Palladium-Catalyzed Cross-Coupling

Reactions

2010 Nobel Prize Awarded to

Richard Heck, Ei-ichi Negishi, and

Akira SuzukiSonam Vijay Sancheti

Alfred Nobel

Introduction

Nobel prize for their roles in discovering and

developing highly practical methodologies for C-C bond

construction.

Strategies and methods of organic synthesis

irreversibly changed for the modern chemist, both in

academia and in industry, due to their original

contributions in the early 1970s

Growth in the number of publications and patents on named reaction components metal-catalyzed cross-coupling reactions.

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History of C-C coupling

1855: Wurtz coupling (Sodium metal catalyzed homodimerization)

1862: Fitting couplig (Sodium metal catalyzed homodimerization)

1901: Ullmann Coupling (Copper catalyzed homodimerization)

1914: Bennett and Turner (chromium(III) chloride , homodimerization)

1939: Meerwein arylations (CuCl2 catalyzed cross coupling)

1943: Kharasch coupling (Cobalt chloride based homodimerization)

Cross Coupling: Selectivity problem

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Selective Cross Coupling History

Kl 1957: Cadiot and

Chodkiewicz

1963 : Castro–

Stephens

1963 : Castro–

Stephens

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The Palladium Complexes as Cross-Coupling

Catalysts

• High toxicity of the

organomercury reagents

• Lack of an obligatory

preformed organometallic

species as one of the

coupling partners.

• The independent and

almost concurrent

discoveries

by Mizoroki and Heck

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Mizoroki–Heck Reaction (1972)

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Sonogashira Reaction (1975)

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Extension of Heck reaction

Heck Reaction uses harsh conditions

Requires only catalytic quantities of transition metals

Homocoupling avoided. So higher selectivity

Harsh conditions

Harsh conditions

Reaction conditions

exceedingly milder

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R

The Negishi Reaction (1977)Organoaluminum and Organozinc as coupling Partners

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Organoaluminum reagents: deterioration of stereospecificity

Magnesium and Lithium could be replaced with other metals that

were capable of participating in the proposed transmetallation step.

Organoaluminium

reagents:

Both Ni and Pd

catalysts are used

Organozinc reagents:

- Mild route

- Impressive

functional group

compatibility

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• Negishi and co-workers carried out metal-screening regimens to

identify other possible organometallic reagents as coupling partners.

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The Stille Reaction (1978)

Milder reaction

conditions

Main disadvantage of Migits-stille Reaction:

TOXICITY OF ORGANOSTANNANES

Organostannane

coupling parteners

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The Suzuki–Miyaura Reaction (1979)

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1986:

Β-Alkyl-9-BBN

Or

Trialkylboranes

1981:

Arylborane

1979:

Alkenyl borane

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Several Advantages of Suzuki Coupling Reactions:

Ready availability of reagents: hydroboration and transmetalation

Mild reaction conditions

Easy use of the reaction both in aqueous and heterogeneous conditions

Toleration of a broad range of functional groups

High regio- and stereoselectivity of the reaction

Insignificant effect of the steric hindrance

Use of a small amount of catalysts

Application in one-pot synthesis

Nontoxic reaction

Easy separation of inorganic boron compounds

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Organosilicon coupling parteners

Hiyama coupling provided more environmentally friendly and safe

than organoboron, organozinc and organostannane.

The Hiyama Reaction (1988–1994)

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Increasing functional group compatibility, broadening substrate scope

Employing cross coupling in synthesis of biologically important

molecules

Following are industrial applications

Recent Work Going…

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C(sp3)-C(sp3) and C(sp2)-C(sp3) cross-coupling reactions

Selective mono α-arylation

Stoichiometric amount of base required, makes process non-green

Use of alternative metals with good results

This reaction also awaits the development of more practical and

economical conditions and procedures for application in large-scale

syntheses whilst finding robust solutions to the selectivity issues

encountered for less straightforward coupling partners.

Coupling Reactions: Challenges…

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References

• For Nobel Lecture, E. Negishi, Angew. Chem. 2011, 123,6870 – 6897

• For Nobel Lecture, A. Suzuki, Angew. Chem. 2011, 123,6854 – 6869

• N. Miyaura, T. Ishiyama, M. Ishikawa, A. Tetrahedron Lett. 1986, 27, 6369 – 6372.

• R. F. Heck, J. Am. Chem. Soc. 1968, 90, 5518 – 5526

• A. Suzuki , Journal of Organometallic Chemistry , 2002,653, 83-90

• A. Suzuki , 1995–1998 Journal of Organometallic Chemistry 576 (1999) 147–168

• R. F. Heck, Contribution from the Research Center of Hercules Inc., Wilmington, Delaware

19899. Received December 7, 1967

• R. F. Heck, Contribution from the Research Center of Hercules, Inc.,Wilmington, Delaware

19899. Received April 7, 1969

• T. Ishiyama, N. Matsuda, N. Miyaura, A. Suzuki, J. Am. Chem.Soc. 1993, 115, 11018 –

11019.

• H. Matsushita, E. Negishi, J. Org. Chem. 1982, 47, 4161 –4165

• Review: E. Negishi, Acc. Chem. Res. 1982, 15, 340 – 348.

• R. Heck, J. P. Nolley, Jr., J. Org. Chem. 1972, 37,2320 – 2322.

• C. C . Carin, J. Seechurn, M. Kitching, T. J. Colacot, and V. Snieckus, Angew. Chem. Int.

Ed. 2012, 51, 5062 – 5085

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