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