On the absolute configuration of 1-cyclopropylethan-1-amine

Article abstract of DOI:10.1016/j.tetasy.2017.08.005

We observed a discrepancy between the reported specific rotation for the enantiomers of 1-cyclopropylethan-1-amine and the values for commercial material. Analyses by VCD of the free amine, by NMR analysis of the derived (S)-O-methylmandelamides and an X-ray crystal structure of one of the mandelamides defined the specific rotation for each enantiomer.

Full text of DOI:10.1016/j.tetasy.2017.08.005

Tetrahedron: Asymmetry 28 (2017) 1135–1138
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
On the absolute configuration of 1-cyclopropylethan-1-amine
⇑
Matthew W. D. Perry , Anders Eriksson, Marie Rydén Landergren
RIA Medicinal Chemistry, Innovative Medicines and Early Development, AstraZeneca Gothenburg, Pepparedsleden, SE-431 83 Mölndal, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
We observed a discrepancy between the reported specific rotation for the enantiomers of 1-cyclopropy-
lethan-1-amine and the values for commercial material. Analyses by VCD of the free amine, by NMR anal-
ysis of the derived (S)-O-methylmandelamides and an X-ray crystal structure of one of the mandelamides
defined the specific rotation for each enantiomer.
Received 16 June 2017
Revised 31 July 2017
Accepted 7 August 2017
Available online 29 August 2017
Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
1-Cyclopropylethan-1-amine 1 is an interesting small amine
that has found considerable use within medicinal chemistry as a
component of both JAK inhibitors1and CRF-1 antagonists.2,3 We
had occasion to use 1-cyclopropylethan-1-amine during the course
of a project within AstraZeneca and were surprised to discover that
commercial material gave a rotation of opposite sign to material
obtained by synthesis. We investigated the original literature on
the preparation of this amine4,5where the absolute configuration
of the isolated hydrochloride salt of the amine was assigned by
NH2
1
Andrés et al as (S) for the isomer with a small negative specific
25
We started by measuring the specific rotations of 1-cyclopropy-
lethan-1-amine 1 obtained from Sigma–Aldrich and Alfa Aesar
labelled as (S) and (R) respectively and the derived HCl salts
(Table 1).
To extend this analysis we ran vibrational circular dichroism
(VCD)6,7 on the Sigma–Aldrich (S)-amine as a solution in CDCl3
and compared the observed results to calculated values. (Fig. 1).
The outcome was consistent with this material having the (S)-
stereochemistry claimed by Sigma–Aldrich and in contrast to that
expected based on the specific rotation.
As a further step we prepared (S)-O-methylmandelamides 2 of
the individual amine isomers and the racemic mixture and exam-
ined the NMR spectra. Using the method developed by Trost et al.8
we assigned the absolute configurations of the amines accordingly
(Table 2, Fig. 2 and Fig. 3).
rotation, [
a
]
D = À3.6 (c 1.5, MeOH). Their assignment to (S) was
made by comparison of the sign of the specific rotation with those
previously described and they cited a value for the free base,
23
[
a]
D = À21.3 (neat), to have been reported by Vogel and Roberts.
Vogel and Roberts however separated the enantiomers by crystalli-
sation of salts and did not assign the absolute stereochemistry; fur-
thermore Vogel and Roberts reported that with their resolution
method, they obtained an enantiomerically pure amine as a free
25
base with [a] D = +21.1–21.8 (four determinations, neat but con-
taining ca. 5% water). Andrés et al may have also assigned the abso-
lute configuration by analogy with other amines synthesised by
their method, which all gave an (S)-absolute configuration.
Once again the data was consistent with the amine 1a having an
(S)-absolute configuration. As a final confirmatory step, we crys-
tallised the amide 2a from heptane and submitted it to X-ray crys-
tallographic analysis using Cu radiation at 100 K. The resulting
structure obtained was in agreement with the amide 2a having
an (S,S)-configuration (Fig. 4).
⇑
Corresponding author.
E-mail address: matthew.perry@astrazeneca.com (M.W.D. Perry).
http://dx.doi.org/10.1016/j.tetasy.2017.08.005
0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.

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M. W. D. Perry et al. / Tetrahedron: Asymmetry 28 (2017) 1135–1138
Table 1
Table 2
Specific rotations for the free base and HCl salt of 1-cyclopropylethan-1-amine
isomers
Chemical shifts of the 2-methyl group of the O-methylmandelamides 2 of amine 1
Amide
Amine origin
NMR shift 2-CH3
d
Absolute configuration
20
Amine origin
[
a
]
(c 1)
D
2a
2b
Sigma-Aldrich (S)
Alfa Aesar (R)
1.18
1.26
(S)
(R)
Free base
HCl salt
1a Sigma-Aldrich (S)
1b Alfa Aesar (R)
+27 (c 1.0, MeCN)
À26 (c 1.0, MeCN)
+8 (c 1.0, MeOH)
-8 (c 1.0, MeOH)
O
H
N
3. Conclusion
O
Based on the combination of all this data we have concluded
that the assignment of the absolute configuration made by Andrés
et al. was in error and that the (S)-isomer of 1-cyclopropylethan-1-
amine has a positive specific rotation (c 1.0, MeCN).
2
H
H
4. Experimental
4.1. General
H
Ph
H
Ph
Me
Me
OMe
(R)-amine
OMe
1H NMR and 13C NMR data were acquired at 25 °C on a Bruker
Avance III 500 MHz spectrometer fitted with a cryogenically cooled
probe. Chemical shifts (d) are given in parts per million (ppm), with
the following solvent residual peaks used as reference: CDCl3 (dH
7.26, dC 77.16), and CD3OD (dH 3.31, dC 49.00). Coupling constants
(J) are reported as Hz. LCMS was conducted using the following
system: Instrument, Waters Acquity UPLC; Mass spectrometer,
Waters SQD/SQD2, ESI+/ESIÀ ionization mode; Column, Acquity
UPLC HSS C18 50 mm  2.1 mm, 1.8 mm particles; Temp, 60 °C;
Flow 1 mL/min; UV spectrum 200–300 nm; Mobile phase A:
100% milli-Q water; 1 mM ammonium formate, 10 mM formic
acid, pH 3; Mobile phase B: 5% milli-Q water 95% acetonitrile;
1 mM ammonium formate, 10 mM formic acid, pH 3; Gradient,
0.01 min 10% B, 0.20–3.70 min 10–99%B, 3.70–3.80 min 99% B,
(S)-amine
methyl shielded
methyl deshielded
Figure 2. Newman projections of the O-methylmandelamides 2 of amine 1.
3.80–3.81 min 99–10% B. All solvents and reagents were obtained
from commercially available sources and used without further
purification including: (S)-1-Cyclopropylethylamine, ChiProsÒ,
produced by BASF, 99%, CAS [195604–39–8] obtained from
Sigma–Aldrich; (R)-1-Cyclopropylethylamine, ChiProsÒ, 98%, ee
98+%, CAS [6240-96-6] obtained from Alfa Aesar and (S)-(+)-a-
Methoxyphenylacetic acid, 99%, CAS[26164-26-1] obtained from
Sigma–Aldrich.
Figure 1. VCD measured for amine 1a compared to calculated for (S)-1 and (R)-1.

M. W. D. Perry et al. / Tetrahedron: Asymmetry 28 (2017) 1135–1138
1137
Figure 3. NMR spectra (upfield region) of the isomers of amides 2a, 2b and the diasteromeric mixture 2c.
4.3. (R)-1-Cyclopropylethan-1-amine hydrochloride 1b
Prepared as described for compound 1a but starting from (R)-1-
cyclopropylethan-1-amine (170 mg, 2.0 mmol) and 4 M HCl
solution in dioxane (2 mL, 8.00 mmol). Compound 1b was obtained
20
as a colourless solid (223 mg, 92%). [
a
]
D = À8 (c 1, MeOH). 1H
NMR (500 MHz, CD3OD) d 0.31–0.41 (m, 1H), 0.41–0.51 (m, 1H),
0.62–0.72 (m, 2H), 0.92–1.01 (m, 1H), 1.38 (d, J = 6.6 Hz, 3H),
2.52–2.61 (m, 1H). 13C NMR (126 MHz, CD3OD) d 3.82, 4.57,
16.10, 18.79, 54.40.
4.4.
(S)-N-((S)-1-Cyclopropylethyl)-2-methoxy-2-phenylace-
tamide 2a
To a suspension of (S)-2-methoxy-2-phenylacetic acid (100 mg,
0.60 mmol) in acetonitrile (1 mL) and ethyl acetate (1 mL) at rt
were added (S)-1-cyclopropylethan-1-amine (74 mg, 0.87 mmol),
DIPEA (0.315 mL, 1.81 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-triox-
atriphosphinane 2,4,6-trioxide (ÒT3P), 50% solution in EtOAc
(0.72 mL, 1.20 mmol), the resulting clear solution was stirred at
rt overnight. Solvents were evaporated, the residue was partitioned
between EtOAc (5 mL) and water (2 mL), and the organic phase
was washed with water (2 mL), NaHCO3 (aq) (2 mL) and brine.
The EtOAc phase was filtered through a 1 g silica column that
was washed with additional EtOAc to elute a product. The filtrate
Figure 4. Amide 2a thermal ellipsoids drawn at the 50% probability level (CCDC
1570948 – 2015scas0052).
4.2. (S)-1-Cyclopropylethan-1-amine hydrochloride 1a
(S)-1-Cyclopropylethan-1-amine (353 mg, 4.15 mmol) dis-
solved in diethylether (15 mL) was treated with 4 M HCl solution
in dioxane (1 mL, 4.00 mmol). The resulting suspension was
diluted with additional diethylether and stirred at rt. The solid salt
was collected by filtration, washed with diethylether and heptane
was concentrated, diluted with heptane and evaporated to dryness
20
and dried to afford compound 1a as a colourless solid (0.43 g, 85%).
to afford compound 2a as a colourless solid (133 mg, 95%). [
a]
=
D
20
[a]
D = +8 (c 1, MeOH). 1H NMR (500 MHz, CD3OD) d 0.31–0.41 (m,
+78 (c 1, MeCN). 1H NMR (500 MHz, CDCl3) d 0.22–0.28 (m, 1H),
0.36–0.42 (m, 1H), 0.45–0.56 (m, 2H), 0.83–0.91 (m, 1H), 1.18 (d,
J = 6.6 Hz, 3H), 3.34–3.42 (m, 1H), 3.38 (s, 3H), 4.59 (s, 1H), 6.72
(d, J = 5.9 Hz, 1H), 7.28–7.41 (m, 5H). 13C NMR (126 MHz, CDCl3)
1H), 0.42–0.51 (m, 1H), 0.62–0.72 (m, 2H), 0.92–1.01 (m, 1H), 1.38
(d, J = 6.7 Hz, 3H), 2.52–2.61 (m, 1H). 13C NMR (126 MHz, CD3OD) d
3.82, 4.59, 16.10, 18.79, 54.41.

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M. W. D. Perry et al. / Tetrahedron: Asymmetry 28 (2017) 1135–1138
d 3.25, 3.40, 17.49, 20.47, 49.42, 57.32, 83.96, 127.12 (2C), 128.47,
128.65 (2 C), 137.39, 169.78. LCMS (ESI) m/z calculated for
C
4.8. VCD Computational spectroscopic simulations
14H19NO2 (M+H)+ 234.2 found 234.2, tR=1.69 min, purity 99%.
A Monte Carlo molecular mechanics search for low energy
geometries was conducted for full structures of both enantiomers,
(R) and (S). MacroModel within the Maestro graphical interface
(Schrödinger Inc.) was used to generate starting coordinates for
the conformers. All conformers within 5 kcal/mol of the lowest
energy conformer were used as starting points for density func-
tional theory (DFT) minimizations within Gaussian09. Optimized
structures, harmonic vibrational frequencies/intensities, VCD rota-
tional strengths, and free energies at STP (including zero-point
energies) were determined for each conformer. In these calcula-
tions, the functional B3LYP and the basis set 6-31G⁄ were used.
Simulations of infrared and VCD spectra for each conformation
were generated using an in–house built program to fit Lorentzian
line shapes (12 cmÀ1 line width) to the computed spectra thereby
allowing direct comparisons between simulated and experimental
spectra.
4.5. (S)-N-((R)-1-Cyclopropylethyl)-2-methoxy-2-phenylacetam-
ide 2b
Prepared as described for compound 2a but starting from (S)-2-
methoxy-2-phenylacetic acid (100 mg, 0.60 mmol) and (R)-1-
cyclopropylethan-1-amine (75 mg, 0.88 mmol) to afford
20
compound 2b as a colourless solid (126 mg, 90%). [a] D = +64
(c 1, MeCN). 1H NMR (500 MHz, CDCl3) d 0.13–0.2 (m, 1H), 0.21–
0.27 (m, 1H), 0.35–0.42 (m, 1H), 0.43–0.5 (m, 1H), 0.8–0.88 (m,
1H), 1.26 (d, J = 6.6 Hz, 3H), 3.36 (s, 3H), 3.38–3.47 (m, 1H), 4.57
(s, 1H), 6.71 (brd, J = 6.7 Hz, 1H), 7.29–7.42 (m, 5H). 13C NMR
(126 MHz, CDCl3) d 2.88, 3.13, 17.44, 20.59, 49.00, 57.22, 84.05,
127.25 (2 C), 128.53, 128.66 (2 C), 137.43, 169.78. LCMS (ESI) m/z
calculated for C14H19NO2 (M+H)+ 234.2 found 234.2, tR=1.69 min,
purity 99%.
Acknowledgements
4.6. (2S)-N-(1-Cyclopropylethyl)-2-methoxy-2-phenylacetamide
2c
We thank Sten Nilsson-Lill (AstraZeneca) and Mark Edward
Light (Southampton University) for determination of the X-ray
structure of 2a.
Prepared as described for compound 2a but starting from (S)-2-
methoxy-2-phenylacetic acid (100 mg, 0.60 mmol) and racemic
1-cyclopropylethan-1-amine (72 mg, 0.88 mmol) to afford the
diastereomeric mixture 2c as a colourless solid (60 mg, 42%). 1H
NMR (500 MHz, CDCl3) d 0.14–0.2 (m, 0.5H), 0.21–0.28 (m, 1H),
0.36–0.42 (m, 1H), 0.44–0.56 (m, 1.5H), 0.8–0.91 (m, 1H), 1.18 (d,
J = 6.6 Hz, 1.5H), 1.26 (d, J = 6.6 Hz, 1.5H), 3.34–3.47 (m+s+s, 4H),
4.57 (s, 0.5H), 4.59 (s, 0.5H), 6.72 (brm, 1H), 7.29–7.42 (m, 5H).
LCMS (ESI) m/z calculated for C14H19NO2 (M+H)+ 234.2 found
234.3, tR=1.74 min, purity 95%.
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The sample was prepared by diluting the colourless liquid of
amine 1a as free base (41 mg) with 100 ll CDCl3. The solution
was transferred to a 0.100 mm BaF2 cells and the VCD spectrum
was acquired for one hour in a BioTools ChiralIR instrument
equipped with dual source and dual photo elastic modulator. The
resolution was 4 cmÀ1
.