S-oxidation products of alkylthioamphetamines

Article abstract of DOI:10.1081/SCC-120006041

The preparation of the sulfoxides and the sulfones of two centrally active alkylthioamphetamine salts, (±)-1-(4-methylthiophenyl)-2-aminopropane hydrochloride (2) (MTA · HCl) and (±)-1-(2,5-dimethoxy-4-ethylthiophenyl)-2-aminopropane hydrochloride (7) (AL

Full text of DOI:10.1081/SCC-120006041

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S-OXIDATION PRODUCTS OF ALKYLTHIOAMPHETAMINES
Marcos Caroli Rezende a , Christián Núñez a , Silvia Sepúlveda-Boza b , Bruce K. Cassels c &
Claudio Hurtado Guzmán c
a Facultad de Química y Biología,, Universidad de Santiago de Chile, Casilla 40, Correo 33,
Santiago, Chile
b Facultad de Ciencias Médicas, Universidad de Santiago de Chile, Casilla 40, Correo 33,
Santiago, Chile
c Departamento de Química, Facultad de Ciencias, Millennium Institute for Advanced Studies
in Cell Biology and Biotechnology, Universidad de Chile
Version of record first published: 20 Aug 2006.
To cite this article: Marcos Caroli Rezende , Christián Núñez , Silvia Sepúlveda-Boza , Bruce K. Cassels & Claudio Hurtado
Guzmán (2002): S-OXIDATION PRODUCTS OF ALKYLTHIOAMPHETAMINES, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 32:17, 2741-2750
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 17, pp. 2741–2750, 2002
S-OXIDATION PRODUCTS
OF ALKYLTHIOAMPHETAMINES
Marcos Caroli Rezende,1, Christian Nunez,1
*
Silvia Sepulveda-Boza,2 Bruce K. Cassels,3
and Claudio Hurtado-Guzman3
2
1Facultad de Quımica y Biologıa, and Facultad de
Ciencias Medicas, Universidad de Santiago de Chile,
Casilla 40, Correo 33, Santiago, Chile
3Millennium Institute for Advanced Studies in Cell
Biology and Biotechnology, and Departamento de
Quımica, Facultad de Ciencias, Universidad de Chile
ABSTRACT
The preparation of the sulfoxides and the sulfones of two cen-
trally active alkylthioamphetamine salts, (ꢀ)-1-(4-methylthio-
phenyl)-2-aminopropane hydrochloride (2) (MTA ꢁ HCl)
and (ꢀ)-1-(2,5-dimethoxy-4-ethylthiophenyl)-2-aminopropane
hydrochloride (7) (ALEPH-2 ꢁ HCl), is described.
Key Words: Alkylthioamphetamines; S-oxidation
Amphetamine analogues substituted at the 4-position with an
alkylthio group constitute a pharmacologically interesting class of com-
pounds exhibiting a wide range of activities in the central nervous system.
The simplest member of the family, (ꢀ)-1-(4-methylthiophenyl)-2-amino-
*Corresponding author. E-mail: mcaroli@lauca.usach.cl
2741
DOI: 10.1081/SCC-120006041
Copyright & 2002 by Marcel Dekker, Inc.
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2742
REZENDE ET AL.
propane (methylthio-amphetamine, MTA) is a potent non-neurotoxic
serotonin-releasing agent,[1–3] and a potent, selective and reversible mono-
amine oxidase-A (MAO-A) inhibitor.[4] Its use as a street drug has been
reported recently,[5,6] and one case of fatal poisoning has been attributed
to its ingestion.[7] (ꢀ)-1-(2,5-Dimethoxy-4-ethylthiophenyl)-2-aminopro-
pane (ALEPH-2), on the other hand, is part of a series of 2,5-
dimethoxy-4-alkylthioamphetamines (ALEPH’s) possessing hallucinogenic
properties in humans.[8] Evidence of its anxiolytic effects in rodents has
been reported.[9] Both hallucinogenic and anxiolytic effects may be
ascribed to interactions with serotonin receptors, and quite recently com-
pound ALEPH-2 has been characterized as a partial 5-HT2A, and a full 5-
HT2c receptor agonist.[10] ALEPH-2 is also a selective MAO-A inhibitor.[4]
There are good reasons for preparing derivatives of these
alkylthioamphetamines with the sulfur atom oxidized. In the first place,
a comparison of the MAO and serotonergic activities of these compounds
with those of the parent amphetamines may shed more light on the role
played by the 4-alkylthio substituent in these drugs. There are several
structure-activity studies on psychotomimetic amphetamine analogues in
the literature.[11–18] In the particular case of the 2,5-dimethoxy-4-X pattern
of ring substitution, their activity has been associated with the lipophilicity
of the X substituent. When this is an RS-group, its oxidation may be
expected to lead to sulfoxides and sulfones with strongly reduced lipophi-
licities, and resulting changes in activity. Furthermore, the presence of
S-oxygen atom(s) may be viewed as a branching of the substituent,
and on the molecular scale as a site of high electron density which is
absent in the parent substances. Examples of such changes in medicinal
compounds, brought about by the oxidation of a sulfide group, have been
reviewed.[19]
A second reason stems from the reportedly variable response to the
psychotropic or behavioral action of the ALEPH series by different human
subjects or laboratory rats.[8,9] This may be due to individual metabolic
characteristics, leading to variations in metabolic inactivation or in the
production of metabolites with increased or qualitatively different activities.
Among these, the sulfoxides and sulfones are strong candidates, but there is
as yet no study on the metabolic modification of any alkylthioamphet-
amines. The preparation of the S-oxidized derivatives of the better charac-
terized MTA and ALEPH-2 is thus a necessary step towards understanding
the somewhat bewildering activity of these compounds.
Phenylisopropylamine salts (2) and (7) were prepared from the corre-
sponding substituted benzaldehydes, by condensation with nitroethane fol-
lowed by reduction with LiAlH4. The preparation of the hydrochloride (2),
starting from 4-methylthiobenzaldehyde, is described in a patent,[20] with an

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S-OXIDATION PRODUCTS OF ALKYLTHIOAMPHETAMINES
2743
overall yield of 23%. We have obtained compound (2) in 72% yield, intro-
ducing some modifications to the reported procedure.
The route to ALEPH-2 from 1,4-dimethoxybenzene was that
described by Shulgin et al.,[8,21,22] and is shown in the scheme below.

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2744
REZENDE ET AL.
i) CF3CO3H, 0ꢂC, 1:1; ii) CF3CO3H, 60ꢂC, 2:1
The oxidation of both alkylthioamphetamines was achieved with tri-
fluoroperacetic acid,[23] which avoided the need of protecting the amino
group and formed in a selective way the corresponding sulfoxides or sulfones.
Oxidation of (2) should in principle give a pair of diastereomeric
1
sulfoxides, but this was not confirmed by the H NMR spectrum of the
product. The spectral evidence pointing to the apparent formation of
essentially one sulfoxide might also be an indication that interconversion
of the two diastereomers is too rapid to be detected at room temperature,
1
or that their H NMR spectra are indistinguishable. In contrast, oxidation

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S-OXIDATION PRODUCTS OF ALKYLTHIOAMPHETAMINES
2745
of (7) led to two diastereomeric sulfoxides (10a) and (10b), separated by
fractional crystallization. Semiempirical calculations of the heats of formation
of the two possible sulfoxide diastereomers at the AM1 level gave for the
optimized structures of (10a), with the S-O bond anti to the adjacent MeO
substituent, and (10b), where the S-O bond was syn to that group, a
difference of ca 4 kcal/mol, suggesting the more stable anti configuration
for this sulfoxide.
EXPERIMENTAL
Melting points were taken using a Kofler hot-stage apparatus, and
were not corrected. IR spectra were recorded with a Perkin-Elmer 750B
spectrometer, and NMR spectra with a Bruker AMX 300 instrument,
employing tetramethylsilane as internal standard in CDCl3 and referring
the spectra to the HDO signal in D2O.
1-(4-Methylthiophenyl)-2-nitropropene (1): A mixture of 4-methylthio-
benzaldehyde (0.075 mol, 11.4 g, 10 mL), anhydrous ammonium acetate
(6 g, 0.081 mol), nitroethane (55 mL) and toluene (100 mL) was refluxed for
12 h with elimination of water in a Dean-Stark apparatus. The mixture was
concentrated to 70mL and cooled to ꢃ20ꢂC. The nitropropene separated as
a bright yellow precipitate, which weighed 8.5 g after drying. The mother
liquor was rotary evaporated, and the dark reddish-brown oily residue was
diluted with 80mL of hot methanol. On cooling, a second crop (5.3 g) of the
nitropropene precipitated, sufficiently pure for use in the next synthetic step.
The methanol was removed, the residue was partitioned between water and
chloroform, and the chloroform layer was dried with Na2SO4, concentrated
and purified by column chromatography (silica gel, elution with chloroform).
In this way, an additional amount of pure nitropropene was recovered
(0.5 g). The overall yield of 1-(4-methylthiophenyl)-2-nitropropene was
14.3 g (91%), recrystallized from methanol, m.p. 67–68ꢂC, m.p. lit.[20]
68.2–69.8ꢂC. 1H NMR (CDCl3) d 2.46 (s, 3H, SCH3), 2.52 (s, 3H,
ArCH¼CHCH3), 7.28 (2H, d, J ¼ 8 Hz, ArH), 7.36 (2H, d, J ¼ 8 Hz, ArH),

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2746
REZENDE ET AL.
8.04 (s, 1H, ArCH¼C); 13C NMR (CDCl3) d 14.09 (SCH3), 14.95 (C1),
125.81 (C20 and C60), 128.51 (C2), 130.44 (C30 and C50), 142.12 (C10),
0
146.80(C4 ). Analysis, found: C, 57.61; H, 5.36; N, 6.89%. Calculated for
C10H11NO2S: C, 57.42; H, 5.26; N, 6.70%.
(1)-1-(4-Methylthiophenyl)-2-aminopropane Hydrochloride (2): A sol-
2
ution of 1-(4-methylthiophenyl)-2-nitropropene (13 g, 0.062 mol) in dry
THF (100 mL) was added dropwise to a stirred suspension of LiAlH4
(13 g, 0.342 mol) in dry THF (200 mL). The reaction mixture was refluxed
with stirring for 24 h and then cooled to 5–10ꢂC in an ice bath and quenched
by cautious addition of 15 mL of water, 13 mL of NaOH 40% and finally
45 mL of water. Filtration and evaporation of the filtrate under reduced
pressure gave the crude product as light yellow oil, purified by bulb-to-
bulb distillation. The pure, colorless (ꢀ)-1-(4-methylthiophenyl)-2-amino-
propane weighed 10g (81% yield). 1H NMR (CDCl3) d 1.08 (d, 3, J ¼ 6.3,
CHCH3), 2.44 (s, 3H, SCH3), 2.47 (dd, 1H, J ¼ 13.4 Hz, J0 ¼ 8.0Hz), 2.64
(dd, 1, J ¼ 12.8 Hz, J0 ¼ 7.9 Hz), 3.11 (m, 1H), 7.08 (2H, d, J ¼ 8 Hz), 7.19
(2H, d, J ¼ 8 Hz).
The (ꢀ)-1-(4-methylthiophenyl)-2-aminopropane hydrochloride (2)
was prepared by adding one equivalent of conc. HCl to a solution of the
aminopropane (10 g, 0.055 mol) in a minimal volume of 2-propanol. The
hydrochloride (11.7 g, 98% yield) crystallized out by addition of ethyl
ether, m.p. 190–192ꢂC, m.p. lit.[20] 190–191ꢂC. Analysis, found: C, 55.67;
H, 7.46; N, 6.69%. Calculated for C10H12ClNO2S: C, 55.19; H, 6.90; N,
6.44%. 1H NMR (D2O) d 1.22 (3H, d, J ¼ 7 Hz, CH3CH), 2.42 (3H, s,
CH3S), 2.85 (2H, d, J ¼ 7 Hz, ArCH2), 3.54 (1H, m, CHCH3), 7.22 (2H, d,
J ¼ 8 Hz, Ar-H meta to MeS), 7.81 (2H, d, J ¼ 8 Hz, Ar-H). 13C NMR
(CDCl3) d 14.98 (SCH3), 17.64 (C3), 39.74 (C1), 49.36 (C2), 127.13
(C20/C60), 130.35 (C30/C50), 133.41 (C10), 136.73 (C40).
2-Ethylthio-1,4-dimethoxybenzene (4): Prepared from the correspond-
ing thiol (3) by the reported procedure,[22] in 86% yield. 1H NMR (CDCl3) d
1.32 (3H, t, J ¼ 7 Hz, CH3CH2), 2.87 (2H, q, J ¼ 7 Hz, CH3CH2), 3.70(3H,
s, OCH3), 3.80(3H, s, OCH ), 6.65 (2H, s, ArH), 6.78 (1H, s, ArH).
3
2,5-Dimethoxy-4-ethylthiobenzaldehyde (5): Prepared by the reported
procedure,[22] in 79% yield, m.p. 86–88ꢂC, lit.[8] m.p. 87–88ꢂC. IR (KBr)
1650cm ꢃ1 (C¼O). 1H NMR (CDCl3) d 1.39 (3H, t, J ¼ 7 Hz, CH3CH2), 2.98
(2H, q, J ¼ 7 Hz, CH3CH2), 3.86 (3H, s, OCH3), 3.88 (3H, s, OCH3), 6.74
(1H, s, ArH), 7.21 (1H, s, ArH), 10.34 (1H, s, CHO).
1-(2,5-Dimethoxy-4-ethylphenyl)-2-nitropropene (6): Prepared by the
reported procedure,[22] in 73% yield, m.p. 110–111ꢂC, lit.[8] m.p. 110–112ꢂC.
1H NMR (CDCl3) d 1.38 (3H, t, J ¼ 7 Hz, CH3CH2), 2.42 (3H, s, CH3C¼C),
2.98 (2H, q, J ¼ 7 Hz, CH3CH2), 3.88 (6H, s, OCH3), 6.75 (1H, s, ArH), 6.78
(1H, s, ArH), 8.28 (1H, s, CH¼C).

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S-OXIDATION PRODUCTS OF ALKYLTHIOAMPHETAMINES
2747
(1)-1-(2,5-Dimethoxy-4-ethylthiophenyl)-2-aminopropane hydrochloride (7):
2
Prepared by LiAlH4 reduction of the corresponding arylnitropropene and
converted into the corresponding hydrochloride,[22] in 50% yield, m.p.
127–129ꢂC, lit[8] m.p. 128–130ꢂC. IR (KBr) 2900 (broad), 1600, 1500,
1210and 1030cm ꢃ1. 1H NMR (CDCl3) d 1.31 (3H, t, J ¼ 7 Hz, CH3CH2S);
1.37 (3H, d, J ¼ 6 Hz, CH3CHNH2); 2.92–3.15 (4H, m, CH2S and ArCH2);
3.71 (1H, m, CHNH2); 3.81 (3H, s, OCH3); 3.86 (3H, s, OCH3); 6.76 (1H, s,
ArH); 6.83 (1H, s, ArH).
(1)-1-(4-Methylsulfoxylphenyl)-2-aminopropane hydrochloride (8): A
2
solution of the hydrochloride 2 (100 mg, 0.460 mmol) in trifluoroperacetic
acid (0.115 mL, 0.460 mmol), prepared from hydrogen peroxide (30%)
(8.6 mL) and trifluoroacetic acid (16.4 mL), was stirred for 5 h in an ice-
bath (0ꢂC) until the complete disappearance of the reacting sulfide, as
shown by thin-layer chromatography. The resulting solution was then
poured into cold water (10mL) and the aqueous solution made basic
(pH ¼ 10) with a 15% NaOH solution. The free amine was then extracted
with chloroform (3 Â 5 mL), and the extracts concentrated to give an oily
residue that was redissolved in 2-propanol (2 mL). To this solution were
then added drops of concentrated HCl and diethyl ether (15 mL) to preci-
pitate the crude hydrochloride. The product was purified through column
chromatography (silica gel 60G Merck, CHCl 3/MeOH 4:1 as eluent), to
give 58 mg (55% yield) of (ꢀ)-1-(4-methylsulfoxylphenyl)-2-aminopropane
hydrochloride, m.p. 236–237ꢂC. Analysis, found: C, 50.92; H, 7.00; N, 6.05;
S, 13.93%. Calculated for C10H16ClNOS: C, 51.39; H, 6.85; N, 6.00;
1
S, 13.70%. IR (KBr) 1040 cmꢃ1 (RSOAr). H NMR (D2O) d 1.20(3H, d,
J ¼ 7 Hz, CH3CH), 2.76 (3H, s, CH3SO), 2.90(2H, d, J ¼ 7 Hz, ArCH2),
3.55 (1H, m, CHCH3), 7.42 (2H, d, J ¼ 8 Hz, Ar-H meta to MeS), 7.60
(2H, d, J ¼ 8 Hz, Ar-H ortho to MeS).
(1)-1-(4-Methylsulfonylphenyl)-2-aminopropane hydrochloride (9): A
2
solution of the hydrochloride 2 (100 mg, 0.460 mmol) in trifluoroperacetic
acid (0.230 mL, 0.920 mmol), prepared from hydrogen peroxide and
trifluoroacetic acid as described above, was allowed to react for 5 h in a
water bath at 60ꢂC until the complete disappearance of the reacting
sulfide, as shown by thin-layer chromatography. The resulting solution
was then poured into cold water and worked up as before. The
precipitated product was purified through column chromatography as
above to give 76 mg (67% yield) of (ꢀ)-1-(4-methylsulfonylphenyl)-2-
aminopropane hydrochloride, m.p. 241–242ꢂC. Analysis found: C, 46.51;
H, 6.59; N, 5.98; S, 12.03%. Calculated for C13H16ClNSO3. 1/2 H2O: C,
46.42; H, 6.58; N, 5.42; S, 12.38%. IR (KBr) 1145 and 1300 cmꢃ1
1
(RSO2Ar). H-NMR (D2O) d 1.25 (3H, d, J ¼ 7 Hz, CH3CH), 3.01 (2H,
d, J ¼ 7 Hz, ArCH2), 3.22 (3H, s, CH3SO2), 3.65 (1H, m, CHCH3), 7.52

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2748
REZENDE ET AL.
(1H, d, J ¼ 8 Hz, Ar-H meta to MeS), 7.88 (1H, d, J ¼ 8 Hz, Ar-H ortho
to MeS).
(1)-1-(2,5-Dimethoxy-4-ethylsulfoxylphenyl)-2-aminopropane hydro-
2
chloride (10): A cooled (0ꢂC) solution of the hydrochloride 7 (100 mg,
0.343 mmol) in an equimolar amount of trifluoroperacetic acid, prepared as
described above, was allowed to react for 6 h, until the complete disappear-
ance of the reacting sulfide, as shown by thin-layer chromatography. The
resulting solution was then poured into cold water and worked up as
before. The precipitated crude hydrochloride was purified through column
chromatography (silica gel 60G Merck, CHCl 3/MeOH 4 : 1 as eluent), to give
51 mg of a mixture of two diastereomeric sulfoxides. The mixture was redis-
solved in 2-propanol (0.5 mL) and diethyl ether was added to precipitate the
hydrochloride (10a) (23 mg, 21% yield), m.p. 199–201ꢂC. Analysis, found: C,
50.45; H, 7.33; N, 4.64; S, 10.21%. Calculated for C13H22ClNO3S: C, 50.73;
H, 7.15; N, 4.55; S, 10.41%. IR (KBr) 2900, 1210, 1030 and 1040 cmꢃ1
.
1H NMR (D2O) d 1.18 (3H, t, J ¼ 6 Hz, CH3CH2SO), 1.22 (3H, d, J ¼ 6 Hz,
CH3CH), 2.95 (3H, m, CH3CH2SO and ArCHaHbCH), 3.14 (1H, m,
ArCHaHbCH), 3.64 (1H, m, CHNHþ), 3.80(3H, s, OCH ), 3.82 (3H, s,
3
3
OCH3), 6.99 (1H, s, ArH meta to RSO), and 7.14 (1H, s, ArH ortho to RSO).
The filtrate was cooled to 0ꢂC and the precipitate which separated was
further purified by column chromatography (silica 60G, CHCl3/MeOH 10:3
as eluent), to give sulfoxide (10b) (18 mg, 17% yield), m.p. 207–208ꢂC.
1H NMR (D2O) d 1.10(3H, t, J ¼ 6 Hz, CH3CH2SO), 1.13 (3H, d,
J ¼ 6 Hz, CH3CH), 2.80(3H, m, CH 3CH2SO and ArCHaHbCH), 3.01
(1H, m, ArCHaHbCH), 3.52 (1H, m, CH NHþ3 ), 3.67 (3H, s, OCH3), 3.71
(3H, s, OCH3), 6.85 (1H, s, ArH meta to RSO), and 6.95 (1H, s, ArH ortho
to RSO). 13C NMR (D2O) d 5.05 (CH3-CS), 17.05 (CH3-CN), 34.80(Ar-
CH2), 46.15 (CH2-S), 47.85 (CH-N), 55.99 (OCH3), 107.05 (arom. C-3),
115.50(arom. C-6), 126.05 (arom. C-4), 129.50(arom. C-1), 149.50(arom.
C-5) and 152.80(arom. C-2).
(1)-1-(2,5-Dimethoxy-4-ethylsulfonylphenyl)-2-aminopropane hydro-
2
chloride (11): A solution of the hydrochloride 7 (100 mg, 0.343 mmol) in
trifluoroperacetic acid (0.255 mL, 1.209 mmol), prepared as described
above, was allowed to react for 6 h in a water bath at 70ꢂC until the com-
plete disappearance of the reacting sulfide, as shown by thin-layer chroma-
tography. The resulting solution was the poured into cold water and worked
up as before. The hydrochloride (11) which separated was filtered to give
57 mg (52% yield) of the pure product, m.p. 201–203ꢂC. Analysis, found:
C, 48.03; H, 6.44; N, 4.86; S, 9.57%. Calculated for C13H22ClNSO4: C 48.22;
H, 6.80; N, 4.33; S, 9.89%. IR (KBr) 2900, 1300, 1140, 1210 and 1030 cmꢃ1
.
1H NMR (D2O) d 1.14 (3H, t, J ¼ 7 Hz, CH3CH2SO2), 1.23 (3H, d, J ¼ 7 Hz,
CH3CH), 2.96 (2H, m, ArCH2CH), 3.46 (2H, q, J ¼ 7 Hz, CH3CH2SO2),

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S-OXIDATION PRODUCTS OF ALKYLTHIOAMPHETAMINES
2749
3.64 (1H, m, CH NHþ3 ), 3.81 (3H, s, OCH3), 3.88 (3H, s, OCH3), 7.11 (1H, s,
ArH meta to RSO2), and 7.34 (1H, s, ArH ortho to RSO2).
ACKNOWLEDGMENTS
This work was funded by Grant no. 1000776 (FONDECYT), Grant
P99-031 of the Millennium Scientific Initiative, and in part by the
Presidential Chair in Sciences (BKC).
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Received in the USA September 18, 2001