The Journal of Organic Chemistry
Note
then dried (Na2SO4), filtered, and concentrated under reduced
pressure to afford a dark-purple oil. Subjection of this material to
flash chromatography (silica, 1:9 v/v ethyl acetate/hexane elution) and
concentration of the appropriate fractions (Rf = 0.35) then gave the
title compound 56 (1.69 g, 74%) as a white, crystalline solid, mp 81−
82 °C (lit.6 mp 79−80 °C) (Found: M+•, 278.8896. Calcd for
C7H779Br2NO: M+•, 278.8894). 1H NMR (CDCl3, 400 MHz) 7.01 (s,
2H), 4.19 (broad s, 2H), 3.72 (s, 3H); 13C NMR (CDCl3, 100 MHz)
152.0, 136.2, 118.0, 109.1, 56.1; IR νmax (KBr) 3401, 3281, 2950, 2928,
2829, 1591, 1551, 1480, 1435, 1313, 1234, 1207, 1045, 836 cm−1;
Mass spectrum (EI) m/z 283, 281, and 279 (M+•, 43, 75, and 45%),
268, 266, and 264 (58, 100, and 61), 240, 238, and 236 (16, 27, and
16), 78 (35).
Compound 7. A magnetically stirred suspension of the carboxylic
acid precursor to compound 6 (261 mg, 1.07 mmol) in dichloro-
methane (10 mL) maintained at 0 °C was treated with oxalyl chloride
(0.12 mL, 1.40 mmol) and DMF (3 drops). The ensuing mixture was
stirred at 0 °C for 0.08 h, then allowed to warm to 18 °C, and stirred
at this temperature for 0.5 h before being cooled back to 0 °C and
then treated, dropwise, with a solution of compound 5 (360 mg, 1.28
mmol) and triethylamine (0.37 mL, 2.65 mmol) in dichloromethane
(5 mL). The resulting solution was stirred at 0 °C for 0.5 h, then
allowed to warm to 18 °C, and stirred at this temperature for 3.5 h
before being poured into ice-cold NaHCO3 (20 mL of a saturated
aqueous solution) and extracted with dichloromethane (3 × 20 mL).
The combined organic extracts were washed with HCl (1 × 30 mL of
a 1 M aqueous solution) and brine (1 × 30 mL), then dried (Na2SO4),
filtered, and concentrated under reduced pressure to give a yellow oil.
Trituration of this material with ice-cold dichloromethane then gave
the title compound 7 (295 mg, 55%) as a white, crystalline solid, mp
material to flash chromatography (silica, 1:9 v/v ethyl acetate/hexane
elution) and concentration of the appropriate fractions (Rf = 0.15)
gave the title compound 116,15 (1.31 g, 40%) as a light-brown oil
1
(Found: M+•, 200.9790. Calcd for C7H879BrNO: M+•, 200.9789). H
NMR (CDCl3, 400 MHz) 7.01 (d, J = 2.4 Hz, 1H), 6.71 (m, 2H), 3.83
(broad s, 2H), 3.71 (s, 3H); 13C NMR (CDCl3, 100 MHz) 152.5,
137.8, 117.4, 116.5, 114.9, 109.4, 55.8; IR νmax (KBr) 3442, 3359,
3203, 2999, 2947, 2832, 1623, 1600, 1574, 1499, 1440, 1274, 1230,
1212, 1037, 865, 808 cm−1; MS (EI) m/z 203 and 201 (M+•, 74 and
75%), 188 and 186 (99 and 100), 160 and 158 (17 and 18), 86 (29),
84 (45).
Compound 12. A magnetically stirred solution of compound 11
(336 mg, 1.66 mmol) in dichloromethane (15 mL) maintained at 0 °C
was treated, dropwise, with boron trichloride (2.5 mL of a 1 M
solution in dichloromethane, 2.50 mmol), α-chloroacetonitrile (0.2
mL, 3.16 mmol), and then titanium tetrachloride (2.5 mL of a 1 M
solution in dichloromethane, 2.50 mmol). The ensuing mixture was
heated at reflux for 72 h before being cooled to 18 °C and poured into
a mixture of ice and HCl (10 mL of a 20% aqueous solution). The
volatile organic component of the resulting biphasic system was
removed by distillation, and the aqueous residue was heated at reflux
for 0.5 h. The cooled reaction mixture was then treated, dropwise at 0
°C, with NaOH (40 mL of a saturated aqueous solution) until pH 4
was attained, and then it was extracted with diethyl ether (3 × 100
mL). The combined organic extracts were washed with brine (1 × 100
mL) before being dried (Na2SO4), filtered, and concentrated under
reduced pressure to give a brown solid. Subjection of this material to
flash chromatography (silica, 1:9 v/v ethyl acetate/hexane elution) and
concentration of the appropriate fractions (Rf = 0.25) gave the title
compound 12 (209 mg, 45%) as a yellow, crystalline solid, mp 80−81
°C (Found: M+•, 276.9506. Calcd for C9H979Br35ClNO2: M+•,
233−235 °C [Found: (M
+
H)+, 505.8238. Calcd for
C15H1079Br3NO4: (M + H)+, 505.8238]. H NMR (DMSO-d6, 400
MHz) 10.13 (s, 1H), 7.35 (s, 2H), 7.32 (s, 1H), 7.14 (s, 1H), 6.16 (s,
2H), 3.82 (s, 3H); 13C NMR (DMSO-d6, 100 MHz) 165.3, 159.0,
149.2, 146.7, 131.1, 127.8, 124.7, 117.7, 113.1, 110.6, 108.7, 102.5,
56.2; IR νmax (KBr) 3216, 3182, 3008, 2960, 2896, 1671, 1594, 1514,
1496, 1475, 1258, 1227, 1038, 935 cm−1; MS (ESI) m/z 532 and 530
[(M + Na)+, 96 and 100%], 510 and 508 [(M + H)+, both 34], 350
and 348 (27 and 30), 339, 337, and 335 (18, 35, and 18), 229 and 227
(36 and 35).
276.9505). H NMR (CDCl3, 400 MHz) 7.36 (d, J = 3.2 Hz, 1H),
1
1
7.15 (d, J = 3.2 Hz, 1H), 4.66 (s, 2H), 3.78 (s, 3H) (signals due to
NH2 group protons obscured/not observed); 13C NMR (CDCl3, 100
MHz) 191.7, 149.3, 143.1, 126.7, 115.3, 113.9, 112.0, 56.3, 46.5; IR
νmax (KBr) 3478, 3342, 2988, 2938, 1664, 1568, 1535, 1455, 1231,
1048, 834 cm−1; MS (EI) m/z 281, 279, and 277 (M+•, 24, 93, and
73%), 230 and 228 (94 and 100), 202 and 200 (30 and 32), 86 (30),
84 (45), 78 (29).
Compound 13. A magnetically stirred solution of compound 11
(570 mg, 2.82 mmol) in 1,2-dichloroethane (13 mL) maintained at 0
°C was treated, dropwise, with boron trichloride (3.4 mL of a 1 M
solution in dichloromethane, 3.40 mmol), α-chloropropionitrile (0.37
mL, 4.18 mmol), and titanium tetrachloride (3.4 mL of a 1 M solution
in dichloromethane, 3.40 mmol). The ensuing mixture was heated at
reflux for 24 h before being cooled to 18 °C and then poured into a
mixture of ice and HCl (10 mL of a 20% aqueous solution). The
volatile organic component of the resulting biphasic system was
removed by distillation, and the aqueous residue was heated at reflux
for 0.5 h. The cooled reaction mixture was treated, dropwise at 0 °C,
with NaOH (40 mL of a saturated aqueous solution) until pH 4 was
attained and then extracted with diethyl ether (3 × 100 mL). The
combined organic extracts were washed with brine (1 × 100 mL)
before being dried (Na2SO4), filtered, and concentrated under reduced
pressure to give a brown solid. Subjection of this material to flash
chromatography (silica, 1:9 v/v ethyl acetate/hexane elution) and
concentration of the appropriate fractions (Rf = 0.30) then gave the
title compound 13 (420 mg, 51%) as a yellow, crystalline solid, mp
107−108 °C (Found: M+•, 292.9646. Calcd for C10H1181Br35ClNO2:
Compound 10. A magnetically stirred solution of compound 7
(200 mg, 0.394 mmol) in DMSO (5 mL) was treated with Cu powder
(125 mg, 1.97 mmol), and the ensuing mixture was stirred at 100 °C
for 48 h. The cooled reaction mixture was diluted with dichloro-
methane (20 mL), and the resulting solution was washed with
NH4OH (2 × 10 mL of a 4% aqueous solution) and then water (1 ×
10 mL) before being dried (Na2SO4), filtered, and concentrated under
reduced pressure to yield a brown oil. Subjection of this material to
flash chromatography (silica, 1:4 v/v ethyl acetate/hexane elution) and
concentration of the appropriate fractions (Rf = 0.15) then gave the
title compound 10 (18 mg, 7%) as a white, crystalline solid, mp 266−
270 °C [Found: (M + Na)+, 714.9328. Calcd for C30H1879Br2N2O8:
1
(M + Na)+, 714.9328]. H NMR (CDCl3, 400 MHz) 7.72 (s, 2H),
7.03 (d, J = 2.0 Hz, 2H), 6.77 (s, 2H), 6.67 (d, J = 2.0 Hz, 2H), 6.10
(broad s, 4H), 3.78 (s, 6H); 13C NMR (CDCl3, 200 MHz) 162.3,
158.1, 151.1, 149.7, 147.4, 136.2, 135.1, 120.1, 115.6, 112.2, 111.2,
109.5, 102.0, 94.9, 56.2; IR νmax (KBr) 3105, 2965, 2909, 2838, 1615,
1598, 1475, 1441, 1307, 1260, 1236, 1202, 1119, 1030, 974, 826 cm−1;
MS (ESI) m/z 719, 717, and 715 [(M + Na)+, 47, 85, and 40%], 697,
695, and 693 [(M + H)+, 48, 78, and 43], 617 and 615 (41 and 40),
169 (100).
Compound 11. A magnetically stirred solution of compound 4
(1.98 g, 16.08 mmol) in dichloromethane/methanol (150 mL of a 2:1
v/v mixture) was treated with benzyltrimethylammonium tribromide
(6.58 g, 16.87 mmol). The ensuing mixture was stirred at 20 °C for 2 h
and then treated with Na2SO3 (100 mL of a saturated aqueous
solution) before being extracted with diethyl ether (1 × 150 mL). The
separated organic extract was washed with water (1 × 100 mL) and
brine (1 × 100 mL), then dried (Na2SO4), filtered, and concentrated
under reduced pressure to afford a dark-red oil. Subjection of this
1
M+•, 292.9641). H NMR (CDCl3, 400 MHz) 7.35 (d, J = 3.2 Hz,
1H), 7.30 (d, J = 3.2 Hz, 1H), 5.24 (q, J = 6.8 Hz, 1 H), 3.78 (s, 3H),
1.73 (d, J = 6.8 Hz, 3H) (signal due to NH2 protons obscured/not
observed); 13C NMR (CDCl3, 100 MHz) 194.4, 149.3, 143.5, 126.7,
115.1, 114.2, 111.9, 56.3, 53.0, 20.3; IR νmax (KBr) 3427, 3314, 2960,
1647, 1568, 1533, 1454, 1363, 1249, 1219, 1049, 896, 844, 784 cm−1;
MS (EI) m/z 295, 293, and 291 (M+•, 15, 58, and 46%), 230 and 228
(98 and 100), 202 and 200 (30 and 31), 78 (28).
Compound 14. A magnetically stirred solution of compound 12
(209 mg, 0.750 mmol) in 1,4-dioxane/water (10 mL of a 9:1 v/v
mixture) was treated with sodium borohydride (29 mg, 0.767 mmol).
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dx.doi.org/10.1021/jo4006987 | J. Org. Chem. 2013, 78, 5103−5109