Iron Catalyzed Cross-Coupling Reaction:Recent Advances and Primary Mechanism

Wang Chao2010.11.6

General:

CheapEnviromentally benignSustainableUnique reactivity

Genesis:

Kochi: J. Am. Chem. Soc. 1971, 93, 1487

BrMeMgBr

Br

FeCl3 Cat. FeCl3 Cat.

MgBr + BrFeCl3 (5 mol%)

0.106 mol 0.1 mol 47% yield

Kharasch: J. Am. Chem. Soc. 1941, 63, 2316

R1C(O)X + R2M[Fe] (cat)

R1 R2

O

Ph

O

Me

Me

n-C7H15

O

OPiv

Ph

O

Cl

89% yield(X = SPh)

(M = MgBr)

89% yield(X = Cl)

(M = ZnR2)

79% yield(X = CN)

(M = MgCl)

O

OOAc

O

n-C6H13

O

MeMe78% yield(X = Cl)

(M = MgBrl)

90% yield(X = Cl)

(M = MgBrl)

NPMBS

OCl

[Fe(acac)3](1.5 mol%)

MeMgBr, THF-78 to 0oC80% yield

O

NPMBS

OMe

O

Latrunculin A

Acid chlorides as electrophiles

R3

R2

R1

X + R4MgBr[Fe] (cat)

R3

R2

R1

R4

Men-Bu

O

( )3 Me

O

O n-Bu

n-C10H21

OMe

N

n-C14H29

Boc

Ph

O

O

80% yield(X = Cl)

70% yield(X = OTf)

78% yield(X = OP(O)(OEt)2)

66% yield(X = SPh)

73% yield(X = OTf)

68% yield(X = OTf)

Me

HTfO HMe

Me

Me

HMe HMe

Me

Fe(acac)3 (10 mol%)

MeMgBr, THF/NMP, -30oC90% yield

Alkenyl electrophiles

(-)-cubebene (5)

OTf

TfO

catalyst

BnMgCl, THF

Bn

Bn

PhPh

9 10+

菲尔斯特纳 Furstner: Angew. Chem., Int. Ed. 2002, 41, 609

CO2Me

X11

Fe(acac)3 (5 mol%)n-C6H13MgBr

THF/NMP0oC to rt, 5 min

CO2Me

R12

Aryl electrophiles:

N n-C6H13

90% yield, cat Fe(acac)3

88% yield, cat FeCl3

96% yield, cat Fe(salen)Cl

MeO2C

n-C6H13

NC

n-C6H13

91% yield, X = Cl

87% yield, X = OTf

83% yield, X = OTs

91% yield, X = Cl

80% yield, X = OTf

74% yield, X = OTs

n-C14H29

OMe

MeO

0% yield, X = Cl

90% yield, X = OTf

0% yield, X = OTs

n-C14H29

O

81% yield, X = OTf

N

N

n-C6H13

93% yield, X = Cl

allyl, vinyl, and aryl Grignard reagents uniformly led to poor yields in reactions performed with FeX3 (X =Cl, acac) in THF/NMP

CO2Me

Cl11

Fe(acac)3 (cat)n-C9H19MgBr

THF/NMP0oC to rt

CO2Me

R13

7 min, 16 g scale79-84% yield

NCl Cl

OBnBrMg( )6

Fe(acac)3 (cat)THF/NMP

0oC, 83% yield

OBn( )6NCl

NNH

H

NH

O

isooncinotine

a valuable component of liquid-crystalline materials

spermidine alkaloid

Masaharu Nakamura: J. AM. CHEM. SOC. 2007, 129, 9844-9845

ClFeX3 (5 mol%)

p-TolMgBrTHF, 60oC

+

Me

21

22

+

23

Me

24 Me

Alkyl halides

Nakamura, Eiichi: J. AM. CHEM. SOC. 2004, 126, 3686-3687

BrFeCl3 (5 mol%)

PhMgBr (1.2 equiv)additive (1.2 equiv)

THF-78oC to 0oC (30 min)

Ph

+ +1 2 3 4

the high barrier to oxidative addition -hydride elimination

Hayashi: Org. Lett. 2004, 6, 1297–1299.

p-TolMgBr (1a)(2.00 mmol)

Ph(CH2)5Br (2m)(1.00 mmol)

+Fe(acac)3 (5 mol%)

solvent, 20oC, 0.5h

(CH2)5Ph

PhPh

3am

4 5 6

(CH2)3Br

OTf

p-TolMgBrFe(acac)3 (5 mol %)

Et2O, reflux, 0.5 h69% TfO

n-C4H9MgBrFe(acac)3 (5 mol %)

THF/NMP, 20oC, 0.5h

90%

Angew. Chem. Int. Ed. 2004, 43, 3955 –3957

L = TMEDA

RX + PhMgBr

[Fe(C2H4)4][Li(tmeda)]25 mol%

THF, -20oCR Ar

PhPhNC

( )6PhOCN

( )3

PhCl( )4

Ph

Et

O

EtO EtO

O

Ph

Me Ph

Me Me

Ph( )3

O

Ph

94% yield(X = Br)

83% yield(X = I)

90% yield(X = I)

86% yield(X = I)

94% yield(X = Br)87% yield

(X = Br)

87% yield(X = Cl)

91% yield(X = I)

PhN

O

87% yield(X = I)

[FeCl (salen)]

Cahiez: Angew. Chem. Int. Ed. 2007, 46, 4364 –4366

Bedford: Chem. Commun.2004, 2822–2823.

N N

O OFe

Cl

Me Et

Br[(FeCl3)2(tmeda)3]

(1.5 mol%)

PhMgBr (1.3 equiv)20oC, THF, 90 min

78% yield, 0.1 mol scale

Me Et

Ph

Bedford: J. Org. Chem. 2006, 71, 1104-1110

Iron-Phosphine, -Phosphite, -Arsine, and -Carbene Catalysts

PPh3

PCy3

AsPh3

P(OPh)3

P(OMe)3

Ph2P PPh2

Ph2PPPh2

Ph2P PPh2

Ph2P

PPh2

Ph2P PPh2

Ph2As AsPh2

Pt-Bu

t-BuP

Cy

Cy

Ph2P PPh2

N NCy Cy

Cl-

N Nt-Bu t-Bu

Cl-N NMes Mes

Cl- N NMes Mes

H C6H5

Kochi, J. J. Org. Chem. 1976, 41, 502

Fe(iii)RMgBr

Fe(i)

Mechanism for the cross coupling:

FeI

FeIIIR

CH=CHCH3FeIII

Br

CH=CHCH3

Br

RMgBrMgBr2

R

FeX3

Fe(MgX)2

R1-Fe(MgX)

R1-Fe(MgX)2

R2

R2MgX

R1-X

MgX2

R1-R2

RMgX

Bogdanovic:

four-electron reduction, formal constitution [Fe(MgCl)2]n1:1 mixture of alkene and alkane is formed from the Grignard reagent in the reduction of FeX2, Bogdanovic proposed a -hydride elimination followed by a reductive elimination as two of the elementary steps

1:1 mixture of alkene and alkane is formed from the Grignard reagent in the reduction of FeX2, Bogdanovic proposed a -hydride elimination followed by a reductive elimination as two of the elementary steps in the formation of [Fe(MgX)2]

COOMe

Cl

MeMgBr

Fe(acac)3(5 mol%)

Fe(acac)3(5 mol%)

EtMgBr

no cross coupling

COOMe

>95% yield

J. AM. CHEM. SOC. 2008, 130, 8773–8787Ferrate: 高铁酸盐

Masaharu Nakamura: Hideo Nagashima: J. AM. CHEM. SOC. 2009, 131, 6078–6079

FeCl3

mesityl-MgBrTMEDA N N

Femesityl mesityl

N NFe

Br mesityl

1 2

1-bromooctane octyl-mesitylene

mesityl-MgBrMgBr2

Br

Br

0.06 mmol

+ N NFe

mesityl mesityl

0.05 mmol

THF, 30oC18h

Br+

hexenyl

+

25%63% 0%

+ N NFe

mesityl mesityl

0.10 mmol

THF, 30oC18h0.20 mmol

+

butenyl

17% 55%

Radical cyclization rate 1.0x105M-1S-1

Radical ring open rate 1.3x108M-1S-1

Possible catalytic cycle for the (TMEDA)FeAr2-catalyzed crosscoupling reaction.

Masaharu Nakamura: J. AM. CHEM. SOC. 2010, 132, 10674–10676

features: (1) divalent iron (+II oxidation state),(2) neutral complex, (3) coordinatively unsaturated,(4) having sufficient spin density on the iron center.

Ar BO

OB

O

OR

ArLi+a b, c

(a) RLi, THF, -78 to 0 oC, 1h, (b) R'X(c) cat. 1 or 2, 20 mol% of MgBr2, THF, 0 to 40oC

Cl + BO

OBu

PhLi+

catalystadditive

THF25oC, 4h

Ph

c-Hept

99% yieldX = Br

c-Hept

77% yieldX = Br

Cl c-Hept

90% yieldX = Br

CO2Mec-Hept

98% yieldX = Br

OMe

EtO Ph

O

( )5

90% yieldX = Br

NC( )5

90% yieldX = Br

NMe

Ph Ph

O

( )4

65% yieldX = Br

N

Cl CO2i-Pr

86% yieldX = Cl

Shi, ZJ: J. AM. CHEM. SOC. 2009, 131, 14656–14657

OPiv

CO2Et

+ n-hexylMgX

1a 2

[Fe] (1.0 mol%)ligand (2.0 mol%)

THF, 0oC, 1h

nhexyl

CO2Et

3a

N N

N NCl-

H2IMes HCl

Me2N NMe2

bipy tmeda

Oxidative homo-coupling

Cahiez: J. AM. CHEM. SOC. 2007, 129, 13788-13789

MgBrMeO

THF, rt

conditionsMeO OMe

Dry air: 5%5% FeCl3: 13%

5% FeCl3, dry air: 88%

MeO OMe

88% yield

85% yield72% yield

EtO2C CO2Et

70% yield at -20oC X=Cl

NC CN

MeO

OMe

Bu

BuBu

Bu

60% yield

Ph

Ph

E/E, E/Z, Z/Z = 92:6:268% yield

72% yield at -20oC X=Cl

RMgX

Dry air5% FeCl3

THF, rt, 45minR R

Angew. Chem. Int. Ed. 2009, 48, 2969 –2972

Zn +Br

Fe(acac)3 (5 mol %)TMEDA (1.5 equiv)

THF, 50oC, 30 min

+

81% 11%

Zn

Fe(acac)3 (15 mol %)BrCH2CH2Br (1 equiv)

THF, 50oC, 30 min58%

Zn)2 + iPr2Zn

Fe(acac)3 (15 mol %)BrCH2CH2Br (1 equiv)

THF, 50oC, 30 min96%

Only one Ph group and one iPr group are transfered

ZnMe + iPr2Zn

Fe(acac)3 (10 mol %)BrCH2CH2Br (1 equiv)

THF, rt, 3h79%

ZnMe +Fe(acac)3 (10 mol %)BrCH2CH2Br (1 equiv)

THF, rt, 3hRR2Zn

benzyl-, allyl-, or tertiary alkylzinc give low yields

J. AM. CHEM. SOC. 2008, 130, 5858–5859

N

PhMgBr (6 equiv)ZnCl2 TMEDA (3 equiv)

Fe(acac)3 (10 mol%)1,10-phenanthroline (10 mol%)

ClCl (2 equiv)

THF, 0oC, 16h

N

Ph

99%

N

H

FeCl3 (x mol%)L (x mol%)ZnCl2 TMEDA (y equiv)PhMgBr (2y equiv)

oxidant (z equiv)THF, 0oC

N

Ph

N

Ph

+Ph

L =bpy, oxidant = DCE, x=15, y=4, z=3, 72h 53% 2%

L =bpy, oxidant = DCIB, x=15, y=4, z=3, 24h 82% 9%

L =phen, oxidant = DCIB, x=10, y=3, z=2, 24h 79% 16%

N NN N

ClCl

ClCl

bpy phen DCE DCIB

Cross-coupling based on C-H activation/C-C bond formation:

Cheap iron and mild condition 0oC

Angew. Chem. Int. Ed. 2009, 48, 2925 –2928

X

HN Ar

Ar = 4-MeOC6H4X = Br, Cl, TfO, TsO etc.

+

MgBr

(5-6 equiv)

+ZnCl2 TMEDA(2.5-3 equiv)

[Fe(acac)3] (10 mol%)dtbpy (10 mol%)

ClCl (2 equiv)

THF, 0oC

H+ XO

83-92% yield

R

OPhOPh OPh

OPh

R

OPh

S

96%87% (R = Cl)88% (R = Br)

91% (R = H)92% (R = Cl)83% (R = Br)89% (R = OTf)89% (R = OTs)94% (R = OMe)90% (R = CF3)57% (R = CN)

99%(3%

J. AM. CHEM. SOC. 2010, 132, 5568–5569

O

solvent

cat. Fe(acac)3/dtbpy2 PhMgBr/ZnCl2 TMEDA4-Iodotoluene

O Ph

dtbpy = 4,4'-di-t-butyl- 2,2'-bipyridyl

NCH2

I

1

RMgBr or 2 RMgBr/ZnCl2 TMEDAFe(acac)3 (2.5-5 mol%)

t-BuOMe, Et2O or THFrt or 50oC, 15-30 min

N I

1

HR

NCH2

R[Fe]I

NC

R[Fe]IH

H NC

H

H[Fe] I

R

A B C

R[Fe] -[Fe]I

N

O

I

N IN IO

N N I

I

Substrates with unsuitable type of internal trigger of C-H bond

N

IBn

D DDD

N

IBn

+ArMgBr (2 equiv)Fe(acac)3 (5 mol%)

t-BuOMe, 50oC(Ar = p-FC6H4)

NDD

N+

HAr

DArD

N

IBn

D DDD +

N

IBn

H HHH

NDD +

DArD NH

H

HArH

ArMgBr (0.5 mmol)Fe(acac)3 (2.5 mol%)

t-BuOMe, rt, 5min(Ar = p-FC6H4)

0.5 equiv 0.5 equiv

(IBn = 2-Iodobenzyl)

(IBn = 2-Iodobenzyl)

0.25 mmol 0.25 mmol

0.12 mmol 0.12 mmol

NBn

NBn N

Bn

NBn

Ph

NBn N

BnNBn

NBn

NBn

NBn

PhPh

Ph84% 82% 82%

67% 8%

X

n-C6H13

47%69%70%

91% (X = H)88% (X = Cl)90% (X = OMe) N

88% 54%

NBn

BuPh+

Yu, XQ: Angew. Chem. Int. Ed. 2008, 47, 8897 –8900

NH

NH

HN

HN

1,4,7,10-tetraazacyclododecane

+Br

(HO)2B

[Fe], base

solvent, 135oCBr

Lei AW: Angew. Chem. Int. Ed. 2010, 49, 2004 –2008

BrMeO H+

FeCl3DMEDA

MeO80oC

48hoursbase

MeHN NHMe

Charette: J. AM. CHEM. SOC. 2010, 132, 1514–1516

I H+R R

Fe(OAc)2 (5 mol%)bathophenanthroline (10 mol%)

KOt-Bu (2 equiv)

80 oC, 20h