Chapter 3

The Catalytic Chemistry of Palladium (0)

Pd(0) _____ Pd(II) ____ Pd(0)

G. Poli

Generation of Pd(0) from Pd(II)

Amines
Me
Me
[Pd(II)]X2

Me

NEt3

Me
NEt3

Me

N [Pd(II)]X
Me

[Pd(0)]

H[Pd(II)]X
dehydropalladation

XHNEt3

reductive elimination

Alkenes
X

[Pd(II)]X2

H2C CH2

H2C

H2C CH2

-coordination

H[Pd(II)]X

halopalladation

X[Pd]

[Pd(0)] + XH

H dehydropallad.

X[Pd]X

Organometallics
2 n-BuLi

[Pd(II)]X2

Bu-Bu

2 LiX
[Pd]

ligand subst.

Bu-n

Bu-n

[Pd(0)]
reductive elim.

G. Poli

Generation of Pd(0) from Pd(II)

Phosphines

O
H3C

(II)

Pd
O

CH3

Pd(OAc)2 + 4 PPh3 + H2O -----> (PPh3)3Pd + O=PPh3 + 2AcOH

2 Ph3P

O
Me

(0)

(II)

Pd
P

[(AcO)Pd(PPh3)]

Me

[AcO-PPh3]

fast

2 PPh3

H2O

AcOH

(0)

(0)

[AcO-Pd(PPh3)3] [AcO-PPh3]

[Pd(PPh3)3]

stable
Me

O
AcOH

O
O
H

P
O

Ozawa, F.; Kubo, A.; Hayashi, T.; Chem. Lett. 1992, 2177
Amatore, C.; Carre, E. Jutand, A.; MBarke, M.A. Organometallics, 1995, 14, 1818
G. Poli

Palladium (0) Sources

PdCl2(PPh3)2

Pd(OAc)2

Dibal, 2 PPh3
or
NH2NH2, H2O, 2 PPh3

PR3 / CO / ROH
NR3 / H2C=CH2 / RM

PPh3 [H]

K2PdCl4
Na2PdCl4

[Pd(0)]

Pd(PPh3)4

O2 (air)

(Ph3P)2PdO2

PPh3
PPh3

O
PdCl2

Ph

Ph

(dba)

NaOAc / MeOH reflux

Pd(dba)2

cryst.
CHCl3

Pd2(dba)3.CHCl3

G. Poli

Pd2(dba)3 and Pd(dba)3

O

Ph

Ph

Ph

Pd

Ph

Ph
Ph

Ph

Pd

Pd
O
O

OO

Ph
Ph

Ph

Tris-dibenzylideneacetone dipalladium (0)

Pd2(dba)3

Ph

Ph

Tris-dibenzylideneacetone palladium (0)

Pd(dba)3
In Pd(dba)3 each dba has one s-cis and one strans configured double bond.
Pd is almost in a planar geometry
Only the s-trans double bonds are involved in
complexation to Pd
G. Poli

The Catalytic Chemistry of Palladium: an Overview

Reduction Potential Pd(II) + 2e- Pd(0) : 0.951V
stoichiometric oxidating agent
H Pd X

reductive elimination

reductive elimination

Pd(0)

HX
dehydropalladation
(-H elimination)

oxidative addition
X

C C

insertion
C C Pd X
H

transmetallation
Pd X

Pd C

C C
H

C C
H

MX
PdX2

dehydropalladation
(-H elimination) Nu

CO insertion
C C

HX

NuH

Nu

M C
MX

O
C Pd X

O
C C

MX
transmetallation

O
C Pd C
PdX2
C C
H

C C Pd X
H

color code:

entering the cycle

exiting the cycle

in the cycle
G. Poli

Syn Carbopalladations:
The Mizoroki-Heck Reaction

G. Poli

The Seminal Papers

Bull. Chem. Soc. Jap.

G. Poli

The Seminal Papers

G. Poli

The Mizoroki-Heck Reaction

Pd(0) cat
base
R

base.HX

and / or
R

aryl, vinyl, benzyl (no - sp3 H, otherwise: dehydropalladation !)

X:

N2BF4, COCl, I, OTf, Br, Cl

R :

Pd cat:
base:

an alkene (neutral, rich, or poor)

a Pd(0) cat. or a Pd(II) cat. which is reduced in situ to Pd(0)
usually: NEt3, AcOK, Na2CO3...

Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev., 2000, 100, 3009; in Transition Metal Catalyzed Reactions,
Eds Murahashi, S.-I. Davies, S. I. Blackwell Science, Oxford, 1999, p. 29; Whitecomb, N. J.; Hii, K. K.;
Gibson, S.E. Tetrahedron, 2001, 57, 7449.
G. Poli

Some special ligands

are more expensive
than palladium !

Choice of the Right Ancillary Ligand

Me
CH3

H3C
O P
Pd
O

O
Pd
P O

H3C

Me

Me Me
Me

CH3

MeO

Me
Me
Me
Me Me Me
P

OMe
PCy2

Me
Me
PCy2

Me
Me

CH3

H3C

(Fu)

Herrmann's palladacycle
Me

Me

Me
P

Ph2P
Me

Me

Me
PPh2

Me

Pd
P

PPh2

PPh2

Me
Me

PCP Pincer
(Milstein)

Sphos (Buchwald)

Tedicyp
(Santelli, Parrain)

Me

Me

Me
N

Xphos (Buchwald)

Me Me
Me
O

C
Me
Me
Me

R
P

Pd

Me

NHC IMes
(Nolan)

Me
Me Me

P R
R R

(Bedford)

In difficult cases electron-rich and bulky phosphines perform better. Electron richness is expected to favor
oxidative addition (with these phosphines the very difficult oxidative addition to aryl chlorides is possible).
Bulkiness is expected to favor the reductive elimination (in the cross-coupling reactions). Very reactive
iodides, diazonium salts and acyl chlorides can be used without ligands. N-heterocyclic carbenes are known
to mimic phosphines. They are very good -donors.
G. Poli

Some Useful Corollary Information

pKa

Cone angle

Me Me
Me
Me
P
Me
Me
Me Me Me

11.4

182

9.7

170

2.7

145

Reviews dealing with ligands in cross-couplings and Heck reactions:

a) Bedford, R. Coord Chem Rev. 2004, 248, 2283. b) Littke, A. E.; Fu, G. Angew. Chem. Int. Ed.,
2002, 41, 4176.
G. Poli

The Ligandless Conditions

Very reactive iodides, diazonium salts and acyl chlorides can be used without ligands.
The system KHCO3 / Bu4NCl in DMF without ligands is very effective. Under these conditions,1 known as the
Jefferys ligandless conditions, R4N+X--stabilized Pd colloids are formed and function as active catalysts.2
1. Jeffery, T. Tetrahedron, 1996, 52, 10113.
2. Reets, M. T., Westermann, E. Angew. Chem. Int. Ed. 2000, 39, 165.

Br
MeO2C

CO2Me

Pd(OAc)2 cat.
Me(Cy)2N (1.5 eq)
NEt4Cl (1 eq)
95C (72%)

MeO

MeO2C

CO2Me

MeO
E : Z 11 : 1

Grtler, C.; Buchwald, S.L. Chem. Eur., 1999, 5, 3107

G. Poli

The Mechanism of the Mizoroki-Heck Reaction

2 PPh3
Pd(OAc)2(PPh3)2

Pd(OAc)2

PPh3 + H2O + NEt3

Ph3P O + AcOH
[Pd(0)(PPh3)2(OAc)] HNEt3

ArX

NEt3
oxidative
addition
HX trapping

reductive
elimination
via cis-trans
isomerization
PPh3
H Pd OAc
PPh3

XHNEt3

[ArPd(OAc)(PPh3)2]

[ArPd(PPh3)2] AcO
14 e-

16 e-

dehydropalladation
carbopalladation

Ar
R

Ph3P
Ar

OAc
Pd
PPh3

Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314

G. Poli

Halides and Pseudohalides

The diazonium salts are very conveniently obtained from the corresponding anilines (via
diazotation), which in turn may derive from the nitro derivatives. The diazonium salts are the most
reactive reaction partners.

Me

NH2

NaNO2
HBF4

BF4 N
Me
N

Ph

Ph
Ph

Pd(OAc)2 cat.
EtOH, 80C

Me

CN

Pd(OAc)2 cat.
NaHCO3 nBu4Cl
DMF, 80C
NC
(Jeffery)

Me

61%

Sengupta, S.; Sadhukhan, S. K.; Tetrahedron Lett., 1998, 39, 715

Order of reactivity in the oxidative addition: N2 >> I >> OTf > Br >> Cl
Jutand, A.; Mosleh, A., Organometallics, 1995, 14, 1810.

G. Poli

Halides and Pseudohalides

Iodides react smoothly even in the absence of a ligand, and bromides in the presence or the absence
of a phosphine ligand. Chlorides react only in the presence of bulky electron-rich phosphines.
Ph

Ph
Cl

Cl

Ph

Me

Pd2(dba)3 (1.5 mol%)

P(t-Bu)3 (3 mol%)
Cy2NMe (1.1 eq)
dioxane, rt, 78%

OMe
O

Me

Ph

Pd2(dba)3 (1.5 mol%)

P(t-Bu)3 (6 mol%)
Cy2NMe (1.1 eq)
dioxane, 120C, 72%

OMe

Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989

These reactions condition do not

racemize aminoacid derivatives.

CO2R
NCbz
OTf

Pd(OAc)2 (10 mol%)

(o-Tol)3P (20 mol%)
BuN4Cl (77%)

CO2R
NCbz

Triflates are conveniently obtained

from the corresponding ketones or
phenols.

Crisp, G. T. Tetrahedron, 1992, 48, 3541

G. Poli

Regioselectivity of the Mizoroki-Heck

[Pd]

[Pd] X

EWG

EWG
more reactive alkenes

Pd(OAc)2 cat
AcOK
Bu4NBr, DMF (84%)

[Pd]
Donor
major

Donor
less reactive alkenes

only

CN

[Pd]

CN

MeO

MeO

Masllorens, J.; Moreno-Manas, M.; Pla-Quintana, A.; Pleixats, R.; Roglans, A. Synthesis, 2002, 48, 1903

Br
Me2N

OBu-n

OBu-n

Pd2(dba)3 (5 mol%)
P(Bu-t)3 (1 mol%)
Cy2NMe (1.1 eq)
dioxane, rt (97%)

OBu-n
Me2N

Me2N

Littke, A. F.; Fu, G. J. Am. Chem. Soc., 2001, 123, 6989

Cabri, W. Acc. Chem. Res. 1995, 2-7

(E : Z

3 : 1)

G. Poli

Allylic Alcohols as Alkenes

When allylic alcohols are used as alkenes dehydropalladation occurs from an oxygenbearing carbon. As a result, carbonyl compounds are generated rather than -arylated
allylic alcohols.
Br

Me

Me

[Pd(0)]

OH

CHO

[Pd]Br
H
Me
OH

Me
OH

Me
OH

Melpolder, J. B.; Heck, R. F. J. Org. Chem. 1976, 41, 265. Buntin, S. A.; Heck, R. F. Org.
Synth. Coll. Vol. 1990, 7, 361.

Mizoroki-Heck
C

OH
CHO

Thus, a dihydrocinnamaldehyde
target can be retrosynthetically
diconnected via a Mizoroki-Heck
reaction.
G. Poli

Intramolecular Mizoroki-Heck Reactions

G. Poli

Formation of 6-Membered Rings

PhS
Pd(dppb) cat.
AcOK, DMA (70%)

TfO

OH

PhS
O
O

OH

cardenonide

No problem for C-C formation

at quaternary center

Hines, J. Jr; Overman, L. E. Nasser, T.; Rucker, P. V. Tetrahedron Lett., 1998, 39, 4647

OMe

N
H

MeO
OBn

Pd(CF3CO2)2
PMP, tol, 120C
(60%)

OBn
morphine

Me R N
PMP: Me N
Me
Me
Me

Overman, L. E. et al. J. Am. Chem. Soc. 1993, 115, 11028

G. Poli

Halo-1,6-Dienes

Type I substrates: 1-halo-1,6-dienes

[Pd(0)], base

EtO2C
I

EtO2C

6-exo cyclization
EtO2C
EtO2C

Type II substrates: 2-halo-1,6-dienes

apparent 6-endo cyclization

[Pd(0)], base
I
OH

OH

Owczarczyk, Z.; Lamaty, F.; Vawter, E. J. Negishi, E.-I. J. Am. Chem. Soc. 1992, 114, 10091
G. Poli

2-Halo-1,6-Dienes
Apparent 6-exo cyclization
PdCl2(PPh3)2, NEt3, DMF, 80C, NEt2H (69%)
OH
I

OH

[Pd(0)]

oxidative
addition

[Pd]X

dehydropalladation

[Pd]I

[Pd]I
5-exo
OH carbopalladation

OH
H

3-exo
carbopalladation

[Pd]I cyclopropylcarbinylhomoallyl
rearrangement
OH
OH

Owing to its mechanism the cyclopropylcarbinyl-to-homoallyl rearrangement can take place

only if the two red bonds (C-C and C-Pd) can become syncoplanar. It can be understood as
an unusually facile retro-carbopalladation. Notice that the double bond configuration of the
final product is reversed with respect to that of the starting material.
G. Poli

1-Halo-1,6-Dienes

Pd(PPh3)4 cat or
Cl2Pd(PPh3)2 cat, HNEt2

EtO2C
EtO2C

[Pd(0)]

oxidative
addition

dehydropalladation
6-exo
carbopalladation

EtO2C
EtO2C

EtO2C
EtO2C

[Pd]I

3-exo
carbopalladation

EtO2C
EtO2C

[Pd]I

tail-biting

EtO2C
EtO2C
[Pd]I

In this case the cyclopropylcarbinyl-to-homoallyl rearrangement cannot take place

since the two red bonds (C-C and C-Pd) cannot become syncoplanar.

G. Poli

Asymmetric Mizoroki-Heck Reactions

G. Poli

Intermolecular Asymmetric Reactions

The non-coordinating triflate anion is crucial
Pd2dba3 cat
L*
i-Pr2NEt, PhH
70C (100% conv)

OTf

L*:

PPh2

Bu-t

96% ee

Gilbertson, S. R.; Fu, Z. Org. Lett, 2001, 3, 161

Pd(OAc)2 cat
L*, 40C (65%)

OTf

L*:

MeO
MeO

P
P

O
98% ee

Trabesinger, G.; Albinati, A.; Feiken, N.; Kunz, R. W.; Pregosin, P. S.; Tschoerner, M. J. Am. Chem.
Soc. 1997, 119, 6315
G. Poli

Intermolecular Asymmetric Reactions

H
[Pd]X

[Pd]X

H[Pd]X
O

H[Pd]X

X[Pd]

H[Pd]X

[Pd]X

H
O

H[Pd]X

The selectivity of this reaction is highly dependent on the nature of the (pseudo)halide and of
the ligand.

Ozawa, F.; Kubo, A.; Matsumoto, Y.; Hayashi, T.; Nishioka, E.; Yanagi, K.; Moriguchi, K. Organometallics
1993, 12, 4188
G. Poli

Intramolecular Asymmetric Reactions

The importance of non-coordinating anions

Me
N

N
Me
N

cationic
O

neutral
I

O
ii

Me

(S) 71% ee

O
(R) 66% ee

i: Pd2(dba)3 5%; (R)-BINAP 11%; DMA; Ag3PO4, 80C, (81%)

ii: Pd2(dba)3 5%, (R)-BINAP 11%, DMA; PMP, 110C (71%)

PPh2
PPh2

(R)-BINAP
Overman, L. E.; Poon, D. J. Angew. Chem. Int. Ed. Engl. 1997, 36, 518
G. Poli

Intramolecular Asymmetric Reactions

The presence of the silicon atom in the precursor directs the dehydropalladation thereby
avoiding -H elimination from the undesired side.

SiMe3
Me

Pd2(dba)3, (R)-BINAP
Ag3PO4, DMF, 80C
(91%, 92% ee)

Me
MeO

MeO
SiMe3
[Pd]

[Pd]SiMe3

Me
MeO

[Pd(0)]

Tietze, L. F.; Schimpf, R. Angew. Chem. Int. Ed. Engl. 1994, 33, 1089

G. Poli

Palladium-ene Cyclizations

oxid. add.
AcOH
OAc
[Pd(0)]

[Pd]OAc insertion

[Pd(0)]

H[Pd]OAc

red. elim.

[Pd]OAc
dehydropallad.

H[Pd]OAc

[Pd]

[Pd]

[Pd]

Oppolzer, W. In Comprehensive Organometallic Chemistry II, Vol. 12, Abel, E. W., Stone, F. G. A.,
Wilkinson, G., Eds. Pergamon, Oxford, 1995, p. 905.
G. Poli

Palladium-ene Cyclizations

OMe

OAc
Pd(PPh3)4 cat AcOH
OMe

Pd2(dba)3CHCl3
AcOH/AcOLi
MeCN

E
E

OAc
R

OAc

E
R

Oppolzer, W.; Swenson, R. E.; Pachinger, W. Helv. Chim. Acta, 1989, 72, 14
Trost, B. M.; Luengo, J.I. J. Am. Chem. Soc. 1988, 110, 8239

G. Poli

Pd Catalyzed C-C Cleavage

- Carbon Elimination

[Pd]X

C [Pd]X

-carbon elimin
carbopallad
Y = CR2, O

[Pd]X

C Y
R

Pd - Carbon elimination is the microscopic reverse reaction of carbopalladation.

Although carbopalladation is usually the thermodynamically favored step, some
particular cases (i.e. strain release and the impossibility of dehydropalladation) may
drive the equilibrium in favor of Pd - Carbon elimination.

G. Poli

Cleavage of CPC-Pd and CP-Pd

The different modes
R
less frequent

decarbo-pd

R
[|Pd]X

[Pd]X

[Pd]X

CP-Pd
R[Pd]X
carbo-pd

decarbo-pd
R

[Pd]X

X[Pd]

CPC-Pd
R
R[Pd]X

carbo-pd

[Pd]X

decarbo-pd

X[Pd]

CPC-Pd

CPC-Pd : cyclopropylcarbinylpalladium
CP-Pd : cyclopropylpalladium
G. Poli

From Methylenecyclopropane
CO2Me

CO2Me
MeO2C

CO2Me

CO2Me
Br

MeO2C

Pd(dba)2 dppe, THF 80C 40h (55%)

70

CO2Me

[Pd(0)]

oxid.
add.

30

CO2Me
Br[Pd]
[Pd]Br
intermolec.
carbo-pd
C-C-C-Pd
syncoplanar
[Pd]Br

cyclopropylcarbinyl Pd
(CPC-Pd)

H migration
(dehydro-Pd +
hydro-Pd)
Br[Pd]

intramolec.
decarbo-pd

H[Pd]Br

Fournet, G.; Balme, G.; Gor, J. Tetrahedron, 1988, 44, 5809

G. Poli

Exercices
Propose a plausible mechanism for the following reactions
CN
PhI
CN

NC

CN

Pd(OAc)2 5%
P(2-furyl)3
NEt3 THF 80C

Nuske, H.; Noltemeyer, M.; de Meijere, A. Angew. Chem. Int. Ed. 2001, 40, 3411
de Meijere, A.; Brase, S. J. Organomet. Chem. 1999, 576, 88.

CO2Et
CO2Et

EtO2C

CO2Et

I
Pd(OAc)2
nBu4NCl
NaOAc, DMF
80C

Larock, R.C.; Yum, E. K. Tetrahedron, 1996, 52, 2743

G. Poli

Exercices
Propose a plausible mechanism for the following reaction

Me

CO2Et
CN

CN
EtO2C
Me

Pd(PPh3)4 10%
THF, heat

Tsukada, N.; Shibuya, A.; Nakamura, I.; Yamamoto, Y. J. Am. Chem. Soc, 1997, 119, 8123
Camacho, D. H.; Nakamura, I.; Oh, B. H.; Saito, S.; Yamamoto, Y. Tetrahedron Lett. 2002, 43, 2903

G. Poli

From Tertiary Cyclopropanols [Pd(II)]

Pd(OAc)2 10%
DMSO
Tol MS 4A, O2, 80C

HO
OTIPS

OTIPS
major regioisomer
75% (+ 18% other regioisomer)
AcOH

AcOH
ligand
exchange

[Pd(OAc)2]

O2, DMSO

[Pd(0)]

dehydro-pd

H[Pd]OAc
reductive
elimination
O

AcO[Pd] O

OTIPS

decarbo-pd
less substituted
bond is preferentially cleaved

AcO[Pd]

Ph

CPC-Pd

Park, S-.B.; Cha, J. K.; Org. Lett. 2000, 2, 147

G. Poli

Dehydropalladation versus Decarbopalladation

X[Pd]

O
H

X[Pd]

O
H

dehydropalladation

+ H[Pd]X

H
aldehyde

dehydropalladation

+ H[Pd]X
C

ketone

X[Pd]

O
C

C [Pd]X
decarbopalladation
C
C O
C

CPC-Pd

To obtain decarbopalladation, competitive dehydropalladation must be forbidden in the substrate

(tertiary substituent) and strain release must operate. Indeed, dehydropalladation of oxypalladium
intermediates is a key step in Pd-mediated oxidations.
G. Poli

From Tertiary Cyclopropanols [Pd(0)]

HO

Ph

Pd(dba)2 5%
MeCN 50C (94%)

Ph

Ph
traces

H2
[Pd(0)]

oxidative
addition

H[Pd]H

O
H[Pd] O

Ph

decarbo-pd
H[Pd]

Ph
H

CPC-Pd

Okumoto, H.; Jinnai, T.; Shimizu, H.; Harasa, Y.; Mishima, H.; Suzuki, A. Synlett, 2000, 629
G. Poli

Arylative Fragmentation , -Disubstituted Arylmethanols

No strain
release in this
case
Bulky
phosphines
are necessary

Pd(OAc)2, PCy3
Cs2CO3
o-xylene reflux (97%)

OH
Cl

[Pd(0)]

ligand
exchange

reductive
elimination

HCl
[Pd]Cl

O [Pd] Ar

R
the more electron
rich R migrates

decarbopalladation
O [Pd]

[Pd]
O

Terao, Y.; Wakui, H.; Satoh, T.; Miura, M.; Nomura, M.; J. Am. Chem. Soc. 2001, 123, 10407
Terao, Y.; Wakui, H.; Nomoto, M.; Satoh, T.; Miura, M.; Nomura, J. Org. Chem. 2003, 68, 5236
G. Poli

Arylative Fragmentation of 2,2-Disubstituted 3-Allen-1-ols

Pd(PPh3)4 3%
K2CO3 dioxane reflux

Ph
OH

PhI

allene
insertion

HI
[Pd(0)]

Ph[Pd]I

reductive
elimination

H[Pd]I
Ph

Ph

82%

dehydro-pd

oxid
add

PhCHO +
87%

OH
I[Pd]

Ph
OH
Ph

Ph
OH
[Pd]I

I[Pd]

Ph

decarbopalladation

No dehydropalladation is possible here

Oh, C. H.; Jung, S. H.; Bang, S. Y.; Park, D. I. Org. Lett. 2002, 4, 3325
G. Poli