The Suzuki cross-coupling reaction involves the coupling of organoboranes and organic halides or triflates catalyzed by nickel or palladium. The reaction proceeds via an oxidative addition, transmetallation, isomerization, and reductive elimination mechanism. It has advantages over similar cross-coupling reactions as it uses cheaper and less toxic boronic acid reagents and produces easily removable inorganic byproducts. The reaction finds applications in synthesizing intermediates for potential CNS agents and active anti-leukemia agents.

1. 1

2. SUZUKI CROSS-COUPLING REACTION
Dr. Shahid Rasool Suzuki Cross-coupling reaction CHEM5128
Advanced Named Reactions
2

3. Key Concepts
• Suzuki Cross-Coupling reactions
• Discussion of reacting species, catalysts, solvents
• Mechanism of reaction
• Explanation of mechanism step by step
• Synthetic applications
3

4. Suzuki Cross-coupling Reaction:
• Suzuki cross-coupling reaction is also known as Suzuki-Miyaura
cross-coupling reaction.
• Ni or Pd catalyzed cross-coupling reaction
• Suzuki cross-coupling reaction is between organoboranes and
organic halides, triflate etc.
• Overall reaction is given as,

5. Similar Cross-coupling Reactions:
• This reaction is similar to following reactions also using Ni or Pd,
• Negishi cross-coupling reaction (Organozinc reagents, RZnX)
• Stille cross-coupling reaction (Organostannanes reagents, R4Sn)
• Hiyama cross-coupling reaction (Organosilicons, RSiF3)
• Kumada cross-coupling reaction (Grignard reagent, RMgX)

6. Alkyl halides (R-X):
• R = Vinyl, Aryl groups
• High rates have been observed for vinyl or aryl groups
• A limitation for alkyl group is that there are chances of elimination
if there is β-hydrogen.
• X = Cl, Br, I
• Order of rate = I > Br > Cl as bond energy R-I > R-Br > R-Cl
C2H5-
C3H7-
Alkyl group
CH2 CH
Vinyl group Phenyl group Aryl group
R
R CH2 CH2 X


7. Triflates and tosylates:
• R = Vinyl, Aryl groups
• If X = OTf then called Triflates,
• If X = OTs then called Tosylates
• Good leaving groups due to resonance stabilized anions.
• The distribution of charge on large number of atoms provides
stability because it becomes easy for the medium molecules to
solvate it.
OTf = F3C S
O
O
O
OTs = S
O
O
OH3C
F3C S
O
O
O F3C S
O
O
O F3C S
O
O
O

8. Organoboranes:
• It is generally referred to vinyl, aryl boronic acids (cheap reagents)
• Side effect of these reagents is the “protodeboration”
• Protodeboration is referred to breakage of C-B bond.
• This problem is solved by using aryl trifluoroborate salts-less
susceptible to protodeboration

9. Catalysts:
• Initially Palladium (Pd), then Nickel (Ni), also Fe, Cu and Ru
• ‘Ni’ was better option but requires large amount for some reactions
• Complexes of these metals are used.
• Bidentate phosphine ligands e.g. dppe, dppp for Pd & Ni
• Pd complexes are air sensitive (Argon/N2 atmosphere)
P
P
Ph
Ph
Ph
Ph
P P
Ph
Ph
Ph
Phdppe dppp

10. Solvent:
• Reaction can run in biphasic (organic & aqueous), only aqueous or
without solvent.
• Water more economical and safe
• Other solvents include Toluene, THF (tetrahydrofuran), dioxane,
DMF (dimethylformamide) etc
Base:
• A number of bases have been employed including
• K2CO3, KOtBu, Cs2CO3, K3PO4, NaOH, NEt3

11. Overall Pd-catalyzed Mechanism-1:
II
II
II

12. Step-1, Oxidative addition:
• This step is known to follow concerted mechanism of addition.
• Pd(0) is oxidized to Pd(II)
• R-X is added in concerted way
• Both ‘R’ and ‘X’ are attached to ‘Pd’ through its primary valency.
• Secondary valency ‘4’ is already justified by bidendate ligands.
Pd
L X
L2Pd(0)
R X
L2Pd(0)
R X
R LII

13. Step-2, Transmetallation:
• It is interchanging of metals attached to different groups.
• First base reacts with organic borane to form a salt.
• 4th bond of boron can be explained as,
• 5B=1s22s22px
12py
02pz
0 (Ground), 5B= 1s22s12px
12py
12pz
0 (Excited)
• Transmetallation in Suzuki cross-coupling reaction is
M1 R M2 X M1 X M2 R
M1
R
X
M2
Pd
L X
R LII
Pd
L X
R LII
BR1
Y
Pd
L R1
R LII
OR2
Y
Na
B
Y
OR2Y NaX
BR1
Y
OR2
Y
Na
B
R1 Y
Y
Na OR2

14. Step-3, Isomerization:
• Isomerization involves the rearragement of complex in such a way
that R- groups move in adjacent position
• This step is thought to be completed along with the last step of
transmetallation.
Pd
L R1
R LII
Pd
L R1
L RII

15. Step-4, Reductive elimination:
• This step is also known to follow concerted mechanism of
elimination.
• Pd(II) is reduced to Pd(0)
• R-R1 is eliminated from the complex in a concerted way
Pd
L R1
L RII
Pd
L R1
L RII
L2Pd(0)R R1

16. 16
Overall Pd-catalyzed Mechanism-2:

17. Step-1 (Oxidative addition): similar to last mechanism
Step-3, Reaction of base & organo-boranes:
Pd
L X
R LII
NaXNa OR 2
Pd
L OR2
R LII
BR1
Y
OR2
Y
Na
B
R1 Y
Y
Na OR2
Step-2, Reaction with base:
Step-4, Transmetallation:
Pd
L OR2
R LII
Pd
L OR2
R LII
BR1
Y
Pd
L R1
R LII
OR2
Y
Na
B
Y
OR2Y Na OR2
Step-5 (Isomerization), Step-6 (Reductive elimination)
similar to last mechanism

18. Advantages of Suzuki cross-coupling reaction:
• Cheap boronic acids
• Mild reaction conditions
• Organoboranes less toxic than Organostannanes or Organozinc
• Easy to remove the inorganic by-products from reaction mixture

19. Synthesis of intermediate for potential CNS agent:
Synthesis of active anti-leukemia agent: