Biographical Sketches
Fabio Bellina was born in Catania (Italy) in 1964. He studied Chemistry at the University of Pisa
and received his Laurea Degree in 1990 under the supervision of Professor R. Rossi.
In 1992, after his national service, he joined the University of Pisa as an Organic
Chemistry Researcher at the Dipartimento di Chimica e Chimica Industriale, working
under the supervision of Professor R. Rossi. In October 2003 he was appointed by the
Faculty of Science of the University of Pisa as an Associate Professor of Organic
Chemistry. Most of his research has been devoted to the study of transition metal-catalysed
reactions and their application to the selective synthesis of bioactive natural and
synthetic heterocyclic compounds, and particularly of substances which are cytotoxic
against human tumor cell lines.
Adriano Carpita was born in San Miniato (Italy) in 1953. He received his Laurea Degree in Chemistry
in 1978 at the University of Pisa and the Scuola Normale Superiore of Pisa, under
the supervision of Professor R. Rossi. After postdoctoral work in 1981, he became
Researcher at the Scuola Normale Superiore and in 1988 he became Associate Professor
of Organic Chemistry at the University of Pisa. His main research interests have focused
on the application of transition metal-catalysed reactions in organic synthesis and
the synthesis of compounds of biological interest, and particularly of antitumor agents.
Renzo Rossi was born in Pisa (Italy) in 1937. He graduated in Chemistry at the University of
Pisa in 1960, working with Professor P. Pino. In 1969, he became Assistant Professor
and, after holding other intermediate positions, in 1980 he became Full Professor
of Organic Chemistry at the University of Calabria. In 1982, he joined again the University
of Pisa where he has held the Chair of Chemistry of Naturally Occurring Compounds
at the Faculty of Sciences. At the beginning of his career he was interested in stereochemistry
and the study of insect pheromones and naturally occurring phototoxins. His current
research interests include transition metal-catalysed carbon-carbon and carbon-heteroatom
bond forming reactions and their synthetic applications in the field of fine chemistry,
and particularly in the field of pharmacologically active compounds, the synthesis
of anticancer compounds, and the total synthesis of biologically active natural products.
Key words
palladium - complexes - boron - catalysis - cross-coupling
1 Introduction
1 Introduction
<P>The Suzuki palladium-catalysed cross-coupling reaction of organoboron compounds
with organic halides or pseudo-halides is a remarkably useful tool in organic synthesis.
During the past decade, this reaction for carbon-carbon bond formation, which proceeds
under mild conditions, is largely unaffected by the presence of water, tolerates a
broad range of functionality and yields nontoxic byproducts. The reaction has largely
been employed in academic laboratories as well as in pharmaceutical and fine chemical
industries to synthesise a large variety of organic molecules. For example, it has
been applied industrially to the production of Losartan (
1 ),
[
1 ]
which is a Merck antihypertensive drug, and has been used for the large scale synthesis
of compound
2 , which is a key intermediate for the synthesis of SB-245570 (
3 ),
[
2 ]
a compound useful for the treatment of depression, and as a key step in a convergent
multikilogram synthesis of CI-1034 (
4 ) (Figure
[
1 ]
),
[
3 ]
a potent endothelian receptor antagonist.</P><P>The scope of the Suzuki reaction for
synthetic applications has been surveyed in several excellent reviews which cover
the work before 1998
[
4-9 ]
and the developments from 1999 to 2001 have been surveyed by Kotha, Lahiri and Kashinath
[
10 ]
and by Miyaura.
[
11 ]
</P>
Figure 1
<P>On the other hand, the review published in 2001 by Lloyd-Williams and Giralt
[
12 ]
concerns the use of the Suzuki coupling for the synthesis of peptide biphenyls, and
a section of the review published in 2002 by Littke and Fu
[
13 ]
summarises several results from 1986 to late 2001 in the area of the palladium-catalysed
Suzuki cross-coupling reactions of aryl chlorides.</P><P>The present review aims to
complete the picture of the studies carried out so far on the Suzuki palladium-catalysed
cross-coupling reactions and, in particular, is intended to give an overview on recent
developments in the area of new efficient catalyst systems for this reaction and their
activity towards challenging substrates. Significant contributions on these aspects
from 1994 to 2001, which have been considered shortly and/or partly in four of the
above mentioned reviews,
[
10-13 ]
are highlighted in this article, which also covers developments which appeared from
2001 to March 2004. </P><P>The topics that are covered in the present discussion include:
i) the description of the structures and applications of palladacycle complexes as
efficient catalyst precursors; ii) the development and use of catalyst systems composed
of Pd(0) or Pd(II) derivatives and electron-rich and/or bulky phosphine ligands; iii)
Suzuki cross-coupling reactions by catalyst systems composed of Pd(0) or Pd(II) derivatives
and nucleophilic
N -heterocyclic carbene ligands; iv) Suzuki cross-coupling reactions by water-soluble
catalyst precursors; v) Suzuki cross-coupling reactions by ligandless catalyst precursors;
and vi) Suzuki cross-coupling reactions by other novel palladium catalyst precursors.</P>
2 Palladacycle Complexes as Catalyst Precursors
2 Palladacycle Complexes as Catalyst Precursors
<P>Recently, there has been considerable interest in the development of new, high-activity
catalysts that can be used in low loadings in Suzuki cross-coupling reactions. In
this regard, palladacycle complexes, where the ligand is in a position to coordinate
to the metal center through both a metalated carbon and a donor atom, have shown considerable
promise.
[
14 ]
[
15 ]
In fact, given their high activity and longevity, palladacycle complexes would appear
to be ideal candidates for recycling protocols. Moreover, these complexes that, according
to Shaw,
[
16 ]
might operate through a Pd(II)-Pd(IV) catalytic cycle instead of by the traditional
Pd(0)-Pd(II) mechanism, exhibit higher air and thermal stability than Pd(0) complexes.
The structures of palladacycles
5-25 used so far as catalyst precursors for Suzuki cross-coupling reactions are illustrated
in Figure
[
2 ]
.</P>
Figure 2a
Figure 2b
<P>Pioneering work in this area was reported in 1995 by Herrmann et al.,
[
17 ]
who found that the thermally stable phosphorus-based palladacycle
5 is able to catalyse Suzuki couplings of activated aryl chlorides with catalyst precursor
loadings as low as 0.1%. Interestingly, complex
5 was also shown to be one of the most efficient palladium catalyst precursors for
a Suzuki-like reaction between aryldiazonium tetrafluoroborates and potassium aryltri-fluoro-borates,
affording the expected biaryls as a result of a cross-coupling.
[
18 ]
</P><P>On the other hand, the dimeric complex
6 , which can be prepared by reaction of tris(2,4-di-
tert -butylphenyl)phosphite with PdCl
2 , was found to be an active catalyst precursor in the reaction of phenylboronic acid
with aryl bromides, giving turnover numbers of up 1,000,000 and turnover frequencies
of nearly 900,000.
[
19 ]
More recently, Bedford et al.
[
20 ]
reported that complex
6 is an excellent catalyst precursor, not only for the Suzuki coupling of aryl bromides
with aryl- and alkylboronic acids, but also, when used in conjunction with tricyclohexylphosphine
(PCy
3 ), for the Suzuki coupling of aryl chlorides. A typical cross-coupling reaction promoted
by
6 is shown in Scheme
[
1 ]
.</P>
Scheme 1
<P>Weissman and Milstein
[
21 ]
introduced the air- and thermally stable phosphine free imine complex
7 as another excellent catalyst for the Suzuki cross-coupling of aryl bromides with
phenylboronic acid. They found that this palladacycle leads to turnover numbers of
more than 10
[
5 ]
with nonactivated aryl bromides.</P><P>Nájera et al.
[
22-26 ]
intensively investigated oxime-derived palladacycles and found that these air- and
water-stable complexes are precatalysts suitable for cross-coupling of boronic acids
with different aryl and heteroaryl bromides and chlorides, and allyl and benzyl halides.
In particular, oxime-derived chloro-bridged palladacycles
8a-d ,
9 ,
20 and
21 were found to be efficient precatalysts for the coupling reaction of phenylboronic
acid with 4-bromoacetophenone in toluene at 110 °C in the presence of K
2 CO
3 as a base,
[
22 ]
[
23 ]
and palladacycle
21 was successfully used in the Suzuki reaction of phenylboronic acid with aryl bromides
and activated and nonactivated aryl chlorides.
[
23 ]
Turnover numbers of up to 4700 and turnover frequencies up to 4700 per hour were found
for reactions involving aryl chlorides. The catalytic activity of palladacycles
8d -
f was tested on a model reaction between phenylboronic acid and 4-chloroacetophenone,
which was carried out either in water at 100 °C in the presence of tetrabutylammonium
bromide (TBAB) as additive and K
2 CO
3 as base (Method A) or in methanol-water (3:1) at room temperature in the presence
of TBAB as additive and KOH as base (Method B).
[
24 ]
[
25 ]
Method A, in which complex
8e was used as a highly active catalyst at low loading, was more efficient than Method
B and was employed for the Suzuki reaction of arylboronic acids with activated and
nonactivated aryl chlorides.
[
24 ]
[
25 ]
Interestingly, complex
8e (0.05 mol%) was also used as precatalyst for the reaction of arylboronic acids with
benzyl chlorides and allyl chlorides and acetates, which was performed at room temperature
in acetone-water (3:2) in the presence of KOH as the base and TBAB as additive.
[
25 ]
[
26 ]
Complex
8e was also used to study the scope of Suzuki reactions involving aryl and heteroaryl
bromides, which were performed using a modification of Methods A and B.
[
25 ]
This modification, in which TBAB was not used as additive, permitted the preparation
of the required biaryls with turnover numbers up to 10
[
5 ]
and turnover frequencies up to 7 × 10
[
4 ]
per hour.
[
25 ]
Interestingly, palladacycle
8e proved also to be able to promote the methylation of 4-bromo- and 4-chloroacylbenzenes
with trimethylboroxine (Scheme
[
2 ]
) and the alkylation of aryl chlorides with butylboronic acid in refluxing water in
the presence of TBAB as additive and K
2 CO
3 as a base.
[
25 ]
</P>
Scheme 2
<P>A metalated phosphorus donor system different from that of complex
5 is present in the bis(phosphinite) PCP-pincer complexes
10a and
10b , which were reported to exhibit excellent activity in the coupling of deactivated
and sterically hindered aryl bromides with phenylboronic acid in toluene at 130 °C
in the presence of K
2 CO
3 .
[
27 ]
On the other hand, the comparatively inexpensive P,C-bidentate phosphinite palladacycles
11a ,
b were found to be extremely active catalyst precursors in the coupling of deactivated
and sterically hindered aryl bromides.
[
28 ]
</P><P>The sulfur-containing cyclopalladated compounds
12a -
d derived from the
ortho -metalation of benzylic
tert -butylthioesters were demonstrated to be excellent catalyst precursors for the cross-coupling
reaction of 4-bromotoluene with phenylboronic acid.
[
29 ]
One of these palladacycles,
12a , proved also to be able to promote the cross-coupling of activated and unactivated
aryl bromides and chlorides with phenylboronic acid in DMF using K
3 PO
4 as a base.
[
29 ]
</P><P>In 1998, Bedford et al. demonstrated that the amine-based palladacycle
13a can be used in aryl bromide cross-coupling reactions.
[
30 ]
Subsequently, Bedford and Cazin
[
31 ]
showed that
14a , the PCy
3 adduct of
13b , is very active in the Suzuki coupling of aryl chlorides even under aerobic conditions.
More recently, these authors explored further the effect of phosphine ligands on the
activity of palladated imine and amine catalyst precursors. In particular, they examined
the activity of complexes
14a -
f and
15a -
d in the coupling reaction of 4-bromoanisole with phenylboronic acid
[
32 ]
and have found that palladacycles
14a -
e ,
15b and
15d show much greater activity than the parent dimers. Moreover, they
observed that while complex
14a performs well in the Suzuki coupling of aryl chlorides,
[
33 ]
this palladacycle shows no advantage compared with the far less expensive triphenylphosphine
analogue
14b , with aryl bromides as substrates.
[
32 ]
</P><P>Bedford et al.
[
34 ]
also investigated the possibility of using silica-supported imine-based palladacycles
such as
16 and
17 , but found that these solid-supported catalyst precursors show considerably lower
reactivity than their homogeneous counterparts in the Suzuki reaction. </P><P>Phosphapalladacyclic
complexes
18 , which can be synthesised from the corresponding
ortho -bromobenzylphosphine ligands,
[
35 ]
were demonstrated to be other effective catalyst precursors for the coupling of activated
aryl chlorides and bromides with phenylboronic acid. The activity of these complexes
was found to be comparable to that of existing palladacycle systems, but did not require
a promoting salt.
[
35 ]
</P><P>Highly active catalyst precursors of general formula
19 , consisting of a palladacycle and a secondary electron rich and bulky phosphine,
were developed by Indolese, Studer et al.
[
36 ]
In the Suzuki reaction between phenylboronic acid and unactivated aryl chlorides with
palladacycle
19a (0.01 mol%), 660 turnovers were achieved in 20 hours.
[
36 ]
This catalytic activity proved to be comparable to screening results by Bedford and
Cazin
[
31 ]
using a combination of a palladacycle of type
13 with PCy
3 . Recently, palladacycle
19a has also been used to catalyse the reaction of 4-aryl-3-chloro-2(5
H )-furanones with arylboronic acids in toluene in the presence of KF as a base.
[
37 ]
However, the required 3,4-diaryl-2(5
H )-furanones were obtained in low yields.</P><P>On the contrary, excellent results
have been obtained in Suzuki reactions performed in the presence of catalytic amounts
of complex
22 or
23a .
[
38 ]
For example, the reaction of 4-chloroanisole with phenylboronic acid in dioxane at
100 °C in the presence of Cs
2 CO
3 , 0.005 mol%
23a and 0.01 mol% PCy
3 (to give
22 in situ) resulted in 100% conversion and gave a turnover number of 10,000.
[
38 ]
Interestingly, palladacycle
23b , which is structurally related to
23a , but in which the two non-
ortho -metalated aryloxide substituents are replaced by a single salicylate residue, showed
in the presence of PCy
3 extremely high activity in the Suzuki cross-coupling of deactivated, activated and
sterically hindered aryl chlorides.
[
39 ]
</P><P>In 2003, Roca and Richards
[
40 ]
reported that air-stable palladacycle
24 is another very effective precatalyst for the Suzuki cross-coupling of aryl chlorides
even at room temperature. In 2004, Sudalai et al.
[
41 ]
synthesised a new family of sulfimine-based palladacycles and found that a member
of this family, complex
25 , exhibits high catalytic activity in the coupling of aryl chlorides with arylboronic
acids, affording coupled products in excellent yields.</P><P>To conclude this section,
it seems advisable to point out, with regard to the involvement of palladacycles in
the catalytic cycle of the Suzuki reaction, that accumulating evidence points to such
Pd(II)-species requiring an in situ transformation into a Pd(0)-species for entry
into the catalytic manifold.
[
42 ]
</P>
3 Catalyst Systems Composed of Pd(0) or Pd(II) Derivatives and Electron-Rich and/or
Bulky Phosphine Ligands
3 Catalyst Systems Composed of Pd(0) or Pd(II) Derivatives and Electron-Rich and/or
Bulky Phosphine Ligands
<P>Before 1997, several examples of Suzuki cross-coupling reactions of electron-deficient
heteroaryl chlorides with organoboron compounds in the presence of traditional palladium
catalyst precursor systems were reported in the literature,
[
13 ]
[
43 ]
but only limited examples concerned aryl chlorides.
[
14 ]
[
44 ]
In 1997, Shen
[
45 ]
established that a bulky and electron-rich phosphine, PCy
3 , is an effective Pd catalyst ligand for the cross-coupling of phenylboronic acid
with aryl chlorides bearing electron-withdrawing groups (Scheme
[
3 ]
).</P><P>Shen speculated that the electron-richness of PCy
3 might make easier oxidative addition of the aryl-chlorine bond to Pd(0) and that
the steric demand of this phosphine might facilitate ligand dissociation to give a
catalytically active monophosphine Pd complex.
[
45 ]
</P>
Scheme 3
<P>Later, catalytic amounts of PdCl
2 (PCy
3 )
2 , or of the system composed of Pd
2 (dba)
3 and PCy
3 , were used for efficient Suzuki reactions of aryl chlorides with boronate esters.
[
46-48 ]
Moreover, through the use of the catalyst system consisting of 5 mol% PdCl
2 and 10 mol% PCy
3 it was possible to synthesise 5-substituted arylfurfurals from 5-formyl-2-furylboronic
acid and aryl bromides or iodides (Scheme
[
4 ]
).
[
49 ]
</P><P>The observations made by Shen
[
45 ]
were confirmed by Monteith,
[
50 ]
[
51 ]
who, during the development of a manifacturing route to 2-cyano-4′-methylbiphenyl,
found that electron-rich and bulky phosphines such as PCy
3 , P(
i -Pr)
3 and P(
i -Bu)
3 are very efficient ligands for Suzuki palladium-catalysed reactions involving activated
aryl chlorides.</P><P>Another sterically demanding and electron-rich trialkylphosphine,
P(
t -Bu)
3 , was used for the first time by Littke and Fu
[
52 ]
in palladium-catalysed cross-couplings between a wide array of electronically and
sterically diverse aryl chlorides and arylboronic acids. In these reactions, Pd
2 (dba)
3 , Cs
2 CO
3 and dioxane were employed as the palladium source, base and solvent, respectively,
and a 1.2:1 ratio between P and Pd was found to be effective. Later, Fu et al.
[
53 ]
established that KF is more effective than Cs
2 CO
3 as a base for Suzuki cross-coupling reactions of activated aryl chlorides with arylboronic
acids, and that it allows for reactions to proceed at room temperature in very good
yields. Other capabilities of the catalyst system composed of Pd
2 (dba)
3 and P(
t -Bu)
3 included: i) the synthesis of di- and tri-
ortho- substituted biaryls in high yields; ii) the selective coupling of an aryl chloride
in preference to an aryl triflate; iii) the use of this catalyst system at low loading;
and iv) the high activity of this catalyst system for reactions of arylboronic acids
with vinyl chlorides, bromides or iodides.
[
53 ]
</P><P>Fu et al.
[
53 ]
also found that through the use of Pd(OAc)
2 /PCy
3 as a catalyst precursor, a diverse array of aryl and vinyl triflates react cleanly
with arylboronic acids at room temperature.</P>
Scheme 4
<P>On the other hand, the catalyst precursor system composed of a 1:4 mixture of Pd
2 (dba)
3 and PCy
3 has recently been found to be effective for cross-couplings of 9-alkyl-9-borabicyclo[3.3.1]nonanes
with alkyl chlorides in dioxane at 90 °C in the presence of CsOH·H
2 O as a base (Scheme
[
5 ]
).
[
54 ]
</P>
Scheme 5
<P>Interestingly, tricyclopentylphosphine [P(
c- C
5 H
11 )
3 ] and P(
i -Pr)
3 , which are phosphines both sterically and electronically similar to PCy
3 , provided catalyst systems for this reaction significantly less active than that
involving PCy
3 .
[
54 ]
Moreover, for phosphines larger [e.g. P(
t -Bu)
3 ] or smaller [e.g. P(
n -Bu)
3 ]
than PCy
3 , essentially no coupling was observed.
[
54 ]
Nevertheless, the palladium species generated in situ from Pd
2 (dba)
3 ·CHCl
3 or Pd
2 (dba)
3 and P(
t -Bu)
3 has been found to be effective for the coupling of arylboronic acids with bromo-
or chloro-substituted 7-azaindoles,
[
55 ]
with 6-chloropurines attached to a Rink-linker via their 9-position,
[
56 ]
with chlorobiphenyls
[
57 ]
and 4-substituted 6-aryl-2-chloropyridines,
[
58 ]
for the Suzuki-type reaction of an activated aryl chloride with a lithium
n -alkylborate prepared in situ via addition of
sec- butyllithium to a boronate ester (Scheme
[
6 ]
),
[
59 ]
and for the regioselective reaction of 4,5-dichloro-1-(dimethyl-amino-sulfonyl)imidazole
at C-5 with phenylboronic acid in toluene at 90 °C in the presence of KF as a base.
[
60 ]
</P>
Scheme 6
<P>However, due to its high activity, the precatalyst system composed of 2.5 mol%
Pd
2 (dba)
3 and 5 mol% of an electron rich phosphine such as P(
t -Bu)
3 , PCy
3 or (
o -biphenyl)P(
t -Bu)
2 proved to be unsuitable for the regioselective monoarylation of 3,4-dichloro-2(5
H )-furanone at C-4 by treatment with 1.3 equivalents of an arylboronic acid in toluene
at 80 °C in the presence of KF as a base.
[
36 ]
[
61 ]
[
62 ]
In fact, although under these conditions the conversion of the reaction was high,
the desired 4-aryl-3-chloro-2(5
H )-furanones were obtained along with comparable amounts of the corresponding 3,4-diaryl-2(5
H )-furanones (Scheme
[
7 ]
).
[
36 ]
[
61 ]
[
62 ]
</P>
Scheme 7
<P>The selective monoarylation of 3,4-dichloro-2(5
H )-furanone at C-4 was, however, achieved using the catalyst system consisting of 2.5
mol% Pd
2 (dba)
3 and 10 mol% P(
o -tolyl)
3 .
[
36 ]
[
61 ]
</P><P>Although the use of electron-rich trialkylphosphines as ligands for palladium-catalysed
Suzuki reactions has permitted the participation of challenging electrophiles such
as deactivated aryl chlorides, the use of these phosphines, especially for large-scale
applications, is limited by the fact that these commercially available ligands cannot
be readily handled in air because of the ease with which they undergo oxidation. However,
in 2001, one of these ligands, P(
t -Bu)
3 , was converted into the air-stable phosphonium salt [(
t -Bu)
3 PH]BF
4 .
[
63 ]
This salt, which by deprotonation under the Suzuki coupling conditions by a Brönsted
base liberates P(
t -Bu)
3 , was used in combination with Pd
2 (dba)
3 to perform efficient cross-coupling reactions of arylboronic acids with activated
aryl chlorides, cyclopentyl chloride and deactivated aryl bromides or iodides in THF
at 20-50 °C in the presence of KF as a base.
[
63 ]
Very recently, this salt has also been used in combination with Na
3 PO
4 in the palladium-catalysed reaction between aryl- or alkenylboronic acids and an unprotected
2,4-disubstituted 5-chloro-1
H -imidazole (Scheme
[
8 ]
).
[
64 ]
</P>
Scheme 8
<P>Electron-rich and bulky trialkylphosphine ligands and their salts have also been
used profitably in palladium-catalysed Suzuki reactions involving alkyl halides. In
fact, Fu et al.
[
65 ]
reported that a combination of Pd(OAc)
2 and P(
t -Bu)
2 CH
3 or [CH
3 (
t -Bu)
2 PH]BF
4 is able to catalyse efficient room-temperature cross-couplings of alkyl bromides
that possess β-hydrogens with a range of aryl-, vinyl- and alkylboronic acids. These
authors also found that alkyl bromides oxidatively add to Pd[P(
t -Bu)
2 CH
3 ]
2 at 0 °C and that the resulting adduct, which was structurally characterised, is able
to react with a boronic acid to provide the expected cross-coupled product.
[
65 ]
</P><P>In 2000, Zapf, Ehrentraut and Beller
[
66 ]
reported that another excellent precatalyst system for Suzuki reactions of chloroarenes
with arylboronic acids is that composed of a mixture of Pd(OAc)
2 and the bulky and electron-rich ligand di-(1-adamantyl)-
n -butylphosphine. In fact, even with deactivated aryl chlorides, turnover numbers of
10,000-20,000 were achieved for good to excellent yields. On the other hand, the air-stable
dimer {PdBr[P(1-adamantyl)(
t -Bu)
2 ]}
2 has recently been found to be able to catalyse room-temperature fast cross-coupling
reactions between aryl bromides and phenylboronic acid.
[
67 ]
</P><P>Since 1998, the use of supporting 1-di(cyclo)alkylphosphinobiphenyl ligands
for the palladium-catalysed Suzuki reaction of aryl chlorides and aryl arenesulfonates
has been intensively investigated by the research group of Buchwald.
[
68-74 ]
The structures of some of these ligands are reported in Figure
[
3 ]
. In particular, phosphine
26 proved to be a very effective supporting ligand for the room-temperature palladium-catalysed
Suzuki reaction of both electron-rich and electron-deficient aryl chlorides.
[
68 ]
Further studies involving ligands
27-29 revealed that catalysts supported by
29 were more efficient than those supported by
26 and catalysed the room-temperature Suzuki coupling of aryl bromides and chlorides
with 0.5-1.0 mol% Pd.
[
69 ]
[
70 ]
The use of
27 as a ligand was successful for the Suzuki coupling of hindered substrates and allowed
these reactions to be carried out at low precatalyst loadings (0.000001-0.02 mol Pd)
[
70 ]
and catalysts employing ligands
26 ,
27 ,
30 and
31 functioned well for the synthesis of biaryls containing more than one
ortho- substituent.
[
70 ]
On the other hand, a catalyst system composed of a mixture of ligand
26 and Pd on carbon was successfully used for the preparation of enantiopure mandelic
acids
[
75 ]
and a mixture of Pd
2 (dba)
3 and the binaphthyl ligand (
S )-(+)-
34 proved to be effective for the synthesis of axially chiral biaryl compounds in up
to 92% ee.
[
71 ]
</P><P>Buchwald et al.
[
72 ]
also reported that a variety of tetra-
ortho -substituted biaryls can be synthesised in 55-98% yield by Suzuki palladium-catalyzed
cross-coupling reactions in which doubly
ortho- substitued phosphine
32a was used as a supporting ligand. Recently, Nguyen, Huang and Buchwald
[
73 ]
found that a mixture of 2 mol% Pd(OAc)
2 and 5 mol% ligand
33 (XPhos) represents a general precatalyst for the reaction of unactivated aryl tosylates
with arylboronic acids.</P><P>In 2004, Buchwald et al.
[
74 ]
have demonstrated that tuning of steric and electronic properties of dialkylphosphinylbiphenyls
affords the new ligand
35 , which they used in combination with Pd(OAc)
2 to perform coupling reactions between electron-rich aryl chlorides and the very hindered
2,4,6-triisopropylphenylboronic acid in toluene at 100-110 °C in the presence of K
3 PO
4 ·H
2 O as a base.</P>
Figure 3
<P>The catalyst system consisting of ligand
35 and Pd(OAc)
2 in a 2.5:1 molar ratio was also found to be remarkably active for the cross-coupling
of unactivated aryl bromides with 2-methyl- and 2-phenylphenylboronic acid.
[
74 ]
Moreover, compound
35 was used as a supporting ligand for the palladium-catalysed synthesis of hindered
biaryls, in high-yielding palladium-catalysed couplings of arylboronic acids with
a variety of heteroaryl chlorides, in Suzuki couplings at room temperature involving
aryl chlorides, and in Suzuki reactions between alkylboron derivatives and aryl halides.
[
74 ]
</P><P>It should also be noted that the use of air-stable and commercially available
phosphine
27 as a supporting ligand permitted successful palladium-catalysed reactions of arylboronic
acids with a variety of electrophiles, including halopyridines and haloquinolines,
[
76 ]
6-halonucleosides
[
77 ]
and the
O
6 -(2-mesitylenesulfonyl) derivatives of 2′-deoxyguanosine (
36 ) (Figure
[
4 ]
),
[
78 ]
the derivatization of aryl halides with fluorescent 4-(4,5-diphenyl)-1
H -imidazol-2-yl)phenylboronic acid (
37 )
[
79 ]
and the cross-coupling reaction of 2-chloro-5-nitrobiphenyl (
38 ) (Figure
[
4 ]
) with arylboronic acids.
[
80 ]
</P>
Figure 4
<P>In 2001, Buchwald et al.
[
81 ]
demonstrated that a palladium catalyst based on polymer-supported dicyclohexylphoshinobiphenyl
39 (Figure
[
4 ]
) is active for reactions of arylboronic acids with aryl iodides, bromides and chlorides.
They also reported that filtration of this resin-bound precatalyst from the reaction
mixture allows for simplified product isolation via an aqueous workup. Interestingly,
the precatalyst could be recycled without additional palladium.</P><P>2-Dicyclohexyl-
and 2-di-
t- butylphosphino-1-phenylpyrrole (
40a and
40b , respectively, Figure
[
4 ]
) are other ligands which have been used for highly efficient Suzuki reactions of
electron-rich, as well as electron-poor, aryl chlorides with phenylboronic acid at
very low precatalyst concentrations.
[
82 ]
</P><P>In recent years, much attention has also been devoted to the synthesis and
application of ligands of the family of ferrocenylphosphines in palladium-catalysed
Suzuki coupling of aryl halides.
[
83-88 ]
The structures of some of these ligands are shown in Figure
[
5 ]
.</P>
Figure 5
<P>Thus, the C
3 -symmetric phosphine (p
S ,p
S ,p
S )-tris(2-methylferrocenyl)phosphine (
41 ),
[
83 ]
[
84 ]
the air-stable ferrocene-derived triarylphosphine
42 ,
[
85 ]
and air-stable elec-tron-rich (pentaphenylferrocenyl)di-
tert -butylphosphine (
43 )
[
86 ]
are ligands which, in combination with Pd(dba)
2 , generate active catalysts for Suzuki reactions of aryl chlorides. Moreover, palladium
catalysts containing ligand
43 have also been shown to be effective for the coupling of electron-rich and electron-poor
aryl bromides with aryl- and primary alkylboronic acids.
[
86 ]
</P><P>Other air-stable ligands of the ferrocenylphosphine family are the aryl-ferrocenyl
derivatives
44 carrying the bis(dicyclohexyl)phosphino moiety.
[
87 ]
These ligands were applied in the palladium-catalysed Suzuki cross-coupling of activated
as well as unactivated aryl chlorides, and in the asymmetric coupling of an aryl bromide
with an arylboronic acid.
[
87 ]
However, the highest ee value (54%) from this ligand series was significantly lower
than those obtained using the catalyst system composed of Pd
2 (dba)
3 and ligand (
S )-(+)-
34
[
71 ]
or PdCl
2 and the tertiary amine phosphine ligand
45 .
[
88 ]
In this last case, chiral binaphthalene derivatives were prepared in up to 85% ee.
[
88 ]
</P><P>The electron-rich and bulky phenyl backbone-derived P,O ligands
46a and
46b (Figure
[
6 ]
) have also been investigated for their utility in palladium-catalysed Suzuki reactions.
[
89 ]
[
90 ]
Thus, it was found that ligand
46a , in combination with Pd(dba)
2 , affords an efficient catalyst for cross-coupling reactions of a wide variety of
arylboronic acids with aryl iodides, bromides and chlorides,
[
89 ]
[
90 ]
and that this ligand is more efficient than
46b in Suzuki reactions involving aryl chlorides.
[
90 ]
</P>
Figure 6
<P>The effectiveness of the Pd-
46a precatalyst was ascribed to the presence of both the PCy
2 and ketal moieties that favour the generation and stability of electron-rich chelating
monophosphine (
P ,
O )-Pd intermediates.
[
89 ]
</P><P>In 2001, Woollins et al.
[
91 ]
prepared the electron-rich amine-functionalised phosphines
47 and
48 (Figure
[
6 ]
) and found that these ligands can also activate palladium complexes to catalyse the
Suzuki coupling reaction of aryl chlorides. More recently, a combination of air-stable
monoamine phosphine
49 and Pd(OAc)
2 has been found to give an efficient catalyst for reaction of aryl bromides with arylboronic
acids.
[
92 ]
However, the reaction between phenylboronic acid and 4-formylchlorobenzene in the
presence of this catalyst system proceeded in a sluggish manner. When aminophosphine
50a or
50b (Figure
[
6 ]
) was used as the ligand, the reactivity was greatly improved and the desired cross-coupled
product was obtained in good yield.
[
92 ]
</P><P>Commercially available bicyclic triaminophosphine
51 is another ligand that has been used successfully in Suzuki reactions.
[
93 ]
In fact, this ligand, in which all three nitrogens linked in the cage to the phosphorus
atom are thought to augment the electron-density on phosphorus, was found to be able
to activate Pd(OAc)
2 to catalyse the cross-coupling reaction of a wide variety of aryl bromides and chlorides
with arylboronic acids, affording the desired biaryls in excellent yields.
[
93 ]
</P><P>In 2003, a significant improvement in the scope of the Suzuki reaction was
realized by Widdowson and Wilhelm,
[
94a ]
who demonstrated that trimethylphosphine (
52 ), in combination with Pd
2 (dba)
3 , provides a catalyst able to promote the cross-coupling reaction of uncomplexed electron-poor
aryl fluorides with arylboronic acids. In this way, a ready access to 2,4-dinitrobiphenyls
was achieved in good yields from Sanger’s reagent. These results were quite interesting
since uncomplexed aryl fluorides have long been considered to be inert to palladium(0)-catalysed
coupling reactions.
[
95 ]
However, Wilhelm and Widdowson
[
94b ]
[
94c ]
had previously found that fluoroarenetricarbonylchromium(0) complexes undergo Suzuki
reaction with arylboronic acids in DMF at reflux in the presence of Pd
2 (dba)
3 /
52 /Cs
2 CO
3 to form biaryltricarbonylchromium(0) complexes.</P><P>Nevertheless, at the present
time it is known that the use of a catalyst system composed of a palladium derivative
and an electron-rich phosphine ligand such as
52 is not necessary for performing successful palladium-catalysed Suzuki reactions of
uncomplexed activated fluoroarenes. In fact, still in 2003, Kim and Yu
[
96 ]
reported that, when activated by strong electron-withdrawing groups, aryl fluorides
are capable of reacting with arylboronic acids in DMF at 65-80 °C in the presence
of four equivalents of Cs
2 CO
3 and 10 mol% Pd(PPh
3 )
4 to give the required biphenyl derivatives in 33-86% yield. </P><P>Recently, it has
also been reported that benzyne complex
53 (Figure
[
7 ]
) can be generated by an intramolecular palladium-catalysed Suzuki reaction occurring
within an arylpalladium(II) complex containing an
ortho -substituted boronic acid.
[
97 ]
The required precursor to this complex was prepared by oxidative addition of bromide
54 to Pd(dba)
2 in the presence of PCy
3 .
[
97 ]
</P>
Figure 7
4 Catalyst Systems Composed of Pd(0) or Pd(II) Derivatives and Nucleophilic
N
-Heterocyclic Carbene Ligands
4 Catalyst Systems Composed of Pd(0) or Pd(II) Derivatives and Nucleophilic
N
-Heterocyclic Carbene Ligands
<P>The nucleophilic
N -heterocyclic carbenes (NHC) represent a versatile class of ligands due to their tunable
electronic and steric properties. In particular, the imidazol-2-ylidenes, which can
be considered phosphine mimics, have been regarded as possible alternatives for the
widely used phosphine ligands in homogeneous catalysis.
[
98-100 ]
In fact, several successful applications of palladium catalyst systems in which these
carbenes are used as supporting ligands have been reported in the literature. The
success of these ligands is due to the fact that they coordinate tightly to palladium,
thus disfavouring the formation of Pd black,
[
101 ]
and that the thermal stability of the Pd-NHC bond avoids the necessity for excess
ligand. Moreover, the electron-rich nature of these ligands enhances the rate of oxidative
addition and their steric bulk favours the formation of catalytically active monocarbene-palladium
species and increases the rate of reductive elimination.
[
102 ]
</P><P>In 1998, Herrmann et al.
[
103 ]
began the studies on the activity in Suzuki reactions of palladium catalyst systems
containing nucleophilic NHCs
as supporting ligands. They found that complex
55 (Figure
[
8 ]
), which is characterised by a bisimidazol-2-ylidene ligand, efficiently promotes
the reaction between phenylboronic acid and aryl bromides or activated aryl chlorides
in toluene at 120 °C in the presence of K
2 CO
3 as the base.</P><P>Later, palladium-1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene
complexes were reported to be active catalysts for cross-coupling of activated and
deactivated aryl chlorides with arylboronic acids, but for effective activation of
electron-neutral and electron-rich aryl chlorides, these catalyst systems required
temperatures higher than 75 °C.
[
104 ]
</P><P>It should be noted that, since IMes (
56 ) is considerably less stable to air and moisture than the corresponding imidazolium
salt
57a (Figure
[
8 ]
), this carbene has sometimes been generated in situ by deprotonotation of
57a and then used for preparation of
the catalytically active palladium complex.
[
102 ]
[
104 ]
</P>
Figure 8
<P>A typical reaction catalysed by the complex prepared in situ from Pd
2 (dba)
3 and
57a in the presence of Cs
2 CO
3 is shown in Scheme
[
9 ]
.
[
104 ]
</P>
Scheme 9
<P>The complex prepared in situ from Pd
2 (dba)
3 and the imidazolium salt
57a or
57b has also been used to synthesise a variety of purine derivatives by cross-coupling
of chloropurines with boronic acids.
[
105 ]
</P><P>Another efficient catalyst system for high-yielding cross-coupling reactions
of aryl chlorides with arylboronic acids is that composed of Pd(OAc)
2 and the bisimidazolium salt
58 (Figure
[
8 ]
).
[
106 ]
On the other hand, through the use of Pd(OAc)
2 and the sterically hindered imidazolium salt
59 (Figure
[
8 ]
) as precatalyst mixture, it was possible to perform efficient cross-coupling reactions
of aryl chlorides with 9-alkyl-, 9-allyl-, 9-(1-alkenyl) or 9-cyclopropyl-9-borabicyclo[3.3.1]nonane
derivatives in the presence of CH
3 OK as the base.
[
107 ]
An example of these reactions is shown in Scheme
[
10 ]
.</P><P>Attention has also been directed toward the evaluation of the catalytic activity
of homoleptic bis(NHC)-complexes of Pd(0) such as
60
[
108 ]
and
61
[
109 ]
in the Suzuki cross-coupling reaction of aryl chlorides (Figure
[
9 ]
). Herrmann et al.
[
109 ]
found that complex
61 is a highly active precatalyst in the Suzuki cross-coupling reactions of aryl chlorides
at room temperature, for which no induction period was observed. However, since it
was found that Pd black precipitates during the conversion, the possibility that active
clusters of the type [Pd
n (NHC)
m ] (n >0.5 m) are formed could not be excluded.
[
109 ]
</P>
Scheme 10
<P>A variety of mixed Pd(II) complexes of general formula
62 bearing
N -heterocyclic carbenes and triaryl- or trial-kylphosphines have also been prepared
(Figure
[
9 ]
). Complexes
62a-d (0.1-1 mol%) were found to efficiently catalyse the reaction of phenylboronic acid
with aryl bromides and chlorides in xylene at 130 °C in the presence of K
2 CO
3 .
[
110 ]
[
111 ]
</P><P>In 2003, a notable advance in palladium-catalysed Suzuki reactions was achieved
by the development of a general, highly efficient catalyst system for the room-temperature
coupling of hindered and unhindered, activated and deactivated aryl chlorides and
arylboronic acids.
[
112 ]
This catalyst system is composed of Pd(OAc)
2 and the
N -heterocyclic carbene with flexible steric bulk, which was prepared in situ by treatment
of the imidazolium salt
63 (Figure
[
9 ]
) with KH in THF in the presence of a catalytic amount of
t- BuOK. For the first time, di- and tri-
ortho- substituted biaryls were formed under these conditions and high turnover numbers were
obtained.
[
112 ]
</P>
Figure 9
<P>Recently, some studies have also been performed on the use of polymer-supported
N -heterocyclic carbenes as ligands for palladium catalysts.
[
113-115 ]
In fact, due to their versatile processing capabilities and ease of separation and
recycling, polymer-supported precatalysts can offer several advantages for industrial
applications. In 2004, Byun and Lee
[
115 ]
prepared the novel polymer-supported Pd-NHC complex
64 (Figure
[
9 ]
) and found that this complex is an efficient precatalyst for the cross-coupling of
aryl iodides and bromides with phenylboronic acid under aqueous conditions.</P><P>Finally,
it is worth mentioning that in 2000, Welton et al.
[
116 ]
found that Pd(PPh
3 )
4 -catalysed Suzuki cross-coupling reactions can be conducted in the ambient temperature
ionic liquid 1-butyl-3-methylimidazolium tetrafluo-roborate (
65 ) (Figure
[
10 ]
), exhibiting unprecedented reactivities in addition to easy product isolation and
precatalyst recycling. Later, these authors observed that complexes
66 (Figure
[
10 ]
) can spontaneously form under these conditions.
[
117 ]
Moreover, they detected the in situ formation of these complexes in all of the catalytically
active solutions derived from reactions of aryl bromides with phenyl- or tolylboronic
acid in
65 at 110 °C in the presence of aqueous Na
2 CO
3 and catalytic amounts of Pd(PPh
3 )
4 or PdCl
2 (PPh
3 )
2 .
[
118 ]
</P>
Figure 10
5 Water-Soluble Pd Catalyst Systems
5 Water-Soluble Pd Catalyst Systems
<P>During the last two decades, attention has also turned to the development of water-soluble
palladium precatalyst systems that can be easily separated from the organic-soluble
products at the end of the Suzuki reactions carried out in aqueous media. In 1990,
Casalnuovo and Calabrese
[
119 ]
found that the water-soluble complex Pd[PPh
2 (
m -C
6 H
4 SO
3 M)]
3 (
67 : M = Na
+ , K
+ ) efficiently catalyses cross-coupling reactions of aryl iodides and bromides with
aryl- and alkenylboronic acids in an aqueous medium. Later, this complex was employed
as precatalyst for the synthesis of poly(
p -quaterphenylene-2,2′-dicarboxylic acid) from 4,4′-dibromodiphenic acid and the ethylene
glycol diester of 4,4′-biphenylenebis(boronic acid) (Scheme
[
11 ]
).
[
120 ]
</P>
Scheme 11
<P>The structures of other water-soluble palladium precatalysts, and some water-soluble
ligands used in combination with palladium compounds to perform Suzuki reactions in
aqueous media, are shown in Figure
[
11 ]
.</P><P>Thus, a combination of the water-soluble ligand tri(3-sulfonatophenyl)phosphine
(TPPTS) (
68 ) and Pd(OAc)
2 was used by Genêt et al. to generate, in situ, a water-soluble catalyst for the Suzuki
reaction of a wide range of arylboronic acids or esters with aryl and alkenyl iodides,
[
121 ]
[
122 ]
and of arylboronic acids with aryl bromides.
[
123 ]
For this last process, which provides an efficient access to sterically hindered biaryls,
good turnover numbers were observed and the catalyst could be recycled three times
without loss of activity.</P>
Figure 11
<P>In 2000, Paetzold and Oehme
[
124 ]
reported that water-soluble complex
69 is an excellent catalyst precursor for the two-phase reaction of aryl halides with
arylboronic acids in toluene-ethanol-water at 78 °C in the presence of Na
2 CO
3 as base and surfactants as phase-transfer agents. It was also observed that with increasing
concentration of surfactant, the reaction rates were increased and the formation of
byproducts was suppressed.</P><P>Compounds
70a and
70b represent another class of ligands designed to solve basic problems of homogeneous
catalysis, such as separation and recycling of the catalyst. These hydrophilic carbohydrate-substituted
triarylphosphines, in combination with Pd(OAc)
2 (ligand:Pd = 3:1), gave better results than the catalyst system composed of a 3:1
mixture of TPPTS (
68 ) and Pd(OAc)
2 in cross-coupling reactions of aryl bromides with phenylboronic acid in ethanol-water-di-
n -butylether (2:3:1) or in ethanol-water-toluene at 78 °C in the presence of Na
2 CO
3 .
[
125 ]
</P><P>
N -(4-Diphenylphoshino)phenylmethyl gluconamide (
71 ) is another water-soluble phosphine ligand which was synthesised to perform efficient
palladium-catalysed reactions of aryl halides with arylboronic acids in water.
[
126 ]
Interestingly, the catalyst precursor prepared from
71 and PdCl
2 (1,5-cyclooctadiene) in acetonitrile revealed higher activity than that synthesised
from the water-soluble ligands
67 or
68 .
[
126 ]
</P><P>Uozumi, Danjo and Hayashi
[
127 ]
used the amphiphilic poly(ethyleneglycol)-polystyrene resin-supported palladium-monophosphine
complex
72 to catalyse the reaction of aryl halides and allyl acetates with arylboron compounds
in aqueous media. This catalyst could be easily removed from the reaction mixture
and reused with no decrease in activity.</P><P>Shaughnessy and Booth
[
128 ]
prepared two sterically demanding, water-soluble alkylphosphines
73 and
74 , which were modeled on the steric and electronic properties of P(
t -Bu)
3 , and found that they give highly active palladium catalysts for Suzuki couplings
of aryl bromides or chlorides with arylboronic acids in aqueous solvents. These authors
also observed that the more sterically demanding ligand
74 gives catalysts with activity toward aryl chlorides higher than that of the catalysts
obtained from
73 .</P><P>Very recently, Moore and Shaughnessy
[
129 ]
have reported that the aqueous-phase Suzuki palladium-catalysed coupling of aryl bromides
can also be performed using the sterically demanding sulfonated arylphosphines
75a and
75b . </P>
6 Ligandless Catalyst Precursors
6 Ligandless Catalyst Precursors
<P>In 1994, Wallow and Novak
[
130 ]
showed that phosphine ligands limit the catalytic efficiency of palladium catalysts
in Suzuki reactions of 2-aryl-1,3,2-dioxaborolanes or phenylboronic acid with aryl
bromides or iodides. At present, problems due to the use of phosphine-based catalyst
systems, namely the two side reactions, aryl-aryl exchange
[
131 ]
[
132 ]
and phosphonium salt formation,
[
133 ]
can be suppressed by employing the ligandless methodology.
[
134 ]
In fact, the use of ligandless palladium species as catalysts gives rise to a marked
improvement in reaction efficiency, allowing for milder reaction conditions and short
reaction times, and suppresses the phosphine-related side reactions.
[
131-137 ]
Scheme
[
12 ]
illustrates the preparation of a biphenyl derivative in high yield by an accelerated
Suzuki reaction performed in the presence of a catalytic amount of Pd(OAc)
2 under ligandless conditions.
[
138 ]
</P><P>Other examples of Pd(OAc)
2 -catalysed Suzuki reactions have been reported in the literature. Thus, the ligandless
Pd(OAc)
2 -catalysed reaction of aryl bromides with aryl- and 1-alkenylboronic acids in water
without cosolvent, in the presence of a stoichiometric amount of TBAB and a molar
excess of K
2 CO
3 , was found to provide the required cross-coupled products in high yields.
[
139 ]
Interestingly, under these reaction conditions, aryl iodides gave incomplete conversion,
[
139 ]
but 5-arylfurfurals and arylthiophene-2-carboxyaldehydes were efficiently prepared
starting from arylboronic acids and 5-bromofurfurals or bromothiophene-2-carboxyaldehydes,
respectively.
[
140 ]
</P>
Scheme 12
<P>Moreover, ligand-free Pd(OAc)
2 was found to be able to catalyse the coupling reaction of aryl iodides and deactivated
aryl bromides with arylboronic acids at room temperature in an aqueous medium
[
141 ]
[
142 ]
and could also be effectively used for preparation of [2]rotaxane
76 from 4,4′-biphenyldiboronic ester
77 and diammonium 1-iodonaphthalene-3,6-disulfonate (
78 ) in the presence of β-cyclodextrin
[
143 ]
as well as of (
R )-2-(4-methoxyphenyl)ferrocenecarboxyaldehyde (
79 ) from (
S )-2-iodoferrocenecarboxyaldehyde (
80 ) and 4-methoxyphenylboronic acid (
81 ) (Figure
[
12 ]
).
[
144 ]
[
145 ]
</P><P>Molander and Biolatto
[
146 ]
recently showed that Pd(OAc)
2 can also efficiently catalyse the reaction of potassium aryl- and heteroarylfluoroborates
with aryl- or heteroaryl bromides or triflates in refluxing methanol in the presence
of K
2 CO
3 (Scheme
[
13 ]
).</P>
Scheme 13
<P>Previously, it had been reported that, in the absence of both base and phosphine
ligand, Pd(OAc)
2 is able to promote the efficient synthesis of unsymmetrical biaryls by reaction of
arenediazonium tetrafluoroborates with arylboronic acids.
[
147 ]
[
148 ]
</P><P>Very recently, Pd(OAc)
2 has also been shown to be an effective precatalyst for the regiospecific cross-coupling
reaction of 3,5-dichloroisothiazole-4-carbonitrile (
82 ) with aryl- and methylboronic acids in refluxing toluene in the presence of KF and
18-crown-6, to give in high yields the 5-substituted 3-chloroisothiazole-4-carbonitriles
83 (Figure
[
12 ]
).
[
149 ]
</P><P>In 2003, Bedford et al.
[
150 ]
determined that Pd(OAc)
2 in a mixture of TBAB and water is an effective precatalyst precursor for the cross-coupling
of deactivated aryl chlorides with phenylboronic acid. Hess and Kirsch
[
151 ]
had previously reported that a catalytic amount of Pd(OAc)
2 promotes the reaction of β-chloroacroleins with arylboronic acids under mild conditions
in aqueous media, in the presence of one equivalent of TBAB and 2.5 equivalents of
K
2 CO
3 .</P>
Figure 12
<P>With regard to the nature of the catalytically active species formed in the ligandless
Pd(OAc)
2 -catalysed cross-coupling reactions involving arylboronic acids, it must be taken
into account that some years ago, the research groups of Moreno-Mañas
[
152 ]
and Marcuccio
[
153 ]
had independently established that Pd(OAc)
2 is reduced to Pd(0) by arylboronic acids, which undergo self-coupling to give symmetrical
biaryls.</P><P>In 2003, Deng et al.
[
154 ]
described ligand-free Pd(OAc)
2 -
or PdCl
2 -catalysed coupling of aryl and alkenyl bromides with arylboronic acids under mild
conditions and, very recently, Shen et al.
[
155 ]
determined that ligandless PdCl
2 catalyses the Suzuki cross-coupling reaction of a series of aryl bromides with arylboronic
acids in pyridine, with K
2 CO
3 as the base, to afford biaryl derivatives in surprisingly high yields.</P><P>Bumagin
and Korolev
[
156 ]
found that ligand-free Pd(OAc)
2 is also able to catalyse the cross-coupling reaction of sodium tetraarylborates with
acyl chlorides in aqueous or non-aqueous media in the presence of Na
2 CO
3 as the base to give high yields of unsymmetric ketones. These authors also synthesized
phenyl aryl ketones in high yields by reaction of arylboronic acids with benzoyl chloride
in aqueous acetone at 20 °C in the presence of 10 mol% PdCl
2 and 1.6 equivalents of Na
2 CO
3 .
[
156 ]
Moreover, they observed that the reaction time for the preparation of phenyl
m -tolyl ketone according to this last procedure was shorter than that of the synthesis
of this ketone performed in the presence of 1 mol% PdCl
2 (PPh
3 )
2 , and that the yield was higher.
[
156 ]
</P><P>Palladium on carbon has been found to be another effective precatalyst for
Suzuki reactions. Thus, tetraester
86 was synthesised in 79% yield by reaction of iodide
84 with benzene diboronate ester
85 in EtOH in the presence of Cs
2 CO
3 as the base and 10 mol% Pd on carbon (Figure
[
13 ]
).
[
157 ]
</P>
Figure 13
<P>Moreover, 5-aryl-2-furaldehydes
88 were synthesised in 78-91% yield via coupling of electron-deficient aryl iodides
with in situ generated boronic acid
87 (Figure
[
13 ]
) in EtOH at 60 °C, in the presence of Et
3 N
and a catalytic amount of 10% Pd on carbon, followed by acidic aqueous workup.
[
158 ]
</P><P>In 2002, Leadbeater and Marco
[
159 ]
used microwave heating to facilitate palladium-catalysed Suzuki reactions under ligandless
conditions. Thus, several biaryl derivatives were synthesized in 50-90% yield by reaction
of arylboronic acids with activated aryl iodides, bromides and chlorides in a mixture
of TBAB and water, in the presence of 0.4 mol% Pd(OAc)
2 and three equivalents of Na
2 CO
3 using microwave heating. In 2003, Leadbeater and Marco found that the Suzuki coupling
of phenylboronic acid with activated and unactivated aryl bromides is possible without
the need for a transition metal catalyst, by using one equivalent of TBAB as additive
and performing the reaction in water under microwave irradiation (a microwave power
of 100 W is optimum).
[
160 ]
</P><P>In 1999, Schotten et al.
[
161 ]
reported that Pd(OAc)
2 , without an additional phase-transfer compound, is able to promote the reaction of
poly(ethyleneglycol)-bound aryl iodides, bromides and triflates with aryl boronic
acids in water under conventional thermal conditions (70 °C, two hours) or under microwave
irradiation (75 W, two to four minutes). Later, these authors used a similar strategy
to synthesise compounds of general formula
89 and
90 (Figure
[
14 ]
).
[
162 ]
</P>
Figure 14
<P>Microwave irradiation was also used by Villemin et al.
[
163 ]
to facilitate the ligandless Pd(OAc)
2 -catalysed reaction of heteroaromatic halides with commercially available sodium tetraphenylborate
in water or monomethylformamide in the presence of Na
2 CO
3 as the base. </P><P>The sulfur-containing palladium complex PdCl
2 (SEt)
2 is another ligandless system which was shown to be an efficient catalyst precursor
for the cross-coupling of aryl bromides and chlorides with arylboronic acids.
[
164 ]
Interestingly, TBAB, which had a beneficial effect for the reactions catalysed by
Pd(OAc)
2 , had no significant effect when PdCl
2 (SEt)
2 was used as the catalyst.
[
164 ]
</P><P>Palladium powder has also been used as a catalyst precursor for Suzuki reactions.
Kabalka et al.
[
165 ]
found that aryl iodides readily couple with arylboronic acids in refluxing methanol
in the open air, in the presence of a catalytic amount of Pd powder and ca. 14 equivalents
of KF. Kabalka and his research group also utilized Pd powder and a commercially available
KF-Al
2 O
3 mixture for solventless cross-coupling reactions of aryl and allyl halides and aryl-
or alkenylboronic acids.
[
166 ]
[
167 ]
Under these experimental conditions, aryl iodides were found to react faster than
the bromides or chlorides.
[
167 ]
Moreover, it was observed that the use of microwave irradiation accelerates the reactions
by decreasing the reaction times from hours to minutes,
[
167 ]
[
168 ]
and that the palladium catalyst can be recycled using a simple filtration and washing
sequence without loss of catalytic activity.
[
167 ]
</P><P>Some other interesting results about Suzuki cross-coupling reactions catalysed
by Pd on carbon have been described.
[
135 ]
[
169-171 ]
For instance, this heterogeneous catalyst proved to be able to catalyse the Suzuki
reaction with aryl chlorides at 80 °C in a 20:1 mixture of dimethylacetamide and water,
in the presence of K
2 CO
3 as the base.
[
170 ]
The ability of heterogeneous Pd to activate the C-Cl bond was explained in terms of
a synergistic anchimeric and electronic effect that occurs between the Pd surface
and the aryl chloride.
[
170 ]
On the other hand, a specially optimised air-stable Pd on activated carbon catalyst
(i.e. E 105 CA/W 5% Pd, product of Degussa AG) was demonstrated to be a highly active
(TON up to 36,000), selective and heterogeneous catalyst for cross-couplings of phenylboronic
acid with aryl bromides or activated aryl chlorides.
[
171 ]
This catalyst allowed very low palladium concentrations (0.005 mol%) and high conversions
of aryl bromides within a few hours.
[
171 ]
</P><P>In recent years, palladium nanoparticles have also been used as catalysts for
Suzuki reactions.
[
172-174 ]
In fact, these particles have a characteristicly high surface-to-volume ratio and,
consequently, a large fraction of the palladium atoms are at the surface and available
for catalysis. Thus, palladium nanoparticles stabilised by poly(
N -vinyl-2-pyrrolidone) were found to be an efficient catalyst for Suzuki reactions
in 40% EtOH
[
172 ]
and a poly(
N ,
N -dialkylcarbodiimide)-Pd nanoparticle composite has been demonstrated to be a robust
catalyst for Suzuki reactions under microwave or regular heating.
[
174 ]
Some evidence was also obtained concerning the presence of nanosized Pd colloids in
Suzuki reactions catalysed by Pd(OAc)
2 .
[
175 ]
</P><P>Good catalytic activity for cross-coupling reactions of phenylboronic acid
with (hetero)aryl iodides and bromides was also shown by hollow palladium spheres
synthesised using silica spheres as templates.
[
173 ]
Interestingly, these hollow palladium spheres could be reused many times without loss
of catalytic activity.</P><P>Suzuki cross-coupling reactions of aryl halides, including
chlorides, with arylboronic acids were also achieved in the phosphonium salt ionic
liquid tetradecylphosphonium chloride in the presence of K
3 PO
4 and a catalytic amount of Pd
2 (dba)
3 ,
[
176 ]
as well as in the ionic liquid 1,3-di-
n -butylimidazolium tetrafluoroborate [bbim][BF
4 ] with methanol as co-solvent under ultrasonic irradiation in the presence of sodium
acetate (for bromo- and iodobenzenes) or sodium methoxide (for chlorobenzenes) and
a catalytic amount of Pd(OAc)
2 .
[
177 ]
</P><P>The heterogeneous catalyst system PdCl
2 /tetraphenylphosphonium bromide-intercalated clay was used in 1999 by Varma and Naicker
[
178 ]
for the preparation of biaryl compounds in high yields from aryl bromides or iodides
and arylboronic acids. It is worth mentioning that this catalyst could be recycled
twice without any loss in activity.</P><P>In 2003, Paul and Clark
[
179 ]
used a novel silica-supported palladium catalyst for the Suzuki reaction between aryl
bromides and phenylboronic acid. The key features of the catalyst included rapid reactions,
excellent catalyst recyclability and total stability under the reaction conditions.</P>
7 Other Novel Palladium Catalyst Precursors
7 Other Novel Palladium Catalyst Precursors
<P>In the last four years, in addition to catalyst systems belonging to the classes
described in the preceding sections of this review, several other types of palladium
catalysts have been developed and used in Suzuki reactions. In 2001, the catalyst
system composed of 5 mol% PdCl
2 (CH
3 CN)
2 and 20 mol% AsPh
3 , which had been previously used for the coupling reaction of cyclopropylboronic acids
with β-tetronic acid triflate
91 ,
[
180 ]
was employed in an unprecedented, general and efficient procedure for the regioselective
synthesis of 4-alkyl-3-bromo-2(5
H )-furanones
93 from alkylboronic acids and easily available 3,4-dibromo-2(5
H )-furanone (
92 ) (Figure
[
15 ]
).
[
181 ]
To circumvent the sensitivity of dibromide
92 to both water and strong bases, the cross-coupling reactions were performed in THF
in the presence of the weak base Ag
2 O.</P>
Figure 15
<P>The catalyst system PdCl
2 (CH
3 CN)
2 /AsPh
3 proved also to be effective for the highly regioselective monoarylation of
92 at C-4 and was found to be much more reactive than Pd(PPh
3 )
4 and the system consisting of 5 mol% Pd(OAc)
2 and 10 mol% PPh
3 .
[
182 ]
</P><P>The structures of some other novel palladium catalyst precursors for Suzuki
couplings and of some unusual ligands used in these palladium-catalysed reactions
are represented in Figure
[
16 ]
.</P><P>In 2000, Griffiths and Leadbeater
[
183 ]
reported the use of a combination of Pd
2 (dba)
3 and trimethylphosphite (
94 ) as an efficient precatalyst for the synthesis of sterically hindered biaryls from
aryl bromides bearing two
ortho substituents and phenylboronic acid. On the other hand, Zapf and Beller
[
184 ]
employed tris(2,4-di-
tert -butylphenyl)phosphite (
95 ) and tri(isopropyl)phosphite (
96 ) as ligands for the efficient palladium-catalysed coupling reaction of aryl bromides
and chlorides with phenylboronic acid. Using these phosphites as ligands, catalyst
turnover numbers up to 820,000 were obtained even with deactivated aryl bromides and,
for the first time, it was shown that the Pd-phosphite complex generated in situ also
catalyses efficiently the Suzuki reaction of aryl chlorides.
[
184 ]
</P><P>Beller et al.
[
185 ]
also demonstrated that the 1,6-diene Pd(0) monophosphine complexes
97-100 (Figure
[
16 ]
) are extremely efficient catalyst precursors for Suzuki reactions of various aryl
chlorides and found that, by variations of both the diene and the phosphine part of
the complex, the catalytic properties of these complexes could be tuned. Interestingly,
these monophosphine complexes were found to be superior to generally applied mixtures
of palladium precatalysts and phosphines.</P>
Figure 16
<P>In 2001, Li
[
186 ]
reported that the air-stable phosphine oxides
103 (Scheme
[
14 ]
) are another promising class of ligands for the palladium-catalysed Suzuki cross-couplings
of unactivated aryl chlorides. These ligands and their less stable phosphinous acid
tautomers
102 were generated by hydrolysis of the diorganophosphorus halides
101 (Scheme
[
14 ]
). In particular, it was found that binding a phosphinous acid
102 to palladium provides an adduct,
104 , which may be deprotonated to give an anionic palladium-phosphine complex suitable
as a catalyst for cross-couplings of aryl chlorides with arylboronic acids.
[
186 ]
[
187 ]
</P><P>An interesting alternative to existing catalytic systems based on the use of
tertiary phosphine ligands was reported in 2001 by Nolan et al.
[
188 ]
who developed a catalyst system consisting of a combination of Pd(OAc)
2 and
N ,
N ′-dicyclohexyl-1,4-diazabutadiene (
105 ) (Figure
[
17 ]
) for the reaction of aryl bromides and activated aryl chlorides with arylboronic
acids. Investigation of other diazabutadiene ligands led to the observation that
N ,
N ′-dialkyl-1,4-diazabutadienes are superior supporting ligands for the palladium-catalysed
Suzuki reaction compared with
N ,
N ′-diaryl-1,4-diazabutadienes.
[
188 ]
</P><P>Recently, Tao and Boykin
[
189 ]
have found that different substituents on the phenyl ring of 2-aryloxazolines have
a dramatic influence on the Suzuki reaction of aryl bromides with arylboronic acids
in dioxane at 80 °C in the presence of Cs
2 CO
3 as the base and the catalyst system consisting of a combination of Pd(OAc)
2 and a 2-aryl-2-oxazoline. Among the 2-aryl-2-oxazolines examined, compound
106 (Figure
[
17 ]
)
was found to be the best ligand, providing the required biaryls in good to excellent
yields.</P>
Figure 17
<P>In 2001, Doucet, Santelli et al. investigated the synthesis
[
190 ]
and use
[
191-195 ]
of a new tetrapodal phosphine ligand,
cis ,
cis ,
cis ,
cis -1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane (
107 ) (Figure
[
18 ]
), and demonstrated that a combination of [PdCl(η
3 -C
3 H
5 )]
2 and this ligand produces an efficient catalyst for cross-couplings of aryl bromides,
[
191-193 ]
heteroaryl bromides
[
191 ]
[
194 ]
and activated aryl chlorides
[
195 ]
with aryl boronic acids. Very high substrate-catalyst ratios (up to 5,000,000) could
be used for the reactions between aryl bromides and arylboronic acids, and a turnover
number of 28,000,000 was obtained for the reaction between 4-bromobenzophenone and
phenylboronic acid in xylene at 130 °C in the presence of K
2 CO
3 as the base.
[
191 ]
</P><P>Recently, attention has also turned toward the application of sterically hindered
phosphines based on a phospha-adamantane framework to palladium-catalysed Suzuki reactions.
It has been demonstrated that the catalyst system consisting of a combination of Pd
2 (dba)
3 and 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phenyl-6-phospha-adamantane (
108 ) (Figure
[
18 ]
) is very active in promoting the coupling reactions of arylboronic acids with aryl
halides, including an activated aryl chloride, at room temperature in high yields.
[
196 ]
</P>
Scheme 14
Figure 18
<P>Interestingly, the air-stable ligand
108 could be recovered by chromatography on silica gel and reused.</P><P>Nájera et al.
[
197 ]
recently reported that the dipyridylmethylamine-based Pd(II) complex
109 (Figure
[
18 ]
) is able to promote the reaction of aryl halides with phenylboronic acid and that
the coupling involving aryl chlorides has to be run in the presence of TBAB as an
additive.</P><P>In 2004, Hong et al.
[
198 ]
employed three cobalt-containing bulky phosphines, compounds
110a-c (Figure
[
18 ]
) as monodentate phosphine ligands in Pd(OAc)
2 -mediated reactions of (hetero)aryl bromides with phenylboronic acid. Mobufu, Clark
and Macquarrie
[
199 ]
had previously described a range of silica-supported phosphine-free palladium-catalysed
Suzuki reactions with notable features including fast and efficient reactions, catalyst
stability under the reaction conditions, and very good catalyst recyclability. The
most active precatalyst precursors were complexes
111a and
111b (Figure
[
18 ]
).</P><P>In 2003, Parlow et al.
[
200 ]
investigated the use of the anthracene-tagged palladium complex
112 (Figure
[
18 ]
) as precatalyst in polymer-assisted solution-phase Suzuki reaction of aryl bromides
with anthracene-tagged boronic acids in the presence of a polymer-supported carbonate
base. They also found that the use of this complex allows for easy removal of the
palladium catalyst along with the dissociated phosphine ligand and phosphine oxide
byproducts by sequestration through a Diels-Alder reaction with a maleimide resin.
It is noteworthy that the coupling reactions performed by using the above mentioned
conditions gave the required products in high purity and yield without the use of
chromatography.</P><P>In 2002, high-throughput screening was used as a powerful tool
in optimising the Suzuki reaction of activated and unactivated aryl bromides with
phenylboronic acid.
[
201 ]
Results from this study indicate that the triphenylphosphine-based polymer-supported
FibreCat
precatalysts
113-116 (Figure
[
19 ]
) can be used to achieve room-temperature couplings in nearly quantitative conversions.</P>
Figure 19
<P>In 2003, an assembled precatalyst, PdAS, prepared from (NH
4 )
2 PdCl
4 and non-cross-linked amphiphilic polymer poly[(
N -isopropylacrylamide)-
co -(4-diphenylstyrylphosphine)] was found to be an excellent catalyst precursor for
heterogeneous Suzuki reactions.
[
202 ]
In fact, the coupling of aryl and alkenyl halides with aryl- and alkenylboronic acids
was efficiently catalysed by 8 × 10
-7 to 5 × 10
-4 molar equivalents of PdAS with turnover numbers reaching up to 1,250,000.</P><P>In
the same year, Hu et al.
[
203 ]
designed and synthesised monophosphine-containing polymer
117 (Figure
[
20 ]
) which was then used for the room-temperature palladium-catalysed reaction between
aryl chlorides and arylboronic acids.</P><P>Very recently, in the course of an investigation
on the asymmetric synthesis of compounds containing quaternary carbon atoms by a Suzuki
reaction, Willis et al.
[
204 ]
found that the optimal catalyst for the enantioselective coupling of ditriflate
118 with arylboronic acids is generated from Pd(OAc)
2 and phosphine
119 (Figure
[
20 ]
). The enantioselectivities obtained were up to 86% ee. </P><P>Also in 2004, Macquarrie
et al.
[
205 ]
prepared the chitosan-pyridine imine-based palladium complex
120 (Figure
[
20 ]
) and found that it is an excellent and reusable precatalyst for Suzuki reactions
involving aryl and heteroaryl bromides.</P>
Figure 20
8 Conclusions
8 Conclusions
<P>From this review, it is clear that recent advances in the design of palladium catalysts
for the Suzuki reaction have resulted in several synthetically useful acquisitions.
Thus, as reported in Section 2, palladacycle complexes have been found to be air-
and thermally stable catalyst precursors that are suitable for recycling protocols
and that can give very high turnover numbers and turnover frequencies. Moreover, some
of them have been proven to be able to promote Suzuki reactions of activated and unactivated
aryl chlorides, also under aerobic conditions. Thus, these complexes appear to be
catalyst precursors superior to traditional palladium/triarylphosphine catalyst precursors,
which are only effective for the coupling of certain activated (hetero)aryl chlorides.</P><P>As
shown in Section 3 of this review, catalyst systems composed of a Pd(0) or a Pd(II)
derivative and an electron-rich and/or bulky phosphine ligand have also been used
for Suzuki reactions of both electron-rich and electron-deficient aryl chlorides.
Moreover, these catalyst precursors have been successfully used for the room-temperature
Suzuki coupling of aryl bromides and chlorides at low catalyst loading.
[
68 ]
This aspect is quite interesting since, before the use of these catalyst precursors,
there were few examples in the literature of Suzuki couplings of aryl bromides that
proceed at room temperature,
[
19 ]
[
140 ]
[
141 ]
[
206 ]
and there were no reports of room-temperature Suzuki reactions involving aryl chlorides.
Other capabilities of these catalyst precursors include the following: synthesis of
hindered di- and tri-
ortho -substituted biaryls;
[
53 ]
cross-coupling of 9-alkyl-9-borabicyclo[3.3.1]nonanes with alkyl chlorides;
[
54 ]
and cross-coupling of uncomplexed electron-poor aryl fluorides with arylboronic acids.
[
94a ]
</P><P>In Section 4 of this review, it was shown that catalyst systems composed of
Pd(0) or Pd(II) derivatives and
N -heterocyclic carbene ligands can be active for Suzuki reactions which can be alternatively
performed, sometimes under similar reaction conditions, using palladacycle complexes
as catalyst precursors or catalyst systems composed of a Pd(0) or a Pd(II) derivative
and an electron-rich and/or bulky phosphine ligand. However, the scope of the Pd/carbene-catalysed
Suzuki reactions of aryl chlorides has been significantly expanded by employing 9-alkyl-,
9-allyl-, 9-(1-alkenyl)- and 9-cyclopropyl-9-borabicyclo[3.3.1]nonane derivatives
as coupling partners.
[
107 ]
</P><P>It should also be mentioned that a drawback of the protocols involving the
use of
N- heterocyclic carbenes
is that these compounds are air- and moisture-sensitive. However, their handling can
be avoided through the use of the corresponding, easier to handle, commercially available
chloride salts, which can be deprotonated in situ to generate the required carbene
ligands.</P><P>Section 5 of this review was devoted to the description of water-soluble
catalyst systems for the Suzuki reaction that can be easily separated from the organic-soluble
products at the end of the transformation. The use of these catalyst systems, which
operate in a two-phase system, could offer advantages for the industrial production
of fine chemicals in comparison to protocols involving homogeneous catalysis.</P><P>Section
6 was devoted to a discussion of the use of ligandless palladium catalyst precursors.
The use of these precatalysts can overcome the problems pertaining to the Suzuki cross-coupling
reactions where expensive palladium complexes, which are difficult to prepare and
recover, are used as catalyst precursors. Nevertheless, it should be mentioned that
although the ligandless palladium precatalysts often achieve significantly fast cross-couplings
in aqueous media, complete conversion is not always possible, particularly for slow
reactions of electron-rich and sterically hindered haloarenes.
[
11 ]
</P><P>Finally, the capabilities of several other novel palladium catalyst precursors
were described in Section 7. Some of these Pd systems, such as PdAS and complex
112 , have been found to be excellent catalyst precursors for heterogeneous Suzuki reactions
and other Pd systems, such as that composed of a combination of [PdCl(η
3 -C
3 H
5 )]
2 and ligand
107 ,
or those composed of the 1,6-diene palladium(0) monophosphine complexes
97 -
100 , have proven to be extremely efficient catalyst precursors for Suzuki cross-coupling
reactions of aryl chlorides, and appear to be superior to generally applied mixtures
of Pd(II)-derivatives and phosphine ligands. These findings are rather important since
there are relatively few examples of Suzuki cross-couplings of aryl chlorides that
proceed at low catalyst loadings (0.05 mol% Pd).
[
66 ]
[
70 ]
[
185 ]
[
192 ]
</P><P>Nevertheless, despite these important results, a number of challenges, especially
with regard to industrial applications of the Suzuki coupling reactions, remain. In
fact, even though some successful results in the preparation and use of efficient
heterogeneous catalyst systems have been obtained, it is still necessary to develop
much more effective and low-cost heterogeneous catalysts which are able to work in
very mild conditions. These ideal catalysts will be characterised by high stability
under the reaction conditions, very good recyclability and very high turnover numbers
and turnover frequencies and, thus, will provide a significant practical benefit to
industry.</P>
