cross-coupling reactions functionnalized organometallic

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’


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


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



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



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



R-M

R’-XR-R’

Secondary Alkyllithium Reagents


Tertiary Alkyllithium Reagents

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’

Alkenyllithium Reagents


Aryllithium Reagents

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



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



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



R-M

R’-XR-R’


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



R-M

R’-XR-R’


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



R-M

R’-XR-R’


Some Kinetics

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’


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



R-M

R’-XR-R’

On the Mechanism – Still Being Discussed


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



R-M

R’-XR-R’

On the Mechanism


R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’


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



R-M

R’-XR-R’


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



R-M

R’-XR-R’

Li-X Permutation of Alkenyl-X Species


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



R-M

R’-XR-R’

Li-X Permutation of Alkenyl-X Species - Selectivity


Minimisation of the Interaction

Having a Coordinating Group

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’

Li-X Permutation of Aryl-X Species


Li-X Permutation of Heteroaryl-X Species

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’


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



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



R-M

R’-XR-R’


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



R-M

R’-XR-R’


a to an oxygen (a-O)

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’


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



R-M

R’-XR-R’


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



R-M

R’-XR-R’


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



R-M

R’-XR-R’


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



R-M

R’-XR-R’


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



R-M

R’-XR-R’


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



R-M

R’-XR-R’


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



R-M

R’-XR-R’


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



R-M

R’-XR-R’



a-lithiation at benzylic sites outpaces enolisation

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’



Pyridinone Core

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’


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



R-M

R’-XR-R’


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



R-M

R’-XR-R’


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



R-M

R’-XR-R’


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



R-M

R’-XR-R’


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



R-M

R’-XR-R’


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



R-M

R’-XR-R’


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



R-M

R’-XR-R’


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



R-M

R’-XR-R’


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



R-M

R’-XR-R’


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



R-M

R’-XR-R’


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



R-M

R’-XR-R’


a to a Silicon (a-Si)

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’


Ortholithiation

Basically works

What Will Affect the Selectivity?

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’


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



R-M

R’-XR-R’


Ortholithiation

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’


R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’


Ortholithiation – Classes of Ortho-Directing Group

Oxazolines

Sulfonamides

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’


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



R-M

R’-XR-R’


Ortholithiation – All there is to know

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’


Ortholithiation - Exemples

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’



Lithium-sulfoxide Exchange

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’



R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’


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



R-M

R’-XR-R’


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



R-M

R’-XR-R’


Lateral Lithiation

Amides

Nitriles

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’


Lateral Lithiation

Carboxylates

Esters

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’


Lateral Lithiation

EnolisableKetones

Non-EnolisableKetones

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’


Lateral Lithiation

RemoteAmine

Methoxy Only Possibility

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’


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



R-M

R’-XR-R’



R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’



Metallates Preferencially Next to Powerful Electron-Withdrawing Groups

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’



R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’



ibuprofen

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’


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



R-M

R’-XR-R’


Stereoselective Formation of Organolithiums – Without Coordinating Group

R-M

R-X-R’

R-X-M

R-B(R’)2

R-Si(R’)3



R-M

R’-XR-R’


Stereoselective Formation of Organolithiums – With Stabilising Effect

Stable for 2,5 h

Stable for 1,5 h

cross-coupling reactions functionnalized organometallic

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