Synthesis of all of the stereoisomers of β3-adrenoceptor antagonist SR 59230 based on the spontaneous resolution of 3-(2-ethylphenoxy)propane-1,2-diol

Article abstract of DOI:10.1016/j.tetasy.2016.05.001

Racemic 3-(2-ethylphenoxy)propane-1,2-diol 2 has been effectively resolved into (S)- and (R)-enantiomers by a preferential crystallization procedure. Non-racemic diols 2, obtained via a Mitsunobu reaction, have been converted into the non-racemic 1,2-epox

Full text of DOI:10.1016/j.tetasy.2016.05.001

Tetrahedron: Asymmetry 27 (2016) 467–474
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Tetrahedron: Asymmetry
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Synthesis of all of the stereoisomers of b3-adrenoceptor antagonist
SR 59230 based on the spontaneous resolution of 3-(2-ethylphenoxy)
propane-1,2-diol
⇑
Zemfira A. Bredikhina, Alexey V. Kurenkov, Dmitry B. Krivolapov, Alexander A. Bredikhin
A.E. Arbuzov Institute of Organic and Physical Chemistry of Kazan Scientific Center of Russian Academy of Sciences, Arbuzov St., 8, Kazan 420088, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Racemic 3-(2-ethylphenoxy)propane-1,2-diol 2 has been effectively resolved into (S)- and (R)-enan-
tiomers by a preferential crystallization procedure. Non-racemic diols 2, obtained via a Mitsunobu reac-
tion, have been converted into the non-racemic 1,2-epoxy-3-(2-ethylphenoxy)propanes (S)- and (R)-5
and then into non-racemic 3-(2-ethylphenoxy)-1(1,2,3,4-tetrahydronaphth-1-ylamino)-2-propanols 1.
The characteristics of all four stereoisomers, (S,S)-1 (SR 59230), (R,R)-1 (SR 59483), (R,S)-1 and (S,R)-1
(SR 59231) and their hydrogen oxalates with a 1:1 composition have been presented. The crystalline oxa-
lates (S,S)-1ꢀC2H2O4 (SR 59230A) and (R,S)-1ꢀ0.5C2H2O4 were studied by single crystal X-ray diffraction.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 23 March 2016
Accepted 3 May 2016
Available online 17 May 2016
1. Introduction
channels, but no relevant inhibitory effects of this compound were
found in cardiac Kv1.5, Kv4.3 and KyLQT1/minK channels.6
Aryloxypropanolaminotetralins are selective antagonists for
atypical b3-adrenoceptors.1,2 Several aryloxypropanolaminote-
tralins isomers with different configurations at stereogenic carbons
presented stringent stereochemical requirements for b3-selectivity,
including high antagonist potency ratios between active and
inactive enantiomers.2 One representative of the aryloxypropa-
nolaminotetralins family is 3-(2-ethylphenoxy)-1(1,2,3,4-tetrahy-
dronaphth-1-ylamino)-2-propanol 1, which contains two
stereogenic centers; therefore this compound may exist as four
individual stereoisomers (Scheme 1). One of these stereoisomers,
3-(2-ethylphenoxy)-1[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-
(2S)-2-propanol, known as SR 59230, as its hydrogen oxalic acid salt
SR 59230A, is used as a popular b3-adrenoceptor antagonist.
Recently it has been found that the binding pocket apparently dif-
fers between human and rodent b3-adrenoceptors, yielding consid-
erable species differences in potency. In this regard, it has been
suggested that SR 59230 is not selective for b3-adrenoceptors, at
least in humans, and may actually be a partial agonist.3,4 Neverthe-
less, this compound is widely used as a tool to study different types
of biological activity. It has a high affinity for b3-adrenoceptors that
occur in the human gut which affect the function of human colonic
circular smooth muscle.5 It has been reported that SR 59230A inhi-
bits the Kir2.1, Kir-2.2 and Kir-2.3 cardiac potassium cloned
It has been shown that the stereoisomers of SR 59230A, i.e.,
(R,R)-1ꢀC2H2O4 (SR 59483A) and (S,R)-1ꢀC2H2O4 (SR 59231A), also
possess biological activity, which is different for all three forms.5,2
In this regard, the development of efficient synthetic approaches to
individual stereoisomers of SR 59230 and its salts is of importance.
It should also be noted that we found no information in the avail-
able literature about any physicochemical characteristics of the
H3C
OH
H3C
OH
HN
O
HN
O
(S,S)-1,
(R,R)-1,
SR 59230
SR 59483
H3C
OH
H3C
OH
HN
O
HN
O
1
1
(R,S)-
(S,R)-
,
SR 59231
Scheme 1. Stereoisomers of 3-(2-ethylphenoxy)-1(1,2,3,4-tetrahydronaphth-1-
ylamino)-2-propanol 1.
⇑
Corresponding author. Tel.: +7 843 2727393; fax: +7 843 2731872.
E-mail address: baa@iopc.ru (A.A. Bredikhin).
http://dx.doi.org/10.1016/j.tetasy.2016.05.001
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.

468
Z. A. Bredikhina et al. / Tetrahedron: Asymmetry 27 (2016) 467–474
iv
v
HO
(S,S)-1
iii
O
O
O
O
Cl
O
O
-1
(R,S)
OH
H
ii
i
H
H
-2
(S)
H
(S)-5
(R)-5
HO
rac-2
+
HO
iv
OH
HO
iii
-1
-1
(S,R)
v
4
rac-3
(R,R)
OH
(R)-2
Scheme 2. Reagents and conditions: (i) NaOH, EtOH, reflux; (ii) resolution by entrainment; (iii) PPh3, DIAD, THF, reflux; (iv) (S)-1,2,3,4-tetrahydro-1-naphthylamine, EtOH,
reflux; (v) (R)-1,2,3,4-tetrahydro-1-naphthylamine, EtOH, reflux.
stereoisomers, either for free bases or their salts. This of course
creates difficulties for dealing with these compounds and for the
control of their chemical and stereoisomeric purity. Therefore,
one of our tasks was to fill that gap.
In the synthesis of biologically active non-racemic ary-
loxypropanolamines the appropriate arylglycidyl ethers and/or
aryloxypropanediols often act as key precursors.7–9 From this point
of view, the obvious precursors for the synthesis of the family of
key step in our approach, ii, was the direct resolution of racemic
diol 2 by an entrainment procedure. We used water for the resolu-
tion, as the least expensive and ‘green’ solvent, and by analogy
with our own successful effective entrainment procedure for the
chiral drug guaifenesin.11 For monitoring the entrainment abilities
of diol 2 during the seed induced crystallization of oversaturated
slightly non-racemic water solutions, we used the mother liquor
enantiomeric composition measured by HPLC.
tetrahydronaphthyl aminopropanols
1
are enantiopure 3-(2-
During the crystallization process, the primary enantiomeric
excess of the solute (ꢁ9–10%) decreased to zero, changed sign,
and climbed back to the initial absolute value (or exceeded this
value for high initial concentrations). The enantiomeric composi-
tion of the mother liquor (and the composition of the deposited
crystalline crop as well) tended towards racemic. By varying the
initial concentration, temperature gap, and crystallization time,
we were able to establish the conditions for the satisfactory reso-
lution of racemic diol 2. An example of a successful resolution of
near racemic 2 is illustrated in Table 1. Table shows only three res-
olution cycles, but the procedure can be continued until the
exhaustion of the consumable racemate. Due to the peculiarities
of phase diagrams of normal conglomerates, to which diol 2
belongs, the enantiomeric purity of scalemic samples can be
increased to any desired value via simple recrystallization.
Conversion of the thus obtained enantiomers of 2 to the target
compounds 1 was carried out in two steps. Initially, we used an
intramolecular Mitsunobu etherification of diols 2 to epoxides
5.13,14 The reaction proceeded with only a slight loss of enan-
tiomeric purity, and the initial configuration of the stereogenic
center was conserved. Individual stereoisomers (S,S)-1, (S,R)-1,
(R,S)-1 and (R,R)-1 were obtained through boiling ethanol solutions
of epoxides (S)-5 or (R)-5 with (S)- or (R)-1,2,3,4-tetrahydro-1-
naphthylamine, respectively. Thus it was possible to obtain all four
individual stereoisomers of amino alcohol 1.
ethylphenoxy)-1,2-propanediols 2 (Scheme 2). We have previously
demonstrated that rac-2 crystallizes as a normal conglomerate, i.e.,
it shows a tendency for spontaneous resolution during crystalliza-
tion.10 Ethylphenoxypropanediol 2 has an obvious structural rela-
tionship with o-methoxyphenyl glycerol ether, an active
pharmaceutical ingredient guaifenesin. For racemic guaifenesin,
an effective direct resolution into individual enantiomers by the
entrainment procedure has been developed.11 Since both guaifen-
esin and ethylphenoxypropanediol 2 have practically the same
characteristics in terms of the crystal packing,12 there may be rea-
sons to expect that rac-2 can also be resolved into enantiomers
without using enantiopure auxiliary substances or materials. The
phenomenon of spontaneous resolution was another reason that
prompted us to carry out this work.
2. Results and discussion
2.1. Synthesis of enantiopure stereoisomers of 3-(2-ethyl-
phenoxy)-1(1,2,3,4-tetrahydronaphth-1-ylamino)-2-propanol
A general approach to the individual stereoisomers of tetrahy-
dronaphthyl aminopropanols 1 is outlined in Scheme 2.
The first step for the synthesis of diol rac-2 was the reaction of
sodium 2-ethylphenol 4 with rac-3-chloropropanediol rac-3. The
Table 1
Resolution by entrainment of rac-3-(2-ethylphenoxy)propane-1,2-diol, rac-2 in water (500 mL; 14 mg crystal seeds of the pure enantiomer on every run; crystallization
temperature 19 0.5 °C)
Run
Added amount of (RS)-2 (g)
Operation amount of
Resolution
time (min)
(R)-2 and (S)-2 obtained
(R)- and (S)-2a (g)
(R)-2
(S)-2
Yield (g)
eeb (%)
YEc
(g)
(%)
1
2
3
4
5
6
4.50d
0.892
0.816
0.926
0.888
0.829
2.750
2.337
2.709
2.302
2.698
2.323
2.250
2.663
2.291
2.698
2.302
2.677
100
120
130
120
110
120
(R) 0.906
(S) 0.830
(R) 0.940
(S) 0.902
(R) 0.843
(S) 0.818
93.3
91.4
88.0
89.4
90.8
90.4
0.830
0.744
0.813
0.792
0.716
0.725
30.2
27.9
30.0
29.4
26.5
27.0
a
b
c
The operation amounts in runs 2–6 were calculated based on the results in runs 1–5 respectively.
ee: enantiomeric excess (HPLC).
YE: Yield of enantiomer; YE (g) = [Yield (g) ꢂ ee (%)]/100 ꢃ 0.014 (seed weight); YE (%) = [YE (g) ꢂ 100]/Operation amount of (R)- or (S)-2 (g).
d
Additional amount of (R)-2 0.5 g.

Z. A. Bredikhina et al. / Tetrahedron: Asymmetry 27 (2016) 467–474
469
2.2. Molecular and crystal structure of (S,S)-1 and (R,S)-1 oxalic
acid salts
As mentioned above, amino alcohols 1 are used in biochemical
procedures in the form of oxalic acid salts; information on their
properties and structures are currently absent in the available lit-
erature. Therefore, all of the obtained stereoisomeric bases were
converted into oxalates by reaction with free oxalic acid in iso-
propanol. The resulting materials were characterized by single
sharp melting peaks on the DSC curves, and according to elemental
analysis, the salts had a 1:1 composition. The salts (S,S)-1ꢀC2H2O4
(SR 59230A) and (R,R)-1ꢀC2H2O4 (SR 59483A) melted at a much
lower temperature (162.1 °C) than their diastereomers (S,R)-1ꢀC2-
H2O4 (SR 59231A) b (R,S)-1ꢀC2H2O4 (207.0 °C). The first pair of
stereoisomers is comparatively readily soluble in common organic
solvents, while the second pair is dissolved satisfactorily in polar
solvents such as DMSO.
Figure 1. Symmetrically independent molecules in the unit cell of the crystal of
(S,S)-1ꢀC2H2O4 (SR 59230A).
All of the hydrogen oxalates obtained at this stage had a fine-
crystalline structure. The good solubility of SR 59230A and SR
59483A allowed us to grow single crystals suitable for X-ray anal-
ysis by slow evaporation of their saturated solutions in i-PrOH/
MeOH. The results c are shown in Table 2. This compound crystal-
lizes in orthorhombic Sohncke space group P212121 with one mole-
cule of the base and one molecule of the acid in the asymmetric
unit, which is shown in Figure 1.
Figure 1 shows that the two stereogenic carbon centers, which
are present in the investigated salt, have the same configuration. It
is also obvious that the nitrogen atom of the amino group is quat-
ernized, and only one of the carboxyl groups of the oxalic acid is
ionized.
The primary supramolecular crystal-formative motif in the
crystal of SR 59230A are 1D columns oriented along the shortest
cell parameter, 0a axis. Figure 2 shows the arrangement of the four
columns in the unit cell. Figure 2a also shows that the general 1D
motif can be conditionally divided into a one dimensional column,
formed by oxalic acid molecules, and a one dimensional column
consisting of molecules of (S,S)-1. The system of intermolecular
hydrogen bonds forming
a primary supramolecular motif is
described more fully in Figure 3.
Table 2
Crystallographic data for crystalline compounds (S,S)-1ꢀC2H2O4 and (R,S)-1ꢀ0.5C2H2O4
Compound, sample
Formula
(S,S)-1ꢀC2H2O4
(R,S)-1ꢀ0.5C2H2O4
(SR 59230A)
C44H56N2O8
C
23H29NO6
M (g/mol)
415.47
740.90
Temperature (K)
Crystal class
Space group
Crystal size (mm3)
Z, Z0
293
Orthorhombic
P212121
293
Monoclinic
P21
0.35 ꢂ 0.010 ꢂ 0.01
0.4 ꢂ 0.01 ꢂ 0.01
4, 1
2, 1
Cell parameters
a = 5.5612(13) Å,
b = 16.566(4) Å,
c = 23.323(6) Å
2148.7(9)
888
a = 15.060(9) Å,
b = 6.134(4) Å,
c = 23.248(9) Å
2067.4(19)
796
V (Å3)
F(000)
qcalc (g/cm3)
1.284
0.93
1.190
0.81
l
(cmꢃ1
)
h (°)
1.635 6 h 6 27.907
19,721
4212 [R(int)
= 0.0452]
288/1
1.869 6 h 6 26.00
10,952
7503 [R(int)
= 0.0821]
488/37
Figure 2. Detail of packing of molecules in the unit cell in the SR 59230A crystal;
view along 0a axis. (a) ‘Capped sticks’ style; intermolecular hydrogen bonds marked
with a green dotted lines. (b) ‘Spacefill’ style.
Reflections measured
Independent reflections
Number of parameters/
restraints
The core of the system is a sequence of hydrogen bonds,
O10AH10ꢀ ꢀ ꢀO4, O1AH1ꢀ ꢀ ꢀO400 etc., between the partially ionized
molecules of oxalic acid. These intermolecular hydrogen bonds
are characterized by being close to the ideal values of geometric
parameters [d (O1ꢀ ꢀ ꢀO400) = 2.489 Å; \OHO = 178°]. One of the NH
Reflections [I > 2
r
(I)]
3253
2459
R1/wR2 [I > 2 (I)]
r
0.0400/0.1080
0.0577/0.1290
0.777
0.199/ꢃ0.220
0.1262/0.3109
0.2772/0.3828
1.137
0.229/ꢃ0.235
R1/wR2 (all reflections)
Goodness-of-fit on F2
qmax
/
qmin (e Ǻꢃ3
)

470
Z. A. Bredikhina et al. / Tetrahedron: Asymmetry 27 (2016) 467–474
Figure 3. Scheme of the intermolecular hydrogen bonds (green dotted lines) in an SR 59230A crystal. The numbering of the atoms do not coincide with the crystallographic
data; hydrocarbon moieties of aminoalcohol molecules 1 are omitted for clarity.
bonds of the quaternary nitrogen atom forms a weak intermolecu-
lar H-bond with
a neighbouring amino alcohol molecule
[N1AH12ꢀ ꢀ ꢀO50; d (N1ꢀ ꢀ ꢀO50) = 2.899 Å; \NHO = 135°]. At the same
time, it is obvious that the main contribution to the creation of a
single whole is made by the middle and weak H-bonds involving
NAH and OAH bonds of the amino alcohol molecules as donors
and oxygen atoms of the oxalic acid as acceptors: N1AH11ꢀ ꢀ ꢀO3
[d
(N1ꢀ ꢀ ꢀO3) = 2.770 Å;
\NHO = 159°],
O50AH50ꢀ ꢀ ꢀO3
[d
(O50ꢀ ꢀ ꢀO3) = 2.725 Å; \OHO = 151°] b O50AH50ꢀ ꢀ ꢀO1 [d (O50ꢀ ꢀ ꢀO1)
= 3.028 Å; \OHO = 135°]. The geometric parameters of the inter-
molecular hydrogen bonds involving molecules 1 are far from ideal
values. We believe that only their cooperative nature, in conjunc-
tion with the Coulomb interaction of charged fragments, ensures
the integrity of the structure.
There is good reason to believe that the crystal packing, as a
whole, is imperfect. From Figure 2b it is clear that it is riddled by
through channels oriented along the 0a axis. Although the dimen-
sions of the channels do not allow the inclusion of solvent mole-
cules, they do reduce the packing index to a very moderate value
of 67.8%. In conjunction with the previously obtained information
concerning the better solubility and lower melting points of hydro-
gen oxalates (S,S)-1 and (R,R)-1 compared with the hydrogen oxa-
lates of (R,S)-1 and (S,R)-1, the latter were expected to have better
organization within their crystals.
Figure 4. Symmetry independent molecules in the unit cell of (R,S)-1ꢀ0.5C2H2O4
crystal.
Unfortunately, the low solubility of SR 59231A and its enan-
tiomer did not allow us to grow their good single crystals in similar
conditions to SR 59230A. Upon slow evaporation of (R,S)-1ꢀC2H2O4
solution in DMSO, the crystals were formed with filiform habitus
and a melting point (168 °C, DSC) which greatly differs from the
melting point (207 °C) of the starting material. As it was shown
by single crystal X-ray analysis, these crystals belonged to the nor-
mal oxalate (R,S)-1ꢀ0.5C2H2O4. The asymmetric unit of the crystal
thus grown is shown in Figure 4. It includes two symmetry inde-
pendent molecules of the quaternized base (R,S)-1 and single oxalic
acid dianion. Figure 4 also shows that the two stereogenic carbon
centers, which are present in the investigated salt, have different
configurations.
The primary crystal-formative motif in this case, once again, are
the 1D columns formed by translation of the asymmetric unit
along the shortest cell dimension, in this case the—0b axis. The
packing of these one-dimensional supramolecular associates in
the unit cell is illustrated in Figure 5.
Figure 5. Detail of packing of molecules in the unit cell in the (R,S)-1ꢀ0.5C2H2O4
crystal; view along 0b axis. Intermolecular hydrogen bonds marked with a green
dotted lines.
When comparing the systems of intermolecular hydrogen bonds,
typical for primary supramolecular motifs in SR 59231A crystal
(Fig. 3) and (R,S)-1ꢀ0.5C2H2O4 crystal (Fig. 6), the lack of ‘good’
H-bonds in the last case is noteworthy. The geometric parameters
of these intermolecular hydrogen bonds (here, subscripts indicate
belonging of the corresponding atom to the symmetry independent
molecules A or B) comprise: NAAH1Aꢀ ꢀ ꢀO300 [d (NAꢀ ꢀ ꢀO300) = 2.735 Å;
\NHO = 153°], NAAH2Aꢀ ꢀ ꢀO4 [d (NAꢀ ꢀ ꢀO4) = 2.809 Å; \NHO = 170°],
NBAH1Bꢀ ꢀ ꢀO300
[d
(NBꢀ ꢀ ꢀO300) = 2.746 Å;
\NHO = 146°],

Z. A. Bredikhina et al. / Tetrahedron: Asymmetry 27 (2016) 467–474
471
The IR spectra were recorded on a Bruker Tensor 27 spectrometer.
Optical rotations were measured on a Perkin–Elmer model 341
polarimeter (concentration c is given as g/100 mL). Melting points
for general purposes were determined using a Boëtius apparatus
and are uncorrected. The melting curves of oxalate salts were mea-
sured on a NETZSCH 204 F1 Phoenix DSC differential scanning
calorimeter in sealing aluminum pans with the rate of heating of
10 °C minꢃ1. The elemental composition was determined using a
EuroVector EA3000 CHN analyzer. Thin-layer chromatography
was performed on Silufol UV-254 plates using EtOAc–hexane
(2:3) as eluent; TLC plates were visualized under UV irradiation
or by treatment with iodine vapor. HPLC analyses were performed
on a Shimadzu LC-20AD system controller, UV monitor 275 nm
was used as detector. The columns used, from Daicel Inc., were Chi-
ralcel OD or OD-H (0.46 ꢂ 25 cm) or Chiralpak AD-RH
(0.46 ꢂ 25 cm). For the determination of enantiomeric composi-
tions of compounds 2 and 5, the columns were calibrated against
the corresponding racemic compounds.
Figure 6. Scheme of the intermolecular hydrogen bonds (green dotted lines) in
(R,S)-1ꢀ0.5C2H2O4 crystal. The numbering of the atoms does not coincide with the
crystallographic data; subscripts indicate the belonging of the corresponding atom
to the symmetry independent molecules A or B. The hydrocarbon moieties of amino
alcohol 1 molecules are omitted for clarity.
The MALDI mass spectra were recorded on a Bruker UltraFlex III
TOF/TOF instrument. The precise m/z values were determined at a
resolution of 10,000 using PEG-400 for external calibration. Sam-
ples were applied to a metal target by the dried drop method using
a 0.1 M solution of p-nitroaniline (matrix) in MeCN (0.5 lL) and a
NBAH2Bꢀ ꢀ ꢀO2 [d (NBꢀ ꢀ ꢀO2) = 2.776 Å; \NHO = 156°], O5BAH5B-
ꢀ ꢀ ꢀO100 [d (O5Bꢀ ꢀ ꢀO100) = 2.617 Å; \OHO = 155°].
0.1 M solution of (R,R)-1ꢀC2H2O4 in MeOH (0.5
lL).
As in the case of SR 59230A crystals, the crystal packing of (R,S)-
1ꢀ0.5C2H2O4 is permeated by the hollow channels (parallel 0b axis)
and the packing index is only 64.5%. On this basis, it can be
assumed that the formation of the crystalline neutral oxalates for
amino alcohols 1 is not advantageous. We were unable to obtain
such a salt for the amino alcohol (S,S)-1 even when double the
excess of the base was used. In principle, the possibility of chang-
ing the composition of the salts of 1 with oxalic acid (even during a
recrystallization) should be taken into account.
4.2. Compounds
2-Ethylphenol (99%), and racemic 3-chloropropane-1,2-diol (99+
%) were purchased from Acros Organics; (R)-3-chloropropane-1,2-
diol (97%, 98% ee), and (S)-3-chloropropane-1,2-diol (98%, 98% ee)
were purchased from Alfa Aesar; (R)- and (S)-1,2,3,4-tetrahydro-1-
naphthylamines (97%) were purchased from Sigma–Aldrich.
4.2.1. Racemic 3-(2-Ethylphenoxy)propane-1,2-diol rac-2
Crystal seeds of (S)-2 and (R)-2 were obtained according to the
literature;10 rac-2: mp 51–53 °C; Rf = 0.1; (R)-2: mp 67–68 °C;
3. Conclusion
[a]
20 = +13.0 (c 1, MTBE); 99.8% ee [chiral HPLC analysis; Chiralpak
D
The ability of racemic 3-(2-ethylphenoxy)-1,2-propanediol to
spontaneous resolution was used for its separation into individual
enantiomers, which were in turn converted by intramolecular Mit-
sunobu reaction to the non-racemic 1,2-epoxy-3-(2-ethylphenoxy)
propanes 5 and then to non-racemic 3-(2-ethylphenoxy)-1(1,2,3,4-
tetrahydronaphth-1-ylamino)-2-propanols 1. In this way (S)-oxi-
rane 5, by reaction with (S)-1,2,3,4-tetrahydro-1-naphthylamine,
was converted into 3-(2-ethylphenoxy)-1[(1S)-1,2,3,4-tetrahy-
dronaphth-1-ylamino]-(2S)-2-propanol (S,S)-1 (SR 59230), whereas
its enantiomer, (R,R)-1 (SR 59483), was obtained by reaction of (R)-5
with (R)-1,2,3,4-tetrahydro-1-naphthylamine. The enantiomeric (R,
S)-1 was obtained from the (S)-oxirane and the (R)-amine. The
opposite enantiomer (S,R)-1 (SR 59231) was obtained from the
(R)-oxirane and the (S)-amine. All stereoisomers have been charac-
terized both as free bases and as salts with oxalic acid (1:1). For the
hydrogen oxalate (R,S)-1ꢀC2H2O4 it was found that the conversion to
a normal salt (R,S)-1ꢀ0.5C2H2O4 is possible upon crystallization from
solution in DMSO. The crystalline oxalates (S,S)-1ꢀC2H2O4 (SR
59230A) and (R,S)-1ꢀ0.5C2H2O4 were studied by single crystal
X-ray analysis. We have shown that the quality of packing in a neu-
tral salt crystal is substantially worse than in the hydrogen salts.
AD-RH column; 40 °C; eluent: 2-propanol/water (1:3), 0.5 ml/min;
tR = 22.0 min]; Rf = 0.1; (S)-2: mp 67–68 °C; [
a
]
20 = ꢃ12.0 (c 1,
D
20
MTBE), [
a
]365 = ꢃ38.3 (c 1, MTBE); 99.0% ee [chiral HPLC analysis,
tR = 25.1 min]; Rf = 0.1.
4.2.2. Resolution of racemic 3-(2-ethylphenoxy)propane-1,2-
diol rac-2 by preferential crystallization (entrainment)
Racemic diol rac-2 (4.5 g) and (R)-2 (0.5 g) were dissolved in
500 ml of water at 45 °C. The solution was cooled to 20 °C and then
seeded with finely pulverized (R)-2 (0.014 g). During the course of
crystallization, we collected aliquots (10
regular intervals. The aliquots were mixed with 1 ml of iPrOH, and
portions of 20 l of the solutions were analyzed with the Chiralpak
ll) of the mother liquor at
l
AD-RH column. After stirring the mixture for 100 min at
19 0.5 °C, precipitated (R)-2 was collected by filtration (0.906 g
after drying; 93.3% ee) (Table 1, run 1). The extra portion of rac-2
(0.892 g) was then dissolved in the mother liquor at 45 °C; the
resulting solution was cooled to 20 °C. After the addition of (S)-2
(0.014 g) as seed crystals to the solution, and stirring the mixture
for 120 min at 19 0.5 °C, (S)-2 (0.830 g after drying; 91.4% ee)
was collected by filtration (run 2). Further resolution was carried
out at 19 0.5 °C by adding amended amounts of rac-2 to the fil-
trate in a manner similar to that described above. Detailed condi-
tions are given in Table 1. A high degree of the enantiomeric
purity of collected diols can be achieved by simple recrystalliza-
tion. For example: a portion of (S)-2 (2.55 g, 90.4% ee) was dis-
solved in the boiling mixture (80 ml) of light petroleum ether/
EtOAc 10:1. After cooling the solution to 20–25 °C the crystallized
(S)-2 was collected by filtration (yield 2.20 g; 99.0% ee). Similarly,
4. Experimental
4.1. General
The NMR spectra were recorded on a Bruker Avance-500 spec-
trometer (500.13 MHz for 1H and 125.75 MHz for 13C) in CDCl3 or
DMSO-d6 with the signals of the solvent as the internal standard.

472
Z. A. Bredikhina et al. / Tetrahedron: Asymmetry 27 (2016) 467–474
after recrystallization of combined portions of (R)-enantiomer
(2.69 g, 90.7% ee), pure (R)-2 was obtained (yield 2.37 g; 99.3% ee).
4.2.4.1. 3-(2-Ethylphenoxy)-1[(1S)-1,2,3,4-tetrahydronaphth-1-
ylamino]-(2S)-2-propanol (S,S)-1. This compound was synthesized
analogously from (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine and
(S)-1,2-epoxy-3-(2-ethylphenoxy)propane (S)-5. A colorless oil; yield
4.2.3. (S)-1,2-Epoxy-3-(2-ethylphenoxy)propane (S)-5
To a stirred solution of diol (S)-2 (2.0 g, 10.2 mmol) and triph-
enylphosphine (3.2 g, 12.2 mmol) in dry THF (10 mL) under an
argon atmosphere, a solution of diisopropyl azodicarboxylate
(2.5 g, 12.2 mmol) in THF (15 mL) was added dropwise for
15 min at +4 °C. The resulting solution was refluxed for 24 h under
an argon atmosphere. The solvent was removed in vacuum. The
oily residue was dissolved by heating in a mixture of petroleum
ether/EtOAc, and the precipitated triphenylphosphine oxide was
filtered off. After evaporation of the filtrate, the residue was puri-
fied by column chromatography (silica gel, eluent: light petroleum
0.67 g, 74.0%. Rf = 0.15; [a D
]
20 = ꢃ11.6 (c 1.2, CHCl3), [a 20
365 = ꢃ59.1
]
(c 1.2, CHCl3); 96.6% ee [chiral HPLC analysis; conditions were the
same as for (R, R)-1; tR = 6.0 min (minor), tR = 12.2 min (major)].
NMR spectra were identical with that cited above for (R,R)-1.
4.2.4.2. 3-(2-Ethylphenoxy)-1[(1R)-1,2,3,4-tetrahydronaphth-1-
ylamino]-(2S)-2-propanol (R,S)-1.
This compound was syn-
thesized analogously from (R)-(ꢃ)-1,2,3,4-tetrahydro-1-naphthy-
lamine and (S)-1,2-epoxy-3-(2-ethylphenoxy)propane (S)-5. After
evaporation of the reaction mixture, the solidified oil was recrys-
tallized from a mixture of petroleum ether/EtOAc (8:2); yield
ether/CH2Cl2/EtOAc = 4:1:0.5) to afford epoxide (S)-5 as a colorless
20
20 = +15.7 (c 1.1, EtOH), [
a
]
=
0.70 g, 76.5%, mp 81–82.5 °C. Rf = 0.1; [a]
20 = ꢃ15.6 (c 1.1, CHCl3),
oil. Yield 0.94 g, 51.8%. Rf = 0.5; [
+36.5 (c 1.1, EtOH); {lit.15 25 = +14.5 (c 1, EtOH), ee 97.8%}; 95.1%
[a]
D
a
]
D
365
D
20
[a]
365 = ꢃ32.4 (c 1.1, CHCl3); 98.1% ee [chiral HPLC analysis; Chiral-
ee [chiral HPLC analysis; Chiralcel OD column, 20 °C; eluent: hex-
ane/2-propanol (9:1), 1 ml/min; tR = 7.2 min (minor), tR = 9.1 min
(major)]. 1H NMR (CDCl3) d: 1.25 (t, J = 7.5 Hz, 3H, CH3), 2.71 (q,
J = 7.5 Hz, 2H, CH2CH3), 2.81 (dd, J = 2.7, 5.0 Hz, 1H, CH2), 2.93 (t,
J = 4.2, 5.0 Hz, 1H, CH2), 3.38–3.41 (m, 1H, CH), 4.03 (dd, J = 5.4,
11.1 Hz, 1H, OCH2), 4.26 (dd, J = 3.1, 11.1 Hz, 1H, OCH2), 6.85 (d,
J = 8.1 Hz, 1H, CAr6H), 6.95 (t, J = 7.4 Hz, 1H, CAr5H), 7.16–7.20 (m,
2H, CAr3,4H). 13C NMR (CDCl3) d: 14.2 (CH3), 23.3 (CH2CH3), 44.6
(CH2), 50.4 (CH), 68.7 (OCH2); 111.5, 121.1, 126.8, 129.2 (CAr),
133.1 (C2Ar-ipso), 156.3 (CA1r-ipso); (cf. lit.15).
cel OD column (0.46 ꢂ 5 cm), 22 °C; eluent: hexane/2-propanol/
diethylamine (8:2:0.1), 1 ml/min; tR = 2.1 min (minor), tR = 3.8 min
(major)]. 1H NMR (CDCl3) d: 1.20 (t, J = 7.5 Hz, 3H, CH3), 1.76–1.82
(m, 1H, CH2CH2), 1.88–1.94 (m, 1H, CH2), 1.95–2.00 (m, 2H, CH2),
2.39 (br s, 2H, OH, NH), 2.65 (q, J = 7.5 Hz, 2H, CH2CH3), 2.74–
2.80 (m, 1H, CH2), 2.83–2.88 (m, 1H, CH2), 2.98 (dd, J = 6.6,
12.2 Hz, 1H, CH2N), 3.05 (dd, J = 4.1, 12.2 Hz, 1H, CH2N), 3.85 (t,
J = 4.7 Hz, 1H, CHN), 4.01–4.05 (m, 1H, OCH2), 4.07–4.13 (m, 2H,
OCH2, CHOH), 6.88 (d, J = 8.4 Hz, 1H, CAr6H), 6.94 (t, J = 7.4 Hz, 1H,
CAr5H), 7.11–7.13 (m, 1H, CArH), 7.17–7.21 (m, 4H, CArH), 7.43–
7.45 (m, 1H, CArH). 13C NMR (CDCl3) d: 14.2 (CH3), 19.1 (CH2),
23.4 (CH2CH3), 28.5 (CH2), 29.4 (CH2), 49.2 (CH2N), 55.4 (CHN),
68.5 (CHOH), 70.5 (OCH2); 111.4, 120.9, 125.9, 126.89, 126.92,
129.0, 129.07, 129.13 (CArH); 132.8, 137.4, 138.8, 156.5 (CAr-ipso).
MALDI mass-spectrum C21H27NO2: m/z 326.2 [MH]+.
4.2.3.1. (R)-1,2-Epoxy-3-(2-ethylphenoxy)propane (R)-5. This
compound was synthesized analogously from diol (R)-2. A color-
less oil; yield 0.96 g, 52.9%. Rf = 0.5; [
a
]
20 = ꢃ14.8 (c 1.3, EtOH),
D
20
[
a
]
365 = ꢃ35.8 (c 1.3, EtOH). 95.4% ee [chiral HPLC analysis;
tR = 7.1 min (major), tR = 8.9 min (minor)]. NMR spectra were
identical with that cited above for (S)-5.
4.2.4.3. 3-(2-Ethylphenoxy)-1[(1S)-1,2,3,4-tetrahydronaphth-1-
ylamino]-(2R)-2-propanol, (S,R)-1.
thesized analogously from (S)-(+)-1,2,3,4-tetrahydro-1-naphthy-
lamine and (R)-1,2-epoxy-3-(2-ethylphenoxy)propane (R)-5.
solidified oil; yield 0.66 g, 72.4%, mp 80.5–82 °C (light petroleum/
This compound was syn-
4.2.3.2. rac-1,2-Epoxy-3-(2-ethylphenoxy)propane rac-5.
This
compound was synthesized analogously from diol rac-2. A color-
less oil; yield 0.88 g, 48.5%, Rf = 0.5. NMR spectra were identical
with that cited above for (S)-5.
A
20
EtOAc (8:2)). Rf = 0.1; [a] a]365 = +36.6 (c
20 = +16.6 (c 1.0, CHCl3), [
D
1.0, CHCl3); 98.1% ee [chiral HPLC analysis; conditions are the same
as for (R,S)-1; tR = 1.2 min (major), tR = 3.1 min (minor)]. NMR spec-
tra were identical with that cited above for (R,S)-1.
4.2.4. 3-(2-Ethylphenoxy)-1[(1R)-1,2,3,4-tetrahydronaphth-1-
ylamino]-(2R)-2-propanol (R,R)-1
To a stirred solution of (R)-(ꢃ)-1,2,3,4-tetrahydro-1-naphthy-
lamine (0.4 g, 2.8 mmol) in EtOH (2 ml), a solution (R)-1,2-epoxy-
3-(2-ethylphenoxy)propane (R)-5 (0.5 g, 2.8 mmol) in EtOH
(2 ml) was added under an argon atmosphere. The resulting solu-
tion was refluxed for 15 h. The solvent was removed in vacuum.
The residue was purified by column chromatography (silica gel,
eluent: light petroleum ether/EtOAc = 6:4) to afford amino-
propanol (R,R)-1 as a colorless oil. Yield 0.68 g, 74.7%. Rf = 0.15;
4.2.5. 3-(2-Ethylphenoxy)-1[(1R)-1,2,3,4-tetrahydronaphth-1-
ylamino]-(2R)-2-propanol hydrogen oxalate (R,R)-1ꢀC2H2O4
To a solution of (R,R)-1 (0.51 g, 1.57 mmol) in isopropanol, a
solution of oxalic acid (0.14 g, 1.57 mmol) in isopropanol was
added. After 8–10 h, the precipitate was filtered, washed with iso-
propanol and dried under vacuum with heating. White solid (yield
20
20 = +16.2 (c 1.0, MeOH), [
a]
=
20
20
[a
]
D
20 = +14.0 (c 1.1, CHCl3), [
a]
365 = +66.2 (c 1.1, CHCl3); [
a]
=
0.59 g, 90.2%), mp 156–160 °C; [
a
]
D
365
D
20
+63.2 (c 1.0, MeOH). After recrystallization of 0.5 g oxalate from
+14.0 (c 1.3, EtOH), [a]365 = +66.8 (c 1.3, EtOH); 95.8% ee [chiral
isopropanol/methanol was obtained 0.34 g (68%) of (R,R)-1ꢀC2H2-
HPLC analysis; Chiralcel OD column, 23 °C; eluent: hexane/2-pro-
panol/diethylamine (7:3:0.1), 1 ml/min; tR = 5.7 min (major),
tR = 13.0 min (minor)]. 1H NMR (CDCl3) d: 1.19 (t, J = 7.5 Hz, 3H,
CH3), 1.74–1.80 (m, 1H, CH2CH2), 1.85–2.00 (m, 3H, CH2CH2),
2.47 (br s, 2H, OH, NH), 2.63 (q, J = 7.5 Hz, 2H, CH2CH3), 2.71–
2.77 (m, 1H, CH2CAr), 2.80–2.90 (m, 2H, CH2CAr, CH2NH), 3.09 (dd,
J = 4.0, 12.0 Hz, 1H, CH2NH), 3.81 (t, J = 4.7 Hz, 1H, CHNH), 3.99–
4.08 (m, 3H, OCH2CHOH), 6.85 (d, J = 8.4 Hz, 1H, CAr6H), 6.92 (t,
J = 7.4 Hz, 1H, CAr5H), 7.09–7.11 (m, 1H, CArH), 7.15–7.18 (m, 4H,
O4: mp 161.5–163.5 °C (162.1 °C, DSC); [a]
20 = +18.3 (c 1.1, MeOH),
D
20
[a]365 = +70.6 (c 1.1, MeOH); 98.6% ee [chiral HPLC analysis; Chiral-
cel OD-H column, 22 °C; eluent: hexane/2-propanol/diethylamine
(7:3:0.1), 0.8 ml/min; tR = 8.2 min (major), tR = 19.3 min (minor)].
1H NMR (DMSO-d6) d: 1.07 (t, J = 7.5 Hz, 3H, CH3), 1.67–1.77 (m,
1H, CH2), 1.93–2.02 (m, 1H, CH2), 2.07–2.13 (m, 2H, CH2), 2.48 (q,
J = 7.5 Hz, 2H, CH2CH2), 2.69–2.76 (m, 1H, CH2), 2.79–2.86 (m, 1H,
CH2), 3.04 (dd, J = 9.1, 12.5 Hz, 1H, CH2N), 3.12 (dd, J = 2.9,
12.5 Hz, 1H, CH2N), 3.91 (dd, J = 6.0, 9.8 Hz, 1H, OCH2), 4.02 (dd,
J = 4.7, 9.8 Hz, 1H, OCH2), 4.25–4.31 (m, 1H, CHOH), 4.63 (t,
J = 5.9 Hz, 1H, CHN), 6.35 (br s, 4H, NH+2, COOH, OH), 6.85–6.91
(m, 2H, CArH), 7.11–7.16 (m, 2H, CArH), 7.19–7.25 (m, 2H, CArH),
7.28–7.31 (m, 1H, CArH), 7.60 (d, J = 7.5 Hz, 1H, CArH). 13C NMR
C
ArH), 7.37–7.40 (m, 1H, CArH). 13C NMR (CDCl3) d: 14.2 (CH3),
19.0 (CH2), 23.4 (CH2CH3), 28.9 (CH2), 29.4 (CH2), 49.7 (CH2N),
55.9 (CHN), 69.0 (CHOH), 70.5 (OCH2); 111.4, 120.9, 125.9,
126.87, 126.92, 128.8, 129.0, 129.2 (CArH); 132.7, 137.4, 138.8,
156.4 (CAr-ipso).

Z. A. Bredikhina et al. / Tetrahedron: Asymmetry 27 (2016) 467–474
473
(DMSO-d6) d: 14.7 (CH3), 19.1 (CH2), 23.1 (CH2CH3), 25.6 (CH2),
28.8 (CH2), 47.1 (CH2N), 55.2 (CHN), 66.0 (CHOH), 70.1 (OCH2);
111.9, 121.1, 126.5, 127.4, 128.9, 129.2, 129.4, 130.0 (CArH);
131.3, 132.2, 139.2, 156.3 (CAr-ipso); 165.3 (2C@O). MALDI mass-
spectrum of C21H27NO2ꢀC2H2O4: m/z 326.2115 [C21H27NO2+H]+.
[C21H28NO2]+. Calculated: [C21H27NO2+H]+ 326.2137.
The X-ray diffraction data of the investigated (S,S)-1ꢀC2H2O4 and
(R,S)-1ꢀ0.5C2H2O4 crystals were collected on a Bruker AXS Smart
Apex II CCD diffractometer in the
x-scan modes using graphite
monochromated MoK (k 0.71073 Å) radiation. The crystal data,
a
data collection, and the refinement parameters are given in Table 2.
Data were corrected for the absorption effect using SADABS pro-
gram.16 The structures were solved by direct method using
SHELXS17 and refined by the full matrix least-squares using
SHELXL-201418 and WinGX19 programs. All non-hydrogen atoms
were refined anisotropically. All hydrogen atoms were inserted at
calculated positions and refined as riding atoms except the hydro-
gen atoms of OH and NH2 groups which were located from differ-
ence maps and refined isotropically.
Data collections: images were indexed, integrated, and scaled
using the APEX2 data reduction package.20 All figures were made
using Mercury program.21 Molecular structures and conformations
were analyzed by PLATON.22 Crystallographic data (excluding
structure factors) for the structures of (S,S)-1ꢀC2H2O4 and (R,S)-
1ꢀ0.5C2H2O4 reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publi-
cation numbers CCDC 1469951 and 1469952 respectively. 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).
4.2.5.1. 3-(2-Ethylphenoxy)-1[(1S)-1,2,3,4-tetrahydronaphth-1-
ylamino]-(2S)-2-propanolhydrogenoxalate(S,S)-1ꢀC2H2O4. This
compound was synthesized analogously from (S,S)-1. White solid,
yield 84.9%. Mp 161–164 °C (isopropanol/methanol); [a D
]
20 = ꢃ17.7
(c 1.0, MeOH), [a 20
]
365 = ꢃ69.6 (c 1.0, MeOH); 99.8% ee [chiral HPLC
analysis; conditions are the same as for (R,R)-1ꢀC2H2O4; tR = 8.2 min
(minor), tR = 19.7 min (major)]. NMR spectra were identical with that
cited above for (R,R)-1ꢀC2H2O4. IR (KBr),
m: 3375, 3250, 3166 (br, OH),
3065 (CAr-H), 3006 (COOH), 2961, 2924, 2874 (CAH), 2678, 2541
(COOH, NH+2), 1719, 1698 (COOH), 1610, 1588, 1494 (COO-, Ar),
1243 (COC), 1123 (COC), 989 (CH), 751 (CH) cmꢃ1. Anal. Calcd for
C23H29NO6: C, 66.49; H, 7.04;N, 3.37. Found: C, 67.02;H, 6.52;N, 3.49.
4.2.5.2. 3-(2-Ethylphenoxy)-1[(1R)-1,2,3,4-tetrahydronaphth-1-
ylamino]-(2S)-2-propanol hydrogen oxalate (R,S)-1ꢀC2H2O4. This
compound was synthesized analogously from (R,S)-1. White solid,
yield 80.6%, mp 203–204.5 °C (207 °C, decomp.; DSC);
20
[
a]
D
20 = ꢃ21.2 (c 1.0, DMSO), [
a]
365 = ꢃ53.2 (c 1.0, DMSO); 99.1%
Acknowledgments
ee [chiral HPLC analysis; conditions were the same as for (R,R)-
1ꢀC2H2O4; tR = 8.9 min (minor), tR = 21.9 min (major)]. 1H NMR
(DMSO-d6) d: 1.07 (t, J = 7.6 Hz, 3H, CH3), 1.69–1.75 (m, 1H, CH2),
1.92–1.99 (m, 1H, CH2), 2.05–2.11 (m, 2H, CH2), 2.52 (q,
J = 7.6 Hz, 2H, CH2CH3), 2.70–2.75 (m, 1H, CH2), 2.79–2.84 (m, 1H,
CH2), 2.96 (dd, J = 9.5, 12.4 Hz, 1H, CH2N), 3.17 (dd, J = 2.4,
12.4 Hz, 1H, CH2N), 3.94 (dd, J = 5.7, 10.0 Hz, 1H, OCH2), 3.99 (dd,
J = 4.3, 10.0 Hz, 1H, OCH2), 4.22–4.26 (m, 1H, CHOH), 4.54 (t,
J = 5.2 Hz, 1H, CHN), 5.89 (br s, 4H, NH+2, COOH, OH), 6.87 (t,
J = 7.6 Hz, 1H, CArH), 6.91 (d, J = 8.1 Hz, 1H, CArH), 7.12–7.15 (m,
2H, CArH), 7.18–7.23 (m, 2H, CArH), 7.28 (t, J = 7.1 Hz, 1H, CArH),
7.54 (d, J = 7.6 Hz, 1H, CArH). 13C NMR (DMSO-d6) d: 14.7 (CH3),
19.1 (CH2), 23.2 (CH2CH3), 25.5 (CH2), 28.8 (CH2), 47.2 (CH2N),
54.9 (CHN), 65.7 (CHOH), 70.3 (OCH2); 112.0, 121.1, 126.4, 127.4,
128.8, 129.3, 129.6, 129.9 (CArH); 131.6, 132.3, 139.1, 156.4
(CAr-ipso); 165.5 (2 C@O). Anal. Calcd for C23H29NO6: C, 66.49; H,
7.04; N, 3.37. Found: C, 66.78; H, 6.78; N, 3.32.
The work was supported by the Russian Fund of Basic Research
and the Government of the Republic of Tatarstan in the framework
of the research project No. 15-43-02238. We also wish to thank
Dr. A.V. Pashagin and Mr. D.V. Zakharychev for their valuable
assistance with chiral HPLC analysis and DSC measuring.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.05.
001.
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3-(2-Ethylphenoxy)-1[(1S)-1,2,3,4-tetrahydronaphth-1-
ylamino]-(2R)-2-propanol hydrogen oxalate (S,R)-1ꢀC2H2O4. This
compound was synthesized analogously from (S,R)-1. White solid,
yield 91.8%, mp 198–202 °C;
[a]365 =+48.8 (c 1.0, DMSO); 99.4% ee [chiral HPLC analysis; condi-
[a]
20 = +20.4 (c 1.0, DMSO),
D
20
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cited above for (R,S)-1ꢀC2H2O4. IR (KBr),
m: 3390, 3235, 3166
(br, OH), 3065 (CAr-H), 2967, 2933–2873 (CH), 2750, 2600, 2540
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2551–2651.
4.3. X-ray analysis
The crystals (needles) of (S,S)-1ꢀC2H2O4 for single crystal X-ray
analysis were prepared by slow evaporation of a saturated solution
of the sample {[
a
]
20 = ꢃ17.7 (c 1.0, MeOH), mp 161–164 °C} in a
D
mixture of i-PrOH and MeOH. The crystals of (R,S)-1ꢀ0.5C2H2O4
for single crystal X-ray analysis were obtained by prolonged stand-
ing of DMSO solution of the sample (R,S)-1ꢀC2H2O4 {[
a]
20 = ꢃ21.2 (c
15. Kong, Xu-Dong; Ma, Q.; Zhou, J.; Zeng, Bu-Bing; Xu, Jian-He Angew. Chem., Int.
Ed. 2014, 53, 6641–6644.
16. Sheldrick, G. M. SADABS, Program for Empirical X-ray Absorption Correction;
Bruker-Nonius: Delft, 2004.
D
1.0, DMSO), mp 203–204.5 °C. Filamentous needles, mp 168.3 °C
(DSC, decomposition).

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17. Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112–122.
18. Sheldrick, G. M. Acta Crystallogr., Sect. C 2015, 71, 3–8.
19. Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837–838.
21. Macrae, C. F.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Shields, G. P.; Taylor, R.;
Towler, M.; van de Streek, J. J. Appl. Crystallogr. 2006, 39, 453–457.
22. Spek, A. L. J. Appl. Crystallogr. 2003, 36, 7–13.
20. APEX2 (Version 2.1), SAINTPlus. Data Reduction and Correction Program (Version
7.31A); Bruker Advanced X-ray Solutions; BrukerAXS: Madison, WI, 2006.