The Buchwald-Hartwig reaction

Question 1

This is an example of the Buchwald-Hartwig reaction for C-N formation
What is the product?

Answer 1

• Ligand exchange occurs because amines are good ligands for palladium
• Same reaction can be used to couple amides to aromatic rings

Question 2

What is the structure of Pd₂(dba)₃ ?

Answer 2

Question 3

What is the product of this reaction?

Answer 3

dba ligands are easily displaced
Forming Pd(0) used to catalysed this reaction

Question 4

What happens in the Buchwald-Hartwig reaction once the Pd(0) catalyst is formed

Answer 4

Oxidative addition

Question 5

What happens in the Buchwald-Hartwig reaction after oxidative addition

Answer 5

x = Br
Ligand exchange
Try to think that nitrogen her is more a good ligand for palladium than it is a nucleophile

Question 6

What happens in the Buchwald-Hartwig reaction after ligand exchange

Answer 6

• Deprotonation at the nitrogen
• Substitution for PR3 ligands

Question 7

What is the last step of the Buchwald-Hartwig reaction

Answer 7

Question 8

When alkyl amines are used in the Buchwald-Hartwig reaction, what can occur?

Answer 8

Competing beta-hydride elimination can lead to unwanted by-products
(PR₃ forms new bond with Pd)
This is a fast reaction
(thought for a long time this eliminatin meant aryl amines couldn’t be used)

Question 9

How can we stop beta-hydride elimination occuring for alkyl amines

Answer 9

• For beta hydride elimination there needs to be a vacant d-orbital on the palladium which can accept electron-density from C-H bond
• Chelating phosphine ligands can suppress beta-hyride elimination by blocking the vacant coordination site required for this process

Question 10

What is the Pd intermediate and product of this Buchwald-Hartwig reaction with an aryl amine

Answer 10

Question 11

The molecule below is a drug to control blood clotting
Identify the bonds that could be made via Buchwald-Hartwig cross coupling

Answer 11

Question 12

The molecule below is a drug used to control blood clotting
Identify the starting material from retrosynthesis

Answer 12

Question 13

There is a selectivity issue forming C-N bonds using the Buchwald-Hartwig reaction from these starting products
What is one way this can be overcome?

Answer 13

Using protecting groups to undertake the Buchwald-Hartwig reaction on just one nitrogen

Question 14

What type of reaction needs to be undertaken to form a C-N bond
And what is the mechansim?

Answer 14

Question 15

What type of reaction needs to be undertaken to form a C-N bond
And what is the mechansim?

Answer 15

Question 16

So if the Buchwald-Hartwig coupling achieves the same nucleophilic aromatic substitution (SₙAR)
Why would you chose nucleophilic aromatic substitution?

Answer 16

• Leaving group: F>Cl>Br>I
• Regiochemistry: there must be an electron-withdrawing group (R’ = F, NO₂ ,CF₃, etc) ortho or para to the leaving group
• No expensive Pd catalyst required

Question 17

So if the Buchwald-Hartwig coupling achieves the same nucleophilic aromatic substitution (SₙAR)
Why would you chose the Buchwald-Hartwig reaction

Answer 17

• Leaving group: I>Br>Cr»F
• Iodide is the best at oxidative addition step, but chloride works as well (aryl chlorides are cheaper)
• Regiochemistry: Any substitution (R’) works