A mild robust generic protocol for the Suzuki reaction using an air stable catalyst

Article abstract of DOI:10.1016/j.tet.2012.05.030

A mild but robust procedure has been developed as a first pass generic protocol for the Suzuki-Miyaura reaction. The protocol employs an air stable palladium pre-catalyst at low loading (<1 mol %) in aqueous solvent mixtures at moderate temperature using potassium carbonate as base. Under these mild conditions, most aryl bromides will react with sterically and electronically demanding aryl boronic acids to give complete conversion to the product biphenyls in less than 1 h. Aryl chlorides are also fully converted in most cases either under identical conditions in 8-24 h, or in 2 h at elevated temperature. A further advantage of these mild conditions of moderate temperature, weak base and benign solvent is that sensitive functional groups and structural motifs are well tolerated. In addition, the lipophilic biphenyl products are readily isolated after a simple work-up procedure. These generic conditions are ideal for proof of transformation, and as the starting point for development and optimization of a specific process. The discovery and fine-tuning of this generic protocol will be presented, supported extensively by examples to illustrate its scope and utility.

Full text of DOI:10.1016/j.tet.2012.05.030

Tetrahedron 68 (2012) 6010e6017
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A mild robust generic protocol for the Suzuki reaction using an air stable catalyst
*
Jonathan D. Moseley , Paul M. Murray, Edward R. Turp, Simon N.G. Tyler, Ross T. Burn
CatScI Ltd, CBTC2, Capital Business Park, Wentloog, Cardiff CF3 2PX, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild but robust procedure has been developed as a first pass generic protocol for the SuzukieMiyaura
reaction. The protocol employs an air stable palladium pre-catalyst at low loading (ꢀ1 mol %) in aqueous
solvent mixtures at moderate temperature using potassium carbonate as base. Under these mild con-
ditions, most aryl bromides will react with sterically and electronically demanding aryl boronic acids to
give complete conversion to the product biphenyls in less than 1 h. Aryl chlorides are also fully converted
in most cases either under identical conditions in 8e24 h, or in 2 h at elevated temperature. A further
advantage of these mild conditions of moderate temperature, weak base and benign solvent is that
sensitive functional groups and structural motifs are well tolerated. In addition, the lipophilic biphenyl
products are readily isolated after a simple work-up procedure. These generic conditions are ideal for
proof of transformation, and as the starting point for development and optimization of a specific process.
The discovery and fine-tuning of this generic protocol will be presented, supported extensively by ex-
amples to illustrate its scope and utility.
Received 7 February 2012
Received in revised form 27 April 2012
Accepted 8 May 2012
Available online 14 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
with homeopathic catalyst loadings,18 reactions in ionic liquids19 and
reactions in water, many of which occur at room temperature.20 In
The SuzukieMiyaura reaction has proven to be a powerful
technique in organic synthesis, particularly for the formation of
unsymmetrical biaryl compounds, and has been widely used since
its discovery in 1979;1 this is due both to the reaction’s excellent
performance and wide utility. For example, the biaryl and hetero-
biaryl motifs occur in numerous compounds of interest,2 and spe-
cifically in many pharmaceuticals,3 some of which have been scaled
up;4 agrochemicals;5 natural products;6 a wide range of fine and
specialty chemicals including dendrimers, dyes, liquid crystals,
materials, (organic) light-emitting polymers and polymers in gen-
eral;7 and of course ligands for catalysis.8 In addition, the Suzuki
reaction is not limited to formation of the biaryl motif, and coupling
with alkenyl (sp2) and alkyl (sp3) boronic acids can also be ach-
ieved, providing alternative structural diversity.
fact, many of the reactions referenced11e20 combine several of these
approaches. Indeed, the Suzuki reaction is in some respects becoming
the victim of its own success, with this plethora of conditions avail-
able, all viable under particular circumstances.
Conscious of the wide array and subtle conditions possible for
many transition-metal catalysed reactions, we have sought to pro-
vide the practising chemist with a simple entry into initial experi-
mental investigations for a number of these reactions, starting with
our protocol for the Heck reaction.21 In this current study we present
a simple and robust generic protocol for the formation of biaryls by
the SuzukieMiyaura reaction, which can be used for efficient proof of
transformation. This has proven successful for biaryl products de-
rived from a diverse variety of aryl halides and aryl boronic acids
without the need to greatly modify the reaction conditions. It is
hoped that this will greatly ease the burden on the synthetic chemist,
fully aware of the power of this transformation but not necessarily
expert in the art, and only wishing in the first instance to conduct an
initial screen when a detailed understanding of the subtly of all these
parameters may not be required; in-depth understanding can (and
should) follow if optimisation of a promising reaction is required.
The Suzuki reaction has been reviewed regularly in books9 and
journals,10 from which it quickly becomes apparent that there is an
almost bewildering variety of conditions available, including a mul-
titude of catalyst and ligand combinations, recommended solvents
and additives, among many other factors. For example, recent de-
velopments have included Suzuki reactions using new catalysts,11
catalysts based on alternative metals (e.g., nickel12 and gold13),
nano-particulate catalysts,14 magnetically separable catalysts,14b,15
polymer-supported catalysts,16 ligand-free catalysts,17 reactions
2. Results and discussion
2.1. Aryl bromides as coupling partners
On the basis of work on active drug projects and some limited
* Corresponding author. Tel.: þ44 2920 837444; e-mail address: jonathan.moseley@
catsci.com (J.D. Moseley).
screening,22 we concluded that 1,10-bis(di-tert-butylphosphino)
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.030

J.D. Moseley et al. / Tetrahedron 68 (2012) 6010e6017
6011
ferrocene palladium dichloride (Pd(dbpf)Cl2) (‘Pd-118’) (Fig. 1) was
an excellent catalyst for many applications. This is a commercially
available, air- and water-stable catalyst23 that has since been shown
to be highly active for other Pd-catalysed coupling reactions.24 This
catalyst would therefore be ideal for use in a generic protocol, and
we chose not to screen any others for this study. Our initial con-
ditions were developed independently to those of Colacot, who also
concluded that Pd-118 was the catalyst of choice after a catalyst
screen.25 Like Colacot we chose K2CO3 as a suitable mild base, but
employed in a range of aqueous organic solvent mixtures at 80 ꢁC,
rather than in DMF at 120 ꢁC. We avoided DMF, which is much used
in aqueous mixtures, because of its toxicity (for a generic protocol)
and to simplify the expected work-up procedure. Its higher bp was
unnecessary for the majority of substrates investigated, and of
doubtful help when higher temperatures are required due to its
thermal instability.
reactions,18 we decided to fix our conditions at 1 mol %, in order to
build in robustness to the procedure for more difficult substrates.
We also decided to reduce the temperature, since for practical
reasons performing reactions off-reflux with volatile solvents re-
duces the potential for undesirable solvent loss (and is significantly
more energy efficient on scale-up). One scouting reaction per-
formed on a simple substrate pair (4-bromobenzaldehyde (29) with
phenyl boronic acid (A)) indicated that the reaction was complete
within a few minutes at essentially room temperature (30 ꢁC).
However, we decided to settle on a temperature of 60 ꢁC, since this
is off-reflux whilst retaining robustness in the generic method for
more demanding substrates. In addition, higher temperatures also
increase solubility, which usually aids the reaction and also the
work-up through improved phase separations.
We surveyed acetonitrile, ethanol and THF in combination with
water at 9:1, 4:1 and 1:1 ratios. Again, all reactions were complete
within 1 h with little difference between them. However, without
stirring, all reaction mixtures were biphasic due to the ionic content
of the aqueous phase (K2CO3 at the start with KBr, KHCO3 and re-
sidual K2CO3 at the end). The 9:1 and 4:1 solvent systems could not
always dissolve the inorganic salts present, leading to some pre-
cipitation, emulsion or indistinct phase separations. Even when
dissolved however, a small aqueous phase remained at the bottom
of the tube, which could present mixing problems on scale-up. The
phase separation was also somewhat less clear in the ethanol and
THF cases than for acetonitrile at 1:1. We therefore chose acetoni-
trile/water at 1:1 v/v since this generally gave the best results for
the physical aspects of the reaction with several substrates (in-
dependent of reaction conversion), and which would also aid
product isolation.
P
P
Cl
Cl
Pd
Fe
Fig. 1. Structure of Pd(dbpf)Cl2.
The rationale for using a modest excess of boronic acid was
firstly that some of this reagent must be consumed to form homo-
coupled products as the catalyst is reduced to its active Pd(0)
form.26 This is directly dependent on the catalyst stoichiometry,
which in this case at 1 mol % is not much of an issue. The use of
a pre-reduced Pd(0) catalyst could be used to reduce further the
excess boronic acid required in cases where the catalyst loading is
higher (e.g., 5e10 mol %). Secondly, if the reaction is slow, it is the
boronic acid, which is most likely to be degraded (via proto-
deboronation) under aqueous conditions10g rather than the aryl
halide. Of course, if the boronic acid is the more valuable compo-
nent, then the aryl halide can be used in excess to give, almost
certainly, a similar result. For process optimization, the substrate
pairing and exact stoichiometry used would be investigated fur-
ther. Lastly, note that although we used fine grade K2CO3 (ꢂ325
mesh) in this study, under the aqueous conditions it remains dis-
solved through-out, so particle size is not a concern.27
In the course of developing these generic conditions for the
bromides we had found that all the initial substrate combinations,
which we had screened reacted very quickly and cleanly. Indeed,
much lower catalyst loadings and temperatures could clearly be
employed, but as stated, we wanted to retain robustness for more
difficult combinations. Therefore, we abandoned our planned ex-
haustive survey of para and meta substituents on the aryl bromide
The initial conditions used 1.2 equiv of boronic acid and
1.5 equiv of K2CO3 with either 1 or 2 mol % catalyst at 80 ꢁC in
aqueous acetonitrile, ethanol or THF combinations. However, all
reactions showed complete and clean conversion to the product
biaryls within 1 h, and usually within minutes when sampled more
quickly. We decided more recently to scope out more fully the
utility of our procedure. We started with aryl boronic acids (AeG)
and simple aryl bromides (1e30) to give the requisite biaryl
products (Scheme 1), leaving room to modify the procedure for
what we expected to be the more challenging substrates.
Ironically, the reactions with 2 mol % catalyst tended to contain
some minor impurities compared to those with 1 mol %. These
impurities were identified by LCeMS as fragments or derivatives of
the catalyst, particularly from the distinctive Fe and Pd isotope
patterns. Otherwise, only the residual excess of boronic acid and
a trace of the homo-coupled products (which is always formed
when starting from a Pd(II) pre-catalyst species)26 could be
detected in the reaction liquors, aside from the product biaryls. We
investigated the catalyst loading from 2 mol % down to 0.1 mol % for
one well-behaved substrate combination (4-bromobenzaldehyde
(29) with 4-tolyl boronic acid (E)), which showed complete con-
version after 1 h even at the lowest loading. Although low catalyst
loadings can clearly be used for these simple substrates, and so-
called homeopathic levels have been reported for several Suzuki
X
Z
Pd-118
Y
Z
+
K2CO3, 60 oC
MeCN/water 1:1
Y
(HO)2B
1-34
A-G
1-34/A-G
Scheme 1. Boronic acid substituent key: A, Z¼H; B, Z¼2-MeO; C, Z¼3-MeO; D, Z¼4-MeO; E, Z¼4-Me; F, Z¼4-CHO; G, Z¼4-COOH. Halide key: X¼Br or Cl as indicated. Aryl halide
substituent (Y) given in Tables 1e3 and text.

6012
J.D. Moseley et al. / Tetrahedron 68 (2012) 6010e6017
partner, and likewise on the boronic acid, and focussed on what we
considered to be the most demanding substituent combination, the
ortho/ortho pairing. We surveyed a comprehensive range of ortho-
substituents on the aryl bromide, investigating both steric and
electronic factors. For the boronic acid component, we further
simplified the study and concentrated on the 2-methoxyphenyl
boronic acid (B), since this is a strongly electron rich boronic acid
that would be most prone to proto-deboronation during slow
reactions;10g the ortho substitution would also crowd the reaction
centre on the catalyst, especially in combination with the ortho
substitution on the aryl bromides. The product biphenyls (1Be27B)
are keyed in Table 1 (note that the numeral keys the aryl bromide
source and the letter the aryl boronic acid).
reaction to proceed faster than the electron-donating ones, since all
reactions were fast, even when earlier sampling points were taken
and lower temperatures used.
Of particular interest, note that potentially base-labile sub-
stituents such as CN and CO2Me, and other sensitive substituents
such as CHO, were stable under these reaction conditions. Com-
plete conversions were achieved with no hydrolysis products
detected by LCeMS; only excess boronic acid B and the homo-
coupled biphenyl BB were typically detected (Fig. 2). Despite the
ortho and electron-donating substituent on boronic acid B,
In fact, it turned out that all aryl bromides investigated gave
essentially complete conversion within 1e2 h at 60 ꢁC (often much
less), with only two exceptions. Dealing first with largely steric
considerations revealed that the catalyst (Pd-118) in this solvent/
base system can cope handsomely with all sterically demanding
aryl bromides, including those bearing 2-isopropyl, mesityl and
2,6-diethyl substituents (entries 7e9); the three aromatically
substituted bromides (entries 10e12) are probably not as sterically
constrained as these alkyl substituted ones. Although not in-
dependent of steric factors, it can be also seen that a wide range of
electronic factors can be comfortably tolerated, from electron-
withdrawing substituents (e.g., CN, CHO, CO2Me) through to
electron-donating ones (e.g., OMe, SMe, NHAc) (entries 13e27). It
was not possible in the case of these aryl bromides to determine
whether the electron-withdrawing substituents enabled the
Z
Z
Z
RA-RG
AA-HH
A: Z = H
E: Z = 4-Me
B: Z = 2-OMe F: Z = 4-CHO
C: Z = 3-OMe G: Z = 4-COOH
D: Z = 4-OMe H: Z = 4-tBu
Fig. 2. Key to homo-coupled boronic acid products (AAeGG), the internal standard
used (HH) and reduced proto-deboronated by-products (RAeRG) possible.
Table 1
Biphenyls prepared from aryl bromides (X¼Br) and 2-methoxyphenyl boronic acid (B)
OMe
OMe
OMe
OMe
OMe
OH
8B
9B
11B
12B
10B
Aryl bromide
Y
Biphenyl product
1
H
1B
2
4-Me
2B
3
3-Me
3B
4
2-Me
4B
5
2-CF3
5B
6
2-Et
6B
7
2-i-Pr
7B
8
9
2,4,6-Me
2,6-diEt
2-Biphenyl
1-Naph
1-Naph-2-OH
4-CN
3-CN
2-CN
4-OMe
3-OMe
2-OMe
4-OH
3-OH
2-OH
2-F
2-Cl
2-CHO
2-CO2Me
2-SMe
2-NHAc
8B
9B
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
10B
11B
12B
13B
14B
15B
16B
17B
18B
19B
20B
21B
22B
23B
24B
25B
26B
27B
All reactions gave 100% conversion as determined by LC in 1e2 h under standard generic conditions except 12B and 21B.

J.D. Moseley et al. / Tetrahedron 68 (2012) 6010e6017
6013
reactions were so fast that no proto-deboronation to by-product RB
was detected in any of the examples investigated. A few reactions
contained minor isobaric products as determined by LCeMS or
GCeMS (<2%), but these products could be traced back to
regioisomers present in the starting aryl bromides. The reaction of
1-bromo-2-chlorobenzene (23) gave as expected a few per cent of
the tri-aryl product from a second reaction of the excess boronic
acid at the chloride, but even after 2 h, the reaction was surprisingly
mono-selective (entry 23).
biphenyls 1F/29A, 2F/29E and 1G/30A were prepared from either
combination of boronic acid and aryl bromide (to give identical
products) with full conversions in the same time and quality (en-
tries 9e14). In such cases, one has the opportunity to choose, which
combination is best considering other factors (e.g., cost or avail-
ability of reaction partners).
2.2. Aryl chlorides as coupling partners
However, aryl bromides bearing a 2-OH substituent (entries 12
and 21) proved to be the exception and both failed to go to com-
pletion. This is perhaps not surprising as one might postulate that
the ortho-hydroxy group is ideally positioned to interact with the
catalyst species. Entries 18, 26 and 27 indicate that the strong
electron-donating nature of the substituent is not likely to be an
issue; and entries 19 and 20 (other bromophenols) prove that the
hydroxyl substituent is itself not a problem, but only when it is in
the ortho position. Even so, some level of conversion was achieved
in both entries 12 and 21 before the reactions stalled. Attempts to
add either the boronic acid B or the aryl bromide 21 in a portion-
wise manner to the other coupling partner (fourteen 0.1 equiv ali-
quots added at 30 min intervals) also resulted in incomplete re-
actions. Indeed, portion-wise addition of the boronic acid B to aryl
bromide 21 gave a very low conversion (w14%) with almost equal
homo-coupled product BB, whereas portion-wise addition the
other way round gave w50% conversion with much less homo-
coupled product but also much unconsumed aryl bromide. The
best result however was simply to add a large excess (2.2 equiv) of
the boronic acid at the start, which gave a 70% conversion, albeit
with 20% homo-coupled product and some residual aryl bromide.
ortho-Hydroxyl substituents might therefore best be prepared via
a protected functionality such as an ortho-methoxy group, which
performs very well in this reaction. Interestingly, direct in situ
coupling of 2-hydroxypyridines with boronic acids has very re-
cently been reported.28
Having determined that all simple aryl bromides, even the most
hindered ones, would couple rapidly under our generic conditions
with this catalyst, we did not investigate aryl iodides, triflates or
diazonium salts on the grounds that these would be expected to
react even faster and often less cleanly. In contrast, we decided to
investigate the scope of reaction with simple aromatic chlorides,
since these are generally more desirable than the bromides as
coupling partners due to their much wider commercial availability
and lower cost. They were coupled with unsubstituted phenyl bo-
ronic acid (A) simply for convenience.
We started with
a small screen of the three electron-
withdrawing chlorobenzonitriles and the three electron-donating
chloroanisoles (13e18) as shown in Table 3. These clearly did not
react as quickly as the bromides, and here the difference between
the electron-withdrawing (activating) and electron-donating
(deactivating) substituents could clearly be seen (24 h time points
only shown). A handful of other substitution patterns were in-
vestigated (4, 20, 25, 31e34), which showed that a non-ortho-
substituted hydroxyl group and
a bulkier ortho-substituent
(CO2Me) did not present problems (entries 7 and 8). However, some
ortho and double ortho-substituents did reduce the reaction rate,
presumably for steric reasons (entries 9e11).
Two other more challenging substituents were also investigated
to make 33A and 34A. The 2-methoxy group with 5-fluoro on the
aryl chloride appeared to benefit from the 5-fluoro group (cf. en-
tries 6 and 12a), but the 2-formyl group (also with 5-fluoro) was
particularly sluggish (entry 13a). However, in both cases, reverting
to the aryl bromides as the coupling partner once again gave
complete conversions at 60 ꢁC (entries 12b and 13b).
To showcase the generality of the procedure, a few additional
examples are included in Table 2 with alternative boronic acids (A,
CeG) and aryl bromides, but this table is limited because the most
difficult combinations (i.e., ortho/ortho) have been presented al-
ready and showed full conversions. Note that by way of example,
For some of these more sluggish simple aryl chlorides, we ap-
plied super-heated conditions by heating in a sealed tube at 120 ꢁC
Table 2
Selected biphenyls prepared from aryl bromides (X¼Br) and boronic acids (A, CeG)
Table 3
Biphenyls prepared from aryl chlorides (X¼Cl) and phenyl boronic acid (A)
Z
CHO
F
F
Me
OMe
33A
CHO
34A
1F or 29A (Z = CHO)
1G or 30A (Z = COOH)
2F or 29E
Entry
Aryl bromide
Y
Boronic
acid
Z
Biphenyl product
Entry
Aryl
Chloride
Y
Biphenyl
Product
Conv. at
24 h (%)
Super-heated
1
2
3
4
5
6
7
8
13
19
28
3
15
2
19
13
1
29
2
4-CN
4-OH
4-SMe
3-Me
2-CN
4-Me
4-OH
4-CN
H
4-CHO
4-Me
4-CHO
H
A
A
A
C
C
D
D
E
F
A
F
E
G
A
H
H
H
13A
19A
28A
3C
15C
2D
19D
13E
1F
29A
2F
1
2
3
4
5
6
7
8
13
14
15
16
17
18
20
25
4
31
32
33
4-CN
3-CN
2-CN
13A
14A
15A
16A
17A
18A
20A
25A
4A
31A
32A
33A
33A
34A
34A
99
92
100
50
76
nd
nd
100
99
99
70
98
nd
100
75
99
nd
nd
80
nd
3-MeO
3-MeO
4-MeO
4-MeO
4-Me
4-CHO
H
4-CHO
4-Me
4-COOH
H
4-MeO
3-MeO
2-MeO
3-OH
2-CO2Me
2-Me
2,6-DiMe
2,6-DiF
2-MeO,5-F
2-MeO,5-F
2-CHO,5-F
2-CHO,5-F
38
100
100
85
50
>97
82
100
30
100
9
9
10
11
12
13
14
10
11
12a
12b
13a
13b
29
1
30
29E
1G
30A
33, X¼Br
4-COOH
34
34, X¼Br
All reactions gave 100% conversion as determined by LC in 1e2 h under standard
generic conditions.
Conversion determined by LC. nd¼not determined.

6014
J.D. Moseley et al. / Tetrahedron 68 (2012) 6010e6017
100
90
80
70
60
50
40
30
20
10
0
for 2 h. This helped to increase conversions for some slower re-
actions, often to completion (entries 4e7 and 9e11) and without
destruction of sensitive functionality (entries 13a).
We investigated the catalyst loading for the reaction of one aryl
chloride (29, X¼Cl) with 4-tolyl boronic acid (E) for comparison
with the aryl bromide (29, X¼Br) tested previously (Scheme 2).
Fig. 3 shows the reaction rate comparison for formation of biphenyl
29E from either aryl bromide or chloride. Suzuki reactions with aryl
chlorides have higher activation energies due to the higher AreCl
bond strength so a slower reaction is expected, in which case the
catalyst loading will be more significant than in the case of the aryl
bromides. Chlorobenzaldehyde (29, X¼Cl) may be an especially
testing example due to the presence of the formyl group, as noted
above.
All values (Br)
2.0% cat (Cl)
1.0% cat (Cl)
0.5% cat (Cl)
0.3% cat (Cl)
0.1% cat (Cl)
0
4
8
12
16
Time (hours)
20
24
Fig. 3. Comparison of the rate of formation as determined by LC of 29E prepared from
aryl halides 29 (X¼Br and Cl) with 4-tolyl boronic acid (E), dependent on the catalyst
loading.
2.3. Heteroaromatic halides as coupling partners
Lastly, we investigated the formation of heteroaromatic bi-
phenyls (35e45) (Fig. 4) from both bromides and chlorides, since
these would be a more meaningful test of the practical synthetic
utility of our generic protocol (Table 4). A cursory survey of Table 4
shows that again nearly all the bromides reacted within 2 h at
60 ꢁC. An ortho-substituent did slow the reaction, for example, on
thiophene 38A compared to unsubstituted 37A (entries 3 and 4),
but did give full conversion easily within 24 h (in contrast to a re-
cently reported result using a different catalyst).11e Once again the
presence of a formyl substituent did slow the reaction rate (cf.
entries 9 and 10), but full conversion could nevertheless be ach-
ieved after 48 h.
The more sluggish chloride counterparts generally required 48 h
for full conversions, although high conversions were often achieved
after 24 h. An exception was the particularly activated triazinyl
chloride (entry 1) with 97% conversion at just 2 h. All three chlor-
opyridines, for example, gave full conversion after 48 h whereas
their bromide analogues were complete after 2 h. Alternately, the
super-heating technique was again applied to some of the slower
heteroaromatic halides, and resulted in full conversions (e.g., 6-
chloroindole, Table 4, entry 6). Incidentally, 4-chloropyridine was
used as its HCl salt directly in the reaction, which had no bearing on
the outcome, as expected, since the base stoichiometry (1.5 equiv of
dibasic K2CO3) is more than sufficient to cope with additional
starting material proton, as well as those produced within the re-
action (i.e., HBr or HCl). Only 5-chloro-2-pyridinol completely failed
to react to give 45A under these conditions, which we again at-
tributed to it bearing an ortho-hydroxy substituent (and adjacent
heteroatom, as noted by Miyaura).10g
OMe
Me
Ph
N
N
N
N
Ph
Ph
MeO
N
Ph
S
S
36A
37A
38A
35A
CHO
Ph
Ph
N
H
N
H
N
Ph
H
39A
40A
41A
Ph
N
N
N
Ph
Ph
Ph
N
OH
42A
43A
44A
45A
Fig. 4. Heteroaromatic biphenyls 35e45.
heated conditions with less catalyst in a shorter time (entries 2, 3
and 6). However, it must be noted that reactions, which were super-
heated had the appearance typical of microwave super-heated re-
actions, with the Pd-catalyst either plated out, or suspended as
(presumably) nanoparticles at the solvent interface. This would
certainly have implications with regards to any future process
scale-up and optimisation.
Conscious that heteroatoms can coordinate with transition-
metal catalysts, we tried some of the more stubborn hetero-
aromatic examples with an increased 2 mol % catalyst for 24 h
(entries 2, 3, 5, 6 and 16). Whilst this approach did result in mar-
ginally higher conversions compared to 1 mol % catalyst for 48 h (cf.
entries 2 and 6), there was no great benefit over simply using super-
Me
X
Me
Pd-118
+
K2CO3, 60 oC
MeCN/water 1:1
OHC
(HO)2B
OHC
29
(X = Br or Cl)
E
29E
Scheme 2. Formation of 29E from aryl halides 29 (X¼Br and X¼Cl) and 4-tolyl boronic acid (E).

J.D. Moseley et al. / Tetrahedron 68 (2012) 6010e6017
6015
Table 4
complete substrate tolerance amongst aryl bromides, and good
tolerance amongst many aryl chlorides and heteroaromatic halides.
These mild conditions will not harm several typically base-labile
substituents that more forcing conditions may hydrolyse. For
more stubborn substrate combinations, super-heated conditions
can be used successfully with no need for other changes to the
reagent/solvent/catalyst combination required. Furthermore, this is
all achieved with an air- and water-stable commercially available
Pd(II) pre-catalyst.
Heteroaromatic biphenyls (35e45) prepared from aryl halides (X¼Br and Cl) and
phenyl boronic acid (A)
Entry Aryl
halide
35
X
Biphenyl Conv.
product
2% Cat.
Super-heateda
at 48 ha (%) at 24 ha (%)
1
2
3
4
5
6
7
9
10
11
12
13
14
15
16
Cl
Cl
Cl
35A
36A
37A
100b
95
nd
99
85
nd
100
74
nd
nd
nd
nd
nd
nd
nd
nd
0
nd
36
37
37
38
39
39
40
41
42
42
43
43
44
45
100
100
nd
100
98
nd
nd
nd
100
nd
98
Br 37A
Br 38A
Cl
Br 39A
Br 40A
Br 41A
Cl
Br 42A
Cl 43A
Br 43A
100b
99c
64
39A
100b
100b
97
4. Experimental
4.1. General
42A
96
97b
97
100
nd
nd
100b
97
Melting points were determined using an aluminium heating
block melting point apparatus and are uncorrected. 1H spectra were
recorded at 300 MHz with chemical shifts given in parts per million
Cl
Cl
44A
45A
0
nd
nd¼not determined.
relative to TMS at
d
¼0. LCeMS and GCeMS conditions are given
a
Conversion determined by LC.
Conversion at 2 h under standard conditions.
Conversion at 24 h under standard conditions.
below. Analytical TLC was carried out on commercially prepared
plates coated with 0.25 mm of self-indicating Kieselgel 60 F254 and
visualised by UV light at 254 nm. Preparative scale silica gel flash
chromatography was carried out using Biotage SNAP cartridges
b
c
(50 mm particle size).
2.4. Summary
This study has allowed us to define with confidence a generic
protocol for the SuzukieMiyaura reaction. This requires 1.0 equiv of
aryl halide dissolved at a concentration of 0.1 g/mL in a 1:1 v/v
solution of acetonitrile/water, with 1.2 equiv of aryl boronic acid,
1.5 equiv of K2CO3 and 1 mol % of catalyst Pd-118 added, and stirred
rapidly at 60 ꢁC. The majority of aryl bromides will give complete
conversion in less than 2 h; aryl chlorides and heteroaryl halides
may require up to 48 h at this temperature, or can be super-heated
in a sealed tube at 120 ꢁC for 2 h to increase the reaction rate.
In addition, we would recommend the following simple ap-
proach be applied when using the prescribed reactions conditions.
Start with the relevant aryl/heteroaryl bromide if cost and avail-
ability are not limiting factors. Alternatively, to reduce costs or
improve atom economy, use the aryl/heteroaryl chloride; if com-
plete conversion is not achieved within a satisfactory time, try
super-heating. When optimising reactions for wider use or greater
scale-up, lower catalyst loadings can almost certainly be employed,
especially for the bromides (which is the recommended strategy by
other practitioners).18c
Finally, a number of examples were performed on preparative
scale (10 mmol) and the biaryl products isolated to confirm that
high conversions did indeed represent high yields. Compound 1D/
16A was isolated in similar yield from both boronic acid/aryl halide
combinations. Other compounds such as 15E and 29E could be
prepared from both their respective aryl bromides and aryl chlo-
rides. Compound 15E, for example, is required in the preparation of
Valsartin.29
4.2. Typical generic protocol
A Mettler-Toledo FlexiWeigh 30 automated solid handling unit
was used to weigh all solid materials into the reaction tubes. Re-
actions were performed in 18 mL glass test tubes seated in metal
heat transfer blocks. Reaction blocks were placed in a cage on
a magnetic heater-stirrer, which provided both heating and stirring.
The tubes were then sealed with a nitrogen atmosphere by a septa
under a metal lid clipped onto the reaction cage.
In a typical generic procedure (1.0 mmol scale), the reaction
tubes were charged with (in order): K2CO3 (207 mg, 1.50 mmol,
1.5 equiv); the relevant boronic acid (AeG) (1.20 mmol, 1.2 equiv);
Pd-118 (6.5 mg, 0.01 mmol, 1.0 mol %); and 4,40-tert-butyldiphenyl
(HH) (13.3 mg, 0.05 mmol) as internal standard for all non-
preparative reactions. The relevant aryl bromide or aryl chloride
(1.00 mmol, 1.0 equiv) was also charged by this method if it was
a free-flowing solid; otherwise, it was charged by pipette after the
reaction solvents had been added. Once all solids and a magnetic
stirrer bar had been added, a 1:1 solution of acetonitrile/water
(2.0 mL) was added to the reaction mixture (followed quickly by the
relevant aryl halide if not added before). The reaction tube(s) were
sealed and transferred to a magnetic heater-stirrer and heated at
60 ꢁC with stirring.
4.3. Analytical protocol
A typical simple work-up procedure for these biaryl products
required separation of the aqueous phase (which removes residual
boronic acid and the inorganic salts), concentration of the aceto-
nitrile phase, and trituration with methanol to yield solid products.
Oils and less pure samples could be purified by flash silica gel
chromatography. Some especially crystalline examples could be
isolated directly from the acetonitrile reaction liquors.
Reaction mixtures were sampled whilst stirred by a Mettler-
Toledo Mini-Mapper automated liquid handling system. Samples
of 50 mL were withdrawn at pre-determined times and diluted into
pre-filled HPLC vials containing a 4:1 acetonitrile/water mixture
(1.5 mL) at room temperature. Sampling times were typically at 1, 2,
4, 8 and 24 h for most reactions, although shorter and longer time
points were also used, depending on the nature of the reaction.
All reaction samples were analysed by at least one technique of
LCeMS or GCeMS (to allow for non-ionising samples by LCeMS
and non-volatile samples by GCeMS), and by both techniques
where possible. All significant peaks were identified by their mass
spectra and fragmentation pattern, and by comparison to reference
samples if available. Reference markers of starting materials were
routinely run to aid identification.
3. Conclusions
We have presented here a simple set of mild and robust generic
conditions as a proof of transformation protocol, one that will work
for the vast majority of substituent combinations on the aryl halide
and boronic acid coupling partners. We have demonstrated almost

6016
J.D. Moseley et al. / Tetrahedron 68 (2012) 6010e6017
4.4. LCeMS conditions
to give a pale grey/brown solid (1.19 g, 65%); mp 87e88 ꢁC; HPLC
purity 99.8% (spectroscopic characteristics as above). A second crop
could be isolated from the methanol liquors in both cases.
Reaction mixtures and products were analysed by LCeMS using
a Waters Acquity Binary uPLC with DAD and coupled to a Waters ZQ
(ESCI) MS. The uPLC used the following conditions: column, Waters
4.6.2. 4-Methylthiobiphenyl (28A).31 Prepared from phenyl boronic
acid (A) and bromothioanisole (28, X¼Br) and isolated by tritura-
tion from methanol to give a pale grey/brown solid (1.86 g, 93%);
mp 109e110 ꢁC (lit. 107e108 ꢁC);31 TLC Rf 0.49 (10% EtOAc in iso-
hexane); HPLC purity 99.2%; 1H NMR (CDCl3, 300 MHz) 7.51e7.59
(4H, m), 7.40e7.46 (2H, m), 7.30e7.36 (3H, m), 2.53 (3H, s); LCeMS
(ESþ) m/z 201 (Mþ1, 100%); GCeMS (EIþ) m/z 200 (Mþ, 100%).
BEH C18 Shield 50 mmꢃ1.0 mm i.d., particle size 1.7
mm; eluent A,
90% purified water, 10% acetonitrile with 0.05% v/v formic acid;
eluent B, acetonitrile with 0.05% v/v formic acid; gradient, at
t¼0 min 0% eluent B, at t¼3.6 min 95% eluent B, at t¼3.9 min 95%
eluent B, at t¼4.0 min 0% eluent B; run time 5.0 min; flow rate
0.20 mL/min.; temperature 50 ꢁC; injection volume 0.2
mL; de-
tection by DAD (230:350 nm). Sample preparation, 50
mL diluted
into 1.5 mL acetonitrile/water (4:1). MS ionisation was by ESIþ with
a capillary voltage of 3.2 kV and a cone voltage of 20 eV. Source
temperature was 120 ꢁC and desolvation temperature 300 ꢁC. The
scan range was m/z 100e1000.
4.6.3. 4-Formyl-40-methylbiphenyl (29E).32 Prepared from 4-tolyl
boronic acid (E) and 4-bromobenzaldehyde (29, X¼Br) and iso-
lated by trituration from methanol to give a light brown solid
(1.45 g, 74%); mp 105e106 ꢁC (lit. 105e107 ꢁC, EtOAc/hexane);32
TLC Rf 0.31 (10% EtOAc in iso-hexane); HPLC purity 93.5% with
5.0% of the homo-coupled 4,40-dimethylbiphenyl (EE); 1H NMR
(CDCl3, 300 MHz) 10.05 (1H, s), 7.94 (2H, d, J¼8.0 Hz), 7.74 (2H, d,
J¼8.0 Hz), 7.55 (2H, d, J¼8.0 Hz), 7.29 (2H, d, J¼8.0 Hz), 2.42 (3H, s);
LCeMS (ESþ) m/z 197 (Mþ1, 100%); GCeMS (EIþ) 96% of m/z 195
(Mꢂ1)þ and 3.3% of m/z 182 (Mþ for EE, C14H14). A second crop
could be isolated from the methanol liquors.
4.5. GCeMS conditions
Reaction mixtures and products were analysed by GCeMS using
a Varian Saturn 2200 GCeMS system. The GC used the following
conditions: column, Varian Rapid-MS WCOT, 10 mꢃ0.53 mm i.d.,
phase DB5 MS equivalent, film thickness 0.25 mm; carrier gas He;
temperature programme, t¼0 min 60 ꢁC, t¼1.0 min 60 ꢁC,
t¼5.1 min 250 ꢁC, t¼5.5 min 250 ꢁC; run time 5.5 min; flow rate
4.6.4. 2-Cyano-40-methylbiphenyl (15E).33 Prepared from 4-tolyl
boronic acid (E) and 2-bromobenzonitrile (15, X¼Br) and purified
by flash silica chromatography eluting with 5e8% EtOAc in iso-
hexane to give a yellow oil, which solidified on standing (1.70 g,
88%); mp 43e46 ꢁC (lit. 47e48 ꢁC, ethyl ether);33 TLC Rf 0.31 (10%
EtOAc in iso-hexane); HPLC purity 96.0%; 1H NMR (CDCl3, 300 MHz)
7.75 (1H, dd, J¼7.8, 1.5 Hz), 7.63 (1H, dt, J¼7.8, 1.5 Hz), 7.39e7.51
(4H, m), 7.30 (2H, d, J¼7.8 Hz), 2.42 (3H, s); LCeMS (ESþ) m/z 194
(Mþ1, 100%); GCeMS (EIþ) m/z 193 (Mþ, 100%).
1.0 mL/min constant flow; split 100:1; injection volume 1.0
m
L;
injection temperature 200 ꢁC. Sample preparation, 50
mL diluted
into 1.5 mL acetonitrile/water (4:1). MS ionisation was by EIþ with
a scan range m/z 60e500.
4.6. Typical preparative procedure
Typical preparative procedures were performed on 10.0 mmol
scale using a Mettler-Toledo FlexiWeigh 30 automated solid han-
dling unit to pre-weigh the aryl halide (10.0 mmol, 1.0 equiv), aryl
boronic acid (12.0 mmol, 1.2 equiv) and Pd-118 (65.2 mg, 0.1 mmol,
1.0 mol %). Acetonitrile (10.0 mL) was added, followed by K2CO3
added as a stock aqueous solution (10.0 mL water containing 2.07 g,
15.0 mmol, 1.5 equiv). NB. No internal standard was added for
preparative reactions. Reaction mixtures were sealed under a N2
atmosphere and heated to 60 ꢁC with magnetic stirring. HPLC
analysis showed that reactions using aryl bromides were complete
within 1 h but that aryl chlorides typically required 24 h.
After reaction mixtures had cooled to room temperature, stir-
ring was stopped and the phases were allowed to separate. The
lower aqueous phase was removed and discarded (cutting away
any interfacial catalyst residues if present) and the acetonitrile
phase concentrated to dryness to give typically a light to dark
brown solid or dark-coloured gum. Solids were triturated with
methanol (20 mL) for 1e2 h, then isolated by filtration, washed
once or twice with methanol (4 mL each wash) and dried under
vacuum. Oils were purified by flash silica gel chromatography as
noted below. All isolated compounds gave 1H NMR data in agree-
ment with published values. Literature data is given for mp values
for comparison.
Acknowledgements
We thank Ewan Galbraith for initial studies performed at
AstraZeneca, PR&D Avlon.
References and notes
1. (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 20, 3437e3440;
(b) Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979, 866e867; (c)
Miyaura, N.; Yano, T.; Suzuki, A. Tetrahedron Lett. 1980, 21, 2865e2868; (d)
Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513e519.
2. (a) Zhao, D.; You, J.; Hu, C. Chem.dEur. J. 2011, 17, 5466e5492; (b) Ashenhurst, J.
A. Chem. Soc. Rev. 2010, 39, 540e548; (c) McGlacken, G. P.; Bateman, L. M. Chem.
Soc. Rev. 2009, 38, 2447e2464; (d) Campeau, L.-C.; Fagnou, K. Chem. Commun.
2006, 1253e1264; (e) Nelson, T. D.; Crouch, R. D. Org. React. 2004, 63, 265e555
(Hoboken, NJ, United States); (f) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.;
Lamaire, M. Chem. Rev. 2002, 102, 1359e1470; (g) Stanforth, S. P. Tetrahedron
1998, 54, 263e303; (h) Bringmann, G.; Gunther, C.; Ochse, M.; Schupp, O.;
Tasler, S. Prog. Chem. Org. Nat. Prod. 2001, 82, 1e293; (i) Sainsbury, M. Tetra-
hedron 1980, 36, 3327e3359.
3. A very recent selection of patents and publications is cited to illustrate the
breadth of activity on biaryls in pharmaceuticals: (a) Stieber, F.; Wienke, D. PCT
Int. Appl. World Patent WO 2011072791, 2011. (b) Nielsen, S. F.; Horneman, A.
M.; Lau, J. F.; Larsen, J. Ch. H. PCT Int. Appl. World Patent WO 2011134468, 2011.
(c) Abraham, S; Holladay, M. W.; Liu, G.; Xu, S. PCT Int. Appl. World Patent WO
2011022473, 2011. (d) Zhong, M.; Li, L. PCT Int. Appl. World Patent WO
2011149856, 2011. (e) Fatheree, P. R.; McKinnell, R. M. U.S. Pat. Appl. US
20,110,178,101, 2011. (f) Boyle, C. D.; Lankin, C. M.; Greenlee, W. J.; Harris, J. M.
PCT Int. Appl. World Patent WO 2011066137, 2011. (g) Guillon, R.; Pagniez, F.;
Rambaud, C.; Picot, C.; Duflos, M.; Loge, C.; Le Pape, P. ChemMedChem 2011, 6,
1806e1815; (h) Xie, L.; Cui, J.; Qian, X.; Xu, Y.; Liu, J.; Xu, R. Bioorg. Med. Chem.
2011, 19, 961e967; (i) Grob, J. E.; Nunez, J.; Dechantsreiter, M. A.; Hamann, L. G.
J. Org. Chem. 2011, 76, 4930e4940; (j) Shen, H. C.; Ding, F.-X.; Raghavan, S.;
Deng, Q.; Luell, S.; Forrest, M. J.; Carballo-Jane, E.; Wilsie, L. C.; Krsmanovic, M.
L.; Taggart, A. K.; Wu, K. K.; Wu, T.-J.; Cheng, K.; Ren, N.; Cai, T.-Q; Chen, Q.;
Wang, J.; Wolff, M. S.; Tong, X.; Holt, T. G.; Waters, M. G.; Hammond, M. L.; Tata,
J. R.; Colletti, S. L. J. Med. Chem. 2010, 53, 2666e2670; (k) Ghosh, S.; Kumar, A. S.;
Mehta, G. N. J. Chem. Res. 2010, 34, 191e193; (l) Sleebs, B. E.; Street, I. P.; Bu, X.;
Baell, J. B. Synthesis 2010, 1091e1096.
4.6.1. 4-Methoxybiphenyl (1D or 16A).30 Prepared from 4-
methoxyphenyl boronic acid (D) and bromobenzene (1, X¼Br)
and isolated by trituration from methanol to give a pale brown solid
(1.42 g, 77%); mp 85e86 ꢁC (lit. 88e89 ꢁC, methanol);30 TLC Rf 0.46
(10% EtOAc in iso-hexane); HPLC purity 100.0%; 1H NMR (CDCl3,
300 MHz) 7.52e7.57 (4H, m), 7.39e7.45 (2H, m), 7.30 (1H, m), 6.98
(2H, d, J¼8.8 Hz), 3.85 (3H, s); LCeMS (ESþ) m/z 185 (Mþ1, 100%);
GCeMS (EIþ) m/z 184 (Mþ, 100%). Alternatively, the title compound
1D/16A could also be prepared from phenyl boronic acid (A) and
bromoanisole (16, X¼Br) and isolated by trituration from methanol

J.D. Moseley et al. / Tetrahedron 68 (2012) 6010e6017
6017
4. (a) Magano, J.; Dunetz, J. R. Chem. Rev. 2011, 111, 2177e2250; (b) de Koning, P.
D.; McAndrew, D.; Moore, R.; Moses, I. B.; Boyles, D. C.; Kissick, K.; Stanchina, C.
L.; Cuthbertson, T.; Kamatani, A.; Rahman, L.; Rodriguez, R.; Urbina, A.; San-
doval, A.; Rose, P. R. Org. Process Res. Dev. 2011, 15, 1018e1026; (c) Elitzin, V. I.;
Harvey, K. A.; Kim, H.; Salmons, M.; Sharp, M. J.; Tabet, E. A.; Toczko, M. A. Org.
Process Res. Dev. 2010, 14, 912e919; (d) Ravn, M. M.; Wagaw, S. H.; Engstrom, K.
M.; Mei, J.; Kotecki, B.; Souers, A. J.; Kym, P. R.; Judd, A. S.; Zhao, G. Org. Process
Res. Dev. 2010, 14, 417e424.
5. (a) Uemura, A.; Shirai, M. Jpn. Kokai Tokkyo Koho JP 2011116749, 2011. (b) Ar-
ora, A. Asian J. Chem. 2010, 22, 1041e1046; (c) Gotta, M. Spec. Chem. 2008, 28,
26e27; (d) Ikegaya, K.; Ozaki, M.; Kawashima, T.; Miura, I.; Muramatsu, N. PCT
Int. Appl. World Patent WO 9910317, 1999.
13. (a) He, Y. Q.; Zhang, N. N.; Liu, Y.; Gao, J. P.; Yi, M. C.; Gong, Q. J.; Qiu, H. X. Chin.
Chem. Lett. 2012, 23, 41e44; (b) Sugie, A.; Kumazawa, K.; Hatta, T.; Kanie, K.;
Muramatsu, A.; Mori, A. Chem. Lett. 2011, 40, 1450e1452; (c) Liang, J.; Yin, J.; Li,
Z.; Zhang, C.; Wu, D.; Liu, S. H. Dyes Pigments 2011, 91, 364e369.
14. (a) Gude, K.; Narayanan, R. J. Phys. Chem. C 2011, 115, 12716e12725; (b) Xuan, S.;
Jiang, W.; Gong, X. Dalton Trans. 2011, 40, 7827e7830; (c) Firouzabadi, H.;
Iranpoor, N.; Ghaderi, A.; Ghavami, M.; Hoseini, S. J. Bull. Chem. Soc. Jpn. 2011,
84, 100e109; (d) Metin, O.; Durap, F.; Aydemir, M.; Oezkar, S. J. Mol. Catal. A
2011, 337, 39e44; (e) Kalviri, H. A.; Kerton, F. M. Green Chem. 2011, 13, 681e686;
(f) Wang, F.; Li, C.-H.; Sun, L.-D.; Wu, H.-S.; Ming, T.; Wang, J.-F.; Yu, J. C.; Yan, C.-
H. J. Am. Chem. Soc. 2011, 133, 1106e1111; (g) Zhang, W.; Wang, Q.; Qin, F.; Zhou,
H.; Lu, Z.; Chen, R. J. Nanosci. Nanotechnol. 2011, 11, 7794e7801.
6. (a) Kozlowski, M. C.; Morgan, B. J.; Linton, E. C. Chem. Soc. Rev. 2009, 38,
3193e3207; (b) Appukkuttan, P.; Van der Eycken, E. Eur. J. Org. Chem. 2008,
5867e5886; (c) Abe, H.; Harayama, T. Heterocycles 2008, 75, 1305e1320; (d)
Bringmann, G.; Gulder, T.; Gulder, T. A. M.; Breuning, M. Chem. Rev. 2011, 111,
563e639; (e) Kwak, J.-H.; Cho, Y. A.; Jang, J.-Y.; Seo, S.-Y.; Lee, H.; Hong, J. T.;
Han, S.-B.; Lee, K.; Kwak, Y.-S.; Jung, J.-K. Tetrahedron 2011, 67, 9401e9404; (f)
Su, X.; Thomas, G. L.; Galloway, W. R. J. D.; Surry, D. S.; Spandl, R. J.; Spring, D. R.
Synthesis 2009, 3880e3896; (g) Prieto, M.; Mayor, S.; Lloyd-Williams, P.; Giralt,
E. J. Org. Chem. 2009, 74, 9202e9205; (h) Waldmann, H.; He, Y.-P.; Tan, H.; Arve,
L.; Arndt, H.-D. Chem. Commun. 2008, 5562e5564.
7. A very recent selection of publications is cited to illustrate the breadth of utility
of biaryls used in new materials: (a) Reuter, R.; Wegner, H. A. Org. Lett. 2011, 13,
5908e5911; (b) Takamiya, K.; Ishikawa, S.; Adachi, D.; Oku, S.; Nagamatsu, S.;
Takashima, W.; Hayase, S.; Kaneto, K. Phys. Procedia 2011, 14, 182e186; (c) Lee,
P.-I.; Hsu, SL.-C.; Lee, J. F. Sol. Energy Mater. Sol. Cells 2011, 95, 1756e1761; (d)
Ren, M.-G.; Guo, H.-J.; Qi, F.; Song, Q.-H. Org. Biomol. Chem. 2011, 9, 6913e6916;
(e) Qiao, Y.; Zhang, J.; Xu, W.; Zhu, D. Tetrahedron 2011, 67, 3395e3405; (f) Duan,
C.; Wang, L.; Zhang, K.; Guan, X.; Huang, F. Adv. Mater. 2011, 23, 1665e1669; (g)
Tumkevicius, S.; Dodonova, J. Synlett 2011, 1705e1708.
8. (a) Dieguez, M.; Pamies, O. Acc. Chem. Res. 2010, 43, 312e322; (b) Wallace, T. W.
Org. Biomol. Chem. 2006, 4, 3197e3210; (c) Shimizu, H.; Sayo, N.; Saito, T. Elim-
inating Barriers in Large-Scale Asymmetric Synthesis. In Asymmetric Catalysis on
Industrial Scale, 2nd ed.; Blaser, H.-U., Federsel, H.-J., Eds.; Wiley-VCH: Weinheim,
2010.
9. (a) Tsuji, J. Cross-Coupling Reactions with Organometallic Compounds of the
Main Group Metals via Transmetallation In Palladium Reagents and Catalysts:
New Perspectives for the 21st Century John Wiley and Sons: Chichester, West
Sussex, England, 2004; (b) Miyaura, N. Metal-Catalyzed Cross-Coupling Reactions
of Organoboron Compounds with Organic Halides In Metal-Catalyzed Cross-
Coupling Reactions, 2nd ed.; de Meijere, A., Diederich, F., Eds.; Wiley-VCH:
Weinheim, 2004; (c) Suzuki, A. Overview of the Suzuki Protocol with B In.
Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E.-I., Ed.;
John Wiley and Sons: New York, NY, 2002; Vol. 1.
15. (a) Cano, R.; Ramon, D. J.; Yus, M. Tetrahedron 2011, 67, 5432e5436; (b) Wu, Y.;
Wang, D.; Zhao, P.; Niu, Z.; Peng, Q.; Li, Y. Inorg. Chem. 2011, 50, 2046e2048.
16. (a) Schweizer, S.; Becht, J.-M.; Le Drian, C. Tetrahedron 2010, 66, 765e772; (b)
Islam, S. M.; Mondal, P.; Roy, A. S.; Mondal, S.; Hossain, D. Tetrahedron Lett. 2010,
51, 2067e2070; (c) Wan, L.; Cai, C. Catal. Lett. 2011, 141, 839e843.
17. (a) Qiu, J.; Wang, L.; Liu, M.; Shen, Q.; Tang, J. Tetrahedron Lett. 2011, 52,
6489e6491; (b) Martins, D. L.; Aguiar, L. C. S.; Antunes, O. A. C. J. Organomet.
Chem. 2011, 696, 2845e2849; (c) Liu, C.; Ni, Q.; Hu, P.; Qiu, J. Org. Biomol. Chem.
2011, 9, 1054e1060; (d) Liu, C.; Ni, Q.; Qiu, J. Eur. J. Org. Chem. 2011, 3009e3015;
(e) Fan, G.; Zou, B.; Cheng, S.; Zheng, L. J. Ind. Eng. Chem. 2010, 16, 220e223.
18. (a) Astruc, D.; Ornelas, C.; Diallo, A. K.; Aranzaes, J. R. Molecules 2010, 15,
4947e4960; (b) Diallo, A. K.; Ornelas, C.; Salmon, L.; Aranzaes, J. R.; Astruc, D.
Angew. Chem., Int. Ed. 2007, 46, 8644e8648; (c) Ager, D. J.; De Vries, A. H. M.; De
Vries, J. G. Chim. Oggi 2007, 25, 35e36; (d) Leadbeater, N. E.; Williams, V. A.;
Barnard, T. M.; Collins, M. J., Jr. Org. Process Res. Dev. 2006, 10, 833e837; (e)
Alimardanov, A.; Schmieder-van de Vondervoort, L.; de Vries, A. H. M.; de Vries,
J. G. Adv. Synth. Catal. 2004, 346, 1812e1817.
19. dos Santos Castro, K. L.; de Lima, P. G.; de Miranda, L. S. M.; de Souza, R. O. M. A.
Tetrahedron Lett. 2011, 52, 4168e4171; (b) Gruttadauria, M.; Liotta, L. F.; Salvo,
A. M. P.; Giacalone, F.; La Parola, V.; Aprile, C.; Noto, R. Adv. Synth. Catal. 2011,
353, 2119e2130.
20. (a) Polshettiwar, V.; Decottignies, A.; Len, C.; Fihri, A. ChemSusChem 2010, 3,
502e522; (b) Liu, N.; Liu, C.; Jin, Z. J. Organomet. Chem. 2011, 696, 2641e2647;
(c) Liu, C.; Ni, Q.; Bao, F.; Qiu, J. Green Chem. 2011, 13, 1260e1266; (d) Lipshutz,
B. H.; Abela, A. R. Org. Lett. 2008, 10, 5329e5332; (e) Lipshutz, B. H.; Petersen, T.
B.; Abela, A. R. Org. Lett. 2008, 10, 1333e1336.
21. Murray, P. M.; Tyler, S. N. G.; Moseley, J. D. Chim. Oggi 2012, 30, 15e18.
22. Limited catalyst screening, early development work, and studies on active drug
projects were conducted at AstraZeneca, PR&D Avlon, from whom thanks is
acknowledged.
23. Pd-118 entries in: (a) http://www.jmcatalysts.com/pharma/_productfinder3.
asp?product¼624. (b) Colacot, T. J. e-EROS doi:10.1002/047084289X.rn01062.
24. (a) Lipshutz, B. H.; Ghorai, S.; Abela, A. R.; Moser, R.; Nishikata, T.; Duplais, C.;
Krasovskiy, A.; Gaston, R. D.; Gadwood, R. C. J. Org. Chem. 2011, 76, 4379e4391;
(b) Bennett, N. J.; Goldby, A.; Pringle, R. Synlett 2010, 1688e1690; (c) Lipshutz,
B. H.; Taft, B. R. Org. Lett. 2008, 10, 1329e1332; (d) Grasa, G. A.; Colacot, T. J. Org.
Lett. 2007, 9, 5489e5492.
10. (a) Suzuki, A. Angew. Chem., Int. Ed. 2011, 50, 6722e6737; (b) Suzuki, A. Het-
erocycles 2010, 80, 15e43; (c) Tobisu, M.; Chatani, N. Angew. Chem., Int. Ed. 2009,
48, 3565e3568; (d) Alonso, F.; Beletskaya, I. P.; Yus, M. Tetrahedron 2008, 64,
3047e3101; (e) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 2419e2440; (f)
Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633e9696; (g)
Miyaura, N. Top. Curr. Chem. 2002, 219, 11e59.
11. (a) Blakemore, J. D.; Chalkley, M. J.; Farnaby, J. H.; Guard, L. M.; Hazari, N.; In-
carvito, C. D.; Luzik, E. D.; Suh, H. W. Organometallics 2011, 30, 1818e1829; (b)
Bulygina, L. A.; Khrushcheva, N. S.; Sokolov, V. I. Russ. Chem. Bull. 2011, 60,
258e260; (c) Felpin, F. X.; Fouquet, E.; Zakri, C. Adv. Synth. Catal. 2009, 351,
649e655; (d) Weeden, J. A.; Huang, R.; Galloway, K. D.; Gingrich, P. W.; Frost, B.
J. Molecules 2011, 16, 6215e6231; (e) Hao, X.-Q.; Liu, F.; Zhang, B.; Jiang, M.-L.;
Gong, J.-F.; Song, M.-P. Transition Met. Chem. 2010, 35, 271e277.
25. Colacot, T. J.; Shea, H. A. Org. Lett. 2004, 6, 3731e3734.
26. Chapter 48 Organometallic Chemistry In Organic Chemistry; Clayden, J.,
Greeves, N., Warren, S., Wothers, P., Eds.; Oxford University Press: Oxford, 2001.
27. Moseley, J. D.; Bansal, P.; Bowden, S. A.; Couch, A. E. M.; Hubacek, I.; Wein-
gaertner, G. Org. Process Res. Dev. 2006, 10, 153e158.
28. Li, S.-M.; Huang, J.; Chen, G.-J.; Han, F.-S. Chem. Commun. 2011, 12840e12842.
29. Blaser, H.-U.; Pugin, B.; Spielvogel, D. Chim. Oggi 2011, 29, 62e65.
30. Dughera, S. Synthesis 2006, 1117e1122.
31. Desmarets, C.; Omar-Amrani, R.; Walcarius, A.; Lambert, J.; Champagne, B.; Fort,
12. (a) Tobisu, M.; Xu, T.; Shimasaki, T.; Chatani, N. J. Am. Chem. Soc. 2011, 133,
19505e19511; (b) Zultanski, S. L.; Fu, G. C. J. Am. Chem. Soc. 2011, 133,
15362e15364; (c) Fan, X.-H.; Yang, L.-M. Eur. J. Org. Chem. 2010, 2457e2460; (d)
Lu, Z.; Wilsily, A.; Fu, G. C. J. Am. Chem. Soc. 2011, 133, 8154e8157; (e) Kuwano,
R.; Shimizu, R. Chem. Lett. 2011, 40, 913e915.
Y.; Schneider, R. Tetrahedron 2008, 64, 372e381.
32. Miura, M.; Koike, T.; Ishihara, T.; Sakamoto, S.; Okada, M.; Ohta, M.; Tsukamoto,
S. Synth. Commun. 2007, 34, 667e674.
33. Fringuelli, F.; Girotti, R.; Piermatti, O.; Pizzo, F.; Vaccaro, L. Org. Lett. 2006, 8,
5741e5744.