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Buchwald-Hartwig Cross Coupling Reaction

Reporter: Ying-Chieh CHAO

Lecturer: Professor Guey-Sheng Liou

Advisor: Professor Ru-Jong Jeng

Data:2013/12/27

Pd-Catalyzed Amination

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Stephen L. Buchwald(1955-)He entered Harvard University as a

National Science Foundation Predoctoral Fellow in 1977 and received his Ph.D. in 1982.

In 1984 he began as an assistant professor of chemistry MIT. He was promoted to the associate professor (1989) and to Professor (1993) and was named the Camille Dreyfus Professor in 1997.

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John F. Hartwig(1964-)

University of California, BerkeleyA.B. Princeton University, 1986 Ph.D. University of California,

Berkeley, 1990 American Cancer Society Postdoctoral

Fellow, Massachusetts Institute of Technology, 1990-1992

research focuses on the discovery and understanding of new reactions catalyzed by transition metal complexes.

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Synthesis of the aromatic amine of history

Disadvantages• Cumbersome step• Harsh reaction conditions

T. Migita et al., Chem. Lett., 1983, 927.

(n-Bu)3SnNEt2 PhBrPdCl2(o-tolyl3P)2

PhCH3, 100°C, 3hPhNEt2 (n-Bu)3SnBr

87%

P.E. Fanta et al., Synthesis, 1974, 9.

Cl

NO2

copper-bronze

220°C, 3hNO2

O2N

2

52%

Reduction

NH2

H2N

Disadvantages• Chlorobenzene and iodobenzene can not react • Water and heat sensitive

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S. Buchawald et al., J. Am. Chem. Soc., 1994, 116, 7901.

(n-Bu)3SnNEt2 HNR1R280°C

(n-Bu)3SnNR1R2PhBr, PdCl2(o-tolyl3P)2

PhCH3, 105°C, NaOH, 4h55%~88%

NR1R2

R3

Br

R1 HNR2R3PdCl2(o-tolyl3P)2

PhCH3, NaOBu-t, 100°C67%~89%

NR2R3

R1

S. L. Buchwald et al., Angew. Chem. Int. Ed., 1995, 34, 1348.

J. F. Hartwig et al., Tetrahedron lett., 1995, 36, 3609.

Br

RNH PdCl2(o-tolyl3P)2

PhCH3, LiN(SiMe3)2, 100°C, 2h72%~94%

N

R

Synthesis of the aromatic amine of history

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Buchwald-Hartwig Cross Coupling Reaction

ArX HNR1R2cat. Pd, ligands, base, additive agent

NR1R2Arsolvent

S. L. Buchwald et al., Angew. Chem. Int. Ed., 1995, 34, 1348.

J. F. Hartwig et al., Tetrahedron lett., 1995, 36, 3609.

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P

P(o-tolyl)3

Can’t castylst for chlorobenzene

Mondentate ligands

P

PCy3

P

P(i-Pr)3

M. Tanaka et al.

M. Tanaka Tetrachedron lett. 1997, 38, 4807.

P

P(t-Bu)3

Y. Kioe Tetrahedron lett. 1998, 39, 617.

AdvantagesCan reacted under mild conditionReduced the amount of catalystReduced formation of byproducts DisadvantagesP(t-Bu)3 is air-sensitive

Electron-rich monodendate phosphine ligands

PR2

R=t-Bu, Cy

S. L. Buchwald et al., Angew. Chem. Int. Ed., 1999, 38, 2413.S. L. Buchwald et al., Angew. Chem. Int. Ed., 1999, 38, 2570.S. L. Buchwald et al., J. Am. Chem. Soc., 2003, 125, 6653.

AdvantagesCan react at room temperatureNot air-sensitive

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Chelating phosphane ligands

PPh2PPh2

BINAP

Fe

PPh2

PPh2

DPPF

P P

DPPP

Common inorganic base: t-BuONa, t-BuOK, NaOCH3, K2CO3, K3PO4, NaOH, LHMDS, Cs2CO3.

Base

Common organic base: DBU, MTBD.

strong base is suitable Mondentate ligands and Electron-rich monodendate phosphine ligands.ex. t-BuONa.

weak base is suitable Chelating phosphane ligands.ex. K2CO3. L. S. Buchwald et al., Tetrahedron lett., 1997, 38, 6359.

L. S. Buchwald et al., Tetrahedron, 1996, 52, 7525.

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Solvent

Common solvent: toluene, xylene, THF, DME, Dioxane, DMF, NMP, DMSO.

J. F. Hartwig et al., J. Org. Chem., 2002, 67, 6479.J. M. McNamara et al., Org. Lett., 2002, 4, 3481.

Most of this reaction catalysts and ligands for water and oxygen sensitive.

10J. F. Hartwig et al., Org. Lett., 2008, 10, 4109-4112.

52-98%

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 S. L. Buchwald et al., J. Am. Chem. Soc., 2010, 132, 15914-15917.

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J. F. Hartwig et al., J. Am. Chem. Soc., 2009, 131, 11049-11061.

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S. L. Buchwald et al., J. Am. Chem. Soc., 2008, 130, 13552-13554.

Z. Zhang et al., Synlett, 2011, 955-958.

S. L. Buchwald et al., J. Org. Chem., 2006, 71, 430-433. W. Song et al., Org. Lett., 2011, 13, 1784-1786.

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water-containing solvent systems

Thank you for your attention!!G. Boche et al., Chem. Commun., 1998, 1509-1510.

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