PAPER
Synthesis of Pharmacologically Active Catecholamines
3841
formed using an isothermal temperature profile of 100 °C for 2 min,
followed by a 10 °C/min temperature gradient until 280 °C for 15
min. The injector temperature was 280 °C.
Anal. Calcd for C14H21NO4: C, 62.90; H, 7.92; N, 5.24. Found: C,
63.00; H, 7.82; N, 5.20.
Oxidation with IBX; General Procedures
Methyl 4-Hydroxyphenethylcarbamate [N-(Methoxycarbon-
yl)tyramine, 5]
(a) Homogeneous conditions: The substrate (1.0 mmol) were dis-
solved in MeOH (8.0 mL), then IBX (336 mg, 1.2 mmol) was add-
ed. The soln was stirred at 0 °C until complete consumption of the
substrate. H2O (8.0 mL) and Na2S2O4 (348 mg, 2.0 mmol) were add-
ed and the soln was stirred at r.t. for 5 min. After evaporation of the
solvent under vacuum, the residue was solubilized with EtOAc and
treated with sat. NaHCO3 soln. The aqueous phase was extracted
with EtOAc. The combined organic phases were washed with sat.
NaCl soln and dried (Na2SO4). After evaporation of the solvent, the
corresponding catecholic compounds were isolated.
Tyramine (4a, 137 mg, 1.0 mmol) was solubilized in DMC (8 mL).
Then, DBU (183 mg, 1.2 mmol) was added and the mixture was
kept under magnetic stirring at reflux temperature for 16 h. When
the substrate had been consumed, the reaction was worked up by
cooling to r.t. and the DMC was evaporated under vacuum. The res-
idue was solubilized in EtOAc and washed with 1 M HCl. The or-
ganic extracts were treated with sat NaCl soln and dried (Na2SO4),
filtered, and concentrated under vacuum. Purification of the crude
mixture by chromatography (silica gel, hexane–EtOAc, 1:1) gave
exclusively 5 as a colorless oil (95% yield). We obtained the same
result starting from tyramine 4b but using an excess of DBU (2.1
mmol). Analytical and spectroscopic data of 5 were identical to
those given in the literature.15
(b) Heterogeneous conditions: The substrate (1.0 mmol) was solu-
bilized in the appropriate solvent (8.0 mL) at r.t. under magnetic
stirring and then commercial polymer-supported IBX (954 mg, 2.1
mmol) was added. When the substrate had been completely con-
sumed, the polymer was recovered by simple filtration and the re-
maining soln was treated with H2O (8.0 mL) and Na2S2O4 (348 mg,
2.0 mmol). After the evaporation of the solvent under reduced pres-
sure, the final products were extracted with EtOAc from the aque-
ous residue. The combined organic phases were washed with sat.
NaCl soln and dried (Na2SO4). After evaporation of the solvent, hy-
droxylated compounds were isolated. Polymer-supported IBX was
regenerated by treating the filtered resin with a soln of tetrabutylam-
monium oxone and MsOH according to the procedure reported by
us in a previous paper.11
Protection of the Amino Group with Di-tert-butyl Dicarbonate;
General Procedure18
The amine (1.0 mmol) was solubilized in MeOH–H2O (2:1, 6 mL).
Then NaHCO3 (252 mg, 3.0 mmol) and (Boc)2O (327 mg, 1.5
mmol) were slowly added. The mixture was kept under magnetic
stirring for 2–24 h depending on the substrate. When the substrate
had been consumed, MeOH was evaporated under vacuum and the
residue was solubilized in EtOAc and washed with 1 M HCl. The
organic extracts were treated with sat. NaCl soln and dried
(Na2SO4), filtered, and concentrated under vacuum. Purification of
crude mixture by chromatography (silica gel, hexane–EtOAc, 1:1)
gave 9, 12, and 15, which were characterized by analytical and spec-
troscopic analysis.
Methyl 3,4-Dihydroxyphenethylcarbamate [N-(Methoxycarbo-
nyl)dopamine, 6]
Colorless oil; yield: 98%. Analytical and spectroscopic data were
according to the literature.15
tert-Butyl 4-Hydroxyphenethylcarbamate [N-(tert-Butoxycar-
bonyl)tyramine, 9]
tert-Butyl 3,4-Dihydroxyphenethylcarbamate [N-(tert-Butoxy-
carbonyl)dopamine, 10]
White solid; yield: >98%; mp 73–74 °C (Lit.21 74–75 °C). Analyti-
cal and spectroscopic data were according to the literature.18,21
White solid; yield: 90%; mp 136–138 °C.22 Analytical and spectro-
scopic data were according to the literature.22
tert-Butyl 2-Hydroxy-2-(4-hydroxyphenyl)ethylcarbamate
[N-(tert-Butoxycarbonyl)octopamine, 12]
White solid; yield: 85%; mp 143–144 °C.
IR (KBr): 3402, 3270, 2969, 2931, 1649, 1303, 1074 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.01 (d, J = 8.5 Hz, 2 H), 6.62 (d,
J = 8.5 Hz, 2 H), 4.48 (dd, J = 4.2, 7.9 Hz, 1 H), 3.18 (dd, J = 4.4,
14.0 Hz, 1 H), 3.02 (dd, J = 8.5, 13.9 Hz, 1 H), 1.27 (s, 9 H).
13C NMR (50 MHz, CDCl3): d = 156.8, 156.2, 132.8, 127.0, 115.1,
79.6, 72.6, 49.5, 28.1.
tert-Butyl 2-(3,4-Dihydroxyphenyl)-2-hydroxyethylcarbamate
[N-(tert-Butoxycarbonyl)norepinephrine, 13]
White solid; yield: 98%; mp 56–57 °C
IR (KBr): 3430, 2974, 2932, 1681, 1517, 1367, 1286 cm–1.
1H NMR (200 MHz, CDCl3–CD3OD): d = 6.69 (d, J = 8.0 Hz, 1 H),
6.62–6.45 (m, 2 H), 4.50 (dd, J = 4.2, 7.9 Hz, 1 H), 3.24 (dd,
J = 4.2, 14.0 Hz, 1 H), 3.07 (dd, J = 7.8, 13.9 Hz, 1 H), 1.33 (s, 9 H).
13C NMR (50 MHz, CDCl3–CD3OD): d = 156.9, 144.3, 144.2,
133.7, 117.8, 115.0, 112.8, 79.8, 72.8, 49.8, 28.2.
MS (EI, 70 eV): m/z (%) = 253 (0.5), 197 (4.6), 179 (3.2), 162 (5.5),
135 (13.5), 123 (100).
MS (EI, 70 eV): m/z (%) = 270 (94), 252 (100), 214 (13), 196 (51).
Anal. Calcd for C13H19NO5: C, 57.98; H, 7.11; N, 5.20; O, 29.71.
Found: C, 57.88; H, 7.22; N, 5.25; O, 29.65.
Anal. Calcd for C13H19NO4: C, 61.64; H, 7.56; N, 5.53. Found: C,
61.56; H, 7.66; N, 5.49.
tert-Butyl [2-(3,4-Dihydroxyphenyl)-2-hydroxyethyl](meth-
yl)carbamate [N-(tert-Butoxycarbonyl)epinephrine, 16]
White solid; yield: 98%; mp 159–160 °C
IR (KBr): 3523, 3288, 2979, 2933, 2877, 1650, 1230 cm–1.
1H NMR (200 MHz, CDCl3–CD3OD): d = 6.71 (s, 1 H), 6.61 (d,
J = 8.1 Hz, 1 H), 6.53–6.49 (m, 1 H), 4.59–4.57 (m, 1 H), 3.21–3.11
(m, 2 H), 2.62 (s, 3 H), 1.24 (s, 9 H).
tert-Butyl [2-Hydroxy-2-(4-hydroxyphenyl)ethyl](methyl)car-
bamate [N-(tert-Butoxycarbonyl)synephrine, 15]
White solid; yield: >98%; mp 45–46 °C
IR (KBr): 3444, 1670, 1367, 1230 cm–1.
1H NMR (200 MHz, CDCl3–CD3OD): d = 7.04 (d, J = 8.0 Hz, 2 H),
6.62 (d, J = 8.0 Hz, 2 H), 4.69–4.65 (m, 1 H), 3.79–3.70 (m, 1 H),
3.38–3.19 (m, 1 H), 2.66 (s, 3 H), 1.21 (s, 9 H).
13C NMR (50 MHz, CDCl3–CD3OD): d = 156.2, 144.3, 143.8,
134.5, 117.6, 114.7, 112.8, 79.7, 72.7, 56.9, 35.6, 28.7.
13C NMR (50 MHz, CDCl3–CD3OD): d = 157.4, 156.2, 133.2,
127.1, 115.1, 80.1, 72.4, 56.8, 35.7, 28.2.
MS (EI, 70 eV): m/z (%) = 269 (25), 251 (100).
MS (EI, 70 eV): m/z (%) = 267 (0.5), 194 (2.9), 145 (11.0), 136
(15.2), 123 (100).
Synthesis 2009, No. 22, 3838–3842 © Thieme Stuttgart · New York