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’
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
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
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
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.
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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)
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
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
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)
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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)
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?
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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 »
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
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 »
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 »
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 »
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
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
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
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
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