Synthesis of Chlorodihydroxybiphenyls
Melting points were determined on a Fisher Scientific hot stage
melting point apparatus and are uncorrected. IR spectra were
recorded on a BOMEM MB-100, MB-120, or MB-Series FT-
infrared spectrophotometer as liquid films on NaCl plates or as
KBr discs. Electron impact mass spectra (EIMS) were performed
on Kratos MS890 (4 kV, 35 eV, 220 °C), Hewlett-Packard 5890
Series II/5971A MSD, or Varian Saturn 2000 spectrometers. The
purity of the compounds was determined by a HP 6890 gas
chromatograph (20% permethylated â-cyclodextrin column). All
reported yields are isolated yields. THF and Et2O were freshly
distilled from sodium benzophenone ketyl under argon prior to use.
Toluene was distilled from sodium. CH2Cl2 and DMF were distilled
from CaH2 (under reduced pressure for DMF). n-BuLi and s-BuLi
were obtained from FMC Corporation or Sigma-Aldrich, as
solutions in hexanes or cyclohexane, respectively, and were titrated
periodically against s-butanol.19 Starting chlorobenzene derivatives
were purchased from Sigma-Aldrich and used without further
purification. All reactions were performed in flame- or oven-dried
glassware under argon, using syringe-septum cap techniques. Flash
chromatography was carried out with Merck silica gel (0.040-
0.063 mm).
2,3-Dimethoxyphenylboronic Acid (9).19 A solution of TMEDA
(26.8 mL, 179 mmol) and n-BuLi (70.8 mL, 2.53 M solution in
hexanes, 179 mmol) in dry Et2O (200 mL) was stirred for 15 min
at 0 °C under an atmosphere of argon. 1,2-Dimethoxybenzene (8)
(19.5 mL, 1.053 g/mL, 149 mmol) in dry Et2O (20 mL) was added
dropwise and the reaction mixture was stirred for 1 h at 0 °C.
B(OMe)3 (34.5 mL, 0.915 g/mL, 298 mmol) was then added and
the pale yellow reaction mixture was stirred until it became clear,
stirred another 10 min, warmed to rt, and adjusted to pH 6 with 1
N aq HCl. The mixture was diluted with CH2Cl2 (150 mL), and
the aqueous layer was separated and extracted twice with CH2Cl2
(50 mL). The combined organic layers were washed with water
and brine, dried (MgSO4), and evaporated in vacuo. Recrystalli-
zation gave 9 (23.8 g, 88%) as colorless crystals: mp 66-68 °C
(EtOAc/hexanes) (lit.20 mp 72-73 °C); 1H NMR (300 MHz, CDCl3)
δ 7.43 (dd, J1 ) 1.67 Hz, J2 ) 7.35 Hz, 1H, ArH), 7.14 (dd, J1)
8.04 Hz, J2 ) 7.39 Hz, 1H, ArH), 7.05 (dd, J1 ) 1.65 Hz, J2 )
8.08 Hz, 1H, ArH), 6.84 (br s, 2H, B(OH)2), 3.95 (s, 3H, OCH3),
3.88(s, 3H, OCH3). The 1H NMR spectrum was shown to be
identical with that reported.20
stirred for 2 h, allowed to warm to rt, and stirred overnight. Water
(100 mL) was added dropwise at 0 °C and the mixture was warmed
to rt. The aqueous layer was separated and extracted twice with
CH2Cl2. The combined organic layers were washed with water and
brine, dried (MgSO4), and concentrated. Purification by flash-
chromatography (EtOAc/n-hexane 30:70) afforded 11a (2.29 g,
64%, >99% purity by GC analysis) as an off-white solid: mp 112-
o
1
113 °C (hexanes/EtOAc) (lit.22 mp 114 C (light petroleum)); H
NMR (300 MHz, CDCl3) δ 7.52-7.30 (m, 5H, ArH), 6.92-6.73
(m, 3H, ArH), 5.51 (br s, 1H), 5.33 (br s, 1H); HRMS calcd for
1
C12H10O2 186.0681, found 186.0683. The H NMR spectrum was
consistent with that reported.10c
2′-Chloro-2,3-dimethoxybiphenyl (10b). To a solution of
1-chloro-2-iodobenzene (5.00 g, 21.0 mmol) in DME (100 mL)
was added Pd(PPh3)4 (2.43 g, 2.10 mmol) and the solution was
stirred for 15 min under argon. 2,3-Dimethoxyphenylboronic acid
(9) (4.95 g, 31.4 mmol) in DME (50 mL) was added dropwise
followed by the addition of 2 M aq Na2CO3 (80 mL, 160 mmol)
and the mixture was then heated at reflux for 16 h. The solvent
was removed in vacuo and the residue was extracted twice with
diethyl ether. The combined organic layers were washed with water,
2 N NaOH, and brine, dried (MgSO4), subjected to filtration, and
concentrated in vacuo. Purification by flash chromatography
(EtOAc/n-hexane 1:6) afforded 10b (2.71 g, 52%) as pale yellow
crystals: 1H NMR (250 MHz, CDCl3) δ 7.47-7.22 (m, 7H, ArH),
7.09 (t, 1H, J ) 7.9 Hz, ArH), 6.95 (dd, 2H, J ) 8.1 Hz, J ) 1.4
Hz, ArH), 6.82 (dd, 2H, J ) 8.1 Hz, J ) 1.3 Hz, ArH), 3.88 (s,
3H, OCH3) 3.60 (s, 3H, OCH3); 13C NMR (125 MHz, CDCl3) δ
152.8, 146.7, 137.4, 133.8, 133.5, 131.6, 129.3, 128.6, 126.3, 123.5,
122.9, 112.1, 60.6, 55.8; LRMS m/z (rel intensity) 250 (M + 2,
33), 248 (M+, 100), 235 (7), 233 (22), 198 (84), 183 (12), 169 (7),
155 (20), 136 (18), 127 (24), 115 (9), 101 (8), 87 (6), 77 (9); HRMS
calcd for C14H13O2Cl 248.0606, found 248.0604.
2′-Chloro-2,3-Dihydroxybiphenyl (11b). To a stirred solution
of 2′-chloro-2,3-dimethoxybiphenyl (10b) (2.65 g, 10.7 mmol) in
dry CH2Cl2 (40 mL) at -78 °C under an atmosphere of argon was
added boron tribromide (5.07 mL, 53.7 mmol) in CH2Cl2. The
mixture was stirred for 2 h, warmed to rt, and stirred overnight.
Water (100 mL) was added dropwise at 0 °C and the mixture was
warmed to rt. The aqueous layer was separated and extracted twice
with CH2Cl2. The combined organic layers were washed with water
and brine, dried (MgSO4), subjected to filtration, and concentrated.
Purification by flash chromatography (EtOAc/n-hexane 25:75)
afforded 11b (2.29 g, 64%, >99% purity by GC analysis) as
2,3-Dimethoxybiphenyl (10a).10c,21,22To a 1000 mL 2-necked
flask equipped with a condenser was added bromobenzene (3.8 mL,
1.491 g/mL, 36.5 mmol), Pd(PPh3)4 (2.11 g, 1.82 mmol), and THF
(300 mL). The clear yellow solution was stirred for 15 min under
an atmosphere of argon. 2,3-Dimethoxyphenylboronic acid (9) (9.95
g, 54.7 mmol) in THF (50 mL) was added dropwise followed by
2 M aq Na2CO3 (45.6 mL, 91.2 mmol) and the mixture was then
heated at reflux for 13 h. The THF was removed and the residue
was extracted twice with diethyl ether. The separated organic layer
was washed with water, 2 N aq NaOH, and brine and dried
(MgSO4). Evaporation in vacuo and purification by flash -chro-
matography (EtOAc/n-hexane 1.5:8.5) afforded 10a (5.94 g, 76%)
as a pale yellow solid: mp 45-46 °C (EtOAc/hexanes) (lit.21 mp
1
colorless crystals: mp 98 - 99 °C; H NMR (250 MHz, CDCl3)
δ 7.45-7.21 (m, 4H, ArH), 6.92-6.78 (m, 3H, ArH), 5.37 (br,
2H, Ar-OH, H/D-exchange); MS m/z (rel intensity) 221 (M + 1,
2), 220 (15), 185 (20), 167 (2), 157 (6), 139 (5), 128 (8), 102 (2),
84 (100), 70 (2); HRMS calcd for C12H9O2Cl 220.0291, found
220.0293.
4-Chloro-2,3-dimethoxybiphenyl (12). A solution of TMEDA
(13.0 mL, 83.0 mmol) and n-BuLi (32.8 mL, 2.56 M, 84.0 mmol)
in dry THF (100 mL) was stirred for 15 min at 0 °C under argon.
2,3-Dimethoxybiphenyl (10) (5.13 g, 24.0 mmol) in dry THF
(15 mL) was added dropwise and the mixture was stirred for 1 h
at 0 °C. Hexachloroethane (14.2 g, 59.9 mmol) in THF (20 mL)
was added and the reaction mixture was stirred for 45 min and
then allowed to warm to rt. The reaction mixture was quenched
with saturated NH4Cl and the aqueous layer was separated and
extracted with diethyl ether. The combined organic layers were
washed with water and brine, dried over MgSO4, subjected to
filtration, and concentrated. Purification by flash chromatography
(9:1 hexanes/EtOAc) afforded 12 (4.54 g, 76%) as a pale yellow
oil: IR (film) νmax 3060, 2998, 2937, 2854, 1602, 1581, 1562, 1464,
1
45 °C (light petroleum)); H NMR (300 MHz, CDCl3) δ 7.59-
7.56 (m, 2H, ArH), 7.46-7.36 (m, 3H, ArH), 7.14 (t, 1H, J ) 7.9
Hz, ArH), 6.96 (dd, 2H, J ) 8.1 Hz, J ) 1.6 Hz, ArH), 3.94 (s,
3H, OCH3), 3.61 (s, 3H, OCH3). The 1H NMR spectrum was shown
to be identical with that reported.21
2,3-Dihydroxybiphenyl (11a). 10c,22 To a stirred solution of 2,3-
dimethoxybiphenyl (10a) (4.13 g, 19.3 mmol) in dry CH2Cl2 (40
mL) at -78 °C under an atmosphere of argon was added boron
tribromide (19.3 mL, 96.5 mmol) in CH2Cl2. The mixture was
1
1399, 1229, 1099, 1007, 866, 814, 788, 700 cm-1; H NMR (300
(19) Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967, 9, 165.
(20) Prevot-Halter, I.; Smith, T. J.; Weiss, J. J. Org. Chem. 1997, 62,
2186.
(21) Allen, G.; Bruce, J. M. J. Chem. Soc. 1963, 1757.
(22) Bruce, J. M.; Sutcliffe, F. K. J. Chem. Soc. 1955, 4435.
MHz, CDCl3) δ 7.54-7.36 (m, 5H, ArH), 7.20 (d, J ) 8.4 Hz,
1H, ArH), 7.05 (d, J ) 8.4 Hz, 1H, ArH), 3.98 (s, 3H, OCH3),
3.68 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3) δ 152.2, 150.4,
137.8, 135.7, 129.5, 128.7, 128.0, 127.9, 126.3, 125.5, 61.34, 61.32;
J. Org. Chem, Vol. 72, No. 16, 2007 5965