C-C bond generation in Organic chemistry

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