Synthesis and Bioactivity of Novel N -Benzylic and N -Phenethylic Ephedrine Derivatives

Article abstract of DOI:10.1055/s-0036-1588523

A range of N -benzylic and N -phenethylic ephedrine derivatives were prepared in a one-pot procedure starting from the two enantiomers of ephedrine using the Potier reagent, and a polyfunctional aryl- or benzylic organozinc halide. The biological activity in indatraline MS Binding Assays addressing hDAT, hNET and hSERT was determined and discussed.

Full text of DOI:10.1055/s-0036-1588523

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–H
paper
A
en
M. Ellwart et al.
Paper
Synthesis
Synthesis and Bioactivity of Novel N-Benzylic and N-Phenethylic
Ephedrine Derivatives
TBSO
Me
N
Mario Ellwart
Georg Höfner
Aaron Gerwien
Klaus T. Wanner
TBSO
Me
NH
i) MeMgCl
ii) [Me2NCH2+CF3COO–]
CO2Et
iii) (CF3CO)2O
Me
81%
Me
iv)
EtO2C
ZnCl
Paul Knochel*
0
0
0
0
0-
0
0
1
7-
9
1
3
4-
3
3
2
MeMgCl
RZnCl
Me
Me
Ludwig-Maximilians-Universität München, Department
Chemie und Department Pharmazie, Butenandtstraße
5–13, Haus F, 81377 München, Germany
H2C
N
O
TBSO
Me
NMgCl
TBSO
Me
N
TBSO
Me
N
TFAA
F3C
O
paul.knochel@cup.uni-muenchen.de
CH2
Me
Me
N
Me
Me
Me
8 examples, up to 91% yield
Received: 28.06.2017
Accepted: 02.07.2017
Published online: 23.08.2017
DOI: 10.1055/s-0036-1588523; Art ID: ss-2017-t0428-op
tonin transporter (SERT) in MS Binding Assays, and to com-
pare these affinities with those determined for the enantio-
mers of ephedrine and pseudoephedrine.
Consequently, we report herein an efficient preparation
of a range of (+)- and (–)-ephedrine derivatives and their
activity in MS binding assays for the three monoamine
transporters. Thus, the treatment of a THF solution of TBS-
protected (+)-ephedrine derivative 5 with MeMgCl (1.1
equiv. 2.8 M in THF, –20 °C, 30 min) provided the corre-
sponding magnesium amide (6), which was added to the
Abstract A range of N-benzylic and N-phenethylic ephedrine deriva-
tives were prepared in a one-pot procedure starting from the two enan-
tiomers of ephedrine using the Potier reagent, and a polyfunctional
aryl- or benzylic organozinc halide. The biological activity in indatraline
MS Binding Assays addressing hDAT, hNET and hSERT was determined
and discussed.
Key words organozinc halides, organomagnesium halides, iminium
ion, ephedrine, binding assays
+
Potiersalt [Me2NCH2 CF3COO–],5 generated by the addition
of trifluoroacetic anhydride (TFAA) (1.0 equiv.) to TMDAM
(1.0 equiv., CH2Cl2, –20 °C, 15 min) (Scheme 1).6,7 The addi-
tion of TFAA (1.0 equiv.) to the mixed aminal thus formed
(7) led selectively after 15 min at –20 °C to the iminium salt
8which was then treated with a variety of benzylic zinc re-
agents of type 98 furnishing the expected tertiary amines of
type 10 in 70-91% yield (Scheme 1 and Table 1).
(–)-Ephedrine ((1R,2S)-(–)-ephedrine, 1) and its stereo-
isomers ((1S,2R)-(+)-ephedrine, 2; (1R,2R)-(–)-pseudo-
ephedrine, 3; (1S,2S)-(+)-pseudoephedrine, 4; Figure 1) are
used for a wide range of purposes, e.g. as bronchodilators,
nasal decongestants, appetite suppressants or energizers, to
name just a few.1 They act as sympathomimetic agents at
adrenergic receptors and are known to be substrates or in-
hibitors at monoamine transporters.2,3 Recently we have
developed a one-pot procedure, which allows the conver-
sion of N,N,N′,N′-tetramethylmethanediamine (TMDAM) di-
rectly into a broad variety of tertiary amines.4 This one-pot
procedure is compatible with the use of a range of function-
alized amines as well as a variety of benzylic organozinc re-
agents, leading selectively to the corresponding phenethyl-
amines. We have shown that this homologative amination
procedure furthermore allowed the conversion of (+)-
ephedrine derivatives to the corresponding benzylic and
phenethylic amines. Due to the importance of the potential
biological properties of all ephedrine stereoisomers we
found it worth to characterize the affinities of the prepared
ephedrine derivatives at the dopamine transporter (DAT), at
the norepinephrine transporter (NET) as well as at the sero-
(4-Methoxybenzyl)zinc chloride (9a) as well as the ester
and trifluoromethyl containing benzylic zinc reagents 9b
OH
OH
H
H
N
N
Me
Me
Me
Me
(–)-ephedrine (1)
(+)-ephedrine (2)
OH
H
OH
H
N
N
Me
Me
Me
Me
(+)-pseudoephedrine (4)
(–)-pseudoephedrine (3)
Figure 1 Chemical structures of ephedrine and pseudoephedrine ste-
reoisomers.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

B
M. Ellwart et al.
Paper
Synthesis
[3H]serotonin uptake assays employing rat brain synapto-
somes.2 For the enantiomers of pseudoephedrine results
similar to those for the ephedrine enantiomers were ob-
tained in MS Binding Assays addressing hDAT, hNET and
hSERT. These binding profiles of the pseudoephedrine en-
antiomers (3 and 4) are in accordance with those known
from radioligand binding experiments targeting DAT, NET
and SERT in monkey brain as well.3 The affinities of the pre-
pared (+)-ephedrine derivatives of type 11 at hNET and
(i) MeMgCl
TBSO
Me
N
TBSO
Me
NH
(ii) [Me2NCH2+CF3COO–]
(iii) (CF3CO)2O
Me
Me
(iv)
10a–h
FG
ZnCl
FG
5
i
iv
9a–h
TBSO
Me
NMgCl
TBSO
Me
N+
CH2
Me
Me
6
8
iii
ii
Table 1 Preparation of (+/–)-ephedrine derivatives of type 10 in a one-
pot procedure
TBSO
Me
N
Me
N
Entry
1
Zinc Reagent[a]
Product[b]
Me
Me
TBSO
Me
N
7
ZnCl
Scheme 1 Preparation of ephedrine derivatives containing a tertiary
amine by cleavage of mixed aminals and subsequent reaction with ben-
zylic zinc reagents. Conditions: i) MeMgCl (1.1 equiv.), –20 °C, 30 min;
ii) [Me2NCH2+CF3COO–] (1.0 equiv.), –20 °C, 30 min; iii) (CF3CO)2O (1.0
equiv.), –20 °C, 15 min; iv) benzylic zinc halide (1.1 equiv.), –78 °C to
25 °C, overnight.
MeO
Me
OMe
9a
10a: 85%
TBSO
Me
EtO2C
ZnCl
N
CO2Et
2
3
Me
9b
10b: 81%
and 9c were added to the iminium ion 8 providing the
phenethylamines 10a-c in 81-85% yield (Table 1, Entries 1-
3). Interestingly, the heterocyclic and the ortho-substituted
zinc reagents 9d,e showed a similar behavior and led selec-
tively to the desired phenethylamines 10d,e in 75% and 91%
yield, respecively (Entries 4-5). Furthermore, the arylzinc
reagent 9f was used according to the same protocol and fur-
nished the benzylic amine 10f in 70% yield (Entry 6). In ad-
dition, the (–)-ephedrine derivatives 10g,h were prepared
from the corresponding TBS-protected (–)-ephedrine deriv-
ative using (4-methoxybenzyl)zinc chloride (9a) and (3-
(trifluoromethyl)benzyl)zinc chloride (9c) (Entries 7-8).
The smooth removal of the TBS-group was shown by
the conversion of several TBS-protected phenethylamines
to the corresponding alcohols using TBAF·4H2O (4 equiv.,
THF, 25 °C, 12 h). Thus, the (+)- and (–)-ephedrine deriva-
tives 11a-h were obtained in 80-99% yield (Scheme 2) after
12 h at ambient temperature. In addition, 11i was produced
in 66% yield starting directly from TBS-protected (+)-
ephedrine without isolation of the intermediate TBS-depro-
tected phenethylamine. The functionalized tertiary amines
of type 11 were converted into their corresponding HCl
salts and their activity in MS binding assays for the three
monoamine transporters was evaluated.
TBSO
Me
F3C
ZnCl
N
CF3
Me
9c
10c: 85%
TBSO
Me
N
ZnCl
4
5
Cl
N
Me
Me
N
Cl
9d
10d: 75%
Cl
TBSO
Me
N
Cl
ZnCl
10e: 91%
9e
CO2Et
TBSO
Me
N
ZnCl
6
EtO2C
Me
Me
9f
10f: 70%
TBSO
Me
N
ZnCl
7
8
MeO
OMe
CF3
9a
10g: 85%
The results obtained for the ephedrine enantiomers (1
and 2) in MS Binding Assays addressing hDAT, hNET and
hSERT, respectively, indicate that both enantiomers bind
with moderate affinity at hNET and little less affinity at
hDAT but – at least up to a concentration of 100 μM –
almost not at hSERT. These results are roughly in agreement
with those from [3H]dopamine, [3H]norepinephrine and
TBSO
Me
N
F3C
ZnCl
Me
9c
10h: 85%
a Complexed LiCl is omitted for clarity.
b Yields refer to analytically pure products.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

C
M. Ellwart et al.
Paper
Synthesis
hDAT tend to be a little bit higher than those observed for
(+)-ephedrine. Interestingly, the synthesized (+)-ephedrine
derivatives showed also considerable affinity towards
hSERT, in some cases (11a and 11i) even with a more than
tenfold selectivity vs NET and DAT. In the series of the (+)-
ephedrine derivatives, the highest affinities for hSERT are in
the high nM range and were observed for 11a and 11i. Re-
garding the affinity towards hSERT a clear enantioselectivi-
ty with the (+)-ephedrine derivative 11a as eutomer and
the (–)-ephedrine derivative 11g as distomer was observed.
In contrast, for the enantiomers 11c and 11h, only poor dif-
ferences regarding their affinities at hDAT, hNET and hSERT
were found.
TBSO
Me
N
OH Me
N
TBAF·4H2O (4 equiv)
THF, 25 °C, 12 h
Ar
Ar
Me
Me
10a–i
11a–i: 80–99% yield
OH Me
N
OH Me
N
CO2Et
Me
Me
OMe
11a: 99%
11b: 94%
OH Me
OH Me
N
N
CF3
Me
11d: 99%
Me
N
Cl
11c: 80%
In summary, we have prepared nine polyfunctional
ephedrine derivatives via a one-pot homologative amina-
tion procedure which led after a TBS-deprotection directly
to the corresponding benzylic and phenethylic amines.
These new ephedrine derivatives were subjected to inda-
traline MS Binding Assays addressing hDAT, hNET and
hSERT showing that affinities of the prepared ephedrine
derivatives at all three transporters tend to be higher than
those observed for the four stereoisomers of (pseudo-)-
ephedrine. Interestingly, in the series of the (+)-ephedrine
derivatives, the highest affinities for hSERT are in the high
nM-range while a poorer affinity was found for the corre-
sponding (–)-ephedrine derivatives.
CO2Et
OH Me
N
Cl
OH Me
N
Me
Me
11f: 98%
11e: 99%
OH Me
OH Me
N
N
CF3
Me
11g: 99%
Me
11h: 80%
OMe
OH Me
N
O
O
Me
11i: 66%a
Scheme 2 TBS-deprotection of tertiary amines 10a-i to the corre-
sponding alcohols 11a-i which were subjected to biological evaluation.
a Yield over two steps starting from 5 without purification of the TBS-
protected intermediate.
Melting points were measured on a Büchi B 540 apparatus and are
uncorrected. Optical rotation values were determined on a P8000-
P8100-T polarimeter from A. Krüss Optronic, running software V3.0
with 5 cm path length. IR spectra were recorded on a PERKIN ELMER
Spectrum BX-59343 instrument. 1H NMR and 13C NMR spectra were
measured on VARIAN Mercury 200, BRUKER AXR 300, VARIAN VXR
400 S and BRUKER AMX 600 instruments in CDCl3 or C6D6 and refer-
Table 2 Affinities (pKi-values as mean values ± S.E.M, n ≥ 3; or for less affine compounds specific binding in the presence of 100 μM test substance in
%) toward the human transporters for serotonin (hSERT), noradrenaline (hNET) und dopamine (hDAT) determined in indatraline MS Binding Assays.
Compound
hSERT
hNET
hDAT
(1R,2S)-(–)-ephedrine·HCl (1)
(1S,2R)-(+)-ephedrine·HCl (2)
(1R,2R)-(–)-pseudoephedrine·HCl (3)
(1S,2S)-(+)-pseudoephedrine·HCl (4)
11a·HCl (C19H26ClNO2)
81 %
4.61 ± 0.03
4.48 ± 0.11
4.49 ± 008
4.83 ± 0.10
5.33 ± 0.13
5.96 ± 0.12
5.07 ± 0.08
52 %
3.89 ± 0.02
4.04 ± 0.03
3.96 ± 0.06
3.58 ± 0.08
4.79 ± 0.04
5.24 ± 0.03
5.00 ± 0.11
61 %
91 %
96 %
87 %
6.63 ± 0.09
6.00 ± 0.05
5.53 ± 0.01
5.90 ± 0.05
6.14 ± 0.01
4.78 ± 0.11
5.09 ± 0.05
5.21 ± 0.03
6.67 ± 0.01
11b·HCl (C21H30ClNO4)
11c·HCl (C19H23ClF3NO)
11d·HCl (C21H30ClNO4)
11e·HCl (C18H23Cl2NO)
5.77 ± 0.05
5.48± 0.14
5.22 ± 0.05
5.65 ± 0.13
5.07 ± 0.09
5.57 ± 0.11
4.88 ± 0.17
5.17 ± 0.11
4.71 ± 0.09
4.93 ± 0.03
11f·HCl (C20H26ClNO3)
11g·HCl (C19H26ClNO2)
11h·HCl (C19H23ClF3NO)
11i·HCl (C19H24ClNO3)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

D
M. Ellwart et al.
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Synthesis
enced to the solvent signal. Low resolution mass spectra were record-
ed on a HP 6890/MSD 5973 spectrometer fitted with a HP-5 column
(30 m× 0.25 mm×0.25 μm). HR-MS EI spectra were recorded on a
FINNIGAN MAT 95Q instrument with an electron energy of 70 eV.
Flash chromatography was accomplished using Merck Kieselgel 60
(230–400 mesh ASTM).
13C-NMR (101 MHz, CDCl3): δ / ppm = 157.9, 145.1, 133.1, 130.0,
129.7, 127.7, 126.9, 113.8, 77.4, 65.4, 56.9, 55.4, 38.1, 34.2, 26.0, 18.3,
9.2, -4.2, -4.7.
IR (Diamond-ATR, neat): ν̃/cm-1 = 2953 (m), 2929 (m), 2865 (m), 1690
(w), 1612 (w), 1511 (s), 1462 (m), 1360 (w), 1300 (w), 1245 (vs), 1176
(m), 1110 (w), 1081 (s), 1060 (vs), 1039 (s), 1005 (m), 863 (s), 832
(vs), 774 (vs), 737 (m), 698 (s), 668 (m).
Procedures
MS (EI, 70 eV): m/z (%) = 398.3 (1), 292.1 (5), 192.2 (100), 135.1 (30),
105.1 (6), 73.2 (10).
HRMS (EI): m/z calc. for [C25H38NO2Si]+: 412.2666; found 412.2674.
Typical Procedure for the Preparation of N-Phenethylic Ephedrine
Derivatives of Type 10 (TP1):
A dry and argon-flushed Schlenk flask, equipped with a magnetic
stirring bar and a septum, was charged with N,N,N’,N’-tetramethyl-
methanediamine (1.0 equiv) and anhydrous CH2Cl2 to obtain a 1 M
solution. After cooling to −20 °C, trifluoroacetic anhydride (1.0 equiv)
was added dropwise and the solution was allowed to stir for 15 min at
−20 °C. A second dry and argon-flushed Schlenk flask, equipped with
a magnetic stirring bar and a septum, was charged with the TBS-
protected ephedrine derivative (1.1 equiv) and THF to obtain a 0.2 M
solution. After cooling to −20 °C, MeMgCl (1.1 equiv., 2.8 M in THF)
was added dropwise and the solution was stirred for 30 min. Next,
the magnesium amide was added over 15 min to the previously pre-
pared methylene(dimethyl)iminium trifluoroacetate at −20 °C and
stirring was continued for another 30 min. Then, trifluoroacetic anhy-
dride (1.0 equiv) was added, resulting in the formation of a white pre-
cipitate. The mixture was stirred for 15 min before the desired or-
ganomagnesium/organozinc reagent (1.1 equiv) was added at –78 °C
and the reaction mixture warmed to room temperature giving a clear
solution. Sat. aq. NaHCO3 was added and the mixture was extracted
with EtOAc (3 x 20 mL). The combined organic layers were dried with
MgSO4, the solvent was removed in vacuo and purification by column
chromatography afforded the expected products.
Ethyl 3-(2-(((1S, 2R)-1-((tert-Butyldimethylsilyl)oxy)-1-phenyl-
propan-2-yl)(methyl)amino)ethyl)benzoate (10b)
Prepared according to TP1 from (+)-5(158 mg, 0.550 mmol, 1.1 equiv)
and (3-ethoxycarbonylbenzyl)zinc chloride (1.56 mL, 0.300 M in THF,
0.550 mmol, 1.1 equiv). Purification of the crude product by flash
chromatography (SiO2, ihexane/EtOAc = 20:1) afforded 10b as a color-
less oil (196 mg, 81% yield).
1H-NMR (600 MHz, CDCl3): δ / ppm = 7.84 (d, J = 7.7), 7.80 (s, 1H),
7.30–7.16 (m, 7H), 4.60 (d, J = 6.0, 1H), 4.38 (q, J = 7.1, 2H), 2.83–2.77
(m, 1H), 2.66–2.51 (m, 4H), 2.30 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H), 1.05 (d,
J = 6.7, 3H), 0.86 (s, 9H), 0.02 (s, 3H), -0.31 (s, 3H).
13C-NMR (151 MHz, CDCl3): δ / ppm = 167.0, 145.0, 141.3, 133.4,
130.5, 129.9, 128.3, 127.7, 127.2, 126.9, 77.2, 65.4, 61.0, 56.4, 38.0,
34.9, 26.0, 18.3, 14.5, 9.4, -4.2, -4.8.
IR (Diamond-ATR, neat): ν̃/cm-1 = 2955 (m), 2929 (m), 2856 (m), 1718
(vs), 1605 (w), 1587 (w), 1462 (m), 1366 (m), 1274 (vs), 1257 (s),
1194 (s), 1104 (s), 1082 (s), 1060 (vs), 1026 (s), 1005 (m), 863 (s), 834
(vs), 774 (vs), 749 (m), 697 (s), 669 (m).
MS (EI, 70 eV): m/z (%) = 440.3 (1), 410.3 (1), 234.2 (100) 177.1 (4),
149.1 (6), 131.1 (6), 105.1 (5), 73.1 (7)
Typical Procedure for the Deprotection of N-Ethylaryl Ephedrine
HRMS (EI): m/z calc. for [C26H38NO3Si]+: 440.2621; found 440.2616.
Derivatives of Type 11 (TP2):
A round bottom flask, equipped with a magnetic stirring bar and a
septum, was charged with the tertiary ephedrine derivative (1.0
equiv), 5 mL dry CH2Cl2and TBAF·3H2O (4.0 equiv). The progress of
the reaction was monitored by GC-analysis of the consumption of the
starting material. Upon complete deprotection after 12 h, 5 mL sat. aq.
NaHCO3solution was added and the product was extracted with EtOAc
(3 x 20 mL). The combined organic layers were dried with MgSO4, the
solvent was removed in vacuo and purification by column chromato-
graphy afforded the expected products.
((1S, 2R)-1-((tert-Butyldimethylsilyl)oxy)-N-methyl-1-phenyl-N-
(3-(trifluoromethyl)phenethyl)propan-2-amine (10c)
Prepared according to TP1 from (+)-5(158 mg, 0.550 mmol, 1.1 equiv)
and (3-(trifluoromethyl)benzyl)zinc chloride (0.350 mL, 1.43 M in
THF, 0.550 mmol, 1.1 equiv). Purification of the crude product by
flash chromatography (SiO2, ihexane/EtOAc = 30:1) afforded 10c as a
colorless oil (187 mg, 83% yield).
1H-NMR (600 MHz, CDCl3): δ / ppm = 7.41 (d, J = 7.9, 1H), 7.35 (s, 1H),
7.34–7.18 (m, 7H), 4.59 (d, J = 6.0 Hz, 1H), 2.80 (p, J = 6.5 Hz, 1H),
2.68–2.50 (m, 4H), 2.29 (s, 3H), 1.06 (d, J = 6.5 Hz, 3H), 0.86 (s, 8H),
0.02 (s, 3H), –0.31 (s, 3H).
Preparation of N-Phenethylic Ephedrine Derivatives of Type 10
13C-NMR (151 MHz, CDCl3): δ / ppm = 144.8, 141.8, 132.1, 130.3 (q, J =
31.8 Hz), 128.5, 127.6, 126.7, 125.3, 124.2 (q, J = 273.3 Hz) 122.6, 77.1,
65.3, 56.2, 37.8, 34.7, 25.8, 18.1, 9.2, –4.4, –5.0.
(1S, 2R)-1-((tert-Butyldimethylsilyl)oxy)-N-(4-methoxypheneth-
yl)-N-methyl-1-phenylpropan-2-amine (10a)
Prepared according to TP1 from (+)-5(306 mg, 1.10 mmol, 1.1 equiv)
and (4-methoxybenzyl)zinc chloride (1.96 mL, 0.560 m in THF, 1.10
mmol, 1.1 equiv). Purification of the crude product by flash chroma-
tography (SiO2, ihexane/EtOAc = 20:1) afforded 10a as a colorless oil
(350 mg, 85% yield).
1H-NMR (400 MHz, CDCl3): δ / ppm = 7.26–7.17 (m, 5H), 6.94 (d, J =
8.7 Hz, 2H), 6.72 (d, J = 8.7 Hz, 2H), 4.57 (d, J = 5.9 Hz, 1H), 3.72 (s, 3H),
2.79–2.70 (m, 1H), 2.59–2.36 (m, 4H), 2.23 (s, 3H), 1.00 (d, J = 6.7 Hz,
3H), 0.81 (s, 9H), -0.03 (s, 3H), -0.36 (s, 3H).
19F-NMR (376 MHz, CDCl3): δ / ppm = –62.48.
IR (Diamond-ATR, neat): ν̃/cm-1 = 2955 (m), 2930 (m), 2857 (m), 1493
(w), 1471 (w), 1450 (m), 1326 (s), 1320 (s), 1256 (m), 1198 (m), 1163
(s), 1123 (vs), 1071 (s), 1061 (s), 1027 (w), 1005 (w), 908 (m), 863 (s),
833 (vs), 774 (vs), 737 (m), 699 (s), 669 (m).
MS (EI, 70 eV): m/z (%) = 436.4 (1), 320.3 (2), 230.2 (100), 173.1 (7),
153.1 (6), 133.1 (5), 73.1 (5).
HRMS (EI): m/z calc. for [C24H33F3N2OSi]+: 436.2284; found 436.2282.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

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M. Ellwart et al.
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Synthesis
(1S, 2R)-1-((tert-Butyldimethylsilyl)oxy)-N-(2-(6-chloropyridin-3-
yl)ethyl)-N-methyl-1-phenylpropan-2-amine (10d)
13C-NMR (75 MHz, CDCl3) δ/ ppm = 166.7, 145.8, 144.8, 129.2, 128.7,
128.1, 127.6, 126.9, 126.9, 64.9, 60.7, 58.7, 37.3, 25.8, 18.1, 14.4, 9.1, -
4.4, -5.0.
IR (cm-1): ν̃= 2957, 2930, 2857, 2794, 1717, 1611, 1472, 1452, 1413,
1365, 1272, 1258, 1172, 1105, 1098, 1084, 1060, 1020, 863, 834, 775,
756, 699.
MS (70 eV, EI) m/z (%) = 441 (1) [M+], 221 (15), 220 (100), 163 (28), 73
(7).
HRMS (EI): m/z calc. for C26H39NO3Si (440.2626, [M–H]+): found:
440.2616.
Prepared according to TP1 from (+)-5(306 mg, 1.10 mmol, 1.1 equiv)
and (3-((6-chloropyridin-3-yl)methyl)zinc chloride (3.33 mL, 0.330 M
in THF, 1.10 mmol, 1.1 equiv). Purification of the crude product by
flash chromatography (SiO2, ihexane/EtOAc = 20:1) afforded the title
compound as a colorless oil (313 mg, 75% yield).
1H-NMR (400 MHz, CDCl3): δ / ppm = 8.03 (dd, J = 2.5, 0.7 Hz, 1H),
7.29–7.16 (m, 5H), 7.11 (dd, J = 8.2, 2.5 Hz, 1H), 7.04 (dd, J = 8.2, 0.7
Hz), 4.50 (d, J = 6.9 Hz), 2.77 (p, J = 6.7 Hz, 1H), 2.67–2.39 (m, 4H), 2.23
(s, 3H), 1.05 (d, J = 6.6 Hz, 3H), 0.84 (s, 9H), 0.00 (s, 3H), -0.33 (s, 3H).
13C-NMR (101 MHz, CDCl3): δ / ppm = 149.7, 148.8, 144.8, 139.2,
135.3, 127.8, 127.0, 126.9, 123.7, 77.4, 65.5, 56.1, 37.1, 30.9, 26.0,
18.2, 9.5, -4.3, -4.8.
IR (Diamond-ATR, neat): ν̃/cm-1 = 2954 (m), 2928 (m), 2855 (m), 1585
(w), 1564 (w), 1458 (s), 1381 (m), 1360 (w), 1250 (s), 1209 (w), 1103
(s), 1082 (s), 1059 (vs), 1025 (s), 1005 (m), 863 (s), 833 (vs), 774 (vs),
737 (m), 699 (s), 669 (m).
(1R, 2S)-1-((tert-Butyldimethylsilyl)oxy)-N-(4-methoxypheneth-
yl)-N-methyl-1-phenylpropan-2-amine (10g)
Prepared according to TP1 from (+)-5(306 mg, 1.10 mmol, 1.1 equiv)
and (4-methoxybenzyl)zinc chloride (1.96 mL, 0.560 M in THF, 1.10
mmol, 1.1 equiv). Purification of the crude product by flash chroma-
tography (SiO2, ihexane/EtOAc = 20:1) afforded 10g as a colorless oil
(350 mg, 85% yield).
1H-NMR (400 MHz, CDCl3): δ / ppm = 7.26–7.17 (m, 5H), 6.94 (d, J =
8.7 Hz, 2H), 6.72 (d, J = 8.7 Hz, 2H), 4.57 (d, J = 5.9 Hz, 1H), 3.72 (s, 3H),
2.79–2.70 (m, 1H), 2.59–2.36 (m, 4H), 2.23 (s, 3H), 1.00 (d, J = 6.7 Hz,
3H), 0.81 (s, 9H), -0.03 (s, 3H), -0.36 (s, 3H).
MS (EI, 70 eV): m/z (%) = 403.2 (1), 287.1 (2), 197.1 (100), 140.1 (12),
104.1 (4), 73.1 (7), 56.1 (2).
HRMS (EI): m/z calc. for [C23H34ClN2OSi]+: 417.2123; found 417.2129.
(1S, 2R)-1-((tert-Butyldimethylsilyl)oxy)-N-(2-chlorophenethyl)-
N-methyl-1-phenylpropan-2-amine (10e)
13C-NMR (101 MHz, CDCl3): δ / ppm = 157.9, 145.1, 133.1, 129.7,
127.7, 126.9, 126.4, 113.8, 77.4, 65.4, 56.9, 55.4, 38.1, 34.2, 26.0, 18.3,
9.2, -4.2, -4.7.
IR (Diamond-ATR, neat): ν̃/cm-1 = 2953 (m), 2929 (m), 2865 (m), 1690
(w), 1612 (w), 1511 (s), 1462 (m), 1360 (w), 1300 (w), 1245 (vs), 1176
(m), 1110 (w), 1081 (s), 1060 (vs), 1039 (s), 1005 (m), 863 (s), 832
(vs), 774 (vs), 737 (m), 698 (s), 668 (m).
Prepared according to TP1 from (+)-5 (279 mg, 1.0 mmol, 1.0 equiv)
and 2-chlorobenzylzinc chloride (0.69 mL, 1.60 M in THF, 1.1 mmol,
1.1 equiv). Purification of the crude product by flash chromatography
(Al2O3, ihexane/EtOAc = 49:1) afforded 10eas a colorless oil (380 mg,
91% yield).
1H-NMR (300 MHz, CDCl3) δ/ ppm = 7.34-7.23 (m, 6H), 7.15-7.08 (m,
3H), 4.63 (d, J = 5.9 Hz, 1H), 2.81 (qi, J = 6.6 Hz, 1H), 2.71-2.61 (m, 4H),
2.32 (s, 3H), 1.06 (d, J = 6.8 Hz, 3H), 0.89 (s, 9H), 0.02 (s, 3H), –0.30 (s,
3H).
MS (EI, 70 eV): m/z (%) = 398.3 (1), 292.1 (5), 192.2 (100), 135.1 (30),
105.1 (6), 73.2 (10).
HRMS (EI): m/z calc. for [C25H38NO2Si]+: 412.2666; found 412.2674.
13C-NMR (75 MHz, CDCl3) δ/ppm = 145.3, 138.7, 134.2, 131.2, 129.6,
127.9, 127.6, 127.1, 127.0, 127.0, 65.8, 54.6, 38.4, 33.0, 26.2, 18.4, 9.7,
–4.0, –4.6.
IR (cm-1): ν̃= 2956, 2929, 2886, 2856, 2796, 1472, 1360, 1251, 1082,
1053, 1028, 1006, 863, 834, 816, 774, 747, 698, 680, 675.
((1R, 2S)-1-((tert-Butyldimethylsilyl)oxy)-N-methyl-1-phenyl-N-
(3-(trifluoromethyl)phenethyl)propan-2-amine (10h)
Prepared according to TP1 from (+)-5(158 mg, 0.550 mmol, 1.1 equiv)
and (3-(trifluoromethyl)benzyl)zinc chloride (0.350 mL, 1.43 M in
THF, 0.550 mmol, 1.1 equiv). Purification of the crude product by
flash chromatography (SiO2, ihexane/EtOAc = 30:1) afforded 10h as a
colorless oil (187 mg, 83% yield).
MS (70 eV, EI) m/z (%) = 417 (1) [M+], 402 (1), 198 (35), 197 (12), 196
(100), 139 (19), 103 (12), 73 (17).
1H-NMR (600 MHz, CDCl3): δ / ppm = 7.41 (d, J = 7.9, 1H), 7.35 (s, 1H),
7.34–7.18 (m, 7H), 4.59 (d, J = 6.0 Hz, 1H), 2.80 (p, J = 6.5 Hz, 1H),
2.68–2.50 (m, 4H), 2.29 (s, 3H), 1.06 (d, J = 6.5 Hz, 3H), 0.86 (s, 8H),
0.02 (s, 3H), -0.31 (s, 3H).
13C-NMR (151 MHz, CDCl3): δ / ppm = 144.8, 141.8, 132.1, 130.3 (q, J =
31.8 Hz), 128.5, 127.6, 126.7, 125.3, 124.2 (q, J = 273.3 Hz) 122.6, 77.1,
65.3, 56.2, 37.8, 34.7, 25.8, 18.1, 9.2, -4.4, -5.0.
HRMS (EI): m/z calc. for C24H3635ClNOSi (402.2025, [M–CH3]+): found:
402.2024.
Ethyl 4-((((1S, 2R)-1-((tert-Butyldimethylsilyl)oxy)-1-phenylpro-
pan-2-yl)(methyl)amino)methyl)benzoate (10f)
Prepared according to TP1 from (+)-5 (279 mg, 1.0 mmol, 1.0 equiv)
and (4-(ethoxycarbonyl)phenyl)zinc chloride (1.7 mL, 0.65 M in THF,
1.1 mmol, 1.1 equiv). Purification of the crude product by flash chro-
matography (Al2O3, ihexane/EtOAc = 99:1) afforded the title com-
pound as a colorless oil (309 mg, 70% yield).
1H-NMR (300 MHz, CDCl3) δ/ ppm = 7.80 (d, J = 8.4 Hz, 2H), 7.28-7.20
(m, 5H), 6.96 (d, J = 8.4 Hz, 2H), 4.56 (d, J = 7.2 Hz, 1H), 4.32 (q, J = 7.0
Hz, 2H), 3.60-3.46 (m, 2H), 2.79 (qi, J = 6.6 Hz, 1H), 2.12 (s, 3H), 1.35
(t, J= 7.0, 3H), 1.11 (d, J = 6.6 Hz, 3H), 0.83 (s, 9H), 0.00 (s, 3H).
19F-NMR (376 MHz, CDCl3): δ / ppm = -62.48.
IR (Diamond-ATR, neat): ν̃/cm-1 = 2955 (m), 2930 (m), 2857 (m), 1493
(w), 1471 (w), 1450 (m), 1326 (s), 1320 (s), 1256 (m), 1198 (m), 1163
(s), 1123 (vs), 1071 (s), 1061 (s), 1027 (w), 1005 (w), 908 (m), 863 (s),
833 (vs), 774 (vs), 737 (m), 699 (s), 669 (m).
MS (EI, 70 eV): m/z (%) = 436.4 (1), 320.3 (2), 230.2 (100), 173.1 (7),
153.1 (6), 133.1 (5), 73.1 (5).
HRMS (EI): m/z calc. for [C24H33F3N2OSi]+: 436.2284; found 436.2282.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

F
M. Ellwart et al.
Paper
Synthesis
Deprotection of the Silylated Ephedrine Derivatives of Type 10 Us-
ing TBAF
13C-NMR (101 MHz, CDCl3): δ / ppm = 142.1, 141.1, 132.0, 130.7 (q, J =
32.0 Hz), 128.8, 127.8, 127.0, 126.1, 125.4 (q, J = 3.8 Hz), 124.2 (q, J =
271.5 Hz), 123.0 (q, J = 3.8 Hz), 73.3, 63.8, 56.3, 39.2, 34.0, 10.0.
IR (Diamond-ATR, neat): ν̃/cm-1 = 2963 (w), 2856 (w), 2800 (w), 1598
(w), 1493 (w), 1450 (m), 1377 (w), 1369 (w), 1329 (vs), 1199 (m),
1161 (s), 1119 (vs), 1072 (s), 1026 (m), 1000 (m), 907 (m), 883 (w),
798 (m), 761 (w), 734 (m), 699 (vs), 661 (m).
(1S, 2R)-2-((4-Methoxyphenethyl)(methyl)amino)-1-phenylpro-
pan-1-ol (11a)
Prepared according to TP2 from 10a(290 mg, 0.700 mmol, 1.0 equiv).
Purification of the crude product by flash chromatography (SiO2,
ihexane/EtOAc = 5:1) afforded 11a as a white solid (208 mg, 99%
yield).
MS (EI, 70 eV): m/z (%) = 318.3 (1), 230.3 (100), 173.2 (12), 153.1 (8),
77.1 (3), 58.9 (4).
HRMS (EI): m/z calc. for [C19H22F3NO]+: 336.1572; found 336.1569.
[α]D19 = +4.65° (c = 0.90; CH2Cl2).
1H-NMR (400 MHz, CDCl3): δ / ppm = 7.35–7.21 (m, 5H), 7.08 (d, J =
8.6 Hz), 6.84 (d, J = 8.6 Hz, 2H), 4.76 (d, J = 4.3 Hz, 1H), 3.79 (s, 3H),
2.92–2.80 (m, 1H), 2.75–2.62 (m, 4H), 2.34 (s, 3H), 0.87 (d, J = 6.9 Hz,
3H).
13C-NMR (101 MHz, CDCl3): δ / ppm = 158.1, 142.3, 132.4, 129.7,
128.2, 126.9, 126.2, 114.0, 73.1, 63.7, 57.1, 55.4, 39.3, 33.3, 10.4.
IR (Diamond-ATR, neat): ν̃/cm-1 = 2934 (m), 2834 (m), 2797 (m), 1611
(m), 1583 (w), 1511 (s), 1462 (m), 1451 (m), 1300 (m), 1244 (vs),
1176 (m), 1035 (w), 996 (w), 960 (w), 909 (m), 849 (w), 821 (s), 733
(s), 700 (s).
(1S, 2R)-2-((2-(6-Chloropyridin-3-yl)ethyl)(methyl)amino)-1-
phenylpropan-1-ol (11d)
Prepared according to TP2 from 10d(253 mg, 0.600 mmol, 1.0 equiv).
Purification of the crude product by flash chromatography (SiO2,
ihexane/EtOAc = 5:1) afforded 11d as a colorless oil (183 mg, 99%
yield).
[α]D1910.75° (c = 0.18; CH2Cl2).
1H-NMR (400 MHz, CDCl3): δ / ppm = 8.16 (dd, J = 2.5, 0.7 Hz, 1H),
7.36 (dd, J = 8.2, 2.5 Hz, 1H), 7.34–7.23 (m, 5H), 7.19 (dd, J = 8.2, 0.7
Hz, 1H), 4.73 (d, J = 4.8 Hz, 1H), 2.86 (qd, J = 6.8, 4.8 Hz), 2.73–2.60 (m,
4H), 2.34 (s, 3H), 0.92 (d, J = 6.8 Hz, 3H).
MS (EI, 70 eV): m/z (%) = 292.1 (4), 192.2 (100), 135.2 (40), 105.1 (4),
73.1 (8).
HRMS (EI): m/z calc. for [C17H20NO2]+: 254.1545; found 254.1586.
13C-NMR (101 MHz, CDCl3): δ / ppm = 149.7, 149.2, 142.2, 138.9,
134.5, 128.0, 127.1, 126.0, 123.8, 73.6, 63.8, 55.8, 38.8, 30.5, 9.9.
IR (Diamond-ATR, neat): ν̃/cm-1 = 2963 (w), 2933 (w), 2897 (w), 1585
(m), 1565 (m), 1455 (vs), 1382 (m), 1360 (w), 1285 (w), 1210 (w),
1135 (m), 1103 (s), 1051 (m), 1024 (s), 996 (m), 915 (w), 824 (m), 798
(w), 761 (m), 736 (s), 700 (vs), 698 (w).
Ethyl 3-(2-(((1S, 2R)-1-Hydroxy-1-phenylpropan-2-yl)(methyl)-
amino)ethyl)benzoate (11b)
Prepared according to TP2 from 10b(156 mg, 0.340 mmol, 1.0 equiv).
Purification of the crude product by flash chromatography (SiO2,
ihexane/EtOAc = 5:1) afforded 11b as a colorless oil (110 mg, 94%
yield).
MS (EI, 70 eV): m/z (%) = 197.2 (100), 140.1 (26).
HRMS (EI): m/z calc. for [C17H19ClN2]+: 286.1236; found 286.1227.
[α]D19 = +13.25° (c = 0.20; CH2Cl2).
1H-NMR (600 MHz, CDCl3): δ / ppm = 7.90–7.79 (m, 2H), 7.37–7.14
(m, 7H), 4.74 (d, J = 4.3 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.57 (br, 1H),
2.91–2.82 (m, 1H), 2.82–2.65 (m, 4H), 2.34 (s, 3H), 1.38 (t, J = 7.1 Hz,
3H), 0.87 (d, J = 6.9 Hz, 3H).
13C-NMR (151 MHz, CDCl3): δ / ppm = 166.7, 142.2, 140.5, 133.2,
130.6, 129.8, 128.4, 127.9, 127.4, 126.9, 126.1, 73.1, 63.6, 60.9, 56.5,
39.1, 33.8, 14.4, 10.0.
(1S,2R)-2-((2-Chlorophenethyl)(methyl)amino)-1-phenylpropan-
1-ol (11e)
Prepared according to TP2 from 10e(100 mg, 0.239 mmol). Purifica-
tion of the crude product by flash chromatography (SiO2, ihex-
ane/EtOAc = 20:1 + 2% NEt3) afforded 11e as a colorless oil (73 mg,
99% yield).
[α]D19 = +16.46° (c = 0.14; CH2Cl2).
IR (Diamond-ATR, neat): ν̃/cm-1 = 2990 (w), 2937 (w), 2797 (w), 1714
(vs), 1604 (w), 1587 (w), 1449 (m), 1367 (m), 1273 (vs), 1195 (s),
1104 (s), 1083 (s), 1024 (m), 1000 (m), 909 (m), 864 (w), 817 (w), 749
(s), 731, (s), 698 (vs), 673 (m).
1H-NMR (600 MHz, CDCl3): δ / ppm = 7.36–7.29 (m, 4H), 7.26–7.14
(m, 4H), 4.98 (s, 1H), 3.09–2.76 (m, 5H), 1.33–1.19 (m, 1H), 0.93 (d, J =
6.8 Hz, 3H).
13C-NMR (150 MHz, CDCl3): δ / ppm = 141.9, 137.4, 134.1, 131.2,
129.7, 128.2, 128.1, 127.2, 127.1, 126.1, 72.8, 64.2, 54.8, 39.1, 31.3,
29.9.
IR (Diamond-ATR, neat): ν̃/cm-1 = 3352 (w), 3062 (w), 3027 (w), 2933
(m), 2853 (w), 2799 (w), 1475 (m), 1450 (m), 1383 (w), 1248 (w),
1198 (w), 1156 (w), 1122 (m), 1052 (s), 1041 (m), 998 (m), 750 (vs),
701 (vs).
MS (EI, 70 eV): m/z (%) = 341.2 (1), 296.3 (6), 234.3 (100), 149.1 (10),
105.1 (10), 70.1 (8).
HRMS (EI): m/z calc. for [C19H22NO2]+: 296.1651 ([M–OEt]+); found
296.1651.
(1S, 2R)-2-(Methyl(3-(trifluoromethyl)phenethyl)amino)-1-phen-
ylpropan-1-ol (11c)
MS (EI, 70 eV): m/z (%) = 302 (M–H)+, 285 (31), 260 (30), 258 (100).
Prepared according to TP2 from 10c(157 mg, 0.350 mmol, 1.0 equiv).
Purification of the crude product by flash chromatography (SiO2,
ihexane/EtOAc = 5:1) afforded 11c as a colorless oil (94 mg, 80% yield).
HRMS (EI): m/z calc. for [C18H21ClNO]+: 302.1317; found 302.1317
[(M–H)+].
[α]D19 = +2.00° (c = 0.15; CH2Cl2).
Ethyl 4-((((1S,2R)-1-Hydroxy-1-phenylpropan-2-yl)(methyl)ami-
no)methyl)benzoate (11f)
1H-NMR (400 MHz, CDCl3): δ / ppm = 7.46–7.42 (m, 1H), 7.39–7.19
(m, 8H), 4.72 (d, J = 4.5 Hz, 1H), 3.22 (br, 1H), 2.85 (qd, J = 6.9, 4.5 Hz,
1H), 2.81–2.62 (m, 4H), 2.33 (s, 3H), 0.88 (d, J = 6.9 Hz, 3H).
Prepared according to TP2 from 10f(100 mg, 0.239 mmol). Purifica-
tion of the crude product by flash chromatography (SiO2, ihex-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

G
M. Ellwart et al.
Paper
Synthesis
ane/EtOAc = 20:1 + 2% NEt3) afforded 11f as a colorless oil (73 mg, 99%
HRMS (EI): m/z calc. for [C19H22F3NO]+: 336.1572; found 336.1569.
yield).
(1S, 2R)-2-((2-(Benzo[d][1,3]dioxol-5-yl)ethyl)(methyl)amino)-1-
[α]D19 = +9.29° (c = 0.07; CH2Cl2).
phenylpropan-1-ol Hydrochloride (11i)
1H-NMR (400 MHz, CDCl3): δ / ppm = 7.92–7.86 (m, 2H), 7.35–7.26
(m, 3H), 7.26–7.16 (m, 4H), 4.79 (d, J = 5.2 Hz, 1H), 4.31 (q, J = 7.1 Hz,
2H), 3.59 (s, 2H), 3.35–2.94 (m, 1H), 2.87 (qd, J = 6.8, 5.2 Hz, 1H), 2.14
(s, 3H), 1.33 (t, J = 7.1 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H).
13C-NMR (101 MHz, CDCl3): δ / ppm = 166.7, 145.1, 142.8, 129.7,
129.3, 128.5, 128.2, 127.2, 126.3, 74.2, 63.8, 61.0, 58.8, 38.8, 14.5, 9.9.
IR (Diamond-ATR, neat): ν̃/cm-1 = 2990, 2937, 2797, 1714, 1604,
1587, 1449, 1367, 1273, 1195, 1104, 1083, 1024, 1000, 909, 864, 817,
749, 731, 698, 673.
Prepared according to TP1 and TP2 from (+)-5 (279 mg, 1.0 mmol, 1.0
equiv) without the purification of the intermediate. Purification of
the crude product by flash chromatography (SiO2, ihexane/EtOAc =
10:1 → 5:1) and acidic extraction afforded 11i·HCl as a white powder
(236 mg, 67% yield). NMR spectra show both diastereoisomers at the
nitrogen center in the ratio A/B = 10:9. Therefore the 1H and 13C atoms
are indicated with A or B, if the chemical shift differs.
1H-NMR (400 MHz, DMSO3): δ / ppm = 10.90 (br, 1H, NHA), 10.81 (br,
1H, NHB), 7.48–7.41 (m, 2H, CH–C), 7.37 (td, J = 7.6, 1.3 Hz, 2H, CH–
CH–C), 7.32–7.23 (m, 1H, CH–CH–CH–C), 6.94 (dd, J = 3.8, 1.7 Hz, 1H,
C–CH–C–O), 6.87 (dd, J = 7.9, 5.1 Hz, 1H, CH–C–O), 6.78 (ddd, J = 7.9,
5.1, 1.7 Hz, 1H, CH–CH–C–O), 6.10 (br, 1H, OHB), 6.06 (br, 1H, OHA),
5.99 (s, 2H, O–CH2,B–O), 5.98 (s, 2H, O–CH2,A–O), 5.51 (br, 1H, CHA–
OH), 5.49 (br, 1H, CHB–OH), 3.72 – 3.64 (m, 1H, N–CH2,B), 3.56 – 3.45
(m, 1H, CH3–CHA,B), 3.42–3.31 (m, 1H, N–CH2,A), 3.30–3.18 (m, 1H, N–
CH2,A), 3.12–3.00 (m, 2H, C–CH2), 2.92 (d, J = 4.0 Hz, 3H, N–CH3,B), 2.90
(d, J = 4.0 Hz, 3H, N–CH3,A), 1.05 (d, J = 6.9 Hz, 3H, CH–CH3,B), 1.03 (d,
J = 6.9 Hz, 3H, CH–CH3,A).
13C-NMR (201 MHz, CDCl3): δ / ppm = 147.8B, 147.8A, 146.5A, 146.4B,
142.8B, 142.7A, 131.4B, 131.3A, 128.5, 127.7A, 127.7B, 126.2, 122.3,
109.6, 108.8B, 108.8A, 101.3, 70.4, 69.6A, 65.9B, 65.4B, 55.7A, 53.6B,
38.1B, 36.4A, 30.1, 6.8B, 5.6A.
IR (Diamond-ATR, neat): ν̃/cm-1 = 3209, (s), 2900 (w), 2647 (m), 1605
(w), 1501 (s), 1489 (m), 1443 (s), 1417 (w), 1378 (w), 1337 (m), 1254
(vs), 1230 (s), 1198 (m), 1189 (m), 1111 (m), 1041 (vs), 1010 (m), 934
(m), 926 (m), 888 (w), 847 (m), 814 (m), 765 (w), 741 (vs), 698 (vs),
667 (m).
MS (EI, 70 eV): m/z (%) = 282 (4), 220 (100), 191 (3), 163 (59), 135
(11), 107 (12).
HRMS (EI): m/z calc. for [C20H24NO3]+: 326.1762 ([M–H]+); found
326.1750.
(1R, 2S)-2-((4-Methoxyphenethyl)(methyl)amino)-1-phenylpro-
pan-1-ol (11g)
Prepared according to TP2 from 10g(290 mg, 0.700 mmol, 1.0 equiv).
Purification of the crude product by flash chromatography (SiO2,
ihexane/EtOAc = 5:1) afforded 11g as a white solid (208 mg, 99%
yield).
[α]D19 = –4.86° (c = 0.82; CH2Cl2).
1H-NMR (400 MHz, CDCl3): δ / ppm = 7.35–7.21 (m, 5H), 7.08 (d, J =
8.6 Hz), 6.84 (d, J = 8.6 Hz, 2H), 4.76 (d, J = 4.3 Hz, 1H), 3.79 (s, 3H),
2.92–2.80 (m, 1H), 2.75–2.62 (m, 4H), 2.34 (s, 3H), 0.87 (d, J = 6.9 Hz,
3H).
13C-NMR (101 MHz, CDCl3): δ / ppm = 158.1, 142.3, 132.4, 129.7,
128.2, 126.9, 126.2, 114.0, 73.1, 63.7, 57.1, 55.4, 39.3, 33.3, 10.4.
IR (Diamond-ATR, neat): ν̃/cm-1 = 2934 (m), 2834 (m), 2797 (m), 1611
(m), 1583 (w), 1511 (s), 1462 (m), 1451 (m), 1300 (m), 1244 (vs),
1176 (m), 1035 (w), 996 (w), 960 (w), 909 (m), 849 (w), 821 (s), 733
(s), 700 (s).
MS (EI, 70 eV): m/z (%) = 206.2 (100), 178.2 (18), 149.1 (68).
HRMS (ESI): m/z calc. for [C19H24NO3]+: 314.17507; found 314.17514.
Affinity Determination at DAT, NET and SERT:
MS Binding Assays at hDAT, hNET and hSERT were performed as pre-
viously described. 9,10
MS (EI, 70 eV): m/z (%) = 292.1 (4), 192.2 (100), 135.2 (40), 105.1 (4),
73.1 (8).
HRMS (EI): m/z calc. for [C17H20NO2]+: 254.1545; found 254.1586.
Acknowledgment
(1R, 2S)-2-(Methyl(3-(trifluoromethyl)phenethyl)amino)-1-phen-
ylpropan-1-ol (11h)
We thank the Deutsche Forschungsgemeinschaft (SFB 749, B2) and
the DIP (German-Israeli Project Cooperation) for financial support.
We thank Albemarle (Germany) for the generous gift of chemicals.
Prepared according to TP2 from 10h(157 mg, 0.350 mmol, 1.0 equiv).
Purification of the crude product by flash chromatography (SiO2,
ihexane/EtOAc = 5:1) afforded 11h as a colorless oil (94 mg, 80%
yield).
Supporting Information
[α]D19 = –0.21° (c = 0.95; CH2Cl2).
1H-NMR (400 MHz, CDCl3): δ / ppm = 7.46–7.42 (m, 1H), 7.39–7.19
(m, 8H), 4.72 (d, J = 4.5 Hz, 1H), 3.22 (br, 1H), 2.85 (qd, J = 6.9, 4.5 Hz,
1H), 2.81–2.62 (m, 4H), 2.33 (s, 3H), 0.88 (d, J = 6.9 Hz, 3H).
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588523.
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13C-NMR (101 MHz, CDCl3): δ / ppm = 142.1, 141.1, 132.0, 130.7 (q, J =
32.0 Hz), 128.8, 127.8, 127.0, 126.1, 125.4 (q, J = 3.8 Hz), 124.2 (q, J =
271.5 Hz), 123.0 (q, J = 3.8 Hz), 73.3, 63.8, 56.3, 39.2, 34.0, 10.0.
IR (Diamond-ATR, neat): ν̃/cm-1 = 2963 (w), 2856 (w), 2800 (w), 1598
(w), 1493 (w), 1450 (m), 1377 (w), 1369 (w), 1329 (vs), 1199 (m),
1161 (s), 1119 (vs), 1072 (s), 1026 (m), 1000 (m), 907 (m), 883 (w),
798 (m), 761 (w), 734 (m), 699 (vs), 661 (m).
References
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MS (EI, 70 eV): m/z (%) = 318.3 (1), 230.3 (100), 173.2 (12), 153.1 (8),
77.1 (3), 58.9 (4).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H