rameshiron catalyzed reactions

8/3/2019 RameshIron Catalyzed Reactions

1/51

Ramesh Giri

Department of Chemistry

Brandeis University

Waltham, MA 02454

02/11/2005


2/51

1. Introduction

2. Discovery and Development3. Application in Target-Oriented Synthesis

4. Summary

Overview


3/51

1. Introduction

1.1. Cross-Coupling Reactions

1.2. Call for New Catalysts

1.3. Is Iron a Good Candidate?


4/51


R'-X + R-MX'Catalyst

R-R' + MXX'

Substrate Coupling Partner Coupling Product Metal Halide

R = Alkyl, aryl, vinyl, allyl, alkynyl, benzyl

R' = Alkyl, aryl, vinyl, allyl, alkynyl, benzyl, acyl

X = I, Br, Cl, OTf, OTsM = Mg, Zn, Cu, Sn, Si, B

(OrganometallicNucleophile)(OrganicElectrophile)

(Ni or Pd)

i. General Scheme of Cross-Coupling Reactions


5/51


R'-X +Catalyst

R-R' +R-MX' MXX'

Cross-CouplingReactions

Catalyst M R R' X

Kumada-Corriu

(1972)

Ni or Pd Mg Aryl, alkyl, vinyl Aryl, alkyl, vinyl Cl, Br, I, OTs

Sonogashira (1975) Pd/CuI Cu Aryl, alkyl Aryl, alkyl, vinyl Br, I

Negishi (1977) Ni or Pd Zn Aryl, allyl, benzyl,propargyl

Aryl, alkyl, vinyl, alkynyl,benzyl, allyl

Cl, Br, I, OTs

Stille (1978) Pd Sn Aryl, vinyl,benzyl,alkynyl Aryl, alkyl, vinyl, benzyl,allyl, acyl Cl, Br, I, OTs

Suzuki (1979) Pd B Aryl, alkyl Aryl, alkyl, alkynyl Cl, Br, I, OTs

Hiyama (1988) Ni or Pd Si Aryl Aryl, alkyl, vinyl Br, I, OTs

ii. 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.


6/51

iii. 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.


7/51

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.


8/51

1.3. Is Iron a Good Candidate?

Fe catalysts are inexpensive and readily available.

Costs per gramPd(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).


9/51

2. 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


10/51

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. Synthesis1971, 303.

RMgBr + R'BrFe(dbm)3 (0.3 mol%)

RR'

(1 equiv) (3 equiv)THF, 25 oC, 45 min

R R' RR' (%)

Methyl CH3CH=CH 99

Ethyl CH3CH=CH 58

Phenyl PhCH=CH 32

Cyclohexyl CH3CH=CH 54

tert-Butyl CH3CH=CH 27

Ph

O O-

Phdbm


11/51

Kochi, J. K. J. Organomet. Chem.2002, 653, 11.Kochi, J. K. et. al. J. Org. Chem.1976, 41, 502.

2.2. Proposed Catalytic Cycle

i. Proposed Catalytic Cycle I: Iron(I) as a catalytic species

Fe(I)

FeIIIX

R'FeIII

R

R'

R'-X

RMgXMgX2

R-R'

Fe(III) RMgX


12/51


Fe(III) + n CH3MgBr Fe(III - n) + X CH4 + Y C2H6

Kochi, J. K. J. Organomet. Chem.2002, 653, 11.Kochi, J. K. et. al. J. Org. Chem.1975, 40, 599.


13/51

Frstner, A. et. al. J. Am. Chem. Soc.2002, 124, 13856.


ii. Proposed Catalytic Cycle II: Iron(-II) as a catalytic species

MgX2

R'-X

[R'-Fe(0)(MgX)][R'-Fe(0)(MgX)2]

RMgX

R-R'

[Fe(-II)(MgX)2]RMgX

Fe(II)

R


14/51


Frstner, A. et. al. J. Am. Chem. Soc.2002, 124, 13856.Bogdanovic, B. et. al.Angew. Chem. Int. Ed. Engl.2000, 39, 4610.

[Fe(MgX)2] + 2 MgX2FeCl2 + 4 RCH2CH2MgX

2 (RCH2CH3 + RCH=CH2 + RCH2CH2CH2CH2R)


15/51

Frstner, A. et. al. J. Am. Chem. Soc., 2002, 124, 13856.

ii. Proposed Catalytic Cycle II: Iron(-II) as a catalytic species

Evidences for iron(-II)iv. Finely dispersed Fe(0)* particles in THF dissolves slowly on treatment with an excess ofn-C14 H29 MgBr and the

resulting solution catalyzes the cross-coupling reaction.


O

OMe

Cl

O

OMe

n-H29C14

[Fe(MgX)2] cat.

FeClx Fe(0)*3 K

n-C14H29MgBr

(excess)

n-C14H29MgBr

(excess)

O

OMe

Cl No Reaction

Very fast, -60 oC

(Pre-treated)

(x = 2, 3)


16/51


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

Fe(I)

FeIIIBrR'

FeIIIR

R'

R'-Br

RMgBrMgBr2

R-R'

R'-Fe(0)(MgX)R'-Fe(0)(MgX)2

RMgX

R-R'

R

Kochi's Cycle Frstner's Cycle

Fe(-II)R'-Br


17/51


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


18/51








19/51

2.3.1. Alkenyl Derivatives as Substrate

I. Low initial temperature (-20 C) is beneficial

Molander, G. A. et. al. Tetrahedron Lett.1983, 24, 5449.

H

BrH

Ph + PhMgX

Reaction condition: Fe(dbm)3 cat., 1-2 h

DME, -20 oC to rt H

PhH

Ph

(1 equiv) (1 equiv)

H

BrH

Ph+ PhMgX

H

PhH

Ph

(1 equiv)(3 equiv)

THF, 25 oC

(32%)

(90%)


20/51


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

Knochel, P. Synlett2001, 1901.

I. Low initial temperature (-20 C) is beneficial

MgBri-PrMgBr

THF, -20 oC, 1-4 h

R

X

Fe(acac)3 (5 mol%)

THF, -20 oC, 15-30 min

R

NfO

EtO2C

NC

Bu

Bu

NfO Ph

TIPSO Ph

60

73

62

62

I

R1

R2R2

R1

R2

R1

Entry X R R1 R2 Product Yield (%)

I

Br

Br

Bu

Ph

Ph

CN H

H ONf

H OTIPS

1

2

3

4 I Bu CO2Et ONf

O O-

acac


21/51


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

under mild conditions

Br+ OctMgCl

Fe(acac)3 Cat.

-5 oC to 0 oC,15 min Oct

THF: 40%THF-NMP: 87%

Cl

Bu

+ BuMgCl

Bu

Bu

BuBu -5o

C to 0o

C,15 min

THF: 5%THF-NMP: 85%

Fe(acac)3 Cat.

Cahiez, G. et. al. Synthesis, 1998, 1199.

II. NMP as a cosolvent is crucial

NMP

N O


22/51

Cahiez, G. et. al. Synthesis1998, 1199.



AcO Cl( )6AcO C4H9( )6

Cl( )3O C4H9( )3

O

O

Cl

O

C4H9

Br

Cl

C4H9

Cl

Br

Ph CHMgClbPh

Entrya R'X RMgCl R-R' Yield(%)

80

80

79

79

60

1

2

3

4

5

6

aFe(acac)3 (1 mol%), THF-NMP, -5oC to 0 oC, 15 min.

b

Reaction carried out at 20 C for entry 6.

C4H9MgCl

C4H9MgCl

C4H9MgCl

C4H9MgCl

Cl

H

C5H11 OH

76

C12H25MgBr C12H25

H

C5H11OH


23/51

Frstner, A. et. al. J. Org. Chem.2004, 69, 3943.Alami, M. at. al. Tetrahedron Lett.2004, 45, 1881.



O OTf 73

OTf

79EtO

O

CH3MgBr

C14H29MgBr

N

OTf

Boc

OTf

O

O

C14H29MgBr 65

C14H29MgBr 73

MeO

OTf

C14H29MgBr 64

Entrya R'X RMgX R-R' Yield (%)

1

2

3

4

5

6

O Me

C14H29

EtO

O

N

C14H29

Boc

C14H29O

O

MeOC14H29

aFe(acac)3 (5-10 mol%), THF-NMP, -30oC to 0 oC, 15 min to 1 h.

b

6% catalyst and 2equiv BuMgCl used.

C10H21

O P(OEt)2O

C10H21

C4H9

78C4H9MgClb


24/51

Frstner, A. et. al. J. Org. Chem.2004, 69, 3943.


1

2

3

4

aFe(acac)3 (5%), THF-NMP, -30oC, 15 min

OTf

O

O OTf(CH2)3MgBrMeO

(CH2)3MgBrO

O

EtO

OTfO

p-ClC6H4MgBr 66

97

84

67

80

O

O OTf

O

O OTfMe3SiCH2MgBr

R

O

O R

EtO

RO

O

O R

O

O R

MeC CH2CHMgBr

5




25/51

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

Knochel, P. et. al. Synlett2001, 1901.

O

OI

O

HO R

1) i-PrMgBr (5 equiv)

THF, -20 oC, 1h

BrR2) (15 equiv)

m- orp-iodobenzoate m- orp-substituted product

(84-94%) High HPLC purity

MgBrO

HO

R

O

HO

Entry RMgBr R-R' Yield (%)

1

2

RO

HO

MgBr

O

HO

84 (R = Ph)90 (R = Bu)

86 (R = Ph)94 (R = Bu)

Fe(acac)3 (5 mol%)

-20 oC, 30 min

3) TFA/CH2Cl2/H2O (9:1:1)15 min, rt

Resin


III. Fe-Catalyzed Cross-Coupling on Solid Phase


26/51

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

Frstner, A. et. al.J. Org. Chem.2004, 69, 3943.

OTfC4H9MgCl

C4H980%

OTf

C4H9MgCl

C4H953%

O OTf

C14H29MgCl

O C14H29

O OTf C14H29MgCl

O C14H29

67%

17%

aFe(acac)3 (5 mol%), THF-NMP, -30oC, 15 min

Entry a R'X RMgX R-R' Yield (%)

1

2

3

4


IV. Reactivity of Fe-Catalyzed Cross-Coupling


27/51








28/51

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

Entry X Yield (GC, %)

a b

1 I 27 46

2 Br 38 50

3 Cl >95 -

4 OTf >95 -

5 OTs >95 -

Frstner, A. et. al.Angew. Chem. Int. Ed. Engl.2002, 41, 609.

X

OMeO

n-HexMgBrFe(acac)3 (5 mol%)

THF-NMP

0oC to rt, 5 minHex

OMe

O

OMeO+

a, coupling product b, reduction product

2.3.2. Aryl Derivatives as Substrate


29/51


Entrya ArX RMgX X = Cl X = OTf X = OTs

CN

X

CF3

X

Me

X

n-C6H13MgBr

n-C6H13MgBr

n-C14H29MgBr

n-C14H29MgBr

n-C14H29MgBr

X

OMe

OMe

X

O

OMe

O

X

n-C14H29MgBr - -81

1

2

3

4

5

6

91

91

94

0

0

87

80

72

90

81

83

74

75

0

0

Ar-R, Yield (%)

a

Fe(acac)3 (5 mol%), THF-NMP, 0

o

C to rt, 5 min


Triflate is necessary with electron-rich aryl substrates


30/51



Various heterocyclic aryl derivatives react with alkyl Grignard reagents

N

N

SMe

Cl

N

N

N

OMe

Cl

MeO

S

NClN

N

O

O Cl

Entry Ar-X Ar-R Yield (%)

1

2

3a

Ar-X +Fe(acac)3 (5 mol%)

THF-NMP, rt, 15 min

Ar-RRMgBr (R = n-C14H29)

89

60

84

68

N

N N

N

Cl

H

NN N

N

Cl

O

OAcAcO

AcON

N N

N

C14H29

H

85 72

Entry Ar-X Ar-R Yield (%)

N

N

N

OMe

C14H29

MeO

S

NC14H29

N

N

SMe

C14H29

N

N

O

O C14H29

4

5

6

NN N

N

C14H29

O

OAcAcO

AcO

aOne extra equivalent of RMgX is needed.


31/51

Dichloroarenes can be regioselectively monoalkylated

Hocek, M. et. al. J. Org. Chem.2003, 68, 5773.Frstner, A. et. al. J. Org. Chem.2004, 69, 3943.

N

N

Cl

Cl N

N

C6H13

Cl

(83%)

N

N N

N

Cl

ClBz

N

N N

N

CH3

ClBz

1

2

4

1

2

4

(72%)

Cl

Cl

N

N

Cl Cl

C8H17

Cl

N

N

Cl C6H13

(66%)

(77%)


1

2

3

aFe(acac)3 (10%), THF, -78oC, 30 min.

41

2

61

2

6

CH3MgBr

C8H17MgBr

C6H13MgBr

C6H13MgBr



32/51

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

Hocek, M. et. al. J. Org. Chem.2003, 68, 5773.Frstner, A. et. al. J. Am. Chem. Soc.2002, 124, 13856.

N OTf Cl

1. Me2CHCH2MgBr (1.1 equiv)

Fe(acac)3 cat.

THF-NMP, 0 oC, 8 minN

n-C6H13MgBr (excess)

Fe(acac)3 cat.

THF-NMP, 0 oC, 5 min

N

Polysubstitution cross-coupling Consecutive cross-coupling

(73% Yield)

(71% Yield)

2. n-C14H29MgBr

N

N N

N

Bn

Cl

Cl

N

N N

N

Bn

Me

Me

CH3MgBr (3 equiv)

Fe(acac)3 cat.THF-NMP,rt, 8 h

(96% Yield)



33/51

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

Frstner, A. et. al. J. Am. Chem. Soc.2002, 124, 13856.Figadre, B. et. al. Tetrahedron Lett.2002, 43, 3547

Ar'-X + ArMgBr Ar-Ar'Fe(acac)3 (5 mol%)

THF, -30 oC, 10 min

N

N

SMe

Cl

N

N

N

Cl

OMeMeO

N Cl

N

N N

N

Me

Cl

Entry Ar'-X ArMgBr Ar-Ar' Yield (%)

2

3

4

5S MgBr

63

53

60

63

N

N Cl

1

N

MgBr

N

N Ar82

MgBrN

N

N

Ar

OMeMeO

MgBr

MgBr

N

N

SMe

Ar

N

N N

N

Me

Ar

N Ar



34/51







S


35/51

I. -Hydride elimination and homocoupling are the major setback with the cross-coupling of 1o and 2o alkyl

substrates with aryl Grignard reagents

Entry Solvent Product Yield (%)

C D E F*

1 THF/NMP 0.25 0.25 0.24 0.26

2 THF 0.27 0.37 0.20 0.25

3 Et2O 0.60 0.19 0.12 0.12

4 Et2O (reflux) 0.69 0.18 0.09 0.08

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

*Amount after 0.05 mmol (equivalent to catalyst) subtracted.

MgBr

+

Br

Fe(acac)3 (5 mol%)

Solvent, 20 oC, 30 min

(CH2)5Ph

C

+

+

+

E F

D

B

A

(Desired product)

2.3.3. Alkyl Derivatives as Substrate

2 3 3 Alk l D i ti S b t t


36/51


ii. TMEDA plays a crucial role to reduce -hydride elimination and homocoupling

Entrya Additive Product Yield (GC, %)

C D E A F

1 None 5 79 0 4 6

2 Et3N 3 78 0 11 5

3 N-Methyl morpholine 8 72 0 4 5

4 DABCO 20 2 0 75 3

5 NMP 15 3 Trace 79 4

6 TMEDA 71 19 3 Trace 10

Nakamura, E. et. al. J. Am. Chem. Soc.2004, 126, 3686.

aPhMgBr (1.2 equiv), additive (1.2 equiv), 30 min.

Br

+ PhMgBr FeCl3 Cat.THF, Additive

Ph

Ph-Ph+ + +

A B C D E F

Me2N NMe2TMEDA

(Desiredproduct)

-78 oC to 0 oC

30 min

2 3 3 Alk l D i ti S b t t


37/51

Hayashi, T. et. al. Org. Lett.2004, 6, 1297.Nakamura, E. et. al. J. Am. Chem. Soc.2004, 126, 3686.

aFe(acac)3 (5 mmol%).bEt2O, reflux, 30 min.cTHF-TMEDA, 0 oC or 25 oC, 30 min.


ii. TMEDA plays a crucial role to reduce -hydride elimination and homocoupling

Entrya RX ArMgBr R-Ar Yield (%)

MeO

MgBr

F

MgBr

MgBr1b

4c

n-C8H17OTs

n-C8H17Br

n-C8H17Br

50

73

60

X

88

MeO

MgBr

MgBr

X

95 (X = I)94 (X = Br)84 (X = Cl)

2b

3b

5c

6c

7cMgBr

EtO2C(CH2)5I

99 (X = I)99 (X = Br)99 (X = Cl)

n-C8H17Ar

n-C8H17Ar

n-C8H17Ar

Ar

Ar

EtO2C(CH2)5Ar

n-C8H17X97 (X = I)91 (X = Br)

MgBrn-C8H17Ar


38/51







2 3 4 Acyl Derivatives as Substrate


39/51

Frstner, 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.

2.3.4. Acyl Derivatives as Substrate

Cl

OClMg

MgCl 72

MgBrCl

O

Cl

O

( )3

Cl

O

O

OMgBr

( )2

MeO

O

Cl

O

( )3

BnO MgBr ( )6

Cl

O

OAcO

OMgBr

( )2

R

85

88

80

78(ee = 99)


1

2

3

4

5OO

( )3

O

MeO

O O

( )3

6

O O

( )2

OBn( )6

O

OAcO

O

( )2

O

O

( )2

R

SPh

O O

( )2MgBr 95

R X

O+ R'-MgBr

Fe(acac)3 (3 mol%)

THF, -78 oC, 15 to 30 min R R'

O

2 3 4 A l D i ti S b t t


40/51

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. A2000, 161,239.

R Cl

O+ R'-MgX

(3 mol%)

THF, rt, 25 min R R'

OFe(aaema)3

aaema = 2-(acetoacetoxy)ethyl methacrylate

O

( )4 ( )3

(98%, first run)

(94%, recycle)

O

(79%)MgCl

MgClO

( )4

MeOMeO

(63%)

Entry R'X RMgX R-R' Yield (%)

1

2

3

Cl

O

( )4

MgCl( )3

Cl

O

Cl

O

( )4

aaemaO

OO

O O


41/51

2.4. Other Organometallic Reagents as Coupling Partners

2.4.1. Organocopper Reagents

2.4.2. Organomanganese Reagents

2.4.3. Organozinc Reagents


2 4 1 Organocopper Reagents


42/51

Konchel, P. et. al.Angew. Chem. Int. Ed. Engl.2004, 43, 2.



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

O

OMe Fe(acac)3 cat.

THF-NMPrt, 10 min

O

OMe

Cl Ph(Ph-Ph)

(Major)

PhMgBr

+

O

OEt Fe(acac)3 cat.

DME-THF80 oC, 2 h

O

OEt

I Ph

PhCu(CN)MgCl

(28%)

(82%)

2 4 1 Organocopper Reagents


43/51

Konchel, P.Angew. Chem. Int. Ed. Engl.2004, 43, 2.


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

NCu(CN)MgCl

PhCO2Et

N

PhCO2Et

CN

I

85

Entry Ar'-X ArCu(CN)MgCl Ar-Ar' Yield (%)

1

2

3

I O

OEt Cu(CN)MgClTfO 62

OOEt

TfO

CN

I O

Bu 68EtO2C Cu(CN)MgClEtO2C

OBu

FGCu(CN)MgCl

Fe(acac)3 (10 mol%)

DME-THF

25 oC to 80 oC, 0.5 to 4 h FG

FG'I FG'

2 4 2 Organomanganese Reagents


44/51

Cahiez, G. et. al. Tetrahedron Lett.1996, 37, 1773.Cahiez, G. et. al. Pure Appl. Chem. 1996, 68, 53.


2.4.2. Organomanganese Reagents

Bu

I

OctMnClFe(acac)3 (3 mol%)

THF-NMP, rt, 1h

Bu

Oct

>(88%, E 98%)>(90%, Z 98%)

O

OMe

Cl

Fe(acac)3 (3 mol%)

THF-NMP, rt, 10 minb, C14H29MnCl

or

a, (C14H29)2Mn

+

O

OMe

C14H29

c, (C14H29)3MnMgCl

or(a, 98%, b, 96%, c, 98%)

EorZ

2 4 3 Organozinc Reagents


45/51

Knochel, P. et. al.Angew. Chem. Int. Ed. Engl. 1996, 35, 1700.


+ R2ZnFeCl3 (10 mol%)

THF-NMP, -10 oC, 1h

)2Zn

R1 Cl

O

R R1O

Entry R1COCl R2Zn Yield (%)

Cl

O

Cl

O

OPiv

)2Zn

OPiv

)2Zn

Cl

O

( )6

1

2

3

80

82

74

OMeO

Cl

Fe(acac)3 (10 mol%)

THF-NMP, rt, 10 minEt3ZnMgBr+

OMeO

Et

Yield (93%)

2.4.3. Organozinc Reagents

3 A li ti t T t O i t d S th i


46/51

3.1. Synthesis ofZ-Jasmone and Dihydrojasmone

3.2. Synthesis of Latrunculin B

3.3. Synthesis of R-(+)-Muscopyridine and immuno-

suppressive agent FTY720

3. Application to Target-Oriented Synthesis

3 1 Synthesis of Z Jasmone and Dihydrojasmone


47/51

3.1. Synthesis ofZ-Jasmone and Dihydrojasmone

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

O

O

Z-Jasmone

Dihydrojasmone

O

O

OO

O

O

MgI

MgBr

Fe-catalyzedcross-coupling


SPh

O

O

O

(93%)

(93%)

SPh

O

O

O

Fe(acac)3 Cat.

THF, 0 oC, 30 min

Fe(acac)3 Cat.

THF, 0 oC, 30 min

2. NaOH/EtOH

Reflux, 5h

Reflux, 5h

1. AectoneHCl cat.

2. NaOH/EtOH

1. AectoneHCl cat.

3 2 Synthesis of Latrunculin B


48/51

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

3.2. Synthesis of Latrunculin B

O

O

O

HNS

O

OH



Latrunculin B

O

OR

TfO

OOR

MgBr

Fe(acac)3 (10 mol%)

THF, -30 oC

RNS

O

O

RNS

O

ClOFe(acac)3 (1.5 mol%)

(97%)

(85%)

THF, -78 oC to 0 oC

MeMgBr

3.3. Synthesis of R-(+)-Muscopyridine and immuno-


49/51

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

y ( ) py

suppressive agent FTY720

N

Fe-catalyzed cross-coupling

(R)-(+)-Muscopyridine

N

NCl OTf

MgBr

MgBr

1.

Fe(salen)Cl 1 (5 mol%)

THF-NMP 0 oC

2.

(60%) Fe(salen)Cl 1

NFe

N

O O

H H

Cl

H2N

OH

OHImmunosuppressive agent FTY720

O

OFe(acac)3 cat.

O

OTfO

THF-NMP, rt, 2 h

(84%)

Fe-catalyzed cross-coupling

OctMgBr

1. RCM

2. H2/cat.


50/51

Summary

I. Iron catalysts activate alkenyl, aryl, alkyl and acyl derivatives.

II. Iron catalysts activate aryl chlorides, triflates and tosylates under

ligand free conditions.

III. 1o

and 2o

alkyl halides possessing -hydrogens are good substrates.

IV. Iron-catalyzed cross-coupling shows excellent functional group

tolerance.

V. 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).


51/51

Thank you.

rameshiron catalyzed reactions

Documents