Synthesis of deuterium labeled (±)-2,5-dimethoxyamphetamine (DMA), (±)-4-bromo-2,5-dimethoxyamphetamine (DOB), and (±)-4- methoxyamphetamine (PMA) as internal standards for quantitative analyses by GC-MS

Article abstract of DOI:10.1002/jccs.200700070

DMA, DOB and PMA are increasingly abused central nervous system stimulants with neurotoxic properties. In recent years, many controlled substance analogs (designer drugs) with a large variety of structures have reached the illegal market, making their ide

Full text of DOI:10.1002/jccs.200700070

Journal of the Chinese Chemical Society, 2007, 54, 493-502
493
Synthesis of Deuterium Labeled (±)-2,5-Dimethoxyamphetamine (DMA),
(±)-4-Bromo-2,5-dimethoxyamphetamine (DOB), and
(±)-4-Methoxyamphetamine (PMA) as Internal Standards for Quantitative
Analyses by GC-MS
Ya-Zhu Xua (
Chang-Ahai Luab,c
), Huei-Ru Linb (
) and Chinpiao Chena* (
),
(
)
aDepartment of Chemistry, National Dong Hwa University, Soufeng, Hualien 974, Taiwan, R.O.C.
bInstitute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan, R.O.C.
cDepartment of Laboratory Medicine and Biotechnology, Tzu Chi University, Hualien 970, Taiwan, R.O.C.
DMA, DOB and PMA are increasingly abused central nervous system stimulants with neurotoxic
properties. In recent years, many controlled substance analogs (designer drugs) with a large variety of
structures have reached the illegal market, making their identification difficult. Therefore, this work stud-
ies the synthesis of DOB-d6, DMA-d6 and PMA-d3 as internal standards for use in gas chromatogra-
phy-mass spectrometry (GC-MS) to identify controlled substances.
Keywords: (±)-2,5-Dimethoxyamphetamine; DMA; (±)-2,5-Dimethoxy-4-bromoamphetamine;
DOB; (±)-4-Methoxyamphetamine; PMA; GC-MS.
INTRODUCTION
Unknown drugs are generally detected and identified
ences the capacity to detect novel amphetamine-controlled
substance analogs.5-6
Some phenethylamines such as 4-bromo-2,5-dimeth-
oxyphenethylamine (2C-B), 4-chloro-2,5-dimethoxyphen-
ethylamine (2C-C), 4-iodo-2,5-dimethoxyphenethylamine
(2C-I), 2,5-dimethoxy-4-ethylthiophenethylamine (2C-T-
2), 2,5-dimethoxy-4-n-propylthiophenethylamine (2C-T-
7) and 5-methoxy-N,N-dimethyltryptamine; and some phen-
isopropylamines, as 2,5-dimethoxyamphetamine (DMA),
4-bromo-2,5-dimethoxyamphetamine (DOB) and 4-meth-
oxyamphetamine (PMA) (Fig. 1) are increasingly abused
by gas chromatography-mass spectrometry (GC-MS) be-
cause of the high sensitivity and ability of this method to
separate organic compounds from complex mixtures. Based
on electron impact (EI), this technique is commonly insuf-
ficient to discriminate between structurally closely related
phenethylamine drug variants, because their mass spectra
are commonly virtually identical to those of extremely poor
molecular and fragment ions.1-4 This fact strongly influ-
H3CO
X
NH2
H3CO
RS
NH2
NMe2
H3CO
OCH3
OCH3
N
2C-B: X = Br
2C-C: X = Cl
2C-I: X = I
H
2C-T-2: R = CH2CH3
2C-T-7: R = CH2CH2CH3
5-MeO-DMT
H3CO
NH2 H3CO
NH2
NH2
CH3
CH3
OCH3
CH3
OCH3
Br
H3CO
DMA
DOB
PMA
Fig. 1. The structures of 2C-B, 2C-C, 2C-I, 2C-T-2, 2C-T-7, 5-MeO-DMT, DMA, DOB and PMA.
* Corresponding author. Tel: +886-3-8633597; Fax: +886-3-8630475; E-mail: chinpiao@mail.ndhu.edu.tw

494 J. Chin. Chem. Soc., Vol. 54, No. 2, 2007
Xu et al.
psychoactive drugs and have been well documented in the
literature.7-13 The widespread consumption of designer
drugs has led to an increase in the number of reports on
abuse and intoxication.
RESULTS AND DISCUSSION
DOB, DMA and PMA are readily prepared using a
number of synthetic routes.25-37 However, the preparation
of DOB-d6, DMA-d6 and PMA-d3 has not been described
previously. Scheme I is the general synthetic scheme for
the preparation of the (±)-2,5-dimethoxyamphetamine-d6
(5) and (±)-4-bromo-2,5-dimethoxyamphetamine hydro-
chloride-d6, (6). 1,4-Dimethoxybenzene-d6 (2) was pre-
pared by reacting hydroquinone with methyl iodide-d3.38-40
Formylation with dichloromethyl methyl ether and TiCl4
gave 2,5-dimethoxybenzaldehyde-d6 (3),41-46 and then con-
densation with nitroethane yielded 1,4-dimethoxy-2-(2-
nitropropenyl)benzene-d6 (4). Reduction with lithium alu-
minum hydride yielded (±)-2,5-dimethoxyamphetamine-
d6 (5), and bromination with bromine in acetic acid gave
(±)-4-bromo-2,5-dimethoxyamphetamine hydrochloride-
d6, (6).25
The abuse of psychoactive drugs from the phenethyl-
amine and phenisopropylamine groups has become a very
serious social problem in Taiwan during the last decade.14-24
Amphetamine, its N-methyl homologues methylamphet-
amine, and ring-substituted analogues, 4-methylenediox-
methylamphetamine (MDMA), 3,4-methylenedioxyethyl-
amphetamine (MDE), DOB, DMA and PMA are among
those most widely taken by young people. Standard sam-
ples for controlled drug analysis in Taiwan are very diffi-
cult to obtain. This study describes synthetic routes to DOB-
d6, DMA-d6 and PMA-d3, and presents relevant character-
istic analytical data. The synthetic approach described
herein is potentially applicable to the synthesis of a wide
variety of other amphetamine drugs. Meanwhile, applica-
tions of DOB-d6, DMA-d6 and PMA-d3 as internal stan-
dards were also investigated in this work. According to the
authors’ knowledge, the literature includes no report on
these compounds.
Scheme II presents the preparation of 4-methoxy-
amphetamine-d3 (10). p-Anisaldehyde-d3 (8) was prepared
by reacting 4-hydroxybenzaldehyde (7) with iodometh-
ane-d3.38-40 The condensation of compound 8 with nitro-
Scheme I
OH
OCD3
OCD3
OCD3
CD3I
KOH
Cl2CHOCH3
TiCl4
CH3CH2NO2
CH3
NO2
CHO
OH
OCD3
OCD3
D3CO
1
2
3
4
OCD3
D3CO
Br
NH2
CH3
LiAlH4
Br2
CH3
NH2
AcOH
OCD3
D3CO
5: DMA-d6
6: DOB-d6
Scheme II
NH2
CH3
NO2
CH3
O
H
O
H
CD3I
KOH
CH3CH2NO2
LiAlH4
OH
OCD3
OCD3
10: PMA-d3
OCD3
7
8
9

Synthesis of Deuterium Labeled DMA, DOB, PMA
J. Chin. Chem. Soc., Vol. 54, No. 2, 2007 495
ethane gave 1-(4-methoxyphenyl)-2-nitropropene-d3 (9),
and reduction with LiAlH4 yielded (±)-4-methoxyamphet-
amine-d3 (10).25
Table 1. Retention times and ions monitored for GC/MS analysis
Retention time
(min)
Ions monitored*
(relative intensity, %)
Compound
DMA-d6
DMA
5.19
5.20
6.12
6.13
4.60
4.61
184, 297 (93.2), 157 (92.5)
178, 291 (95.4), 151 (91.0)
235, 262 (86.8), 375 (60.8)
229, 256 (85.5), 369 (57.3)
124, 151 (40.3), 264 (11.32)
121, 148 (40.1), 261 (10.32)
Both labeled and unlabeled compounds were deriva-
tized by trifluoroacetic anhydride and analyzed by gas
chromatography (GC). The retention times of GCs of three
sets of labeled and unlabeled compounds vary very little
(0.01 min), and the quantification by MS with the selected
ion monitoring technique in order enhanced the perfor-
mance of quantitative analysis (Table 1). The mass spectra
of the compounds under investigation were obtained by
conventional EI mass spectrometry (Figs. 2-7). The linear-
ity of the method was determined by applying calibration
standards at 0, 500, 1000 and 2000 ng of analyte. Linear re-
gression of the calibration curves gave r2 values of between
0.9968 and 1.000, with most values > 0.9900 (Table 2).
The EI mass spectrum of the (±)-N-[2-(2,5-dimeth-
DOB-d6
DOB
PMA-d3
PMA
*Quantification ions marked by bold.
Table 2. The linear regression of the calibration curves
Coefficient of correlation
Compound
Regression line
(r2)
DMA
DOB
PMA
0.9992
0.9995
0.9968
y = 0.0016x - 0.0214
y = 0.0023x + 0.0473
y = 0.0022x - 0.0406
Fig. 2. The mass spectra of (±)-N-[2-(2,5-dimethoxyphenyl)-1-methylethyl]-2,2,2-trifluoroacetamide-d6.
Fig. 3. The mass spectra of (±)-N-[2-(2,5-dimethoxyphenyl)-1-methylethyl]-2,2,2-trifluoroacetamide.

496 J. Chin. Chem. Soc., Vol. 54, No. 2, 2007
Xu et al.
Fig. 4. The mass spectra of (±)-N-[2-(4-bromo-2,5-dimethoxyphenyl)-1-methylethyl]-2,2,2-trifluoroacetamide-d6.
Fig. 5. The mass spectra of (±)-N-[2-(4-bromo-2,5-dimethoxyphenyl)-1-methylethyl]-2,2,2-trifluoroacetamide.
Fig. 6. The mass spectra of (±)-N-[2-(4-methoxyphenyl)-1-methylethyl]-2,2,2-trifluoroacetamide-d3.

Synthesis of Deuterium Labeled DMA, DOB, PMA
J. Chin. Chem. Soc., Vol. 54, No. 2, 2007 497
Fig. 7. The mass spectra of (±)-N-[2-(4-methoxyphenyl)-1-methylethyl]-2,2,2-trifluoroacetamide.
oxyphenyl)-1-methylethyl]-2,2,2-trifluoroacetamide-d6
(Fig. 2) has a base peak ion at m/z 184. This odd electron
ion was formed by a McLafferty rearrangement to elimi-
nate a trifluoroacetamide (Scheme III). The ion m/z 157
was also generated by eliminating an N-ethylidene-2,2,2-
trifluoroacetamide from the molecular ion m/z 297. Ion m/z
125 was formed from ion m/z 157 by the well-known spe-
cific six-center H-rearrangement of a g-D-atom of the meth-
oxy-d3 (OCD3) side chain to the benzylic part eliminating
neutral formaldehyde-d2 (CD2O). This rearrangement was
proven by comparing the mass spectrum of (±)-N-[2-(2,5-di-
methoxyphenyl)-1-methylethyl]-2,2,2-trifluoroacetamide
(Fig. 2) and (±)-N-[2-(2,5-dimethoxyphenyl)-1-methyleth-
yl]-2,2,2-trifluoroacetamide-d3 (Fig. 3), because the ion
m/z 121 corresponds to ion m/z 125 in N-[2-(2,5-dimeth-
oxyphenyl)-1-methylethyl]-2,2,2-trifluoroacetamide-d3,
and ion m/z 125 has four deuterium atoms.
The EI mass spectrum of the (±)-N-[2-(4-bromo-2,5-
Scheme III Spectral interpretation of (±)-N-[2-(2,5-dimethoxyphenyl)-1-methylethyl]-2,2,2-trifluoro-
acetamide-d6

498 J. Chin. Chem. Soc., Vol. 54, No. 2, 2007
Xu et al.
dimethoxyphenyl)-1-methylethyl]-2,2,2-trifluoroacet-
amide-d6 (Fig. 4) has a base peak ion at m/z 235, which was
formed by eliminating an N-ethylidene-2,2,2-trifluoroacet-
amide the from molecular ion m/z 375 (Scheme IV). Ion
m/z 262 was formed from ion m/z 375 by McLafferty rear-
rangement, eliminating trifluoroacetamide. Ion m/z 203
was formed from ion m/z 235 by the well-known specific
six-center H-rearrangement of a g-D-atom on the meth-
oxy-d3 (OCD3) side chain to the benzylic part, eliminating
neutral formaldehyde-d2 (CD2O). This rearrangement was
proven by comparing the mass spectra of Fig. 4 and Fig. 5.
DOB-d6 contains a bromine, and ions m/z 375, 262, 235 and
203, which always have corresponding isotopic ions m/z
377, 264, 237 and 205.
The EI mass spectrum of the (±)-N-[2-(4-methoxy-
phenyl)-1-methylethyl]-2,2,2-trifluoroacetamide-d3 (Fig.
6) has a base peak ion at m/z 124, which was formed by
eliminating an N-ethylidene-2,2,2-trifluoroacetamide from
molecular ion m/z 264 (Scheme V). Ion m/z 151 was
formed from ion m/z 264 by McLafferty rearrangement to
eliminate a trifluoroacetamide.
In conclusion, this study demonstrates the syntheses
Scheme IV Spectral interpretation of (±)-N-[2-(4-bromo-2,5-dimethoxyphenyl)-1-methylethyl]-2,2,2-
trifluoroacetamide-d6
Scheme V Spectral interpretation of (±)-N-[2-(4-methoxyphenyl)-1-methylethyl]-2,2,2- trifluoroacetamide

Synthesis of Deuterium Labeled DMA, DOB, PMA
J. Chin. Chem. Soc., Vol. 54, No. 2, 2007 499
of (±)-2,5-dimethoxyamphetamine-d6, (±)-4-bromo-2,5-
dimethoxyamphetamine-d6 and (±)-4-methoxyamphet-
amine-d3. Although the retention times of GCs of three sets
of labeled and unlabeled compounds vary very little (0.01
min), the quantification by MS with the selected ion moni-
toring (SIM) technique enhances the performance of quan-
titative analysis. Therefore, three deuterium-labeled com-
pounds possess the potential to be used as the internal stan-
dard for GC-MS analysis.
GC/MS analysis.
General Chemical Procedures
1H NMR spectra were acquired at 300 MHz (indi-
cated in each case), and 13C NMR were acquired at 75.5
MHz on a Bruker NMR spectrometer. Chemical shifts (d)
are reported in ppm relative to CHCl3 (7.26 and 77.0 ppm).
Mass spectra (MS) were obtained on a Micromass Platform
II mass spectrometer at a 70 eV. High resolution mass spec-
tra (HRMS) were obtained on a Finnigan/Thermo Quest
MAT 95XL mass spectrometer. Infrared spectra were re-
corded on an ATI Mattson spectrometer. All reactions were
performed in anhydrous solvents. Tetrahydrofuran and di-
ethyl ether were distilled from sodium-benzophenone in ar-
gon. Toluene, acetonitrile, dichloromethane, and hexane
were distilled from calcium hydride. All air sensitive reac-
tions were performed in dry glassware under nitrogen using
a standard glovebox. Flash column chromatography was
performed using MN silica gel 60 (70-230 mesh) which
was purchased from Macherey-Nagel.
EXPERIMENTAL SECTION
Methanol and ethyl acetate were obtained from
Mallinckrodt (Paris, KY, USA). Trifluoroacetic anhydride
(TFA) was purchased from Fluka (Buchs, Switzerland).
Stock solutions of analytes and their deuterium analog (100
mg/mL) were prepared in methanol. Subsequent working
solutions for calibration samples were prepared by diluting
stock solutions with methanol.
A Hewlett Packard 6890 gas chromatograph, coupled
to a Hewlett Packard 5973 quadrupole mass spectrometer
under EI conditions, was employed. Injection was per-
formed in splitless mode. The flow rate of the carrier gas
(He) was 0.6 mL/min. An HP-5MS column (12.5 m ´ 0.20
mm ID, 0.33 µm film thickness; Agilent Technologies,
Palo Alto, CA, USA) was employed. The injection port
temperature was maintained at 250 °C. The GC oven tem-
1,4-Dimethoxybenzene-d6 (2)
Adequate amounts of potassium hydroxide pellets
(4.30 g, 77.0 mmol) were ground to powder; tetrabutyl-
ammonium bromide (0.39 g, 1.2 mmol) and hydroquinone
(3.40 g, 30.0 mmol) were then added and blended in a nitro-
gen atmosphere at room temperature.38-40 Methyl iodide-d3
(5.6 mL, 93.0 mmol) was then added and the mixture was
heated in an oil bath for 3 days at 40-45 °C. The crude mix-
ture was then transferred to a separating funnel with water
and diethyl ether and extracted using diethyl ether. The ex-
tracts were dried over anhydrous magnesium sulfate. Fil-
tration and concentration yielded a residue, which was pu-
rified by flash column chromatography using silica gel as
the stationary phase and ethyl acetate-hexane (1:19) as the
mobile phase producing a white crystal 2 (4.22 g, 29.0
o
perature program started at 70 C, at which temperature
was maintained for 0.5 min, before it was increased at 30
°C/min to 250 °C, at which it was maintained there for 0.5
min. 1 mL of the sample was injected for GC/MS analysis in
full scan monitoring mode. The total analytic time was 12
min per sample with a solvent delay of 3.0 min. The trans-
fer line temperature and MS source temperature were 280
°C and 230 °C, respectively. The electron energy of MS
was set to 70 eV. Full scan mass spectra of analytes and
their deuterium analogs were collected in the range m/z
50-450 at a scan rate of 3.62 scan/sec.
1
mmol). Yield: 98%. mp: 56-57 °C. H NMR (300 MHz,
CDCl3, d): 6.90 (s, 4H). 13C NMR (75 MHz, CDCl3, d):
153.7, 114.6, 55.2-54.6 (m). IR (KBr, thin film): 3164,
3106, 3061, 3044, 2505, 2217, 2065, 1943, 1867 cm-1.
To a clean 12-mL screw-cap glass tube was added
analyte and 500 ng of deuterium analog. The mixture was
evaporated to dryness under a stream of nitrogen gas at
50-60 °C. The dried extract was dissolved in 50 mL of ethyl
acetate and derivatized with 50 mL of trifluoroacetic anhy-
dride for 30 min at 60 °C. Samples were then cooled to
room temperature, evaporated to dryness, and reconstituted
by adding 50 mL of ethyl acetate. 1 mL was injected for
2,5-Dimethoxybenzaldehyde-d6 (3)
To a solution of 2 (3.50 g, 25.0 mmol) in dry dichloro-
methane (478 mL) cooling in an ice bath was added tita-
nium tetrachloride (5.0 mL, 46.0 mmol), and dichlorometh-
oxymethane (CHCl2OCH3) (4.2 mL, 46.5 mmol) under ar-
gon atmosphere.41-46 The dark red reaction solution was

500 J. Chin. Chem. Soc., Vol. 54, No. 2, 2007
Xu et al.
stirred at room temperature for 15 min until the starting ma-
terial was completely consumed, by monitoring with TLC.
The reaction was quenched by adding 185 mL of water, and
the dichloromethane layer was washed with 140 mL of wa-
ter and then dried over anhydrous magnesium sulfate. The
solution was filtered, and the filtrate was concentrated by
rotary vacuum evaporation. The residue was purified by
flash column chromatography using silica gel as the sta-
tionary phase and ethyl acetate-hexane (1:39) as the mobile
phase producing a white crystal 3 (3.15 g, 18.3 mmol).
sion mixture of lithium aluminum hydride (1.19 g, 31.4
mmol) in anhydrous diethyl ether (10.8 mL). The mixture
was then brought up to a reflux and maintained there for 20
h, cooled with an external ice bath, and the excess hydride
was destroyed by the cautious addition of water. The
quenched mixture was filtered through celite, washed with
diethyl ether, and the filtrate was diluted with water to a to-
tal volume of 54 mL. Then potassium sodium tartrate (3.30
g, 113.0 mmol) was added, and sufficient aqueous sodium
hydroxide added to bring the pH above 9. The two phases
were separated, and the aqueous phase was extracted with
dichloromethane. The combined organic phases were dried
over anhydrous magnesium sulfate. Filtration and concen-
tration yielded a residue, which was dissolved in dry dieth-
yl ether, and saturated with hydrogen chloride. The formed
crystals of 2,5-dimethoxyamphetamine hydrochloride-d6
(2,5-DMA-d6, 5) were collected by filtration, washed with
anhydrous diethyl ether, and dried to constant weight. The
hydrochloric acid salt of 5 was crystallized from ethanol/
diethyl ether, and gave 5 (1.27 g, 5.48 mmol). Yield: 70%.
1H NMR (300 MHz, CDCl3, d): 6.79-6.69 (m, 3H), 3.22-
3.15 (m, 1H), 2.74-2.46 (m, 2H), 1.11 (d, J = 3.6 Hz, 3H).
13C NMR (75 MHz, CDCl3, d): 153.1, 151.7, 129.1, 117.1,
111.1, 111.0, 55.0-54.1 (m), 46.9, 43.2, 41.1, 23.4. IR
(KBr, thin film): 3359, 3289, 3066, 3043, 2962, 2923,
2869, 2248, 2213, 2129, 2067, 1589, 1496, 1234, 1110, 686
cm-1. MS-EI (m/z): 201 (6), 194 (15), 192 (50), 174 (33),
158 (100), 140 (26). HRMS-EI (m/z): [M+] calcd for
C11H11D6NO2, 201.1629; found 201.1637.
1
Yield: 73%. mp: 51 °C. H NMR (300 MHz, CDCl3, d):
10.48 (s, 1H), 7.33 (d, J = 3.2 Hz, 1H), 7.15 (dd, J = 9.1, 3.3
Hz, 1H), 6.95 (d, J = 9.1 Hz, 1H). 13C NMR (75 MHz,
CDCl3, d): 189.5, 156.7, 153.5, 124.9, 123.4, 113.3, 110.4,
55.6-54.7 (m). IR (KBr, thin film): 3098, 3052, 2873, 2231,
2070, 1674, 1616, 1495, 1432, 1401, 1293, 1221 cm-1.
MS-FAB (m/z): 173 (M+ + 1, 100). HRMS-FAB (m/z):
[M+] calcd for C9H4D6O3, 172.1004; found 172.1002.
1,4-Dimethoxy-2-(2-nitropropenyl)benzene-d6 (4)
A solution of 2,5-dimethoxybenzaldehyde-d6 (3)
(3.00 g, 18.0 mmol) in glacial acetic acid (15.5 mL) was
treated with nitroethane (2.17 g, 29.0 mmol) and anhydrous
ammonium acetate (1.39 g, 18.0 mmol).5-a This mixture
was heated in a steam bath for 3 h and then the excess re-
agent and solvent was removed under vacuum. The residue
was suspended in water and extracted with dichlorometh-
ane. The extracts were dried over anhydrous magnesium
sulfate. Filtration and concentration yielded a residue,
which was purified by flash column chromatography using
silica gel as the stationary phase and using ethyl acetate-
hexane (1:39) as the mobile phase producing compound 4
(3.53 g, 15.4 mmol). Yield: 86%. mp: 77-78 °C. 1H NMR
(300 MHz, CDCl3, d): 8.23 (s, 1H), 6.69 (q, J = 3.0 Hz, 1H),
6.87 (s, 1H), 6.85 (d, J = 2.9 Hz, 1H), 2.39 (s, 3H). 13C
NMR (75 MHz, CDCl3, d): 153.1, 152.7, 147.7, 130.1,
122.5, 115.7, 115.4, 111.7, 55.4-54.6 (m), 14.11. IR (KBr,
thin film): 3070, 2923, 2854, 2356, 2248, 2225, 2071,
1646, 1496, 1427, 1295, 1268, 1238 cm-1. MS-FAB (m/z):
230 (M++1, 3), 214 (9), 184 (100), 115 (1). HRMS-FAB
(m/z): [M]+ calcd for C11H7D6NO4, 229.1251; found
229.1221.
(±)-1-(4-Bromo-2,5-dimethoxyphenyl)-2-propaneamine-
d6 (6)
To a well-stirred solution of 2,5-dimethoxyamphet-
amine hydrochloride-d6 (5) (0.38 g, 1.9 mmol) in glacial
acetic acid (3 mL) was added a solution of elemental bro-
mine (0.06 mL, 1.2 mmol) in acetic acid (0.5 mL) over 5
min. The slightly exothermic reaction was allowed to stir
for 3 h, and then added to water (20 mL). The cloudy solu-
tion was washed with diethyl ether, made basic with aque-
ous sodium hydroxide, and extracted with dichlorometh-
ane. Evaporation of the solvent from the pooled extracts
gave a pale amber oil which was dissolved in 20 mL anhy-
drous diethyl ether and saturated with anhydrous hydrogen
chloride. The fine white crystals of (±)-2,5-dimethoxy-4-
bromoamphetamine hydrochloride-d6 (6), were collected
by filtration, Et2O washed, and air dried to give product 6
(0.40 g, 1.4 mmol). Yield: 74%. 1H NMR (300 MHz, CDCl3,
(±)-1-(2,5-Dimethoxyphenyl)-2-propaneamine-d6 (5)
A solution of (±)-1-(2,5-dimethoxyphenyl)-2-nitro-
propene-d6 (4) (1.75 g, 7.8 mmol) in anhydrous diethyl
ether (53.0 mL) was added slowly to a well-stirred suspen-

Synthesis of Deuterium Labeled DMA, DOB, PMA
J. Chin. Chem. Soc., Vol. 54, No. 2, 2007 501
d): 7.02 (1H), 6.72 (s, 1H), 3.21 (t, J = 6.9 Hz, 1H), 2.71-
2.44 (m, 2H), 1.11 (d, J = 6.3 Hz, 3H). 13C NMR (75 MHz,
CDCl3, d): 152.1, 149.7, 128.3, 115.8, 115.3, 108.9, 46.9,
41.0, 23.6. IR (KBr, thin film): 3336, 3239, 3154, 2954,
2919, 2873, 2213, 2071, 1488, 1392, 1230 cm-1. MS-EI
(m/z): 281 (8), 279 (6), 265 (4), 263 (5), 238 (99), 236 (100),
220 (13), 218 (11), 205 (10), 203 (11), 143 (10), 78 (38).
HRMS-EI (m/z): [M+] calcd for C11H10D6NO2Br, 279.0734;
found 279.0733.
1H NMR (300 MHz, CDCl3, d): 8.07 (s, 1H), 7.41 (d, J =
2.9 Hz, 2H), 6.99 (d, J = 3.0 Hz, 2H), 2.47 (s, 3H). 13C NMR
(75 MHz, CDCl3, d): 161.1, 145.6, 133.6, 131.7, 125.7,
114.8, 55.2-55.3 (m), 14.0. IR (KBr, thin film): 2221, 2069,
1643, 1598, 1513, 1494, 1307, 1267, 1176 cm-1. MS-FAB
(m/z): 197 (M++1, 48), 181 (59), 150 (27), 149 (100), 132
(50). HRMS-FAB (m/z): [M]+ calcd for C10H8D3NO3,
196.0924; found 196.0925.
(±)-1-(4-Methoxyphenyl)-2-propaneamine-d3 (10)
4-Methoxybenzaldehyde-d3 (8)
To a suspension of lithium aluminum hydride (0.84 g,
22.1 mmol) in anhydrous diethyl ether (30.0 mL) was
added a solution of (±)-1-(4-methoxyphenyl)-2-nitropro-
pene-d3 (9) (0.87 g, 4.4 mmol) in diethyl ether (30.0 mL),
and it was added at a rate that maintained a reflux. After the
addition was complete, reflux was continued for 48 h. The
reaction mixture was cooled, and the excess hydride was
destroyed by the cautious addition of dilute sulfuric acid.
The quenched mixture was filtered through celite and
washed with diethyl ether. The organic phase was separated
and extracted with additional aqueous sulfuric acid. A solu-
tion of potassium sodium tartrate (21.00 g, 74.4 mmol) in
water (18 mL) was added, and the pH brought to > 9 with
25% sodium hydroxide. This aqueous phase was extracted
using dichloromethane; after removal of the solvent, it pro-
vided a clear amber oil 10. Compound 10 was dissolved in
10 mL 2-propanol, saturated with hydrogen chloride, and
then diluted with 10 mL anhydrous diethyl ether. After
standing overnight, white crystals of 4-methoxyamphet-
amine hydrochloride-d3 (10.HCl) were obtained; after fil-
tering, diethyl ether washing and drying gave product
Adequate amounts of potassium hydroxide pellets
(0.92 g, 16.0 mmol) were ground to powder; tetrabutylam-
monium bromide (83 mg, 0.3 mmol) and 4-hydroxybenz-
aldehyde (2.00 g, 16.0 mmol) were then added and blended
in a nitrogen atmosphere at room temperature.5-a Methyl io-
dide-d3 (0.52 g, 819 mmol) was then added and the mixture
was heated in an oil bath for three days at 40-45 °C. The
crude mixture was then transferred to a separating funnel
with water and extracted using dichloromethane. The com-
bined extracts were dried over anhydrous magnesium sul-
fate. Filtration and concentration yielded a residue, which
was purified by flash column chromatography using silica
gel as the stationary phase and ethyl acetate-hexane (1:39,
1:19) as the mobile phase producing compound 8 (1.02 g,
1
7.3 mmol). Yield: 89%. H NMR (300 MHz, CDCl3, d):
9.88 (s, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.7 Hz,
2H). 13C NMR (75 MHz, CDCl3, d): 190.8, 164.6, 131.9,
129.9, 114.3, 55.3-54.1 (m). IR (KBr, thin film): 3358,
3066, 2922, 2743, 2258, 2222, 2070, 1693, 1598, 1504,
1316 cm-1. MS-FAB (m/z): 140 (M++1, 17), 138 (45), 124
(100), 105 (62), 75 (45). HRMS-FAB (m/z): [M+H]+ calcd
for C8H6D3O2, 140.0787; found 140.0790.
1
10.HCl (0.57 g, 2.8 mmol). Yield: 63%. H NMR (300
MHz, D2O, d): 7.15 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.7 Hz,
2H), 3.52-3.41 (m, 1H), 2.83-2.70 (m, 2H), 1.18 (d, J = 6.6
Hz, 3H). 13C NMR (75 MHz, D2O, d): 157.9, 130.6, 128.5,
114.3, 55.1-53.9 (m), 49.3, 49.2, 39.2, 17.4. IR (KBr, thin
film): 2942, 2802, 2748, 2603, 2213, 2190, 2065, 1513,
1261, 1114, 993 cm-1. MS-FAB (m/z): 169 (M+-Cl, 100),
152 (92), 151 (8), 150 (4). HRMS-FAB (m/z): [M-Cl] +
calcd for C10H13D3NO, 169.1416; found 169.1417.
1-Methoxy-4-(2-nitropropenyl)benzene-d3 (9)
A solution of p-anisaldehyde-d3 (8) (0.94 g, 6.8 mmol)
in glacial acetic acid (3.8 mL) was treated with nitroethane
(0.97 g, 14.0 mmol) and anhydrous ammonium acetate
(0.78 g, 10.1 mmol).5-a This mixture was refluxed for 60
min and then the excess reagent and solvent was removed
under vacuum. The residue was suspended in water and ex-
tracted with dichloromethane. The extracts were dried over
anhydrous magnesium sulfate. Filtration and concentration
yielded a residue, which was purified by flash column chro-
matography using silica gel as the stationary phase and
ethyl acetate-hexane (1:39) as the mobile phase producing
compound 9 (0.87 g, 4.4 mmol). Yield: 66%. mp: 46-47 °C.
ACKNOWLEDGEMENTS
The authors thank Ms. Hsu, L. M. at the Instruments
Center, National Chung Hsing University, and Ms. Lin, S.
C. at the Instrument Center, National Tsing Hwa Univer-

502 J. Chin. Chem. Soc., Vol. 54, No. 2, 2007
Xu et al.
Hsiao, C. C.; Chiang, Y. L.; Ree, S. C.; Chen, C. K. Psychia-
try Clin. Neurosci. 2004, 58, 206.
sity, for their help in obtaining HRMS spectra. We would
also like to thank the National Bureau of Controlled Drugs,
Department of Health, Taiwan, Republic of China, for fi-
nancially supporting this research under Contract DOH94-
NNB-1007.
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