Recent Development of Iron-CatalyzedCross-Coupling Reactions

Physical Organic Chemistry Laboratory (Nakamura Laboratory)D2 Arimasa Matsumoto

Organic Seminar 2010.06.14

1

Transition-Metal Catalyzed Cross-CouplingTransition-Metal Catalyzed Cross-CouplingReactionsReactions

R

R

R

X

X

X

R–metal

TM cat.

X = I, Br, Cl, OTf, ...

metal = Mg

Zn, Al, Zr

(Kumada-Tamao-Corriu)

(Negishi)

(Suzuki-Miyaura)B

(Migita-Kosugi-Stille)Sn

(Hiyama)Si

• Fundamental reaction for C–C bond formation• Widely Used for the synthesis of natural products,building blocks for supramolecular, and organicdevice etc.• Typically require palladium or nickel as catalyst

Metal-Catalyzed Cross-Coupling Reactions, 2nd Edition; A. Meijere, F. Diederich Ed.; Wiley-VCH: Weinheim, 2004.

2

IronIron asas AttractiveAttractive CatalystCatalyst

• Iron is a cheap,ubiquitous, and non-toxic metal.• Attractive alternativeto expensive and toxicrare metal

market price of rare metal

M. Beller et al. Angew. Chem. Int. Ed. 2008, 47, 3317.

E. Nakamura, N. Yoshikai, J. Org. Chem. 2010, ASAP; J. Wangelin et al.ChemSusChem, 2009, 2, 396.; A. Fürstner et al. Acc.Chem. Res. 2008, 41, 1500.

• Iron as a Lewis acid catalyst are well known. • Reactivity of low-valent iron is still unknown.• There is a possibility of a new reactivity.

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InitialInitial Finding of Finding of The Iron-Catalyzed Cross-The Iron-Catalyzed Cross-Coupling ReactionCoupling Reaction

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

initial reportsK. Tamao, M. Kumada et al. J. Am. Chem. Soc. 1972, 94, 4374.R. J. P. Corriu et al. J. Chem. Soc., Chem. Commun. 1972, 144.

Kumada-Tamao-Corriu Cross-Coupling

XRMgX

orRLi

+Ni or Pd cat.

R

Iron-catalyzed alkenylation of Grignard reagent

4

FeCl3 (0.6 mol%)

THF, rt, 45 min

Br Me

MeMgBr +

(3 equiv)

MeBr

> 95%

or or

Development of Cross-Coupling with Development of Cross-Coupling with Alkenyl-XAlkenyl-X

RMetalFe cat.

X + R

5

Metal–R Fe cat. referencesolventX

G.Cahiez et al.Pure & Appl. Chem. 1996, 68, 669.AlkylMnCl, AlkylMgCl Fe(acac)3 THF/NMPCl, Br, I

M. Julia et al.Tetrahedron Lett. 1982, 23, 2469.PhMgBr, AlkylMgBr Fe(acac)3 THFSO2R

G. A. Molander et al.Tetrahedron Lett. 1983, 24, 5449.ArMgBr Fe(DBM)3 DMEBr, I

P. Knochel et al.Synlett 2006, 407.ArCu(CN)MgCl Fe(DBM)3 THF/DMEOTf, ONf

G.Cahiez et al.Synthesis 1998, 1192.AlkylMgCl Fe(acac)3 THF/NMPOPO(OEt)2

K. Itami, J. Yoshida et al.Org. Lett. 2005, 7, 1219.ArMgBr Fe(acac)3 THFSPh

A. Fürstner et al.J. Org. Chem. 2004, 69, 3949.AlkylMgBr, ArMgBr Fe(acac)3 THF/NMPOTf

Z.-J. Shi et al. J. Am. Chem. Soc. 2009, 131, 14656AlkylMgCl FeCl2/NHC THFOCOtBu

acac = acetylacetone, DBM = dibenzoylmethane, NHC = N-heterocyclic carbene

Cross-Coupling with Aryl-X withCross-Coupling with Aryl-X with Alkyl MetalAlkyl Metal ReagentReagent

A. Fürstner et al. Angew. Chem. Int. Ed. 2002, 41, 609. J. Am. Chem. Soc. 2002, 124, 13856.

Inverse reactivity profile: OTs, Cl > Br > I

L. N. Pridgen et al. J. Org. Chem.. 1989, 54, 1523.

N

n-BuMgBr (1.4 equiv)Fe(acac)3 (4 mol%)

THF, 73 °C,16 hCl

N

n-Bu

85%

X

OMe

O

OMe

O

n-C6H13

n-C6H13MgBr (1.2 equiv)Fe(acac)3 (5 mol%)

THF/NMP0 °C to rt, 5 min

+OMe

O

I 27% 46%X =

Br 38% 50%

Cl > 95% –

OTf > 95% –

OTs > 95% –

R3ZnMgBrR3MnMgCl, R2Mn, RMnCl

also reactive

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Cross-Coupling of Alkyl-X with SpCross-Coupling of Alkyl-X with Sp22 Metal Reagent Metal Reagent

Fe cat. referencesolvent etc.M.Nakamura, E. Nakamura et al.

J. Am. Chem. Soc. 2004, 126, 3686.FeCl3 THF/TMEDA, slow addition

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

Fe(acac)3 Et2O

A. Fürstner et al.Angew. Chem. Int. Ed. 2004, 43, 3955.

[Li(TMEDA)]2[Fe(C2H4)4] THF, low-valent iron

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

[FeCl(salen)] Et2O

P. Gaertner et al.Org. Lett. 2006, 8, 733.

Fe containing ionic liquid Et2O

M.Nakamura, E. Nakamura et al. Synlett. 2005, 1794.

FeCl3 THF, ZnCl2•TMEDA + 2ArMgBr

M.Nakamura et al.Org. Lett. 2009, 11, 4306.

FeCl3 THF, X = TsO, ZnI2•TMEDA + 2ArMgBr

J. Cossy et al.Angew. Chem. Int. Ed. 2007, 46, 6641.

FeCl3 THF/TMEDA, AlkenylMgBr

G. Cahiez et al.Org. lett. 2007, 9, 3253.

Fe(acac)3 THF/TMEDA/HMTA, AlkenylMgBr

P. Vogel et al.Angew. Chem. Int. Ed. 2008, 47, 1305.

Fe(acac)3 THF/NMP, X = SO2Cl

TMEDA = tetramethylethylenediamine, salen = N,N'-ethylenebis(salicylimine), HMTA =hexamethylenetetramine

Alkyl X XMgFe cat.

+ AlkylRX = Cl, Br, I R

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Fe(0)/Fe(II)Fe(0)/Fe(II) or Fe(I)/Fe(III) Mechanismor Fe(I)/Fe(III) Mechanism

oxidativeaddition

reductiveelimination

transmetallation

Ar–R

FeXn

Ar–X

MgX2 RMgX

Fe(0)/Fe(II)cycle

Fe Ar

L

X

LII

[Fe]0

Fe Ar

L

R

LII

oxidativeaddition

reductiveelimination

transmetallation

Ar–R Ar–X

MgX2 RMgX

Fe(I)/Fe(III)cycle

Fe Ar

L

Ar

XIII

Fe Ar

L

Ar

RIII

Fe Ar

L

LI

reductionreduction

Recent calculation study: P.-O. Norrby et al. ChemCatChem 2009, 1, 152.

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Inorganic Grignard ReagentInorganic Grignard Reagent

B. Bogdanović et al. Angew. Chem. Int. Ed. 2000, 39, 4610.

J. Wangelin et al. Angew. Chem. Int. Ed. 2009, 48, 607.

Fe(acac)3 (5 mol%)TMEDA (1.2 equiv)

THF, 0 °C+ Mg+

(1.2 equiv)R1

X

R3 Y

R2

X, Y = Br, Cl

R1

R2

R3

Application to halide-halide coupling

Mg

THF

FeCl2 "Fe(MgX)2"Inorganic Grignard reagent

R–X + Mg R–MgX cat. "Fe(MgX)2"

• Inorganic Grignard reagent prepared from metal halide andmagnesium was good catalyst for preparation of Grignard reagent

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Fe(Fe(––II)/Fe(0) Cycle: Low II)/Fe(0) Cycle: Low Valent Valent Iron-ComplexIron-Complex

A. Fürstner et al. J. Am. Chem. Soc. 2008, 130, 8773.

A. Fürstner et al. Angew. Chem. Int. Ed. 2004, 43, 3955.

Fe(0)*AlkylMgBr

THFdoes not insert to Ar-X

homogeneous solutionreact with Ar-X

K. Jonas et al. Angew. Chem. Int. Ed. 1979, 18, 550.

Li Fe Li

[Li(TMEDA)]2[Fe(C2H4)4]

–II

efficient catalyst precurser

N

NN

N

Ar–R

FeX2

RMgX(R = Et or higher)

Ar–X

MgX2

[Ar–Fe(MgX)][Ar–Fe(MgX)2]

[Fe(MgX)2]

R

RMgX

–II

00

RMgX(R= Me, Ar)

"R4Fe(MgX)2"

R'–X

R'–R

oranoferratemechanism

low-valentredox mechanismR–R

undesiredhomo-coupling

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RadicalRadical MechanismMechanism

radical coupling pathway

complete loss of optical purity

Fe cat.

PhMgX n-C6H13n-C6H13

Br

98% ee rac.

Ph

ring-open in the reaction

Br Fe cat.

PhMgXPh

R. B. Bedford et al.Chem. Commun. 2006, 1398.A. Fürstner et al.Angew. Chem. Int. Ed. 2004, 43, 3955.

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"Fe"

R–X

Ar–R

FeXn

ArMgX Ar–Ar

reduction"Fe"X

R•

electron transfer

(n+1)(n)

elimination

ArMgX

MgX2

transmetallation"Fe"Ar

R•

(n+1)

Fe(II)/Fe(III) Cycle of Iron TMEDA ComplexFe(II)/Fe(III) Cycle of Iron TMEDA Complex

M. Nakamura et al. J. Am. Chem. Soc. 2009, 131, 6078.

Ar FeII

Ar

N

NAr FeIII

Ar

N

N

Br• R

Ar FeII

Br

N

N

R–Br

Ar–R

FeCl3

n LnMgArX

LnMgArX

LnMgX2

Ln = TMEDA

both complex were characterized by X-ray crystallography

N NFe

Ar Ar

N NFe

Br Ar

R-Br R–Ar

Ar = mesithyl ArMgBrMgBr2

R-Br R–Ar

very slow

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Cross-CouplingCross-Coupling forfor Biaryl Biaryl Synthesis ISynthesis I

N

N

PhMgBr (2.3 equiv)Fe(salen)Cl (5 mol%)

THF, –30 °C, 10 min

Cl

N

N

P.Knochel et al. Angew. Chem. Int. Ed. 2005, 44, 1654.

Using heteroaryl chloride

Using aryl copper reagentA. Fürstner et al. J. Am. Chem. Soc. 2002, 124, 13856.

I

R

O PhCu(CN)MgCl (3 equiv)Fe(acac)3 (10 mol%)

DME/THF, rt, 30 min

Br, Cl, OTf are less reactiveOTs has no reactivity

R

O

• Aryl-aryl cross-coupling wasdifficult due to the homodimerization of Grignard reagent.

M. S. Kharasch et al. J. Am. Chem. Soc. 1941, 63, 2316.

MgBrMetal salt

R–X

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Cross-Coupling forCross-Coupling for Biaryl Biaryl Synthesis IISynthesis II

M. Nakamura et al. J. Am. Chem. Soc. 2007, 129, 9844.

N N+

iPr

iPr iPr

iPrCl–

SIPr•HCl

• Fluoride counter anion efficientlysuppress the homo coupling.• Electron-rich aryl chloride also canuse.• The amount of Grignard can reducedto 1.2 equiv by preactivation of cat. byEtMgBr• The reaction rate is slow

Cl MeBrMg+

Me Me Me+ +

Fe salt (5 mol%)SIPr•HCl (15 mol%)

THF, 60 °C, 24 h

98% < 1% 4%FeF3•3H2O

(2.5 equiv)

32% 2% 32%FeCl3

Using fluoride counter anion

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FluorideFluoride Effect inEffect in Cross-Coupling ReactionCross-Coupling Reaction

FeX3 MeBrMg+ Me MeSIPr•HCl (3 equiv)

THF, 0 °C, 12 h

99%

FeF3•3H2O

(20 equiv)

11% (60 °C)

FeCl3(1 equiv)

• DFT calculation also suggest reduction of iron fluoride is difficult.

M. Nakamura et al. J. Am Chem. Soc. 2009, 131, 11949.

L Fe

Ar1F

F

Ar2–X

Ar1–Ar2

FeFn

Ar1MgX

Ar1MgX

MgX2

L = SIPr

MgX

+IIL Fe

Ar1

F

F MgX

+IV

L Fe

X

F

F MgX

+II

X

Ar2

fast reductiveelimination

L Fe

Ar1

F

F MgX

+IV

Ar1

Ar2

Ar1–Ar1trans metallation

oxidative addition(rate limiting step)

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AlkylAlkyl––Alkyl Cross-Coupling ReactionAlkyl Cross-Coupling Reaction

L. L. Chai et al. Adv. Synth. Cat. 2007, 349, 1015.

alkyl–alkyl coupling is challenging due to their β-hydride elimination

O

PPh2 PPh2Xantphos

• Alkyl–alkyl coupling achieved by iron• Bisphosphine ligand is effective tosuppress β-hydride elimination• The yield was still moderate

MgBrBr( )8

( )8

Fe(OAc)2 (3 mol%)Xantphos (6 mol%)

Et2O, rt, 15 min 64%(1.5 equiv)

+

MgBrBr( )8

( )8TM cat.

+

( )8

( )7

etc.

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Iron-Catalyzed CIron-Catalyzed C––N Bond FormationN Bond Formation

M. Taillefer et al. Angew. Chem. Int. Ed. 2007, 46, 934.

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

N H NX+

Fe(acac)3 (30 mol%)CuO (10 mol%)

Cs2CO3 (2 equiv)DMF, 100 °C, 15 h

(1.5 equiv) X = Br, I

NN

up to 91%

Fe–Cu co-catalyst

Fe catalyst ??

Actually, Cu salt in FeCl3 act as catalyst.

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R XH XI+

"impure FeCl3" (10 mol%)

DMEDA or TMHD

K3PO4 or Cs2CO3 or NaOtBu

DMF or toluene,135 °C, 24 h(1.5 equiv)

R

X = NR, O, S

Iron-Catalyzed Iron-Catalyzed Suzuki-Miyaura Suzuki-Miyaura Coupling?Coupling?

R. Franzén et al. Tetrahedron. Lett. 2008, 49, 6679. RETRACTED.

• No one can reproduce, Pd contamination might be possible.

C. Darcel et al. Adv. Synth. Catal. 2009, 351, 1732.

D. J. Young et al. Tetrahedron. Lett. 2008, 49, 5620.

R. B. Bedford, M. Nakamura et al. Tetrahedron. Lett. 2009, 50, 6110.

B(OH)2 Br+

[Fe(py)4]Cl2 (1 mol%)TBAB(1.3 equiv)

K2CO3 (3 equiv)EtOH/H2O, 80 °C, 20 h(1.3 equiv) R = NO2, COMe

R R

99%

B(OH)2 X+

FeCl3 (5 mol%)2-PPh2Py (10 mol%)

KF, KOH (1.5 equiv)15 kbar, THF, 100 °C, 36 h(1.2 equiv)

R R

X = Br, I 67–97%

B(OH)2 X+

FeCl3 (10 mol%)KF (3 equiv)

EtOH, 100 °C, 16 h(2 equiv)

R R

X = Br, I 35–98%

Other report also exist

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Other Type Coupling ReactionsOther Type Coupling Reactions

cat. FeCl3/DMEDA base: CsCO3, C. Bolm et al. Angew. Chem. Int. Ed. 2008, 47, 4862. cat. FeCl3/PPh3 base: K3PO4, B. M. Bhanage et al. Tetrahedron Lett. 2010, 51, 2758.

P. Vogel et al. Tetrahedron Lett. 2008, 49, 5961.

Sonogashira coupling

Mizoroki-Heck reaction

R H RI+

Fe(acac)3 (10 mol%)CuI (10 mol%)

Cs2CO3 (2 equiv)NMP, 140 °C(2 equiv) 79–98%

R H RI+Fe cat.

basetoluene, 135 °C

P. Vogel et al. Adv. Synth. Cat. 2008, 350, 2859.

I+

FeCl2 (20 mol%)

2-PyCOOH (80 mol%)

KOtBu (4 equiv)

DMSO, 60 °C(2 equiv) 43–87%

R R

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SummarySummary

• Iron is a cheap and environmental friendlyalternative to Pd and Ni in cross-coupling reactions.

• In some case, Iron-catalyst has superior reactivitythan Pd and Ni.

• Recent studies partly reveal the mechanism oflow-valent iron catalyst.

• Sometimes, contamination of other metal makes“false-achievement”

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