A R T I C L E S
Choi and Hamilton
electrothermal melting point apparatus (Fisher) and are uncorrected.
Elemental analyses were performed at Atlantic Microlabs, Norcross,
GA.
(MeOH/CH2Cl2) to give the product as white solid (1.26 g, 95%): mp
1
191-193 °C; H NMR (500 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.27
(2H), 3.90 (s, 3H); HRMS (FAB) m/z 280.9427 ([M + Na]+, calcd for
C9H7O4BrNa 280.9425).
3,5-Dimethyl-3′-nitro-1,1′-biphenyl (2). 3-Nitrophenylboronic acid
(3.65 g, 1.06 equiv) was dissolved in 50 mL of toluene/15 mL of EtOH.
3,5-Dimethyliodobenzene (3 mL, 20.6 mmol) and Na2CO3 solution (2
N in H2O, 25 mL) were added and then followed by Pd(Ph3P)4 (0.80
g, 3.3 mol %). The reaction mixture was refluxed for 3 h and then
allowed to cool to room temperature. The mixture was partitioned
between ether and water. The organic layer was washed with saturated
NaHCO3 solution and brine and dried over anhydrous Na2SO4. After
filtering off the solid, the solvent was removed by evaporation. The
residue was purified by SiO2 chromatography (hexane/EtOAc, 19:1)
5-(Methoxycarbonyl)-3′-nitro-1,1′-biphenyl-3-carboxylic Acid (5).
Compound 4 (0.26 g, 1 mmol), 3-nitrophenylboronic acid (0.17 g, 1
equiv), and Pd(OAc)2 (7 mg, 0.03 equiv) were dissolved in 4 mL of
DMF, and the solution was degassed. A 1.5 M aqueous Cs2CO3 (2
mL, 3 equiv) solution was added, the mixture was heated to 45 °C,
and the stirring was continued for 1.5 h. After the mixture was cooled
to room temperature, 10 mL of H2O was added and the solution was
slightly acidified with 2 N HCl. The mixture was extracted with EtOAc/
THF (1:1), and the organic layer was washed with brine and dried over
Na2SO4. After the solid was filtered off, the solvent was removed by
evaporation. The residue was purified by recrystallization (THF/hexane)
to give the product as an off-white solid (0.24 g, 81%): mp 246-248
°C; 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.51 (s, 1H), 8.48
(s, 1H), 8.47 (s, 1H), 8.30 (d, J3 ) 8.2 Hz, 1H), 8.25 (d, J3 ) 7.8 Hz,
1H), 7.79-7.83 (m, 1H), 3.94 (s, 3H); 13C NMR (100 MHz, DMSO-
d6) δ 166.22, 165.33, 148.50, 139.81, 139.13, 133.77, 132.48, 132.13,
131.59, 131.15, 130.83, 129.53, 123.15, 121.76, 52.70; HRMS (FAB)
m/z 324.0487 ([M + Na]+, calcd for C15H11NO6Na 324.0484).
3-[(tert-Butoxycarbonyl)amino]-5-iodobenzoic Acid (7). Com-
pound 612 (1.36 g, 4.6 mmol) was dissolved in 20 mL of concentrated
NH3/H2O. To the solution, ammonium iron(II) sulfate hexahydrate (10.6
g, 5.8 equiv) in 20 mL of H2O was added. After refluxing for 10 min,
the mixture was filtered through a Celite pad and the filtrate was cooled
in an ice/water bath. The pH was adjusted to ∼4 with concentrated
HCl, and the mixture was extracted with EtOAc (×3). The combined
organic layers were washed with brine and dried over Na2SO4. The
solvent was removed by evaporation to give the aniline product (1.07
g, 88%). This aniline compound (0.94 g, 3.6 mmol) was dissolved in
4 mL of 1,4-dioxane and 4 mL of 2 N KOH/H2O. To the solution,
(Boc)2O (1.58 g, 2.0 equiv) was added, and stirring was continued
overnight. After removal of dioxane by evaporation, the mixture was
diluted with 6 mL of 1 N KOH and washed with ether. The aqueous
layer was cooled in an ice/water bath and neutralized with 6 N HCl.
The precipitate was collected by filtration and dried under vacuum (1.04
g, 80%): 1H NMR (500 MHz, DMSO-d6) δ 13.2 (br s, 1H), 9.68 (s,
1H), 8.08 (s, 1H), 8.07 (s, 1H), 7.80 (s, 1H), 1.48 (s, 9H); 13C NMR
(100 MHz, DMSO-d6) δ 165.83, 152.55, 141.18, 133.11, 130.98,
129.81, 118.11, 94.42, 79.87, 28.02; HRMS (FAB) m/z 385.9867 ([M
+ Na]+, calcd for C12H14NO4INa 385.9865).
1
to give the product as a white solid (4.4 g, 94%): mp 68-70 °C; H
NMR (300 MHz, CDCl3) δ 8.44 (m, 1H), 8.16-8.20 (m, J3 ) 8.0 Hz,
1H), 7.89-7.92 (m, J3 ) 7.8 Hz, 1H), 7.56-7.61 (m, 1H), 7.24 (s,
2H), 7.08 (s, 1H), 2.41 (s, 6H); HRMS (FAB) m/z 227.0945 (M+, calcd
for C14H13NO2 227.0945).
5-(Ethoxycarbonyl)-3′-nitro-1,1′-biphenyl-3-carboxylic Acid (3).
Compound 2 (4.4 g, 19.3 mmol) was dissolved in 40 mL of pyridine/
20 mL of H2O by heating. KMnO4 (24.8 g, 8 equiv) was added
portionwise while the mixture was refluxing. The mixture was refluxed
for an additional 6 h and then allowed to cool to room temperature.
After overnight stirring, the mixture was filtered through a Celite pad
and the filtrate was concentrated. A 1 N NaOH solution was added to
the residue, and the undissolved material was removed by filtration.
The filtrate was acidified with concentrated HCl in an ice/water bath
and extracted with EtOAc (×3). Combined EtOAc layers were washed
with 0.1 N HCl solution and brine and then dried over Na2SO4. The
solvent was removed by evaporation and the residue was further dried
under vacuum to give the crude dicarboxylic acid (4.57 g). This
dicarboxylic acid and p-toulenesulfonic acid (0.30 g, 0.1 equiv) were
dissolved in EtOH (300 mL). The mixture was refluxed overnight. After
the solution was cooled, its volume was reduced to 1/3 by evaporation.
The residue was diluted with THF and washed with 5% NaHCO3
solution and brine. The organic layer was dried over Na2SO4, and the
solvent was removed by evaporation. The residue was purified by
recrystallization (EtOAc/hexane) to give the diester (50%, two steps).
This diester was dissolved in 60 mL of THF/20 mL of EtOH. To the
solution, NaOH (1.0 equiv) in 20 mL of H2O was added slowly, and
the stirring was continued overnight. The mixture was extracted with
ether, and the aqueous layer was acidified with 2 N HCl. The resulting
mixture was extracted with CH2Cl2, and the organic layer was dried
over Na2SO4. The solvent was removed by evaporation, and the residue
was purified by SiO2 chromatography (MeOH/CH2Cl2, 2:98) to give
the product as a white solid (1.58 g, 52%): mp 190-192 °C; 1H NMR
(400 MHz, CDCl3) δ 8.82 (m, 1H), 8.53-8.58 (m, 3H), 8.29-8.32
(m, J3 ) 8.1 Hz, 1H), 8.01-8.04 (m, J3 ) 7.6 Hz, 1H), 8.69-8.73 (m,
1H), 4.49 (q, J ) 7.1 Hz, 2H), 1.47 (t, J ) 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 169.14, 165.24, 148.87, 140.66, 139.65, 133.19,
133.09, 132.69, 132.26, 131.04, 130.60, 130.21, 123.13, 122.16, 61.87,
14.38; HRMS (FAB) m/z 338.0644 ([M + Na]+, calcd for C16H13NO6-
Na 338.0641).
5-[(tert-Butoxycarbonyl)amino]-3′-nitro-1,1′-biphenyl-3-carbox-
ylic Acid (8). Compound 7 (0.97 g, 2.7 mmol) and 3-nitrophenylboronic
acid (0.45 g, 1.0 equiv) were dissolved in 8 mL of DMF. To the
solution, Na2CO3 solution (1.6 N in H2O, 4 mL) was added and followed
by Pd(OAc)2 (18 mg, 3 mol %). The mixture was then stirred at 80 °C
for 4 h, after which it was cooled to room temperature and 20 mL of
H2O was added. The mixture was acidified (pH ∼4) by adding 2 N
HCl and then was extracted with EtOAc (×3). The combined organic
layers were washed with brine and dried over Na2SO4. The solvent
was removed by evaporation and the residue was purified by SiO2
chromatography (MeOH/CH2Cl2, 4:96) to give the product as a white
Monomethyl 5-Bromoisophthalate (4). Monomethyl 5-nitroiso-
phthalate was hydrogenated using MeOH as solvent. DMF was added
to dissolve the product before filtration through a Celite pad. The
product (1 g, 5.1 mmol) was dissolved in 15% aqueous HBr (22.5 mL),
and the mixture was cooled in an ice bath. A 2.5 M aqueous NaNO2
(2.3 mL, 1.1 equiv) solution was slowly added to generate the diazonium
salt. CuBr (0.98 g, 1.3 equiv) was dissolved in 15% HBr (9 mL), and
this mixture was cooled in an ice bath. The diazonium salt solution
was added to CuBr solution, and the temperature was raised to room
temperature. After 30 min, the mixture was heated to 70 °C and stirring
was continued for an additional 1 h. After the mixture was cooled in
an ice bath, the precipitate was collected by filtration and washed with
water. The product was purified by passing through a short SiO2 column
1
solid (0.79 g, 83%): mp 301-304 °C; H NMR (500 MHz, DMSO-
d6) δ 9.72 (s, 1H), 8.37 (m, 1H), 8.25-8.27 (m, J3 ) 8.2 Hz, 1H),
8.19 (s, 1H), 8.10-8.12 (m, J3 ) 7.8 Hz, 1H), 8.05 (s, 1H), 7.86 (s,
1H), 7.78-7.81 (m, 1H), 1.50 (s, 9H); 13C NMR (125 MHz, DMSO-
d6) δ 166.97, 152.83, 148.45, 140.97, 140.75, 138.66, 133.29, 132.37,
130.80, 122.70, 121.28, 121.13, 120.45, 118.78, 79.71, 28.10; HRMS
(FAB) m/z 381.1064 ([M + Na]+, calcd for C18H18N2O6Na 381.1063).
General Procedure for 2-(Trimethysilyl)ethyl Ester Synthesis.
The carboxylic acid was dissolved in CH2Cl2/THF (4:1). To the solution,
(12) Auman, B. C.; Myers, T. L.; Highley, D. P. J. Polym. Sci. A 1997, 35,
2441-2451.
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10248 J. AM. CHEM. SOC. VOL. 125, NO. 34, 2003