMOSELECTIVITY

Br

O

OEtPhMgBr, 5 min, -20°C

O

OEt

Li2[Fe(C2H4)4] (5 mol%)

-II

87%

A. F. with R. Martin, Angew. Chem. Int. Ed. 2004, 43, 3955; J. Am. Chem. Soc. 2008, 130, 8773

PhPh

O

OEt

O

Ph

C NPh

Ph N C O

ClPh

PhN

O

87%

83%

91% 88% 90%

86%

PhOEt

O

94%

S. L. Buchwald, C. Bolm, Angew. Chem. Int. Ed. 2009, 48, 5586

ARE YOU SURE IT„S IRON?

Li LFeL LiO

O

LiFe

C. Bolm et al., Angew. Chem., Int. Ed. 2007, 46, 8862

PUZZLING OBSERVATIONS

Li1

C2*C2

C4

Fe1

C1

Li2*Li2

O7*

C9*

C6*

O7

C8*

C6

C3

C9

C8

C5*C5

Li Li

Fe

Li

OEt2

Et2O

Me

LiMe

Li

MeLi

Fe

Me

Me

OEt2

Et2O

MeLi (excess) + FeCl3

Et2O, < -30°C

1/2 ethane

[(Me4Fe) . (MeLi)] [Li(OEt2)]2 + 3 LiCl

A. F. with H. Krause, C. W. Lehmann, Angew. Chem. Int. Ed. 2006, 45, 440

„... the catalytic species produced from the reaction

of iron(III) complexes and methylmagnesium

bromide is highly labile and strongly discourage

attempts at isolation...“

J. Kochi et al., JOC 1975, 40, 599-606

methyl-, phenyl-, vinyl donors lead to

organoferrate complexes which react

with activated electrophiles only

A. Fürstner et al., JACS 2008, 130, 8773

the “Bogdanovic postulate“

(Angew. Chem. Int. Ed. 2000, 39, 4610)

C8*

C10

C7*

C3*C4*

N1*

C6A

N2

C5B*

C1*

C7

Li1*

C2*

Li1

C9

C5A

C6B*

Fe1

N1 C3

N2*

C4

C9*C2

C8

C1

C10*

more than one „active“ species?

ill defined intermetallic cluster

size distribution

extremely air and moisture sensitive

rapidly aging

paramagnetic

K. Jonas et al., Angew. Chem. Int. Ed. Engl.

1979, 18, 549 and 550

Cp2Fe

Li LFeL Li-2

0N

N

LiFe

0O

O

LiFe

0N

N

LiFe

L = TMEDA

formal oxidation states

N

N

LiFe

Br

Fe

C5

C4

C6

C3

C2

D3

C10

C7

D2

C12

Fe1

C13

C1

C9C8

D1

C11

C14C15

Fe

Cl

PMe3

Fe

PMe3

PMe3

C15

C4

C3

C14

N2

C9 C8

Fe1

C11

Li1

C2C1

C5C7

C10

C6

N1

C13

C12

C8

C9

C16

C15

C7

C10

P2

C6

C11

C17

C13

C1

Fe1

C2

C5

P1

D1

C3C4

C14

C12

A. F. with R. Martin, H. Krause, G. Seidel, R. Goddard,

C. W. Lehmann, J. Am. Chem. Soc. 2008, 130, 8773

Li LFeL Li

N

N

LiFe

Fe

Cl

FeFe

Me

FeL L

Cl

Fe

Cl

X-ray

X-ray

X-ray

X-ray

X-ray

isolated

SiMe3Me3Si

Br

X-ray

SiMe3Me3Si

Fe Li

SiMe3

Me3Si

SiMe3

Me3SiFe

X-ray

14-electron (!)

A. F. with R. Martin, H. Krause, G. Seidel, R. Goddard, C. W. Lehmann, J. Am. Chem. Soc. 2008, 130, 8773

C13

C23

C22

C3

Fe1

C24

C21

C14

C12

C4

C2

C5

C1

C15

C11

YET ANOTHER “NOBLE” TASK ?

LiFe L

[Fe]

product

0O

O

LiFe

ferrate catalyst

C15C14C16

C13C11 C12

C10

C4

C3

C5

C27

C3AC2

C25

C24

C6

C26

C23

C9A

N1

C21

C22

C7

C8

C9S1

O2

O1

FERRATE-CATALYZED ALDER-ENE REACTIONS

A. F. with R. Martin, K. Majima, J. Am. Chem. Soc. 2005, 127, 12236

N

Ph

Ts

[CpFe(C2H4)2]Li (5 mol%)

toluene

N

Ph

Ts

94%

ALDER-ENE REACTIONS

M

M

M

THOUGHT EXPERIMENT

N

N

LiFecatalyst:

J. Am. Chem. Soc. 2008, 130, 1992

FERRATE-CATALYZED [5+2] CYCLOADDITIONS

E E

R

R

E E76%, R = H

81%, R = Ph

70%, R = Me

95%, R = TMS

toluene, 80°C

FeN

N

Li

cat.

A. F. with K. Majima, R. Martin, H. Krause, E. Kattnig, R. Goddard, C. W. Lehmann,

J. Am. Chem. Soc. 2008, 130, 1992

OTHER FERRATE-CATALYZED CYCLOADDITIONS

EE

E E

cat.

toluene, 89%

EE

E

E

E E

R R

EE

67% (R = H)

66% (R = SiMe3)

O

O

LiFe

cat.

toluene, 80°C

O

O

LiFe

for early work on Fe(0)-catalyzed Diels-Alder reactions, see: H. tom Dieck, R. Diercks, Angew. Chem. 1983, 95, 801;

J. Fichini et al., Tetrahedron Lett. 1979, 20, 1499; G. dall‘Asta et al., JOC 1968, 33, 3948

C9

C8

C10

C13

C14

C7

C12

C15C5

C6

C16

C11

C1

C35

C2

C28

C4

C27

C3

C30

C34

Fe1

C23

C29 C36C31

C17

C26

C18

C22C24

C33

C32

C19

C25

C21

C20

C38

C37

J. Am. Chem. Soc. 2008, 130, 1992

FeFe

PhPh

Fe

PhPh

PhPh

tolane

pentane

-78°C to 0°C77%

stable 17e complex!

C13

C23

C22

C3

Fe1

C24

C21

C14

C12

C4

C2

C5

C1

C15

C11

0O

O

LiFe

X

RX

R

H

H

X

R

X

R

Alder-ene [5+2]

X

X

Diels-Alder

X

X

[2+2+2]

X

X

A. F. with K. Majima, R. Martin, H. Krause, E. Kattnig, R. Goddard, C. W. Lehmann,

J. Am. Chem. Soc. 2005, 127, 12236; J. Am. Chem. Soc. 2008, 130, 1992

tolerates esters, ketones, sulfonamides,

acetals, ethers, cyclopropanes, remote

alkenes, amines, aryl halides etc

A POOR MAN„S

CATALYST