One-pot preparation of unsymmetrical biaryls via Suzuki cross-coupling reaction of aryl halide using phase-transfer catalyst in a biphasic solvent system

Article abstract of DOI:10.1080/00397910601130983

A one-pot synthetic method of unsymmetrical biaryls was developed via the Suzuki cross-coupling reaction of aryl halide using a phase-transfer catalyst in a biphasic solvent system. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910601130983

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One‐Pot Preparation of Unsymmetrical Biaryls
via Suzuki Cross‐Coupling Reaction of Aryl
Halide using Phase‐Transfer Catalyst in a
Biphasic Solvent System
Masanori Miura a , Takanori Koike a , Tsukasa Ishihara a , Shuichi Sakamoto a
,
Minoru Okada a , Mitsuaki Ohta a & Shin‐ichi Tsukamoto a
a Institute for Drug Discovery Research, Astellas Pharma Inc. , Ibaraki, Japan
Published online: 09 Mar 2007.
To cite this article: Masanori Miura , Takanori Koike , Tsukasa Ishihara , Shuichi Sakamoto , Minoru Okada ,
Mitsuaki Ohta & Shin‐ichi Tsukamoto (2007) One‐Pot Preparation of Unsymmetrical Biaryls via Suzuki
Cross‐Coupling Reaction of Aryl Halide using Phase‐Transfer Catalyst in a Biphasic Solvent System, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:5,
667-674, DOI: 10.1080/00397910601130983
To link to this article: http://dx.doi.org/10.1080/00397910601130983
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Synthetic Communicationsw, 37: 667–674, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601130983
One-Pot Preparation of Unsymmetrical
Biaryls via Suzuki Cross-Coupling Reaction
of Aryl Halide using Phase-Transfer
Catalyst in a Biphasic Solvent System
Masanori Miura, Takanori Koike, Tsukasa Ishihara,
Shuichi Sakamoto, Minoru Okada, Mitsuaki Ohta,
and Shin-ichi Tsukamoto
Institute for Drug Discovery Research, Astellas Pharma Inc.,
Ibaraki, Japan
Abstract: A one-pot synthetic method of unsymmetrical biaryls was developed via the
Suzuki cross-coupling reaction of aryl halide using a phase-transfer catalyst in a
biphasic solvent system.
Keywords: biphasic solvent, one-pot reaction, phase-transfer catalyst, Suzuki coupling
reaction, tetra(alkoxo)diboron, unsymmetrical biaryls
The one-pot Suzuki cross-coupling reaction is one of the easiest and most
efficient methods for the synthesis of unsymmetrical biaryls; however, most
methods require air- and moisture-sensitive reagents such as lithium
reagents[1a–e] and dialkoxyborane[2a,b] for the preparation of the boronated
intermediate.
On the other hand, a method based on the cross-coupling reaction of
aryl halides or triflates with commercially available bis(pinacolato)diboron
1 in the presence of a palladium catalyst[3] overcomes these drawbacks
Received May 16, 2006
Address correspondence to Masanori Miura, Institute for Drug Discovery Research,
Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. E-mail:
masanori-miura@jp.astellas.com
667

668
M. Miura et al.
because of the thermal stability and insensitivity to air and moisture of bis(pi-
nacolato)diboron 1. As in the case of aryl halide, only one method has been
reported, by Giroux and coworkers, in which they describe the one-pot unsym-
metrical biaryl synthesis using bis(pinacolato)diboron 1 in DMF.[3a] Though
their procedure is applicable to several aryl halides, some unsymmetrical
biaryls that have electron-withdrawing substituents or heterocyclic rings are
not obtained in good yield. Moreover, their method requires 2 equivalents
of aryl halide for the second coupling reaction compared to the starting aryl
halide for the first borylation reaction.
Recently, we reported the one-pot synthetic procedure for 2,20-disubsti-
tuted biaryls via the Suzuki cross-coupling reaction of aryl triflates in a
biphasic solvent system.[4] Results showed that the toluene/H2O biphasic
solvent system was effective in the second coupling reaction in achieving
high yields. On this basis, we attempted to apply our biphasic solvent
system to aryl halides to the synthesis of unsymmetrical biaryls. That is, the
cross-coupling reaction of the aryl halide A with bis(pinacolato)diboron 1 in
toluene is followed by the next reaction with another aryl halide B in
toluene/H2O without isolation of the aryl boronate 2 (Scheme 1). (In our pre-
liminary work, the yield of the cross-coupling reaction of aryl triflate was
barely affected by the use of palladium catalysts such as PdCl2(PPh3)2
PdCl2(dppf), so we selected PdCl2(PPh3)2 with regard to cost. In our prelimi-
nary work, the yield substantially decreased without addition of another
palladium catalyst for the second cross-coupling reaction.)
We employed various aryl halides for the one-pot biaryl synthesis (Table 1).
A strong influence of the substituents was observed. For example, cross-coupling
of electron-withdrawing aryl bromides (3 and 4) gave good yields in the corre-
sponding biaryl products (run 1). On the other hand, yields were reduced when
the aryl bromides such as 4-bromotoluene 5 or 1-bromo-4-methoxybenzene 6
were employed for the cross-coupling reaction (runs 3 and 4). The sterically
demanding aryl bromide 8 reacted more slowly to result in a reduced yield for
the corresponding product (run 7). In this case, with corresponding aryl iodide
9, the desired biaryl was obtained in 54% yield (run 8).
As previously observed for the Suzuki coupling reaction, the use of a
phase-transfer catalyst as promoter increases the reaction rate.[5] On this
Scheme 1.

One-Pot Preparation of Unsymmetrical Biaryls
669
Table 1. Effect of a phase-transfer catalyst in a biphasic solvent system on the one-
pot cross-coupling reactions of various aryl halides
Yield (%)
Run
1
A
B
None
Bu4NHSO4
71
72 (43)a
2
(50)a
70
3
4
48
11
73
48b
5
6
7
8
NT
53b
49b
85
NT
6 (38)c
54
NT
9
NT
51
(continued)

670
M. Miura et al.
Table 1. Continued
Yield (%)
Run
10
A
B
None
NT
Bu4NHSO4
38
11
12
NT
56
77
(40)a
Notes: Yield of isolated product based on the halides used for the second coupling
reaction.
aYields reported by Giroux and coworkers are shown in parentheses.
bYields obtained by the PdCl2(dppf)/dppf system instead of PdCl2(PPh3)2/PPh3.
cYields obtained by us using the Giroux method.
basis, 10 mol% of Bu4NHSO4 was tested in the cross-coupling of various aryl
halides, as summarized in Table 1.
With this improved method, the phase-transfer catalyst system efficiently
promotes the cross-coupling of electronic variation in the aryl halides. (Other
phase-transfer catalysts such as Bu4NBr and CH3(CH2)11SO3Na also
promoted the cross-coupling reaction.) For example, when aryl bromide had
electron-withdrawing substituents such as CHO and Cl groups, the cross-
coupling reaction proceeded smoothly, and the corresponding biaryl was
isolated in good yield (runs 1 and 2). The 4-bromotoluene 5 and aryl
bromide 3 also gave the corresponding biaryls in 73% yield (run 3). On the
other hand, when the aryl bromide B for the second cross-coupling reaction
had an electron-donating substitutent such as a MeO group, cross-coupling
of aryl bromide 3 with 6 occurred in only 33% yield. In this case a substantial
amount of by-product, biphenyl-4-carbaldehyde, was isolated. This product
was formed by the reaction between a phenyl group from triphenylphosphine
with the corresponding aryl bromide 3.[6] To suppress this unwanted side
reaction, we employed a PdCl2(dppf)/dppf system instead of PdCl2(PPh3)2/
PPh3 for the coupling of 3 with 6 and obtained the corresponding biaryl in
48% yield (run 4). (In the case of the cross-coupling of 5 with 3 (Table 1,
run 3), a difference in yield was scarcely shown through the use of

One-Pot Preparation of Unsymmetrical Biaryls
671
palladium–ligand system such as PdCl2(PPh3)2/PPh3 and PdCl2(dppf)/dppf).
The reaction also tolerates the cross-coupling of 3 with aryl iodide 7 and 4--
bromotoluene 5 with 6 (runs 5 and 6). This phase-transfer catalyst efficiently
promotes the cross-coupling of sterically demanding substrates. Thus, it is
noteworthy that the yield of the cross-coupling reaction of 3 with 8 is remark-
ably increased from 6% to 85% by the addition of a phase-transfer catalyst (run
7). (No coupled product was isolated when the reaction was done in the reverse
order. That is, 2-bromo-1,3-dimethylbenzene 8 was employed for the first
borylation reaction and 4-bromobenzaldehyde 3 was employed for the second
cross-coupling reaction.) Other sterically demanding aryl bromides also
coupled with 3 in moderate yields (runs 9–11).[7] Heteroaromatic bromides
(13 and 14) were cross-coupled without difficulty (run 10). Compared to the
Giroux method, our biphasic phase-transfer catalyst system provides efficient
synthesis of biaryls that have electron-withdrawing substituents, sterically
demanding substituents, and heterocyclic rings (runs 1, 2, 7, and 12).
In conclusion, these results demonstrate that for a wide range of aryl
halides the Suzuki coupling can be readily promoted by use of a phase-
transfer catalyst in a biphasic solvent system. In particular, this procedure is
efficient for the cross-coupling of aryl halides with electron-withdrawing sub-
stituents and sterically demanding substituents. This procedure also allows
cross-coupling between heteroaromatic bromides without difficulty.
GENERAL PROCEDURE
Melting points were determined on a Yanaco micromelting apparatus or Bu¨chi
melting-point apparatus B-545 and are uncorrected. Proton magnetic resonance
(1H NMR) spectra were obtained in CDCl3 or dimethylsulfoxide-d6 (DMSO-d6)
using a Jeol JNM-EX400, JNM-GX500, or JNM-A500 spectrometer. Chemical
shifts are recorded in parts per million (d), downfield relative to tetramethylsi-
lane as the internal standard. Mass spectra (MS) were recorded on a Jeol JMS-
DX300 or a Hitachi M-80 mass spectrometer. Elemental analysis was carried
out on a Yanaco MT-3 or MT-5 CHN analyzer and a Yokogawa IC7000S
ion chromatoanalyzer. Chromatographic separations were performed using a
silica-gel column (Merck Kieselgel 60).
General Procedure for the One-Pot Suzuki Coupling Reaction
of Aryl Halides using Phase-Transfer Catalyst in a Biphasic
Solvent System
To a stirred solution of the halide A (1.1 mmol), bis(pinacolato)diboron
(1.2 mmol), PPh3 (0.06 mmol) and PdCl2(PPh3)2 (0.03 mmol) in toluene
(10 ml), AcOK (1.5 mmol) was added at room temperature under an argon
atmosphere. The mixture was refluxed overnight, and then the halide B

672
M. Miura et al.
(1.0 mmol), Pd(PPh3)4 (0.03 mmol), Bu4NHSO4 (0.1 mmol), and 2 mol dm23
aq. Na2CO3 (4 ml) were added to the reaction mixture. The solution was
refluxed overnight. The mixture was extracted with AcOEt, and the organic
layer was dried over MgSO4, filtered, and concentrated in vacuo. The
residue was purified by silica-gel column chromatography (hexane/AcOEt)
to give the target biaryl.
Data
40-Chlorobiphenyl-4-carbaldehyde (runs 1 and 2): colorless crystals: mp
1
114–1158C (AcOEt–hexane) (lit.[3a] mp 113–1148C); H NMR (300 MHz,
DMSO-d6) d: 7.58 (2H, d, J ¼ 8.4 Hz), 7.82 (2H, d, J ¼ 8.4 Hz), 7.92 (2H,
d, J ¼ 8.2 Hz), 8.01 (2H, d, J ¼ 8.2 Hz), 10.06 (1H, s); FAB-MS (m/z):
217 (M þ H)þ; anal. calcd. for C13H9ClO: C, 72.07; H, 4.19; Cl, 16.36.
Found: C, 71.87; H, 4.29; Cl, 16.49.
40-Methylbiphenyl-4-carbaldehyde (run 3): colorless crystals: mp 105–
1
1078C (AcOEt–hexane) (lit.[8] mp 1078C); H NMR (300 MHz, DMSO-d6)
d: 2.38 (3H, s), 7.33 (2H, d, J ¼ 8.3 Hz), 7.68 (2H, d, J ¼ 8.3 Hz), 7.89
(2H, d, J ¼ 8.3 Hz), 7.98 (2H, d, J ¼ 8.3 Hz), 10.04 (1H, s); FAB-MS (m/z):
197 (M þ H)þ; anal. calcd. for C14H12O: C, 85.68; H, 6.16. Found: C, 85.48;
H, 6.15.
40-Methoxybiphenyl-4-carbaldehyde (runs 4 and 5): colorless crystals: mp
103–1048C (AcOEt–hexane) (lit.[9] mp 104–1058C); colorless solid: 1H
NMR (300 MHz, DMSO-d6) d: 3.82 (3H, s), 7.08 (2H, d, J ¼ 8.5 Hz), 7.75
(2H, d, J ¼ 8.5 Hz), 7.87 (2H, d, J ¼ 8.5 Hz), 7.96 (2H, d, J ¼ 8.5 Hz),
10.03 (1H, s); FAB-MS (m/z): 213 (M þ H)þ; anal. calcd. for C14H12O2:
C, 79.22; H, 5.70. Found: C, 79.16; H, 5.71.
4-Methoxy-40-methylbiphenyl (run 6): colorless crystals: mp 109–1108C
1
(AcOEt–hexane) (lit.[10] mp 109–1108C); H NMR (400 MHz, CDCl3) d:
2.38 (3H, s), 3.84 (3H, s), 6.96 (2H, d, J ¼ 9.1 Hz), 7.22 (2H, d,
J ¼ 8.1 Hz), 7.45 (2H, d, J ¼ 8.1 Hz), 7.51 (2H, d, J ¼ 9.1 Hz); EI-MS (m/z):
198 (M)þ.
20,60-Dimethylbiphenyl-4-carbaldehyde (runs 7 and 8): colorless crystals:
mp 66–678C (AcOEt–hexane); 1H NMR (300 MHz, DMSO-d6) d: 1.97
(6H, s), 7.12–7.24 (3H, m), 7.40 (2H, d, J ¼ 8.1 Hz), 8.00 (2H, d,
J ¼ 8.1 Hz), 10.07 (1H, s); EI-MS (m/z): 210 (M)þ; anal. calcd. for
C15H14O: C, 85.68; H, 6.71. Found: C, 85.60; H, 6.70.
20,60-Diethylbiphenyl-4-carbaldehyde (run 9): colorless crystals: mp 36–
388C (AcOEt–hexane); 1H NMR (400 MHz, CDCl3) d: 1.01 (3H, t,

One-Pot Preparation of Unsymmetrical Biaryls
673
J ¼ 7.3 Hz), 2.30 (2H, q, J ¼ 7.3 Hz), 7.16 (2H, q, J ¼ 7.3 Hz), 7.28–7.66
(1H, m), 7.37 (2H, d, J ¼ 8.3 Hz), 7.94 (2H, d, J ¼ 8.1 Hz), 10.08 (1H, s);
EI-MS (m/z): 238 (M)þ.
20,40,60-Triisopropylbiphenyl-4-carbaldehyde (run 10): colorless crystals:
mp 152–1558C (AcOEt–hexane); 1H NMR (300 MHz, CDCl3) d: 1.08
(12H, d, J ¼ 6.9 Hz), 1.31 (6H, d, J ¼ 7.0 Hz), 2.43–2.58 (2H, m), 2.89–
3.02 (1H, m), 7.07 (2H, s), 7.37 (2H, d, J ¼ 8.2 Hz), 7.93 (2H, d,
J ¼ 8.2 Hz), 10.08 (1H, s); FAB-MS (m/z): 309 (M þ H)þ; anal. calcd. for
C22H28O: C, 85.66; H, 9.15. Found: C, 85.56; H, 9.19.
20-Isopropylbiphenyl-4-carbaldehyde (run 11): colorless crystals: mp 172–
1
1748C (benzene); H NMR (300 MHz, CDCl3) d: 1.17 (6H, d, J ¼ 6.9 Hz),
2.91–3.06 (1H, m), 2.89–3.02 (1H, m), 7.14–7.18 (1H, m), 7.21–7.25
(1H, m), 7.35–7.43 (2H, m), 7.47 (2H, d, J ¼ 8.2 Hz), 7.93 (2H, d,
J ¼ 8.2 Hz), 10.08 (1H, s); EI-MS (m/z): 224 (M)þ.
3-(3-Thienyl)quinoline (run 12): colorless crystals: mp 86–878C (AcOEt–
1
hexane) (lit.[3a] mp 88–898C); H NMR (400 MHz, CDCl3) d: 7.50 (1H, dd,
J ¼ 2.9 Hz, 4.9 Hz), 7.53–7.59 (2H, m), 7.66–7.68 (1H, m), 7.68–7.73
(1H, m), 7.86 (1H, d, J ¼ 8.1 Hz), 8.12 (1H, d, J ¼ 8.1 Hz), 8.29 (1H, d,
J ¼ 2.2 Hz), 9.21 (1H, d, J ¼ 2.2 Hz); EI-MS (m/z): 211 (M)þ; anal. calcd.
for C13H9NS: C, 73.90; H, 4.29; N, 6.63; S, 15.18. Found: C, 73.88; H,
4.33; N, 6.53; S, 15.09.
ACKNOWLEDGMENTS
The authors acknowledge Yuji Koga for his many helpful discussions during
the preparation of this manuscript. We are also grateful to the staff of the
Division of Analytical Science Laboratories of Astellas Pharma Inc. for
elemental analysis and spectral measurements.
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