Facile access to biaryls and 2-acetyl-5-arylbenzofurans via Suzuki coupling in water under thermal and microwave conditions

Article abstract of DOI:10.1055/s-0030-1258181

The phosphine-free Suzuki-Miyaura carbon-carbon cross-coupling reactions of activated and deactivated aryl halides and 2-acetyl-5-bromobenzofuran with various aryl-or heteroarylboronic acids were investigated. A benzothiazole-based palladium(II) complex was used as a precatalyst for the reactions under both thermal and microwave conditions in air using water as a solvent. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258181

PAPER
3163
Facile Access to Biaryls and 2-Acetyl-5-arylbenzofurans via Suzuki Coupling
in Water under Thermal and Microwave Conditions
B
iaryls and 2-Acet
h
yl-5-arylben
m
zofurans via Suzuki
e
Coupling i
d
n Water F. Darweesh,a Mohamed R. Shaaban,a,b Ahmad M. Farag,a Peter Metz,c Kamal M. Dawood*a
a
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
Fax +20(2)35727556; E-mail: dr_dawood@hotmail.com
b
c
Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University, Makkah Almukarramah, Saudi Arabia
Fachrichtung Chemie und Lebensmittelchemie, Organische Chemie I, Technische Universität Dresden, Bergstraße 66, 01069 Dresden,
Germany
Received 12 March 2010; revised 10 May 2010
OMe
Abstract: The phosphine-free Suzuki–Miyaura carbon–carbon
cross-coupling reactions of activated and deactivated aryl halides
and 2-acetyl-5-bromobenzofuran with various aryl- or heteroaryl-
boronic acids were investigated. A benzothiazole-based palladi-
um(II) complex was used as a precatalyst for the reactions under
both thermal and microwave conditions in air using water as a sol-
vent.
MeO
O
O
O
I
O
MeO
HO
O
II
OMe
MeO
MeO
MeO
Key words: palladium, catalysis, microwave irradiation, Suzuki re-
actions, benzofuran
O
O
O
O
MeO
III
IV
Figure 1 Examples of natural benzofuran derivatives
The formation of carbon–carbon bonds is a fundamental
reaction in organic synthesis. Aryl–aryl bond formation
has been known for more than a century and was one of
the first reactions involving a transition metal.1 Modern
synthetic chemistry is also underpinned by the use of tran-
sition-metal catalysts as powerful tools for carbon–carbon
bond-forming processes.2 The Suzuki–Miyaura cross-
coupling reaction is widely applied in academic and in-
dustrial research.3 Over the past two decades, it has be-
come one of the most-efficient methods for the
construction of biaryls or substituted aromatic compounds
that constitute important building blocks of polymers,4
ligands,5 a wide range of natural products, such as alka-
loids, and numerous biologically active pharmaceuticals.6
port herein new palladium(II) complex 3 and evaluate its
suitability for the synthesis of biaryls and 5-aryl- or 5-het-
eroarylbenzofuran derivatives via Suzuki reactions. The
syntheses use aryl or heteroaryl halides and 2-acetyl-5-
bromobenzofuran with a variety of aryl- or heteroarylbo-
ronic acids under thermal as well as microwave condi-
tions.
For the synthesis of complex 3, the substrate 1-benzothia-
zol-2-ylethanone oxime (1) was prepared as described in
the literature.17 Treatment of oxime 1 with benzyl chloride
in the presence of potassium hydroxide (KOH) gave O-
benzyloxime 2. Palladium(II) complex 3 was prepared by
dissolving O-benzyloxime 2 in a mixture of 1,4-dioxane–
methanol, followed by the addition of an equimolar
amount of sodium tetrachloropalladate(II) in methanol at
room temperature (Scheme 1).
Microwave irradiation has recently seen widespread ap-
plication in research laboratories.7,8 In addition, organic
reactions that can proceed well in water offer advantages
over those occurring in organic solvents.9
The benzofuran moiety is incorporated in various pharma-
cologically active compounds10 and constitutes a structur-
al unit of several natural products.11 For example,
cicerfuran (I) has been isolated from the roots of wild
chickpea (Cicer bijugum),12a and 2-acetylbenzofurans
calebertin (II), caleprunin A (III), and caleprunin B (IV)
have been isolated from Calea species (Figure 1).12b
The Suzuki cross-coupling of aryl and heteroaryl halides
using complex 3 was then investigated. First, we evaluat-
ed the effect of palladium(II) complex 3 loading on the
a
N
N
N
N
Ph
O
S
S
OH
S
1
2
Cl
In continuation of our research directed towards the chem-
istry of 2- and 3-substituted benzofurans13,14 and towards
the use of palladium(II) complexes as precatalysts in car-
bon–carbon cross couplings in aqueous media,15,16 we re-
b
Pd
N
Cl
N
Ph
O
3
SYNTHESIS 2010, No. 18, pp 3163–3173
Advanced online publication: 16.07.2010
DOI: 10.1055/s-0030-1258181; Art ID: Z06410SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
0
Scheme 1 Preparation of palladium complex 3. Reagents and con-
ditions: (a) BnCl, EtOH, KOH, 100 °C, 30 min, 93% yield; (b)
Na2PdCl4, 1,4-dioxane–MeOH (1:1), r.t., 2 h, 88% yield

3164
A. F. Darweesh et al.
PAPER
reaction was carried out without palladium complex 3 (en-
try 11).
Table 1 Concentration Effect of Palladium Complex 3 on the
Suzuki Coupling of 1-(4-Bromophenyl)ethanone with Phenylboronic
Acid in Water Using Thermal Heatinga
Palladium complexes have been reported to serve as ‘dor-
mant species’18 that are not involved in the real catalytic
cycle, but are sources of catalytically active species of an
unknown nature. Therefore, our palladium(II) complex 3
may serve here as a reservoir that is not involved in the
real catalytic cycle, but is a source of a considerable
amount of colloidal palladium(0), which can show cata-
lytic activity at low concentrations.
B(OH)2
KOH, TBAB
Br
Pd cat. 3
+
H2O, 100 °C, 1 h
O
O
4
5a
6
Entry
Loading of catalyst 3 Conversion
(mol%)
TON
(%)b
To achieve full conversion and, hence, maximum yield for
the cross-coupling reaction, various parameters that may
affect such results were optimized. Solvents and bases are
among the most important controlling factors for such
purposes. In our work, the choice of base was still empir-
ical, and no general rule for its selection had been estab-
lished, so the suitabilities of some bases and solvents for
the coupling reaction between 1-(4-bromophenyl)ethan-
one (4) and phenylboronic acid (5a) were evaluated. In all
cases, palladium precatalyst 3 was used in 0.25 mol% and
the reaction was carried out under microwave irradiation
for 3 minutes in different solvents, i.e. water, N,N-dimeth-
ylformamide (DMF), toluene, and tetrahydrofuran (THF),
using KOH or potassium carbonate (K2CO3) as the base
(Table 2). The best result was obtained with water as the
solvent in the presence of TBAB after 3 minutes of micro-
wave irradiation at 160 °C (entry 1). The conversion,
based on GC analysis, was 100% and the cross-coupled
product 4-acetylbiphenyl (6) was obtained in 96% isolat-
ed yield. Repeating the reaction under these conditions us-
1
2
1
100
100
0.75
0.5
100
133
200
3
100
4
0.25
0.125
0.05
0.025
0.0125
0.005
0.001
0
100 (96)
100
400
5
800
6
100
2000
4000
8000
20000
100000
0
7
100
8
100 (93)
100
9
10
11
100
0
a Reaction conditions: aryl bromide/PhB(OH)2/KOH/TBAB
(1:1.2:2:0.6), H2O (3 mL), 100 °C, 1 h.
b Conversions are based on GC analysis and the values in parentheses
refer to isolated yields.
Table 2 Base and Solvent Effects on the Suzuki Coupling of 1-(4-
Bromophenyl)ethanone with Phenylboronic Acid under Microwave
Irradiationa
cross-coupling reaction of phenylboronic acid and 1-(4-
bromophenyl)ethanone in water using KOH as a base and
tetrabutylammonium bromide (TBAB) as a co-catalyst
under thermal conditions of 100 °C for 1 hour (Table 1).
The reaction was initially conducted using 1 mol% of
complex 3 with 1-(4-bromophenyl)ethanone (4)/phenyl-
boronic acid (5a)/KOH/TBAB in a molar ratio of
1:1.2:2:0.6 to give 4-acetylbiphenyl (6) with 100% con-
version based on GC analysis (entry 1). In our second ex-
periment, we used 0.75 mol% of catalyst 3 to give full
conversion, based on GC analysis, after 1 hour of heating
at 100 °C (entry 2). The reaction was repeated with differ-
ent loadings (mol%) of complex 3 as shown in Table 1. In
all cases, full conversion was obtained even in the pres-
ence of 0.001 mol% of complex 3. It is important to men-
tion that when palladium complex 3 was used in 0.001
mol%, the number of moles of the reacting species were
raised [1-(4-bromophenyl)ethanone (4) (60 mmol),
PhB(OH)2 (5a) (75 mmol), KOH (125 mmol), and TBAB
(37.5 mmol) in H2O (100 mL)] to give 4-acetylbiphenyl
(6) with 100% conversion, based on GC analysis, and a
turnover number (TON) of 100000 (entry 10). It can be
concluded from the data in Table 1 that palladium com-
plex 3 shows excellent catalytic activity, giving rise to ex-
tremely high TONs. Interestingly, the bromide starting
B(OH)2
Br
Pd cat. 3 (0.25 mol%)
+
MW, 3 min
6
5a
4
O
O
Entry
Base
Solvent
H2O (TBAB)
H2O (TBAB)
DMF
Yieldb (%)
100 (96)c,d
100 (96)
80 (71)
1
2
3
4
5
6
KOH
K2CO3
KOH
K2CO3
KOH
KOH
DMF
73 (61)
toluene
100 (91)
60 (50)
THF
a Reaction conditions: aryl bromide/PhB(OH)2/base/TBAB (in the
case of H2O as solvent) (1:1.2:2:0.6), solvent (3 mL), microwave ir-
radiation (250 W) at 160 °C (H2O and DMF), 130 °C (toluene), and
90 °C (THF), 3 min.
b Conversions are based on GC analysis and the values in parentheses
refer to isolated yields.
c Using thermal heating at 100 °C for 1 h gave full conversion with
94% isolated yield.
material was completely recovered unchanged when the d Performing the reaction at r.t. for 12 h gave 96% conversion.
Synthesis 2010, No. 18, 3163–3173 © Thieme Stuttgart · New York

PAPER
Biaryls and 2-Acetyl-5-arylbenzofurans via Suzuki Coupling in Water
3165
ing thermal heating at 100 °C for 1 hour also gave full acid (5a) were carried out using thermal heating and mi-
conversion and the product in 94% isolated yield. In addi- crowave irradiation, and resulted in the formation of the
tion, when these optimum conditions were used for the re- corresponding biaryl derivatives 17–26 in high yields.
action conducted at room temperature for 12 hours, The molar ratio of the reaction components aryl bromide/
product 6 was obtained with 96% conversion, based on phenylboronic acid (5a)/KOH/TBAB was 1:1.2:2:0.6
GC analysis. Replacing water with DMF, toluene, or THF used with 0.25 mol% of complex 3 in water (3 mL). Pal-
gave 80, 100, and 60% conversions, based on GC analy- ladium(II) complex 3 was found to efficiently catalyze the
sis, and product 6 was isolated in 71, 91, and 50% yield coupling of a wide range of aryl bromides in good to ex-
after 3 minutes of microwave irradiation (entries 3, 5, and cellent yields regardless of their activating or deactivating
6, respectively). Next, the replacement of KOH with substituents. Activated aryl bromides bearing electron-
K2CO3 as the base in the reaction using different solvents withdrawing groups required shorter reaction times to
(H2O and DMF) was examined. Again, water proved itself give the products in excellent yields (entries 7 and 8) com-
as the suitable solvent in comparison with DMF (entries 2 pared with the deactivated aryl bromides bearing electron-
and 4, respectively).
donating groups (entries 2–4 and 9). Chemoselectivity
was encountered when phenylboronic acid (5a) was treat-
ed with 1-bromo-4-chlorobenzene (11) under thermal as
well as microwave conditions, with the chlorine atom sur-
viving to give 4-chlorobiphenyl (21) in excellent yield
(entry 5).
The choice of solvent, specifically its complexing proper-
ties, is crucial for palladium catalysts. Solvents other than
water, such as DMF, can give supernatants that, unlike
those cases involving aqueous solvents, still show catalyt-
ic activity in carbon–carbon coupling reactions. However,
oxime ligands have the potential to scavenge any catalytic Arylpyridines have been reported to be among the most-
species that may have leached into solution during the cat- prevalent heterocycles incorporated into pharmaceutical-
alytic process, particularly if DMF is used as a solvent.19 ly active compounds20 and commercial drugs.21–23 We
Water as an ecofriendly ‘green’ solvent and KOH as a prepared phenylpyridin-2-amines 29 and 30 by the Suzuki
cheap and common base were chosen for carrying out all cross-coupling of bromopyridin-2-amines 27 and 28, re-
the Suzuki cross-coupling reactions of aryl halides that are spectively, and phenylboronic acid (5a) using palladi-
performed in this work.
um(II) complex 3. The cross-coupling reaction was
performed using thermal heating and microwave irradia-
tion (Table 4). The coupling reaction of 6-bromopyridin-
2-amine (27) and 5-bromopyridin-2-amine (28) with phe-
nylboronic acid (5a) resulted in the formation of the cor-
Under the optimized conditions, the general utility of
complex 3 in the Suzuki–Miyaura cross-coupling reaction
was investigated as described in Table 3. The Suzuki cou-
pling reactions of aryl bromides 7–16 with phenylboronic
Table 3 Palladium(II) Complex 3 in the Suzuki Coupling of Aryl Bromides with Phenylboronic Acid in Water under Thermal and Microwave
Conditionsa
Ar
B(OH)2
H2O, TBAB, KOH
+
Ar Br
7–16
Pd cat. (0.25 mol%)
5a
17–26
Entry
Substrate
Ar
Time
Product
Yieldb (%)
Thermal
Thermal (h)
Microwave (min)
Microwave
(85)
1
2
7
8
Ph
2
4
2
2
2
3
1
1
3
4
5
6
6
6
6
5
2
2
5
6
17
18
19
20
21
22
23
24
25
26
92 (87)
100 (86)
100 (96)
(94)
4-MeOC6H4
4-EtOC6H4
4-HOC6H4
4-ClC6H4
100 (78)
100 (85)
100 (96)
(96)
3
9
4
10
11
12
13
14
15
16
5
98 (95)
(88)
6
3-AcC6H4
4-O2NC6H4
2,4-(O2N)2C6H3
1-naphthyl
4-BzC6H4
100 (91)
100 (95)
100 (90)
97 (92)
100 (94)
7
(94)
8
(80)
9
(88)
10
(90)
a Reaction conditions: aryl bromide (1 mmol), PhB(OH)2 (1.2 mmol), KOH (2 mmol), TBAB (0.6 mmol), H2O (3 mL), 0.25 mol% Pd complex,
microwave irradiation (250 W) at 160 °C or thermal heating at 100 °C.
b Conversions are based on GC analysis and the values in parentheses refer to isolated yields.
Synthesis 2010, No. 18, 3163–3173 © Thieme Stuttgart · New York

3166
A. F. Darweesh et al.
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Table 4 Suzuki Coupling of Bromopyridin-2-amines with Phenylboronic Acid under Thermal and Microwave Conditionsa
B(OH)2
H2O, TBAB, KOH
+
Br
Pd cat. (0.25 mol%)
H2N
N
H2N
N
27, 28
5a
29, 30
Entry
Substrate
Bromo substituent Time
Thermal (h) Microwave (min)
Product
Yieldb (%)
Thermal
Microwave
86 (79)
1
27
6-Br
5-Br
6
3
15
10
(84)
(87)
H2N
N
29
2
28
92 (82)
H2N
N
30
a Reaction conditions: bromopyridine (1 mmol), PhB(OH)2 (1.2 mmol), KOH (2 mmol), TBAB (0.6 mmol), H2O (3 mL), 0.25% Pd complex,
microwave irradiation (250 W) at 160 °C or thermal heating at 100 °C.
b Conversions are based on GC analysis and the values in parentheses refer to isolated yields.
responding cross-coupled products 29 and 30 in 79 and and 81% isolated yield after 12 minutes of microwave ir-
82% isolated yield after 15 and 10 minutes, respectively, radiation and 4 hours of thermal heating, respectively.
of microwave irradiation. When the same reactions were Similarly, 1-chloro-4-nitrobenzene (32) was coupled with
repeated under similar conditions, but with thermal heat- phenylboronic acid (5a) under microwave (10 min) and
ing at 100 °C, phenylpyridines 29 and 30 were obtained in thermal conditions (2 h) with 100% conversion to give
84 and 87% yield after 6 and 3 hours, respectively. The in- product 23 in 89 and 85% isolated yield, respectively, us-
ductive effect of the pyridine nitrogen is clear in these re- ing 0.25 mol% of palladium complex 3.
actions as 6-bromopyridin-2-amine (27) gave lower
yields after a longer reaction time (entry 1) than the 5-bro-
mo derivative 28 (entry 2) under thermal as well as micro-
wave conditions.
Palladium(II) precatalyst 3 was next applied to the Suzuki
coupling of N,N¢-bis(4-bromobenzylidene)ethane-1,2-di-
amine (33) and 1,2-bis(4-bromophenoxy)ethane (34) with
phenylboronic acid (5a) using thermal heating as well as
Aryl chlorides are cheaper and more-readily available microwave irradiation to give bis(biaryl) products 35 and
than the corresponding bromides and iodides, and their 36, respectively (Table 5). The reaction components’
cross-coupling reactions are of particular importance for quantities were 1 millimole of dibromide 33 or 34, 2.4
highly active catalysts.24 Therefore, the Suzuki cross-cou- millimoles of phenylboronic acid (5a), and 4 millimoles
pling of aryl chlorides 31 and 32 with phenylboronic acid of KOH using 0.25 mol% of complex 3 in toluene (4 mL).
(5a) was examined under thermal and microwave condi- Bis(biaryls) 35 and 36 were obtained in 69 and 55% iso-
tions as shown in Scheme 2. Firstly, 1-(4-chlorophe- lated yield, respectively, after 10 minutes of microwave
nyl)ethanone (31) (1 mmol) was coupled with irradiation and in 74 and 52% isolated yield, respectively,
phenylboronic acid (5a) (1.2 mmol) in water (3 mL) in the after 4 hours of thermal heating.
presence of TBAB (0.6 mmol) using KOH (2 mmol) as
Next, we investigated the Suzuki cross-coupling of 2-
the base and 0.25 mol% of palladium complex 3. Under
acetyl-5-bromobenzofuran using complex 3. Among the
these conditions, coupled product 6 was obtained in 87
5-arylbenzofuran derivatives that we prepared during this
work, 2-acetyl-5-phenylbenzofuran was the only reported
B(OH)2
example in the literature and appears as a patent.25 There-
Cl
H2O, TBAB, KOH
fore, developing new practical synthetic routes to 5-aryl-
benzofuran derivatives with potential biological
+
Pd cat. 3 (0.25 mol%)
X
applications is of great importance. In our work, 2-acetyl-
5-bromobenzofuran was envisaged as a key synthon in
Suzuki reactions for the synthesis of 5-arylbenzofurans.
X
5a
31 X = COMe
32 X = NO2
6
X = Ac; thermal (100 °C, 4 h): 81%
MW (250 W, 160 °C, 12 min): 87%
23 X = NO2; thermal (100 °C, 2 h): 85%
MW (250 W, 160 °C, 10 min): 89%
To select the proper catalyst system for the Suzuki reac-
tion between 2-acetyl-5-bromobenzofuran (37) and aryl-
boronic acids, the effect of different bases and solvents on
Scheme 2 Suzuki coupling of aryl chlorides with phenylboronic
acid under thermal and microwave conditions
Synthesis 2010, No. 18, 3163–3173 © Thieme Stuttgart · New York

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Biaryls and 2-Acetyl-5-arylbenzofurans via Suzuki Coupling in Water
3167
Table 5 Suzuki Coupling of Dibromides with Phenylboronic Acid under Thermal and Microwave Conditionsa
toluene, KOH
X
X
B(OH)2
+
Ph
Ph
Br
Br
Ph
Pd cat. 3 (0.25 mol%)
33, 34
5a
35, 36
Entry
Substrate
Product
Yieldb (%)
Thermal
Microwave
88 (69)
Br
Ph
N
N
1
90 (74)
62 (52)
N
N
Br
Ph
33
35
Ph
Br
O
O
2
60 (55)
O
O
Br
Ph
34
36
a Reaction conditions: microwave irradiation (250 W) at 130 °C for 10 min, or thermal heating at 110 °C for 4 h.
b Conversions are based on GC analysis and the values in parentheses refer to isolated yields.
the cross-coupling between substrate 37 and phenylbo- catalyst under similar conditions and the reason for this
ronic acid (5a) using thermal heating was studied in detail difference is not yet clear.15a,c
as a model example (Table 6). First, the reaction was car-
Table 6 Base and Solvent Effects on the Suzuki Coupling of 2-
ried out using KOH as the base in different solvents, i.e.
water, DMF, and toluene. The best result was obtained
with water as the solvent in the presence of TBAB after 2
hours of thermal heating at 100 °C (entry 1). The conver-
Acetyl-5-bromobenzofuran with Phenylboronic Acid Using Thermal
Heatinga
B(OH)2
sion was 100% and the cross-coupled product 2-acetyl-5-
phenylbenzofuran (38) was isolated in 96% yield. Repeat-
ing the synthesis using these conditions at room tempera-
ture for 12 hours gave only 11% conversion, based on GC
5a
Pd cat. 3 (0.25 mol%)
+
analysis, of cross-coupled product 38. When the same re-
action was repeated using microwave conditions instead
of thermal heating, full conversion was obtained after 10
minutes of irradiation at 160 °C. When water was replaced
by DMF or toluene, the reaction using KOH as the base
with the same reaction time gave conversions of 100 and
7%, based on GC analysis (entries 4 and 7, respectively).
This finding revealed that toluene is not a suitable solvent
for such cross-coupling reactions. Although the use of
DMF gave 100% conversion, the isolated yield of 89%
was slightly lower than that achieved in the case using wa-
ter. Next, the effect of using triethylamine (Et3N) as an or-
ganic base instead of KOH was examined using different
solvents. Again, water and DMF proved themselves as
suitable solvents for such carbon–carbon cross-coupling
reactions (entries 3 and 5, respectively).
reflux, 2 h
O
O
Br
38
O
O
37
Entry
Base
KOH
KOH
Et3N
KOH
Et3N
Et3N
KOH
Et3N
Solvent
Yield (%)b
100 (96)c,d
100 (94)
100 (91)
100 (89)
100 (95)
58
1
2
3
4
5
6
7
8
H2O (TBAB)
H2O
H2O (TBAB)
DMF (TBAB)
DMF (TBAB)
DMF
toluene
7
The effect of TBAB on the above-mentioned conversion
was also evaluated. When the reaction was conducted in
DMF using Et3N in the absence of TBAB, the conversion
was only 58%, based on GC analysis, after thermal heat-
ing for 2 hours (entry 6). However, the use of water result-
ed in full conversion with or without TBAB when KOH
was used as the base (entries 1 and 2). The last finding is
in contrast to our previous work using an analogous pre-
toluene
14
a Reaction conditions: 2-acetyl-5-bromobenzofuran (1 mmol),
PhB(OH)2 (1.2 mmol), base (2 mmol), TBAB (0.6 mmol), solvent (3
mL), 0.25 mol% Pd complex, reflux, 2 h.
b Conversions are based on GC analysis and the values in parenthesis
refer to isolated yields.
c Conversion was 11% after 12 h of stirring at r.t.
d Full conversion with 88% isolated yield after 10 min of microwave
irradiation at 160 °C.
Synthesis 2010, No. 18, 3163–3173 © Thieme Stuttgart · New York

3168
A. F. Darweesh et al.
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The general utility of palladium complex 3 in the Suzuki ucts 39–43 in good to excellent isolated yields (entries 2–
cross-coupling of 2-acetyl-5-bromobenzofuran (37) with 6). For the reaction shown in entry 4, there was no evi-
several aryl- and heteroarylboronic acids 5a–f was then dence of any byproduct relating to the further coupling of
investigated (Table 7). Thus, as mentioned previously, chlorophenyl derivative 41.
when 0.25 mol% of precatalyst 3 was employed in the re-
action of bromide 37 with phenylboronic acid (5a) under
microwave irradiation for 10 minutes in water with KOH
as the base and TBAB as a phase-transfer agent, full con-
version was observed giving 2-acetyl-5-phenylbenzofu-
ran (38) in 88% isolated yield (entry 1). In the same
manner, aryl- and heteroarylboronic acids 5b–f coupled
smoothly with bromide 37 under similar experimental
The structures of the coupling products were confirmed
13
by their 1H and C NMR and MS spectra and elemental
analyses. The 1H NMR spectrum of 2-acetyl-5-(4-
tolyl)benzofuran (39), as an example of the series pre-
pared, revealed four characteristic singlet signals at d =
2.42, 2.64, 7.54, and 7.87 relating to the methyl protons of
the 4-tolyl and acetyl substituents and H-3 and H-4 of the
benzofuran moiety, respectively. The 13C NMR spectrum
conditions to give the corresponding cross-coupled prod-
of derivative 39 showed two aliphatic carbons at d = 21.0
Table 7 Suzuki Cross-Coupling of 2-Acetyl-5-bromobenzofuran with Arylboronic Acids under Microwave Irradiationa
(Het)Ar
Br
Pd cat. 3 (0.25 mol%)
B(OH)2
+
(Het)Ar
H2O, TBAB, KOH
MW
O
O
O
O
5a–f
37
38–43
Entry
1
Arylboronic acid Ar
Time (min)
Product
Yieldb (%)
100 (88)
5a
5b
Ph
10
10
O
O
38
2
3
4-Tol
100 (65)
100 (96)
O
O
39
MeO
5c
4-MeOC6H4
15
10
O
O
40
Cl
4
5d
4-ClC6H4
100 (92)
O
O
41
O
O
5
6
5e
5f
3,4-methylenedioxyphenyl 15
100 (78)
100 (74)
O
O
42
S
3-thienyl
20
O
O
43
a Reaction conditions: 2-acetyl-5-bromobenzofuran (1 mmol), ArB(OH)2 (1.2 mmol), KOH (2 mmol), TBAB (0.6 mmol), H2O (3 mL), 0.25
mol% Pd complex, microwave irradiation (250 W) at 160 °C.
b Conversions are based on GC analysis and the values in parenthesis refer to isolated yields.
Synthesis 2010, No. 18, 3163–3173 © Thieme Stuttgart · New York

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Biaryls and 2-Acetyl-5-arylbenzofurans via Suzuki Coupling in Water
3169
mg, 1 mmol) in 1,4-dioxane–MeOH (1:1, 4 mL). After stirring for
2 h at r.t., a yellow precipitate was formed that was collected by fil-
tration, washed with MeOH (5–7 mL), H2O (5–7 mL), and then with
EtOH (5–7 mL), and finally dried to give Pd complex 3 as a yellow
powder. Complex 3 was obtained in a pure state and was used with-
out further purification. Yield: 403 mg (88%); mp >300 °C.
and 26.4, relating to the methyl carbons of the 4-tolyl and
acetyl groups, in addition to twelve aromatic carbons and
one carbonyl carbon at d = 188.6. The mass spectrum of
compound 39 showed a peak (M+) at m/z = 250 relating to
its molecular ion.
1H NMR (DMSO-d6): d = 2.41 (s, 3 H, CH3), 5.33 (s, 2 H, CH2),
In conclusion, palladium(II) complex 3 was found to be an
efficient and highly active precatalyst for the Suzuki–
Miyaura cross-coupling reactions of activated and deacti-
vated aryl and heteroaryl bromides, under thermal as well
as microwave conditions, resulting in very high TONs.
Complex 3 was also a highly active precatalyst when ap-
plied to the synthesis of new 5-arylbenzofuran derivatives
from 2-acetyl-5-bromobenzofuran. The high TON associ-
ated with the catalytic activity of precatalyst 3 is highly
important for mass production at an industrial scale.
7.36–7.56 (m, 7 H, ArH), 8.05–8.12 (m, 2 H, ArH).
13C NMR (DMSO-d6): d = 12.8, 77.5, 123.2, 124.1, 127.4, 127.5,
129.0, 129.3, 129.4, 135.1, 137.8, 153.3, 153.4, 165.5.
Anal. Calcd for C16H14Cl2N2OPdS: C, 41.80; H, 3.07; N, 6.09.
Found: C, 41.68; H, 3.31; N, 6.03.
Concentration Effect of Palladium Complex 3 on the Suzuki
Coupling of 1-(4-Bromophenyl)ethanone (4) with Phenylboron-
ic Acid (5a) in Water Using Thermal Heating; General Proce-
dure
A mixture of 1-(4-bromophenyl)ethanone (4) (199 mg, 1.0 mmol),
PhB(OH)2 (5a) (146 mg, 1.2 mmol), TBAB (194 mg, 0.6 mmol), Pd
complex 3 (4.59 mg, 1 mol%), KOH (112 mg, 2.0 mmol), and H2O
(3 mL) was stirred at 100 °C under open air for 1 h to give 4-acetyl-
biphenyl (6). The same experiment was repeated using different
concentrations of palladium complex 3. The amount (mol%) of pal-
ladium complex 3 was changed with respect to 1-(4-bromophe-
nyl)ethanone (4) for further experiments [0.75, 0.5, 0.25, 0.125,
0.05, 0.025, 0.0125, 0.005, and 0.001 mol% of complex 3 with 1, 1,
1, 2, 2, 5, 10, 20, and 60 mmol of 1-(4-bromophenyl)ethanone (4),
respectively]. The molar ratio of the reaction components 1-(4-bro-
mophenyl)ethanone (4)/PhB(OH)2 (5a)/KOH/TBAB was, in all
cases, 1:1.2:2:0.6. The volume of H2O varied, depending on the
amount of bromide 4 used (1–5 mmol 4: 3 mL/mmol; 10 mmol 4:
25 mL; 20 mmol 4: 40 mL; 60 mmol 4: 100 mL). The yields corre-
sponding to the use of different concentrations of palladium com-
plex 3 are outlined in Table 1.
Melting points were determined in open glass capillaries with a Gal-
lenkamp apparatus. The IR spectra were recorded using KBr disks
on a Pye Unicam SP 3-300 or a Shimadzu FTIR 8101 PC IR spec-
trophotometer. The NMR spectra were recorded with a Varian Mer-
cury VXR-300 NMR spectrometer at 300 and 75 MHz (1H and 13
C
NMR spectra, respectively) using CDCl3 and DMSO-d6 as a solvent
1
and internal standard (d = 7.27 and 77.36 ppm for the H and 13C
NMR spectra, respectively). Capillary GC analyses were performed
with a Shimadzu GC-14A or GC-14B apparatus, a Shimadzu C-
R6A integrator, and an HP 5 column (25-m length, 0.25-mm i.d.,
0.25-mm film) or were recorded with an Agilent GC 6890N appara-
tus. Mass spectra (EI) were obtained at 70 eV with a Shimadzu GC-
MQP 1000 EX spectrometer. Analytical TLC was performed using
precoated silica gel 60778 plates (Fluka), and the spots were visual-
ized with UV light at 254 nm. Fluka silica gel 60741 (70–230 mesh)
was used for flash column chromatography. Microwave experi-
ments were carried out using a CEM Discover LabMate microwave
apparatus (300 W with ChemDriver Software). 1-Benzothiazol-2-
ylethanone oxime (1),17 N,N¢-bis(4-bromobenzylidene)ethane-1,2-
diamine (33),26 1,2-bis(4-bromophenoxy)ethane (34),27 and 2-
acetyl-5-bromobenzofuran (37)28 were prepared following the liter-
ature procedures.
Base and Solvent Effects on the Suzuki Coupling of 1-(4-Bro-
mophenyl)ethanone (4) with Phenylboronic Acid (5a) under
Microwave Irradiation
A mixture of 1-(4-bromophenyl)ethanone (4) (199 mg, 1.0 mmol),
PhB(OH)2 (5a) (146 mg, 1.2 mmol), TBAB (194 mg, 0.6 mmol),
Pd(II) precatalyst 3 (1.15 mg, 0.25 mol%), KOH (112 mg, 2.0
mmol), and H2O (3 mL) was heated under microwave conditions at
160 °C and 250 W for 3 min (monitored by GC) to give 4-acetylbi-
phenyl (6). The same experiment was repeated using different sol-
vents and bases; those reactions involving toluene and THF were
conducted at 130 and 90 °C, respectively, and 250 W. The molar ra-
tio of the reaction components 1-(4-bromophenyl)ethanone (4)/
PhB(OH)2 (5a)/base/TBAB (in the case of H2O as solvent) was, in
all cases, 1:1.2:2:0.6 used with the chosen solvent (3 mL). The
yields corresponding to the use of different solvents and bases are
outlined in Table 2.
2-[1-(Benzyloxyimino)ethyl]benzothiazole (2)
To a solution of 1-benzothiazol-2-ylethanone oxime (1) (1.92 g, 10
mmol) in abs EtOH (30 mL) was added KOH (0.79 g, 14 mmol),
followed by BnCl (1.77 g, 14 mmol) to the resulting mixture. The
mixture was left to stir for a few min at r.t. and then was heated at
100 °C for 30 min. Then, the mixture was diluted with H2O (30 mL)
and extracted with EtOAc (3 × 20 mL). The extracts were dried
(MgSO4) and the solvent was evaporated under reduced pressure.
The solid product that formed was recrystallized (petroleum ether
60–80) to afford O-benzyloxime 2 as colorless crystals. Yield: 2.62
g (93%); mp 107–108 °C.
Suzuki Coupling of Aryl Bromides 7–16 and Chlorides 31 and
32 with Phenylboronic Acid (5a) in Water Using Thermal Heat-
ing; General Procedure
1H NMR (CDCl3): d = 2.46 (s, 3 H, CH3), 5.32 (s, 2 H, CH2), 7.34–
7.48 (m, 7 H, ArH), 7.84–8.04 (m, 2 H, ArH).
13C NMR (CDCl3): d = 12.3, 77.0, 121.9, 123.8, 126.3, 126.4, 128.5,
128.8, 128.9, 135.3, 137.3, 152.9, 153.5, 165.8.
MS (EI, 70 eV): m/z (%) = 282 (5.7) [M+], 265 (10), 135 (12.8), 91
(100), 77 (4.3).
A mixture of the selected aryl bromide 7–16 or chloride 31 or 32
(1.0 mmol) with PhB(OH)2 (5a) (146 mg, 1.2 mmol), TBAB (194
mg, 0.6 mmol), Pd complex 3 (0.25 mol%), KOH (112 mg, 2.0
mmol), and distilled H2O (3 mL) was stirred at 100 °C under open
air for the appropriate reaction time, as listed in Table 3 and
Scheme 2 (reaction was monitored by TLC). The product was then
extracted with EtOAc (3 × 20 mL). The combined organic extracts
were dried (anhyd MgSO4) and filtered, and the solvent was evapo-
rated under reduced pressure. The residue was then subjected to
separation via flash column chromatography (petroleum hexane–
Anal. Calcd for C16H14N2OS: C, 68.06; H, 5.00; N, 9.92. Found: C,
67.84; H, 4.79; N, 9.84.
{2-[1-(Benzyloxyimino)ethyl]benzothiazole-k2N,N¢}dichloro-
palladium(II) (3)
A solution of Na2PdCl4 (294 mg, 1 mmol) in MeOH (2 mL) was
added portionwise to a stirred solution of O-benzyloxime 2 (282
Synthesis 2010, No. 18, 3163–3173 © Thieme Stuttgart · New York

3170
A. F. Darweesh et al.
PAPER
EtOAc, 9:1) to give the corresponding pure cross-coupled product
17–26 (see Table 3), 6, or 23 (see Scheme 2).
3-Acetylbiphenyl (22)
Yellow oil.35
1H NMR (CDCl3): d = 2.62 (s, 3 H, COCH3), 7.37–7.39 (m, 1 H),
7.42–7.45 (m, 2 H), 7.48 (d, J = 6.6 Hz, 2 H), 7.59–7.61 (m, 1 H),
7.75 (d, J = 8.1 Hz, 1 H), 7.91 (d, J = 7.8 Hz, 1 H), 8.19 (s, 1 H).
MS (EI, 70 eV): m/z (%) = 196 (66) [M+], 181 (100), 152 (73.1), 127
(6.2), 76 (10.5).
Suzuki Coupling of Aryl Bromides 7–16 and Chlorides 31 and
32 with Phenylboronic Acid (5a) in Water under Microwave Ir-
radiation; General Procedure
The selected aryl bromide 7–16 or chloride 31 or 32 (1.0 mmol),
PhB(OH)2 (5a) (146 mg, 1.2 mmol), TBAB (194 mg, 0.6 mmol), Pd
complex 3 (0.25 mol%), KOH (112 mg, 2.0 mmol), and distilled
H2O (3 mL) were mixed in a process glass vial. The vial was capped
properly, and thereafter the mixture was heated under microwave ir-
radiation at 160 °C and 250 W for the appropriate reaction time, as
listed in Table 3 and Scheme 2. After the reaction was almost com-
plete (monitored by TLC), the mixture was extracted with EtOAc (3
× 20 mL). The combined organic extracts were dried (anhyd
MgSO4) and filtered, and the solvent was evaporated under reduced
pressure. The product was purified by flash column chromatogra-
phy as described above.
4-Nitrobiphenyl (23)
Pale-yellow powder; mp 106–108 °C (Lit.36 mp 107.5–108.5 °C).
1H NMR (CDCl3): d = 7.47–7.51 (m, 3 H), 7.63 (d, J = 7.8 Hz, 2 H),
7.75 (d, J = 8.4 Hz, 2 H), 8.31 (d, J = 8.7 Hz, 2 H).
MS (EI, 70 eV): m/z (%) = 199 (100) [M+], 169 (53.1), 141 (21.9),
127 (34.4), 115 (46.9), 101 (28.1), 76 (31.3), 63 (43.8).
2,4-Dinitrobiphenyl (24)
Yellow powder; mp 110–112 °C (Lit.37 mp 110 °C).
1H NMR (CDCl3): d = 7.33–7.36 (m, 3 H), 7.47–7.50 (m, 2 H), 7.69
(d, J = 8.4 Hz, 1 H), 8.47 (d, J = 8.4 Hz, 1 H), 8.71 (s, 1 H).
4-Acetylbiphenyl (6)
Colorless solid; mp 118–120 °C (Lit.29 mp 119–120 °C).
MS (EI, 70 eV): m/z (%) = 244 (17.9) [M+], 216 (20.5), 169 (20.5),
151 (53.8), 115 (53.8), 102 (46.2), 87 (38.5), 63 (87.2), 50 (100).
1H NMR (CDCl3): d = 2.60 (s, 3 H, COCH3), 7.31–7.38 (m, 1 H),
7.42–7.50 (m, 2 H), 7.74 (d, J = 6.9 Hz, 2 H), 7.82 (d, J = 7.5 Hz, 2
H), 8.03 (d, J = 7.5 Hz, 2 H).
1-Phenylnaphthalene (25)
MS (EI, 70 eV): m/z (%) = 196 (49.3) [M+], 181 (100), 152 (61.4),
127 (5.2), 76 (9).
Colorless oil.38
1H NMR (CDCl3): d = 7.65–7.76 (m, 9 H), 8.08 (d, J = 7.8 Hz, 1 H),
8.13 (d, J = 7.8 Hz, 1 H), 8.25 (d, J = 8.1 Hz, 1 H).
MS (EI, 70 eV): m/z (%) = 204 (100) [M+], 189 (10.1), 176 (12.3),
Biphenyl (17)
Colorless powder; mp 68–70 °C (Lit.30 mp 68–70 °C).
1H NMR (CDCl3): d = 7.38–7.40 (m, 2 H), 7.45–7.56 (m, 4 H), 7.67
(d, J = 8.1 Hz, 4 H).
163 (6.7), 150 (8.1), 101 (42.0), 88 (10.5).
4-Benzoylbiphenyl (26)
MS (EI, 70 eV): m/z (%) = 154 (36.8) [M+], 77 (100), 50 (42.1).
Yellow crystals; mp 100–102°C (Lit.39 mp 101–102 °C).
1H NMR (CDCl3): d = 7.41–7.56 (m, 5 H), 7.59 (d, J = 7.8 Hz, 2 H),
7.67–7.71 (m, 1 H), 7.77 (d, J = 8.1 Hz, 2 H), 7.83 (d, J = 8.7 Hz, 2
H), 7.87 (d, J = 8.7 Hz, 2 H).
MS (EI, 70 eV): m/z (%) = 258 (73.5) [M+], 181 (100), 152 (51.3),
105 (21.0), 77 (28.0).
4-Methoxybiphenyl (18)
Pale-yellow powder; mp 87–88 °C (Lit.31 mp 87–88 °C).
1H NMR (CDCl3): d = 3.87 (s, 3 H, OCH3), 6.99 (d, J = 8.7 Hz, 2
H), 7.31–7.45 (m, 3 H), 7.54 (d, J = 9.0 Hz, 2 H), 7.57 (d, J = 7.2
Hz, 2 H).
MS (EI, 70 eV): m/z (%) = 184 (100) [M+], 169 (54.0), 141 (37.4),
115 (16.6), 89 (12.5), 76 (49.8), 63 (25.7).
Suzuki Coupling of Bromopyridin-2-amines 27 and 28 with
Phenylboronic Acid (5a) in Water Using Thermal Heating;
General Procedure
4-Ethoxybiphenyl (19)
A mixture of bromopyridin-2-amine 27 or 28 (1.0 mmol),
PhB(OH)2 (5a) (146 mg, 1.2 mmol), TBAB (194 mg, 0.6 mmol), Pd
complex 3 (0.25 mol%), KOH (112 mg, 2.0 mmol), and distilled
H2O (3 mL) was stirred at 100 °C under open air for the appropriate
reaction time, as listed in Table 4 (reaction was monitored by TLC).
The product was then extracted with EtOAc (3 × 20 mL). The com-
bined organic extracts were dried (anhyd MgSO4) and filtered, and
the solvent was evaporated under reduced pressure. The residue was
then subjected to separation via flash column chromatography (hex-
ane–EtOAc, 9:1) to give the corresponding pure cross-coupled
product 29 or 30.
Colorless powder; mp 72–74°C (Lit.32 mp 76 °C).
1H NMR (CDCl3): d = 1.46 (t, J = 6.9 Hz, 3 H), 4.10 (q, J = 6.9 Hz,
2 H), 6.98 (d, J = 9.0 Hz, 2 H), 7.30–7.34 (m, 1 H), 7.40–7.45 (m, 2
H), 7.53 (d, J = 8.7 Hz, 2 H), 7.56 (d, J = 7.5 Hz, 2 H).
MS (EI, 70 eV): m/z (%) = 198 (56.7) [M+], 170 (100), 141 (38.0),
115 (48.7), 50 (16.0).
4-Hydroxybiphenyl (20)
Colorless solid; mp 164–166 °C (Lit.33 mp 164–165 °C).
1H NMR (CDCl3): d = 5.05 (s, 1 H, OH), 6.92 (d, J = 7.8 Hz, 2 H),
7.30–7.38 (m, 1 H), 7.40–7.45 (m, 2 H), 7.49 (d, J = 8.1 Hz, 2 H),
7.56 (d, J = 8.4 Hz, 2 H).
Suzuki Coupling of Bromopyridin-2-amines 27 and 28 with
Phenylboronic Acid (5a) in Water under Microwave Irradia-
tion; General Procedure
MS (EI, 70 eV): m/z (%) = 170 (100) [M+], 141 (32.3), 115 (20.0),
63 (10.3), 51 (12.9).
Bromopyridin-2-amine 27 or 28 (1.0 mmol), PhB(OH)2 (5a) (146
mg, 1.2 mmol), TBAB (194 mg, 0.6 mmol), Pd complex 3 (0.25
mol%), KOH (112 mg, 2.0 mmol), and distilled H2O (3 mL) were
mixed in a process glass vial. The vial was capped properly, and
thereafter the mixture was heated under microwave irradiation at
160 °C and 250 W for the appropriate reaction time, as listed in
Table 4. After the reaction was almost complete (monitored by
TLC), the mixture was extracted with EtOAc (3 × 20 mL). The com-
4-Chlorobiphenyl (21)
Colorless powder; mp 76–78 °C (Lit.34 mp 76–78 °C).
1H NMR (CDCl3): d = 7.37–7.48 (m, 3 H), 7.53 (d, J = 8.4 Hz, 2 H),
7.56 (d, J = 7.5 Hz, 2 H), 8.27 (d, J = 7.2 Hz, 2 H).
MS (EI, 70 eV): m/z (%) = 189 (31.6) [M+ + 1], 188 (57.9) [M+],
104 (63.2), 62 (100).
Synthesis 2010, No. 18, 3163–3173 © Thieme Stuttgart · New York

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Biaryls and 2-Acetyl-5-arylbenzofurans via Suzuki Coupling in Water
3171
bined organic extracts were dried (anhyd MgSO4) and filtered, and
the solvent was evaporated under reduced pressure. The product
was purified by flash column chromatography as described above.
Base and Solvent Effects on the Suzuki Coupling of 2-Acetyl-5-
bromobenzofuran (37) with Phenylboronic Acid Using Thermal
Heating
A mixture of 2-acetyl-5-bromobenzofuran (37) (239 mg, 1.0
mmol), PhB(OH)2 (5a) (146 mg, 1.2 mmol), TBAB (194 mg, 0.6
mmol), Pd(II) precatalyst 3 (1.15 mg, 0.25 mol%), KOH (112 mg,
2.0 mmol), and H2O (3 mL) was stirred at 100 °C under open air for
2 h (monitored by GC) to give 2-acetyl-5-phenylbenzofuran (38).
The same experiment was repeated using different solvents and
bases; those reactions involving other solvents were conducted at
110 °C (toluene) and 160 °C (DMSO). The molar ratio of the reac-
tion components bromobenzofuran 37/PhB(OH)2 (5a)/base/TBAB
(for those cases specified in Table 6) was, in all cases, 1:1.2:2:0.6
used with the chosen solvent (3 mL). The yields corresponding to
the use of different solvents and bases are outlined in Table 6.
6-Phenylpyridin-2-amine (29)
Yellow powder; mp 70–72 °C (Lit.40 mp 71–72 °C).
1H NMR (CDCl3): d = 5.07 (s, 2 H, NH2), 6.45 (d, J = 8.4 Hz, 1 H,
H-3 py), 7.05 (d, J = 7.5 Hz, 1 H, H-5 py), 7.39–7.50 (m, 4 H), 7.92
(d, J = 7.2 Hz, 2 H).
MS (EI, 70 eV): m/z (%) = 170 (100) [M+], 143 (11.2), 135 (1.9),
115 (1.9), 77 (3.7).
5-Phenylpyridin-2-amine (30)
Pale-yellow crystals; mp 130–132 °C (Lit.41 mp 132 °C).
1H NMR (CDCl3): d = 6.01 (s, 2 H, NH2), 6.52 (d, J = 8.4 Hz, 1 H,
H-3 py), 7.22–7.28 (m, 1 H), 7.37–7.46 (m, 2 H), 7.55 (d, J = 8.1
Hz, 2 H), 7.68 (d, J = 8.7 Hz, 1 H, H-4 py), 8.18 (d, J = 2.7 Hz, 1 H,
H-6 py).
Suzuki Coupling of 2-Acetyl-5-bromobenzofuran (37) with
Arylboronic Acids 5a–f in Water under Microwave Irradiation;
General Procedure
2-Acetyl-5-bromobenzofuran (37) (239 mg, 1.0 mmol), ArB(OH)2
(1.2 mmol), TBAB (194 mg, 0.6 mmol), Pd complex 3 (1.14 mg,
0.25 mol%), KOH (112 mg, 2.0 mmol), and H2O (3 mL) were
mixed in a process vial. The vial was capped properly, and thereaf-
ter the mixture was heated under microwave irradiation at 160 °C
and 250 W for the appropriate reaction time, as listed in Table 7. Af-
ter the reaction was almost complete (monitored by TLC), the mix-
ture was extracted with EtOAc (3 × 20 mL). The combined organic
extracts were dried (anhyd MgSO4) and filtered, and the solvent was
evaporated under reduced pressure. The residues in each reaction
were purified by flash column chromatography (hexane–EtOAc,
7:1) to give the corresponding pure products 38–43.
MS (EI, 70 eV): m/z (%) = 170 (100) [M+], 143 (29.5), 115 (70.5),
91 (33.3), 71 (28.2), 51 (30.8).
Suzuki Coupling of Dibromides 33 and 34 with Phenylboronic
Acid (5a) Using Thermal Heating; General Procedure
A mixture of dibromide 33 or 34 (1.0 mmol), PhB(OH)2 (5a) (292
mg, 2.4 mmol), Pd complex 3 (0.25 mol%), KOH (224 mg, 4.0
mmol), and toluene (4 mL) was stirred at 110 °C under open air for
4 h (reaction was monitored by TLC). The product was then extract-
ed with EtOAc (3 × 20 mL). The combined organic extracts were
dried (anhyd MgSO4) and filtered, and the solvent was evaporated
under reduced pressure. The residue was then subjected to separa-
tion via flash column chromatography (petroleum hexane–EtOAc,
7:1) to give the corresponding pure cross-coupled product 35 or 36.
2-Acetyl-5-phenylbenzofuran (38)
Yellow powder; mp 114–116 °C; Rf = 0.23 (hexane–EtOAc, 10:1).
IR (KBr): 3090, 2056, 1676, 1299, 1150 cm–1.
Suzuki Coupling of Dibromides 33 and 34 with Phenylboronic
Acid under Microwave Irradiation; General Procedure
Dibromide 33 or 34 (1.0 mmol), PhB(OH)2 (5a) (292 mg, 2.4
mmol), Pd complex 3 (0.25 mol%), KOH (224 mg, 4 mmol), and
toluene (4 mL) were mixed in a process glass vial. The vial was
capped properly, and thereafter the mixture was heated under mi-
crowave irradiation at 130 °C and 250 W for 10 min. After the re-
action was almost complete (monitored by TLC), the mixture was
extracted with EtOAc (3 × 20 mL). The combined organic extracts
were dried (anhyd MgSO4) and filtered, and the solvent was evapo-
rated under reduced pressure. The product was purified by flash col-
umn chromatography as described above.
1H NMR (CDCl3): d = 2.64 (s, 3 H, COCH3), 7.35–7.41 (m, 1 H),
7.45–7.50 (m, 2 H), 7.55 (s, 1 H), 7.61 (d, J = 8.1 Hz, 2 H), 7.64 (d,
J = 8.4 Hz, 1 H), 7.72 (d, J = 8.7 Hz, 1 H), 7.89 (s, 1 H).
13C NMR (CDCl3): d = 26.4, 112.6, 113.1, 121.4, 127.3, 127.4,
127.5, 128.1, 128.8, 137.6, 140.8, 153.2, 155.2, 188.6.
MS (EI, 70 eV): m/z (%) = 236 (94.9) [M+], 221 (100), 165 (69.6),
139 (11.7), 115 (10.4), 63 (5.3).
Anal. Calcd for C16H12O2: C, 81.34; H, 5.12. Found: C, 81.23; H,
5.12.
2-Acetyl-5-(4-tolyl)benzofuran (39)
Yellow powder; mp 92–94 °C; Rf = 0.53 (hexane–EtOAc, 7:1).
IR (KBr): 3029, 2918, 1678, 1549, 1299, 1156 cm–1.
1H NMR (CDCl3): d = 2.42 (s, 3 H, CH3), 2.64 (s, 3 H, COCH3),
7.28 (d, J = 7.8 Hz, 2 H), 7.51 (d, J = 8.1 Hz, 2 H), 7.54 (s, 1 H),
7.63 (d, J = 8.7 Hz, 1 H), 7.70 (d, J = 8.7 Hz, 1 H), 7.87 (s, 1 H).
13C NMR (CDCl3): d = 21.0, 26.4, 112.5, 113.2, 121.1, 127.2, 127.5,
128.0, 129.5, 137.1, 137.6, 137.9, 153.1, 155.1, 188.6.
N,N¢-Bis(biphenyl-4-ylmethylene)ethane-1,2-diamine (35)
Yellow powder; mp 136–138 °C.
IR (KBr): 2912, 2848, 1641, 1583, 1480 cm–1.
1H NMR (CDCl3): d = 3.86 (s, 4 H), 7.31–7.50 (m, 6 H), 7.64 (d,
J = 7.2 Hz, 4 H), 7.71 (d, J = 7.8 Hz, 4 H), 7.78 (d, J = 7.8 Hz, 4 H),
8.32 (s, 2 H).
13C NMR (CDCl3): d = 61.5, 127.1, 128.5, 128.8, 129.4, 131.8,
134.9, 140.3, 143.4, 161.4.
MS (EI, 70 eV): m/z (%) = 250 (100) [M+], 235 (80.4), 179 (63.8),
152 (13.6), 63 (13).
GC/MS (EI): m/z = 388 [M+].
Anal. Calcd. for C28H24N2: C, 86.56; H, 6.23; N, 7.21. Found: C,
86.64; H, 6.17; N, 7.11.
Anal. Calcd for C17H14O2: C, 81.58; H, 5.64. Found: C, 81.52; H,
5.56.
1,2-Bis(biphenyl-4-yloxy)ethane (36)
2-Acetyl-5-(4-methoxyphenyl)benzofuran (40)
Yellow powder; mp 110–112 °C; Rf = 0.25 (hexane–EtOAc, 7:1).
IR (KBr): 3125, 2958, 1685, 1560, 1516, 1272, 1236 cm–1.
Yellow powder; mp 216–218 °C (Lit.42 mp 219 °C).
1H NMR (CDCl3): d = 4.29 (s, 4 H), 6.96 (d, J = 7.8 Hz, 4 H), 7.32–
7.47 (m, 6 H), 7.61 (d, J = 8.7 Hz, 4 H), 7.77 (d, J = 7.8 Hz, 4 H).
GC/MS (EI): m/z = 366 [M+].
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1H NMR (CDCl3): d = 2.57 (s, 3 H, COCH3), 3.81 (s, 3 H, OCH3),
7.04 (d, J = 9.0 Hz, 2 H), 7.62 (d, J = 9.0 Hz, 2 H), 7.64 (s, 1 H),
7.72 (d, J = 7.5 Hz, 1 H), 7.76 (d, J = 7.5 Hz, 1 H), 7.98 (s, 1 H).
13C NMR (CDCl3): d = 26.4, 55.3, 112.5, 113.1, 114.2, 120.8, 127.5,
127.8, 128.3, 133.3, 137.3, 153.1, 154.9, 159.1, 188.5.
MS (EI, 70 eV): m/z (%) = 266 (100) [M+], 251 (66.2), 223 (27.7),
195 (17.9), 152 (21.1).
References
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Anal. Calcd for C17H14O3: C, 76.68; H, 5.30. Found: C, 76.62; H,
5.34.
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2-Acetyl-5-(4-chlorophenyl)benzofuran (41)
Yellow powder; mp 106–108 °C; Rf = 0.4 (hexane–EtOAc, 7:1).
IR (KBr): 3133, 2920, 1676, 1554, 1156 cm–1.
1H NMR (CDCl3): d = 2.64 (s, 3 H, COCH3), 7.43 (d, J = 8.7 Hz, 2
H), 7.53 (d, J = 8.7 Hz, 2 H), 7.54 (s, 1 H), 7.64 (d, J = 8.1 Hz, 1 H),
7.67 (d, J = 8.1 Hz, 1 H), 7.85 (s, 1 H).
13C NMR (CDCl3): d = 26.5, 112.7, 112.9, 121.4, 127.6, 127.8,
128.6, 129.0, 133.5, 136.4, 139.2, 153.3, 155.2, 188.6.
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MS (EI, 70 eV): m/z (%) = 272 (32) [M+ + 2], 271 (15) [M+ + 1],
270 (100) [M+], 255 (89.6), 199 (47.5), 163 (23.2), 63 (12.9).
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4.25.
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2-Acetyl-5-(3-thienyl)benzofuran (43)
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63 (11).
Anal. Calcd for C14H10O2S: C, 69.40; H, 4.16; S, 13.23. Found: C,
69.33; H, 4.28; S, 13.14.
Acknowledgment
K.M.D. and his student A.F.D. are very thankful to the Alexander
von Humboldt Foundation (AvH) for granting them fellowships du-
ring July to September 2008 at TU Dresden. K.M.D. is also deeply
indebted to the AvH for donating him a CEM Discover LabMate
microwave apparatus.
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