Development of Palladium-Catalyzed
C-N Bond Formation Reaction
Wu Hua
2010.4.24
First Intermolecular Carbon-Nitrogen
Bond Formation
In 1983 Kosugi et al. published report of intermolecular carbon-nitrogen bond
formation. Only electron neutral aryl bromides gave products in good yields.
Vinyl Bromides and aryl bromides containing electron donating or electron
withdrawing groups gave products in low yields.
R
R
Br
+
Bu3SnNR 2
[(o-MeC6H4)3P)2PdX2
NR2 +
Bu3SnBr
Only Unhindered dialkyl amides gave good yields of amination products.
M. Kosugi, M. Kameyama, T. Migita, Chem. Lett. 1983, 927
First Intramolecular Carbon-Nitrogen
Bond formation
First example of palladium(0) mediated carbon-nitrogen bond formation using
stoichiometric quantities of palladium(0) was reported by Boger in 1984
O
O
O
N
O
N
EtO
OEt
EtO
OEt
Pd(PPh3)4
H2N
HN
Br
eq. Pd(PPh3)4
Solvent
Temperature/oC
Time/h
Yield/%
1.0
THF(sealed tube)
80
20
50
1.2
THF(sealed tube)
80
21
81
1.5
THF(sealed tube)
80
21
84
1.2
Dioxane
100
20
50
1.5
Dioxane
100
24
73-80
1.2
Toluene
100
24
43
0.01
THF(sealed tube)
80
24
0
D. L. Boger, J. S. Panek, Tetrahedron Lett. 1984, 3175
Catalytic examples using amino stanannes
Work reported by S. Buchwald:
R''
Br
R''
o
Bu3Sn-NEt 2 + HNRR'
~80 C
-HNEt 2
Bu3Sn-NRR'
NRR'
1-2.5 mol% Pd cat.
Toluene, 105oC
Examples:
Ph
EtO2C
N
88 %
Ph
Me2N
N
81 %
H
N
66 %
N
55 %
A. S. Guram, S. L. Buchwald, J. Am. Chem. Soc. 1994, 7901.
Catalytic examples using amino stanannes
Work reported by J. Hartwig:
R
Br
+
Bu3SnNMe 2
[(o-MeC6H4)3P)2PdX2
R
75-85%
Catalytic cycle:
NMe2
L2PdX2
L(NHR 2)PdX2
R=Me,Et
reduction/
L2Pd
ArNR2
dissoc.
ArBr
L-Pd
L
L
NR2
Br
Ar
Ar
Pd
Pd-L
Pd
Ar
n=1,2
Br
Br
Pd
Ar
L
A lot of advantages !
BrSnBu3
R2NSnBu 3
F. Paul, J. Patt, J. F. Hartwig, J. Am. Chem. Soc. 1998, 5969.
Achieving the Same Chemistry Without
the use of Tin Reagents
Work reported by J. Hartwig:
L2Pd or L 2PdCl2
ArBr + HNRR'
LiN(SiMe3)2
L=P(o-tol) 3
ArNRR'
Catalytic cycle:
reduction
L2PdCl2
L2Pd
ArNR 2
ArBr
L-Pd
L
Ar
NR2
Br
Pd
Pd
Pd-L
L
H
HN(TMS) 2 + LiBr
Ar
Br
Ar
Br
Br
Pd
Ar
NR 2
Pd
L
Ar
HNR 2
LiN(TMS) 2
J. Louie, J. F. Hartwig, Tetrahedron Lett. 1995, 3609.
L
Achieving the Same Chemistry Without
the use of Tin Reagents
Work reported by S. Buchwald:
I
+
cat. Pd 2(dba)3
P(o-tolyl) 3
t
NaO Bu
Dioxane
o
o
65 C or 100 C
HNRR'
R
NRR'
R
Tested a variety of aryl iodides with primary and secondary amines:
I MeO
I
I Cl
I
O
H
N
MeO
HN
HNBu 2
HN
O
O
H2N
I I
NBu2
Good yields for all, 59-79%.
J. P. Wolfe, S. L. Buchwald, J. Org. Chem. 1996, 1133.
NH2
n-Hexyl-NH 2
Catalyst Development
Buchwald found dramatic improvements in yield and substrate generality by
using BINAP as the ligand
Catalyst loadings are also significantly reduced
PPh2
Ph2P
Br
+
RNH 2
Pd2(dba)3
BINAP
t
NaO Bu
Toluene
o
80 C
NHR
R
Mol% Pd
Reaction time/h
Yield/%
n-hexyl
0.5
2
88
Bn
0.5
4
79
Bn
0.05
7
79
Cyclohexyl
0.5
18
83
Compared with 35% when using P(o-tolyl)3 and R = n-hexyl
J. P. Wolfe, S. Wagaw, S. L. Buchwald, J. Am. Chem. Soc. 1996, 7215.
BINAP Reaction Mechanism
Pd2(dba)3 + BINAP
(BINAP)Pd(dba)
ArNRR'
ArBr
(BINAP)Pd
(BINAP)Pd(Ar)[NRR']
(BINAP)Pd(Ar)(Br)
NaBr + HOtBu
NHRR'
(BINAP)Pd(Ar)(Br)
t
NaO Bu
Catalyst development
Hartwig developed a dppf based system that shows enhanced catalytic qualities
PPh2
Fe
PdCl2
P
Ph2
Good for primary amines and works on electron deficient aryl halides
R
t
X + H2NR + NaO Bu
5mol% (DPPF)PdCl2
DPPF
THF
o
100 C/~3h
R
M. S. Driver, J. F. Hartwig, J. Am. Chem. Soc. 1996, 1133.
NHR
Coupling of Secondary Acyclic Amines
Bu
0.25 mol% Pd2(dba)3
0.75 mol% Ligand
Br
N
t
+
Bu2NH
Bu
1.4 equiv. NaO Bu
toluene
o
80 C
t-Bu
t-Bu
PPh2
Fe
(rac)-BPPFA
PPh2
OMe
NMe2
NMe 2
PPh2
PPh2
PPh2
Fe
Fe
Fe
FcPPh2
(rac)-PPFA
(rac)-PPF-OMe
Ligand
Time/h
Isolated yield/%
P(o-tolyl)3
48
77
BINAP
48
-
DPPF
48
-
(rac)-BPPFA
48
-
FcPPh2
48
-
(rac)-PPFA
24
89
(rac)-PPF-OMe
5
93
J. Marcoux, S. Wagaw, S. L. Buchwald, J. Org. Chem. 1997, 1568.
Coupling of Aryl Triflates
Buchwald:
2 mol% Pd(OAc)2
BINAP or Tol-BINAP
OTf
+
HNRR'
R
NaOtBu
Toluene
80oC
NRR'
R
Hartwig:
1-5 mol% Pd(OAc)2
3-10 mol% BINAP or DPPF
OTf
R
+
HNRR'
1.5 equiv. NaOtBu
Toluene
85oC
NRR'
R
Both systems use electron rich and electron poor aryl triflates with primary
and secondary amines (cyclic and acyclic)
J. P. Wolfe, S. L. Buchwald, J. Org. Chem. 1997, 1264.
J. Louie, M. S. Driver, B. C. Hamann, J. F. Hartwig J. Org. Chem. 1997, 1268.
Intermolecular Markovnikov Hydroamination
of vinylarenes with alkylamines
NRR'
5 mol% Pd(O2CCF3)2
10 mol% DPPF
HNRR'
+
20 mol% CF3SO3H
R
o
R
Dioxane, 120 C, 24 h
Via:
HNRR'
(DPPF)Pd
OTf
Bn
Amines:
HN
O
HN
NR
HN
HN
n = 1,2
Me
Products formed in 43-79 % yield
M. Utsunomiya, J. F. Hartwig, J. Am. Chem. Soc. 2003, 14286.
n-hexyl
HN
Me
Synthesis of Enamines and Imines
R1
Pd(OAc)2/BINAP or
Pd2(dba)3/BINAP
Br
R2
+
N
H
R2
t
NaO Bu
R3
R1
N
Toluene
R3
Examples:
O
N
N
N
96 %
96 %
75 %
O
N
O
O
O
N
N
N
Bn
95 %
BnO
86 %
C7H15
96 %
96 %
M. Fernández, F. Aznar, C. Valdés, J. Barluenga, Chem. Eur. J. 2004, 494.
Scope and Limitations of the Pd/BINAP-Catalyzed
Amination of Aryl Bromides
Catalytic Amination of Aryl Bromides Using NaO-t-Bu as the Base.
Note: When the weak base Cs2CO3 is employed, a much wider variety of functional
groups are tolerated.
John P. Wolfe, Stephen L. Buchwald. J. Org. Chem. 2000, 65, 1144-1157
Application In The Synthesis
Cl
Cl
N
O
N
NO
O
N
NH
Pd2(dba)3, BINAP
O
Br
N
N
N
NaOBu-t, 81%
OTBS
Cl
Cl
N
N
NO
O
O
O
N
N
N
N
N
OTBS
Tanoury, G. J. Senanayake. Tetrahedron Lett. 1998, 39, 6845
Selective Cross-Coupling Using BINAP
Pd2(dba)3
N
Cl
N
N
BINAP
+
H2N
NH
N
NH
NaOBu-t
F
F
Selectivity
35:1
Yield: 85%
Hong. Y. Tetrahedron Lett. 1998, 39, 3121
NH
Stephen L. Buchwald. J. Am. Chem. Soc. 2003, 125, 6653-6655
Jacqueline E. Milne, Stephen L. Buchwald. J. Am. Chem. Soc. 2004, 126, 13028-13032
Catalyst Activation Mechanism
Eric R. Strieter, Stephen L. Buchwald. Angew. Chem. Int. Ed. 2006, 45, 925 –928
O
X
R
+HN
2
H
N
Pd2dba3, Ligand
R'
K3PO4, t-BuOH
R
R'
O
Stephen L. Buchwald. J. Am. Chem. Soc. 2007, 129, 13001-13007
A New Class of Air- and Moisture- stable
Pd Precatalysts
They are particularly useful in cases where a highly active Pd complex is required
to promote a difficult cross-coupling reaction or where functional group instability
requires the use of low temperatures.
Mark R. Biscoe, Brett P. Fors, Stephen L. Buchwald. J. Am. Chem. Soc. 2008, 130, 6686–6687
Chemoselective Cross-coupling Reactions
Debabrata Maiti and Stephen L. Buchwald. J. Am. Chem. Soc. 2009, 131, 17423–17429
Stephen L. Buchwald. J. Am. Chem. Soc. 2009, 131, 16720–16734
Application In Suzuki-Miyaura Reaction
Reduce the loading of catalyst !
Kelvin Billingsley , Stephen L. Buchwald. J. Am. Chem. Soc. 2007, 129, 3358 3366
N
O
O
O
O
O
O
TDA
Brett P. Fors, Stephen L. Buchwald. J. Am. Chem. Soc. 2009, 131, 12898–12899
Cross-coupling Reaction With Ammonia
Difficulties Suffered:
First, the dative ancillary ligands can be displaced by ammonia to form a
catalytically unreactive complex.
Second, reductive elimination from an Ar-Pd-NH2 complex has never been
observed, perhaps because complexes of the parent amido group often adopt
stable bridging structures.
Third, if reductive elimination did form the arylamine, this product would likely be
more reactive than ammonia and would further react to form the diarylamine.
Qilong Shen and John F. Hartwig. J. Am. Chem. Soc. 2006, 128, 10028-10029
(i) many kinds of transition metals are deactivated by ammonia to give stable amine
complexes and
(ii) when a reaction forms a primary amine, this product is more reactive than ammonia
and causes problematic overreactions.
It is noteworthy that the use of aqueous ammonia is essential and that
ammonia gas did not react at all !
.
Takashi Nagano and Shu Kobayashi. J. Am. Chem. Soc. 2009, 131, 4200–4201
Palladium-Catalyzed Asymmetric Dearomatization
of Naphthalene Derivatives
Stephen L. Buchwald. J. Am. Chem. Soc. 2009, 131, 6676–6677
Conclusion
First-generation catalyst: Pd/P(o-tolyl)3
Second-generation catalyst: Pd/aromatic phosphines
PPh2
PPh2
Fe
PdCl2
Ph2P
P
Ph2
BINAP
DPPF
Third-generation catalyst: Pd/Hindered alkylphosphines
i-Pr
PCy2
i-Pr
1. One kind of the Buchwald-Hartwig cross-coupling reaction
substrates must be aryl halides and aliphatic halides have not
been reported.
2. It will be paid more attention to its use in asymmetric synthesis.