![Page 1: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/1.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Cross-Coupling Reactions
Functionnalized Organometallic Reagents
C-N, C-O and C-S Bond Formation
Introduction to Organoboron Chemistry
Introduction to Organosilicon Chemistry
Carbometallation Reactions
R-M
R’-XR-R’
![Page 2: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/2.jpg)
Functionnalized Organometallic Reagents
Organolithium Chemistry
Generalities
Organomagnesium / Grignard Reagents
Organozinc Reagents
Organoalane Derivatives
Organoindium Chemistry
Organomanganese Reagents
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
R-M
R’-XR-R’
Metallation with Sterically Hindered Bases
![Page 3: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/3.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Generalities
R-M
R’-XR-R’
Organometallic = C-M bond
Synthesis via
DeprotonationInsertionExchangeTransmetallation
66
![Page 4: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/4.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Availability
MeLi
EtLi
n-BuLi
i-PrLi
s-BuLi
t-BuLi
PhLi
![Page 5: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/5.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Insertion
Primary Alkyllithium Reagents
Solvent :Et2O, THF or PE
Solid at r.t.
![Page 6: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/6.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Secondary Alkyllithium Reagents
Preparation via Insertion
Tertiary Alkyllithium Reagents
![Page 7: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/7.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Alkenyllithium Reagents
Preparation via Insertion
Aryllithium Reagents
![Page 8: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/8.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
- Usually working good on I / Br
- Cheaper but more difficult with Cl
- Alkenyl group are more difficult to react
- High degree of substitution leads to less reactivity
- Limited in group tolerance
Preparation via Insertion - Summary
![Page 9: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/9.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Permutation
Missed discoveries
C. S. Marvel et al. J. Am. Chem. Soc. 1927
K. Ziegler et al. Liebigs Ann. Chem. 1929
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R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Permutation
G. Wittig et al. Ber. Dtsch. Chem. Ges. 1940
H. Gilman et al. J. Am. Chem.Soc. 1939
Simultaneous Discovery
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R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Permutation
Gilman’s Observations
1. Aryl Fluorides DO NOT Undergo Exchange
2. Rates of Interchange Decrease from I > Br > Cl
3. Interchange is a Reversible Process that Leads to an Equilibrium Favoring the More Stable RLi
![Page 12: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/12.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Permutation
Some Kinetics
![Page 13: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/13.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Permutation
To summarize
1. Relative Stabilities of Carbanions:sp >> sp2 >> sp3
2. The Less Hindered, the More Stable, the Less Reactive
Relative Reactivity
Relative Reactivity
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R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
On the Mechanism – Still Being Discussed
Preparation via Permutation
Radical Process
Ate-complex formation
Radical Ions Caged Species
Ate-complex
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R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
On the Mechanism
Preparation via Permutation
![Page 16: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/16.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Permutation
Commonly Used Lithium Species for Li-X Exchange
t-BuLi s-BuLi n-BuLi MeLi
General Rule
![Page 17: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/17.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Permutation
Li-X Permutation of Alkyl-X Species
Li-X Permutation of Alkenyl-X Species
![Page 18: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/18.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Li-X Permutation of Alkenyl-X Species
Preparation via Permutation
Retention of Configuration
Li-X Permutation of Hetero-substituted Alkenyl-X Species
![Page 19: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/19.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Li-X Permutation of Alkenyl-X Species - Selectivity
Preparation via Permutation
Minimisation of the Interaction
Having a Coordinating Group
![Page 20: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/20.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Li-X Permutation of Aryl-X Species
Preparation via Permutation
Li-X Permutation of Heteroaryl-X Species
![Page 21: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/21.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Permutation
Li-X Permutation of Halogeno-Alkyl-X Species
Have Usually to Be Usedin-situ
at the Same Temperature
![Page 22: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/22.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Enolate Formation
Direct Deprotonation
![Page 23: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/23.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to an oxygen (a-O)
Tetrahedral System : Unfavoured
The exception: CarbamatesStabilisation by Intramolecular Coordination
Trigonal System : More Favoured
![Page 24: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/24.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to an oxygen (a-O)
![Page 25: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/25.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to an oxygen (a-O) – Stabilization by Delocalization
![Page 26: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/26.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to an oxygen (a-O) – Stabilization by Delocalization
![Page 27: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/27.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to an oxygen (a-O)- Stabilization by Coordination
(Zimmermann-Traxler)
![Page 28: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/28.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to an oxygen (a-O)- Stabilization by Coordination
Metallic Electrophile
![Page 29: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/29.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to an oxygen (a-O) – Case of Cyclic Ethers
![Page 30: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/30.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to a nitrogen (a-N)
Destabilising Effect – Worse than Oxygen
Stabilising Effect
Dipole-Stabilised Carbanions
![Page 31: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/31.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to a nitrogen (a-N) – Case of Amides
Azetine Core Pyrrolidine Core Oxazolidine Core
![Page 32: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/32.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to a nitrogen (a-N) – Case of Amides
Primary Alkyl-lithiumMore Stable than
Secondary Alkyl-lithium
Benzylic Postion = More Easy to Deprotonate
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R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to a nitrogen (a-N) – Case of Secondary Amides
![Page 34: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/34.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to a nitrogen (a-N)
a-lithiation at benzylic sites outpaces enolisation
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R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to a nitrogen (a-N)
Pyridinone Core
![Page 36: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/36.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to a nitrogen (a-N) – 5-membered N-Heterocycles
![Page 37: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/37.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to a nitrogen (a-N) – Lithiation of Formamidines
Stabilising Effect
Dipole-Stabilised Carbanions
![Page 38: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/38.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to a nitrogen (a-N) – Lithiation of Formamidines
![Page 39: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/39.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to a nitrogen (a-N) – Lithiation of Nitrosoamines
![Page 40: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/40.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to a nitrogen (a-N) – Lithiation of Nitrosoamines
![Page 41: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/41.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to a nitrogen (a-N) – Lithiation of Imines and Hydrazones
![Page 42: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/42.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to a nitrogen (a-N) – Lithiation of N-Oxides and Amine-Boron Complexes
![Page 43: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/43.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to a sulfur (a-S)
Stabilising Effect
Interaction with C-S s*
Dithiane Chemistry
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R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to a sulfur (a-S) – Lithiation of Thioethers
![Page 45: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/45.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to a sulfur (a-S) – Lithiation of Allyl Sulfides
Retention of Configuration
Double Stabilisation
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R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to a sulfur (a-S) – Synthesis of Thiiranes
![Page 47: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/47.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to a sulfur (a-S) – Lithiation of Thiophenes
If a-S Lithiation is possible,Lithiation Reaction a to Se Remains Impossible
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R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
a to a Silicon (a-Si)
![Page 49: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/49.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Ortholithiation
Basically works
What Will Affect the Selectivity?
![Page 50: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/50.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Ortholithiation - A Comparison
Softer Bases
Stronger BaseElectronically Stabilised
Ortholithiation
![Page 51: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/51.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Ortholithiation
![Page 52: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/52.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
![Page 53: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/53.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Ortholithiation – Classes of Ortho-Directing Group
Oxazolines
Sulfonamides
![Page 54: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/54.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Ortholithiation – Classes of Ortho-Directing Group
3ry amides
carbamates
sulfonessulfonamides
oxazolinesMOM-ether halogen
ether alkoxide
2ry amidessulfoxides
2ry sulfonamidesimines
N-carbamates trifluoromethylanilines amines
![Page 55: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/55.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Ortholithiation – All there is to know
![Page 56: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/56.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Ortholithiation - Exemples
![Page 57: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/57.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Ortholithiation - Exemples
![Page 58: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/58.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Ortholithiation - Exemples
Lithium-sulfoxide Exchange
![Page 59: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/59.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Ortholithiation - Exemples
![Page 60: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/60.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Ortholithiation - Exemples
![Page 61: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/61.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Ortholithiation - Exemples
![Page 62: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/62.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Ortholithiation - Exemples
![Page 63: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/63.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Lateral Lithiation
Ortholithiation VS Lateral Lithiation
- Coordination Effect- Inductive Electron Withdrawal
- Coordination Effect- Conjugation
![Page 64: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/64.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Lateral Lithiation
Can be Seen as an Extended Enolisable System
![Page 65: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/65.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Lateral Lithiation
Amides
Nitriles
![Page 66: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/66.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Lateral Lithiation
Carboxylates
Esters
![Page 67: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/67.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Lateral Lithiation
EnolisableKetones
Non-EnolisableKetones
![Page 68: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/68.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Lateral Lithiation
RemoteAmine
Methoxy Only Possibility
![Page 69: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/69.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Schlosser’s Base – « Superbase »
Known as LiKOR Li-C + K-OR
Mixture of
![Page 70: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/70.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Schlosser’s Base – « Superbase »
![Page 71: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/71.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Schlosser’s Base – « Superbase »
Metallates Preferencially Next to Powerful Electron-Withdrawing Groups
![Page 72: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/72.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Schlosser’s Base – « Superbase »
![Page 73: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/73.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Schlosser’s Base – « Superbase »
![Page 74: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/74.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Schlosser’s Base – « Superbase »
![Page 75: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/75.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Schlosser’s Base – « Superbase »
ibuprofen
![Page 76: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/76.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Stereoselective Formation of Organolithiums – Without Coordinating Group
Fast racemisation
Complete RetentionEven at 0°C
![Page 77: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/77.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Stereoselective Formation of Organolithiums – Without Coordinating Group
![Page 78: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/78.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Stereoselective Formation of Organolithiums – With Stabilising Effect
Stable for 2,5 h
Stable for 1,5 h
![Page 79: Cross-Coupling Reactions Functionnalized Organometallic](https://reader030.vdocuments.us/reader030/viewer/2022012708/61a872a6efb1266df313092b/html5/thumbnails/79.jpg)
R-M
R-X-R’
R-X-M
R-B(R’)2
R-Si(R’)3
Functionnalized Organometallic Reagents
Organolithium Chemistry
R-M
R’-XR-R’
Preparation via Deprotonation
Stereoselective Formation of Organolithiums – With Stabilising Effect
Stable for 2,5 h
Stable for 1,5 h