Suzuki – Miyaura coupling, Sonogashira coupling ,Stille coupling, Negishi coupling Suzuki Miyaura- Pd catalyzed cross coupling reaction of organoboron compounds with organic halides. Sonogashira coupling - coupling of a terminal alkynes with aryl or vinyl halides with a Pd catalyst,a Cu(1) co-catalyst and an amine base. Stille coupling- Pd catalyzed cross coupling reaction involving organotin based reagents and organohalides.

1. SHAFNA JOSE
ASSISTANT PROFESSOR
DEPARTMENT OF CHEMISTRY
ST. MARY’S COLLEGE
THRISSUR – 680020
KERALA
COUPLING REACTIONS – PART 2

2. Contents
Sonogashira coupling
Stille coupling
Negishi coupling
Suzuki – Miyaura coupling

3. Suzuki Coupling ReactionSuzuki – Miyaura Coupling
• It is a Pd catalyzed cross coupling reaction of organoboron compounds
with organic halides.

4. • It is one of the most powerful reactions in synthetic chemistry for c-c bond
formation as it can tolerate the presence of functional groups in the coupling
partners.
• This requires conditions milder than that for Heck reaction.
• The boronic acids are air and water stable as well as nontoxic. The
pharmaceutical industry therefore prefers this reaction.
• Trifluroborates,organoboranes or cyclic boronate esters can also be used in
the place of boronic acids.

5. • A necessary component of the reaction is the base
• Difference between the Suzuki reaction and the Stille coupling is that the
boronic acid must be activated with a base.
• The activation of the boron atom enhances the polarization of the organic
ligand and thus facilitates transmetallation.
• Suzuki coupling has been used in the synthesis of retinol and
polypataphenylene.

6. • Synthesis of retinol :
• The scope and utility of this reaction includes
- the use of aryl chlorides as substrates
- the ability to conduct the reaction at very low catalyst loading
- to carry out the reaction at room temperature
- to couple highly hindered substrates and to carry out assymetric
synthesis.

7. Catalytic cycle for Suzuki – Miyaura coupling

8. • A wide variety of phosphine component in the metal catalyst has been used.
Stephen Buchwald used Pd with an electron rich phosphine bearing biphenyl
while Gregory Fu used a bulky aliphatic phosphine P(t-Bu)3.
Sterically hindered and electron rich Buchwald phosphines.

9. The success of these ligands over conventional phosphines has been due to a
combination of two factors:
a)Their electron richness enhances the rate of oxidative addition of aryl
chlorides to Pd and prevents the palladium complex from precipitating out.
b)Their steric bulk enhances the rate of reductive elimination.

10. • Suzuki reaction has been extended to coupling between alkyl and aryl
groups.
• Nickel based catalysts along with amine bases are often required for these
reactions

11. Sonogashira Coupling
• The coupling of a terminal alkynes with aryl or vinyl halides with a Pd
catalyst,a Cu(1) cocatalyst and an amine base.
• In this reaction, alkynylcuprate, formed by the reaction of copper with
alkyne,reacts further with a palladium catalyst.
• Sonogashira reaction is similar to Castro-Stevens coupling.
• This reaction usually uses mild conditions, often room temperature and
therefore it can tolerate a large number of functional groups.

12. • A common strategy for used for introducing terminal alkyne group is the
Sonogashira coupling of trimethylsilyl alkyne followed by treatment with a strong
base or a fluoride source.
• The geometry about the double bond is preserved if the Sonogashira reaction is
performed on a halo alkene.
• This is extremely useful for the synthesis of enyne molecules with specific
geometry.

13. Catalytic cycle for Sonogashira coupling

14. • This reaction provides a method for making even conjugated acetylenic compounds
and this type of molecules have found application in wide areas ranging from natural
products and pharmaceuticals to molecular organic materials in nanoscience.
• Sonogashira coupling has been used
a) in the synthesis of (Z)-enediynes.
b) has been extended to unactivated alkyl bromides using NHC ligands such as
IAd.

15. Stille Coupling
• It is a Pd catalyzed cross coupling reaction involving organotin based
reagents and organohalides.

16. Catalytic cycle for Stille Coupling

17. • The R group of the halide covers a broad range but do not contain β hydrogens as this
will initiate β hydrogen elimination instead of reductive elimination.
• The organostannane however can have β hydrogens.
• No base is required for this reaction.
• No activation of the organostannyl reagent is required.
• In this mechanism, a cyclic transmetallation leads to the exchange of L for R2 and
forces retention of configuration.

18. Negishi coupling
• Cross coupling reaction that involves an organozinc compound, an
organic halide and a nickel or palladium catalyst and creates a new c-c
bond.
• Coupling of heterocyclic rings is done by this method
• Active catalyst is Pd(0)
• The reaction proceeds through
oxidative addition of the organic halide,
transmetalllation with zinc compound,
reductive elimination.

19. • Compounds prepared by Negishi coupling include hexaferrocenyl benzene and
pentaferrocenyl cyclopentadienyl manganese tricarbonyl.
• Negishi coupling is preferred over Stille coupling for alkenylation; Eg:

20. • Aryl chlorides can be further alkynated by Negishi coupling, whereas
Sonogashira coupling occurs preferentially on aryl iodides

21. Catalytic cycle for Negishi coupling

22. Catalytic cycle involves
 oxidative addition of RX to the Pd(0) catalyst
 transmetallation of RZnX on the palladium
 Cis/trans isomerization
 Reductive elimination

23. Buchwald- Hartwig C-N Cross coupling
• Coupling of aryl halide with an amine in the presence of Pd catalyst
forming aromatic amines
• This reaction is used in the synthesis of many natural products and
nitrogen containing heterocycles

24. Synthesis of indoles and carbazoles by Buchwald–Hartwig coupling

25. Catalytic cycle for Buchwald-Hartwig – C-N cross coupling

26. • The palladium precursor is stabilized in solution by an adequate ligand which
increases the electron density at the metal to facilitate oxidative addition and is
sufficiently bulky to accelerate reductive elimination of the product.
• A base is required to deprotonate the amine substrate prior to or after coordination
to the palladium centre.
• The solvent plays a prominent role due to the heterogeneous nature of the reaction

27. Thank you