Modern Synthetic Methods - 4

R-M
R-R’
Functionnalized Organometallic Reagents
R’-X
Metallation with Sterically Hindered Bases
R-M
Direct Metallation of Aromatic and Heteroaromatic Compounds
R-X-R’
Requirements:
R-X-M
Basic Enough to Allow for Direct Deprotonation
R-B(R’)2 Sterically Hindered to Avoid Nucleophilic Attack
Tolerance to a Broad Range of Functional Groups
R-Si(R’)3
R-M
R-R’
R’-X
R-M How to Synthesize Metallic Bases ?
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M Deprotonation a to Electron Withdrawing Groups (EWG)
R-X-R’
R-X-M
Deprotonation at Benzylic Position
R-B(R’)2
R-Si(R’)3 Directed Deprotonation of Aromatic and Heteroaromatic Substrates

R-M
R-R’
R’-X
a to EWG
R-M
Previous Work
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
J. F. Hartwig et al. J. Am. Chem. Soc. 2002, 124, 9330.

R-M
R-R’
R’-X
a to EWG
R-M
Stabilization by delocalization
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
P. Knochel et al. Org. Lett. 2011, 13, 1690.

R-M
R-R’
R’-X
a to EWG
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
P. Knochel et al. Org. Lett. 2011, 13, 1690.

R-M
R-R’
R’-X
a to EWG
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
a to EWG
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
EDG EWG
R-M
R-R’
R’-X
a to EWG
R-M
Remote Positions
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
a to EWG
R-M
Remote Positions
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
a to EWG
R-M
Remote Positions
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
At Benzilic Position
R-M
R-X-R’ Deprotonation at Benzylic Position
R-X-M
R-B(R’)2
R-Si(R’)3 More Efficient When Delocalization is Possible (TMP-ZnX / TMP-MgX)
Otherwise, Need for a Better Base (TMP-Li)

R-M
R-R’
R’-X
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
P. Knochel et al. Angew. Chem. Int. Ed. 2011, 50, 7686.

R-M
R-R’
R’-X
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
Effect of a Lewis Acid
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
Selectivities – Inductive Effects
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
Selectivities – Lewis Acid Effect
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
Other Heterocycles
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
Other Heterocycles
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
Other Heterocycles
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
Other Heterocycles
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
Other Heterocycles
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
On Benzyl Acetylenes
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
On Benzyl Acetylenes
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
On Methyl Bisacetylenes
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
Direct Deprotonation
R-M
Directed Deprotonation of Aromatic and Heteroaromatic Substrates

R-X-R’
R-X-M
R-B(R’)2
Directing Group = Very Important for Regioselectivity

R-Si(R’)3
1) Coordinating Group for the Orientation of the Base

2) Steric Hindrance Play an Important Role
R-M
R-R’
R’-X
R-M
Metallation a to Heteroatoms
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Orientation Partially Controlled by Br

R-M
R-R’
R’-X
R-M
Halogen-Assisted Metallation
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
Directing Group for Metallation
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
Rules: Has to be Next to a Directing Group

R-X-R’
R-X-M
R-B(R’)2
Hindered Base = Avoid Steric Hindrance

R-Si(R’)3
R-M
R-R’
R’-X
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
Playing With Steric Hindrance
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
On Other Metallic Species
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R-R’
R’-X
R-M
Conclusion
R-X-R’
R-X-M
R-B(R’)2
For Selectivity:
R-Si(R’)3
Coordination Effects
Steric Effects

Modern Synthetic Methods - 4

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Modern Synthetic Methods - 4

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R-M

R-B(R’)2 Sterically Hindered to Avoid Nucleophilic Attack

Tolerance to a Broad Range of Functional Groups

R-M How to Synthesize Metallic Bases ?

R-M Deprotonation a to Electron Withdrawing Groups (EWG)

R-Si(R’)3 Directed Deprotonation of Aromatic and Heteroaromatic Substrates

J. F. Hartwig et al. J. Am. Chem. Soc. 2002, 124, 9330.

P. Knochel et al. Org. Lett. 2011, 13, 1690.

P. Knochel et al. Org. Lett. 2011, 13, 1690.

R-X-R’ Deprotonation at Benzylic Position

R-Si(R’)3 More Efficient When Delocalization is Possible (TMP-ZnX / TMP-MgX)

Otherwise, Need for a Better Base (TMP-Li)

P. Knochel et al. Angew. Chem. Int. Ed. 2011, 50, 7686.

Directed Deprotonation of Aromatic and Heteroaromatic Substrates

Directing Group = Very Important for Regioselectivity

1) Coordinating Group for the Orientation of the Base

Orientation Partially Controlled by Br

Rules: Has to be Next to a Directing Group

Hindered Base = Avoid Steric Hindrance

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