Ramesh Giri Department of Chemistry Brandeis University Waltham, MA 02454 02/11/2005

Overview
1. Introduction 2. Discovery and Development 3. Application in Target-Oriented Synthesis 4. Summary

1.

Introduction

1.1. Cross-Coupling Reactions 1.2. Call for New Catalysts 1.3. Is Iron a Good Candidate?

1.1. Cross-Coupling Reactions

i. General Scheme of Cross-Coupling Reactions

R'-X Substrate (Organic Electrophile)

R-MX'

Catalyst (Ni or Pd)

R-R' Coupling Product

MXX' Metal Halide

Coupling Partner (Organometallic Nucleophile)

R = Alkyl, aryl, vinyl, allyl, alkynyl, benzyl R' = Alkyl, aryl, vinyl, allyl, alkynyl, benzyl, acyl X = I, Br, Cl, OTf, OTs M = Mg, Zn, Cu, Sn, Si, B

1.1. Cross-Coupling Reactions

ii. Summary of Cross-Coupling Reactions
Kumada et. al. and Corriu et. al. in 1972 independently described the first Ni-catalyzed crosscoupling of the Grignard reagents with alkenyl and aryl halides.

R'-X
Cross-Coupling Reactions Kumada-Corriu (1972)

R-MX'
M Mg Cu Zn

Catalyst
R

R-R'

MXX'
R' X Cl, Br, I, OTs Br, I Cl, Br, I, OTs

Catalyst Ni or Pd

Aryl, alkyl, vinyl Aryl, alkyl Aryl, allyl, benzyl, propargyl Aryl, vinyl,benzyl, alkynyl Aryl, alkyl Aryl

Aryl, alkyl, vinyl Aryl, alkyl, vinyl Aryl, alkyl, vinyl, alkynyl, benzyl, allyl Aryl, alkyl, vinyl, benzyl, allyl, acyl Aryl, alkyl, alkynyl Aryl, alkyl, vinyl

Sonogashira (1975) Pd/CuI Negishi (1977) Ni or Pd

Stille (1978)

Pd

Sn

Cl, Br, I, OTs

Suzuki (1979) Hiyama (1988)

Pd Ni or Pd

B Si

Cl, Br, I, OTs Br, I, OTs

1.1. Cross-Coupling Reactions

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.

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.

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).

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

2.1. Kochis Pioneering Work

Cross-coupling of alkenyl halides with Grignard reagents

RMgBr + R Br (1 equiv) (3 equiv)

R Methyl Ethyl Phenyl Cyclohexyl tert-Butyl

'

Fe(dbm)3 (0.3 mol%) THF, 25 C, 45 min

R' CH3CH=CH CH3CH=CH PhCH=CH CH3CH=CH CH3CH=CH
o

RR'

O OPh dbm Ph

RR' (%) 99 58 32 54 27

Kochi, J. K. et. al. J. Am. Chem. Soc. 1971, 93, 1487. Kochi, J. K. et. al. Synthesis 1971, 303.

2.2. Proposed Catalytic Cycle

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

Fe(III) R-R'

RMgX

Fe(I)

R'-X

R Fe
III

X FeIII R' RMgX

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

R' MgX2

2.2. Proposed Catalytic Cycle

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.

2.2. Proposed Catalytic Cycle

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

Fe(II) R-R'

RMgX

[Fe(-II)(MgX)2] R'-X

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

MgX2 [R'-Fe(0)(MgX)]

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

2.2. Proposed Catalytic Cycle

2 (RCH2CH3 + RCH=CH2 + RCH2CH2CH2CH2R) FeCl2 + 4 RCH2CH2MgX [Fe(MgX)2] + 2 MgX2

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

2.2. Proposed Catalytic Cycle

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 of n-C14 H29 MgBr and the resulting solution catalyzes the cross-coupling reaction.

O OMe FeClx (x = 2, 3) 3K Fe(0)* Cl No Reaction

n-C14H29MgBr (excess) O OMe Cl

n-C14H29MgBr (excess) (Pre-treated) O

[Fe(MgX)2] cat. Very fast, -60 oC n-H29C14

OMe

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

2.2. Proposed Catalytic Cycle

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

R-R'

Fe(I)

R'-Br R-R'

Fe(-II)

R'-Br

R Fe
III

R' MgBr2

Fe

III

Br

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

R'

RMgBr

RMgX Frstner's Cycle

Kochi's Cycle

2. 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

2. 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

2.3.1. Alkenyl Derivatives as Substrate

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

Ph

H Br (3 equiv) Ph H H Br

+ PhMgX (1 equiv) + PhMgX (1 equiv)

THF, 25 oC

Ph

H Ph (32%) DME, -20 oC to rt Ph H H Ph

(1 equiv)

(90%)

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

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

2.3.1. Alkenyl Derivatives as Substrate

I. Low initial temperature (-20 C) is beneficial
Less stable functionalized aryl Grignard reagents can be coupled at low temperature

R2 R
1

i-PrMgBr THF, -20 oC, 1-4 h

R2 R1

MgBr

R X

R2 R1

O-

Fe(acac)3 (5 mol%) THF, -20 oC, 15-30 min

acac

Entry

R1

R2

Product Bu

Yield (%)

Bu

CN

H NC NfO Ph

60

Br

Ph

ONf TIPSO Ph

62

Br

Ph

OTIPS EtO2C NfO Bu

62

Bu

CO2Et

ONf

73

Knochel, P. Synlett 2001, 1901.

2.3.1. Alkenyl Derivatives as Substrate

II. 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
N O

Br

OctMgCl

Fe(acac)3 Cat. -5 oC to 0 oC,15 min THF: THF-NMP: Oct 40% 87% Bu Bu 5% 85% Bu

NMP

Bu Bu Cl + BuMgCl

Fe(acac)3 Cat. -5 oC to 0 oC,15 min THF: THF-NMP:

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

2.3.1. Alkenyl Derivatives as Substrate

II. NMP as a cosolvent is crucial
Entrya 1 Cl 2 3 4 5 C5H11 6
a

R'X O

RMgCl C4H9MgCl

R-R' O C4H9

Yield(%) 79

AcO( ) Cl 6 O ( )3 Cl Br H OH Cl Cl

C4H9MgCl C4H9MgCl C4H9MgCl

AcO ( ) O

C4H9

80 80 79 76 C12H25 60

( )3 C4H9 Cl C4H9

C12H25MgBr CHMgClb

H C5H11 Ph OH

Ph Br

Fe(acac)3 (1 mol%), THF-NMP, -5 oC to 0 oC, 15 min. b Reaction carried out at 20 C for entry 6.

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

2.3.1. Alkenyl Derivatives as Substrate

II. NMP as a cosolvent is crucial
Entrya 1 O R'X OTf RMgX CH3MgBr O O C14H29MgBr OTf 3 Boc N OTf 4 O O OTf MeO 5 6 C10H21 O P(OEt)2 O C14H29MgBr C4H9MgClb C10H21 C4H9 MeO C14H29MgBr C14H29MgBr Boc N C14H29 O O C14H29 64 65 EtO C14H29 73 R-R' Me C14H29 79 Yield (%) 73

O 2 EtO

OTf

78

a b

Fe(acac)3 (5-10 mol%), THF-NMP, -30 oC to 0 oC, 15 min to 1 h. 6% catalyst and 2equiv BuMgCl used. Frstner,

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

2.3.1. Alkenyl Derivatives as Substrate

II. NMP as a cosolvent is crucial
Entrya 1 O EtO O O O O O O
a

R'X OTf

RMgX p-ClC6H4MgBr

R-R' R

Yield (%) 66

OTf

MeC CH2CHMgBr

O EtO O O O O O O

97 R

OTf

MeO O O

(CH2)3MgBr

84

OTf

(CH2)3MgBr

67

OTf

Me3SiCH2MgBr

80

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

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

2.3.1. Alkenyl Derivatives as Substrate

III. Fe-Catalyzed Cross-Coupling on Solid Phase
Iron-catalyzed reactions can be carried out on solid phase supports
1) i-PrMgBr (5 equiv) THF, -20 oC, 1h R (15 equiv) 2) Br Fe(acac)3 (5 mol%) -20 oC, 30 min 3) TFA/CH2Cl2/H2O (9:1:1) 15 min, rt RMgBr O 1 HO MgBr MgBr 2 HO O HO O O HO R-R' R R 86 (R = Ph) 94 (R = Bu)

O O
Resin

O HO R

m- or p-iodobenzoate

m- or p-substituted product (84-94%) High HPLC purity Yield (%) 84 (R = Ph) 90 (R = Bu)

Entry

Knochel, P. et. al. Synlett 2001, 1901.

2.3.1. Alkenyl Derivatives as Substrate

IV. Reactivity of Fe-Catalyzed Cross-Coupling
Iron-catalyzed cross-coupling is sensitive to steric hindrance exerted by ortho-substituents

Entry a 1

R'X OTf

RMgX C4H9MgCl

R-R' C4H9

Yield (%) 80%

2 O 3

OTf

C4H9MgCl O C14H29MgCl

C4H9

53%

OTf

C14H29 67%

4
a

OTf

C14H29MgCl

C14H29

17%

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

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

2. 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

2.3.2. Aryl Derivatives as Substrate

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

O OMe X

n-HexMgBr O O Fe(acac)3 (5 mol%) OMe + OMe THF-NMP Hex 0oC to rt, 5 min a, coupling product b, reduction product

Entry 1 2 3 4 5

X a I Br Cl OTf OTs 27 38 >95 >95 >95

Yield (GC, %) b 46 50 -

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

2.3.2. Aryl Derivatives as Substrate

Triflate is necessary with electron-rich aryl substrates
Entrya 1 X 2 3 4 X CF3 X Me X OMe 5 X 6 O
a

ArX O OMe CN

RMgX n-C6H13MgBr n-C6H13MgBr n-C14H29MgBr n-C14H29MgBr

Ar-R, Yield (%) X = Cl X = OTf X = OTs 91 87 83

91 94 0

80 72 81

74 75 0

n-C14H29MgBr OMe X n-C14H29MgBr

90

81

Fe(acac)3 (5 mol%), THF-NMP, 0 oC to rt, 5 min

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

2.3.2. Aryl Derivatives as Substrate

Various heterocyclic aryl derivatives react with alkyl Grignard reagents
Ar-X + RMgBr Entry 1 N Ar-X Cl N SMe N Ar-R C14H29 N SMe 89 4 MeO N N Fe(acac)3 (5 mol%) THF-NMP, rt, 15 min Entry Ar-R (R = n-C14H29) Ar-X Cl N OMe MeO N N Ar-R C14H29 N OMe 84 Yield (%)

Yield (%)

O 2 O N N Cl O N

O 60 N C14H29 Cl 5

N S

Cl

N S

C14H29

68

Cl 3a N N
a

N N H

C14H29 N N N N H

N N 85 6 AcO

N N O OAc

C14H29 N N N AcO AcO N O OAc 72

AcO

One extra equivalent of RMgX is needed. Frstner, A. et. al. J. Am. Chem. Soc. 2002, 124, 13856.

2.3.2. Aryl Derivatives as Substrate

Dichloroarenes can be regioselectively monoalkylated

Entrya 1

R'X Cl Cl

RMgX C8H17MgBr

R-R' C8H17

Yield (%) (77%)

Cl N C6H13MgBr (66%) C6H13 N

2

2 Cl
4

N N Cl N
2

Cl

Cl

N
4

C6H13 (83%) Cl N N Bz (72%) N

1

N
1 6

Cl N

C6H13MgBr

Cl N Bz a Fe(acac)3 (10%), THF, -78 oC, 30 min. Cl

2

CH3 CH3MgBr
1

N
2

Cl

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

2.3.2. Aryl Derivatives as Substrate

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

N (73% Yield)

n-C6H13MgBr (excess) Fe(acac)3 cat. Cl o THF-NMP, 0 C, 5 min N

1. Me2CHCH2MgBr (1.1 equiv) Fe(acac)3 cat. THF-NMP, 0 oC, 8 min OTf 2. n-C14H29MgBr

Polysubstitution cross-coupling Me N Me N N N Bn (96% Yield) CH3MgBr (3 equiv) Fe(acac)3 cat. THF-NMP,rt, 8 h N Cl N Cl N

Consecutive cross-coupling

(71% Yield)

N Bn

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

2.3.2. Aryl Derivatives as Substrate

Various -electron-deficient heterocycles can be coupled with aryl Grignard reagent
Ar'-X + ArMgBr Entry 1 MeO Cl 2 N Cl 3 N N 4 5 N N N Cl N N Me Cl N S MgBr MgBr N SMe MgBr Ar'-X Cl N N N OMe MgBr Fe(acac)3 (5 mol%) THF, -30 oC, 10 min ArMgBr MgBr MeO Ar N N Ar N N N N N Ar N N Me Ar 60 SMe 53 Ar-Ar' Ar-Ar' Ar N N N OMe 63 Yield (%)

82 63

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

2. 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

2.3.3. Alkyl Derivatives as Substrate

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

MgBr A + Br B Fe(acac)3 (5 mol%) Solvent, 20 oC, 30 min

(CH2)5Ph + C (Desired product) + E F D

Entry

Solvent C

Product Yield (%) D 0.25 0.37 0.19 0.18 E 0.24 0.20 0.12 0.09 F* 0.26 0.25 0.12 0.08

1 2 3 4

THF/NMP THF Et2O Et2O (reflux)

0.25 0.27 0.60 0.69

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

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

2.3.3. Alkyl Derivatives as Substrate

ii. TMEDA plays a crucial role to reduce -hydride elimination and homocoupling
Br Ph + PhMgBr FeCl3 Cat. + + THF, Additive B C D -78 oC to 0 oC (Desired 30 min product) + Ph-Ph E F Me2N NMe2 TMEDA

Entrya 1 2 3 4 5 6
a

Additive C None Et3N N-Methyl morpholine DABCO NMP TMEDA 5 3 8 20 15 71

Product Yield (GC, %) D 79 78 72 2 3 19 E 0 0 0 0 Trace 3 A 4 11 4 75 79 Trace F 6 5 5 3 4 10

PhMgBr (1.2 equiv), additive (1.2 equiv), 30 min. Nakamura, E. et. al. J. Am. Chem. Soc. 2004, 126, 3686.

2.3.3. Alkyl Derivatives as Substrate

ii. TMEDA plays a crucial role to reduce -hydride elimination and homocoupling
Entrya 1b
b

RX

n-C8H17OTs n-C8H17Br

ArMgBr MgBr MgBr MeO MgBr F MgBr MgBr MeO MgBr MgBr

R-Ar n-C8H17Ar n-C8H17Ar

Yield (%) 50

73

n-C8H17Br n-C8H17X

n-C8H17Ar n-C8H17Ar EtO2C(CH2)5Ar Ar

60 97 (X = I) 91 (X = Br) 88 99 (X = I) 99 (X = Br) 99 (X = Cl) 95 (X = I) 94 (X = Br) 84 (X = Cl)

5c EtO2C(CH2)5I 6
c

7c
a b

Ar

Fe(acac)3 (5 mmol%). Et2O, reflux, 30 min. c THF-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.

2. 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

2.3.4. Acyl Derivatives as Substrate

O R X
Entrya 1

+ R'-MgBr
R'X O Cl O

Fe(acac)3 (3 mol%) THF, -78 oC, 15 to 30 min

RMgX O O
( )2

O R R'
Yield (%)

R-R' O O
( )2

MgBr

80

SPh O O MeO
( )3

MgBr

O
( )2

95

Cl Cl

BnO ( ) MgBr
6

O O MeO
( )3

( )6

OBn

88

O 4 5

ClMg

O O MgCl
( )2

72 85 78 (ee = 99)

O O Cl
( )3

Cl O

MgBr O O

O O
( )3

Cl OAc

MgBr ()
2

O O
( )2

OAc

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

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

O R Cl

+ R'-MgX

Fe(aaema)3 (3 mol%) THF, rt, 25 min

O R R' O

O O O aaema

aaema = 2-(acetoacetoxy)ethyl methacrylate Entry 1 R'X O

( )4

RMgX MgCl ()
3

R-R' O
( )4 ( )3

Yield (%) (98%, first run) (94%, recycle) (79%) O

( )4

Cl O Cl

MgCl

O
( )4

MgCl Cl MeO MeO

(63%)

Marchese, G. et. al. J. Mol. Catal. A 2000, 161, 239.

2. 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

2.4.1. Organocopper Reagents

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

O OMe Cl

O PhMgBr Fe(acac)3 cat. OMe + (Ph-Ph) THF-NMP Ph (Major) rt, 10 min (28%)

O OEt I

PhCu(CN)MgCl Fe(acac)3 cat. DME-THF 80 oC, 2 h

O OEt Ph (82%)

Konchel, P. et. al. Angew. Chem. Int. Ed. Engl. 2004, 43, 2. Frstner, A. et. al. Angew. Chem. Int. Ed. Engl. 2002, 41, 609.

2.4.1. Organocopper Reagents

Aryl-aryl cross-coupling can be achieved using organocopper reagents
FG FG' I Cu(CN)MgCl FG' FG Ar-Ar' CN 1 I I 2 O OEt I 3 O Bu EtO2C Cu(CN)MgCl EtO2C TfO Cu(CN)MgCl TfO O Bu 68 CN N Ph Cu(CN)MgCl CO2Et N Ph 85 CO2Et O OEt 62 Yield (%)

Fe(acac)3 (10 mol%) DME-THF 25 C to 80 oC, 0.5 to 4 h

o

Entry

Ar'-X

ArCu(CN)MgCl

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

2.4.2. Organomanganese Reagents

O OMe Cl +

a, (C14H29)2Mn or Fe(acac)3 (3 mol%) b, C14H29MnCl THF-NMP, rt, 10 min or c, (C14H29)3MnMgCl C14H29

O OMe (a, 98%, b, 96%, c, 98%)

Bu I E or Z

OctMnCl Fe(acac)3 (3 mol%) THF-NMP, rt, 1h

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

Cahiez, G. et. al. Tetrahedron Lett. 1996, 37, 1773. Cahiez, G. et. al. Pure Appl. Chem. 1996, 68, 53. Frstner, A. et. al. J. Am. Chem. Soc. 2002, 124, 13856.

2.4.3. Organozinc Reagents

R1 Cl + R2Zn Entry 1 O 2 3 O OMe Cl + Et3ZnMgBr Fe(acac)3 (10 mol%) THF-NMP, rt, 10 min O ( )6 Cl Cl R1COCl O Cl )2Zn OPiv )2Zn OPiv O FeCl3 (10 mol%) THF-NMP, -10 oC, 1h R2Zn )2Zn R O R1

Yield (%) 80

82 74 O OMe Et Yield (93%)

Knochel, P. et. al. Angew. Chem. Int. Ed. Engl. 1996, 35, 1700. Frstner, A. et. al. J. Am. Chem. Soc. 2002, 124, 13856.

3.

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 immunosuppressive agent FTY720

3.1. Synthesis of Z-Jasmone and Dihydrojasmone

O O O

SPh

MgI Fe(acac)3 Cat. THF, 0 oC, 30 min

O (93%)

1. Aectone HCl cat. 2. NaOH/EtOH Reflux, 5h

Fe-catalyzed cross-coupling O

Z-Jasmone Fe-catalyzed cross-coupling O

O O O

SPh

MgBr Fe(acac)3 Cat. THF, 0 oC, 30 min

O O O (93%)

1. Aectone HCl cat. 2. NaOH/EtOH Reflux, 5h

Dihydrojasmone

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

3.2. Synthesis of Latrunculin B

MgBr TfO O OR Fe(acac)3 (10 mol%) THF, -30 oC Fe-catalyzed cross-coupling O OR (97%) O O RN O Cl S MeMgBr Fe(acac)3 (1.5 mol%) THF, -78 C to 0 C
o o

O O OH S

O RN S

HN

O (85%)

O Latrunculin B

Fe-catalyzed cross-coupling

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

3.3. Synthesis of R-(+)-Muscopyridine and immunosuppressive agent FTY720

1.

MgBr N

Fe-catalyzed cross-coupling
H
1. RCM 2. H2/cat.

Cl

OTf

Fe(salen)Cl 1 (5 mol%) THF-NMP 0 oC 2. MgBr

N O

Fe

O Cl

(60%)

(R)-(+)-Muscopyridine

Fe(salen)Cl 1

Fe-catalyzed cross-coupling O O OTf OctMgBr Fe(acac)3 cat. THF-NMP, rt, 2 h O O (84%) OH OH Immunosuppressive agent FTY720 H2N

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

Summary
I. II. Iron catalysts activate alkenyl, aryl, alkyl and acyl derivatives. Iron catalysts activate aryl chlorides, triflates and tosylates under ligand free conditions. III. IV. 1o and 2o alkyl halides possessing -hydrogens are good substrates. 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
o

C to 0 oC).

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