Synthesis of deuterium labeled phenethylamine derivatives

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.¹Shulgin 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.²Phenethy-

lamine derivatives are increasingly abused psychoactive drugs and well

documented in literature.^3–8The 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.^9–15Amphetamine, 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,²preparing [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.^16–19Compound 2 was treated with

OCD₃

OH

OCD₃

CH₃NO₂

Cl₂CHOCH₃

TiCl₄

CD₃I

KOH

CHO

NO₂

OCD₃

OH

1

2

3

4

D₃CO

Br

Br₂,AcOH

NH₂

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.

J Label Compd Radiopharm 2006; 49: 1187–1200

DOI: 10.1002/jlcr

SYNTHESIS OF DEUTERIUM LABELED PHENETHYLAMINE DERIVATIVES 1189

dichloromethyl methyl ether and TiCl₄gave 2,5-[²H₆]-dimethoxybenzaldehyde

(3),^20–25which was then condensed with nitromethane to yield 1,4-[²H₆]-

dimethoxy-2-(2-nitrovinyl)benzene (4). Reduction of compound 4 with

LiAlH₄produced 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 SO₂Cl₂gave

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

ClSO₃H

Zn, HCl

R-Br

a: R = C₂H₅

b: R = C₃H₇

SH

SR

SO₂Cl

OCD₃

10

2

9

11a: R = C₂H₅

11b: R = C₃H₇

OCD₃

D₃CO

NH₂

CHO

RS

CH₃NO₂

LiAlH₄

DMF

POCl₃RS

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.

J Label Compd Radiopharm 2006; 49: 1187–1200

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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 cm^À1

.

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.^20–25The

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 cm^À1. 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 cm^À1

.

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 cm^À1. 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 cm^À1. 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 cm^À1. 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 cm^À1. 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 cm^À1. 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).

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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 cm^À1. 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 cm^À1

.

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 cm^À1

.

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 cm^À1. 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.

J Label Compd Radiopharm 2006; 49: 1187–1200

DOI: 10.1002/jlcr

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 cm^À1. 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 cm^À1. 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

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 cm^À1. MS-FAB

(m/z): 247 (M⁺+1, 100), 246 (38), 133 (10), 75 (6), 43 (4). HRMS-FAB: [M⁺]

calculated for C₁₂H₁₀D₆O₂S, 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 cm^À1. 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 cm^À1. MS-FAB (m/z):

290 (M⁺+1, 46), 289 (12), 274 (46), 260 (8), 246 (19), 244 (1 0 0), 218 (12), 43

J Label Compd Radiopharm 2006; 49: 1187–1200

DOI: 10.1002/jlcr

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 cm^À1.

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

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 cm^À1.

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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J Label Compd Radiopharm 2006; 49: 1187–1200

DOI: 10.1002/jlcr

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Synthesis of deuterium labeled phenethylamine derivatives

DOI: 10.1002/jlcr.1139

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