7.93 (s, 1H), 7.94 (dd, J ) 9.3, 2.4 Hz, 1H), 8.06 (dd, J )
9.4, 1.0 Hz, 1H), 8.21 (d, J ) 1.2 Hz, 1H) and 8.60 (d, J )
6.2 Hz, 2H). Anal. Calcd for C12H10NOBr: C, 54.57; H, 3.82;
N, 5.30; Br, 30.25. Found: C, 54.58; H, 3.90; N, 5.32; Br,
30.1.
Anal. Calcd for C12H12BNO3: C, 62.93; H, 5.28; N, 6.12.
Found: C, 62.53; H, 5.29; N, 6.16.
4.2. Procedures for Pilot-Plant Syntheses. 4-Bromo-
2-nitrobenzenamine (3). A suspension of NBS (119 g, 0.67
mol) in HOAc (400 mL) was prepared at 20-25 °C and
transferred from reactor to reactor into a solution of 2-ni-
troaniline (2, 90 g, 0.65 mol) in HOAc (530 mL) at 60 °C
at such a rate to maintain the temperature in the range 60-
65 °C. After rinsing with HOAc (44 mL) the reaction mixture
was kept at 60-65 °C until the reaction was complete (3-5
h). A volume of HOAc (345 mL) was then distilled from
the reaction mixture at 50-60 °C under reduced pressure.
Crystallization was induced by gradual addition of water (975
mL) and by maintaining the temperature at 40 °C. The
resulting suspension was slowly cooled to 5 °C, filtered,
washed with water (176 mL), and dried at 35-50 °C under
reduced pressure to give 3 (133 g, 94%) as an orange-red
solid. On larger scale (210-fold) the product was converted
to 4 without drying on the basis of the calculated dry weight.
5-Bromo-2,1,3-benzoxadiazole-3-oxide (4). Aqueous
KOH (164 g of 50%, 1.3 mol) was added over 15 min to a
suspension of 3 (240 g, 1.11 mol) in water (180 mL) and
tert-butyl alcohol (306 mL) at 25 °C. An aqueous sodium
hypochlorite solution (796 g of 12%, 1.12 mol) was added
slowly (60 min) to maintain the temperature at 27 °C. After
the addition, the mixture was warmed to 30 °C, stirred for
5 h, and then treated with aqueous sodium thiosulfate solution
(100 mL of 10%) at 15 °C. The mixture was cooled to 10
°C, and the yellow solids were filtered, washed with cold
water (300 mL), and dried under reduced pressure at 40-
50 °C to give 4 (226 g, 95%). For safety considerations on
larger scale (420-fold) the water-wet product (average dry
mass 83%, Fe content < 2 ppm) was used for the production
of 5 on the basis of the calculated dry weight.
5-Bromo-2,1,3-benzoxadiazole (5). Triethyl phosphite
(93 g, 0.56 mol) was added to a solution of 4 (107.5 g, 0.5
mol) in EtOH (1080 mL) at 70 °C over 60 min, so that the
temperature did not exceed 75 °C. After another 60 min at
75 °C, a volume of EtOH (670 mL) was distilled from the
reaction mixture under reduced pressure at 35 °C. Water (400
mL) was slowly added over 60 min at 35 °C, and the
resulting mixture was cooled to 10 °C. The crude product
was filtered, washed with water-ethanol (240 mL, 3:1, v/v),
dried at 40 °C under reduced pressure, and recrystallised from
hexane (415 mL) to yield 5 (77 g, 77%; HPLC assay >
99%).
(2E,4Z)-3-Bromo-hexa-2,4-dienedinitrile (13; ca. 0.8%
based on 4) was isolated as a minor side product from the
concentrated mother liquor by chromatography on silca gel
using toluene (Rf : 0.32) as eluent. 1H NMR (δ CDCl3; 200
MHz): 5.82 (d, J ) 10.5 Hz, 1H), 6.15 (s, 1H), 7.19 (d, J
) 10.5 Hz, 1H). IR (KBr): 3440, 3207, 3067, 3040, 2924,
2853, 2218, 1929w, 1740w, 1551, 1534, 1464, 1397, 1098,
993, 835, 778 cm-1. MS (EI): m/z 184 (M + H), 182, 103,
76, 75, 63.
5-[2-Methoxy-5-(4-pyridinyl)phenyl]-2,1,3-benzoxadi-
azole (1). Suzuki Method. A stirred mixture of 9 (1.43 g,
5.4 mmol), 6 (1.10 g, 6.7 mmol), tri-o-tolylphosphine (0.164
g, 0.54 mmol), palladium (II) acetate (0.061 g, 0.27 mmol),
Na2CO3 (1.73 g, 16.2 mmol), and water (16 mL) in DMF
(56 mL) was heated at 60 °C for 5 h. The mixture was then
treated with water (100 mL) and extracted with EtOAc (3
× 80 mL). The combined extracts were washed (saturated
NaCl), dried (Na2SO4) and filtered, and the solvent was
evaporated off under reduced pressure to yield the crude
product which was purified by chromatography (EtOAc) and
recrystallised from acetone-methyl tert-butyl ether to give
1 (0.56 g, 34%) as a colorless needles, mp 206-207 °C; 1H
NMR (DMSO-d6): 3.89 (s, 3H), 7.34 (d, J ) 8.9 Hz, 1H),
7.79 (d, J ) 6.2 Hz, 2H), 7.83 (dd, J ) 9.4, 1.3 Hz, 1H),
7.93 (s, 1H), 7.94 (dd, J ) 9.3, 2.4 Hz, 1H), 8.06 (dd, J )
9.4, 1.0 Hz, 1H), 8.21 (d, J ) 1.2 Hz, 1H) and 8.60 (d, J )
6.2 Hz, 2H). Anal. Calcd for C18H13N3O2‚0.2 H2O: C, 70.44;
H, 4.40; N, 13.69. Found: C, 70.46; H, 4.41; N, 13.67.
Negishi Method. A solution of n-BuLi in hexane (8.8 mL
of 2.5 M, 22 mmol) was added to a stirred solution of 9
(5.28 g, 20 mmol) in a mixture of dry THF (100 mL) and
pentane (10 mL, to prevent crystallization of solvent) at -100
°C under an argon atmosphere. The yellow suspension was
stirred for 30 min at -90 °C, treated with a solution of ZnCl2
in THF (46 mL of 0.5 M, 23 mmol), and allowed to warm
to 0 °C over 60 min. Tetrakis(triphenylphosphine)palladium
(2.0 g, 1.7 mmol) was then added to the brown suspension,
which was stirred for 5 min, treated with 5 (3.80 g, 20 mmol),
and stirred at 20 °C for 3 h. The resulting mixture was treated
with a saturated aqueous solution of ammonium chloride (250
mL) and extracted with EtOAc (2 × 100 mL). The combined
extracts were washed (25% aqueous NH3), dried (Na2SO4)
and filtered, and the solvent was evaporated off under
reduced pressure to yield the crude product which was
recrystallised from acetone-methyl tert-butyl ether to give
1 (2.3 g, 38%) as colorless needles, mp 206-208 °C.
2-Methoxy-5-(4-pyridinyl)phenylboronic Acid (12). A
solution of n-BuLi in hexane (15 mL of 2.5 M, 37.5 mmol)
was added to a stirred solution of 9 (7.92 g, 30 mmol) and
triethylborate (6.34 mL, 37.5 mmol) in dry THF (150 mL)
at -85 °C under an argon atmosphere. The mixture was
stirred for 15 min at -80 °C, then treated with a saturated
aqueous solution of ammonium chloride (200 mL), and
extracted with a mixture of 10% EtOH in EtOAc (2 × 120
mL). The combined extracts were dried (Na2SO4) and
filtered, and the solvent was evaporated off under reduced
pressure to yield the crude product which was purified by
recrystallization from EtOAc-hexane to give 12 (6.1 g, 89%)
1
as a cream crystalline solid, mp 196-200 °C; H NMR
(DMSO-d6): 3.88 (s, 3H), 7.13 (d, J ) 8.7 Hz, 1H), 7.68
(d, J ) 6.1 Hz, 2H), 7.88 (s, 1H), 7.85 (dd, J ) 8.7, 2.4 Hz,
1H), 7.97 (d, J ) 2.4 Hz, 1H) and 8.60 (d, J ) 6.1 Hz, 2H).
4-(4-Methoxyphenyl)pyridine (11). (a) An aliquot (10
mL) of a solution of 4-bromoanisole (9, 80 g, 0.43 mol) in
toluene (60 mL) was added to Mg turnings (11.1 g, 0.46
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