ꢀ
~
A. Gonzalez-Antuna et al. / Tetrahedron 67 (2011) 5577e5581
5580
reduced pressure. The crude material was extracted with
dichloromethane (3ꢃ20 mL), the organic layers were combined,
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was subjected to flash chromatog-
raphy (silica gel) using ethyl acetate/hexane mixtures as eluent,
chloroform (5ꢃ2 mL). The organic layers were combined, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pres-
sure. The solid was diluted in 3 mL of anhydrous chloroforme and
HCl/diethylether was added dropwise to afford the chlorhydrate.
Some drops of diethylether were added to improve the pre-
cipitation. The resulting solid was filtered, washed with diethylether
(2ꢃ3 mL), and dried under reduced pressure obtaining 10a$HCl. Due
to its instability, we subsequently proceeded with the reduction.
affording 5a in 61% isolated yield. Solid, mp 103e107 ꢂC; IR (NaCl)
n
740, 896, 1266, 1422, 1596, 2306, 2987, 3055, 3405; 1H NMR
2
(300 MHz, CDCl3)
d
2.50 (d, 3H, H2, JCH 5.8 Hz), 6.64 (d, 2H, Hm, 3JHH
3
3
8.6 Hz), 7.80 (dd, 2H, Ho, JHH, 8.4 JCH 3.5 Hz); 13C NMR (75 MHz,
13
CDCl3)
d
26.4 (d, C2, 1JCC 42.3 Hz), 114.1 (d, Cm, 3JCC 3.9 Hz), 128.3 (d,
4.1.6. C1-1-(40-Amino-30,50-dichlorophenyl)-2-(tert-butylamine)
Ci, 1JCC 55.8 Hz), 131.1 (d, Co, JCC 2.6 Hz), 151.4 (Cp), 196.8 (C1); MS
[EIþ, m/z (%)] 137 (4), 136 (48), 121 (100), 92 (42); HRMS calcd for
13CC7H9NNaO [(MþNa)þ] 159.0615, found 159.0609.
ethanol$HCl or 13C1-clenbuterol$HCl (1a$HCl). To a solution of
10a$HCl (0.25 mmol, 80 mg) in water (1.5 mL) and methanol
(2 mL), NaOH 1 N was added until pH 7, and afterwards a NaBH4
solution in water (0.05 mmol, 2 mg of NaBH4 in 0.5 mL of water)
was added in portions. The mixture was stirred at room tempera-
ture and after 1 h, the mixture was basified with NaOH 2 N until pH
10. The progress of the reaction was followed by TLC (50%
dichloromethane/methanol) until the starting material was totally
consumed. Methanol was removed by evaporation at reduced
pressure. The aqueous phase was extracted with dichloromethane
(3ꢃ10 mL). The organic layers were combined, dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced pressure.
The solid was dissolved with dichloromethane (1 mL) and drops of
HCl/diethylether (pH 3e4) were added to afford the chlorhydrate.
Then, 1 mL of diethylether was added and the product was left at
ꢁ20 ꢂC to allow the precipitation of the final product 1a$HCl (25%
yield from 7a). The resulting solid was filtered, washed with
diethylether (2ꢃ5 mL) and dried under reduced pressure. Solid, mp
2
13
4.1.3. C1-40-Amino-30,50-dichloroacetophenone$HCl (6a$HCl). N-
Chlorosuccinimide (3.14 mmol, 420 mg) was added into a solution
of 5a (1.26 mmol, 170 mg) in HCl 2 N (2 mL). The reaction was
heated at 50 ꢂC and stirred during 10 h. The progress of the reaction
was followed by TLC (60% ethyl acetate/hexane), until the starting
material was totally consumed. The formed solid was filtered,
washed with water at 0 ꢂC (2ꢃ20 mL), and dried under reduced
pressure to give the corresponding product in 75% isolated yield.
Solid, mp 163e168 ꢂC; IR (NaCl)
n 740, 896, 1266, 1422, 1610, 2307,
2
2987, 3055, 3399; 1H NMR (300 MHz, CDCl33)
d 2.50 (d, 3H, H2, JCH
5.9 Hz), 4.93 (s, 2H, NH), 7.82 (d, 2H, Ho, JCH 3.8 Hz); 13C NMR
(75 MHz, CDCl3) d
25.9 (d, C2, 1JCC 42.9 Hz), 118.7 (d, Cm, 3JCC 5.7 Hz),
127.5 (d, Ci, 1JCC 54.6 Hz), 128.5 (d, Co, 2JCC 3.0 Hz), 144.1 (Cp), 194.4
(C1); MS [EIþ, m/z (%)] 208 (8), 206 (30), 204 (48), 193 (16), 191 (64),
189 (100), 164(2), 162 (10), 160 (14), 124 (22); HRMS (ESIþ) calcd for
13CC7H7Cl2NNaO [(MþNa)þ] 226.983, found 226.9832.
decompose. IR (NaCl) n 740, 896, 1265, 1421, 1626, 2306, 2987, 3055,
t
3402; 1H NMR (300 MHz, MeOD-d4)
d 1.42 (s, 9H, Bu), 2.99e3.18
(m, 2H, H2), 4.81 (ddd, 1H, H1, 1JCH 157.6, 3JHH 13.1, 3JHH 3.2 Hz), 7.37
13
3
4.1.4. C1-40-Amino-2-bromo-30,50-dichloroacetophenone (7a). To
(d, 2H, Ho, JCH 4.2 Hz); 13C NMR (75 MHz, MeOD-d4)
d
26.4 (C4),
a solution of 6a$HCl (1.70 mmol, 350 mg) in dichloromethane
(8 mL), a bromine solution [(1.02 mmol, 52 mL) in dichloromethane
58.9 (d, C2, 1JCC 7.4 Hz), 70.2 (C1), 80.0 (C3), 121.3 (d, Cm, 3JCC 5.6 Hz),
127.5 (d, Co, 2JCC 3.4 Hz),133.1 (d, Ci, 1JCC 48.8 Hz), and 142.4 (Cp); MS
[ESIþ, m/z (%)] 282 (10), 280 (63), 278 (100), 262 (15), 260 (24), 206
(19), 204 (30); HRMS (ESIþ) calcd for 13CC11H18Cl2N2O [Mþ]
278.0902, found 278.0900.
(2 mL)] was added dropwise under strong agitation. The progress of
the reaction was followed by TLC every few minutes (60% hexane/
dichloromethane), and when no progress was observed, other
0.2 equiv of Br2 in 0.5 mL of CH2Cl2 was added until the formation
of 2,2-dibrominated derivative was detected by TLC. The reaction
was kept at room temperature and the total time was usually 2 h.
The solvent was removed by evaporation at reduced pressure and
the residue was subjected to flash chromatography (silica gel) using
dichloromethane/hexane mixtures as eluent, affording 7a in 70%
Acknowledgements
Financial support from the Spanish Ministerio de Ciencia e
ꢀ
Innovacion (MICINN, Project CTQ2007-61126/PPQ and CTQ2009-
12814) is gratefully acknowledged. A.G.-A. acknowledges the
isolated yield. Solid, mp 153e158 ꢂC; IR (NaCl)
1265, 1421, 1488, 1583, 1619, 2306, 2987, 3054, 3394, 3492; 1H NMR
(300 MHz, MeOD-d4)
4.55 (d, 2H, H2, 2JCH 3.4 Hz), 7.92 (d, 2H, Ho,
3JCH 3.8 Hz); 13C NMR (75 MHz, MeOD-d4) 31.9 (d, C2, 1JCC 44.3 Hz),
n 739, 896, 1076,
ꢀ
ꢀ
Fundacion para el Fomento en Asturias de la Investigacion
Científica Aplicada y la Tecnología (FICYT) for her predoctoral grant.
Finally, I.L. and P.R.-G acknowledge MICINN for their research
contract under the Ramon y Cajal Program.
d
d
119.8 (d, Cm, 3JCC 6.0 Hz), 124.7 (d, Ci, 1JCC 59.2 Hz), 131.0 (d, Co, 2JCC
3.0 Hz), 148.0 (Cp), 190.8 (C1); MS [ESIþ, m/z (%)] 208 (MꢁBr, 9), 206
(MꢁBr, 29), 204 (MꢁBr, 46), 193 (14),;191 (64), 189 (100).
Supplementary data
As byproduct, 13C1-40-amino-2,2-dibromo-30,50-dichloroacetop-
henone 8a was also obtained. Solid, 1H NMR (300 MHz, CDCl3)
Supplementary data associated with this article can be found in
d
5.13 (s, 2H, NH2), 6.53 (d, 1H, H2, 2JCH 0.7 Hz), 7.98 (d, 2H, Ho, 3JCH
3.8 Hz). 13C NMR (75 MHz, CDCl3)
d
38.9 (d, C2, 1JCC 44.1 Hz), 118.6
References and notes
3
1
2
(d, Cm, JCC 6.2 Hz), 120.1 (d, Ci, JCC 62.6 Hz), 129.9 (d, Co, JCC
2.8 Hz), 145.2 (Cp), 182.8 (C1); HRMS (ESIþ) calcd for 13CC7H5Br2
Cl2NNaO [(MþNa)þ] 382.804, found 382.8044.
1. (a) Prather, I. D.; Brown, D. E.; North, P.; Wilson, J. R. Med. Sci. Sports Exercise
1995, 27, 1118e1121; (b) Elliott, C. T.; McCaughey, W. J.; Shortt, H. D. Food Addit.
Contam. 1993, 10, 231e244.
2. (a) Harkins, J. D.; Woods, W. E.; Lehner, A. F.; Fisher, M.; Tobin, T. J. Vet. Phar-
macol. Ther. 2001, 24, 7e14; (b) Harkins, J. D.; Robinson, N. E.; Woods, W. E.;
Lehner, A. F.; Smith, M. D.; Gates, R. S.; Fisher, M.; Tobin, T. J. Vet. Pharmacol.
Ther. 2000, 23, 251e260.
13
4.1.5. C1-1-(40-Amino-30,50-dichlorophenyl)-2-(tert-butylamino)
ethanone$HCl (10a$HCl). In a sealed tube 7a (0.52 mmol, 150 mg)
was dissolved in anhydrous chloroform (3 mL) and then tert-
3. Cockman, M. D.; Jones, M. B.; Prenger, M. C.; Sheldon, R. J. Muscle Nerve 2001,
24, 1647e1658.
butylamine (8.20 mmol, 860 mL) was added. The solutionwas heated
at 50 ꢂC with agitation for 24 h. After this time, the solution had an
intense orange color. After cooling to room temperature, the solvent
and the excess of tert-butylamine were removed by evaporation
under reduced pressure and the residue was extracted with
€
4. (a) Parr, M. K.; Opfermann, G.; Schanzer, W. Bioanalysis 2009, 1, 437e450; (b)
Prezelj, A.; Obreza, A.; Pecar, S. Curr. Med. Chem. 2003, 10, 281e290.
5. He, P.; Wang, Z.; Zhang, L.; Yang, W. Food Chem. 2009, 112, 707e714.
ꢀ
~
ꢀ
ꢀ
ꢀ
6. Lopez-Erroz, C.; Vinas, P.; Cerdan, F. J.; Hernandez-Cordoba, M. Talanta 2000, 53,
47e53.