Stereospecific synthesis of amphetamines

Article abstract of DOI:10.1016/S0957-4166(03)00438-5

Regioselective addition of aryl lithium to commercially available (S)-(+)-propylene oxide provides the corresponding (S)-aryl-2-propanol. The (R)-amphetamine is obtained by conversion of the alcohol to the tosylate followed by azide displacement and hydrogenation. Mitsunobu conversion of the alcohol to the (R)-bromide followed by azide displacement and hydrogenation affords the (S)-amphetamine.

Full text of DOI:10.1016/S0957-4166(03)00438-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2119–2125
Stereospecific synthesis of amphetamines
Jared M. Wagner, Charles J. McElhinny, Jr., Anita H. Lewin* and F. Ivy Carroll
Chemistry and Life Science Unit, Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, USA
Received 6 February 2003; revised 7 April 2003; accepted 10 April 2003
Abstract—Regioselective addition of aryl lithium to commercially available (S)-(+)-propylene oxide provides the corresponding
(S)-aryl-2-propanol. The (R)-amphetamine is obtained by conversion of the alcohol to the tosylate followed by azide displacement
and hydrogenation. Mitsunobu conversion of the alcohol to the (R)-bromide followed by azide displacement and hydrogenation
affords the (S)-amphetamine.
© 2003 Elsevier Ltd. All rights reserved.
approach is demonstrated by the use of this reaction
1. Introduction
sequence to prepare (R)-(−)-2,5-dimethoxy-4-methyl-
Although amphetamines can be resolved using classical
methods, specific conditions must be determined for
each compound and the yields are often quite poor. An
effective method for the preparation of enantiomeri-
cally pure amphetamines utilizes commercially available
homochiral a-methylbenzylamine as a chiral auxiliary1
(Scheme 1). Condensation of the appropriate phenyl-2-
propanone 1 with homochiral a-methylbenzylamine 2
(e.g. (R)-2 in Scheme 1), followed by hydrogenation of
the resulting imine 3 over Raney-nickel affords a pair
of diastereomeric N-(a-phenethyl)phenylisopropyl-
amines (RR)-4 and (SR)-4; separation of the
diastereomers by crystallization followed by debenzyla-
tion of the pure diastereomer (RR)-4 by hydrogenolysis
affords the enantiomerically pure amphetamine (R)-5.
Use of (S)-a-methylbenzylamine (S)-2 affords (S)-5.
For amphetamines requiring commercially unavailable
phenyl-2-propanones (e.g. 1b), this method can become
quite tedious.
This report describes an alternative approach which
involves regioselective boron trifluoride diethyl etherate
promoted ring opening of propylene oxide 8 with an
aryl anion 72 to afford the phenyl-2-propanol 9, conver-
sion of the alcohol 9 to a tosylate 10, and SN2 displace-
ment of the leaving group (Scheme 2). Starting from
commercially available bromoarene 6a and (S)-(−)-pro-
pylene oxide (S)-8 this approach is expected to provide
(R)-amphetamine (R)-5a. The feasibility of this
* Corresponding author. Tel.: 919-541-6691; fax: 919-541-8868;
e-mail: ahl@rti.org
Scheme 1.
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00438-5

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J. M. Wagner et al. / Tetrahedron: Asymmetry 14 (2003) 2119–2125
mechanism and, consequently, stereochemical integrity
would be lost in this step. Therefore, the tosylate 10b
was converted to the azide 11b, and this product was
hydrogenated over a palladium catalyst. Racemic 2,5-
dimethoxy-4-methylamphetamine 5b was recovered in
80% yield. Based on this promising result the reaction
sequence was repeated with optically active propylene
oxide. Reaction of (2,5-dimethoxy-4-methyl)phenyl
lithium 7b with (S)-(−)-propylene oxide (S)-8 gave (S)-
(2%,5%-dimethoxy-4%-methylphenyl)-2-propanol (S)-9b in
74% yield. The stereochemical integrity of (S)-9b, based
on GC analysis of the (−)-menthyl chloroformate
(MCF) derivative, was >99%. The alcohol (S)-9b was
converted to the tosylate (S)-10b in 77% yield and
inversion with sodium azide provided (R)-(2%,5%-
dimethoxy-4%-methylphenyl)-2-propylazide (R)-11b in
91% yield. Hydrogenation of (R)-11b over palladium
catalyst afforded (R)-(−)-2,5-dimethoxy-4-methylam-
phetamine (R)-5b in 77% yield.
Assessment of the enantiomeric excess by GC analysis
of the N-trifluoroacetyl-L-prolyl chloride (TPC) deriva-
tive of the product confirmed >98% enantiomeric excess
and the negative specific rotation confirmed the
configuration.4
Treatment of the alcohol (S)-9b with carbon tetra-
bromide and triphenylphosphine, followed by sodium
azide and hydrogenation as above, gave (S)-(+)-2,5-
dimethoxy-4-methylamphetamine (S)-5b with >97%
enantiomeric excess (based on GC analysis).
Scheme 2.
Preparation of (R)-2,5-dimethoxyamphetamine (R)-5c
was carried out analogously. Low temperature lithia-
tion of commercially available 1-bromo-2,5-dimethoxy-
benzene 6c with n-butyl lithium, followed by boron
trifluoride diethyl etherate promoted reaction with (S)-
propylene oxide (S)-8 gave 100% enantiomerically pure
(S)-2%5%-dimethoxyphenyl-2-propanol (S)-9c in 67%
yield. Reaction with p-toluenesulfonyl chloride in pyri-
dine provided the tosylate (S)-10c in 57% yield, and
reaction with sodium azide converted (S)-10c to the
azide (R)-11c in 96% yield. Hydrogenation afforded
2,5-dimethoxyamphetamine (R)-5c in 100% yield. Stereo-
chemical integrity was confirmed by specific rotation,
GC analysis of the TPC derivative and comparison
with an authentic sample.
amphetamine (R)-5b, (R)-(−)-2,5-dimethoxyamphet-
amine (R)-5c and (R)-(−)-2,5-dimethoxy-4-iodoamphet-
amine (R)-5d.
The key chiral intermediate, (S)-phenyl-2-propanol (S)-
9a, was expected to provide (S)-(+)-amphetamine (S)-
5a by utilization of a double inversion procedure
(Scheme 2). Thus, Mitsunobu inversion of the configu-
ration of the alcohol (S)-9a to a bromide (R)-12a,
followed by SN2 displacement of the bromide was
expected to lead to (S)-(+)-amphetamine (S)-5a. The
feasibility of this approach was investigated.
2. Results
Direct iodination of (R)-2,5-dimethoxyamphetamine
(R)-5c in the presence of silver sulfate5 (Scheme 3) gave
(R)-2,5-dimethoxy-4-iodoamphetamine (R)-5d in 60%
yield after column chromatography. The purified mate-
rial, as the hydrochloride salt, had mp and specific
rotation in excellent agreement with the literature
values.6
Bromination of commercially available 2,5-dimethoxy-
toluene with bromine in buffered acetic acid afforded
4-bromo-2,5-dimethoxytoluene 6b,3 as a white solid, in
78% yield. Because of the expense of optically active
propylene oxide, the subsequent steps in the synthesis
were investigated using racemic materials. Conversion
of 4-bromo-2,5-dimethoxytoluene 6b to the lithium
reagent 7b and reaction with racemic propylene oxide 8
provided (2%,5%-dimethoxy-4%-methylphenyl)-2-propanol
9b in 85% yield. This material was converted to the
tosylate 10b in 90% yield and reaction with ammonia
gave
( )-2,5-dimethoxy-4-methylamphetamine
5b.
However, the fact that the reaction proceeded very
slowly suggested that it may be proceeding via an SN1
Scheme 3.

J. M. Wagner et al. / Tetrahedron: Asymmetry 14 (2003) 2119–2125
2121
3. Discussion
a,a-dichloromethylmethylether and tetrachloride and
involves isolation and purification of 2,5-dimethoxy-
tolualdehyde 13, which can be challenging. In the
reduction of the phenylnitropropene 14 to the phenyl-2-
propanone 1b, the isolation of pure 1b from the reac-
tion mixture is difficult as well. Neither of these
reactions is amenable to scale-up. Our reaction
sequence sidesteps these problems. The reactions are all
experimentally simple to carry out and can be per-
formed without purification of intermediates. In fact,
the preparation of (S)-(+)-2,5-dimethoxy-4-methylam-
phetamine (S)-5b, which was carried out to demon-
strate the feasibility of using a double-inversion to
obtain the (S)-enantiomer (S)-5b from the commer-
cially available (S)-epoxide (S)-8, was completed with-
out purification of the intermediates. Thus, the bromide
(R)-12b was isolated as an oil from treatment of the
alcohol (S)-9b with carbon tetrabromide and triphenyl
phosphine, and was converted to the azide (S)-11b by
treatment with sodium azide in dimethylformamide.
This reaction was quenched with water and the product
(S)-11b was isolated by extraction and evaporation of
the solvent. Hydrogenolysis of (S)-11b without purifica-
tion afforded the product, (S)-5b, in >90% purity.
The described approach to the preparation of optically
active amphetamines provides a straightforward enan-
tiospecific synthesis of chiral amines with predeter-
mined configuration. It offers significant advantages
over previously utilized methods in cases where the
appropriately substituted phenyl-2-propanone is not
readily available. For (R)-(−)-2,5-dimethoxy-4-methyl-
amphetamine (R)-5b the previously reported synthesis1
involved
condensation
of
(2%,5%-dimethoxy-4%-
methyl)phenyl-2-propanone 1b with (R)-a-methylben-
zylamine (R)-2, Raney-nickel promoted reduction to
(R,R)- and (S,R)-N-(a-phenethyl)-(2,5-dimethoxy-4-
methyl)phenylisopropylamines (RR)-4 and (SR)-4,
purification of (RR)-4 and debenzylation (Scheme 1).
The commercially unavailable (2%,5%-dimethoxy-4%-
methyl)phenyl-2-propanone 1b was prepared from
(2%,5%-dimethoxy-4%-methyl)phenyl-2-nitropropene 14,7
which, in turn, had been prepared by the reaction of
2,5-dimethoxytolualdehyde
13
with
nitroethane
(Scheme 4).8 The aldehyde 13 is referred to in the
literature,9,10 but is currently not commercially avail-
able; no synthesis for 13 is given. We have prepared 13
in 81% yield by formylation11 of commercially available
2,5-dimethoxytoluene
methylether (Scheme 4). An alternate synthesis of (2%,5%-
dimethoxy-4%-methyl)phenyl-2-propanone 1b that
with
a,a-dichloromethyl-
Finally, the boron trifluoride diethyl etherate promoted
regioselective ring opening of propylene oxide 8 with
aryl lithium reagents, followed by oxidation of the
resulting phenyl-2-propanol 9, provides a convenient
route to phenyl-2-propanones. Since a large variety of
substituted aryl halides is readily available, many
racemic and optically active amphetamines are syntheti-
cally accessible using this general approach.
likewise utilizes 2,5-dimethoxytolualdehyde 13 has also
been reported.9 The six-step reaction sequence that has
been applied to the synthesis of (R)-(−)-2,5-dimethoxy-
4-methylamphetamine (R)-5b (Scheme 4 followed by
Scheme 1)1 results in a 7% overall yield from commer-
cially available 2,5-dimethoxy toluene, based on the
literature yields. Our six-step procedure (Scheme 2)
provided (R)-(−)-2,5-dimethoxy-4-methylamphetamine
(R)-5b in 38% yield from commercially available 2,5-
dimethoxy toluene.
4. Conclusion
The boron trifluoride diethyl etherate promoted addi-
tion of aryl lithium to propylene oxide is the basis for
a convenient approach to the stereospecific synthesis of
amphetamines. Use of commercially available (S)-pro-
pylene oxide leads to the (S)-aryl-2-propanol and, after
displacement of the tosylate with inversion of configu-
ration, to the (R)-amphetamine. Mitsunobu conversion
of the (S)-alcohol to the (R)-bromide followed by
displacement of the bromide with inversion of configu-
ration affords the (S)-amphetamine. Alternatively, use
of racemic propylene oxide and oxidation of the
racemic aryl-2-propanol, provides a generalized syn-
thetic route to a number of aryl-2-propanones which
are useful in a published stereospecific preparation of
chiral amphetamines.
5. Experimental
Melting points were determined on a Thomas-Hoover
capillary tube apparatus. All optical rotations were
determined at the sodium D line using a Rudolph
Research Autopol III polarimeter (1 dm cell). Nuclear
magnetic resonance (NMR) spectra were recorded on a
Bruker DPX-300 spectrometer using tetramethylsilane
as internal standard. Thin layer chromatography was
Scheme 4.
Furthermore, two of the steps in the preparation of
2%,5%-dimethoxy-4%-methylphenyl-2-propanone 1b are
relatively unpleasant: the formylation of 2,5-dimethoxy-
toluene and the conversion of the phenylnitropropene
14 to the phenyl-2-propanone 1b. The first requires

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J. M. Wagner et al. / Tetrahedron: Asymmetry 14 (2003) 2119–2125
carried out using Whatman silica gel 60 TLC plates and
eluting with CHCl3, unless otherwise noted; visualiza-
tion was under UV or in an iodine chamber, as appro-
priate. Gas chromatography was carried out using a
Hewlett–Packard 5890 Series II Plus instrument
equipped with FID detector, split/splitless injection
port, a HP-5 column (crosslinked 5% PhMe siloxane;
30 m×0.32 mm×0.25 mm film thickness) and nitrogen
carrier gas.
prepared while stirring a 1000 mL round-bottomed
flask, in an ice bath. The mixture was transferred to the
freezer and after 48 h crystals had formed. The reaction
mixture was poured over ice, forming a white solid
which was filtered, washed with hexanes and water, and
dried under vacuum to give 10b (1.56 g, 90%): mp
1
99–100°C, H NMR (CDCl3) l (ppm): 1.39 (d, J=6
Hz, 3H, ArCH2CHCH3), 2.17 (s, 3H, ArCH3), 2.40 (s,
3H, ArCH3), 2.70-2.83 (m, 2H, ArCH2), 3.62 (s, 3H,
OCH3), 3.69 (s, 3H, OCH3), 4.75–4.86 (m, 1H,
ArCH2CH), 6.43 (s, 1H, ArH), 6.44 (s, 1H, ArH), 7.13
(d, J=2 Hz, 2H, ArH), 7.50 (d, J=1.5 Hz, 2H, ArH),
13C NMR (CDCl3)l (ppm): 16.25 (ArCH3), 21.27
(ArCH2CHCH3), 21.58 (ArCH3), 37.79 (ArCH2), 55.63
(OCH3), 55.86 (OCH3), 80.06 (ArCH2CH), 113.4
(ArH), 113.8 (ArH), 122.4 (ArC), 125.7 (ArC), 127.5
(ArH), 129.2 (ArH), 134.0 (ArC), 143.8 (ArS), 151.0
(ArO), 151.2 (ArO).
5.1. 4-Bromo-2,5-dimethoxytoluene 6b
To a solution of 2,5-dimethoxytoluene (100 g, 0.657
mol) and NaOAc (56.6 g, 0.690 mol) in HOAc (400
mL) in a 1000 mL three necked, round bottomed flask
equipped with N2 inlet, magnetic stirrer, and addition
funnel was added Br2 (110 g, 0.688 mol), dropwise. The
solution changed from clear to yellow and eventually to
dark orange. After stirring for 20 min the reaction was
quenched with a solution of saturated NaHSO3 and the
mixture was extracted with CHCl3 (3×500 mL). The
combined organic extract was dried over Na2SO4 and
concentrated to a yellow solid. Recrystallization from
hot EtOAc/hexane gave 6b as a white crystalline solid;
5.4. (2%,5%-Dimethoxy-4%-methylphenyl)-2-propyl azide
11b
After stirring overnight in a round bottomed flask, a
mixture of 10b (1 g, 0.003 mol) and NaN3 (0.75 g, 0.012
mol) in DMF (20 mL) was taken up in water and
extracted with Et2O. The organic layer was dried over
Na2SO4, filtered, and evaporated to dryness to give 11b
1
mp 90°C (lit.3 91°C), H NMR (CDCl3) l (ppm): 2.22
(s, 3H, ArCH3), 3.75 (s, 3H, OCH3), 3.84 (s, 3H,
OCH3), 6.81 (s, 1H, ArH), 7.06 (s, 1H, ArH).
1
(640 mg, 95%) as a light brown oil. H NMR (CDCl3)
5.2. (2%,5%-Dimethoxy-4%-methylphenyl)-2-propanol 9b
l (ppm): 1.24 (d, J=6.6 Hz, 3H, ArCH2CHCH3), 2.21
(s, 3H, ArCH3), 2.69–2.83 (m, 2H, ArCH2), 3.77 (s, 3H,
OCH3), 3.79 (s, 3H, OCH3), 6.64 (s, 1H, ArH), 6.67 (s,
1H, ArH), 13C NMR (CDCl3) l (ppm): 16.63 (ArCH3),
19.70 (ArCH2CHCH3), 37.70 (ArCH2), 56.30 (OCH3),
56.54 (OCH3), 58.28 (ArCH2CH), 114.1 (ArH), 114.3
(ArH), 124.3 (ArC), 126.2 (ArC), 151.6 (ArO), 151.9
(ArO).
To a solution of 4-bromo-2,5-dimethoxytoluene 6b (20
g, 0.087 mol) in dry THF (700 mL) in a 1000 mL round
bottomed flask equipped with N2 inlet at −72°C was
added a solution of 2.0 M n-BuLi in pentane (43 mL,
0.086 mol). After stirring for 10 min, propylene oxide 8
(2.51 g, 0.043 mol) was added. Stirring was continued
for 10 min and BF3·Et2O (9.22 g, 0.065 mol) was
added. The reaction was allowed to stir for 15 min. It
was then quenched with satd NH4Cl and extracted with
Et2O (3×250 mL). The combined organic extract was
dried over Na2SO4, filtered, and evaporated to dryness
leaving a residual oil. Treatment with MeOH resulted
in a white ppt. The ppt was separated by filtration and
discarded, and the MeOH filtrate was evaporated to
dryness leaving brown crystals. Purification by column
chromatography (SiO2; hexane:EtOAc 5:1) afforded 9b
(7.67 g, 84%) as white powdery crystals: mp 80–81°C
5.5. 2,5-Dimethoxy-4-methylamphetamine hydrochloride
5b
To a solution of 11b (640 mg, 2.7 mmol) in MeOH (20
mL) in a Parr flask was added 10% Pd/C catalyst (60
mg) and the mixture was rocked under 40 psi H2 for 12
h. The catalyst was removed by filtration through a
Celite pad and the filtrate was evaporated to dryness.
The residual solid was taken up in Et2O and HCl gas
was allowed to bubble through. No solids formed. The
Et2O was evaporated and the residual solid was taken
up in a minimal amount of MeOH; Et2O was added
dropwise. The crystals that formed overnight were
filtered, washed with Et2O, and dried to yield 5b (400
1
(lit.9 80.5–81.5°C), H NMR (CDCl3) l (ppm): 1.23 (d,
3H, CHCH3), 2.13 (d, 1H, OH), 2.21 (s, 3H, ArCH3),
2.75 (ABX, 2H, ArCH2CH), 3.78 (s, 6H, OCH3), 4.04
(m, 1H, ArCH2CH), 6.65 (s, 1H, ArH), 6.70 (s, 1H,
ArH), [lit.9 in DMSO-d6), 1.01 (d, J=6 Hz, 3H,
CHCH3), 2.12 (s, 3H, ArCH3), 2.65 (m, 1H, ArCH2CH
overlapping with DMSO), 3.60–4.27 (8H, overlapping
ArCH2CH and OCH3), 4.27 (br, 1H, exchanges with
D2O, OH), 6.72 (s, 2H, ArH)].
1
mg, 60%): mp 188–190°C (lit.12 184–185°C), H NMR
(CD3OD) (ppm): 1.28 (d, J=6.6 Hz, 3H,
l
ArCH2CHCH3), 2.21 (s, 3H, ArCH3), 2.81–2.99 (dd,
2H, ArCH2), 3.52–3.63 (m, 1H, ArCH2CH), 3.805 (s,
3H, OCH3), 3.815 (s, 3H, OCH3), 6.78 (s, 1H, ArH),
6.83 (s, 1H, ArH), 13C NMR (MeOH) l (ppm): 15.32
(ArCH3), 17.58 (ArCH2CHCH3), 35.66 (ArCH2), 48.45
(ArCH2CH), 55.32 (OCH3), 55.53 (OCH3), 113.9
(ArH), 114.0 (ArH), 121.8 (ArC), 126.8 (ArC), 151.7
(ArO), 152.1 (ArO).
5.3. (2%,5%-Dimethoxy-4%-methylphenyl)-2-propyl tosylate
10b
A mixture of 9b (1 g, 0.005 mol), p-toluenesulfonyl
chloride (1 g, 0.005 mol), and pyridine (20 mL) was

J. M. Wagner et al. / Tetrahedron: Asymmetry 14 (2003) 2119–2125
2123
5.6. (S)-(2%,5%-Dimethoxy-4%-methylphenyl)-2-propanol
(S)-9b
5.9. (R)-(−)-2,5-Dimethoxy-4-methylamphetamine
hydrochloride (R)-5b
A solution of 6b (33 g, 0.143 mol) in freshly distilled
THF (1000 mL) in a 2000 mL round bottomed flask
was cooled to −72°C. To the chilled, stirring solution
was added a solution of 2.0 M n-BuLi (71 mL, 0.142
mol) dropwise. After 10 min, S-(−)-proplyene oxide
(S)-8 (5 mL, 0.072 mol) was added, followed by
BF3·Et2O (13.6 mL, 0.107 mol). After stirring for 15
min the reaction was quenched with saturated NH4Cl
and extracted with Et2O (3×400 mL). The combined
organic extract was dried over Na2SO4, filtered, and
evaporated to dryness. The residue was taken up in
MeOH, causing a white precipitate to form. The ppt
was separated by filtration and discarded, and the
MeOH was evaporated to dryness. The residual solid
was recrystallized from hot EtOAc/hexanes several
times. Evaporation of the combined mother liquors
afforded a brown oil which, when eluted through a
silica column (hexanes:EtOAc 4:1), afforded additional
(S)-9b, which was combined with the previously recrys-
tallized batches. A further recrystallization from hot
EtOAc/hexanes yielded pure (S)-9b (13.00 g, 74%): mp
90-92°C, [h]2D2=+10.5 (c 1.01, MeOH), 1H NMR
(CDCl3): identical to racemic 9b; 13C NMR (CDCl3) l
(ppm): 16.6 (ArCH3), 23.4 (ArCH2CHCH3), 40.8
(ArCH2), 56.43 (ArOCH3), 56.46 (ArOCH3), 68.62
(ArCH2CH), 114.37 (ArH), 114.39 (ArH), 125.1 (ArC),
125.9 (ArC), 151.6 (ArOCH3), 152.0 (ArOCH3).
To a solution of (R)-11b (7.3 g, 0.032 mol) in MeOH
(200 mL), in a Parr flask, was added 10% Pd/C catalyst
(600 mg) and the mixture was rocked under 40 psi H2
for 12 h. The catalyst was removed by filtration
through a Celite pad and the filtrate was evaporated to
dryness. The residual solid was then taken up in CHCl3
and extracted with 1 M HCl. The combined extract was
basified with NaOH and extracted with CHCl3. After
drying over Na2SO4, the solvent was evaporated and
the residual solid was taken up in Et2O. Treatment with
HCl gas followed by evaporation of the solvent resulted
in a solid hydrochloride salt. The solid was taken up in
a minimal amount of MeOH and Et2O was added
dropwise. Crystals formed overnight, which were
filtered, washed with Et2O, and dried under vacuum to
yield (R)-5b (5.3 g, 70%): mp 198–200°C (lit.1 204–
205°C), [h]2D2=−16.2 (c 1.00, H2O) (lit.1 −17.2, c 2
1
H2O). H NMR and 13C NMR (CD3OD): identical to
racemic 5.
5.10. S-(−)-2,5-Dimethoxy-4-methylamphetamine (S)-5b
To a solution of (S)-(2%,5%-dimethoxy-4%-methylphenyl)-
2-propanol (S)-9b (0.4 g, 0.002 mol) in dry THF (5 mL)
was added triphenylphosphine (1 g, 0.004 mol) and
CBr4 (1.26 g, 0.004 mol). After stirring overnight the
solids were removed by filtration and the filtrate was
evaporated to dryness. The residual oil was taken up in
DMF, sodium azide (0.5 g, 0.008 mol) was added and
stirring was continued overnight. The reaction was
quenched with H2O and the mixture was extracted with
CHCl3. The organic extract was dried and evaporated
to dryness. The residue was dissolved in EtOH, treated
with 10% Pd/C and shaken under 40 psi of H2
overnight. The catalyst was removed by filtration and
the solvent was evaporated to near dryness. The residue
was taken up in H2O and the pH was adjusted to 7.
After washing with Et2O the pH was adjusted to 11 and
the solution was extracted with CHCl3. The organic
extract was dried over Na2SO4 and evaporated to dry-
ness. GC analysis showed the product to be (S)-5b of
97% optical purity.
5.7. (S)-(2%,5%-Dimethoxy-4%-methylphenyl)-2-propyl
tosylate (S)-10b
A mixture of (S)-9b (9.88 g, 0.048 mol), p-toluenesul-
fonyl chloride (10.8 g, 0.057 mol), and pyridine (200
mL) was prepared while stirring in a 1000 mL round
bottomed flask, in an ice bath. The mixture was trans-
ferred to the freezer and after 48 h crystals had formed.
These crystals were removed by filtration and washed
with hexanes. The volatiles were evaporated from the
combined filtrate and washings and the residual liquid
was poured over ice. Since no solid was formed, the
mixture was extracted with CHCl3. After drying over
Na2SO4 and evaporation of the solvent, the residue was
triturated with hexanes to afford a white solid which
was filtered, washed with hexane and water, and dried
under vacuum to give (S)-10b (13.2 g, 77%): mp 77–
5.11. (S)-2,5-Dimethoxyphenyl-2-propanol (S)-9c
To a solution of 1-bromo-2,5-dimethoxybenzene 6c
(43.41 g, 0.200 mol) in dry THF (700 mL) in a 1000 mL
three necked round bottom flask equipped with an N2
inlet and cooled to −72°C was added a solution of 2.0
M n-BuLi in pentane (100 mL, 0.200 mol). After
stirring for 10 min, (S)-propylene oxide (S)-8 (6.00 g,
0.103 mol) was added. Stirring was continued for 10
min and BF3·Et2O (21.29 g, 0.15 mol) was added. After
stirring for 15 min the solution was quenched with
saturated NH4Cl and extracted with Et2O (3×250 mL).
The combined organic extract was dried over Na2SO4,
filtered, and evaporated to dryness leaving an oil with a
precipitated solid. The solid was filtered off, washed
with MeOH and discarded. The oil was again evapo-
rated, dried in vacuo and purified by column chro-
1
78°C, H and 13C NMR (CDCl3): identical to racemic
10b.
5.8. (R)-(2%,5%-Dimethoxy-4%-methylphenyl)-2-propyl
azide (R)-11b
After stirring overnight, a mixture of (S)-10b (12 g,
0.035 mol) and NaN3 (8.96 g, 0.138 mol) in DMF (200
mL), in a round-bottomed flask, was treated with H2O
and extracted with Et2O. The organic layer was dried
over Na2SO4, filtered, and evaporated to dryness to
1
give (R)-11b (7.4 g, 91%) as a light brown oil. H and
13C NMR (CDCl3): identical to racemic 11b.

2124
J. M. Wagner et al. / Tetrahedron: Asymmetry 14 (2003) 2119–2125
matography (SiO2; hexane:EtOAc 5:1). The fractions
that contained the product were evaporated and
recrystallized from EtOAc/hexane yielding (S)-9c.
(13.60 g, 67% yield) as clear colorless needle crystals.
The chiral purity of the product was determined to
be 100% by GC analysis of a diastereomeric mixture
obtained by derivatizing with menthyl chloroformate
(MCF). The compound had mp 56–57°C and [h]2D3=
5.14. (R)-2,5-Dimethoxyamphetamine (R)-5c
To a solution of (R)-2,5-dimethoxyphenyl-2-propyl-
azide (R)-11c (6.19 g, 0.028 mol) in MeOH (200 mL)
was added 10% Pd/C (0.65 g) and the slurry was
hydrogenated at 40–45 psi overnight. The catalyst
was removed by filtration through celite and the
MeOH was evaporated to leave (R)-5c (5.42 g, 100%
yield) as a clear light yellow colored oil. 1H NMR
(CDCl3) l (ppm): 1.10–1.13 (d, 3H, CHCH3), 2.48–
2.55 (q, 1H, ArCH2CH), 2.68–2.75 (q, 1H,
ArCH2CH), 3.16–3.23 (m, 1H, ArCH2CH), 3.75 (s,
3H, OCH3), 3.77 (s, 3H, OCH3), 6.70–6.74 (m, 2H,
ArH’s), 6.77–6.80 (q, 1H, ArH). GC analysis indi-
cated 98% enantiomerically pure (R)-5c.
1
+14.8 (c 1.01, MeOH). H NMR (CD3OD) l (ppm):
1.09–1.12 (q, 3H, CHCH3), 2.61–2.67 (q, 1H,
ArCH2CH), 2.73–2.79 (q, 1H, ArCH2CH), 3.72 (d,
3H, OCH3), 3.75 (d, 3H, OCH3), 3.95–3.99 (m, 1H,
ArCH2CH), 6.70–6.75 (m, 2H, ArH’s), 6.82–6.85 (m,
1H, ArH). Anal calcd for C11H16O3; C, 67.32; H,
8.22. Found: C, 67.49; H, 8.22.
5.12. (S)-2,5-Dimethoxyphenyl-2-propyl tosylate (S)-
10c
5.15. (R)-4-Iodo-2,5-dimethoxyamphetamine (R)-5d
To a solution of (S)-2,5-dimethoxyphenyl-2-propanol
(S)-9c (10.19 g, 0.052 mol) in pyridine (70 mL) in a
1000 mL round bottomed flask was added p-toluene-
sulfonyl chloride (11.88 g, 0.062 mol) while stirring in
an ice bath. The flask was then transferred to the
freezer and left for three days. The flask was full of
crystals, which were collected by filtration. The pyri-
dine solution was washed with a cold biphase of
aqueous 3% NaOH and CHCl3. The CHCl3 layer was
drawn off and washed with cold aqueous 2% HCl.
The CHCl3 layer was dried over MgSO4 and evapo-
rated to an oil. The oil was then recrystallized from
EtOAc and hexane yielding (S)-10c (10.38 g, 57%
yield) as white crystals. 1H NMR (CDCl3) l (ppm):
1.35–1.37 (d, 3H, CHCH3), 2.41 (s, 3H, ArCH3),
2.77–2.80 (d, 1H, ArCH2CH), 3.63 (s, 3H, OCH3),
3.71 (s, 3H, OCH3), 4.78–4.88 (m, 1H, ArCH2CH),
6.55–6.60 (q, 2H, ArH’s), 6.65–6.69 (q, 1H, ArH),
7.15–7.18 (d, 2H, ArH’s), 7.55–7.58 (d, 2H, ArH’s).
Anal calcd for C18H22O5S: C, 61.69; H, 6.33. Found:
C, 61.72; H, 6.30.
To a solution of (R)-2,5-dimethoxyamphetamine (R)-
5c (5.42 g, 0.028 mol) in EtOH (100 mL) was added
I2 (14.10 g, 0.066 mol) and Ag2SO4 (17.32 g, 0.066
mol) and the reaction mixture was allowed to stir
overnight. The precipitated yellow solid was collected
by filtration and the EtOH evaporated. The solid
residue was dissolved in CHCl3 and washed with
aqueous 5% NaOH (250 mL). The aqueous layer was
extracted with CHCl3 (2×300 mL) and the organic
layers were combined and washed with H2O. The
organic layer was then dried over Na2SO4, filtered,
and evaporated down to a purplish brown solid (8.45
g). Column chromatography (SiO2, 8% EtOH/CHCl3)
gave (R)-5d (4.31 g, 48% yield) as an off white solid.
1H NMR (CDCl3)
l (ppm): 1.10–1.13 (d, 3H,
CHCH3), 2.48–2.55 (q, 1H, ArCH2CH), 2.68–2.74 (q,
1H, ArCH2CH), 3.17–3.24 (m, 1H, ArCH2CH), 3.76
(s, 3H, OCH3), 3.83 (s, 3H, OCH3), 6.74 (s, 1H,
ArH), 7.22 (s, 1H, ArH). 13C NMR (CDCl3) l
(ppm): 152.61 (ArOCH3), 152.40 (ArOCH3), 129.63
(ArCH2CH), 121.69 (ArC), 114.30 (ArC), 82.58 (ArI),
57.13
(CH2CHCH3),
(CH2CHCH3).
(ArOCH3),
56.12
(ArOCH3),
(CH2CHCH3),
47.00
23.72
5.13. (R)-2,5-Dimethoxyphenyl-2-propyl azide (R)-11c
41.28
To a solution of (S)-2,5-dimethoxyphenyl-2-propyl
tosylate (S)-10c (10.17 g, 0.029 mol) in DMF (80
mL) was added sodium azide (7.55 g, 0.116 mol) and
the solution was stirred for 5 days. TLC indicated
complete conversion. The mixture was taken up in
water and extracted with Et2O (3×300 mL). The Et2O
layers were combined and washed with H2O to
remove excess DMF. The aqueous layer was back-
extracted with Et2O (200 mL). The combined organic
extract was dried over Na2SO4, filtered, and evapo-
rated to give (R)-11c (6.19 g, 96% yield) as a clear
5.16. (R)-4-Iodo-2,5-dimethoxyamphetamine (R)-5d
hydrochloride
Treatment of a CHCl3 solution of (R)-5d (6.29 g,
0.020 mol) with HCl/MeOH, followed by evaporation
of the solvent gave a solid that was recrystallized
using MeOH/Et2O. The white crystals were collected
and washed with Et2O giving R-5d hydrochloride
(5.50 g, 0.015 mol, 79% yield): TLC single spot using
1
light yellow colored oil. H NMR (CDCl3) l (ppm):
1.23–1.25 (d, 3H, CHCH3), 2.69–2.75 (q, 1H,
ArCH2CH), 2.79–2.86 (q, 1H, ArCH2CH), 3.77 (s,
3H, OCH3), 3.79 (s, 3H, OCH3), 6.76–6.77 (d, 2H,
ArH), 6.78–6.79 (d, 1H, ArH’s); the proton corre-
sponding to ArCH2CH is overlapped by the two
methoxy groups. Anal calcd for C11H15O2N3: C,
59.71; H, 6.83; N, 18.99. Found C, 59.88; H, 6.95; N,
18.69.
UV
visualization
Rf
0.72
(chloroform:
methanol:ammonium hydroxide (80:18:2)), mp 222–
223°C (lit.6 218–219°C), [h]D23=−12.7 (c 1.01, H2O).
1H NMR (CDCl3)
l (ppm): 1.34–1.36 (d, 3H,
CHCH3), 2.82–2.89 (q, 1H, ArCH2CH), 3.05–3.11 (q,
1H, ArCH2CH), 3.66–3.73 (m, 1H, ArCH2CH), 3.80
(s, 3H, OCH3), 3.84 (s, 3H, OCH3), 6.72 (s, 1H,
ArH), 7.24 (s, 1H, ArH).

J. M. Wagner et al. / Tetrahedron: Asymmetry 14 (2003) 2119–2125
2125
5.17. Determination of enantiomeric excess
and a minor peak at 19.3 min. After applying the
correction factor (R)-5c was 97% enantiomerically
pure.
5.17.1. (2%,5%-Dimethoxy-4%-methylphenyl)-2-propanol 9b.
In a solution of 0.1 M of (−)-MCF in toluene, (1.5 mL)
was dissolved 9b (15 mg) and pyridine (1 drop) was
added. The solution was shaken, then washed with
H2O, dried over Na2SO4, and used for GC analysis at
215°C. Analysis of the racemate gave two peaks of
equal area at 17.7 and 18.2 min.
5.17.5. 2,5,-Dimethoxy-4-iodoamphetamine 5d. Attempts
to determine the enantiomeric excess of 2,5-dimethoxy-
4-iodo-amphetamine hydrochloride using TPC and
MTPA1 followed by GC analysis were unsuccessful. In
each case GC analysis of the racemic derivatization
product failed to yield two separate peaks.
Application of this procedure of the chiral alcohol
(S)-9b yielded a single peak at 17.4 min.
Acknowledgements
5.17.2. (2%,5%,-Dimethoxyphenyl)-2-propanol 9c. The pro-
cedure used for 9b was followed. Analysis of the
racemic alcohol gave two peaks of equal area at 15.02
and 15.48 min. Analysis of (S)-9c gave a single peak at
14.88 min.
This research was supported in part by Contract Num-
ber NO1DA-6-7054 from the National Institute on
Drug Abuse.
5.17.3. 2,5-Dimethoxy-4-methylamphetamine 5b. In a
vial, racemic 2,5-dimethoxy-4-methylamphetamine (25
mg) was dissolved in CHCl3 (1 mL) and 2 mL of 0.1 M
TPC in CHCl3 (3.4% D isomer present) was added
along with TEA (1 drop). This mixture was kept at
ambient temperature for 10 min, then washed with HCl
(6.0 M); the CHCl3 layer was used for GC analysis:
100–280°C @ 6°C/min, 5 min final hold. The racemate
exhibited two peaks, one at 26.3 and 26.8 min. Since
the second peak integrated larger, a correction factor of
0.906 was applied to the second peak to equalize the
areas. Analysis of (R)-5b showed a major peak at 26.4
min and a minor peak of 26.7 min. After applying the
correction factor (R)-5b was found to be 98% enan-
tiomerically pure.
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5.17.4. 2,5-Dimethoxyamphetamine 5c. The procedure
used for 5b was followed. Analysis of the racemic
amphetamine gave two peaks, one at 19.0 min and 19.5
min. Since the second peak integrated larger, a correc-
tion factor of 0.908 was applied to the second peak.
Analysis of (R)-5c showed a major peak at 18.9 min