Chem 332 Spring 2014
Palladium-Catalyzed Cross Coupling Chemistry:
Modern Nucleophilic Aromatic Substitution
Prof. Donald Watson
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Transition Metals
Orbitals: 2s
http://winter.group.shef.ac.uk/orbitron/AOs/
Orbitals: 2p
http://winter.group.shef.ac.uk/orbitron/AOs/
Orbitals: 3s
http://winter.group.shef.ac.uk/orbitron/AOs/3d/index.html
Orbitals: 3p
http://winter.group.shef.ac.uk/orbitron/AOs/3d/index.html
Orbitals: 3d
dx2-y2
dz2
dxy
dxz
dyz
http://winter.group.shef.ac.uk/orbitron/AOs/3d/index.html
Heck Reaction
Me
LnPd(0)
Br
+
Et3N
Me
UD Prof. Emeritus Richard Heck, 2010 Nobel Prize in Chemistry
The Heck Reaction
Et3N·HBr
Me
LnPd(0)
Et3N
Br
Oxidative Addition
H
LnPd
Me
Br
Me
LnPd
Br
H
β-hydride elimination
Me
PdLnBr
Me
PdLnBr
Migratory Insertion
Substrates for Heck Reactions
Aryl halides and “psuedo-halides” can be coupled in Heck reactions:
R
X
R
LnPd(0), base
O
O S CF3
O
X = I, Br, Cl, or
(triflate)
Vinyl halides and “psuedo-halides” can also be coupled in Heck reactions”
R1
X
R2
LnPd(0), base
R1
R2
Three Types of Precatalysts
1) Pd(0) Precatalyst
CF3SO2O
Me
Me
Me
OR
Me
O
O
Me
Me
Me
Pd(PPh3)4
O
H
O
OR
Me
OBn
Cs2CO3, MeCN, 90 °C
O
H
O
O
O
OBn
Three Types of Precatalysts
1) Pd(0) Precatalyst
1.5 mol% Pd2(dba)3
6 mol% tBu3P
Cl
+
MeO
CO2Me
Cs2CO3, dioxane, 120 °C
CO2Me
MeO
with PPh3 no reaction with ArCl!
O
dba:
Ph
Ph
Three Types of Precatalysts
2) Pd(II) Precatalyst
TBSO
NHR
TBSO
I
MeO
N
O
2 mol% Pd(OAc)2
6 mol% PPh3
Et3N, MeCN, 80 °C
TBSO
NHR
TBSO
MeO
N
O
MeO
MeO
Pd(II)(OAc)2 is reduced in situ by PPh3 (and trace water) to give Pd(PPh3)n
Three Types of Precatalysts
3) Jeffery “Ligandless” Conditions
I
+
CO2Me
5 mol% Pd(OAc)2
NaHCO3, Bu4NCl
DMF, 50 °C
Pd nanoparticles
Pd atom (or small cluster)
active catalyst
CO2Me
Palladium Sources
Palladium (0) Sources
Palladium (II) Sources
(Reduced In Situ)
O
Pd(OAc)2
Pd2(dba)3
dba:
Ph
Ph
Pd(Cl)2
(MeCN)2PdCl2
Pd(PPh3)4
Note: dba and PPh3 are ligands.
Pd
Cl
2
Ligands
Ar X
X = TfO, I, Sometimes Br (easy oxidative addition)
PPh3
Ph2P
PPh2
PPh2
Fe
dppe
PPh2
dppf
X = Br
P(o-tol)3
O
PPh2
PPh2
R'
X = Cl
PR'2
Pt-Bu3, PCy3, NHC's
R
R'=Cy, t-Bu
Ligand is the most important part of the catalyst for controlling reactivity
Notes on the Heck Reaction
Intermolecular (alkene and halide on different molecules):
•  Somewhat limited scope.
•  Normally limited to CH2CH2, mono- and di-substituted alkenes.
•  Tri- and tetra-sub. alkenes are too poor of ligands to engage Pd(II)
intermediate.
Electron-rich alkenes generally better than electron-poor.
•  Regioselectivity is often poor.
Intramolecular (alkene and halide tethered together):
•  Much better scope.
•  Can form carbocycles and hetereocycles of all types.
•  Mono-, di-, tri- and tetra-substituted, electron-rich and electronpoor alkenes all work.
Asymmetric Intramolecular Heck Reaction
MeO
I
OSiR3
O
N
Me
OSiR3
Me
Pd(OAc)2
(S)-Binap
MeO
O
N
Me
84% yield
95% ee (97.5:2.5)
Me
PPh2
PPh2
Binap:
Chiral
Can be resolved
Overman, JACS, 1998, 120, 6500
The Suzuki Reaction
LnPd(0)
Br
+
Me
HO B
OH
NaOH
+ B(OH)3 + NaBr
Me
Note: Aryl halide can be electron-rich or electron-poor, both work!
Aryl boronic acid can also be electron-rich or poor!
Works for aryl chloride, bromides, iodides, triflates, etc.
Akira Suzuki – Hokkaido University, Japan
2010 Nobel Prize
Negishi Reaction
LnPd(0)
Br
+
Me
BrZn
+ ZnBr2
Me
Ei-ichi Negishi– Purdue University
2010 Nobel Prize
Related Cross Coupling Reactions
Kumada Coupling:
LnPd(0)
Br
+
BrMg
CsF
Me
+ MgBr2
Me
Stille Coupling:
LnPd(0)
Br
+
Me
Bu3Sn
CsF
+ Bu3SuBr
Me
Hiyama Coupling:
LnPd(0)
Br
+
Me
Me3Si
CsF
+ Me3SiF + CsBr
Me
All Proceed By Similar Mechanism
Me
Me
LnPd(0)
X
Reductive Elimination
X = Cl, Br, I, OTf, etc
Oxidative Addition
Me
Me
LnPd
LnPd
X
M = metal [ B(OH)2, Bu3Sn, MgBr, etc]
MX
M
Transmetallation
Reactions Also Work With Vinyl Substrates
Bu
Bu
Me
Br
+
HO B
OH
Me
NaOH
Me
+ B(OH)3 + NaBr
Me
LnPd(0)
Br
+
Ph
LnPd(0)
BrZn
+ ZnBr2
Ph
Example of Hiyama Reaction
MeO
I
MeO
CO2Me
MeO
OMe
O
EtOMe2Si
MeO
O
[{(C3H5)PdCl}2], P(OEt)3
TBAF, THF, 60 ºC, 2 h
OMe
O
MeO
MeO
O
OMe
> 76%
O
MeO
MeO
O
N
Me
nitidine
antileukemic
Hanaoka, Tetrahedron Lett., 1995, 9505
Cross Coupling With Heteroatomic Nucleophiles
Cl
+ tBuOH
+
N
Me
H
N
LnPd(0)
H2N
tBuONa
N
Me
Me
Me
Me
O
LnPd(0)
Cl
+
HO
Me
O
KOH
O
+ H2O + KBr
Buchwald-Hartwig Coupling
Stephen Buchwald, MIT
John Hartwig, UC Berkeley
Similar Mechanism to C-C Bond Forming Reactions
Me
Me
LnPd(0)
Br
Oxidative Addition
NR2
Reductive Elimination
Me
Me
LnPd
LPd
Br
NR2
Me
HNR2
BHX
B
LPd Br
N R
H
R
Transmetallation
R3NH+ like (pKa ~ 9)
Olefin Metathesis
R1
R1
R2
R2
cat.
R1
+
R1
R1
R2
Me
Me
Me
R2
R2
R1
R2
Me
Me
O
R2
R1
"G2"
Me
Me
Ph
Me
PCy3
Cl
Ru
iPr
N
O Mo
R1
+
"G1"
iPr
R2
Cl
N
Me
Ph
PCy3
Me
Cl
Me
Ru
Ph
Cl
PCy3
Me
Me
molybdenum(IV) alkylidene
(Schrock, MIT)
N
ruthenium carbenes
(Grubbs, CalTech)
Schrock, Grubbs, and Chauvin Nobel 2005
Me
General Mechanism
Chauvin-­‐Katz “Chauvin Mechanism”
mechanism R2
R1
retro [2+2]
M CH2
M CH2
M CH2
R2
R1
R1
M
[2+2]
CH2
R1
CH2
R1
CH2
M CH2
CH2
R2
[2+2]
retro [2+2]
R1
M
R2
CH2
R1
CH2
CH2
waste ethylene
Types of Alkene Metathesis
Cross Metathesis:
cat.
R1
CH2
+
H2C
R2
M CHR
R2
R1
Ring Closing Metathesis (most useful for small molecule synthesis):
cat.
R
H2C
R
M CHR
CH2
Ring Opening Polymerization (widely used for making polymers):
cat.
R
M CHR
R
R
n
Ring Closing Metathesis
BOC
GII
BOC N
O
R3SiO
Bn
OBn
H2C CH2 (Gas evolution)
O
N
O
N
OTBS
GI
0.005M
O
O
NR2
Bn
JACS 1999, 121, 5653 (Crimmins)