PdCatalyzed aArylation of c

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Palladium-Catalyzed Intermolecular Arylation of
Ketones and AmidesTiansheng MeiBrandeis
UniversityMarch 7, 2007
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Outline

• I.) Introduction
• II.) Palladium-Catalyzed Arylation of Alkali
  Metal Ketone Enolates
• A. Initial Discoveries
• B. Mechanism and Catalyst Improvement
• C. Asymmetric Arylation
• III.) Palladium-Catalyzed Arylation of Silyl Enol
  Ethers
• A. Initial Discoveries
• B. Palladium Catalyzed Arylation of
  Diphenylsilyl Enol Ethers
• C. Palladium Catalyzed Arylation of
  Trimethyl Silyl Enol Ethers
• IV.) Palladium-Catalyzed Arylation of Amides
• IV.) Summary

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Introduction
Functionalization of aromatic compounds
Suzuki and Stille Reactions
Heck Reaction
Arylation of Carbon Nucleophiles
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Introduction
Aldehydes, Esters, Ketones and Amides
Muratake, H. Nakai, H. Tetrahedron Lett. 1999,
40, 2355. Kawatsura, M. Hartwig, J. F. J. Am
.Chem. Soc. 1999, 121, 1473.
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Outline

• I.) Introduction
• II.) Palladium-Catalyzed Arylation of Alkali
  Metal Ketone Enolates
• A. Initial Discoveries
• B. Mechanism and Catalyst Improvement
• C. Asymmetric Arylation
• III.) Palladium-Catalyzed Arylation of Silyl Enol
  Ethers
• IV.) Palladium-Catalyzed Arylation of Amides
• IV.) Summary

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Initial Discoveries
First arylation of a ketone enolate
Satoh, T. Kawamura, Y. Miura, M. Angew. Chem.
Int. Ed. 1997, 36, 1740.
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Initial Discoveries
Coupling of sodium alkoxides with electron-rich
aryl bromides
Arylation of alkali metal Ketone Enolates
Michael, P. Buchwald, S. L. J. Am. Chem. Soc.
1997, 119, 11108.
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Initial Discoveries
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Amination or Arylation?
Hamann, B. C. Hartwig, J. F. J. Am. Chem. Soc.
1997, 119, 12382.
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Initial Discoveries
Considering the instability of the tertiary alkyl
complex toward decomposition by either ß-
hydrogen elimination or M-C bond homolysis, it is
remarkable that arylation occurs to form a
quarternary center in moderate yield.
Hamann, B. C. Hartwig, J. F. J. Am. Chem. Soc.
1997, 119, 12382.
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Outline

• I.) Introduction
• II.) Palladium-Catalyzed Arylation of Alkali
  Metal Ketone Enolates
• A. Initial Discoveries
• B. Mechanism and Catalyst Improvement
• C. Asymmetric Arylation
• III.) Palladium-Catalyzed Arylation of Silyl Enol
  Ethers
• IV.) Palladium-Catalyzed Arylation of Amides
• IV.) Summary

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Mechanism
Plausible catalytic cycle for addition of
enolates to aryl halides
Culkin, D. A. Hartwig, J. F. Acc. Chem. Res.
2003, 36, 234.
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Mechanism
Coordination modes (Palladium-Carbon or
Palladium-Oxygen bonds)
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Yield 44-81
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Hamann, B. C. Hartwig, J. F. J. Am. Chem. Soc.
1997, 119, 12382.
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• Three postulates
• Because the oxidative addition of aryl halides
  and reductive elimination of product
• both involve a low-coordinate Pd(0)
  intermediate, Hartwig and co-workers reasoned
  that increased steric bulk of the ligands should
  increase the energy of the stable,
  higher-coordinate species. This would increase
  the energy of the ground state and decrease the
  relative energy of the intermediate, increasing
  the overall reaction rate.

Pd(II)
Bulkyl ligand
Less bulky ligand
Pd(0)
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Catalyst Improvement

• 2. Compared to phenyl substituents, alkyl
  substituents at phosphorus would promote
  oxidative addition by making the metal more
  electron-rich.

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Catalyst Improvement
Bulky, Electron rich Phosphine Ligands
Culkin, D. A. Hartwig, J. F. Acc. Chem. Res.
2003, 36, 234.
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Catalyst Improvement
3. Chelating ligands would inhibit
ß-elimination of the aryl-palladium enolates by
forming a four-coordinate Palladium intermediate.
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Catalyst Improvement
Sterically hindered, electron-rich o-biphenyl
monophosphines
Buchwald, S. L and co-workers
Hartwig, J. F. and co-workers
These ligands also generate highly active
palladium catalysts for the arylation of ketones
and provide high selectivity for the reaction at
the less hindered position of dialkyl ketones.
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Catalyst Improvement

Culkin, D. A. Hartwig, J. F. et al. Acc. Chem.
Res. 2003, 36, 234-245.
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Outline

• I.) Introduction
• II.) Palladium-Catalyzed Arylation of Alkali
  Metal Ketone Enolates
• A. Initial Discoveries
• B. Mechanism and Catalyst Improvement
• C. Asymmetric Arylation
• III.) Palladium-Catalyzed Arylation of Silyl Enol
  Ethers
• IV.) Palladium-Catalyzed Arylation of Amides
• IV.) Summary

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Asymmetric Arylation

• Asymmetric Arylation (Initial Discovery)

Ahman, J. Wolfe, J. P. Buchwald, S. L. J. Am.
Chem. Soc. 1998, 120, 1918.
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Asymmetric Arylation
Hamada, T. Chieffi, A. Buchwald, S. L. J.
Am. Chem. Soc. 2002, 124, 1261.
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Asymmetric Arylation

• Optically active 2-methyl-2-arylcyclopentanones
  are known to be important intermediates for
  natural products

Takano, S. Inomata, K. Ogasawara, J. J. Chem.
Soc., Chem. Commun. 1990, 290.
Srikrishna, A. Reddy, T. J. Tetrahedron 1998,
54, 8133.
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Srikrishna, A. Reddy, T. J. Tetrahedron 1998,
54, 8133.
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Conclusions

• Advantages
• 1. The palladium-catalyzed arylation of alkali
  metal ketone enolates has provided a general way
  to prepare arylated ketones.
• 2. The use of bulky, electron-rich phosphine
  ligands not only increases the rate of arylation
  but also allows the use of aryl chlorides as
  substrates.
• Drawbacks
• 1. Difficult to selectively couple at the more
  hindered of two enolizable positions
• 2. Difficult to form acidic tertiary
  stereocenters
• Palladium-catalyzed arylation of silyl enol
  ethers might solve these
• problems.

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Outline

• I.) Introduction
• II.) Palladium-Catalyzed Arylation of Alkali
  Metal Ketone Enolates
• III.) Palladium-Catalyzed Arylation of Silyl Enol
  Ethers
• A. Initial Discoveries
• B. Palladium Catalyzed Arylation of
  Diphenylsilyl Enol Ethers
• C. Palladium Catalyzed Arylation of
  Trimethyl Silyl Enol Ethers
• IV.) Palladium-Catalyzed Arylation of Amides
• IV.) Summary

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Initial Discoveries
III. Palladium-Catalyzed Arylation of Silyl Enol
Ethers (Pioneering work)

• Kuwajima, I. Urabe, H. J. Am. Chem. Soc. 1982,
  104, 6831.
• Kosugi, M. Hagiwara, I. Sumiya, T. Migita. T.
  Bull. Chem. Soc. Jpn. 1984, 57, 242.

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Initial Discoveries
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Mechanism
Plausible Mechanism for the Pd-Catalyzed
Arylation of TMS enol ethers
Iwama, T. Rawal, V. H. Organic Lett. 2006, 8,
5725.
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Diphenylsilyl enol ethers
Chae, J. Yun, J. Buchwald S. L. Org. lett.
2004, 6, 4809.
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Diphenylsilyl enol ethers
Preparation of Diphenylsilyl Enol Ethers
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Diphenylsilyl enol ethers
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Trimethylsilyl enol ethers
III. Pd-Catalyzed a-Arylation of Trimethylsilyl
Enol Ethers
Su, W. Raders, S. Verkade, J. G. Hartwig, J.
F. Angew. Chem. Int. Ed. 2006, 45, 5852.
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Trimethylsilyl enol ethers
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Trimethylsilyl enol ethers
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Conclusions
Palladium-Catalyzed Arylation of Silyl Enol Ethers

• Advantages
• 1. Functional-group tolerance
• 2. Form acidic tertiary stereocenters
• 3. Couple at the more hindered of two enolizable
  positions

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Outline

• I.) Introduction
• II.) Palladium-Catalyzed Arylation of Alkali
  Metal Ketone Enolates
• A. Initial Discoveries
• B. Mechanism and Catalyst Improvement
• C. Asymmetric Arylation
• III.) Palladium-Catalyzed Arylation of Silyl Enol
  Ethers
• A. Initial Discoveries
• B. Palladium Catalyzed Arylation of
  Diphenylsilyl Enol Ethers
• C. Palladium Catalyzed Arylation of
  Trimethyl Silyl Enol Ethers
• IV.) Palladium-Catalyzed Arylation of Amides
• IV.) Summary

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IV. Palladium-Catalyzed Intermolecular
a-Arylation of Amides
Arylation of Amides
Shaughnessy, K. H Hamann, B. C. Hartwig, J. F.
J. Org. Chem. 1998, 63, 6546.
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• The need for a strong base limits the scope of
  coupling reactions to aryl halides that lack
  electrophilic functionality.
• 2. Strongly basic conditions lead to catalyst
  decomposition, and the coupling of amides has
  required higher loadings of palladium than the
  coupling of ketones.
• To overcome these problems, a reaction that
  occurs with enolates that
• are less basic than alkali metal enolates of
  amides must be developed.

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Arylation of Amides
Reaction of a silyl ketimine acetal
The conditions for the arylation of the silyl
enolates are neutral enough to prevent silyl
group migration and epimerization of
base-sensitive stereocenters.
Hama, T. Liu, X. Culkin, D. A. Hartwig, F. H.
J. Am. Chem. Soc. 2003, 125, 11176.
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Arylation of Amides
Plausible Coupling Mechanism of Zinc Enolates of
N,N-Dialkylacetamides Generated via Lithium
Enolates
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Arylation of Amides
Reaction of Reformatsky Reagents
Hama, T. Liu, X. Culkin, D. A. Hartwig, F. H.
J. Am. Chem. Soc. 2003, 125, 11176.
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Arylation of Amides
Reaction of Reformatsky Reagents Generated in
Situ.
Hama, T. Culkin, D. A. Hartwig, J. F. J. Am.
Chem. Soc. 2006, 128, 4976.
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Coupling of Zinc Enolates of N,N-Dialkylacetamides
Generated via Lithium Enolates.
Arylation of Amides
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Summary

• 1. The palladium-catalyzed arylation of
  alkali metal ketone enolates has provided a
  general way to prepare arylated ketones.
• 2. The use of bulky, electron-rich phosphine
  ligands not only increases the rate of arylation
  but also allows the use of aryl chlorides as
  substrates
• 3. Using silyl enolates and zinc enolates can
  avoid strongly basic conditions, allowing
  functional group tolerance and formation of a
  tertiary carbon center without racemization.
  These methods expand the application of the
  palladium-catalyzed arylation of carbonyl
  compounds.

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Thank youDr. Jinquan, Yu (Advisor) Ramesh,
Giri Jiaojie, Li Donghui, Wang Nathan,
Maugel Brian, Provencher