New progress in palladium catalyzed coupling reactions

1. New Progress in Palladium
Catalyzed Coupling Reactions
Yiming Chen
May 2nd, 2011

2. New Progress in Palladium
Catalyzed Coupling Reactions
• List of Reactions
• Mechanism of Catalysis
• New Progresses
• Summary

3. Palladium Catalyzed
Coupling Reactions
• Heck Reaction • Stille Reaction
• Suzuki Reaction • Hiyama Reaction
• Negishi Reaction • Sonogashira Reaction
• Fukuyama Reaction
• Buchwald–Hartwig Reaction

4. Palladium Catalyzed
Coupling Reactions
Name Reactant I Reactant II
Heck Reaction alkene R-X
Sogonashira Coupling alkyne R-X
Negishi Coupling R-Zn-X R-X
Stille Coupling R-SnR3 R-X
Suzuki Reaction R-B(OR)2 R-X
Hiyama Coupling R-SnR3 R-X
Buckward-Hartwig
R2-NR SnR3 R-X
Amination
Fukuyama Coupling RCO(SEt) R-Zn-I

5. New Progress in Palladium
Catalyzed Coupling Reactions
• List of Reactions
• Mechanism of Catalysis
• New Progresses
• Summary

6. Heck Reaction
Pd (0) R
R X + R'
Base R'
• R-X: X=Br, Cl, OTf; R=Aryl, Vinyl or Benzyl;
• Alkene: at least one -H, often electron-deficient;
• Metal: PdCl2, Pd(OAc)2, Pd(PPh3)4;
• Ligand: PPh3, BINAP;
• Base: Et3N, K2CO3, NaOAc;
• Trans product.
J. Org. Chem., 1972, 37 (14), pp 2320–2322

7. Heck Reaction
OCH3
OCH3
Br
L
O L Br +II
Pd
O
Pd
+II L
H3CO
H L
O H H
L Br
Pd
+II
H L
OCH3
OCH3
Br O Br
L L
O
Pd
Pd
Br +II +II
L
L L
0
Pd
L

8. Suzuki Reaction
Pd catalyst
R1-B-Y2 + R2-X R1-R2
Base
• Aryl- or Vinylboronic acid with aryl- or
vinyl-halide;
• Reactivity: R-I > R-OTf > R-Br >> R-Cl
• Catalyst: Pd (0), like Pd(PPh ) 3 4
Chem. Rev., 1995, 95 (7), pp 2457–2483

9. Suzuki Reaction
R1-R2 Pd (0)
R2-X
+II
R2-Pd-X
Y t-BuONa
R1 B- Ot-Bu
+II Y
R1-Pd-R2 +II
R2-Pd-Ot-Bu
t-BuONa
Y
R1 B
Y

10. Neigishi Coupling
MLn
R-X + R'-Zn-X' R-R'
• Reactant: Organic halide and organozinc compound;
• Catalyst: zerovalent palladium or nickle;
• Ligand: PPh3, dppe, BINAP, chiraphos;
• X=Cl, Br, I, OTf, RCOO; R=alkenyl, aryl, allyl, alkynyl
or propargyl;
• X’=Cl, Br, I; R’=alkenyl, aryl, allyl or alkyl.
Chem. Commun., 1977, 683-684

11. Neigishi Coupling
Pd(0)
R-R' R-X
R-Pd-R' R-Pd-X
+II +II
X-Zn-X' R'-Zn-X'

12. Stille Reaction
R-SnR3 + R'-X R-R' + X-SnR3
• Reactant: Organotin compound and sp2-
hybridized organic halide;
• Catalyst: palladium;
• Trimethylstannyl or tributylstannyl
compounds are used.
J. Am. Chem. Soc., 1978, 100 (11), pp 3636–3638

13. Stille Reaction
+II
Pd
R1-R2
0
PdLn R1-X
+II +II
R1-PdLm-R2 R1-PdLm-X
XSnBu3 R2SnBu3

14. Buchwald–Hartwig
Amination
• Reactant: Aryl Halide
(X could be OTf) and
amine;
•
R
Metal: Palladium X R
MLn
N
R'
+ H-N
base
• Ligand: wide range of
R'
phosphines;
• Could be extended
to C or O Nu.
J. Am. Chem. Soc., 1994, 116 (17), pp 7901–7902

15. Buchwald–Hartwig
Amination
L-Pd-L
R
Pd-L
Ar-X
Ar N
R' Ar
Ar R Ar L Pd X
L Pd
Pd N X Pd L
X
L R'
Ar
Ar R R
H
L Pd N HN
R' R'
X

16. Sonogashira Coupling
R-X Pd/Cu+
H R' R R'
base
• X=Cl, Br, I, OTf; R=Ar, alkenyl;
• Catalyst: zerovalent palladium and halide
salt of Cu(I);
• Cu(I) reacts with terminal alkyne and yields
copper(I) acetylide, which is activated
species.
Tetra. Lett., 1975, 16 (50),pp 4467-4470

17. Sonogashira Coupling
R R'
Ph3P-Pd-PPh3 R-I
R
PPh3
Ph3P-Pd-Ph3P
Ph3P-Pd-R
R
I
Ph3P-Pd-Ph3P
R'
R'
Cu+ R' Cu
R' H
Cu+
R' H
Cu

18. Hiyama Coupling
Pd (cat.)
R X + R''3Si R' R R'
F- or base
• Reactant: aryl, alkenyl, or alkyl halides (or or
pseudohalides) and organosilanes;
• Requires activation reagent like F- or base;
J. Org. Chem., 1988, 53 (4), pp 918–920

19. Hiyama Coupling
L2Pd X-R
L
R
R Pd X
L Pd R'
L
L
R''3Si-R'
L
R Pd R'
L
R''3Si-X

20. Fukuyama Coupling
O
O
+ Zn R2 Pd
R1 S I
R1 R2
Et
• Reactant: thioester and organozinc halide;
• Product: ketone;
• Reaction will stop at the ketone, won’t
produce tertiary alcohol;
Tetra. Lett., 1998, 39(20), pp 3189-3192

21. Fukuyama Coupling
O O
R R’
SEt
Pd R SEt
O
O
SEt
R
R Pd
R Pd
EtSZnI R'ZnI

22. Palladium Catalyzed
Coupling Reactions
1. Pd (0) complexes are prepared in situ from
Pd (II);
2. Oxidative Addition of Pd (0) complexes;
3. Transmetallation or ligand exchange;
4. Trans - Cis Isomerization;
5. Reductive Elimination.

23. Mechanism Study:
Oxidative Addition
• The author
postulates the
mechanism of
oxidative addition,
theoretical kinetics
property agrees with
experiment
observations.
J. Am. Chem. Soc., 2009, 131, 8141– 8154

24. Mechanism Study:
Oxidative Addition
1. Double-coordinated Pd forms π-complex
with aryl halide;
2. Ligand L is replaced by aromatic ring;
3. σ-complex forms between C-X bond and
Pd atom;
4. Pd inserts into C-X bond.
J. Am. Chem. Soc., 2009, 131, 8141– 8154
Dalton Trans., 2010, 39, 10833-10836

25. Mechanism Study:
Oxidative Addition
• Another paper
shows similar
mechanism on allyl
bromide.
Organometallics, 2006, 25, 3647-3658

26. Mechanism Study:
Transmetalation
Organometallics, 2006, 25, 3647-3658

27. Mechanism Study:
Reductive Elimination
• The mechanism
depends on
ligands and R-
groups
coordinated with
Pd atom.
J. Am. Chem. Soc., 2009, 131 (10), pp 3650–3657

28. Mechanism Study:
Reductive Elimination
1. There is no universal elimination
mechanism;
2. In most cases, elimination is direct;
3. When R= CH3 and L=CH3CN, elimination
is stepwise, initiated by dissociation of L.
J. Am. Chem. Soc., 2009, 131, 8141– 8154
Dalton Trans., 2010, 39, 10833-10836

29. Palladium Catalyzed
Coupling Reactions
1. Many Pd (0) complexes are sensitive to air
or moisture;
2. Long reaction time, high temperature;
3. Highly toxic compounds are use as ligands
in reaction;
4. Activated reactants are required.

30. New Progress in Palladium
Catalyzed Coupling Reactions
• List of Reactions
• Mechanism of Catalysis
• New Progresses
• Innovative Catalyst
• Improved Reaction Condition
• New Reaction Category
• Summary

31. Innovative Catalyst (1)
• Link ligands to nanoparticles to improve recyclability of catalyst. Could be used to
catalyze Heck reaction, Sonogashira reaction as well as cyanation reaction.
Tetrahedron, 2007, 63, pp6784–6790

32. Innovative Catalyst (1)
The new catalyst
shows good yield
on these coupling
reactions.

33. Innovative Catalyst (II)
• Magnetic nanoparticle-supported heterogeneous catalyst for Suzuki, Sonogashira,
and Stille Coupling.
Angew. Chem., 2010, 122, 1137 –1140

34. Innovative Catalyst (II)
(HO)2B
Suzuki: 71%-95%
0.5 mol% cat.
Cl +
K2CO3, TBAB, H2O
R1 R1 R2
R2
Sonogashira: 74%-96%
0.5 mol% cat.
Cl + R2 R2
piperdine TBAB, H2O
R1 R1
Stille: 81%-96%
0.5 mol% cat.
Cl + Bu3Sn-R2 R2
CsF, H2O/Et2O
R1 R1
Easy to recycle
& reuse.

35. Innovative Catalyst (III)
• Polymerized ligand also could be utilized to produce recyclable heterogeneous
palladium catalyst in aqueous system, like polyaniline (PANI) complexes.

36. Innovative Catalyst (III)
• As well as many polymer-supported catalysts shown below.

37. Innovative Catalyst (IV)
• Pd(II)/Pd(IV) high state catalytic cycle also could catalyzed coupling reactions, form
C-C, C-O, C-X, C-N bonds with reasonable yields, for both alkyl and aryl groups.
Angew. Chem. Int. Ed., 2009(48), pp9412 – 9423

38. Innovative Catalyst (IV)

39. Improved Condition (I)
• Microwave-assisted Palladium-catalyzed cross coupling reactions have been well
developed in recent years, the reaction time could be shorten a lot, yield is also
improved.
Suzuki Reaction:
Yield: 50%-99%
Ligand-Free
Tetra. Lett., 2006, 47, 6887–6889

40. Improved Condition (I)

41. Improved Condition (I)
• Microwave-assisted Palladium-catalyzed cross coupling reactions have been well
developed in recent years, the reaction time could be shorten a lot, yield is also
improved.
Stille Reaction:
Yield: 57%-94%
Eur. J. Org. Chem., 2008, 1133–1155
Synlett., 2006, 10, 1491–1496

42. Improved Condition (II)
• Besides microwave, ultrasound-promoted ligand-free Heck reaction is also
investigated recently in aqueous system.
The reactions finished in 20 min with high yield and good chemoselectivity without ligand.
Syn. Comm., 2011, 41, pp1464–1471

43. New Reactions (I)
• Some new palladium catalyzed coupling reactions have been developed in recent
years. One of them is decarboxylation cross coupling reaction with aryl halide.
J. AM. CHEM. SOC., 2006, 128, 11350-11351

44. New Reactions (II)
• Aryl halides can be coupled with potassium oxalate monoester to synthesize
aromatic esters.
With different palladium salts/ligands/aryl bromides combination, the yield is up to 98%.
J. Am. Chem. Soc., 2009, 131 (16), pp 5738–5739

45. New Reactions (II)
• Mechanism of this
reaction is also
studied by theoretical
calculation.

46. New Reactions (III)
• Similarly, decarboxylation coupling reactions catalyzed by palladium complexes also
work for sp3 carbon atom (yield is up to 96%).
J. Am. Chem. Soc., 2010, 132 (41), pp 14391–14393

47. New Reactions (III)
• Mechanism is also
studied. The
coordination of Pd
activate carboxylate
group.

48. New Reactions (IV)
Synthesis of α-Aryl Nitriles through Palladium-Catalyzed Decarboxylative
Coupling of Cyanoacetate Salts with Aryl Halides and Triflates.

49. New Reactions (IV)

50. New Progress in Palladium
Catalyzed Coupling Reactions
• List of Reactions
• Mechanism of Catalysis
• New Progresses
• Summary

51. Summary
• Palladium catalyzed coupling reactions have
been widely applied in synthetic chemistry;
• Mechanisms are well studied;
• Reactions have been improved from
different aspects, new catalysts and
reactions are developed in recent years.

52. Thanks!