PALLADIUM(II) CHLORIDE

1

Palladium(II) Chloride

1

PdCl

2

[7647-10-1]

Cl

2

Pd

(MW 177.32)

InChI = 1/2ClH.Pd/h2*1H;/q;;+2/p-2/f2Cl.Pd/h2*1h;/q2*-1;m
InChIKey = PIBWKRNGBLPSSY-LCTIVKCBCE

(used as an oxidizing agent and to a lesser extent as a source of

Pd

0

complexes)

Physical Data:

mp 678

◦

C (dec).

Solubility:

slightly sol H

2

O; sol H

2

O in the presence of chloride

ion; sol aqueous HCl; sol PhCN, forming Pd(PhCN)

2

Cl

2

; insol

organic solvents.

Form Supplied in:

commercially available as a rust-colored stable

powder or crystalline solid.

Handling, Storage, and Precautions:

air stable; not hygroscopic.

Original Commentary

Jiro Tsuji
Okayama University of Science, Okayama, Japan

General Considerations.

Many of the reactions described

below can be accomplished using derivatives of palladium
chloride such as Potassium Tetrachloropalladate(II), Disodium
Tetrachloropalladate(II)

, Bis(benzonitrile)dichloropalladium(II),

dichlorobis(acetonitrile)palladium,

and

dichlorobis(tripheny-

lphosphine)palladium. The physical properties of these alterna-
tive reagents are described under their separate entries, but their
chemistry is included in this article.

Synthetic applications of PdCl

2

and its derivatives can be classi-

fied into three types: use as oxidizing agents, use as Pd

II

catalysts,

and use as a source of Pd

0

catalysts. Characteristic features of

these applications are briefly summarized below.

Use as Oxidizing Agents.

PdCl

2

and Palladium(II) Acetate

are representative Pd

II

salts used for various oxidation reactions,

but their uses are different. For example, oxidative reactions of
aromatic compounds are possible only with Pd(OAc)

2

; PdCl

2

and

its derivatives cannot be used. Oxidation reactions of various sub-
strates with PdCl

2

are stoichiometric and Pd

0

is formed after the

oxidation. Sometimes, but not always, Pd

0

can be reoxidized in

situ to Pd

II

with proper reoxidizing agents. In such a case, the

oxidation reaction can be carried out with a catalytic amount of
PdCl

2

. Examples of reoxidants include CuCl

2

, CuCl, Cu(OAc)

2

,

MnO

2

, HNO

3

, benzoquinone, alkyl nitrites, H

2

O

2

, and organic

peroxides. Since solubility of PdCl

2

in water and organic solvents

is small, the more soluble Dilithium Tetrachloropalladate(II),
Na

2

PdCl

4

, K

2

PdCl

4

, and Pd(PhCN)

2

Cl

2

are sometimes used for

similar purposes.

Use as Pd

II

Catalyst.

Pd(PhCN)

2

Cl

2

is used as a homogeneous

Pd

II

catalyst for some non-oxidative reactions such as rearrange-

ment reactions.

Use as Source of Pd

0

Catalyst.

Pd

II

salts are reduced to Pd

0

catalysts with various reducing agents. Although Pd(OAc)

2

is

more convenient for this purpose than PdCl

2

and its derivatives,

PdCl

2

derivatives are used in many cases. Typically, Pd(Ph

3

P)

2

Cl

2

is reduced to form a Pd

0

phosphine complex.

Oxidations.

Oxidative Reactions of Alkenes.

2

Oxidative reactions of

alkenes can be classified into two types: oxidative substitution and
oxidative addition, as shown in eq 1. Here X

−

and Y

−

represent

nucleophiles such as HO

−

, RO

−

, RCO

2

−

, R

2

N

−

and CO, as well

as soft carbon nucleophiles such as active methylene compounds.

R

X

R

PdCl

X

R

Y

(1)

+

PdCl

2

X

R

HY

X

–

+

Pd

0

+

HCl

+

Pd

0

+

HCl

X

–

and Y

–

= nucleophiles

Reaction with Water.

2a,b

Oxidation of ethylene to acetalde-

hyde under oxygen atmosphere is an industrial process called the
Wacker process. PdCl

2

and Copper(II) Chloride in aqueous HCl

are used as the catalysts. As shown by eq 2, the Wacker process
comprises three unit reactions; CuCl

2

is a unique reoxidant of Pd

0

.

CH

2

=CH

2

+

H

2

O

+

PdCl

2

MeCHO

+

2 HCl

+

Pd

0

Pd

0

+

2 CuCl

2

PdCl

2

+

2 CuCl

2 CuCl

+

2 HCl

+

0.5 O

2

2 CuCl

2

+

2 H

2

O

CH

2

=CH

2

+

0.5 O

2

MeCHO

(2)

Higher terminal alkenes are also oxidized in organic solvents

containing water; DMF is most widely used as the solvent.

3

On

a laboratory scale the oxidation can be carried out easily in a
way similar to the hydrogenation of alkenes under atmospheric
pressure. Instead of Pd black and hydrogen, the oxidation is car-
ried out with PdCl

2

and the copper salt under an oxygen atmo-

sphere at room temperature using a similar apparatus. Since the
reaction proceeds under mild neutral conditions, many functional
groups such as esters, acetals, THP ethers, alcohols, halogens,
and amines are tolerated. The ketones obtained by the oxidation
are sometimes chlorinated with CuCl

2

to give chloro ketones as

byproducts. For this reason, nonchlorinating Copper(I) Chloride
is recommended as the reoxidizing agent. This is easily preoxi-
dized to the Cu

II

state with oxygen.

4

In a laboratory synthesis, a

stoichiometric amount of 1,4-Benzoquinone is conveniently used
as the reoxidant.

The reaction is a unique method for the one-step synthesis of

ketones from alkenes, and allows alkenes to be regarded as masked
ketones which are stable to acids, bases, and nucleophiles. Partic-
ularly useful is the oxidation of terminal alkenes, which provides
methyl ketones (eq 3).

5

As a typical application, the allylation

of a ketone, followed by the oxidation, affords a 1,4-diketone.
A cyclopentenone can then be prepared by an aldol condensa-
tion (eq 4).

5

The annulation method has widespread uses in the

Avoid Skin Contact with All Reagents

2

PALLADIUM(II) CHLORIDE

synthesis of natural products such as pentalenene,

6

muscone,

7

and coriolin.

8

1,5-Diketones are prepared by 3-butenylation of a

ketone followed by the oxidation. This process has been used to
prepare cyclohexenones (eq 5).

5

R

PdCl

2

, CuCl

(3)

RCOMe

O

2

, DMF

PdCl

2

, CuCl

(4)

O

O

O

O

O

O

2

, DMF

68%

O

CO

2

Me

O

CO

2

Me

O

PdCl

2

, CuCl

(5)

O

O

2

, DMF

58%

Simple internal alkenes are difficult to oxidize. However, the

regioselective oxidation of internal alkenes takes place in the pres-
ence of suitably disposed oxygen functional groups by neigh-
boring group participation. For example, α,β-unsaturated esters
are oxidized to β-keto esters using Na

2

PdCl

4

as catalyst and

tert-Butyl Hydroperoxide

as the reoxidant (eq 6).

9

Allylic ethers

are oxidized to β-alkoxy ketones which can be converted to
α

,β-unsaturated ketones for use in annulation reactions (eq 7).

10

Cyclohexene and cyclopentene can not be oxidized under the usual
conditions, but are oxidized to cyclohexanone and cyclopentanone
under different conditions. For example, chloride-free Pd

II

salts,

prepared from Pd(OAc)

2

and HClO

4

, H

2

SO

4

, or HBF

4

, are active

catalysts (eq 8).

11

For additional examples of the Wacker pro-

cess, see Palladium(II) Chloride–Copper(I) Chloride and Palla-
dium(II) Chloride–Copper(II) Chloride

.

CO

2

Me

CO

2

Me

O

(6)

Na

2

PdCl

4

t

-BuOOH

83%

O

OBn

OBn

PdCl

2

, CuCl

(7)

O

O

MeONa

DMF

67%

(8)

O

Pd(OAc)

2

, HClO

4

benzoquinone

Reaction with Alcohols and Phenols.

2c

The reaction of alco-

hols with terminal alkenes affords acetals of ketones (eq 9).

12

An

elegant application of the reaction was a brevicomin synthesis
(eq 10).

13

R

MeO

OMe

R

(9)

+

2 MeOH

+

PdCl

2

+

Pd

0

+

2 HCl

(10)

OH

OH

O

O

PdCl

2

, CuCl

2

DME

45%

Alkenes with an electron-withdrawing group such as styrene,

Acrylonitrile

, and acrylate are converted to acetals of the aldehy-

des rather than the ketones. The reaction of styrene with ethylene
glycol affords the cyclic acetal (eq 11).

12a

3,3-Dimethoxypropio-

nitrile is produced commercially using methyl nitrite as the reoxi-
dant. The nitrite can be regenerated easily by the oxidation of NO
with oxygen (eq 12).

14

Ph

(11)

+

HO OH

Ph

O

O

PdCl

2

CuCl

2

90%

+

2 MeONO

CN

MeO

MeO

CN

(12)

+

NO

2 NO

+

2 MeOH

+

0.5 O

2

2 MeONO

+

H

2

O

PdCl

2

The intramolecular reaction of phenols or enols affords furans

and pyrans (eq 13).

15

(13)

O

NaO

O

O

O

O

O

O

O

PdCl

2

(PhCN)

2

+

40–46%

42–50%

benzene

Reaction with Carboxylic Acids.

2c

The intramolecular reac-

tion of carboxylic acids with alkenes affords unsaturated lactones
(eq 14).

16

(14)

CO

2

H

O

O

PdCl

2

(MeCN)

2

Na

2

CO

3

86%

Reaction with Amines and Amides.

2c

Reaction of amines with

alkenes proceeds most smoothly as an intramolecular version.
Amides can be used in the intramolecular reaction to afford var-
ious heterocyclic compounds. In the example shown in eq 15, it
should be noticed that the Pd

II

species is regenerated by the β-

elimination of OH, rather than the β-hydrogen. For this reason the
reaction proceeds catalytically without a Pd

0

reoxidant.

17

A list of General Abbreviations appears on the front Endpapers

PALLADIUM(II) CHLORIDE

3

OH

N

Ts

CO

2

Me

MeCON

N

N

Pd

OH

CO

2

Me

COMe

Ts

Cl

N

N

CO

2

Me

COMe

Ts

+

PdCl

2

95%

(15)

PdCl

2

(MeCN)

2

MeCN

Reaction with Carbon Nucleophiles.

The cyclooctadiene (cod)

complex of PdCl

2

, which is insoluble in organic solvents, reacts

in ether with malonate or acetoacetate under mild heterogeneous
conditions; facile carbon–carbon bond formation takes place to
give a new complex in a quantitative yield. Further intramolecu-
lar reaction of the complex with a base affords the cyclopropane
derivative. Attack of a second malonate on the complex yields the
[3.3.0] system (eq 16).

18

Carbopalladation of the double bond of

N

-vinylcarbamate with acetoacetate at −78

◦

C, and subsequent

carbonylation of the Pd–carbon bond, proceeds smoothly to yield
the carbocarbonylation product in 92% yield (eq 17).

19

Pd

Cl

Cl

Pd

Cl

CO

2

Me

CO

2

Me

CO

2

Me

CO

2

Me

MeO

2

C

CO

2

Me

MeO

2

C

CO

2

Me

CO

2

Me

CO

2

Me

(16)

+

CO

2

Me

CO

2

Me

Na

2

CO

3

base

100%

(17)

Pd

N

OBn

O

CO

2

Bn

O

O

O

CO

2

Bn

NHCO

2

Bn

MeO

2

C

CO

2

Bn

NHCO

2

Bn

+

Pd(PhCN)

2

Cl

2

Cl

CO

Et

3

N, –78 °C

MeOH

92%

π

-Allypalladium Complex Formation.

20

π

-Allylpalladium

complexes are prepared by the reaction of alkenes with PdCl

2

or its soluble forms under various conditions (eq 18).

21

These

π

-allylpalladium chloride complexes react with carbon nucle-

ophiles in DMSO as a coordinating solvent to form carbon–carbon
bonds.

22

Thus π-allylpalladium complexes are clearly different

in chemical reactivity from other organometallic reagents, which
normally react with electrophiles (eq 19).

(18)

R

2

R

1

R

1

R

2

Pd

Cl

+

PdCl

2

+

HCl

(19)

Pd

Cl

CO

2

Me

CO

2

Me

+

CO

2

Me

CO

2

Me

NaH

DMSO

Based on this reaction, allylic alkylation of alkenes is possi-

ble. Active methylene compounds, such as malonates and β-keto
esters, can be introduced to a steroid skeleton by the reaction of
the steroidal π-allylpalladium complex in DMSO (eq 20).

23

The

reaction of carbon nucleophiles also proceeds in the presence of
an excess of Triphenylphosphine (eq 21).

24

CO

2

Me

CO

2

Me

(20)

+

Na

2

PdCl

4

R

O

O

O

Pd

Cl

CO

2

Me

MeO

2

C

DMSO, NaH

90%

THF

(21)

CO

2

Me

SOPh

Pd

Cl

SOPh

CO

2

Me

+

PdCl

2

CuCl

2

Ph

3

P, THF

, NaH

AcONa, AcOH

ortho-Palladation of Aromatic Compounds and Cyclopallada-

tion of Allyl and Homoallyl Compounds.

25

Azobenzene,

26

N,N

-

dimethylbenzylamine,

27

and related aromatic compounds react

with Na

2

PdCl

4

in ethanol to form stable ortho-palladation com-

plexes. These carbon–palladium σ-bonded complexes are useful
for the preparation of ortho-substituted aromatic compounds by
the facile insertion of alkenes, alkynes, and CO. For example,
insertion of CO to the azobenzene complex affords 2-aryl-3-
indazolone (eq 22),

28

and facile insertion of styrene to the benzy-

lamine complex yields a stilbene derivative (eq 23).

1a,29

(22)

+

Na

2

PdCl

4

N

N

N

N

Pd

Cl

N

HN

O

CO

MeOH

97%

Avoid Skin Contact with All Reagents

4

PALLADIUM(II) CHLORIDE

+

Na

2

PdCl

4

AcOH

(23)

NMe

2

NMe

2

Pd-Cl

Ph

NMe

2

Ph

The cyclopalladation of allylic or homoallylic amines and sul-

fides proceeds due to the chelating effect of N and S atoms,
and has been used for functionalization of alkenes. For exam-
ple, i-propyl 3-butenyl sulfide is carbopalladated with methyl cy-
clopentanecarboxylate and Li

2

PdCl

4

. Reduction of the chelated

complex with Sodium Cyanoborohydride affords the alkylated
keto ester in 96% yield (eq 24).

30

Functionalization of 3-N,N-

dimethylaminocyclopentene for the synthesis of a prostaglandin
skeleton has been carried out via a N-chelated palladium com-
plex as an intermediate. In the first step, malonate was intro-
duced regio- and stereoselectively by carbopalladation (eq 25).

31

Elimination of a β-hydrogen generated a new cyclopentene, and
its oxypalladation with 2-chloroethanol, followed by insertion of
1-octen-3-one and β-elimination, afforded the final product.

+

Li

2

PdCl

4

S

O

CO

2

Me

O

+

NaBH

3

CN

96%

CO

2

Me

S

(24)

Oxidative Carbonylation.

32

Oxidative Carbonylation of Alkenes.

Oxidative carbonylation

of alkenes with PdCl

2

in benzene affords β-chloroacyl chlorides

(eq 26).

33

Oxidative carbonylation of alkenes in alcohol affords

α

,β-unsaturated esters and β-alkoxy esters by monocarbonylation

and succinate derivatives by dicarbonylation (eq 27).

34

N

Me

Me

N

Me

Me

N

PdCl

Me

Me

CO

2

Me

CO

2

Me

CO

2

Me

CO

2

Me

Cl

OH

O

N

Me

Me

CO

2

Me

CO

2

Me

CO

2

Me

CO

2

Me

(25)

+

Li

2

PdCl

4

Li

2

PdCl

4

+

O

O

Cl

50%

92%

R

COCl

Cl

R

(26)

+

CO

+

PdCl

2

+

Pd

0

R

R

CO

2

Me

R

OMe

+

CO

+

MeOH

PdCl

2

, CuCl

2

R

CO

2

Me

CO

2

Me

+

+

CO

2

Me

(27)

O

2

Intramolecular oxycarbonylation and aminocarbonylation are

also known. As an example, frenolicin has been synthesized
using oxycarbonylation at 1.1 atm of CO as a key step (eq 28).

35

The intramolecular aminopalladation of a carbamate group
and subsequent carbonylation of the substituted 3-hydroxy-4-
pentenylamine proceeds smoothly in AcOH (eq 29).

36

(28)

+

CO

+

MeOH

Pd(MeCN)

2

Cl

2

OH

MeO

O

O

Pr

Pr

O

O

MeO

O

CO

2

Me

CuCl

2

70%

(29)

+

CO

PdCl

2

, CuCl

2

NHCO

2

Me

OH

NCO

2

Me

O

O

AcOH, AcONa

95%

Oxidative Carbonylation of Alkynes.

Terminal alkynes are car-

bonylated to give acetylenecarboxylates using PdCl

2

and CuCl

2

as catalysts (eq 30).

37

The acetylenecarboxylate in a β-lactam has

been prepared by this procedure and then converted to a β-keto
ester (eq 31).

38

(30)

R

R

+

CO

+

MeOH

CO

2

Me

PdCl

2

, CuCl

Et

3

N

N

Ar

O

R

3

SiO

N

Ar

O

R

3

SiO

CO

2

Me

(31)

N

Ar

O

R

3

SiO

O

CO

2

Me

+

CO

+

MeOH

PdCl

2

CuCl

2

86%

86%

Oxidative dicarbonylation of acetylene with Pd(PhCN)

2

Cl

2

in

benzene affords the chlorides of maleic, fumaric, and muconic
acids (eq 32).

39

Methyl muconate is obtained by passing acetylene

and oxygen through MeOH containing thiourea and a catalytic
amount of PdCl

2

.

40

The oxidative dicarbonylation of alkynes pro-

duces maleate derivatives as a main product using PdCl

2

and

CuCl

2

as catalysts under oxygen in alcohol.

41

A list of General Abbreviations appears on the front Endpapers

PALLADIUM(II) CHLORIDE

5

H

H

(32)

+

CO

+

Pd(PhCN)

2

Cl

2

100 °C

MeOH

CO

2

Me

MeO

2

C

CO

2

Me

CO

2

Me

MeO

2

C

CO

2

Me

+

+

Oxidative Carbonylation of Alcohols.

Oxalates and carbonates

are formed by the oxidative carbonylation of alcohols. The reac-
tion can be made catalytic by using PdCl

2

and CuCl

2

under oxygen

in the alcohol.

42

Either oxalate or carbonate is obtained chemose-

lectively under different conditions (eq 33). Alkyl oxalates are pro-
duced commercially using alkyl nitrites as reoxidants (eq 34).

43

O

OMe

OMe

(33)

PdCl

2

CuCl

2

CO

2

Me

CO

2

Me

CO

+

MeOH

+

(34)

2 NO

+

2 BuOH

+

0.5 O

2

CO

2

Bu

CO

2

Bu

2 BuONO

+

H

2

O

+

2 NO

PdCl

2

2 BuONO

+

2 CO

Reactions via Transmetallation of Organometallic Reagents.

Transmetalation of organometallic compounds of Hg, B, Sn,
Si, Tl, etc., with PdCl

2

produces the reactive organopalladium

species, which undergoes insertion and coupling reactions. Aryl-
or alkenylpalladium complexes, generated in situ from aryl- or
alkenylmercury compounds, undergo insertion reactions with
alkenes;

44,45

an example is shown in eq 35.

46

The arylmercury

compound with 1,3-cyclohexadiene and Li

2

PdCl

4

generates a π-

allylpalladium intermediate, which then attacks the amide group
intramolecularly to yield the cyclized product (eq 35).

46

CO inser-

tion produces ketones and esters.

47

The ortho-thallation of ben-

zoic acid and subsequent transmetalation with Pd

II

generates a

reactive arylpalladium complex, which reacts with butadiene to
give an isocoumarin (eq 36).

48

NHCOMe

HgCl

+

+

Li

2

PdCl

4

MeCN

N

COMe

NH

COMe

(35)

PdCl

74%

CO

2

H

CO

2

H

CO

2

H

Tl(O

2

CF

3

)

2

O

O

PdCl

+

Tl(O

2

CCF

3

)

3

Li

2

PdCl

4

(36)

87%

α

,β-Unsaturated esters are obtained by the carbonylation

of alkenylboranes

49

and alkenyl- or arylpentafluorosilicates

(eq 37).

50

Conjugated dienes and diaryls are formed by the cou-

pling of alkenyl- and arylstannanes. The homocoupling of the
vinylstannane of benzoquinone is catalyzed by PdCl

2

(PhCN)

2

with benzoquinone as the reoxidant (eq 38).

51

C

6

H

13

B(Sia)

2

C

6

H

13

CO

2

Me

PdCl

2

, LiCl

benzoquinone

AcONa

73%

+

CO

+

MeOH

(37)

Pd(PhCN)

2

Cl

2

benzoquinone

CuI

80%

(38)

SnBu

3

O

O

O

O

O

O

Miscellaneous Oxidation Reactions.

Some oxidative reac-

tions can be carried out only with Pd(OAc)

2

, but not with PdCl

2

.

However, Pd(OAc)

2

can be generated in situ by the reaction of

PdCl

2

with AcOK or AcONa. The oxidative coupling of aromatic

rings is a typical example of a Pd(OAc)

2

-promoted reaction. The

following coupling reaction proceeds by Pd(OAc)

2

generated in

situ from PdCl

2

(eq 39).

52

Li

2

PdCl

4

AcONa

87%

(39)

O

MeO

Bu

O

MeO

MeO

MeO

MeO

O

Bu

MeO

O

The following oxidative rearrangement of a propargylic ester

proceeds with a catalytic amount of PdBr

2

under oxygen. Inter-

estingly, the reoxidation of Pd

0

takes place with oxygen without

addition of other reoxidants (eq 40).

53

K

2

PdBr

4

O

2

95%

(40)

O

O

O

i

-Pr

O

CHO

O

O

i

-Pr

i

-PrOCO

O

O

base

95%

Avoid Skin Contact with All Reagents

6

PALLADIUM(II) CHLORIDE

Catalytic Reactions with Pd

II

.

Exchange Reactions of Vinyl Ethers and Esters.

54

Vinyl

ethers are activated by Pd

II

. Exchange with other alcohols to

give mixtures of acetals and vinyl ethers is catalyzed by PdCl

2

(eq 41).

55

This reaction was used as the key step in the total syn-

thesis of rhizobitoxine (eq 42).

56

OR

1

+

R

2

OH

OR

2

Pd(PhCN)

2

Cl

2

+

R

1

OH

(41)

PdCl

2

(PhCN)

2

(42)

+

BnO

OH

MeO

CO

2

Bn

BnO

O

CO

2

Bn

BnCO

2

NH

NHCO

2

Bn

NHCO

2

Bn

NHCO

2

Bn

The exchange reaction of the acid component of vinyl esters

with other acids is catalyzed by PdCl

2

(eq 43).

54

Thus various

vinyl esters are prepared from easily available Vinyl Acetate. As an
example, vinyl itaconate is prepared by the reaction of vinyl ac-
etate with itaconic monomethyl ester (eq 44).

57

N

-Vinyllactams

and cyclic imides are prepared by the exchange reaction of lactams
and imides with vinyl acetate (eq 45).

58

OCOR

1

+

R

2

CO

2

H

OCOR

2

Pd(PhCN)

2

Cl

2

+

R

1

CO

2

H

(43)

OAc

+

CO

2

H

CO

2

Me

Li

2

PdCl

4

68%

+

AcOH

CO

2

CO

2

Me

(44)

OAc

+

Na

2

PdCl

4

+

AcOH (45)

NH

O

O

N

85%

Pd

II

-catalyzed Rearrangement Reactions.

Cope rearrange-

ments are accelerated by catalytic amounts of Pd(PhCN)

2

Cl

2

,

such that they proceed at room temperature in benzene or CH

2

Cl

2

(eq 46).

59

Successful Pd

II

catalysis appears to require that atoms

2 and 5 of the substituted 1,5-hexadienes have one H and one
‘nonhydrogen’ substituent.

60

Oxy–Cope rearrangements proceed

at room temperature using Pd(PhCN)

2

Cl

2

catalysis (eq 47).

61

+

(46)

Pd(PhCN)

2

Cl

2

87%

Ph

Ph

Ph

93:7

Pd(PhCN)

2

Cl

2

65%

(47)

OH

O

The Pd(PhCN)

2

Cl

2

catalyzed Claisen rearrangement of allyl

vinyl ethers has been studied to a lesser extent. The Claisen rear-
rangement shown in eq 48 proceeds smoothly even at room tem-
perature to give the syn product with high diastereoselectivity.

62

The Claisen rearrangement of 2-(allylthio)pyrimidin-4-(3H)-one
affords the N-1 allylation product as a main product rather than
the N-3 allylation product (eq 49).

63

syn

98%

Pd(PhCN)

2

Cl

2

rt

95%

(48)

MeO

O

MeO

O

H

Pd(PhCN)

2

Cl

2

rt

80%

(49)

N

N

H

S

O

N

S

HN

O

O

HN

N

S

+

76:24

The rearrangement of allylic esters, a useful reaction, is

catalyzed efficiently by Pd

II

.

64

The allylic rearrangement shown

in eq 50, used in a prostaglandin synthesis, proceeds in one di-
rection irreversibly, yielding the thermodynamically more stable
product possibly due to steric reasons.

65

The diacetate of a 1,5-

diene-3,4-diol is isomerized to the more stable conjugated diene
with complete transfer of chirality (eq 51).

66

The Pd

II

-catalyzed

allylic rearrangement has been explained by an oxypalladation or
cyclization-induced rearrangement. It is mechanistically different
from rearrangements catalyzed by Pd

0

complexes, which proceed

by formation of π-allylpalladium intermediates.

Pd(MeCN)

2

Cl

2

THF
93%

(50)

AcO

C

5

H

11

Br

O

O

C

5

H

11

AcO

O

O

Br

Pd(MeCN)

2

Cl

2

THF
82%

(51)

OBn

BnO

BnO

OBn

OAc

OAc

OAc

OAc

Skeletal rearrangements of some strained compounds, such

as bulvalene to bicyclo[4.2.2]deca-2,4,7,9-tetraene,

67

cubane to

cuneane,

68

hexamethyl Dewar benzene to hexamethylbenzene

(eq 52),

69

and quadricyclane to norbornadiene (eq 53),

70

are cat-

alyzed by derivatives of PdCl

2

.

Pd(PhCN)

2

Cl

2

(52)

(53)

Cl

Pd

Cl

100%

A list of General Abbreviations appears on the front Endpapers

PALLADIUM(II) CHLORIDE

7

Intramolecular Reactions of Alkynes with Carboxylic Acids,

Alcohols, and Amines.

Addition of carboxylic acids, alco-

hols, and amines to alkynes via oxypalladation and aminopal-
ladation proceeds with catalysis by Pd

II

salts. Intramolecu-

lar additions are particularly facile.

71

Unsaturated γ-lactones

are obtained by the treatment of 3-alkynoic acid and
4-alkynoic acid with Pd(PhCN)

2

Cl

2

in THF in the presence

of Et

3

N (eq 54), and δ-lactones are obtained from 5-alkynoic

acids.

72

5-Hydroxyalkynes are converted to the cyclic enol ethers

(eq 55).

71

The oxypalladation is a trans addition. Thus stere-

oselective enol ether formation by reaction of the alkynoic
alcohol with Pd(PhCN)

2

Cl

2

, followed by reduction with Am-

monium Formate

, has been applied to the synthesis of prosta-

cyclin (eq 56).

73

Intramolecular addition of amines affords

cyclic imines. 3-Alkynylamines are cyclized to 1-pyrrolines while
5-alkynylamines are converted to 2,3,4,5-tetrahydropyridines
(eq 57).

74

(54)

CO

2

H

O

O

Pd(PhCN)

2

Cl

2

95%

(55)

Bu

O

Bu

Pd(PhCN)

2

Cl

2

90%

OH

Pd(PhCN)

2

Cl

2

HCO

2

NH

4

71%

(56)

CO

2

Me

HO

R

3

SiO

O

CO

2

Me

R

3

SiO

R

3

SiO

R

3

SiO

(57)

C

8

H

17

N

C

9

H

19

NH

2

Pd(MeCN)

2

Cl

2

70%

Simple alkynes cannot be hydrated with a palladium catalyst,

but triple bonds are hydrated regioselectively to yield ketones
with participation of suitably located carbonyl or hydroxy groups.
1,5-Diketones are prepared by the participation of a 5-keto group
(eq 58).

75

4-Hydroxyalkynes are converted to 4-hydroxy ketones

and then oxidized to 1,4-diketones (eq 59).

71

Pd(MeCN)

2

Cl

2

H

2

O, MeCN

77%

(58)

HO

O

CO

2

Me

OH

OH

CO

2

Me

O

HO

O

HO

C

6

H

13

Pd(PhCN)

2

Cl

2

MeCN

95%

+

H

2

O

(59)

C

6

H

13

O

OH

O

O

C

6

H

13

Cyclopentenone formation by the isomerization of 3-acetoxy-

1,4-enynes is catalyzed by Pd(PhCN)

2

Cl

2

(eq 60).

76

(60)

AcO

C

6

H

13

C

6

H

13

O

Pd(PhCN)

2

Cl

2

68%

Generation of Carbenes from Diazo Compounds.

Both PdCl

2

and Pd(OAc)

2

are used for carbene generation from azo

compounds.

77

The cyclopentenone carboxylates have been

prepared by intramolecular insertions of the carbenes generated
from α-diazo-β-keto esters (eq 61).

78

Pd(PhCN)

2

Cl

2

55%

O

CO

2

Me

N

2

O

CO

2

Me

(61)

Generation of Pd

0

catalysts.

Pd

0

catalysts can be generated

in situ from Pd

II

in the presence or absence of phosphine lig-

ands. Tetrakis(triphenylphosphine)palladium(0) is a commer-
cially available Pd

0

complex used frequently as a catalyst, but it is

air unstable. Therefore in situ generation of Pd

0

(Ph

3

P)

n

catalysts

by the reduction of Pd

II

in the presence of Ph

3

P is convenient to

use. In many cases the in situ reduction to Pd

0

takes place without

addition of reducing agents. Alkenes, alcohols, CO, and phos-
phines, present in the reaction medium, behave as the reducing
agent and react with Pd

II

to give Pd

0

. Generation of Pd

0

by reduc-

tion of Pd(OAc)

2

with phosphines has been reported.

79

Similarly,

PdCl

2

and its derivatives have been converted to Pd

0

species with

phosphines and bases.

PdCl

2

itself is used for the carbonylation of an aryl iodide in the

presence of a base (eq 62).

80

More frequently, Bis(benzonitrile)

dichloropalladium(II)

is used for various Pd

0

-catalyzed reac-

tions. The coupling reaction of an acyl chloride with a disi-
lane is catalyzed by Pd

0

, generated from Pd(PhCN)

2

Cl

2

and

Ph

3

P (eq 63).

81

The intermolecular coupling of a vinylenedis-

tannane with two alkenyl iodides has been carried out using
Pd(PhCN)

2

Cl

2

without addition of Ph

3

P in a total synthesis of

rapamycin (eq 64).

82

Avoid Skin Contact with All Reagents

8

PALLADIUM(II) CHLORIDE

PdCl

2

, K

2

CO

3

benzene

12 atm

70%

(62)

OMe

I

PhS

MeO

MeO

PhS

OMe

OH

O

O

I

O

O

O

O

I

+

CO

+

Pd(PhCN)

2

Cl

2

Ph

3

P

(63)

O

O

O

ClCO

Si

O

O

O

Cl Si Si Cl

MeMe

MeMe

Me

Me

Cl

+

+

Cl

2

SiMe

2

83%

(64)

+

Pd(PhCN)

2

Cl

2

, DMF

i

-Pr

2

NEt, 25 °C

28%

SnBu

3

Bu

3

Sn

I

O

O

OMe

OH

O

H

OMe

OH

OH

H

OMe

I

O

OH

30% recovery of starting material

Dichlorobis(triphenylphosphine)palladium is used for Pd

0

-

catalyzed reactions without adding a reducing agent. For ex-
ample, the coupling of terminal alkynes with halides is carried
out with Pd(Ph

3

P)

2

Cl

2

and Copper(I) Iodide in the presence of

Triethylamine

without addition of a reducing agent. Hexaethynyl-

benzene is prepared by the coupling of hexabromobenzene with
trimethylsilylacetylene (eq 65).

83

Similarly, the carbonylation of

cinnamyl acetate, to give naphthyl acetate, is carried out in the
presence of Et

3

N (eq 66).

84

Pd(Ph

3

P)

2

Cl

2

CuI, Et

3

N

(65)

Br

Br

Br

Br

Br

Br

TMS

+

KF

28%

(66)

OAc

OAc

+

CO

+

Ac

2

O

Pd(Ph

3

P)

2

Cl

2

Et

3

N

76%

In some cases, Pd(Ph

3

P)

2

Cl

2

is reduced to Pd

0

in situ with

reducing agents such as metal hydrides, and used for Pd

0

catalyzed

reactions. For example, Pd(Ph

3

P)

2

Cl

2

is reduced with Diisobutyl-

aluminum Hydride

and used for coupling reactions (eq 67).

85

Pd(Ph

3

P)

2

Cl

2

i

-Bu

2

AlH

(67)

O

Br

O

Cp

2

ZrCl

Bu

Bu

+

The carbonylation of alkenes in alcohols to give saturated es-

ters proceeds smoothly with PdCl

2

or Pd(Ph

3

P)

2

Cl

2

as a cata-

lyst (eq 68).

86

Alkynes are carbonylated efficiently to give α,β-

unsaturated esters with the same catalyst in the presence of
Iodomethane

(eq 69).

87

In some reactions the Pd

0

species gen-

erated from PdCl

2

–Ph

3

P and Pd(OAc)

2

–Ph

3

P show different re-

activities. For example, in the carbonylation of 1,3-Butadiene, 3-
pentenoate is obtained with PdCl

2

–Ph

3

P, while 3,8-nonadienoate

is obtained with Pd(OAc)

2

–Ph

3

P. The presence of chloride anion

in the coordination sphere of palladium gives different catalytic
activity (eq 70).

88

Pd(Ph

3

P)

2

Cl

2

(68)

R

R

CO

2

Me

R

CO

2

Me

+

CO

+

MeOH

+

+

CO

+

Et

2

NH

Pd(Ph

3

P)

2

Cl

2

MeI

92%

(69)

O

O

CONEt

2

O

O

A list of General Abbreviations appears on the front Endpapers

PALLADIUM(II) CHLORIDE

9

+

CO

+

MeOH

(70)

CO

2

Me

CO

2

Me

Pd(OAc)

2

, Ph

3

P

96%

PdCl

2

, Ph

3

P

First Update

V. Sridharan
University of Leeds, Leeds, UK

Cascade Reactions.

Cascade reactions can be defined as multi

reaction ‘one pot’ sequences in which the first reaction creates
the functionality to trigger the second reaction and so on. Cas-
cade reactions have also been termed tandem or domino processes
by some authors. This section is concerned with Pd(PPh

3

)

2

Cl

2

-

[to generate Pd(0)] or PdCl

2

-catalyzed processes in which two or

more carbon-carbon/carbon-heteroatom bonds are formed.

Cycloaddition Cascades.

These processes involve combina-

tions of a starter molecule, which comprises a vinyl, aryl,
allylic, or benzylic halide, triflate, etc., with one (or more)
acceptor molecules (alkene, alkyne, 1,2-diene, 1,3-diene, etc.).
Carbon monoxide is also a valuable one-carbon acceptor
molecule. Other cycloaddition processes include Diels–Alder re-
actions, 1,3-dipolar cycloaddition reactions, etc., catalyzed by Pd
(MeCN)

2

Cl

2

.

Three-membered Rings.

[2 + 1] processes: Several examples of

PdCl

2

-catalyzed cascade cyclopropanation processes have been

reported in the literature.

89

Thus, enyne ketone reacted with

styrene in the presence of PdCl

2

to afford the cyclopropanated

product in excellent yield and in high diastereoselectivity (eq 71)
via a palladium 2-furyl carbene complex.

O

Ph

PdCl

2

Ph

O

Ph

Ph

O

Pd

Ph

+

THF, rt

80%

21:79 (cis:trans)

(71)

Four-membered Rings.

[2 + 2] processes: PdCl

2

-catalyzed

[π

2s

+ π

2a

] cycloaddition reactions of α-bromoalkyl ketenes and

cyclopentadiene were found to occur in increased yield and exo-
selectivity compared with the uncatalyzed reaction (eq 72).

90

Br(CH

2

)

3

COCl

PdCl

2

Br

R

O

R

Br

O

+

Et

3

N

THF, rt

+

1:1
1.7:1(without PdCl

2

)

91
40

(72)

R = Br(CH

2

)

3

Yield (%) endo:exo

Five-membered Rings.

[4 + 1] processes: Several examples of

Pd(PPh

3

)

2

Cl

2

-catalyzed [4 + 1] processes have been reported in

which carbon monoxide was used as a one-carbon component.
A typical example is shown in eq 73. The choice of catalyst and
additives are important to obtain either indanone or indenone in
this particular cascade reaction.

91,92

Pd(PPh

3

)

2

Cl

2

Pd(OAc)

2

n

-Bu

4

NCl

C

5

H

5

N

DMF, 80

°C

Et

3

N

MeCN/C

6

H

6

, 80

°C

CO

I

O

O

+

50%

100%

(73)

Kundu et al.

93

have reported a highly regio- and stereoselec-

tive synthesis of (Z)-arylidene isoindolin-1-ones via a palladium-
catalyzed [4 + 1] cycloaddition process using alkynes as acceptor
molecules (eq 74).

N

I

O

H

Ph

OMe

NPh

H

OMe

O

+

(74)

CuI, Et

3

N, DMF

89%

Pd(PPh

3

)

2

Cl

2

[3 + 2] processes: Most of the reported examples of

five-membered

ring

formation

have

involved

a

[3 + 2]

process. In this manner, Balme and co-workers

94

have

developed a formal [3 + 2] cycloaddition process based

Avoid Skin Contact with All Reagents

10

PALLADIUM(II) CHLORIDE

I

OH

Ph

CO

2

Et

EtO

2

C

O

Ph

CO

2

Et

CO

2

Et

H

O

CO

2

Et

CO

2

Et

Pd

I

O

Ph

CO

2

Et

CO

2

Et

H

Pd

+

+

Pd(PPh

3

)

2

Cl

2

/n-BuLi

X = H, 89%
X = m-CF

3

, 78%

X = p-OMe, 80%

(75)

_

THF/DMSO, rt

X

X

X

X

on a palladium-catalyzed three-component reaction. Thus
propargyl alcohol or amine (as Michael donor), aryli-
dene or alkylidene malonate (as Michael acceptor), and
aryl/vinyl halide or triflate in the presence of Pd(PPh

3

)

2

Cl

2

cata-

lyst afforded highly substituted 3-arylidene- (or 3-alkenylidene-)
tetrahydrofurans in excellent yield (eq 75).

A closely related two-component process to synthesize pyrroles

has also been reported to occur in good yield.

95

Mono- and

di-substituted alkynes have been successfully employed as two-
carbon components in the palladium-catalyzed [3 + 2] cycload-
dition process. Thus Garibay and co-workers

96

have described a

palladium-catalyzed [3 + 2] cycloaddition process to synthesize
aceanthrylenes in good yield using mono-substituted alkynes as
acceptor molecules (eq 76).

Br

H

R

R

+

(76)

Pd(PPh

3

)

2

Cl

2

, PPh

3

R = CMe

2

OH, 91%

R = SiMe

3

, 93%

CuSO

4

, Al

2

O

3

, Et

3

N

C

6

H

6

, 80

°C

Mono-substituted alkynes have also been used as two-carbon

components in the palladium-catalyzed [3 + 2] cycloaddition pro-
cess affording benzo[b]thiophenes in good yield.

97

1,2-Dienes,

1,3-dienes, and hetero-cumulenes have been successfully em-
ployed as acceptor molecules in the palladium-catalyzed [3 + 2]
cycloaddition process.

98

Thus, γ-lactones (eq 77) and azaindoli-

nones (eq 78) have been synthesized in good yield via a palladium-
catalyzed [3 + 2] cycloaddition process using 1,3-dienes or 1,2-
dienes as acceptor molecules.

99,100

Finally, in the [3 + 2] theme, 1,3-dipolar cycloadditions of

nitrones and vinyl ethers were found to be catalyzed by PdCl

2

affording the diastereomeric adducts as a 1:1 mixture in 60% yield
(eq 79). No reaction occurred without the catalyst in chloroform
at 70

◦

C.

101

Oximes also underwent a PdCl

2

-catalyzed stereo-

specific and highly facially selective cascade to afford enantiopure

adducts in 80% yield (9:1) (eq 80).

102

An intramolecular PdCl

2

-

catalyzed oxime to metallonitrone to isoxazoline cascade has also
been reported to occur in good yield.

103

Br

HO

O

O

O

+

(77)

K

2

CO

3

NMP, 80

°C

52%

Pd(PPh

3

)

2

Cl

2

N

H

I

CO

2

t

Bu

OMe

N

CO

2

t

Bu

OMe

+

.

(78)

Pd(PPh

3

)

2

Cl

2

n

-BuEt

3

NCl

Na

2

CO

3

MeCN, 90

°C

80%

N

Me

O

OEt

PdCl

2

(MeCN)

2

N

O

Me

Ph

OEt

N

O

Me

Ph

OEt

+

_

+

+

1:1

(79)

CHCl

3

, 70

°C

60%

A list of General Abbreviations appears on the front Endpapers

PALLADIUM(II) CHLORIDE

11

N

N OH

Ph

N
Me

O

O

N
Me

O

H
N

O

O

H

H

N

Ph

N
Me

O

H
N

O

O

H

H

N

Ph

+

+

9:1

(80)

Et

3

N, DCM

80%

PdCl

2

(MeCN)

2

Six-membered Rings.

[4 + 2] processes: Larock and co-workers

have utilized both alkynes

104,105

and 1,2-dienes

106

as accep-

tor molecules to prepare isoquinolines, pyridines, and β- or
γ

-carbolines via palladium-catalyzed [4 + 2] cycloaddition pro-

cess in good yield (eq 81). This process could also be adapted
to synthesise analogous carbocycles via a [4 + 2] cycloaddition
process.

107

PdCl

2

has also been found to catalyze intermolecular

and intramolecular Diels–Alder reactions. Recently asymmetric
Diels–Alder reactions mediated by palladium catalysts have
been reported.

108

–

111

A highly efficient catalytic asymmetric

Diels–Alder reaction using PdCl

2

with chiral 1,3-oxazoline lig-

ands is shown in eq 82.

N
Me

I

N

t

Bu

Ph

Ph

I

N

t

Bu

Ph

N

Ph

Ph

N
Me

N

Ph

+

+

(81)

CuI, Et

3

N

DMF, 100

°C

64%

CuI, Et

3

N

DMF, 55

°C

59%

Pd(PPh

3

)

2

Cl

2

Pd(PPh

3

)

2

Cl

2

[3 + 2 + 1] processes: A three-component palladium-catalyzed

cascade cycloaddition process using carbon monoxide and allene
as relay species has been shown to occur in good yield (eq 83)

112

with formation of thiochroman-4-one derivatives. Closely related
processes using oxygen and nitrogen nucleophiles have also been
reported to occur efficiently.

113,114

O

N

O

O

N

O

H

CMe

2

OMe

PPh

2

Pd

Cl

Cl

N

O

O

O

O

N

O

O

+

AgSbF

6

DCM, − 78

°C

91%

9:1

91% ee

(82)

+

I

XH

CO

X

O

X = S, O, NTs

+

+

PdCl

2

, DPPF

(83)

i

Pr

2

NEt, 400 psi

C

6

H

6

, 50

°C

77%

Cyclization-anion-capture Process.

Grigg et al.

115

were in-

terested in devising ring-forming processes with concomitant in-
troduction of functionality by replacing the β-hydride elimination
step of the Heck reaction with a group or atom transfer. This led to
the development of cascade cyclization-anion-capture processes.

Carbonylation Cascades.

The norbornene enamide shown un-

derwent a palladium-catalyzed 5-exo-trig cyclization followed by
carbonylation (1 atm) to give a spirocyclic product as a single di-
astereoisomer (eq 84). In this case ring strain prevents the compet-
ing β-hydride elimination pathway.

116

Similar diastereoselective

three-component cascade processes proceed smoothly in excellent
yield (eq 85).

117

N

MeO

2

C

Ph

O

N

I

O

Ph

(84)

Pd(PPh

3

)

2

Cl

2

CO (1 atm), TlOAc

MeCN, 65

°C

86%

Avoid Skin Contact with All Reagents

12

PALLADIUM(II) CHLORIDE

t

BuMe

2

SiO

H

H

I

t

BuMe

2

SiO

H

CO

2

Me

(85)

Pd(PPh

3

)

2

Cl

2

CO (1 atm), Et

3

N

DMF-MeCN-H

2

O, 85

°C

94%

A novel, three-component, palladium-catalyzed, cascade cycli-

zation-anion-capture process which involves in situ generation
of a zipper molecule has been reported.

118

Thus, 2-iodobenzoyl

chloride, an acetophenone imine, and carbon monoxide react in
the presence of Pd(PPh

3

)

2

Cl

2

to give isoindolin-1-one in moderate

yield (eq 86).

Cl

I

O

Ph

Me

N

N

O

Ph

CO

2

Me

N

I

O

Ph

N

O

Ph

O

PdI

+

CO

(14 atm)

(86)

Pd(PPh

3

)

2

Cl

2

Et

3

N

MeOH-MeCN, 100

°C

56%

+

Recently Aggarwal et al.

119

reported a palladium-catalyzed

cyclization-carbonylation (2 atm) of bromodienes to give γ,δ- un-
saturated esters in good yield (eq 87). Carbonylation occurs at a
much faster rate than β-hydride elimination under these reaction
conditions.

TsN

Br

TsN

TsN

CO

2

Me

Pd(PPh

3

)

2

Cl

2

, PPh

3

x

(87)

CO (2 atm), Et

3

N

MeOH-DMF-H

2

O (1:2:0.1)

85 °C, 69%

Double Carbon Monoxide Insertions.

Cyclization forming a

four-membered ring was likely to be slower than carbonylation
under 1 atm. A series of substrates was designed to take advan-
tage of this rate differential and permit incorporation of two carbon
monoxide molecules into the product (eq 88).

120

In the above case

(eq 88), the first CO insertion occurs faster than slow 4-exo-trig
carbopalladation allowing a facile 5-exo-trig acylpalladation. The
relative rates of CO insertion and intramolecular carbopallada-
tion are dependent on CO pressure (CO insertion is a reversible

process) and on the size of the incipient ring in the cyclization-
carbopalladation.

121

The effect of pressure is appropriately illus-

trated by the studies of Negishi and co-workers.

122

For example,

at a CO pressure of 40 atm, carbonylation is faster than 5-exo-trig
cyclization and β-hydride elimination as illustrated by the triple
carbonylation process (eq 89).

N

I

EtO

2

C

N

EtO

2

C

O

CO

2

Et

(88)

TlOAc, CO (1 atm)

EtOH, 80

°C

50%

Pd(PPh

3

)

2

Cl

2

I

R

O

H

R

O

CO

2

Me

H

(89)

CO (40 atm)

Et

3

N, MeOH

MeCN/ C

6

H

6

, 95

°C

Pd (PPh

3

)

2

Cl

2

This constitutes a pentamolecular queuing process and pro-

duces mixtures of diastereomers (5:1). Finally, a series of penta-
molecular queuing cascades employing aryl (triflate, iodide) and
vinyl (bromide, triflate) as starter species and carbon monoxide, al-
lenes as relay species have been achieved (eq 90).

123

The strategy

employed in these cascades is analogous to that in eq 88 in which
the initial oxidative product undergoes CO insertion in preference
to a 4-exo-trig cyclization.

I

CO

N
H

+

Pd(PPh

3

)

2

Cl

2

O

N

O

+

+

75%

(90)

toluene, 110

°C

A list of General Abbreviations appears on the front Endpapers

PALLADIUM(II) CHLORIDE

13

Novel Palladium Chloride-based Catalysts for Carbon–

Carbon/Carbon–Heteroatom

Bond

Formations.

The

past

decade has witnessed the development of novel palladacycles as
a new class of catalysts for carbon-carbon/carbon-heteroatom
bond-forming reactions.

124,125

Several types of palladacycles

(derived

from

PdCl

2

)

have

appeared

in

the

literature.

These include PC type,

126

PCP pincer type,

127

phosphite

palladacycles,

128

–

131

NC type,

132

–

140

NCN pincer type,

141

and sulfur containing palladacycles.

142,143

Heterogeneous

palladacycles have also been reported in the literature.

144

These

palladacycles are obtained via direct metallation from appropriate
ligands with either PdCl

2

or Na

2

PdCl

4

. Typical examples are

shown in Scheme 1.

Pd

P

R

2

Cl

t

Bu

Bu

t

Pd

P

O

Cl

OAr

OAr

Pd

N

Me

Me

Cl

N
Me

Pd Cl

PR

2

Pd

NMe

2

NMe

2

Cl

Pd

PR

2

O

O

PR

2

Cl

Pd

SR

2

R

1

Cl

Pd

SR

1

SR

1

Cl

R

2

Ar = 2,4,

t

Bu

2

C

6

H

3

R = naphthyl

R = i-Pr, 4MeO-C

6

H

4

R

1

= Me, R

2

=

t

Bu

R = H, R

1

=

t

Bu

R = NHAc, R

1

=

t

Bu

2

2

2

Other highly active palladium chloride-based catalysts include

di-2-pyridylmethylamine-based palladium,

145

trans

-bidentate

pyridine,

146

and PdCl

2

/phosphinous acid complexes.

147

–

150

Typical examples are shown in Scheme 2. This section is con-
cerned with the coupling reactions of aryl chlorides using the
above PdCl

2

-based catalysts. Chloro arenes are cheap to man-

ufacture and therefore play a vital role as intermediates in the
chemical industry. The low reactivity of chlorides is usually at-
tributed to the strength of the C-Cl bond. Remarkable progress has
been achieved since 1998 in the development of palladium-based
catalysts that can in fact accomplish cross-couplings and Heck
reactions.

151

Heck Reaction.

The palladium-catalyzed coupling of aryl, het-

eroaryl, vinyl halides, and triflates with olefins is referred to
as the Heck reaction (the reaction shown in Table 1),

152

and

constitutes an important carbon-carbon bond-forming reaction in
organic synthesis. The Heck reactions of activated aryl chlorides
involving PdCl

2

-based catalysts are summarized in Table 1. Reetz

et al.

153

have reported the use of simple Pd(II) complexes such

as PdCl

2

(MeCN)

2

in conjunction with tetraphenylphosphonium

salts (Table 1, entry 1) in the Heck reaction of electron-poor and
electron-neutral aryl chlorides with styrene. The addition of N,N-

dimethylglycine improves the regioselectivity of the reaction. Her-
rmann et al.

154

pioneered the use of palladacycles and palladium

carbenes as catalysts in conjunction with n-Bu

4

NBr for Heck re-

action of activated aryl chlorides (Table 1, entry 3). These condi-
tions were not effective for electron-neutral or electron-rich aryl
chlorides. Nitrogen and sulfur-containing palladacycles have also
been effective in catalyzing the Heck reaction of activated aryl
chlorides (Table 1). Li et al.

148

have demonstrated that the com-

mercially available air stable Pd(II) complexes of phosphinous
acid ligands are useful for the Heck reaction of electron-poor aryl
chlorides (Table 1, entry 5). Finally, Dupont and co-workers have
reported the use of PdCl

2

(SEt)

2

/n-Bu

4

NBr in catalyzing the Heck

reaction of aryl chlorides.

155.eps

N

Pd

N

Cl

Cl

NH

S

C

6

H

13

HN

N

Pd N

Cl

Cl

Pd

Cl

Cl

P

P

t

Bu

t

Bu

HO

t

Bu

Bu

t

OH

Cl

Pd

Cl

Pd

Cl

P

P

Cl

OH

Bu

t

Bu

t

OH

t

Bu

t

Bu

Cl

Pd

Cl

Pd

P O

H

O

P

P

O

H

O P

Bu

t

t

Bu

t

Bu

Bu

t

t

Bu

Bu

t

Bu

t

t

Bu

The most versatile method that has been reported to date

for the Heck reaction of unactivated aryl chlorides employs
Pd(0)/P (

t

Bu)

3

as the catalyst (Table 2, entry 1). Recently, In-

dolese and co-workers

156

have developed a palladacycle and sec-

ondary phosphane catalyst for the Heck reaction of electron-rich
aryl chlorides (Table 2.eps, entry 2).

Carbon–Nitrogen Bond-forming Process.

Palladium-cataly-

zed carbon-nitrogen bond formation has recently emerged as
one of the most powerful method for the synthesis of ani-
line derivatives. Buchwald

157

and Hartwig

158

have pioneered

the above process. This section is concerned with the use of
PdCl

2

-based catalysts in the amination of chloro arenes. In 1997,

Tanaka and co-workers

159

described the first example of palla-

dium chloride-catalyzed amination of unactivated aryl chlorides,
using PdCl

2

(PCy

3

)

2

as the catalyst (Table 3, entry 1). Reactions of

cyclic secondary amines furnish the highest yield, and secondary
anilines reacted smoothly. PCy

3

appears to be effective at achiev-

ing oxidative addition of the aryl chloride to palladium, but it is not
always ideal for promoting reductive elimination over β-hydride
elimination. The amination reactions of aryl chlorides with sec-
ondary or primary aryl amines catalyzed by PdCl

2

-based catalysts

are summarized in Table 3. N-Heterocyclic carbine palladacycles
are also found to be active in aryl amination reactions (Table 3,
entry 3).

160.eps

Avoid Skin Contact with All Reagents

14

PALLADIUM(II) CHLORIDE

R

R

1

Entry

Catalyst

Conditions

Yield (%)

R

Cl

R

1

NMe

2

Pd

Cl

Pd

N OH

Cl

N

Pd

N

Cl

N

Me

O

P

i

Pr

2

Pd

P

i

Pr

2

O

Cl

N

Pd

Ph

Cl

Cl

Me

2

4-NO

2

4-CHO

CO

2

Bu

4-COMe

Ph

4-NO

2

CO

2

Bu

Ph

Me

R

1

2

Ph, CO

2

Et

2

K

2

CO

3

, NMP, 150

°C

51–71

3

4-CN, NO

2

Ph, CO

2

Et

K

2

CO

3

, NMP, 150

°C

60–79

4

NaOAc, DMF, 120

°C

75

5

CO

2

t

Bu

PdCl

2

P(

t

Bu)

2

(OH)

2

NaOAc, DMF, 130

°C

66

6

4-CHO, Me

CsOAc, dioxane, 120

°C

81–99

7

NaOAc, DMA
Bu

4

NBr, 150

°C

60

+

catalyst

1

4-CHO, H

PdCl

2

(MeCN)

2

/PPh

4

Cl

NaOAc, NMP, 150

°C

96–98

2

2

base, solvent

temp

R

Table 1

Heck reactions of activated aryl chlorides

n

-Bu

4

NBr

Cl

R

1

R

R

1

Me

2

N Pd PHR

2

Cl

CO

2

Bu

CO

2

Bu

R

1

Entry

Catalyst

Conditions

Yield (%)

2

4-OMe, 4-Me

Na

2

CO

3

, DMA, 140

°C

100

catalyst

1

4-OMe, 2-Me,
2,6-diMe

Pd

2

(dba)

3

/P(

t

Bu)

3

Cy

2

NMe, dioxane, 120

°C

72–89

R = norbornyl

+

base, solvent

temp

R

R

Table 2

Heck reactions of unactivated aryl chlorides

A list of General Abbreviations appears on the front Endpapers

PALLADIUM(II) CHLORIDE

15

R

Amine

Cl

R

N

R

2

R

1

H

N

R

2

R

1

PdCl

2

(PCy

3

)

2

N Pd

Me

2

Cl

N

N

Entry

Catalyst

Conditions

Yield (%)

+

catalyst

1

4-C, H, Me

secondary cyclic,
secondary aryl

NaOMe, toluene, 120

°C

56–88

2

4-Me

primary aryl

PdCl

2

P(

t

Bu)

2

(OH)

2

NaOMe, dioxane, 110

°C

97

3

4-MeO

secondary acyclic,
primary aryl,
primary alkyl

NaO

t

Bu, dioxane, 80

°C

92

base, solvent

temp

R

Table 3

Amination of aryl chlorides

Enantioselective Oxidation of Alcohols.

Recently two groups

have reported the oxidative kinetic resolution of secondary
alcohols using a simple procedure involving a commercially
available palladium complex, sparteine, and molecular oxy-
gen (eq 91).

161

–

163

The addition of Cs

2

CO

3

and t-BuOH pro-

vides a dramatic rate acceleration in the palladium-catalyzed
aerobic oxidative kinetic resolution of secondary (benzylic,
allylic) alcohols while maintaining the selectivity of the
process.

MeO

OH

MeO

O

MeO

OH

+

Pd(nbd)Cl

2

MS 3Å, O

2

80

°C, 67% conversion, 98% ee, 96 h

with Cs

2

CO

3

/t-BuOH, 60

°C, 67.4% conversion, 99.5% ee, 9.5 h

(91)

Conditions and Yields:

toluene

(–)-sparteine

Related Reagents.

Palladium(II) Chloride–Copper(I) Chlo-

ride; Palladium(II) Chloride–Copper(II) Chloride; Palladium(II)
Chloride–Silver(I) Acetate.

1.

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(c) Henry, P. M., Palladium Catalyzed Oxidation of Hydrocarbons;
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2.

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Tsuji, J.; Nagashima, H.; Nemoto, H., Org. Synth. 1984, 62, 9.

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6.

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7.

Tsuji, J.; Yamada, T.; Shimizu, I., J. Org. Chem. 1980, 45, 5209.

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Avoid Skin Contact with All Reagents

16

PALLADIUM(II) CHLORIDE

17.

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