A. A. Bredikhin et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
7
was added dropwise a solution of diol (R)-2 (1.0 g, 5.1 mmol) in
THF (10 ml). The resulting solution was refluxed for 24 h under
an argon atmosphere. The solvent was removed in vacuum. The
oily residue was dissolved in ether, kept for 24 h in refrigerator,
and the precipitated triphenylphosphine oxide was filtered off.
After evaporation of the filtrate, the residue was purified by col-
umn chromatography (silica gel, eluent: light petroleum ether/
CH2Cl2/EtOAc = 6:2:1) to afford epoxide (R)-3 as a colorless oil.
+36.7 (c 1.0, CHCl3); 96.9% ee [chiral HPLC analysis; Chiralcel OD-
H (0.46 ꢃ 25 cm); column temperature 23 °C; flow rate: 0.85 ml/
min; eluent: hexane/2-propanol/diethyl amine (62:38:0.05);
20
tR = 5.7 min]; {Cf. lit.4 for (+)-1-d5ꢁHCl: mp 147–148 °C; [
a]
=
D
+25.7 (c 1, EtOH)}. IR (KBr, cmꢀ1): 3371 (OH), 2986, 2882 (CH3,
CH2); 2795, 2720, 2679, 2633, 2544, 2513, 2405 (NH+2); 1585,
1480, 1460 (Ar); 1382 (CH3), 1258 (C(CH3)3); 1135, 1103 (CAOAC).
1H NMR (400 MHz) d: 1.52 (s, 9H, CH3), 2.15 (s, 3H, 20-CH3), 2.25 (s,
3H, 30-CH3), 3.11–3.18 (m, 1H, CH2N), 3.34–3.39 (m, 1H, CH2N),
3.97 (dd, J = 9.5, 6.4 Hz; 1H, OCH2), 4.10 (dd, J = 9.5, 4.4 Hz; 1H,
OCH2), 4.64–4.71 (m, 1H, CH), 5.35 (br. s, 1H, OH), 6.66 (d,
J = 8.1 Hz, 1H, C6ArH), 6.79 (d, J = 7.6 Hz, 1H, C4ArH), 7.02 (t,
J = 7.9 Hz, 1H, C5ArH), 8.35 (br. s, 1H, NH2+), 9.71 (br. s, 1H, NH2+).
13C NMR (125.75 MHz) d: 11.8 (20-CH2), 20.0 (30-CH3), 25.9
(C(CH3)3), 45.8 (CH2N+), 57.6 (CMe3), 66.0 (CH), 70.0 (OCH2),
109.2 (C6Ar), 122.9 (C4Ar), 125.2 (C2Ar-ipso), 126.0 (C5Ar), 138.0
(C3Ar-ipso), 156.2 (C1Ar-ipso).
Yield 0.41 g, 45%; Rf = 0.5 (light petroleum ether/CH2Cl2/
20
EtOAc = 4:2:1); [
a]
20 = ꢀ16.9 (c 1.3, EtOH), [
a
]
365 = ꢀ42.9 (c 1.3,
D
20
EtOH), [
a]
20 = ꢀ7.1 (c 2.1, CHCl3), [
a]
365 = ꢀ11.4 (c 2.1, CHCl3);
D
96% ee [chiral HPLC analysis; eluent: hexane/2-propanol (8:2);
1
tR = 7.1 min]. H NMR (500 MHz) d: 2.19 (s, 3H, 20-CH3), 2.29 (s,
3H, 30-CH3), 2.79 (dd, J = 5.0, 2.7 Hz; 1H, CH2), 2.91 (t, J = 5.0 Hz,
1H, CH2), 3.36–3.39 (m, 1H, CH), 3.98 (dd, J = 11.0, 5.4 Hz; 1H,
OCH2), 4.21 (dd, J = 11.0, 3.2 Hz, 1H, OCH2), 6.71 (d, J = 8.1 Hz, 1H,
C6ArH), 6.82 (d, J = 7.6 Hz, 1H, C4ArH), 7.05 (t, J = 7.9 Hz, 1H,
C5ArH). 13C NMR (100.5 MHz) d: 11.7 (2-CH3), 20.1 (3-CH3), 44.7
(CH2), 50.4 (CH), 69.1 (OCH2), 109.4 (C6Ar), 122.9 (C4Ar), 125.6
(C2Ar-ipso), 125.8 (C5Ar), 138.1 (C3Ar-ipso), 156.5 (C1Ar-ipso).
4.2.5.1. (S)-Xibenolol hydrochloride (S)-1.
HCl was obtained
analogously from the (S)-1 as described for (R)-1ꢁHCl. Yield 0.127 g,
92%; Mp 146–148 °C (Et2O/MeOH); [
a
]
20 = ꢀ27.0 (c 1.0, EtOH),
D
20
4.2.3.1. (S)-1,2-Epoxy-3-(2,3-dimethylphenoxy)propane (S)-
[
a
]
365 = ꢀ81.6 (c 1.0, EtOH); 99.2% ee [chiral HPLC analysis; condi-
3.
(S)-1,2-Epoxy-3-(2,3-dimethylphenoxy)propane (S)-3 was
tions were the same as for (R)-1ꢁHCl; tR = 16.2 min]. {Cf. lit.4 for
synthesized analogously from (S)-2. A colorless oil, yield 0.43 g,
(ꢀ)-1-d5ꢁHCl: mp 147–148 °C; [
a]
20 = ꢀ25.5 (c 1, EtOH)}. NMR
D
20
47%; Rf = 0.5; [
a
]
20 = +16.4 (c 1.1, EtOH), [
a
]
365 = +40.8 (c 1.1, EtOH),
spectra were identical with those cited above for (R)-1ꢁHCl
D
20
[
a]
D
20 = +6.7 (c 1.1, CHCl3), [
a]
365 = +10.5 (c 1.1, CHCl3); 96.4% ee
(chiral HPLC analysis; tR = 9.5 min);{cf. lit.8
[a
]
D
27 = +13.8 (c 1.0,
4.3. X-ray analysis
EtOH), 96.6% ee; lit.7
[
a]
20 = ꢀ6.52 (c 2.3, CHCl3)}.
D
The X-ray diffraction data of the investigated (S)-(ꢀ)-1ꢁHCl and
(R)-(+)-1ꢁHCl crystals were collected on a Bruker AXS Smart Apex II
4.2.4. (R)-1-(tert-Butylamino)-3-(2,3-dimethylphenoxy)-2-pro-
panol, (R)-xibenolol (R)-1
CCD diffractometer in the
x-scan modes using graphite monochro-
A mixture of 1,2-epoxy-3-(2,3-dimethylphenoxy)propane (R)-3
(0.12 g, 0.67 mmol), t-Bu-NH2 (0.14 ml, 1.35 mmol) and water
(0.05 ml) was refluxed for 1–2 h. The excess amine was removed
under reduced pressure to afford (R)-1 as a colorless oil. With pro-
mated MoK (k 0.71073 Å) radiation. The crystal data, data collec-
a
tion, and the refinement parameters are given in Table 2. Data
were corrected for the absorption effect using SADABS program.23
The structures were solved by direct method using SHELXS24 and
refined by the full matrix least-squares using SHELXL-201425 and
WinGX26 programs. All non-hydrogen atoms were refined
anisotropically. All hydrogen atoms were inserted at calculated
positions and refined as riding atoms except the hydrogen atoms
of OH and NH2 groups which were located from difference maps
and refined isotropically. During data collections the images were
indexed, integrated, and scaled using the APEX2 data reduction
package.27
The Flack parameters for both investigated crystals were calcu-
lated both by the classical procedure18 and by the modified Par-
son’s method.19 For (S)-(ꢀ)-1ꢁHCl crystal the corresponding
results were as follows: ꢀ0.050(97) by classical fit to all intensities
and ꢀ0.013(25) from 1127 selected quotients (Parsons’ method);
for (R)-(+)-1ꢁHCl crystal: ꢀ0.054(216) and ꢀ0.138(264) from 129
selected quotients, respectively. Table 2 shows the values with bet-
ter statistical characteristics, and they are discussed in the text.
Crystallographic data for (S)-1ꢁHCl and (R)-1ꢁHCl has been
deposited with the Cambridge Crystallographic Data Centre as sup-
plementary publication numbers CCDC 1561629–1561630 respec-
tively. 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).
longed standing, the oil crystallizes. Yield 0.168 g, 99%; mp 35–
20
39 °C; [
a]
20 = +11.0 (c 1.1, EtOH), [
a]
365 = +25.5 (c 1.1, EtOH),
D
20
[
a]
D
20 = +15.4 (c 1.1, CHCl3), [
a]
365 = +45.9 (c 1.1, CHCl3); 94.2% ee
[chiral HPLC analysis; eluent: hexane/2-propanol/diethyl amine
(6:4:0.1); tR = 5.2 min]. IR (KBr, cmꢀ1): 3336, 3244 (OH, NH);
2972, 2873 (CH3, CH2); 1585, 1465 (Ar); 1364 (CH3), 1266, 1215
(C(CH3)3); 1091, 1026 (CAOAC). 1H NMR (400 MHz) d: 1.13 (s,
9H, CH3), 2.17 (s, 3H, 20-CH3), 2.28 (s, 3H, 30-CH3), 2.34 (br. s, 2H,
NH, OH), 2.75 (dd, J = 11.9, 6.8 Hz; 1H, CH2N), 2.89 (dd, J = 11.9,
3.9 Hz; 1H, CH2N), 3.93–4.04 (m, 3H, OCH2, CHOH), 6.73 (d,
J = 8.1 Hz, 1H, C6ArH), 6.80 (d, J = 7.6 Hz, 1H, C4ArH), 7.05 (t,
13
J = 7.9 Hz, 1H, C5ArH). C NMR (125.75 MHz) d: 11.7 (20-CH3),
20.1 (30-CH3), 29.2 (C(CH3)3), 44.9 (CH2N), 50.3 (CMe3), 68.9 (CH),
71.1 (OCH2), 109.2 (C6Ar), 122.6 (C4Ar), 125.2 (C2Ar-ipso), 125.9
(C5Ar), 138.0 (C3Ar-ipso), 156.7 (C1Ar-ipso).
4.2.4.1. (S)-Xibenolol (S)-1.
(S)-Xibenolol (S)-1 was obtained
analogously from oxirane (S)-3. An oil, yield 0.167 g, 98%;
20
[
[
a
a
]
]
20 = ꢀ10.8 (c 1.1, EtOH),
[a
]
365 = ꢀ25.3 (c 1.1, EtOH),
D
20
20 = ꢀ15.6 (c 1.1, CHCl3), [
a]
365 = ꢀ46.8 (c 1.1, CHCl3); 96.4% ee
D
[chiral HPLC analysis, conditions were the same as for (R)-1;
tR = 15.7 min]. Cf. lit.7: [
a
]
D
20 = ꢀ17.58 (c 1.0, CHCl3); 67% ee. NMR
spectra were identical with those cited above for (R)-1.
Acknowledgments
4.2.5. (R)-Xibenolol hydrochloride (R)-1ꢁHCl
The (R)-xibenolol (R)-1 (0.120 g) was dissolved in ether and dry
HCl gas was passed through it for 15 min, the solvent was removed
under reduced pressure and resulting solid recrystallized from
Et2O to afford xibenolol as its hydrochloride salt. Yield 0.114 g,
The authors thank the Russian Fund of Basic Research and the
Government of the Republic of Tatarstan for partial financial
support (Grant No. 15-43-02238). The authors also thank Dr. A.V.
Pashagin and D.V. Zakharychev for valuable assistance with chiral
HPLC analysis and Dr. D.B. Krivolapov for valuable help with the
X-ray data.
83%; Mp 144–146 °C (Et2O/MeOH); [
a
]
D
20 = +26.0 (c 1.0, EtOH),
20
20
[
a]365 = +79.3 (c 1.0, EtOH); [
a]
20 = +13.0 (c 1.0, CHCl3), [
a
]
=
D
365