PAPER
Synthesis of Brombuterol
130.21, 128.64, 107.65, 25.92.
1473
Melting points were determined using in a Melt-Temp apparatus.
1H and 13C NMR spectra were obtained in GEMINI-200 MHz spec-
trometer with TMS (d = 0.00) as internal standard using as solvents
CDCl3 or MeOD. LR-MS were obtained in an Auto Specq, in EI
mode at 70 eV and HRMS using a Varian MAT-CH7 instrument at
70 eV. All chemicals commercially available were purchased from
Aldrich Co. (USA) or TermoVida (Rio de Janeiro, Brazil).
MS: m/z (%) = 295 (25), 293 (46), 278 (100), 250 (19), 170 (19), 90
(21), 63 (11), 43 (13).
HRMS (CI): calcd for C8H7Br2NO: 292.9691; found: 292.9763.
2-Bromo-4¢-(pivaloylamino)acetophenone (13)
White solid; yield: 0.850 g (95%); mp 133–135 °C.
1H NMR (200 MHz, CDCl3): d = 1.25 (s, 9 H), 4.34 (s, 2 H), 6.76
(s, 1 H), 4.34 (s, 2 H), 7.61 (d, J = 8.8 Hz), 7.87 (d, J = 8.8 Hz).
Bromination with Trimethylphenylammonium Tribromide;
General Procedure
To a soln composed of 3 (0.405 g, 0.003 mol) or 11 (0.657 g, 0.003
mol), THF (30 mL) and ethylene glycol (15 mL), a soln of
Me3PhNBr3 (3.0 equiv for the preparation of 5 and 6; 1.0 equiv for
the preparation of 9; 2.0 equiv for the preparation of 10; 1.0 equiv
for the preparation of 13) in THF (15 mL) was added via a cannula,
with agitation, under an inert atmosphere and in an ice bath at 0 °C.
The progress of the reaction was followed by TLC, until the starting
material had been totally consumed. After 18–20 h, the mixture was
acidified with 3 M HCl or 3 M HBr, until pH ~1, and agitation was
continued for an additional 1 h. The mixture was then partitioned
with EtOAc (100 mL) and washed with 10% aq NaHCO3 (3 × 30
mL). The organic phase was separated, washed with H2O until neu-
tral pH, dried (anhyd Na2SO4), and finally concentrated by evapo-
ration at reduced pressure. The residue obtained was submitted to
purification by flash column chromatography11 (20% EtOAc–
hexane).
13C NMR (50 MHz, CDCl3): d = 190.27, 177.15, 143.38, 130.52,
130.50, 129.56, 119.43, 119.41, 40.06, 30.90, 27.65.
MS: m/z (%) = 283 (15), 212 (63), 202 (19), 188 (100), 122 (53).
HRMS (CI): calcd for C13H16BrNO2: 298.1856; found: 298.1901.
1-(4-Amino-3,5-dibromophenyl)-2-bromoethanol (7) and 1-(4-
Amino-3,5-dibromophenyl)-2-chloroethanol (8)
A soln of a mixture of 5 and 6 (1.40 g, 0.002 mol of each compound)
in dioxane (12 mL) was added dropwise, under strong agitation, to
a soln containing NaBH4 (0.155 g, 0.0041 mol) in H2O (8.0 mL), an
intensification of the yellow color of the mixture occurred through-
out the addition. After 1 h, 2 M H2SO4 was added dropwise, to pH
~2. The mixture was poured into a separating funnel containing cold
H2O (40 mL) and extracted with EtOAc (2 × 60 mL). The combined
organic phases were washed with brine (2 × 50 mL), dried (anhyd
Na2SO4), and the solvent removed by evaporation at reduced pres-
sure. The residue obtained was submitted to purification on a flash
chromatography column (20% EtOAc–hexane) to give a mixture of
7 and 8 (1:1) as a white powder; yield: 1.407 g (100%).
4¢-Amino-2,3¢,5¢-dibromoacetophenone (5) and 4¢-Amino-3¢,5¢-
dibromo-2-chloroacetophenone (6)
White solid; yield: 1.863 g (79%); ratio 5/6 1:1 (NMR).
Compound 5
1-(4-Amino-3,5-dibromophenyl)-2-bromoethanol (7)
1H NMR (200 MHz, CDCl3): d = 4.31 (s, 2 H), 5.18 (s, 2 H), 8.03
1H NMR (200 MHz, MeOD): d = 3.63 (dd, J = 4.74 Hz, J = 11.20
Hz, 2 H), 4.67 (d, J = 4.75 Hz, 1 H), 4.87 (s, 1 H), 7.43 (s, 2 H).
(s, 2 H).
13C NMR (50 MHz, CDCl3): d = 189.13, 156.45; 128.34, 127.77,
117.56, 30.81.
13C NMR (50 MHz, MeOD): d = 149.91, 129.89, 127.93, 115.31,
65.85, 41.87.
MS: m/z (%) = 373 (8), 371 (9), 278 (100), 250 (12), 211 (2), 185
(4), 170 (16), 143 (2), 104 (12), 90 (18), 63 (14).
MS: m/z (%) = 375 (60), 373 (40), 356 (22), 294 (32), 280 (100),
279 (90), 269 (21), 172 (10).
Compound 6
1-(4-Amino-3,5-dibromophenyl)-2-chloroethanol (8)
1H NMR (200 MHz, CDCl3): d = 4.55 (s, 2 H), 5.17 (s, 2 H), 8.01
1H NMR (200 MHz, MeOD): d = 3.64 (dd, J = 4.78 Hz, J = 12.1
Hz, 2 H), 4.68 (d, J = 4.78 Hz, 1 H), 4.87 (s, 1 H), 7.41 (s, 2 H).
(s, 2 H).
13C NMR (50 MHz, CDCl3): d = 190.17, 155.91, 128.73, 126.72,
118.07, 45.33.
13C NMR (50 MHz, MeOD): d = 150.11, 131.02, 129.27, 110.33,
69.88, 43.01.
MS: m/z (%) = 331 (2), 329 (9), 327 (19), 278 (100), 250 (16), 223
(2), 199 (2), 143 (2), 168 (16), 139 (4), 119 (12), 90 (16), 62 (10).
MS: m/z (%) = 375 (60), 373 (40), 356 (22), 294 (32), 280 (100),
279 (90), 269 (21), 172 (10).
4¢-Amino-3¢-bromoacetophenone (9)
Pale oil; yield: 0.597 g (93%).
Brombuterol (2)
t-BuNH2 (5 mL) was added to a soln containing 7 and 8 (1:1, 0.375
g) in MeOH (2.5 mL), and the mixture kept under reflux for 22 h.
After cooling to r.t., the solvent and excess t-BuNH2 were removed
by evaporation at reduced pressure and the residue was purified by
flash column chromatography (30% EtOAc–hexane) to give 2;
yield: 0.360 g (98%). With the purpose of comparing melting
points, 2 was transformed into the corresponding chlorohydrate; mp
218–219 °C (Lit.6 219–220 °C).
1H NMR (200 MHz, CDCl3): d = 1.03 (s, 9 H), 3.23 (dd, J = 10.5
Hz, J = 8.7 Hz, 1 H), 3.49 (dd, J = 4.8 Hz, J = 10.5 Hz, 1 H), 3.72
(dd, J = 4.8 Hz, J = 8.7 Hz, 1 H), 4.49 (s, 2 H), 7.32 (s, 2 H).
1H NMR (200 MHz, CDCl3): d = 2.49 (s, 3 H), 4.19 (s, 2 H), 6.74
(d, J = 8.5 Hz, 1 H), 7.72 (dd, J = 1.9 Hz, J = 8.5 Hz, 1 H), 8.4 (d,
J = 2.0 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 195.21, 148.26, 133.61, 129.21,
128.67, 114.10, 108.08, 25.86.
MS: m/z (%) = 215 (37), 213 (39), 200 (100), 198 (90), 172 (23),
143 (4), 119 (6), 90 (25), 77 (4), 63 (14).
HRMS (CI): calcd for C8H8BrNO: 214.0675; found: 214.0673.
4¢-Amino-3¢,5¢-dibromoacetophenone (10)
Yellow oil; yield: 0.835 g (95%).
1H NMR (200 MHz, CDCl3): d = 2.48 (s, 3 H), 5.04 (s, 2 H), 8.01
(s, 2 H).
13C NMR (50 MHz, CDCl3): d = 140.91, 135.69, 130.15, 130.14,
127.76, 127.51, 66.95, 57.40, 51.28, 30.30.
MS: m/z (%) = 365 (7), 335 (80), 279 (100), 254 (90), 198 (23), 171
(4), 116 (6), 91 (25), 73 (60), 57 (38).
13C NMR (50 MHz, CDCl3): d = 194.13, 145.88, 133.71, 132.47,
HRMS (CI): calcd for C12H18Br2N2O: 366.1071; found: 366.1321.
Synthesis 2007, No. 10, 1471–1474 © Thieme Stuttgart · New York