Suzuki-Miyaura and related cross-couplings in aqueous solvents catalyzed by di(2-pyridyl)methylamine-palladium dichloride complexes

Article abstract of DOI:10.1002/adsc.200404195

Di(2-pyridyl)methylamine-based palladium dichloride complexes 4 are versatile catalysts for different types of cross-coupling reactions in water or aqueous solvents under aerobic conditions. The Suzuki-Miyaura reaction of arylboronic acids can be performed with bromoarenes under water reflux using K₂CO₃ as base or at room temperature or 60°C in aqueous methanol using KOH as base. For aryl chlorides the corresponding cross-couplings with arylboronic acids can be carried out in refluxing water with K₂CO₃ as base and TBAB as additive to provide biaryls and heterobiaryls. Arylboronic acids react with benzylic chlorides and allylic substrates such as chlorides, acetates or carbonates also in refluxing water with K₂CO₃ as base or at room temperature in aqueous acetone and KOH as base, to give diarylmethanes and arylpropenes. Trimethylboroxine and alkylboronic acids are coupled with bromo- and chloroarenes under water at reflux with K₂CO₃ as base and TBAB as additive to furnish methyl- and butylarenes. These cross-couplings have also been performed in shorter times under microwave irradiation. Several important intermediates such as, 4′-methylbiphenyl-2-carbonitrile, 4-biphenylacetic acid, 3-(3-methylphenyl)benzoic acid, 4,5-diphenyl-2-methyl- 3(2H)pyridazinone and 2-(4′-fluorobenzyl)thiophene have been prepared under aqueous and aerobic conditions in good yields.

Full text of DOI:10.1002/adsc.200404195

FULL PAPERS
Suzuki–Miyaura and Related Cross-Couplings in Aqueous
Solvents Catalyzed by Di(2-pyridyl)methylamine-Palladium
Dichloride Complexes
a,
a
a, b
Carmen N a´ jera, * Juan Gil-Molt o´ , Sofia Karlstrçm
a
Departamento de Química Org a´ nica and Instituto de Síntesis Org a´ nica (ISO), Universidad de Alicante, Apartado 99,
3080 Alicante, Spain
0
Fax: (þ34)-965-903-549, e-mail: cnajera@ua.es
b
Present address: AstraZeneca R&D Sçdertälje, S-151 85 Sçdertälje, Sweden
Received: June 22, 2004; Accepted: September 28, 2004
th
Dedicated to Prof. Peter Stannety on occasion of his 60 anniversary
Abstract: Di(2-pyridyl)methylamine-based palladium ous acetone and KOH as base, to give diarylmethanes
dichloride complexes 4 are versatile catalysts for dif- and arylpropenes. Trimethylboroxine and alkylboron-
ferent types of cross-coupling reactions in water or ic acids are coupled with bromo- and chloroarenes un-
aqueous solvents under aerobic co nditions. The Suzu-
der water at reflux with K CO as base and TBAB as
2 3
ki–Miyaura reaction of arylboronic acids can be per- additive to furnish methyl- and butylarenes. These
formed with bromoarenes under water reflux using cross-couplings have also been performed in shorter
K CO as base or at room temperature or 608C in times under microwave irradiation. Several important
2
3
aqueous methanol using KOH as base. For aryl chlor- intermediates such as, 4’-methylbiphenyl-2-carboni-
ides the corresponding cross-couplings with arylbor- trile, 4-biphenylacetic acid, 3-(3-methylphenyl)benzo-
onic acids can be carried out in refluxing water with ica ci d, 4,5-diphenyl-2-methyl-3(2 H)pyridazinone and
K CO as base and TBAB as additive to provide biar- 2-(4’-fluorobenzyl)thiophene have been prepared un-
2
3
yls and heterobiaryls. Arylboronic acids react with der aqueous and aerobic co nditions in good yields.
benzylic chlorides and allylic substrates such as chlor-
ides, acetates or carbonates also in refluxing water Keywords: biaryls; boronic acids; cross-coupling reac-
with K CO as base or at room temperature in aque- tions; N ligands; palladium
2
3
[
3]
Introduction
tion. Suzuki–Miyaura reactions have been carried
out in neat water by using aqueous soluble substrates
[
4]
[5]
The Suzuki–Miyaura reaction has became in the last 10 with Pd(OAc)2 or Pd/C as catalysts under phos-
years the method of choice for biaryl and heterobiaryl phane-free conditions. A second strategy employs hy-
synthesis. These moieties are widely present in numer- drophilicphosphanes as ligands. For non-hydrophilic
ous classes of organic compounds, such as natural prod- substrates the presence of high amounts of an ammoni-
ucts, pharmaceuticals, agrochemicals and ligands for um salt as additive, e.g., tetra-n-butylammonium bro-
[1]
[6]
[
7]
asymmetricsynthesis and in new materials, su ch as liq-
mide (TBAB), and Pd(OAc) as catalyst accelerates
2
[8] [9]
[2]
uid crystals. The wide-ranging applications of the Su- the cross-coupling of bromoarenes and chloroarenes
zuki–Miyaura reaction are based on the use of less toxic in water. Aqueous surfactants have proved to be good
[10]
materials, boronica ci ds and esters, mild and operation-
additives for Suzuki-Miyaura reactions in water. We
ally easy reaction conditions, the use of aqueous inor- reported for the first time the coupling of aryl chlorides
ganic bases, tolerance to many functional groups and in water in the presence of substoichiometric amounts of
its suitability for sterically hindered substrates. Some TBAB by using an oxime-derived palladacycle 1 as cat-
[
11]
of the challenges related to the industrial applications alyst. This catalyst has been immobilized by covalent
of this cross-coupling reaction are focused on the use anchoring to silica, and employed as a reusable hetero-
of aryl chlorides as substrates, the recovery of the cata- geneous catalysts for Suzuki–Miyaura reactions in wa-
[
12]
lyst, to avoid toxicphosphanes and to perform the proc-
ess in neat water.
ter.
N,N-Type ligands have shown excellent properties for
Reactions in water have important economical and palladium complexation and also as catalysts for cross-
safety implications, specially for large-scale produc- coupling reactions compared to P,P-type ligands, due
1798
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/adsc.200404195
Adv. Synth. Catal. 2004, 346, 1798–1811

Suzuki–Miyaura and Related Cross-Couplings in Aqueous Solvents
FULL PAPERS
Figure 2.
Figure 1.
to the stronger s-donation which favors both oxidative
addition and slow reductive-elimination steps in the cat-
[13]
alytic ycl ce .
Polymer-bound di-2-pyridylamine-de-
rived ligands have shown a high binding selectivity for
[
14]
mercury and palladium ions, and the corresponding
palladium(II) chloride complex 2 presents a high tem-
perature and pH stability, palladium not being removed
[
15]
from the ligand within a pH range of 0–12. Moreover,
the catalytic activity of this complex 2 in Heck, Sonoga-
shira, amination and polymerization reactions has been
[
15]
studied in organicsolvents. Suzuki–Miyaura reactions
ofaryl iodides and bromides have been studied withpoly-
mer-bound di-2-pyrimidylamine-based complexes 3 un-
[
16]
der THF reflux with moderate catalytic activity. Very
recently, as part of our studies to find robust and easily
prepared systems to catalyze CÀC bond forming reac-
Scheme 1.
tions, we have communicated that di(2-pyridyl)methyl-
amine-derived palladium(II) chloride complexes 4 with in 73 and 94% yield after reaction of ligands 6 with fresh
[
17]
less electron-rich ligands are very active homogeneous prepared H PdCl (Scheme 1). These complexes 4a
2
4
catalysts for Heck, Suzuki and Sonogashira couplings and 4b showed a low solubility in most organicsolvents
[
17]
in organicand aqueous solvents.
We report here the and their NMR spectra revealed a mixture of conforma-
scope of this type of catalyst in homogeneous Suzuki– tional isomers I and II (Figure 2) in 6:1 and 3:1 ratios,
Miyaura reactions between bromo- or chloroarenes respectively. Both isomers interconverted when com-
and arylboronica ci ds in water and aqueous solvents.
plex 4a was heated to 568C in DMSO-d in an NMR
6
3
2
In addition, related C(sp )ÀC(sp ) bond formation reac- tube. Similar conformers have been observed for [di(2-
tions in water between alkylboronica ci ds and aryl hal- pyridyl)methylphenylsilane]palladium(II) dichloride,
ides and between arylboronic acids and benzylic chlor- used as a catalyst in the Stille reaction. In the case of
[
19]
ides and allylicsubstrates are also dis cu ssed.
compound 4a, isomer I could be isolated by recrystalli-
zation from the isomericmixture and its structure deter-
mined by single-crystal X-ray analysis showing a six-
membered chelate ring in a boat conformation with
the acetamido substituent at the bowsprit position,
Results and Discussion
[17]
with the CH and palladium ends being out of plane.
Synthesis of Di(2-pyridyl)methylamine-derived
Palladium Complexes
The coordination sphere about the palladium is square
planar, which guaranteed a good stability and catalytic
[
20]
1
activity. In the H NMR spectrum (500 MHz), the hy-
For the preparation of complexes 4, the known di(2-pyr- drogen at the flagpole position in the isomer of the type I
[
18]
idyl)methylamine (5), prepared from di-2-pyridyl ke- appears shifted to lower fields than in isomers of the type
tone, was acylated with acetic anhydride and cyclohexyl II. Complex 4b was also prepared because the urea moi-
isocyanate affording the acetamide 6a and urea 6b in 88 ety is a more robust functional group than acetamido to
and 84% yield, respectively. The corresponding palla- work under aqueous basic co nditions at high tempera-
dium(II) chloride complexes 4a and 4b were obtained tures and long reaction times.
Adv. Synth. Catal. 2004, 346, 1798–1811
asc.wiley-vch.de
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1799

FULL PAPERS
Carmen N a´ jera et al.
[
15]
Suzuki–Miyaura Coupling of Aryl Halides with
Arylboronic acids
vents and are superior to Buchmeiserꢁs complexes 2
[16]
and 3 in organicsolvents.
The stability and reactivity of complex 4b during the
Initial studies about the reaction conditions for the Suzuki–Miyaura cross-coupling reaction were studied
cross-coupling of aryl bromides were performed with for 4-bromoacetophenone and phenylboronic acid
4-bromoacetophenone and phenylboronic acid as reac- with KOH as base in aqueous NaOH at 608C
tion model in different solvents with complexes 4, using (Scheme 3). After filtration, fresh reagents were added
K CO as base in the absence of additives (Scheme 2 and to the filtrate and almost quantitative conversions
2
3
Table 1). The process took place in shorter reaction were obtained during 4 consecutive catalytic cycles, al-
times and with lower catalyst loadings in refluxing water though an increase of the reaction time was observed,
than in toluene or in aqueous DMF (Table 1, entries 1– probably due to successive work-ups.
3). Experiments about the catalyst activity with the two
Cross-couplings of different bromoarenes with aryl-
complexes 4b, 4a or Pd(OAc) under water reflux indi- boronica ci ds to give biphenyls 7 were performed with
2
cated that the former gave the best results, TON up to catalyst 4b in refluxing water with K CO as base
2
3
5
4
1
0 and TOF 8Â10 (Table 1, entries 3–5). For room (Scheme 4 and Table 2). Good yields were obtained
temperature couplings, the reaction failed in water and with bromoarenes bearing electron-withdrawing and -
was faster in toluene than in aqueous solvents such as releasing groups as well as with ortho-substituted deriv-
DMF or MeOH, probably due to solubility reasons (Ta- atives. It is worthy of note that 4-bromophenol gave high
ble 1, entries 6–8). When KOH was used instead of conversions under water reflux and at room tempera-
K CO in aqueous MeOH, a higher TON was obtained ture with KOH as base in aqueous methanol, probably
2
3
(
Table 1, compare entries 8 and 9). When the reaction due to its solubility in aqueous basicmedia (Table 2, en-
in aqueous MeOH and KOH as base was carried out tries 2 and 3). Biaryl 7c, which is an intermediate in the
at 608C with 4b as catalyst more higher TON (up to preparation of modern angiotensin II receptor antago-
À1
9
200) and TOF (up to 7369 h ) than at room tempera- nists, such as the antihypertensive drugs losartan, valsar-
ture were obtained (Table 1, compare entries 8 and 9
with entries 10 and 11). These results can be compared
[
11]
to those described with palladacycle 1 in aqueous sol-
Scheme 3.
Scheme 2.
[a]
Table 1. Suzuki–Miyaura coupling of PhB(OH) and 4-BrC H COMe: reaction conditions study.
2
6
4
[
b]
À1
Entry
Cat. [mol % Pd]
Solvent
T [8C]
t [h]
Yield [%]
TON
TOF [h ]
À2
1
2
3
4
5
6
7
8
9
4b (10
4b (10
4b (10
4a (10
)
)
)
toluene
DMF/H O
110
110
100
100
100
rt
rt
rt
rt
60
9
97
87
99
79
64
85
41
82
9700
8700
10
79000
64000
850
205
410
870
1000
9200
1078
2486
80000
63200
51200
850
2
68
36
2000
7360
À2
À3
À3
[c]
3.5
1.25
1.25
1.25
1
92
6
24
0.5
1.25
2
5
H O
2
)
H O
2
À3
Pd(OAc) (10
)
H O
2
2
À1
4b (10
)
toluene
DMF/H O
MeOH/H O
MeOH/H O
MeOH/H O
MeOH/H O
[c]
4b (0.2)
4b (0.2)
2
[
d]
2
À1
[d, e]
[f, e]
[f, e]
4b (10
4b (10
4b (10
)
)
)
87 (82)
100 (99)
92
2
À1
À2
1
1
0
1
2
60
2
[
[
a]
Reaction conditions: 4-bromoacetophenone (1 mmol), PhB(OH) (1.5 mmol), K CO (2 mmol), solvent (2 mL).
Of compound 7a, determined by GLC, based on 4-bromoacetophenone using decane as internal standard. In parenthesis
2
2
3
b]
isolated yield after flash chromatography or recrystallization.
Volume ratio 95/5.
Volume ratio 2/3.
KOH was used as base.
[
[
[
[
c]
d]
e]
f]
Volume ratio 3/1.
1800
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 1798–1811

Suzuki–Miyaura and Related Cross-Couplings in Aqueous Solvents
FULL PAPERS
[21]
tan etc., was prepared quantitatively by reaction of o- rather fast coupling took place with phenylboronic
bromobenzonitrile with p-tolylboronica icd (Table 2,
acid by using 1 mol % of complex 4b (Table 2, entry 9).
entry 4). The anti-inflammatory 4-biphenylacetic acid
Reaction conditions for the cross-coupling between 4-
7f was obtained in 91% yield by reaction of p-bromophe- chloroacetophenone and phenylboronic acid using com-
nylacetic acid with phenylboronic acid (Table 2, en- plexes 4 or Pd(OAc) as catalysts and K CO as base in
2
2
3
[22]
try 8). Basicsubstrates su ch as p-bromo-N,N-dime- different solvents (Scheme 5 and Table 3) needed the
thylaniline and 2-bromopyridine could be coupled presence of tetra-n-butylammonium bromide (TBAB,
with phenylboronic acid with a higher loading of catalyst 0.5 equivs.), as was previously found out in our previous
(
1
0.1 mol %) in moderate yields (Table 2, entries 6 and work with aryl chlorides and palladacycle 1 as cata-
0). The coupling of p-bromo-N,N-dimethylaniline lyst. When toluene was used as solvent, only 6% con-
[
11]
with phenylboronicacid also was performed in aqueous
version after one day was observed. However, aqueous
[
23]
DMF giving rise to a higher yield than in water but with a DMF at 1308C or water at reflux were adequate con-
longer reaction time (Table 2, entries 6 and 7). In the ditions to achieve a full conversion with 0.1 mol % of
case of the hindered 2,6-dimethyl-1-bromobenzene a complex 4b (Table 3, entries 1–3). The reaction time
can be reduced at 5 min under microwave irradiation
at 120 W in water as solvent at 1208C (Table 3, entry 4).
The efficiency of complexes 4a, 4b and Pd(OAc) as cat-
2
alysts were studied also in water at reflux with
0.01 mol % of palladium during 3 d; 4b was the most ac-
tive with a TON of up to 6,500 (Table 3, entries 5–7).
Scheme 4.
This process can be performed with complex 4b in high-
[a]
Table 2. Suzuki–Miyaura coupling of aryl bromides and arylboronic acids in water with complex 4b.
[
b]
Entry ArÀBr
BoronicA ci d
Mol % Pd
t
No. Product
Yield [%]
100 (91)
TON
À3
1
PhB(OH)2
10
75 min 7a
100,000
2
PhB(OH)2
”
7.6Â10À4 2 h
7b
7b
95 (82)
75
125,000
750
[c]
3
4
”
0.1
120 h
”
4-MeC H B(OH)
2
0.1
1 h
7c
100 (99)
1000
6
4
5
6
PhB(OH)2
PhB(OH)2
0.1
1
2 h
5 h
7d
7e
100 (97)
59
1000
59
[
d]
7
8
”
”
1
48 h
7e
”
96 (84)
96
PhB(OH)2
0.1
30 min 7f
100 (91)
1000
9
0
PhB(OH)2
PhB(OH)2
1
3 h
7g
7h
83
62
83
1
0.1
22.5 h
620
[
[
[
[
a]
Reaction conditions: aryl bromide (1 mmol), arylboronic acid (1.5 mmol), cat. 4b (see column), K CO (2 mmol), H O
2
3
2
(
2 mL), 1008C.
b]
Determined by GLC, based on aryl bromide using decane as internal standard. In parenthesis isolated yield after flash chro-
matography or recrystallization.
c]
Reaction conditions: aryl bromide (1 mmol), arylboronic acid (1.5 mmol), KOH (2 mmol), MeOH/H O: 2/3 (2 mL), room
2
temperature.
d]
The reaction was performed in DMF/H O at 1108C.
2
Adv. Synth. Catal. 2004, 346, 1798–1811
asc.wiley-vch.de
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1801

FULL PAPERS
Carmen N a´ jera et al.
er yields than with Pd(OAc) at lower temperatures, ei-
2
ther 608C or room temperature, in aqueous MeOH with
KOH as base (Table 3, entries 8 to 10).
Several reaction cycles were also performed between
p-chloroacetophenone and phenylboronic acid in the
presence of catalyst 4b (1 mol %) in aqueous methanol
at 608C and KOH as base in short periods of time, 10
to 30 min, giving around 70% isolated yield without
loosing catalytic activity. This study was carried out by
adding fresh reagents (p-chloroacetophenone, phenyl-
boronicacid and KOH) to the obtained solution after fil-
tration of the formed biphenyl 7a (Scheme 6).
Scheme 6.
[
25]
Different types of activated and deactivated aryl afford products 7h and 7m, respectively (Table 4, en-
chlorides were coupled with arylboronic acids in reflux- tries 7 and 8).
ing water using catalyst 4b (0.1 to 1 mol %), K CO as
2
3
base and TBAB as additive (Scheme 7 and Table 4).
The synthesis of the biphenyl unit of antihypertensive Suzuki–Miyaura Coupling of Benzylic Chlorides and
[
21]
drugs, 4’-methylbiphenyl-2-carbonitrile (7c), was car- Allylic Derivatives withArylboronic Acids
ried out in this case also in good yield with 2-chloroben-
zonitrile using a higher catalyst loading and longer reac- Palladium-catalyzed cross-coupling between benzylme-
tion time (compare Table 3, entry 4 and Table 4, en- tals and aryl halides or benzyl halides and arylmetals are
try 2). 3-(3-Methylphenyl)benzoicacid ( 7l), a precursor two convenient strategies for the preparation of sym-
[
26]
of non-peptide Ras CAAX mimetics which are farnesyl- metrical and unsymmetrical diarylmethanes.
This
[
24]
transferase inhibitors, was prepared from 3-chloro- type of unit is present in natural and biologically active
[
27]
[28]
benzoica ci d and m-tolylboronica ci d (Table 4, entry 6).
products and in supramolecular structures. The ex-
Heterocyclic chlorides, such as 3-chloropyridine and tension of the Suzuki–Miyaura coupling to benzyl hal-
[
23,29]
[11]
4,5-dichloro-2-methyl-3(2H)pyridazinone were cou- ides and arylboronicacids in organic
and aqueous
pled with one and two equivs. of phenylboronica ci d to
solvents has became an excellent methodology for the
synthesis of these compounds. We have used the reac-
tion conditions already set up for the coupling of benzyl-
ic chlorides with arylboronic acids catalyzed by the ox-
[
11]
ime-derived palladacycle 1. Thus, by using water un-
der reflux and K CO as base or aqueous acetone with
2
3
KOH as base at room temperature, complex 4b cata-
lyzed the coupling of different benzylic chlorides and ar-
ylboronic acids in the presence of TBAB as additive to
Scheme 5.
[a]
Table 3. Suzuki–Miyaura coupling of PhB(OH) and 4-ClC H COMe: reaction conditions study.
2
6
4
0
[b]
Entry
Cat. [mol % Pd]
Solvent
Base
T [ C]
t
Yield [%]
TON
À1
1
2
3
4
5
6
7
8
9
4b (10
4b (10
4b (10
4b (10
4b (10
4a (10
)
)
)
)
)
toluene
DMF/H O
K CO
110
130
100
22 h
1.5 h
7.5 h
5 min
72 h
72 h
72 h
10 min
64 h
6
95 (91)
100 (97)
88
65
48
29
76
42
1.5
60
950
1000
880
6500
4800
2900
76
2
3
3
3
3
3
3
3
À1
À1
À1
À2
À2
[c]
K CO
2
2
H O
K CO
2
2
[d]
H O
K CO
120
2
2
H O
K CO
100
100
100
60
rt
rt
2
2
)
H O
K CO
2
2
À2
Pd(OAc) (10
)
H O
K CO
2
2
2
[
[
[
e]
e]
e]
4b (1)
4b (1)
MeOH/H O
MeOH/H O
MeOH/H O
KOH
KOH
KOH
2
42
1.5
2
1
0
Pd(OAc) (1)
18 h
2
2
[
a]
Reaction conditions: 4-chloroacetophenone (1 mmol), PhB(OH) (1.5 mmol), base (2 mmol), TBAB (0.5 mmol), solvent
2
(2 mL).
[
b]
Of compound 7a, determined by GLC, based on 4-chloroacetophenone using decane as internal standard. In parenthesis
isolated yield after flash chromatography or recrystallization.
Volume ratio 95/5.
The reaction was performed under microwave irradiation conditions (120 W, 1208C).
Volume ratio 3/1.
[
[
[
c]
d]
e]
1802
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 1798–1811

Suzuki–Miyaura and Related Cross-Couplings in Aqueous Solvents
FULL PAPERS
give diarylmethanes 8 (Scheme 8 and Table 5). The sol- synthesis of the very potent 5-lipoxygenase inhibitor
[
31]
vent at room temperature in these cases was acetone in- ABT-761, has been prepared by coupling 4-fluoro-
stead of methanol in order to avoid competitive nucleo- benzyl chloride with 2-thiopheneboronic acid (Table 5,
philicsubstitution. The rea ct ion of benzyl and 3-me-
thoxybenzyl chlorides and phenylboronic acid in water
entries 12 and 13).
1,3-Diarylpropenes are interesting alkenes which
was performed under reflux and under microwave irra- have been recently used for the synthesis of the cycloli-
diation with different loadings of catalyst 4b to give good gnans, dihydrodibenzo[a, c]cycloheptenes, by benzyla-
yields in short reaction times (Table 5, entries 1–3 tion of phosphonium salts followed by Wittig olefina-
[
32]
and 5–7, respectively). For the room temperature cou- tion. This type of olefins can be prepared in a very di-
plings, higher complex loadings and longer reaction rect regio- and stereoselective manner by coupling of ar-
times were necessary for achieving high yields without ylboronica icd s with allylicsubstrates, although this
[
11,23,26,33]
deactivation of the catalyst (Table 5, entries 4 and 8). cross-coupling has been less studied.
We have
In the case of other benzylic chlorides, both reaction used the reaction conditions mentioned for benzylic
conditions were used (Table 5, entries 9–15). 2-(4’-Flu- chlorides in the coupling of different types of allylic sub-
[
30]
orobenzyl)thiophene (8e), a key intermediate in the strates, such as chlorides, acetates and methyl carbon-
ates, with arylboronic acids to provide compounds 9 in
good yields (Scheme 9 and Table 6). Cinnamyl chloride
was phenylated in aqueous DMFat 1308C with low effi-
ciency, achieving much better results in water at reflux
(
with TON up to 2000) or under microwave irradiation
À1
Scheme 7.
(with TOF up to 8400 h ) (Table 6, entries 1–3). Alter-
[a]
Table 4. Suzuki–Miyaura coupling of aryl chlorides and arylboronic acids in water with complex 4b.
[
b]
Entry
ArÀCl
BoronicA ci d
Mol % Pd
t [h]
No.
Product
Yield [%]
100 (97)
1
PhB(OH)2
0.1
7.5
7a
2
4-MeC H B(OH)
2
1
7.5
7c
99 (92)
6
4
3
4
5
PhB(OH)2
PhB(OH)2
PhB(OH)2
0.1
1
7.5
7.5
47
7i
99
7j
7k
73 (52)
40
0.1
6
7
8
3-MeC H B(OH)
2
1
21
46
9
7l
69 (51)
100 (72)
99 (93)
6
4
PhB(OH)2
PhB(OH)2
1
7h
7m
[c]
0.1
[
[
[
a]
b]
c]
Reaction conditions: aryl chloride (1 mmol), arylboronic acid (1.5 mmol), K CO (2 mmol), TBAB (0.5 mmol), 4b (see col-
2
3
umn), H O (2 mL), 1008C.
2
Determined by GLC, based on aryl chloride using decane as internal standard. In parenthesis isolated yield after flash chro-
matography or recrystallization.
3
mmol of PhB(OH) were used.
2
Adv. Synth. Catal. 2004, 346, 1798–1811
asc.wiley-vch.de
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1803

FULL PAPERS
Carmen N a´ jera et al.
1804
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 1798–1811

Suzuki–Miyaura and Related Cross-Couplings in Aqueous Solvents
FULL PAPERS
Adv. Synth. Catal. 2004, 346, 1798–1811
asc.wiley-vch.de
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1805

FULL PAPERS
Carmen N a´ jera et al.
natively, the allylation can be performed at room tem- ble 6, entries 5–8) and for allylica ce tates (Table 6, en-
perature (with TON up to 950) in aqueous acetone tries 9–12) and methyl carbonates (Table 6, en-
and KOH as base (Table 6, entry 4). For the coupling tries 13–17) two different conditions, water at reflux
of other allylic chlorides with phenylboronic acid (Ta- and aqueous acetone at room temperature, were used.
À1
Under these reaction conditions the TOF (h ) numbers
follow the order carbonate>chloride>acetate for reac-
tions under water reflux (Table 6, compare entries 1, 10
and 16) and chloride>acetate>carbonate for reactions
at room temperature (Table 6, compare entries 4, 11 and
17). Allylic carbonates have been coupled for the first
time with phenylboronicacid, the amount of base being
reduced to 0.5 equivs. (Table 6, entry 14).
Scheme 10.
Table 7. Suzuki–Miyaura coupling of aryl bromides or chlorides and trimethylboroxine or alkylboronic acids in water with
[a]
complex 4b.
[
b]
Entry
ArÀHal
Boronica ci d
Mol % Pd
t
No.
Product
Yield [%]
1
2
3
(MeBO)3
MeB(OH)2
(MeBO)3
5
5
5
7.5 h
24 h
10a
10a
10b
100 (87)
64
”
”
[c]
48 h
100
4
5
6
(MeBO)3
(MeBO)3
(MeBO)3
5
9.5 h
56 h
25 h
10c
10a
10d
35
41
59
63
5
10
7
8
9
n-BuB(OH)2
n-BuB(OH)2
n-BuB(OH)2
1
1
1
72 h
10e
10e
10f
[d]
[e]
”
10 min
72 h
”
80
89 (63)
[
f]
10
n-BuB(OH)2
1
23 h
10g
100 (89)
1
1
1
2
n-BuB(OH)2
n-BuB(OH)2
1
1
72 h
70 h
10e
10f
89 (63)
70
[
[
a]
Reaction conditions: aryl halide (1 mmol), TMB or alkylboronic acid (1.5 mmol), K CO (2 mmol), TBAB (0.5 mmol) in
2
3
the case of aryl chlorides, 4b (see column), H O (2 mL), 1008C.
2
b]
Determined by GLC, based on aryl halide using decane as internal standard. In parenthesis isolated yield after flash chro-
matography.
The reaction was performed in a pressure tube.
The reaction was performed under microwave irradiation conditions (120 W, 1208C).
[
[
[
[
c]
d]
e]
f]
2
3
0% of 4,4’-diacetylbiphenyl was also obtained.
equivs. of n-BuB(OH) were used.
2
1806
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 1798–1811

Suzuki–Miyaura and Related Cross-Couplings in Aqueous Solvents
FULL PAPERS
Suzuki–Miyaura Coupling of Aryl Bromides and
Chlorides with Alkylboronic Acids
Experimental Section
General
Alkylboronica ci ds are less prone to rea ct with aryl hal-
ides than arylboronica ci ds. The methylation of bromo-
The reagents and solvents were obtained from commercial
and chloroarenes has been performed with trimethyl- sources and were generally used without further purification.
Flash chromatography was performed on silica gel 60
boroxine with Pd(PPh ) (10 mol %) in refluxing aque-
3
4
[
34]
(0.040–0.063 mm, Merck). Thin layer chromatography was
performed on Polygram SIL G/UV plates. Melting points
were determined on a Reichert Thermovar apparatus. Gas
chromatographic analyses were performed on a HP-6890 in-
strument equipped with a WCOT HP-1 fused silica capillary
column. IR data were collected on a Nicolet Impact-400D-
ous dioxane for 1 d
and with palladacyle 1
[11b]
ꢂ
2
54
(
10 mol %) in refluxing water.
We have used the
last reaction conditions with aryl bromides and chlorides
and trimethylboroxine or methylboronicai cd using
complex 4b (5 to 10 mol %) as catalyst, K CO as base
2
3
À1
1
and TBAB as additive for the preparation of methylar-
FT spectrophometer (n, c m ). H NMR spectra were record-
enes 10 (Scheme 10 and Table 7, entries 1–6). Trime- ed on a Bruker AC-300 (300 MHz) and when specified on a
thylboroxine gave better results than methylboronic Bruker Advance-DRX-500 (500 MHz). Chemical shifts are re-
acid as methylating agent (Table 7, compare entries 1 ported in ppm using either tetramethylsilane (TMS, 0.00 ppm)
1
3
or DMSO as internal standards. C NMR spectra were record-
and 2). As expected, activated aryl bromides gave better
yields and faster conversions than unactivated or chlor-
ides. However, a very low yield (8%) was obtained when
ed at 75 MHz with CDCl or DMSO-d as the internal refer-
3
6
ence. EI-MS were measured on a Mass Selective Detector
G2579A from Agilent Technologies 5973N in m/z (rel. intensi-
ty in % of base peak). HRMS were performed on a Finningan
MAT95S apparatus. Elemental analyses were carried out in a
Carlo Erba EA 1108 (CHNS-O) by the corresponding services
at the University of Alicante. The catalysts were weighed up in
an electronic microscale (Sartorius, XM1000P) with a preci-
4-trifluoromethylbromobenzene was allowed to react
with trimethylboroxine under microwave irradiation at
1208C (120 W) during 5 min.
The alkylation with n-butylboronica ci d of aryl halides
was also carried out under the aqueous conditions descri-
[
11b]
bed with palladacyle 1
avoiding the use of silver sion of 1 mg. The reactions were set up in parallel with the aid
[35]
TM
salts. For these couplings between n-butylboronica ci d
of an RR98030 12 place Carousel Reaction Station equipped
and aryl bromides and chlorides, complex 4b (1 mol %) with gas-tight threaded caps with valve, cooling reflux head sys-
tem and digital temperature controller from Radleys Discov-
as catalyst, K CO as base and TBAB as additive were
2
3
ery Technologies. Microwave reactions were performed with
a CEM Discover Synthesis Unit in glass vessels (10 mL) sealed
with a septum under magneticstirring.
employed. Lower catalyst loading was used but long reac-
tion times (ca. 3 d) were necessary to achieve good yields
of butylarenes 10 (Scheme 10 and Table 7, entries 7–12).
For this type of coupling, thermal and microwave irradia-
tion gave similar conversions but microwave conditions
needed shorter times (Table 7, compare entries 7 and
8
). For deactivated 6-methoxy-2-bromonaphthalene, a
6% yield was obtained after 33 h with 1.5 equivs. of bu-
Synthesis of Di(2-pyridyl)methylamine (5)
5
tylboronic acid, but faster and higher conversion was ob- Hydroxylamine hydrochloride (750.5 mg, 10.8 mmol) and
NaOAc(886 mg, 10.8 mmol) were heated at 60 8C in H O
served when 3 equivs. were used (Table 7, entry 10).
2
(
10 mL) for one hour. Di(2-pyridyl) ketone (1 g, 5.43 mmol)
in MeOH (2 mL) was then added. The resulting mixture was
stirred at 608C overnight. The oxime solidified upon cooling
the reaction mixture to room temperature. The product was
cooled on ice and then collected by filtration. The oxime was
Conclusion
In conclusion, di(2-pyridyl)methylamine-derived palla-
dium(II) chloride complexes 4 are thermally stable cat-
alysts not sensitive to air or moisture and can be synthe-
sized from readily available starting materials using a
washed with a little cold H O and dried under vacuum. The
2
crude oxime, a pink solid, was used in the next step without fur-
ther purification.
Oxime (1 g, 5 mmol), NH OAc(655 mg, 8.5 mmol), NH 3
4
straightforward procedure. Their high efficiency in dif- (25% aqueous, 15 mL), EtOH (20 mL) and H O (10 mL)
2
ferent Suzuki–Miyaura processes contrasts with the were mixed and heated at 808C. Zn dust (1.47 g, 22.5 mmol)
was added in small portions over 30 min. The resulting mixture
was refluxed for 3 h and then stirred at room temperature over-
night. The mixture was filtered to remove the solids, which
low activity shown by related di-2-pyridylamine-derived
Buchmeiserꢁs complexes 2. Several types of cross-cou-
2
3
plings between sp and sp hybridized bromides, chlor-
ides and boronic acids can be carried out in organic sol-
vents and even better in water or in aqueous solvents.
This general catalytic activity makes these complexes
very promising catalysts, and studies focused to support
were washed with MeOH and H O. The filtrate was concen-
2
trated to yield an aqueous solution that was made strongly al-
kaline with aqueous 10 M NaOH. The amine was extracted
with CH Cl and the organicphase was then washed with brine,
2
2
dried over Na SO and concentrated under vacuum to afford 5
2
4
these complexes in order to recover and further reuse as a pale yellow oil; yield: 780 mg (78%). Spectral data were in
[18]
the catalyst are underway.
accordance with those previously reported.
Adv. Synth. Catal. 2004, 346, 1798–1811
asc.wiley-vch.de
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1807

FULL PAPERS
Carmen N a´ jera et al.
Synthesis of N-Di(2-pyridyl)methylacetamide (6a)
Compound 4b is insoluble in DMF, H O, MeOH and spar-
2
ingly soluble in DMSO; mp 240–2458C (dec.). The NMR spec-
Compound 5 (92 mg, 0.5 mmol) and Et N (76 mg, 0.75 mmol)
3
trum of 4b shows the presence of two isomers in an approxi-
were mixed in dry CH Cl (2 mL) under an argon atmosphere.
1
2
2
mate ratio 3:1; H NMR (500 MHz, DMSO-d ): d¼8.95 (d,
6
Ac O (77 mg, 0.75 mmol) was added dropwise via asyringe and
2
2
(
2
1
H, J¼6.1 Hz, minor), 8.86 (d, 2H, J¼4.9 Hz, major), 8.19
the resulting mixture was stirred at room temperature for 4 h.
CH Cl (15 mL) and H O (5 mL) were added and the phases
m, 2H, major), 8.10 (m, 2H, minor), 7.91 (m, 1H), 7.68 (d,
2
2
2
H, J¼7.3 Hz), 7.57 (t, 2H, J¼6.1 Hz), 7.14 (d, 1H, J¼
separated. The organicphase was washed with H O and dried
2
1.0 Hz, major), 6.80 (d, 1H, J¼7.3 Hz, minor), 6.43 (d, 1H,
over Na SO . Evaporation of the solvent followed by column
13
2
4
J¼7.3 Hz), 3.51 (m, 1H), 1.90–1.00 (m, 10H); C NMR
chromatography with EtOAc:MeOH (80:20) as eluent fur-
(
DMSO-d of both isomers): d¼156.4, 156.0, 155.4, 154.0,
1
6
nished 6a as a white solid; yield: 104 mg (88%). H NMR
1
4
3
1
53.6, 153.4, 141.1, 140.8, 127.0, 125.2, 124.9, 121.4, 61.3, 59.9,
(
4
6
DMSO-d ): d¼8.82 (d, 1H, J¼8.6 Hz), 8.47 (d, 2H, J¼
6
8.3, 32.3, 25.2, 24.3; IR (KBr): n¼3372, 3347, 3112, 3077,
.9 Hz), 7.76 (m, 2H), 7.46 (d, 2H, J¼7.3 Hz), 7.25 (m, 2H),
041, 2928, 2871, 2850, 1674, 1605, 1548, 1468, 1440, 1337,
1
3
.21 (d, 1H, J¼8.6 Hz), 1.98 (s, 3H); C NMR (DMSO-d ):
À1
6
282, 1236, 1220, 1147, 1165, 1037, 985, 778, 633, 550 cm
;
d¼168.9, 160.1, 148.8, 136.8, 122.3, 121.9, 59.5, 22.6.
elemental analysis: calcd. for C H Cl N OPd: C 44.33,
1
8
22
2
4
H 4.55, N 11.49; found: C 44.35, H 4.52, N 11.13.
Synthesis of N-Cyclohexyl-N’-di(2-pyridyl)methylurea
(
6b)
Typical Experimental Procedure for Suzuki–Miyaura
The amine 5 (185 mg, 1 mmol) and cyclohexyl isocyanate Coupling of Aromatic and Heteroaromatic Bromides
(
138 mg, 1.1 mmol) were mixed in CH Cl (5 mL) and stirred and Chlorides with Arylboronic Acids in Water
2
2
for 1 h. Then, CH Cl (10 mL) was added and the mixture
was washed with H O. The organicphase was dried over
Na SO and concentrated under vacuum to afford 6b as a white
2
2
A
mixture of aryl halide (1 mmol), arylboronic ai dc
2
(
1.5 mmol), potassium carbonate (2 mmol, 276 mg), tetra-n-
2
4
1
butylammonium bromide (0.5 to 1 mmol, only with aryl chlor-
ides) complex 4 (see Tables 1–4) and water (2.5 mL) was stir-
red under reflux in air and the reaction progress was analyzed
by GC. After the reaction was completed or stopped, the reac-
tion mixture was extracted with ethyl acetate (3Â10 mL). The
organicphases were dried and evaporated (15 mm Hg). The
subsequent residue was purified by recrystallization or by flash
chromatography on silica gel to give pure products 7.
solid; yield: 260 mg (84%). H NMR (500 MHz, CDCl ): d¼
3
8
7
4
.51 (d, 2H, J¼4.8 Hz), 7.63 (m, 2H), 7.42 (d, 2H, J¼7.9 Hz),
.15 (m, 2H), 6.90 (d, 1H, J¼6.7 Hz), 6.08 (d, 1H, J¼6.1 Hz),
.86 (d, 1H, J¼7.3 Hz), 3.55 (m, 1H), 2.0–1.0 (m, 10H);
13
C NMR (CDCl ): d¼159.8, 156.8, 148.8, 137.0, 122.4, 122.3,
3
6
0.1, 49.0, 33.7, 25.5, 24.8.
Synthesis of N,N-Di(2-pyridyl)methylamine-Derived
Palladium Chloride Complexes (4)
Typical Experimental Procedure for Suzuki–Miyaura
Coupling of Aromatic and Heteroaromatic Bromides
and Chlorides with Arylboronic Acids in Aqueous
Methanol
PdCl (33 mg, 0.186 mmol) was dissolved in concentrated HCl
2
(
1 mL). The resulting mixture was stirred until the PdCl was
2
completely dissolved (ca. 10 min.). A few drops of aqueous
5% NaOH were added until a pale precipitate of Pd(OH)2
1
just began to form. The ligand 6 (0.22 mmol) was dissolved in
methanol (2.5 mL) and the resulting solution was added to
the solution of H PdCl . The initially dark solution gradually
became paler and a yellow precipitate was formed. Stirring
was continued for 2–3 hours after which the precipitate was
A mixture of aryl halide (1 mmol), arylboronic ai dc
(1.5 mmol), potassium hydroxide (2 mmol, 112 mg), tetra-n-
butylammonium bromide (0.5 to 1 mmol, only with aryl chlor-
ides), complex 4 (see Tables 1–4) and methanol/water: 3/1
(2.5 mL). The mixture was stirred at room temperature or at
608C (see Tables 1–4) and the reaction progress was analyzed
by GC. Normally, the product was not soluble in the solvent
mixture. In those cases, when the reaction was completed or
stopped, the mixture was filtered and the solid obtained was
washed with methanol/water: 3/1 and purified by recrystalliza-
tion. When both aryl halide and biaryl were soluble, the reac-
tion mixture was poured into an excess of water and extracted
with ethyl acetate (3Â10 mL). The organicphases were dried,
evaporated (15 mm Hg) and the crude product 7 purified by re-
crystallization or flash chromatography on silica gel.
2
4
collected by filtration and washed with H O and MeOH. The
2
yellow powder obtained was dried under vacuum to afford 4a
(
73%) or 4b (94%). Compound 4a is insoluble in H O,
2
MeOH, CH Cl , CHCl and EtOAc, sparingly soluble in
2
2
3
MeCN and soluble in DMSO and DMF. Crystals suitable for
X-ray analysis were grown from a concentrated solution of
1
4
a in DMSO; mp 2958C (dec.). H NMR (500 MHz, DMSO-
d ): major isomer (ca. 84%) d¼9.84 (d, 1H, J¼9.9 Hz), 8.87
6
(
7
d, 2H, J¼5.6 Hz), 8.19 (t, 2H, J¼6.7 Hz), 7.91 (d, 2H, J¼
.8 Hz ), 7.59 (t, 2H, J¼6.5 Hz), 7.35 (d, 1H, J¼9.8 Hz), 2.26
(
(
(
1
1
1
s, 3H); minor isomer (ca. 14%) d 9.69 (1H), 8.89 (2H), 8.09
The compounds 4-phenylacetophenone, 4-phenylphenol, 2-
phenylbenzonitrile, 4’-methylbiphenyl-2-carbonitrile, biphe-
nylacetic acid, 3-(3-methylphenyl)benzoic acid, (4-phenyl)ace-
tanilide, 4-phenylaniline, 2-phenylacetanilide, 2-phenylpyridine
1
3
2H), 7.91 (2H), 7.55 (2H), 6.30 (1H), 2.03 (3H). C NMR
DMSO-d ): both isomers d¼170.1, 154.3, 153.6, 141.1, 125.1,
6
21.6, 58.5, 22.7; IR (KBr): n¼3320, 3074, 3113, 1692, 1604,
519, 1477, 1466, 1441, 1363, 1282, 1252, 1211, 1161, 1097,
and 3-phenylpyridine are commercially available. The com-
À1
[34]
038, 766, 658, 640, 543 cm ; elemental analysis: calcd. for
pounds 4,5-diphenyl-2-methyl-3(2H)pyridazinone, N,N-di-
[36]
[37]
C H Cl N OPd: C 38.69, H 3.00, N 10.41; found: C 38.54, H
methyl(4-phenyl)aniline,
2,6-dimethylbiphenyl,
have
13
12
2
3
3.18, N 10.04.
been previously reported.
1808
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 1798–1811

Suzuki–Miyaura and Related Cross-Couplings in Aqueous Solvents
FULL PAPERS
Typical Experimental Procedure for Suzuki Coupling
of Benzylic Chlorides and Allylic Chlorides, Acetates
or Methyl Carbonates with Arylboronic Acids in
Water
Typical Experimental Procedure for Suzuki Coupling
of Aromatic Bromides and Chlorides with n-
Butylboronic Acid
A solution of aryl halide (1 mmol), n-butylboronicaicd
(1.5 mmol, 153 mg), potassium carbonate (2 mmol, 276 mg),
tetra-n-butylammonium bromide (1 mmol, 322 mg, only with
aryl chlorides), complex 4b (0.01 mmol, 4.88 mg, 1 mol %
Pd) and water (3 mL) was stirred under reflux in air and the re-
action progress was analyzed by GC (Table 7). After the reac-
tion was completed or stopped, the reaction mixture was ex-
tracted with ethyl acetate (3Â10 mL). The organicphases
were dried and evaporated (15 mm Hg). The subsequent resi-
due was purified by flash chromatography on silica gel to give
products 10.
A mixture of benzylicor allylicsubstrate (1 mmol), arylboron-
ic acid (1.5 mmol), potassium carbonate (2 mmol, 276 mg), tet-
ra-n-butylammonium bromide (0.5 to 1 mmol), decane
(
1 mmol, 194 mL), complex 4b (see Tables 5 and 6) and water
(
2.5 mL) was stirred under reflux in air and the reaction prog-
ress was analyzed by GC. After the reaction was completed or
stopped, the reaction mixture was extracted with ethyl acetate
(
(
3Â10 mL). The organicphases were dried and evaporated
15 mm Hg). The subsequent residue was purified by recrystal-
lization or by flash chromatography on silica gel to give pure
products 8 or 9.
The compound 4-butylacetophenone is commercially availa-
[44]
ble and the compound butyl-4-trifluoromethylbenzene has
been previously reported.
2
-Butyl-6-methoxynaphthalene (10g): mp 55–568C (hex-
1
ane). H NMR (CDCl ): d¼7.64 (m, 2H), 7.52 (br s, 1H),
Typical Experimental Procedure for Suzuki Coupling
of Benzylic Chlorides and Allylic Chlorides, Acetates
or Methyl Carbonates with Arylboronic Acids in
Aqueous Acetone
3
7
.27 (m, 1H), 7.11 (m, 1H), 7.08 (br s, 1H), 3.87 (s, 3H), 2.72
(
t, 2H, J¼7.6 Hz), 1.65 (m, 2H), 1.37 (m, 2H), 0.93 (t, 3H,
1
3
J¼7.3 Hz); C NMR (CDCl ): d¼157.0, 138.0, 132.8, 129.1,
3
1
28.8, 127.9, 126.6, 126.1, 123.5, 118.5, 105.6, 55.2, 35.6, 33.6,
þ
A solution of the benzyli chc loride or allylicsubstrate
22.4, 14.0; MS: m/z¼214 (24, M ), 172 (16), 171 (100), 128
(
(
1 mmol), arylboronica ci d (1.5 mmol), potassium hydroxide
2 mmol, 112 mg), tetra-n-butylammonium bromide (0.5 to
(21); HRMS: m/z¼214.1356 (calcd.: 214.1358).
1
mmol), decane (1 mmol, 194 mL), complex 4b (see, Tables 5
and 6) and acetone/water: 3/2 (3 mL). The mixture was stirred
at room temperature in air and the reaction progress was ana- Acknowledgements
lyzed by GC. After the reaction was completed or stopped, the
reaction mixture was extracted with ethyl acetate (3Â10 mL).
The organicphases were dried and evaporated (15 mm Hg).
The subsequent residue was purified by distillation or by col-
umn chromatography on silica gel to provide products 8 or 9.
The compounds diphenylmethane, 1-benzyl-4-chloroben-
zene, 1-benzyl-4-fluorobenzene, 2-methyl-3-phenylpropene
and 3-phenylpropene are commercially available and 3-benzyl-
We thank DGES of the Spanish Ministerio de Ciencia y Tecno-
logia (MCyT) (BQU2001-0724-C02-01) for financial support.
S. K. thanks the Stiftelsen Bengt Lundquists minne (Sweden),
the Swedish Institute and the Spanish Ministerio de Asuntos Ex-
teriores for postdoctoral fellowships. J. G. M. thanks MCyT for
a predoctoral fellowship.
[
38]
[39]
anisole, 2-(4’-fluorobenzyl)thiophene, 5-benzyl-2-chloro-
[11]
[40]
pyridine,
1-phenyl-2-(phenylmethyl)propene,
(E)-1,3-di-
and (E)-3-(4-fluorophenyl)-1-phenylpro-
have been previously reported.
[41]
References and Notes
phenylpropene,
[
42]
pene
[
1] For recent reviews, see: a) A. Suzuki, in: Handbook of
Organopalladium Chemistry for Organic Synthesis,
(
Eds.: E.-I. Negishi, A. de Meijere), Wiley, New York,
Typical Experimental Procedure for Suzuki Coupling
of Aromatic and Heteroaromatic Bromides and
Chlorides with Trimethylboroxine
2002, pp. 249–262; b) N. Miyaura, J. Organomet. Chem.
2002, 653, 54–57; c) A. Suzuki, J. Organomet. Chem.
1999, 576, 147–168; d) N. Miyaura, in: Cross-coupling
Reactions, (Ed.: N. Miyaura), Springer, Berlin, 2000, pp.
A solution of aryl halide (1 mmol), trimethylboroxine
1
1–59; e) A. Suzuki, in: Metal-catalyzed Cross-coupling
(
1 mmol, 140 mL), potassium carbonate (3 mmol, 415 mg), tet-
Reactions, (Eds.: F. Diederich, P. J. Stang), Wiley-VCH,
Weinheim, 1998, Chapter 2; f) A. Suzuki, in: Advances
in Metal-Organic Chemistry, (Ed.: L. S. Liebeskind),
JAI, London, 1998, pp. 187–243.
2] a) J. Hassan, M. S e´ vignon, C. Gozzi, E. Schulz, M. Lem-
aire, Chem. Rev. 2002, 102, 1359–1469; b) S. Kohta, K.
Lahiri, D. Kashinath, Tetrahedron 2002, 58, 9633–9695;
c) E. J.-G. Anctil, V. Snieckus, J. Organomet. Chem.
ra-n-butylammonium bromide (1 mmol, 322 mg, only with aryl
chlorides), complex 4b (5 to 10 mol % Pd) and water (3 mL)
was stirred under reflux in air and the reaction progress was an-
alyzed by GC (see Table 7). After the reaction was completed
or stopped, the reaction mixture was extracted with ethyl ace-
tate (3Â10 mL). The organicphases were dried and evaporat-
ed (15 mm Hg). The subsequent residue was purified by flash
chromatography on silica gel to afford products 10.
[
2
002, 653, 150–160; d) A. F. Littke, G. C. Fu, Angew.
The compounds 4-methylacetophenone, 4-trifluoromethyl-
toluene and 2-methylquinoline, are commercially available
and 2-methoxy-6-methylnaphthalene has been previously re-
ported.
Chem. Int. Ed. 2002, 41, 4176–4211; e) S. P. Standford,
Tetrahedron 1998, 54, 263–303; f) L. Pu, Chem. Rev.
1998, 98, 2405–2494.
[43]
Adv. Synth. Catal. 2004, 346, 1798–1811
asc.wiley-vch.de
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1809

FULL PAPERS
Carmen N a´ jera et al.
[
3] a) A. Lubineau, J. Auge, in: Modern Solvents in Organic
Synthesis, (Ed.: P. Knochel), Springer, Berlin, 1999;
b) Organic Synthesis in Water, (Ed.: P. A. Grieco), Black-
ie Academic & Professional, London, 1998; c )Aqueous-
Phase Organometallic Catalysis, Concepts and Applica-
tions, (Eds.: B. Cornils, W. A. Herrmann), Wiley-VCH,
Weinheim, 1998; d) C.-J. Li, T.-H. Chen, Organic Reac-
tions in Aqueous Media, Klewer Academic Publishers,
Dordrecht, 1997.
[19] Similar conformations have been observed in the com-
plex [di(2-pyridyl)methylphenylsilane]palladium (II) di-
chloride: M. E. Wright, C. K. Lowe-Ma, Organometallics
1990, 9, 347–352 and in the case of complex 3 (X¼CH,
[15]
R¼CH ).
3
[20] Methyl-substitution in the pyridyl ring of complexes 3
(X¼CH) results in lower stability and lower coupling
yields because of the significant perturbation of the
square planar coordination of palladium: J. Silber, T.
Schareina, R. Kempe, K. Wurst, M. R. Buchmeiser, J.
Organomet. Chem. 2001, 622, 6–18.
[
[
[
4] N. A. Bumagin, V. V. Bykov, Tetrahedron 1997, 53,
1
4437–14450.
5] H. Sakurai, T. Tskuda, T. Hirao, J. Org. Chem. 2002, 67,
721–2722.
6] a) A. L. Casalnuovo, J. C. Calabrese, J. Am. Chem. Soc.
990, 112, 4324–4330; b) J.-C. Galland, M. Savignac, J.-
[
21] B. Schmidt, B. Schieffer, J. Med. Chem. 2003, 46, 2261–
270.
2
2
[
22] This coupling has been carried out with 5 mol % of Pd/C
in refluxing aqueous isopropanol: D. Gala, A. Stamford,
J. Jenkins, M. Kugelman, Org. Process Res. Dev. 1997, 1,
1
P. Gen eˆ t, Tetrahedron Lett. 1999, 40, 2323–2326; c) Y.
Uozumi, H. Danjo, T. Hayasi, J. Org. Chem. 1999, 64,
1
63–164.
3
384–3388; d) A. E. S. Gelpke, J. J. N. Weerman, M. S.
[
23] These reaction conditions were previously used with ox-
ime-derived palladacycles: D. A. Alonso, C. N a´ jera,
M. C. Pacheco, J. Org. Chem. 2002, 67, 5588–5594.
24] Y. Qian, A. Vogt, S. M. Sebti, A. D. Hamilton, J. Med.
Chem. 1996, 39, 217–223.
25] 4,5-Diarylpyridazinones present important agrochemical
and pharmaceutical applications: P. Tapolcs a´ nyi; P. M a´ -
tyus, Targets in Heterocyclic Systems 2002, Vol. 6, 369–
Goedheijt, P. C. J. Kamer, P. W. N. van Leeuwen, H.
Hiemstra, Tetrahedron 1999, 55, 6657–6670; e) C. Du-
puis, K. Adiey, L. Charruault, V. Michelet, M. Savignac,
J.-P. Gen eˆ t, Tetrahedron Lett. 2001, 42, 6523–6526; f) M.
Nishimura, M. Ueda, N. Miyaura, Tetrahedron 2002, 58,
[
[
5
774–5787.
[
[
[
7] It is known that TBAB stabilizes colloidal palladium
nanoparticles acting as catalysts in cross-coupling reac-
tions: M. T. Reetz, E. Westermann, Angew. Chem. Int.
Ed. 2000, 39, 165–168.
3
98.
[
[
26] E. Negishi, F. Liu, in: Handbook of Organopalladium
Chemistry for Organic Synthesis, (E. Negishi, Ed.),
John Wiley & Sons, New York, 2002, pp. 551–589.
8] a) D. Badone, M. Baroni, R. Cardamone, A. Ielmini,
U. J. Guzzi, J. Org. Chem. 1997, 62, 7170–7173; b) J. C.
Bussolari, D. C. Rehborn, Org. Lett. 1999, 1, 965–967;
c) S. Hesse, G. Kirsh, Synthesis 2001, 755–758.
9] R. B. Bedford, M. E. Blake, C. P. Butts, D. Holder,
Chem. Commun. 2003, 466–467.
27] a) T. Rische, P. Eilbracht, Tetrahedron 1999, 55, 1915–19
2
4
0; b) X. Fan, N.-J. Xu, J.-G. Shi, J. Nat. Prod. 2003, 66,
55–458; c) A. Rosowsky, R. A. Forsch, C. H. Sibley,
C. B. Inderlied, S. F. Queener, J. Med. Chem. 2004, 47,
475–1486.
28] J. C. Ma, D. A. Dougherty, Chem. Rev. 1997, 97, 1303–
324.
29] a) S. Chowdhury, P. E. Georghiou, Tetrahedron Lett.
999, 40, 7599–7603; b) L. Chahen, H. Doucet, M. San-
1
[
10] A. Arcadi, G. Cerichelli, M. Chiarini, M. Correa, D. Zor-
[
[
zan, Eur. J. Org. Chem. 2003, 4080–4086.
1
[
11] a) L. Botella, C. N a´ jera, Angew. Chem. Int. Ed. 2002, 41,
1
79–181; b) L. Botella, C. N a´ jera, J. Organomet. Chem.
1
2
002, 663, 46–57.
telli, Synlett 2003, 1668–1672; c) S. Langle, M. Abarbri,
A. Duch eˆ ne, Tetrahedron Lett. 2003, 44, 9255–9258.
30] This compound 8e has been prepared by copper-cata-
lyzed reaction of thienylmagnesium bromide with 4-fluo-
[
12] a) C. Baleizao, A. Corma, H. García, A. Leyva, Chem.
Commun. 2003, 606–607; b) C. Baleizao, A. Corma, H.
García, A. Leyva, J. Org. Chem. 2004, 69, 439–446.
13] J. P. Collman, L. S. Hegedus, J. R. Norton, R. G. Finke,
Principles and Applications of Organometallic Chemis-
[
[
[31]
robenzyl iodide.
[31] Y.-Y. Ku, R. R. Patel, D. P. Sawick, Tetrahedron Lett.
996, 37, 1949–1952.
32] B. Kramer, S. R. Waldvogel, Angew. Chem. Int. Ed. 2004,
3, 2446–2449.
nd
try, 2 edn., University Science Books, Mill Valley, CA,
1
1
987.
[
[
[
14] F. Sinner, M. R. Buchmeiser, R. Tessadri, M. Mupa, K.
4
Wurst, G. K. Bonn, J. Am. Chem. Soc. 1998, 120, 2790–
2
33] a) M. Moreno-Ma n˜ as, F. Pajuelo, R. Pleixats, J. Org.
Chem. 1995, 60, 2396–2397. b) D. Boussy, V. Gerusz,
G. Balme, Eur. J. Org. Chem. 2002, 2445–2448.
797.
15] M. R. Buchmeiser, K. Wurst, J. Am. Chem. Soc. 1999,
21, 11101–11107.
[
[
[
1
16] M. R. Buchmeiser, T. Schareina, R. Kempe, K. Wurst, J.
Organomet. Chem. 2001, 634, 39–46.
17] For a preliminary communication, see: C. N a´ jera, J. Gil-
Molt o´ , S. Karlstrçm, L. R. Falvello, Org. Lett. 2003, 5,
[34] M. Gray, I. P. Andrews, D. F. Hook, J. Kitteringham, M.
Voyle, Tetrahedron Lett. 2000, 41, 6237–6240.
[35] a) J. R. Falck, P. S. Kumar, Y. K. Reddy, G. Zou, J. H.
Capdevila, Tetrahedron Lett. 2001, 42, 7211–7212; b) G.
Zou, Y. K. Reddy, J. R. Falck, Tetrahedron Lett. 2001,
42, 7213–7216.
1
451–1454.
18] a) A. P. Krapcho, J. R. Powell, Tetrahedron Lett. 1986, 27,
713–3714; b) M. Reuz, C. Hemmert, B. Meunier, Eur. J.
Org. Chem. 1998, 1271–1273.
[
3
[36] J. A. Miller, J. W. Dankwardt, J. M. Penney, Synthesis
2003, 1643–1648.
1810
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 1798–1811

Suzuki–Miyaura and Related Cross-Couplings in Aqueous Solvents
FULL PAPERS
[
37] W. Su, S. Urgaonkar, J. G. Verkade, Org. Lett. 2004, 6,
[42] R. J. Bushby, G. J. Ferber, J. Chem. Soc. Perkin Trans. 2
1976, 1683–1688.
1
421–1424.
[
[
38] K. Laali, J. Org. Chem. 1985, 50, 3638–3640.
39] J. Srogl, G. D. Allred, L. S. Liebeskind, J. Am. Chem.
Soc. 1997, 119, 12376–12377.
40] K.-T. Wong, T.-M. Yuan, M. C. Wang, H.-H. Tung, T.-Y.
Luh, J. Am. Chem. Soc. 1994, 116, 8920–8929.
41] M. M. Bokadia, B. R. Brown, D. Cobern, A. Roberts,
G. A. Somerfield, J. Chem. Soc. 1962, 1658–1666.
[43] J. H. P. Utley, G. G. Rozenberg, Tetrahedron 2002, 58,
5251–5265.
[44] K. Tamao, K. Sumitani, Y. Kiso, M. Zembayashi, A. Fu-
jioka, S. Kodama, I. Nakajima, A. Minato, M. Kumada,
Bull. Chem. Soc. Jpn. 1976, 49, 1958–1969.
[
[
Adv. Synth. Catal. 2004, 346, 1798–1811
asc.wiley-vch.de
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1811