Facile construction of biaryls by homocoupling of aryl halides

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Facile Construction of Biaryls by
Homocoupling of Aryl Halides
Abdol R. Hajipour a b & Fatemeh Abrishami a
a Pharmaceutical Research Laboratory, Department of Chemistry ,
Isfahan University of Technology , Isfahan , 84156 , Iran
b Department of Pharmacology , University of Wisconsin Medical
School , 1300 University Avenue, Madison , WI , 53706-1532 , USA
Published online: 16 May 2013.
To cite this article: Abdol R. Hajipour & Fatemeh Abrishami (2013): Facile Construction of Biaryls by
Homocoupling of Aryl Halides, Organic Preparations and Procedures International: The New Journal
for Organic Synthesis, 45:3, 227-231
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Organic Preparations and Procedures International, 45:227–231, 2013
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2013.786568
Facile Construction of Biaryls by
Homocoupling of Aryl Halides
Abdol R. Hajipour1,2 and Fatemeh Abrishami1
1Pharmaceutical Research Laboratory, Department of Chemistry, Isfahan
University of Technology, Isfahan 84156, Iran
2Department of Pharmacology, University of Wisconsin Medical School, 1300
University Avenue Madison, WI 53706-1532, USA
Biaryls and their heteroaromatic analogues are some of the most attractive structural units
in natural products, bioactive compounds, photonic materials, functional polymers, theo-
retically interesting molecules,1 liquid crystals,2 chiral host molecules for inclusion com-
pounds, and chirality-recognition reagents for chromatography.3 When substituted at the
ortho and orthoꢀ positions, they form atropisomers and are therefore employed as chiral
ligands for asymmetric syntheses.4 Because of their prevalent applications, the development
of straightforward and environmentally friendly methods for the construction of biaryls has
elicited much attention5 and several modern methods for the preparation of biaryls, such as
the Suzuki,6,7 Stille,8–10 Negishi,11 Kumada,12 and Hiyama13–15 reactions have been reported
involving cross-coupling between aryl halides and organometallic counterparts. However,
the preparation of the aryl metal nucleophiles is tedious, and their use in stoichiometric
amounts is time-consuming. A more convenient and easier method for the synthesis of sym-
metrical biaryls is the direct homocoupling of aryl halides, because it avoids the synthesis
of the aryl organometallic reagent.16 The uses of palladium,1,5,17 nickel,18–20 indium,21–23
copper,24 rhodium,25 and zinc26 as the catalyst to perform this reaction have been reported.
These compounds can be also synthesized using Lipshutz cuprates.27
Although, copper was for a long time practically the only metal useful for aryl–aryl
bond formation (the Ullmann reaction), its use requires both high temperature and stoichio-
metric amount; in addition, many functional groups cannot survive such drastic conditions
which place severe restrictions in the preparation of the functionalized biaryls.2 As a result,
palladium catalysts currently are much more often used than their copper or even nickel
counterparts.17 The palladium-catalyzed homocoupling of aromatic halides has been shown
to be a more convenient and straightforward route for biaryl synthesis.2 For this purpose,
homogeneous and heterogeneous palladium catalysts supported on a number of solid ma-
terials have been widely investigated.28 We now report the utilization of ortho-palladated
Received January 9, 2012; in final form December 6, 2012.
Address correspondence to Abdol R. Hajipour, Pharmaceutical Research Laboratory, Depart-
ment of Chemistry, Isfahan University of Technology, Isfahan 84156, Iran. E-mail: haji@cc.iut.ac.ir
227

228
Hajipour and Abrishami
Scheme 1
complex,29 [Pd{C6H3(CH2CH2NH2)-4-OMe-5-κ2-C,N}(μ-Br)]2, in the homocoupling of
various aryl halides (Scheme 1).
To optimize the reaction conditions, we chose the homocoupling of iodobenzene as
the test substrate. At first, different types of bases were examined using 0.5 mol% of cat-
alyst and N,N-dimethylformamide (DMF) at 130◦C. These palladium-catalyzed reductive
homocouplings require appropriate bases to neutralize the acidic products generated in the
reaction; otherwise the acidic products increase the acidity of the medium and suppress the
reactions. No reductive homocoupling product (biphenyl) was formed in the absence of
base. We found that K2CO3 is the best base for this reaction, while Cs2CO3, NaOAc, KOH,
and Na2CO3 led to 80%, 70%, 78% and 45% conversions to biphenyl, respectively. Of
the several organic solvents such as acetonitrile, toluene, methanol, tetrahydrofuran (THF),
N-methyl-2-pyrrolidone (NMP) and DMF investigated employing 0.5 mol% of the pal-
ladacycle. The best solvent was DMF; toluene and THF were not efficient in this reaction.
Although Panvela et al.30 reported that isopropanol as a reducing reagent could accelerate
the regeneration of Pd(0), it was not efficient in this reaction.
The loading of catalyst was also optimized by employing various amounts of catalyst
for the homocoupling of 4-iodoanisole, and 0.5 mol% gave the best results. The optimal
reaction conditions (aryl halide, 1 mmol; K2CO3, 1 mmol; and DMF as solvent) were then
used for homocoupling reaction of different aryl iodides, and bromides. The homocoupling
of aryl chlorides required longer times for completion (Table 1).
The effect of steric hindrance was examined by the reaction of 2-, 3-, 4-bromoanisoles
and the results shows that an increase in reaction time and a decrease in the yields (Entries
6–8) with increase in steric crowding. Coupling occurred chemoselectively at the carbon
bearing the bromine atom in the reaction with 1-bromo-4-chlorobenzene (Entry 4). All the
biaryls reported in this article have been previously described and were characterized by
comparison with the literature data.31–33 The efficiency of this palladacycle catalyst was
determined by comparison with other catalytic systems and it gave a better yield in shorter
time (Table 2). The main advantages of this catalyst are its easy preparation, handling,
stability and insensitivity to moisture.
Experimental Section
Melting points were determined in open capillaries on a Gallenkamp instrument and are
uncorrected. FT-IR spectra were obtained on a Jasco-680 spectrophotometer (Japan) as

Construction of Biaryls by Homocoupling of Aryl Halides
229
Table 1
Cross-coupling of Various Aryl Halides Catalyzed by Palladacycle 1a
Time
(h)
Yieldb
(%)
mp (◦C)
(lit. mp)
Entry
Aryl Halides
Iodobenzene
Bromobenzene
Chlorobenzene
1-Bromo-4-chlorobenzene
4-Iodoanisole
2-Bromoanisole
3-Bromoanisole
4-Bromoanisole
4-Bromobenzonitrile
1-Iodo-3-nitrobenzene
1-Iodo-4-nitrobenzene
1-Bromo-4-nitrobenzene
4-Bromoacetophenone
4-Chloroacetophenone
4-Bromobenzaldehyde
2-Bromopyridine
Products
Biphenyl
Biphenyl
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1.45
2.5
3.15
3
92
94
89
95
91
67
83
90
81
80
92
90
91
82
89
58
69–70 (70–71)31
69–70 (70–71)31
69–70 (70–71)31
140–142 (142–143)31
175–177 (177–178)31
155.5–156 (154–156)32
36–38 (36–37)32
175–177 (177–178)31
235–237 (235–238)31
200v201 (198–199)32
237–238 (238–239)31
237–238 (238–239)31
186–187 (188–189)31
186–187 (188–189)31
187–189 (188–191)33
69–72 (69–71)32
Biphenyl
4,4ꢀ-Dichlorobiphenyl
4,4ꢀ-Dimethoxybiphenyl
2,2ꢀ-Dimethoxybiphenyl
3,3ꢀ-Dimethoxybiphenyl
4,4ꢀ-Dimethoxybiphenyl
4,4ꢀ-Dicyanobiphenyl
3,3ꢀ-Dinitrobiphenyl
4,4ꢀ-Dinitrobiphenyl
4,4ꢀ-Dinitrobiphenyl
4,4ꢀ-Diacetylbiphenyl
4,4ꢀ-Diacetylbiphenyl
4,4ꢀ-Diformylbiphenyl
2,2ꢀ-Bipyridyl
4
19
12
7.5
7
7
3
5
10
12
14
19
aReactions were carried out with aryl halide (1 mmol), K2CO3 (1 mmol), palladacycle 1 (0.5 mol%)
in DMF (3 ml).
bYields refer to pure isolated products, properly characterized by spectral data.
KBr disks. 1H and 13C NMR spectra were recorded in CDCl3 at room temperature (TMS
as an internal standard) on a Bruker spectrometer at 500 and 125 MHz, respectively. A
BEIFIN 3420 Gas Chromatograph equipped a Varian CP SIL 5CB column-30 m, 0.32 mm,
0.25 μm was used to monitor the completion of the reactions. All reagents and solvents
were of reagent grade quality, obtained from commercial suppliers (Acros, Merck and
Aldrich) and used without further purification.
Table 2
Comparison of Various Catalysts in Biphenyl Formation
Entry
Catalyst
Solvent Temp (◦C) Time (h) Yield (%)
Ref.
a
1
2
3
4
5
6
7c
8c
9c
Pd(dppf)Cl2
DMSO
DMF
PEG4000
EtOH
120
135
120
90
115b
130
80
10
24
24
5
20
2.5
48
48
48
96
71
87
63
35.7
94
62
69
55
2
3
5
16
PdCl2(CH3CN)2
Pd(OAc)2
Pd nanoparticle
Rh/C
Water
25
This work
34
Palladacycle catalyst DMF
NbCl5
Mo(OAc)2
Co(acac)3
C6H6
C6H6
C6H6
80
100
34
34
adppf = 1,1’-bis(diphenylphosphino)ferrocene,
bThe reaction was carried out in an autoclave.
cvia C–H activation.

230
Hajipour and Abrishami
Synthesis of Palladacycle Complex
[Pd{C6H3(CH2CH2NH2)-4-OMe-5-κ2-C,N}(μ-Br)]2 as a palladacycle complex was syn-
thesized according to our previous work.28 In a 25 ml round-bottom flask equipped with
a magnetic stir bar and a condenser, a mixture of 258 mg (1.7 mmol) of 2-methoxy-
phenethylamine and 382 mg (1.7 mmol) of Pd(OAc)2 was heated in acetonitrile (20 ml) for
6 h at 55◦C. After cooling, the resulting suspension was filtered through a plug of MgSO4
and the filtrate was vaporated under reduced pressure on a rotary evaporator to give complex
2 as a yellow solid. Solid sodium bromide (165 mg, 1.6 mmol) was added to a suspension
of complex 2 (500 mg, 0.79 mmol) in acetone (30 ml) and the mixture was stirred for 8 h.
The solvent was removed and CH2Cl2 (10 ml) was added to the solid yellow residue. The
resulting suspension was filtered through a plug of MgSO4 and the filtrate was concentrated
to 2 ml under reduced pressure on a rotary evaporator. Upon addition of n-hexane (15 ml) a
yellow solid precipitated. It was collected, washed with water and n-hexane and air dried.
General Procedure
The appropriate aryl halide (1 mmol), the palladacycle complex (0.5 mol%) and K2CO3
(1 mmol) were added consecutively to DMF (3 ml) in a round-bottom flask equipped with
a condenser. The mixture was heated and stirred using magnetic stirring bar at 130◦C.
After the reaction was completed as indicated by TLC (silica-gel, n-hexane:EtOAc, 9:1),
the mixture was cooled to room temperature and diluted with water (5 ml) and n-hexane
(2 × 10 ml). The organic layer was dried over CaCl2, then filtered (by gravity) and the
filtrate was evaporated in vacuo. The solid residue was purified by recrystallization from
ethanol and water.
Acknowledgments
We gratefully acknowledge the funding support received for this project from Isfahan
University of Technology (IUT), Iran and the financial support from the Center of Excel-
lence in Sensor and Green Chemistry Research.
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