Chapter 2

Mechanisms and Fundamental Reactions

Masayuki Iwasaki and Yasushi Nishihara

Abstract It is widely accepted that the catalytic cycle of cross-coupling reactions of

organometallic reagents with aryl halides catalyzed by transition metals consists of
three fundamental processes: oxidative addition, transmetalation, and reductive
elimination. Although the details of oxidative addition and reductive elimination
have been extensively studied, little research on detailed mechanisms for trans-
metalation has been exploited until recently. In this chapter, recent examples of the
transmetalation process (a transfer of organic groups to palladium) are generally
outlined, vis-à-vis the intermediate complexes after transmetalation in Suzuki–Mi-
yaura coupling and the effect of added copper salts in Migita–Kosugi–Stille coupling.


Keywords Reaction mechanism Transmetalation  Suzuki–Miyaura coupling 

Migita–Kosugi–Stille coupling Copper effect

2.1 Transmetalation in Suzuki–Miyaura Coupling

The cross-coupling reactions of organometallic reagents with organic halides

catalyzed by transition metals such as palladium and nickel are extremely useful
and reliable methods for the construction of carbon–carbon bonds [1, 2]. The
cross-coupling reactions can be applicable to a variety of organometallic
compounds from Grignard reagents to organosilicon compounds. In particular,
Suzuki–Miyaura coupling (as shown in Eq. 2.1) [3], using organoboron reagents

M. Iwasaki  Y. Nishihara (&)

Division of Earth, Life, and Molecular Sciences, Graduate School of Natural Science
and Technology, Okayama University, 3-1-1 Tsushimanaka, Kita-ku,
Okayama 700-8530, Japan
e-mail: [email protected]

Y. Nishihara (ed.), Applied Cross-Coupling Reactions, Lecture Notes in Chemistry 80, 17

DOI: 10.1007/978-3-642-32368-3_2, Ó Springer-Verlag Berlin Heidelberg 2013
18 M. Iwasaki and Y. Nishihara

(especially organoboronic acids) with the aid of a base as an activator, is exten-

sively utilized for the synthesis of natural products and biologically active sub-
stances. Suzuki–Miyaura coupling is also widely used for the production of
functional organic materials with biaryl motifs in a variety of research fields. This
versatility is due to: (1) the stability of organoboronic acids to water, air, and heat;
(2) the high functional group tolerance of organoboron compounds; and (3) a
lower toxicity of the boron-containing by-products produced by the reactions.

Pd cat.
Ar1 X Ar 2 B(OH) 2 Ar1 Ar2 ð2:1Þ
Base

However, unlike the more reactive Grignard and organozinc reagents, the transfer of
the organic groups (transmetalation) from boron to the palladium center is limited by
the poor nucleophilicity of organoboronic acids. In 1979, Suzuki and Miyaura disclosed
that the addition of a base to the reaction system enhances transmetalation between
organoboron reagents and palladium to undergo the reaction efficiently [4]. Since that
time, Suzuki–Miyaura coupling has been significantly refined and has brought
important technical improvements to the field of carbon–carbon bond formation.
Generally, the cross-coupling reactions are believed to occur through three funda-
mental steps: oxidative addition, transmetalation, and reductive elimination, in a cat-
alytic cycle as shown in Scheme 2.1. In Suzuki–Miyaura coupling, as well as in other
cross-coupling reactions, both the oxidative addition and reductive elimination stages
have been well studied; on the other hand, the mechanisms of transmetalation involving
an accelerating effect by the addition of bases have scarcely been examined until lately.
Recently, many experimental and theoretical aspects of the transmetalation mecha-
nisms in Suzuki–Miyaura coupling have been explored. Herein, the transmetalation
step in Suzuki–Miyaura coupling is reviewed from the perspective of a series of cross-
coupling reactions, examining the effects of the bases on transmetalation.

Pd cat.
Ar1 X Ar 2 M Ar 1 Ar2

Ar 1 Ar 2 Pd Ar 1 X

reductive elimination oxidative addition

Ar1 Pd Ar 2 Ar 1 Pd X

X M Ar 2 M

transmetalation

Scheme 2.1 A catalytic cycle of the palladium-catalyzed cross-coupling reactions

2 Mechanisms and Fundamental Reactions 19

2.1.1 Stoichiometric Reactions of Suzuki–Miyaura Coupling

To provide mechanistic insight into the transmetalation, each stoichiometric

reaction of Suzuki–Miyaura coupling is elucidated, as depicted in Scheme 2.2.
Oxidative addition of organic halides to palladium is already known, and the
formed halogeno(aryl)palladium(II) complexes can be isolated [5–9], whereas
diarylpalladium(II) complexes as intermediates have not been isolated until
recently due to spontaneous reductive elimination after transmetalation. Osakada
has succeeded in the isolation and structural determination of the diarylpalladi-
um(II) complexes after transmetalation by using arylboronic acids substituted with
fluorine in the ortho position, leading to a retardation of the reductive elimination
[10–12]. Upon heating of the isolated diarylpalladium(II) complexes, reductive
elimination occurs smoothly to afford biaryls as cross-coupled products. These
experimental results suggest that the rate-determining step in Suzuki–Miyaura
coupling is transmetalation. Moreover, it is noteworthy that in this stoichiometric
transmetalation reaction, the reaction does not occur at all when no Ag2O additive
is added.

(oxidative addition)
OMe
p-iodoanisole
TMEDA
Pd(dba)2 N
Pd
N I

(transmetalation)
OMe
OMe
F
B(OH)2 Ag 2O N
N F
Pd
Pd
I F N
N
F

(reductive elimination)
OMe
OMe

N F
Pd F Δ
N
F
F

Scheme 2.2 Three fundamental reactions

20 M. Iwasaki and Y. Nishihara

2.1.2 Base-Assisted Transmetalation

An accelerating effect on the transmetalation step of Suzuki–Miyaura coupling was

observed when the bases were added to the reactions of halogeno(aryl)palladium(II)
complexes with trialkylboranes or organoboronic acids. This is not seen in other
types of cross-coupling reactions. Organoboronic acids are generally inert toward
halogeno(aryl)palladium(II) complexes without any assistance of bases. However,
highly nucleophilic organoborates can enhance transmetalation across halo-
geno(aryl)palladium(II) complexes without bases, and reductive elimination spon-
taneously follows to form the cross-coupled products, as shown in Eq. 2.2 [13–19].

Pd cat.
R1 X R2 B No Base R1 R 2

[R-C ≡ C-BR 3]Li [R 3B-OMe]Na R4 BLi [Ar-BR 3]Li

Negishi Suzuki and Miyaur a Suzuki and Miy aur a Suzuk i and Miy aura
ð2:2Þ
(1982 ) (1989) (1995 ) ( 1995)

[Ar-B(R)(OR)2]Li [ArBF3 ]K Ph4 BNa [ArB(OH) 3]Na

K obayashi Genêt Bumagin ( 1999) Cammidge

(1996) (1997) Haddach (1999) (2006)

On the other hand, Suzuki and Miyaura have reported that when the oxo
complexes such as methoxo-, hydroxo-, and acetoxopalladium complexes
(Fig. 2.1) were used as the starting compounds, the transmetalation with boronic
acids occurred smoothly even under neutral conditions [20, 21].

H Ac
Cl Cl Ph 3P O Ph3P O
Pd Pd
2 2
Cl Pd(OMe)(PPh 3)2

Fig. 2.1 Various oxopalladium complexes

Other examples of Suzuki–Miyaura coupling have been reported under neutral

conditions by using the electrophiles shown in Fig. 2.2, because the oxopalladium
complexes were immediately obtained by oxidative addition of these reagents
[22–27]. In sharp contrast, oxidative addition of Ph2IX, PhI(OH)OTf, or ArN2BF4
generates the cationic palladium species, which also rapidly undergo transmeta-
lation without the addition of bases [28–31].
2 Mechanisms and Fundamental Reactions 21

O OR
OPh
O
O
Suzuki and Miyaur a Suzuki and Miyaur a Suzuki and Miyaur a

(1987) (1994 ) (1982)

O O O O
CF3
R SR' Ph O R O R
[ with Cu salt ] Y amamoto Y amamoto

Liebeskind and Srogl (2001) (2002)

(2000)

Ph 2IX (X = BF4, OTs, OTf ) PhI(OH)OTf ArN 2BF4

K ang K ang Genêt (1996)

(1996) (1996 ) Sengupt a (1997 )

Str ongin (2000 )

Fig. 2.2 Organic electrophiles directly yielding oxopalladium complexes via oxidative addition

An example of the above-mentioned reactions, the Liebeskind–Srogl coupling,

is shown in Scheme 2.3 [22]. The coupling reactions of the arylboronic acids with
thioesters afforded the corresponding ketones under the palladium catalysis with
the assistance of copper(I) 2-thiophenecarboxylate (CuTC) under neutral condi-
tions. The reaction is thought to occur without the base because thiolatopalladi-
um(II) complexes are converted into the carboxylatopalladium complexes by
copper(I) carboxylates [32–42].

Pd(dba)2 (1 mol%)
P(2-furyl) 3 (3 mol%)
O CuTC O
R 2 B(OH)2
R THF, 50 C o
R1 S R1 R2

O O O
CuTC R2 B(OH) 2
Pd SR Pd O Pd R 2
R1 – CuSR R1 R' – B(OH) 2TC R1
O
oxopalladium

Scheme 2.3 Reaction of arylboronic acids with thioesters

22 M. Iwasaki and Y. Nishihara

2.1.3 The Turnover Limiting Step in Suzuki–Miyaura Coupling

Transmetalation is believed to be the rate-determining step in most Suzuki–

Miyaura couplings from the research on substituent effect of organic halides and
organoboronic acids [43, 44]. This hypothesis is also supported from theoretical
calculations; but, the presumption that transmetalation is the rate-determining step
in all Suzuki–Miyaura couplings has become uncertain in recent years owing to the
diversity of substrates and reaction conditions. For instance, Buchwald achieved
cross-coupling reactions at room temperature by promoting transmetalation with
sterically bulky phosphine ligands bearing biaryl backbones [45–47]. Furthermore,
Fu reported that the less reactive alkyl chlorides can be used as electrophiles in
Suzuki–Miyaura couplings [48]. Fu et al. proposed that the rate-determining step of
these reactions is not transmetalation but oxidative addition. However, in most
Suzuki–Miyaura couplings, under typical reaction conditions, transmetalation is the
rate-controlling reaction in the catalytic cycle. Because a smooth transmetalation is
essential for an efficient cross-coupling reaction, future investigation to improve
this class of reactions should pay close attention to the transmetalation process.
Brown compared the reaction rates by using arenes substituted with both triflates
and bromides in a series of cross-coupling reactions. The results disclosed that the
bromide chemoselectively reacted in Suzuki–Miyaura coupling, whereas the tri-
flates preferentially reacted in Negishi, Kumada–Tamao–Corriu, and Migita–Ko-
sugi–Stille couplings and Buchwald–Hartwig aminations (Scheme 2.4) [49]. It is
clear that these very different results are ascribed to the transmetalation process in
each coupling reaction, because the oxidative addition step is reversible [50].

Kumada-Tamao-Corriu Migita-Kosugi-Stille
Negishi
OTf
Br Br

OTf O
Br
Suzuki-Miyaura Buchwald-Hartwig N

Br

Scheme 2.4 Transformations of 3-bromophenyl triflate

2 Mechanisms and Fundamental Reactions 23

2.1.4 Pathways for Transmetalation

Two possible mechanisms of transmetalation in the base-accelerated Suzuki–

Miyaura coupling can be considered. One involves the formation of the nucleo-
philic borates from the reactions of boronic acids with the added bases, which leads
to a nucleophilic attack on the halogenopalladium(II) complexes (Scheme 2.5, Path
A); the other contains a nucleophilic attack of the base (a hydroxyl ion) on ha-
logenopalladium(II) complexes to generate the hydroxopalladium(II) intermediate,
which further reacts with the neutral organoboron compounds to complete trans-
metalation (Scheme 2.5, Path B). Although to date there has been no definitive
evidence to explain which transmetalation mechanism is correct, recently Hartwig
et al. provided insight on the process [51].

Ar 1 Ar 2 Ar1 Ar2

Pd

Ar 2 B(OH) 3 Ar2 B(OH)2

OH Ar1 X Ar 1 Pd OH

X
Ar 2 B(OH)2
Path A Ar 1 Pd X
OH
Path B

Scheme 2.5 Two possible pathways of transmetalation in Suzuki-Miyaura coupling

First of all, Hartwig examined a series of stoichiometric reactions of isolated

arylpalladium(II) complexes with several organoboron reagents; the results indi-
cated that the respective reactions of an arylboronic acid with a hydroxopalladi-
um(II) complex (Eq. 2.3) and of an arylborate with an iodopalladium complex
(Eq. 2.4) are much faster than the net catalytic reaction (Eq. 2.5). Therefore, both
of the mechanisms (Paths A and B) may be involved in the catalytic cycle of
Suzuki–Miyaura coupling.

H B(OH)2
Ph 3P O
Pd PPh3
Pd(PPh3 )4
2 THF/H 2 O
Me rt, < 2 min
81% Me
ð2:3Þ
24 M. Iwasaki and Y. Nishihara

Ph3 P I B(OH)3 K
Pd PPh3
PPh 3 Pd(PPh3 )4
THF/H2 O
Me 18-crown-6
rt, 10 min Me
93%
ð2:4Þ
B(OH)2 Pd(PPh3 )4 (1 mol%)
I K2 CO 3
ð2:5Þ
THF/H 2O
Me 80 oC, 3 h
93% Me

Next, the concentrations of the boronic acid, the borate, the halogenopalladi-
um(II), and the hydroxopalladium complexes were measured by monitoring the
31
P and 11B NMR spectra in the reactions. As a result, it was found that the ratio
between boronic acid and borate is 1:1 to 1:3 under general conditions, i.e., a
slightly basic condition in the organic solvent containing water (Eq. 2.6).

B(OH) 2 B(OH) 3K
K2 CO 3 H 2O KHCO3
acetone/H 2 O
F 20 o C F

[Ar-B(OH)2] 0 = 0.011 M [K2 CO3 ]0 [Ar-B(OH)3 -]

0.15 M 0.043 M
0.10 M 0.040 M
0.03 M 0.030 M

ð2:6Þ

It was also clarified that there was no difference in the ratio between iodopal-
ladium and hydroxopalladium complexes at equilibrium (shown in Eq. 2.7).

H PPh3
Ph3 P O NBu4 X Ph 3P OH Ph3 P X
Pd Pd Pd
THF/H 2 O PPh3 PPh 3
2
20 o C

[(Pd-OH) 2] 0 = 0.011 M X= [(Pd-OH) 2] [Pd-OH] [Pd-X]

I 0.0049 M 0.0028 M 0.0032 M
Br 0.0043 M 0.0038 M 0.0028 M
Cl 0.0032 M 0.0045 M 0.0031 M

ð2:7Þ
2 Mechanisms and Fundamental Reactions 25

Finally, the reaction rates of a boronic acid with a hydroxopalladium complex

and of a borate with a bromopalladium complex were compared. When each
reaction was monitored by 31P NMR, a rate constant for the reaction of a boronic
acid and a hydroxopalladium complex was found to be 2.4 9 10-3 s-1 (Eq. 2.8);
whereas that of a bromopalladium complex and a potassium borate was
1.7 9 10-7 s-1 (Eq. 2.9), giving rise to significantly different ratios by a factor of
1.4 9 104.

H
Ph3 P O B(OH)2
Pd PPh3 (0.15 M)
2
+
THF/H 2O
Me -40 oC
Me
0.015 M 0.15 M k OH = 2.4 x 10 -3 s -1

ð2:8Þ

Ph3 P Br B(OH) 3K
Pd PPh3 (0.15 M)
PPh 3 +
THF/H 2O
Me -40 oC
Me
0.030 M 0.15 M k Br = 1.7 x 10 -7 s -1

k OH/kBr = 1.4 x 10 4

ð2:9Þ

These experimental results thus indicate that the transmetalation progresses

via Path B in Scheme 2.5. However, it is noteworthy that: (1) this experimental
data cannot be applied to all of Suzuki–Miyaura reactions; (2) although weak
bases such as carbonates and phosphates are used in most cases of Suzuki–
Miyaura reactions, Path B would compete with Path A when stronger bases are
employed, leading to the prior generation of the borates; and (3) these data do
not reflect any detailed mechanism for a transfer of the organic groups from
boron to palladium.

2.1.5 Computational Studies of the Transmetalation Step

in Suzuki–Miyaura Coupling

The theoretical calculations for the mechanism of the transmetalation process

in Suzuki–Miyaura coupling support the experimental evidence provided by
26 M. Iwasaki and Y. Nishihara

Hartwig [51]. Maseras has performed the DFT calculations and the energy profiles
corresponding to Paths A and B are shown in Figs. 2.3 and 2.4, respectively [52].
The energy profile of the reaction of a bromopalladium complex with vinylborate
shown in Fig. 2.3, indicates that transmetalation proceeds exothermically, and the
largest activation barrier in this route is rather small at 4.2 kcal/mol. Therefore,
this calculation result supports that the bromo(vinyl)palladium complex can react
with vinylborate in a catalytic cycle.

PH3 PH3
Pd Br B(OH)3 Pd B(OH)3
PH3 PH3

PH 3
Pd OH
CH2 =CHB(OH)3 – PH 3 B
OH OH
E HO
PH 3 PH 3 B OH H3 P OH TSA3
Pd Br Pd OH Pd B
Br O OH 4.2 PH3
PH 3 PH 3 PH 3 H
Pd
0.0 TSA1 TSA2
PH3
–3.8 IA2
–1.9
IA2 –5.8 B(OH)3
IA1 PH 3
–12.2
–16.2 Pd OH –17.4
OH
OH PH 3 B PH 3 B
B OH
OH HO
OH Pd O
O
PH 3 PH 3
H
Pd Br + Br –
PH 3

Fig. 2.3 An energy profile for Path A

On the other hand, Fig. 2.4 shows an energy profile for the reaction of vinyl-
boronic acid with a hydroxo(vinyl)palladium(II) complex. This route is also
exothermic, and the activation barrier was found to be only 0.6 kcal/mol.
Comparison of the respective energy profiles for paths A and B, shown in Figs. 2.3
and 2.4, indicates that the energy of the transmetalation product TSC3, divinyl-
palladium(II) complex in Fig. 2.4, is much smaller. Therefore, path B is favored,
which is consistent with the experimental outcomes by Hartwig.
2 Mechanisms and Fundamental Reactions 27

In addition, Maseras calculated the direct reaction of a bromo(vinyl)palla-

dium(II) complex with vinylboronic acid in the absence of the base. The most
probable structures in this mechanism are shown in Fig. 2.5. This reaction pathway
consists of the following processes: (1) a coordination of the double bond of the
boronic acid to the palladium center; (2) a transfer of the bromide from palladium

PH 3 PH 3
Pd OH B(OH) 2 Pd B(OH) 3
PH 3 PH 3

CH 2=CHB(OH)2 PH3
E Pd OH
PH 3 OH H3 P OH
PH3 B PH3 B
Pd OH Pd B OH
Pd O OH O HO
PH 3 PH 3H OH PH3
PH3 H TSC3
Pd
0.0 TSA1 TSC2 0.6 PH3
IC2
–5.7 –5.6
IC2 –9.4 B(OH)3
IC1
–15.9 PH 3
–19.2 –21.0
Pd OH
B OH PH 3 OH PH 3 B
B OH
O Pd O HO
PH 3 OH
H PH 3 H
Pd O
PH 3 H

Fig. 2.4 An energy profile for Path B

to boron; and (3) a transfer of the vinyl group from boron to palladium to generate
the divinylpalladium complex. Calculated results shown in Fig. 2.5 suggest that
this path is endothermic (31.6 kcal) and that there is a large energy barrier
(39.3 kcal) from the intermediate I02 to the transition state TS02. This result
signifies that the direct transmetalation between the bromopalladium complex and
boronic acid in the absence of a base does not occur, which is also supported by
experimental data.
28 M. Iwasaki and Y. Nishihara

Fig. 2.5 An energy profile for the reaction of a bromo(vinyl)palladium(II) complex with
vinylboronic acid

2.1.6 An Interconversion Between Trifluoroborate

and Boronic Acid

Very recently, Lloyd-Jones experimentally clarified that in Suzuki–Miyaura coupling

of potassium trifluoroborate, hydrolysis of the trifluoroborate takes place to generate
the corresponding boronic acid, which further reacts with a hydroxopalladium(II)
complex (Scheme 2.6) [53]. This evidence indicates that the transmetalation of
potassium trifluoroborate proceeds through Path B shown in Fig. 2.4.
2 Mechanisms and Fundamental Reactions 29

BF3K BF3-n (OH)n K B(OH)3 K

slow
THF/H2 O
F 0.5 eq K2 CO3 F F
unreactive

B(OH) 2 fast

F
reactive

Scheme 2.6 Hydrolysis of potassium trifluoroborate

Cs2 CO 3
D 4 /D 0 D4 /D0
BF3 K THF/D 2O B(OH)2

F F
[D 0]-1 / [D4 ]-1 [D0 ]-4 / [D 4]-4
Pd cat.
CF3

Br CF 3
2

CF3

D4 /D0
CF 3

F
[D 0]-3 / [D 4 ]- 3

Scheme 2.7 Competitive reaction between an arylborate and an arylboronic acid

In addition, the mechanism of Suzuki–Miyaura coupling was investigated by

using different molar ratios of an arylborate [D0]-1 and a deuterated arylboronic
acid [D4]-4 (Scheme 2.7). When the mixture of a 1:1 ratio of [D0]-1 and [D4]-4
was used, the formation of the deuterated cross-coupled product [D4]-3 had a
priority over [D0]-3. Surprisingly, even when a 9:1 mixture of [D0]-1 and [D4]-4
was used, the deuterated product [D4]-3 was obtained preferentially over [D0]-3.
These results indicate that trifluoroborates can be a precursor of the corresponding
boronic acids in the presence of a base in water.
Amatore and Jutand experimentally proved that the reaction becomes slower as
the concentration of the hydroxide ion increases in the reaction of phenylboronic
acid with a bromopalladium complex, as shown in Scheme 2.8 [54]. This obser-
vation is consistent with the experimental results from Hartwig and Lloyd-Jones,
considering that Path B becomes inferior as the concentration of borates increases
over boronic acids (under stronger basic conditions).
30 M. Iwasaki and Y. Nishihara

CN CN
B(OH) 2 PPh 3 (2 eq)
Bu4 NOH (α eq)
Ph 3P DMF, 25 o C
Pd
Br PPh3

Scheme 2.8 The reaction of phenylboronic acid with a bromopalladium complex in the presence
of the hydroxide ion

Herein the effect of the added bases and possible reaction paths in the Suzuki–
Miyaura coupling have been discussed. However, the results of experiments by
Hartwig and calculations by Maseras must be interpreted carefully. First, the data
shown herein are not applicable to all reaction systems using various transition
metals/ligands. Second, under the reaction conditions that use a stronger base, Path
A competes with Path B because the concentration of the existing borates increases
in the reaction mixture. Overall, these results have greatly contributed to the
understanding of the transmetalation process because in most cases Suzuki–Mi-
yaura coupling employs relatively weak bases such as carbonates and phosphates.

2.2 The ‘‘Copper Effect’’ in Migita–Kosugi–Stille Coupling

The Migita–Kosugi–Stille coupling, the palladium-catalyzed coupling reactions of

organotin reagents with organic halides, as well as Suzuki–Miyaura coupling, are
very useful carbon–carbon bond-forming reactions (Eq. 2.10) [55–57].

Pd cat. ð2:10Þ
Ar 1 X Ar 2 SnR 3 Ar1 Ar2

2.2.1 A Cine Substitution Reaction

Mechanistic investigation of the Migita–Kosugi–Stille coupling has persisted since

its discovery. The traditional cycle of oxidative addition, transmetalation, and
reductive elimination, prevalent in transition metal catalyzed carbon–carbon bond-
forming reactions, has been widely accepted. When the bulky alkenyltin reagents
are employed, a side reaction, the cine substitution reaction, is observed due to
slow transmetalation (Eq. 2.11) [58].

Pd cat. R2
1
R X SnBu3 R1 R1
R2 R2
(ipso) (cine) ð2:11Þ
R 1 = aryl, vinyl; X = Cl, Br, I, OTf, OTs
R 2 = phenyl, alkyl, ester
2 Mechanisms and Fundamental Reactions 31

Kikukawa et al. found in 1986 that the reaction of ArN2BF4 with trialkyl(a-
styryl)stannanes selectively produces the desired stereodefined (Z)-stilbene deriva-
tives in high yields, not the a-arylated styrenes (Eq. 2.12) [59]. Due to slow trans-
metalation, this unexpected cine substitution reaction is observed in Migita–Kosugi–
Stille coupling by using the bulky organotin reagents. In addition, it is reported that
when an excess of diazonium salts are added, isomerization to the Z-stereoisomer
becomes more substantial. The hydridopalladium complex plays an important role in
this isomerization, which does not occur at all in the absence of the palladium catalyst.
Pd(dba)2
Ph Ar
Ar N 2 BF 4 SnR3
Ph CH 3CN/Et 2O
rt, 82-92%
ð2:12Þ
Ar = C6 H4 X, X = H, 4-Me, 4-I, 4-COMe, 4-CO 2Et, 3-NO 2, 4-NO2
R = Me, Et, n-Bu

At present, two different reaction mechanisms giving rise to the cine substi-
tution products are postulated, as shown in Scheme 2.9. One is the addition–
elimination mechanism (path a) and the other is via the palladium carbene com-
plex (path b). In both mechanisms, the reaction starts from a regioselective
addition of the arylpalladium complex to the double bond of the a-substituted
alkenylstannane.

R Ar

path a R 3 Sn H
Ar Pd X H PdX
R H
R3 Sn H R Ar
Pd Ar
R
path b R H
R 3 Sn H
Pd Ar

Scheme 2.9 Two reaction pathways of the cine substitution reaction

In the addition–elimination mechanism shown in Scheme 2.10, first carbopal-

ladation occurs to the alkenylstannane regioselectively to generate intermediate 5.
The carbon–carbon bond in 5 rotates to give the syn configuration, from which
b-hydrogen elimination takes place. The hydridopalladium complex adds to the
generated alkenylstannane at the opposite position to give intermediate 6. Finally,
the Z-alkene is formed by the anti-elimination of a trialkylstannyl group and
palladium, regenerating the catalyst [59]. However, definitive evidence to support
this hypothesis has not been found to date, although many attempts to detect and
identify the in situ formed alkenylstannanes have been made.
32 M. Iwasaki and Y. Nishihara

Ar Pd X Ph H Ph Ar
Me3 Sn H Me3 Sn H
X Pd Ar X Pd H

Ph SnMe3 5

Me 3Sn Ar Ph Ar
Ph Ar H
Ph
Me3 Sn H H Pd X
H PdX 6

Scheme 2.10 The addition-elimination mechanism of the cine substitution reaction

Another considered mechanism is via a palladium carbene complex. The reg-

ioselective insertion of an alkenylstannane into a carbon–palladium bond of the
arylpalladium complex gives intermediate 7. Iodostannane is released by a-elim-
ination from the four-centered transitional state to generate the palladium carbene
complex 8. A 1,3-hydrogen shift from complex 8 forming the hydridopalladium
complex 9 and the subsequent reductive elimination can afford the cine product
(Scheme 2.11) [60]. The occurrence of the 1,3-hydrogen shift was confirmed by
experiments with deuterated alkenyltin reagents.

CO2 Me
CO 2Me
CO2Me
SnBu3 SnBu 3
Pd
I Pd - ISnBu3 Pd
7 I
8

CO2 Me CO 2Me
Pd
H
9

Scheme 2.11 Mechanism of the cine substitution reaction via a palladium carbene complex

2.2.2 The Copper Effect

Although many reaction condition variables (including electrophiles, solvents,

ligands, additives, etc.) were evaluated to avoid the cine substitution reaction as a
side reaction in Migita–Kosugi–Stille coupling, the improvements of the product
yields were not attained. The use of the bulky alkenyltin compounds and the slow
transmetalation contribute to the cine substitution reactions. Only acceleration of
transmetalation, the rate-determining step, can enable the desired reaction. The
unambiguous improvement of the ipso selectivity and an accelerating effect for
transmetalation have been observed by adding copper iodide and other copper(I)
salts (Eq. 2.13) [61–73].
2 Mechanisms and Fundamental Reactions 33

Pd cat.
CuI ð2:13Þ
1 2
Ar X Ar SnR 3 Ar 1 Ar2

In 1993, for example, Levin reported that the reaction takes place in the ipso
selective manner in Migita–Kosugi–Stille coupling when the sterically bulky
alkenyltin reagents are employed with the copper iodide as a co-catalyst; no for-
mation of the cine substitution product was observed (Eq. 2.14) [74].

Pd(PPh 3) 4
R R
X CuI (75 mol%)
CO2 Me ð2:14Þ
Bu3 Sn CO2 Me DMF, rt
66-92%

This so-called ‘‘copper effect’’ was researched first by Farina and Liebeskind
[75]. They compared the reaction rates of the cross-coupling of vinyltributyltin
with iodobenzene in the presence and in the absence of copper iodide. As a result,
it has been disclosed that the reaction with the addition of copper iodide
(kobs = 5.90 9 10-3 min-1) is about 100 times faster than that without any copper
additive (kobs = 2.66 9 10-5 min-1) (Eq. 2.15).

I Pd2 (dba) 3
Bu3 Sn dioxane, 50 oC
ð2:15Þ
without CuI: kobs = 2.66 x 10–5 min–1
with CuI: kobs = 5.90 x 10 –3 min–1

The rate-determining step in Migita–Kosugi–Stille coupling is believed to be

the transmetalation process based on recent research [76, 77]. Farina and
Liebeskind explained the ‘‘copper effect’’ as follows. The added copper(I) salt
traps the triphenylphosphine dissociated from the metal center in oxidative adduct
10 to generate the unsaturated palladium complex 11, and promotes the trans-
metalation process (Scheme 2.12). It is noteworthy that the added copper iodide
does not promote the dissociation of the ligand from the oxidative adduct 10, but it
traps the ligand dissociated after oxidative addition. Also, the addition of copper
salts was reported to prevent the progress of the reverse reaction from 11 to 10.

L [S]
PdL 4 CuI Ar2 SnR 3
Ar1 I Ar 1 Pd I L CuILn Ar 1 Pd I Ar1 Ar2
L L
10 11

Scheme 2.12 ‘‘Copper effect’’ in Migita-Kosugi-Stille coupling

34 M. Iwasaki and Y. Nishihara

The soft arsine ligands did not show any accelerating effect, compared with the
harder phosphine ligands, as shown in Eq. 2.16. This is because copper iodide has a
stronger interaction with phosphine ligands than with arsine ligands [78, 79].
Moreover, when Pd(AsPh3)4 is used as a catalyst, the association rate of free ligands
to the metal center becomes slower than that observed in the case of Pd(PPh3)4.

cat. tr ans-[Pd(C6 Cl2F3 )I(L)2 ]

C 6Cl2F3 I Bu3 Sn C6 Cl2 F3 I SnBu3
L = PPh 3 or AsPh3
ð2:16Þ

It is known that the organic groups transmetalate from tin to copper in polar
solvents (Scheme 2.13) [80]. The generation of tin halides was confirmed by
measuring the 119Sn NMR in NMP as the solvent. The newly formed organo-
copper(I) species showed a higher activity of transmetalation to palladium than the
corresponding organotin reagents. Therefore, the generated organocopper reagents
take part in transmetalation in Migita–Kosugi–Stille coupling.

CuX Ar 1 Pd X
Ar 2 SnR3 Ar2 Cu Ar 1 Pd Ar 2
X SnR3 CuX

Scheme 2.13 Transmetalation from tin to copper

2.2.3 Perspectives

Clearly, there is an accelerating effect in Migita–Kosugi–Stille coupling when

copper(I) salts are added. In the future, considering the effect of copper(I) salts,
expanded use of Migita–Kosugi–Stille-type carbon(sp3)–carbon(sp3) bond-form-
ing reactions is expected. These types of reactions are very challenging
because alkyl electrophiles are undesirable for oxidative addition and the syn-
chronal b-hydrogen elimination competitively takes place. However, unprece-
dented carbon(sp3)–carbon(sp3) couplings in the Migita–Kosugi–Stille reaction
can be achieved by accelerating transmetalation, the rate-determining step, with
the addition of copper(I) salts (Eq. 2.17).

Pd cat.
CuX ð2:17Þ
C X R3 Sn C C C
C( sp3 )-C( sp3 ) coupli ng
2 Mechanisms and Fundamental Reactions 35

2.3 Summary

This chapter focuses on the transmetalation of Suzuki–Miyaura and Migita–Ko-

sugi–Stille coupling reactions, the various pathways and the mechanisms involved,
and the effect of the bases and of copper(I) salts. It has been concluded that the
reactions of the arylboronic acids with a hydroxopalladium complex are much
faster than that of arylborates with a halogenopalladium(II) complex from
experimental and theoretical findings. However, it cannot be asserted that the
mechanism in all Suzuki–Miyaura reactions has been proven because only the
general reaction conditions have been examined at this present stage. In the future,
it can be expected that further research on the mechanisms will develop from the
studies clarified to date. This will lead to the development of more efficient cross-
coupling reactions.

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