Synthesis of deuterium labeled phenethylamine derivatives

Article abstract of DOI:10.1002/jlcr.1139

The synthesis of a series of five deuterium labeled phenethylamine derivatives, 4-bromo-2,5-[²H₆]-dimethoxyphenethylamine (2C-B), 4-chloro-2,5-[²H₆]-dimethoxyphenethylamine (2C-C), 2,5-[²H₆]-dimethoxy-4-iodophenethylamine (2C-I), 2,5-[²H₆]-dimethoxy-4-ethylthiophenethylamine (2C-T-2) and 2,5-[²H₆]-dimethoxy-4-n-propylthiophenethylamine (2C-T-7) from 1,4-[²H₆]-dimethoxybenzene is described. The isotopically labeled compounds are used as internal standards in gas chromatography-mass spectrometry (GC-MS) assays. Copyright

Full text of DOI:10.1002/jlcr.1139

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2006; 49: 1187–1200.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.1139
Research Article
Synthesis of deuterium labeled phenethylamine
derivatives
Ya-Zhu Xu and Chinpiao Chen*
Department of Chemistry, National Dong Hwa University, Soufeng, Hualien 974,
Taiwan, Republic of China
Summary
The synthesis of a series of five deuterium labeled phenethylamine derivatives,
4-bromo-2,5-[2H6]-dimethoxyphenethylamine (2C-B), 4-chloro-2,5-[2H6]-dimethoxy-
phenethylamine (2C-C), 2,5-[2H6]-dimethoxy-4-iodophenethylamine (2C-I), 2,5-[2H6]-
dimethoxy-4-ethylthiophenethylamine (2C-T-2) and 2,5-[2H6]-dimethoxy-4-n-propy-
lthiophenethylamine (2C-T-7) from 1,4-[2H6]-dimethoxybenzene is described. The
isotopically labeled compounds are used as internal standards in gas chromatography-
mass spectrometry (GC-MS) assays. Copyright # 2006 John Wiley & Sons, Ltd.
Received 28 August 2006; Revised 14 September 2006; Accepted 15 September 2006
Key Words: deuterium labeling; phenethylamine; designer drugs; 2C-C; 2C-B; 2C-I;
2C-T-2; 2C-T-7
Introduction
The increased availability of 2C-series (phenethylamine derivatives) on the
illicit drug market has become a serious societal problem.1 Shulgin et al. in
their publication Phenethylamines I Have Known And Loved (PiHKAL),
documented over 179 phenethylamine derivatives, including 3,4-methylene-
dioxymeth-amphetamine (NMDA), mescaline, 2C-B, 2C-C, 2C-I, 2CT-2 and
2C-T-7, and described the procedures for producing these drugs.2 Phenethy-
lamine derivatives are increasingly abused psychoactive drugs and well
documented in literature.3–8 The continuing designer drug exploration of
*Correspondence to: Chinpiao Chen, Department of Chemistry, National Dong Hwa University, Soufeng,
Hualien 974, Taiwan, Republic of China. E-mail: chinpiao@mail.ndhu.edu.tw
Contract/grant sponsor: National Bureau of Controlled Drugs, Department of Health, Taiwan, the
Republic of China; Contract/grant number: DOH94-NNB-1007
Copyright # 2006 John Wiley & Sons, Ltd.

1188
Y.-Z. XU AND C. CHEN
homologous series and their widespread consumption has resulted in an
increasing number of reports regarding abuse and intoxication.
The abuse of psychoactive drugs derived from phenylethylamine and
phenylisopropylamine groups has became a serious societal problem in
Taiwan in the recent decade.9–15 Amphetamine, its N-methyl homologues
methylamphetamine, and ring-substituted analogues, MDMA and 3,4-
methylenedioxyethylamphetamine (MDE) are among the most widely abused
drugs among young individuals.
Stable isotope labeled internal standards for controlled drugs analyses in
Taiwan are extremely difficult to obtain. This work describes synthetic routes
to, and characterization of, [2H6]-2C-C, [2H6]-2C-B, [2H6]-2C-I; [2H6]-2C-T-2
and [2H6]-2C-T-7, and presents their characteristic analytical data for them.
The synthetic method presented herein is promising for synthesizing a wide
variety of other amphetamine-based drugs. According to our knowledge, these
compounds have never been investigated in literature.
Results and discussion
Although 2C-B, 2C-C, 2C-I 2C-T-2 and 2C-T-7 have been readily prepared by
several synthetic routes,2 preparing [2H6]-2C-B, [2H6]-2C-Cl, [2H6]-2C-I, [2H6]-
2C-T-2 and [2H6]-2C-T-7 has not been described previously. Scheme 1 presents
the general synthetic scheme to prepare [2H6]-2C-B (6), [2H6]-2C-C (7) and
[2H6]-2C-I (8). 1,4-[2H6]-Dimethoxybenzene (2) was prepared by reacting
hydroquinone and [2H3]-methyl iodide.16–19 Compound 2 was treated with
OCD3
OCD3
OH
OCD3
CH3NO2
Cl2CHOCH3
TiCl4
CD3I
KOH
CHO
NO2
OCD3
OCD3
OCD3
OH
1
2
3
4
D3CO
Br
Br2,AcOH
NH2
OCD3
OCD3
6
LiAlH4
NH2
OCD3
NH2
OCD3
D3CO
Cl
SO2Cl2
NH2
OCD3
7
8
5
a. phthalic anhydride
b. ICl
D3CO
I
c. H2NNH2
Scheme 1. Synthesis of compounds 6–8
Copyright # 2006 John Wiley & Sons, Ltd.
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DOI: 10.1002/jlcr

SYNTHESIS OF DEUTERIUM LABELED PHENETHYLAMINE DERIVATIVES 1189
dichloromethyl methyl ether and TiCl4 gave 2,5-[2H6]-dimethoxybenzaldehyde
(3),20–25 which was then condensed with nitromethane to yield 1,4-[2H6]-
dimethoxy-2-(2-nitrovinyl)benzene (4). Reduction of compound 4 with
LiAlH4 produced 2-(2,5-[2H6]-dimethoxyphenyl)ethylamine (5). The bromina-
tion of 5 with bromine in acetic acid yielded 2-(4-bromo-2,5-[2H6]-
dimethoxyphenyl)ethylamine (6), and chlorination of 5 with SO2Cl2 gave
2-(4-chloro-2,5-[2H6]-dimethoxyphenyl)ethylamine (7). Treatment of 5 with
phthalic anhydride gave 2-[2-(2,5-[2H6]-dimethoxyphenyl)ethyl]isoindole-1,
3-dione, which was then reacted with iodine monochloride (ICl) and gave
2-[2-(4-iodo-2,5-[2H6]-dimethoxyphenyl)ethyl]isoindole-1,3-dione, which was
treated with hydrazine to generate 2-(4-iodo-2,5-[2H6]-dimethoxyphenyl)
ethylamine (8).
Scheme 2 presents the preparation of [2H6]-2C-T-2 (14a) and [2H6]-2C-T-7
(14b). 2,5-[2H6]-Dimethoxybenzenesulfonyl chloride (9) was prepared by
reacting 1,4-[2H6]-dimethoxybenzene (2) with chlorosulfonic acid. Compound
9 was reduced to generate 2,5-[2H6]-dimethoxybenzenethiol (10) by zinc in
hydrochloric acid. Alkylation of compound 10 by bromoethane yielded
2,5-[2H6]-dimethoxyphenyl ethyl sulfide (11a), and the formylation by
N,N-dimethylformamide and phosphoryl chloride produced 4-ethylsulfanyl-
2,5-[2H6]-dimethoxybenzaldehyde (12a). Condensation of compound 12a with
nitromethane formed 1-ethylsulfanyl-2,5-[2H6]-dimethoxy-4-(2-nitrovinyl)
benzene (13a). Reduction of compound 13a by lithium aluminum hydride
gave 2,5-[2H6]-dimethoxy-4-ethylthiophenethylamine hydrochloride (14a).
Next, compound 10 was treated with bromopropane, and the same procedures
as described earlier generated the corresponding 2,5-[2H6]-dimethoxyphenyl
n-propyl sulfide (11b), 2,5-[2H6]-dimethoxy-4-propylsulfanylbenzaldehyde
OCD3
OCD3
OCD3
OCD3
ClSO3H
Zn, HCl
R-Br
a: R = C2H5
b: R = C3H7
SH
SR
SO2Cl
OCD3
OCD3
OCD3
OCD3
10
2
9
11a: R = C2H5
11b: R = C3H7
OCD3
OCD3
OCD3
D3CO
NH2
CHO
RS
CH3NO2
LiAlH4
DMF
POCl3 RS
RS
OCD3
NO2
OCD3
12a: R = C2H5
12b: R = C3H7
13a: R = C2H5
13b: R = C3H7
14a: R = C2H5
14b: R = C3H7
Scheme 2. Synthesis of compounds 14a and 14b
Copyright # 2006 John Wiley & Sons, Ltd.
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Y.-Z. XU AND C. CHEN
(12b), 1,4-[2H6]-dimethoxy-2-(2-nitrovinyl)-5-propylsulfanylbenzene (13b) and
2,5-[2H6]-dimethoxy-4-n-propylthiophenethylamine hydrochloride (14b).
Experimental
General
1H NMR spectra were acquired at 300 MHz (indicated 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 CDCl3 (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 spectra (HRMS) were obtained
on a Finnigan/Thermo Quest MAT 95XL mass spectrometer. Infrared spectra
were recorded on a JASCO FT/IR 410 spectrometer. All reactions were
performed in anhydrous solvents. Tetrahydrofuran and diethyl ether were
distilled from sodium-benzophenone in argon. Toluene, acetonitrile, dichlor-
omethane, and hexane were distilled from calcium hydride. All air sensitive
reactions 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.
All reactions were initially optimized using unlabeled compounds.
Synthesis of 1,4-[2H6]-dimethoxybenzene (2). Potassium hydroxide pellets
(4.30 g, 77.0 mmol) were ground to a powder, tetrabutylammonium bromide
(0.39 g, 1.2 mmol) and hydroquinone (3.40 g, 30.0 mmol) were then added, and
ground under a nitrogen atmosphere at room temperature.16–19 [2H3]-Methyl
iodide (5.6 ml, 93.0 mmol; isotopic abundance 99.5%, Cambridge Isotope
Laboratories Inc.) was then added and the mixture was heated in an oil bath
for 3 days at 40–458C. The crude mixture was then transferred to a separating
funnel with water and diethyl ether, and aqueous phase was extracted using
diethyl ether. The extracts were dried over anhydrous magnesium sulfate.
Filtration and concentration yielded a residue that was purified by flash
column chromatography using silica gel as the stationary phase and ethyl
acetate–hexane (1:19) as the mobile phase to give (2) as a white crystalline solid
(4.22 g, 29.0 mmol). Yield: 98%. m.p.: 56–578C. 1H NMR (300MHz, CDCl3, d):
6.90 (s, 6 H). 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 cmÀ1
.
Synthesis of 2,5-[2H6]-dimethoxybenzaldehyde (3). To a solution of 2 (3.50 g,
25.0 mmol) in dry dichloromethane (478 ml) cooled in an ice bath was added
titanium chloride (5.0 ml, 46.0 mmol), and dichloromethyl methyl ether
(C12CHOCH3) (4.2 ml, 46.5 mmol) under an argon atmosphere.20–25 The
dark red reaction solution was stirred at room temperature for 15 min until the
starting material was completely consumed as monitored by thin layer
Copyright # 2006 John Wiley & Sons, Ltd.
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SYNTHESIS OF DEUTERIUM LABELED PHENETHYLAMINE DERIVATIVES 1191
chromatography (TLC). The reaction was quenched by adding water (185 ml),
and the dichloromethane layer was washed with water (140 ml) 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 stationary phase and ethyl
acetate–hexane (1:39) as the mobile phase to give (3) as a white crystalline solid
1
(3.15 g, 18.3 mmol). Yield: 73%. m.p.: 50–518C. H NMR (300 MHz, CDCl3,
d): 10.48 (s, 1 H), 7.33 (d, J=3.2 Hz, 1 H), 7.15 (dd, J=9.1, 3.3 Hz, 1 H), 6.95
(d, J=9.1 Hz, 1 H). 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 cmÀ1. MS-FAB (m/z): 173
(M++1, 100). HRMS-FAB (m/z): [M+] calculated for C9H4D6O3, 172.1000;
found 172.1002.
Synthesis of 1,4-[2H6]-dimethoxy-2-(2-nitrovinyl)benzene (4). A solution of
2,5-[2H6]-dimethoxybenzaldehyde (3) (2.90 g, 17.0 mmol) in nitromethane
(5.77 ml, 105.0 mmol) was treated with anhydrous ammonium acetate
(0.29 g) and heated at 1008C for 2.5 h until the starting material was
completely consumed by TLC monitoring. The solvent was removed under
vacuum yielding 2,5-[2H6]-dimethoxy-b-nitrostyrene (4) (3.50 g, 16.0 mmol) as
1
a yellow crystal. Yield: 73%. m.p.: 121–1228C. H NMR (300 MHz, CDCl3,
d): 8.14 (d, J=13.6 Hz, 1 H), 7.88 (d, J=13.7 Hz, 1 H), 7.03-6.99 (dd, J=9.0,
3.0 Hz, 1 H), 6.96 (d, J=2.9 Hz, 1 H), 6.91 (d, J=8.9 Hz, 1 H). 13C NMR
(75 MHz, CDCl3, d): 153.9, 153.5, 138.4, 135.3, 119.4, 119.1, 116.3, 112.4.
IR (KBr, thin film): 3104, 2221, 2075, 1616, 1496, 1346, 1253, 1234 cmÀ1
.
MS-FAB (m/z): 216 (M++1, 10), 170 (19), 75 (1 0 0). HRMS-FAB (m/z):
[M+H]+ calculated for C10H6D6NO4, 216.1137; found 216.1145.
Synthesis of 2-(2,5-[2H6]-dimethoxyphenyl)ethylamine (5). A suspension
of lithium aluminum hydride (2.70 g, 70.0 mmol) in anhydrous tetrahydrofur-
an (68.0 ml) under an inert atmosphere was stirred and heated to reflux. A
solution of 2,5-[2H6]-dimethoxy-b-nitrostyrene (4) (3.50 g, 16.0 mmol) in
tetrahydrofuran (15.0 ml) was added dropwise, and the reaction mixture was
maintained at reflux for 24 h. After cooling in an ice bath, excess hydride was
destroyed using a mixture of tetrahydrofuran and water (1:1) (20 ml), followed
by adding 2 N aqueous sodium hydroxide (20 ml). The solid was removed by
filtration through celite, and the filter cake was washed with additional
tetrahydrofuran. The combined filtrate and washes were concentrated under
vacuum, and the residue acidified by dilute hydrochloric acid. Washing with
dichloromethane (2 Â 30 ml) removed most color, and the aqueous phase was
basified with aqueous sodium hydroxide and extracted with dichloromethane
(3 Â 50 ml). After removing the solvent, the residue was readily converted to
Copyright # 2006 John Wiley & Sons, Ltd.
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Y.-Z. XU AND C. CHEN
hydrochloride salt by dissolving its in diethyl ether, neutralizing it with HCl(g),
and producing a permanent turbidity. The product was reprecipitated from
methanol/diethyl ether. Crystals of 2,5-[2H6]-dimethoxyphenethylamine hy-
drochloride (5) (1.55 g, 6.9 mmol) spontaneously formed and were removed
by filtration and washed with Et2O. Yield: 43%. 1H NMR (300 MHz, D2O, d):
6.92 (d, J=8.9 Hz, 1 H), 6.84-6.80 (dd, J=8.9, 3.0 Hz, 1 H), 6.78
(d, J=3.0 Hz, 1 H), 3.13 (t, J=6.8 Hz, 2 H), 2.86 (t, J=6.9 Hz, 2 H). 13C
NMR (75 MHz, CD3OD, d): 153.7, 151.7, 125.4, 116.5, 112.4, 111.2, 39.4,
28.6. IR (KBr, thin film): 2965, 2908, 2832, 2753, 2653, 2564, 2464, 2217, 2063,
1500, 1238 cmÀ1. MS-FAB (m/z): 188 (M+-Cl, 100), 185 (8), 171 (42), 158 (10),
75 (8). HRMS-FAB (m/z): [M+-Cl] calculated for C10H10D6NO2, 188.1552;
found 188.1553.
Synthesis of 2-(4-bromo-2,5-[2H6]-dimethoxyphenyl)ethylamine (6). Bromine
(0.43 ml, 8.4 mmol) dissolved in acetic acid (2.5 ml) and added to a well-stirred
solution of 2,5-[2H6]-dimethoxyphen-ethylamine (1.50 g, 8.0 mmol) in glacial
acetic acid (2.5 ml). After a few minutes, a solid precipitated with the
simultaneous evolution of considerable heat. The reaction mixture was
allowed to return to room temperature, filtered, and the solids were washed
sparingly with cold acetic acid. The entire mass of acetic acid-wet salt was
dissolved in warm water, and made basic to a pH 11 with 2 M aqueous sodium
hydroxide, and extracted with dichloromethane. Removal of the solvent gave 6
1
(0.50 g, 1.9 mmol). Yield: 24%. H NMR (300 MHz, CD3Cl, d): 7.02 (s, 1 H),
6.74 (s, 1 H), 2.93 (t, J=6.9 Hz, 2 H), 2.74 (t, J=7.2 Hz, 2 H). 13C NMR
(75 MHz, CD3Cl, d): 151.9, 149.6, 118.3, 115.7, 115.0, 110.7, 56.3-54.8(m),
42.0, 31.9. IR (KBr, thin film): 3367, 2938, 2854, 2217, 2129, 2071, 1581, 1492,
1488, 1392, 1106 cmÀ1. MS-EI (m/z): 267 (16), 265 (17), 250 (12), 248 (12), 238
(91), 236 (1 0 0), 157 (3). HRMS-EI (m/z): [M+] calculated for C10H8D6
BrNO2, 265.0578; found 265.0580.
Synthesis of 2-(4-chloro-2,5-[2H6]-dimethoxyphenyl)ethylamine (7). Sulfuryl
chloride (0.5 ml, 6.0 mmol) was added dropwise to an ice-cold and well-stirred
solution of 2,5-[2H6]-dimethoxyphenethylamine (5) (0.90 g, 4.0 mmol) in
glacial acetic acid (8.0 ml), and the temperature kept 5308C. The clear
solution was stirred at room temperature for 3 h, and diethyl ether (10 ml)
added. The mixture was stirred for further 30 min, and the solid was collected
by filtration. The collected solid was purified by recrystallization from a
mixture of methanol and diethyl ether, thereby producing 7d Á HCl (0.30 g,
1
1.2 mmol). Yield: 29%. H NMR (300 MHz, D2O, d): 6.96 (s, 1 H), 6.85
(s, 1 H), 3.08 (t, J=6.7 Hz, 2 H), 2.87 (t, J=6.8 Hz, 2 H). 13C NMR (75 MHz,
CD3OD, d): 151.6, 149.1, 124.1, 121.1, 115.2, 112.8, 39.2, 28.2. IR (KBr, thin
film): 3422, 2935, 2900, 2225, 2071, 1496, 1454, 1400, 1222, 1095 cmÀ1. MS-EI
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SYNTHESIS OF DEUTERIUM LABELED PHENETHYLAMINE DERIVATIVES 1193
(m/z): 223 (5), 221 (15), 194 (34), 192 (1 0 0), 176 (10), 174 (31), 75 (17).
HRMS-EI (m/z): [M+] calculated for C10H8D6ClNO2, 221.1084; found
221.1081.
Synthesis of 2-(4-iodo-2,5-[2H6]-dimethoxyphenyl)ethylamine (8). A mixture
of phthalic anhydride (0.58 g, 3.9 mmol) and 2,5-[2H6]-dimethoxyphenethyla-
mine (4) (0.49 g, 2.6 mmol) was heated to 1308C, and a clear phase was formed.
After the hot melt had settled for a few moments, it was cooled to room
temperature, and yielded a crude solid product. The crude product was
purified by flash column chromatography using silica gel as the stationary
phase and ethyl acetate–hexane (1:9) as the mobile phase and produced a white
crystal 8a (0.59 g, 1.86 mmol). Yield: 71%. m.p.: 109–1108C. 1H NMR
(300 MHz, CDCl3, d): 7.82–7.79 (m, 2 H), 7.70–7.67 (m, 2 H), 6.71–6.68 (m,
3 H), 3.96 (t, J=6.9 Hz, 2 H), 2.99 (t, J=7.1 Hz, 2 H). 13C NMR (75 MHz,
CDCl3, d): 168.2, 153.3, 152.0, 133.7, 132.2, 127.6, 123.0, 116.6, 112.6, 112.2,
111.1, 37.8, 29.7. IR (KBr, thin film): 3073, 2938, 2217, 2063, 1774, 1708, 1504,
1392, 1295 cmÀ1. MS-EI (m/z): 317 (1 0 0), 170.2 (96), 160 (63), 157 (38), 77
(25), 75 (6). HRMS-EI (m/z): [M+] calculated for C18H11D6NO4, 317.1528;
found 317.1533. A solution of iodine monochloride (0.1 ml, 2.0 mmol) in acetic
acid (1.0 ml) was added to to a solution of N-(2-(2,5-[2H6]-dimethoxypheny-
l)ethyl)phthalimide (8a) (0.49 g, 1.5 mmol) in warm (358C) acetic acid (5.0 ml)
that was being vigorously stirred. This mixture was stirred for 1 h at about
308C. The reaction mixture was poured into water (40 ml) and extracted with
dichloromethane. The extracts were washed with a solution of sodium sulfite
(0.06 g) in water (4.5 ml), and the solvent was removed under vacuum to give a
crude product. The crude product was purified by flash column chromato-
graphy using silica gel as the stationary phase and ethyl acetate–hexane (1:10)
as the mobile phase and produced a white crystal 8b (0.65 g, 1.5 mmol). Yield:
1
95%. m.p.: 154–1558C. H NMR (300 MHz, CDCl3, d): 7.82–7.79 (m, 2 H),
7.72–7.68 (m, 2 H), 7.15 (s, 1 H), 6.60 (s, 1 H), 3.96 (t, J=6.8 Hz, 2 H),
2.99 (t, J=7.0 Hz, 2 H). 13C NMR (75 MHz, CDCl3, d): 168.2, 152.5, 152.3,
133.9, 132.0, 127.8, 123.1, 121.4, 113.6, 83.6, 37.5, 29.6. IR (KBr, thin film):
3459, 3058, 2931, 2857, 2225, 2129, 2071, 1770, 1712, 1484, 1392 cmÀ1. A
solution of N-(2-(2,5-[2H6]-dimethoxy-4-iodophenyl)ethyl)phthalimide (8b)
(0.65 g, 1.5 mmol) in hot 2-propanol (8 ml) was treated with hydrazine hydrate
(0.2 ml, 53.9 mmol), and the clear solution was heated to 1008C. After a few
minutes, a milky solid was generated. Heating was continued for 1.5 h, the
reaction mixture was cooled, and the solids removed by filtration. These solids
were washed with ethanol, and the combined filtrates and washes removed the
solvent under vacuum giving a syrupy product 8. This crude product was used
for the identification without further purification. 1H NMR (300 MHz, CD3Cl,
d): 7.20 (s, 1 H), 6.66 (s, 1 H), 2.93 (t, J=6.6 Hz, 2 H), 2.74 (t, J=6.8 Hz, 2 H).
Copyright # 2006 John Wiley & Sons, Ltd.
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Y.-Z. XU AND C. CHEN
13C NMR (75 MHz, CD3Cl/CD3OD, d): 151.9, 151.8, 128.2, 120.9, 113.2, 82.0,
40.6, 33.19. IR (KBr, thin film): 2927, 2861, 2221, 2067, 1631, 1577, 1484,
1388, 1303, 1226 cmÀ1. MS-EI (m/z): 313 (26), 284 (1 0 0), 266 (14), 251 (9), 78
(28). HRMS-EI (m/z): [M+] calculated for C10H8D6NO2I, 313.0440; found
331.0444.
Synthesis of 2,5-[2H6]-dimethoxybenzenesulfonyl chloride (9). Chlorosulfonic
acid (22.33 ml, 336 mmol) was cautiously added to a solution of 1,4-[2H6]-
dimethoxybenzene (2) (6.00 g, 42.0 mmol) in dichloromethane (37.8 ml) under
good ventilation and stirring. With approximately half of the chlorosulfonic
acid added, a vigorous evolution of hydrogen chloride gas occurred and a
substantial amount of solids were generated. As the addition of chlorosulfonic
acid was continued, these solids redissolved, forming a clear, dark-green
solution. Toward the end of the addition, some solids again formed, and the
solution turned dark red. After stirring for 20 min, the reaction solution was
added to ice water. The two phases were separated, and the aqueous phase was
extracted with dichloromethane. The original organic phase and the extracts
were combined and dried over anhydrous magnesium sulfate. The solvent was
then removed under vacuum, and the residue was purified by flash column
chromatography using silica gel as the stationary phase and ethyl acetate–
hexane (1:9) as the mobile phase and produced a yellowish crystal of 2,5-[2H6]-
dimethoxybenzene-sulfonyl chloride (9), (5.06 g, 21.0 mmol). Yield: 50%. m.p.:
119–1208C. 1H NMR (300 MHz, CDCl3, d): 7.46 (d, J=3.1 Hz, 1 H), 7.25 (dd,
J=9.1, 3.1 Hz, 1 H), 7.07 (d, J=9.1 Hz, 1 H). 13C NMR (75 MHz, CDCl3, d):
152.6, 151.5, 131.8, 123.8, 114.7, 113.4, 56.5–54.7 (m). IR (KBr, thin film):
3120, 3061, 2236, 2078, 1571, 1495, 1414, 1365, 1230, 1172, 1100 cmÀ1
.
Synthesis of 2,5-[2H6]-dimethoxybenzenethiol (10). The following reaction is
also extremely vigorous and must be performed in a well-ventilated enclosure.
The 2,5-[2H6]-dimethoxybenzenesulfonyl chloride (9) (5.00 g, 20.0 mmol) was
added to a solution of 25% sulfuric acid (v/v) (22.4 ml) in a beaker, and the
mixture was heated at 1008C. The acid chloride yellow crystals floated on the
aqueous layer surface. Under vigorous stirring, zinc dust (6.74 g, 103.0 mmol)
was added using a small amount for each addition. Following the addition of
zinc dust, the mixture was heated for 1 h at 1008C. Next, the reaction mixture
was cooled to room temperature, and then filtered through celite in a Buchner
funnel, and the residual metal was washed with diethyl ether. The two-phase
filtrate was separated, and the aqueous phase was extracted with diethyl ether.
The combined organic phases were dried over anhydrous magnesium sulfate,
and concentrated under vacuum. The residue was then purified by flash
column chromatography using silica gel as the stationary phase and ethyl
acetate–hexane (1:19) as the mobile phase, which produced a yellowish crystal
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 1187–1200
DOI: 10.1002/jlcr

SYNTHESIS OF DEUTERIUM LABELED PHENETHYLAMINE DERIVATIVES 1195
2,5-[2H6]-dimethoxythiophenol (10), (2.53 g, 14.4 mmol). Yield: 72%. 1H
NMR (300 MHz, CDCl3, d): 6.84 (d, J=2.9 Hz, 1 H), 6.78 (d, J=8.9 Hz,
1 H), 6.65 (dd, J=8.9, 2.9 Hz, 1 H), 3.88 (s, 1 H). 13C NMR (75 MHz, CDCl3,
d): 153.2, 148.5, 121.2, 114.4, 111.1, 110.8, 52.2–53.9 (m). IR (KBr, thin film):
3160, 3066, 3034, 2572, 2249, 2222, 2128, 2070, 1598, 1585, 1485 cmÀ1
.
MS-FAB (m/z): 177 (M++1, 35), 176 (1 0 0), 144 (73), 115 (22). HRMS-FAB
(m/z): [M+] calculated for C8H4D6O2S, 176.0772; found 170.0775.
Synthesis of 2-ethylsulfanyl-1,4-[2H6]-dimethoxybenzene (11a). A solution of
2,5-[2H6]-dimethoxythiophenol (10) (2.53 g, 14.4 mmol) in ethanol (14.5 ml)
was added to a solution of potassium hydroxide (0.89 g, 15.8 mmol) in ethanol
(21.0 ml), and then ethyl bromide (2.15 ml, 28.8 mmol) was added. A white
solid was immediately precipitated, and the reaction was further refluxed for
1.5 h. After the reaction mixture had cooled to room temperature, it was added
to water (45 ml), acidified with hydrochloric acid, and the aqueous phase was
extracted with dichloromethane. The pooled extracts were washed with 5%
sodium hydroxide, dried over anhydrous magnesium sulfate and the solvent
was removed under vacuum. The residue was purified, by flash column
chromatography, using silica gel as the stationary phase and ethyl acetate–
hexane (1:49) as the mobile phase, and produced a yellowish liquid 2,5-[2H6]-
1
dimethoxyphenyl ethyl sulfide (11a), (2.81 g, 13.7 mmol). Yield: 95%. H
NMR (300 MHz, CDCl3, d): 6.82 (d, J=2.9 Hz, 1 H), 6.77 (d, J=8.8 Hz, 1 H),
6.68 (dd, J=8.8, 2.9 Hz, 1 H), 2.95 (q, J=7.4 Hz, 2 H), 1.35 (t, J=7.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3, d): 153.8, 151.2, 126.3, 114.9, 111.1, 110.5,
56.0–54.3 (m), 25.8, 13.9. IR (KBr, thin film): 3072, 3034, 2965, 2968, 2872,
2212, 1481, 1477 cmÀ1. MS-FAB (m/z): 205 (M++1, 43), 204 (1 0 0), 175 (6.5),
75 (11). HRMS-FAB (m/z): [M+] calculated for C10H8D6O2S, 204.1085;
found 204.1085.
Synthesis of 1,4-[2H6]-dimethoxy-2-propylsulfanylbenzene (11b). A solution
of 2,5-[2H6]-dimethoxythiophenol (10) (1.19 g, 6.8 mmol) in ethanol (6.9 ml)
was added to a solution of potassium hydroxide (0.42 g, 7.4 mmol) in ethanol
(9.2 ml), and then 1-bromopropane (1.23 ml, 13.5 mmol) was added. A white
solid was immediately precipitated, and the reaction was further refluxed for
1.5 h. After the reaction mixture had cooled to room temperature, it was added
to water (30 ml), acidified with hydrochloric acid, and the aqueous phase was
extracted with dichloromethane. The pooled extracts were washed with 5%
sodium hydroxide, dried over anhydrous magnesium sulfate and the solvent
was removed under vacuum. The residue was purified, by flash column
chromatography, using silica gel as the stationary phase and ethyl acetate–
hexane (1:19) as the mobile phase, and produced a yellowish liquid 2,5-[2H6]-
dimethoxyphenyl n-propyl sulfide (11b), (1.43 g, 6.6 mmol). Yield: 97%.
Copyright # 2006 John Wiley & Sons, Ltd.
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1196
Y.-Z. XU AND C. CHEN
1H NMR (300 MHz, CDCl3, d): 6.82 (d, J=2.9 Hz, 1H), 6.77 (d, J=8.8 Hz, 1 H),
6.67 (dd, J=8.8 Hz, 3.0, 1 H), 2.88 (t, J=7.2 Hz, 2 H), 1.73–1.66 (m, 2 H), 1.06
(t, J=7.4 Hz, 3 H). 13C NMR (75 MHz, CDCl3, d): 153.8, 151.3, 126.6, 114.9,
111.1, 110.4, 55.7–54.5 (m), 33.7, 22.2, 13.6. IR (KBr, thin film): 3070, 3033,
2958, 2927, 2869, 2246, 2215, 2069, 1589, 1481, 1280, 1222, 1106 cmÀ1. MS-
FAB (m/z): 219 (M++1, 56), 218 (1 0 0), 204 (6), 191 (14), 176 (15), 144 (44).
HRMS-FAB (m/z): [M+] calculated for C11H10D6O2S, 218.1242; found
218.1257.
Synthesis of 4-ethylsulfanyl-2,5-[2H6]-dimethoxybenz-aldehyde (12a). A mix-
ture of phosphoryl chloride (POCl3) (3.08 ml, 39.8 mmol) and N,N-dimethyl-
formamide (3.10 ml, 33.3 mmol) was heated to 1008C. To this solution was
added 2,5-[2H6]-dimethoxyphenyl ethyl sulfide (11a), (2.71 g, 13.3 mmol) and
the mixture was heated for additional 20 min at 1008C. This mixture was then
added to a well-stirred warm water (pre-heated to 558C) and stirred for 1.5 h
by which time the oily phase had completely solidified. The solid was isolated
by filtration, and washed with additional water. These solids were dissolved in
ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was
removed under vacuum. The residue, which was purified by flash column
chromatography using silica gel as the stationary phase and using ethyl
acetate–hexane (1:19) as the mobile phase, produced a white solid 2,5-[2H6]-
dimethoxy-4-ethylthiobenzaldehyde (12a), (2.90 g, 12.5 mmol). Yield: 94%.
1
m.p.: 85–868C. H NMR (300 MHz, CDCl3, d): 10.35 (s, 1 H), 7.24 (s, 1 H),
6.76 (s, 1 H), 3.03 (q, J=7.4 Hz, 2 H), 1.44 (t, J=7.4 Hz, 3 H). 13C NMR
(75 MHz, CDCl3, d): 188.8, 156.9, 150.0, 137.6, 121.2, 109.0, 107.2, 55.9–54.8
(m), 25.0, 13.3. IR (KBr, thin film): 3120, 3066, 3039, 2967, 2927, 2869, 2231,
2208, 2123, 2069, 1660, 1594, 1477 cmÀ1. MS-FAB (m/z): 233 (M++1, 100),
232 (44), 204 (2), 203 (3), 75 (15). HRMS-FAB (m/z): [M+] calculated for
C11H8D6O3S, 232.1034; found 232.1040.
Synthesis of 2,5-[2H6]-dimethoxy-4-propylsulfanyl-benzaldehyde (12b). A
mixture of POCl3 (1.39 ml, 14.9 mmol) and N,N-dimethylformamide
(1.39 ml, 18.0 mmol) was heated to 1008C. To this solution was added
2,5-[2H6]-dimethoxyphenyl n-propyl sulfide (11b), (1.30 g, 6.0 mmol) and the
mixture was heated for additional 20 min at 1008C. This mixture was then
added to a well-stirred warm water (pre-heated to 558C) and stirred for 1.5 h
by which time the oily phase had completely solidified. The solids was isolated
by filtration, and washed with additional water. These solids were dissolved in
ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was
removed under vacuum. The residue, which was purified by flash column
chromatography using silica gel as the stationary phase and using
ethyl acetate–hexane (1:19) as the mobile phase, produced a yellow solid
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 1187–1200
DOI: 10.1002/jlcr

SYNTHESIS OF DEUTERIUM LABELED PHENETHYLAMINE DERIVATIVES 1197
2,5-[2H6]-dimethoxy-4-(n-propyl-thio)benzaldehyde (12b), (1.26 g, 5.1 mmol).
1
Yield: 86%. m.p.: 82–838C. H NMR (300 MHz, CDCl3, d): 10.35 (s, 1 H),
7.24 (s, 1 H), 6.76 (s, 1 H), 2.96 (t, J=7.2 Hz, 2 H), 1.82–1.75 (m, 2 H), 1.12
(t, J=7.4 Hz, 3 H). 13C NMR (75 MHz, CDCl3, d): 188.6, 156.9, 150.1, 137.8,
121.3, 110.4, 107.3, 56.0–55.2 (m), 32.9, 21.7, 13.6. IR (KBr): 3037, 3035, 2964,
2927, 2859, 2221, 2069, 1670, 1589, 1481, 1405, 1267, 1226 cmÀ1. MS-FAB
(m/z): 247 (M++1, 100), 246 (38), 133 (10), 75 (6), 43 (4). HRMS-FAB: [M+]
calculated for C12H10D6 O2S, 246.1191; found 246.1195.
Synthesis of 1-ethylsulfanyl-2,5-[2H6]-dimethoxy-4-(2-nitrovinyl)benzene
(13a). Anhydrous ammonium acetate (92 mg) was added to a solution of 2,5-
[2H6]-dimethoxy-4-(ethylthio)benzaldehyde (12a), (2.80 g, 12.0 mmol) in ni-
tromethane (22.9 ml, 420.0 mmol), and the mixture was heated under reflux for
80 min (the reaction progress must be monitored by thin layer chromato-
graphy (TLC), to determine the point at which the starting aldehyde has been
consumed). Excess nitromethane was removed under vacuum leaving an
orange–red crystal of 1-ethylsulfanyl-2,5-[2H6]-dimethoxy-4-(2-nitrovinyl)ben-
zene (13a), (3.15 g, 11.4 mmol). Yield: 95%. m.p.: 153–1548C. 1H NMR
(300 MHz, CDCl3, d): 8.14 (d, J=13.5 Hz, 1 H), 7.86 (d, J=13.5 Hz, 1 H),
6.82 (s, 1 H), 6.76 (s, 1 H), 3.03 (q, J=7.4 Hz, 2 H), 1.42 (t, J=7.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3, d): 154.3, 150.2, 137.1, 135.2, 134.3, 115.4,
112.1, 109.5, 56.1–55.0 (m), 25.3, 13.5. IR (KBr, thin film): 3097, 2975,
2931, 2227, 2069, 1612, 1594, 1490, 1413, 1342, 1247, 1226 cmÀ1. MS-FAB
(m/z): 276 (M++1, 3), 257 (2), 247 (2), 217 (7), 215 (3), 75 (1 0 0), 74
(17). HRMS-FAB (m/z): [M+] calculated for C12H9D6NO4S, 275.1092;
found 275.1104.
Synthesis of 1,4-[2H6]-dimethoxy-2-(2-nitrovinyl)-5-propylsulfanylbenzene
(13b). Anhydrous ammonium acetate (39 mg) was added to a solution of
2,5-[2H6]-dimethoxy-(n-propylthio)benzaldehyde (12b), (1.26 g, 5.1 mmol) in
nitromethane (9.79 ml, 180.0 mmol, and the mixture was heated under
reflux for 1 h (this reaction progress must be monitored by TLC, to determine
the point at which the starting aldehyde has been consumed). Excess
nitromethane was removed under vacuum leaving an orange–red crystal of
1,4-[2H6]-dimethoxy-2-(2-nitrovinyl)-5-propylsulfanylbenzene (13b), (1.41 g,
1
4.9 mmol). Yield: 95%. m.p.: 121–1228C. H NMR (300 MHz, CDCl3, d):
8.14 (d, J=13.5 Hz, 1 H), 7.85 (d, J=13.6 Hz, 1 H), 6.82 (s, 1 H), 6.76 (s, 1 H),
2.96 (t, J=7.2 Hz, 1 H), 1.83–1.71 (m, 2 H), 1.11 (t, J=7.3 Hz, 3 H). 13C NMR
(75 MHz, CDCl3, d): 154.3, 150.2, 136.9, 135.2, 134.6, 115.3, 112.0, 109.3,
56.1–54.7 (m), 33.1, 21.9, 13.6. IR (KBr, thin film): 3142, 2967, 2940, 2070,
1616, 1602, 1553, 1490, 1387, 1342, 1275, 1239, 1100 cmÀ1. MS-FAB (m/z):
290 (M++1, 46), 289 (12), 274 (46), 260 (8), 246 (19), 244 (1 0 0), 218 (12), 43
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1198
Y.-Z. XU AND C. CHEN
(46). HRMS-FAB (m/z): [M+] calculated for C13H11D6NO4S, 289.1249;
found 289.1250.
Synthesis of 2-(4-ethylsulfanyl-2,5-[2H6]-dimethoxyphenyl) ethylamine (14a). A
suspension of lithium aluminum hydride (2.20 g, 58.0 mmol) in anhydrous
tetrahydrofuran (93.4 ml) in an ice-bath was stirred under helium and fuming
sulfuric acid (1.54 ml) added to this mixture, (Caution: Add fuming sulfuric
acid with extreme caution, as adding too fast may catch fire.) After stirring for
1 min, to this solution was added a solution of 1-ethylsulfanyl-2,5-[2H6]-dimethoxy-
4-(2-nitrovinyl)benzene (13a), (3.15 g, 11.4 mmol) in tetrahydrofuran (44.8 ml), and
the mixture was stirred for further 5 min at 08C. After the reaction mixture had
warmed to room temperature, it was stirred for 1 h and the temperature was
increased to 408C, and stirred for a further 30min. Excess hydride was destroyed
by the cautious addition of wet tetrahydrofuran (2.4 ml of water and 11.6 ml of
tetrahydrofuran), followed by adding 5% aqueous sodium hydroxide to stop the
reaction. The reaction mixture was filtered through celite, and the filter cake was
washed with tetrahydrofuran. The solvents were removed from the combined
filtrates, and the residue was acidified by adding sulfuric acid (1 M). The acidic
aqueous phase was washed with dichloromethane. After making the aqueous
phase basic with 25% aqueous sodium hydroxide, aqueous phase was extracted
with dichloromethane. The extracts were pooled and the solvent was removed
under vacuum to provide 2,5-[2H6]-dimethoxy-4-ethylthiophenethylamine
(14a). This crude product was dissolved in diethyl ether (50 ml), and then treated
with hydrogen chloride. The solid was collected by filtration, and then purified
by recrystallization using ethanol and diethyl ether to give 2,5-[2H6]-dimethoxy-4
1
-ethylthiophenethylamine.HCl (14a.HCl), (2.17 g, 7.64 mmol). Yield: 67%. H
NMR (300 MHz, D2O, d): 6.90 (s, 1 H), 6.84 (s, 1 H), 3.14–3.09 (t, J=7.1 Hz, 2 H),
2.88–2.81 (m, 4 H), 1.16 (t, J=7.3 Hz, 3 H). 13C NMR (75MHz, D2O, d): 151.7,
151.0, 124.0, 122.8, 114.3, 113.4, 55.9–55.4 (m), 39.6, 27.8, 26.2, 13.3. IR (KBr, thin
film): 2956, 2904, 2751, 2657, 2555, 2061, 2048, 1608, 1486, 1400, 1226, 1059 cmÀ1.
MS-FAB (m/z): 248 (M+-Cl, 95), 233 (8), 231 (1 0 0), 218 (32), 217 (14), 75 (6).
HRMS-FAB (m/z): [M+-Cl] calculated for C12H14D6NO2S, 248.1585;
found 248.1597.
Synthesis of 2-(2,5-[2H6]-dimethoxy-4-propylsulfanyl-phenyl)ethylamine (14b). A
suspension of lithium aluminum hydride (0.77 g, 20.0 mmol) in anhydrous
tetrahydrofuran (20.2 ml) in an ice-bath was stirred under helium and fuming
sulfuric acid (0.50 ml) added to this mixture, (Caution: Add fuming sulfuric acid
with extreme caution, as adding too fast may catch fire.) After stirring for 1 min,
to this solution was added a solution of 1,4-[2H6]-dimethoxy-2-(2-nitrovinyl)-5-
propylsulfanylbenzene (13b), (1.30 g, 4.5 mmol) in tetrahydrofuran (7.5 ml), and
the mixture was heated under reflux for 10 hr. After the reaction mixture had
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 1187–1200
DOI: 10.1002/jlcr

SYNTHESIS OF DEUTERIUM LABELED PHENETHYLAMINE DERIVATIVES 1199
cooled to room temperature, excess hydride was destroyed by the cautious
addition of 2-propanol (3.32 ml), followed by 5% aqueous sodium hydroxide to
stop the reaction. The reaction mixture was filtered through celite, and the filter
cake was washed with tetrahydrofuran, 2-propanol and diethyl ether. The solvents
were removed from the combined filtrates, and the residue was acidified by adding
sulfuric acid (1 M). The acidic aqueous phase was washed with dichloromethane.
After making the aqueous phase basic with 25% aqueous sodium hydroxide, the
aqueous phase was extracted with dichloromethane. The extracts were pooled and
the solvent was removed under vacuum to provide 2,5-[2H6]-dimethoxy-4-n-
propylthiophenethylamine hydrochloride (14b). This crude product was dissolved
in diethyl ether (50 ml), and then treated with hydrogen chloride. The solid was
collected by filtration, and then purified by recrystallization using ethanol and
diethyl ether to give 2,5-[2H6]-dimethoxy-4-n-propylthiophenethylamine.HCl
1
(14a.HCl), (0.47 g, 1.8 mmol). Yield: 40%. H NMR (300 MHz, D2O, d): 6.92
(s, 1 H), 6.85 (s, 1 H), 3.16 (t, J=7.1 Hz, 2 H), 2.90–2.82 (m, 4 H), 1.57–1.49 (m,
2 H), 0.92 (t, J=7.3 Hz, 3 H). 13C NMR (75MHz, CD3OD, d): 151.8, 151.7,
124.4, 122.9, 113.8, 112.5, 55.1–54.0 (m), 39.4, 33.7, 28.3, 22.1, 12.3. IR (KBr, thin
film): 2958, 2923, 2904, 2819, 2753, 2657, 2460, 2213, 2048, 1484, 1400, 1222 cmÀ1.
MS-FAB (m/z): 262 (M+-Cl, 96), 247 (5), 245 (1 0 0), 232 (22), 203 (7), 189 (7).
HRMS-FAB (m/z): [M+-Cl] calculated for C13H16D6NO4S, 262.1742; found
262.1744.
Acknowledgements
The authors thank Ms Hsu, L. M. at Instruments Center, National Chung
Hsing University, and Ms Lin, S. C. at Instrument Center, National Tsing
Hwa University for their help in obtaining HRMS spectra, and the National
Bureau of Controlled Drugs, Department of Health, Taiwan, the Republic of
China for financially supporting this research under contract DOH94-NNB-
1007.
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