A two-step method for the preparation of homochiral cathinones

Article abstract of DOI:10.1016/S0957-4166(03)00317-3

A simple method for the preparation of homochiral ring-substituted 1-aryl-2-aminopropanones 2 ('cathinones') is described, involving initial Friedel-Crafts acylation of aromatics with (S)- or (R)-N-trifluoroacetylalanyl chloride, followed by acid hydrolysis of the intermediate trifluoroacetamido intermediates 1, for which X-ray diffraction analysis confirmed the structures.

Full text of DOI:10.1016/S0957-4166(03)00317-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1473–1477
A two-step method for the preparation of homochiral cathinones
Mauricio Osorio-Olivares,a Marcos Caroli Rezende,a,* Silvia Sepu´lveda-Boza,b Bruce K. Cassels,c
Ricardo F. Baggiod and Juan C. Mun˜oz-Acevedoe
aFacultad de Qu´ımica y Biolog´ıa, Universidad de Santiago, Casilla 40, Correo 33, Santiago, Chile
bFacultad de Ciencias Me´dicas, Universidad de Santiago, Av. B. O’Higgins 3363, Santiago, Chile
cMillennium Institute for Advanced Studies in Cell Biology and Biotechnology and Departamento de Qu´ımica,
Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Santiago, Chile
dDepartamento de F´ısica, Comisio´n Nacional de Energ´ıa Ato´mica, Avenida del Libertador 8250, 1429, Buenos Aires, Argentina
eFacultad de Ciencias F´ısicas y Matema´ticas, Universidad de Chile, Blanco Encalada 2008, Casilla 487-3, Santiago, Chile
Received 17 January 2003; accepted 12 March 2003
Abstract—A simple method for the preparation of homochiral ring-substituted 1-aryl-2-aminopropanones 2 (‘cathinones’) is
described, involving initial Friedel–Crafts acylation of aromatics with (S)- or (R)-N-trifluoroacetylalanyl chloride, followed by
acid hydrolysis of the intermediate trifluoroacetamido intermediates 1, for which X-ray diffraction analysis confirmed the
structures. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
Natural cathinones constitute
substituted cathinones for pharmacological studies,
both as racemates and in enantiomerically pure forms.
The interest in the latter may be illustrated by a
recently reported method for the microscale separation
of ( )-methcathinone.5
a
pharmacologically
important family of compounds, related to the ephedri-
nes and amphetamines and well recognized as CNS
stimulants. The parent compound, 1-phenyl-2-
aminopropanone, is responsible for the long known
stimulant properties of khat (Catha edulis Forsk.), the
use of which is widespread in Yemen and the Horn of
Africa.1,2 Its N-methylated derivative (N-methylcathi-
none, methcathinone, ‘CAT’), has been known for
some time as a drug of abuse in the former Soviet
Union and is now classified as a Schedule I substance in
the USA.3
When larger amounts of pure, chiral derivatives are
needed, the access to novel substituted cathinones
should rely on simple and cheap synthetic methods. In
connection with our interest in QSAR studies of these
amines as MAO-A inhibitors,6,7 we needed to compare
some amphetamine derivatives which had exhibited sig-
nificant IMAO activity with their cathinone analogs.
The use of chiral alanine derivatives offered us the
possibility of obtaining enantiomerically pure cathi-
nones for pharmacological studies.8–11 In the present
report we describe a simple, two-step method for the
preparation of chiral cathinones 2, illustrated with four
of these compounds (Scheme 1).
The analogies between cathinone and amphetamine
have suggested that cathinone derivatives with a given
ring substitution pattern may behave similarly to the
identically ring-substituted amphetamine derivatives. A
comparison between 3,4-methylenedioxy- (MDA) and
N-methyl-3,4-methylenedioxyamphetamine (MMDA)
and their cathinone analogs partially confirmed these
expectations. However, because of significant pharma-
cological differences between the studied compounds, it
was concluded that new cathinone derivatives should
require individual investigations in the future.4 This
justifies the interest in the preparation of novel ring-
4-Methylthio-, 4-ethylthio- and 4-methoxyamphetamine
are among the most potent MAO-A inhibitors
described to date.6 Furthermore, 4-methylthioam-
phetamine (MTA) is a potent, selective, non-neurotoxic
serotonin releaser.12,13 Therefore, the corresponding
cathinone analogs were synthesized for the sake of
comparison, and as possible intermediates en route to
other b-funtionalized amphetamine derivatives. In view
of the successful acylation of anisole using our method,
* Corresponding author. E-mail: mcaroli@lauca.usach.cl
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00317-3

1474
M. Osorio-Oli6ares et al. / Tetrahedron: Asymmetry 14 (2003) 1473–1477
ride and AlCl3. The alanyl derivative was prepared by a
slight modification of a reported procedure.11,12 The use
of 1,1,3,3-tetramethylguanidine as base,9,14 instead of
triethylamine,11 reduced the reaction time and led to the
isolation of a cleaner crude product which, after wash-
ing with hexane, was sufficiently pure for all subsequent
reactions. The acylation reaction proceeded reasonably
well with toluene and anisole, following the procedure
described in the literature.8,9 However, for methyl- and
ethylthiobenzene, the use of excess acid chloride and
AlCl3 led to a very low yield of the corresponding
ketone. This could be considerably improved when
equimolar amounts of the three components were made
to react. This modification, which was also successful
with toluene and anisole, was therefore adopted in all
cases.
Scheme 1.
the series was extended to include toluene as a precur-
sor.
From the molecular pharmacological viewpoint it was
of interest to establish the coplanarity of the aromatic
ring and the carbonyl group, expected due to conjuga-
tion. Previous work had revealed the importance of
electron-donation by ring substituents to the IMAO
activity of phenethylamines.7 However, good crystals of
the salts of the cathinone analogs could not be
obtained. On the other hand, trifluoroacetamides 1a–c
crystallized nicely, and were therefore subjected to X-
ray diffraction. Relevant crystallographic data for all
three structures are presented in Table 1, while Figures
Three intermediate N-protected cathinone trifluoroac-
etamides 1, obtained by modifying the existing method-
ology of Friedel–Crafts acylation of aromatics with
N-protected alanyl chlorides, had their structures con-
firmed by X-ray diffraction analysis.
2. Results and discussion
The Friedel–Crafts acylation of the aromatic substrates
was carried out with (S)-N-trifluoroacetylalanyl chlo-
Table 1. Relevant crystallographic data for compounds
1a–c
1a
1b
1c
Empirical
formula
C12H12F3NO2 C12H12F3NO3 C12H12F3NO2S
Molecular
weight
259.2
1.352
275.2
1.427
291.3
1.389
Figure 1. ORTEP projection of 1a.
Figure 2. ORTEP projection of 1b.
Figure 3. ORTEP projection of 1c.
Density (g
cm−3
)
Crystal system Orthorhombic Orthorhombic Orthorhombic
Space group
Z (formula
units/cell)
P212121
4
P212121
4
P212121
4
Cell dimensions
,
a (A)
9.898(1)
13.956(2)
9.218(1)
1273.3(3)
4.987(2)
8.726(4)
29.45(1)
1281.(1)
5.020(1)
9.095(2)
30.509(7)
1393.1(5)
,
b (A)
,
c (A)
Cell volume
3
,
(A )
Reflections
Collected
Unique
I>2|(I)
2q Range (°)
R(F)
6127
2771
1714
5.04–56.10
5650
2753
1288
2.76–55.90
6712
3042
1005
4.68–55.92
All
0.087
0.050
0.142
0.069
0.183
0.051
I>2|(I)
wR(F2)
All
0.126
0.110
0.221
0.189
0.964
0.099
0.074
0.841
I>2|(I)
Goodness-of-fit, 1.012
S(F2)

M. Osorio-Oli6ares et al. / Tetrahedron: Asymmetry 14 (2003) 1473–1477
1475
ues of +29.0 and +28.6, respectively (cf. −28.5 and
−28.7 for their respective enantiomers). These results,
and the fact that the acid hydrolysis of the chiral
amides 1 in 2-PrOH/HCl did not affect the chiral
center, confirmed this as a general, two-step route for
the preparation of chiral substituted cathinones.
1–3 show the corresponding molecular diagrams. The
three compounds were obtained as orthorhombic crys-
tals in space group P212121, with four formula units per
cell, thus presenting a single enantiomer each.
Structures 1b and 1c are isostructural, while 1a presents
different cell parameters and a different packing
arrangement. The molecules, however, do not differ
significantly except for slight variations in the torsion
angles around free rotation bonds (C5ꢀN7, N7ꢀC8,
etc.). Even the H-bonding scheme is similar, with a
single H-bond N7ꢀH7ꢀO6[x−1,y,z] which defines
pseudo chains along the shortest crystallographic axis,
a, with the molecular axis evolving normal to the chain
direction. All three molecules are in a conformation in
which the trifluoromethyl group is maximally separated
from the aromatic moiety. The amide group is essen-
tially flat, but the carbonyl oxygen lies a small distance
out of the median plane of the aromatic ring. Thus, the
dihedral angles O10ꢀC11ꢀC12ꢀC17 are 18.2, 12.6 and
4.2° for 1a–c, respectively. Conjugation between the
keto group and the para-phenyl substituent is reflected
in the O10ꢀC11 carbonyl bond distance. It increases in
3. Experimental
3.1. General
All reagents and solvents were commercially available
and were used without any purification. L- and D-Ala-
nine were purchased from Merck. Melting points were
obtained with an Electrothermal apparatus and were
not corrected. NMR spectra were recorded using a
Bruker AMX 300 spectrometer at 300 (1H) and 75 (13C)
MHz, employing tetramethylsilane as an internal stan-
dard. Chemical shifts are reported relative to TMS
(l=0.00) and coupling constants (J) are given in Hz.
Optical rotation values were obtained with a Perkin–
Elmer 241 polarimeter.
,
,
the order 1.200 A (1a, p-Me)<1.228 A(1c, p-MeS)<
,
1.239 A (1b, p-MeO), in parallel with the capacity of
these groups to act as electron-donors to the ring. A
measure of this capacity is provided by the correspond-
ing |p Hammett constants, that increase, in absolute
3.2. X-Ray diffraction analysis
+
For each of the three structures a single crystal (0.50×
0.30×0.30 mm for 1a, 0.40×0.20×0.20 mm for 1b, 0.40×
0.25×0.20 mm for 1c), was mounted on a glass fiber and
a highly redundant data set collected at room tempera-
ture (T=295 K), up to a 2q max. of ca. 58°, with a
Bruker AXS SMART APEX CCD diffractometer using
values, in the same order, −0.3 (Me)<−0.6 (MeS)<−0.78
(MeO).
Attempts to hydrolyze the protected cathinones under
basic conditions, as described in the literature for other
trifluoroacetamides,8,11 were unsuccessful, and the use
of more rigorous conditions was avoided because of
their likelihood to lead to racemization of the stereo-
genic center. We adapted with success for this reaction,
with minor modifications, the acidic conditions
described for the hydrolysis of N-formylcathinones.13
Because of the low solubility of the amides 1 in aqueous
HCl, an alcoholic cosolvent was added to the reaction
mixture. 2-Propanol proved superior to methanol for
this purpose. The reaction proceeded with complete
retention of chirality, as confirmed by a comparison of
the specific rotation of the isolated hydrochloride of
(S)-2-amino-1-(p-methylphenyl)-1-propanone with the
value reported in the literature.15
,
monochromatic Mo Ka radiation, u=0.71069 A. In all
cases the structure resolution was achieved routinely by
direct methods and difference Fourier analysis. The
structures were refined by least-squares on F2, with
anisotropic displacement parameters for non-H atoms.
The terminal CF3 groups in all three structures pre-
sented rotational disorder around the CꢀC bond. This
was accounted for by means of a split model consisting
of two sets of fluorine atoms (A and B), which were
allowed to rotate independently as a rigid body around
the CꢀC axis, as well as to expand/contract. The model
was found to be quite suitable as it left a very low
residual electron density unaccounted for. H atoms
bound to carbon were introduced at ideal positions and
allowed to ride. H7, attached to N7 and taking part in
H bonding, was refined with an isotropic displacement
parameter. All calculations to solve the structures,
refine the models proposed and obtain derived results
were carried out with the computer programs
SHELXS-97 and SHELXL-97,16 and SHELXTL-PC.17
In order to confirm the general scope of the above
method, and because of our specific interest in the
MAO inhibitory activity of the corresponding enan-
tiomeric cathinones and phenylisopropylamines,6,7 we
carried out the Friedel–Crafts acylation of methyl- and
ethylthiobenzene with (R)-N-trifluoroacetylalanine
chloride. These reactions, without further purification
Crystallographic data (excluding structure factors) for
the structures in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supple-
mentary publication number CCDC 199457–199459.
Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge,
CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk].
from ethyl trifluoroacetate and
tions similar to those used for the (S)-alanyl deriva-
tives, gave the corresponding
D-alanine, under condi-
(R)-2-trifluoroacetamido-1-(4-methylthiophenyl)-1-
propanone and (R)-2-trifluoroacetamido-1-(4-ethylthio-
phenyl)-1-propanone in yields comparable to those of
their enantiomers. The two amides exhibited [h]2D4 val-

1476
M. Osorio-Oli6ares et al. / Tetrahedron: Asymmetry 14 (2003) 1473–1477
3.3. (S)-N-Trifluoroacetylalanine
3.4.2. (S)-2-Trifluoroacetamido-1-(4-methoxyphenyl)-1-
propanone 1b. Yield 60%, prisms, mp 97–99°C; [h]D24
1
1,1,3,3-Tetramethylguanidine (3.75 mL, 30 mmol) was
−32.2 (c 1.03 g/100 mL, MeOH); H NMR (CDCl3) l
added to a suspension of
L
-alanine (2.0 g, 22 mmol) in
1.52 (d, 3H, J=6.9, CH3CH), 3.91 (s, 3H, CH3O),
MeOH (11 mL). After 5 min, ethyl trifluoroacetate (3.3
mL, 28 mmol) was added and the reaction was stirred
for 4 h at room temperature. The solvent was then
removed by rotary evaporation and the residue dis-
solved in H2O (35 ml) and acidified with concentrated
HCl (4 mL). After stirring for 15 min, the mixture was
extracted with EtOAc (2×30 mL) and the organic layers
were combined and washed with brine (30 mL), dried
over Na2SO4 and rotary evaporated to give a solid
which was washed with n-hexane and dried to afford
the crude amide, mp 62–64°C, lit.12 mp 70–71°C, yield
3.5 g (86%), sufficiently pure for all subsequent uses. 1H
5.44–5.53 (m, 1H, CH
3,5), 7.70 (d, 1H, J=3.7, NH
ArH-2,6). 13C NMR (CDCl3) l 19.6 (C
(CH3O), 55.7 (CHCH3), 114.4 (ArC-3,5), 121.2 (ArC-
4), 131.3 (ArC-2,6), 135.4 (ArC-4), 156.2, 156.7
(CF3CO), 164.7 (ArC-1) and 195.3 (COCH).
6
CH3), 7.00 (d, 2H, J=9.0, ArH-
), 7.98 (d, 2H, J=9.0,
H3CH), 50.5
6
6
6
6
6
6
3.4.3. (S)-2-Trifluoroacetamido-1-(4-methylthiophenyl)-
1-propanone 1c. Yield 40%, prisms, mp 129–130°C; [h]D24
1
−28.5 (c 1.03 g/100 mL, MeOH); H NMR (CDCl3) l
1.52 (d, 3H, J=7.1, CH3CH), 2.55 (s, 3H, CH3S),
NMR (CDCl3) l 1.57 (d, 3H, CHCH3
(m, 1H, CHCH3, 7.3), 7.22 (d, 1H, NH3
(s, 1H, COOH
48.4 (CHCH3), 109.7, 113.5, 117.3, 121.1 (quartet,
F3CO), 156.2, 156.7, 157.2, 157.7 (quartet, CF3CO),
176.1 (COOH).
6
, J=7.3), 4.66
6 , J=6.8), 10.00
5.44–5.51 (m, 1H, CH
3,5), 7.65 (d, 1H, J=4.4, NH
ArH-2,6). 13C NMR (CDCl3) l 14.60 (C
(CH3S), 50.59 (CHCH3), 113.8, 117.6 (C
6
CH3), 7.32 (d, 2H, J=8.2, ArH-
6
6
), 7.89 (d, 2H, J=8.8,
6
). 13C NMR (CDCl3) l 17.2 (CHC
6 H3),
6
H3CH), 19.52
6 F3CO), 125.1
6
6
6
C6
6
(ArC-3,5), 128.9 (ArC-4), 129.2 (ArC-2,6), 148.4 (ArC-
1), 156.2, 156.7 (CF3CO) and 195.8 (ArCOCH).
6
6
6
3.4. General procedure for the preparation of (S)-2-
trifluoroacetamido-1-aryl-1-propanones 1
3.4.4. (S)-2-Trifluoroacetamido-1-(4-ethylthiophenyl)-1-
propanone 1d. Yield 27%, prisms, mp 104–106°C; [h]D22
1
−28.7 (c 1.02 g/100 mL, MeOH); H NMR (CDCl3) l
To a stirred suspension of (S)-N-trifluoroacetylalanine
(1 g, 5.4 mmol) in dry CH2Cl2 (20 mL), cooled to 0°C
in an ice-water bath, was added oxalyl chloride (1.1
mL, 12.8 mmol) followed by pyridine (1 drop). The
reaction mixture was allowed to warm gradually to
room temperature and was then stirred further for 5 h.
The solvent and excess oxalyl chloride were removed by
rotary evaporation at 35°C to afford the crude acid
chloride. To this chloride was then added with stirring
a solution of the aromatic compound (5.4 mmol) in
CH2Cl2 (5 mL), followed by AlCl3 (0.72 g, 5.4 mmol)
and the resulting mixture was allowed to react for 18 h.
The reaction mixture was then cooled in an ice-water
bath and slowly quenched with 1N HCl (30 mL) and
CH2Cl2 (30 mL). The aqueous layer was extracted with
CH2Cl2 (2×30 mL) and the organic layers were com-
bined, dried over Na2SO4, and rotary evaporated to
give the crude product, which was crystallized in hex-
ane. In this way the following acetamides 1 were
prepared:
1.40 (t, 3H, J=7.7, CH3CH2S), 1.52 (d, 3H, J=7.1,
CH3CH), 3.05 (q, 2H, J=7.1, CH3CH2S), 5.47 (m, 1H,
CH3CH
J=4.9, NH
(CDCl3) l 13.8 (C
(CH3CH2S), 50.6 (C
126.1 (ArC-3,5), 129.1 (ArC-4), 129.2 (ArC-2,6), 147.4
(ArC-1), 156.2, 156.7 (CF3CO) and 195.8 (ArCOCH).
6
), 7.33 (d, 2H, J=8.8, ArH-3,5), 7.63 (d, 1H,
), 7.87 (d, 2H, J=8.2, Ar-2,6). 13C NMR
H3CH), 19.5 (CH3CH2S), 25.8
HCH3), 113.8, 117.6 (CF3CO),
6
6
6
6
6
6
6
6
3.4.5. (R)-2-Trifluoroacetamido-1-(4-methylthiophenyl)-
1-propanone. Prepared in the same way as compound
1c, yield 45%, prisms, mp 131–132°C; [h]2D4 +29.0 (c 1.03
1
g/100 mL, MeOH); H NMR (CDCl3) l 1.53 (d, 3H,
J=7.1, CH3CH), 2.55 (s, 3H, CH3S), 5.45–5.52 (m, 1H,
CH
J=4.4, NH
(CDCl3) l 14.6 (C
113.8, 117.6 (CF3CO), 125.1 (ArC-3,5), 128.9 (ArC-4),
129.2 (ArC-2,6), 148.4 (ArC-1), 156.2, 156.7 (CF3CO)
and 195.8 (ArCOCH).
6
CH3), 7.31 (d, 2H, J=8.2, ArH-3,5), 7.66 (d, 1H,
), 7.89 (d, 2H, J=8.8, ArH-2,6). 13C NMR
H3CH), 19.5 (CH3S), 50.6 (CHCH3),
6
6
6
6
6
6
6
3.4.1.
(S)-2-Trifluoroacetamido-1-(4-methylphenyl)-1-
propanone 1a. Prepared from 5.4 mmol of (S)-N-trifl-
uoroacetylalanine and 7 mL of toluene, which also
acted as solvent, instead of CH2Cl2, yield 43%, prisms,
3.4.6. (R)-2-Trifluoroacetamido-1-(4-ethylthiophenyl)-1-
propanone. Prepared in the same way as compound 1d,
yield 25%, prisms, mp 105–107°C; [h]2D4 +28.6 (c 1.03
mp 77–78°C; [h]2D4 −48.7 (c 1.0 g/100 mL, MeOH); H
g/100 mL, MeOH); H NMR (CDCl3) l 1.39 (t, 3H,
1
1
NMR (CDCl3) l 1.52 (d, 3H, J=7.1, CH3CH), 2.45 (s,
J=7.7, CH3CH2S), 1.51 (d, 3H, J=7.1, CH3CH), 3.06
3H, CH3Ar), 5.46–5.56 (m, 1H, CH
J=8.0, ArH-3,5), 7.67 (s, 1H, NH), 7.89 (d, 2H, J=8.3,
ArH-2,6). 13C NMR (CDCl3) l 19.8 (C
H3CH), 22.2
(CH3Ar), 51.1 (CHCH3), 110.4, 114.2, 118.0, 121.8
(CF3CO), 129.4 (ArC-3,5), 130.2 (ArC-2,6), 130.8
(ArC-4), 146.2 (ArC-1), 156.6, 157.1 (CF3CO) and
196.9 (COCH).
6
CH3), 7.34 (d, 2H,
(q, 2H, J=7.1, CH3CH2S), 5.47 (m, 1H, CH3CH
(d, 2H, J=8.8, ArH-3,5), 7.64 (d, 1H, J=4.9, NH
7.87 (d, 2H, J=8.2, Ar-2,6). 13C NMR (CDCl3) l 13.8
(CH3CH), 19.5 (CH3CH2S), 25.8 (CH3CH2S), 50.6
(CHCH3), 113.8, 117.6 (CF3CO), 126.1 (ArC-3,5), 129.1
(ArC-4), 129.2 (ArC-2,6), 147.4 (ArC-1), 156.2, 156.7
(CF3CO) and 195.8 (ArCOCH).
6
), 7.33
6
),
6
6
6
6
6
6
6
6
6
6
6
6

M. Osorio-Oli6ares et al. / Tetrahedron: Asymmetry 14 (2003) 1473–1477
1477
3.5. General procedure for the preparation of (S)-2-
CH3CH2
6
S), 5.07 (d, 1H, J=5.2, CH
6
CH3), 7.44 (d, 2H,
amino-1-aryl-1-propanone hydrochlorides 2
J=8.5, ArH-3,5), 7.98 (d, 2H, J=8.5, ArH-2,6), 8.52
(broad singlet, 3H, NH3
). 13C NMR (DMSO-d6) l
14.61 (CHCH3), 18.10 (CH3CH2S), 25.53 (CH3CH2S),
51.44 (CHCH3), 126.8 (ArC-3,5), 129.9 (ArC-1), 130.2
(ArC-2,6), 147.0 (ArC-4) and 196.3 (ArCOCH).
6
A modification of the reported procedure for the
hydrolysis of N-formylcathinones15 was employed, with
the use of 2-propanol as solvent. The (S)-2-trifluoroac-
etamido-1-aryl-1-propanone derivatives 1 (0.7 mmol)
were dissolved in 2-propanol (16 mL) and concentrated
HCl (12 mL). The resulting solutions were then stirred
at 40°C for 12 h. Elimination of the solvent by rotary
evaporation, followed by addition of diethyl ether (15
mL) and 2-propanol (0.5 mL) precipitated the hydro-
chloride salts 2. In this way the following cathinone
hydrochlorides were prepared:
6
6
6
6
6
Acknowledgements
This work was supported by FONDECYT Grant Nos.
1000776 and 1020802, FONDAP Grant No. 11980002
Fundacio´n Andes (C-13575) and USACH-DICYT.
J.C.M.-A. is a grateful recipient of a DAAD scholar-
ship, and M.O.-O. of CONICYT and MECESUP
(USA 9903) scholarships.
3.5.1.
(S)-2-Amino-1-(4-methylphenyl)-1-propanone
hydrochloride 2a. Yield 55%, prisms, mp 192–193°C;
[h]2D2 −32.0 (c 1.06 g/100 mL, MeOH). Analysis, calcu-
lated for C10H14NOCl·0.5H2O: C, 57.57; H, 7.19%;
1
References
found: C, 57.20; H, 6.86%. H NMR (D2O) l 1.48 (d,
3H, J=7.3, CHCH3
J=7.3, CHCH3), 7.34 (d, 2H, J=8.4, ArH-3,5), 7.80
(d, 2H, J=8.3, ArH-2,6). 13C NMR (D2O) l 19.70
(CHCH3), 23.86 (CH3Ar), 54.67 (CHCH3), 131.9 (ArC-
3,5), 132.5 (ArC-1), 132.8 (ArC-2,6), 150.0 (ArC-4) and
200.5 (ArCOCH).
6 ), 2.32 (s, 3H, CH6 3Ar), 5.05 (q, 1H,
1. Connor, J. D.; Makonnen, E.; Rostom, A. J. Pharm.
Pharmacol. 2000, 52, 107–110.
2. Connor, J. D.; Rostom, A.; Makonnen, E. J. Ethnophar-
macol. 2002, 81, 65–71.
3. Young, R.; Glennon, R. A. Psychopharmacol. 1998, 140,
250–256.
6
6
6
6
6
4. Dal Cason, T. A.; Young, R.; Glennon, R. A. Pharmacol.
Biochem. Behav. 1997, 58, 1109–1116.
5. Wallenborg, S. R.; Lurie, I. S.; Arnold, D. W.; Bailey, C.
3.5.2.
(S)-2-Amino-1-(4-methoxyphenyl)-1-propanone
hydrochloride 2b. Yield 43%, prisms, mp 198°C; [h]D23
−32.1 (c 1.01 g/100 mL, MeOH). Analysis, calculated
for C10H14NO2Cl: C, 55.70; H, 6.50%; found: C, 55.33;
G. Electrophoresis 2000, 21, 3257–3263.
1
6. Scorza, M. C.; Carrau, C.; Silveira, R.; Zapata-Torres,
G.; Cassels, B. K.; Reyes-Parada, M. Biochem. Pharma-
col. 1997, 54, 1361.
H, 6.39%. H NMR (DMSO-d6) l 1.46 (d, 3H, J=7.1,
CHCH3
1H, CH
2H, 8.9, ArH-2,6), 8.50 (broad singlet, 3H, NH
NMR (DMSO-d6) l 17.77 (CHCH3), 50.77 (CHCH3),
56.10 (CH3O), 114.8 (ArC-3,5), 125.9 (ArC-1), 131.6
(ArC-2,6), 164.5 (ArC-4) and 195.2 (ArCOCH).
6
), 3.91 (s, 3H, CH3
CH3), 7.15 (d, 2H, J=8.9, ArH-3,5), 8.08 (d,
3). 13C
6 O), 5.09 (broad multiplet,
6
7. Vallejos, G.; Rezende, M. C.; Cassels, B. K. J. Comp.-
6
Aided Mol. Design 2002, 16, 95–103.
6
6
8. Nordlander, J. E.; Payne, M. J.; Njoroge, F. G.; Balk, M.
A.; Laicos, G. D.; Vishwanath, V. M. J. Org. Chem.
1984, 49, 4107–4111.
6
6
9. Nordlander, J. E.; Njoroge, F. G.; Payne, M. J.; War-
man, D. J. Org. Chem. 1985, 50, 3481–3484.
10. Itoh, O.; Honnami, T.; Amano, A.; Murata, K.; Koichi,
Y.; Sugita, T. J. Org. Chem. 1992, 57, 7334–7338.
11. Chambers, J. J.; Kurrasch-Orbaugh, D. M.; Parker, M.
A.; Nichols, D. E. J. Med. Chem. 2001, 44, 1003–1010.
12. Huang, X.; Marona-Lewicka, D.; Nichols, D. E. Eur. J.
Pharmacol. 1992, 229, 3.
3.5.3. (S)-2-Amino-1-(4-methylthiophenyl)-1-propanone
hydrochloride 2c. Yield 42%, prisms, mp 194–195°C;
[h]2D2 −30.4 (c 0.98 g/100 mL, MeOH). Analysis, calcu-
lated for C10H14NOSCl·0.5H2O: C, 49.89; H, 6.24; N,
1
5.82%; found: C, 49.35; H, 5.89; N, 5.90%. H NMR
(DMSO-d6) l 1.43 (d, 3H, J=7.1, CHCH3
3H, CH3S), 5.07 (q, 1H, J=7.1, CHCH3), 7.42 (d, 2H,
J=8.4, ArH-3,5), 7.98 (d, 2H, 8.4, ArH-2,6), 8.58
(broad singlet, 3H, NH
3). 13C NMR (DMSO-d6) l
14.14 (CHCH3), 17.50 (CH3S), 50.82 (CHCH3), 125.4
(ArC-3,5), 129.1 (ArC-1), 129.5 (ArC-2,6), 147.7 (ArC-
4) and 195.7 (ArCOCH).
6 ), 2.56 (s,
6
6
13. Scorza, M. C.; Silveira, R.; Nichols, D.; Reyes-Parada,
6
M. Neuropharmacol. 1999, 38, 1055.
6
6
6
14. Curphey, T. J. J. Org. Chem. 1979, 44, 2805–2807.
15. Berrang, B. D.; Lewin, A. H.; Carroll, F. I. J. Org. Chem.
1982, 47, 2643–2647.
6
16. Sheldrick, G. M. SHELXS-97 and SHELXL-97: Pro-
grams for Structure Resolution and Refinement (1997)
Univ. of Go¨ttingen, Germany.
17. Sheldrick G. M. SHELXTL-PC. Version 5.0 (1994).
Siemens Analytical X-ray Instruments, Inc., Madison,
Wisconsin, USA.
3.5.4.
(S)-2-Amino-1-(4-ethylthiophenyl)-1-propanone
hydrochloride 2d. Yield 50%, prisms, mp 197–198°C;
[h]2D4 −22.9 (c 1.03 g/100 mL, MeOH). Analysis, calcu-
lated for C11H16NOSCl: N, 5.70%; found: N, 5.83%. 1H
NMR (DMSO-d6) l 1.30 (t, 3H, J=7.3, CH3
1.43 (d, 3H, J=7.1, CHCH3), 3.12 (q, 2H, J=7.3,
6 CH2S),
6