Nonracemic Dimethylphenyl Glycerol Ethers in the Synthesis of Physiologically Active Aminopropanols

Article abstract of DOI:10.1134/S1070428019060149

Six regioisomeric nonracemic dimethylphenyl glycerol ethers were synthesized by asymmetric dihydroxylation of the corresponding allyl dimethylphenyl ethers. The enantioselectivity of the reaction with o-methyl derivatives was lower (down to 34% ee) than with m-methylphenyl ethers (up to 86% ee). Enantiomeric 3-(3,4-dimethylphenoxy)propane-1,2-diols were used to obtain enantiomerically pure physiologically active amino alcohols and their derivatives.

Full text of DOI:10.1134/S1070428019060149

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 6, pp. 837–844. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Zhurnal Organicheskoi Khimii, 2019, Vol. 55, No. 6, pp. 945–953.
Nonracemic Dimethylphenyl Glycerol Ethers
in the Synthesis of Physiologically Active Aminopropanols
Z. A. Bredikhinaa,* A. V. Kurenkova, and A. A. Bredikhina
a Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences,
Kazan, Tatarstan, Russia
*e-mail: zemfira@iopc.ru
Received December 27, 2018; revised March 1, 2019; accepted March 15, 2019
Abstract—Six regioisomeric nonracemic dimethylphenyl glycerol ethers were synthesized by asymmetric
dihydroxylation of the corresponding allyl dimethylphenyl ethers. The enantioselectivity of the reaction with
o-methyl derivatives was lower (down to 34% ee) than with m-methylphenyl ethers (up to 86% ee). Enantio-
meric 3-(3,4-dimethylphenoxy)propane-1,2-diols were used to obtain enantiomerically pure physiologically
active amino alcohols and their derivatives.
Keywords: asymmetric dihydroxylation, glycerol ethers, enantiopure aminopropanols.
DOI: 10.1134/S1070428019060149
Since the beginning of the XXI century, newly
designed drugs are represented mainly by enantio-
merically pure chiral compounds [1], and this trend
can be regarded as long-term. For example, 45 new
drugs have been approved in the USA in 2015, 12 of
which were complex biological products of the protein
or other nature, and 33 were individual chiral com-
pounds. The latter, with only one exception, were pure
enantiomers [2]. The needs of pharmacology and me-
dicinal chemistry stimulate extension of the range of
accessible enantiomerically pure compounds and study
of their properties which often remain unknown or
relevant data are contradictory.
individual enantiomers) in the treatment of neuro-
degenerative and neuromuscular disorders, as well as
of Friedreich’s ataxia [14]. Nonracemic 3-(2,4-, 2,5-,
and 3,4-dimethylphenoxy)propane-1,2-diols 1b, 1c,
and 1e were not reported. Both enantiomers of 3,5-di-
methylphenyl derivative 1f were isolated in the course
of multistep syntheses from natural mannitol [15]. Pure
enantiomers of 1a and 1d were isolated by us pre-
viously as a result of spontaneous optical resolution
upon crystallization [10, 11, 16]. Therefore, the goal of
the present work was to develop a general procedure
for the synthesis of pure enantiomers of 1 by asym-
metric dihydroxylation of the corresponding allyl
phenyl ethers, estimate advantages and disadvantages
of this approach, and obtain enantiomerically pure
practically useful amino alcohols using diols 1 as
precursors.
Chiral aromatic glycerol ethers of the general
formula ArOCH2CH(OH)CH2OH exhibit diverse bio-
logical activity [3–5] and are also used as synthetic
precursors to medicines possessing various activities
[6–9]. In this work we studied regioisomeric phenyl
glycerol ethers 1 bearing two methyl groups in the
aromatic ring (Scheme 1). Compounds of this series
were used in the synthesis of enantiopure drugs such as
mexiletine [10], xibenolol [11], and metaxalone [12].
Aminopropanol 2 hydrochloride coded as T0502-1048
was reported as a promising β2-adrenoceptor anta-
gonist [13]. Furthermore, there are patent data ac-
cording to which stereoisomers of 1-(3,4-dimethyl-
phenoxy)-3-(morpholin-4-yl)propan-2-ol (3) show
useful activities (but different for the racemate and
The Sharpless asymmetric dihydroxylation has
found wide application in modern organic chemistry
[17, 18], which is largely determined by the acces-
sibility of the commercial chiral catalysts AD-mix-α
and AD-mix-β. In most cases, dihydroxylation of allyl
ethers derived from para-substituted phenols was
characterized by a satisfactory enantioselectivity (89–
95% ee). The presence of an ortho substituent in the
initial ether reduced the enantioselectivity (28–63% ee;
in particular 36% ee for (S)-1d [19]). It is also believed
that AD-mix-β favors S configuration of the newly
837

BREDIKHINA et al.
838
Scheme 1.
Me
O
CH3
*
Me
NH2
Mexiletine
O
HN
NHBu-t
HO
O
O
OH
*
Me
Me
O
OH
O
Me
1a–1f
Me
Me
Me
Xibenolol
Metaxalone
Me
OH
*
Me
O
N
X
2, 3
1, 2,3-Me2 (a), 2,4-Me2 (b), 2,5-Me2 (c), 2,6-Me2 (d), 3,4-Me2 (e), 3,5-Me2 (f); 2, X = CH2; 3, X = O.
formed chiral center and that AD-mix-α gives rise
to the corresponding R isomers; the only known
exception is dihydroxylation of allyl o-nitrophenyl
ether [20].
Enantiomeric diols 1a and 1f were converted by us
previously to xibenolol and metaxalone, respectively
[11, 12]. In this work, amino alcohols 2 and 3 were
synthesized from enantiomeric diols 1e according to
Scheme 3. Aryloxypropanediols themselves can be
precursors to amino alcohols of the general formula
ArOCH2CH(OH)CH2NR1R2, though their preliminary
activation via conversion to cyclic sulfites [21, 22] or
oxiranes [19] is necessary for this purpose. The latter
transformation offers a number of advantages. A re-
liable procedure for the synthesis of oxiranes from
vicinal diols is based on the Mitsunobu reaction [23].
The reaction of 1e with triphenylphosphine and diethyl
azodicarboxylate was accompanied by a small loss of
enantiomeric purity [from 99% ee for (R)-1e to 96% ee
for (R)-6]. By analogy with the cyclizations performed
by us previously [10, 11], we presumed that the initial
Precursors to the target compounds, ethers 4a–4f
were synthesized in moderate yields (~50–70%) from
the corresponding phenols 5a–5f and allyl bromide in
the presence of potassium carbonate (Scheme 2). In
fact, o-methyl derivatives 1b–1d were obtained with
reduced ee values (35–53%), whereas the dihydroxyla-
tion of 4a, 4e, and 4f gave diols 1a, 1e, and 1f with ee
values exceeding 80%. In the latter cases, the substrate
molecules contained a methyl group in the meta
position; however, this factor may not be related to the
obtained result. It should be noted that all diols 1a–1e
can be brought to a high degree of enantiomeric purity
by recrystallization.
Scheme 2.
OH
OH
OH
O
O
K2CO3
CH2
AD-mix-α
CH2
Me
Me
Me
Me
Me
Me
+
Br
5a–5f
4a–4f
(R)-1a–(R)-1f
1, 4, 5, 2,3-Me2 (a), 2,4-Me2 (b), 2,5-Me2 (c), 2,6-Me2 (d), 3,4-Me2 (e), 3,5-Me2 (f); 2, X = CH2; 2·HCl = T0502-1048; 3, X = O.
1, ee = 86 (a), 50 (b), 53 (c), 35 (d), 83 (e), 82% (f).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 6 2019

NONRACEMIC DIMETHYLPHENYL GLYCEROL ETHERS
839
Scheme 3.
OH
OH
X
HN
PPh3, DEAD
Me
Me
O
Me
Me
O
O
Me
Me
O
N
X
OH
(R)-1e
(R)-6
(R)-2, (R)-3
OH
H
HCl
Me
Me
O
N
X
Cl–
(R)-2·HCl, (R)-3·HCl
2, X = CH2; 3, X = O.
ence. The IR spectra were recorded in KBr on a Bruker
Tensor 27 spectrometer. The optical rotations were
measured on a Perkin Elmer 341 polarimeter. The
melting points were determined with a Boetius hot
stage and are uncorrected. The elemental analyses
were obtained on a Euro Vector EA3000 CHN ana-
lyzer. Silufol UV-254 plates were used for analytical
TLC; spots were visualized under UV light or by
treatment with iodine vapor. HPLC analyses were
performed on a Shimadzu LC-20AD chromatograph
equipped with an SPD-20A UV detector (λ 275 nm);
Chiralpak AD-RH (0.46 ×25 cm), Chiralpak AS-H
(0.46×25 cm), or Chiralcel OD (0.46×25 cm) column
(Daicel), eluent flow rate 1 mL/min. The correspond-
ing racemic compounds were used as calibration stan-
dards. Racemic diols rac-1a–rac-1f were synthesized
from racemic 3-chloropropane-1,2-diol and the corre-
sponding phenols by analogy with the procedure
reported in [10]; their melting points were as follows:
rac-1a: mp 80–89°C (81.5–90°C [16]); rac-1b: 91–
93°C (92–93°C [24]); rac-1c: 67–69°C (69–70°C [25]);
rac-1d: 50–52°C (49–50°C [10]); rac-1e: 75–77°C
(75–76°C [25]); rac-1f: 65–66°C (66–67°C [25]).
configuration of the chiral center is retained. Pure
enantiomers (R)-2 and (R)-3 were synthesized by
heating epoxide (R)-6 with an equimolar amount of
piperidine or morpholine in boiling ethanol in the
presence of a catalytic amount of pyridine. Taking into
account that enantiomer (S)-3 was reported [14] to
possess the highest physiological activity, from diol
(S)-1e we synthesized enantiomerically pure amino
alcohols (S)-3 and (S)-2 according to a similar scheme.
Amino alcohols 2 and 3 were converted to hydro-
chlorides by passing gaseous hydrogen chloride
through a solution of the free base in acetone. All
isolated compounds were fully characterized.
It should be noted that there are no published data
on enantiomeric amines 2 and 3 hydrochlorides,
whereas the optical rotation of free base 3 given in [14]
is erroneous since the value [α]D20 = –13.10° (c = 0.6,
CHCl3) was reported for both enantiomers [14]. We
obtained the following data: (R)-3: [α]D20 = +19.5° (c =
1.0, CHCl3), 96% ee; (S)-3: [α]D20 = –19.7° (c = 1.05,
CHCl3), 96% ee.
Thus, the Sharpless asymmetric dihydroxylation is
appropriate for the synthesis of chiral 3-(3,4-, 3,5-, and
2,3-dimethylphenoxy)propane-1,2-diols which can be
used to obtain physiologically active compounds. The
reactions with 2,4-, 2,5-, and 2,6-dimethyl analogs are
characterized by a low enantioselectivity, so that alter-
native approaches should be sought for in these cases.
Racemic 3-chloropropane-1,2-diol and substituted
phenols (Acros Organics), allyl bromide (Alfa Aesar),
and AD-mix-α and AD-mix-β (Aldrich) were com-
mercial products.
General procedure for the synthesis of allyl aryl
ethers 4a–4f. A suspension of 1.00 g (8.3 mmol) of
phenol 5a–5f, 1.06 g (8.8 mmol) of allyl bromide, and
1.21 g (8.8 mmol) of ground fused potassium car-
bonate in 13 mL of anhydrous acetone was refluxed for
about 12 h (TLC, Rf ~ 0.7, hexane–ethyl acetate, 9:1).
The mixture was diluted with 40 mL of water and
EXPERIMENTAL
The NMR spectra were recorded on a Bruker
1
Avance-400 spectrometer at 399.9 MHz for H and
100.6 MHz for 13C using CDCl3 as solvent and refer-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 6 2019

BREDIKHINA et al.
840
extracted with diethyl ether (3×50 mL). The extract
was washed with 20 mL of a 1 M aqueous solution of
sodium hydroxide and dried over MgSO4, the solvent
was distilled off under reduced pressure, and the oily
residue was purified by column chromatography on
silica gel using hexane–ethyl acetate (9:1 to 8:2) as
eluent.
5.42 d.d.d (1H, =CH2, J = 17.3, 3.3, 1.7 Hz), 6.02–
6.12 m (1H, =CH), 6.57 s (2H, 2′-H, 6′-H), 6.62 t (1H,
4′-H, J = 0.6 Hz) (cf. [28]).
Sharpless asymmetric dihydroxylation (general
procedure) [19]. A suspension of 1.4 g of AD-mix-α in
a mixture of 5 mL of tert-butyl alcohol and 5 mL of
water was cooled to 0°C, 1 mmol of allyl phenyl ether
4a–4f was added, and the mixture was stirred for 20 h
at 0°C. The mixture was then treated with 1.5 g of
sodium sulfite and stirred for 30 min at room tempera-
ture. The organic layer was separated, and the aqueous
layer was extracted with ethyl acetate (3×30 mL). The
extracts were combined with the organic phase,
washed with 20 mL of brine, and dried over MgSO4,
the solvent was removed under reduced pressure, and
the residue was purified by silica gel column chro-
matography using hexane–ethyl acetate (8:2 to 4:6) as
eluent. The enantiomeric composition of the product
was determined by HPLC. The enantiomeric purity
was increased by recrystallization from hexane–ethyl
acetate (3:1).
2,3-Dimethyl-1-(prop-2-en-1-yl)benzene (4a).
Yield 69%, nD20 = 1.5161. H NMR spectrum, δ, ppm:
1
2.23 s (3H, CH3), 2.31 s (3H, CH3), 4.56 d.t (2H,
OCH2, J = 5.0, 1.6, 1.6 Hz), 5.30 d.d.d (1H, =CH2, J =
10.6, 3.0, 1.5 Hz), 5.47 d.d.d (1H, =CH2, J = 17.3, 3.4,
1.7 Hz), 6.07–6.16 m (1H, =CH), 6.74 d (1H, 6′-H, J =
8.2 Hz), 6.82 d (1H, 4′-H, J = 7.5 Hz), 7.07 d (1H,
5′-H, J = 7.9 Hz) (cf. [26]).
2,4-Dimethyl-1-(prop-2-en-1-yl)benzene (4b).
Yield 52%, nD20 = 1.5125. H NMR spectrum, δ, ppm:
1
2.23 s (3H, CH3), 2.26 s (3H, CH3), 4.52 d.t (2H,
OCH2, J = 5.0, 1.6, 1.6 Hz), 5.26 d.d.d (1H, =CH2, J =
10.6, 3.0, 1.5 Hz), 5.42 d.d.d (1H, =CH2, J = 17.3, 3.4,
1.7 Hz), 6.02–6.12 m (1H, =CH), 6.72 d (1H, 3′-H, J =
8.2 Hz), 6.92–6.96 m (2H, 5′-H, 6′-H) (cf. [27]).
(R)-3-(2,3-Dimethylphenoxy)propane-1,2-diol
(R-1a). Yield 0.15 g (77%), mp 95–102°C, [α]D20
=
2,5-Dimethyl-1-(prop-2-en-1-yl)benzene (4c).
Yield 56%, n2D0 = 1.5120. H NMR spectrum, δ, ppm:
1
+9.6° (c = 1.0, MeOBu-t), 86.1% ee [Chiralcel OD,
20°C; hexane–propan-2-ol, 4:1; tR, min: 8.9 (major),
10.7 (minor)]; mp 102–103°C (after recrystallization);
2.23 s (3H, CH3), 2.33 s (3H, CH3), 4.54 d.t (2H,
OCH2, J = 5.0, 1.6, 1.6 Hz), 5.28 d.d.d (1H, =CH2,
J = 10.6, 3.1, 1.5 Hz), 5.45 d.d.d (1H, =CH2, J = 17.3,
3.3, 1.7 Hz), 6.05–6.14 m (1H, =CH), 6.67 d.d (2H,
4′-H, 6′-H, J = 18.3, 7.4 Hz), 7.03 d (1H, 3′-H, J =
7.5 Hz) (cf. [28]).
published data: mp 101–102.5°C [11, 16], [α]D20
=
+13.4° (c = 1.0, MeOBu-t), [α]D20 = +1.4° (c = 1.0,
EtOH), 99.3% ee. IR spectrum: ν 3267 cm–1 (OH).
1H NMR spectrum, δ, ppm: 1.99 br.s (2H, OH), 2.16 s
(3H, CH3), 2.28 s (3H, CH3), 3.78 d.d (1H, CH2OH,
J = 11.4, 5.5 Hz), 3.87 d.d (1H, CH2OH, J = 11.4,
3.9 Hz), 4.04 d (2H, OCH2, J = 5.3 Hz), 4.11–4.16 m
(1H, CHOH), 6.72 d (1H, 6′-H, J = 7.6 Hz), 6.81 d
(1H, 4′-H, J = 7.6 Hz), 7.05 t (1H, 5′-H, J = 7.9 Hz).
2,6-Dimethyl-1-(prop-2-en-1-yl)benzene (4d).
Yield 61%, nD20 = 1.5005. H NMR spectrum, δ, ppm:
1
2.37 s (6H, CH3), 4.38 d.t (2H, OCH2, J = 5.6, 1.5,
1.5 Hz), 5.33 d.d.d (1H, =CH2, J = 10.4, 2.9, 1.4 Hz),
5.51 d.d.d (1H, =CH2, J = 17.2, 3.3, 1.7 Hz), 6.24–
6.14 m (1H, =CH), 6.99 d.d (1H, 4′-H, J = 8.2,
6.2 Hz), 7.08 d (2H, 3′-H, 5′-H, J = 7.7 Hz).
(R)-3-(2,4-Dimethylphenoxy)propane-1,2-diol
(R-1b). Yield 0.16 g (82%; after column chromatog-
raphy), mp 90–93°C, [α]D20 = +5.0° (c = 1.0, MeOBu-t),
50.5% ee [Chiralpak AD-RH, 26°C, acetonitrile–water,
22.5:77.5, 0.4 mL/min; tR, min: 25.0 (major), 28.5
(minor)]. After recrystallization: mp 103–104°C,
[α]D20 = +0.9° (c = 1.0, EtOH), [α]D20 = +11.7° (c = 1.0,
MeOBu-t), 99.4% ee. IR spectrum: ν 3224 cm–1 (OH).
1H NMR spectrum, δ, ppm: 2.15 s (3H, CH3), 2.22 s
(3H, CH3), 2.65 s (2H, OH), 3.72 d.d (1H, CH2, J =
11.5, 5.7 Hz), 3.80 d.d (1H, CH2, J = 11.5, 3.7 Hz),
3.96 d (2H, OCH2, J = 5.2 Hz), 4.04–4.09 m (1H,
CHOH), 6.67 d (1H, 6′-H, J = 8.1 Hz), 6.88–6.91 m
(2H, 3′-H, 5′-H). 13C NMR spectrum, δC, ppm: 16.1
(2′-CH3), 20.4 (4′-CH3), 63.9 (CH2), 69.5 (OCH2), 70.6
3,4-Dimethyl-1-(prop-2-en-1-yl)benzene (4e).
Yield 73%, nD20 = 1.5095. H NMR spectrum, δ, ppm:
1
2.20 s (3H, CH3), 2.24 s (3H, CH3), 4.51 d.t (2H,
OCH2, J = 5.3, 1.5, 1.5 Hz), 5.27 d.d.d (1H, =CH2, J =
10.5, 2.9, 1.4 Hz), 5.40 d.d.d (1H, =CH2, J = 17.3, 3.3,
1.6 Hz), 6.01–6.11 m (1H, =CH), 6.66 d.d (1H, 6′-H,
J = 8.3, 2.7 Hz), 6.74 d (1H, 2′-H, J = 2.6 Hz), 7.02 d
(1H, 5′-H, J = 8.3 Hz).
3,5-Dimethyl-1-(prop-2-en-1-yl)benzene (4f).
Yield 71%, nD20 = 1.5110. H NMR spectrum, δ, ppm:
1
2.30 s (6H, CH3), 4.52 d.t (2H, OCH2, J = 5.3, 1.5,
1.5 Hz), 5.28 d.d.d (1H, =CH2, J = 10.5, 2.9, 1.4 Hz),
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NONRACEMIC DIMETHYLPHENYL GLYCEROL ETHERS
841
(CH), 111.4 (C6′), 126.5 (C2′), 127.1 (C5′), 130.3 (C4′),
131.7 (C3′), 154.4 (C1′). Found, %: C 67.52; H 8.14.
C11H16O3. Calculated, %: C 67.32; H 8.22.
(S)-3-(3,4-Dimethylphenoxy)propane-1,2-diol
(S-1e) was synthesized according to the general proce-
dure using AD-mix-β. Yield 0.16 g (84%), mp 90–
95°C, [α]D20 = +5.6° (c = 1.2, EtOH), 89% ee [tR, min:
9.0 (minor), 13.4 (major)]. After recrystallization:
mp 96–97.5°C, [α]D20 = +6.7° (c = 1.0, EtOH), 99.5%
ee. Found, %: C 67.20; H 8.05. C11H16O3. Calculated,
%: C 67.32; H 8.22. The NMR spectra of (S)-1e were
similar to those of (R)-1e.
(R)-3-(2,5-Dimethylphenoxy)propane-1,2-diol
(R-1c). Yield 0.15 g (77%), mp 71–76°C, [α]D20 = +5.2°
(c = 1.0, MeOBu-t), 53.0% ee [Chiralpak AS-H, 28°C,
hexane–propan-2-ol, 9:1; tR, min: 10.7 (major), 12.2
(minor)]. After recrystallization: mp 80–82°C, [α]D20
=
+0.9° (c = 1.1, EtOH), [α]D20 = +9.5° (c = 1.1,
MeOBu-t), 99.9% ee. IR spectrum: ν 3313 cm–1 (OH).
1H NMR spectrum, δ, ppm: 2.19 s (3H, CH3), 2.31 s
(3H, CH3), 3.41 s (2H, OH), 3.77 d.d (1H, CH2OH, J =
11.5, 5.9 Hz), 3.86 d.d (1H, CH2OH, J = 11.5, 3.6 Hz),
4.01 d (2H, OCH2, J = 5.3 Hz), 4.10–4.15 m (1H,
CHOH), 6.65 s (1H, 6′-H), 6.70 d (1H, 4′-H, J =
7.5 Hz), 7.01 d (1H, 3′-H, J = 7.5 Hz). 13C NMR spec-
trum, δC, ppm: 15.8 (2′-CH3), 21.3 (5′-CH3), 63.9
(CH2), 69.1 (OCH2), 70.7 (CH), 112.3 (C6′), 121.6
(C4′), 123.5 (C2′), 130.5 (C3′), 136.8 (C5′), 156.4 (C1′).
Found, %: C 67.20; H 8.34. C11H16O3. Calculated, %:
C 67.32; H 8.22.
(R)-3-(3,5-Dimethylphenoxy)propane-1,2-diol
(R-1f). Yield 0.13 g (66%), mp 66–69°C, [α]D20 = –6.1°
(c = 1.0, EtOH), 81.9% ee [Chiralcel OD, 22°C,
hexane–propan-2-ol, 4:1; tR, min: 6.7 (major), 9.3
(minor)]. After recrystallization: mp 73–74°C (74.5–
75.5°C [15]), [α]D20 = –7.8° (c = 1.0, EtOH), [α]D20
=
+2.3° (c = 1.0, MeOBu-t), [α]D20 = –4.4° (c = 1.1,
CHCl3), 99.9% ee. IR spectrum: ν 3260 cm–1 (OH).
1H NMR spectrum, δ, ppm: 2.28 s (6H, CH3), 2.77 s
(2H, OH), 3.73 d.d (1H, CH2OH, J = 11.5, 5.6 Hz),
3.82 d.d (1H, CH2OH, J = 11.5, 3.6 Hz), 3.97–4.03 m
(2H, OCH2), 4.06–4.11 m (1H, CHOH), 6.55 s (2H,
2′-H, 6′-H), 6.64 s (1H, 4′-H). 13C NMR spectrum, δC,
ppm: 21.4 (3′-CH3, 5′-CH3), 63.8 (CH2), 69.2 (OCH2),
70.4 (CH), 112.4 (C2′, C6′), 123.1 (C4′), 139.4 (C3′, C5′),
158.5 (C1′).
(R)-3-(2,6-Dimethylphenoxy)propane-1,2-diol
(R-1d). Yield 0.14 g (71%), mp 53–66°C, [α]D20 = +1.4°
(c = 1.0, MeOBu-t), 35% ee [Chiralcel OD, 20°C,
hexane–propan-2-ol, 4:1; tR, min: 8.6 (minor), 11.1
(major)]. After recrystallization: mp 75–76°C (75–
75.5°C [10]), [α]D20 = +5.6° (c = 1.0, MeOBu-t), [α]D20 =
–2.5° (c = 1.0, EtOH), 99.3% ee. IR spectrum:
Mitsunobu intramolecular etherification of diols
1e (general procedure). A solution of 1.07 g
(6.12 mmol) of diethyl azodicarboxylate in 10 mL of
anhydrous THF was added dropwise over a period of
5 min to a solution of 1.00 g (5.10 mmol) of diol 1e
and 1.61 g (6.12 mmol) of triphenylphosphine in
10 mL of anhydrous THF with stirring at 4°C under
argon. The mixture was then refluxed for 24 h, the
solvent was removed under reduced pressure, and the
residue was purified by column chromatography on
silica gel (0.125–0.25 mm) using petroleum ether–
methylene chloride–ethyl acetate (9:2:1 to 8:2:1) as
eluent to isolate ~0.59 g (65%) of oily oxirane 6;
Rf 0.45 (petroleum ether–methylene chloride–ethyl
acetate, 4:2:1).
1
ν 3265 cm–1 (OH). H NMR spectrum, δ, ppm:
2.23 br.s (2H, OH), 2.29 s (6H, CH3), 3.79–3.91 m
(4H, CH2O, CH2OH), 4.08–4.12 m (1H, CH), 6.94 d.d
(1H, 4′-H, J = 8.3, 6.5 Hz), 7.02 d (2H, 3′-H, 5′-H,
J = 7.3 Hz).
(R)-3-(3,4-Dimethylphenoxy)propane-1,2-diol
(R-1e). Yield 0.17 g (87%), mp 90–95°C, [α]D20 = –6.2°
(c = 1.0, EtOH), 83% ee [Chiralcel OD, 22°C, hexane–
propan-2-ol, 4:1; tR, min: 9.4 (major), 14.5 (minor)].
After recrystallization: mp 96–98°C, [α]D20 = –7.7° (c =
1.0, EtOH), [α]D20 = +2.3° (c = 1.0, MeOBu-t), [α]D20
=
–2.9° (c = 1.1, CHCl3), 99.7% ee. IR spectrum:
1
ν 3227 cm–1 (OH). H NMR spectrum, δ, ppm: 2.19 s
(R)-2-[(3,4-Dimethylphenoxy)methyl]oxirane
(3H, 4′-CH3), 2.22 s (3H, 3′-CH3), 2.72 s (2H, OH),
3.73 d.d (1H, CH2OH, J = 11.5, 5.6 Hz), 3.83 d.d (1H,
CH2OH, J = 11.5, 3.8 Hz), 3.97–4.03 m (2H, OCH2),
4.07–4.11 m (1H, CHOH), 6.65 d.d (1H, 6′-H, J = 8.2,
2.7 Hz), 6.73 d (1H, 2′-H, J = 2.7 Hz), 7.02 d (1H,
5′-H, J = 8.2 Hz). 13C NMR spectrum, δC, ppm: 18.8
(4′-CH3), 20.0 (3′-CH3), 63.8 (CH2), 69.2 (OCH2), 70.6
(CH), 111.5 (C6′), 116.2 (C2′), 129.2 (C4′), 130.4 (C5′),
137.8 (C3′), 156.6 (C1′). Found, %: C 67.18; H 8.45.
C11H16O3. Calculated, %: C 67.32; H 8.22.
(R-6) was synthesized from diol (R)-1e. Yield 0.59 g
20
(65%), [α]D20 = –3.1° (c = 1.0, CHCl3), [α] = +2.1°
365
(c = 1.0, CHCl3); [α]D20 = –11.2° (c = 1.1, EtOH),
20
365
[α] = –24.3° (c = 1.1, EtOH); 95.2% ee [Chiralcel
OD, 25°C; hexane–propan-2-ol, 9:1; tR, min: 7.8
1
(major), 10.0 (minor)]. H NMR spectrum, δ, ppm:
2.25 s (3H, 4′-CH3), 2.29 s (3H, 3′-CH3), 2.77 d.d (1H,
CH2, J = 5.1, 2.7 Hz), 2.91 d.d (1H, CH2, J = 5.1,
4.3 Hz), 3.35–3.39 m (1H, CH), 3.97 d.d (1H, OCH2,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 6 2019

BREDIKHINA et al.
842
J = 11.1, 5.6 Hz), 4.21 d.d (1H, OCH2, J = 11.1,
3.2 Hz), 6.72 d.d (1H, 6′-H, J = 8.3, 2.7 Hz), 6.80 d
(1H, 2′-H, J = 2.6 Hz), 7.08 d (1H, 5′-H, J = 8.3 Hz).
13C NMR spectrum, δC, ppm: 18.7 (4′-CH3), 19.9
(3′-CH3), 44.6 (CH2), 50.2 (CH), 68.8 (OCH2), 111.6
(C6′), 116.3 (C2′), 129.1 (C4′), 130.3 (C5′), 137.7 (C3′),
156.7 (C1′) (cf. [14]).
(OCH2), 111.4 (C6′), 116.2 (C2′), 128.6 (C4′), 130.1
(C5′), 137.4 (C3′), 156.9 (C1′).
(R)-1-(3,4-Dimethylphenoxy)-3-(piperidin-1-yl)-
propan-2-ol hydrochloride [(R)-2·HCl]. mp 175–
20
176°C; [α]D20 = +40.8° (c = 1.0, CHCl3), [α]
=
365
+129.3° (c = 1.0, CHCl3), [α]D20 = +26.0° (c = 1.0,
EtOH), [α]32605 = +78.2° (c = 1.0, EtOH); 99.7% ee [the
HPLC conditions were the same as for (R)-2; tR, min:
5.5 (major), 7.0 (minor)]. IR spectrum, ν, cm–1: 3268
(S)-2-[(3,4-Dimethylphenoxy)methyl]oxirane
(S-6) was synthesized from diol (S)-1e. Yield 0.50 g
(OH), 2726, 2651, 2633, 2586, 2542 (NH+). H NMR
1
20
(55%); [α]D20 = +2.1° (c = 1.0, CHCl3), [α] = –2.7°
365
(c = 1.0, CHCl3); [α]D20 = +10.4° (c = 1.0, EtOH),
spectrum, δ, ppm: 1.39–1.48 m (1H) and 1.84–1.87 m
(3H) (CH2, piperidine), 2.16 s (3H, 4′-CH3), 2.19 s
(3H, 3′-CH3), 2.24–2.36 m (2H, CH2, piperidine),
2.72–2.88 m and 3.14–3.27 m (2H each, N+CH2,
piperidine), 3.67 d (2H, N+CH2, J = 9.6 Hz), 3.85 d.d
(1H, OCH2, J = 9.5, 7.9 Hz), 4.09 d.d (1H, OCH2, J =
9.5, 4.6 Hz), 4.54–4.63 m (1H, CH), 5.44 br.s (1H,
OH), 6.59 d.d (1H, 6′-H, J = 8.2, 2.5 Hz), 6.67 s (1H,
2′-H), 6.99 d.d (1H, 5′-H, J = 8.2, 5.0 Hz), 11.25 br.s
(1H, NH+). 13C NMR spectrum, δC, ppm: 18.9
(4′-CH3), 20.1 (3′-CH3); 22.0, 22.76, 22.83 (CH2,
piperidine); 54.2 (NCH2); 56.0, 56.2, 62.6, 62.9
(NCH2, piperidine); 64.4 (CH), 69.2 (OCH2), 111.6
(C6′), 116.1 (C2′), 129.6 (C4′), 130.5 (C5′), 138.0 (C3′),
156.2 (C1′). Found, %: C 64.29; H 8.94; N 4.45.
C16H26ClNO2. Calculated, %: C 64.09; H 8.74; N 4.67.
20
365
[α] = +23.1° (c = 1.0, EtOH); 95.9% ee [Chiralcel
OD, 25°C; hexane–propan-2-ol, 9:1; tR, min: 7.8
(minor), 10.0 (major)]. The NMR spectra of (S)-6 were
similar to those of (R)-6.
rac-2-[(3,4-Dimethylphenoxy)methyl]oxirane
(rac-6) was synthesized from diol rac-1e. Yield
0.54 g (60%).
Amino alcohols 2 and 3 (general procedure). A so-
lution of 0.20 g (1.12 mmol) of oxirane 6, 1.12 mmol
of piperidine or morpholine, and a catalytic amount of
pyridine in 10 mL of ethanol was refluxed for 4 h with
stirring. The mixture was concentrated under reduced
pressure, and the residue was purified by column
chromatography on silica gel (0.125–0.25 mm) using
methylene chloride–methanol (100:3) as eluent. Com-
pounds 2 and 3 were isolated as oily materials in
almost quantitative yield (≥97%). The free bases were
converted to the corresponding hydrochlorides by
passing gaseous hydrogen chloride through a solution
of the base in acetone, followed by recrystallization of
the precipitated salt from methanol–ethyl acetate.
(S)-1-(3,4-Dimethylphenoxy)-3-(piperidin-1-yl)-
propan-2-ol (S-2) was synthesized from oxirane (S)-6
and piperidine. Yield 0.29 g (98%), [α]D20 = –26.9°
(c = 1.0, CHCl3), 95% ee [tR, min: 5.5 (minor),
7.0 (major)].
(S)-1-(3,4-Dimethylphenoxy)-3-(piperidin-1-yl)-
propan-2-ol hydrochloride [(S)-2·HCl]. mp 175.5–
177.5°C; [α]D20 = –40.6° (c = 1.0, CHCl3), [α]
=
(R)-1-(3,4-Dimethylphenoxy)-3-(piperidin-1-yl)-
propan-2-ol (R-2) was synthesized from oxirane (R)-6
20
365
–128.2° (c = 1.0, CHCl3), 99.4% ee [tR, min:
5.5 (minor), 7.0 (major)]. The NMR spectra were
similar to those of (R)-2·HCl.
and piperidine. Yield 0.27 g (92%), Rf 0.03 (CH2Cl2);
[α]D20 = +27.4° (c = 1.1, CHCl3), [α] = +77.2° (c =
20
365
20
1.1, CHCl3); [α]D20 = –1.2° (c = 1.1, EtOH), [α]
=
365
rac-1-(3,4-Dimethylphenoxy)-3-(piperidin-1-yl)-
propan-2-ol (rac-2) was synthesized from oxirane
rac-6 and piperidine. Yield 0.29 g (98%), mp 75–77°C
(from aqueous EtOH) [29]).
–5.1° (c = 1.1, EtOH); 96% ee [Chiralcel OD, 22°C;
hexane–propan-2-ol–diethylamine, 6:4:0.01; tR, min:
1
5.5 (major), 7.0 (minor)]. H NMR spectrum, δ, ppm:
1.47–1.51 m (2H, CH2) and 1.59–1.66 m (4H, CH2)
(piperidine), 2.21 s (3H, 4′-CH3), 2.25 s (3H, 3′-CH3),
2.37–2.43 m (2H, NCH2, piperidine), 2.48–2.55 m
(2H, NCH2), 2.60–2.65 m (2H, NCH2, piperidine),
3.85 s (1H, OH), 3.93–4.00 m (2H, OCH2), 4.07–
4.13 m (1H, CH), 6.70 d.d (1H, 6′-H, J = 8.3, 2.6 Hz),
6.78 d (1H, 2′-H, J = 2.6 Hz), 7.04 d (1H, 5′-H, J =
8.3 Hz). 13C NMR spectrum, δC, ppm: 18.7 (4′-CH3),
19.9 (3′-CH3), 24.2 and 26.0 (CH2, piperidine), 54.7
(NCH2, piperidine), 61.4 (NCH2), 65.5 (CH), 70.6
rac-1-(3,4-Dimethylphenoxy)-3-(piperidin-1-yl)-
propan-2-ol hydrochloride (rac-2·HCl). mp 171–
174°C (171–173°C [29]). IR spectrum, ν, cm–1: 3234
(OH), 2730, 2681, 2543 (NH+).
(R)-1-(3,4-Dimethylphenoxy)-3-(morpholin-4-
yl)propan-2-ol [(R)-3] was synthesized from oxirane
(R)-6 and morpholine. Yield 0.28 g (95%), Rf 200.03
(CH2Cl2); [α]D20 = +19.5° (c = 1.0, CHCl3), [α]365
+56.1° (c = 1.0, CHCl3); published data [14]: [α]D20
=
=
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 6 2019

NONRACEMIC DIMETHYLPHENYL GLYCEROL ETHERS
843
–13.10° (c = 0.6, CHCl3); 96% ee [the HPLC condi-
tions were the same as for (R)-2; tR, min: 7.2 (major),
17.3 (minor)]. H NMR spectrum, δ, ppm: 2.21 s (3H,
7.3 (minor), 16.7 (major)]. The spectral parameters
were the same as those of (R)-3·HCl.
1
rac-1-(3,4-Dimethylphenoxy)-3-(morpholin-4-
yl)propan-2-ol (rac-3) was synthesized from oxirane
rac-6 and morpholine. Yield 0.29 g (97%).
4′-CH3), 2.25 s (3H, 3′-CH3), 2.47–2.52 m (2H,
NCH2CH2O), 2.54–2.61 m (2H, NCH2), 2.65–2.70 m
(2H, NCH2CH2O), 3.21 s (1H, OH), 3.73–3.76 m (4H,
NCH2CH2O), 3.97 d (2H, OCH2, J = 5.0 Hz), 4.08–
4.14 m (1H, CH), 6.68 d.d (1H, 6′-H, J = 8.3, 2.7 Hz),
6.75 d (1H, 2′-H, J = 2.5 Hz), 7.04 d (1H, 5′-H, J =
8.3 Hz). 13C NMR spectrum, δC, ppm: 18.9 (4′-CH3),
20.1 (3′-CH3), 54.0 (CH2, NCH2CH2O), 61.3 (NCH2),
65.7 (CH), 67.1 (NCH2CH2O), 70.4 (OCH2), 111.6
(C6′), 116.4 (C2′), 129.1 (C4′), 130.4 (C5′), 137.8 (C3′),
157.0 (C1′) (cf. [14]).
rac-1-(3,4-Dimethylphenoxy)-3-(morpholin-4-
yl)propan-2-ol hydrochloride (rac-3·HCl). mp 148–
151°C. IR spectrum, ν, cm–1: 3229 (OH), 2735, 2695,
2596, 2465 (NH+). The spectral parameters were
similar to those of (R)-3·HCl.
ACKNOWLEDGMENTS
The authors thank the Joint Spectral and Analytical
Center (Kazan Scientific Center, Russian Academy of
Sciences) for technical support of this study.
(R)-1-(3,4-Dimethylphenoxy)-3-(morpholin-4-
yl)propan-2-ol hydrochloride [(R)-3·HCl]. mp 169–
20
171°C; [α]D20 = +35.2°C (c = 1.0, CHCl3), [α]
=
365
+112.2° (c = 1.0, CHCl3); [α]D20 = +22.9° (c = 1.0,
EtOH), [α] = +68.1° (c = 1.0, EtOH); 99.9% ee [the
CONFLICT OF INTERESTS
20
365
HPLC conditions were the same as for (R)-2; tR, min:
7.3 (major), 16.7 (minor)]. IR spectrum, ν, cm–1: 3259
The authors declare the absence of conflict of
interests.
1
(OH), 2731, 2644, 2596, 2469 (NH+). H NMR spec-
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(2H, N+CH2, J = 6.2 Hz), 3.71 d.d (2H, N+CH2CH2O,
J = 22.3, 12.0 Hz), 3.89 d.d (1H, OCH2, J = 9.6,
7.3 Hz), 3.93–3.99 m (2H, NCH2CH2O), 4.09 d.d (1H,
OCH2, J = 9.6, 4.6 Hz), 4.28 t (2H, NCH2CH2O, J =
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propan-2-ol [(S)-3]. Yield 0.29 g (97%), [α]D20
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365
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20
365
HPLC conditions were the same as for (R)-2; tR, min:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 6 2019

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