One-pot synthetic procedure for 2,2′-disubstituted biaryls via the Suzuki coupling reaction of aryl triflates in a biphasic solvent system

Article abstract of DOI:10.1080/00397910600948088

A one-pot synthetic procedure for 2,2′-disubstituted biaryls was developed via a Suzuki cross-coupling reaction of aryl triflates in a biphasic solvent system. The effects of various bases and solvents were investigated. Results showed that the Na₂

Full text of DOI:10.1080/00397910600948088

Synthetic Communicationsw, 36: 3809–3820, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600948088
One-Pot Synthetic Procedure for
2,20-Disubstituted Biaryls via the Suzuki
Coupling Reaction of Aryl Triflates in a
Biphasic Solvent System
Masanori Miura, Takanori Koike, Tsukasa Ishihara,
Fukushi Hirayama, Shuichi Sakamoto, Minoru Okada,
Mitsuaki Ohta, and Shin-ichi Tsukamoto
Institute for Drug Discovery Research, Astellas Pharma Inc.,
Tsukuba-shi, Ibaraki, Japan
Abstract: A one-pot synthetic procedure for 2,20-disubstituted biaryls was developed
via a Suzuki cross-coupling reaction of aryl triflates in a biphasic solvent system. The
effects of various bases and solvents were investigated. Results showed that the
Na2CO3–toluene/H2O combination gave the highest yields.
Keywords: Biphasic solvent, 2,20-disubstituted biaryls, one-pot reaction, Suzuki
coupling reaction, tetra(alkoxo)diboron
In our recent studies of serine protease inhibitors, we found an interesting
biaryl compound 1, which is prepared from the 2,20,4,40-tetrasubstituted
analogue 2 (Scheme 1).[1] The functionalized 2,20-disubstituted biaryls consti-
tute an important class of compounds that includes numerous pharmacologi-
cally active products and various compounds with applications in
materials.[2] Although the Suzuki cross-coupling reaction is one of the most
efficient methods for the preparation of asymmetrical biaryls,[3] the
synthesis of 2,20-disubstituted biaryls is limited. Most of the methods
require special ligands such as biphenyl-2-yl(dicyclohexyl)phosphine and
Received in Japan February 23, 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
3809

3810
M. Miura et al.
Scheme 1.
dicyclohexyl(20,60-dimethoxybiphenyl-2-yl)phosphine for the coupling
reaction[4] or have limited functional groups.[5]
Among several synthetic procedures for aryl boronic acids or esters,[6] the
most useful method is based on the cross-coupling reaction of an aryl halide or
aryl triflate with tetra(alkoxo)diboron in the presence of a palladium
catalyst.[7] This method allows the use of commercially available bis(pinaco-
lato)diboron, which is not only thermally stable but also insensitive to air and
moisture. Moreover, this method can be utilized for the one-pot preparation of
asymmetrical biaryls without the isolation of the aryl boronic esters.[8] On this
basis, we planned to develop a method for the preparation of functionalized
2,20-disubstituted biaryls by the use of bis(pinacolato)diboron.
We first tried to prepare the biaryl 2 based on a stepwise cross-coupling
reaction. We employed an aryl triflate as the coupling reagent, because
from the synthetic point of view, the use of aryl triflate had several advantages,
including the easy access from phenols. The synthesis of the starting materials
(6 and 9) is shown in Scheme 2. Dimethyl 4-hydroxyisophthalate 3 can be
converted to the monomethyl ester 4 in pyridine under reflux conditions.[9]
The monoacid 4 is protected by the tert-butyl group and converted to the cor-
responding triflate 5 by treatment with trifluoromethanesulfonic anhydride. At
the borylation step, we employed a method reported by Ishiyama and
coworkers, except for the particular palladium catalyst,[8a] and obtained the
aryl boronate 6 in 82% yield. (In our preliminary work, the yield of the aryl
boronate 6 was barely affected by use of palladium catalysts such as
Scheme 2.

2,20-Disubstituted Biaryls
3811
PdCl2(PPh3)2 and PdCl2(dppf), and so we selected PdCl2(PPh3)2 with regard
to cost.) The triflate 9 was synthesized in two steps from 2-hydroxy-5-nitro-
benzoic acid 7.
Next, the coupling reaction of the aryl boronate 6 with the triflate 9 was
examined. In this step, the yield of biaryl 2 was affected by the base and
solvent. When K3PO4 was employed as the base, biaryl 2 was obtained in
only 45% yield, whereas the yield increased remarkably to more than 80%
with weak bases such as K2CO3 and Na2CO3 in dioxane. Toluene was
found to be more suitable as a solvent than dioxane and N,N-dimethylforma-
mide (DMF). Thus, biaryl 2 was obtained in 87% yield in a reaction with
Na2CO3 as base and toluene as solvent. This result suggests that mild
reaction conditions might be suitable for the cross-coupling reaction,
because of the base sensitivity of triflates.
Encouraged by this result, we subsequently investigated the one-pot
procedure from the triflate 5 to biaryl 2 (Scheme 3). To date, only two
methods of one-pot biaryl synthesis using bis(pinacolato)diboron have been
reported.[8] Ishiyama and coworkers reported an efficient in situ cross-coupling
reaction of aryl triflates in the presence of K3PO4 for the second coupling
reaction.[8a] Giroux and coworkers described a one-pot preparation of biaryls
using DMF/H2O as a solvent.[8b] As described in Table 1, obtaining biaryl 2
in high yield requires the use of a toluene–weak base system. However,
because these prior methods used K3PO4 as a base or DMF as a solvent, we
could not utilize them for the one-pot synthesis of biaryl 2. We therefore
attempted to apply our toluene–weak base system to one-pot biaryl synthesis.
That is, after coupling between the triflate 5 and bis(pinacolato)diboron in
toluene, another triflate 9 was added in the presence of Na2CO3 without
isolation of the aryl boronate 6. It is noteworthy that the desired biaryl 2 is not
obtained in the toluene alone, but that the addition of H2O in the second cross-
coupling reaction affords biaryl 2 in 74% yield without hydrolysis of the ester
groups. The reason why addition of H2O produces a good result is not clearly
understood. The yield substantially decreased without addition of another
palladium catalyst for the second cross-coupling reaction.
Various asymmetrical biaryls were synthesized by this one-pot procedure
in a biphasic solvent system (Table 1). Cross-coupling between variously sub-
stituted aryl triflates proceeded in good yield (runs 1–7), whereas with the
Scheme 3.

3812
M. Miura et al.
Table 1. Cross-coupling reactions of various aryl triflates using the one-
pot procedure
Yield (%)
69
Run
A
B
1
2
79
3
4
5
72
79
88 (37)[8a] (0)[8b]
6
7
84
80
8
45
(continued)

2,20-Disubstituted Biaryls
3813
Table 1. Continued
Run
A
B
Yield (%)
86
9
Notes. Yield of isolated products is based on the triflates used for the
second coupling reaction. Yields obtained using reported methods are
shown in parentheses. 8a) K3PO4-dioxane combination for the second
cross-coupling reaction. 8b) Na2CO3–DMF/H2O combination for the
second cross-coupling reaction; 2.0 eq. of triflate 13 was employed.
prior methods (K3PO4–dioxane combination[8a] and Na2CO3–DMF/H2O
combination[8b] for the second cross-coupling reaction) the yield decreased
to 37% and 0%, respectively (run 5). As is often the case with cross-
coupling reaction of the electron-rich substituent,[3] the triflate 14 reacted
more slowly to result in a reduced yield for the corresponding product
(run 8). Interestingly, the ortho-disubstituted triflate 15 reacted and ortho-
trisubstituted biaryl was obtained without difficultly (run 9).
In conclusion, we have modified the one-pot Suzuki cross-coupling
reaction by the use of a biphasic solvent system. This method allows the pre-
paration of asymmetrical biaryls from aryl triflates with various functional
groups, including CO2Et, CN, NO2, and CHO, and even from those with sub-
stituents in the ortho position.
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 spec-
trometer. Chemical shifts were recorded in parts per million (d), downfield
relative to tetramethylsilane 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 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).
2-Hydroxy-5-(methoxycarbonyl)benzoic Acid (4)
Pyridine (500 mL) was added to 3 (36.0 g, 171 mmol), and the mixture was
refluxed for 17 h. The mixture was then concentrated in vacuo, and the

3814
M. Miura et al.
residue was acidified with 1 M HCl/H2O (200 mL). The resulting precipitate
was filtered, washed with H2O, and dried in vacuo to give 4 (33.4 g, 100%) as
1
a brown solid: H NMR (300 MHz, DMSO-d6) d: 3.84 (3H, s), 7.07 (1H, d,
J ¼ 8.8 Hz), 8.06 (1H, dd, J ¼ 2.2 Hz, 8.8 Hz), 8.39 (1H, d, J ¼ 2.2 Hz);
FAB-MS (m/z): 197 (M þ H)þ.
3-tert-Butyl 1-Methyl 4-f[(Trifluoromethyl)sulfonyl]oxyg-
isophthalate (5)
Conc. H2SO4 (5.9 mL, 111 mmol) and 2-methylpropan-2-ol (53.0 mL, 554 mmol)
were added to a solution of 4 (10.0 g, 51.0 mmol) and MgSO4 (53.4 g,
444 mmol) in CH2Cl2 (500 mL), and the mixture was stirred at room tempera-
ture for 12 h. The mixture was then filtered and partitioned between CHCl3 and
5% NaHCO3 in H2O, and the organic layer was dried over MgSO4, filtered, and
concentrated in vacuo to give a colorless oil (9.91 g). Trifluoromethanesulfonic
anhydride (13.0 mL, 77.3 mmol) was added to a solution of the compound
obtained above (9.90 g) and pyridine (16.0 mL, 197 mmol) in CH2Cl2
(100 mL), and the mixture was stirred at room temperature for 30 min. The
mixture was partitioned between CH2Cl2 and H2O, and the organic layer was
dried over MgSO4, filtered, and concentrated in vacuo. The residue was
purified by silica-gel column chromatography (hexane/AcOEt ¼ 9 : 1) to
1
give 5 (13.3 g, 88%) as a colorless oil: H NMR (300 MHz, DMSO-d6) d:
1.58 (9H, s), 3.91 (3H, s), 7.72 (1H, d, J ¼ 8.6 Hz), 8.30 (1H, dd, J ¼ 2.4 Hz,
8.6 Hz), 8.43 (1H, d, J ¼ 2.4 Hz); FAB-MS (m/z): 385 (M þ H)þ.
3-tert-Butyl 1-Methyl 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-
2-yl)isophthalate (6)
AcOK (3.09 g, 31.5 mmol) was added to a stirred solution of 5 (8.07 g,
21.0 mmol), bis(pinacolato)diboron (5.85 g, 23.1 mmol), PPh3 (330 mg,
1.26 mmol), and PdCl2(PPh3)2 (442 mg, 0.630 mmol) in 1,4-dioxane
(130 ml) at room temperature under an argon atmosphere. The mixture was
stirred at 808C for 12 h and then concentrated in vacuo. The residue was
purified by silica-gel column chromatography (hexane/AcOEt ¼ 9 : 1) to
1
give 6 (6.26 g, 82%) as a colorless solid: H NMR (300 MHz, DMSO-d6) d:
1.33 (12H, s), 1.57 (9H, s), 3.89 (3H, s), 7.61 (1H, d, J ¼ 7.7 Hz), 8.12 (1H,
dd, J ¼ 1.5 Hz, 7.7 Hz), 8.28 (1H, d, J ¼ 1.5 Hz); FAB-MS (m/z): 363
(M þ H)þ.
Benzyl 2-Hydroxy-5-nitrobenzoate (8)
To a solution of 7 (49.8 g, 271 mmol) and KHCO3 (32.5 g, 325 mmol) in
DMF (270 mL) was added benzyl bromide (38.6 mL, 325 mmol), and the

2,20-Disubstituted Biaryls
3815
mixture was stirred at room temperature for 12 h. The mixture was parti-
tioned between AcOEt and 5% NaHCO3 in H2O, and the organic layer
was dried over MgSO4, filtered, and concentrated in vacuo to give 8
1
(68.6 g, 93%) as a yellow solid: H NMR (300 MHz, DMSO-d6) d: 5.40
(2H, s), 7.19 (1H, d, J ¼ 9.2 Hz), 7.33–7.47 (3H, m), 7.47–7.55 (2H,
m), 8.33 (1H, dd, J ¼ 2.9 Hz, 9.2 Hz), 8.54 (1H, d, J ¼ 2.9 Hz), 11.61
(1H, br s); FAB-MS (m/z): 272 (M-H)2.
Benzyl 5-Nitro-2-f[(trifluoromethyl)sulfonyl]oxygbenzoate (9)
Trifluoromethanesulfonic anhydride (13.8 mL, 82.0 mmol) was added to a
solution of 8 (14.9 g, 54.5 mmol) and pyridine (8.8 mL, 109 mmol) in
CH2Cl2 (300 mL), and the mixture was stirred at room temperature for
30 min. The mixture was partitioned between CH2Cl2 and H2O, and the
organic layer was dried over MgSO4, filtered, and concentrated in
vacuo. The residue was purified by silica-gel column chromatography
(hexane/AcOEt ¼ 9 : 1) to give 9 (11.2 g, 51%) as a colorless solid: 1H
NMR (300 MHz, DMSO-d6) d: 5.44 (2H, s), 7.35–7.53 (5H, m), 7.92
(1H, d, J ¼ 9.2 Hz), 8.63 (1H, dd, J ¼ 2.8 Hz, 9.2 Hz), 8.73 (1H, d,
J ¼ 2.8 Hz).
Ethyl 2-f[(Trifluoromethyl)sulfonyl]oxygbenzoate (10)
Compound 10 was synthesized from ethyl salicylate according to the same
procedure as that for 9. Compound 10 was obtained as a colorless
oil (99% yield): 1H NMR (300 MHz, DMSO-d6) d: 1.33 (3H, t,
J ¼ 7.1 Hz), 4.36 (2H, q, J ¼ 7.1 Hz), 7.57 (1H, d, J ¼ 8.2 Hz), 7.62–
7.70 (1H, m), 7.80–7.88 (1H, m), 8.07 (1H, d, J ¼ 7.9 Hz); FAB-MS
(m/z): 299 (M þ H)þ.
2-Methylphenyl Trifluoromethanesulfonate (11)
Compound 11 was synthesized from o-cresol according to the same procedure
1
as that for 9. Compound 11 was obtained as a colorless oil (73% yield): H
NMR (300 MHz, DMSO-d6) d: 2.34 (3H, s), 7.34–7.44 (3H, m), 7.46–7.51
(1H, m); GC-MS (m/z): 240 (M)þ.
2-Cyanophenyl Trifluoromethanesulfonate (12)
Compound 12 was synthesized from 2-hydroxybenzonitrile according to the
same procedure as that for 9. Compound 12 was obtained as a colorless oil

3816
M. Miura et al.
(95% yield): 1H NMR (300 MHz, DMSO-d6) d: 7.69–7.77 (1H, m), 7.83 (1H,
d, J ¼ 8.4 Hz), 7.92–8.00 (1H, m), 8.16 (1H, d, J ¼ 7.7 Hz); ESI-MS (m/z):
252 (M þ H)þ.
2-Nitrophenyl Trifluoromethanesulfonate (13)
Compound 13 was synthesized from 2-nitrophenol according to the same
procedure as that for 9. Compound 13 was obtained as a colorless oil
(100% yield): 1H NMR (300 MHz, DMSO-d6) d: 7.76–7.85 (2H, m),
7.95–8.03 (1H, m), 8.35 (1H, d, J ¼ 8.3 Hz); FAB-MS (m/z): 272
(M þ H)þ.
2-Methoxyphenyl Trifluoromethanesulfonate (14)
Compound 14 was synthesized from 2-methoxyphenol according to the
same procedure as that for 9. Compound 14 was obtained as a colorless
oil (96% yield): 1HNMR (300 MHz, DMSO-d6) d: 3.90 (3H, s), 7.04–
7.10 (1H, m), 7.33 (1H, d, J ¼ 8.3 Hz), 7.40–7.48 (2H, m); EI-MS (m/
z): 256 (M)þ.
2-Ethoxy-6-Formylphenyl Trifluoromethanesulfonate (15)
Compound 15 was synthesized from 3-ethoxy-2-hydroxybenzaldehyde
according to the same procedure as that for 9. Compound 15 was obtained
1
as a colorless solid (69% yield): HNMR (300 MHz, DMSO-d6) d: 1.38
(3H, t, J ¼ 7.0 Hz), 4.23 (2H, q, J ¼ 7.0 Hz), 7.57–7.62 (1H, m), 7.65–
7.70 (2H, m), 10.07 (1H, s).
GENERAL PROCEDURE FOR THE ONE-POT SUZUKI
COUPLING REACTION OF ARYL TRIFLATES IN A BIPHASIC
SOLVENT SYSTEM
AcOK (1.5 mmol) was added to a stirred solution of the triflate 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) at room temperature under
an argon atmosphere. The mixture was refluxed overnight, and then the
triflate B (1.0 mmol), Pd(PPh3)4 (0.05 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.

2,20-Disubstituted Biaryls
3817
20-Benzyl 2-tert-Butyl 4-Methyl 40-Nitrobiphenyl-2,20,
4-tricarboxylate (2)
1
Colorless oil; H NMR (300 MHz, DMSO-d6) d: 1.15 (9H, s), 3.93 (3H, s),
5.05 (2H, s), 7.04–7.11 (2H, m), 7.20–7.30 (3H, m), 7.33 (1H, d,
J ¼ 8.1 Hz), 7.56 (1H, d, J ¼ 8.4 Hz), 8.05 (1H, dd, J ¼ 1.5 Hz, 8.1 Hz),
8.28 (1H, d, J ¼ 1.5 Hz), 8.44 (1H, dd, J ¼ 2.3 Hz, 8.4 Hz), 8.72 (1H, d,
J ¼ 2.3 Hz); FAB-MS (m/z): 491 (M)2; HRMS (FAB) calcd. for
C27H25NO8: 491.1580; found: 491.1588.
2-tert-Butyl 20-Ethyl 4-Methyl Biphenyl-2,20,4-tricarboxylate (Run 1)
Colorless oil; 1H NMR (300 MHz, DMSO-d6) d: 0.90 (3H, t, J ¼ 7.1 Hz), 1.11
(9H, s), 3.91 (3H, s), 3.95 (2H, q, J ¼ 7.1 Hz), 7.25 (1H, d, J ¼ 7.5 Hz), 7.36
(1H, d, J ¼ 7.9 Hz), 7.52–7.60 (1H, m), 7.62–7.70 (1H, m), 7.97 (1H, d,
J ¼ 7.9 Hz), 8.11 (1H, dd, J ¼ 1.8 Hz, 7.9 Hz), 8.35 (1H, d, J ¼ 1.8 Hz);
FAB-MS (m/z): 385 (M þ H)þ; anal. calcd. for C22H24O6: C, 68.74; H,
6.29; found: C, 68.60; H, 6.23.
2-tert-Butyl 4-Methyl 20-Methylbiphenyl-2,4-dicarboxylate (Run 2)
1
Colorless oil; H NMR (300 MHz, DMSO-d6) d: 1.12 (9H, s), 2.02 (3H, s),
3.91 (3H, s), 7.04 (1H, d, J ¼ 7.3 Hz), 7.20–7.36 (3H, m), 7.41 (1H, d,
J ¼ 8.0 Hz), 8.13 (1H, dd, J ¼ 1.8 Hz, 8.0 Hz), 8.29 (1H, d, J ¼ 1.8 Hz);
FAB-MS (m/z): 327 (M þ H)þ; anal. calcd. for C20H22O4: C, 73.60; H,
6.78; found: C, 73.30; H, 6.78.
Benzyl 20-Cyano-4-nitrobiphenyl-2-carboxylate (Run 3)
1
Yellow oil; H NMR (300 MHz, DMSO-d6) d: 5.16 (2H, s), 7.16–7.25 (2H,
m), 7.30–7.37 (3H, m), 7.48 (1H, d, J ¼ 7.9 Hz), 7.54–7.62 (1H, m),
7.70–7.79 (2H, m), 7.87 (1H, d, J ¼ 7.7 Hz), 8.54 (1H, dd, J ¼ 2.2 Hz,
8.4 Hz), 8.73 (1H, d, J ¼ 2.2 Hz); ESI-MS (m/z): 359 (M þ H)þ; HRMS
(FAB) calcd. for C21H14N2O4: 358.0954; found: 358.0963.
Benzyl 20-Methyl-4-nitrobiphenyl-2-carboxylate (Run 4)
1
Yellow oil; H NMR (300 MHz, DMSO-d6) d: 1.97 (3H, s), 5.07 (1H, d,
J ¼ 13.7 Hz), 5.12 (1H, d, J ¼ 13.7 Hz), 7.03–7.13 (3H, m), 7.19–7.26
(2H, m), 7.27–7.35 (4H, m), 7.59 (1H, d, J ¼ 8.4 Hz), 8.44 (1H, dd,
J ¼ 2.6 Hz, 8.4 Hz), 8.63 (1H, d, J ¼ 2.6 Hz); FAB-MS (m/z): 348

3818
M. Miura et al.
(M þ H)þ; anal. calcd. for C21H17NO4: C, 72.61; H, 4.93; N, 4.01; found: C,
72.50; H, 4.94; N, 4.01.
20-Nitrobiphenyl-2-carbonitrile (Run 5)
Pale yellow crystals: mp 128–1308C (AcOEt–hexane) (lit.[10] mp 128–
1
1318C); H NMR (300 MHz, DMSO-d6) d: 7.55 (1H, d, J ¼ 7.7 Hz), 7.59–
7.69 (2H, m), 7.76–7.84 (2H, m), 7.86–7.94 (1H, m), 7.79 (1H, d,
J ¼ 7.7 Hz), 8.24 (1H, d, J ¼ 8.1 Hz); ESI-MS (m/z): 225 (M þ H)þ; anal.
calcd for C13H8N2O2: C, 69.64; H, 3.60; N, 12.49; found: C, 69.55; H,
3.73; N, 12.48.
Ethyl 20-Nitrobiphenyl-2-carboxylate (Run 6)
Yellow oil; 1H NMR (300 MHz, DMSO-d6) d: 0.94 (3H, t, J ¼ 7.1 Hz), 3.98
(2H, q, J ¼ 7.1 Hz), 7.33 (1H, d, J ¼ 7.7 Hz), 7.37 (1H, d, J ¼ 7.5 Hz), 7.53–
7.61 (1H, m), 7.62–7.73 (2H, m), 7.73–7.81 (1H, m), 7.98 (1H, d,
J ¼ 7.7 Hz), 8.12 (1H, d, J ¼ 8.1 Hz); FAB-MS (m/z): 272 (M þ H)þ;
anal. calcd. for C16H13NO2: C, 76.48; H, 5.21; N, 5.57; found: C, 76.37; H,
5.19; N, 5.55.
Ethyl 20-Cyanobiphenyl-2-carboxylate (Run 7)
Colorless oil; 1H NMR (300 MHz, DMSO-d6) d: 0.96 (3H, t, J ¼ 7.4 Hz), 4.04
(2H, q, J ¼ 7.4 Hz), 7.42 (1H, d, J ¼ 7.7 Hz), 7.43 (1H, d, J ¼ 7.7 Hz), 7.54–
7.67 (2H, m), 7.69–7.79 (2H, m), 7.90 (1H, d, J ¼ 7.7 Hz), 8.01 (1H, d,
J ¼ 7.7 Hz); FAB-MS (m/z): 252 (M þ H)þ; anal. calcd. for C15H13NO4:
C, 66.41; H, 4.83; N, 5.16; found: C, 66.37; H, 4.84; N, 5.15.
Ethyl 20-Methoxybiphenyl-2-carboxylate (Run 8)
1
Colorless oil; H NMR (300 MHz, CDCl3) d: 1.02 (3H, t, J ¼ 7.1 Hz), 3.71
(3H, s), 4.08 (2H, q, J ¼ 7.1 Hz), 6.89 (1H, d, J ¼ 8.1 Hz), 6.99–7.06 (1H,
m), 7.21–7.27 (2H, m), 7.29–7.44 (2H, m), 7.48–7.57 (1H,m), 7.87 (1H, d,
J ¼ 7.8 Hz); FAB-MS (m/z): 257 (M þ H)þ; HRMS (FAB) calcd. for
C16H16O3: 257.1178; found: 257.1176.
Ethyl 20-Ethoxy-60-formylbiphenyl-2-carboxylate (Run 9)
1
Colorless crystals; mp 75–768C (hexane); HNMR (300 MHz, DMSO-d6)
d: 0.89 (3H, d, J ¼ 7.1 Hz), 1.08 (3H, d, J ¼ 6.9 Hz), 3.88–4.06 (4H,

2,20-Disubstituted Biaryls
3819
m), 7.26 (1H, d, J ¼ 7.5 Hz), 7.31–7.36 (1H, m), 7.47–7.59 (3H, m),
7.61–7.68 (1H, m), 7.94 (1H, d, J ¼ 7.5 Hz), 9.62 (1H, s); FAB-MS (m/
z): 299 (M þ H)þ; HRMS (FAB) calcd. for C18H18O4: 299.1283; found:
299.1294.
ACKNOWLEDGMENT
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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