efﬁcient iron-catalyzed n-arylation of aryl halides with ...ccc.chem.pitt.edu/wipf/current...

1

Efficient Iron-Catalyzed N-Arylation of ArylHalides with Amines

Guo, D.; Huang, H.; Xu, J.; Jiang, H.; Liu, H Org. Lett. ASAP

John MaciejewskiCurrent Literature - 9/27/08

Ar X NR1H

R2

Fe2O3, L-proline, NaOtBu

DMSO

NR1Ar

R2

Recent advances in aromatic carbon-nitrogen bond formation

John Maciejewski @ Wipf Group of 15 10/7/2008

2

Ullmann Reaction

Ma, D.-W.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem.Soc. 1998, 120, 12459.

- Coupling between aromatic halides with either aliphatic and aromatic amines using copper salts and base- Drawbacks: high reaction temperatures (>150 oC) and stoichiometric copper usage- Using ligands that include phosphines, amines, and amino alcohols improve yields and applications- Current methods use readily available ligands, catalytic copper salts at temperatures as low as 40 oC

Ma, D.; Cai, Q. Acc. Chem. Res. ASAP.Yang, M.; Liu, F. J. Org. Chem. 2007, 72, 8969.Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453.Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382.

NHN

O

OH

benzolactam-V8

protien kinase C activator

H2N CO2H

Br

CuI, K2CO3

DMA, 90oC, 48 h

81%

HN CO2H


3

Goldberg Reaction

Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4120 (kinetic study)Deng, W.; Wang, Y.-F.; Zou, Y.; Liu, L.; Guo, Q.-X. Tetrahedron Lett. 2004, 45, 2311 (ligand studies).Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 16911.

- Amidation of aryl halides using primary and secondary amides (cyclic or acyclic)- Drawbacks similar to Ullmann reaction (high temp., strong base and stoichiometric copper salts)- Efficiency of reaction depends on choice of ligand, temperature and base (similar to Ullmann reaction)- Aryl amidation using copper salts is less expensive on industrial scale compared to palladium catalysis

N

OH

I CuI (5 mol%), K3PO4

glycine, dioxane, 100 oC, 24 h

97%

N

O

representative example


4

Mechanism for Ullmann & Goldberg Couplings

- Two possible mechanisms, but oxidation state of copper intermediates are not known- Radical mechanisms have been ruled out- Ligand choice is critical for reaction efficiency

Kurti, Laszlo, Barbara Czako. Strategic Applications of Named Reactions in Organic Synthesis. San Diego: Elsevier, 2005.

XAr1

Cu(I)X

L2Cu(III)

Ar1

X

L2Cu(III)

Ar1

NHAr2

Cu(I)XL2

2 L -2 LZ Ar1

Cu(II)X2

L2Cu(II)

Ar1

Z

L2Cu(II)X2

2 L -2 L

Cu0 ox.

L2Cu(II)

Ar1

HNAr2

Ar1 NAr2

H

oxidative addition

X-H2N Ar2

transmetallation

X-

H2N Ar2

reductiveelimination

reductiveelimination

+ e-

- e-

X = I, Br, ClY = NH2, HNCOR

Z = B(OH)2, BF3K, Sn(R)3Y = NH2, HNCOR


5

Transition-Metal Free Aryl Amination

Beller, M.; Breindl, C.; Riermeier, T. H.; Eichberger, M.; Trauthwein, H Angew. Chem. Int. Ed.,1998, 37, 3389.Beller, M.; Breindl, C.; Riermeier, T. H.; Tillack, A. J. Org. Chem. 2001, 66, 1403 (hydroamination/cyclization studies)

Cl

Ph-NH2

tBuOK, toluene, 135oC

sealed tube, 36 h

N

Ph53%

OMe

OMe

Br KNH2/NH3

C3H7NH2

OMe

OMe

NH

94%

Han, Y. X.; Jovanovic, M. V.; Biehl, E. R.J. Org. Chem. 1985, 50, 1334Biehl, E. R.;Razzuk, A.; Jovanovic, M. V.; Khanapure, S. P.J. Org. Chem. 1986, 51, 5157. (addition of amines, nitriles andmercaptans)

via a benzyne intermediate


6

Mechanism for Benzyne Addition

Shi, L.; Wang, M.; Fan, C.-A.; Zhang, F.-M.; Tu, Y.-Q. Org. Lett. 2003, 5, 3515 (and references therein).

Br

N

OtBuOK

H

N O

amine attack

proton transferdeprotonation/benzyne formation

tBuOH + KBr

BrN

O

tBuOK H

N O

amine attack


tBuOH + KBr

CH3H3C

H3C

N O

H3C

m:p = 1:1

Br

NO

tBuOK HN O

amine attack


tBuOH + KBr

N O

H3C

m:p = 2:1

H3C CH3

N OH

H3C

or

and

and

(1)

(2)

(3)

H3C

BrtBuOK, DMSO

µW

N

O

H

R

N O

R


7

Buchwald-Hartwig Coupling- Kosugi, M.; Kameyama, M.; Migita, T. Chem. Lett. 1983, 927 (Stille-type coupling with amino stannanes)- Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem. Int. Ed. 1995, 34, 1348.- Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609.

OMs

t-Bu

NH2Pd(OAc)2 (1 mol%), 1

t-BuOH, 110 oC

99% t-Bu

N

H

OMe

PCy2

i-Pr

i-Pr

i-Pr

MeO

1

Fors, B. P.; Watson, D. A.; Briscoe, M. R.; Buchwald, S. L. J. Am. Chem. Soc. ASAP

N

O

O

OMOM

CH3

H2N

O

O

OMOM

CH3Br

Br

Pd2(dba)3 (20 mol%)ligand studyt-BuONa (3 equiv)

toluene, 130 oC, 13 h

(sealed tube)

59%

double aryl amination

N O

CH3

murrayazoline1

Ueno, A.; Kitawaki, T.; Chida, N. Org. Lett. 2008, 10, 1999.


8

Buchwald-Hartwig Coupling

Urgaonkar, S.; Xu, J.-H.; Verkade, J. G. J. Org. Chem. 2003, 68, 8416.

- Advantage over Ullmann and Goldberg reactions due to the mild reaction conditions- Ligand choice is critical for the stabilization of the active Pd0 species in catalytic cycle- Broadening reaction scope and new ligand design remains a popular research area

Reddy, C. V.; Kingston, J. V.; Verkade, J. G. J. Org. Chem. 2008, 73, 3047 (aryl chloride coupling)Christensen, H.; Kiil, S.; Dam-Johansen, K. Org. Proc. Res. Dev. 2006, 10, 762.


9

Iron/Copper-catalyzed Aryl AminationI N

HN

Entry Iron (mol%) Copper (mol%) Yield (%)

2 equiv. Cs2CO3, DMF

100 oC, 15 h

Fe/Cu catalyst loadings NN

1 Fe(acac)3 (30) Cu0 (10) 100

2 Cu0 (10) 0

3 Fe(acac)3 (30) 0

Taillefer, M.; Xia, N.; Ouali, A. Angew. Chem. Int. Ed. 2007, 46, 934.

- Various iron catylsts were studied, but Fe(acac)3 worked most efficiently with copper metal- First bimetallic catalysis (Fe/Cu) for N-arylation (works for aryl iodides and bromides)- Efficient for heterocyclic amines and 2-pyrrolidinone but not for aliphatic amines

PhI

NH

NH

O

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

Cs2CO3 (2 equiv)

DMF, 90 oC, 30 h

PhI

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

Cs2CO3 (2 equiv)

DMF, 90 oC, 30 h

N

Ph

NPh

O

93%

81%


10

First Iron only Aryl Amination

- First ligand-assisted iron (only) catalyzed aryl amination process- Scope included pyrazoles, indoles and 2-pyrrolidinone- Aliphatic and aromatic amines failed (gave low yields)- Ligand study showed that catalytic system will work for both electron rich and deficient substrates- No mention of regioselectivity problem using unsymmetrical substrates

Correa, A.; Bolm, C. Angew. Chem. Int. Ed. 2007, 46, 8862.

I N

HN

K3PO4, toluene

135 oC, 24 h

FeCl3 (10 mol%),dmeda (20 mol%) N

N

80%

I N

HN

K3PO4, toluene

135 oC, 24 h


N

82%

H3C

H3C

I N

HN

K3PO4, toluene

135 oC, 24 h


N

87%

Cl

Cl

N

HN

K3PO4, toluene

135 oC, 24 h


N

87%

MeO MeOI


11

Iron-catalyzed Aryl Amidation

Correa, A.; Elmore, S.; Bolm, C. Chem. Eur. J. 2008, 14, 3527

- First ligand-assisted iron catalyzed aryl amidation- Yields complement those of palladium-catalyzed processes

S

O

NH2 I

F

K2CO3, toluene

135 oC, 24 h

FeCl3 (10 mol%),dmeda (20 mol%)

80%

S

O

NH

F

NH2

O

I

CO2Me

H3C K2CO3, toluene

135 oC, 24 h


86%

NH

O

CO2Me

CH3

K3PO4, toluene

135 oC, 24 h


79%

NH2

O

I

OMe

NH

O

OMe


12


- Coupling observed when using no catalyst or ligand- Entry 3 shows slightly improved yield of product- Entry 4 shows different iron catalyst improves yield- DMSO is superior solvent compared to dioxane, toluene or DMF

Guo, D.; Huang, H.; Xu, J.; Jiang, H.; Liu, H Org. Lett. ASAP

Fe, ligand, t-BuONa (2 equiv)

DMSO, 135 oC, 24 h

Entry catalyst (10 mol%) ligand (20 mol%) Yield (%)

1 53

2 L-proline 52

3 77

4 85

FeCl3 L-proline

L-proline

I

HN

ONO

Fe2O3


13


- System works well with aromatic and aliphatic amines- Reaction not as efficient with pyrazole (entry 3 - Bolm observed 80% yield)- What role does iron play in this reaction?

Entry amine product Yield (%)

1 72

2 90

3 67

I

N

R1

R2

Fe2O3 (10 mol%)L-proline (20 mol%)t-BuONa (2 equiv)

DMSO, 135 oC, 24 h

NHNH2

N

R2

R1 H

(amine)

NH N

NNH N

N


14


- Unsymmetrical aryl iodides affords regioisomeric mixtures - reminiscent of TM free benzyne mechanism(?)- What type of reaction mechanism does this transformation fall under?- Bolm and co-workers do not note any selectivity issues in previous papers using iron catalysis


DMSO, 135 oC, 24 h

I

ONH ON


DMSO, 135 oC, 24 h

I

ONH

ON


DMSO, 135 oC, 24 h

I

ONH

85%

CH3

H3C

ON

H3C

and

m:p - 1:1

66%

H3C

ON

H3C

m:p - 4:1

ONH3C

and

72%


15

Conclusions

- Aryl amination and amidation using iron catalysis is an emerging field with environmental benefits- Scope of process will need to be improved to compete with palladium-based Buchwald-Hartwig systems- Some results in title paper do not agree with those of Bolm and co-workers- Is iron really being used catalytically, or is regioselectivity issue a result of a benzyne intermediate

I

N

R1

R2


DMSO, 135 oC, 24 h

N

R2

R1 H

(amine)


efﬁcient iron-catalyzed n-arylation of aryl halides with ...ccc.chem.pitt.edu/wipf/current...

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